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OBSTRUCTION SYNDROME POST-TUBERCULOSIS

Created by
Andre Prasetyo Mahesya

1018011109

Perceptor:
dr. Dedy Zairus, Sp.P

CLINICAL WORK OF INTERNAL MEDICINE


SMF PULMONOLOGY
PERIOD DECEMBER 2014 TO MARCH 2015
ABDUL MOELOEK HOSPITAL
BANDAR LAMPUNG

I. PATIENT STATUS

PATIENT IDENTITY
Initial Name

: Ms. E

Sex

: Female

Age

: 44 years old

Nationally

: Indonesia (javanese)

Marital Status

: married

Religion

: Islam

Occupation

: Unemployed

Educational Background

: Senior High School

Address

: Teluk Betung, Lampung

ANAMNESIS
Taken from

: Autoanamnesis

Date

: December, 30st, 2014

Time

: 11.00

Chief Complain

: Out of breath since a week ago

Additional Complaint : Cough with phlegm, since 1 weeks ago, nausea; Emesis; loss of
wheight.
History of The Present Illness :
One weeks ago, patients felt cough with phlegm heavely in debt, and become a shortness of
breath 7 mounth later, the symptom is intermitten. The pleghm was transparant, thick, and
has no blood appearance (-). She has approximately 10 times entered the hospital the same
complaints since last 7 mounts. Another sypmtoms are loss of apetite and loss of wheight
(from 40 kg to 34 kg). Patiens also often nausea, vomiting, and frequent belching. Vomiting is
not much, just like a little fluid out of the stomach, the symptoms is felt afer teh patient eats.
She could have had tuberculosis treatment for 6 months and decleared by doctors completed
in 4 years ago. Patient deny have previous high blood preassure, diabetes melitus, and
asthma. But the Patient was ever smoker before illness.
2

The History of Illness :


(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)

Small pox
Chicken pox
Difthery
Pertusis
Measles
Influenza
Tonsilitis
Kholera
Acute Rheumatoid Fever
Pneumonia
Pleuritic

(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(+)

Malaria
Disentri
Hepatitis
TifusAbdominalis
Skirofula
Siphilis
Gonore
Hipertension.
Ventrikuli Ulcer
Duodeni Ulcer
Gastritis

(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(+)
(-)

Kidney stone
Hernia
Prostat
Melena
Diabetic
Alergy
Tumor
Vaskular Disease
Tuberculosis
Operation

Familys diseases History :


Father still alive, Hipertension.
Mother still alive, Tuberculosis.
Seven siblings still alive, healthy.
Children are still alive, healthy.
Is there any family who suffer :
Her mother suffer with the same symptoms or had been diagnose with tuberculosis.
Her father had been diganose with hipertensian.
SYSTEM ANAMNESE
Note of Positive Complaints beside the title
Skin
(-) Boil

(-)

Hair

(-) Night sweat

(-) Nail

(-)

Yellow /Werus

(-) Cyanotic
(-) Others

Head
(-) Trauma

(-)

Headache

(-) Syncope

(-)

Pain of the sinus

Ear
(-)

Pain

(-) Tinitus

(-)

Secret

(-) Ear disorders


(-) Deafness

Nose
(-) Trauma

(-) Clogging

(-) Pain
(-) Sekret
(-) Epistaksis

(-) Nose disorders


(-) common cold

Mouth
(-) Lip

(-) Dirty Tongue

(-) Gums
(-) Membrane

(-) Mouth disorders


(-) Stomatitis

Throat
(-) Throat Pain

(+) Voice Change

(-) Protruding

(-) Neck Pain

Neck

Cor/ Lung
(-) Chest pain

(+) Dyspneu

(-) Pulse

(-) Hemoptoe

(-) Ortopneu

(+) Cough, with white thick phlegm

Abdomen (Gaster/ Intestine)


(-) Puffing

(-)

Acites

(+)
(+)
(-)
(-)
(-)

(-)
(-)
(-)
(-)
(-)
(-)

Hemoroid
Diarrhea
Melena
Pale colour of feses
Black colour of feses
Nodul

Nausea
Emesis
Hematemesis
Disfagi
Colic

Urogenital
(-) Dysuria

(-)

Pyuria

(-)
(-)
(-)
(-)
(-)
(-)

(-)
(-)
(-)
(-)
(-)
(-)

Kolik
Oliguria
Anuria
Urine retention
Drip urine
Prostat

Stranguria
Polyuria
Polakysuria
Hematuria
Kidney stone
Wet the bed

Katamenis
(-)

Leukorhoe

(-)

Other

(-)

Bleeding

Muscle and Neuron


(-)

Anestesi

(-)

Hard to bite

(-)
(-)
(-)
(-)
(-)

Parestesi
Weak muscle
Afasia
Amnesis
Others

(-)
(-)
(-)
(-)
(-)

Ataksia
Hipo/hiper-estesi
Tick
Vertigo
Disartri

(-)

Convultion

(-)

Syncope

Extremities
(-) Edema

(-)

Deformitas

(-) Hinge pain

(-)

Cyanotic

Weight
Average weight (kg) : 40 kg
Height (cm)

: 166 cm

Present Weight

: 34 kg

(-) steady
(+) down
(-) up

THE HISTORY OF LIFE


Birth place
(-) in home

(-) matrinity

(+) matrinity hospital

Helped by:
(-) Traditional matrinity

(+) Doctor

(-) Nurse

(-) Others

(-) DPT

(-) Polio Tetanus

Imunitation History (Unknown)


(-) Hepatitis

(-) BCG

(-) Campak

Food History
Frequency/day

: 3x/day

Amount/day

: 1 place/eat (health)

Variation/day

: Rice, vegetables, fish

Appetite

: Decrease when sick

Educational
(-) SD

(-) SMP

(+) SMA

(-)SMK

(-) Course Academy

Problem
Financial

: low

Works

: not working

Family

: normal

Others

:-

Body Check Up
General Check Up
Height

: 166 cm

Weight

: 34 kg

Blood Pressure

: 110/70mmHg

Pulse

: 80 x/minute, regular, tense and feeling enough

Temperature

: 36.7 0C

Breath (Frequence&type)

:28x/minute, regular, thorako-abdominal

Nutrition Condition

: low
6

Consciousness

: Compos Mentis

Cyanotic

: (-)

