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Tropical medicine rounds
Lepromatous leprosy treated with combined chemotherapy and immunotherapy (injection BCG): three case reports
Article first published online: 15 MAY 2013
© 2013 The International Society of Dermatology
International Journal of Dermatology
Volume 53, Issue 1, pages 61–65, January 2014
How to Cite
Lakshmi, C. and Srinivas, C. R. (2014), Lepromatous leprosy treated with combined chemotherapy and immunotherapy (injection BCG): three case reports. International Journal of Dermatology, 53: 61–65. doi: 10.1111/ijd.12164
Conflict of Interest: None
- Issue published online: 18 DEC 2013
- Article first published online: 15 MAY 2013
Lepromatous leprosy is associated with suppressed cell-mediated immunity (CMI). This results in failure of the body to mount an efficient immune response and may render chemotherapy ineffective. The lack of sufficient response may mimic drug resistance. Three case reports in which the immunity was stimulated by administering Injection BCG are presented. All three patients were initially anergic and showed no reaction at the Mantoux testing site, showing an inability to mount type IV hypersensitivity and characterized by live bacilli in smears. Following 1-4 doses of Injection BCG, all three showed dead bacilli in smears.
The first case, a 61-year-old man with lepromatous leprosy who continued to show live bacilli in smears after prolonged chemotherapy, was administered a total of four BCG injections, following which he achieved clearance. The second, a 40-year-old man with borderline lepromatous leprosy and severe type 2 reactions, achieved bacterial clearance and control of severe reactions following a single injection. The third, a 67-year-old man with histoid leprosy, achieved effective bacterial killing with a single dose of Injection BCG.
All three patients achieved good results when chemotherapy was combined with Injection BCG. Following Injection BCG, all three showed a reaction at the Mantoux testing site.
Suppressed CMI may be responsible for the lack of response in recalcitrant cases of lepromatous leprosy. These case reports would lead to the trend in combination therapy (immunotherapy combined with chemotherapy) for such cases, and help lower the tendency for inappropriate diagnosis of drug-resistant leprosy.
Patients with highly bacillated lepromatous leprosy who show solid bacilli even after a full course of multi-drug therapy (MDT) may not be drug-resistant.
The suppressed cell-mediated immunity (CMI) in lepromatous leprosy secondary to the excessive mycobacterial antigen load impedes efficient bacterial elimination. Immunotherapy (BCG) combined with chemotherapy can upgrade the CMI and result in faster clearance of bacilli. Three cases are presented in whom effective bacterial killing and faster clearance of bacilli was achieved after administration of Injection BCG along with regular multibacillary MDT.
A 61-year-old male patient with lepromatous leprosy presented with nodular lesions over the earlobes and trunk. Smears from the nodules showed bacillary index (BI) 3+, morphological index (MI) 3%. His skin smear showed solid bacilli after four months of MDT (BI 6+; MI 7%; Figure 1.
Drug resistance was suspected, and ROM (rifampicin 600 mg; ofloxacin 400 mg; minocycline 100 mg) therapy was administered daily for 28 days followed by regular MDT for one year. Skin smear examination after this period revealed solid bacilli (BI 4+; MI 1%).
Suspecting immunosuppression to be responsible, Injection BCG was considered. A Mantoux test done prior to starting Injection BCG showed no reaction at the site, showing that the patient was anergic.
Mantoux testing was repeated six weeks after each every dose of Injection BCG (0.1 mg/dose).
Injection BCG (a total of four doses: 0.1 mg/dose) was combined with chemotherapy (MDT) and administered in the following frequency: first injection; second after one year; third followed three months after the second; and fourth after one month of the third injection. A total of four injections were given in a span of about 1.5 years. There was no reaction to the first three injections of BCG at the injected site even after follow-up for six weeks. The fourth resulted in a papulonodule after four weeks, which ulcerated.
Skin smears were taken monthly for MI and BI, which dropped to BI 1+; MI 0% one year after the first injection. Following the second injection, skin smears showed BI 1+; MI 0%. The patient achieved smear negativity following the fourth injection (BI 0; MI 0%).
