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Tuberculosis & other mycobacterial infections II Assoc Prof Meral Sönmezoğlu Division of Infectious Diseases Yeditepe University Hospital Tuberculosis • Important new findings at the global level are: • The absolute number of TB cases has been falling since 2006 (rather than rising slowly as indicated in previous global reports); • TB incidence rates have been falling since 2002 (two years earlier than previously suggested); • Estimates of the number of deaths from TB each year have been revised downwards; • In 2009 there were almost 10 million children who were orphans as a result of parental deaths caused by TB. Tuberculosis • Of the 8.6 million (range, 8.3‒9 million) incident cases of TB estimated to have occurred in 2012, • less than one third of the reported TB patients estimated to have MDR-TB (and about one-fifth of estimated incident cases) were actually detected in 2012 . • An estimated 1.1 million (13%) of the 8.6 million people who developed TB in 2012 were HIV-positive. • About 75% of these cases were in the African Region. • • Globally in 2012, an estimated 450 000 people developed MDR-TB and there were an estimated 170 000 deaths from MDR-TB . • Most TB cases and deaths occur among men, but TB remains among the top three killers of women worldwide. • There were an estimated 410 000 TB deaths among women in 2012, including 160 000 among HIV-positive women. • Half of the HIV-positive people who died from TB in 2012 were women. Of the estimated 8.6 million new TB cases worldwide in 2012, 2.9 million were women. • • There were an estimated 530 000 TB cases among children (under 15 years of age) and 74 000 TB deaths (among HIV-negative children) in 2012 (6% and 8% of the global totals, respectively). • The majority of cases worldwide in 2012 were in the South-East Asia (29%), African (27%) and Western Pacific (19%) regions. India and China alone accounted for 26% and 12% of total cases, respectively. Tuberculosis: current problems • About 3.8 million cases per year; 90% (and 98% of the 3 million deaths) are in developing countries • Multidrug resistance (“MDR-TB”) • AIDS: atypical presentations and distribution • Nosocomial spread • Foreign-born Millennium Development Goals set for 2015 Goal : Combat HIV/AIDS, malaria and other diseases Target: Halt and begin to reverse the incidence of malaria and other major diseases Indicator: Incidence, prevalence and death rates associated with TB Indicator: Proportion of TB cases detected and cured under DOTS Stop TB Partnership targets set for 2015 and 2050 By 2015: Reduce prevalence and death rates by 50%, compared with their levels in 1990 By 2050: Reduce the global incidence of active TB cases to <1 case per 1 million population per year History of TB Scientific Discoveries in 1800s • Until mid-1800s, many believed TB was hereditary • 1865 Jean AntoineVillemin proved TB was contagious • 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB Mycobacterium tuberculosis STOP TB World TB Day 24th March 1882 when Dr Robert Koch astounded the scientific community by announcing that he had discovered the cause of tuberculosis, the TB bacillus Robert Koch, discoverer of the tubercle bacillus, concluded his Nobel Lecture on December 12, 1905 Treatment 22 millionlives were saved through the Stop TB Strategy, 1995-2012. Fact sheet on tuberculosis MDR-TB cases 450 000people developed multidrugresistant tuberculosis (MDR-TB) in the world in 2012. Q&A on MDR-TB Funding 2 billionUS dollars per year needed to fill resource gap for implementing existing TB interventions. Prevalence of MDR Tuberculosis among New Cases of Tuberculosis, 2007, and Countries with at Least One Reported Case of XDR Tuberculosis as of December 2008 Donald P and van Helden P. N Engl J Med 2009;360:2393-2395 Tuberculosis Tuberculosis Tuberculosis Tuberculosis Tuberculosis Tuberculosis Tuberculosis Tuberculosis Mycobacterium tuberculosis • MTB is a bacterium belonging to the Mycobacterium genus • Its identification is based on the following characteristics:shape of the colonies, growth rate, and biochemical reactivity. • subdivided in two main groups based on their growth rates (fast vs. slow) Mycobacterium tuberculosis Mycobacterium tuberculosis • The rapidly growing Mycobacterium species (Mycobacterium abscessus, M. fortuitum, M. porcinum), whereas the majority are nonpathogenic • Majority of the slowly growing Mycobacterium species are pathogenic for humans and/or animals (e.g., all the species of the MTB complex [MTBC], M. leprae, M. ulcerans, M. avium), and only a few of them are nonpathogenic (e.g., M. terrae, M. gordonae). • MTB complex: MTB (Koch,1882), M. bovis (Karlsen and Lessel, 1970), M. africanum [25], M. microti (Reed, 1957),“M. canettii’ Mycobacterium tuberculosis • rod-shaped bacteria (0.2–0.6 m wide, 1–10 m