General Edema

: normal

The way of walk

: normal

Mobility

: Active

The age predicyion based on check up

: 50 years old

Mentality Aspects
Behavior

: Normal

Nature of Feeling

: Sad

The thinking of process

: Normal

Skin
Color

: Brown

Keloid

: (-)

Pigmentasi

: (-)

Hair Growth

: Normal, Black, Simetris

Arteries

: Touchable

Touch temperature

: Afrebris

Humid/dry

: Dry

Sweat

: Normal

Turgor

: Normal

Icterus

: An icterus

Fat Layers

: Thin

Efloresensi

: (-)

Edema

: (-)

Others

: (-)

Lymphatic Gland
Submandibula

: no enlargement

Neck

: no enlargement

Supraclavicula

: no enlargement

Armpit

: no enlargement

Head
Face Expression

: Sad

Face Symmetric

: Symmetric

Hair

: Black

Temporal artery

: Normal

Eye
Exopthalmus

: (-)

Enopthalmus

: (-)

Palpebra

: edema (-)/(-)

Lens

: Clear/Clear

Conjunctiva

: Anemis -/-

Visus

: Normal

Sklera

: Icteric -/-

Ear
Deafnes

: (-)

Foramen

: (-)

Membrane tymphani : intact


Obstruction

: (-)

Serumen

: (-)

Bleeding

: (-)

Liquid

: (-)

Mouth
Lip

: (-)

Tonsil

: (-)

Palatal

: Normal

Breath

: No

Teeth

: Caries

Trismus

: (-)

Farings

: Unhiperemis

Liquid Layers

: (-)

Tongue

: Normal
8

Neck
JVP

: Normal, not increased

Tiroid Gland

: no enlargement

Limfe Gland

: no enlargement

Chest
Shape

: not simetric

Artery

: Normal

Breast

: Small

Lung
Inspection

: Left : good breath, no lession


Right : breath left behind, no lession

Palpation

: Left : vokal fremitus normal, pain (-)


Right : vokal fremitus decrease, pain (-)

Percussion

: Left : resonance
Right : dim

Auscultation : Left : bronkial, wheezing (+), ronkhi (+)


Right : bronkial, wheezing (+), ronkhi (+), decreased breath sounds
Cor
Inspection

: Ictus cordis not visible

Palpation

: Ictus Cordis no palpable

Percussion

: top: difficult to determinate


Right: difficult to determinate
Left: difficult to determinate

Auscultation : Heart Sound 1 & 2 Regular, murmur (-), gallop (-). The cor is on the right.
Artery
Temporalic artery

: No aberration

Caritic artery

: No aberration

Brachial artery

: No aberration

Radial artery

: No aberration

Femoral artery

: No aberration
9

Poplitea artery

: No aberration

Posterior tibialis artery

: No aberration

Stomach
Inspection

: flat

Palpation

: Stomach Wall

: undulation (-), pain (-)

Heart

: Hepatomegali (-)

Limfe

: Splenomegali (-)

Kidney

: Ballotement (-)

Percussion

: Shifting Dullness (-)

Auscultation

: Intestine Sounds (+)

Genital (based on indication)


Male

: no indication

Penis

: no indication

Testis

: no indication

Movement Joint
Arm

Right

Left

Muscle

Normal

Normal

Tones

(+)

(+)

Mass

(-)

(-)

Joint

Normal

Normal

Movement

Active

Active

Strength

Heel and Leg


Wound/injury
Varices

: not found
: (-)

Muscle (tones&mass)

: (+)/(-)

Joint

: Normal

Movement

: Active

Strength/Power

:5

Edema

: (-) (pitting edema)

Others

: (-)
10

Reflexs
Right

Left

Tendon Reflex

Normal

Normal

Bisep

Normal

Normal

Trisep

Normal

Normal

Pattela

Normal

Normal

Achiles

Normal

Normal

Cremaster

Normal

Normal

Skin Reflex

Normal

Normal

Patologic Reflex

Not Found

Not Found

Laboratory
Hematology (24-12-2014)

Normal

Haemoglobin

: 12.2 gr/dl

12-16 gr/dl

Leucocyte

: 10.600 /ul

4500-10700 / ul

Basophils

:0%

0-1%

Eusinophils

:0%

1-3%

Bands

:0%

2-6%

Segmens

: 60 %

50-70%

Lymphocytes

: 25 %

20-40%

Monocytes

: 15 %

2-8%

: 277.000 /ul

150.000-400.000/ul

Variety count

Trombocyte

11

Radiology
28-5-2014 AP chest radiograph: destroyed lung dextra, atelektasis, deviasi trachea to the
dextra, cor pushed to the dextra + post TB

24-12-2014 AP chest radiograph: destroyed lung dextra, atelektasis, deviasi trachea to the
dextra, cor pushed to the dextra + post TB

12

Resume
Patient Ms. ER (44th), One weeks ago, patients felt cough with phlegm heavely in debt, and
become a shortness of breath 7 mounth later, the symptom is intermitten. The pleghm was
transparant, thick, and has no blood appearance (-). She has approximately 10 times entered
the hospital the same complaints since last 7 mounts. Another sypmtoms are loss of apetite
and loss of wheight (from 40 kg to 34 kg). Patiens also often nausea, vomiting, and frequent
belching. Vomiting is not much, just like a little fluid out of the stomach, the symptoms is felt
afer ter patient eats. She could have had tuberculosis treatment for 6 months and decleared by
doctors completed in 4 years ago. Patient deny have previous high blood preassure, diabetes
melitus, and asthma. But the Patient was ever smoker before illness.
Working Diagnose
-

Syndrome Obstructive Post Tuberculosis + destroyed lung dextra + Gastroesofageal


Refluks Disease

Basic Diagnose
-

Anamnesa: shortness of breath, cough with phlegm; transparant, thick, blood


appearance (-), loss of apetite and loss of wheight (from 40 kg to 34 kg). Post
treathment tuberculosis.

The sound of breath is not same, breath sound on the dextra is decrease.

BTA (-) in hospital earlier

Vomiting is not much, just like a little fluid and felt after patient eats.

PA chest radiograph: destroyed lung dextra.


Differential Diagnose

Effusion Pleura e.c. Pulmonary TB

Massa pulmo e.c. Carsinoma.


Support Check Up
-

Spirometri

13

Treatment Plan
(1) General Treatment
-

Bed Rest, half sitting.

