Received Date: May 25, 2012; Accepted Date: June 14, 2012; Published Date: June 16, 2012
Citation: Rajagopala S, Devaraj U, D’Souza G, V Aithal V (2012) Co-Infection with M. tuberculosis and M. leprae-Case Report and Systematic Review. J Mycobac Dis 2:118. doi:10.4172/2161-1068.1000118
Copyright: © 2012 Rajagopala S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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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
Mycobacterium tuberculosis; Mycobacterium leprae; Leprosy; Tuberculosis; Drug-resistant extra-pulmonary tuberculosis
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 was started for newly detected diabetes mellitus. He had significant reduction in the number of cutaneous patches at two months follow-up; however ulcers continued to discharge. Drug susceptibility testing of BACTEC cultures was reported as M. tuberculosis resistant to isoniazid and rifampicin. The patient denied any contact with patients diagnosed with multi-drug resistant tuberculosis (MDR-TB). His regimen was modified to observed levofloxacin 750 mg/day, kanamycin 750 mg/ day, ethionamide 250 mg and cycloserine 250 mg thrice a day. He had resolution of discharge from these ulcers with healing at two months follow-up. Kanamycin was continued till 6 months and stopped. He completed one year of dual treatment and multi-bacillary leprosy treatment was stopped with no recurrences. MDR-TB regimen was stopped at 22 months. He remains asymptomatic four months after completion of this regimen.
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 (Table1).
|Reference||Year||Number (if series)||Age/ sex||First infection||Time between the two infections||Leprosy spectrum (Jopling)||Clinical presentation of tuberculosis||Mode of diagnosis of tuberculosis||Aggravating co-morbidity||Clinical features at diagnosis||Out come|
|Gajwani et al.||1968||3||60/M||Tuberculosis||6 months; diagnosed simultaneously||BT||Pulmonary tuberculosis (SP)||Sputum smear||Malnutrition||Fever, cough, hemoptysis||NA|
|30/M||Leprosy||2 years; diagnosed simultaneously||TT||Pulmonary tuberculosis (SP)||Sputum smear||Fever, cough||NA|
|60/M||Tuberculosis||2 years; diagnosed simultaneously||BT||Pulmonary tuberculosis (SP)||Sputum smear||Cough, expectoration||NA|
|Gupta et al.||1971||2||50/M||Leprosy||1 year; diagnosed simultaneously||TT||Pulmonary tuberculosis (SP)||Sputum smear/ culture||Diabetes, CAD||Asymptomatic||Lepra reaction, better|
|25/F||Leprosy||6 months; diagnosed simultaneously||Euthyroid nodular goitre||Fever, Cough, expectoration||Better|
|Agnihotri et al.||1973||3||65/M||Tuberculosis||1 year; diagnosed simultaneously||TT||Pulmonary tuberculosis (SP)-relapse||Sputum smear||Malnutrition||Fever, emaciation||Better|
|18/M||Tuberculosis||4 year; relapse simultaneously diagnosed||TT||None||Cough, expectoration, hemoptysis|
|Bhargava et al.||1976||4||39/M||Leprosy||3 years||LL||Pulmonary tuberculosis (SP)||Sputum smear||None||Fever, cough||NA|
|50/M||Leprosy||1 year||LL||Pulmonary tuberculosis (SP)||Sputum smear||None||Cough, weakness||NA|
|45/M||Leprosy||4 years||LL||Pulmonary tuberculosis (SP)||Sputum smear||None||Cough, expectoration||NA|
|35/M||Leprosy||15 years||LL||Pulmonary tuberculosis (SP)||Sputum smear||None||Cough, expectoration||NA|
|Premnath et al.||1976||40(in 2 years)||Median 27; range 21-64 years||Leprosy||1-25 years; individual data NA||LL (72.5%); BL (27.5%)||Pulmonary tuberculosis (SP)||Sputum smear||Malnutrition||Cough, expectoration (87.5%), fever (57.5%), and weight loss (35%)||Died (30%), LAMA (20%), Improved (50%)|