long), nonmotile, nonencapsulated, Grampositive, • aerobes (growing most successfully in tissues with a high oxygen content such as lungs), or facultative anaerobes. • They are facultative intracellular pathogens, usually infecting mononuclear phagocytes (e.g., macrophages). Mycobacterium tuberculosis • An obligate aerobe: prefers P02 of 130 torr • Replicates every 20 hours • Natural resistance to one drug is one in every 105 to 107 cells • Natural resistance to two or more drugs is 1 in every 109 to 1012 cells Tuberculosis: the basics • The Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, M. africanum • Transmitted primarily by airborne droplet nuclei • Persons with positive AFB sputum smears are especially effective transmitters • Between 5% and 15% of infected persons will develop active disease (involving any organ) within two years Tuberculosis: the basics (2) • Populations at increased risk of infection: medically-underserved, low-income groups; immigrants; residents of long-term care or correctional facilities • Infected persons with increased risk of active disease: close contacts of cases; children < 5 years old; persons with chronic diseases (renal failure; silicosis; diabetes); immunosuppressed; HIV-positive persons Immunology of tuberculosis • Tubercle bacillus + macrophages --> processed antigen • Antigen recognition by lymphocytes --> activated lymphocytes --> lymphokines • Lymphokines--> attraction, stimulation, and retention of macrophages at antigen site • Activated macrophages--> lytic enzymes with mycobactericidal but also tissue-necrosing capacity Mycobacterium tuberculosis (MTB) enters the host within inhaled droplets. Immunology of tuberculosis (2) • Interferon-gamma probably stimulates macrophages to produce interferon-alfa and 1,25-dihydroxyvitamin D, both of which are mycobacterial inhibitors • Cytokines secreted by alveolar macrophages: interleukin 1 (fever); interleukin 6 (hyperglobulinemia), and tumor necrosis factor alpha (killing of organisms, granuloma formation, fever and weight loss) Primary tuberculous infection • Inhalation leads to infection at periphery of middle lung zone • Pneumonia 2 to 6 weeks after infection followed by lymphohematogenous dissemination • Cell-mediated immunity (manifested by positive PPD) usually contains the infection • Some organisms remain viable Pathogenesis of tuberculosis Reactivation of tuberculosis • Occurs most often in persons > 50 years of age; more common in men • Higher risk in elderly persons and in those with malnutrition, diabetes mellitus, post-gastrectomy, immunocompromise, alcoholism, HIV infection, or corticosteroid therapy Residua of primary infection • Ghon complex (after Anton Ghon, German bacteriologist): calcified peripheral focus of tuberculous infection with calcified regional (hilar) lymph node (also called Ranke complex) • Simon focus (after Georg Simon, German pediatrician): focus at apex of lung, containing viable organisms and manifested on x-ray as “fibrous cap” Axioms on Simon foci • “If humans did not have apices to their lungs, the tubercle bacillus would not have survived as a human pathogen.” • “Once a Simon focus has formed, one will eventually die of tuberculosis if something else doesn’t cause death first.” TB Pathogenesis (1) Pathogenesis is defined as how an infection or disease develops in the body. TB Pathogenesis (2) Latent TB Infection (LTBI) • Occurs when tubercle bacilli are in the body, but the immune system is keeping them under control • Detected by the Mantoux tuberculin skin test (TST) or by blood tests such as interferon-gamma release assays (IGRAs) which include: – QuantiFERON®-TB Gold test (QFT-G) – QuantiFERON®-TB Gold In-Tube (QFT-GIT) – T-Spot®.TB test (T-SPOT) TB Pathogenesis (3) TB Disease • Develops when immune system cannot keep tubercle bacilli under control – May develop very soon after infection or many years after infection • About 10% of all people with normal immune systems who have LTBI will develop TB disease at some point in their lives • People with TB disease are often infectious TB Pathogenesis (4) Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli) TB Pathogenesis (5) 2 bronchiole blood vessel tubercle bacilli alveoli Tubercle bacilli multiply in alveoli, where infection begins TB Pathogenesis (6) 3 brain bone lung kidney A small number of tubercle bacilli enter bloodstream and spread throughout body TB Pathogenesis (7) LTBI 4 special immune cells form a barrier shell (in this example, bacilli are in the lungs) • Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli • These cells form a barrier shell that keeps the bacilli contained and under control (LTBI) TB Pathogenesis (8) TB Disease 5 shell breaks down and tubercle bacilli escape and multiply (in this example, TB disease develops in the lungs) • If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease • This process can occur in different places in the body LTBI vs. TB Disease Latent TB Infection (LTBI) TB Disease (in the lungs) Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli in the body in the body TST or blood test results usually positive TST or blood test results usually positive Chest x-ray usually normal Chest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures may be positive No symptoms Symptoms such as cough, fever, weight loss Not infectious Often infectious before treatment Not a case of TB A case of TB Caseous necrosis of tuberculosis • This walled-off, friable, cheesy nodule in the subapical region (a Simon focus) develops from organisms spread hematogenously from the initial focus of infection in the lower half of the lung. Reactivation of this lesion would probably destroy the capsule, and the caseous material would be expectorated leaving a cavity. Tuberculous pleuritis non-necrotizing granulomas the Langhans' giant cells, the epithelioid cells, and the lymphocytes. Progression to active tuberculosis • One year after infection: approximately 5% • Thereafter: approximately 5% (lifetime) • It now seems that many people eventually outlive their tubercle bacilli and are consequently vulnerable to reinfection (Stead, studies in Arkansas, early 1980s) • Tuberculin-positive persons with HIV infection: risk is 7% to 10% per year Insights from genotyping of M. tuberculosis isolates (N Engl J Med 2003; 349: 1149-1155) • Previously, it was thought that 90% of TB cases in industrialized nations resulted from reactivation of infection acquired in remote past. • It now seems that recent transmission causes 40% to 50% of TB cases in urban areas. The cavity (1) • Formation of the cavity is the pivotal event in the evolution of pulmonary tuberculosis. • Mortality of cavitary pulmonary tuberculosis without treatment approaches 90%. • All therapies prior to 1948 were aimed at closing cavities. The cavity (2) • Even healed, cavities are unstable. • The walls of cavities contain extensive sheets of bacilli (up to 1011 bacilli/gram). • The cavity is thinnest at the point of penetration of bronchi. • Open cavities may persist for years, constantly draining bacilli into the rest of the bronchial tree. Complications of pulmonary tuberculosis • Cough, fever, night sweats, weight loss, anemia • Massive hemoptysis (erosion of a vessel in the wall of a cavity; a dilated vessel in a cavity (Rasmussen’s aneurysm; or an aspergilloma) • Progressive pulmonary disease, rarely ARDS • Hyponatremia due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Major syndromes of extrapulmonary tuberculosis • Disseminated (miliary) tuberculosis • “Serosal” tuberculosis (anatomic spaces or cavities): pleurisy, pericarditis, meningitis, peritonitis, arthritis • Tuberculosis of solid organs: renal (genitourinary), osteomyelitis, adrenal glands (Addison’s disease), lymph nodes Miliary tuberculosis: diagnostic aids • Repeat physical examination: choroidal tubercles, palpable lymph nodes • Repeat CXR and tuberculin test • Cultures: sputum (up to 63% positive), urine, bone marrow, CSF, gastric aspirate, pleural fluid • Biopsy: palpable nodes, marrow, liver • Therapeutic trial “Cryptic miliary tuberculosis” • An occult illness with gradual decline in general health • Often no significant fever • Non-reactive tuberculin skin test • Normal chest x-ray Frequency order of extrapulmonary sites 1. Lymph node 2. Pleura 3. Genitourinary tract 4. Bone and joints 5. Meninges 6. Peritoneum Tuberculous pleurisy • Subpleural focus ruptures into the pleural space • Usually younger adults, 3 to 7 months after primary tuberculous infection • Abrupt or insidious onset. DDx: pneumonia, pulmonary infarct, tumor, others • Natural history untreated: 65% of 141 patients developed active tbc (Roper & Waring) Tuberculous meningitis • Rupture of subependymal tubercle into subarachnoid space (“Rich focus”; Rich and McCormack, 1933) • The intrathecal tuberculin reaction (instillation of PPD material into CSF of PPD-positive volunteers) • Usually occurs within first 6 months of infection; now seen in older adults Tuberculous pericarditis • Rupture of a tuberculous mediastinal lymph node into the pericardial sac • Mortality 80% to 90% without treatment. Major problems even with appropriate Rx • Diagnosis is difficult to make short of total pericardiectomy • Constrictive pericarditis • Can extend into myocardium --> fiber atrophy Tuberculous peritonitis • Onset is usually insidious. Mortality 45% to 55% untreated but as low as 0% to 4% with treatment • Polar types: plastic or adhesive type (“doughy abdomen”) and exudative or serous peritonitis with ascites • Presentations: debilitating FUO; chronic abdominal pain; ascites of unknown origin Tuberculous arthritis • Tuberculous focus in bone ruptures into joint space; trauma predisposes • Adults: spine 50%, hips 15% • Children: Knees 15% • Insidious joint pain and swelling, most often involving large weight-bearing joints • Absence of proteolytic enzymes explains preservation of joint space Genitourinary tuberculosis • Tubercle of the glomerulus ruptures into the calyceal system • May progress to involve the entire kidney (“autonephrectomy”) and/or may spread throughout the GU tract (prostatitis, epididymitis, salpingitis) • Insidious onset Tuberculous osteomyelitis Subchondral osteoporosis with surrounding ring of sclerosis Spine: anterior involvement of vertebral bodies with disk collapse (Pott’s disease) Suspect: Monoarticular arthritis of insidious onset; paraspinous mass; back pain Tuberculosis of the adrenal glands (Addison’s disease) • Tuberculosis formerly the major cause of the disease as described by Thomas Addison (now rare; most common cause is idiopathic [autoimmune]) • Wasting, hyperpigmentation, low blood pressure, hyponatremia, hyperkalemia Tuberculosis in HIV-positive patients • Present in 5% to 35% of patients diagnosed with AIDS • Precedes diagnosis of AIDS in 67% of patients • Although most of these cases result from reactivation, CXR often resembles progressive primary tuberculosis • Multiple drug resistance a major problem AFB smears • Three morning specimens • Fluorescent methods are more sensitive than traditional Kinyoun or Ziehl-Neelsen method • Predictive value of a positive test decreases strikingly as prevalence of the disease decreases (Bayes’ s theorem) Tuberculin skin test guidelines • 5 mm for close contacts; for persons with compatible chest x-rays; and for HIV-infected persons • 10 mm for recently-infected persons, persons with high-risk medical conditions, and high-risk patients under 35 years of age • 15 mm for low-risk persons under age 35 Rapid laboratory confirmation • Fluorochrome smear on concentrated specimens • Rapid methods of detection: Bactec system; polymerase chain reaction • Rapid mechanisms of identification: DNA probes; HPLC • Rapid methods of susceptibility testing • Handle reports as critical laboratory values Non tuberculos mycobacteria • M. avium Complex (MAC) • M. gordonae • M. haemophilum • M. immunogenum • M. malmoense • M. marinum • M. mucogenicum • M. chelonae • M. nonchromogenicum • M. scrofulaceum • M. fortuitum • M. simiae • M. smegmatis • M. szulgai • M. terrae complex • M. ulcerans • M. xenopi • M. kansasii • M. abscessus • M. genavense Nontuberculous mycobacteria (NTM) • Synonyms: atypical mycobacteria, mycobacteria other than tuberculosis (MOTT), nontuberculous mycobacteria (NTM) • Numerous species; widespread • Can be difficult to treat • “MAC” = M. avium-intracelluare complex Pulmonary disease due to NTM in immunocompetent persons • Isolation of organism from sputum does not necessarily imply disease • M. avium-intracelluare (especially in the Southeast) and M. kansasii (especially in the west) cause disease resembling tuberculosis (clinically milder but more difficult-to-treat) Mycobacterium avium-intracelluare (“MAC”) in HIV disease • Disseminated “MAC” infection with or without pulmonary involvement • Prolonged fever, weight loss, hepatosplenomegaly, diarrhea, abdominal pain • Positive blood cultures; AFB also found in bone marrow, liver, and often stool Lymphadenitis due to NTM • Usually due to M. scrofulaceum or M. avium-intracelluare • “Scrofula”: cervical lymphadenitis, usually in children • Usual treatment of choice: surgical excision without chemotherapy Swimming pool and fish-tank granuloma • Caused by Mycobacterium marinum • Small violet nodule or pustule at the site of minor trauma may evolve into crusted ulcer or abscess • Multiple lesions can resemble lymphocutaneous sporotrichosis Infections related to injections or surgery • “M. fortuitum complex”: Mycobacterium fortuitum, M. chelonae, M. abscessus (all “rapidly-growing mycobacteria”) • Opportunistic pathogens causing wound infections (which can be epidemic) and skin infections Leprosy (Hansen’s disease) A chronic granulomatous infection attacking superficial tissues, especially the skin and peripheral nerves M. leprae has not been successfully cultured. It can be propagated in armadillos and in the footpads of mice Phenolic glycolipid I binds to C3 which mediates phagocytosis by macrophages Tuberculoid leprosy Delayed hypersensitivity to M. leprae antigens is present (in contrast to lepromatous leprosy) Large, erythematous, anesthetic plaques with flat, dry, hairless centers and raised outer edges Limited but severe involvement of peripheral nerves Lepromatous leprosy Anergy to M. leprae antigens B-cell over-activity: polyclonal hyperimmunoglobulinemia with many unusual antibodies (e.g., false-positive VDRL [RPR]; secondary amyloidosis) Massive infiltration of dermis--> leonine facies Nerve involvement is diffuse but less severe than in tuberculoid form