Nutrition (high calory, high protein)

(2) Special Treatment


-

Medicamentosa

o IVFD RL gtt 20X/minute


o O2 3 liter
o Aminophiline 24 mg/12 hours
o Combivent 8,5ml/8hours nebulizer
o Ambroxol syr 3x1 cth
o Sulcarfat syr 3x1 cth
o Omeprazole tab 2x1
o Aminofluid kolf/day
o Ciprofloxacin 2x1 amp
Prognose
Quo ad Vitam

: Dubia ad malam

Quo ad Functonam

: Dubia ad malam

Quo ad Sanationam

: Dubia ad malam

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II. REVIEW LITERATURE


TUBERCULOSIS
A. Complications of Pulmonary Tuberculosis
Tuberculosis is an ancient disease which continues to be a major health problem in most
developing countries. In developed countries, it is gaining importance with the emergence of
HIV pandemic. Pulmonary tuberculosis (TB) is caused by the bacteria Mycobacterium
tuberculosis. According to the defenses of the host and virulence of the organism tuberculosis
can occur in the lungs or extrapulmonary organs. Various forms of sequelae and
complications may result from primary and post-primary pulmonary tuberculosis in both
treated and untreated patients. Mycobacterium tuberculosis can affect almost every organ in
the body. Major manifestations of the disease usually occur in the lung. Pulmonary
tuberculosis can manifest for the first time as a complication. A variety of complications can
occur in pulmonary tuberculosis. They can be categorized as follows:
Complications of Pulmonary Tuberculosis
Parenchymal lesions
Thin walled cavity (Open negative syndrome)
Aspergilloma
End stage lung destruction
Scar carcinoma
Airway Lesions
Tuberculous Laryngitis
Bronchiectasis
Tracheobronchial stenosis
Anthracofibrosis
Broncholithiasis
Vascular Lesions
Rasmussen aneurysm
Pleural Lesions
Dry pleurisy
Pleural effusion
Empyema & Bronchopleural fistula
Pneumothorax
General Complications
Cor-pulmonale
Secondary amyloidosis
Chronic respiratory failure

Parenchymal lesions
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1.Open Negative Syndrome


Cavitation is a hallmark of pulmonary tuberculosis. Residual thin walled cavities may be seen
in both active and inactive disease. The cavity may disappear after antituberculous
chemotherapy. Occasionally the wall becomes thin and remains as an air filled cystic space
even after a bacteriological cure, when it is called as open negative syndrome. Tuberculous
cavities heal by two processes, open and closed depending on the status of the draining
bronchus. In the open form, the wall of the cavity becomes free of tubercle bacilli with
chemotherapy and wall undergoes fibrosis with subsequent epithelialization. The lumen of
the draining bronchus usually remains patent.

Chest X-ray PA and HRCT Thorax showing right upper lobe thin walled cavity (see arrow marks)

These are thin walled cavities with epithelialization extending from bronchioles. The wall
may be smooth and the thickness varies from 1 cm to less than 1mm. These cavities may be
16

associated with complications such as haemoptysis, secondary infection with pyogenic


organisms resulting in a lung abscess. Aspergilloma can form in a cavity. Rupture of the
cavity can give rise to a spontaneous pneumothorax. Rarely relapse of tuberculosis can occur.
In the closed type, the draining bronchus gets occluded and the cavity undergoes atelectasis
and scar formation.
2 Aspergilloma
The most common cause of human aspergillosis and pulmonary aspergilloma is Aspergillus
fumigatus. Published data indicate that saprophytic colonization of the lung that has been
destroyed by tuberculosis, sarcoidosis, bronchiectasis, lung abscess & neoplasms lead to
intracavitary aspergilloma. Of these tuberculosis is the most common. Most patients are
asymptomatic. Symptomatic patients present with fever, cough and haemoptysis.
Haemoptysis could be life threatening. The source of bleeding is usually the bronchial blood
vessels. Dyspnea, malaise and weight loss may be there due to the underlying pulmonary
disease. Physical examination may be normal or signs of the underlying lung disease may be
present. The diagnosis is based on the characteristic radiological finding. Chest radiography
reveals a mass in a pre existing cavity with a crescent of air outlining the mass called as air
crescent sign (Felson, 1988), seen usually in the upper lobe as shown in the image. CT scan
images provide better definition of the mass within a cavity.

17

Figure 2: Chest X-ray PA and CECT Thorax showing right upper lobe aspergilloma.

Laboratory abnormalities are uncommon. Aspergillus precipitin antibody test for IgG are
usually positive in Aspergilloma. Treatment is considered when patients develop symptoms,
usually presenting as haemoptysis. Bronchial artery embolization may be used for patients
with massive haemoptysis. Prolonged oral itraconazole may provide partial or complete
resolution of aspergillomas in 60% of patients. Itraconazole has a high tissue penetration. In a
small number of patients intracavitary therapy with Amphotericin B has also been used with
some success. Surgical resection is curative and may be considered for patients with recurrent
haemoptysis if the patient has adequate pulmonary reserve.
3 Destroyed Lung
Unilateral destruction of the lung due to tuberculosis has been a recognized entity.
Rajasekaran et al. Analyzed patients with unilateral lung destruction and found pulmonary
tuberculosis as the cause in 83.3% of patients. It may occur after primary disease or
reinfection. Cicatrization atelectasis is a common finding after postprimary tuberculosis.
Marked fibrotic response is seen in up to 40% of patients with post primary tuberculosis.
Reduced lung volume, cavities, bronchiectasis and fibrosis are the predominant findings in
destroyed lungs. Fibrotic response manifests as retraction of the hilum and mediastinal shift
towards the fibrotic lung. Opposite lung will show compensatory hyperinflation. These
patients might seek medical help for the first time for diagnosis or after completion of
treatment or referred as non-responders due to treatment failure.

18

Figure 3: Chest X-ray PA and HRCT Thorax showing destroyed lung on left side with compensatory
hyperinflation on the right side.

Several studies have shown that pulmonary haemodynamics play a part in the pathogenesis
and spread of tuberculous infections. The characteristic localisation of pulmonary
tuberculosis seems to be associated with lymph stasis secondary to reduced arterial flow at
the apex and also with increased oxygen tension at that site. Pulmonary arterial flow is
reduced or absent when there is bronchial obstruction, stasis of secretions, or parenchymal
infection. Ligation of the pulmonary artery of patients and experimental animals with
pulmonary tuberculosis is reported to exacerbate the disease, as does anastomosis of a major
systemic vessel to the pulmonary artery. In our patients angiography showed pulmonary
arterial flow to be absent, bronchial arteries were prominent, and there was radiological
evidence of systemic flow into the pulmonary arterial tree. It seems likely that these factors
led to lymph stasis and a raised oxygen tension, favouring progression of the disease and
eventual lung destruction.