|Ganapathi et al.||1976||1||30/M||Leprosy||NA||LL||Cutaneous (lupus vulgaris)||Histopathology||None||NA||NA|
|Vachharajani et al.||1977||4||50/M||Tuberculosis||4 months||TT||Pulmonary tuberculosis (SP)||Sputum smear||None||Hypopigmented anesthetic patches||Better|
|26/M||Tuberculosis||4 months||TT||Pulmonary tuberculosis (SP)||Sputum smear||None||Single hypopigmented anesthetic patch||Better|
|30/M||Tuberculosis||2 months||LL||Pulmonary tuberculosis (SP)||Sputum smear||None||Macular rash||Better|
|29/M||Tuberculosis||1.5 months||TT||Pulmonary tuberculosis (SP)||Sputum smear||None||Multiple patches||Better|
|Nigam et al.||1979||20 (2.5% of 793)||16-58, mean 28.4; M(15); F(5)||Leprosy||10-15 years||LL (15), BL (3), TT (2)||Pulmonary tuberculosis (SP-16, SN-4), pleural effusion (2)||Sputum smear(16); chest radiograph (4)||Malnutrition||Cough, expectoration (100%), fever (80%), weight loss (60%), hemoptysis (25%)||Died (4); LAMA (5) Better (11)|
|Kaur et al.||1979||2 out of 25 (8%)||Age, Sex NA||Leprosy||4.2 years||LL (2)||SP-1 Pulmonary tuberculosis; SN-1||Sputum smear; chest radiograph||Malnutrition||Individual data NA||NA|
|Gatner et al.||1980||13.4% (15 of 112 active; 8 healed)||Age, Sex NA||Leprosy||NA||LL(4), BL (3),BB(1),BT(7)||Pulmonary tuberculosis SP-8; SN-7||Sputum smear; chest radiograph||Malnutrition||Screening||10/15 improved; rest NA|
|Kumar et al.||1982||9 (7.7% of 117)||NA||Leprosy||NA||LL (4), BL (3), TT (2)||Pulmonary tuberculosis (SP-3, SN-6)||Sputum smear (3), chest radiograph (6)||NA||Screening||NA|
|Singh et al.||1987||25 (2.9% of 846)||NA||Leprosy||NA||Individual data NA||Pulmonary tuberculosis||Sputum, chest radiograph||NA||Screening||NA|
|Saha et al.||1989||18 of 133 (13.5%)||15(M); 3(F) 15-65||Leprosy||NA||LL||Pulmonary tuberculosis (SP)||Sputum, chest radiograph||Malnutrition||Screening||NA|
|Patki et al.||1990||1||35/F||Leprosy||5 years||BL||Multicentric lupus vugaris||Histopathology||None||Swelling||Better|
|Pinto et al.||1991||1||36/M||Simultaneous occurrence||BT||Cutaneous tuberculosis||Histopathology||Thorn prick||Warty lesion||Jaundice|
|Inamadar et al.||1994||1||23/M||Simultaneous occurrence||TT||Cutaneous and pulmonary tuberculosis (SP)||Sputum smear||None||Patch, ulcer and discharge||Type 1 reaction, better|
|Arora et al.||1994||1||40/M||Simultaneous re-occurrence due to HIV||BL||Lymph nodal tuberculosis||Histopathology||HIV||Patch, sinus||Better|
|Agarwal et al.||2000||1||40/M||Simultaneous occurrence||LL||Pulmonary tuberculosis (SP)||Sputum smear/ culture||CKD, transplantation, immunosuppression||Fever, cough, anesthetic patch||Reaction, resolved|
|Srilakshmi et al.||2003||1||32/ M||Leprosy||10 years||LL||Pulmonary tuberculosis (SP)||Sputum smear||Nil||Fever, cough||Dead|
|Lee et al.||2003||1||62/M||Tuberculosis||6 months||BL||Pulmonary tuberculosis (SP)||Sputum smear/ culture||Nil||Cough, expectoration||Type I reversal reaction, better|
|Agarwal et al.||2007||1||36/F||Simultaneous occurrence||BL||Pulmonary tuberculosis (SP)||Sputum smear||Rheumatoid arthritis, methotrexate, steroids leflunomide||Fever, weight loss||ENL, better|
|Sreerama Reddy et al.||2007||2||65/M||Leprosy||3 months||BL||Pulmonary tuberculosis (SP), pleural effusion||Sputum smear||Steroids for ulnar neuritis||Cough, expectoration, chest pain||Better|
|2 years||LL||Pulmonary tuberculosis (SP)||Prednisolone, thalidomide||Fever, cough|
Table 1: Summary of all reported cases of co-infection with leprosy and tuberculosis (English literature).
