ATYPICAL MYCOBACTERIAL INFECTIONS AND THEIR MANIFESTATIONS

Infections caused by nontuberculous mycobacteria (NTM) are increasing for several reasons, including diagnostic advances, increased awareness and a larger at-risk population. NTM pulmonary disease is surpassing tuberculosis (TB) in some low incidence areas.

1. ATYPICAL MYCOBACTERIAL INFECTIONS DR MOHNISH SEKAR

2. INTRODUCTION Non- tuberculous (“atypical”) mycobacteria were first isolated in 1931 by Pinners, who also discovered that these organisms were different from M. tuberculosis – not virulent in the guinea pig model & responded poorly to antituberculous therapy NTM are Mycobacterium species other than M. tuberculosis and M. leprae . Referred to as ‘atypical’, as they were thought to be unusual M.tuberculosis strains

3. Found in water, wet soil, house dust, dairy products, cold-blooded animals, vegetation and human feces. Transmitted by inhalation, ingestion or percutaneous penetration, which can result in pulmonary, lymph node or skin disease Type of disease depends on the species of mycobacteria, the route and degree of exposure, and the immune status of the host Recognition is important given the increasing incidence in immunosuppressed as well as normal hosts

4. Mycobacterium kansasii infection Slow‐growing Cutaneous infection is rare and more likely to occur in immunocompromised patients. Clinical presentation  nodules, pustules, verrucous lesions, erythematous plaques, ulcers, and abscesses Cellulitis, osteomyelitis and septic arthritis

5. HPE Granulomatous histology and a mixed inflammatory infiltrate with acid‐fast bacilli in the histiocytes Treatment Combination of isoniazid, rifampin, ethambutol ; clarithromycin may be used instead of isoniazid; linezolid is an alternative

6. Rapidly Growing Mycobacteria Cutaneous NTM infections are transmitted via direct inoculation through skin barrier breaks Trauma, surgical procedures, plastic surgery (including liposuction), injections, tattoos, acupuncture, and body piercings Cosmetic procedures such as mesotherapy

7. Mycobacterium marinum infection Also known as Swimming pool granuloma Fish tank granuloma Natural habitat  fresh or salt water, particularly enclosures of water , such as swimming pools and aquariums H uman infection follows contact with fishes or contaminated water Optimal temperature for growth is around 30°C, hence ,cutaneous lesions most frequently occur in the upper or lower extremities and tip of the nose.

8. Clinical presentation  nodule or a psoriasiform or verrucous plaque at the site of inoculation, usually the hands, feet, elbows, or knees , spreads in a sporotrichoid pattern ( lymphangitic spread)

9. Suppurative > granulomatous & multiple in both normal or immunosuppressed hosts. Deep tissue involvement( tenosynovitis, osteomyelitis bursitis and septic arthritis) & disseminated disease among severely immunocompromised hosts Heal spontaneously within 1–2 years, with residual scarring. Treatment Combination of at least two drugs, including a macrolide, ethambutol , trimethoprim- sulfamethoxazole , or rifamycin , x 2-6 months depending on the degree of cutaneous involvement .

10. Diagnosis History of contact with water, fish tanks, aquariums, etc. Pathology First few months  non‐specific inflammation Older lesions  well‐formed tuberculoid granulomas with fibrinoid masses rather than caseation. Intracellular acid‐fast bacilli – longer and broader than tubercle bacilli (10% of cases) Chronic lesions U lceration and pseudoepitheliomatous hyperplasia

11. Culture 30-33°C. Colonies will be seen in 10–28 days. PCR– reverse cross blot hybridization assay with species‐specific gene probes Treatment Combination of at least two drugs, including a macrolide, ethambutol , trimethoprim- sulfamethoxazole , or rifamycin , x 2-6 months depending on the degree of cutaneous involvement .

12. Mycobacterium kansasii Slow growing Cutaneous involvement of M. kansasii is usually present in immunocompromised hosts and sometimes with concomitant pulmonary disease or disseminated disease Clinical presentation  nodules,pustules , verrucous lesions, erythematous plaques, ulcers, and abscesses . Complications  osteomyelitis and septic arthritis.

