Tuberculosis1

Med II Tuberculosis Denise Etiologic Agent

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With the dev’t of specific immunity & the accumulation of large #s of activated macrophages  granulomatous lesions form (contains lymphocytes, epithelioid cells & giant cells)

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Bacillary antigens  stimulate T lymphocytes  release lymphokines  aggregate around the lesion’s center  neutralize tubercle bacilli  necrotic material resembles soft cheese (caseous necrosis)  healed lesions undergo calcification Bacilli transported by macrophages to regional lymph nodes: same evolution in other organs & they tend to heal In young children with poor natural immunity, hematogenous dissemination may result in fatal military TB or TB meningitis

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Mycobacterium tuberculosis: most frequent, most impt agent of human agent

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M. bovis: once an impt cause of TB transmitted by unpasteurized milk

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M. africanum

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M. microti: “vole” bacillus, less virulent, rarely encountered

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M. canettii

Mycobacterium tuberculosis

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Rod-shaped, nonspore-forming, thin aerobic bacterium (0.5umx3um)

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Acid fast: due to high content of mycolic acids, long-chain cross-linked FAs and other cell wall lipids (also exhibited by Nocardia, Rhodococcus, Legionella, Isospora, Crypstosporidium Genome sequence: ~4000 genes + GC content

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From Exposure to Infection

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M. tuberculosis: transmitted by droplet nuclei, which are aerosolized by coughing, sneezing or speaking  remain suspended in the air for several hours  gain direct access to the terminal passages when inhaled Impt determinants of transmission: a. intimacy and duration of contact b. degree of infectiousness of the case c. shared environment of the contact Pxs with sputum containing AFB visible by microscopy: highly infectious; they often have cavitary pulmonary disease or TB of the respiratory tract Pxs with sputum smear (-)/culture (+): less infectious Pxs culture (-) + extrapulmonary TB: noninfectious

From Infection to Disease

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Primary TB: clinical illness ff infection; common among children up to 4 years old; may be severe and disseminated; usually not transmissible Majority of infected individuals develop TB within the first year or two after infection Secondary TB: dormant bacilli that has persist for years before reactivating; often infectious Age: impt determinant of the risk of disease after infection  Late adolescence & early adulthood: highest incidence of TB  Among women peaks at 25-34 y/o

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Risk may ↑ in elderly due to waning immunity & comorbidity

HIV co-infection: most potent risk factor for TB

Pathogenesis & Immunity  Inhaled bacilli trapped in the upper airways and expelled by ciliated mucosal cells and some reach the alveoli

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In the alveoli, activated alveolar macrophages ingest the bacilli  association of C2a with the bacterial cell wall  C3b opsonization of the bacteria  recognition by the macrophages  phagocytosis Genes to confer virulence to M. Tb:  katG—encodes for catalase protective against oxidative stress  rpoV—main sigma factor initiating transcription  erp—CHON required for multiplication

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Initial stage of host-bacterium interaction: host’s macrophages contain bacillary multiplication by producing proteolytic enzymes and cytokines or the bacilli begin to multiply  their growth quickly kills the macrophages which lyse  monocytes ingest bacilli released from the macrophages

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2-4 wks after infection: 2 more host responses: tissuedamaging response (due to delayed type hypersensitivity) + macrophage-activating response (cell-mediated phenomenon)

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Cell mediated immunity confers protection against M. Tb Humoral immunity: no defined role in protection  Macrophages: directly phagocytize tubercle bacilli  T cells (CD4+): protection thru prod’n of lymphokines Macrophages secrete a number of cytokines:  Il-6: cause hyperglobulinemia  TNF-a: kill mycobacteria, formation of granuloma, fever, weight loss

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Macrophages: critical in processing and presenting antigens to T lymphocytes  proliferation on CD4+ lymphocytes  that is why in HIV-infected ones, inability to contain mycobacterial proliferation is apparent

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Reactive CD4+ T cells  produce cytokines of the TH1 pattern and participate in MHC class II-restricted killing of cells infected with M. Tb M. Tb possesses various CHON antigens present in the cytoplasm and cell wall Coincident with the appearance of immunity, DTH to M. Tb develops: basis of the PPD skin test Cellular mechanisms responsible for PPD reactivity: related to previously sensitized CD4+ lymphocytes which are attracted to the skin-test site

