Pulmonology, Hematology and Infection

Table of contents :
Cover
Pulmonology
Content
Introduction
Respiratory function tests
Chest Examination
Symptomatology
Acute Pleurisy
Pleural effusion
Pneumothorax
Hemo, Hydro, Pyo-Pneumothorax
Empyema
Pneumonia
Lung abscess
Lung collapse & fibrosis
Chronic Obstructive Pulmonary Disease (COPD)
Bronchial Asthma
Bronchiectasis
Cystic Fibrosis
Pulmonary Tuberculosis
Sarcoidosis
Bronchogenic Carcinoma
Mediastinal syndrome
Cor-Pulmonale
Respiratory Failure
Lung Transplantation
Hematology
Content
Introduction
Hematopoiesis
Normal blood indices
Anemia
Iron deficiency anemia
Sideroblastic anemia
Post Hemorrhagic anemia & Anemia of chronic disease
Aplastic Anemia
Hemolytic Anemia
Megaloblastic Anemia
Secondary anemia
Myelodysplastic syndrome
Myelofibrosis (Myelosclerosis)
Polycythemia (Erythrocytosis)
Leukemia
Thrombocytosis
Lymphoma
Multiple Myeloma
Waldenstrom's macroglobulinemia
Hemostasis
Purpura & Coagulopathy
Immune thrombocytopenia purpura & Hemophilia A
Henoch-Schonlein purpura & Hypoprothrombinemia
Von WilleBrand disease
Disseminated Intravascular Coagulation
Splenomegaly & generalized lymphadenopathy
Transfusion therapy
Complications of blood transfusion
Bone marrow transplantation
Infection
Contents
Introduction
Fever Of Unknown Origin (FUO)
Differential diagnosis of common fever
Streptococcal & Staphylococcal infection
Enteric Fever: Typhoid fever & Paratyphoid Fever
Brucellosis
Cholera
Infectious Mononucleosis (IMN)
Acquired Immune Deficiency Syndrome (AIDS)
Malaria
Parasitic & helminthic infections
Leishmaniasis
Antibiotics

Citation preview

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫‪A‬‬

‫^‪ft‬‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Pulmonology Topic

Page

Introduction

1

Respiratory function tests

2

Chest Examination

4

Symptomatology Acute Pleurisy

7

9

Pleural effusion

12

Pneumothorax

16

Hemo,Hydro,Pyo-Pneumothorax Empyema

19 21

Pneumonia

22

Lung abscess Lung collapse & fibrosis

28 32

Chronic Obstructive Pulmonary Disease(COPD)

36

Bronchial Asthma

48

Bronchiectasis

55

Cystic Fibrosis Pulmonary Tuberculosis

59 61

Sarcoidosis

70

Bronchogenic Carcinoma Mediastinal syndrome

73

Cor-Pulmonale

81

Respiratory Failure Lung Transplantation

84

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

78

85

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Introduction

Anatomical & Physiology: Hflum of lung (site of

innated lung

entry of rocH of lung) Suprapleural membrane

Cerw^al pleura Mediastinai

Nasal cavity Pharynx (throat)

Mouth

Alveolus

Epiglottis

(airspace)

Costal part

Larynx (voice box)

Type I pneumocyte

Trachea (windpipe)

Capillary^

Bronchus

[bronchial tubas)

Left lung

•t

Right lung ^

Type II pneumocyte

Lamellar body Bronch olea

{•mail airways

1

Alveoli

(air sacs)

Alveolus

Di^m^natic

^ part

(aitepace)

Parts of

^^netal pleura

Alvedite

(airspace)

Endc^raac fascia MediastinMn

Vrscerat pleura

(contains heart)

Diaphragm

I. Lung: Anatomy

The upper respiratory tract(URT)includes the nose, nasopharynx and larynx The lower respiratory tract(LRT)includes the trachea and bronchi. The trachea divides at the carina into right and left main bronchi. The large bronchi divide into smaller bronchi which divide into small bronchioles then terminal bronchiole then respiratory bronchioles. Eventually the respiratory bronchioles form alveolar ducts then alveoli

The alveoli are lined with flattened epithelial cells (type I pneumocytes) and cuboidal cells (type II pneumocytes). Physiology : To heat, moisten the air and remove particulate matter 2.

3. o o

❖ o o

Rich in sensory receptors involved in the cough reflex Type II pneumocytes: Divide and reconstitute type I pneumocytes after injury. Produce the surfactant which reduces the surface tension ofthe alveolar wall to prevent collapse. Nerve supply to the lung:

The parasympathetic supply is from vagus and the sympathetic from the sympathetic chain. The parietal pleura is innervated from intercostal and phrenic nerves while the visceral pleura has no innervation. II.

Pleura:

Pleura is a formed of2 layers of serous membrane formed of mesothelial cells rich in microvilli,

which deliver glycoprotein rich in hyaluronic acid, to decrease friction between lung & chest wall 2 layers are separated by a potential space filled with 10-30 ml of fluid

0 0 0 0

A. Parietal Layer Cover chest wall, diaphragm, mediastinum Blood supply from systemic circulation Sensitive to pain, pressure, temperature & touch Supplied by somatic nerves : intercostal & phrenic nerves

B. Visceral Layer 0 Cover surface of lung & interlobar fissures 0 Blood supply from pulmonary circulation 0

Sensitive to stretch

0 Supplied by : autonomic innervation from the pulmonary plexus (a network of nerves derived from the sympathetic trunk and vagus nerve)

❖ Function : 1. Ventilation:

a. b. c. 2. 3.

Ventilation of alveoli: ability to move air up & down respiratory passages Conduction : proper transfer of air through air ways Distribution : proper mixing of air inside alveoli Perfusion : Blood flow through the lungs and its distribution Diffusion: exchange of O2 and CO2 across alveolo-capillary membrane

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Respiratory function tests

L Test For Ventilatory Function: measured by spirometry 0 Inspiratory reserve volume

0

Forced Vital

o

capacity

normal inspiration & expiration o Expiratory

o Inspiratory capacity

Tidal volume:

o

Functional residual

reserve volume o

o Total lung capacity

capacity

Residual volume

Tidal volume(TV): The volume air passed in & out of the lung under resting condition(N = 500 ml).

Inspiratory reserve volume(IRV): The additional volume of air inspired after normal inspiration(N = 3 L). Inspiratory capacity (IC): the maximum volume of air can be inspired after normal expiration i.e. TV+IRV (3.5L) Expiratory reserve volume(FRY): The additional volume of air expired after normal expiration(N = 1200 ml). Residual volume(RV): volume of air remaining in the lung after maximum expiration(N = 1200 ml). Functional residual capacity(FRC): volume of air remaining in the lung after normal expiration i.e. ERV + RV (2400 ml)

Forced Vital capacity(FVC): the maximum volume of air that can be expired after maximum inspiration (IC + ERV = 4.7L)

8. Total lung capacity(TLC): the volume of air in the lung after maximum inspiration(VC+RV ~ 6L) 9. Maximum breathing capacity(MBC):

o The maximum volume of air that can be respired in one minute with the fastest and deepest respiratory effort(80160 L/min) o Test is performed in 15 second only and we multiply volume by 4 10. Forced expiratory volume in the first second (FEVl):

Monitor

Nof« ciip Spiromttor

Tina (sec)

o The volume of air expired by maximum effort after maximum inspiration o Normally : 97% of air is expired in 3 seconds = timed FVC o FEV in first second (FEVl)normally >75-80% = 3-4 L

o It is usually expressed as a percentage of forced vital capacity(FEVl/FVC)and normally it is > 75-80"/o. 11. Peak expiratory flow rate(PEFR):

o The maximum rate of air flow / min during forceful expiration (400-600L/min)

\

o Used to establish the pattern of obstructive airway disease & monitor response to treatment especially in asthma 12. Lung compliance: o Ratio of change in lung volume in relation to change in pleural pressure.(150-200mL/cmH20) 13. Radioactive xenon:

o Xe'^^ in small amounts is added to inspired air, then we measure radioactivity over different part of lungs 14. Helium wash out time :

o Patient takes a single breath of helium, and its concentration in expired air is measured. o This falls gradually as air replaces Helium in lungs, and takes about minute for volume of helium in expired air to reach constant

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ These parameters are measured by spirometry and are affected in respiratory diseases as obstructive & restrictive lung disease:

0 E.g. •

A. Obstructive hypoventilation

B. Restrictive hypoventilation

0

0 Interstitial lung fibrosis & Kyphoscoliosis

COPD & Bronchial asthma

Residual volume.

• Functional residual capacity. 0 1 i.e. there is air trapping • Total lung capacity • Forced expiratory volume in 0 m due to increased airway C second (FEVi). resistance 0 Normal or| slight • Forced vital capacity

0 1 i.e. there is no air trapping 0 Normal or slight J, due to normal airway resistance

0 m due to decreased expansion of the lung & chest wall

•

0 1 i.e. < 75 % predicted

FEVi / FVC ratio

0 Normal or f i.e. > 75 % predicted

II. Test For Diffusion Pulmonary

Venous blood in Mveoi

Afi/eolus

Oxygenated

Red blood cells

in capittary

C02 out

blood out

Kesptraioiy bronclHote

\ Alveoldr wall Alvec4ar

gas

Pi.3sma / Hct)

%

A. Blood gas analysis:

o Arterial blood gases: PO2: 100 mmHg, PCO2: 40 mmHg o Pulse oximetry : simple, non-invasive device that estimate functional oxyHb saturation o Normally 02 & C02 diffusion across alveolocapillary membrane takes 0.8 sec.

A^/ec■(ar oapdlary

Rnij Mood

memMane

ce-ti

B. Transfer factor for carbon monoxide (TCO):

o Quantity of gas e.g. CO, transported across alveolocapillary membrane in each minute for every unit of pressure o o 1. 2.

gradient In CO: normally 25 ml / min / mmHg pressure at rest Abnormally : disturbed in 2 ways: I in number of alveoli: as in emphysema

I in interstitial space : as in alveolocapillary block due to fibrosis.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

III. Test For Perfusion Airways

Airway c^strucUon

Normal

(shynO

Artfirial

Venous" blood

Pulmonary ©mbdus (^d

o Perfusion without ventilation

Ventilation without Alveolus

(shunt)

❖ Perfusion test by:

perfusion

y (dead space) V/Q =

V/Q =0 Normal

1. Plain X-ray(oligemic or plethoric lung) 2. Pulmonary arteriography

V/Q=0.8

3. Lung scans:

❖ Ventilation / perfusion scan (V/Q)done by simultaneous radioactive gallium 67 gas inhalation &. Radioactive 99m Tc- labeled albumin IV:

o Normally ventilation / perfusion (V/Q ratio)= Alveolar ventilation (4L/min)/ perfusion (5L/min)= 0.8 o Abnormally:

a. I V/Q ratio (shunt): bad ventilation, good perfusion e.g. pulmonary collapse b. tV/Q ratio (dead space); good ventilation , bad perfusion e.g. pulmonary embolism Chest Examination

❖ For more details see clinical book for the author

I.

Inspection

0

1) o o o o o o o 2)

r

Shape & Symmetry: Normally: Symmetrical chest Shape : elliptical Diameter: antro-posterior < transverse diameter Subcostal angle: < 90° Ribs : oblique Intercostal space: narrow normal Spine & vertebral column : normal curvature Chest wall abnormality e.g. scars : chest tube scar

3) Position of mediastinum:

a. Apex: apical pulsation: the outermost lowermost visible pulsating point over the chest wall localized in left 5"^ intercostal space in midclavicular line in supine position b. Trachea:

o

Central

o Shifted (Trail's sign): in THIN patients: unilateral bulge of stemomastoid tendon on side of tracheal shift due to displacement of trachea behind the tendon.

4) Respiratory Movement: in all chest diseases, movement are limited over the affected side.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II.

Palpation:

X.

i

1) Tenderness: palpate gently overt the chest wall while inspecting the patient's face. 2) Mediastinum: position of apex (the strongest palpable pulsation)& Trachea. 3) Movement: chest expansion by tape test & distance between both hands. 4) Tactile vocal fremitus(TVF):

o Palpable vibration of vocal cords transmitted through respiratory passage to be felt on chest wall, o It is done by applying palm of the hand on chest wall and ask patient to repeat 99 in English or 44 in Arabic

o Normally TVF is equally on in each two corresponding areas of the chest except right l""* space in parastemal line (right upper lobe) TVF is increased because ; a. Trachea is in contact with right lung apex b. Right apical bronchus is more superficial (superior)

5) Palpable adventitious sounds: palpable wheezy, crepitations, pleural rub in pleurisy III.

Percussion :

o Tidal percussion for the liver. o Chest wall Percussion; front, side, back : normally resonance IV.

Auscultation:

A. Breath sounds:

i.

Intensity: normal,increased or decreased.

ii. Type: 1. Vesicular breathing : o

Normallv:

■ Fieard over the lungs & best heard over axilla & infrascapular regions ■ Inspiration is longer than expiration o Abnormallv: Vesicular breathing with prolonged expiration (Harsh vesicular) 2. Bronchial breathing: o Normallv heard over trachea & large airway

o Abnormallv = causes of t TVF = causes of t vocal resonance (see later) o Types: tubular, cavernous & amphoric. B. Conducted sounds: vocal resonance confirm bronchial breathing 1. Aagophony 2. Bronchophony 3. Whispering pectoriloquy C. Additional Adventitious sounds: 1. Pleural rub

2. Crepitations = Crackles = Rales

3. Wheezes = Ronchi

lllllll lllll 1. Size

0 Small, medium, coarse size

2. Area

0

Generalized or localized

3. Cough 4. Timing

o

Changeable or not, disappear or not

5. Pitch

WWSAV o Monophonic: sibilant, sonorous o Polyphonic

o Inspiratory (early, mid, late, pan)

o Expiratory

O

O O

Inspiratory & expiratory

Expiratory & inspiratory Inspiratory

o Consonating & non Consonating

D. Special test: o

Post- tussive suction

o Succussion splash o

Coin test.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Cavitation

Emphysema &

■

■

Fibrosis

Pleurisy

Pleural effusion

Pneumothorax

Hydropneumothorax

■

■

■

■

■

o

o

o

o

o

o

o

o

o

■

Bulge

Bulge

Bulge

Normal

Retraction

Retraction

Barrel

Normal

Normal

i

i

J,

o

J,

o i

o

o i

o

o i

o

o i

o i

I. Inspection Shape & ■ Respiratory Symmetry movement

o

o

o

o

o

o

o

o

o

■

II.

opposite side

Shifted to

opposite side

Shifted to

opposite side

Shifted to

Central

same side

Shifted to

same side

Shifted to

Central

Central

Central

o

o

o

o

o

o

o

O

o

Consolidation

Cavity if: big, superficial & surrounded by Consolidation Collapse & fibrosis if associated with patent bronchus

■

■ ■

■

J.

J,

i

J,

i

i

i

t

T

TVF

Palpation

Mediastinum

"l* N.B.: Causes of 1 TVF = Bronchial breathing = causes of f vocal resonance:

Collapse

■

chronic bronchitis

Consolidation

■

❖ Chest disease

o

o

o

o

o

o

o

o

o

o

Shifting dullness

resonance above it

upper limit & tympanitic

with horizontal

Stony dullness

resonance

Stony dullness rising to axilla Tympanitic

Normal

Dull

Dull

dullness

o

o

o

o

o

o

o

Decreased

Decreased

Decreased

Decreased

bronchial

±

Decreased

bronchial

±

Decreased

decreased

Later:

with

prolonged expiration

normal cardiac

Vesicular

Bronchial

Bronchial

sounds

Breath

and hepatic

o

o

o

■

breathing

Percussion

Hyper-resonance encroaching on the

Dull

Dull

III.

o

o

o

o

o

o

■

IV.

Auscnitation

Rub

& Wheezes

Crepitations

& Wheezes

Crepitations

Wheezes

Crepitations

Crepitations

sounds

Adventitious

o

o

o

■

splash

Succussion

Coin test.

suction

tussive

Post-

test

Special

Symptomatology Hemoptysis ❖ ❖ ❖ ❖

Definition: Expectoration of blood originating from below vocal cords. Etiology : Causes of hemoptysis: see later Common causes of hemoptysis:

1. Acute bronchitis

3. MS,EVE

5. Bronchiectasis

2. Pulmonary TB

4. Pneumonia

6. Bronchial adenoma & carcinoma

7. Lung abscess 8. Pulmonary infarction

❖ Diagnosis: I. Exclude false (spurious) hemoptysis : o Bleeding originating from above vocal cords due to nasopharyngeal disease o

Local examination reveal cause.

II. III.

Full clinical history & examination : chest, heart & abdominal examination Differential Diagnosis: ❖ Hemoptysis ❖ Hematemesis ■ Before attack: 0 Cough 0 Nausea, vomiting ■ During attack: 1. Symptoms 0 Coughing blood 0 Vomiting blood 2. Colour 0 Bright red blood 0 Dark; Coffee-ground (hematine) 3. Content 0 Mixed with air (frothy) 0 Mixed with food 4. Chemical reaction(pH) 0 Alkaline 0 Acidic ■

After attack

■

Examination

0 Blood tinged sputum for a while 0 Chest, CVS signs

0 Melena and constipation 0 GIT signs

V. Investigate the cause: Sputum examination 2. X-ray chest CT scan & MRI 1.

3. ECG 4. 5.

Bronehoseope Blood tests for bleeding tendency

❖ Treatment: 1. Treatment of the cause

2.

In massive hemoptysis: hospitalization & blood transfusion in severe cases. Periodic breathing

I. Cheyne-Stokes breathing: ❖ Description: o Gradual increase in respiration followed by gradual decrease in respiration with periods of apnea ❖ Mechanism:

o The respiratory center is not sensitive to O2 but remains sensitive to CO2.

o Hyperapnea will wash CO2 leading to apnea during which CO2 accumulate with stimulation of respiration ❖ Cause: respiratory center depression: 1. Drugs e.g. opioids, barbiturates, or alcohol

2. Hypoxia or ischemia as in respiratory failure, heart failure & vertebrobasilar insufficiency 3. Fevers

II.

Blot's breathing:

o Rapid shallow respiration followed by periods of apnea. o Occurs in meningitis, head injuries & subaraehnoid hemorrhage

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

1

1

1

Chest wall causes:

Pulmonary: pulmonary embolism, and infarction Aorta: aortic aneurysm, DAA,DAA Huge cardiomegaly Hysterical: cardiac neurosis

Myocardium: myocardial ischemia & infarction Endocardium : mitral valve prolapse

cardiac tamponade

Lung abscess and bronchiectasis

Goodpasture's syndrome

Abdominal :

Subphrenic abscess

Acute PU & GERD.

Cholecystitis

o

❖

o

o

o

o

Cardiovascular causes:

Awareness (difficulty) of respiration, concerning rate, depth or rhythm.

Dyspnea

2. Chest causes:

audience

Brain tumors. Stroke, or encephalitis.

cough center e.g.

CNS due to central irritation of

Brain stem: Infraction, hemorrhage,tumors Drugs: opioid, benzodiazepines overdose Anterior horn cells: poliomyelitis, MND Peripheral nerve lesions e.g. GBS Neuromuscular junction : myasthenia gravis & myasthenic crisis 5) Muscle lesions : myopathies

CNS:

❖ ETIOLOGY OF ACUTE ONSET IN BLUE COLOR.

o

❖

1) 0 0 2) 3) 4)

0

❖ Abdominal distension: ascites, pregnancy. 0 ❖ Blood : acidosis, anemia (bleeding), shock

3. Other causes: Abdominal, Blood, CNS:

Bronchial asthma (acute severe asthma)& COPD

alkalosis

Acute Bronchitis(The most common Cause)

Tuberculosis, Bronchial adenoma & Bronchogenic carcinoma Hysterical: Neurotic females, dry o Hysterical: Sighing & voluntary cough barking in front of hyperventilation leading to CO2 washout &

o

o o

Laryngeal causes : laryngitis, inhaled FB,tumor Laryngeal edema & spasm

o

0

Hemoptysis

cords

Expectoration of blood originating from below vocal

sasf .5 -

Hemorrhagic blood diseases : hemophilia, purpura, anticoagulants Hemorrhagic fever : typhus, plague

Pulmonary congestion : MS & LVF Acute pulmonary edema Acute pulmonary infarction & infection Aortic aneurysm, dissecting aortic aneurysm(DAA),rupture aortic aneurysm (RAA). Pericardial effusion & cardiac tamponade 0 Rupture of bronchial varices Huge cardiomegaly & LAE compressing left bronchus 0 Severe HTN ACEI o Acute myocardial ischemia & infarction

1.

aiming at expulsion of inhaled particles from respiratory tract ❖ Etiology :

Protective reflex mechanism

❖ Definition :

o

o

o

o o o o o o

o

Cough

Pleurisy, Pleural effusion. Pneumothorax (especially tension type),Hydropneumothorax Lung Consolidation (pneumonia), acute massive lung collapse & fibrosis Mediastinum: mediastinal mass e.g. LN,tumors or mediastinitis.

o

o o o

3. Intercostal muscles: myositis, strain 4. Intercostal nerves: neuritis, herpes zoster (herpetic neuralgia), root compression. 5. Ribs: fracture, tumors, osteomyelitis, Tietze syndrome

1. Skin: wound trauma ,abscess 2. Breast: mastitis, tumor or abscess

❖

2. 3. 4. 5. 6. 7.

1. Pericardium: acute pericarditis, pericardial effusion &

Chest pain

|

|

|

Diseases of the pleura: o Acute pleurisy o

Pleura! effusion

o

Pneumothorax

o Hemo, Hydro, Pyo-Pneumothorax o Empyema o

Mesothelioma

Acute Pleurisy Normal

Inflamed

pleura

pleura

Definition: dry inflammation ofthe two layers of pleura. ❖ Etiology: I.

Primary pleurisy

1. Tdiopathic. 2. Infection: the most common cause:

A. Bacterial, TB, Fungal infection B. Viral infection: the commonest cause: pleurodynia, epidemic myalgia or Bornholm disease: o

Cause : coxsackie B yirus

o Disease occur in epidemics affecting young age, it is self-limited (1 week)& tends to be recurrent o Start by URT infection followed by pleuritic chest pain with tender muscles& upper abdominal pain o Complication : aseptic meningitis and orchitis

3. Inflammation ; FMF

4. latrogenic e.g. procainamide, hydralazine. 5. Irradiation

6. Immunological: o Dressier's Syndrome o Post-cardiotomy Syndrome o

Rheumatic feyer.

o

Rheumatoid arthritis, SEE, Scler oderma.

7. Renal failure.

8. Myxedema 9. Myocardial Infarction

10. Malignant Infiltration e.g. leukemia 11.

Secondary pleurisy :

1. Chest wall causes:

o Osteomyelitis, fracture ribs, myositis. 2. Lung causes:

o Pneumonia, lung abscess, bronchiectasis, pulmonary infarction. 3. Mediastinal causes;

o Pericarditis, esophageal tumors, mediastinitis. 4. Subdiaphragmatic causes: o Amebic liver abscess, subphrenic abscess

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Clinical picture: ❖ Symptoms: I.

General:

o Constitutional symptoms: fever headache, anorexia & malaise: with inflammatory causes, o Symptoms of cause e.g. TB toxemia o Symptoms of complications II.

Local:

1. Pleuritic chest pain : A. Cause: inflammation of parietal pleura. B. Site : localized

C. Radiation : according to the part affected in the parietal pleura: ■ If diaphragmatic part is inflamed —»• referred to shoulder & root of neck through phrenic nerves. ■ If costal part is inflamed ^ referred to upper abdomen & lumbar region through intercostal nerves D. Character:

■ ■

Cenricai

Sudden Stitching Stretching dull aching with development of effusion.

E. Duration : continuous

F. t By • inspiration & cough G. I By: by holding breathing and lying on affected side. 2. Pleuritic cough : o Dry cough due to irritation of visceral pleura (via vagus nerve) 3. Dyspnea: o False: due to muscular spasm. o True: due to initial cause of pleurisy or after development of pleural effusion

Medlastlnal

Diaphragmatic

❖ Signs:

I. II.

General: signs of the cause & complications Local:

1. Inspection: o Shape of chest: normal o o

Movement: limited on affected side Mediastinum : central

Normal

Inflamed

pleura

pleura

2. Palpation: o

Tenderness over the affected side,

o Movement: limited chest expansion on affected side o

Mediastinum is central

o

TVF is normal

o Palpable pleural rub 3. Percussion : normal note with tenderness

4. Auscultation : plenral rub

a. Cause: due to friction between two inflamed pleura

^

b. Site: Localized

» /

c. Character:

■ ■

Leathery (gritty sound) Loud with Low pitched

d. t by: with inspiration, and by pressing the stethoscope against the chest wall e. I by: holding breath or occurrence of pleural effusion

10

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Complications:

o Pleural effusion : chest pain disappear although illness is worth o Pleural adhesion & fibrosis (thickening) Differential diagnosis:

o Causes of acute chest pain o

Causes of acute abdomen

Investigations: 1. o 2. o o

Laboratory : CBC: leucocytosis, f ESR,+ve C-reactive protein in case of infection. Radiological: Chest X-ray & CT Chest: May show underlying chest disease e.g. pneumonia, May show complicating pleural effusion.

3. Instrumental:

o Lung biopsy e.g. in suspected malignancy. 4. Investigations of cause e.g. TB : tuberculin test Treatment:

1) 2) o o o

Treatment of cause e.g. antituberculous drugs for TB Symptomatic: Analgesics for pain e.g. NSAIDs. Antipyertics for fever e.g. paracetamol, Dry cough: cough sedative e.g. codeine phosphate.

11

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Pleural effusion

Definition: accumulation offluid in pleural space

Nofikul

Etiology: 1. Hemothorax (Blood accumulation):

A. Hemorrhagic blood diseases e.g. Hemophilia. B. Post-traumatic: fracture rib, stab wounds & tapping of effusion. C. Pulmonary infarction D. Rupture of aortic aneurysm into pleura

E. Malignant effusion: due to bronchogenic carcinoma, metastatic tumor, leukemia, lymphoma 2. Hydrothorax (Transudate accumulation):

o All causes of generalized edema (cardiac, hepatic, renal, nutritional, allergic) o Myxedema

o Meigs' syndrome: ovarian fibroma, ascites & right sided hydrothorax 3. Sero-thorax (Exudate accumulation) o All causes of dry pleurisy (primary & secondary) especially T.B is the most common cause. 4. Suppurative effusion (empyema): see later.

5. Chylothorax:lymph accumulation:(due to impaired lymphatic drainage): o Rupture or obstruction of thoracic duct by trauma, tumor & filariasis. o Yellow nail syndrome : primary lymphedema associated with yellow nails and pleural effusion Mechanism of pleural effusion:

1. 2. 3. 4.

Due to t hydrostatic pressure or I plasma oncotic pressure. Due to t capillary permeability Due to I pressure in pleural space Due to movement of fluid from peritoneal space

Pleural Sp»»

Pleural efl'usiion

Clinical picture: Healthy Lung

❖ Symptoms: I.

General:

o Constitutional symptoms: fever headache, anorexia & malaise: with inflammatory causes, o Symptoms of cause e.g. TB toxemia o Symptoms of complications. II.

Local:

1. Chest pain:

o Starts as pleuritic stitching pain in inflammatory cases (describe) with collection of pleural fluid it becomes dull aching due to pleural stretch. 2. Cough: dry irritating 3. Dyspnea proportional to volume of fluid present

12

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Signs

I. II.

General: Evidence of cause e.g. cachexia & wasting in cases of TB Local:

i. Inspection: 1. Shape: o

Normal in minimal effusion

o Unilateral bulge in moderate to massive effusion 2. Movement: diminished chest expansion on affected side. 3. Mediastinum : apical pulsations may be shifted to the opposite side. 4. Littin's sign is absent(negative). 5. Skin: may show evidence of trauma. ii. Palpation: 1. Tenderness on affected side.

2. Movement: limited chest expansion on affected side. 3. Mediastinum position according to the amount: A. No mediastinal shift in : mild effusion

B. Mediastinal shift to opposite side: ■ Moderate effusion: apical pulsafions is shifted to opposite side ■ Massive efftision: apical pulsation & tracheal shifted to opposite side C. Mediastinal shift to same side in cases of:

o Malignant pleural effusion with underlying lung collapse o

Fibrosis

4. TVF: I on affected side. 5. Palpable rub may be present on affected side, iii.

Percussion:

Basal stony dullness rising to axilla.

Skodiac hyper-resonance: band of hyper-resonance above the level of effusion due to compensatory emphysema. Garlands triangle of dullness above the level of effusion posteriorly due to underlying lung collapse. Grocco's triangle of dullness: triangular area of paravertebral dullness on the side opposite a pleural effusion due to mediastinal shift to healthy side, iv.

Auscultation:

1. Diminished breathing sound over the effusion. 2. At the upper level of effusion the following may be present:

a. Bronchial breathing, with aegophony, whispering pectorilioquy & crepitations, due to underlying compression collapse if associated with patent bronchus. b. Pleural rub.

Complications :

1. Infection with empyema. 2. Fibrosis.

3. Permanent lung collapse. 4. Respiratory distress in massive or bilateral effusion

13

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis:

A. From other causes of dyspnea with chest pain e.g. myocardial infarction. B. Syndrome of multiple negatives(f Movement, J,TVF, J, percussion note (dull), J, intensity of breath sounds): Pleural effusion, lung Collapse & Fibrosis C. From other causes of basal dullness: diagnosed by tidal percussion: 1. Supra-diaphragmatic causes (negative tidal percussion): o Chest wall causes e.g. tumors, o Pleural effusion, fibrosis or hydropenumothorax. o Basal consolidation, cavity or collapse, o Pericardial effusion or cardiomegaly. 2. Diaphragmatic paralysis detected by: o Reversed tidal percussion, o

Paradoxical movement under screen.

3. Infra-diaphragmatic causes (positive tidal percussion):

o Subphrenic abscess & Amebic liver abscess, o Ascites & Huge abdominal mass. D. Of the cause: can be differentiated by the nature offluid. Investigations: -J

1. Laboratory: CBC: leucocytosis, f ESR,+ve C-reaetive protein in case of infection. 2. Radiological: 1) Chest X-ray: A. Free effusion :

o Appears as homogenous opacity obliterating costophrenie angle & rising laterally to axilla & pushing the mediastinum to opposite side, o Lung may show primary disease B. Localized effusion:

o At lung periphery: encysted effusion appears as D-shaped opacity o Within fissure : interlobar fissure appears as rounded or oval opacity that may disappear with diuretics(phantom tumor = fissural pseudotumor)

2) Chest CT: may reveal the cause & allow guidance for drainage of encysted pleural effusion 3. Instrumental:

1.

Pleural aspiration: diagnostic thoracocentesis to differentiate of the nature offluid:

A. Hemothorax: blood stained with many RBCS B & C: Transudate «& exudate: B. Transudate

C. Exudate

o

3. Cholesterol

o Colorless , Clear o 200IU/L

❖ Light's criteria :> 1 diagnose

5. Pleural Fluid proteins /Serum Proteins o

>0.5

o

> 0.6

1. Aspect: 2. Proteins

o

Yellowish Turbid

o >3 gm/dl o > 45mg/dl

1000/mm^

9. Specific gravity

o

o

10. Glucose

o >60 mg/dl

8. WBCs

1016

o g abscess

!—l-RIb Pus in pleural space

20

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Chronic empyema

Acute empyema Definition

o

o

Pus in pleural space for < 2 months

Pus in pleural space for > 2 months.

❖ Etiology

1. Secondary to chest wall cause e.g. abscess and osteomyelitis of ribs. 2. Secondary to lung disease e.g.:

o Syn-pneumonic empyema occurring with bronchopneumonia e.g. staphylococcal pneumotoceles.

o o 3. 4. 5.

Meta-pneumonlc empyema occurring after lobar pneumonia. Lung abscess, bronchiectasis or carcinoma. Secondary to infection of pleural effusion. Secondary to mediastinal cause e.g. mediastinitis. Secondary to subdiaphragmatic cause e.g. subphrenic abscess or

Unresolved acute empyema due to: 1. Low body resistance. 2. Resistant organism e.g. T.B. 3. Underlying disease e.g. bronchiectasis or lung abscess.

4. Inadequate treatment (i.e. incomplete aspiration or improper antibiotic). 5. FB in pleural space.

amebic liver abscess.

6. Secondary to septicemia. ❖ Symptoms

As pleural effusion but with severe constitutional manifestations.

o As acute empyema with bad general condition & Loss of body weight.

❖ Signs I.

o General: as pleural effusion with bad general condition, o Local: as pleural effusion with marked tenderness.

General:

o Loss of body weight, o

Clubbing,

o LL edema secondary to hypoproteinemia or amylodosis of kidney. II.

Lung '^Pleura

Local:

i. Inspection: Shape: retraction on affected side.

Pleural space

Movement: limited on affected side.

t

Mediastinum: apical pulsations shifted to same side of lesion.

Littin's sign: -ve Chest wall may show evidence of fistula. ii. Palpation:

Excess fluid

Tenderness on affected side. Movement restricted on affected side

- .— Chest wall

,r-l-Rib ^ f

Mediastinum: trachea & apical pulsations shifted to same side of lesion.

I TVF on affected side. 1 Palpable rub on affected side. iii. Percussion: as pleural effusion. iv. Auscultation: as pleural effusion. Complications

1. Chronic empyema. 2. Rupture:

o

Through chest wall —> external fistula.

o Through bronchus -> bronchopletu-al fistula -+ features of suppurative lung syndrome with pyopneumothorax 3. Empyema necessitans: cystic intercostal swelling with impulse on cough. 4. Hypoproteinemia with repeated aspiration. 5. Local spread —> mediastinitis, pericarditis, and lung abscess. 6. Dissemination: bacteremia or septicemia 7. Pleural fibrosis with fibrothorax

(pleuropulmonary fibrosis) 8. Amyloidosis.

❖ Investigation

o

As pleural effusion,

o

Aspiration reveals pus.

o o

As pleural effusion. Antibiotics according to culture & sensitivity

o

As pleural effusion but with evidence of fibrosis.

❖

Treatment

A. Treatment ofcause of chronicity. B. Surgical treatment: o Decortication if the lung is normal(allow lung to expand) o Pleuropneumonectomy if the lung is damaged

21

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

visceral

Mesothelioma

^532

pleiva

parietal pleura

{ /

fj

11

(i

pleural epace

The tumor arises from the pleural surface Types : localized & diffuse mesothelioma

The incidence is increased with asbestos exposure(> 20 years of exposure)

Clinical picture: chest pain, cough, dyspnea, clubbing & bypertropbic pulmonary osteoarthropathy Investigations : chest x-ray (pleural mass & thickening)& pleural biopsy Treatment: Surgical, radiotherapy & chemotherapy. Pneumonia

❖ Definition: Inflammatory consolidation of alveoli i.e. alveoli out offunction ❖ Classification Inflammation

of the lung

1.

Anatomical:

1. Lobar pneumonia: unilateral inflammation of single lung lobe. 2. Lobular pneumonia(Bronchopneumonia): bilateral inflammation of lung lobules 3. Interstitial pneumonia: inflammation of interstitial tissue between the alveoli II.

Etiological: i. Infective:

A. Typical pneumonia : Bacterial: e.g.

i.

Gram positive cocci: o Streptococcus pneumonia o Group A streptococci o Staphylococcus aureus ii. Gram negative bacilli: 1. Anaerobes

ii. Non infective:

B. Atypical pneumonia (walking pneumonia): 1. Allergic: Loffler's 1. Bacterial: syndrome. o Mycoplasma 2. Irradiation. o Legionella pneumophila 3. Immunological: e.g. 2. Chlamydia SEE 3. Rickettsia

4. Viral: e.g. o Influenza virus, respiratory syncytial virus.

2. Aerobic :

C. Others:

a. Haemophilus influenza

1. Mycobacterium tuberculosis 2. Fungal: o Aspergillosis

b. Moraxella catarrhalis

c. Pseudomonas aeruginosa Proteus

o Actinomycosis 0 Pneumocystis carinii

d. Enterobacteriaceae : o o

E.coli

0

0

Enterobacter

3. Parasitic:

0

Klebsiella

o

o

Serratia

o Ancylostoma o Bilharzia, filarial & hydatid disease.

❖ N.B.: Pseudomonas aeruginosa & enterobacteriaceae : represent 20% of CAP in seriously ill patients e.g.

Candida albicans. Ascaris

COPD, Cancer, Chronic alcoholism

22

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

III. 1.

According to source of infection:

Aspiration pneumonia :

Definition: acute aspiration (inhalation) of gastric content into lung: Predisposing factors: Absent cough reflex e.g.: A. Anesthesia (Mendelson's syndrome) B. Bulbar paralysis & stroke C. Convulsions

D. Disturbed conscious level & coma

E. GIT: Esophageal disorders e.g. aehalasia, GERD Management: o o

2. o o

Piperacillin tazobaetam Ceftriaxone + levofloxacin + metronidazole or clindamycin Community acquired pneumonia (CAP):

Infection acquired from eommunity, caused by typical & atypical agents(see before) Bacterial pneumonia especially streptococcus pneumonia (pneumococcal pneumonia)is the most common cause of CAP

o

Hospital(Nosocomial) acquired: Pneumonia developing > 2 days after hospital admission, The most common organisms are gram negative bacteria

o

Predisposing factors:

3. o

A.

Aspiration , predisposing factors: see before

B.

