Lecture 23. TUBERCULOSIS and FUNGAL INFECTIONS.

Tissue response in tuberculosis represents classical example of chronic granulomatous inflamma-

tion in humans.
CAUSATIVE ORGANISM. Tubercle bacillus or Koch's bacillus (named after discovery of the
organism by Robert Koch in 1882) called Mycobacterium tuberculosis causes tuberculosis in the
lungs and other tissues of the human body. The organism is a strict aerobe and thrives best in
tissues with high oxygen tension like in the apex of the lung.
The organism has 5 distinct pathogenic strains: hominis, bovis, avium, murine, and cold-blooded
vertebrate strain. A sixth nonpathogenic strains, M. smegmatis, is found in the smegma and as
contaminant in the urine of both men and women. Out of these, the first two strains (hominis and
bovis) are definitely infective to human beings while infection with avium strain (M. avium
inracellulare) is common in patients with AIDS.
M. tuberculosis hominis is a slender rod-like bacillus, 4 m in length.
INCIDENCE. In spite of great advance, in chemotherapy and immunology, tuberculosis still
continues to be worldwide in distribution, more common in poorer countries of Africa, Latin
America and Asia. Apart from other factors contributing to higher incidence of tuberculosis are
malnutrition, inadequate medical care, chronic debilitating conditions like uncontrolled diabetes,
alcoholism etc and immunocompromised states like AIDS. However, the exact incidence of dis-
ease cannot be determined as all patients infected with M. tuberculosis may not develop the
clinical disease and many remain reactive to tuberculin without developing symptomatic disease.
MODE OF TRANSMISSION. Human beings acquire infection with tubercle bacilli by one of the
following routes:
1. Inhalation of organisms present in fresh cough droplets or in dried sputum from an open case
of pulmonary tuberculosis.
2. Ingestion of the organisms leads to development to tonsillar or intestinal tuberculosis. This
mode of infection of human tubercle bacilli is from self-swallowing of infected sputum of an
open case of pulmonary tuberculosis, or ingestion of bovine tubercle bacilli from milk of
diseased cows.
3. Inoculation of the organisms into the skin may rarely occur from infected postmortem tissue.
4. Transplacental route results in development of congenital tuberculosis in foetus from infected
mother and is a rare mode of transmission.
SPREAD OF TUBERCULOSIS. The disease spreads in the body by various routes:
1. Local spread. This takes place by macrophages carrying the bacilli into the surrounding
tissues.
2. Lymphatic spread. Tuberculosis is primarily an infection of lymphoid tissues. The bacilli
may pass into lymphoid follicles of pharynx, bronchi, intestines or regional lymphnodes resulting
in regional tuberculous lymphadenitis, which is typical of childhood infections. Primary complex
is primary focus with lymphangitis and lymphadenitis.
3. Haematogenous spread. This occurs either as a result of tuberculous bacillaemia because of
the drainage of lymphatics into the venous system or due to caseous material escaping through
ulcerated wall of a vein. This produces millet seed-sized lesions in different organs of the body
like lungs, liver, kidneys, bones and other tissues and is known as miliary tuberculosis.
4. By the natural passages. Infection may spread from:
i) lung lesions into pleura (tuberculous pleurisy);
ii) transbronchial spread into the adjacent lung segments;
iii) tuberculous salpingitis into peritoneal cavity (tuberculous peritonitis);
iv) infected sputum into larynx (tuberculous laryngitis);
v) swallowing of infected sputum (ileocaecal tuberculosis); and
vi) renal lesions into ureter and down to trigone of bladder.
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TYPES OF TUBERCULOSIS
Lung is the main organ affected in tuberculosis. Depending upon the type of tissue response and
age, the infection with tubercle bacilli is of 2 main types:
A. Primary tuberculosis; and B. Secondary tuberculosis.
A. Primary Tuberculosis
The infection of an individual who has not been previously infected or immunised is called pri-
mary tuberculosis or Ghon's complex or childhood tuberculosis.
Primary complex or Ghon's complex is the lesion produced at the portal of entry with foci in
the draining lymphatic vessels and lymphnodes. The most commonly involved tissues for
primary complex are lungs and hilar lymphnodes. The other tissues which may show primary
complex are tonsils and cervical lymphnodes, and in the case of ingested bacilli the lesions may
be found in small intestine and mesenteric lymphnodes.
Primary complex or Ghon's complex in lungs consists of 3 components:
1. Pulmonary component. Lesion in the lung is the primary focus or Ghon's focus. It is 1-2 cm
solitary area of tuberculous pneumonia located under the pleura, just above or just below the
interlobar fissure between the upper and lower lobes of lung. Microscopically, the lung lesion
consists of tuberculous granulomas with caseation necrosis.
2. Lymphatic vessel component. The lymphatics draining the lung lesion contain phagocytes
containing bacilli and may develop beaded, miliary tubercles along the path of hilar lymphnodes.
3. Lymphnode component. This consists of enlarged hilar and tracheo-bronchial lymphnodes in
the area drained. The affected lymphnodes are matted and show caseation necrosis. Microscopi-
cally, the lesions are characterised by extensive caseation, tuberculous granulomas and fibrosis.
Nodal lesions are potential source of re-infection later.
In the case of primary tuberculosis of alimentary tract due to ingestion of tubercle bacilli, a
small primary focus is seen in the intestine with enlarged mesenteric lymphnodes producing
tabes mesenterica. The enlarged and caseous mesenteric lymphnodes may rupture into peritoneal
cavity and cause tuberculous peritonitis.
FATE OF PRIMARY TUBERCULOSIS. Primary. complex may have one of the following
sequelae:
1. The lesions of primary tuberculosis of lung commonly do not progress but instead heal by
fibrosis, and in time undergo calcification and even ossification.
2. In some cases, the primary focus in the lung continues to grow and the caseous material is
disseminated through bronchi to the other parts of the same lung or the opposite lung. This is
called progressive primary tuberculosis.
3. At times, the bacilli may enter the circulation through erosion in a blood vessel and spread to
various tissues and organs. This is called primary miliary tuberculosis and the lesions are seen in
organs like liver, spleen, kidney, brain and bone marrow.
4. In certain circumstances like in lowered resistance and increased hypersensitivity of the host,
the healed lesions of primary tuberculosis may get reactivated. The bacilli lying dormant in
acellular caseous material are activated and cause progressive secondary tuberculosis. It affects
children more commonly but adults may also develop this kind of progression.
B. Secondary Tuberculosis
The infection of an individual who has been previously infected or sensitised is called secondary,
or post-primary or re-infection or chronic tuberculosis
The infection may be acquired from:
endogenous source such as reactivation of dormant primary complex; or
exogenous source such as fresh dose of reinfection by the tubercle bacilli.
Secondary tuberculosis occurs most commonly in lungs. Other sites and tissues which can be
involved are tonsils, pharynx, larynx, small intestine and skin.

