Mycobacterial Diseases• Tuberculosis can infect – Immunocompromised and competent• Atypical Mycobacteria can infect – Immunocompromised (TB-like, non-TB-like)• Atypical Mycobacteria still can infect – Immunocompetent (rare, syndromes)• Other Mycobacteria
Nontuberculous Mycobacteria• 1954 Runyon first NTM classification• >100 NTM species• Other names – Mycobacteria other than tuberculosis (MOTT) – Atypical – Environmental – Opportunistic• Variable pathogenicity and geographic regions• 40% cause diseases in human• Immunosuppressed host
MYCOBACTERIA what they can Cause• Mycobacteria tuberculosis • Mycobacteria kansasii – Ghon complex in primary TB (middle lobe – Chronic pulmonary disease similar to or apical lower lobe) classic TB except it is noninfectious – Secondary TB in apical portion of upper and has less extrapulmonary or lobes disseminated diseases – Tuberculous effusions - mature – 15% of patients have disseminated lymphocytes disease• Mycobacteria avium-intracellular – Disseminated disease in the immunocompromised and patients with – High incidence in AIDS patients and late stage AIDS elderly women – Sepsis and positive blood cultures • Mycobacteria marinum common – Superficial granulomatous skin – AIDS: fever of unknown origin and weight infection (“swimming pool” or “fish tank” loss common; pulmonary disease granulomas) involving traumatized skin uncommon of the extremities in contact with poorly chlorinated fresh water – Immunocompetent hosts or elderly: – Sporotrichosis-like lesions (chain of pulmonary disease common ulcers up the arm along the lymphatics) – Most common AFB involving bone marrow • Mycobacteria simiae• Mycobacteria gordonae – Pulmonary disease in humans – Rare human infections • Mycobacteria scrofulaceum• Mycobacteria szulgi – Scrofula---unilateral painless – Rare human infections lymphadenitis, involving lymph nodes high in the neck in healthy children
MYCOBACTERIA what they can Cause• Mycobacteria fortuitum/chelonae • Mycobacteria haemophilum complex – Painful subcutaneous nodules, – Skin infections with draining abscesses swellings and ulcers progressing into – May have involvement of lungs, bone, abscesses and draining fistulas CNS, and prosthetic heart valves, and – Disseminated disease in AIDS patients disseminated disease • Mycobacteria xenopi – Associated with post-surgical wound, – TB-like pulmonary disease; Rare needle injections, renal transplant infection in AIDS patients and recipients immunocompetent hosts – Sporotrichosis-like lesions (chain of ulcers • Mycobacteria paratuberculosis up the arm along the lymphatics) in immunocompromised hosts – Associated with Crohn’s disease• Mycobacteria ulcerans • Mycobacteria bovis – “Bairnsdale (Buruli) ulcer”---a painless – Typical produces TB in cattle, but may “boil” or lump in skin of extremities at the infect humans site of previous trauma, developing into a – Human disease similar to that caused shallow non-healing ulcer with a necrotic by M. tuberculosis base (Tropical disease) – Urinary bladder infections with BCG• Mycobacterium leprae chemo of bladder cancer – Most usual presentation: numbness in the earlobes or nose – Several varieties: • Lepromatous leprosy • Tuberculoid leprosy
Atypical Mycobacterium• Investigations have defined >100 facultative saprophytes and entities that are acid-fast mycobacteria but do not cause tuberculosis or leprosy. These mycobacteria or atypical mycobacteria (ATM) exist in almost all habitats. Dr.T.V.Rao MD 7
Nontuberculous MycobacteriaWater, soil, food and animalsDoes not spread from person to anotherRelatively resistant to chlorination and ozonizationOutbreak and Pseudo-outbreak in the hospitalHIV and dialysis patientsImprove laboratory methods reportingMAC 40%,rapidly growing 10%,15% unknown,25% M.gordonae,2.5% M.kansasii(MW USA and UK) and 1% M.xenopi (Ontario)
Runyon classifies Atypical Mycobacterium• 1959, botanist Ernest Runyon put these human disease-associated bacteria into four groups (Runyon classification• Photochromogens, which develop pigments in or after being exposed to light. Examples include M. kansasii, M. simiae and M. marinum.• Scotochromogens, which become pigmented in darkness. Examples include M. scrofulaceum and M. szulgai Dr.T.V.Rao MD 9