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Clinical Manifestations Primary TB (1) Primary Disease  Results from an initial infection with tubercle bacilli  In areas of high TB prevalence, often seen in children and frequently localized to the middle and lower lung zones  Lesion after infection: peripheral and accompanied by hilar or paratracheal lymphadenopathy  Small calcified nodule—Ghon lesion

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In immunocompromised & malnourished, primary Tb may progress rapidly to clinical illness

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Initial lesion ↑ in size

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Progressive primary TB: primary site enlarges  central portion goes necrotic  acute cavitation develops In young children, hilar or mediastinal lymphadenopathy due to the spread of the bacilli from the lung parenchyma thru lymphatic vessels develop

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Pleural effusion—due to penetration of bacilli into the pleural space from an adjacent subpleural focus

Enlarged lymph nodes may  compress bronchi  obstruction  segmental or lobar collapse Partial obstruction: may cause emphysema & bronchiectasis Hematogenous dissemination: common & symptomatic, may result in severe manifestations

(2) Postprimary Disease  Results from endogenous reactivation of latent infection  Localized to the apical and posterior segments of the upper lobes where the high O2 conc favors mycobacterial growth

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With cavity formation, liquefied necrotic contents are ultimately discharged into the airways  satellite lesions within the lungs that may in turn undergo cavitation

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Discovered only after severe destructive lesions of the kidneys Diagnosis: IV pyelogram; when calcifications and ureteral strictures are present, they are suggestive of GUT TB More common in females affecting the fallopian tubes and endometrium that may cause infertility, pelvic pain and menstrual abnormalities Responds well to chemotherapy

E. Skeletal TB  Pathogenesis related to reactivation of hematogenous foci or spread from adjacent paravertebral lymph nodes  Weight bearing joints: affected most commonly  Spinal TB (Pott’s disease or tuberculous spondylitis)— involved two or more adjacent vertebral bodies  Upper thoracic spine: most common site of spinal TB in children; lower thoracic and upper lumbar vertebrae in adults   

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Tuberculous pneumonia: massive involvement of pulmonary segments or lobes with coalescence of lesions Nonspecific S/S: night sweats, weight loss, anorexia, general malaise & weakness Cough: in the majority of cases Massive hemoptysis: due to erosion of a fully patent vessel located in the wall of a cavity; may also result from rupture of a dilated vessel in a cavity (Rasmussen’s aneurysm) or from aspergilloma formation in an old cavity Pleuritic chest pain: in pxs with subpleural parenchymal lesions but can also result from muscle strain due to persistent coughing PE: of limited use in PTB

Extrapulmonary TB In order of frequency: a. lymph nodes b. pleura c. genitourinary tract d. bones e. joints f. meninges g. peritoneum h. pericardium A. Lymph Node TB (Tuberculous Lymphadenitis)  Most common presentation of extrapulmonary TB  Mainly due to M. Tb  Presents as painless swelling of the lymph nodes, most commonly at cervical and supraclavicular sites (scrofula)  Discrete in early disease but may be inflamed and have a fistulous tract draining caseous material  Diagnosis: FNAB B. Pleural TB  Penetration by tubercle bacilli into the pleural space  PE: dullness to percussion & absence of breath sounds  CXR reveals effusion & some shows parenchymal lesion  Thoracentesis: to ascertain nature of effusion  Fluid can be straw-colored, sometimes hemorrhagic; can be an exudate with a CHON conc >50% of that in serum, a normal to low glucose conc, pH < 7.2, detectable WBCs  Neutrophils: early stage, Mononuclear cells: late stage

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Tuberculous empyema: less common complication; due to a rupture of a cavity, with delivery of a large # of organisms into the pleural space or of a bronchopleural fistula  CXR: pyopneumothorax with an air-fluid level  Effusion: purulent, thick, contains large #s of lymphocytes  AFB smear and culture is often (+)

C. TB of the Upper Airways  Nearly always a complication of advanced cavitary pulmonary TB  May involve larynx, pharynx, epiglottis  S/S: hoarseness, dysphagia, chronic productive cough  Acid-fast smear often (+)  Can may have similar features but is usually painless D. Genitourinary TB  ~15% of all extrapulmonary cases; due to hematogenous seeding ff primary infection  Common presentations: urinary frequency, dysuria, hematuria, flank pain

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Kyphosis: with collapse of vertebral bodies in advanced disease CT or MRI: reveals the characteristic lesion and suggest its etiology Diagnosis: aspiration of the abscess or bone biopsy Paraplegia: catastrophic complication of Pott’s disease TB of the hip joints causes pain and limping TB of the knee: pain and swelling ff trauma If unrecognized bones may be destroyed

