Tuberculosis

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In children, there is a faster rate of progression to disease, the risk of progression to disease is higher, and severe disease is more common.
Most children with pulmonary TB are asymptomatic.
Treatment of pediatric TB should involve four drugs and be directly observed (DOT).

EPIDEMIOLOGY

Incidence

Worldwide (2013): 9 million (13% HIV coinfected)
United States (2013): 9,582 (3.0/100,000), 82 MDR, and 75 of those were foreign born (1).

Prevalence
Worldwide (2013): 157 cases/100,000 population (41% decrease since 1990); highest in Asia and Africa (1)

ETIOLOGY AND PATHOPHYSIOLOGY

Mycobacterium tuberculosis, Mycobacterium bovis, or Mycobacterium africanum are causative organisms.
Cell-mediated response by activated T lymphocytes and macrophages forms a granuloma that limits bacillary replication. Destruction of the macrophages produces early "solid necrosis. " In 2 to 3 weeks, "caseous necrosis " develops and latent tuberculosis infection (LTBI) ensues. In immunocompetent, granuloma undergoes "fibrosis " and calcification. In immunocompromised patients, primary progressive TB develops.

RISK FACTORS

For infection: homeless, ethnic minorities, close quarters (correctional facilities, nursing homes, barracks); close contact with infected individual; persons from areas with high incidence of active TB (Asia, Africa, Latin America, former Soviet Union states); health care workers; medically underserved, low income, substance abuse
For development of disease once infected: HIV; lymphoma; silicosis; diabetes mellitus; chronic renal failure; cancer of head, neck, or lung; children <5 years of age; malnutrition; systemic corticosteroids, immunosuppressive drugs; IV drug abuse, alcohol abuse, cigarette smokers; <2 years since infection with M. tuberculosis; history of gastrectomy or jejunal bypass; <90% of ideal body weight

GENERAL PREVENTION

Screening and treatment of LTBI. Active cases must be reported to health department for identification; test and treat all close contacts.
Bacille Calmette-Guerin (BCG) vaccine: Live attenuated M. bovis prevents 50% of pulmonary disease and 80% of meningitis and miliary disease in children. Use is more common in countries with endemic TB. In the United States, consider BCG for high-risk children with negative PPD and HIV tests or for health workers at risk for drug-resistant infection.

COMMONLY ASSOCIATED CONDITIONS

Immunosuppression; HIV-coinfection; malignancy

DIAGNOSIS

HISTORY

Known exposure to individual with active TB
Immunosuppression
Tobacco use; recreational drug use
Signs and symptoms
- General: fever, night sweats, weight loss, malaise, painless lymph node swelling
- Pulmonary TB: cough, hemoptysis
- Abdominal TB: presents acutely as surgical abdomen; chronic abdominal TB varies in presentation, vague abdominal symptoms, abdominal mass, "doughy " abdomen.
- Meningitis: See "Tuberculosis, CNS. "
- Miliary: See "Tuberculosis, Miliary. "

PHYSICAL EXAM

Often entirely normal. Specific findings depend on organs involved: adenopathy, rales, or hepatosplenomegaly.
Late findings: renal, bone, or CNS disease

DIFFERENTIAL DIAGNOSIS

Pulmonary TB: pneumonia (bacterial fungal, atypical), malignancy, tularemia, actinomycosis
Extrapulmonary TB: syphilis, cat-scratch disease, leishmaniasis, leprosy; rheumatoid disease; erythema nodosum, erythema induratum, syphilis, other mycobacterial infections

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (Immunogenesis)
To determine immune response to mycobacterium