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4 Scar Carcinoma
The development of lung cancer in a pulmonary scar was first described by Friedrich as scar
or cicatricial cancer of the lung. Scar cancers are associated with high incidence of
adenocarcinoma. Ying U et al studied the relationship between lung cancer risks following
detection of pulmonary scarring and found that baseline diagnosis of pulmonary scarring was
associated during subsequent follow up with an increased risk of lung cancer. Lung cancer
occurring in pulmonary tuberculosis patients after completing treatment are mistaken for
relapse. Although the pathogenesis is unclear uncontrolled epithelial hyperplasia in relation to
fibrosis is considered as a possible mechanism. Other possibility is the concentration of
carcinogens by sca. Cigarette smoking contributes to the lung cancer risk associated with
scarring.

Figure 4: Chest X-ray PA view showing the post tubercular scarring in the (R) upper zone.

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Figure 5: Chest X-ray showing the development of complete collapse of (R) lung due to
bronchogenic carcinoma in the same patient.

Vascular Lesions
1 Haemoptysis
Haemoptysis is defined as expectoration of blood originating from the lungs or tracheobronchial tree. Haemoptysis is a common symptom of pulmonary tuberculosis. Haemoptysis
is most commonly associated with cavitary lesions. Changes in the vasculature of tuberculous
lungs are implicated in haemoptysis. Fritz Valdemar Rasmussen, a Danish physician
described the aneurysmal dilatation of pulmonary vessels in the wall of tuberculous cavity as
the cause for haemoptysi. Calmette in 1923 mentioned that branches of pulmonary artery
which traverse the wall of tuberculous cavities contain small pedunculated aneurysms of
Rasmussen. Wood & Miller showed that the wall of tuberculous cavities have dilated
bronchial arteries.
Haemoptysis may occur in the active stage of tuberculosis or as late sequelae, due to
aneurysmalrupture or secondary to bronchiectasis. Aspergillomas can form in pre-existing
cavitary lesions and lead to haemoptysis. Erosion of a blood vessel by a calcified lesion can
also lead to haemoptysis. Definition of massive Haemoptysis is not clear. It can range from
100 milliliters per day to 1000 milliliters over a few days . Massive haemoptysis can be fatal
and lead to asphyxiation. Majority of patients with massive haemoptysis have a poor
pulmonary reserve and are not fit for any surgical procedures. The lungs have a dual blood
supply. The pulmonary arterial circulation is a low pressure system and bronchial arteries, a
high pressure system. The source of massive haemoptysis is most commonly the bronchial
21

circulation (90%) and pulmonary circulation constitutes only 5%. Patients with mild
haemoptysis need a conservative approach. Treatment options available for patients with
massive haemoptysis are endobronchial tamponade, single or double lumen intubation,
bronchial artery embolization, or surgery. Presently, the main life-saving modality used to
control bleeding in massive haemoptysis is angiography and bronchial artery embolization.
Shin et.al, have retrospectively analyzed the outcomes of bronchial artery embolization for
the treatment of haemoptysis in patients with pulmonary tuberculosis and reported 163
patients out of 169 (96.4%) had significant clinical improvement after the procedure.

Figure 6: Chest X-ray PA view showing bilateral cavitary lesions.

Airway Lesions
1 Tuberculous Laryngitis
Laryngeal tuberculosis is usually a complication of pulmonary tuberculosis. The sputum
positive rate is 90-95% in patients with active pulmonary tuberculosis with tuberculous
laryngitis. Clinical features include hoarseness of voice, odynophagia, cough and dysphagia.
The larynx becomes infected either by a direct contact from pulmonary tuberculosis or by a
lymphatic/ hematogenous spread from sites other than lungs. It can manifest as edema,
hyperemia, ulcerative lesion, nodule or an exophytic mass. Most common site is posterior
part of larynx. Laryngeal TB is uncommon in developed countries and authors from
developed countries feel that it should be considered as a differential diagnosis in any
laryngeal disease in particular laryngeal carcinoma. Antituberculous drugs are the primary
treatment for laryngeal tuberculosis. Complications of laryngeal tuberculosis if not treated
early can result in subglottic stenosis and vocal cord paralysis.

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2 Bronchiectasis
Bronchiectasis is an abnormal and permanent dilatation of bronchi. Tuberculosis is a major
cause of bronchiectasis worldwide. Bronchiectasis may be present in various stages of
pulmonary tuberculosis. Bronchiectasis is seen in 30% -60% of patients suffering from active
post primary tuberculosis. Various factors may cause bronchiectasis in pulmonary
tuberculosis, mainly atelectasis and pulmonary fibrosis. Bronchial stenosis as a consequence
of tuberculous inflammation and scarring of the bronchi can lead to retention of secretions.
When this is followed by bacterial infection it can lead to destruction and dilatation of the
airways. Compression of the bronchi by enlarged lymph nodes produces consequences
similar to intraluminal obstruction. Bronchiectasis may follow as sequelae of healing of
pulmonary tuberculosis. Fibrosis of lung parenchyma can lead to bronchial dilatation.
Parenchymal retraction due to fibrosis can also cause bronchial dilatation and bronchiectasis.
Three types of bronchiectasis have been described, cylindrical bronchiectasis wherein the
involved bronchi appear uniformly dilated, varicose bronchiectasis, where the affected
bronchi have a beaded pattern of dilatation resembling varicose veins, saccular (cystic)
bronchiectasis which shows ballooned appearance of the bronchi ending in blind sacs.
In adults tuberculosis usually occurs in the upper lobes. Other infections often involve
dependent parts of the lungs. When upper lobes are involved secretions are drained and
superinfection with pyogenic organisms does not usually occur. This is known as dry
bronchiectasis or bronchiectasis sicca. Bronchiectasis in the apical and posterior segments of
the upper lobe is highly suggestive of tuberculous etiology. The main complaints are
persistent or recurrent cough, purulent sputum, haemoptysis, dyspnea, wheezing, fatigue,
fever and failure to thrive. Haemoptysis is a common symptom in 50 70% of cases of
bronchiectasis and is more common in dry bronchiectasis. On physical examination, clubbing
may be present. Coarse crepitation and rhonchi may be heard over the area of bronchiectasis.
Chest radiograph may show nonspecific findings. The definitive diagnosis is made by
thoracic CT. HRCT has replaced lipiodol bronchography to establish the presence, severity
and distribution of bronchiectasis. HRCT has only 2% false negative and a 1% false positive
rate. It is a noninvasive investigation.