Runyon classifies Atypical Mycobacterium• Non-chromogens, which includes a group of prevalent opportunistic pathogens called M. avium complex (MAC). Other examples are M. ulcerans, M. xenopi, M. malmoense, M. terrae, M. haemophilum and M. genavense• Rapid growers include four well recognized pathogenic rapidly growing non-chromogenic species: M. chelonae, M. abscessus, M. fortuitum and M. peregrinum. Other examples cause disease rarely, such as M. smegmatis and M. flavescens. Dr.T.V.Rao MD 10
Atypical mycobacteria may cause• Atypical mycobacteria may cause many different types of infections such as septic arthritis, abscesses and skin and bone infection. They may also affect the lungs, gastrointestinal tract, lymphatic system and other parts of the body Dr.T.V.Rao MD 11
Atypical Mycobacterium are• Unclassified• Anonymous• Non tuberculosis mycobacterium• Present in soil, water,• Causes opportunistic infections in AIDS Dr.T.V.Rao MD 12
Groups of Atypical Mycobacterium• Group 1 - Photochromogens (eg, Mycobacterium kansasii, M marinum, Mycobacterium simiae)• Group 2 - Scotochromogens (eg, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium gordonae)• Group 3 - Nonphotochromogens (eg, Mycobacterium malmoense, Mycobacterium xenopi, M avium- intracellulare)• Group 4 - Fast growers (3-5 d) (eg, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium abscessus)• M chelonae is an atypical fast-growing mycobacteria that is a rare cause of human infection. Dr.T.V.Rao MD 13
Group I - Photochromogens• Non pigmented in the dark• When young culture exposed to light for 1 hour and reincubated for at 24-48 a yellow orange pigment is produced• Slow growing are M kansasii.infects Volves M.marinum M simiae M asiacticum Present in tap water, second most common infection after M.aviumintracellulare Dr.T.V.Rao MD 14
Photochromogens• M.marinum causes warty skin lesions• Causes swimming pool granulomas• Poor growth at 37 c• Negative by nitrate test• Others M simiae M asiacticum Dr.T.V.Rao MD 15
Group II Scotochromogens• Pigmented colonies even in the dark• M.scrofulaceium, causes scrofula ( cervical adenitis in children )• M. gordonae• Present in tap water Scotochromogens• Contaminates clinical specimens• Fail to hydrolyses urea Dr.T.V.Rao MD 16
M scrofulaceum• M scrofulaceum is a slow-growing atypical mycobacteria that is found in environmental water sources, tap water, and the human respiratory tract. It causes scrofula, a granulomatous cervical adenitis in children and pulmonary disease in adults. It is usually unilateral. Few reports of it causing skin disease exist. Dr.T.V.Rao MD 17
Group III- Non Photochromogens• Do not form pigment even on exposure to light like tubercle bacilli• M. avium, M. intracellare• M.xenopi• Mostly occurs as opportunistic infection• Called MAI complex Dr.T.V.Rao MD 18
Mycobacterium avium-intracellulare• Mycobacterium avium-intracellulare frequently affects AIDS patients and causes lung disease.• Mycobacterium marinum cause skin infections and is also responsible for swimming pool granuloma.• Mycobacterium ulcerans cause skin infections.• Mycobacterium kansasii causes lung disease Dr.T.V.Rao MD 19
Mycobacterium avium complex• Mycobacterium avium complex (MAC) consists of two species— M avium and M intracell ulare. Because these species are difficult to differentiate, they are also collectively referred to as Mycobacterium avium- Dr.T.V.Rao MD 20 intracellulare (MAI)
Mycobacterium avium-intracellulare• Also known as MAC (Mycobacterium avium complex)• Most common non-tuberculous mycobacterial infection associated with AIDS• Symptoms include fever, swollen lymph nodes, diarrhoea, fatigue, weight loss and shortness of breath• May develop into pulmonary MAC Dr.T.V.Rao MD 21
Mycobacterium avium-intracellulare• Disseminated M avium complex (MAC) disease is most commonly diagnosed using culture of blood and bone marrow or other normally sterile tissues or body fluids. Other ancillary studies, such as acid-fast bacilli smear or radiographic imaging of the abdomen or mediastinum for detection of lymphadenopathy, may provide supportive diagnosis information. Dr.T.V.Rao MD 22
M avium and AIDS• M avium is the isolate in more than 95% of patients with AIDS who develop MAC infections, M intracellulare is responsible for 40% of such infections in immunocompetent patients. MAC is the most common cause of infection by nontuberculous mycobacteria (NTM) in patients with AIDS. Dr.T.V.Rao MD 23