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Secondary Pulmonary Tuberculosis
The lesions in secondary pulmonary tuberculosis are usually located at the subapical region of
one or both the lungs, probably due to spread of infection from Simon's focus. Simon's focus is
haematogenous spread of infection from primary complex to the apex of the affected lung where
the oxygen tension is high and favourable for growth of aerobic tubercle bacilli.
The lesion begins as an area of tuberculous pneumonia, less than 3 cm in diameter.
Microscopically, the appearance is typical of tuberculous granulomas with caseation
necrosis.
FATE OF SECONDARY PULMONARY TUBERCULOSIS. The subapical lesions in lungs
can have the following courses:
1. The lesions may heal-with fibrous scarring and calcification.
2. The lesions may coalesce together to form larger area of tuberculous pneumonia and produce
progressive secondary pulmonary tuberculosis with the following pulmonary and extra-
pulmonary involvements:
(i) Fibrocaseous tuberculosis
(ii) Tuberculous caseous pneumonia
(iii) Miliary tuberculosis
(i) Fibrocaseous tuberculosis. The original area of tuberculous pneumonia undergoes massive
central caseation necrosis which may:
either break into a bronchus from a cavity (cavitary or open fibrocaseous tuberculosis); or
remain as a soft caseous lesion without drainage into a bronchus or bronchiole to produce a non-
cavitary lesion (chronic fibrocaseous tuberculosis).
The cavity provides favourable environment for proliferation of tubercle bacilli due to high
oxygen tension. The cavity may communicate with bronchial tree and become the source of
spread of infection (open tuberculosis). The open case of secondary tuberculosis may implant
tuberculous lesion on the mucosal lining of air passages producing endobronchial and
endotracheal tuberculosis. Ingestion of sputum containing tubercle bacilli from endogenous
pulmonary lesions may produce laryngeal and intestinal tuberculosis.
Grossly, tuberculous cavity is spherical with thick fibrous wall, lined by yellowish, caseous,
necrotic material and the lumen is traversed by thrombosed blood vessels. Around the wall of
cavity are seen foci of consolidation. The overlying pleura may also be thickened.
Microscopically, the wall of cavity shows eosinophilic, granular, caseous material which may
show foci of dystrophic calcification. Widespread coalesced tuberculous granulomas composed
of epithelioid cells, Langhans' giant cells and peripheral mantle of lymphocytes and having
central caseation necrosis are seen. The outer wall of cavity shows fibrosis.
Complications of cavitary secondary tuberculosis are:
(a) aneurysms of patent arteries crossing the cavity producing haemoptysis;
(b) extension to pleura producing bronchopleural fistula; .
(c) tuberculous empyema from deposition of caseous material on the pleural surface; and
(d) thickened pleura from adhesions of parietal pleura.