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Figure 7: Chest X-ray PA and HRCT Thorax showing right upper lobe bronchiectasis.

Management may be medical or surgical. Medical management is with antibiotics and chest
physiotherapy. If the lesion is localized to a resectable area and the medical management
fails, elective surgery is indicated.
3 Broncholithiasis
The presence of calcified lymph node masses within the bronchi is referred as
broncholithiasis. This is an uncommon complication of pulmonary tuberculosis.
Broncholithiasis is caused commonly by erosion and extrusion of a calcified adjacent lymph
node into the bronchial lumen. Symptoms may include cough, haemoptysis, lithoptysis or
symptoms related to bronchial obstruction. Chest radiography often does not show the
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calcification within the bronchus. CT usually provides useful information. Radiologic


findings include calcified
peribronchial nodes. In addition to this there may be segmental or lobar atelectasis,
obstructive pneumonitis and rarely focal hyperinflation. If a broncholith is free completely
within the bronchus, it can be removed bronchoscopically. Most of the symptomatic
broncholiths should be removed at thoracotomy by lobectomy or segmentectomy.
4 Tracheobronchial stenosis
The most common cause of benign tracheobronchial stenosis is endobronchial tuberculosis in
Asian countries. Endobronchial tuberculosis is caused either by direct inoculation of the
bacilli from the lung parenchymal lesions or by infiltration of the airway by bacilli from
adjacent

mediastinal

lymph

nodes.

Despite

adequate

anti-tuberculosis

treatment

endobronchial tuberculosis can result in major airway obstruction from stenosis. Studies have
found predominance in the female sex. Significant bronchial stenosis of major bronchi is rare.
Left main bronchus is the common site of stenosis. This could be because the left main stem
bronchus is easily compressed by the arch of the aorta and lymph node TB is also more often
noted on the left side. CT scans show concentric narrowing of the lumen, uniform thickening
of the wall and long bronchial segment involvement. Flexible bronchoscopy is the most
useful modality for diagnosis and assessment of tracheobronchial stenosis. Minimally
invasive endoscopic techniques such as balloon dilation, Nd YAG laser therapy and tracheobronchial stent placement are used to establish patency. The use of silicone stents could
provide an effective means of managing PTTS patients. In subjects not responding to
interventional bronchoscopic treatment surgical resection may be indicated.
5 Anthracofibrosis
Anthracofibrosis is bronchial stenosis due to local mucosal fibrosis that also presents
anthracotic pigment in the mucosa. The exact cause has not been well defined. There is a
frequent association with tuberculosis and exposure to smoke from biofuel or biomass
combustion. It is a bronchoscopic finding. Hwang J. et al have studied the frequency of
anthracofibrosis in foreign born Pulmonary TB patients in Canada. According to them
patients from the Indian subcontinent were more likely to have anthracofibrosis compared to
patients from other Asian countries. Most of the patients present with cough, sputum and
dyspnea. CT and bronchoscopy has to be done to exclude bronchogenic carcinoma if chest
radiographs show segmental or lobar atelectasis.
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Pleural Lesions
1 Pleural Effusion
Inflammation of the pleura is called as pleurisy and when fluid accumulates in the pleural
cavity, it is called as pleural effusion. Tuberculous pleural effusion remains as the leading
inflammatory pleural disease in countries where tuberculosis is more common. Although
tuberculosis is considered as a chronic illness, tuberculous pleuritis can present as an acute
illness of less than 1 week duration. In USA, 2% of all effusions are attributed to
tuberculosis. In children, effusion may occur as part of primary tuberculosis. It also occurs
with increased frequency in middle-aged and elderly people. Pleural effusion usually occurs
3-6 months after the primary infection. It occurs when the subpleural parenchymal focus or a
caseating lymph node ruptures into the pleural space. Delayed hypersensitivity plays an
important role in tuberculous pleural effusion. Direct contiguous spread to the pleura or
haematogenous spread can also lead to pleural effusion. The usual presenting symptoms are
non-productive cough, fever, pleuritic chest pain and breathlessness in most patients. Patients
with chronic infection present frequently with weight loss, malaise and dyspnea. Physical
findings reveal dullness on percussion and absence of breath sounds. Tuberculous pleural
effusions are usually unilateral and in approximately one-third of patients co-existing
parenchymal disease is seen radiologically. Pleural effusions generally appear as dense
homogeneous opacities. Chest radiograph will show blunting of the costophrenic angle with
small quantities of free pleural fluid. Ultrasonography of the chest detects smaller effusions.
Tuberculous pleural effusion is often unilateral and occupies about one-third to half of the
hemithorax. Radiologically, it appears as a lateral opacity concave medially extending
upwards in the axilla with the base obscuring the hemidiaphragm. It can also present rarely as
massive pleural effusion obscuring the whole hemithorax and displacing the mediastinum to
the opposite side. Sub-pulmonic effusions may present with fluid collection below the
diaphragm in some patients.

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Figure 8: Chest X-ray PA view showing massive left pleural effusion.