F. Tuberculous Meningitis & Tuberculoma  TB of the CNS: ~5%

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Results from the hematogenous spread of primary or Postprimary pulmonary disease or from rupture of a subependymal tubercle into the subarachnoid space Common presentations: headache, mental changes or acutely as confusion, lethargy, altered sensorium and neck rigidity Evolves over 1-2 weeks Paresis of CNs: frequent finding Involvement of cerebral arteries  focal ischemia Hydrocephalus: common Diagnosis: Lumbar puncture CSF content:  High leukocyte count (predominance of lymphocytes)  CHON content of 1-8g/dL  Low glucose conc  AFB on direct smear of CSF sediment  Culture: diagnostics in 80% of cases Tx: glucocorticoids (dexamethasone) enhance the chances of survival and reduce the frequency of neurologic sequelae

G. GIT TB  Pathogenetic mechanisms:  Swallowing of sputum with direct seeding  Hematogenous spread  Ingestion of milk from cows affected by bovine TB  Terminal ileum & cecum: sites most commonly involved

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Common presentations: abdominal pain, diarrhea, obstruction, hematochezia and palpable mass in the abdomen, fever, night sweats, weight loss Tuberculous peritonitis: follows either from the direct spread of tubercle bacilli from ruptured lymph nodes and intraabdominal organs or hematogenous seeding Diagnosis of tuberculous peritonitis: paracentesis

H. Pericardial TB  Due to direct progression of a primary focus within the pericardium, to reactivation of latent focus, or to rupture of an adjacent lymph node  Subacute onset  Effusion develops in many cases  Diagnosis: pericardiocentesis under echocardiographic guidance  Fluid subject for biochemical, cytological and microbiologic study; exudative in nature

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Tx. Glucocorticoids in the management of acute disease, reducing effusion, facilitating hemodynamic recovery and thus ↓ mortality

I. Miliary or Disseminated TB  Due to hematogenous spread of tubercle bacilli

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In children, due to primary infection. IN adults, due to either recent infection or reactivation of old disseminated foci

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Lesions are usually yellowish granulomas (1-2mm) Clinical manifestations: fever, night sweats, anorexia, weakness and weight loss Pxs may have cough and some have abdominal symptoms PE: hepatomegaly, splenomegaly, lymphadenopathy CXR: miliary reticulonodular pattern; large infiltrates; interstitial infiltrates, pleural effusion Sputum smear (-) in 80% of cases Diagnosis: bronchoalveolar lavage and transbronchial biopsy

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solitary pulmonary nodule to diffuse alveolar infiltrates in a patient with ARDS — may be seen PPD Skin Testing & Diagnosis of Latent TB Infection

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Test is of limited value in the diagnosis of active TB because of its low sensitivity & specificity  (+) rxns obtained: when px have been infected with M. Tb but do not have active disease when pxs have been sensitized by nontuberculous mycobacteria Cytokine Release Assays

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HIV-Associated TB

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TB can appear at any stage of HIV infection When cell mediated immunity is only partially compromised, PTB presents with upper lobe infiltrates & cavitation without significant lymphadenopathy or pleural effusion In late stages, a primary TB pattern with diffuse interstitial or miliary infiltrates, little or no cavitation and intrathoracic lymphadenopathy is more common Extrapulmonary TB forms are lymphatic, disseminated, pleural and pericardial

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Diagnosis is difficult due to ↑ frequency of sputum smear (-)and atypical CXR findings, lack of classic granuloma and (-) PPD skin tests

Diagnosis  Key to diagnosis: high index of suspicion  Diagnosis is first entertained when the CXR of a px is abnormal

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If the px has no complicating medical conditions that favor immunosuppression, the CXR may show the typical picture of upper lobe infiltrates with cavitation The longer the delay between the onset of symptoms and the diagnosis, the more likely is the finding of cavitary disease AFB Microscopy:  Presumptive diagnosis is based on this

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Permit the diagnosis of tuberculosis in as little as several hours

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Applicability is limited by low sensitivity (lower than culture, but higher than AFB18 smear microscopy) & high cost

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Most useful for the rapid confirmation of tuberculosis in persons with AFB-positive sputa

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May also have utility for the diagnosis of AFB-(-) pulmonary & extrapulmonary TB in selected pxs Drug Susceptibility Testing

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Initial isolate of M. Tb should be tested for susceptibility to HRE