M avium and AIDS• M. avium-intracellulare (MAC or MAI) is a rare cause of lung disease in otherwise healthy humans but a frequent cause of infection among those whose resistance has been lowered by another disorder (opportunistic infection). According to some experts, MAC infection is an almost inevitable complication of HIV. Dr.T.V.Rao MD 24
Causes• Lymphadenopathy• Pulmonary lesions• Disseminated disease• Patients with AIDS are predisposed• M. malmoense Causes pulmonary disease• M. xenopi Contaminates water taps Dr.T.V.Rao MD 25
Atypical mycobacterium is it common ? NO• The rate of atypical mycobacterial infections is rare, but it is increasing as the AIDS population grows. Populations at risk include individuals who have lung disease and weakened immune system Dr.T.V.Rao MD 26
Symptoms No typical Manifestations• Fever• Weight loss• Enlarged lymph glands• Diarrhea• Sweating, excessive -- night sweats• Fatigue• General discomfort, uneasiness or ill feeling (malaise)• Cough• Shortness of breath (dyspnea)• Skin lesions• Joint pain• Bone pain Dr.T.V.Rao MD 27
Type IV- Rapid growers• Heterogeneous group• Rapid growers• Grows in < 7 days• Grows at 37 – 25• Present• Photochromogens• Scotochrogens• Non Photochromogens Dr.T.V.Rao MD 28
Mycobacterium marinum• Also known as fish tank granulomas• Uncommon infection that occurs most often in people with recreational or occupational exposure to contaminated freshwater or saltwater• Usually a single lump or pustule that breaks down to form a crusty sore or abscess• Other lumps may occur around the initial lesion, particularly along the lines of lymphatic drainage (sporotrichoid forms)• Most often affects elbows, knees, feet, knuckles or fingers• Multiple lesions and widespread disease may occur in immunocompromised patients• Rarely causes red, swollen and tender joints Dr.T.V.Rao MD 29
Mycobacterium ulcerans• Also known as Buruli ulcers• Infection most common in Central and West Africa around areas of lush vegetation and swamps but may also occur in Australia• Solitary, painless and sometimes itchy nodule of 1-2 cm develops about 7-14 days after infection through broken skin• Over one to two months the nodule may break down to form a shallow ulcer that spreads rapidly and may involve up to 15% of the patients skin surface• Severe infections may destroy blood vessels, nerves, and invade bone Dr.T.V.Rao MD 30
Buruli ulcer• Buruli ulcer is a chronic ulcerative skin disease, caused by M ulcerans, that mostly affects the limbs. The lack of acute inflammatory response is typical and is likely due to an immunosuppressive toxin called mycolactone, which is produced by mycobacteria. Buruli ulcer mainly affects children living in humid areas of the tropical rain forest.. Dr.T.V.Rao MD 31
Mycobacterium chelonae• Worldwide distribution: found in tap water and other water sources• May cause lung disease, joint infection, eye disease and other organ infections• May result in non-healing wound, subcutaneous nodule or abscess• Immunosuppression may cause disseminated lesions throughout the body Dr.T.V.Rao MD 32
Cutaneous Infections Produced by other Atypical Mycobacterium• M. kansasii• M. haemophilum• M. scrofulaceum• M. szulgai• M. gordonae• M. avium-intracellulare complex• M. fortuitum• M. abscessus• M. chelonae Dr.T.V.Rao MD 33
Other species infecting skin• Two are common pathogens• M. ulcerans• M. marinum• Causes skin infections, and causes granulomatoous lesions• Systemic infections – regional lymph nodes. Dr.T.V.Rao MD 34
M.ulcerans• Uganda - Buruli ulcer• Few weeks indolent ulcers• Edge contain large number of bacilli• Grows on L J medium in 4 to 8 weeks• Grows between 30 to 33 c , But not at 23 or at 37 c• Produces toxins inflamation and necrosis. Dr.T.V.Rao MD 40
M.marinum• Infects cold blooded animals• Papules, indolent ulcers• Swimming pool granulomas• Undergoes spontaneous healing• Bacilli are scanty• Two weeks at 30 c• Low grade Tuberculin reaction Dr.T.V.Rao MD 41
Diagnosis• Need to demonstrate organisms by:• special stains• cultures• PCR Dr.T.V.Rao MD 42
We Miss the Diagnosis of AtypicalMycobacterium on many occasions ?