A tuberculous pleural effusion is usually a serous exudate with high protein level (>4 gm/ml).
The fluid is defined as an exudate if it fulfils one of the Lights criteria such as pleural /serum
ratio of total protein >0.5, pleural/serum ratio of LDH >0.6,or LDH greater than 2/3 of the
upper limit of serum value.
Adenosine deaminase (ADA) level greater than 70 IU/L has been shown to be highly
sensitive and spe cific for the diagnosis of tuberculous pleural effusion. Increased ADA levels
have also been found in malignancy or empyema. Low glucose (<60 mg/ml) and low pH
(<7.30) are found in approximately 20% of patients. Analysis of the pleural fluid for
differential cell count shows predominance of lymphocytes in tuberculous pleural effusion.
Pleural fluid smear is positive for acid fast bacilli in less than 10% of patient. Culture of
pleural fluid is often negative for tubercle bacilli. Chances of positive culture increases in
proportion to the quantity of fluid sent to the laboratory. Pleural
biopsies show granulomas in about two-thirds of patients. Pleural aspiration and pleural
biopsy using Abrams punch can be done in one sitting. Treatment involves pleural fluid
aspiration and administration of anti-tuberculosis drugs. Therapeutic aspiration of pleural
fluid will relieve symptoms of dyspnea. Aspiration should be done relatively slowly. Rapid
removal of large quantity of pleural fluid may result in unilateral pulmonary edema due to
increased microvascular permeability in the expanded lung.
1.1 Empyema
An empyema is pus in the pleural cavity. In the developing world, tuberculosis remains as the
common cause of empyema. Studies done in India have shown tuberculous empyema as the
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common cause of empyema. Tuberculous empyema occurs usually as a result of the rupture
of a subpleural caseous focus into the pleural cavity. Rarely, hematogenous spread from the
involved thoracic lymph nodes or from a sub diaphragmatic focus can cause empyema. The
presenting clinical symptoms are fever, cough with expectoration, chest pain and
breathlessness. On examination, patients might have digital clubbing due to chronic
secondary infection by pyogenic organisms. Tenderness of the chest wall is seen in some of
the patients. Radiological investigation shows a dense homogeneous opacity of the
hemithorax. Broncho-pleural fistula is a common complication in empyemas of tubercular
origin, when there is a delay in treatment. Development of bronchopleural fistula is
characterized by expectoration of a large quantity of sputum and volume depends on the
position of the patient. If the patient develops bronchopleural fistula, it can present as
pyopneumothorax. Pus aspirated from the pleural cavity can be positive for acid fast bacilli.
Secondary infection by staph, streptococcus, pseudomonas and K. pneumoniae are common.
If tuberculous empyema is not treated properly, it may spontaneously perforate the pleura and
extend through fascial planes and collect in the chest wall. This condition is known as
empyema necessitates. It is an unusual complication of empyema. Other sites of extension
of empyema include the paravertebral soft tissue and retroperitoneum. Rarely, pus can track
down posterior to the diaphragm and will accumulate in the groin or lumbar region (Behera,
2010). Chest x-ray shows a soft tissue mass in the chest wall with or without bony destruction
in empyema necessitates. Contrast enhanced CT is helpful in identifying the direct
communication between the pleural and the chest wall collection. Management consists of
appropriate antibiotics and anti-tubercular treatment. Repeated aspirations are attempted in
the initial stage, but intercostal tube drainage is required to remove the pus, since the chances
of developing pleural thickening are more with empyema. In some patients surgical
debridement of the pleura with physical removal of loculation, fibrous septae and thick
exudate is required. Minimal access surgery using video-assisted thoracoscopy techniques
have succeeded in achieving equivalent results to open thoracotomy in the past few years.
Surgical procedures like thoracoplasty and decortication are required in some cases.
Decortication via thoracotomy is the standard treatment method for chronic empyema.
Decortication is an elective surgical procedure, in which fibrous wall of the empyema cavity,
the cortex or rind is stripped off the visceral and parietal pleura.This procedure allows the
expansion of the underlying lung. Some patients may require thoracoplasty.

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2 Spontaneous Pneumothorax
Spontaneous pneumothorax is a well known complication in cavitary tuberculosis.
Pneumothorax is defined as the presence of gas in the pleural space. The term Pneumothorax
was first coined by Itard, a student of Laennec in 1803 and Laennec himself described the
clinical picture of pneumothorax in 1819. Pneumothorax may be primary or secondary.
Secondary pneumothorax occurs in persons with significant underlying pulmonary disease.
Pneumothorax complicating pulmonary tuberculosis can occur at any age. In countries where
tuberculosis
is a common problem, pulmonary tuberculosis remains the commonest cause of secondary
spontaneous pneumothorax (SSP). According to Gupta et al., the commonest cause of
spontaneous secondary pneumothorax in India is pulmonary tuberculosis. In tuberculosis, the
rupture of the sub pleural focus and rupture of a cavity are the common causes for
pneumothorax. Other causes are rupture of a bleb or bulla which has developed adjacent to
fibrosis.
All the patients will have chest pain and dyspnea. The clinical symptoms are dependent on
the degree of collapse of the underlying lung. Cough is also a common symptom. Patients
with tension pneumothorax will have acute onset of chest pain and dyspnea. On examination
diminished movements of chest and reduced vocal fremitus are found on the affected side.
Trachea deviates away from the affected side. The affected side may also be hyper resonant
on percussion with diminished or absent breath sounds. Hypotension, tachycardia, hypoxia,
jugular venous distension may be present. Radiography of the chest shows hyper-translucent
area without bronchovascular markings on the affected side with the lung being compressed
towards the hilum.

Figure 9: Chest X-ray PA view showing Pyopneumothorax on left side.


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In tension pneumothorax the mediastinum will be displaced to the opposite side.


Pneumothorax secondary to tuberculosis is frequently associated with untreated empyema,
when it is called as pyopneumothorax. Pneumothorax is uncommon in miliary tuberculosis,
and thus only few cases have been reported.

Figure 10: Chest X-ray PA view showing right tension pneumothorax with mediastinal shift
to left side.
Management of pneumothorax consists of conservative approach and active management.
Both ACCP and BTS guidelines recommend treatment based on the severity of symptoms
and the degree of collapse of the underlying lung as determined by chest radiographs
Conservative approach is indicated if patient has minimal symptoms and volume of
pneumothorax is very small i.e. less than 20% of the hemi thoracic volume. The principle of
this approach is based on natural tendency for the gas to get absorbed. The absorption is
hastened by giving 100% supplementary oxygen. Patients with pre-existing lung disease are
unable to tolerate pneumothorax in which case active management is indicated. Active
management consists of simple aspiration or intercostal tube drainage. Aspiration is less
likely to be successful in patients with SSP. Blanco et.al studied pneumothorax in active
pulmonary tuberculosis.
Patients with pulmonary tuberculosis showed a lesser and slower response to catheter
aspiration in their study. It can be considered in patients with small pneumothoraces, who are
symptomatic in order to avoid chest tube drainage. Otherwise, underwater seal chest tube
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drainage which allows gradual re-expansion of the lung is recommended. In case of persistent
air leak or recurrent pneumothorax surgical intervention is recommended. Surgical
intervention consists of limited thoracotomy with pleurectomy or pleural abrasion. Chemical
pleurodesis by using sclerosing agents is indicated in patients with recurrent pneumothorax
who are unwilling or unable to undergo surgery. Over the past years, widespread use of less
invasive video-assisted thoracic surgery (VATS) has been more commonly used in the
management of pneumothorax.
3 Calcification
The term calcification refers to the deposition of the calcium salts in tissues. It may be limited
or diffuse. Diffuse can be metastatic calcification where calcium deposits are found in normal
tissues. In dystrophic calcification it occurs in injured lung tissues. Dystrophic calcifications
are frequently seen in granulomatous infections like tuberculosis, histoplasmosis and
coccidiodomycosis. Tuberculous lung lesions heal by calcification. The calcification can
either be microscopic or macroscopic. In parenchymal disease calcification presents as
discrete radio opacities. Sheet like calcification can be seen in pleural disease. Tuberculous
pleuritis leaves sequelae ranging from minimal pleural thickening to extensive calcification
encompassing and restricting the lung. Occasionally calcified lymph nodes or concretions can
get detached and erode through the bronchial walls or blood vessels causing massive
haemoptysis. Extensive calcification can lead to respiratory failure or cor pulmonale.

