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Tuberculosis

I. Introduction/Background

A. Epidemiology:

1. Global: TB remains leading infectious cause of death in adults: 8 million new cases, 2-3 million deaths each year 

2. One-third the world's population infected 

3. US: Rise in cases since 1985

B. Resurgence of Tb in the past 15 years: Sociopolitical developments leading to the resurgence

1. Globally: HIV

2. USA: Decline in public health programs in the 1970s, worsening poverty and living conditions of the population with growth of homelessness, HIV

3. Immigration

II. Pathophysiology Review

A. Primary infection-unimpeded replication and dissemination

1. Reaches alveoli, replicates extracellularly and intracellularly, unimpeded for several weeks throughout the body secondary to lack of host immune response

a. Prevents acidification of intracellular vacuoles by blocking fusion of phagosome with lysosome

b. escapes antibody and complement mediated mechanisms of host defense

c. dissemination of organisms throughout body which cause no disease until years later (see below, reactivation)

2. Development of immune response-6-14 weeks after initial infection

a. Eventual activation of CD4 T-cells which replicate, produce cytokines and recruit and activate macrophages at sites of infection

b. Activated macrophages kill MTB and can cause host tissue damage, encircle MTB foci to contain infection, fuse to form multinucleated giant cells (Langhans cells), tubercles or granulomas

3. Clinical events- Primary infection with resolution

a. Patients asymptomatic or have mild viral-like syndrome which resolves.

b. Accompanied by enlargement of hilar and peribronchial lymph nodes which resolve

c. Ghon complex with fibrosis and calcification of hilar nodes and peripheral lung focus correlates with the development of a +PPD and no evidence of active disease

4. Clinical events- Primary infection with progression

a. Primary tuberculosis- common in AIDS patients -Multiple nosocomial outbreaks of TB in AIDS wards in hospitals, homeless shelters and prisons.

  • Presents with cough, fever and hilar adenopathy, with or without perihilar infiltrate
  • Time from exposure/infection to disease usually weeks

b. Progressive primary disease

  • Very young children and/or the immunocompromised
  • Initial infection does not resolve as above, but progresses to active disease, with miliary or disseminated disease and CNS involvement

c. Tuberculous pleurisy- Hypersensitivity reaction to small number of organisms which reach the pleura during primary infection; exudative effusion, culture negative B. Reactivation

1. Persistence of viable organisms

a. Despite containment of infection and lack of active disease, organisms remain viable but dormant for years, perhaps by being sequestered from CD4 T-cells which have been sensitized to TB

b. Certain sites favorable for persistence of organisms-lung apices, lymph nodes, meninges, bones, kidneys-correlates with sites common for reactivation

c. Despite persistence, 85% of immunocompetent patients infected never develop active disease. Fifteen percent lifetime risk; 50-80% of active disease within 1-2 years of infection

d. AIDS patients infected with TB previous to infection with HIV have at least 8% per year risk of developing active disease, 100% lifetime risk if live long enough.

2. Clinical disease

a. Illness occurs months or years after infection

b. Cellular immune response no longer able to contain MTB organisms so get proliferation and spread of organism, tissue destruction and clinical disease c. Pulmonary location most frequent (85% of TB disease)

  • Replication of MTB induces inflammatory response consisting of alveolar exudate containing inflammatory cells which leads to caseating necrosis, liquefaction with drainage into the bronchial tree, and cavity formation
  • Cavitary lesions have huge number of organisms=109-1011 organisms per gram of tissue, 5-6 log fold greater than non-cavitary lesions
  • Importance of cavitary disease in terms of spread to others and development of resistance

d. Extrapulmonary most commonly lymph node, pleural, bone/joint, CNS, and can also have both pulmonary and extrapulmonary

