Co-Infection with M. tuberculosis and M. leprae-Case Report and Systematic Review

Background: Co-infection with Mycobacterium tuberculosis and M. leprae is infrequent and conflicting views on their interaction exist. Methods: We describe an immunocompetent male with simultaneously diagnosed primary multi-drug resistant extra-pulmonary tuberculosis and borderline lepromatous leprosy; we also review all cases of dual infection reported in English literature Results: Our search yielded 156 cases of dual infections. Most dual infections were reported in middle-aged males. The sentinel infection was leprosy in 90.4%. Most affected patients had lepromatous leprosy (52.5%) but tuberculosis occurred throughout the disease spectrum of leprosy. The time to development of the second infection varied from 1 month-25 years (median 1.5 years). Tuberculosis was reported to occur in 2.5-13.5% of cases in six series of patients with lepromatous leprosy. Most patients were diagnosed by sputum smears and radiography. Comorbid conditions predisposed to development of tuberculosis in most patients. The most common pre-disposing factor was malnutrition (92.5%). Dual infections were associated with high mortality (37.2%) and morbidity (5.3%) Conclusions: Dual mycobacterial infections occur despite partial cross-immunity between both species. Directly observed treatment for tuberculosis with intensive medical monitoring is required to prevent poor outcomes during management of these complex patients

A 55-year-old male farmer presented with swelling and purulent discharge from his right foot for six months. There was no history of fever, cough, and foot trauma or weight loss. He denied any smoking, alcohol and substance abuse. He had received several courses of oral antibiotics with no reduction in the ulcer or discharge. He denied any contact with patients having tuberculosis or leprosy. General physical examination showed a firm 6 x 5 centimeters nodular swelling on the dorsum of the right foot, with discharging sinuses. Two punched out ulcers, about 3 x 3 centimeters, with clean base and pale granulation tissue were seen. The discharge was about 5-10 mL/ day, mucopurulent and without any granules. Multiple hypopigmented anesthetic macules over the trunk and limbs along with icythosis and scaling were also noticed. No deformity or digit resorption was observed. Neurological examination revealed thickened ulnar and peroneal nerves with loss of touch, vibration and joint position till ankle. Respiratory examination was normal. Investigations showed normal hemoglobin (12.3 g/dL) and peripheral smear. Renal function tests, serum electrolytes and liver function tests were normal. Chest radiograph was normal and radiographs of the right foot did not show any evidence of osteomyelitis. Fasting serum glucose was 130 mg/dL and HbA1c was 6.5%. Human Immunodeficiency virus ELISA was non-reactive and Mantoux test was negative (four millimeters, 1 TU at 48 hours). Pus from the right foot ulcer was sterile by aerobic bacterial cultures. Stains for nocardia and actinomyces were negative. Zeihl-Neelson's staining showed acid-fast bacilli. Biopsy form edge of ulcer showed granulomatous inflammation with necrosis; multiple langhans giant cells, histiocytes and lymphocytes were present. BACTEC culture showed M. tuberculosis and he was initiated on isoniazid 300 mg, rifampicin 600 mg, pyrazinamide 1250 mg and ethambutol 1 gm/day. Biopsy from the hypo-anaesthetic patches showed features of tuberculoid leprosy; six site slit smears were negative. He was also initiated on regimen for multi-bacillary leprosy with dapsone 100 mg/day and clofazamine 50 mg/day and monthly clofazamine 300 mg. Metformin 1 gram/day

Patients and Methods
Two of the authors (R.S and U.D) independently performed a MEDLINE search using the free text terms tuberculosis and leprosy, M. tuberculosis and M. leprae in the English literature. This was further supplemented by direct search of the references and our personal databases. Both abstracts and full text articles, where available, were reviewed and only those articles which documented both infections by microbiological criteria were included for analysis. Data was extracted regarding the clinical features, first infection, time to development of second infection, leprosy spectrum of patients, mode of diagnosis, comorbidities, site of tuberculosis and outcomes where available (Table  1).

Discussion
The exact nature of the interaction between leprosy and tuberculo-sis has been debated for over a century. They share common antigens as evidenced by conversion of lepromin intradermal tests after the administration of Bacille-Calmette-Guerin (BCG) and the partial protection offered by BCG against leprosy [23]. Though an increased frequency of pulmonary tuberculosis in patients with lepromatous leprosy may occur as a result of malnutrition, tuberculosis occurs across the spectrum of leprosy [20]. An inherent impaired immunity against both mycobacterial organisms has been postulated as the etiology for dual infection; however, it appears that the anergy in leprosy is pathogen-specific [24]. Some investigators have speculated that leprosy and tuberculosis are antagonistic diseases on the basis of immunologic, clinical, and epidemiologic data [25]. Low rates of leprosy have been observed in areas which have high rates of tuberculosis despite large scale migration of patients with leprosy into them. The historical high rates of tuberculosis have also been postulated as one reason for the decline of leprosy in Europe. Recent analysis of bone material from human remains at sites in Israel, Egypt and Europe showed DNA traces of both M. tuberculosis and M. leprae infection in 42% of the samples. Since tuberculosis is a more aggressive illness than leprosy, the authors suggest that patients with tuberculosis and leprosy were more likely to have died faster, reducing the reservoir for M. leprae [26]. The relationship between the two mycobacterial diseases continues to be enigmatic despite decades of research.
Our review shows that while co-infection is not uncommon in high endemic areas, it has been reported from throughout the globe. Though pulmonary tuberculosis has been reported in the vast majority, extra-pulmonary tuberculosis is also described (3.2%) The association of tuberculoid leprosy and tuberculosis (26.2%) and simultaneous occurrence of dual mycobacterial infections suggests a mycobacterial genera-specific anergy as a predisposing factor. Dual infections are associated with high mortality (37.2%) and major morbidity (5.5%). Management of these patients requires inter-disciplinary management and social support.
In conclusion, dual mycobacterial infections occur despite partial cross-immunity between both species. Recognition of tuberculosis is important to prevent emergence of rifampicin-resistant tuberculosis during treatment of leprosy. Directly observed treatment for tuberculosis with intensive medical monitoring is required to prevent poor outcomes during management.