Chest X-ray PA view showing bilateral extensive calcification.

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Chest X-ray PA view showing bilateral extensive pleural calcification.


General Complications
1 Cor Pulmonale
Cor pulmonale is right ventricular dysfunction (enlargement) due to pulmonary hypertension
secondary to diseases of the lung, bony thorax, lung ventilation or pulmonary circulation.
Virchow in nineteenth century found changes like right ventricular hypertrophy in autopsies
of patients who died of pulmonary tuberculosis. Bilateral and extensive tuberculosis can
cause pulmonary hypertension due to extensive fibrosis which causes distortion of
parenchyma. The basic underlying pathophysiology is increase in the pulmonary vascular
resistance and pulmonary hypertension. Clinical diagnosis depends on right ventricular
dysfunction, pulmonary hypertension and evidence of primary lung disease. Early treatment
prevents this late complication of pulmonary tuberculosis.
2 Amyloidosis
Tuberculosis is the commonest underlying cause for renal amyloidosis in developing
countries, whereas Rheumatoid arthritis is the most frequent underlying inflammatory disease
in developed countries. Amyloidosis is caused by deposition of insoluble fibrillar proteins in
various tissues which leads to organ dysfunction or failure. Amyloidosis commonly involves
kidneys. Secondary renal amyloidosis is seen in disorders that usually includes chronic
inflammatory disease or infectious diseases. Pro-inflammatory mediators/cytokines such as
interleukin -1, tumor necrosis factor alpha, and interleukin 6 stimulate the serum amyloid A
synthesis in liver and other sites. This accumulates in renal tissue. Proteinuria is the most
consistent feature of renal amyloidosis. In patients with tuberculosis, presence of pedal
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edema, proteinuria and grossly abnormal kidneys on ultrasonography should be evaluated by


renal biopsy for amyloidosis.
The time interval between the onset of predisposing disease and first evidence of amyloidosis
has shown variable results in different studies, varying from one to thirty years or two months
to seven years. Secondary amyloidosis has now become a rarity as a complication of
pulmonary tuberculosis due to availability of effective anti-tuberculosis treatment.
3 Chronic Respiratory Failure
Chronic respiratory failure may complicate pulmonary tuberculosis. Tuberculosis continues
to be a chronic infection with very high rates of morbidity and mortality. Delays in the
diagnosis and treatment of tuberculosis can lead to pulmonary sequelae that are characterized
by impairments in the bronchial and parenchymal structure. The structural changes include
bronchovascular distortions, bronchiectasis, emphysema and fibrosis. This leads to greater
ventilation perfusion (V/Q) mismatch. Tuberculosis destroyed lung term is used to describe
the destructive lung parenchymal changes which occur over many years following pulmonary
tuberculosis (WHO Report. 2008) Non- invasive ventilation has greatly improved the outlook
for patients with previous tuberculosis who develop chronic respiratory failure. Acute
respiratory failure can occur over a chronic respiratory failure due to respiratory infection
with pyogenic organisms.
GASTROESOFAGEAL REFLUKS DISEASE
A. Definision
Gastroesophageal reflux disease occurs when the amount of gastric juice that refluxes into
the esophagus exceeds the normal limit, causing symptoms with or without associated
esophageal mucosal injury (ie, esophagitis).
B. Patophisiology
Schematically, the esophagus, lower esophageal sphincter (LES), and stomach can be
envisioned as a simple plumbing circuit as described by Stein and coworkers. The esophagus
functions as an antegrade pump, the LES as a valve, and the stomach as a reservoir. The
abnormalities that contribute to GERD can stem from any component of the system. Poor
esophageal motility decreases clearance of acidic material. A dysfunctional LES allows
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reflux of large amounts of gastric juice. Delayed gastric emptying can increase volume and
pressure in the reservoir until the valve mechanism is defeated, leading to GERD. From a
medical or surgical standpoint, it is extremely important to identify which of these
components is defective so that effective therapy can be applied.

Esophageal defense mechanisms


Esophageal defense mechanisms can be broken down into 2 categories (ie, esophageal
clearance and mucosal resistance). Proper esophageal clearance is an extremely important
factor in preventing mucosal injury. Esophageal clearance must be able to neutralize the acid
refluxed through the lower esophageal sphincter. (Mechanical clearance is achieved with
esophageal peristalsis; chemical clearance is achieved with saliva.) Normal clearance limits
the amount of time the esophagus is exposed to refluxed acid or bile and gastric acid
mixtures. Abnormal peristalsis can cause inefficient and delayed acid clearance.
Whether peristaltic dysfunction is secondary to esophageal exposure to acids or a primary
defect is not understood clearly. In a review by Kahrilas et al, peristaltic dysfunction was
progressively more common in patients with greater degrees of esophagitis.Abnormal
peristalsis was identified in 25% of patients with mild esophagitis and 48% of patients with
severe esophagitis.
Buttar and associates described the importance of esophageal mucosal resistance as a
protective mechanism.They classified the factors into pre-epithelial, epithelial, and
postepithelial defenses. When the defenses fail, esophagitis and other complications of reflux
disease arise.