Our search yielded 2194 citations. These included 22 citations [1-22], including 156 cases of dual infection. Full text was available for all cases in the articles reviewed (Table 1). Dual infections have been reported from throughout the globe. The mean age was 37.8 (N=87) years (Table 2). Males accounted for 81.25% of cases [(12:3 (N=64)]. The first infection was leprosy in most patients (90.4%) but tuberculosis was diagnosed prior to symptoms of leprosy in 5.7% of patients [1,2,3]. In some instances, symptoms of both the mycobacterial infections occurred simultaneously.[4-8] Most affected patients suffered from borderline lepromatous leprosy [9-14] (20.5%) and lepromatous leprosy [7,9-11,14-19] (52.5%), but tuberculosis occurred throughout the disease spectrum [3,5,10,20]. The time to development of the second infection varied from 1 month to 25 years (median 1.5 years). When series of lepromatous leprosy in which screening for tuberculosis was done were examined, tuberculosis has been reported to complicate leprosy in 2.5-13.5% of cases in endemic areas. [9-11,18,20,21] Most patients presented with cough, expectoration, weight loss and fever. The site of tuberculosis was reported as lung (96.7%); cutaneous [4,5,12,16] and lymph nodal tuberculosis  have also been reported in association with leprosy. Most patients were diagnosed by sputum smears and radiography. Co-morbid conditions predisposed to development of tuberculosis in most patients (67.9%). Malnutrition was the most common pre-disposing factor (85.8%) in the development of tuberculosis ; human immunodeficiency virus infection , diabetes mellitus type 2 , systemic steroid use  and immunosuppressive therapies  and chronic kidney disease  have also been implicated. Dual infections were associated with high mortality [9,10,19] (37.2%). Leprosy reversal reactions , both type 1 [5,7,13] and type 2 , and jaundice  also complicated 4.25% of treatments for dual infections.
|Total number of cases||N=156|
|Age (Mean)||37.8 (N=87)|
|Sex (M:F)||12:3 (N=64)|
|First infection||Tuberculosis 5.7% (9/156)|
|Leprosy 90.4% (141/156)|
|Simultaneous diagnosis 3.9% (6/156)|
|Time from first infection diagnosis to the second||Median 1.5 years (range 1 month-25 years)|
|Leprosy spectrum (Data available N=122/156)||TT 10.6% (13/122)|
|BT 15.6% (19/122)|
|BB 0.8% (1/122)|
|BL 20.5% (25/122)|
|LL 52.5% (64/122)|
|Clinical presentation of tuberculosis||Pulmonary tuberculosis 96.7% (151/156)|
|Extra-pulmonary tuberculosis 2.6% (4/156)|
|Both 0.8% (1/122)|
|Cutaneous tuberculosis 2.6% (4/156)|
|Lymph-nodal tuberculosis 0.6% (1/156)|
|Malnutrition 85.8 % (91/106)|
|HIV 0.9% (1/106)|
|Steroid treatment/ Immunosuppression 3.6% (4/106)|
|Chronic kidney disease 0.9% (1/106)|
|Diabetes 0.9% (1/106)|
|Goiter 0.9% (1/106)|
|Outcome||Died 37.2% (35/94)|
|Better 72.8% (59/94)|
|Reactions 4.2% (4/94)|
|Jaundice 1.1 % (1/94)|
Table 2: Summary of findings of co-infection with leprosy and tuberculosis (English literature).
The exact nature of the interaction between leprosy and tuberculosis 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 . 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 . 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 . Some investigators have speculated that leprosy and tuberculosis are antagonistic diseases on the basis of immunologic, clinical, and epidemiologic data . 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 . 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.