Tuberculosis Flashcards
Trends in TB
• Worldwide trends
o Infects 1/3 of world’s population
o Most cases occur in SE Asia, sub-Saharan Africa, and Eastern Europe
• National trends
o Greatest number of TB cases:
• In foreign-born persons from high prevalence countries
• Racial/ethnic minorities (African-Americans)
• Certain populations (living in congregate settings like corrections, long term care facilities)
• Wisconsin Trends
o 70 cases in 2011 (>40% were in Milwaukee county)
o >50% cases were in persons born outside U.S.
Transmission of TB
o Humans are only natural reservoir for M. tuberculosis
o Spread person-to-person by aerosols
o Equally affects males and females
Populations with increased risk of TB
- Elderly
- Infants
- Immunocompromised (especially with HIV = TB is leaded killer)
Patients at high risk:
• AFB smear positive (because need 10^5 organisms for positive test)
• Cavitary lung disease (~10^9-10^12 organisms)
• Laryngeal disease
• Cough and fail to cover mouth
• Procedures that increase aerosolization
• Untreated disease
Describe the structure and properties of TB
• Structure
o Unusual waxy coating on cell surface
o Made of mycolic acid (>60%)
• High lipid content = impermeable to usual stains (Gram stain)
o Also includes: sulfolipids, LAM (lipoarabinomannan)
• Properties
o Intracellular pathogen
o Ingested by macrophages but not killed
o Inhibits phagolysosome fusion → prevents acidification of vacuole → can multiply within macrophages
o Obligate aerobe
o Slow growing (24 hour generation time)
o Resistant to drying and common disinfectants
Virulence mechanisms of TB
o Key virulence = ability to multiply in macrophages
o Cell wall components disrupt phagosome-lysosome interactions → interfere with oxidative killing
o LAM induces macrophages → produce TNF-α → fever, weight loss, tissue damage
o Increases IL-10 production → immuosuppression
o Cord factor = surface glycolipid only in virulent strains
• Triggers TH1 response, enhances macrophage survival
Describe the transmission of tuberculosis infection
o Reservoir: people with cavitary lung lesions with large amounts of M. tuberculosis
o Into environment via coughing or sneezing
o Transferred when another person inhales aerosolized droplet nuclei
o Small droplet nuclei (1-5 μm) may reach alveoli in mid to lower lobes → infection
• Likelihood of infection depends on: o Number of organisms expelled into air o Concentration of organisms in air (influenced by room size, ventilation) o Length of time exposed o Immune status of exposed person
Describe the pathogenesis of tuberculosis infection
o Primary TB/ TB infection = response in person who has not been previously infected
• Inhaled droplet nuclei (containing bacilli) are deposited in lung
• Some bacilli are taken up by alveolar macrophages:
Outcome:
• Myobacteria can multiply in macrophages and alveolar spaces
• Circulating macrophages can carry organisms to distant sites (lymph nodes, bloodstream) → antigen is presented to helper T cells
• Silent bacteremia = carries organisms to body sites
• Results:
• Unrestrained replication in initial and metastatic foci
• Elicits CMI response
• Activated T cells circulate → Delayed type hypersensitivity
o Surround bacilli
o Form granulomas
o Stop further multiplication and spread
Granuloma fates:
o Most heal through fibrosis an calcification
• Bacilli slowly die
o Well-oxygenated sites = bacilli may remain viable even if walled off
• Source of disease later on
o At primary sites in lung and regional nodes:
• Central necrosis lesion, surrounded by macrophages and T cells (Ghon complex/ primary complex)
• Visible on chest x-ray
- Overall = infected by not infectious to others (Latent TB infection)
- 10% chance over lifetime infection will proceed to disease (if not treated with chemoprophylaxis)
- Highest risk is within first 2 years (50% of cases occur)
Active disease (symptoms present)
• Due to a compromise of CMI = dormant bacilli begin to replicate
• Can manifest at one site or as a disseminated disease
• Reactivation often occurs in upper, well-oxygenated lobes of lung
• Lesions become necrotic, caseate, and liquefy
• Form cavities → can erode through bronchial walls
• Visible on chest x-ray
• Person is infectious to others
Signs and symptoms of TB infection
From intense cellular response
• Release of many cytokines (especially IL-1 and TNF-α)
• Cough (possible producing blood-tinged sputum)
• Weight loss
• Night sweats
• Fever and chills
Extrapulmonary TB
o From contiguous spread or lymphohematogenous dissemination from lung Results in TB in extrapulmonary site: • Bones and joints • Pleura • Lymphatic system • GU tract • CNS • GI tract More common in children and immunocompromised
Disseminated TB (military TB)
o Serious form
o Spread via blood to multiple sites throughout body
o Organs are seeded with millet-like lesions
o Commonly seen in people co-infected with HIV; young children
o High mortality if not quickly diagnosed and treated
Explain the significance of co-infection with HIV and the mycobacteria involved.