13. HPE  Granulomatous histology and a mixed inflammatory infiltrate with acid‐fast bacilli in the histiocytes Treatment Combination of isoniazid, rifampin, ethambutol x 18months; clarithromycin may be used instead of isoniazid;Linezoild is an alternative drug

14. Mycobacterium ulcerans ( Buruli ulcer disease) 3rd most frequent mycobacterial pathogen, after M. tuberculosis and M. leprae . S low‐growing , affects the skin and subcutaneous tissues. Mode of transmission  unnoticed skin trauma that permits the inoculation of M. ulcerans Pathogenesis Inoculation into skin P roduction of polyketone toxin mycolactone Mycolactone destroys tissues by 1.apoptosis and necrosis 2. suppresses host immune response 3. induces hypoesthesia Altering the signaling pathways of the type 2 angiotensin II receptors  leading to hyperpolarization of neurons

15. Presentation mean incubation period of Buruli  135 days or 4.5 months (range 34–264 days) . 70% of patients  children < 15 years of age. Early lesions  papular , nodular or oedematous and are usually on an arm or leg, but can be on the trunk or head nodule will break down to form a shallow necrotic ulcer, which extends rapidly and irregularly, with deeply undermined edges Most ulcers are painless unless secondarily infected.

16. Ulcer may reach a diameter of several cms over the course of few weeks. Floor  formed of necrotic fat, with clear mucoid discharge. Usually single, though satellites may develop. Large lesions may be surrounded by extensive induration

17. Complications osteomyelitis ( lymphohaematogenous spread) Fibrosis and calcification (Healing)  contractures and severe deformity Diagnosis ( i )Direct smear (with acid‐fast stains auramine O or Ziehl – Neelsen ) (ii) culture at 32°C (iii) histopathology Granulomatous inflammation with substantial necrosis, predominantly in the subcutaneous fat & deep dermis and destruction of nerves, appendages and blood vessels. Inflammatory cells are few in number in active lesion ( immunosuppressive activity of the toxin.) With healing, there is a granulomatous response. Mulltiple acid-fast bacilli in characteristic clumps, particularly in the center of the lesion (iv) PCR

18. Patients with lesions < 5 cm (category I, small)  receive antibiotics alone lesions 5–15 cm (category II, moderate)  receive 4 weeks of antibiotics and then undergo surgery, if necessary, followed by 4 more weeks of antibiotics. Lesions >15 cm (category III, advanced)  antibiotics for at least 1 week before surgery; the antibiotics are then continued for a total of 8 weeks

19. First line oral rifampicin (10 mg/kg) + IM streptomycin (15 mg/kg) daily X 8 weeks under supervision. Amikacin (15 mg/kg) can be substituted for streptomycin -administered intramuscularly or intravenously. Second line Rifampacin 10 mg/kg + amikacin 15 mg/kg x 8 weeks. Third line Rifampicin and clarithromycin x 8 weeks or rifapentine + moxifloxacin x 8 weeks

20. Mycobacterium avium complex ( M. avium and M. intracellulare ) infection MAC is composed of several different slowly growing mycobacterial species, including M. avium , M. intracellulare , Mycobacterium indicus pranii , Mycobacterium chimera , Mycobacterium arosiense , and many others. Both the respiratory and gastro‐intestinal tracts serve as portals for systemic infection. As many as 30% of samples of normal human feces yield isolates of MAC

21. Cutaneous involvement of M. avium-intracellulare complex (MAC) infections has been rarely reported Include multiple ulcers , nodules , ulcerated nodules, abscesses , painless nodules and plaques resembling lepromatous leprosy or lupus vulgaris as well as lesions resembling prurigo nodularis Sporotrichoid spread and lichen scrofulosorum have been reported with MAC infection

22. In HIV‐infected patients most common manifestation  mycobacteraemia , but skin lesions may provide a clue to the presence of disseminated MAC infection. tends to occur late in HIV disease ;CD4+ cell counts < 50 cells/ μL [9]. The incidence is decreasing due to ART and the MAC IRIS  On starting ART due to restoration of delayed hypersensitivity and cytokine production  fever , lymphadenitis and cutaneous lesions