2. E. Tortoli Clinical Features of Infections Due to Nontuberculous Mycobacteria Cesme – Symposium of Mycobacteriology, December 10, 2004

3. Nontuberculous mycobacteria Environmental Opportunistic About 3 new species per year Over 100 species, 60% of which described in the last 15 years

4. Diseases due to NTM Pulmonary infections Lymphonodal infections Cutaneous infections Osteo-articular infections Disseminated infections Sepsis

5. Pulmonary disease The most frequent NTM disease with the main route of infection being the inhalation HIV-negative patients Disease: undistinguishable from tuberculosis, very slow progression manifestations ranging from lack of symptoms to cavitary disease radiographic picture presenting fibrosis, upper lobe cavitation, nodular or parenchymal opacity, pleural thickening Target: elderly patients with other pulmonary problems (silicosis, OPD, pneumoconiosis, previous TB, bronchiectasis, cancer) Symptoms: cough, fever, weight loss, weakness, respiratory insufficiency AIDS patients Disease: chest X-ray often normal or presenting mediastinal / hilar adenopathy, rapid progression Target: patients with CD4 <100/mL Symptoms: cough, fever, weight loss

6. Agents of pulmonary diseases M. avium complex M. kansasii M. xenopi M. malmoense “new mycobacteria” M. celatum mainly in AIDS with CD4 <100/mL rifampicin resistant possible misdiagnosis as M. tuberculosis M. goodii from patients with lipoid pneumonia M. immunogenum isolated from aerosols of metal- working fluids which are associated with hypersensitivity pneumonitis

7. M. xenopi: TB-like pulmonary infiltrates (X-ray) 61-year male Hodgkin’s lymphoma in the past

8. M. xenopi: TB-like pulmonary infiltrates (CT scan) 61-year male Hodgkin’s lymphoma in the past

9. M. intracellulare: upper lobe pulmonary infiltrate 67-year, female previously healthy

10. M. avium: massive upper mediastinum adenopathy (CT scan) 41-year, male AIDS

11. Lymphadenitis Scrofula: disease of childhood, exceptional in adults Unilateral swelling of cervical lymph nodes without pain and without thoracic involvement Evolution with softening and fistula formation Oral route of infection including throat, gingivae and lips Surgical treatment, antimicrobial therapy ineffective

12. Agents of cervical lymphadenitis M. scrofulaceum, classically considered the main responsible of scrofula M. avium complex, the current most frequent agent of NTM lymphadenitis M. malmoense “new mycobacteria” M. bohemicum M. interjectum M. lentiflavum A number of pigmented slow growing new species

13. Disease of skin and soft tissue Consequent to trauma or surgical wound (mainly plastic or cardiac interventions) Nodular granulomatous lesions of cutis or subcutaneous developing in about a month and often involving lymph nodes Frequent dissemination with ulcer formation or cellulitis Almost only rapidly growing species involved

14. Agents of skin and soft tissue infections M. abscessus M. chelonae M. fortuitum M. smegmatis “new mycobacteria” M. goodii (following pacemaker implantation and breast plastic interventions) M. mageritense (following liposuction) M. wolinskyi (following facial plastic surgery and responsible of post traumatic cellulitis)

15. M. abscessus: painful red nodular lesions of the forearm 45-year, male kidney transplanted aquarium-lover

16. Bone and articular infections Targets: synovia, tendon sheaths, bursa, bone tissue, vertebral discus Consequent to open fracture, penetrating trauma or surgical wound (mainly cardiac) Possible evolutions: lost of function, swelling, fistula or granuloma formation, osteomyelitis and/or cellulitis, bone necrosis Predisposing conditions: chronic rheumatism and steroid treatment

17. Agents of bone and articular infections M. abscessus M. chelonae M. fortuitum M. smegmatis “new mycobacteria” M. goodii many cases of osteomyelitis and/or cellulitis in young people with open fractures or penetrating trauma M. wolinskyi

18. Disseminated infections Target: immunocompromised patients AIDS, leukemia, organ transplantation, protracted steroid treatment Symptoms: fever, weight loss, abdominal pain, splenomegaly, diarrhea Very frequent several years ago, their role has been scaled down following the introduction of HAART

19. Agents of disseminated infections M. avium estimated to affect more than 50% of severely immunocompromised AIDS patients not treated with HAART M. genavense Young subjects, prevalently male, with <25 CD4/mL Isolated predominantly from blood but also from lymph nodes and duodenal biopsies Extremely rare in HIV-negative patients M. celatum Responsible of disseminated infections combined, or not, with pulmonary disease

20. Sepsis Several cases of catheter-related sepsis have been reported for rapidly growing mycobacteria M. immunogenum (bone marrow transplantation, leukemia, pacemaker holder)

21. Rare NTM-related diseases Genital infections Hepatic infections Ocular infections

22. Conclusions 1 In AIDS patient the large majority of the mycobacterial infections are disseminated, their number has dramatically decreased following the introduction of HAART In HIV-negative subjects Slowly growing mycobacteria are prevalently responsible of pulmonary and lymphonodal disease Rapidly growing mycobacteria are prevalently responsible of cutaneous, osteo-articular and septic diseases The number of cases due to “new” mycobacteria is certainly underestimated because of the problematic identification of these strains The role of rapid growers is more important than commonly believed

23. Conclusions 2 Slowly growing mycobacteria Isoniazid and pirazinamide are not effective Aminoglycosides, quinolones, macrolides, rifamycins may be effective M. celatum is rifampin-resistant The species genetically related to M. simiae are dramatically multidrug-resistant Rapidly growing mycobacteria The spectrum of potentially active drugs includes: amikacin, cefoxitin, ciprofloxacin, clarithromycin, trimetoprim- sulfametoxazole, doxycycline, imipenem drug susceptibility

24. Conclusions 3 Minimal requirements for diagnosing a pulmonary infection due to NTM Case 1. Three samples have been investigated in the last year 3 cultures are positive, even with negative microscopy 2 cultures are positive, at least one of which with positive microscopy Case 2. One sample only has been investigated Culture and microscopy are strongly positive Case 3. The involvement in the disease of an agent other than a NTM cannot be excluded The NTM has been grown from a biopsy The histologic picture is compatible with a mycobacterial infection and the isolation (even single and with low charge) has been obtained from the sputum the ATS criteria