Bacterial invasion e.g. ETT, mechanical ventilation, tracheostomy, bronchoscope & catheter sepsis.

C.

ImmunoCompromised patients, predisposing factors: see later

4.

Pneumonia in immunocompromised patients:

o o

The most common organism is pneumocystis jirovecii (pneumocystis carinii) Predisposing factors: see later. Bronchopneumonia

Lobar pneumonia

Healthy

Small

Small

Airway With

Airway

Pneumonia .Germs,

\ /white .ij

A

c\

Bfood Ceils,

Mucus

(««r- - »r>cim>ccca-«

p." ^

.'■j ft

Oaosifv

Atyeoupwroott

cnmf

23

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Lobar pneumonia(Pneumococcal Pneumonia)

o

Bronchopneumonia(Lobular pneumonia) ❖ Definition Localized unilateral inflammation ofsingle lung lobe. o Diffuse bilateral inflammation of lung lobules ❖ Etiology

❖ Organism : Rest of organisms ❖ Age: Extremes of age (pediatrics & geriatrics)

Organism: streptococcus pneumoniae ❖

Age: 15 -45 years old

❖

Mode of transmission: Dronlet infection

❖ Predisposing factors: 1. Crowdedness, lack of ventilation.

2. Cold weather, Cigarette smoking, Chest disease e.g. COPD & bronchiectasis 3. Post-Splenectomy 4. Infection especially viral infection. 5. Immunocompromised patients: predisposing factors: A. AIDS, Alcoholism

B. Poor nutrition, anemia. Post transplantation. Post-operative. C. Cancer: Leukemia, Lymphoma

D. Drugs: Corticosteroids ,Chemotherapy, Drug addicts, immunosuppressant drugs E. Debilitating diseases e.g. CRF,DM ,, HF Pathology Unilateral uniform lobar consolidation of alveoli with

Bilateral patchy lobular consolidation of alveoli with

pleurisy

pleurisy, bronchitis & bronchiolitis.

a

1.

Stage of lung congestion:

o

Inflammatory reaction ^ VD ^ marked congestion with minimal exudates in alveoli & small number of neutrophils

2.

Stage of hepatization: consolidation (solidification)

a) b)

Red hepatization: vascular congestion with extravasation of RBCs with t numbers of neutrophils & fibrin Grey hepatization: invasion with macrophages, RBC disintegrate with persistence of neutrophils & fibrin

3.

Stage of resolution: the exudate is digested by proteolytic enzymes & cleared by macrophages or cough ❖ Symptoms Duration : 7- 10 days

Duration :3-4 weeks

1. Constitutional manifestations: fever, headache, malaise, anorexia, nausea. 2. Pleuritic chest pain (describe). 3. Cough: o Dry in early stage

40° C

o Rusty sputum (yellowish or greenish with blood streaks) during hepatization o 4. 5. o

Excessive watery sputum during resolution. Dyspnea: secondary to consolidation & pleurisy. Symptoms of complications e.g.

Crisis

Convulsions in children. Confusion & delirium in old patients. Signs

I.

General:

Temperature:Fever (39-40° C): Onset: Sudden acute onset

o o

2. 3. 4. 5. 6. II.

o

Onset: Gradual onset

Offset by crisis (drop to normal within 12 hours) o Offset by lysis (drop to normal within 2-4 days). Tachycardia & Tachypnea: Working ala nasi & cyanosis in severe cases. Tinge ofjaundice because of RBCs lysis. Toxic facies with herpes labialis CNS; delirium , confusion, convulsion GIT: anorexia, nausea, vomiting, abdominal pain & rigidity Local:

Unilateral and uniform signs i. Inspection:

Bilateral and patchy signs

o

Shape of chest: Normal

o

Movement: limited on affected side & Mediastinum central.

ii. Palpation: o Tendemess on affected side & Movement: limited chest expansion on affected side o Mediastinum: Trachea & apical pulsations: central, o t TVF over the affected lobe. Palpable rub may be present iii.

Percussion:

o Dullness taking shape of affected lobe -i- tendemess due to pleurisy. iv. Auscultation: on the affected side there may be: o i breath sounds in the affected side o Bronchial breathing of tubular type with aegophony & whispering pectriliquy. o Crepitations:

■

Fine inspiratory in early stage —> medium sized consonating during hepatization

Inflammation

ofthe lung

coarse non consonating during

resolution.

o

Pleural mb.

24

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

1

Complications I.

o o

General:

Bacteremia: meningitis, pericarditis, endocarditis & peritonitis, Septicemia : Shock & DIG

II.

Local:

A. Lung:

1. Lung abscess, fibrosis, acute respiratory failure & recurrent pneumonia. 2. Unresolved pneumonia (lasting > 2 weeks despite of treatment) due to: o Poor immunity e.g. AIDs, renal failure. o Resistant organism e.g. T.B.

o Underlying disease e.g. bronchiectasis or bronchogenic carcinoma, o

Improper treatment,

o

Complicating empyema or lung abscess.

B. Pleura:

2) Syn-pneumonic empyema (during infection) ❖ Criteria for diagnosis of severe pneumonia:CURB 65:

2. Meta-pneumonic empyema (after infection)

o o o

Confusion : 1 point Urea > 20 mg/dl(7mmoml/L): 1 point Respiratory rate > 30 / minute : 1 point

o

BP < — mmHg: 1 point

o ❖ o o

Age > 65 years old: 1 point Interpretation of score: Score 0-1: treated as outpatient score 2: hospital admission

o

score > 3; ICU admission

90

Investigations 1) Laboratory : A. Blood : o o

B.

CBC show leucocytosis Blood culture positive for causative organism Sputum examination : Gram stain show:

o

Pneumococci as gram-positive capsulated diplococcic Staphylococci as gram-positive spherical cocci arranged in grape-like clusters. Culture & sensitivity.

o

2) Radiological : Chest x-ray:

o

Unilateral uniform homogenous opacity taking the shape

o

Bilateral irregular opacities give fluffy cotton appearance with central mediastinum

of the affected lobe with central mediastinum

o May show complications e.g. lung abscess 3) Investigation of the cause e.g. TB Differential diagnosis

1) Other causes of acute chest pain, dyspnea & chest dullness. 2) Pulmonary edema, infraction, TB 3) Fever with chest symptoms e.g. Typhoid

4) Abdominal pain e.g. appendicitis Treatment

1.

Symptomatic:

o

Bed rest

o o o

Cough sedatives for initial dry cough followed by expeetorant & mucolytics for productive cough e.g. Bromhexine Analgesic for pain & Antipyretics for fever, Treatment of complications e.g. respiratory failure.

11.

Antibiotics:

For streptoccoal pnemonia A. In uncomplicated cases:

For Staphylococcal hronchopneumonia

o If no antibiotic use within 3 month : clarithromycin 500 mg PO 712 hours for 1-2 weeks

o Antibiotic use within 3 months or presence of comorbidities e.g. COPD : levofloxacin or {clarithromycin -i- amoxicillin} B. o o ■

In complicated cases : hospitalization is needed if CRUB65 > 2 Non ICU patient: levofloxacin 750 mg PO/IV once daily for 1-2 weeks ICU patient: No pseudomonal infection: ceftriaxone + levofloxacin

❖ N.B.: If patient is pencillin alergic or cross-reactivity with

C. Standard empirical regimen -I- linezolid 600mg/12hr PO/lV

cephalosporins use aztreonam

for 2 weeks or yancomycin 15mg//kg/8-12 hour IV

D. If no response —> antibiotics according to culture & sensitivity.

25

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Special types of pneumonia, caused by: ❖ Staphylococcal

❖ Hemophilus

❖

influenza

aureus

❖

Klebsiella :

Pseudomonas

❖ Pneuniocystis

aeruginosa

Friedlander's

carinii(jiroveci)

pneumonia

❖ Predisposing factors:

1 o

Post viral infection.

o 0

1

Immunosuppression especially AIDS ;

Lung disease e.g COPD & bronchiectasis

0

Aspiration &

S- --A

''-v.:

mechanical ventilation

❖ Clinical picture & complications: as bronchopneumonia with : o

Severe course.

o

Toxic shock

o

syndrome. Formation of multiple

o o

thin walled abscess

Blood tinged sputum.

consolidation and

Severe pneumonia with high mortality

Epiglottitis, meningitis &

cavitation of the

rate

bacteremia.

—> rupture of abscesses ^ empyema or

pyopneu mothorax.

o

o

Apical

1 o

The commonest

0

infection (fungus found in air) causing pneumonia in immunocompromise d patients Atypical pneumonia

o

ARDS and acute RF

0 Cefepime +

0

Cotrimoxazole

levofloxacin

0

Pentamidine

affected lobes(DD pulmonary T.B) o Brick red sputum (DD broncbogenic carcinoma).

opportunistic

❖ Treatment 0 Standard empirical regimen -i- linezolid

0

Ceftriaxone

0

Cefatrioxone ±

1

gentamycin

or vancomycin

Atypical pneumonia

o Caused by atypical organisms (see before) o Organism are intracellular or para-cellular o Not detected by ordinary sputum staining & culture

o No alveolar exudate, alveoli are air filled & the infiltrate in the interstitium with ground glass appearance on X-ray ❖ Mycoplasma pneumonia

❖ Legionnaire's disease ❖ Predisposing factors:

o Usually affects children and young adults

o

Infection from contaminated water sources used for

showers & cooling systems 0 Infection occurs in outbreaks or sporadically

❖ Clinical picture & complications:: 1. CNS: meningitis, encephalitis, peripheral neuritis 2. CVS: myocarditis, pericarditis

1) CNS: Confusion 2) CVS: myocarditis

3) Chest: atypical pneumonia: constitutional symptoms more than respiratory symptoms o Severe constitutional manifestations (Fever, HAM)with moderate chest pain, dry cough, dyspnea & minimal local 4. 5. 6. 7. 1. A.

B. C.

chest signs GIT: vomiting and diarrhea 4) GIT: vomiting and watery diarrhea Hematological: cold autoimmune hemolytic anemia 5) Acute renal failure. 6) SIADH: Hyponatremia Skin: erythema multiform & erythema nodosum 7) Skeletal: myalgia and arthralgia Skeletal: myalgia and arthralgia ❖ Investigations: 1. Laboratory : Laboratory : A. CBC:lympbopenia,electrolytes: J, Na^ CBC: normal white blood eount, anemia B. Culture:sputum culture on specific agar(BCYE) Culture: sputum culture (2-3 weeks) C. Serum antibodies to organism by ELISA test Serum antibodies to organism by ELISA test

D. Immunofluorescence test

D. Immunofluorescence test

£. Cold agglutination test:

E. Urinary antigen Test 2. Radiological: Chest X-ray: o Lobar consolidation or interstitial infiltrates(GGA), or mixed pattems with small pleural effusion

o IgM antibodies that agglutinate human 0 blood group at 4°C but not at 37°C.

2. Radiological: Chest X-ray: interstitial pneumonia o Bilateral reticulonodular opacities in the interstitial tissue of the lung giving ground glass appearance (GGA)

❖ N.B.: Pontiac fever : mild form of Legionnaire's disease: mild flu-like illness without pneumonia

❖ Treatment:

o Erythromycin 500mg/5hours or Clarithromyein 500 mg /12hr for 2 weeks o ± Rifampicin 600mg/12h in severe cases

26

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I

Viral pneumonia

Caused by : Influenza, adenovirus, respiratory syncytial virus, cytomegalovirus, measles and chieken pox viruses, Manifested as atypical pneumonia which may be self-limited or complicated secondary bacterial infection Investigation: Detection of virus in the sputum by culture, immunofluorescence techniques or PGR Treatment: supportive with hot drinks and rest -i- treatment of secondary bacterial infection. Fungal Infections Of Lung Acquired by inhalation offungal spore mycelia Include : Aspergillosis, Actinomyces, Nocardia Aspergillosis: saprophyte in respiratory tract especially in chronic pulmonary disease, types o Type 1. Allergic bronchopulmonary 2. Aspergilloma: Fungus 3. Invasive aspergillosis o

aspergillosis o Hypersensitivity reaction with mucus plugging of bronchi & atelectasis o In patient with bronchial asthma

Clinical

picture

o

Treatment

o

ball o

Colonization in

pulmonary cavities with hemoptysis 0 In patient with pulmonary TB 0 Chest X-ray : halo sign 0 Surgical resection

Steroids

o Severe fatal pneumonia o

In

immunocompromized

o IV amphotericin & flucytosine

Eosinophilic Pneumonia Definition:

Eosinophilic pneumonias are composed of syndromes characterized by eosinophilic pulmonary infiltrates and peripheral blood eosinophilia. Etiology: Idiopathic hypcreosinopbilic syndrome :

Presence of> 1500 eosinophils/ml for >6 month without any cause of eosinophilia with multisystem dysfunction (heart, lung, liver, spleen, brain) Allergic Bronchopulmonary aspergillosis. Vasculitis e.g. Churg strauss vasculitis.

Drug reactions e.g. penicillin, sulfonamides, gold, penicilliamine and nitrofurantion. Tropical Eosinophilia(a filarial infection e.g. Wuchereria bancrofti) Loeffler's syndrome(a parasitic infection e.g. Ascaris & Ancylostoma) Clinical picture : Fever, cough, dyspnea & wheezy chest Investigations: CBC: Eosinophilia. Specific investigations for the cause. Treatment:

o

Treatment of the cause

o

Steroids.

Suppurative lung syndrome (cavitary syndrome)

dl

Definition:

It's a syndrome characterized by excessive expectoration of purulent sputum, usually foetid & related to posture. Causes:

Lung abscess. Bronchiectasis.

Polycystic lung disease. Empyema with bronchopleural fistula

27

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Lung abscess Definition:

Localized suppuration in lung associated with cavity formation with fluid level that is NOT due to tuberculosis.

Etiology: 1. Primary (Aspiration or inhalation)lung abscess: ❖ Introduction of infected material down the respiratory passages, to the lungs, due to A. Absent cough reflex: see before. B. Source of infected material:

o o o ❖ o ❖ a.

FB aspiration in children, Vomiting. Blood (in upper airway surgery or with hematemesis). The commonest causative organisms include: Anaerobes, staphylocoecus, streptococcus & haemophilus influenza. Pathology : site & number : Usually unilateral & single

b. Site:

o Mainly in right lung : right bronchus is shorter, wider & more vertical (in continuity with trachea) o More in base (gravitational effect). 2. Secondary lung abscess: Etiology :

o

Chest wall diseases e.g.: penetrating chest injuries & osteomyelitis of ribs Lung disease e.g.: Pneumonia (especially staphylococcal & Klebsiella). Bronchieetasis, lung cyst. Lung collapse, septic pulmonary infarctions.

o

Bronchial carcinoma.

1.

2.

3.

Mediastinal causes: cancer esophagus invading the lung.

4.

Subdiaphragmatic disease e.g.: Subphrenic abscess & amebie lever abscess.

5.

Pyaemic abscess:

Secondary to bacteremia as in infective endocarditis or septic thrombophlebitis Pathology : site & number in pyemie abscess: Bilateral & multiple. Small, uniform in size & shape.

28

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Stages of abscess formation & clinical picture

Pneumonic stage; pleurisy + consolidation

Symptoms & signs as pneumonia with overlying acute dry pleurisy. Stage of chronic abscess(> 2 ni): Acute abscess stage (after 9-12 days): ❖ Pathology ; o The wall of the abscess becomes thick & regular due Suppurative liquefaction of the pneumonic area starts to fibrosis. by 9-12 days. o The overlying pleural show fibrosis The abscess opens in a nearby bronchus with expectoration of purulent sputum.

The resulting cavity will have irregular thin wall with overlying acute pleurisy & surrounding areas of consolidation

❖ Symptoms: 1. Constitutional manifestations (fever, headache, malaise, ❖ As acute abscess i.e. suppurative syndrome + 1. Deterioration of general health anorexia) which improve with clearing of pus by cough 2. Retention syndrome: 2. Pleuritic chest pain o Attacks of bronchial obstruction by thick mucus 3. Suppurative syndrome : Productive cough with: pellets —>• fever + cessation of purulent sputum —> this o Amount: Excessive purulent sputum. is followed by violent cough with expectoration of o Postural (Trepopnea): T with lying on healthy side thick, blood tinged mucus pellet & return of o Odor: Fetid (anaerobic bacteria). suppurative syndrome features & drop offever. 4. Dyspnea: secondary to pleurisy & consolidation. 5. Hemoptysis may occur. Signs : Signs of cavity are variable according to size, site, contents & patency of draining bronchus: I. General: I. General: Fever, tachycardia. o Bad general condition with II. Local: loss of body weight & recurrent fever —> Cavity + pneumonic consolidation o Buffy eye lids from chronic cough, i. Inspection: o Clubbing & possibly pulmonary osteodystrophy. o Shape of the chest: normal, o o

II.

Movement: limited on affected side, Mediastinum: Central.

ii.

i.

Palpation:

Local signs: —> Cavity ± Fibrosis Inspection:

o

Tenderness on affected side,

o Shape of the chest: normal but may be retracted

o o o o

Movement: limited chest expansion on affected side Mediastinum: Trachea & apical pulsation: Central, t TVF on affected side, Palpable rub.

o

Movement: limited on affected side,

o Mediastinum: central but may be shifted to same side of lesion.

ii.

Palpation:

iii.

Percussion: Dullness on affected site.

o

iv.

Auscultations:

o Movement: limited chest expansion on affected side, o Mediastinum : Trachea & apical pulsation: central

o I breath sounds in the affected side

o Bronchial breathing of cavernous type with aegophony & whispering pectriliquy. o Crepitations: consonating o Post tussive suction may be heard after prolonged cough in collapsible cavity.

Tenderness on affected side,

but may be shifted to same side ofthe lesion o I TVF on affected side, o Palpable rub on affected side. iii.

Percussion: Dullness over the abscess.

iv.

Auscultation: As acute abscess

29

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Complications: A. General:

o Toxemia: cause anemia & amyloidosis. o Pyemia: cause metastatic abscesses especially to brain B. Local A.

Lung:

B. Pleura:

o

Pneumonia.

0

o

Bronchiectasis.

o

o

Fibrosis.

o

Pleurisy. Empyema. Pyopneumothorax.

o

Spread to other lung.

o

Fibrosis.

Differential diagnosis :

1. From other causes of suppurative lung syndromes (see later.) 2. From other causes of lung cavities e.g. T.B., tumors, hydatid cyst. 3. Primary causes from secondary lung abscess Investigations:

1. Laboratory : A. Biood:

o CBC: leukocytosis

o Blood culture may be positive in pyaemic abscess B. Sputum :sputum culture & sensitivity:

o Aspiration abscess is usually caused by gram +ve organisms (e.g. staphylococcus aureus) with secondary growth of anaerobes (e.g. bacteroids). 2. Radiological: A. Chest X-ray:

❖ Homogeneous ring opacity showing air fluid level, the wall of cavity : o In acute abscess: irregular thin wall cavity usually with consolidation & central mediastinum o In chronic abscess : regular thick wall cavity usually with pulmonary fibrosis & ± mediastinal shift to the same side o May show the cause & complications B. CT-chest: o

Localizes abscess site

o

May show cause & complications

3. Instrumental : A.

Bronchoscopy: Bronchoscope

Diagnostic value : To detect cause e.g. F.B. or tumor.

❖

Therapeutic value:

o

o

To remove FBs.

0

To localize site of abscess.

o

o

To aspirate pus for culture & sensitivity.

o

❖

To aspirate pus. To locally inject antibiotics

Oesophagus (gullet) Trachea (windpipe) Right lung Left bronchus

B. Lung biopsy in suspected malignancy 4. Investigation of the cause e.g. amebic lever abscess 5. Investigations to exclude TB

Left lung

30

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Treatment:

1. o o o

Symptomatic: Analgesics for pain, Antipyertics for fever e.g. paracetamol. Mueolytics(Bromhexine)& steam inhalation to liquefy thick sputum.

2. Antibiotics:

o Initial treatment should cover both aerobes & anaerobes then continue according to culture & sensitivity, o

Treatment should include:

A. rV Amoxieillin/ clavulanic acid Igm IV / 8 hrs. B. lY Metronidazole 500 mg/8 hrs or clindamycin 600 mg/8 hrs (for anaerobes). Camera-

3. Drainage of pus: Bronchi

Trachea

Fiber-optic bronchoscope

A. Postural drainage:

o Patient should lie on the healthy side 2-3 times/day for few minutes with percussion of affected side. B. Bronchoscopic aspiration: Allows removal of thick pus and any bronchial obstmction. C. CT guided percutaneous drainage by catheter insertion

o

Surgical(lobectomy or segmentectomy) if: Huge abscess(> 4 cm).

o

Failed medical treatment.

4.

Suspected malignancy. Complicating as empyema,pyopneumothorax & massive hemoptysis.

31

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Lung collapse

Heatlhy lung

Collapsed King

❖ Absorption collapse

❖ Cicatricial collapse

0

f/j

fl

❖ Compression collapse

Fl

Fluid

n

1

Lung fibrosis Thickened alveolar

Hypoxemia

capillary membrane

Alveoli In pulmonary fibrosis

Pulmonary

Pulmonary

artery

vein

irregular, abnormal air spaces Large areas of scarring (fibrosis)

Caibon dioxhto

Oxygen Pulmonary

capillary

Scarring(pumonafy fbmsia)

Air sac damaged by IPF Air to and from mouth/no$e

Inflammation

Scarring

Irregular, thickenir>g of tissue between alveoli

8bod vessel

Restrictive

Carbon dioxide

> Pleuropulmonary fibrosis (Fibrothorax

> Interstitial lung fibrosis

32

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Lung fibrosis

❖ Lung collapse (Atelectasis) ❖ Definition:

i* Etiology & types: I. Pulmonary fibrosis:

o Reduction of lung volume due to absorption of Fibrosis complicating parenchymatous Inng lesions e.g. lung abscess, or repeated lung infarction.

alveolar air.

❖ Etiology: I. Congenital: 1. Hyaline membrane disease: o

i INTERSTT'llllllllllMfTNn FIRROSIIS ftl Ft:

Diffuse inflammatory disorders target the alveolar interstitium, epithelium, capillary endothelium, perivascular & perilymphatic tissues resulting in alveolitis, diffuse thickening of alveolar wail &

Due to failure of surfactant secretion,

o It usually occurs in premature infants & 02 toxicity. 2. Congenital non expansion of lung. 3. Aspiration of meconium or mucus during labor. II.

fibrosis of interstitial tissne.

Acquired:

1. Absorption collapse: o Due to complete obstruction of bronchi followed by air absorption from the alveoli, o Obstruction may be: A. In lumen: FB, secretions.

A. o

2. Cicatricial collapse:

o Due to parenchymatous lung fibrosis leading to partial collapse

Idiopathic pulmonary fibrosis = Cryptogenic fibrosing alveolitis = Hamman Rich syndrome

B. Secondary causes : 1) Inherited e.g. Neurofibromatosis & Neiman -Pick

disease.

B. In wall: tumor or stricture. C. From outside: tumor or LN.

Etiology: Primary lung disease:

2) Infection :Pnenmocystis carinii, TB 3) Inflammatory granuloma : Sarcoidosis 4) latrogenic :

Amiodarone, busulfan, sulphasalazine, gold,

3. Relaxation-Compression collapse:

methotrexate

o In pleural diseases e.g. pleural effusion, pneumothorax 5) Irradiation & hydropneumothorax 6) Immnnological: o Rheumatoid arthritis & SEE. A. Progressive rise of intrapleural pressure (less -ve < zero)^ passive recoil of alveoli (passive relaxation). o Scleroderma, polymyositis and dermatomyositis. o Auto-immune hepatitis. B. When intrapleural becomes +ve it will cause further Inhalational (Occupational)lung diseases: compression of alveoli & more collapse 7) (compression). A. Organic dust(extrinsic allergic alveolitis = Hvpersensitivitv pneumonitisi:

> carbon dlodde

rather than clears

0.'

ro^gen

36

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I.

Chronic bronchitis

Definition:

o Excessive mucus production from bronchial tree leading to recurrent productive cough every day or most days: o For at least 3 months per year o For at least 2 successive years

❖ Etiology & predisposing factors:

1. Bronchial irritation:

o Smoking (the most common cause).

o Occupational exposure to irritant fumes or dust, o Atmospheric pollution. 2. Chronic upper respiratory tract infection: o

With chronic bronchial irritation as in chronic sinusitis & bronchiectasis.

o The causative organisms involved are streptococcus pneumoniae & haemophilus influenzae o Release of enzymes from granulocytes adds to lung damage.

3. Allergic; especially in patients with intrinsic asthma. 4. Bronchial edema:

o This will increase liability for infection as in cases of pulmonary congestion with LVF or pulmonary plethora in congenital heart diseases with shunt.

Pathology:

J

Enlarged

submucgsal gland MUCUS

Inflammation BACTEBU

of epithelium

DAMA9EPCUA

INCREASED NUMBER Of eOBlET CELLS

1.

Mucus accumulation

Simple chronic bronchitis :

o

Mucosal edema and congestion due to chronic bronchial irritation. It is reversible if patient stops smoking

2.

Mucopurulent stage :

o

❖ Persistence of irritation leads to : A.

Bronchospasm

B.

Hypertrophy and hyperplasia of mucous secreting glands —> t number of goblet cells of bronchial tree

T

mucous production C. o o

Paralysis of cilia with stasis of the mucus blanket All of this leads to secondary infection commonly with streptococcus pneumoniae & hemophilus influenza Micro-abscesses forms in wall of bronchi & mucopurulent discharge occur, with distortion of airway ending in irreversible bronchial obstruction.

Chronic obstructive bronchitis : with or without bronchiolitis

B.

Chronic irreversible obstruction, mainly affect small airways, due to : Impaction of mucous in lumen Hypertrophy of bronchial mucosa with infiltration by inflammatory cells

C.

Hypertrophy of smooth muscles

A.

Mucus hypersecretion.

Mucosa

exudate(chronic bronchitis)

innammation

and hbrosis

(chronic obstructiw

bronchioiiti^

D. Peribronchial fibrosis

37

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Pathophysiology:Blue Bloater = Type B = non-fighter type of COPD

❖ Normally RC controlled by: 1. Central chemoreceptors which are sensitive to hypercapnla

I

(tH^)

I 2. Peripheral(carotid & aortic ill O2

}

bodies) chemoreceptors which

i

are sensitive mainly to hypoxia.

+ HCO3

H2CO3 NaHC03

NaHCOa

1. Diffusion is normal: free alveolo-capillary membrane 2. Wide spread airway obstruction leads to alveolar hypoventilation 3. Affinity of hemoglobin(HB)to O2 is very high compared to CO2, so initially no hypoxia occurs, since HE will

4.

5.

absorb any O2 On other hand f CO2 content of alveoli leads to rise is CO2 in blood, this hypercapnla leads to stimulation of central chemoreceptors —> hyperventillation to wash CO2 With further progress of bronchial narrowing, collapse of some areas occur with under-ventilation despite good perfusion, hence hypoxia starts, with further rise in PCO2 and more hypercapnia. Chronic CO2 retention in chronic bronchitis, does not cause hyperventilation The RC being set for a higher level of PCO2, only remaining stimulus for respiration is hypoxia through peripheral chemoreceptor

6. Patient is termed blue bloater :

A. Blue : central cyanosis B. Bloater: edematous due to;

o Hypoxia end in pulmonary hypertension with cor pulmonale o Hypoxia^ f renin & aldosterone salt and water retention o Renal compensation for respiratory acidosis by reabsorption of NaHCOs

38

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II.

Pulmonary Emphysema

Definition:

o Permanent(pathological) dilatation of air spaces distal to terminal respiratory bronchioles, due to destruction of the alveolar wall and interalveolar septa . Etiology & predisposing factors:

1. o

2. o

o o o

I. o o

I. False emphysema: dilatation of air spaces without destruction of their walls Senile (atrophic)emphysema: Due to atrophy of alveolar wall with age. Compensatory emphysema: Occurs in healthy parts of lungs to compensate for reduction in diseased lung e.g. : Bronchiectasis —> emphysema of upper lung zone. Unilateral lung disease e.g. lung collapse, fibrosis, or resection —» contralateral compensatory emphysema Kyphoscoliosis —> contralateral compensatory (skeletal) emphysema II. True emphysema: dilatation of air spaces with destruction of the alveolar wall & interalveolar septa Congenital: al - antitrypsin deficiency: Transmitted as an autosomal codominant pattern al antitrypsin is a protease inhibitor produced by the liver that prevents the proteolytic activity of eiastase enzymes in the lungs that produced by pulmonary neutrophil and macrophages in response to infection & pollutions So in al antitrypsin deficiency, the proteases will destroy the alveoli ^ middle age(30 years old) patient presented hy primary emphysema(Lung)& Liver cirrhosis Acquired: ui^ at

2.

A. Localized emphysema :

o Localized partial bronchial obstruction e.g. by impacted secretions, FB,LN & tumors —>■ t intra-alveolar pressure —» alveolar rupture or compression of inter-alveolar blood vessels with ischemia of alveolar wall

o

Macleod's syndrome: unilateral emphysema due to post-infectious obliterative bronchiolitis during childhood

B. Generalized (diffuse) emphysema: o

Bronchial asthma

o

Emphysema with chronic obstructive bronchitis (the most common cause) due to destruction of alveoli by:

a. Air pollution & SMOKING: ■ t release of O2 free radicals ■ ), al antitrypsin actiyity ■ I the number of the neutrophil in the lung leading to f proteolytic actiyity of eiastase enzymes b. Infection & inflammation of bronchi —>■ airway narrowing f intra-alyeolar pressure ❖ N.B. Extra-pulmonary emphysema: o Mediastinal emphysema e.g. rupture esophagus & subcutaneous (surgical) emphysema e.g. chest wall injuries Types of emphysema : 2. Paraseptai emphysema

1. Centri-acinar

emphysema:

Alveolar

duct

Terminal bronchiole

4. Irregular

3. Pan-acinar

emphysema: Septum

Septum

/ \ 0 x- Stages of COPD :GOLD criteria for severity:

❖ Stage: ❖ Degree o

0

0

At risk

o

1

o

Mild

o

2

o

Moderate

o

3

o

Severe

0 4

❖ Symptoms o Chronic productive cough

❖ FEV1 :... % predicted ❖ FEV1/FVC...% o

Normal

o

80

o With or without symptoms

o Very severe 0 Chronic respiratory failure

o

50-80

o

30-50

o

50 years old heavy smokers 2. General fatigue, headache, anorexia, malaise.

3. Lower limb edema: due to cor pulmonale or salt & water retention due to renal regulation 4. Symptoms of complications: respiratory failure(CO2 narcosis) see later. II. Chest:

1. Chest pain, due to :

o Strain of intercostal muscles due to chronic cough o Pleurisy, secondary to complicating pneumonia o Rupture emphysematous bulla, causing tearing pain (pneumothorax) 2. Chronic cough with moderate amount of expectoration with: A. Amount: small to moderate

B. No postural variations C. Color & Character : 0 0

■

COPD

0 COPD with secondary infection ■ ■

Color

Whitish

0 ■

Greenish (anaerobic infection) ■ Yellowish (pyogenic infection)

Character

Mucoid

Muco-purulent

D. Diurnal variation:

o More at the morning(up regulation of bronchial receptors at early morning + stored secretions) E. Seasonal variation: winter exacerbations(> 3 months in 2 years) F. Odor:odorless, may be offensive (fetid) if there is secondary infection by anaerobes 3. Dyspnea: gradual onset, progressive course, P'on exertion, late at rest. 4. Hemoptysis : blood tinged sputum can occur,during infective exacerbation

5. Wheezes due to narrow bronchi (both due to bronchitis & due to loss of bronchial support by alveoli in cases of emphysema). III. Cardiac:

A) Right ventricular hypertrophy ± failure due to pulmonary HTN: hypoxic cor pulmonale:

i O2

ED C™D C

Polycythemia

Myocardial depression

I. Pulmonary hypertension which results from: A. Hypoxia which causes:

1. Direct VC of pulmonary arteries —> f pulmonary vascular resistance ^ P.HTN

2. VD of peripheral arterioles^ J, peripheral vascular resistance ^ hypotension with tachycardia —>■ f VR with hyperdynamic circulation ^ | pulmonary blood flow 3. t Blood viscosity due to polycythemia ^ f pulmonary vascular resistance ^ P.HTN ^ | load on right ventricle B. Reduction of pulmonary vascular bed due to:

1. Compression of pulmonary capillaries by f intra-alveolar pressure 2. Loss of pulmonary capillaries due to destmction of alveolar septa H. Depression of myocardial contractility by hypoxia & acidosis HI. t Fluid retention —>■ f load on right ventricle.

42

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

B) Left-sided HF may occur in COPD due to:

Left Atrium

Right Atrium

A#

Trlcuspid regurgitation

1. Effect of hypoxia: A. P.HTN ^ opening of patent foramen ovale

B. o C. 2. 3. 4.

t Blood viscosity due to polycythemia: t peripheral vascular resistance —> systemic HTN —> f load on left ventricle Depression of myocardial contractility by hypoxia & acidosis Reversed Bernheim effect: push TVS to the left with J, LV capacity Associated disease of left side especially coronary heart disease t Fluid retention —+ f load on left ventricle.

Right Ventricle

S Left Ventricle

deviation

to left

Pulmonary Artery

Signs:

1501

100-

I. General examination:

50

/UVJWAfv Expiration

1. Vital signs :

Inspiration

Expiration

A. Pulse :

o o o o

Tachycardia & big pulse volume due to YD effect of hypercapnia & hypoxia Small pulse volume : in severe pulmonary hypertension & RVF Pulsus paradoxus ; in severe cases AF & multifocal atrial tachycardia: in severe hypoxia

B. Respiratory rate: tachypnea with working ala nasi & accessory respiratory muscles? o Contraction of trapezius, scalenus muscles & stemomastoids o

Contraction of abdominal muscles & latissimus dorsi

o Exaggerated indrawing of supraclavicular fossae & suprastemal 2. Head:

o o o 3. o o

Puffmess of eye lids due to chronic cough Flushed face due to polycythemia Mouth : central cyanosis may be present, Pursing of lips Neck veins: Congested neck veins with expiratory filling due to : t Intrathoracic pressure from chronic Cough RVF as a result of Cor-pulmonale

4. UL:

o Mild clubbing due to hypoxia

o Marked clubbing if there is associated bronchiectasis or bronchogenicTarcinoma 5. LL:edema LL may occur due to : o RVF as a result of cor-pulmonale

o Salt and water retention as a result of Renal compensation 6. Signs of complications : respiratory failure:

o Activation of accessory muscle of respiration and working ala nasi o Asterixis (flapping tremors)& inverted sleeping rhythm o Big pulse volume & warm extremities o Papilledema & headache(tICT) O Tachycardia, hypertension, Tachypnea & dyspnea o Central cyanosis & Clubbing o

CO2 narcosis (hypercapnic encephalopathy): hypersomnia ,drowsiness & mental dullness

o

Confusion, convulsions. Coma and death

43

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II. Chest examination:

i. Inspection: 1. Shape: barrel shaped chest; hyperinflated chest:

o Shape : barrel & symmetrical bilateral hyperinflated chest o Diameter: Antro-posterior diameter > transverse diameter o Subcostal angle: wide > 90° o

Ribs : horizontal

o Intercostal spaces: wide o

'fflHli

Shoulders : raised

o Sternum : prominent o Spine : Kyphosis 2. Movement:

A. B. o o C. 3.

Limited bilaterally Exaggerated Hoover's sign Abnormal movement of accessory muscles during inspiration e.g. Littin's Sign Contraction of inspiratory accessory muscles : trapezius, scalenus muscles & stemomastoids Exaggerated Littin's Sign : exaggerated indrawing of lower intercostal spaces Hoover's Sign: inspiratory indrawing of costal margin due to low flat diaphragm (reverse of the normal) Mediastinum: apical pulsations may not be seen.

ii.

Palpation:

1) 2) A. B. o

Movement: limited chest expansion bilaterally Mediastinum: Trachea is central & apical pulsations may be not felt. Campbell's Sign or tracheal tug with inspiration or false tracheal tug: Descent of cricoid cartilage with inspiration due to pulling on the trachea during inspiration by strong diaphragmatic contraction C. Crico-Sternal distance = tracheal length: less than 3 finger breadths. 3) TVF: I bilaterally. 4) Palpable wheezes iii. Percussion: hyperesonance with encroachment on hepatic & cardiac dullness. iv.

Tracheal Tug

Auscultation:

o Vesicular breathing with prolonged expiration o Wheezes : bilateral polyphonic expiratory wheezes o Crepitations:

Crico-Sternai distance

■

Mild: due to secretions in recurrent chest infections

■

Marked: if there is associated bronchiectasis or bronchopneumonia or associated LVF III. Cardiac examination:

1. Signs of pulmonary hypertension : see cardiology 2. Signs of RYE ± RVF secondary to cor-pulmonale: see cardiology ❖ N.B: as the patient Is emphysematous :

o Left parasternal & apical pulsation maybe not felt o Epigastric pulsation may be detected due to RYE as a result of cor-pulmonale 3. ± Signs of LVF TV. Abdominal examination:

1. Lower border of liver may be felt due to :

o Depression of the liver by flat diaphragm : not tender o Enlarged liver due to cor pulmonale : tender 2. Ascites may be present due to RVF.

44

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Complications: Ptounli|U(t-^

V f

TtithtilsNfi

CAibpt^lunQ

OtMtWUl

ffSMmf/Ba

iittntrritg

1. Pulmonary infections leading to : A. Acute exacerbation of COPD,presented by:

o o B. 2. 3.

