Tuberculosis

Mycobacteria

• Slender

• Aerobic

• In straight or branching chains

• Waxy cell wall composed of unusual glycolipids and lipids including mycolic acid

• Retain stains even on treatment with a mixture of acid and alcohol…so called: acid-fast

• Sometimes considered weakly gram (+)

Tuberculosis (TB)

• Chronic pulmonary and systemic disease

• Caused (mainly) by: Mycobacterium tuberculosis

• Source of transmission: humans with active tuberculosis who release mycobacteria present in sputum

• Oropharyngeal and intestinal TB can be caused by Mycobacterium bovis (from infected cows) in milk…rare nowadays except in countries where milk pasteurization is not performed

TB, epidemiology

• Decreasing

• Older adults and immigrants from high-burden areas

• Infection with HIV makes people susceptible to rapidly progressive tuberculosis

• Poverty, crowding, and chronic debilitating illnesses

• Diabetes mellitus, Hodgkin lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression

Only a scar will remain

More details in slide #7

Progressive pulmonary or disseminated

Progressive pulmonary or disseminated

TB, pathogenesis in details• Entry into macrophage:

…receptors for M.TB: CR3, mannose binding lectin…etc.

• M.TB continues to replicate inside the phagosome and inhibits phagolysosome formation…protected from microbicidal actions

…at this stage: bacteremia can occurs within the 1st 3 weeks with only flu-like symptoms. Seeding in different organs may occur

• These “infected” macrophages will become APCs for T cells, especially presenting the peptide antigens of these “phagocytosed extracellular microbes” in the draining lymph nodes

• TLR-2 on APCs (macrophages and dendritic cells) binds glycolipids and lipoproteins on M.TB (PAMPs)

• After the 3 weeks: APCs will present the antigens in the draining lymph nodes and Th1 response will occur (IL-12 induced Th1 differentiation)…IL-12 can be secreted from APCs after their TLR-2 binds PAMPs

• Th1 response will occur mainly in the lymph nodes and in the lung itself and this includes secretion of interferon-gamma (classical macrophage activation)…phagolysosome maturation, increased killing by the phagocyte and granuloma formation…Ghon complex is formed

• Secretion of cytokines and reactive oxygen species occur with chemotaxis of lymphocytes around the granulomas and caseation

TB, pathogenesis…cont’d

• With activity (1ry or 2ry), the granulomatous reaction which is supposed to protect will become a cause of collateral damage besides the intractable infection

Usually as an acute bacterial pneumonia (lobar consolidation) with hilar lymphadenopathy & pleural effusion

Usually apical disease with caseationClassically: the apex of the upper lobes of one or both lungs

In active TB, erosion of the cavities into bronchial wall will cause airborne spread by cough

Here is the start point in infection(Ghon focus or Ghon complex) …mainly in the upper part of the lowerlobe or lower part of the upper lobe

Elsevier. Kumar et al. Robbins and Cotran pathologic basis of diseases 9th…modified

TB, clinical features

• Before becoming dormant or eliminated: may be only fever and pleural effusion

• If 1ry active in the lung: similar to acute bacterial pneumonia with pleural effusion and hilar lymphadenopathy

• If 2ry active localized in the lung: asymptomatic then insidious onset of manifestations (low-grade fever, weight loss, anorexia, malaise), hemoptysis, sputum, night sweats, pleuretic pain due to pleural involvement…etc.

• If active outside the lung: according to the organ involved

…sometimes activity occurs in only one organ seeded by the organism

Miliary pulmonary disease

• Millet seeds-like lesions

• When organisms draining through lymphatics enter the venous blood and circulate back to the lung

• Individual lesions are either microscopic or small, visible (2-mm) foci of yellow-white consolidation scattered through the lung parenchyma

• Miliary lesions may expand and coalesce, resulting in consolidation of large regions or even whole lobes of the lung

• Systemic military TB: Mainly liver, bone marrow, spleen or any other organ

Check https://www.amazon.com/Organic-Millet-Seed-25-Bag/dp/B000RHUWU4... for references

Pleural involvement

• With progressive pulmonary tuberculosis, the pleural cavity is invariably involved:

-Serous pleural effusions

-Tuberculous empyema

-Obliterative fibrous pleuritis

Isolated TB outside the lung

Scrofula

• = Cervical tuberculous lymphadenitis

• The most common extrapulmonary manifestation

TB in GI tract

• Mainly due to M. bovis in certain countries (unpasteurized milk)

• In countries where milk is pasteurized: more often caused by the swallowing of coughed-up infective material in patients with advanced pulmonary disease…seeding to mucosal lymphoid aggregates with resultant granulomatous reaction then ulceration of overlying mucosa and strictures may occur

…Ileum is the most common site

TB, diagnosis

1- History, physical examination and radiographic findings:Cavitation and consolidation in lung apices

2-Smears of sputum (Ziehl-Neelsen special stain to demonstrate the acid-fast bacilli)…less sensitive than culture

3-Culture of sputum…the most effective and sensitive but the result needs 6 weeks…shows drug sensitivities…PCR is more rapid with good sensitivity and detects rifampin-resistant M.TB

…but also: less sensitive than culture

TB, diagnosis*** Tuberculin (PPD, or Mantoux) skin test

• About 2 to 4 weeks after infection, intracutaneous injection of purified protein derivative of M. tuberculosis induces a visible and palpable induration that peaks in 48 to 72 hours

• A positive tuberculin test signifies T-cell–mediated immunity to mycobacterial antigens but does not differentiate between infection and active disease (It only detects sensitized patients)

• False-negative reactions (called: anergy to skin test):

-Certain viral infections

-Sarcoidosis (abnormalities in CD4+ T cells)

-Malnutrition

-Hodgkin lymphoma

-Immunosuppression, e.g., AIDS…granulomas may be less and PPD may be negative

-Overwhelming active tuberculous disease

• False-positive reactions may result from:

-Infection by atypical mycobacteria

-Prior vaccination with BCG (Bacillus Calmette-Guerin), an attenuated strain of M. bovis that is used as a vaccine in some countries

Treatment

• Multidrug resistant M. tuberculosis is an increasing problem

…Nowadays, in USA, at least 4 drugs are used to treat TB (except if the case is with known susceptibility)