Tuberculin skin test (TST) (e.g., PPD): 5 U (0.1 mL) intermediate-strength intradermal injection into volar forearm. Measure induration at 48 to 72 hours:
- PPD positive if induration
  - >5 mm and HIV infection, recent TB contact, immunosuppressed, disease on x-ray
  - >10 mm and age <4 years or other risk factors
  - >15 mm and age >4 years and no risk factors
  - Two-step test if no recent PPD, age >55 years, nursing home resident, prison inmate, or health care worker. Second test 1 to 3 weeks after initial test; interpret as usual.
- Context of PPD results:
  - False positive: BCG (unreliable, should not affect decision to treat)
  - False negative: HIV, steroids, gastrectomy, alcoholism, renal failure, sarcoidosis, malnutrition, hematologic or lymphoreticular disorder, very recent exposure
  - If positive once, no need to repeat.
  - No need for control with Candida/other
Interferon- ³ release assays (IGRAs) measure interferon release after stimulation in vitro by M. tuberculosis antigens (2)[A]:
- Lack of cross-reaction with BCG and most nontuberculous mycobacteria
  - IGRA is preferred (better specificity) for testing persons who have had BCG (vaccine or for cancer therapy) and for homeless persons, drug abusers and other groups with historically low rates of returning to have TST 's interpreted (2)[A].
  - TST is still preferred if age <5 years (3)[A].
  - Either TST or IGRA may be used as periodic screening for persons in high-risk occupations and for recent contacts of persons with known or suspected active TB (2)[A].
  - Cotesting with TST and IGRA may be indicated when the initial test is negative but the risk for poor prognosis is increased (e.g., HIV-infected persons or children <5 years old) (2)[A].

Initial Tests-Active TB (lab, imaging)

Three consecutive sputum samples (8 to 24-hour intervals with at least one in early in the morning) for acid-fast bacilli (AFB) stain and culture by aerosol induction, gastric aspirate (children), or bronchoalveolar lavage
Positive AFB: Treat immediately. Culture and sensitivity ultimately guide treatment.
Chest radiograph
- Primary TB: infiltrate with or without effusion, atelectasis, or adenopathy. Ghon lesion: calcified tuberculous caseating granuloma (tuberculoma); if associated with calcified ipsilateral hilar lymph node then Ghon (or Ranke) complex
- Recrudescent TB: cavitary lesions and upper lobe disease with hilar adenopathy
- HIV: atypical findings with primary infection, right upper lobe atelectasis
CT chest: good sensitivity, tree-in-bud (centrilobular nodules with branching linear opacities)

Follow-Up Tests & Special Considerations

Baseline CBC, creatinine, AST, ALT, bilirubin, alkaline phosphatase, visual acuity, and red " green color discrimination (regimens involving ethambutol)
HIV: If positive, get baseline CD4 count.
High risk: Check hepatitis B and C (injection drug users, Africa or Asia born, HIV infected).
Extrapulmonary: urine, CSF, bone marrow, and liver biopsy for culture as indicated
Nonspecific laboratory findings: anemia, monocytosis, thrombocytosis, hypergammaglobulinemia, SIADH, sterile pyuria

Diagnostic Procedures/Other

Culture: takes several weeks for definitive results
Xpert MTB/RIF: The World Health Organization endorses use as the initial test for diagnosis of pulmonary TB and detection of rifampicin resistance in adults and children presumed to have MDR-TB, HIV-associated TB, or TB meningitis (4)[A].
- Results are available within 2 hours (5).

TREATMENT

GENERAL MEASURES

If clinical suspicion, treat immediately. Prescribing physician is responsible for treatment completion.
Respiratory and droplet precautions
Not infectious if favorable clinical response after 2 to 3 weeks of therapy and three negative AFB smears

MEDICATION

Use ideal body weight for dosing. Directly observed therapy (DOT) strongly recommended for all, but required for children, institutionalized patients, nonadherent patients, and nondaily regimens.
First Line