Exaggeration of symptoms & signs Presented by complications e.g. respiratory failure & cor-pulmonale. 1 susceptibility to bronchiectasis or bronchopneumonia Bronchial obstruction & secondary collapse Pneumotborax due to rupture emphysematous bulla s peptic ulcer

4. Respiratory failure 5. Right sided heart failure secondary to cor-pulmonale

Mr'

6. Left sided heart failure & IHDs

7. Peptic ulcer in 20 % of cases due to : A. Devitalization of mucosa by hypoxia

B. Hypercapnea : ++ vagal center leading to hyperchlorhydria C. Drugs : steroids 8. Complications of prolonged cough may lead to :

a) t Intracranial pressure: cerebral & subarachnoid hemorrhage, Insomnia b) t Intra-ocular pressure: puffmess of eye lids, subconjunctival & retinal hemorrhage c) Dissemination of infection (air born) d) t Intra-thoracic pressure: o Hemoptysis

o Pneumothorax (rupture emphysematous bulla), muscle strain (pain)& rib fracture o Tussive syncope due to prevention of blood inlet & exit e) t Intra-abdominal pressure: o

Hernia

o Prolapse (rectal, vaginal, uterine) o

Stress incontinence

9. t Hazards of smoking: A. CNS: stroke B. CVS:

o Ischemic heart disease, arrhythmias, peripheral vascular diseases C. Chest:

o Chronic bronchitis, COPD o Bronchogenic carcinoma o Cancer: lip, tongue, pharynx & larynx D. GIT:

o Peptic ulcer & gastritis o Cancer: esophagus, stomach, bladder

45

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations I.

Laboratory:

1. Blood:

o CBC: Polycythemia(f HB & HCT)& Leucocytosis. o ABG: type II respiratory failure ■ i P02, t PC02 , t HC03 2. Sputum culture & sensitivity:

o Streptococcus pneumoniae & Haemophilus influenza are the most common organisms. II. 1.

A.

B.

C. 2. III. A.

Radiological: Chest x-ray: Increased bronchovascular markings of voluminous lungs Signs of hyperinflation : o Hypertransluceny of lung o Heart shadow is elongated : ribbon shaped heart o Wide transverse ribs & intercostal spaces o Low flat diaphragm o Emphysematous bulla maybe present Complications e.g. pneumonia or pneumothorax. Chest CT(high resolution): diagnostic. Instrumental: Respiratory function tests: Ventilation tests by spirometer: obstructive hypoventilation 0

Residual volume.

0 Functional residual capacity. 0 t i.e. there is air trapping 0 Total lung capacity ■ Forced expiratory volume in ■ iiJ, due to increased airway resistance L'second (FEVi). ■ Improves 15 % in FEVi, tapering of steroids should be done with replacement by inhaled steroids to avoid the side effects of systemic steroids. III. Treatment of complications: 1.

2.

3. A. B.

C.

Treatment of polycythemia: treated by vensection if HCT > 55%. Treatment of heart failure: diuretics, digitalis, dilators o N.B.: digitalis toxicity : t with hypoxia o Correction of hypoxia ^ I pulmonary artery pressure Treatment of acute respiratory failure: Admission to respiratory ICU & treatment ofthe cause Oxygen therapy via oral/nasal masks < 3L/min Non-invasive ventilation via oral-nasal continuous positive airway pressure(CPAP)

D. Invasive ventilation: mechanical ventilation with endotracheal intubation in severe cases. 4. A.

Treatment of chronic respiratory failure: Home (domiciliary)02 therapy: Indication: Nasal cannula

o Stage 3 & 4 COPD i.e. FEVi < 50% o Severe hypoxia PO2 70 mEq/L is diagnostic DNA analysis : gene mutation for CFTR ❖

Small intestine

Treatment:

1. For Lungs:

o Antibiotics and mucolytic agents o Postural drainage, adequate hydration o Gene therapy o Lung or heart lung transplantation 2. For intestinal obstruction:

o Enema by gastrografin o

Surgery.

3. For pancreatic insufficiency: pancreatic enzymes and adequate nutrition. 4. Drugs: A. Amiloride:blocking of Na reabsorption

B. Adenosine & triphosphate nucleotide:stimulating chloride secretion C. Dornase-a: making sputum less viscid

D. Ivacaftor/tezacaftor: | lung function & helps move the CFTR protein to the correct position on the cell surface

59

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis of suppurative lung syndrome

■

History

❖ Lung abscess

❖ Bronchiectasis

o Operation,

0

Pneumonia

❖ Infected cystic lung o Long - since

Coma

❖ Empyema with bronchopleural fistula o Empyema

birth

■

Onset

o

Acute

0

Gradual

o

Gradual

o

■

Signs

0

Unilateral

o

Bilateral basal

o

Bilateral

■

Sputum

o t on lying on healthy side

o Unilateral pyopneumothorax o No special character

consolidation

consolidation

o t on leaning forward (stooping) o

■

Chest X-ray

o Cavity with

consolidation

o No special

Acute

character

More in winter.

♦> Investigation o Honey comb o Soap bubble

o Pyo-pneumothorax

o Multiple dilatation

o

fluid level

■

Bronchography o - ve filling

o Multiple dilatation

Not done

o Positive methylene blue test

Allergic bronchopulmonary aspergillosis Fungus breathed in

Etiology: allergy to fungus aspergillus fumigatus Presentation

1. o o o

2.

1. Allergic bronchial asthma & central bronchiectasis 2. Extrinsic allergic alveolitis 3. Pulmonary eosinophilia 4. Intracavitary aspergillosis leading to hemoptysis Investigations: Laboratory: Eosinophilia High serum IgB Positive skin prick test Radiological: Chest X-ray:

Glove finger shadow due to mucoid impaction in central bronchiectasis Meniscus sign or halo sign : nodular consolidation surrounded by ground glass opacity Treatment:

Steroids: Prednisolone

TV amphotericin in invasive forms Bronchoscopic aspiration of mucus plug

60

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Pulmonary Tuberculosis

Definition: Chronic granulomatous pulmonary infection.

Members of the genus Mycobacterium: 1.

Mycobacterium tuberculosis, it causes most of cases of tuberculosis.

2.

Mycobacterium bovis: in cows and spread to man through infected milk causing gastrointestinal tuberculosis. Atypical mycobacterium (non tuberculous mycobacteria) in immunocompromised patients: M. Marinum, M.

3.

Kansasii, M. Avium 4. 5.

Myeobacterium leprae: the causative organism of leprosy. Saprophytic mycobacteria: rarely ineriminated in human diseases.

Characters: Acid fast- alcohol fast (i.e. resists de-staining), obligate aerobic bacilli. Predisposing factors:

1. Age: o < 5 y : high susceptibility to infection and hematogenous spread

o 5-15 y: relative resistance

(golden age).

o > 15y: more liable to post-

primary T.B

2. Race: more in black races

3. Residence: overcrowding & lack of adequate ventilation (as in military recruits). 4. Occupation: more in doctors, nurses & Miners of silica & asbestos. 5. Diseases & drugs: causes ofimmunocompromised patient (see before) Mode of transmission:

1. Droplet infection from patients with open T.B. 2. Ingestion of milk from infected animals 3. Reactivation of dormant foeus.

Pathogenesis:

o Entry of the organism through respiratory tract through inhalation of infected droplets produced by the coughing or sneezing ofinfected individuals,

o After entry into the lungs, tubercle bacilli are ingested by maerophages and transported to regional lymph nodes, then it may disseminate widely,

o The reaction of the body towards tubercle bacilli depends on the individual's hypensensitivty, resistance and whether those bacilli are first seen by the body or it is the second exposure so if: 1. First exposure = primary TB = childhood TB: o In individuals lacking previous contact with tubercle bacilli 11. Second exposure = secondary (post primary) TB = Adulthood TB = reactivation:

o In individuals with previous contact with tubercle bacilli i.e. previously sensitized individuals.

61

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

L

First exposure = primary TB = childhood TB inrection with Mycobacterium

Pathology:

Multinudeated

Epitheiioid

giant cell

macrophages

'

tuberculosis

Lymph

Response ofthe body to initial infection with TB bacilli known as primary complex. Occurs in : In individuals lacking previous contact with tubercle bacilli Primary complex = Ghon's complex which is a triad of : Pulmonary component: Ghon's focus

Lymphocytes

Area of initial infection of airborne TB bacilli.

Ghon

complex

Single granulomatous lesion formed by sub pleural aggregation of tubercles in the lower part of upper lobe or upper part of lower lobe.

Microscopically there's a granulomatous lesion with central caseating lesion surrounded bjy lymphocytes, Langhans giant cells, epitheiioid cells, macrophages & fibroblast. Lymph node(Glandular)component: tuberculous lymphadenitis (bilar L.N) Lymphatic vessel component: tuberculous lymphangitis

Lyrnon nod* csRipanM

Fate & clinical picture: 1.

Healing(90%):

2.

Complete resolution : TB bacilli are destroyed alveolar macrophages Incomplete resolution by fibrosis & calcification around viable bacilli ^ dormant(latent) Gohn's focus healing for months or years then reactivation occurs during periods of low resistance —> exacerbation Hypersensitivity reaction to tubercle bacilli may occur (after 6 weeks) leading to:

o

Positive Tuberculin test

o o

o o o

3.

Phlyctenular conjunctivitis. Erythema nodosum Epituberculosis: pleural based triangular shadow that represents parenchyma hypersensitivity reaction Progression (10%)of: B)Lymph node component

A)Pulmonary component n

jn_

C)Lymphatic vessel component XL

o General TB toxemia: night sweat, night fever, loss of appetite, loss of weight

"TF

m 1.

LN enlargement: Mediastinal syndrome (tracheobronchial ln)

2.

Middle lobe syndrome (Bronchiectasis)

3. 4.

Lung collapse D'espine sign

B.

LN rupture into:

A.

o

Pleurisy

o

Pleural effusion

o

Consolidation

(bronchopneumonia) o

Cavitation

❖ N.B.: D'espine sign:

Hematogenous spread with miliary T.B.(ExtraPulmonary TB)

1) Pericardium; T.B pericarditis, effusion 2) Pleura : T.B pleurisy & effusion 3) Pulmonary vessel: hematogenous spread with miliary T.B (Extra-Pulmonary TB) U.

o Normally : if you auscultate below the body of T4(tip of T2 spine), you will hear vesicular breathini o Abnormally : if you heard bronchial breathing below T4 confirmed by t of vocal resonance o Significance: indicates enlarged mediastinal(interbronchial) LN e.g.: TB or neoplastic

62

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II.

Second exposure = post primary TB - secondary TB = Adulthood TB = reactivation

Response of the body in a previously sensitized individuals due to secondary exposure to TB bacilli due to : 1) Re-infection from patients with open TB 2) Reactivation of dormant primary (Ghon's)focus 3) Reactivation of hematogenous spread from unhealed L.N. Site of reactivation :

More in apical segment of the lung due to high O2 levels which favors growth of TB bacilli

❖ Pathology: > According to immunity & virulence of organism different types of lesions may form:

1.

Pulmonary:

❖ Type

❖ Immunity

1. Fibroid TB

0 Immunity > infection 0 T 0 Infection > Immunity 0 ttt 0 Immunity = infection 0 ttt

2. Caseaus TB 3. Fibrocaseous TB

II.

❖ Caseation with cavitation

❖ Fibrosis

0 ttt 0 t 0 ttt

Extra-Pulmonary TB .

❖ Clinical picture: 1.

Symptoms :

A. Asymptomatic: discovered accidentally on radiological examination

B. General symptoms : TB toxemia: night sweat, night fever, loss of appetite, loss of weight C. Local symptoms:

1. Chest pain : due to muscular strain, pleurisy or pneumothorax 2. Cough :

o Productive cough with expectoration of a mucopurulent sputum, which may be coin-shaped (nummular sputum) o Dry cough in hronchiectasis sicca hemorrhagica in fibroid type TB. 3. Dyspnea due to consolidation, cavitation, fibrosis, pleural effusion or pneumothorax 4. Hemoptysis:is common & result from :

Bleeding from vascular granulation tissue Bleeding from aspergilloma developed in TB cavity Erosion of a big blood vessel traversing TB cavity Rupture of submucous blood vessels in wall of bronchi

o Rupture of TB pulmonary artery pseudoaneurysm (Rasmussen's aneurysm)

D. Symptoms of complications : erosion of blood vessels by tuberculous lesion-+ hematogenous spread II.

Signs :

A. Toxic face, fever, loss of body weight & pallor B. Clubbing

C. Signs of hematogenous spread (miliary T.B.)

63

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

D. Chest signs : depend on nature of lesion:

2)Caseaus TB:

1) Fibroid TB:

3)Fibrocaseous TB:

❖ Marked fibrosis with bronchiectasis

sicca haemorrhagica: o Apical bronchiectasis, dry cough & frank hemoptysis.

o Apical cavitation

o Apical cavitation & fibrosis (the commonest)

4)Endobronchial TB

o

TB bronchitis & ulceration of bronchi connected to TB cavities.

o Complicated hy fibrosis —> bronchostenosis —> tension cavity ending by rupture: TB pyopneumothorax

5)Pleurisy with pleural effusion 6)TB bronchopneumonia (apical consolidation)

❖ Complications:

1. Respiratory failure with extensive pulmonary destruction and fibrosis. 2. Spread: lymphatic & hematogenous spread 3. Secondary Amyloidosis

4. Aspergilloma: Fungal colonization of the cavities with aspergillus 5. Side effects of Anti-tuberculous drugs.

64

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Hematogenous spread of TB = Miliary T.B.= Extra-Pulmonary TB: I.

Source:

o Lymphatic spread to blood stream, o Erosion of blood vessels by tuberculous lesion. II. Types: A. Sub-cIinical type:

o The organism will remain dormant for a period of time till body immunity is depressed according to their site e.g. T.B. meningitis, arthritis or pyelonephritis.

multiply & manifest

B. Clinical miliary T.B:

o With massive spread or low immunity o Present by:

1. 2. 3. 4. 5. 6.

General: Bad general condition with marked toxemia: Fever, anorexia & prostration. CNS: Meningitis & tuberculoma in CNS. Eye: choroid tubercles in retina presenting on fundus examination as raised yellowish shiny lesion. CVS: Tuberculous pericarditis, effusion & constrictive pericarditis Lung: Miliary tubercules, tuberculoma of lung & pleural effusion. RES: Generalized lymphadenopathy & hepatosplenomegaly

7. GIT: o o

Tuberculous enteritis follows swallowing heavily infected sputum. Intestinal tuberculosis: the terminal ileum and caecum are common sites. This leads to abdominal pain, diarrhea and palpable abdominal mass Tuberculous peritonitis with ascites & hepatosplenomegaly. Genitourinary system: affection of: Adreinsl glena^ Oer^l^ Kidney: pyelonephritis with sterile pyuria Siiaidymfs Adrenal: Addison's disease

Epididymis: epididymitis. Fallopian tubes & uterus : Salpingitis or endometritis Bone: Pott's disease of spine, osteomyelitis & arthritis . 10. Bone marrow: Anemia, leucopenia & thrombocytopenia III. Investigations : 1. Tuberculin test: may be false negative 2. CXR & biopsy

1 Ureter tv^^aeddei

Prostete, semirtal

veeiciee

Differential diagnosis:

1. Fever of unknown etiology. 2. Cases of with bronchopneumonia, pleural effusion & mediastinal lymph node enlargement e.g. sarcoidosis or lymphoma. 3. Miliary, coin shadows, fluffy cotton appearance in chest x ray 4. Latent TB infection & Pulmonary TB disease ❖ Latent TB infection a.

Tubercle bacilli

b. c. d. e. f.

Spread of infection o Not infectious, not a case of TB Symptoms o No Sputum smears & culture o Negative Tuberculin skin test and Quantiferon test o Positive Chest x-ray o Normal

o

Inactive dormant

❖ Pulmonary TB disease o Active multiplying o Infectious, a case of TB o

Yes TB toxemia

o

Positive

o

Abnormal

65

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Investigations; I.

Laboratory:

A. Blood:

o Leucopenia with relative lymphocytosis o Anemia of chronic disease & f ESR

}

B. Microbiological examination :

1. Specimen:

o Three early morning sputum specimens collected on consecutive days, from a deep productive cough, o In absence of sputum : Broncho-alveolar lavage or gastric lavage o In Extra-pulmonary TB: CSF,serous fluid, urine & stool. 2. Direct detection:

a. Smears prepared directly from sputum are subjected to acid-fast staining methods e.g. Ziehl-Neeisen (Z-N)stain & repeated for at least 6 times: they appear pink in a blue background b. Molecular methods by PGR to detect T.B. DNA allowing diagnosis within 48 hours

5 mm : in immunocompromised patients e.g. HIV An induration of > 10 mm: in sick patients without immunosuppression e.g. DM An induration of > 15 mm: in immunocompetent patients

D. Value :

❖ Positive reaction: o

Active infection,

o

Old infection,

o Vaccination by BCG o If it becomes positive in a nonvaccinated child ( right supraclavicular LNs. Right lung & left lower lobe: To interbronchial Left upper lobe: to left supraclavicular Ins. Spread to cervical LNs, axillary & abdominal LNs. interstitial pulmonary disease & subacute Retrograde lymphatic spread —> lymphangitis carcinomatosa cor-pulmonale

3. Hematogenous spread: to liver, brain & bone.

73

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Clinical Picture:

I. General manifestation:

o Low grade fever, anorexia, and marked loss of weight II. Intra-thoracic manifestation:

A. Broncho-pulmonary: 1. Asymptomatic: discovered accidentally in chest x-ray as coin shadow. 2. Bronchial obstruction :

o o 3. o o

4. o

o o

5.

Partial: localized wheezes, emphysema ,bronchiectasis Complete : collapse ^ Un- resolving or recurrent pneumonia Pneumonia & lung abscess due to: Necrosis and secondary infection of tumor center. Secondary infection of lung collapse Cough & hemoptysis: Frank hemoptysis. *

Blood tinged sputum.

*

Red current jelly sputum (blood + necrotic tissue) Subacute cor-pulmonale due to lymphangitis carcinomatosa.

B. Pleura] manifestations: a.

Dry pleurisy (pleural irritation): dry cough, pleuritic chest pain & pleural rub.

b. Pleural effusion: 1.

Malignant effusion is hemorrhagic effusion characterized by :

Massive, rapidly re-accumulating after aspiration, rich in malignant cells Mediastinal shift to opposite side but may be to the same side of effusion due to underlying collapse from bronchial obstruction 2. 3.

Transudate (hydrothorax): due to obstruction of azygous vein. Empyema: due to rupture of malignant abscess in the pleura.

4.

Chylous: due to obstruction ofthoracic duct.

C.

Pancost syndrome (thoracic inlet syndrome, or superior sulcus syndrome): bronchial carcinoma in the apex of the lung:

Phrenic nerve •

^Sympathetic I trunk

Vagus nerve Brachiai

plexus

o o o o o o

Upper 2-3 ribs pain & pathological fractures. Subclavian artery —> unilateral ischemia with unequal pulse & BP, unilateral clubbing, Subclavian vein: edema of UL & dilated engorged veins. SVC —> congested, non-pulsating neck veins & dilated veins over the chest and syncope, Sympathetic chain ^ Homer's syndrome Lower trunk of brachiai plexus weakness & wasting of small muscles of the hand + pain a long medial side of arm & forearm.

D. Mediastinal syndrome:

1. Secondary to: o Central (hilar) tumors. o Peripheral tumor with mediastinal LN metastases

2. Manifestations e.g.: Phrenic nerve —> diaphragmatic palsy & Recurrent laryngeal nerve -

hoarseness of voice

74

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

III. Extra-thoracic manifestation:

i.

Metastatic:

A. Lymphatic spread: enlarged cervical, axillary, supraclavicular or abdominal LNs. B. Hematogenous spread:

1. Brain —>■ t ICT & neurological manifestations. 2. Bones —> bone pains & pathological fractures. 3. Liver ^jaundice, irregular enlarged liver. 11. Non-metastatic: para-malignant syndrome ❖ These manifestations occur in oat ceil carcinoma secondary to secretion of abnormal metabolites by the tumor: A. CNS manifestations:

1. 2. 3. 4. 5. B.

Cerebral encephalopathy. Cerebellar atrophy. Peripheral neuropathy. Myopathy. Myasthenia gravis: Eaton Lambert syndrome Skeletal —> clubbing & bypertropbic osteodystropby.

C. Endocrinal:

1. 2. 3. 4. 5. 6. D. 1.

Hypercalcemia(tPTHrP) Hypoglycemia (finsulin like substance) Dilutional Hyponatremia (SIADH: fADH)} Gushing syndrome (fcortisol like substance) Carcinoid syndrome (fserotonin ) Gynecomastia(tLH like substance) Dermatological: Acanthosis nigricans

2. Pruritis.

3. 4. 5. 6. E. 1. 2.

Hyperpigmentation. Migratory thrombophelibitis. Myositis & dermatomyositis. Herpes Zoster. Hematological: Anemia: Aplastic, Hemolytic & Megaloblastic anemia . Polycythemia

3. Leukmoid reaction.

❖ Neurological manifestation of broncbogenic carcinoma : A. Intra-tboracic manifestations :

1. Thoracic inlet syndrome: o Sympathetic chain —> Homer's syndrome,

o Lower trunk of bracbial plexus ^ weakness & wasting of small muscles of the hand + pain a long medial side of arm & forearm. 2. Mediastinal manifestation :

o Phrenic nerve : diaphragmatic palsy o Recurrent laryngeal nerve : hoarseness of voice B. Extra-thoracic manifestations :

1. Metastatic manifestation :)• ICT & neurological manifestation 2. Non metastatic manifestations : para-malignant syndrome

75

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Differential diagnosis: In an old, heavy smoker male patient with chest manifestations not resolving for two weeks the possibility of bronchogenic carcinoma should be raised. Wi—_■

Bronchogenic carcinoma should be differentiated from: Other causes of bronchial obstruction.

1.

2. Other causes of pneumonia & lung abscess. 3. Other causes of cough & hemoptysis e.g. T.B. Other causes of pleural effusion. Other causes of mediastinal syndrome. Pancost tumor : DD from other causes of thoracic inlet syndrome e.g. cervical rib or subclavian artery aneurysm 7. Differential diagnosis from : A. Apical lung lesions:

B. Coin shadow or Cannon balls

A. Pleural thickening e.g. Mesothelioma B. Pancoast tumor

1. TB (tuherculoma I

haemorrhagica: TB

1. Bronchogenic

A. Benign : bronchial adenoma

1. Infections :

carcinoma

o

TB

2. Ghon's focus

o

Viral i IMN

3. LN (if lobulated

o Fungal : histoplasmosis 2. Neoplastic: o Bronchogenic

2. Tumor :

C. Pneumonia: Klebsiella D. Bronchiectasis sicca

C. Hilar opacity (mediastinal) Unilateral hilar opacity ❖ Bilateral hilar opacity

B. Primary malignant: bronchogenic carcinoma

"festooned" rise the

C. Secondary : single metastasis e.g. hypernephroma 3. Lung cyst(hydatid) 4. Pneumonic patch

LN)

suspicious to malignant

carcinoma

o Lymphomas, lymphatic leukemia 3. Sarcoidosis 4. Inhalational: Silicosis Apical lung cancer

❖ Investigations: I.

Laboratory:

A. Blood: o

CBC : anemia , polycythemia, leukmoid reaction

o

Endocrinal effect e.g. increased serum Ca"^"^.

Cefliral lung cancer Hilar lynipli nod* enlargsment

Peiiph^ lung canear

B. Sputum examination to detect malignant cells 11.

Radiological ;

A. Chest x-ray: May reveal: 1. 2.

Lung collapse, pneumonia, lung abscess Pleural effusion with mediastinal shift to opposite side or to the same side of efftxsion

3. Pancost tumor:

o

Apical shadow & erosion of upper ribs Paralyzed diaphragm: raised copula with paradoxical movement under screen

4.

Coin shadow (single unilateral) or Cannon balls (multiple bilateral): rounded opacity

o

5. Hilar shadow: unilateral or bilateral due to central tumor or LN. 6. B.

Mediastinal mass(tumor or LNs). CT & MRl: for better localization, detection of mediastinal LNs & metastasis.

76

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

III.

A. o o o B. ❖ o o ❖ o o o

Biopsy

Instrumental :

Cytology: Aspiration of pleural fluid or pleura! biopsy Lung biopsy: CT guided transthoracic needle aspiration biopsy, LNs biopsy for detection of metastasis. Bronchoscopy: Diagnostic: Biopsy from central lesions Bronchoalveolar lavage(BAL)& cytology for peripheral lesions

Biopsy needle

Tumour

Prognostic: may determine suitability for surgery: Vocal cord mobility : exclude RLN paralysis Mobility of trachea: exclude tracheal fixation Widening of carina : exclude carinal LN enlargement

❖

Treatment:

Tumor

Bronchi Metallic

I. Surgical: Operable cases ❖ Surgery: total pleuro-pneumonectomy.

Stent

❖ Indications: o

Localized tumor without metastasis or local invasion,

o Adequate pulmonary function to with stand pneumonectomy. o No other high risk factors for surgery e.g. isehemic heart disease. II. Non operable cases: 1. Combination of chemotherapy with radiotherapy 2. To relief obstructive lesions:

o Transbronchial stenting o Palliative surgery 3. Symptomatic treatment: Analgesics, Antibiotics for infection

Prognosis:

o Prognosis is poor with survival rate of 10-60% for 5 years depending on stage & type of tumor, o Small cell carcinoma carries the worst prognosis.

77

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Mediastinal syndrome

❖ Anatomy of mediastinum:

❖ The mediastinum is the central part of thorax occupying space between two Stemal

Superior mediastinum

Boundaries:

o

Anterior: sternum

o

Posterior: Thoracic vertebrae

o Lateral: parietal (Mediastinal) pleura o Superior: Thoracic inlet o Inferior: Diaphragm

mediartt

Divisions:

❖ The mediastinum is divided by imaginary line that passes between the angle of Lewis and the lower border of the T4 vertebra into:

1. Superior mediastinum 2. Inferior mediastinum: may be further divided by the pericardial sac into: o

Anterior mediastinum

o

Middle mediastinum

o

Posterior mediastinum

❖ Content of mediastinum & Etiology of Mediastinal syndrome:

78

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

'■-siJ-aSi

Thoracic Q) n

inlet

zr

(0 Q)

Aortic,

Transverse r

thoracic plane HEART

1

L recurrent

I

laryngeal n.

I I I

1 I I

Vagus n,

I

(L&R)

I i

Phrenic n.

I

Middle

i

'mediastinum' ❖ Etiology of Mediastinal syndrome

❖ Content of mediastinum

❖ Superior mediastinum

1 1. Vessels:

o Aortic arch and its major branches o Innominate veins and Superior vena cava 2. Nerves:

o Sympathetic chain, left Recurrent laryngeal nerve, vagus nerve & phrenic nerve

1. 2. 3. 4. 5.

|

Aneurysm of the aorta or one of its major branches Tumors e.g. esophageal, bronchial and metastatic Enlarged LNs: lymphoma,leukemia, cold abscess Retrostemal goiter Mediastinal emphysema

3. Tubes:

o Trachea, esophagus & thoracic duct 4. Lymph nodes & fat

❖ Anterior mediastinum

1 o Thymus gland o Lymph nodes & fat

1

*X* Middle mediastinum 1. Pericardial sac ; heart & big vessels

1. Pericardial effusion & Aneurysm in the ascending aorta

2. Phrenic nerves

2. Bronchogenic carcinoma 3. Enlarged LNs

3. Tubes :Trachea & main bronchi

I

1. Thymoma,Lipoma 2. Teratoma or dermoid cysts 3. Intrathoracic goiter

I

4. LN

❖ Posterior mediastinum

1 1. Vessels: Descending Aorta & Azygos vein

1. Aneurysm of the descending aorta

2. Nerves: Spinal nerves & Vagus nerve 3. Tubes: Esophagus & Thoracic duct

2. Neurofibroma

4. LN

3. Tumors in the esophagus 4. Enlarged LNs 5. Hiatus hernia

79

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

1

Clinical picture:

1. Compression on vessels:^ Arch of

Superior

aorto

vena cava

1. o 2. o o 3. o

Compression of aorta and its major branches: Leads to unequal pulse and BP + Unilateral clubbing Compression of SVC: Congested non-pulsating neck veins

Azygos vein

Edema of UL and neck (change in the size of T-shirts ,necklace or ring) Compression of Azygos vein: Dilated tortuous veins over the chest fdling from above downwards

2. Compression on nerves: j 1. Intercostal nerves : intercostal neuralgia 2. Brachial plexus: brachial neuralgia

3. Sympathetic chain: Homer syndrome (Anhidrosis, partial ptosis, enophthalmos and miosis) 4. Phrenic nerve: Hiccough, later on diaphragmatic paralysis 5. Vagus or left recurrent laryngeal nerve: hoarseness of voice and bovine cough Esophagus

duct

Trachea

3. Compression on tubes

1. Esophagus: dysphagia & regurgitation 2. Trachea:

o o o 3.

Dyspnea that increases by lying and improves by leaning forward Cough with metallic tone (Brassy cough) Bronchial obstmction : emphysema, Bronchiectasis & collapse. Thoracic duct: Chylous ascites, pleural ad pericardial effusion. Suprasternal

Superior

notch

4. Pressure on bones:

mediastinum

Angle of

1. Sternum: retrostemal pain

Louis

2. Ribs: leading to rib erosion and pain

3. Spine: back pain with spinal cord compression may lead to paraplegia

Anterior

mediastinum

Posterior metfiastinum

Xiphoid

5. Manifestation of the cause

Middle

mediastinum

Investigations: Laboratory :

Blood & BM examination in leukemia & lymphoma Tuberculin test

Radiological :

Chest X-ray: may show wide mediastinum, erosion of ribs, paralyzed diaphragm CT & MRI chest.

Aortography, venography, lymphangiography, thyroid scanning Biopsy : LN, Mediastinal mass Endoscopy: esophagoscopy, bronchoscopy, thoracoscopy. Exploratory thoracotomy in undiagnosed cases Treatment: of the cause.

80

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Cor-Pulmonale

❖ Definition:

P.HTN

L-—.

Right ventricular dilation

Lung disease

Right ventricular hypertrophy

'I* Right ventricular enlargement ± RV failure secondary to pulmonary hypertension that results from lung (chest) disease, after exclusion of left sided heart failure & congenital heart disease Lymph node

Etiology:

Lymphatic capillaries 1. Acute Cor-Pulmonale:

1. Acute massive pulmonary embolisr 2. Acute massive lung collapse. 3. Tension pneumothorax.

Pulmonary blood capillaries

2. Subacute Cor-Pulmonale:

1. Lymphangitis carcinomatosa 2. Recurrent showering of pulmonary emboli. 3. Chronic Cor-Pulmonale

1.

II.

Hypoxic Cor-pulmonale

Vascular (Obliterative) Cor-pulmonale

a Air in/oul

Venous

Pulmonary hypertension

nraT i/

blood in

Red Wood (jells

1. Oxygenation failure due to diffusion defect(see later) 1) Pulmonary vasculitis e.g. PAN,SLE & scleroderma e.g. Interstitial lung fibrosis 2) Thrombo-embolic pulmonary hypertension 2. Ventilation failure (see later): 3) Pulmonary Schistosomiasis A. Obstructive hypoventilation e.g. COPD 4) Syphilis of pulmonary arteries: B. Restrictive hypoventilation e.g. interstitial lung fibrosis o Pulmonary hypertension (Ayerza's disease) 5) Sickle cell anemia

81

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Pathogenesis: Pulmonary hypertension in these disorders results from: 1. Hypoxia which causes: 1. Pulmonary arterioles vasoconstriction.

2. Peripheral VD —> f venous return —> f pulmonary blood flow. 3. Polycythemia leading to increased blood viscosity. II.

Reduction of pulmonary vascular bed due to:

1) Compression of blood vessels by emphysema, or fibrous tissue. 2) Obstruction of blood vessels in vascular disease. Pulmonary hypertension results in: 1. RV dilatation in acute cases.

2. RV hypertrophy in chronic cases 3. ± RV failure

❖ Clinical picture:

1) Symptoms & signs of pulmonary hypertension. 2) Symptoms & signs of right ventricular enlargement & failure. 3) Symptoms & signs of the underlying chest disease. 4) Symptoms & signs of cor-pulmonale:

A. Hypoxic cor-pulmonale e.g. COPD

B. Obliterative (vascular) cor-pulmonale

❖ Symptoms 1. Dyspnea

o

Marked

o

Minimal

2. Sputum

o

Mucopurulent

o

Absent

❖ General examination

1. Cyanosis 2. Clubbing

o

Central due to hypoxia

o Peripheral due to low COP

o

Common

o

Absent

3. Hands

o

Warm

o

Cold

4. Pulse

o

Water Hammer

5. BP

o Big pulse pressure

1. Shape

o

Normal

2. Breath sounds

o Barrel shaped o Prolonged expiration

o

Normal

3. Adventitious sounds

o

Wheezes

o

Absent

❖ Investigations May be masked

o

Marked

Hypoxia ± hypercapnia

o Usually normal

IKk

o

Weak

o

Small

❖ Chest examination

1. Pulmonary hypertension 2. Pulmonary function test

o o

Investigations:

Chest X-ray: evidence of RVE, pulmonary artery dilatation & of underlying disease ECG: Right axis deviation, P-pulmonale & RV strain pattern. Echocardiography: RV enlargement & f Pulmonary artery pressure by Doppler. Cardiac catheterization: | Pulmonary artery systolic pressure > 30 mmHg & dilated RV by angiography. Lung biopsy may reveal the underlying disease. ❖

Treatment:

1. Treatment of the cause 2.

Reduction of Pulmonary Pressure :

Bosentan : endothelin receptor antagonist. Phosphodiesterase 5 Inhibitors e.g. Sildenafil Prostanoids:

Iloprost: inhalation o Treprostinil: IV or SC | o Epoprostenol: IV VD as CCB & ACEI. 3. 4.

Treatment of right-sided HF: best response is to Diuretics ± Digoxin. Heart lung transplantation is the only radical treatment.

82

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Bilharzial Cor-Pulmonale

Etiology: B. Schistosoma haematobium eggs:

A. Schistosoma mansoni eggs:

Their natural habitat is mesenteric vessels, accordingly for ova to reach the lungs, there should be proto-systemic shunts.

Bilharzial hepatosplenomegaly is present so that collateral circulation between portal & systemic veins permit massive embolization of lungs by ova from mesenteric veins They produce more destructive lesions & most cases that

o Natural habitat is urinary venous plexus o The worm lives in vesical & pelvic venous plexus which drain into systemic veins & hence to pulmonary vessels (lungs) o They produce mild lesions & usually do not present clinically

present clinically are due to schistosoma mansoni Pathogenesis: 1 Pulmonary hypertension results from:

1.

Necrotising arteriolitis of pulmonary arterioles resulting from miracidial metabolites | released from ova —> healing occurs by fibrosis —>■ endarteritis obliterans. Mechanical obstruction by embolized ova or dead warms. Immunological granuloma formation in pulmonary arteries secondary to sensitization by antigens liberated from

o o

dead warms.

Pulmonary hypertension leads to RVE and RVF. Pulmonary artery dilation (aneurysmal) may occur due to: Weakness of pulmonary arterioles secondary to deposition of bilharzial ova in their wall Pulmonary artery hypertension.

2. 3. o o

❖ Clinical picture:

1. II.

Symptoms of low COP & of systemic congestion. Signs: A. General:

o Signs of low CO & systemic congestion, o Shrunken liver & splenomegaly. B. Local: Signs of pulmonary hypertension & Signs of RVE. Investigations: A. Chest X-ray:

o Dilatation of main pulmonary arteries (Dumbbell shaped heart), o Pulmonary oligemia with blunt branches of pulmonary arteries, o RV enlargement.

B. ECG:P-pulmonale & RV hypertrophy. C. Detection of schistosomiasis:

o Sputum examination for bilharzial ova (rarely positive), o Urine, stool & rectal biopsy for ova detection, o Detection of antibodies against schistosoma.

o Treatment: Treatment of HE & Antibilharzial drugs e.g. Praziquantel.

83

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Respiratory Failure ❖ Definition:

❖ Failure of the respiratory system to maintain its function leading to hypoxemia(PO2 < 60 mmHg)with or without hypercapnia(PCO2 > 50 mmHg).

*1* Respiratory failure is a laboratory diagnosis. ❖ Types: Type II respiratory failure:

mmjmssiemti ❖ Definition :

venous

blooci in Alvet^i

Red blood

Oxygenated

in capiHary

blood out

o Oxygenation failure characterized by hypoxemia (PO2 < 60 mmHg)with normal or

o Ventilation failure characterized by hypoxemia(PO2 < 60 mmHg)and hypercapnia(PCO2 > 50 mmHg).

low PCO2 A. Acute:

1. Pneumonia.

2. Pulmonary Embolism. 3. Pulmonary Edema (Cardiogenic & Non cardiogenic) B. Chronic:

1. Pure Emphysema. 2. Interstitial lung fibrosis. A. Mechanism: due to disturbed diffusion or

perfusion: Decreased 02 in the inspired air. Alveolo-capillary block as in case of fibrosis or edema. Decrease in diffusion surface areas as in

emphysema.

