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Mycobacterial Diseases

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

Srinivas Rajagopala1*, Uma Devaraj2, George D’Souza3 and Vijay V Aithal4

1Division of Chest diseases, Department of Medicine, St John’s Medical College Hospital, India

2Division of Chest diseases, Department of Medicine, St John’s Medical College Hospital, India

3Division of Chest diseases, Department of Medicine, St John’s Medical College Hospital, India

4Department of Dermatology, St John’s Medical College Hospital, India

Corresponding Author:
Srinivas Rajagopala
Assistant Professor, Division of Chest diseases
Department of Medicine, St John’s Medical College Hospital
Sarjapur Road, Bangalore, India-560034
Tel: +91 80 22065353
Fax: +91 80 25501144
E-mail: [email protected]

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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Abstract

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

Keywords

Mycobacterium tuberculosis; Mycobacterium leprae; Leprosy; Tuberculosis; Drug-resistant extra-pulmonary tuberculosis

Case Report

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.

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 (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
30/F Leprosy 1 month TT None Cough
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).

Results

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 [6] 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 [18]; human immunodeficiency virus infection [6], diabetes mellitus type 2 [22], systemic steroid use [14] and immunosuppressive therapies [8] and chronic kidney disease [7] have also been implicated. Dual infections were associated with high mortality [9,10,19] (37.2%). Leprosy reversal reactions [22], both type 1 [5,7,13] and type 2 [8], and jaundice [4] also complicated 4.25% of treatments for dual infections.

Parameter Value
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)
Co-morbidity 67.9% (N=106/156)
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).

Discussion

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 [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.

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