Diagnosis of NTM• A positive AFB smear combined with negative MTB-PCR denotes infection with NTM• DNA-DNA hybridization for the M.avium-complex• 16S rDNA-sequencing remain the gold standard in sophisticated species diagnosis of cultured NTM Dr.T.V.Rao MD 44
Laboratory Diagnosis• Rapid Growers • Slow Growers• Days in broth and < 1 • 1-2 weeks in broth week in solid media and 2-4 weeks in• M.abscessus solid media• M.chelonae • M.avium• M.fortutum • M.kansasii • M.scrofulaceum • M.ulcerans • M.xenopi • M.gordonae
Special Diagnostic Problems• M.marinum lower temperature required• M.haemophilum lower temperature required and iron need to be added• M.ulcerans lower temperature required• M.genavense very slow growth in broth• DNA probes for MAC, M. kansasii and M. gordonae available• Identification and sensitivity
Tissue Biopsy Issue Report With RCC AFB Culture Necrotizing? Stains? Sent? FFPE PCR with Sequencing/Granulomas? Issue consistent report Host? Prior to biopsy (via discussion with clinicians or from the history) you may have a high suspicion of mycobacterial disease (or simply infection NOS). This is usually because of some particular host factor (e.g., history of TB, iatrogenic immunosuppression, AIDs, malignancy, classic associations, mononeuropathy not from US, clinical Consider Buruli ulcer, etc). Other In these situations, despite the fact that granulomas are missing (or lack necrosis if present), it is diagnoses prudent to order AFB stains to rule out these organisms. If a patient is a perfectly normal host with no clinical reason to suspect a mycobacterial infection, other diagnosis (including other infections) should be considered (this branch, of course, takes you back into the rest of surgical pathology).
Need for better Diagnostic Methods Laboratory Studies• Organisms from blood, biopsy material, bone marrow, and stools grow on routine bacterial media, but growth is best achieved using selective mycobacterial media, such as a Lowenstein-Jensen medium or Middle brook• Nucleic acid hybridization probes using target sequences or ribosomal RNA are available for rapid identification of clinical isolates. Dr.T.V.Rao MD 48
Better diagnosis of Atypical Mycobacterial Infections• The anti- NTM drug susceptibility patterns often typical for the species. Therefore, the correct and exact species identification is a key issue for clinical NTM isolation.
Routine Laboratory Methods are not adequate for Diagnosis• Atypical Mycobacterial infection is not diagnosed on routine bacteriological screening of sputum or bronchial washings and the instigation of investigation to identify an NTM species may be prompted by the suggestion of the radiologist based on imaging feature alone.
Treating Atypical Mycobacterial Infections• Treatment of atypical mycobacterial infections depends upon the infecting organism and the severity of the infection. In most cases a course of antibiotics is necessary. These include rifampicin, Ethambutol, isoniazid, minocycline, ciprofloxacin, clarithromycin, azithromycin and cotrimoxazole. Usually treatment consists of a combination of drugs. Some points to consider when treating atypical mycobacterial infections Dr.T.V.Rao MD 51
Nontuberculous Mycobacterial DiseasePrinciples of Treatment of NTM Disease1. Patients should be carefully evaluated to determine the significance of an NTM isolate. The presence of the organism in a sterile site or repeatedly from airway secretions in association with a compatible clinical and radiologic picture confirms the diagnosis.2. Treatment of rapidly growing mycobacteria should be guided by in vitro susceptibilities. Other drug susceptibility testing is not standardized.
Nontuberculous Mycobacterial Disease• 3. Treatment should usually combine at least two drugs of proven efficacy.• 4. Contact follow-up is not necessary since NTM are not transmitted from person to person.• 5. Duration of therapy has not been determined; in general, 6-12 months is required following negative cultures.
Nontuberculous Mycobacterial Disease• 6. In soft tissue infections, because of rapidly growing mycobacteria, a combination of debridement and treatment with antimicrobials is recommended. For selection of antimicrobial agents, consultation with the laboratory should be undertaken regarding the reliability of in vitro testing.
Theraputic options in Atypical Mycobacterial InfectionsMAC Clarithromycin or azithromycin + ethambutol+RifampinM. xenopi Rifampin+Ethambiotol +INHM. kansasii Rifampin + EthambutolM. malmoense Rifampin or EthambutolM. marinum Rifampin or Clarithromycin + Ethambutol 2-3 monthsRapid growers doxycycline, amikacin, imipenem, quinolones, sulfonamides, cefoxitin, clarithromycin
Treatment of atypical mycobacterial infection• Mycobacterium marinum species are often resistant to isoniazid. Treatment with other antibiotics should be for at least two months.• Mycobacterium kansasii should be treated for at least 18 months.• Mycobacterium chelonae is best treated by clarithromycin in combination with another agent, Sometimes surgical excision is the best approach. Dr.T.V.Rao MD 56
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