Shunting arterial blood to venous circulation without oxygenation e.g. right to left shunt V/Q mismatching.

Etiology 1) Obstruction hypoventllation:

A. Upper airway: inhaled foreign body, laryngeal edema, spasm & tumor B. Lower airway: o Chronic obstructive pulmonary disease(COPD): Chronic bronchitis & Emphysema, o

Bronchial Asthma & Asthmatic bronchitis

o Bronchiectasis & Cystic fibrosis. 2) Restrictive hypoventllation : i.

Disorders of neuromuscular apparatus :

1) Depression of respiratory center as in head injury, stroke, encephalitis, brain tumors, and drugs (opiates). 2) Interference in the impulse transmission to respiratory muscles:

o Lesions in spinal cord e.g. Transverse myelitis, spinal fracture, anterior spinal artery occlusion o Lesions anterior horn cells : poliomyelitis o Lesions in peripheral nerves e.g. Guillain-Barre syndrome o Lesion in neuromuscular junction: myasthenia gravis. 3) Lesions in respiratory muscles: myopathy. ii.

Decreased compliance:

A. Lung diseases e.g. Interstitial lung fibrosis B. Pleural diseases e.g. pleural fibrosis, tension pneumothorax, massive pleural effusion C. Chest wall diseases :

o Ankylosing spondylitis o Pickwickian syndrome(marked obesity) o Pectus excavatum, Kyphoscoliosis & Scleroderma D. Abdominal disease: e.g. Ascites B. Mechanism: j ventilation, t resistance & t dead space.

84

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖

A. Clinical picture of acute hypoxemia: 1. Tachypnea & Dyspnea 2. Tachycardia & Hypertension 3. Central Cyanosis. 4. Final event will be bradycardia, hypotension. confusion, convulsions, coma and death. B. Clinical picture of chronic hypoxia: 1. Activation of accessory muscle of respiration 2. Polycythemia with plethoric facies. 3. Pulmonary hypertension and Cor-pulmonale 4. Central cyanosis. 5. Clubbing.

Clinical picture

a) b) o o

Clinical picture of hypoxia. Clinical picture of acute hypercapnia: Asterixis (flapping tremors) Tachycardia, hypertension

o

Mental dullness & drowsiness

o

Confusion, convulsions, coma and death

c) o o o o

Clinical picture of chronic hypercapnia: Asterixis, inverted sleeping rhythm Bounding pulse & warm extremities Papilledema & headache (tICT) CO2 narcosis (hypercapnic encephalopathy): hypersomnia, drowsiness

d) Clinical picture of the cause.

6. Drowsiness & mental dullness

C. Clinical picture of the cause. 4♦

1. Arterial blood bases:

Investigations 1. Arterial blood gases:

Low P02.

0

Normal or low C02.

o Normal or high PH.

0 HighC02. 0 HC03 high or normal

2. Chest X-ray to reveal the underlying cause.

0 PH varies according to whether it is acute or chronic

o

o

Low 02.

condition.

2. Investigation of the cause: C. Treatment: see before in COPD.

Lung Transplantation ❖ Indications:

1. a 1 antitrypsin deficiency 2. Bronchiectasis & Advanced COPD.

5. Cystic fibrosis 3. Pulmonary fibrosis 4. Primary pulmonary hypertension 6. Eisenmenger's syndrome.

Types:

o Single lung transplant can be done in emphysema, pulmonary fibrosis, and pulmonary hypertension, o Bilateral lung transplantation is usually done in infective conditions to prevent spread of infection to the transplant, o Heart and lung transplant is done in Eisenmenger's syndrome and in cases of primary pulmonary hypertension Donor & Drugs:: A. Donor selection :

o Age < 40 years

o Good cardiac and lung function and chest measurements slightly smaller than those of the recipient, o ABO matching is essential.

B. Immunosuppression with cyclosporine or tacrolimus, azathioprine or mycophenolate and prednisolone. Complications:

1. Early post transplantation pulmonary edema,this requires diuretics, ventilator. 2. Infections

o

Bacterial —> Antibiotics

o Pneumocystis carinii —> co-trimoxazole. o

CMV ^ Ganciclovir

o Herpes simplex

Acyclovir

3. Immunosuppression 4. Rejection :

o Early (first few weeks): High dose I.V steroids o Late (after 3 months): High dose steroids less effective

85

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Drug induced Respiratory disease 1. ARDS: Streptokinase, P2 agonist I.V

2. Opportunistic infection: Steroid, Cytotoxic drugs 3. Interstitial lung disease: Amiodarone, Nitrofurantoin 4. Cough: ACE inhibitors

5. 6. 7. 8.

Pleural diseases: SEE like with Phenytoin, Hydralazine, Proeainamide. Respiratory center depression : Sedatives, Opioids Pulmonary eosinophilia: Penicillin, sulfonamides, Gold, Peniciilamine. Bronchospasm : Aspirin, non-selective p blockers

j Lung involvement in systemic diseases A. Rheumatology

'

1. Rheumatoid disease —> Pleurisy, pleural effusion, caplan's syndrome, and fibrosing alveolitis. 2. Ankylosing spondylitis —>■ Diminished chest expansion, interstitial pulmonary disease. 3. Churg Strauss syndrome —> Asthma.

4. SEE —> Pleurisy, interstitial pulmonary disease and shrinking lung syndrome. 5. Scleroderma ^ Pulmonary fibrosis and pulmonary hypertension. 6. Wegener's granuioma —>■ Hemoptysis, cavitation and pleurisy. 7. FMF —> Recurrent pleurisy. B. Endocrine

1) DM —>-Chest infection, TB. 2) Myxedema —>-pleural effusion. C. Immunology: Sarcoidosis

D. GIT: Eiver failure ^ hepato-pulmonary syndrome. E. Hematology:

o Eeukemias and lymphoma ^ Eung infiltration, mediastinal EN-l~l- and pneumonia in immunocompromised patient. F.

Renal:

1) Renal failure—> ARDS.

2) Good pasture's syndrome

intra-alveolar hemorrhage

Extra-pulmonary manifestations (organs involvement) of lung diseases 1) ) Nervous system: o TB : Pott's disease, cerebral tuberculoma.

o

Paramalignant syndrome of bronchogenic carcinoma.

2) Heart:

o Cor pulmonale with COPD, interstitial lung diseases and bronchiectasis. o

TB pericarditis in TB.

3) Liver:

o

Congestion with cor pulmonale, miliary TB, affect the liver.

4) Kidney:

o Amyloidosis occurs with bronchiectasis and chronic lung abscess, o Miliary TB can affect the kidney, ureteric stricture may occur. 5) Blood:

o Secondary polycythemia with COPD and interstitial lung disease, o Paramalignant syndrome of bronchogenic carcinoma. 6) Endocrinal glands: o

TB : Addison's disease.

o

Paramalignant syndrome of bronchogenic carcinoma.

7) Skin:

o

TB :erythema nodusum,

o Paramalignant syndrome of bronchogenic carcinoma. 8) Eye: TB : phlyctenular conjunctivitis, choroid tubercles in miliary TB. 9) Systemic diseases with involved lung : Sarcoidosis, polycystic lung, Eosinophilic Granuioma (Histiocytosis X) & al antitrypsin deficiency are, so you can enumerate their extrapulmonary manifestations

86

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hematology Topic

Page

Introduction

1

Hematopoiesis

2

Normal blood indices

3

Anemia

8

Iron deficiency anemia

10

Sideroblastic anemia

13

Post Hemorrhagic anemia & Anemia of chronic disease Aplastic Anemia Hemolytic Anemia Megaloblastic Anemia Secondary anemia Myelodysplastic syndrome Myelofibrosis (Myelosclerosis) Polycythemia (Erythrocytosis)

14 15 17 28 31

33 34 35

Leukemia

38

Thrombocytosis Lymphoma Multiple Myeloma Waldenstrom's macroglobulinemia

42

Hemostasis

50

Purpura & Coagulopathy Immune thrombocytopenia purpura & Hemophilia A Henoch-Schonlein purpura & Hypoprothrombinemia

57

Von WilleBrand disease

60

Disseminated Intravascular Coagulation Splenomegaly & generalized lymphadenopathy Transfusion therapy Complications of blood transfusion Bone marrow transplantation

61

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

43 46

49

58 59

63 66 67 64

‫‪-•vi .‬‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Introduction

Hematopoiesis: is the production of blood cells(RBCs, WBCs & platelets):

I 1. Intrauterine life:

o 3"''' week : hematopoiesis in yolk sac o 3''* month : hematopoiesis migrates to liver, spleen, LN

o 4* month : bone marrow(BM)start to share, then take upper hand till birth (medullary hematopoeisis) 2. At birth : medullary hematopoiesis occur in red marrow 3. Adult life : BM is found only in : o Flat bones (axial skeleton): skull, sternum, ribs & iliac bones o Upper & lower ends of long bones e.g. head offemur In anemia: active BM reappears in shafts of long bones

> Anemia in children: extra-medullary hematopoiesis occur since no extraspaces are present (this means produetion of blood cells in organs other than bone marrow) Precursor cells

Unipotent stem cell for erythropoiesis

—^(proerythroblast^ erytbroblast^

Mature RBCs

uormoblast —>

reticulocyte)

Pluripoteut stem cell

Unipotent stem cell for leucopoiesis

Unipotent stem cell for thrombopoiesis

Precursor cells

(myeloblast —> myelocyte)

Mature WBCs

Precursor cells

(megakaryoblast —> megakaryocyte)

Mature Platelets

Pluripotent Stem Cell

1

f

1 Lymphoid Stem Cell H

Myeloid Stem Cell CFU-E

CFU-Meg

I Monoblast ■

Proerythroblast | Megakaryoblast |

i 1 T

I

\

B

I

NK

jHjUIIII mHLymphoblastlLymphoblastILymphoblast I

Reticulocyte

Megakaryocyte

i m

% Red Blood Cell

Platelates

(Erythrocyte)

(Thrombocytes)

Eosinophil H Basophil I Neutrophit ■ Monocyte Granular Leukocytes

T

B

Natural Killer

Lymphocyte (TCell)

Lymphocyte (BCell)

Lymphocyte (NKCell)

Agranuiar Leukocytes

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hematopoiesis 1. Erythropoiesis: under the effect of colony forming unit- erythrocyte: o Totipotent stem cell —> pluripotent stem cell or colony forming unit(CPU) ^ CPU committed cell for

erythropoiesis —>• proerythroblast^ erythroblast^ early normoblast —> late normoblast^ retieuloeyte containing reticulum of residual RNA

o Reticulocytes remain for 24 hours in bone marrow & is then released into circulation ,where they lose their RNA & became mature RBCs(non-nucleated biconcave disc) o Factors essential for erythropoiesis: A. Hormones:

■ Erythropoietin hormone : synthesized by kidney, stimulated by hypoxia ■ Others : regulates erythropoiesis (pituitary, thyroid, adrenal, gonadotropin hormones) B. Proteins : R'class protein (essential for globin synthesis) C. Vitamins : B12,Polie, B6, Vitamin C & E D. Minerals : Pe: essential for hem formation, Cu: essential for Pe metabolism. Others : zinc & cobalt

2. Granulocytopoiesis : under the effect of colony forming unit - granulocyte: Pluripotent stem cell

Myeloid stem cell

Lymphoid stem cell

X

X

Myeloblast —> Promyelocyte Myelocyte —> Metamyeloeyte Neutrophil

Basophil blast —>

Basophil

Eosinophil

Monoblast

Lymphoblast —> Pre-lymphocyte ^ Lymphocyte

blast

Eosinophil

Monocyte

o Pluripotent stem cell ^ Unipotent stem cell for leucopoiesis ^ precursor cells —> mature WBCs A. Common myeloid precursor: Granuloeytes (neutrophils, eosinophils and basophils), monocytes/ maerophages B. Common lymphoid precursor: A. T lymphocytes ® Production ® Maturation ® Functions

B. B lymphocytes • Both are produced in the bone marrow

• In the thymus ^

•

There are two main kinds of T cells:

In the bone marrow

• When B eells beeome active, they ehange into plasma cells which secrete protein molecules called antibodies (immunoglobulins).

A. Helper T(Th)cells: secrete cytokines which help other cells of the immune system (subdivided into Thl &Th2) B. Cytotoxic T(Tc)cells: to kill abnormal cells

3. Thrombocytopoiesis : under the effect of colony forming unit megakaryocyte o Pluripotent stem cell ^ Unipotent stem cell for thrombopoiesis —> megakaryoblast -

megakar

Thrombopoietin

mature platelets (thrombocytes) o Platelets produeed from megakaryocyte by budding in BM under influence ofthrombopoietin Biochemistry of hemoglobin : Hem (iron protoporphyrin): ferrous iron + protoporphyrin (Protoporphyrin is formed of4 pyrrole rings)

■

HbF (fetal): normal Hb during intrauterine life & R'6 months of

■

Hb Ai (Adult)

■

o

97%

o

1-2 %

o

2a - 28 chain

Hb Az

life then it's replaeed by HbA o

1-2%

o 2a - 2y chain

o 2a - 2p chain

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Normal blood indices

❖ Red blood cell parameters:

❖ RBCs parameters are variable according to age & sex 1. Life span of RBCs is about 120 days. 2. Shape:

❖ Normally: rounded biconcave disc with absent nucleus ❖ Abnormally : value of blood film RED BLOOD CELL MORPHOLOGY

Hemoglobin Size variation

distribution

Normal

Hypochromia

Shape variation Target cell ; Acanthocyte

Pappenheimer bodies Agglutination (siderotic granules)

O O Microcyte

Spherocyte

Macrocyte

Ovalocyte 3+

Oval I

Red cell distribution

Inclusions

:rocyte

Stomatocyte

Helmet cell (fragmented ceil)

Cabot's ring

Schistocyte

Basophilic stippling

(fragmented cell)

(coarse)

fear drop

Howell-Jolly

Burr cell

Crystal formation

Rouleaux

4+

Hypochromic macrocyte

Polychromasia Sickle cell

HbC

HbSC

(Reticulocyte) ❖ Shape

❖ Disease

o

o

Sickle cell

Sickle cell anemia

o Spherocyte

o Spherocytosis & post o splenectomy

o Schistocytes (helmet)

o

o Stomatocyte (mouth cell) o Punctate basophilia (basophilic stippling): blue dots representing

❖ Shape • Tear drop cells • Target cell

Mechanical (Traumatic) • Acanthocytes (Spur

hemolysis o Hereditary o Lead poisoning

❖ Disease

• Myelofibrosis • Thalassemia, liver disease, iron deficiency • Splenectomy, liver

cells) •

Burr cell

• Howell Jolly bodies (small round nuclear remnants)

disease •

Uremia

• Megaloblastic anemia • Post-splenectomy, hyposplenism

DNA residues

o Poikilocytosis : variation in shape, in hyperactive BM. o Polychromasia: variation in color usually bluish tinge & corresponds to Increased reticulocyte count

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. Count:

• $ = 3.8 - 4.8 million/mm^ • c? = 4.5 -6 million/mm^ • I Count = Anemia

• t Count = Polycythemia

4. Diameter (size):

❖ Normally: diameter of RBC = 7.2 ^m ❖ Abnormaiiy: o Microcyte < 6.7 micron o Macrocyte > 8 micron o Anisocytosis: variation in size, in hyperactive BM

o

Megalocytes > 12 micron

5. Hemoglobin (Hb):

o ? = 11.5-13.5 g/dl o (^ = 13.5 - 16 g/dl o It decreases in anemia - overhydration (bypervolemia) o It increases in polycythemia — dehydration

n6.

Hematocrit value(HCT)or Packed cell volume

(PCV):"] Plasma:

"1 Til

■ Water, proteins, nutrients, hormones,

RBCS 45 %

Plasma 55 %

MM M

etc.

Buffy coat: - White biood cells, platelets Hematocrit:

■ Red blood cells

Normal Blood:

o It is the volume of packed RBCs in 100 ml blood

Polycythemia:

9 37%-47% hematocrit

Elevated

Cf 42%-52% hematocrit

hematocrit %

o 9 = 35-45% o c? = 40-50% o It decreases in anemia - overhydration (hypervolemia) o It increases in polycythemia - dehydration 7. Mean corpuscular volume(MCV): o Average volume of RBCs o

Hematocrite (volume of RBCs)X10 450 . . on inn v ^ ——; = = 90 cubic micron (Normal range = 80- 100 lemtoliter = Cubic micron) RBC count million/mm3 5 ^ ® ^

o < 80: microcytic anemia o 80- 100: normocytic anemia o > 100: macrocytic anemia

8. Mean corpuscular hemoglobin(MCH):

o Average amount of hemogiobin in each RBCs Hb / 100 ml blood

o —

RBCs count/mm

HbHbHb

X 10 = 27-32 pg

9. Mean corpuscular hemoglobin concentration(MCHC):

o Average concentration of hemoglobin in a volume of RBCs

o "'^/^"O ml bloody 100 = 32-36% Hematocrite o < 32: hypochromic anemia o 32-36: normochromic anemia o > 36: hyperchromic anemia

D

10. Colour index(CD HB%

O

RBC%

100

,

= —= 1 100

o N.B.: Clinically not used as there are no absolute numbers, only %

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

11. Osmotic fragility

o Osmotic fragility test; adding RBCs to different dilutions of NaCl: A. Normally hemolysis starts at 0.4 % and completed at 0.33 % NaCl B. In spherocytosis hemolysis starts at 0.6 % NaCl ^ f Osmotic fragility

yyyyiHiiiiii 0.85

0.75

O.ftS

O.SS

0.50

0.«S

0.40

0.3S

0.30

0.20

0.11

Reticulocyte

12. Reticulocytes: Mature RBC

Nnrmohlast j Nnrmohlast

o It is the cell which remains after extrusion of the nucleus from late normoblast, and it is the stage before erythrocyte (mature RBC)

o Normally represent 0.2-2 % of RBC concentration (25,000-100,000) o Its percentage is a reflection of B.M. activity o

Abnormalities:

B. Reticulocytopenia = j reticulocyte count o Bone marrow failure e.g. aplastic anemia

A. Reticulocytosis = treticulocyte count

o Hemolytic anemia o Anemia under treatment e.g. vitamin BI2 replacement in megaloblastic anemia o Acute hemorrhage o Acute hypoxia

o Bone marrow infiltration: myelophthisic anemia o Dyshemopoietic anemia e.g. megaloblastic anemia

>

13. Erythrocyte sedimentation rate(ESR): hour

The distance in mm,the RBCs fall in

1 hour, is the sedimentation rate

>=> 1.

Definition: distance sedimented by RBCS in a vertical blood column at the end of 1 or 2 hours.

2. Mechanism : o o o

Normally RBCs are negatively charged and repel each other. Negative charges prevents RBCs to from rouleaux & to sediment. Negative charges on RBCs: | Albumin & J, fibrinogen & globulin The increase in plasma globulin & fibrinogen causes decrease in these negative charges, allowing RBC to form rouleaux & increase their sedimentation. Normal value: Westergren's method (Blood + Na citrate): •

4.

o

Male

o

o

female

o

P'hour •

2""^ hour

5 mm

o

8 mm

10 mm

o

16 mm

Clinical significance : ESR is used to follow up disease progress & response to treatment not for diagnosis

5. Causes of increase ESR : o o o

Physiological(f fibrinogen):females during menses & pregnancy Pathological(f Globulin): infection (TB), Malignancy, multiple myeloma, rheumatic fever & collagen diseases. Pathological (J, Albumin): nephrotic syndrome

6. Causes of decreased ESR :

o

Afibrinogenaemia, Hypofibrinogenemia e.g. DIC or partially clotted blood sample Anemia : sickle cell & spherocytosis Polycythemia Congestive heart failure. N.B.: C reactive protein : Acute phase reactant protein, with same ESR significance Normal level < 10 mg / L

o

Formed in liver & rises within 6 hours of an acute event

o o o o

❖ o

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ White blood cell(WBCs)parameters: ❖ Total leucocytic count: ■

Leucopenia

■

o

< 4000/mm^

o 4000-11,000/mm^

Normal total leucocytic count(TLC) ■ o

Leucocytosis > 11000/mm^

❖ Differential count:

Cell type o Neutrophil o Basophils o Eosinophil

%(relative value) ❖ Granular Leukocytes:

Function

Absolute count / ul

Phagocytosis Heparin secretion

40- 75 % 0-1 %

10-100

Histamine secretion

1- 3%

50-500

2,500 - 7,500

❖ Non granular leukocytes o Lymphocytes o Monocytes

Immunity Phagocytosis

20-40 %

1,500 -4000

3-8 %

200 - 800

❖ NB: All leucocytes except lymphocytes develop from bone marrow while lymphocytes develop from lymphoid tissue, therefor in any neutropenia there is lymphocytosis

❖ Neutrophils development: J

o Immature WBCs(juvenile = staff = stab = non segmented cells) —> mature WBCs(segmented cells) o

Normal ratio:

■ Staff: Segmented ratio : 1:5 to 1:10 o Abnormally : A. Shit to the left:

B. Shift to the right:

0 t percentage of staff above normal(5 %)in hyperactive BM o t segmentation in delayed BM o Staff: segmented 1: 10 o Causes : in any leukocytosis

o Cause : megaloblastic anemia

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I 0 Color index (CI): 1 MCV: i 0 MCV: normal 0 MCV: t MCH:i 0 MCH: normal 0 MCH: t MCHC:i 0 MCHC: normal 0 MCHC: normal Investigation ofthe cause.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Pathophysiology: j Anemia ^ tissue hypoxia leading to compensatory mechanisms: Increased erythropoiesis.

peripheral vasodilatation ^ J, BP — sympathetic nervous system, RAAS (Aldosterone)& ADH: Increased COP ^ hyperdynamic circulation Retention of fluid —> t plasma volume Increased Level of 2,3-diphosphoglycerate(DPG) —>], Hb affinity to O2 —02release to the tissues Clinical manifestation of anemia :

A. General picture of anemia(FPES)

38.0

General: FPE

1. Fatigue & Fever up to 38 °C but exclude L' other causes. 2. Fundal changes: retinal hemorrhages, exudates & papilledema. 3. Pallor: the most important sign, best seen in conjunctiva, inner side of lips, tongue, mm of nail bed & palmer creases 4. Lower limbs Edema: due to:

o o o o

Hypoxia —> t capillary permeability. Hypovolemia hyperaldosteronism ^ salt & water retention Hypoproteinemia (associated nutritional deficiency) Anemic Heart failure (high COP failure)

rrmr i . .1: . :i

H.

.. i

. 'I

Systems:

A. CNS:

o

Lack of concentration, blurred vision, headache, dizziness & tinnitus

o Tingling & numbness (ischemia ofPN). o B. o o

Pseudotumor cerebri (flCT)

o

Functional murmurs.

o C. D. o o

Angina & Anemic heart failure (high COP failure). GIT: anorexia & dyspepsia Reproductive organs: In females: amenorrhea or menorrhagia. In males : impotence

CVS: Hyperdynamic circulation: Tachycardia & palpitation Capillary pulsations & increased pulse pressure : water hummer pulse

B. Specific clinical picture for each anemia

C.Specific clinical picture for the cause.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I.

Microcytic hypochromic anemia Iron deficiency anemia(IDA)

❖ Physiology:

Ferric sate

❖ N.B.:

Ferrous state

1. Total iron binding capacity(TIBC): blood capacity to bind iron with transferrin o TIBC: 250-450 pg/dL o The unsaturated transferrin(70%)+ Serum iron

2. Transferrin saturation : how much serum

Apoferritin: 10 %

iron is bounded to transferrin Serum iron

■X 100 = 25-50% TIBC

Transferrin saturation :

30 % saturated with iron

Transferrin Active form

Storage form

Heme

Ferritin Heme

1. 2. 3. o o

Source: in meat, liver & spinach. Requirements: 10 mg /day (only 1 mg is absorbed) Absorption: Iron is converted from ferric to ferrous state in the stomach by HCL. Absorption in the duodenum is facilitated by apoferritin transport system, which is saturable system that allows only 10 % of iron intake to be absorbed (Mucosal block theory).

4. Transport system:

o

Iron is transported in the blood bound to transferrin, which is only 30% saturated by iron.

5.

Functions:

o Myoglobin & Hemoglobin synthesis o Synthesis of heme containing enzymes e.g. cytochrome oxidase and catalase. 6. Storage: I gm stored as ferritin or hemosiderin in reticuloendothelial system (RES)

Some ferritin is circulating ($ 10- 200 ng/ml, S 15-400 ng/ml). Each I pg/L of circulating ferritin is equivalent to 10 mg stored iron. N.B.:

Ferritin is a water soluble complex of iron, so it's available for hemoglobin synthesis Hemosiderin is an insoluble complex of iron & is difficult for utilization

10

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Etiology: 1. Diminished intake:

a. b. 2. a.

Starvation, dysphagia, prolonged parenteral feeding without iron supplement In children dependent on milk after age of 6 months (mother stores are depleted) Diminished absorption: Atrophic Gastritis Gastrectomy Gastric carcinoma

Malabsorption syndrome Excess Phytate & Phosphate. 3. Increased loss: A. Parasitic infestation:

i. o o

Ancylostoma duodenale infestation : ii. Necator Americanos infestation The most common cause in Egypt ❖ Daily blood loss from one worm 0.15 ml

o

0.03 ml

B.

Intravascular hemolysis with haemoglobinuria e.g. PNH

C.

Chronic bleeding e.g. Peptic ulcer, esophageal varices, gastritis, cancer colon, piles, hematuria, hemoptysis, menorrhagia.

Increased requirements: Pregnancy, lactation b. Puberty

4. a.

❖ Clinical picture: 1. General clinical picture of anemia:(FPES) 2. Specific clinical picture of iron deficiency anemiar

❖ Due to enzymatic defect, cells with high turnover e.g. epithelial are the first to be affected: A. Atrophic glossitis: red glazed tongue

B. Atrophic gastritis ± Achlorhydria leading to dyspepsia, anorexia ,nausea & vomiting C. Pica (Perverted appetite) i.e. eating unusual substances e.g. earth or ice. D. Dyspiastic changes : Koilonychia (spooning of nails) with Loss of Luster o o

Loss of hair

Specific clinical picture of the cause : A. Ancylostoma infestation: chronic blood loss:

3.

o o o o

Anemia: iron deficiency anemia e.g. marked pica Protein loss (hypoproteinemia): protein losing enteropathy Pain: epigastric pain & tenderness Dyspepsia, nausea, vomiting, alternating Diarrhea & constipation

o

Dermatitis in feet

B. Plummer-Vinson syndrome:

o Angular Stomatitis, Spooning of nails & iron deficiency anemia o Splenomegaly.

o Dysphagia due to esophageal web of desquamated epithelial cell in upper 1/3 of the esophagus, it carries high risk of post-cricoid cancer esophagus.

11

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis of microcytic hypochromic anemia: J ♦> Serum iron

❖ Serum Ferritin

❖ Serum transferrin

i t

o

t

o

I

T

o

i

❖ TIBC

❖ Transferrin saturation

❖ Iron deficiency anemia

o

i

❖ Anemia of chronic disease

o

1

o o

O

t

o

❖ Sideroblastic anemia Thalassemia

❖ Investigations:

1. To prove anemia: J, RBCs count, J, Hb, J,HCT 2. Type of anemia: A. Microcytic hypochromic: MCV,MCH,MCHC :J, B. Iron deficiency anemia : nt Serum iron

o

o

Transferrin saturation

o Increased total iron binding capacity(TIBC)

o

Serum Ferritin

o

Serum transferrin

o BM biopsy: hyperplasia with normoblasts & decreased BM iron stores (normoblasts

mature RBCs)

3. Cause of anemia: e.g.

o Ancyiostoma: esinophilia, stool analysis for ancylostoma ova & occult blood (Benzidine Guiacum test), o Upper or lower GIT Endoscopy o Platelet count may increase with active blood loss.

4. Therapeutic test: iron treatment leads to reticulocytosis Treatment

I.

Ferrous Sulphate|

IRON DEXTRAN INJECIIOtt

Tablets FZiBl

!

Iron replacement: 2. Parenteral iron

1. Oral iron:

Preparations: Iron dextran (IM, IV), iron sorbitol(IM) Dose: calculated by the formula:

Preparation & Dose: Ferrous sulfate 200 mg tab/8hr or Ferrous gluconate 300 mg/12 hour, within meals or shortly after eating. Complications: Nausea, vomiting & constipation Black stool(DD melena)

2.4 X Body weight x (Target Hb - Actual Hb)+ 500 mg for iron stores Indications:

Contraindication to oral iron e.g. Peptic ulcer & Malabsorption Complications of oral iron

Gastric ulcers.

Duration of treatment:

4-10 weeks till FIB is normal, then small doses for at

Failure of oral iron treatment.

least 6 months to fill stores

Need for rapid correction as in late pregnancy. Complications: Allergy, Anaphylactic shock Abscess, Pain, Pigmentation Thrombophlebitis and hemochromatosis

Assessment:

Fib starts to rise after one week and rises by 1 gm/week

Reticulocyte count starts to increase on 4* day and persists for 12 days

II.

Treatment of cause: e.g. Ancylostoma: Mebendazole:100 mg twice daily for 3 days

III.

Blood transfusion if:

o Hb < 7 gm/dl o Ischemic heart disease or heart failure if Hb < 10 gm/dl.

Causes of failure to respond to therapy: refractory iron deficiency anemia

2.

Wrong diagnosis e.g. thalassemia Wrong oral preparation e.g. enteric coated not well

3.

Incompliant patient to treatment

4.

Insufficient time to show the response

1.

5.

6.

Chronic bleeding not controlled. Concomitant deficiencies e.g. Vitamin B12 deficiency

absorbed. 7.

Concomitant illness limiting erythropoietic response e.g. chronic infection

12

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Sideroblastic anemia

Pathophysiology: Protoporphyrin

Iron

Cytoplasm

V'

Uro—► Copro

PBG

A

• Iron deficiency • Sideroblastic anemia

• Chronic innammation

or malignant

T

Succinyl CoA +

Prdtopqrphfiri

~

HEME

Glycine Fe

Thalassemia

Mitochondrta Vitamin 63

Iron

o

Impaired heme synthesis due to failure of incorporation of iron with protoporphyrin to form heme due to defect in

o

delta amino-levulinic acid synthase (ALA), Iron entering RBCs will saturate intracellular ferritin, then deposits as insoluble form as hemosiderin in the

o

mitochondria with formation of ringed sideroblasts (normoblast with ringed granules) These cells are destroyed in the BM but some may appear in the peripheral blood Etiology : I.

Hereditary: X linked recessive disease due to deficiency of ALA synthase or defect vitamin B6 metabolism. II. Acquired: A. Primary : Myelodysplastic syndrome B. Secondary: 1. Lead poisoning interferes with ALA synthase soniazic Lead: 2. Isoniazid (INH) interferes with vitamin B6 metabolism. 207^ 3. Inflammation e.g. rheumatoid arthritis 4. Organ failure.

o

❖ Clinical picture : as IDA Differential diagnosis of microcytic hypochromic anemia: see before. Investigations : 1. To prove anemia: J. RBCs count, J, Hb, J,HCT 2. Type of anemia:

A. Microcytic hypochromic(due to diminished hemoglobin level in RBCs): MCV,MCH,MCHC: J, B. Sideroblastic anemia:

Normal or J,J,| ttt 0 Serum transferrin, 0 Serum iron, Transferrin saturation 0 TIBC (because iron stores are high) 0 Serum Ferritin

o BM biopsy: ringed sideroblasts i.e. normoblast with ringed granules o Free erythrocyte protoporphyrin: J, (can't synthesize the protoporphyrin ring) Treatment:

J 1. Treatment of cause

2. Pyridoxine (Vitamin B6) 3. Folic acid due to increase erythropoiesis 4. Blood transfusion in severe cases N.B.IRON IS ABSOLUTELY CONTRAINDICATED.

13

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II.

Normocytic normochromic anemia Post Hemorrhagic anemia

I. Acute Hemorrhage (Loss of more than one liter of blood acutely) * Causes ; trauma, surgery, GIT ulcers, IT? & hemophilia

N.B.: Acute hemorrhagic anemia is normocytic normochromic anemia

while chronic hemorrhagic anemia is microcytic hypochromic anemia

Normal

Chronic anemia

Acute blood loss

1. Immediately:

o There's proportional loss of RBCs & plasma —>■ HCT is normal in acute bleeding, but with f platelets & neutrophils within few hours (migration from margins of blood vessels) 2. Within 1-3 day: manifestation of hypovolemia

o

Expansion of plasma volume —> hemodilution —>• I HCT slowly over 3 days —> normocytic normochromic anemia

3. After 3-4 days: o Manifestation of hypovolemia disappear o Manifestation of anemia with | BM activity —>• reticulocytosis. II. Chronic hemorrhage:

o Clinical picture as iron deficiency anemia (microcytic hypochromic anemia). ❖ Treatment of the cause, anemia & hypovolemia e.g. fluid & blood transfusion Anemia of chronic disease(ACD)

Etiology:

1. Chronic infections e.g. T.B, subacute bacterial endocarditis, osteomyelitis & bronchiectasis 2. Chronic inflammation e.g. rheumatoid arthritis & inflammatory bowel disease 3. Cancer.

Pathogenesis:

1. I RBCs production & life span. 2. I Erythropoietin response to anemia 3. t Hepcidin ^ J, iron release from stores to the developing erythroblasts

okines

❖ Clinical picture of anemia + underlying chronic illness ❖ Investigations: iRBC production and survival

1. To prove anemia: | RBCs count, J, Hb,|HCT, | ESR 2. Type of anemia:

A. EARLY normocytic normochromic anemia & LATER microcytic hypochromic anemia B. Anemia of chronic disease:

J,J,J. o Serum iron, Transferrin saturation o Serum transferrin, TIBC

Normal or ftt o

Serum Ferritin

o t Acute phase reactants: fibrinogen, gamma globulin, C3 & al antitrypsin. o BM biopsy: normal or increased iron stores Treatment of the cause

14

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Aplastic Anemia •/!.

m. ■

y

Deflnition: anemia of BM failure

o Failure of development of BM stem cells leading to aplasia of BM with pancytopenia (empty BM,& empty blood). ❖ Classifications & etiology:

Bone marrow

I. Pluripotent potent cell failure : APLASTIC Anemia o Affects all blood elements, Pancytopenia

N.

1. Inherited : Fanconi anemia:

II. Unipotent stem cell failure o Affects one element of blood, monocytopenia I. Erytbrocytic aplasia:

o

1. Congenital:

Autosomal recessive presenting with:

o Diamond - Blackfan syndrome : Triphalangeal

a. Pancytopenia

b. Skeletal deformities: absent thumb & syndactyly.

thumb

c. Chromosomal breaks : high incidence of leukemia

2. I Erythropoietin or secreting anti-

2. Idiopatbic : the most common cause :50% of cases

o Due to suppression of BM by cytotoxic T-cells

enythropoietein: a.

Renal failure.

3. Infection: TB, HBV,HCV,HIV, EBV, parvovirus B19

b. Oat cell carcinoma

4. latrogenic (drugs):

c. Thymoma

❖ Dose related or non-dose related (idiosyncrasy):

3. Hemolytic crisis of hemolytic anemias.

o Antibiotics: Chloramphenicol

II.

Granulocytic aplasia:

o

Anticonvulsants: Phenytoin

o Cyclic neutropenia

o

Antidiabetics: Chlorpropamide

III.

o

Antiemetics: Chlorpromazine

1. Wiskott- Aldrich syndrome:

o

Antithyroid: Carbimazole

o

5. Irradiation & toxins e.g. insecticides & benzene

Megakaryocytic aplasia :

Thrombocytopenia + eczema +

immunodeficiency & bloody diarrhea.

6. Immunological : Systemic lupus erythematosus

2. TAR syndrome:

7. Infiltration of BM : Myelophthisic anemia

o Thrombocytopenia + absent radii

8. Miscellaneous:

o Paroxysmal noctumal hemoglobinuria(PNH)& Pregnancy

Clinical picture: 1. General features of anemia (J, RBCs): FPES 2. Clinical picture of leucopenia (J, WBCs): o t Infections e.g. monilial infections with necrotic mouth & sore throat due to ulcers.

3. Clinical picture of thrombocytopenia (J, Platelets): bleeding tendency —> purpura 4. Clinical picture of the cause e.g. skeletal deformities. Differential diagnosis:

Differential diagnosis from other causes of pancytopenia e.g.: A. Anemias:

B. Malignancy:

1. Aplastic anemia (the most important) 2. Aplastic crisis of hemolytic anemia

1) Myelodysplastic syndrome. 2) Leukemia & Lymphomas

3. Megaloblastic anemia

4. Myelophthisic anemia(BM infiltration) 5. Paroxysmal Noctumal Hemoglobinuria

C. 1. o o 2.

Infections & immunological: Massive infection e.g. Miliary TB Septicemia Systemic lupus erythematosus

6. Hypersplenism

15

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis from myelophthisic anemia(BM infiltration with non hematopoietic cells)= Causes of leukoerythroblastic picture

1. 2. 3. 4. 5. 6.

