Tuberculosis

By: Shefaa’ Q’aqa’

• Tuberculosis is a communicable chronic granulomatous disease caused by Mycobacterium tuberculosis. It usually involves the lungs but may affect any organ or tissue in the body. Typically, the centers of tubercular granulomas undergo caseous necrosis.

• Among medically and economically deprived persons throughout the world, tuberculosis remains a leading cause of death.

• Tuberculosis flourishes under conditions of poverty, crowding, and chronic debilitating illness, elderly persons, with their weakened defenses are vulnerable.

• Certain disease states also increase the risk: diabetes mellitus, Hodgkin lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression (AIDS).

• It is important that infection be differentiated from disease.

• Most infections are acquired by direct person-to person transmission of airborne droplets of organisms from an active case to a susceptible host.

• Tuberculin (Mantoux) test:

About 2 to 4 weeks after the infection has begun, intracutaneous injection of 0.1 mL of PPD induces a visible and palpable induration

(at least 5 mm in diameter) that peaks in 48 to 72 hours. Sometimes, more PPD is required to elicit the reaction.

• A positive tuberculin skin test result signifies cell-mediated hypersensitivity to tubercular antigens.

• It does not differentiate between infection and disease.

• Mycobacteria are slender rods that are acid-fast (i.e., they have a high content of complex lipids that readily bind the Ziehl-Neelsen stain and subsequently resist decolorization).

• M. tuberculosis hominis

• Mycobacterium bovis

• Mycobacterium avium complex

• The earliest phase of primary tuberculosis (in the first 3 weeks) in the nonsensitized patient is characterized by bacillary proliferation within the pulmonary alveolar macrophages and air spaces, with resulting bacteremia and seeding of multiple sites.

• Despite the bacteremia, most persons at this stage are asymptomatic or have a mild flu-like illness.

• The development of cell-mediated immunity occurs approximately 3 weeks after exposure.

• Processed mycobacterial antigens reach the draining lymph nodes and are presented to CD4 T cells by dendritic cells and macrophages.

• Under the influence of macrophage-secreted IL12, CD4+ T cells of the TH1 subset are generated that are capable of secreting IFN-γ.

• IFN-γ released by the CD4+ T cells of the TH1 subset is crucial in activating macrophages.

• Activated macrophages:

(1) TNF: recruitment of monocytes -- epithelioid histiocytes

(2) Inducible nitric oxide synthase (iNOS) Gene -- nitric oxide (antibacterial activity)

(3) Reactive oxygen species (antibacterial activity)

• false-negative reactions (skin test anergy): Certain viral infections, Sarcoidosis, Malnutrition Hodgkin lymphoma Immunosuppression Overwhelming active tuberculous disease Elderly • False positive reactions Atypical mycobacteria

Primary Tuberculosis

• Primary tuberculosis is the form of disease that develops in a previously unexposed and therefore unsensitized patient.

• the inhaled bacilli implant in the distal air spaces of the lower part of the upper lobe or the upper part of the lower lobe.

• Ghon focus: As sensitization develops, a 1- to 1.5-cm area of gray-white inflammatory consolidation often with caseous necrosis

• Tubercle bacilli, either free or within phagocytes, travel in lymph drainage to the regional nodes, which also often caseate.

• Ghon complex: Combination of parenchymal lesion and nodal involvement

• During the first few weeks, there is also lymphatic and hematogenous dissemination to other parts of the body. In approximately 95% of cases, development of cellmediated immunity controls the infection.

• Ranke complex:

The Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification

• On histologic examination, sites of active involvement are marked by a characteristic granulomatous inflammatory reaction that forms both caseating and noncaseating granulomas, which consist of epithelioid histiocytes and multinucleate giant cells.

• The foci of scarring may harbor viable bacilli for years, perhaps for life, and thus be the nidus for reactivation at a later time when host defenses are compromised.

• progressive primary tuberculosis:

- occurs in patients who are immunocompromised (HIV with CD4+ counts

below 200 cells/μL)

- inability to mount a CD4+ T cell–mediated immunologic reaction

- absence of the characteristic caseating granulomas (nonreactive tuberculosis)

Secondary Tuberculosis (Reactivation Tuberculosis)

• Secondary tuberculosis is the pattern of disease that arises in a previously sensitized host.

• it arises from reactivation of dormant primary lesions many decades after initial infection, particularly when host resistance is weakened

• only a few patients (less than 5%) with primary disease subsequently develop secondary tuberculosis.

• Secondary pulmonary tuberculosis is classically localized to the apex of one or both upper lobes. The reason is obscure but may relate to high oxygen tension in the apices.

• Because of the preexistence of hypersensitivity, the bacilli excite a prompt and marked tissue response that tends to wall off the focus. As a result of this localization, the regional lymph nodes are less prominently involved early in the disease.

• cavitation occurs readily in the secondary form, leading to erosion into and dissemination along airways. Such changes become an important source of infectivity, because the patient now produces sputum containing bacilli.

• HIV patients:

- CD4+ counts greater than 300 cells/mm3:

secondary tuberculosis (apical disease with cavitation)

- CD4+ counts below 200 cells/mm3:

progressive primary tuberculosis (lower and middle lobe consolidation, hilar lymphadenopathy, and noncavitary disease).

• The extent of immunosuppression also determines the frequency of extrapulmonary involvement, rising from 10% to 15% in mildly immunosuppressed patients to greater than 50% in those with severe immune deficiency.

• Localized, apical, secondary pulmonary tuberculosis may heal with fibrosis either spontaneously or after therapy, or the disease may progress and extend along several different pathways.

• Progressive pulmonary tuberculosis: - apical lesion enlarges with expansion of the area of caseation. - Erosion of blood vessels results in hemoptysis. - With adequate treatment, healing by fibrosis. - If the treatment is inadequate, or if host defenses

are impaired, the infection may spread by direct expansion, by means of dissemination through airways, lymphatic channels, or within the vascular system.

• Progressive pulmonary tuberculosis

- Miliary pulmonary disease:

- Pleural effusions,

- tuberculous empyema,

- Obliterative fibrous pleuritis

• Systemic miliary tuberculosis: ensues when the organisms disseminate through the systemic arterial system to almost every organ in the body. Isolated-organ tuberculosis Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually occurring in the cervical region(“scrofula”)

• intestinal tuberculosis:

- drinking of contaminated milk

- Swallowing of coughed-up infective material

- complication of protracted advanced secondary tuberculosis

• Clinical Features:

malaise, anorexia, weight loss, and fever. Commonly, the fever is low grade and remittent

(appearing late each afternoon and then subsiding), and night sweats occur.

Sputum

Hemoptysis

Pleuritic pain

• Extrapulmonary manifestations of tuberculosis are legion and depend on the organ system involved (for example, tuberculous salpingitis may present as infertility, tuberculous meningitis with headache)

• The diagnosis of pulmonary disease is based in part on the history and on physical and radiographic findings of consolidation or cavitation in the apices of the lungs.

- acid-fast organisms in sputum by acid-fast stains

- cultures for mycobacteria

- PCR