III. Diagnosis

A. Symptoms

1. Systemic=non-specific: fever, fatigue, night sweats, weight loss

2. Pulmonary=productive cough; hemoptysis suggests erosion of bronchial wall and can be an emergency

B. Laboratory findings

1. Sputum smear

a. Likely to be AFB pos in cavitary disease

b. Up to 50% AFB neg in non-cavitary disease

2. Sputum culture

a. positive in 2-6 weeks=gold standard

b. culture negative TB does exist=clinical or x-ray improvement on treatment; should be up to 15% of diagnosed TB cases, (CDC guidelines)

3. Amplification Technology: Polymerase Chain Reaction (PCR)

a. Clinical studies indicate PCR more sensitive and specific than smear 

b. Cost up to 30 times more per specimen than smear 

B. Treatment Regimens: All should be DOT=Directly observed therapy; most health departments will provide this service

1. Immunocompetent DRUG SENSITIVE

a. Six months total=2 months INH, RMP, PZA, EMB + 4 months INH, RMP

  • EMB to be stopped as soon as sensitivity is known
  • Can be daily for entire 6 months
  • Can be daily for first 2 months, then change to 2 or 3 times weekly, increasing the INH to 15 mg/kg and leaving the RMP at 600 mg 2 or 3 times weekly
  • -Can be 3 times weekly from outset for 6 months

b. Nine months=INH, RMP, EMB pending sensitivities

  • Again, drop EMB as soon as know organism is sensitive to INH and RMP
  • Nine months necessary as not including PZA
  • Use for pregnant women, elderly who cannot tolerate PZA

2. HIV, drug sensitive=same regimens as above but extend treatment for 3 months

3. Drug resistance: IMPORTANT DISTINCTION BETWEEN TB resistant to BOTH INH and RMP (MDRTB), and TB resistant to only INH or only RMP

a. INH resistance alone: use same 4 drug regimen initially, drop the INH when resistance known, continue with RMP, EMB, PZA for total of 6-9 months or 6 months after culture conversion, whichever is longer 

b. RMP resistance alone: INH, EMB, PZA or INH, EMB, SM for 18-24 months; data is poor; no clinical trials 

c. MDRTB=resistance to both INH and RMP with or without resistance to other agents: At least 6-9 months of an injectable and 24 months of 3 oral agents to which the organism is sensitive

V. Prophylaxis

A. Positive PPD

1. Five millimeter or greater

2. Ten millimeter or greater: All patients from areas where TB common

3. Fifteen millimeter or greater: Patients from areas where TB is rare

B. Regimens: Immunocompetent

1. All patients <35, if PPD 10mm or greater

a. INH 300mg for 6 months if >18

b. INH 10 mg/kg up to 300 mg for 9 months if <18

2. All patients with known negative PPD within 2 years, now PPD positive, INH 300 mg for 6 months regardless of age

3. All patients with chest x-ray evidence of old disease granuloma), INH 300 mg for 12 months if PPD 5mm or greater

4. Close contacts of infectious cases if chest x-ray negative, PPD 5mm or greater, INH 300 mg for 6 months

C. Regimens: Immunocompromised with Positive PPD

1. HIV positive: Anergy testing no longer recommended a) INH 300mg for 12 months if PPD 5 mm or more b)New regimen of Rifampin and Pyrazinamide for 2 months or Rifabutin and Pyrazinamide

2. Immunosuppressive therapy, including prolonged high-dose corticosteroids, INH 300 mg for 6 months

3. Certain medical conditions, INH for 6 months: -Malignancies(lymphoma, leukemia, head and neck carcinoma) -Insulin dependent diabetes mellitus -End stage renal disease -Silicosis

D. Patients exposed to INH resistant cases

1. If case susceptible to RMP, use RMP, 600mg daily for 6 months unless HIV positive or old healed tuberculosis on chest x-ray, in which case treat for 12 months 2.If index case MDR, consult Health Department

E. BCG Vaccine = Bacillus Calmette Guerin; most controversial vaccine in the world

1. Derived from strain of Mycobacterium bovis attenuated through years of serial passage through culture

2. No standardized strain or procedure for making strain