TB = most common HIV-associated opportunistic disease
o Major cause of death of people with HIV/AIDS
HIV = strongest risk factor for latent TB to progress to active disease
o HIV modifies clinical TB presentation
o Increased frequency of radiographically and atypical pulmonary TB, extrapulmonary and disseminated disease
Complicated treatment of TB/HIV
o Many drug-drug interactions
o Development of IRIS (Immune Reconstitution Inflammatory Syndrome:
• Improvement of CD4 cells
• Able to react to TB
• Result: pathologically inflammatory response
At risk for developing Mycobacterium avium complex (MAI, or MAC)
o Mycobacterial disease
o Caused by mycobacteria in environment (water, soil, food)
o Usually only infects birds
o Rarely causes disease in normal individuals
o Acquired primarily through respiratory tract; also through GI tract
o Widespread dissemination throughout body
• Especially liver, spleen, bone marrow, and intestines
o In HIV patients = results in chronic wasting disease
• Nonspecific symptoms
• Persistent fever, night sweats, fatigue, weight loss
• Intestinal involvement → abdominal pain and chronic watery diarrhea
o Diagnose with blood cultures
o Treatment: second-line anti-TB drugs
Discuss why young children need to be identified soon after contact with an individual who has active disease, including predisposing factors.
• Increased risk of developing severe disease (weeks to months of infection)
• Predisposing factors:
o Close contact with adult with active TB
o Close contact with high-risk adult
o Foreign-born or travel to TB-prevalent country
o Chronic conditions:
• Diabetes
• Malnutrition
• HIV
• Increased risk for developing TB meningitis
• Leads to deafness, blindness, paralysis, mental impairments
• Immunodeficiency
List the laboratory tests available to diagnose M. tuberculosis.
Acid-Fast Stain (Ziehl-Neelsen stain, Auramine-Rhodamine stain) Nucleic acid amplification Culture Drug susceptibility testing TB skin testing TB blood tests (IGRA)
Acid-Fast Stains
o To detect acid fast bacilli = need 5,000-10,000 bacili/ml
o Only 50-80% patients with TB have a positive smear
o If positive smear = assumed to have infectious TB
Ziehl-Neelsen stain
• Acid-fast because retain carbol fuschsin stain even after decolorizing with acid alcohol
• Appear = magenta rods on blue background
Auramine-Rhodamine Stain
• Fluorescent dye followed by acid decolorization
• Mycobacteria fluoresce bright yellow
Nucleic acid amplification
(M. tuberculosis direct test)
o Available for respiratory specimens
o Detects TB genetic material
o Performed on:
• All smear-positive specimens
• Specimens from patients with symptoms of clinical TB (even if smear-negative)
o Advantages:
• Results within 24 hours
o Disadvantages:
• Low sensitivity in smear-negative patients
• No viable organisms available for susceptibility testing
• Not applicable in resource limited stings
o A negative test does not exclude TB diagnosis
TB culture Test
o Requires 6-8 weeks
o Newer methods only need 7 days
o Identify using biochemical reactions (M. tb and M. simiae are only niacin test [+] of slow-growing mycobacteria), chromatographic analysis of mycolic acid, nuclei acid probes
TB Drug susceptibility Testing
o To first line anti-TB drugs (isoniazid, rifampin, ethanbutol, pyrazinamide)
o May take 5 weeks before know TB identification and susceptibility by traditional techniques
Resistance classification:
• Drug-resistant: to at least one of first-line anti-TB drugs
• Multi-drug resistant (MDR-TB): to at least isoniazid and rifampin
• Longer treatment (~2 years)
• More drugs and toxicity
• Increased costs
• Poorer outcomes (higher mortality, significant probability of surgery, chronic renal/neurologic toxicities)
• Extensively drug-resistant (XDR-TB): to all of first line anti-TB agents, fluoroquinolones, and at least one of three injectable 2nd line anti-TB drugs
Molecular drug-resistance tests
• Results within 1-2 days
• Sensitivity of 95% to detect rifampin resistance
• Moderate sensitivity of 85% for isoniazid resistance
TB skin testing
o Still gold standard
Process:
• Intradermal injection of purified protein derivative (PPD)
• Causes localized inflammatory response when infected with TB
• Measure induration (palpable raised area; NOT erythema) 48-72 hours after injection
• Record induration in mm (if no reaction = 0 mm)
Limitations: Problems with implementation • Requires patient follow-up • Significant inter-rater variability • Prone to rounding up errors Prone to false-negatives (reduced sensitivity) • Anergy • Booster phenomenon • Active TB (IL-10 effect) Prone to false positives (reduced specificity) • Due to rounding up error • Due to endemic NTM • Due to prior BCG vaccination
TB blood tests
(interferon-gamma release assays = IGRAs)
Process:
• Collect peripheral blood sample
• Incubate with mycobacterial antigens (present in TB but not BCG vaccine)
• If infected = WBC’s release INF-γ
• Assess amount of INF-γ released using ELISA
Advantages over TB skin testing
• Increased specificity
• More sensitive to identify recent infection
• Only one visit required
• Little inter-observer variability
• No booster responses with repeated testing
• Not affected by prior BCG vaccination
Disadvantages:
• Cannot distinguish between latent or active TB
• Still need additional tests
• Expense
• Can cross react with several non-TB mycobacterial species
• M. marinum, M. kansasii
• Only moderate agreement between different IGRA assays
• Moderately high rates of indeterminate results in children and people with advanced immunosuppression
• Variable INF-γ levels → high frequency of conversions/reversions in people who get tested often
• Not validated to detect remote TB exposure (theoretical concern about impaired sensitivity)
Explain the rationale of targeted tuberculin testing
o Skin testing only in well-defined groups:
• Due to chances of false-positives
At higher risk for TB exposure or infection
• Close contacts of person with TB
• Foreign-born people from high TB prevalence areas
• Residents and employees of high risk congregate settings
• Health care workers
• High risk racial or ethnic minorities
• Infants and youth exposed to high-risk adults
• Persons who abuse drugs or alcohol
• People with chest radiographs suggestive of prior TB
At higher risk for TB disease once infected
• HIV infection
• Recently infected with TB
• Medical conditions known to increase risk
• History of inadequately treated TB
• Children less than 4 years old
Why does TB reaction occur?
o Type IV hypersensitivity reaction (DTH)
o Indirectly detects latent TB infection
Biphasic cellular response
1) Non-specific
2) Specific:
• Neutrophils → CD4+ cells → macrophages
• CD4+ cells predominant; mostly memory cells
• Local production of IFN-γ, TNF-α, TNF-β
• Stimulate endothelial changes → increase permeability → erythema and induration
Explain the booster effect in TB skin testing
o A false-negative skin test in people with latent TB for many years may occur
o TB test stimulates (boosts) immune system of someone previously infected
o Result: positive/boosted reaction to subsequent tests
• May be interpreted as a new infection
o Prevent:
• Retest non-reactors 1-3 weeks after 1st test
• If 2nd test is positive = boosting, not a recent infection (takes >3 weeks to convert a new infection)
Describe false-negatives with TB skin testing
- Cutaneous anergy (with weakened immune system)
- Recent TB infection (within 8-10 weeks)
- Very old TB infection (many years)
- Very young age (< 6 months)
- Recent live-virus vaccination (measles)
- Overwhelming TB disease
- Some viral illnesses
- Incorrect administration of skin test
- Incorrect interpretation of reaction
Describe false-positives with TB skin testing
- Exposure to environmental mycobacteria
- Previous BCG vaccination
- Incorrect skin test administration
- Incorrect interpretation of reactions
Explain the importance of timely reporting of all TB cases (or suspected cases) to local public health departments.
- Reported within 24 hours
- Notify state epidemiologist
- Failure to report → delays in instituting treatment plan and protecting contacts
Discuss the role of the non-tuberculous mycobacteria in human disease.
Mycobacterium leprae
o Causes leprosy
o Chronic granulomatous disease of peripheral nerves and superficial tissues
Environmental mycobacteria o AKA non-tuberculous mycobacteria or atypical mycobacteria o Includes: M. avium, M. gordonae, M. chelonae o Acquired by aspiration or inoculation o Common source = water o No person to person transmission o Resistance to many 1st line anti-TB drugs o Common manifestations: • Pulmonary disease • Lymphadenitis • Skin/soft tissue infection • Disseminated infection Diagnose: • Isolation • Identification of pathogen by smears, culture, nucleic acid tests Treatment • Multi-drug regimen
Explain the concepts that are important in effective treatment of tuberculosis disease and latent infection with antimicrobials.
• ALWAYS multi-drug treatment
o Use at least 4 drugs
o Add more if resistance epidemiologically indicated
• Utilize rapid resistance testing for rifampin and INH
• Monitor adherence
• Assess response at 2 months
• Continue for appropriate length of time
o Prolonged therapy (6-9 months)
Susceptible TB:
o Non-infectious 2-3 weeks after treatment
o Cure rate > 90%
Resistant TB
o Non-infectious after several weeks- months
o Cure rate < 50%
Latent TB
o Physical exam and chest x-ray
o Standard treatment: isoniazid for 9 months
o Alternative treatment: rifampin for 4 months; isoniazid-ripapentene 1x/week for 12 weeks