LTBI
- Isoniazid (INH) for 9 months at 5 mg/kg/day (max of 300 mg) or 15 mg/kg (max of 900 mg) 2 times per week (6)[A] or
- INH 15 mg/kg + rifapentine 300 to 900 mg weekly for 12 weeks by DOT for patients age ≥12 years (6)[A]
Active TB infection
- Regimen 1 (preferred) (6)[A]
  - Initial phase:
    - INH 5 mg/kg, rifampin (RIF) 10 mg/kg (max 600 mg), pyrazinamide (PZA) 15 to 30 mg/kg, and ethambutol (EMB) 15 to 20 mg/kg daily for 8 weeks or
    - INH/RIF/PZA/EMB 5 days/week for 8 weeks
- Continuation phase:
  - INH/RIF daily for 18 weeks; or, if DOT, INH/RIF 5 days/week for 18 weeks (recommended for HIV positive with CD4 <100 cells/mm3 due to increased risk of resistance) or
  - INH/RIF 2 to 3 times per week for 18 weeks (not used if HIV positive with CD4 <100 cells/mm3; may have increased risk of relapse) or
  - INH/rifapentine once weekly for 18 weeks (acceptable only for HIV patients without cavitary disease, may have increased risk of relapse) (6)[A]
- Regimen 2
  - Initial phase:
    - INH/RIF/PZA/EMB daily for 2 weeks, then twice weekly for 6 weeks or
    - INH/RIF/PZA/EMB 5 days/week for 2 weeks, then twice weekly for 6 weeks
  - Continuation phase:
    - INH/RIF 2 to 3 times per week for 18 weeks (not recommended if HIV positive with CD4 <100 cells/mm3; may have increased risk of relapse) or
    - INH/rifapentine once weekly for 18 weeks (acceptable only for HIV patients without cavitary disease; may have increased risk of relapse) (6)[A]
    - Treat TB in pregnancy with INH, RIF, and EMB; add pyridoxine 25 mg/day.

Pregnancy Considerations

Streptomycin: ototoxic and nephrotoxic; do not use in pregnancy. Pyrazinamide is not used in pregnant women in the United States.
Congenital infection: from maternal miliary or endometrial TB. PPD, CXR, lumbar puncture, and culture placenta. Start treatment promptly if suspected.
Breastfeeding: OK while taking TB drugs; supplement with pyridoxine 25 mg/day.

Pediatric Considerations

Children: Ethambutol is not used.
Children on medication may attend school.

ALERT

Maximum drug doses: RIF 600 mg all regimens, PZA 2,000 mg/day or 4,000 mg 2 times per week, EMB, 600 mg/day or 4,000 mg 2 times per week
If patient does not receive PZA during entire first 2 months, extend treatment to 9 months.
M. bovis is resistant to PZA; must be treated 9 months
Continue EMB until organism susceptibility to INH plus RIF is determined (6)[A].

Second Line
Fluoroquinolones and injectable aminoglycosides. Use when MDR is suspected or patient intolerance.

ISSUES FOR REFERRAL

ALERT

Notify public health authorities for all cases of active TB. Consult infectious disease specialist for cases of drug-resistant TB and for cases involving HIV-positive patients on antiretroviral therapy.

ADDITIONAL THERAPIES

Pyridoxine: 50 mg may prevent INH-associated peripheral neuropathy, especially for patients who are malnourished or have comorbidities that increase risk of neuropathy (7)[A].
Steroids: recommended for TB meningitis (8)[A] or pericarditis (8)[B], with concomitant anti-TB therapy

SURGERY/OTHER PROCEDURES

For extrapulmonary complications (spinal cord compression, bowel obstruction, constrictive pericarditis)

COMPLEMENTARY & ALTERNATIVE MEDICINE

Vitamin D deficiency may increase susceptibility to TB and development of active TB (9)[C]. There is conflicting evidence regarding the utility of vitamin D supplementation in TB treatment.