Myelofibrosis Miliary tuberculosis , Sarcoidosis Marrow necrosis ; Sickle cell anemia & Septicemia Malignancy : Leukemia , Lymphoma ,BM metastases Metabolic disorders e.g. Lipid storage disease (Gaucher's disease) Marble bone disease: Osteopetrosis: failure of osteoclasts development

Leukoerythroblastic picture refer to anemia or

pancytopenia with : Immature RBCs

(nucleated),fragmented RBCs (schistocytes), tear

❖ Differential diagnosis from other causes of fever with sore throat e.g.:

drop shaped RBCS Immature WBCs

1. Local infection e.g. tonsillitis, pharyngitis(Abscess, TB, malignant ulcers), Vincent angina (Fusospirochetal infection) 2. Specific infection e.g. diphtheria, IMN & scarlet fever 3. Blood diseases e.g. aplastic anemia, leukemia , leucopenia & hypersplenism

(myelocytes) 3.

Megakaryocytic fragments

Investigations: 1. To prove anemia: J, RBCs | count, Hb,|HCT 2. Type of anemia:

A. Normocytic normochromic anemia(MCV,MCH,MCHC: Normal) B. Aplastic Anemia : Pancytopenia I. Blood picture : i RBCs:

I count < 5 million/mm^ & Hb < 11 gm/dl in female & < 13 gm/dl in male Absent reticulocytes (the most specific)

J, WBCs: leucopenia(< 4000 / mm^)with relative lymphocytosis J, Platelet: thrombocytopenia(< 150 000/mm^) | + bleeding time 11. Bone marrow biopsy: Hypoplasia of all elements, or one series only Myelophthisic anemia may show the cause. Treatment:

1. Treatment of the cause

1. Immunosuppressant in idiopathic type to J, hyperactive T suppressor: o Prednisone 1 mg/kg/day o Cyclosporine A

o Anti - lymphocyte globulin(ALG)^ polycolonal antibodies —> inhibit T cells 2. Stop the causative drug

2. Supportive treatment: 1. Anemia:

2. Leucopenia:

3. Thrombocytopenia:

o

o Immunoglobulin transfusion, o Antibiotics, antifungal & antiviral.

o

Platelet transfusion

o

Avoid trauma e.g. IM injection

Fresh blood transfusion or

packed RBCs. 3. BM stimulation:

1. Stimulate RBCs:

2. Stimulate WBCs:

o Androgen (anabolic steroids) o G-CSF: Granulocyte colony-stimulating factors o

Prednisone

o Erythropoietin hormone

o GM-CSF : Granulocyte-macrophage colony-stimulating factor o

Lithium carbonate

3. BM/stem cell transplantation.

16

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hemolytic Anemia

Definition: Shortening of RBCs life span & increase BM erythropoiesis.

Pathophysiology: | o The normal life span of RBCs is 120 days. o Premature destruction of RBCs^ the bone marrow can compensate for shortening of this life span of RBCs by increasing their production up to 6 - 8 times normal, so that anemia will not result unless life span of RBC is diminished to 1/6 - 1/8 of normal (15-20 days)^ uncompensated hemolytic anemia, o Hemolysis in 90% of cases is extravascular(RES; spleen, liver & BM)& 10% of cases is intravascular. ❖ Extravascular Hemolysis:

1.

o

2.

o

3.

MacrophaQe

Extravascular hemolysis of RBCs leading to : Indirect bilirubin (liemobilirubin = unconjugated bilirubin) —> the liver can increase its capacity of conjugation (8-10)folds so jaundice may not occur or may be mild. In severe hemolysis ^ frank hemolytic jaundice. Anemia ^ B.M can increase RBCs production up to 8 folds so some cases present without evident anemia(Compensated hemolytic state). Severe hemolysis —> frank anemia (uncompensated hemolytic state). RBCs are removed from the circulation by macrophages in reticuloendothelial system (RES)particularly the spleen.

ProtopcKOhyrtfi

BUlrubin Binds to

transferrin Amino

actdt

Unconjugated bilirubin

^

❖ Intravascular Hemolysis:

€ € « UrotMlinogcn

Stercob«Mnogtn

(ufine)

(faeces)

HaptogioMn(Hp) Met Kb

/\ Feniheme

Gktbtn

EnteiDl^palic

uncor^ugated Kitrubin

recirculate KIDNEY

LIVER

Hemopexin (Hpx) Awumin

INTESTINE r

[HEME-Hpx Bilirubin

HemoglotMnuna Hemosidennuria Urobilinuria

I Urobilinogen j

METHEMALBUMIN

URINE

Hemolysis of RBCs in the vascular stream leads to : 1.

Release of free HB in blood so it's combined with specific plasma protein forming a complex to prevent its escape to urine

the complex taken up by RES —»• indirect bilirubin—> hemolytic jaundice.

These proteins are: a) Haptoglobin(a globulin) b) Hemopexin (P globulin) combine with oxidized Hb (methemoglobin) c) Albumin with metheme ^ methemalbumin o

2.

Excessive hemolysis with statured haptoglobin & hemopexin

free hemoglobin in blood

hemoglobinemia ^

excreted in urine ^ hemoglobinuria & hemosiderinuria

17

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Classifications & etiology:

I.

Corpuscular causes: all causes are hereditary except PNH is acquired

1. Cell wall defect:

o o o o 2. o o 3.

Hereditary spherocytosis (J, speetrin & ankyrin) Hereditary elliptocytosis (J, speetrin & glyeophorin) Hereditary stomatoeytosis (J, stomatin) PNH: Paroxysmal nocturnal hemoglobinuria Enzymatic defect: Glucose -6- phosphate dehydrogenase(G6PD)deficiency, Pyruvate kinase deficiency. Hemoglobin defect:

o

Thalassemia.

o

Sickle cell anemia

II.

Extra-corpuscular causes: all causes are acquired:

n

1) Immunological:

A. Autoimmune antibodies: cold or warm hemolytic anemia. B.

Alloimmune antibodies: incompatible blood transfusion, RH incompatibility (hemolytic disease of new bom)

2)

Infection:

o

Sepsis, malaria, P hemolytic streptococci & clostridium welehii

3) Toxic: o o

Snake or Spider venom Lead poisoning.

4) Mechanical trauma: A. Prosthetic valves or calcific valves

B. March hemoglobinuria:

Affect marathon runners or army recruits after mnning on hard surface for long time. It's transient process.

Microangiopathic hemolytic anemia(MAHA):

Due to hemolysis of RBCs exposed to rough vascular intima Characteristics: Fragmented RBCs(schistocytes) and thrombocvtopenia o Causes:

/

■ Die & Scleroderma

/

■ ■ ■

Malignant hypertension Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura

5) Miscellaneous:

o Hypersplenism o

Liver disease & renal disease

'

/ Schi^ocyte

» 18

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Clinical picture of hemolytic anemia: of anemia + of hemolytic anemia + ofthe cause: I.

Clinical picture of anemia(FPES): when hemolysis is uncompensated.

11.

Clinical picture of hemolytic anemia :

iaitar.ffTiiiiirlBia^

1.

Feature of hemolytic jaundice :

a) Sclera: lemon yellow jaundice in severe hemolysis fee b) Stool: dark due to excess stercobilinogen c) Urine: normal (Acholuric jaundice): darkens if left to stand, hemolytic crisis or development of pigment stones. 2. 3.

4.

Hepatosplenomegaly due to hemolysis, extramedullary hematopoiesis(RES hyperplasia)& hemosiderosis. Gall stones(pigment stone)^ obstruction of bile ducts —Obstructive (Olive green)jaundice Leg ulcers in the ankle area surrounded by pigmentation due to deposition of hemosiderin under skin.

5. Crises: ❖ Causes

A. Hemolytic crisis o Sudden hemolysis with excess HB

B. Aplastic crisis o Sudden depression

C. Megaloblastic crisis

o Depletion of folic acid mainly or vitamin B12

ofBM

❖ Clinical picture: o Anemia & pallor 0

Jaundice

o

Others

o t O T o Fever, rigors, dyspnea, bone pain (hyperactive BM), abdominal pain, dark urine (hemoglobinuria)

Parvovirus B19

o Mild change o Mild change o Pancytopenia, CNS &

(pancytopenia)

GIT manifestations

o

t

o

Constant

o

& acute renal failure

❖ Investigations: o Reticulocytes o

Bilirubin

o

Bone marrow

o t O t

o

i

o i

o

Normal

o

o Hypoplasia of all

o Hyperplastic BM (erythroid hyperplasia = hypercellular normoblastic)

Normal

o Megaloblastic changes

elements

D. Sequestration crisis :

o Aggravation of anemia due to sudden pooling of blood in spleen with hypotension & shock E. Vaso-occlusive (infarctive) crisis: in sickle cell anemia ONLY:

*1* Painful occlusion of microcirculation by sickled RBCs:

1. Cerebral infarction: stroke: hemiplegia 2. Retinal infarction : retinal detachment & blindness 3. Chest:

o Acute chest syndrome: pulmonary infection or infarctions with fever, hypoxia, leukocytosis, lung infiltrates in Xray & may progress to ARDS. o Pulmonary hypertension & cor-pulmonale 4. CVS: myocardial infarction and cardiomyopathy. 5. GIT: mesenteric infarction with pneumococcal peritonitis —> acute abdomen.

19

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

6. Spleen :

c=^l a) Splenomegaly in the first years of life due to extramedullary hematopoiesis, congestion & sequestration. b) Autosplenectomy (shrunken spleen) by the 10 years old as a result of repeated infraction with loss of function (hyposplenism)causing splenic fibrosis, regression in size & f liability of infection by pneumococci & salmonella.

7. Renal infarction & renal failure

8. Priapism: painful, persistent erection of the penis due to venous thrombosis. 9. Aseptic necrosis of head offemur and salmonella osteomyelitis 10. BM infarction causing fat embolism. 11. Chronic leg ulcers due to occlusion of cutaneous blood vessels 12. Hand and foot syndrome: o Recurrent painful attacks of swollen digits (Dactylitis) that result from ischemia of phalanges. II.

o o o o o o III.

|3nncalT»cfur^nnffavascu!anjeinotysi^

Rigors and fever, Hemolytic jaundice Chest pain & Hypotension Lumbar pain & acute renal failure Hemoglobinuria(dark urine; red urine or black if acid hematin forms) Iron deficiency anemia (loss of iron in urine). Clinical picture of the cause.

Investigations of hemolytic anemia : of anemia + of hemolytic anemia + of the cause

20

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

1. General investigations of hemolytic anemia: I. To prove anemia: o i RBCs count, i Hb, i HCT

o N.B.: t ESR in all types of anemia except sickle celi anemia & spherocytosis ESR | is II.

Type of anemia:

o Microcytic hypochromic anemia e.g. in thalassemia o Normocytic normochromic anemia: the usual picture.

o Macrocytic anemia e.g. in megaloblastic crisis or during hemolytic crisis (reticulocytosis). III. For hemolytic anemia: 1. Blood picture: A. RBCs:

o Shortening of life span of RBCs as detected by chromium 51 labeled RBCs. o Reticulocytosis due to hyperactive BM in hemolysis o Reticulocytopenia in aplastic or megaloblastic crisis B. WBCs «& platelets are : o

Normal

o Increased due to hyperactive BM

o Decreased (Pancytopenia) in aplastic or megaloblastic crisis, PNH & hypersplenism. 2. Blood chemistry : A. I Serum LDH level.

B. t Total bilirubin mainly indirect bilirubin (hemobilirubin = unconjugated bilirubin) C. t Stercobilinogen in stool

D. f Urobilinogen in urine {Absent bilirubin in urine

Acholuric jaundice}

3. Bone marrow biopsy :

o Hyperplastic BM (erythroid hyperplasia = hypercellular normoblastic): the usual picture, o Hypoplastic BM in aplastic crisis or PNH o Megaloblastic BM in megaloblastic crisis 4. Imaging : o Abdominal US: Hepatosplenomegaly and gall bladder stones o BM expansion in thalassemia: X-ray on: ■ Long bones : widening of medulla and thinning of cortex ■ Skull: hair on end appearance IV. In intravascular hemolysis e.g. PNH,G6PD deficiency & Cold AIHA there is: o Hemoglobinemia o Hemoglobinuria (cause red urine or black if acid hematin forms) o Hemosiderinuria (Iron taken by sheded tubular cells is detected in urine; positive Perl's stain.) o Decrease haptoglobin. o Decreased hemopexin. o Methemalbumin is detected in the blood by spectrophotometer(positive Schumm's test).

2. Specific investigations for the cause: 1. o 2. o

Hereditary spherocytosis: Microspherocytes in blood film & Osmotic fragility test Paroxysmal nocturnal hemoglobinuria(PNH): Ham's test, Sucrose test, DNA analysis & Flow cytometry

3. G6PD deficiency: o Heinz bodies & Enzyme Assay 4. Sickle cell anemia:

o Sickled RBCs in blood film precipitated by adding Na metabisulfite & HB electrophoresis: HbS. 5. Thalassemia:

o I Serum transferrin, TIBC

o t Serum iron, Transferrin saturation } Serum Ferritin

o Target cells in blood film & Hb electrophoresis: i HbAl & f HbF & HbA2. 6. Autoimmune Hemolytic Anemia: o

+ve Coomb's test

o t IgM in cold AIHA o t IgG in warm AIHA

21

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Treatment:

A. Prevention : Genetic eounseling & antenatal diagnosis B. Treatment of the cause.

1. Immunosuppressant in idiopathic cases as in FNH:

❖ N.B.:

o Prednisone 1 mg/kg/day o Cyelosporine A

o Anemia : in all causes of hemolytic anemia o Pancytopenia: in aplastic or megaloblastic crisis, PNH & Hypersplenism.

o Anti- lymphocyte globulin(ALG) 2. Treatment of precipitating factors C. Supportive treatment: 1. Anemia:

2. Leucopenia:

3. Thrombocytopenia: 4. Thrombocytosis

0 Keep Hb > 10 gm/dl by:

A. Immunoglobulin transfusion. B. Antibiotics, antifungal &

0 Avoid trauma e.g.

A. Whole blood transfusion B. Packed RBCs transfusion

0 Platelet transfusion

IM injection

antiviral.

0 In PNH: Oral

anticoagulants to prevent thrombosis,

(never heparin) 5. o o

Exchange transfusion : in sickle cell anemia : to lower HbS < 50 % Transfusion with RBCs containing HbA to replace HbS by HbA. Indicated in severe cases, before surgery and in pregnancy.

6. Iron :

a) In PNH : Oral iron (never parenteral) b) In thalassemia & sickle cell anemia : o o

7. o

Iron is contraindicated to avoid overload

Iron chelating agent: Desferrioxamine SC Azacitidine or Hydroxyurea In sickle cell anemia(f HbS)& thalassemia (J, a chain) | —> HbF

J, hemolysis

8. For crisis: A. B.

For hemolytic & sequestration crisis: Blood transfusion For aplastic crisis: bone marrow stimulation : A. Stimulate RBCs:

C. D.

B. Stimulate WBCs:

0 Androgen (anabolie steroids) 0 G-CSF: Granulocyte colony-stimulating factors 0 GM-CSF : Granulocyte-macrophage colony-stimulating factor 0 Prednisone 0 Lithium carbonate 0 Erythropoietin hormone For megaloblastic crisis : folic acid and vitamin B12 replacement For Vaso-occiusive crisis : in sickle cell anemia only : Avoid precipitating factors by IV fluids for hypotension & hypovolemia (dehydration) Analgesics for pain Warming for hypothermia O2 therapy for hypoxia IV NaHCOs for acidosis

Antibiotics for infection & Dextran for stasis.

C.

Spienectomy :

1.

Aim :to prolong the life span of RBCs Timing of operation : better after age of 4 years to decreased the risk of infection

2.

3. Indications: o o o o

Hypersplenism (pancytopenia | & blood transfusion requirements) High blood transfusion requirements Splenic Sequestration Family history of death due to Spherocytosis

N.B.: Spienectomy only done in extravascular hemolysis & has no role in intravascular hemolysis

4. Precautions: o o o

Vaccination against the pneumococci, haemophilus influenza, meningiococci,> 2 weeks pre-splenectomy Influenza vaccine every winter to prevent secondary bacterial infection Antibiotics prophylaxis post-splenectomy for two years or until the age of sixteen years old is reached, whichever is longer.

o o

D. E.

If cholecystectomy is needed; it should be done after spienectomy to avoid obstructive jaundice Recurrenee may occur following spienectomy due to secondary spienuies or splenic autotranspiant. BM/stem cell transplantation(BMT) Gene therapy: in sickle cell anemia «& thalassemia

Inserting normal gene in BM stem eells in vitro then transplanting these cells in BM after ablative treatment.

22

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hereditary spherocytosis Band 3

y y y y 11

J:i ;; i^Lipid bilayer i :! Ankyrin Concentration

0.85

0.75

0.65

0.60

0

0

0-5

5-10

0.55

0.50

Sodium

Chloride {%)

Spectrin

Hemolysis

20-80% 60-100%

Paroxysmal nocturnal hemoglobinuria(PNH)

CD55 ^ Ham's test Sucrose test

«=> Glucose -6- phosphate dehydrogenase(G6PD)deficiency Qlucose-6-

phosphalo NADP+

Reduced

Oxidants

^utathione

G6PD

NADPH

Oxidized

6-Pbosphogluconate

Helnz bodies

Water

glutathione

Sickle cell anemia

6 r

GiU

SODIUM

^

METABISULFITE

I » # _)^>J

.

Na^iO,(Anhydrous) 99.9%

^8 Ounces•(227pams)^ Normal Red Blood Cell

HbA2 iibS

HbF HbA

1

Sickle

Beta-Thalassemla major (bomozygous)= Cooley's anemia = Mediterranean anemia = target cell anemia

■

Q

i ChromoBomG 16

a globin gene

Chromosome 11

HbA2

p globin gene

HbF HbA

23

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Paroxysmal nocturnal hemoglobinuria(PNH)

Hereditary spherocytosis

Glucose -6- phosphate dehydrogenase(G6PD)deficiency

❖ Etiology o

Autosomal dominant disorder

o Idiopathic, acquired BM stem cell

o

X-linked disease affect males & females are carriers

disorder

❖ Pathogenesis

❖ Abnormal stem cell proliferation

❖ Protein defect in RBCs

membrane (spectrin & ankyrin) —» f Na influx osmotic pressure intracellular I water inside RBCs —>• swelling of RBCs leading to : A. J. Surface area of RBCs — small & spherical in shape (microspherocytes) with deep staining (relatively more HB). B. Rigid RBCs (less deformable) —>■ hemolysis in the spleen

leading to: 1. Defect in RBCs: failure to

produce phosphatidylinositol glycan| A ^ GPI; glycosyl phosphatidyl inositol linked proteins(CD55,CD59)^ t RBCs destruction by complement activated by alternative pathway.

1. G6PD enzyme in RBCs catalyze the R'step in hexose monophosphate shunt(HMP)of carbohydrate metabolism 2. The shunt is responsible for regenerating reduced Glutathione from oxidized Glutathione by

NADPH (H"" donor). 3. Reduced glutathione is the P'

2. Defect in WBCs —> defective

protective line to prevent

chemotaxis & leucopenia 3. Defect in platelet: a. Thrombocytopenia & bleeding tendency

oxidation of Hb to met Hb.

4. |G6PD

oxidation of SH groups

in RBCs membrane ^

denaturation of Hb which attaches

to RBCs cell membrane (Heinz bodies) —» such RBCs become

b. Sometimes platelet activation with

thrombosis(complement destroyed in liver & spleen mediated activation of platelets). Clinical picture 1. General clinical picture of anemia(FPES) 2. Clinical picture of extravascular ❖ Clinical picture of intravascular hemolysis : hemolysis ❖ Intravascular hemolysis 1. Intravascular hemolysis 3. Positive family history precipitated by oxidizing agents: precipitated by Acidity: 1. Infection. A. Sleep (J, RR ^ t C02) 2. latrogenic : Oxidant Drugs: B. Parenteral iron & heparin (acid a. Analgesics: Aspirin & medium). Acetaminophen C. Infection & exercise (lactic b. Antibiotics : penicillin, acidosis). Sulfonamides 2. C Liability for infection. c. Anti-malarial & Anti-tuberculous. 3. Venous THROMBOSIS e.g. mesenteric occlusion abdominal d. Synthetic vitamin K. 3. Metabolic acidosis e.g. OKA pain, MI or stroke. 4. Meal: fava beans (favism). 4. Aplastic anemia(25% of cases). 5. Acute leukemia.

1. To prove anemia 2. Morphology of anemia : o

Investigations : as general but add the specific investigations 1. To prove anemia 1) To prove anemia

2) Type of anemia: normocytic

2. Type of anemia: normocytic normochromic

normochromic

MCH : Normal

3) For hemolytic anemia MCV: normal (normocytic) or 4) For intravascular hemolysis l(microspherocytes) 5) Specific for PNH: o MCHC : 1 Hyperchromic 3. For hemolytic anemia : Specific: A. Pancytopenia. B. Ham's test: hemolysis of patient's blood film for RBC blood in acid medium. morphology: spherocytes 4. Of cause: Osmotic fragility C. Sucrose test: mixture of patient's test: adding RBCs to different blood with sucrose —^ hemolysis. dilutions of NaCl: D. DNA analysis. o In spherocytosis hemolysis E. Flow cytometry to detect the starts at 0.6 % NaCl | ^ RBCs defect; absent CDS5 & Osmotic fragility CD59 o

3. 4. 5. A.

For hemolytic anemia For intravascular hemolysis Specific for G6PD deficiency: Heinz bodies seen during the attack (stained with methyl violet): composed of denatured precipitated hemoglobin B. Enzyme Assay : J, G6PD activity: o This should be done only 2 months after the last hemolytic attack as the newly generated RBCs during crises have normal level ofG6PD

❖ Treatment

o

See general

o

See general

o

In crisis: blood transfusion,

o Treatment of the causes e.g. infection & stop causative drug

24

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Sickle cell syndrome o

Thalassemias

Autosomal recessive disorder where the abnormal

Hb gene(HbS)on chromosome 11.

o Autosomal recessive disorder due to impaired production of one of the polypeptide chains in hemoglobin.(N.B.: small % as autosomal dominant)

❖ Types:

I

A. Sickle cell trait due to heterozygous state(HbSA) I. a -Tbalassemia (defect production of a-chain): causing mild clinical picture. Four genes are responsible for a chain production on chromosome 16. o Sickle cell trait protects against plasmodium falciparum malaria (sickle RBCs are more resistant) 1. a -Tbalassemia minor (trait) due to heterozygous sate causing mild to moderate clinical picture. B. Sickle cell anemia due to homozygous state 2. a -Tbalassemia major due to homozygous sate causing (HbSS)causing severe clinical picture. severe clinical picture incompatible with life. C. Other types: H. P" Tbalassemia (defective production of p-chain 1. Sickle cell - Hb C anemia : HbS + Hb C (in the of HbA): two genes are responsible for p chain

latter, glutamic acid in the 6"' position of the p

chain is replaced by lysine 2. Sickle cell - Hb E anemia : HbS + Hb E(in the latter, there is a single substitution on the p chain)

production on chromosome 11

1. Beta-Thalassemia minor (trait) due to heterozygous sate causing mild clinical picture 2. Beta-Thalassemia intermedia: due to a double

chain of Hb.(Splenomegaly instead of shrunken spleen)

heterozygous or homozygous state causing moderate CP 3. Beta-Thalassemia major due to homozygous sate(= Cooley's anemia = Mediterranean anemia = target

❖ Sickle cell anemia

■ agglutination —>■ +ve test

with antibodies.

2. Drug Induced Hemolytic anemia A. Direct damage to RBCs membrane: amphotericin B B. Oxidant drugs in G6PD defieiency C. Immunological mechanisms:

A

Hemoiysis by complement or phagocytosis

+

Drug

1. Hapten can bind to RBCs surface rendering them antigenic e.g. penicillin

or

Drug Carrier protein Antibody against drug

C3b

Hemoiysis by complem«it

C3b receptors

2. Innocent by stander reaction:

o Drug react with its antibody on RBCs surface ^ activate complement —» hemoiysis e.g. sulphonamides.

Hemoiysis by phagocytosis

Normal RBC antigens

3. Induction of antibodies against RBCs by altering their wall antigens e.g. a methyldopa

27

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

III.

Macrocytic normochromic anemia

Dofecliw

Megaloblastic Anemia

DNA synthesis

- - Folic acid H4 DNA

Vit. Bi2

synthesis H,C-

Folic acid

Fplib secid H4

H3C- Vlt. 8,2 Vit. Bi2

Memogtobfnisation19

Transcobalamin II

StOfclQd

supply for f

ntnnsic

Vit. B-io

3 years

factor

Parieta cell

Microcytosis (TMCV)

Definition & pathophysiology:

In dividing cells there's duplication of DNA & cytoplasm expansion (RNA). Vitamin B12 and folic acid are needed for methylation of homocysteine to methionine which is needed for conversion of uracil to thymidine to he incorporated in DNA.

Abnormal DNA synthesis due to deficiency of vitamin B12 and/or folic acid leading to : I.

Nucleo-cytoplasmic asynchrony: arrest of nuclear maturation (jDNA) while cytoplasm maturation proceeds (RNA is not affected)^ delay in cell division ^ more cell growth —> formation of megalohlasts instead of normoblast —> ineffective erythropoiesis.

2. In hone marrow: A.

Destruction of RBCs precursors : intramedullary hemolysis

C.

I Hemosiderin in BM,f | LDH, serum iron, bilirubin in blood. Destruction of WBCs precursors —> f serum muramidase. Destruction of platelets precursors ^ thrombocytopenia.

3.

In Peripheral blood :

o

B.

o

Released cells are at variable stage of development & undergo further destruction in RES (spleen) —>

pancytopenia:

^

A.

RBCs : extramedullary hemolysis;

o

Anisocytosis, poikilocytosis, cabot ring & Howell-Jolly bodies(nuclear remnants).

B. C. 4. 5.

| '.

WBCs: leucopenia with hypersegmented (multi-segmented) neutrophils Platelets: more thrombocytopenia. GIT: Atrophy of epithelial cells occurs due to rapid turn-over of these cells. CNS in vitamin B12 deficiency : Defective myelination of nerve fibers ^ impaired nerve conduction Vitamin B12 Deficiency

Folic acid deficiencv

Physiology 2.

Source: in animal sources only, not in plants Requirements: 1 pg/day

3.

Absorption:

1.

4. 5.

Vitamin 312 binds to intrinsic factor produced by the parietal cells in the stomach to be absorbed in the terminal part of ileum where it binds to a specific receptor. Transport: in the plasma bound to transcohalamin II Stores: in the liver sufficient for 2-3 years of normal consumption

1. 2. 3. 4.

Source: In vegetables. Requirements: 50 pg / day. Absorption: Intestine. Stores: In liver 5-15 mg (sufficient for only 2-3 months). 5. Function: For DNA synthesis.

6. Function:

Synthesis of DNA in dividing cells & Myelination of nerve Fibers

28

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Etiology Folic acid deficiency

Vitamin Bn Deficiency o

I Utilization : Inborn enzyme deficiency

o

Lack of transcobalamin II.

1.

1. I Utilization:

I intake: o Dysphagia, starvation o Lack of animal product(Vegetarians) 3. I absorption: A. Gastrectomy, gastritis, gastric carcinoma Pernicions anemia (Addison anemia):

2.

B.

^ Blocking antibody

Q ♦

o

Inborn enzyme deficiency

o

Trimethoprim & methotrexate

2.

l Intake:

o

Anorexia, Alcoholism

o

Lack of vegetable intake.

3.

I Absorption:

o

Malabsorption syndrome,

o

Drugs: Anticonvulsants, methotrexate.

^Vit.B 12

IntrinSi|

Vit.B 12

factor jg

4. I Storage: liver cirrhosis. Binding antibody

Autoimmune destruction of parietal gastric ceils leading to failure ofintrinsic factor secretion —♦ no vitamin B12 absorption ^ o o o

o

a.

megaloblastic anemia Genetically determined : associated with HLA A3 & B7

Usually affects Northem Europe, females > males, in old age. Associated with other autoimmune disorders e.g. thyroiditis & vitiligo.

5.

I Requirements:

o

Pregnancy,

o

Malignancy,

o

Hemodialysis.

o

Hemolytic anemia.

Types of antibodies: Anti-parietal cells antibodies.

b. Anti-intrinsic factor antibodies :

Blocking antibodies: AB that prevents binding of vitamin B12 to intrinsic factor Binding antibodies:

AB that prevents binding of intrinsic factor-vitamin BI^ complex to terminal ilenm receptors c. Heal disease: o o

D. 4. 5.

Regional ileitis, T.B, Diphylopotharium latum Blind loop syndrome & Malabsorption syndrome Drugs e.g. colchicine & neomycin. I storage: Liver cirrhosis I requirements: Pregnancy, malignancy Clinical picture

1. 2. o

Clinical picture of anemia in general (FPES). Blood: pancytopenia (due to delayed maturation & early destruction by BM & spleen) Anemia (| RBCs), Liability for infection (| WBCs) & Bleeding tendency (J, platelets)

4.

GIT:

o

Atrophic glossitis: red glazed tongue

o

Atrophic gastritis leading to dyspepsia, anorexia, nausea & vomiting

o

o

5. o o o

|g

Intestine atrophy : diarrhea Hepatosplenomegaly (RES hyperplasia) CNS: see neurology book. Psychosis (megaloblastic madness) Peripheral neuropathy Subacute combined degeneration (SCD).

5) Clinical picture of the cause: e.g. Malabsorption syndrome.

B.

Clinical picture of the cause: e.g. Pemicious anemia Usually blue eyed Northem Europeans, old age. Other autoimmune disease e.g. Addison, vitiligo & Grave's disease.

C.

There's increased incidence of gastric carcinoma (due to j HCL)

6. A.

29

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Investigations

1. To prove anemia: J, RBCs count, J, Hb, J,HCT 2. Type of anemia:

o Megaloblastic normochromic anemia : f MCV {large RBCs},f MCH,normal MCHC 3. For megaloblastic anemia: i. Blood picture : pancytopenia 1.

RBCs:

o I count < 5 million/mm^ o Anisocytosis, Poikilocytosis, Cabot ring & Howell-Jolly bodies o

Absent reticulocytes

o Therapeutic test: small doses of vitamin B12 or folic acid ^ reticulocytosis occurs with treatment ^ 2. i WBCs : leucopenia with shift to the right, with hypersegmented neutrophils 3. 4 Platelet: thrombocytopenia with megakaryocytes fragments. ii.

Blood chemistry:

o t Serum LDH,{ indirect bilirubin, f serum iron & t muramidase. o

Low serum vitamin B12 or folic acid

iii. IV.

Bone marrow biopsy: Megaloblastic hyperplasia & hemosiderin deposition in BM iv. Investigation for Folic acid Investigation for the Vitamin Biz Deficiency:

❖

Schilling test:

a.

Procedure:

deficiency:

❖ Formiminoglutamic Acid(FIGLU)

1000 pg B12 IM (to saturate the stores) —> Then 1 pg oral

o

Test:

radioactive B12.

a) Normally:

b.

Normally:

o Histidine —> Formiminoglutamic Acid

o

25% of oral radioactive vitamin B12 appears in urine / 24 hrs

(FIGLU) ^ glutamic acid. b) In folic acid deficiency anemia: o t FIGLU in urine. V. Investigation for the cause : e.g. o Investigations for malabsorption

c.

V.

1.

Abnormal response:

< 5% of radioactive B12 / 24 hr urine Malabsorption: Correction by giving intrinsic factor —> prenicious anemia. Correction by antibiotic course —» bacterial over growth. Correction by pancreatic enzymes ^ pancreatic insufficiency Investigation for the cause : e.g. Investigations for malabsorption syndrome.

Folic acid

syndrome.

2. Pernicious anemia:

Detection of antibodies: Anti-parietal cells antibodies & Anti-

o

intrinsic factor antibodies o

Gastric function test for achlorhydria: absent gastric secretion

o

Endoscopy to exclude gastric carcinoma. ❖ Treatment

1. o

2. o

Replacement therapy:

Vitamin B12(hydroxyl-cobalamin or cyano-cobalamin) 1000 pg IM daily till RBCs count to 5 million /mm^ Then 1000 pg IM/ month for life especially in cases of malabsorption. Treatment of cause e.g. in pernicious anemia. Diluted HCL -i- pepsin during meals

1. Replacement therapy: o Folic acid 5-15 mg orally/day till improvement then l-5mg/day 2. Treatment of the cause e.g. stop methotrexate. 3. Blood transfusion.

3. Blood transfusion if: o

o

HB < 7 gm/dl. Ischemic heart disease or heart failure if Hb < 10 gm/dl.

Worsening CNS B12 Folic acid

Folinic acid (active)

Improve anemia

❖ NB: folic acid is NEVER given alone in SCD :

o Empirical treatment by folic acid in patients with vitamin B12 deficiency will improve the anemia but will exacerbate CNS manifestations due to consumption of already low vitamin B12 in activating folic acid.

30

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

0

deficiency: 1 stores

Vitamin B12 or Folic acid

excess alcohol intake

0 1 Hepatic factor of erythropoiesis 0 Hemolytic especially after

varices & ulcer

0 Blood loss from piles,

failure

❖ Anemia of liver cell

bleeding & dialysis

Blood loss from

0 Folic acid deficiency: Lost in dialysis

0 i Renal erythropoietin 0 Hemolytic due to dialysis

0

failure

❖ Anemia of renal

Vitamin B12 or Folic acid

deficiency 0 Associated pemicious anemia

0

0 1 Thyroxin —>■),tissue O2 needs -^J,renal production of erythropoietin

0 Secondary to malabsorption & menorrhagia in females

❖ Anemia of hypothyroidism

o Ancylostoma & Necator Americanns^iron deficiency anemia + eosinophilia. o Malaria —»• hemolytic anemia o Diphyllobothrium latum ^ J, Vitamin B12 megaloblastic anemia

❖ N.B.: Parasites give different types of anemia:

31

o Normocytie anemia: J, androgens(androgen normally stimulate erythropoiesis in BM)

5. Anemia of gonadal dysfunction in male

o Normocjdic anemia: I cortisol ^ J. tissue O2 needs ^J.renal production of erythropo

4. Anemia of Addison's disease

o Normocytie anemia: | GH —J,tissue O2 needs ^jrenal production of erythropoietin

3. Anemia of hypopituitarism :

o Normocytie anemia in hyperparathyroidism due to J, renal production of erythropoietin & BM calcification

1. Anemia of hypothyroidism: see before 2. Anemia of parathyroid dysfunction :

Anemia of endocrine disorders:

❖ Macrocytic

❖ Normocytie

(Iron deficiency anemia)

❖ Microcytic

Type

Secondary anemia

0

cancer cachexia

acid deficiency:

Vitamin B12 or Folic

(myelophthisic anemia)

secondaries

Toxic BM inhibition

BM infiltration by

0

Chronic blood loss

0

0

❖ Anemia of cancer

0

0

Folic acid deficiency : t requirement

Vitamin B12 or

Aplastic anemia (toxemia of pregnancy —> Toxic BM inhibition)

0 f requirement

pregnancy

❖ Anemia of

Hematological Malignancy

Bone Marrow

Lymphoid

Myeloid

Stem Cells

Stem Cells

Precursor Blast Cells

Precursor Blast Cells

White Blood Cells (leukocytes)

Red Blood Cells (erythrocytes)

White Blood Cells (leukocytes)

Platelets (megakmyocytes)

I

Lymphocytes j

Monocytes

Neutrophiis

Eosonophlls

Basophils

Mast Cells

Granulocyte Macrophages B-Cells

NK Cells

T-Cells Dendritic Cells

Plasma Cells

t malignant I stem cell

\ malignant

ESSENTIAL

I.