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(ii) Tuberculous caseous pneumonia. The caseous material from a case of secondary tuberculosis in
an individual with high degree of hypersensitivity may spread to the rest of lung producing caseous
pneumonia.
Microscopically, the lesions show exudative reaction with oedema, fibrin, polymorphs and monocytes
but numerous tubercle bacilli can be demonstrated in the exudates.
(iii) Miliary tuberculosis. This is lymphohaematogenous spread of tuberculous infection from
primary focus or later stages of tuberculosis The spread is either by entry of infection into pulmonary
vein producing disseminated or isolated organ lesion in different extra-pulmonary sites (e.g liver,
spleen, kidney, brain and bone marrow) or into pulmonary artery restricting the development of
miliary lesions within the lung. The miliary lesions are millet seed-sized (1 mm diameter), yellowish,
firm area without grossly visible caseation necrosis.
Microscopically, the lesions show the structure of tubercles with minute areas of caseation necrosis.
Clinical Features of Tuberculosis
The clinical manifestations in tuberculosis may be variable depending upon the location, extent and
type of lesions. However, in secondary pulmonary tuberculosis which is the common type, the usual
clinical features are as under:
1 Referable to lungssuch as productive cough, may be with haemoptysis, pleural effusion,
dyspnoea, orthopnea etc. Chest X-ray may show typical apical changes like pleural effusion,
nodularity, miliary or diffuse infiltrates in the lung parenchyma.
2 Systemic featuressuch as fever, night sweats, fatigue, loss of weight and appetite. Long-standing
and untreated cases of tuberculosis may develop systemic secondary amyloidosis
Causes of death in pulmonary tuberculosis are usually pulmonary insufficiency, pulmonary
haemorrhage, sepsis due to disseminated miliary tuberculosis, cor pulmonale or secondary
amyloidosis

DISEASES CAUSED BY FUNGI

Of the large number of known fungi, only a few are infective in human beings. Many of the human
fungal infections are opportunistic i.e. they occur in conditions with impaired host immune mecha-
nisms. Such conditions include defective neutrophil function, administration of corcicosteroids,
immunosuppressive therapy and immunodeficiency states (congenital and acquired).

MYCETOMA
Mycecoma is a chronic suppurative infection involving a limb, shoulder or other tissues and is
characterised by draining sinuses. The material discharged from the sinuses is in the form of grains
consisting of colonies of fungi or bacteria. Mycetomas are of 2 main types:
Mycetomas caused by actinomyces (higher bacteria) comprising about 60% of cases; and
Eumycetomas caused by true fungi comprising the remaining 40% of the cases.
Most common fungi causative for eumycetoma are Madurella mycetomatis or Madwella grisea,
both causing black granules from discharging sinuses. Eumycetomas are particularly common in
northern and tropical Africa, Southern Asia and tropical America. The organisms are inoculated
directly from soil into bare feet, from carrying of concaminced sacks on the shoulders and into the
hands from infected vegetation.
PATHOLOG1C CHANGES. After several months of infection, the affected site, most commonly
foot, is swollen. The lesions extend deeply into the subcutaneous tissues, along the fascia and even-
tually invade the bones. They drain through sinus tracts which discharge purulent material and grains.
The surrounding tissue shows granulomatous reaction.

