BASICSSwati Avashia, MD, FAAP, FACP, ABIHM
BASICS
DESCRIPTION
• Active tuberculosis (TB)
– Occurs from primary infection or reactivation of latent infection
– Affects 10% of infected individuals without preventive therapy
– Risk increases with immunosuppression: Highest risk is in the first 2 years after infection.
– Well-described forms: pulmonary (85% of cases), miliary (disseminated), meningeal, abdominal
• Usually acquired by inhalation of airborne bacilli from an individual with active TB. Bacilli multiply in alveoli and spread via macrophages, lymphatics, and blood. Three possible outcomes:
– Eradication: Tissue hypersensitivity halts infection within 10 weeks.
– Primary TB
– Latent TB (See “Tuberculosis, Latent [LTBI].”)
Pediatric Considerations
• 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 (directly observed therapy [DOT]).
EPIDEMIOLOGY
Incidence
• Worldwide (2014): 9.6 million: 133 cases/100,000 population; highest incidence in Asia and Africa (1)
• United States (2014): 9,421 (3.0/100,000). Incidence in foreign-born persons was 13 times that of U.S.-born persons (2).
Prevalence
Worldwide (2014): 174 cases/100,000 population
Mortality
Worldwide (2014): 1.5 million deaths due to TB
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 the 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 person, living in areas with high incidence of active TB, 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
• Screen for and treat LTBI. Report active TB to health department; test and treat all close contacts.
• Bacillus Calmette-Guérin (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 endemic countries. 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
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-γ release assays (IGRAs) measure interferon release after stimulation in vitro by M. tuberculosis antigens (3)[A]:
– Lack of cross-reaction with BCG and most nontuberculous mycobacteria
IGRA preferred for testing persons who have had BCG (vaccine or for cancer therapy) and for groups with low rates of returning to have TST’s interpreted (e.g., homeless persons and drug abusers) (3)[A].
TST is still preferred if age <5 years (4)[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 (3)[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) (3)[A].
Initial Tests-Active TB (lab, imaging)
• Three consecutive sputums (8 to 24 hours apart with at least one early morning sample) 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)
• Diabetes screen if risk factors present
• HIV: If positive, get baseline CD4 count.
• Check hepatitis B and C if injection drug users, Africa or Asia born, HIV infected or otherwise high risk.
• Extrapulmonary: urine, CSF, bone marrow, and liver biopsy for culture as indicated
• Nonspecific findings: anemia, thrombocytosis, SIADH, hypergammaglobulinemia, monocytosis, sterile pyuria
Diagnostic Procedures/Other
• Culture: takes several weeks for definitive results
• Xpert MTB/RIF: The World Health Organization endorses use 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 (5)[A]. Results in 2 hours (6).
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
Use ideal body weight for dosing. DOT recommended for all but required for children, institutionalized patients, nonadherent patients, and nondaily regimens.
First Line
• LTBI (7)[A]
– 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 or
– INH 15 mg/kg + rifapentine 300 to 900 mg weekly for 12 weeks by DOT for patients age ≥12 years
• Active TB infection (8)[A]
– Regimen 1 (preferred)
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
– Regimen 2 (preferred when more frequent DOT in continuation phase is difficult to achieve)
Initial phase:
INH/RIF/PZA/EMB daily for 8 weeks or
INH/RIF/PZA/EMB 5 days/week for 8 weeks
Continuation phase:
INH/RIF 3 times per week for 18 weeks
– Regimen 3 (use with caution if HIV infected or with cavitary disease. Missed doses can lead to treatment failure, relapse, and acquired drug resistance)
Initial phase: INH/RIF/PZA/EMB 3 times per week for 8 weeks
Continuation phase: INH/RIF 3 times per week for 18 week
– Regimen 4 (do not use if HIV positive, smear positive, or cavitary disease)
Initial phase: INH/RIF/PZA/EMB daily for 14 doses and then twice a week for 12 doses
Continuation phase: INH/RIF twice a week for 18 weeks
Pregnancy Considerations
• Treat TB in pregnancy with INH, RIF, and EMB; add pyridoxine 25 mg/day.
• 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. Treat promptly if suspected.
• Breastfeeding: OK while taking TB drugs; supplement with pyridoxine 25 mg/day.
Pediatric Considerations
• Children on medication may attend school.
• Ethambutol can be used in infants and children (8)
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 (7)[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 should be given to all persons at risk for INH-neuropathy: pregnant women, breastfeeding infants, HIV positive, diabetes, alcoholism, malnutrition, chronic renal failure, or advanced age (8)[A].
• Steroids: recommended for TB meningitis (8)[A]. Not routinely recommended for TB pericarditis (8)[B], but may be used for those at highest risk of inflammatory complications.
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.
ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS
• Negative pressure isolation with personal respirators and droplet precautions
– Three consecutive negative sputum AFB smears are necessary for release from isolation.
• Once TB has been excluded or the patient has demonstrated response to therapy 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 sputum for AFB smear and culture until 2 consecutive cultures are negative. Must confirm this prior to starting continuation phase.
• Monthly visits to assess treatment adherence and adverse medication effects; CXR after 2 months of treatment
• 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
1. World Health Organization. Global tuberculosis report 2015. http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf?ua=1. Accessed October 28, 2016.
2. Salinas JL, Mindra G, Haddad MB, et al. Leveling of tuberculosis incidence—United States, 2013–2015. Morb Mortal Wkly Rep. 2016;65(11):273–278.
3. 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.
4. Centers for Disease Control and Prevention. National shortage of purified-protein derivative tuberculin products. Morb Mortal Wkly Rep. 2013;62(16):312.
5. World Health Organization. Tuberculosis diagnostics: Xpert MTB/RIF test. http://www.who.int/tb/publications/Xpert_factsheet.pdf. Accessed October 28, 2016.
6. Lawn SD. Diagnosis of pulmonary tuberculosis. Curr Opin Pulm Med. 2013,19(3):280–288.
7. 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.
8. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63(7):e147–e195.
9. Luong Kv, Nguyen LT. Impact of vitamin D in the treatment of tuberculosis. Am J Med Sci. 2011;341(6):493–498.
SEE ALSO
• Tuberculosis, CNS; Tuberculosis, Latent (LTBI); Tuberculosis, Miliary
• Algorithm: Weight Loss, Unintentional
CODES
ICD10
• A15.9 Respiratory tuberculosis unspecified
• A15.0 Tuberculosis of lung
• A19.9 Miliary tuberculosis, unspecified
CLINICAL PEARLS
• TB is fully curable when diagnosed and treated appropriately.
• Children and elderly patients exhibit fewer classic clinical features of TB.
• Involve public health authorities early in the diagnostic and treatment process for suspected cases of TB.
• DOT is preferred.