Macropliages

progenitor

THROMBOCYTHEMIA(ET)

Myeloid disorder:

plaiciets (abnormal)

MYELODYSPLASTIC

SYNDROMES(MDS)

1. Acute myeloid leukemia 2. Chronic myeloid disorders: a. Myelodysplastic syndrome(MDS)

1

immature blood cells

POLYCYTHEMIAVERA VERA

(PV)

• • •!

ned blood cells

ACUTE MYEL06EN0U5 LEUKEMIA(AML)

(abnormal}

b. Myeloproliferative disorders(MPD):

Immature white cells

❖ Deilnition : o

MYELOFIBROSiS(HF)

Primary malignant disease of BM stem cells

Etiology: o Idiopathic

« 4

^m

collagen andi reticulin fibers(fibfosis)

❖

\

wBm

o May be due to JAK2 kinase mutation: the cytoplasmic tyrosine kinase Janus Kinase 2, a gene found on the short arm of chromosome 9. ❖ Classifications:

o They are dividing according to the predominant hyper-proiiferative ceil type: A. Myelofihrosis

B. Polycythemia ruhra

C. Chronic myeloid

o

Dominant increase of

dysplastic megakaryocytes

11.

o

D. Essential

thromhocytosis

leukemia

vera

Dominant increase of

o

Dominant increase

of myeloid ceils

RBCs precursors

o

Dominant increase of

megakaryocytes

Lymphoid disorders:

1. Acute & chronic lymphoid leukemia 2. Hodgkin's Lymphoma & Non Hodgkin lymphoma 3. Multiple myeloma & Waldenstrom's macroglobulinemia

32

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Myelodysplastic syndrome(MDS) Platelets

Definition

o Group of acquired BM disorders due to a defect in stem cells, o They are characterized by BM failure with abnormalities in all 3 myeloid cell lines(RBC, granulocytes / monocytes & platelets)

Red blood cells

Etiology: leMi I j

V

Bone marrow

1. Idiopathic : White blood cells

o The deletion in the long arm of chromosome 5 may be associated with MDS 2. Infection : viral

3. Irradiation & chemotherapy The French American British (FAB)classification:

❖ Myeloblasts in the bone marrow

❖ Name

1. Refractory anemia

o

2. Refractory anemia with ringed sideroblasts > 15 %(sideroblastic anemia) 3. Refractory anemia with excess blasts (pre-leukaemia)

o

6 million/mm^ o Hb > 18 gm/dl

o Red cell volume > 36 ml/Kg in males & 32 ml/Kg in females by chromium 51 labelled RBCs

o

o BSR: ii o Erythropoietin: J,J,

HCT >55%

B. Platelets:

o Count > 450,000/mm^

C. WBCs:

o

Count > 12.000/mm3

o Absolute basophilia

o The presence of JAK2 kinase mutation in blood cells o Defective platelet ftinction ^ ]. adhesion & i release of ADP. o 1 Uric acid & histamine o t serum vitamin B12

o t Leukocyte alkaline phosphatase(DD from CML) 3. BM biopsy: o Hypercellular of all elements

36

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Criteria for diagnosis: mn

Diagnosis done by 1. A1+A2 + A3 + A4

2. or A1 + A2 + any 2 from category B; Criteria :

❖ o o o o

Major criteria: A1: Red cell volume >36 ml/Kg in males & 32 ml/Kg in females A2: normal oxygen saturation A3: splenomegaly A4 : abnormal BM karyotype

❖ Minor Criteria :

o o o o

B1: Thrombocytosis > 450,000/mm3 B2 : leukocytosis > 12.000/mm3 B3: t Leukocyte alkaline phosphatase B4: 11 Erythropoietin

❖ Treatment

1. Symptomatic: A. Erythrocytosis

o Venesection (phlebotomy): 500 ml /2-7 days till HCT < 50% o

Dextran to raise blood volume

B. Granulocytosis

o Allopurinol for hyperuricemia o Antihistaminic: for pruritus o Ranitidine: for peptic ulcer

C. Thrombocytosis

o Venesection and antiplatelets (aspirin)for thrombosis

2. Therapeutic:

A. Radioactive phosphorus(P32): 1®' to fall platelets

WBCs -> RBCs

B. Chemotherapy: o Busulfan (f incidence of AML) o Hydroxyurea (doesn't f incidence of AML) o

Interferon.

❖ N.B.:: Hyperviscosity syndrome: tiiBtannffi

Increase blood viscosity due to : A. 1 blood cells o tRBCs: polycythemia with HCT > 55 % o t WBCs: leukemia with TLC > 50,000 mm^

B. t Plasma proteins o Multiple Myeloma o Waldenstrom's Macroglobulinemia

o t Platelets: thrombocytosis > 700,000/mm^.

37

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Leukemia

Definition & pathogenesis

X Lymphold stem cell

ALL

L^mphokj blast

^^elo{d st^cell

^^old blast

AML

Autoantibodies in CLL

I CLL I

CML

Dissemination & infiltration to peripheral blood & tissues B lymphocyte T lymphocyte Monocyte Granulocyte

❖ Abnormal, uncontrolled, malignant proliferation of leucopoietic system with discharge of abnormal immature leucocytes in the bone marrow & peripheral blood. ❖ The abnormal cells :

o In acute leukemia are immature primitive (blast) cells: o In chronic leukemia : the abnormal cells retain most of their normal counterparts —> mature (cyte) cells

❖ Proliferation occurs initially within BM —»• BM infiltration with abnormal leukemic cells —> BM failure (anemia, leucopenia and thrombocytopenia) ❖ Dissemination & infiltration to peripheral blood & tissues e.g. spleen & lymph nodes ❖ In CLL: production of immunological incompetent B cells in blood with abnormal function | ^ immunoglobulin level| with abnormal immunoglobulin (autoantibodies) autoimmune hemolytic anemia & thrombocytopenia. Changed chromosome 9

Etiology: 1. A,

Genetic (chromosomal) factors: High incidence of leukemia with:

Normal chromosome 9

Changed

o

Fanconi aplastic anemia, Down syndrome, Klinefelter syndrome. Polycythemia vera,PNH, myelodysplastic syndrome

B.

Philadelphia chromosome :

o

o

o o

Chramosomss break

Normal chromos 60 y. o Mostly, the cell of origin is B

Occur in young adult

o o

B. Chronic myelocytic (myeloid)leukemia(CML) = chronic granulocytic leukemia Age: Middle age (40-60

years).

lymphocyte,

Mostly, the cell of origin is

Asymptomatic in 25% and discovered accidentally Sub type : Hairy cell

granulocytes (neutrophils, eosinophils and basophils) Equal incidence in both sexes

leukemia

It is one of

myeloproliferative disorders

Clinical picture A. General manifestation : 1.

Fever:

o

Infection, high metabolic rate of leukemic cells & Released pyrogens from damaged cells (tissue destruction)

2. Weight loss, anorexia, malaise, and asthenia. B. Manifestation of BM failure : BM infiltration by leukemic cells

1. Anemia (general clinical picture of anemia; FPES): Warm AIHA

2. Neutropenia : f Infection; monilial infections with necrotic mouth & sore throat o Hypogammaglobulinemia: j, antibody response to infection.

3. Thrombocytopenia (bleeding tendency; CP of purpura) o

C. In promyelocytic leukemia —

incidence of DIC.

Autoimmune

thrombocytopenia C. Monoclonal gammopathy

C. Blastic crisis: sudden

(5% of cases): t IgA or IgM.

transformation of CML to

AML(70%)or all(30%) D. Manifestation of metabolic abnormalities : o o

Hyperuricemia(f purine turn over): Gout arthritis & uric acid stones Hyponatremia(SIADH)& hypokalemia (renal tubular defect)

E. Manifestation of leukemic infiltration : I Reticuloendothelial system : Jll Generalized lymphadenopathy : Common

o

30%

o

The most important

o

Rare

b) c) o o o

Hepatomegaly Splenomegaly: Huge spleen : dragging pain Mofti's sign: pits on pressure Splenic infarction due to thrombosis from early thrombocytosis or leukostasis causing stabbing or stitching pain with splenic rub (perisplenitis) & multiple

manifestation

LNs: small to moderate size, firm, discrete, symmetrical & painless not tender Enlarged mediastinal LNs: Mediastinal syndrome. o Enlarged porta hepatis LNs : Obstructive jaundice o Enlarged retroperitoneal LNs: ureter, IVC, spinal nerves compression obstructive uropathy, edema of LL & focal neurological manifestation o Enlarged epitrochlear LN. b) Hepatosplenomegaly. o

o

notches on palpation II. 1.

Organ infiltration: Early

Late

B.

Skin: Chloroma (soft tissues masses)& itching due to leukemic cutis Bone: generalized bony pain with sternal tenderness & pathological fractures.

2.

Leukostasis:

A.

o

3. 4.

Retinal: scotoma & hemorrhages. Oral:

o

Salivary gland enlargement, Gingival(gum) hypertrophy & bleeding.

7.

I=»«»

Excessive blast cells ^ occlusion of microcirculation —> ischemia e.g. CNS,CVS,Chest, eyes & penis (priapism) CNS: meningitis, compression of spinal cord & spinal roots causes focal neurological deficits & cranial nerve palsy.

5. 6.

Rare

Musculoskeletal system :

CVS: hemorrhagic pericardial effusion. Chest: hemoptysis & hemorrhagic pleural effusion.

8.

Abdomen: ascites, ulcers, hemorrhage & malabsorption

9.

Kidney: Infections & compression of ureters by enlarged LNs

39

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II

'> Classification/Staging: ❖ French-American-British(FAB)classification LI: small homogenous o MO: undifferentiated cells (child variant), o Ml: Myeloblastic without maturation L2: Large and heterogeneous cells (adult o M2: Myeloblastic with maturation variant), L3: Burkitt type like cells o M3: Promyelocytic

o o

o

with vacuolated

cytoplasm (aggressive type).

o

(fDIC is common) M4: Myelomonocytic In M3 & M4 :]tissue

o

o

o

Stage 0: BM & blood lymphocytosis Stage I: Stage 0 + enlarged LN. Stage II: Stage 0 + splenomegaly ± liver enlargement Stage III: Stage 0 + anemia(Hb < 11 gm/dl). Stage IV: Stage 0 + thrombocytopenia (platelets
!♦ Investigation 1. Blood picture:

Blood picture;

CLL

I.

Blood picture:

RBCs:

1.

RBCs:

1.

RBCs:

Normocytic normochromic anemia (myelopthitic). Platelet: Thrombocytopenia & f bleeding time.

o

Normocytic normochromic

o

Early increase ^later on normocytic normochromic

3.

WBCs: Count:

o

A.

Leukocytosis: fff TLC may exceed 100,000/ mm^, with predominant blast cells 30-90% (lymphoblast or myeloblast)

1. . o

2.

B. Subleukemic

C. Aleukemic leukemia

leukemia

Normal or

o

subnormal TLC count with blast cells in blood 4.

o

Normal or subnormal TLC count & absent blast cells in blood

Blast cells only in BM

Differentiation between : AML

ALL

A. Microscopic o

Cell size

o

Small

o

Large

o

Cytoplasmic granules

o

-ve

o

+ve

o

Auer bodies

o

-ve

+ve (in 20%)

o

-ve

o

+ve

o

+ve

o

-ve

B. Chemical

o o

Peroxidase Periodic acid

Schiff(PAS) C. Genetics: T-cell receptor gene

o

+ve

o

-ve

D. Immunological

o

B-ALL:

o

CD13,

o

T-ALL:

anemia

CD33

Platelets:

2.

Platelet:

o

o

Thrombocytopenia & t bleeding time.

Early increase —> later on thrombocytopenia with f bleeding time.

3.

WBCs:

3.

WBCs:

A. Count: Leukocytosis, ttt TLC may exceed B. Cells:

III.

o

Absolute lymphocytosis with small lymphocyte (7590%). ■ Hairy cells: large lymphocytes with cytoplasmic projections II. Blood chemistry : o t LDH o t Uric acid,

o Hypogammaglobulinemia o Monoclonal gammopathy III. Immunological marker o CD 19, CD20 IV. BM biopsy:

o

IV.

Investigation for organ infiltration

Hypercellular full of small lymphocytes. V.

Investigation for organ infiltration:

o

BM biopsy:

Hypercellular full with blast cells > 30% (lymphoblasts or myeloblasts)

o o

■

Blood chemistry :

t Serum LDH & t Uric acid, 1 vitamin B12 in AML

A. Count:

100,000,000/ mm^-

CD 2,3,5

o o

anemia 2.

for lymphocyte : CD 19, 20

II.

Autoimmune hemolytic anemia: +ve Coomb's test

o

CSF, X-ray bone, splenic biopsy LN biopsy: destroyed architecture & replaced by small lymphocytes.

Leukocytosis, ftt TLC may exceed 100,000,000/ mm' Sudden reduction in leucocyte

count may occur with blastic transformation &

chemotherapy. B. Cells:

o o o o

Mainly promyelocytes, myelocytes, and Myeloblasts: 10-20 %. t neutrophiis, basophils & esinophils Leucocyte ALP very low. II.

Blood chemistry:

o t LDH & Uric acid. o (Vitamin B12 due to t

production of transcobalamin I by granulocytes. III.

BM biopsy :

1. Hypercellular full of myelocytes & few myeloblasts < 20% 2. Myeloblasts increase in blastic crisis > 20-30 %

3. Philadelphia chromosome: see before.

IV.

Investigation for organ infiltration.

40

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Treatment

I. ,

Supportive measures:

Anemia: Blood transfusion

2.

Infection: Immunoglobulin transfusion, antibiotics, antifungal. Antiviral, G-CSF & GM-CSF

3.

Thrombocytopenia: platelets transfusion Gout: Allopurinol. Leukopharesis: for leukostasis.

4. 5.

Prevention acute tumor lysis syndrome following chemotherapy: This is characterized by(t K^,PO4, uric acid),(J, Ca"^ & Mg o Management: adequate hydration, allopurinol, treatment of electrolyte disturbances ± hemodialysis. II. Immunologieal therapy: to stimulate immune system to reject leukemic cells:

6. o

A. Monoclonal Antibodies against certain surface markers. B. BCG vaccination.

C. Allogenic externally irradiated leukemic Cells re-introduced to circulation. III.

Chemotherapy

A. Treatment of ALL:

1.

Chlorambucil

Induction of remission (for 4 Weeks): ❖ Destruction of tumor bulk by :

2.

Fludarabine. Prednisone with autoimmune

1.

a.

Prednisone & Vincristine

b.

± Adriamycin & L-Asparaginase

❖

Criteria of Remission:

o

No clinical manifestations.

o

CBC: No blast cells, platelets >100,000 mm^ & absolute neutrophil count > 1000 mm^.

o

B.M.: blast cells < 5%

2.

Consolidation therapy (for 4 weeks):

❖

To attack residual disease:

a.

Cyclophosphamide Cytosine arabinoside 6-mercaptopurine

b. c.

3.

Maintenance therapy (for at least 2 years):

o

6-mercaptopurine

o

Methotrexate

4.

CNS prophylaxis:

o

Irradiation or Interathecal methotrexate

5.

BM transplantation:

o

Age < 50 + matched donor + refractory or relapse.

3.

hemolytic anemia or thrombocytopenia.

1.

Imatinib.

2.

Busulfan

3.

Hydroxyurea

4.

a-interferon

IV. Radiotherapy: o Irradiation: for LNs or spleen, o Radioactive phosphorus(P32) V.

BM transplantation VI.

Treatment of blastic crisis: as AML or ALL.

B. Treatment of AML: 1. Induction of remission for 1 week: combination

of 3 drugs:

Cyclophosphamide, 6-mercaptopurine & Methotrexate. 2.

Consolidation therapy for 1 year by the same drugs.

3.

BM transplantation

Prognosis

o

Children: 80%.

Chronic lymphocytic leukemia rarely transforms to an aggressive high grade

o

Adult: 40%.

lymphoma, so called

chromosome with treatment

Richter's transformation.

do best.

success rate of treatment A. ALL:

B. AML:40%

Chronic myeloid leukemia, patients who have significant reduction in the Philadelphia

41

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Leukemoid reaction: Leukemoid blood picture

Dermition: marked leukocytosis > 25,000 / mm^ with immature leucocytes A. Lymphatic - leukemoid reaction: DD from ALL

B. Myeloid leukemoid reaction: DD from AML

❖

infections :

1.

BM stimulation:

o

Viral: infectious mononucleosis, CMV,HIV

o

Acute Hemolysis, acute Hemorrhage, acute Hypoxia

o

Bacterial: tuberculosis, bmcellosis & pertussis.

2. BM infiltration: myelophthisic anemia

Differentiation between :

❖ Chronic myeioid leukemia

❖

Leukemoid reaction

o

Splenomegaly

o

Common

o

Rare

o

Leukocyte ALP

o

Low up to zero

o

Normal

+ve 90% of cases

o o

High in PRV Negative

o

Philadelphia chromosome

o

Thrombocytosis(Thrombocythemia) ❖ Definition :

Rise of platelet count above > 450,000/mm^ ❖ Types:

1. Essential (primary) thrombocytosis 2. Reactive (Secondary)thrombocytosis Essential thrombocytosis Definition :

o It's It is one of myeloproliferative disorders characterized by malignant proliferation of megakaryocytes in BM leading to increase platelets in peripheral blood Etiology:

❖ Idiopathic, maybe genetic mutation(JAK2 Gene)leading to activation of thrombopoietin promoting proliferation of megakaryocytes ❖ Clinical picture:

1. Thrombosis(f platelet count)& bleeding (platelet dysfunction) 2. Huge splenomegaly 3. Transformation to acute leukemia or myelofibrosis( 1,000,000/mm^ o BM: Hypercellular full of atypical megakaryocytes. Treatment:

o

Treatment of the cause,

o Drugs: Acetyl salicylic acid, Alpha - interferon, Busulfan & Hydroxyurea. o Plateletpheresis.

42

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Lymphoma {♦ Non Hodgkin lymphoma Hodgkin's Lymphoma ❖ Definition: Malignant tumors of lymphoid system (B-cell origin: 70 %, T cell origin : 30 %) o These are tumors derived from the RES, o Malignant proliferation involving the reticulum cells of the but unlike Hodgkin lymphoma, spread lymphoid tissue with tendency to giant cell formation. may not be contiguous and presentation in the extra-nodal site is common

❖ Etiology

1. Genetic predisposition 2. Defective apoptosis in lymphoma cells

1. Genetic predisposition 2. Immunodeficiency e.g. AIDs or

3. Irradiation

immunosuppressive therapy 3. Immunological : Sjogren's syndrome

4. Infection; Epstein Barr virus

4. Irradiation 5. Infection:

o EBV: linked to Burkitfs lymphoma o Helicobacter pylori associated with gastric lymphoma: mucosal associated lymphoid tissue(MALT) ❖ N.B.: Cutaneous T cell lymphoma: caused by a mutation of T cells unlike most non-Hodgkin lymphomas

❖ Clinical picture

I

A. General manifestation:

A. General manifestation:

1) Type of patient: o Age: bimodal onset with peaks at age of25 and 70 years

1. Type of patient: o the Mean age of presentation 50 years

o

2. Fever, weight loss, night sweats, anorexia, malaise, and asthenia.

Sex: Males are more affected than females

i

o Gradual onset & slowly progressive course \

>—\

/ \

2) Fever:

■ ■

Continuous or irregular Cyclic Pel-Ehstein fever: fever for 1-2 weeks followed by similar afebrile period. 3) Alcohol ingestion: causes pain at the sites involved with

Hodgkin lymphoma due to the release of prostaglandin 4) B. C. a.

Weight loss, night sweats, anorexia, malaise, and asthenia. Manifestation of pancytopenia: due to BM infiltration & autoimmune mechanism. RES involvement: Lymphadenopathy : Lymphadenopathy: a. Lymphadenopathy :

1. Localized in one group at onset (cervical or mediastinal) and 1. Generalized at onset, not following a logic then becomes generalized in a logic anatomical pattem anatomical progression (non-contiguous (contiguous spread) spread) 2. LNs are rubbery, discrete without affection of paraglandular 2. LNs are hard, amalgamated with tissue, painless except for alcohol ingestion. affection of paraglandular tissue & 3. They form satellite (biggest LN in the center and surrounded by painless except in rapidly growing types smaller ones) 3. They may cause pressure manifestations : mediastinal syndrome, obstructive jaundice & obstructive uropathy b. Hepatosplenomegaly(Huge) D. Organ infiltration: Extra-nodal o

1) A. B. 2) o o 3) 4)

o

Uncommon

Common

Musculoskeletal : Skin: pruritus, hyperpigmentation, nodules Bone: generalized bony pain with sternal tendemess & pathological fractures CNS: Compression of spinal cord & spinal roots causes focal neurological deficits & cranial nerve palsy, Herpes zoster is common in these patients CVS: pericardial effusion Chest: pleural effusion and dyspnea

0

5) Abdomen: ascites, ulcers, hemorrhage & malabsorption

43

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Ann Arbor staging; stages should be sub -classified to indicate absence(A)or presence(B)of systemic

symptoms(weight loss > 10% within 6 months, fever > 38°C, night sweats). o o o o

Stage 0: No detectable lesions due to prior excision for biopsy, Stage I: Single abnormal group of LN or single extra lymphatic site Stage II: Two or more anatomic sites to one side of the diaphragm Stage III: Involvement of both sides of the diaphragm but limited to LNs, spleen or Waleyers's ring

o Stage IV: Extra-lymphatic spread to bones or liver Investigations

1. Blood picture: o RBCs: normocytic normochromic(BM infiltration, or autoimmune hemolytic) o Thrombocytopenia Stage I

o Granulocytosis with eosinophilia, monocytosis and lymphopenia o tt ESR 2. Blood chemistry :

Stage Hi

JT

o High level of serum ALP (osteolytic bone lesions) o Monoclonal gammopathy: t IgA or IgM o

Stage II

Stage IV

Q

Impaired liver function

3. BM aspiration to demonstrate BM infiltration 4. LN biopsy: the most important for diagnosis : ❖ There is destruction of normal architecture and replaced by Hodgkin tissue that consists of: A. Pleomorphic cells : o Epithelioid cells, lymphocytes, eosinophils & fibroblasts B. Reed- Sternberg(RS)cells: 'A mirror image giant cells containing 1-6 nuclei.

❖ The prognosis can be predicted by the ratio

%-,y

of lymphocytes and RS cells: o

Nodular sclerosis: 60% of cases

o o

Mixed cellularity: 25% of cases Lymphocytic predominance: 10% of cases & the best prognosis

o

Lymphocytic depiction: 5% with greatest number ofRS cells and the worst prognosis

❖ Classification according to proliferation rate:

1. Low grade lymphoma o E.g. follicular, small cleaved cell lymphoma 2. Intermediate grade lymphoma o E.g. diffuse, small cleaved cell lymphoma 3. High grade lymphoma o E.g. non-cleaved cell (Burkitt & nonBurkitt)

5. Negative tuberculin test 6. X-rays: osteolytic bone lesions ❖ Treatment

1.

Radiotherapy:

o For stage I, II, III-A, or combined with chemotherapy. 11. Chemotherapy: 1. Indications: stage III-B & stage IV 2. Duration & Regimen : o For 6 cycles each lasting 2 weeks with intervening 2 weeks rest 3. Drugs: each cycle consist of: A. The first combination includes MOPP:

o

Mustine hydrochloride, Oncovin (Vincristine), Procarbazine, Prednisone.

B. The more recent combination ABVD:

o Adriamycin, Bleomycin, Vinblastine, Dacarbazine III. Surgical: o Exclusion of one group of LNs may be curative in localized disease or may be indicated to relief pressure symptoms. IV. Treatment of complications e.g.: o NSAID for fever and pruritus o Corticosteroids for autoimmune hemolytic anemia.

I. Radiotherapy: o For localized low grade lymphoma if symptomatic. II. Chemotherapy: 1. Low grade lymphoma: o

Chlorambucil

o 2. o 3. ❖

Monoclonal antibody (Rituximab) Intermediate grade lymphoma: chemotherapy & radiotherapy High grade lymphoma: Combination chemotherapy is used : RCHOP:

o Rituximab, Cyclophosphamide, Hydroxydoxorubicin (adriamycin), Oncovin (Vincristine)& Prednisone

HI.

BM transplantation

V.

❖ Prognosis

❖ Depends on the stage and histological grade of the tumor. The 5 year survival rate is: o

Stage I and II: 85% o

Stage III-A: 70% o

Stage IV: 60%

44

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Gammopathies

❖ Introduction: Immunoglobulins (Igs)= Antibodies:

Definition: glycoproteins that bind specifically to the antigen that induced their formation. Production :

When B lymphocytes cells become active under cooperation of T helper cells ,they change into plasma cells which secrete protein molecules called antibodies(immunoglobulins) —> IgM is first secreted, then the B cell can switch to the production of another isotype of the same immunologic specificity The most of the immunoglobulins are present within the gamma globulin fraction of plasma proteins on electrophoresis Antibody structure :

Variable region /

\

Heavy chain

Light chain

The basic structure is common to all classes of Igs. An antibody molecule is roughly Y-shaped and consists of4 polypeptide chain : o \ Constant region 1. 2 identical light(L)chains 2. 2 identical heavy(H)polypeptide chains linked together by disulphide (S-S) bonds in the region known as the hinge region ❖ The heavy chains ❖ The light chains ❖ Subtypes: ❖ They are one of two ♦♦♦ There are 5 main types corresponding to the 5 isotypes of Igs: GAMED types: o Gamma(y)^ IgG, Alpha(a) —> IgA, Mu(p) —> IgM o Epsilon (e) —+ IgE, Delta (5) —>• IgD o Kappa(k) ❖ So the heavy chains determine the isotype of an Ig o Lambda(X) ❖ The light and heavy chains are subdivided into regions or domains: ❖ Domains or regions: ❖ These regions are: A. Variable domains: that bind antigen & show a wide variation in amino acid composition B. Constant domains: that bind complement & show a uniform (constant) amino acid sequence o

❖ Ig ❖ Function ❖ IgG o Secondary immune response o The only Ig that can cross the placenta to the fetal circulation —> provide passive protection to the newborn during the first few months of life, o

Anti-Rh antibodies

❖ IgA

o Provides local immunity at the mucosal surfaces (saliva, tears, colostrum, respiratory, GIT and

❖ IgM

genitourinary secretions) o Primary immune response o Cannot cross the placenta

o It is the only antibody made to thymus-independent antigens e.g. ABO blood group antigens of human RBCs

IgE ❖ IgD

o Type I hypersensitivity reactions. o Antigen receptor

❖ Monoclonal Antibodies:

o Antibodies in vivo almost always are polyclonal (produced by > 1 clone of B cells) except in the case of monoclonal gammopathy(Plasma cell dyscrasia), produced by a single clone of B cells. b. If the monoclonal Ig is of the IgM class : the disease is Waldenstrom's macroglobulinemia c. If the monoclonal Ig is of the IgG,IgA, or rarely IgD or IgE class, the disease is the multiple myeloma o Monoclonal Antibodies can be artificially produced to be used in :

A. Diagnostic applications e.g. determination of lymphocyte markers e.g. CD markers. B. Therapeutic applications e.g. treatment of digitalis toxicity

45

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Gammopathies

Detlnition; diseases characterized by increase production of immunoglobulin Types of gammopathies: Normal

Polyclonal

serum

Ij

Monoclonal

gammopatby i!

protein electropboresis

gammopalhy

JIa/vx/\^

"alba,

^

^

A. Polyclonal gammopatby :

alb

^

ctj p

7

B. Monoclonal gammopatby: The abnormal protein produced is called paraprotein or M component

YYYYYYYYY

YYYYYY

o Diffuse increase in several immunoglobulin clone o Local increase of one clone of immunoglobulin ❖ Etiology o Chronic infections o Multiple myeloma & Waldenstrom's Macroglobulinemia o Cancer o Primary amyloidosis & Primary M band o Chronic liver disease e.g. primary biliary cirrhosis, o Heavy chain disease chronic hepatitis, alcoholic cirrhosis o Non Hodgkin's Lymphoma & CLL o Collagen disease e.g. SLE o Some old people o

Sarcoidosis

Plasma cell dyscrasias: Multiple Myeloma & Waldenstrom's Macroglobulinemia Multiple Myeloma ❖ Definition :

o B cell neoplasms with malignant byperplasia of plasma cells with synthesis formation of one abnormal form of immunoglobulin while synthesis of normal immunoglobulin is decreased. ❖ Types : 1. Intact immunoglobulin multiple myeloma (80%):

>^ // >^ // ^ //

cha

WWW'=> IMI Heavy chain

II II

II II

II II

o Production of intact monoclonal antibodies : M component in 75% of cases is IgG, 25% of cases is IgA & rarely IgB or IgD) 2. Light chain multiple myeloma (15%): the Bence - Jones protein :

■=>/// o

Production of monoclonal free light chains only (kappa and lambda) which are then excreted in urine,

o Bence - Jones proteinuria detected by : a. Urine electropboresis.

b. Urine specimen which is characterized by : ■ It can be precipitated when the urine is heated to 55°C ■ It disappears when point of boiling is reached > > 85 °C ■

It reappears on cooling

3. Non secretory multiple myeloma (5%): absent monoclonal proteins 46

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Clinical picture:onset is 50- 70 years, more common in males: 1. Effects of excessive plasma cells & abnormal immunoglobulin: 1. Hyperproliferation of plasma cells leads to:

Red blood cells

i-'t V:'*

ne marrow

White Uood cells

A. Osteolytic bone lesion:

o Malignant plasma cells secrete cytokines that activate osteoclasts leading to : ■ Osteoporosis with fractures of long bones or vertebral collapse with spinal cord compression ■ Hypercalcemia. B. Generalized bony pain especially on motion & pathological fractures C. ± Palpable bone masses(myeloma)on flat bones (ribs, skull, scapulae) D. BM replacement with pancytopenia E. Weight loss & Weakness

Hyperviscosity syndrome: see before in polycythemia vera Hands : Raynaud's phenomenon: Ig G & Ig A are cryoglobulins

Hemolytic anemia: coating of RBC leads to rouleaux formation (marked t ESR)with subsequent hemolysis. t susceptibility to infection : J, production & t destruction of immunoglobulin Coagulopathy : IgG coats coagulation factors —> coagulation defect Pathologic effect of Bence-Jones proteins: A. Amyloidosis:

o Light chains of immunoglobulin traverse capillary bed & precipitate with protein & polysaccharides forming amyloid material causing peripheral neuropathy, carpal tunnel syndrome, cardiomyopathy & macroglossia B. Nephrotoxicity : light chain precipitate in kidney with release of lysosomes 2. Renal impairment with multiple myeloma:

1. Hypercalcemia (osteolytic bone lesion)& nephrocalcinosis

2. Hyperuricemia(f turnover of plasma cells) leading to gout & uric acid stones (urate nephropathy) 3. Acute renal failure from dehydration especially with I.V.P. or treatment with aminoglycoside 4. Amyloidosis of the kidney 5. Bence- Jones proteins(myeloma kidney) 6. Pyelonephritis : f susceptibility to infection " ■■

I-

^

i 3. Anemia with multiple myeloma : j 1. B.M. inhibition due to :

o o 2. 3.

Replacement by plasma cell (myelophthisic anemia) Radiotherapy & chemotherapy Hemolytic anemia due to rouleaux formation Renal insufficiency with I erythropoietin

I 47

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Investigation

1.

Blood picture :

1. Normocytic normochromic anemia ± pancytopenia 2. Marked "f in ESR (the paraprotein causes rouleaux of RBCs) 3. Plasma cells in serum

4. Alkaline phosphatase is normal(multiple myeloma stimulates osteoclasts and not osteoblasts) II. Blood chemistry : 1. Plasma protein electrophoresis : f M component 2. t serum Ca & serum uric acid

III.

Immunoelectrophoresis to detect type of immunoglobulin;

o Showing monoclonal protein spike of IgG or IgA IV. Bone marrow biopsy: o Plasmacytosis :\ plasma cells > 10 %(normally < 5%) V. Investigation for complications : A. Renal changes: 1. Proteinuria, casts

2. Bence Jones proteins in urine (coagulate at 55 °C, dissolve at 85 °C) 3. Urine electrophoresis for M protein (kappa or lambda light chain) B. X-ray skull:

o Multiple ,rounded punched out osteolytic areas without new bone formation together o Diffuse osteoporosis ❖ Diagnostic Criteria: 1 major criteria and 1 minor criteria I.

1. 2. 3. o o

Major diagnostic criteria :

Plasmacytoma on tissue biopsy Bone marrow plasmacytosis of> 30% M component: Serum: IgG >3.5 g/dL, IgA > 2 g/dL Urine : kappa or lambda light chain (Bence Jones proteins)> 1 g / 24 hours in absence of amyloidosis

II. Minor diagnostic criteria: A. Marrow plasmacytosis of 10-30%

B. M component: but lessor amounts than major criteria C. Osteolytic bone lesions D. Reduced normal immunoglobulin < 50% of normal

Treatment:

I.

Symptomatic measures:

1. Anemia: whole blood transfusion, Packed RBCs transfusion

2. Infection: Immunoglobulin transfusion, Antibiotics, antifungal & Antiviral drugs 3. Analgesics for pain 4. Allopurinol for gout 5. Bisphosphonates for bony lesion 6. Diuretics & good hydration for hypercalcemia II. Chemotherapy: o Melphalan o

Prednisone

o Cyclophosphamide o VAD : vincristine, adriamycin and dexamethasone o

Thalidomide

o

Bortezomib

III.

Radiotherapy.

IV.

BMT : the only curative treatment, done in young age

48

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Waldenstrom's macroglobulinemia (Lympho-plasmacytic lymphoma) ❖ Definitional;,

Lymph Node Germinal center

Bone Marrow B cell

Pre B cell

Rasma cell

Immune stimulation and

genetic factors

i lgM MGUS

Smoldering WM

A. Malignant proliferation of lymphocytes & plasma cells (lympho-plasmacytoid cells) with excess IgM release(IgM paraproteins are macroglobulins & cryoglobulins).

B. Waldenstrom's macroglobulinemia is commonly preceded by two clinically asymptomatic but progressively more pre-malignant phases: o IgM monoclonal gammopathy of undetermined significance(IgM MGUS) o Smoldering Waldenstrom's macroglobulinemia C. Bence-Jones protein occur in 10-15 % of patients.

♦> Clinical picture :

anaa 1. Hyperviscosity syndrome . 2. Hands: Raynaud's phenomenon (cryoglobulins) 3. Hepatospienomegaly & lymphadenopathy 4. Myopathy 5. Rheumatoid like arthropathy

6. Anemia: B.M replacement, hemolytic anemia & hypersplenism 7. Coagulopathy: coating of coagulation factors coagulation defect

❖ N.B.: Unlike muitiple myeloma, renal impairment, osteolytic lesion & hypercaicemia, amyloidosis are rare.

.❖ Investigation: ■wif I

1. Blood picture:

2. Normocytic normochromic nemia, pancytopenia ,eosinophilia + absolute lymphocytosis 3. Immunoelectrophoresis IgM >3 g/dl 4. BM biopsy : o Increase in lymphocytes & plasma cells (lympho-plasmacytoid cells) ❖ Treatment:

1. Plasmapheresis 2. Chemotherapy : chlorambucil, azathioprine ,steroids

49

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hemostasis

*t* Normal hemostasis:

Injury to blood vessel

1)Blood Vessels:

Bleeding

J

o The P'response to injury of BYs is VC to allow clotting & J, blood loss, o VC occurs due to local axon reflex & serotonin released from activated platelets, o

Time : 1 minute

® Vasospasm 2)Formation of platelet plug (primary hemostasis):

o Produced from megakaryocyte by budding in BM under influence of thrombopoietin o Life span of platelet is about 7-10 days o Contains 2 types of granules: dense bodies & a granules o

Platelet count:

■

Normal count: 150,000 - 450,000 / mm'

d)Platelet plug formation

• I Count = Thromhocytopenia, f Count = Thromhocytosis o

Function :

1. Adhesion:

• Attachment of platelets to damaged subendothelium through glycoprotein receptors(GpIb/IX) on platelet surface connected to collagen

by the factor VIIWon Willebrand factor complex.

Platelet

Gpiib-iiia complex Fibrinogen

2. Primary aggregation: by prostaglandin E2, F2 & thromboxane A2. 3. Activation: Release of granular contents e.g.: •

Serotonin

VC.

• Adenosine diphosphate(AD?)^ t aggregation. Platelet factor 3(PF3) ■ coagulation.

von Willebrand factor

Endothelium

Retractozyme ^ clot retraction.

Subendothelium

Secondary aggregation: Under effect of ADP & is maintained by GpIIb / Ilia that binds fibrinogen. Normal bleeding time : 2- 4 minute

3)Formation of a firm fibrin clot (coagulation): secondary hemostasis: ❖ Coagulation pathway (cascade) leading to :

1. Formation of prothrombin converting principle(Xa,factor 5, Ca++,PF3) = prothrombinase or plasma thromboplastin 2. Conversion of prothrombin to thrombin

Cf)Fibrin clot formation

3. Conversion of fibrinogen to fibrin monomer —> fibrin polymer that stabilize the hemostatic plug of platelets ❖ Clotting time: 5-10 minute.

4)Fihrinolytic system: o Function : dissolution of fibrin clot to restore blood vessel patency

(4)Fibiinotysis

Tissue plasminogen activators

Plasminogen ■

^ Plasminogen Urokinase

(endothelium, platelets, leukocytes)

Fibrin «& fibrinogen

Fibrin degradation products(FDPs)& D dimer

50

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Coagulation pathway(cascade) Intrinsic Pathway

Extrinsic Pathway

Endothelial damage

Tissue trauma

Activated factor: ^-

Pre-kallikrein -»kallikrein

12 —;

Tissue

-lla

thromboplastin (3)

High molecular weight kininogen 11^ 11a

9^ 9a

8 + Ca^^ & PF3

Factor 7 + Ca"^

Common Pathway: 10

10a N

^: p'fe

V Prothrombin converting principle(10a,5, Ca^,PF3)= Prothrombinase or plasma thromboplastin

V Thrombin (2a)

Prothrombin (2)

V Fibrinogen (1)

0

Fibrin monomer(la)

13a

V Fibrin

BLOOD

Platelet

Plug ❖ N.B.:

Fibrin polymer that stabilize the bemostatic

plug of platelets

o

Factor 4: calcium ions

o

There is no factor 6

51

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Natural anticoagulant system 1. Intact endotheliuin secrets:

o Prostacyclin: VD & J. platelet aggregation, o Plasminogen activator: initiate fibrinolysis. 2. Protein C & S:

o Protein C activated by thrombin-thrombomodulin complex in the presence of protein S

inhibits factor V & VIII.

3. Heparin cofactor II. 4. Tissue factor inhibitor (extrinsic pathway):

Removes the tissue factor - factor VII a complex that initiates coagulation. 5. Pibrinolytic system 6. Anti-thrombin III :

o It inhibits the serine proteases (thrombin & plasmin)

o Enhanced by heparin (so in Anti thrombin III deficiency^ lack of heparin response) 7. Clearance of activated clotting factors by liver. Investigation for hemostasis t 1. Test for blood vessels & platelets:

A. Vascular & platelet integrity 1. Bleeding time:

o The time that is taken for bleeding to cease from a small superficial wound, o Normally 2-4 min.

o Method: Skin prick by needle

remove blood by filter paper till bleeding stops.