INPATIENT CONSIDERATIONS

Negative pressure isolation with personal respirators and droplet precautions
Three consecutive negative sputum AFB smears are necessary for release from isolation

Discharge Criteria
Once TB has been excluded or the patient has effective therapy, is clinically improving, and is not an infectious risk, arrange outpatient follow-up with a provider comfortable managing TB and coordinate case management with local public health authorities.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Monthly visits to assess treatment adherence and adverse medication effects; CXR at 3rd month
For HIV positive: CD4 count, CBC, and liver enzymes q3mo
Liver enzymes monthly if chronic liver disease, alcohol use, pregnant, or postpartum. Temporarily halt medications if asymptomatic and enzymes ≥5 times normal or if symptomatic and enzymes ≥3 times normal.
Visual acuity and red " green color monthly if on ethambutol >2 months or doses >20 mg/kg/day
If culture-positive after 2 months of therapy, reassess drug sensitivity, initiate DOT, coordinate care with public health authorities, and consider infectious disease consultation (if not already involved).

PATIENT EDUCATION

Emphasize medication adherence.
Screen and treat close contacts.
Alert patient that health authorities must be notified.
http://www.cdc.gov/tb/publications/factsheets/general/tb.htm

PROGNOSIS

Few complications and full resolution of infection if medications are taken for full course as prescribed

COMPLICATIONS

Cavitary lesions can become secondarily infected.
Risk for drug resistance increases with HIV positive, treatment nonadherence, or residence in area with high incidence of resistance.
MDR-TB: resistance to INH and rifampicin
XDR-TB: resistant to fluoroquinolones (9% of MDR)

REFERENCES

11 World Health Organization. WHO global tuberculosis report 2014. http://www.who.int/tb/publications/global_report/en/. Accessed August 23, 2015.22 Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection " United States. MMWR Recomm Rep. 2010;59(RR-5):1 " 25.33 Centers for Disease Control and Prevention. National shortage of purified-protein derivative tuberculin products. MMWR Morb Mortal Wkly Rep. 2013;62(16):312.44 World Health Organization. Tuberculosis diagnostics: Xpert MTB/RIF test. http://www.who.int/tb/publications/Xpert_factsheet.pdf. Accessed 2015.55 Lawn SD. Diagnosis of pulmonary tuberculosis. Curr Opin Pulm Med. 2013,19(3):280 " 288.66 Hall RG, Leff RD, Gumbo T. Treatment of active pulmonary tuberculosis in adults: current standards and recent advances. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29(12):1468 " 1481.77 Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep. 2011;60(48):1650 " 1653.88 World Health Organization. The Treatment of Tuberculosis: Guidlines. 4th ed. Geneva, Switzerland: World Health Organization; 2010.99 Luong Kv, Nguyen LT. Impact of vitamin D in the treatment of tuberculosis. Am J Med Sci. 2011;341(6):493 " 498.

ADDITIONAL READING

Centers for Disease Control and Prevention. Trends in tuberculosis " United States, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(11):201 " 205.

CODES

ICD10

A15.9 Respiratory tuberculosis unspecified
A15.0 Tuberculosis of lung
A19.9 Miliary tuberculosis, unspecified
A18.89 Tuberculosis of other sites
A17.9 Tuberculosis of nervous system, unspecified
A18.32 Tuberculous enteritis
R76.1 Nonspecific reaction to test for tuberculosis

ICD9

011.90 Pulmonary tuberculosis, unspecified, unspecified
011.20 Tuberculosis of lung with cavitation, unspecified
018.90 Miliary tuberculosis, unspecified, unspecified
013.00 Tuberculous meningitis, unspecified
795.51 Nonspecific reaction to tuberculin skin test without active tuberculosis
014.80 Other tuberculosis of intestines, peritoneum, and mesenteric glands, unspecified

SNOMED

56717001 Tuberculosis (disorder)
154283005 Pulmonary tuberculosis (disorder)
47604008 Miliary tuberculosis (disorder)
58437007 Tuberculosis of meninges (disorder)
268376005 Mantoux positive (finding)
447330002 Tuberculosis of abdomen (disorder)

CLINICAL PEARLS

Consider TB in patients with chronic cough and one additional risk factor.
TB is fully curable when diagnosed and treated appropriately.
Children and elderly clinically exhibit fewer classic features of TB.
Involve public health authorities early in the diagnostic and treatment process for suspected cases of TB.

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