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Although the "classic" picture is that of upper lobe disease with infiltrates and cavities, virtually any radiographic pattern — from a normal film or a

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injectables: streptomycin (formerly a first-line agent), kanamycin, amikacin, and capreomycin

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oral: ethionamide, cycloserine, and paraaminosalicylic acid

fluoroquinolone antibiotics have become the most commonly used second-line drugs: levofloxacin, gatifloxacin, moxifloxacin Regimens: initial phase & a continuation phase

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Initial phase: the majority of the tubercle bacilli are killed, symptoms resolve & the px becomes noninfectious Continuation phase: required to eliminate persisting mycobacteria & prevent relapse Tx regimen of choice: 2-month initial phase of HRZE followed by a 4-month continuation phase of HR Tx may be daily or 3x weekly or twice weekly ff an initial phase of daily therapy

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May be conducted directly (with the clinical specimen) or indirectly (with mycobacterial cultures) on solid or liquid medium Radiographic Procedures

bactericidal activity (ability to rapidly reduce the number of viable organisms and render patients noninfectious)  sterilizing activity (ability to kill all bacilli and thus sterilize the affected organ, measured in terms of the ability to prevent relapses)  low rate of induction of drug resistance Second line agents:

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recommended on the basis of their:

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A sputum specimen obtained from a patient with a productive cough

Specimens may be inoculated onto egg- or agarbased medium (e.g., Lowenstein-Jensen or Middlebrook 7H10) & incubated at 37°C under 5% CO2  Because most species of mycobacteria, including M. tuberculosis, grow slowly, 4 to 8 weeks may be required before growth is detected Nucleic Acid Amplification

Add’l Diagnostic Procedures  Sputum induction by ultrasonic nebulization of hypertonic saline: for pxs who cannot produce a sputum  fiberoptic bronchoscopy with bronchial brushings or transbronchial biopsy of the lesion  Bronchoalveolar lavage of a lung segment containing an abnormality may also be performed Adjunctive Diagnostic Test  Serologic diagnosis based on detection of Ab to a variety of mycobacterial Ags

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Requires overnight incubation of a peripheralblood sample with PPD & control antigens followed by measurement of IFN released by sensitized lymphocytes in an ELISA

Treatment  2 aims of TB: interrupt TB transmission by rendering pxs noninfectious prevent morbidity & mortality by curing pxs with TB disease  4 first-line agents: HRZE well absorbed after oral administration peak serum levels: 2-4h complete elimination within 24h

Auramine-rhodamine staining and fluorescence microscopy—commonly used by modern labs

Staining with Kinyoun or Ziehl-Neelsen basic fuchsin dyes—more traditional, satisfactory but time consuming  3 sputum specimens, collected preferably early in the morning Mycobacterial culture  Definitive diagnosis is based on this

Most widely used in screening for M. tuberculosis infection

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Continuation phase of once-weekly rifapentine & isoniazid: equally effective for HIV-seronegative patients with noncavitary PTB who have (-) sputum cultures at 2mos Pxs with PTB & delayed sputum-culture conversion: tx extended by 3mos, for a total course of 9mos Pxs with sputum culture-(-) PTB: tx may be reduced to a total of 4mos To prevent isoniazid-related neuropathy, pyridoxine (10 to 25 mg/d) should be added to the regimen given to persons at high risk of vitamin B6 deficiency Lack of adherence to tx: most impt impediment to cure Direct observation of tx & provision of FDC products: addition to measures addressing noncompliance

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FDC products: H/R, H/R/Z & H/R/Z/E

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Strongly recommended as a means of minimizing the likelihood of prescription error and of the development of drug resistance as the result of monotherapy

Monitoring Tx Response & Drug Toxicity  Bacteriologic evaluation: preferred method  Sputum examined monthly until cultures become (-)

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With the recommended regimen, >80% of pxs will have (-) sputum cultures at the end of the 2nd month of tx In some pxs, especially those with extensive cavitary disease & large # of organisms, AFB smear conversion may follow culture conversion When a px's sputum cultures remain (+) at 3mos, tx failure & drug resistance should be suspected After the completion of tx, neither sputum examination nor CXR is recommended for follow-up purposes Hepatitis: most common adverse rxn

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All adult pxs should undergo baseline assessment of liver function (e.g., measurement of serum levels of hepatic aminotransferases & serum bilirubin) Hypersensitivity: require discontinuation of all drugs rechallenge to determine which agent is the culprit Hyperuricemia & arthralgia: caused by pyrazinamide can usually be managed by the administration acetylsalicylic acid; if gouty arthritis develops, pyrazinamide should be stopped