2. Hess capillary fragility test: o

Mark area 5 cm in diameter on the antecubital fossa,

o Inflate sphygmomanometer to 80 mmHg for 5 min. o Normally < 5 petichea are seen. ^ 1 & 2 positive in all types of purpura

o

B. Platelet assessment: 1. Count:

o

Normal count: 150,000 - 450,000 / mm^

o I Count e.g. 40,000 / mm^ thrombocytopenic purpura o t Count = Thrombocytosis

2. Blood nim: large platelets indicate t peripheral consumption while small ones indicate BM failure. 3. Platelet function:

o Aggregation: using aggregometer. o Adhesion: Platelet AD? content, PF3 activity o I Platelet function : thrombasthenia 4. Platelet antibodies in autoimmune thrombocytopenia. 2. Test for coagulation: 1. Clotting (coagulation) time: o

Normal: 5-10 min

o Prolonged in all typed of coagulation disorder. 2. Activated partial thromboplastin time(APTT) o Kaolin (-ve charge) -I- Ca + patient plasma —> clotting

3. Prothrombin time(PT)

o

o

o Tissue thromboplastin -I- patient plasma ^ clotting

Normal clot forms in: 30 - 40 sec

o For intrinsic (12,11,9,8)& common pathway (10,5,2,1) o Prolonged in deficiency of factors (12,11,9,8)& (10,5,2,1).

Normal clot forms in: 10-14 sec

o For extrinsic (3,7) & common pathway (10,5,2,1)

o Prolonged in deficiency of factors (3,7)&(10,5,2,1). o

Prothrombin concentration is 100 % if PT is normal

o INR (international normalized ratio)= patient PT/ control PT

o Used to control anticoagulant treatment

52

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

4. Thrombin time (TT):

o Thrombin is added to patient plasma, o

Clot forms in 10-20 sec.

o It tests the common pathway (2, 1) o

Abnormal test: increased in :

A. Afibrinogenemia, hypofibrinogenemia & Dysfibrinogenemia. B. DIG.

C. Heparin therapy

5. Assay for specific factors e.g. factor VIII in hemophilia N.B.: Factor VIII (Anti-hemophilic globulin) has two components: 1. VIII related protein (VIIIR)or 2. VIII:C: the antihemophilic factor VIII Von Willebrand factor (VIIIVWF) 0 It's necessary for platelets adhesion 0 It's necessary for coagulation: co-factor in intrinsic pathway o If deficient

Von Willebrand's disease.

o If deficient -> Hemophilia A

❖ VIII-Ag; is the antigenic portion: Antigenic determinants on VIII that can be detected by antibodies o Factor VIII related antigen (VIIIR: Ag)

o Factor VIII procoagulant antigen (VIIFC Ag)

3. Test for fibrinolytic system: 1.

Plasma fibrinogen level: o N= 150-400 mg/dl o Decreases in excess fibrinolysis

2.

Plasma fibrin degradation products(FDPs): o Normal < 10 pg/ml o t In Die.

Anti-thrombotic drugs: drugs used to treat clotting disorders ❖ Indications: 1. CVS:

o

Rheumatic heart disease with embolization

o Recent myocardial infarction & unstable angina o Pulmonary embolism

o AF if recent & during its conversion to sinus rhythm to prevent thrombus formation & embolization o

Patient with artificial cardiac valves

o Patient predisposed to thrombosis(hypercoagulable state) 2. CNS:

o Cerebral embolism & cerebrovascular insufficiency 3. Other indications: o

DVT

o

Arterial embolism or thrombosis

o Vascular surgery Contraindication:

1. Diseases with hemorrhage:

o Hemophilia, liver cell failure, peptic ulcer, pulmonary TB , salicylate treatment 2. CVS:

o Subacute bacterial endocarditis for fear of cerebral hemorrhage

o Myocardial infarction complicated by extensive pericarditis for fear of hemopericardium o Severe hypertension & Dissecting aneurysm

53

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Drugs:

I^^^S^mulusJ

1. Anti-platelet drugs: Aspirin

\

Antiplatelet drugs Arachidoiiic acid

4 Aspirin

Thromboxaae

stimulates!

(fruity activated platelets)

I

Ciopidogrel ticdnpidine

AD I' A

i

ciopidogrel Ticlopidine

Dipyridamoie ^cAMP

A^idiiljit

P2Y receptor

TXA; recep clotting

r

Lowers cAM Activation of GPiib/iiia receptor

Increased cAMP

ciotting GPllb/llla antagonists

Prevents clottin;

I

Dipyridatnolc Eptillbatide Abcixiinitl)

Receptor for fibrinogen and platelet adbesion

(prevents breakdown by

Platelet aggregation Thrombosis formation

phosphodiesterase)

Tirofiban

❖ Mechanism of action

❖ Drug

o COX inhibitor J, thromboxane A2. 1. Aspirin (acetylsalicylic acid) 2. Ciopidogrel, ticlopidine, prasugrel & ticagrelor o ADP receptor blocker o Glycoprotein lib / Ilia inhibition 3. Abciximab, eptifibatide and tirofiban o Phosphodiesterase inhibitors —> fcAMP

4. Dipyridamoie

2. Injectable anti-coagulant & new oral anticoagulant drugs:

Inittotion

AT til

(inactive

^Warfarin Thrombin

Rivaroxaban

Propsffttion

AT II! -;

Apixaban FondapatinuxL

tteparinL^^

(active)

._

Fondaparinux Dablga

Fibrin formation

LMWHfibrinogen

» Fibrin

HMWH^ ❖ Drug ❖ Form o Injectable 1. Unfractionated heparin: prevent conversion of prothrombin to thrombin 2. Low molecular weight heparin(LMWH = fractionated heparin) e.g. enoxaparin,

❖ Mechanism of action

o Indirect Xa or thrombin inhibitors by potentlation of the anticoagulant action of antithrombin III which inhibits activated

clotting factors mainly Xa & thrombin (Factor Ila)

tinzaparin, nadroparin & dalteparin 3. o Oral 4. o Injectable 5. o Oral 6. o

Oral

Fondaparinux Rivaroxaban, apixaban, edoxaban Hirudin, bivalirudin Dabigatran

o

Direct Xa inhibitors

o Direct thrombin (Ila) inhibitors

7. Vitamin K antagonist e.g. Warfarin

o Compete with vitamin K in the liver, o It inhibits vitamin K dependent coagulation factors (2,7,9,10)

54

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. Fibrinolytic(Thrombolytic) drugs: « ■

-

Rasminogen

Plasmin Activation

Fibrin ^P'>

Fibnn^

^

Degradation

Fibrin

Oegradation

Products* 'A''«

❖ Drug:

♦> Mechanism of action : convert plasminogen to plasmin which

1. Streptokinase, urokinase, anistreplase

o Non fibrin specific agents : binds equally to circulating and noncirculating plasminogen local & systemic fibrinolysis o Fibrin specific agents: binds to plasminogen at the fibrin surface (non-cireulating) rather than circulating plasminogen in blood ^

lyses the fibrin clot

2. Tissue plasminogen activator: Alteplase, Reteplase & Tenecteplase

local fibrinolysis

Comparison between heparin & oral anticoagulant drugs: ❖ Unfractionated Heparin 1. Action

o

Potentiate the action of Antithrombin III

o

❖ Oral anticoagulants e.g. Warfarin Compete with vitamin K in the liver,

o It inhibits vitamin K dependent coagulation factors (2,7,9,10) 3. Dose

o Immediate onset, short duration A. Prophylaxis : 5000 lU SC /8hr

4. Control

B. Therapeutie : o DVT & PE: 80 units/kg IV bolus, then continuous infusion of 18 units/kg/hr o STEMI:60 units/kg IV bolus, then continuous infusion of 12 units/kg/hr o APTT (should be 2-3 times normal)

2. Onset & duration

o Start after few day, prolonged duration o Loading: 10 mg/day PO for 2 days o Maintenanee : 1 - 10 mg/d.

Warfarin ^ t-'S/jts o PT expressed as INR (international normalized ratio) should be 2-3 times

isaggat

normal 5. Antidote

6. On coagulation screen

o

Protamine sulfate

o

Vitamin K

o

Fresh blood

o

Fresh blood

0 tAPTT,FT, TT 0 Normal fibrinogen

o tAPTT,PT o Normal TT & fibrinogen

Low molecular weight heparin(LMWH = fractionated heparin) has the following properties : 1. 2. 3. 4. 5.

Greater activity against factor Xa than thrombin Greater bioavailability after SC injection

CLEXANE'

4Q0\)mn

Enoxaparin sodium)

Longer half life so can be given onee or twice daily Lower thrombocytopenic and osteoporotic effects Does not require PTT monitoring Interpretation of the coagulation screen

Fibrinogen

Platelet

Bleeding

Hess

Clotting

eount

time

test

time

Immune Thrombocytopenia Purpura (ITP)

4

T

+ve

N

N

N

N

N

Henoch-Schonlein purpura Hemophilia A Vitamin K deficiency

N

t

+ve

N

N

N

N

N

N

Von Willebrand Disease Disseminated Intravascular

N

N

-ve

N

N

-ve

N

T T

+ve

i

+ve

t T t t

APTT

PT

TT

FDPS& D-dimer

T T T t

N

N

N

N

N

T

N

N

N

N

N

N

N

t

T

i

r

Coagulation (DIC)

❖ N B.: N stands for Normal, t : prolonged, i decreased ,+ve : positive, -ve : negative

55

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hypercoagulable state (thrombophilia)

❖ Definition: local or systemic diseases which increase the risk of thrombosis ❖ Etiology: ViiaaiMntit'.iii i'inl-iii'irii nff

1. Congenital: 1. Antithrombin III deficiency.

2. Activated protein C resistance: Factor V Leiden mutation 3. Protein C & S deficiency. 4. Prothrombin mutation.

5. Dysfibrinogenemia.. 6. Hyperhomocysteinemia 11.

1. 2. 3. 4.

Acquired:

Anti-phospholipids syndrome: SLE. Post-operative Pregnancy, contraceptive pills Paroxysmal noctumal hemoglobinuria

5. Cancer: Trousseau's syndrome. 6. Dehydration 7. Die

8. Myeloproliferative disorders 9. Massive infection & septicemia 10. Nephroic syndrome

11. Heparin induced thrombocytopenia, TTP: Thrombotic thrombocytopenic purpura 12. Hyperlipidemia & obesity

Bleeding disorders are classified into two main types:

hVTHMM

■ .y

1. Purpura

'

2. Coagulopatby

56

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

o

Purpurii Bleeding tendency due to defects in vessel wall or platelets.

o

M. Coagiilopatliv Bleeding tendency due to defects in coagulation factors.

Vascular purpura (non-thrombocytopenlc purpura): I.

Hereditary:

o Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), o Bhlers-Danlos syndrome o Marfan syndrome,

1. Hemophilia A : o Factor VIII deficiency

o

2. Hemophilia B (Christmas disease):

Von Willebrand disease

ff^Scqmreffl

o Factor IX deficiency: x-linked

1. Idiopathic: Purpura simplex 2. Infection: Purpura fulminans (ineningococcal septicemla), SBE 3. latrogenic : steroids 4. Immunological: vasculitis

recessive disorders

3. Parahemophilia o Factor V deficiency: autosomal recessive diseases

o Henoch - Schonlein Purpura (Anaphylactoid purpura) o

SLE,PAN.

5. 6. o o o

Mechanical: malignant hypertension. Mesenchyme weakness: J, collagen synthesis Senile purpura Scurvy: vitamin C Steroids & Gushing syndrome

II.

4. Afibrinogenemia 5. Dysfibrinogenemia. 6. Deficiency in factors: o i VII, XI, XII, XIII: autosomal recessive diseases

Platelet defect purpura:

TffSmBocyfopem^urpur^

H.

Acquired:

A. Decreased platelet production:

1. 2. 3. 4.

Aplastic anemia. Megaloblastlc anemia. Myelophthisic anemia Myelodysplastic syndrome.

1.

2. 3.

Gold (Hypothermia) Gardiopulmonary bypass. Circulating anticoagulants e.g. SLE.

5. Paroxysmal nocturnal hemoglobinuria

4. DIG.

B. Increased platelet destruction :

5.

Deficiency of vitamin K

6.

Drugs: Heparin Oral anticoagulant Fibrinolytic drugs.

1.

DIG.

2. 3. 4. 5.

Heart: prosthetic valve Hemodialysis Hypersplenism. Immunological:

a) b) o o o o o o

Alloimmune: Post blood transfusion Autoimmune: SLE & Evan's syndrome GEL: Chronic lymphocytic leukemia & lymphoma HIT: Heparin induced thrombocytopenia HUS: Hemolytic uremic syndrome TTP: Thrombotic thrombocytopenic purpura. ITP: immune thrombocytopenia purpura Drugs: a-methyldopa, sulphonamides, penicillins

7. Failure: Liver & Renal failure.

1. Congenital:

A.[Adhesion: o Von Willebrand disease(i VIIIVWF & VIII C). o Bemard-Soulier disease (J,GIycoprotein Ib/IX). B.[Aggregation: o Glanzman disease (J, Glycoprotein Ilb/IIIa).

G. Storage pool disease (J, platelet granules). 2. Acquired:

A. Acute & chronic renal failure.

B. Antiplatelet drugs e.g. aspirin.

C. Polycythemia, thrombocytosis, multiple myeloma D. Gold (Hypothermia)

57

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hemophilia A (factor VIll deficiency). Immune (idiopathic) thrombocytopenia purpura(ITP) ❖ Etiology: ❖ X - linked recessive disease: ❖ Autoimmune disease characterized by autoantibodies

(IgG) against glycoprotein llb/IlIa of platelets causing;

o

Affect males.

1. Premature removal & destruction of modified

o

Females are carries.

platelets by spleen 2. jproduction of platelet by (.budding of megakaryocytes

❖ Due to deficiency of factor VIII-C. ❖ There is positive family history

❖ Clinical picture

1. Males: clinical picture of coagulopathy:

1. Presents in 2 forms: A. Acute ITP

B. ChronielTP

o

Age

o Children (2-9 y)

o

20-40 y.

o

Sex

o

o

Females.

o

Course

o Spontaneous

Both sexes,

0

remission in 90%,

Remission & exacerbation.

A. Site of bleeding :

while 10% —> chronic ITP

2. Clinical picture of purpura: A. Site of bleeding : i.

Skin:

Skin: large ecchymosis (in cm) Mucous membrane & orifices:

o Epistaxis, bleeding gums, hemoptysis,

o

Petechiae(< 3 mml:

■ ■ ■ o

Occur in groups in limb or trunk Flat in platelet defect, raised edges in vascular disorder Recent spots are red —> brown —> disappear, Small ecchymosis

ii.

i. ii.

hematemesis, hematuria & hematochezia iii. Internal bleeding: o Intracerebral hemorrhage. o Muscle hematoma, hemarthrosis

o Retroperitoneal hematoma —> calcified hematoma (pseudotumor syndrome) —^ femoral neuropathy

Mucous membrane «& orifices:

o Epistaxis, bleeding gums, hemoptysis, hematemesis, hematuria & hematochezia

B. Characters of bleeding :

iii. B. ❖ o o o

Internal bleeding: intracerebral hemorrhage. 1. Bleeding occurs spontaneous or post traumatic Character : bleeding occurs spontaneously 2. Prolonged bleeding after laceration, circumcision & N.B.: To diagnose ITP there should be: tooth extraction No fever. Normal HSR & serology. 2. Females: No clinical presentation No lymphadenopathy or marked splenomegaly No apparent cause for secondary immune thrombocytopenia e.g. SEE & CLL 3. Clinical picture of the complications e.g. Aeute or chronic post hemorrhagie anemia.

I Platelet count: 20,000 - 100,000 mm^

❖ Investigation 1. Normal platelet count

Prolonged bleeding time, +ve Hess capillary fragility. Normal clotting time, APTT,PT, TT. Microcytic hypochromic anemia from bleeding.

2. Normal bleeding time & Hess capillary fragility test 3. Prolonged clotting time & Prolonged APTT 4. Normal PT,TT.

5. Microcytic hypochromic anemia from bleeding.

Antiplatelet antibodies : antiglycoprotein Ilb/IIIa antibodies positive in 70% of cases BM biopsy: Abundant megakaryocytes with defective budding.

6. Factor Vlll-C level: marked decreased (VIIIVWF is normal)

7. Diagnosis by DNA analysis of villous biopsy.

Treatment:

1) General measures: avoid trauma & antiplatelets drugs 2) Specific measures:

1) General measures: o Avoid trauma & antiplatelets drugs

A. For the ITP:

o o 2) A. o

Antihemophilic globulin: preoperative prophylaxis Hemophilic cards. Specific measures: Replacement of factor VIII : Antihemophilic factor concentrates

o

Fresh frozen Plasma

1. Prednisone 1 mg/kg/day.

2. Immunosuppressive e.g. Azathioprine & Cyclophosphamide 3. Danazol in steroid resistant cases

B. For severe cases i.e. severe bleeding : 1. IV gamma globulin:

o To block Fc receptors in macrophages ^ I removal of platelets

o Cryoprecipitate B. 1 VIII release from endothelium: Desmopressin C. Procedures:

2. Platelet transfusion

1. Minor wounds: local compression

C. Procedures :

2. Hemboarthrosis:

1. Plasmapheresis to remove antibodies. 2. Spleneetomy in steroid resistant cases

o Analgesics & fixation in position of comfort, o Aspiration after giving VIII concentrate, to avoid

ankylosis.

58

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Henoch-Schdnlein purpura (Anaphylactoid Purpura)

Vitamin K dependent factor deficiency e.g. Hypoprothrombinemia Warfarin Oxidized vit K

HCtase Functional form

VltK

prothrombin FVII FIX

Reduced vit

FX

inactive form

prothrombin FVII FIX

FX ^ PlHlToHU.

Etiology:

Physiology of vitamin K :

Allergic form of purpura (type III hypersensitivity), affecting children, usually following streptoeoccal sore throat by 1 -3 week. The reaction involves formation of immune complex (IgA + antigen + complement) Vasculitis (Capillaritis & arteriolitis) ❖

Clinical Picture:

Source:

Vitamin K is present in green leafy vegetables & synthesized by GIT flora (main source). Absorption: It's fat soluble vitamin that needs bile for

absorption. Function;

1.

Purpura:

Carboxylation of factors II, VII, IX, X ^ allows

o

Describe: as IT?

their binding to Ca"^"^'

o

Petechiae mainly on extensor surface of arms, legs &

Etiology of vitamin K Deficiency: I Intake (rare). I flora synthesis:

buttocks. 2. Arthritis:

Periarticular hemorrhage ^ tender, swollen joints. Glomerulonephritis: Nephritic syndrome (only 5-10% ^ CRF). Abdominal pain : Bloody stool due to affection of submucosal intestinal BVs(DD intussusception).

Premature infants.

Investigation:

Liver cell failure.

2.

Normal platelet count Prolonged bleeding time,+ve capillary fragility test.

Clinical Picture:

3.

Normal CT, APTT,PT, TT.

4.

Anemia from bleeding. Renal function: Impaired + RBCs casts.

o

3. o

4. o

1.

5.

Prolonged intake of oral antibiotics. I absorption: Obstructive jaundice. Malabsorption syndrome. I activation: Oral anticoagulants. Clinical picture of coagulopathy D.D. of the cause of hypoprothrombinemia: Vitamin K deficiency corrected by parenteral

❖ Treatment:

vitamin K

1. Corticosteroids.

Liver cell failure not corrected by parenteral

2.

Symptomatic treatment.

vitamin K

Investigations: Normal platelet count Normal bleeding time, Hess capillary fragility test Prolonged clotting time, APTT & PT Treatment:

Vitamin K IM or IV. Plasma transfusion.

Treatment of cause e.g. stop oral anticoagulants.

59

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Von WilleBrand disease (Vascular hemophilia) ❖ Definition :

o Complex syndrome characterized by deficient formation of all component of factor VIII ❖ Etiology & clinical picture : Deficiency: Bernard-Souiier

syndrome

t

Deficiency: Glanzmann thrombasthenia

Intrinsic Pathway

Platelet

Endothelial damage

T Gpllb-llla complex

Fibrinogen

Activated factor: Pre-kallikrein

12

kallikrein

12a

High molecular weight kininogen* ll-»lla

Endothelium

9

ADR induces

9a

conformational

change

von Willebrand factor

8 + Ca++&PF3

V

Deficiency: von Wiiiebrand

Subendothelium

o

Autosomal dominant disease,

o

Due to defect in VIII:

Common Pathway: 10 —»10a

disease

1. J, VIII-VWF^ i platelets adhesion —» vascular purpura + f bleeding time 2. J,VIII-C ^ ^coagulation ^ hemophilia —Clotting time, f APTT 3. iVIIIAg Investigation:

o Normal platelet count, J, Platelet aggregation, o t Bleeding time and +ve capillary fragility test, o t Clotting time, 1 APTT o

Normal PT & TT

❖ Treatment: as hemophilia A

N.B.: Platelet consumption syndromes include TTP,HUS & DIG.

Hemolytic uremic syndrome(HUS)

Thrombotic thrombocytopenic purpura(TTP)

♦> Etiology /associations : 1. Infection : E.Coli, mycoplasma & viral infection

2. Drugs e.g. Cyclosporin A & oral contraceptive pills 3. Others : pregnancy, sepsis, SEE, malignancy & uremia

❖ Clinical pictnre

1 1. Fever 2, 3.

Thrombocytopenia Microangiopathic hemolytic anemia

4. Renal affection 5. CNS affection

1

❖ Investigations : Thrombocytopenia, anemia & schistoeytes o ± Shiga toxin ❖ Treatment o Supportive treatment

J, ADAMTS13 (J. Von Willebrand cleaving protease) i

1 Plasmapheresis

60

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

1 | I |

Disseminated Intravascular Coagulation(PIC)- Consumption Coagulopathy| i* Definition :inappropriate triggering of coagulation cascade ir- II - maiiiiturn-M

"■

.r.,.[r

■

■ ■ ■■■-■

T

❖ Etiology: 8ifc(iii»m.ri«

White blood cells

1. Obstetric; Amniotic fluid embolism, antepartum hemorrhage, puerperal sepsis & intrauterine fetal death. 2. Organ failure e.g. Liver cell failure 3. Malignancy 4. Major bums

5. Major surgery e.g. lung or hepatic surgery. 6. Massive & incompatible blood transfusion.

7. Massive infection: septic shock and other types of shock 8. M3 AML : promyelocytic leukemia 9. Fat embolism.

❖ Pathogenesis:

Thromboplastin like substance (extrinsic pathway)& direct activation offactor 12 (intrinsic pathway)

Consumption of coagulation factors Consumption of platelet

MAHA

Thrombosis

IZ Bleeding

Secondary activation offibrinolytic system Rasminogen Activation

Fibrin


2 weeks pre-splenectomy Influenza vaccine every winter to prevent secondary bacterial infection

Antibiotics prophylaxis post-splenectomy for two years or until the age of sixteen years old is reached, whichever is longer.

65

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

o

hemorrhage

Acute severe

o

(mention)

Anemia

responding to antibiotics

bacterial infection not

o Neutropenic patient with

contain 10' granulocytes

15 ml/kg, each concentrate

1 day

Stored at 24"C

250 ml

*1* N.B.: alternative strategies for ordinary blood transfusion:

o

Granulocyte

o One unit(concentrate) =

o

C

Stored at 4°

450-330 ml

One unit =

o Each unit will rise Hb by Ig/dl

o

o

o

o

Up to 35 days

Stored at 4° C

450-510 ml

One unit =

Packed RBCs

Up to 42 days

o

o

o

Whole blood ❖ Prenaration

❖ Indications

15ml/kg will rise coagulation activity by 30% (4-6 units)

»:♦ Shelf life: 1 year

Stored at -30° C

One unit = 200 ml

o Coagulopathy o Plasma exchange/ Plasmapheresis

o

o

o

o

Fresh frozen Plasma

Transfusion therapy Platelets

5 days

Stored at 24° C

Dose : 2 pack (=10 units)

VIII & vWF

fibrinogen & 80 lU of factor

Each unit contain 200 mg

1 year

■

■

■

■

ocular surgery

< 100,000/mm^ in CNS or

puncture

< 75,000/mm^ in lumbar

surgeries

< 50,000/mm^ in most

active bleeding

< 10-20,000/mm^ with no

o Bleeding in uremic patients

Used for DIG

o

o Hemophilia A or vWD

o

o

o

ml stored at 30 ° C

o Blood lost during surgery may be collected and re-transfused.

66

B. Donation of 1-2 units of blood immediately before surgery ,then the volume is replaced by fluids (hemodilution)to keep the patient normovolemic.

2. Blood Salvage:

|

o Each pack contain 5 unit (20 ml/unit lOOml/pack) o Thawing plasma to 4° C and removing supematant —>■ 20

Cryoprecipitate

o Thrombocytopenia, If platelets count;

o Each pack will rise platelets by 30,000-60,000/mm3 o Dose : 2 pack (= 12 units)

o

o

o Each pack contain 6 unit (50ml/unit—s- 300ml/pack)

1. Autologous transfusion: it is collection and re-inllision of the patient's own blood or blood components : A. Donation of 3-4 units of blood in the 4- 5 weeks before elective surgery, with iron supplementation therapy

1

1

1 1

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Complications Of Blood Transfusion

I. Immune complications A. Hemolytic reaction :

II. Non immune complications: a) Complications of massive blood transfusion : o Acute intravascular(IgM mediated) hemolysis with 1. Dilutional coagulopathy shock 2. DIG & fibrinolysis o Delayed extravascular(IgG mediated) hemolysis with 3. Cold: Hypothermia unexpected J, of Kb 1. Febrile reaction 2. Urticarial reaction

4. Citrate toxicity leading to hypocalcemia, hypomagnesemia, hypokalemia & metabolic alkalosis 5. Acid base & electrolyte imbalance : Metabolic acidosis & hyperkalemia

3. Anaphylactic reaction

6. Volume overload

B. Non hemolytic reaction :

4. Graf versus host disease

b) Complications of old stored blood :

5. Post transfusion purpura 6. Immune suppression

o Metabolic acidosis & hyperkalemia

7. Transfusion related acute lung injury (non-cardiogenic

c) Infections:

o

pulmonary edema)& ARDS

Micro-embolization.

o Parasites; Malaria, Trypanosomiasis, Toxoplasmosis o Bacterial : gram -t-ve e.g. staphylococcal & gram -ve e.g. citrobacter

o Viral: HBV,HCV,HIV,EBV,CMV,human T cell lymphotropic virus I & 11.

Bone marrow transplantation

Indications:

1. Aplastic anemia

2. Thalassemia major 3. Sickle cell anemia Cortical

4. Leukemia

5. Lymphoma 6. Myelodysplastic syndromes

Spongy bone Marrow

❖ Types: 1. Autologous BMT: BM harvested from the patient during remission and stored 2. Matched donor: BM is obtained by aspiration from iliac crest ❖ Complications : 1. Infections : HSV,CMV,pneumocystis carinii, fungal infections 2. Complications of cytotoxic drugs 3. Recurrence of the original disease Graft versus host disease:

It is due to the cytotoxic activity of donor T lymphocytes which become sensitized to their new host. Types: A. Acute GVHD:

■ It appears 14-21 days after the grafting, it can affect the skin, liver, and gut. ■

It is treated by cyclosporine, methotrexate and steroids.

B

Chronic GVHD:

This may follow acute GVHD,It is similar to connective tissue disease, with rash. It can be treated by steroids and cyclosporine.

67

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Organ involvement in blood diseases

1. CNS:

o Cerebral infarction in sickle cell anemia,

o Hyperviscosity syndrome (sluggish cerebral circulation) o Infiltration of meninges by leukemia and lymphoma. o Thrombophilia^ cerebral infarction, o Cerebral hemorrhage with severe bleeding tendency. 2. CVS:

Hyperdynamic circulation with anemia, o Hypertension with hyperviscosity syndrome, o Myocardial infarction in sickle cell anemia.

o

3. Chest:

o Chest infections with leukemia, lymphoma.

o Acute chest syndrome in sickle cell anemia,

o Pulmonary infiltration in leukaemia and lymphoma. o Thrombophilia leading to pulmonary embolism. 4. GIT:

o GIT lymphoma e.g. MALT o

Hepatosplenomegaly in leukemia and lymphoma.

o Mesenteric occlusion in sickle cell anaemia, o Budd Chiari syndrome in PNH. 5. Kidney:

o Hematuria (leukemia, hemorrhagic diseases) o Glomerulonephritis (anaphylactoid purpura)

o Leukemia, Lymphoma, Sickle cell anemia, multiple myeloma 6. Skin:

o Itching in polycythemia, leukemia, lymphoma & hemolytic anemia, o Leg ulcers in sickle cell anemia.

o Raynaud's phenomenon in waldenstrom's macroglobulinemia o Eruption of purpura, haemophilia. Hematological manifestations of systemic disease

1. CVS:

o Malignant hypertension: microangiopathic hemolytic anemia. 2. Paramalignant syndromes:

o Erythrocytosis with renal cell and hepatic carcinoma, o o o o

Pure red cell aplasia with thymoma. Autoimmune hemolytic anemia with lymphoma or chronic lymphocytic leukemia, Die with malignancy of pancreas and stomach. Thrombocytosis with some malignancies e.g. Hodgkin's lymphoma, lung cancer, ovarian tumours

3. Endocrine:

o Cushing's syndrome Erythrocytosis. o Addison's disease ^ Eosinophilia.

o Hypothyroidism —>■ Anemia of chronic disease, Macrocytosis.

o DM: RBCs deformability, disordered fibrinolysis, increase of platelet aggregation as there is high level of TA2. 4. Rheumatology:

o SEE: autoimmune hemolytic anemia, thrombocytopenia, lymphopenia.

o Rheumatoid disease: anemia of chronic disease, hypersplenism (Felty's syndrome). 5. Hepatic: look chronic liver cell failure 6.

Renal: look chronic renal failure

68

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Topic

Page

Introductioii

1

Fever Of Unknown Origin(FUO)

2

Differential diagnosis of common fever

3

Streptococcal & Staphylococcal infection

4

Enteric Fever: Typhoid fever & Paratyphoid Fever

6

Brucellosis

9

Cholera

11

Infectious Mononucleosis(IMN)

13

Acquired Immune Deficiency Syndrome(AIDS)

15

Malaria

17

Parasitic & helminthic infections

24

Leishmaniasis

25

Antibiotics

26

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Introduction

Normal oral temperature :36.5 - 37.2 "C

Axillary temperature is 0.5 °C lower & anal temperature is 0.5 °C higher. "F(Fahrenheit)=("C x 9/5)+ 32

Normal diurnal variation < 1 °C : lowest in the early morning at 6 am, reaching peak in afternoon at 6 pm, then decreases again, this is due to heat regulating center in the brain Fever : temperature > 37.2 °C am or 37.7 °C pm Grades of temperature : •

Grade

1. Hypothermia

3. Low grade

2. Normal

4. High- grade

fever

• Range o

41"C

Difference between hyperpyrexia & hyperthermia: temperature > 41°C: ❖ Hyperpyrexia

❖ Hyperthermia ❖ Pathogenesis:

o Raised thermostat set-point above normal body temperature

o Normal hypothalamic thermostat setpoint i.e. not mediated by pyrogens o Exogenous heat exposure or Endogenous

then generate heat to achieve these temperature

o Elevated levels of PGE2 in the hypothalamus is the trigger for raising thermostat set-point —> stimuiate vasomotor center: A. 1 heat loss e.g. VC of skin vessels (cold sensation) B. t heat production e.g. shivering

heat production exceeds normal heat loss capacity

A & B —> fever

❖ Etiology : o

Severe infection

o

o CNS hemorrhage

Heat stroke

o Thyrotoxic crisis o Malignant hyperthermia o Malignant neuroleptic syndrome o

Anticholinergics e.g. atropine

❖ Treatment: treatment of the cause +

o Physicai cooling & antipyretics

0 Physical cooling (not antipyretics)

Types of fever: 1. Continuous

2. Remittent

KxicswC,'

"t-

I

r

—

-f" I

!

-"pAijvvkW I

I

I

I

I

I

I

!

I

I

4. Relapsing or cyclic

3. Intermittent or hectic -^•Wvvvv

1. Continuous

• Type

(sustained) • Description o Temperature is always high & daily fluctuations less than

2. Remittent

o Temperature is always high & daily fluctuations o

lEC

o

o o

Viral infection Tuberculosis

o Urinary tract infection

o Temperature falls to normal level once or more

o Empyema o

Pus under tension

0 Short days of fever intercepted by short days of normal temperature.

during the day

more than 1 °C

0 Typhoid Pneumonia

4. Relapsing or cyclic

hectic

1 °C

• Example

3. Intermittent or

o Benign tertian malaria

o

Visceral leishmaniasis

o

Brucellosis,

o Hodgkin's disease (Pel-Ebstein fever)

0 Pyaemia/septicemia

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Fever (Pyrexia) Of Unknown Origin(FUO = PUO) ❖ Definition:

o Fever over 38.38 °C lasting > 3 weeks and in whom the diagnosis cannot be made during at least 1 week of intensive evaluation. ❖ Classification of FUO :

1. Classic

2. Nosocomial

o

o Patient hospitalized

> 38.38 °C

A. Temperature B. Duration

4. HIV associated: HIV 3. Neutropenic infection confirmed (immune deficient)

>3

> 24 hours but no

weeks

o Neutrophil count > 4 weeks for outpatient < 500/mm^

fever on admission C. Evaluation of at least

o

1 week

or

> 3 days for inpatients

o 3 days

❖ Causes : 1. Infections:

Abscesses : hepatic, splenic & perinephric Bacterial: TB,SEE,typhoid, brucellosis, pneumonia & pyelonephritis

2.

Viral: IMN,CMV,AIDS & Hepatitis Protozoal: malaria, amoebic liver abscess & toxoplasmosis Fungal: Moniliasis Immunological & connective tissue disease:

Collagen diseases: rheumatic fever, rheumatoid arthritis , SEE,PAN Granuloma : Sarcoidosis, irritable bowel disease e.g. Crohn's disease & ulcerative colitis 3.

Malignancy:

Blood malignancies :lymphoma & leukemia Solid malignancies : Cancer kidney, liver, pancreas, GIT & lung. 4. Miscellaneous:

a) Pulmonary emboli b) Penicillins, sulphonamides & barbiturates c) Psychogenic fever: factitious fever & habitual hyperthermia d) Periodic fever: FME, autoimmune thyroiditis, pheochromocytoma, & cyclic neutropenia 5. Undiagnosed.

❖ Diagnosis : 1. o o o o

History : Personal history e.g. tricuspid endocarditis in IV drug abusers Complaint e.g. cardiac symptoms : infective endocarditis Past history e.g. Recent operations : intra abdominal abscesses Family history: Familial Mediterranean fever

2. Examination :

o LN: leukemia & lymphoma o

o

Chest: TB CVS: infective endocarditis

3. o o o o 4.

Laboratory investigations: Blood picture e.g. monocytosis & lymphocytosis in IMN Blood chemistry e.g. liver function tests in liver disease Immunological tests e.g. connective tissue disorders Serology e.g. For EBV Imaging: Chest X-ray, ultrasound, MRl,CT & radioactive studies

5. Biopsies: BM,LN & any suspected lesion e.g. liver. 6. Therapeutic tests e.g. Aspirin for rheumatic fever . 7. Exploratory laparotomy.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis of common fever ❖ Fever with rash :

❖ Fever with specific rash: exanthematous fever

❖ Fever with non-specific rash

1. Varicella zoster virus

1. SBE & rheumatic fever.

2. Scarlet fever

2. 3. 4. 5.

3. Small Box

4. Measles

5. Typhus 6. Typhoid fever

Syphilis (secondary). Skin disease: serum sickness, drug eruption. Skin bleeding: purpura, leukemia. Meningococcal meningitis

Fever with rigors: ❖ Infections:

❖ Reactions:

1. Amebic hepatitis, Acute pyelonephritis 1. Pyogenic reaction 2. Abscess, Pyaemia, Septicemia 2. Hemolytic crisis 3. Brucellosis & Malaria

3. Charcot's fever

Fever with arthritis :

1. Septic arthritis

2. Reactive arthritis (Reiter's arthritis)

3. Collagen & autoimmune : rheumatic fever, rheumatoid arthritis, SLE Fever with sore throat:

1. Local infection e.g.

o Tonsillitis, pharyngitis (Abscess,IB, malignant ulcers), Vincent angina (Fusospirochetal infection) 2. Specific infection e.g. diphtheria, IMN & scarlet fever

3. Blood diseases: aplastic anemia, leukemia , granulocytopenia & hypersplenism Fever with relative bradycardia:

o Any fever is associated with an increase in heart rate by 10 beats / minute for every 1 °C rise of temperature . o Some fever are associated with lower rise of pulse i.e. tachycardia not matching the degree offever as: A. Specific fevers:

B. CNS lesion with increased intracranial tension :

1. Typhoid fever 1. Brain abscess 2. Fever with obstructive jaundice (Charcot's fever) 2. Pontine hemorrhage 3. Viral infections e.g. influenza, yellow fever, mumps, 3. Malignancy 4. Meningitis infective hepatitis , atypical pneumonia

❖ Fever with jaundice: A. Fever with hemolytic jaundice

B. Fever with hepatocellular jaundice

C. Fever with obstructive jaundice

❖ Any hemolytic crisis is

1. Infection: viral hepatitis, IMN, yellow fever & septicemia 2. Drug hepatitis

2. Calcular cholecystitis 3. Cancer head pancreas

3. Liver cirrhosis

4. Secondaries in liver

associated with fever e.g. 1. Blood disease: o PNH with infection

1. Charcot's fever

o G6PD deficiency with infection o

Sickle cell anemia with infection

o

Thalassemia with transfusion reaction

2. Malaria

3. Pulmonary infarction

Fever with lymphadenopathy & splenomegaly: see hematology book.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

INFECTIONS

I- Bacterial infections;

❖ Streptococcal infection, Staphylococcal infection, Salmonella, Brucellosis & Cholera. 1. Streptococcal infection: Beta Hcmolytic Streptococci A. Group A Streptococcus : Streptococcus pyogenes I

1.