Dysfunction of the lower esophageal sphincter


The lower esophageal sphincter (LES) is defined by manometry as a zone of elevated
intraluminal pressure at the esophagogastric junction. For proper LES function, this junction
must be located in the abdomen so that the diaphragmatic crura can assist the action of the
LES, thus functioning as an extrinsic sphincter. In addition, the LES must have a normal
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length and pressure and a normal number of episodes of transient relaxation (relaxation in
the absence of swallowing).
LES dysfunction occurs via one of several mechanisms: transient relaxation of the LES
(most common mechanism), permanent LES relaxation, and transient increase of intraabdominal pressure that overcomes the LES pressure.

Delayed gastric emptying


The postulated mechanism by which delayed gastric emptying may cause GERD is an
increase in gastric contents resulting in increased intragastric pressure and, ultimately,
increased pressure against the lower esophageal sphincter. This pressure eventually defeats
the LES and leads to reflux. However, objective studies have produced conflicting data
regarding the role of delayed gastric emptying in the pathogenesis of GERD.

Hiatal hernia
When discussing mechanisms for GERD, the issue of hiatal hernia must be addressed. Hiatal
hernias can be encountered frequently in patients with reflux disease; however, it has been
well proven that not all patients with hiatal hernias have symptomatic reflux.
Buttar and coworkers state that a hiatal hernia may contribute to reflux via a variety of
mechanisms.(See the image below). The lower esophageal sphincter may migrate proximally
into the chest and lose its abdominal high-pressure zone (HPZ), or the length of the HPZ
may decrease. The diaphragmatic hiatus may be widened by a large hernia, which impairs
the ability of the crura to function as an external sphincter. Finally, gastric contents may be
trapped in the hernial sac and reflux proximally into the esophagus during relaxation of the
LES. Reduction of the hernias and crural closure is key to restoring an adequate intraabdominal length of esophagus and recreating the HPZ.

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Obesity as contributing factor


Some studies have shown that GERD is highly prevalent in patients who are morbidly obese
and that a high body mass index (BMI) is a risk factor for the development of this condition.
The hypothesis that obesity increases esophageal acid exposure is supported by the
documentation of a dose-response relationship between increased BMI and increased
prevalence of GERD and its complications. Therefore, the pathophysiology of GERD in
patients who are morbidly obese might differ from that of patients who are not obese. The
therapeutic implication of such a premise is that the correction of reflux in patients who are
morbidly obese might be better achieved with a procedure that first controls obesity.
The mechanism by which a high BMI increases esophageal acid exposure is not completely
understood. Increased intragastric pressure and gastroesophageal pressure gradient,
incompetence of the lower esophageal sphincter (LES), and increased frequency of transient
LES relaxations may all play a role in the pathophysiology of GERD in patients who are
morbidly obese.
C. Sign and symtom
Typical esophageal symptoms include the following:

Heartburn

Regurgitation

Dysphagia

Abnormal reflux can cause atypical (extraesophageal) symptoms, such as the following:

Coughing and/or wheezing

Hoarseness, sore throat

Otitis media

Noncardiac chest pain

Enamel erosion or other dental manifestations

A history of nausea, vomiting, or regurgitation should alert the physician to evaluate for
delayed gastric emptying.
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D. Diagnose
Testing
The following studies are used to evaluate patients with suspected gastroesophageal reflux
disease:

Upper gastrointestinal endoscopy/esophagogastroduodenoscopy: Mandatory

Esophageal manometry: Mandatory

Ambulatory 24-hour pH monitoring: Criterion standard in establishing a diagnosis of


gastroesophageal reflux disease

Imaging studies
Upper gastrointestinal contrast-enhanced studies are the initial radiologic procedure of choice
in the workup gastroesophageal reflux disease. Plain chest radiographic findings are not
useful in evaluating of this condition, but they are helpful in assessing pulmonary status and
basic anatomy. Chest images may also demonstrate a large hiatal hernia, but small hernias
can be easily missed. Currently, no role exists for computed tomography scanning, magnetic
resonance imaging, or ultrasonography in the routine evaluation of patients with reflux
disease.
E. Management
Treatment of gastroesophageal reflux disease involves a stepwise approach. The goals are to
control symptoms, to heal esophagitis, and to prevent recurrent esophagitis or other
complications. The treatment is based on lifestyle modification and control of gastric acid
secretion through medical therapy with antacids or proton pump inhibitors or surgical
treatment with corrective antireflux surgery.
Nonpharmacotherapy
Lifestyle modifications used in the management of gastroesophageal reflux disease include
the following:

Losing weight (if overweight)

Avoiding alcohol, chocolate, citrus juice, and tomato-based products

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Avoiding peppermint, coffee, and possibly the onion family

Eating small, frequent meals rather than large meals

Waiting 3 hours after a meal to lie down

Refraining from ingesting food (except liquids) within 3 hours of bedtime

Elevating the head of the bed 8 inches

Avoiding bending or stooping positions

Pharmacotherapy
The following medications are used in the management of gastroesophageal reflux disease:

H2 receptor antagonists (eg, ranitidine, cimetidine, famotidine, nizatidine)

Proton pump inhibitors (eg, omeprazole, lansoprazole, rabeprazole, esomeprazole,


pantoprazole)

Prokinetic agents (eg, aluminum hydroxide)

Antacids (eg, aluminum hydroxide, magnesium hydroxide)

Surgical option
Transthoracic and transabdominal fundoplications are performed for gastroesophageal reflux
disease, including partial (anterior or posterior) and circumferential wraps. Open and
laparoscopic techniques may be used.
Placement of a device to augment the lower esophageal sphincter is another surgical option.
Indications for fundoplication include the following:

Patients with symptoms that are not completely controlled by proton pump inhibitors

Patients with well-controlled reflux disease who desire definitive, one-time treatment

The presence of Barrett esophagus

The presence of extraesophageal manifestations

Young patients

Poor patient compliance with regard to medications

Postmenopausal women with osteoporosis


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Patients with cardiac conduction defects

Cost of medical therapy

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REFERENCE

Gayathri D. Complications Of Pulmonary Tuberculosis. Departement of Respiratory


Medicine M.S. Ramaiah Medical Collage. India.
Gastroesofageal

Refluks

Disease:

http://emedicine.medscape.com/article/176595-

overview#a0104 view at 6 january 2015


Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, and Loscalzo J. 2012. Harrisons
Principles of Internal Medicine 18th Edition. United States : McGraw-Hill eBooks.

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