CANDIDIASIS
Candidiasis is an opportunistic fungal infection caused most commonly by Candida albicans and
occasionally by Candida tropicalis. In human beings, Candida species are present as normal flora of
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the skin and mucocutaneous areas, intestines and vagina. The organism becomes pathogenic when the
balance between the host and the organism is disturbed. Various predisposing factors are: impaired
immunity, prolonged use of oral contraceptives, long-term antibiotic therapy, corticosteroid therapy,
diabetes mellitus, obesity, pregnancy etc.
PATHOLOGIC CHANGES. Candida produces superficial infections of the skin and mucous mem-
branes, or may invade deeper tissues as described under:
1. Oral thrush. This is the commonest form of mucocutaneous candidiasis seen especially in early
life. Full-fledged lesions consist of creamy white pseudomembrane composed of fungi covering the
tongue, soft palate, and buccal mucosa. In severe cases, ulceration may be seen.
2. Canadidal vaginitis. Vaginal candidiasis is characterised clinically by thick, yellow, curdy
discharge. The lesions form pseudomembrane of fungi on the vaginal mucosa. They are quite pru-ritic
and may extend to involve the vulva (vuluovaginitis) and the perineum.
3. Cutaneous candidiasis. Candidal involvement of nail folds producing change in the shape of nail
plate (paronychia) and colonisation in the intertriginous areas of the skin, axilla, groin, infra-and
inter-mammary, intergluteal folds and interdigital spaces are some of the common forms of cutaneous
lesions caused by Candida, abbicans.
4. Systemic candidiasis. Invasive candidiasis is rare and is usually a terminal event of an underlying
disorder associated with impaired immune system. The organisms gain entry into the body through an
ulcerative lesion on the skin and mucosa or may be introduced by iatrogenic means such as via
intravenous infusion, peritoneal dialysis or urinary catheterisation. The lesions of systemic
candidiasis are most commonly encountered in kidneys as ascending pyelonephritis and in heart as
candidial endocarditis.
Fungal Infections of Lung
Fungal infections of the lung are more common than tuberculosis in the United States of America.
These infections in healthy individuals are rarely serious but in immunosuppressed individuals may
prove fatal. Some of the common examples of fungal infections of the lung are briefly outlined
below:
1. Histoplasmosis. It is caused by oval organism, Histoplasma capsulatum, by inhalation of infected
dust or bird droppings. The condition may remain asymptomatic or may produce lesions similar to the
Ghon's complex.
2. Coccidiodomycosis. Coccidiodomycosis is caused by Coccidioides immitis which are spherical
spores. The infection in human beings is acquired by close contact with infected dogs. The lesions
consist of peripheral parenchymal granuloma in the lung.
3. Cryptococcosis. It is caused by Cryptococcus neoformans which is round yeast having a halo
around it due to shrinkage in tissue sections. The infection occurs from infection by inhalation of
pigeon droppings. The lesions in the body may range from a small parenchymal granuloma in the
lung to cryptococcal meningitis.
4. Blastomycosis. It is an uncommon condition caused by Blastomyces dermatitidis. The lesions re-
sult from inhalation of spores in the ground. Pathological features may present as Ghon-complex like
lesion, as a pneumonic consolidation, and as multiple skin nodules.
5. Aspergillosis. Aspergillosis is the most common fungal infection of the lung caused by Aspergillus
fumigatus. The fungus exists as thin septate hyphae with dichocomous branching and grows best in
cool, wet climate. The infection may result in allergic bronchopulmonary aspergillosis, aspergilloma
and nec-rotising bronchitis. Immunocompromised persons develop more serious manifestations of
aspergillus infection, especially in leukaemic patients on cytotoxic drug therapy. Extensive
haematogenous spread of aspergillus infection may result in widespread changes in lung tisue due to
arterial occlusion, thrombosis and infarction.
6. Mucormycosis. Mucormycosis or phycomycosis is caused by Mucor and Rhizopus. The infection
in the lung occurs in a similar way as in aspergillosis.The pulmonary lesions are especially common
in patients of diabetic ketoacidosis.

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7. Candidiasis. Candidiasis or moniliasis caused by Candida albicam is a normal commensal in oral
cavity, gut and vagina but attains pathologic form in immunocompromised host. Angioinvasive
growth of the organism may occur in the airways.