Localized infections:

Pharyngitis (sore throat, tonsillitis) the commonest

Alpha Hemolytic Streptococci a. Viridans Streptococci: o

Dental caries.

o Subacute bacterial endocarditis(SBE)

infection. 2.

Scarlet fever caused by streptococcal pyrogenic exotoxins A (erythrogenic).

3. Skin and soft tissue infections:

Impetigo (pyoderma).

•

Cellulitis.

Erysipelas.

•

II

1.

Invasive infections:

Puerperal fever.

2. Acute endocarditis. 3.

4.

Necrotizing fasciitis caused by Streptococcal pyrogenic exotoxins B (protease)(flesh-eating bacteria). Toxic shock syndrome caused by Streptococcal pyrogenic exotoxins A,B «& C.

N.B.: Post-Streptococcal Sequelae : Acute Rheumatic Fever and Acute Glomerulonephritis B. Group B Streptococcus: Streptococcus agalactiae

Neonatal sepsis which may manifest as pneumonia, septicemia and meningitis Infections in adults e.g. pneumonia and endocarditis

b. Streptococcus pneumonia: pneumococci o Pneumonia, meningitis and otitis media o Sinusitis, conjunctivitis, endocarditis and septic pericarditis may also occur.

2. Staphylococcal infection:

1. Coagulase Positive Staphylococci: Staphylococcus Aureus A. Pyogenic diseases: a. Localized skin infections, the most common: o ■ Folliculitis, furuncles, carbuncles, or abscesses Surgical site infections.

Traumatic wound infections following skin injury and bums. Staphylococcal pneumonia is a complication of prior viral infections e.g. influenza. Invasive conditions occur in immunocompromised patients ending by hacteremia & septicemia leading to deep infections e.g. osteomyelitis, endocarditis and meningitis.

II. Coagulasc Negative Staphylococci Staphylococcus epidermidis: Opportunistic pathogen associated with: Device related infections e.g., catheter related sepsis, prosthetic valve endocarditis, prosthetic joints and shunt infections, ■ Urinary tract and surgical wound infections h. Staphylococcus saprophyticus:

o Urinary tract infections: honeymoon cystitis (endogenous infection)

Toxin mediated diseases:

Staphylococcal food poisoning caused by enterotoxins(A, B, C, D,E and G)

Toxic shock syndrome caused by toxic shock syndrome toxin-1 Staphylococcal scalded skin syndrome caused by exfoliatin toxins.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. Salmonella

o Salmonella are commonly found in the intestinal tract of mammals, birds particularly poultry and reptiles, o Salmonella is a genus of gram-negative bacteria of the family enterobacteriaceae. Clinical classifications:

I.

Typhoidal species:

o Salmonella Typhi that causes typhoid fever.

o S. Paratyphi A, S. Paratyphi B and S. Paratyphi C that cause paratyphoid fever. II.

Nontyphoidal species:

o S. Enteritidis and S. Typhimurium that cause enterocolitis. o S. Choleraesuis that causes septicaemia and metastatic infections Clinical presentation: o Salmonella Food Poisoning, Septicemia & Chronic salmonellosis. o Enteric Fever: Typhoid fever & Paratyphoid Fever

Salmonella Food Poisoning (Gastroenteritis or Enterocolitis) Infection caused by S. Enteritidis and S. Typhimurium. Pathogenesis : Mode of transmission :

'Jl%r

Food of animal and poultry origins (particularly raw eggs).

■/•il r

Water or food contaminated with rat excreta.

The incubation period is 8-48 hours. Symptoms: Fever, nausea, vomiting, severe diarrhea, and abdominal cramps. The condition is usually self-limited, lasting only for few days. Diagnosis by isolation of the organism from stools. Treatment:

Correction of dehydration and electrolyte imbalance. Antibiotic therapy Septicemia

Infection caused by S. Choleraesuis, usually occurs in immunocompromised. Symptoms :

Bacteremia results in metastatic infections such as osteomyelitis, arthritis, pneumonia, meningitis & mycotic aneurysm

Prolonged bacteremia for months in patients with hepatosplenic bilharziasis & AIDS Diagnosis: Blood culture or form localized infection Treatment: as enteric fever ± treatment of bilharziasis Chronic salmonellosis

Occur in patients with active bilharziasis, salmonella lives on the surface of bilharzial cutis Clinically: hepatosplenomegaly & prolonged fever for months (fever of unknown origin) Investigations : ■

For salmonella : blood culture

■

For bilharziasis: urine, stool & ELISA

Treatment: alternating course of chloramphenicol and praziquantel.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Enteric Fever: Typhoid fever & Paratyphoid Fever Etiology: A. Causative organism:

■ ■

Typhoid fever : salmonella typhi Paratyphoid Fever : salmonella paratyphi A,B & C

B. Source of infection: patient or carrier (gall bladder, intestinal or urinary carrier)| C. Mode of infection: feco-oral route, through contaminated food or water. D. Incubation period: 1- 4 weeks

Ulceration

of Peyer's patches

Pathogenesis :

Intestinal Perforation

Organism multiplies in small intestine, penetrate mucosa to reach intestinal lymphatic (Peyer's patches) to be carried to the blood stream causing initial transient bacteremia & is terminated by ingestion of bacilli by cells of reticuloendothelial system.

After intracellular multiplication of viable bacilli, they reenter the blood stream, producing a continuous bacteremia for days or weeks.

The reappearance of bacteremia coincides with the onset of clinical picture & the organism settle in various body systems

Clinical picture : First week:

2"** week:

-ft \ ' /

■m

-H -f-i

-H

/'I ! i

o o

i

i

;

h'" jH"ji 'rii i,ji|i,|„ !

]

;

:

i

M

r ■

1

:

Age: common in young age (children & adults) The course is divided into 4 stages:

A. General

1.

1*" week

2. 2"'' week

3. 3'^'' week

4. 4"" week

o

Severe headache, malaise & body

0

o

o

ache o

Sore throat

o

Coated tongue

o

Cough (dry)

C. Pulse

o o o

Step ladder rise of temperature Higher in evening reaching 40° c Relative bradycardia is

D. Abdomen

o

o o

B. Fever

headache

0

o

Drowsiness, apathy Delirium (status typhosus) High continuous fever

0

Tachycardia (toxic myocarditis)

Anorexia, Pain

0

Distention

Constipation rather than diarrhea Splenic enlargement (soft, tender) at end of the P' week Rosy red papules (10 %): rash mainly in chest, abdominal & back

o

Diarrhea (pea soup) More splenic enlargement

characteristic

o

Disappearance of

o

Clinical

improvement

Resolution of

or

symptoms

Complications

but

occur

Relapses

(dangerous week)

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

may occur

(10%)

Clinical variants:

1. Mild form: abortive.

2. Ambulatory form: patient does not feel the disease in 1®* week. 3. Afebrile form : absence of fever

4. Grave form : with severe nervous form

5. Sudoral form : with excessive sweating resembling malaria

6. Localized form : Pneumo-typhoid, pleuro-typhoid & meningo-typhoid. Complications: Necrotic and

hemorrhagic intestine,

peritonitis

1. Relapses:in 10% of cases 2. Carriers:fecal, in GB with stones, urinary bladder with bilharziasis 3. Local complications; GIT:

o Intestinal hemorrhage : pain, bloody stool, hypothermia, hypotension with tachycardia & leukocytosis o Perforation with subsequent peritonitis 4. Systemic complications :toxemia - organ localization:

Mr A. CNS:

o o B. C.

Meningoencephalitis Status typhosus : delirium with confusion, convulsion, coma CVS: toxic pericarditis & myocarditis Chest: bronchitis, pneumonia, epistaxis

D. Blood :anemia due to ; o

Toxic inhibition of BM

o Chronic variant causes iron deficiency anemia & anemia of chronic disease o Drug induced : chloramphenicol E. Renal: pyelonephritis, cystitis F. Musculoskeletal system: hyaline degeneration of muscles, periostitis, spondylitis, typhoid spine

N.B.: Paratyphoid Fever differs from typhoid fever in ; 1. Usually milder : fever shorter & more irregular 2. Usually insidious onset, maybe acute with marked abdominal pain, nausea, vomiting & diarrhea 3. Headache & Skin rash are prominent 4. Complications & toxemia are rare 5. Widal test is positive for A,B,C antigens

❖ Differential diagnosis o

FUO

o Fever with splenomegaly

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

*t* Investigations: A. Blood picture: o

Anemia

o Leucopenia with relative lymphocytosis o Leukocytosis denotes hemorrhage or intestinal perforation B. Culture : 1. Blood culture

2. Stool culture

3. Urine culture

o

o

o

+ve in 1st week

-l-ve in 2"'' week

+ve in 3'''' week

C. Serologic test: Widal agglutination test: agglutination test for diagnosis of salmonella infection:

Salmonella antigens: somatic antigen(O) Flagellar antigen(H) Virulence or capsular antigen (Vi)

1. Principle:

1/80

1/160

1/640

o To measure the titre of antibodies directed against salmonella antigens 2. Antibodies :

o

Anti O antibodies: indicate recent infection or active infection,

o Anti Vi antibodies: it is the last to rise and its persistence denotes carrier status. o Anti H antibodies to detect the type of infection either salmonella typhi or salmonella paratyphi A,B & C 3. Results : A. Positive :

o The test is positive from the 2"^ week. o Titre is positive if it is > 1/80 or with four fold increase in the titre in sequential blood samples. B. False positive test may occur with: o

Previous salmonella infection & vaccination.

o Anamnestic reaction :improper antibody response to non-related antigen caused by febrile illness causing sharp rise of H antibody and low O titre ❖ Treatment:

I.

Prophylactic :

1. Hygienic measures to control feco-oral infections 2. Isolation of patients

3. TAB vaccine: A heat killed vaccine containing S. Typhi, S. Paratyphi A and S. Paratyphi B. 4. Treatment of carriers by Ciprofloxacin & Cholecystectomy II.

Therapeutic:

A. General: bed rest & light diet B. Symptomatic: o Fever: antipyretics o Headache: analgesics o Constipation: enema o Diarrhea: loperamide o Hemorrhage : blood transfusion & antishock measures o Perforation: surgical treatment C. Specific :

1. Ciprofloxacin (of choice): 500 mg 712 hour for 10 days 2. Cotrimoxazole : 2 tablets twice daily for 2 weeks 3. Chloramphenicol: 50 mg/ kg/ day till temperature drops, then give '/2 dose & continue for 2 weeks 4. Ampicillin 100 mg/ kg/ day for 2 weeks 5. Corticosteroids in severe toxemia

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

4. Brucellosis: Mediterranean fever, Malta fever, Undulant fever

❖ Etiology: A. Causative organism : gram -ve coccobacilli transmitted from animals B. Source of infection: zoonotic disease o

Brucella abortus from cattle

o Brucella canis from dogs o Brucella suis from pigs o Brucella melitensis from sheep and goats. C. Mode of infection:

o Ingestion of infected milk or cheese from infected animals

o Skin contact with infected meat or placenta of aborted animals o Inhalation of infected aerosol during handling of infected animals or brucella cultures in the laboratories. D. Incubation period : 1-2 weeks but may be months

❖ Pathogenesis :

o After entry, organism spread via lymphatic to regional LN & via blood to RES as BM,liver, spleen & other organs as kidneys, bones & endocardium,

o Brucella multiply intracellular forming characteristic granulomas which either suppurate with abscess formation (as in B. melitensis & suis) or heal by fibrosis & calcification. ❖ Clinical picture :

37.0

1. 2. o 3. o o o 4.

Onset: Acute or gradual Temperature: undulant fever : High fever (39-40° C)lasts for 1-3 weeks and then apyrexia for 10 days and then relapses and so on. Constitutional symptoms : Profuse sweating Bony pains, arthralgia & myalgia, Headache, anorexia, malaise & loss of weight Major symptoms with minimal signs: 10-20 % of cases A. Lymphadenopathy B. Hepatosplenomegaly *X* Clinical variants:

1. Acute brucellosis:

o Undulant type o Intermittent: evening fever and sweat with normal morning temperature o Continues fever type: fever lasts for 1 -3 month 2. Chronic brucellosis :

o o 3. 4. 5.

Defined as ill health for > 1 year following onset of brucellosis, They are either patients with relapsing illness or with organ localization . Localized brucellosis with systemic complication (septicemia). Mild ambulatory type

Malignant type marked toxicity with severe complications

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Complications:

1. CNS: meningoencephalitis, myelitis, radiculitis, neuropathy 2. 3. 4. 5. 6.

CVS: bacterial endocarditis (the commonest cause of death) Chest: pleura! effusion & pneumonia Abdomen: Splenic abscess

Genitourinary:renal infection, prostatitis & epididymo-orchitis. Musculoskeletal: Arthritis & osteomyelitis. Differential diagnosis :

o

FUO

o Fever with splenomegaly, lymphadenopathy o

Rheumatic fever

Investigations: A. Blood picture: o

Anemia

o Leucopenia with relative lymphocytosis or monocytosis B. Blood culture :

o +ve in P' week but rarely done because risk of infection by inhalation & long incubation . C. Serologic test:

1. Brucella agglutination test +ve from 2"^ week: o Titre is positive if it is > 1/160 or with four fold increase in the titre in sequential blood samples. 2. Brucella immunoglobulin (IgM & IgG)by ELIZA 3. t Serum Ig M: by extraction with 2-mercaptoethanol, absent in patient cure D. Others: BM culture, LN biopsy, splenic puncture

Treatment:

I. II.

Prophylactic: hygienic measures to control infections Therapeutic:

A. General: bed rest & light diet B. Symptomatic : Fever : antipyretic & Fleadache: analgesics C. Specific: antibiotics 1. P'Regimen: o Doxycycline 200mg/day orally for 6 weeks with

2. 2"'' Regimen: o Tetracycline 2 gm /day orally for 6 weeks with

rifampicin 900 mg /day orally for 6 weeks

streptomycin 1 gm/day IM for first two weeks

10

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

5. Cholera

Etiology: A. Causative organism o Gram -ve bacilli with curved motile flagella o Species : 1. Vibrio cholerae is the most clinically important species:

2. B.

C. D.

There are two serogroups of vibrio cholera causing epidemic human disease: 01 & 0139. Serogroup 01 has two main biotypes : classical & El Tor biotype Other important species are V. parabaemolyticus and V. vulnificus Source of infection: patients and carrier Mode of infection: feco-oral route, through contaminated food or water. Incubation period: from hours up to 5 days Patbogenesis

A subunit 8 subunit

jChdera toxin a-

Ganglioside Receptor ^

Epithelial Cell

G-Protein

Protein kinase

activation

6-protein-* cvdase

Organisms proliferate in intestinal lumen & secrete powerful exotoxin (enterotoxin)formed of A & B subunits B units binds to ganglioside receptor in the intestinal mucosa without penetration. A subunit enter intestinal epithelial cells then activates adenyl cyclase of intestinal mucosa with formation of excessive cyclic AMP.

This causes massive secretion of electrolytes (Na"^, K , Cl", and HCO3')and water into the lumen of the small intestine causing profuse diarrhea & dehydration. Clinical picture : phases: 1. Evacuation phase: A. Diarrhea : ■

Acute onset

■ ■ ■

Profuse up to 1 litter / hour. Painless, effortless, frequent up to 25 time /day. Character: rice watery stool: containing fluid, mucosal tissue vibrio cholera, floating in watery stool but

B.

Vomiting characterized by large volume, effortless & explosive.

2.

Collapse phase : if no treatment Dehydration : Signs of dehydration : Sunken eye, dry tongue & dry inelastic skin

without fecal matter.

A.

Hypothermia, hypotension with rapid pulse & decrease urine output. B. Coma & death : ■

3.

Occur if the patient is not treated due to hypovolemic shock & acute renal failure. Recovery phase : clinical & biochemical parameters return to normal i* Clinical variants: Cholera sicca:

o Ileus & abdominal distention with massive outpouring of fluids & electrolytes into dilated intestinjd loops without vomiting or diarrhea, o Fatal out come since it is not easily diagnosed.

11

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

*1* Complications :

o Hypo-electrolytes e.g. hypokalemia o Hypovolemic shock o

Acute renal failure

Differential diagnosis: From other causes of acute diarrhea especially : 1.

Food poisoning:

o Vomiting before diarrhea, o Diarrhea is painful & there is fecal matter in stool.

Baciliary dysentery:fever, tenesmus, blood & mucus in stools Others: arsenical poisoning & malignant malaria.

Investigations: | ❖ Stool analysis to detect the organism:

1. Freshly passed stool: rapidly motile curved flagellated organism

2. Immobilization: by vibro antiserum using dark field microscope or using immunofluorescence 3. Culture:

o In peptone water & subculture on alkaline agar or TCBS (Thiosulfate-citrate bile salt-sucrose) o

Colonies occur within 24 hours.

Treatment:

I.

Prophylactic

1. Hygienic measures to control feco-oral infections 2. Isolation of patients 3. Cholera vaccine

4. Treatment of carriers: treatment by tetracycline 11.

Therapeutic:

A. General: bed rest & light diet after stopping of vomiting

0

B. Symptomatic :

1. Fluid & electrolytes replacement either intravenously or orally. 2. Antidiarrheal drug: Loperamide o o

Chlorpromazine is used recently to decrease cAMP

C. Specific : Antibiotics:

o Tetracycline of choice, 2gm single dose o

Ciprofloxacin Igm single dose

o

Cotrimoxazole in children

12

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II- Viral infections: EBV & Retroviruses

1. Epstein-Barr Virus(EBV)

1. 2. 3. 4.

Epstein-Barr Virus(EBV)is a B-iymphotropic human herpes virus, it is associated with Infectious mononucleosis (glandular fever). Oral hairy leukoplakia (seen in AIDS patients) Nasopharyngeal carcinoma. Lymphoma (Hodgkin's, Burkitt's & T-cell)

5. Chronic fatigue syndrome:fatigue or hypersomnia may persist for 6 months Infectious Mononucleosis(IMN): Glandular fever Etiology:

# /

o Acute febrile infection caused by Epstein-Barr Virus o

Mode of infection : droplet infection

o

IP: 4-8 weeks

Anti-vims

antibodies

KAAA

Pathogenesis virus

¥

The vims attacks B cells and leads to polyclonal activation that result in the appearance of antibodies directed against a wide range of self and heteropbile antigens.

Infection of B lymphocytes is followed hy a marked T cell response which is detected as large number of atypical lymphocytes in the peripheral blood IT

Clinical picture :

1. 2. 3. 4.

Constitutional symptoms : fever with maculopapular skin rash , headache, anorexia, malaise Sore throat due to severe pharyngitis Cervical lymphadenopathy which becomes generalized with or without hepatosplenomegaly Clinical course: IMN is self-limiting illness and rarely exceeds 3 weeks.

❖ N.B.: skin rash occurs especially after administration of ampicillin Clinical variants & Complications: 1. CNS:

o o o o 2.

Meningoencephalitis Guillain-Barre syndrome Peripheral neuropathy Bell's palsy CVS : pericarditis, myocarditis

3. Chest: o

Pneumonia

o Airway obstmction from severe pharyngitis o

Peritonsillar abscess

Nasophvyngul Tumor

4. Blood:

o Autoimmune hemolytic anemia, thrombocytopenia & aplastic anemia

i

5. Abdominal:

o Acute hepatitis & splenic mpture 6. Renal: Acute interstitial nephritis

7. EBV associated complications e.g. nasopharyngeal carcinoma

13

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I

*X* Differential diagnosis:

1. FUO

2. Fever with splenomegaly & lymphadenopathy 3. From other causes of fever with sore throat.

4. From other causes of mononncleosis like syndrome :

o Definition : diseases resembling IMN in clinical picture & investigation except with a negative heterophil antibody o

Causes :

1. The most common causes : cytomegalovirus, toxoplasmosis 2. Other viral: HIV, viral hepatitis, human herpes virus 6

3. Bacterial diseases e.g. infective endocarditis, tuberculosis, brucellosis 4. Lymphoma

5. Drugs: phenytoin & dapsone.

Investigations: 1.

Blood:

Large atypical

Normal

lymphocyte

lymphocyte

1. A high total leucocytic count with predominance of monocytes and atypical lymphocytes (T-cell with atypical morphology; larger, vacuolated with deeper stain) 2. Mild neutropenia & thrombocytopenia 3. ESR is raised

II.

Serological :

1. Anti-EBV antibodies in serum

2. Detection of heterophile antibodies(IgM): COLOR SUOE MONO

X-reactivity >

Patient's blood; IgM against viral antigens

Sheep RBCs

rm

m

Agglutination

A. Paul-Bunnell test: serum of the patient + sheep RBCs —> agglutination B. Monospot slide test (the most reliable):

o Serum of patient + guinea pig kidney + ox red cells on a side III.

agglutination

Others:

1. BM biopsy : to exclude leukemia 2. LN biopsy : to exclude lymphoma 3. Throat swab: to exclude other cause of sore throat.

Treatment:

1. 2. 3. o o ❖

General: bed rest & light diet Symptomatic : Fever : antipyretic & Headache: analgesics Specific : Antiviral treatment: Acyclovir & Alpha-interferon Steroid are indicated in airway obstruction & hemolytic anemia N.B.: Ampicillin is contraindicated (allergy & rash).

14

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

2. Retroviruses

Etiology :

Retroviruses are enveloped positive sense single-stranded RNA viruses that contain the enzyme reverse

transcriptase. This enzyme is responsible for a unique feature of replication not found in other viruses. Important members of Retroviridae family that affect humans are: ❖ Genus ❖ Virus

B. Delta-retrovirus

A. Lenti-virus

• Human immunodeficiency viruses 1 and 2

species

• Human T-lymphotropic virus 1 and 2(HTLV1 and HTLV-2}

(HlV-1 andHlV-2)

Acquired Immune Deficiency Syndrome(AIDS)

Etiology : A. Human immunodeficiency viruses I and 2(HIV-I and HIV-2) B. Mode of transmission:

1. Parenteral transmission: Contaminated blood & IV drug abuse 2. Sexual transmission: hetero & homosexual.

3. Transplacental (vertical) transmission: from infected mother to her child ^ Pathogenesis :

o HIV infects both T & B lymphocytes but has high affinity for CD4 T helper lymphocytes & monocytes o

It binds to CD4 cells & becomes internalized

o o o o

The viral reverse transcriptase uses the virus RNA as a template to form complementary DNA. Viral DNA becomes incorporated into the host DNA,enabling further replication Progression from HIV infection to AIDS occurs at a median of 10 years after infection T helper/ T suppressor ratio is decreased or even inverted (normally 2:1).

o

IP:

■ ■

Early stage : 2-4 weeks Middle stage: 10 years Clinical picture

• The clinical picture of HIV infection can be divided into 3 stages:

I.

Acute (early) stage:

• After an incubation period of2-4 weeks & lasts for 7-10 days. • Acute retroviral syndrome: infectious mononucleosis-like illness: fever with maculopapular skin rash, headache, anorexia, malaise , sore throat with oral ulcers & lymphadenopathy H.

Latent(middle) stage:

• The patient is usually asymptomatic (clinical latency) • The duration of this period may extend up to 10 years HI. Immunodeficiency (late) stage: AIDS • This occurs when CD4 T cell count falls below 200/mm3(normal count: 800-1200/mm3). •

1.

2. 3. 4.

Patients suffer from:

General: FUO,chronic weight loss & diarrhea Generalized lymphadenopathy ± HSM Neurologic manifestations e.g. myopathy & neuropathy Cancers characteristic of AIDS such as Kaposi's sarcoma and certain lymphomas e.g. non-Hodgkin's lymphoma

15

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

5. Opportunistic infections include: .Brain.

A. Fungal infections:

Toxoplasnuxsis(Toxo) Crytococcal ineningisits

• Pneumocystis jiroveci (carinii) ipneumonia • Cryptococcus neoformans: meningitis •

.Eyes. Cytomegalovisus(C.VIV)

Candida albicans: oral thrush

B. Protozoa]: toxoplasmosis

JVluuth and Thn>at

C. Helminthic infection : strongyioides

Candidiasi.s(Yeast)

D. Bacterial infections: tuberculosis

.Lungs.

E. Viral infections: CMV,HSV, VZV

Pmmnocystis carinii pneumonia(PCP) Tuberculosis(TB)

I

Differential diagnosis :

Histoplasmosis Gut

Cytomegalovisus(CMV) Ciyptcsporidiosis Mycobactcrium avium complex(MAC)

1. FUG

2. Fever with splenomegaly & lymphadenopathy 3. From other causes of fever with sore throat.

Skin

4. From other causes of mononucleosis like syndrome

Herpes simplex Shingles

Investigations:

.Genitals-

Genital Herpes Human paillomavirus(HPV) Vaginal Candidiasis (Yeast)

1. Blood:

Leucopenia & absolute lymphocytopenia

o

Decreased or inverted CD4 / CDS ratio

o o

2.

CD4 count: < 200 cells / mm^ Serologic test:

A. Anti-HIV antibodies:by ELISA or Western blot techniques B. HIV viral load :by PCR 3. Others : Imaging :

o Chest X-ray: Pneumocystis carinii pneumonia, TB o

Brain CT: Toxoplasmosis ❖ Treatment: 1.

Prevention of HIV transmission:

o Parenteral transmission: proper selection of donors, screening of donated blood o Screening of pregnant women for HIV o Sexual transmission: sex education, safe sex practices. 11.

o

Prophylaxis against opportunistic infections :

Vaccination against the pneumococci, haemophilus influenza, meningiococci

HI. Therapeutic: A. Symptomatic: 1. Treatment of opportunistic infection e.g. Pneumocystis carinii: Cotrimoxazole (trimethoprim-sulfamethoxazole) 2. Hematopoietic stimulating factors : o Anemia: erythropoietin SC injection o Neutropenia: granulocyte colony stimulating factor(G-CSF)SC injection B. Specific : combined antiretroviral treatment: Cellular ONA

Reverse Uninlegrated

Integral

transcnptase

linear

inhibitors

Reverse

iranscriplase f 11 Genomic RNA Gertomk: RNA

mRNA

Wv

004 molecule

Protea tnhibito

Corecej^t

Mature s, HiV virion

^l^usion/entry ^inhibitors

2.

Nucleoside reverse transcriptase inhibitors e.g. Zidovudine(AZT)& Lamivudine Non-nucleoside reverse transcriptase inhibitors e.g. Nevirapine

3.

Integrase inhibitors e.g. raltegravir

4.

Protease inhibitors e.g. Ritonavir Entry & fusion inhibitors e.g. Enflivirtide.

1.

5.

16

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Ill- Protozoal infections

Malaria

Etiology :

A. Causative organism & incubation period : protozoa: plasmodium ■ 1-2 weeks in Plasmodium oval, plasmodium vivax, plasmodium falciparum ■ 3-6 weeks in plasmodium malaria B. Source of infection : malaria patient C. Mode of infection :

■

The protozoan is transmitted from man to man by the bite offemale anopheles mosquitoes

■

During transfusion of contaminated blood. Life cycle :

salivary gland sporozoite

Liver stage

midgut sporozoite merozoite

Mosquito stage

schizont^.^^

oocyst

^ ookinete

trophozoite

zygote

Blood stage

d9 gametocytes

I.

Sexual phase (in the mosquito):

o Blood ofthe patient contains microgametocytes (male), and macrogametocyte (female) that unites with each other in o

the stomach of the mosquito to form the zygote that changes to ookinete. The Ookinete penetrates the gastric wall and changes to oocyst

o The Oocyst ruptures releasing the sporozoites that migrate to the mosquito salivary gland to be injected into human. II. Asexual phase (in the host): 1. Exo-erythrocytic phase (in the liver):

o The sporozoites enter into liver cells where it undergoes different stages of development to form the merozites that enter the blood stream again. 2. Erythrocytic stage:

o The merozoites invade the RBCs and gives the signet ring to be followed by the trophozoite and then schizont. o This liberates many merozoites which will invade other RBCs. o After several cycles the gametocytes are formed with production of male microgametocytes and female macrogametocyte.

17

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Pathogenesis Vim

RBC wm

1. Rigors & rise of temperature in periodic attacks:

o Due to liberation of merozoites and hem pigments from ruptured RBCs 2. Causes of anemia are :

relesed

A. Rupture of affected RBCs(massive in black water fever) _ B. I Phagocytic activity of RES with sequestration of both non parasitized & parasitized RBC

merozoites

C. Damping of erythropoiesis 3. Thrombocytopenia :

o Results from both splenic pooling & shortened platelet life span 4. Circulatory changes are :

A. Sticky RBCs adhere to vascular endothelium & leads to obstruction of small blood vessels causing tissue anoxia in various organs. B. Hepatic degeneration C. Renal anuria and acute renal failure

D. t Brain capillary permeability with leakage of proteins & fluids in CSF which may end in coma E. Algid Malaria : o Severe shock develops occasionally without apparent cause, may be secondary to gram -ve septicemia

❖ N.B.: Presence of certain red cell abnormalities are capable of limiting the intensity of malaria and even total PROTECTION e.g.

1. Patient with sickle cell trait: tactoid formed during sickling damage parasite as well as it render deformed red cell susceptible to phagocytosis. 2. Patient with thalassemia: maturation of P. falciparum is retarded in patient with HbF 3. Patient with G6PD deficiency: may be related to f susceptibility of such erythrocytes to oxidant damage

❖ Clinical picture 1. Malarial paroxysm in all types except falciparum, typical paroxysm is formed of: ■

A. Cold phase

Phase

merpzolt^s Mechanism

C. Wet(sweating) phase

§

relesed

■

B. Hot phase

o The fever and rigors results from the rupture ofthe RBCs with

o The fever disappears after

liberation of merozoites and the heme pigments. ■

Duration

o

■

Clinically

o Sudden onset of fever (39-

It lasts 20-60 minute

40°C) with rigors, sense of coldness, nausea & vomiting

the end of RBCs rupture

o

It lasts 3-8 hours

o

o

Relief of cold sensation,

o Profuse sweating with rapid fall of temperature & nausea & vomiting stop, but patient is markedly exhausted

o Fever(40-4TC)persists with sense of hotness, nausea & vomiting

It lasts 2-3 hours

2. Abdomen :

■ Spleen is hugely enlarged, soft, tender & prone to rupture ■ Liver may be slightly enlarged & tender 3. Anemia & jaundice 4. Course & fate:

■ ■

The attacks become gradually infrequent denoting disappearance of the parasite from the blood with the termination of the primary attack. Relapses may occur when sporozoites persisting in the liver & reinvade blood stream.

18

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Clinical variants ;

1. Tertian malaria (plasmodium ovale or vivax): o The attacks occur every two days and passes into three phases

o Splenomegaly occurs at the end of the 2""* week 2. Quartan malaria (Plasmodium Malariae):

o The attacks occur every three days and passes into three phases o

The most common cause of transfusion malaria

o Nephritis may occur due to :

• Deposition ofimmune complex (P. Malariae + C3+ IgG or IgM)in the GBM with resulting hematuria (should not be confused with black water fever) 3. Plasmodium Falciparum malaria; A. Ordinary (Uncomplicated)type: L

Phases:

o The attacks occur every two days and passes into three phases but manifestation are more severe: No actual rigors but only chills Hot stage is prolonged Sweating is minimal with marked nausea and vomiting Fever is either continuous, remittent or irregular ii.

Splenomegaly occurs rapidly within one week

B. Pernicious(complicated)type :

Mr 1. Cerebral malaria: severe headache, confusion, convulsion, coma & death. 2. Algid malaria:

o 3. 4. 5.

Severe shock develops occasionally without apparent cause, may be secondary to gram -ve septicemia Respiratory failure Liver cell failure (jaundice) Renal failure may result from:

■ Volume depletion ■ The plugging of blood vessels ■ Immune complex deposition ■ Hemoglobinuria from intravascular hemolysis 6. Hypoglycemia & hyperinsulinemia 7. Placental involvement may lead to spontaneous abortion

t t Normal urine

Haemogloblnuria C. Black water fever: 1 Definition : autoimmune hemolytic anemia leads to intravascular hemolysis of RBCs 2. Etiology: either spontaneously or after quinine therapy. 3. Clinical picture of intravascular hemolysis (see hematology)

Differential diagnosis :

SYRUffI 10X19 Tao

o

FUO

o Fever with rigor,jaundice & splenomegaly

19

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations;

1. Demonstration of parasite: o

Stained blood film

o BM & splenic puncture 2. Blood picture : hemolytic anemia 3. Serologic test: o Indirect immunofluorescense technique : the most specific o Monoclonal antibody & DNA probes.

4. Therapeutic test: fever respond to antimalarial therapy

Treatment:

❖ Species

I.

II.

Prophylaxis:

Therapeutic:

❖ Start one week before traveling to endemic malaria's area & continue for 4

weeks after leaving it o Chloroquine 500 mg /week orally

1. P. Malariae &

sensitive form of P.

Falciparum 2. Hepatic forms of P. Ovale & P. Vivax

3. Cloroquine resistant P. Falciparum

o Chloroquine: Igm —> then 500 mg after 6 hrs —> then 500 mg/day for 2 days orally

o Which persist in liver in the exoerythrocytic stage, are not affected by chloroquine & unless destroyed they will reinvade blood stream producing relapse: ■ Chloroquine(same dose for same regimen)followed by primaquine 15 mg/day for 2 weeks during the last 2 weeks of chloroquine treatment. ❖ Quinine sulphate 650 mg/8hr orally 0 Doxycycline: lOOmg/day for 3 days + one of the following: 0 Mefloquine: 250mg/week 1. Doxycycline: lOOmg/12 hours for 1 week

2. Mefloquine: 1200mg orally onee. 3. Clindamycin: 900mg orally /8hr for 3 days 4. Fansidar (Sulfadoxine and

Pyrimethamine): 500/25mg/12hr for 3-5 days

III. Treatment of complication in P. Falciparum : 1. Hospitalization & care of comatose

2. Treatment of Pernicious (complicated) type: treatment of complications: A. Cerebral malaria :

o Dexamethasone, mannitol, dextran & heparin (low value versus their side effects) o Antibodies which reserve cytoadherence of parasitized RBCs B. Acute renal failure need: dialysis

3. Treatment of black water fever: Stoppage of Quinine, steroids, blood transfusion.

N.B.: Shigelia (bacillary dysentery), amebiasis, bilharziasis: see GIT book.

20

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

1®' week :

Delirium

Drowsiness, apathy

ofheadache

Constipation Splenic o enlargement (soft, tender) o Rosy red papules 3. 3"' week : Clinical improvement or Complications(dangerous week) 4. 4"" week: Resolution ofsymptoms but Relapses may occur(10%)

o

Pain

o

o o

Distention

Diarrhea (pea soup) More splenic enlargement

o

bradycardia Anorexia,

Tachycardia

o

Relative

o

fever

Higher in evening reaching 40°

o

temperature

o

2'"' week :

Disappearanee

(status typhosus) High

2.

continuous

Step ladder

o

o

o

o

rise of

Cough (dry)

o

tongue

Coated

o

headache

Severe

Sore throat

1.

IP: 1-4 weeks

contaminated food or water.

CO:

o

o

4.

■ ■

1.

Bruceliosis IMN AIDS

Clinical picture Evacuation phase: 1.

Constitutional

Cervical

10-20 % of cases

3.

B.

after administration

normal.

21

Recovery phase: clinical & biochemical parameters return to

failure

If the patient is not treated due to hypovolemic shock & acute renal

of ampicillin

output. Coma & death :

occurs especially

N.B.: skin rash

Clinical course:

rapid pulse & decrease urine

Hypothermia, hypotension with

❖

exceeds 3 weeks.

Sunken eye, dry tongue & dry inelastic skin

malaise & loss of

Dehydration :

weight Major symptoms with minimal signs:

A.

IMN is self-limiting illness and rarely

Collapse phase : if no treatment

2.

Bony pains, arthralgia & myalgia Headache, anorexia,

without

hepatosplenomegaly

generalized with or

without fecal matter.

Vomiting : Characterized by large volume, effortless, explosive.

B.

lymphadenopathy

Constitutional

4.

3.

Sore throat

malaise

which becomes

2.

skin rash , headache, anorexia,

symptoms : fever with maculopapular

Profuse (1 litter / hour) Painless, effortless, frequent (25 time /day) Character: rice watery stool: containing fluid, mucosal tissue, vibrio cholera, floating in watery stool but

Acute onset

A. Diarrhea :

I.

Early stage : 2-4

■

illness.

syndrome: IMN like

Acute retroviral

IP: 2-4 weeks

4.

3.

2.

1.

•

•

Hodgkin's lymphoma

sarcoma & non-

Neurologic manifestations e.g. myopathy & neuropathy Malignancy: Kaposi's

HSM

lymphadenopathy ±

Generalized

diarrhea

chronic weight loss &

General: FUO,

Patients suffer from:

200/mm3

CD4 T cell