Tx Failure & Relapse  Current isolate be tested for susceptibility to first- and second-line agents  Cardinal rule in the is deteriorating px: add more than one drug at a time to a failing regimen: at least 2 & preferably 3 drugs that have never been used & to which the bacilli are likely to be susceptible should be added  Mycobacterial strains infecting pxs who experience a relapse after apparently successful tx are less likely to have acquired drug resistance than are strains from pxs in whom tx has failed  It is prudent to begin the tx of all relapses with all five first-line drugs pending the results of susceptibility testing HIV-Associated TB  Amithiozone: not recommended to HIV-infected pxs with TB due to fatal skin rxns  3 impt considerations relevant to TB tx in HIV pxs:

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an ↑ frequency of paradoxical rxns drug interactions between HAART & rifamycins

dev’t of rifampin monoresistance with widely spaced intermittent treatment  HIV infected TB pxs: candidates for HAART  Highly active antiretroviral therapy (HAART): paradoxical rxns: exacerbations in S/S & lab or radiographic manifestations of TB  Pathogenesis of paradoxical rxns: immune response to antigens released as bacilli are killed by effective chemotherapy  Glucocorticoids: used for more severe rxns  Rifampin, a potent inducer of enzymes of the cytochrome P450 system, lowers serum levels of many HIV protease inhibitors & some nonnucleoside reverse transcriptase inhibitors, essential drugs used in HAART regimens Drug-Resistant TB  Strains of M. TB resistant to individual drugs arise by spontaneous point mutations in the mycobacterial genome, which occur at low but predictable rates  Because there is no cross-resistance among the commonly used drugs, the probability that a strain will be resistant to two drugs is the product of the probabilities of resistance to each drug and thus is low  Dev’t of drug-resistant TB: invariably the result of monotherapy  Primary drug resistance is that in a strain infecting a patient who has not previously been treated  Acquired resistance develops during tx with an inappropriate regimen  Although the 6-month regimen is generally effective for pxs with initial isoniazid-resistant disease, it is prudent to include ethambutol & pyrazinamide for the full 6mos

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For strains resistant to isoniazid and rifampin, combinations of a fluoroquinolone, ethambutol, pyrazinamide & streptomycin For pxs with bacilli resistant to all of the first-line agents, cure may be attained with a combination of four secondline drugs, including one injectable agent

Prevention of TB BCG vaccination  Safe & rarely causes serious complications  Side effects: ulceration at vaccination site & regional lymphadenitis  Recommended for routine use at birth in countries with high TB prevalence Tx of Latent TB Infection  Based on the results of a large # of randomized, placebocontrolled clinical trials demonstrating 6-12mos course of isoniazid reduces the risk of active TB in infected TB by 90%  Optimal duration of tx: 9-10mos  Candidates for tx of latent TB: identified by PPD skin testing of persons in defined high risk-groups  Reactions are read at 48 to 72 h as the transverse diameter in millimeters of induration; the diameter of erythema is not considered

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Area of induration =5mm in diameter: (+) reactions for close contacts of infectious cases, persons with HIV infection, persons receiving drugs that suppress the immune system, & previously untreated persons whose chest radiograph is consistent with healed TB 10-mm cutoff is used to define positive reactions in most other at-risk persons Infants & children who have come into contact with infectious cases should be treated and should have a repeat skin test 2 or 3 months after contact ends Isoniazid is administered at a daily dose of 5 mg/kg (up to 300 mg/d) for 9 months a 6-month period of treatment has been recommended in the past and may be considered for HIV1-negative adults with normal chest radiographs when financial considerations are important An alternative regimen for adults is 4 months of daily rifampin Isoniazid should not be given to persons with active liver disease

Basics of Control  Highest priority in any tuberculosis control program: prompt detection of cases & the provision of short-course chemotherapy to all TB pxs  DOTS strategy promoted by the WHO:

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political commitment by the gov’t to sustained TB control

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case detection through microscopic exam of sputum from pxs who present to health care facilities with cough of >2-3 wks' duration

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administration of standard short-course chemotherapy to all sputum smear-(+) pxs under proper case-management conditions, including direct observation of drug ingestion

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establishment & maintenance of a system of regular drug supply

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establishment & maintenance of an effective surveillance & monitoring system that allows assessment of tx outcomes