The Mantoux test was non-reactive (cutaneous anergy) after the first three injections. Six weeks after the fourth injection, the Mantoux test became reactive, and an induration of about 8 mm developed at the site.
The patient remains well with negative skin smears at five years follow-up.
A 40-year-old male with borderline lepromatous leprosy and type 2 reaction (BI 2+; MI 0) diagnosed three years previously was started on multibacillary multi-drug therapy (MB-MDT), which he took for a year. He developed severe type 2 reaction with suppurative axillary lymphadenopathy one year later (Fig. 2). Histopathology showed multiple granulomas in the dermis composed of foamy macrophages, lymphocytes with neutrophils around adnexa and neurovascular bundles (Fig. 3). Few acid fast bacilli, both fragmented and intact, were seen in Fite's stain (Fig. 4). Skin smears showed BI 4+; MI 1%.
A Mantoux test was performed, which was non-reactive. The patient was administered systemic steroids and thalidomide 100 mg BID to control the reactions. Monthly ROM (rifampicin 600 mg; ofloxacin 400 mg; minocycline 100 mg) was started and continued for three years. His smears showed a decrease in BI to 2+ and MI to 0.
The patient continued to have severe type 2 reactions intermittently warranting admission and also developed iatrogenic diabetes mellitus. After tapering the steroids under the cover of thalidomide, a single Injection BCG was administered. A papulonodule developed at the site of Injection BCG after four weeks. Following Injection BCG, the severity and frequency of reactions decreased. He achieved smear negativity three months later (BI 0; MI 0%). He was advised thalidomide 100 mg on alternate days, which was tapered to 50 mg on alternate days and finally withdrawn. The Mantoux tested site showed a reaction of 10 mm following Injection BCG.
The patient remains free from reactions for the past two years and is not on any medication (Fig. 5).
A 67-year-old male with marked earlobe infiltration and plaques of about 20 years duration suggestive of lepromatous leprosy (Figs. 6 and 7) developed shiny nodules showing a histoid picture (Fig. 8) on histopathology. The skin smears showed a BI of 2+ from lepromatous plaque and 6+ from the histoid lesion; MI was 3% from the lepromatous plaque and 6% from the histoid lesion. The bacilli in the smears were long and thin, as seen in the histopathology of histoid leprosy (Fig. 9). The patient had taken multibacillary treatment about one year previously for two months. A Mantoux test done prior to starting MDT was non-reactive. He was started on regular MB (MDT) and administered a single injection BCG. He developed a papule over the injected site six weeks later, which ulcerated. At the next follow-up, five months later, the BI was 4+ from the lepromatous plaque and 6+ from the histoid nodule. Both lesions showed considerable flattening (Fig. 10), and the MI was zero from both types of lesions. The infiltration over the ear lobes also showed signs of resolution. A Mantoux test performed two months after administering BCG showed a reaction of 11 mm. The patient is currently under follow-up.
Highly bacilliferous cases of leprosy may not respond to chemotherapy alone. The presence of solid bacilli in these cases even after one year of fixed-dose therapy may not always imply drug resistance.
Mycobacterium leprae is an obligate intracellular parasite, and protective immunity is critically dependent on the development of CMI. The CMI is suppressed in lepromatous leprosy consequent to the high mycobacterial antigen load and is clinically manifested as cutaneous anergy. Thus, there is a failure of the body to mount an immune response evidenced by a lack of reactivity at the site of Mantoux testing and at the site of Injection BCG. The suppressed CMI impairs bacterial killing and elimination and makes chemotherapy ineffective (dormant organisms do not multiply and thus escape the action of the drug).
The T-lymphocyte populations vary in tuberculoid (TT) and lepromatous (LL) leprosy. LL lesions have increased CD8+ suppressor T-cells (TT-CD4+/CD8+ ratio of 1.9 : 1; LL CD4+/CD8+ of 0.6 : 1). BCG stimulates the host immune system to mount a delayed hypersensitivity reaction. It is a potent inducer of CD4+ T-cells via antigen presentation through the MHC class II pathway and activates TH1 T-cells for memory T-cell production. Katoch et al.  have used BCG at 6-month intervals in bacilliferous leprosy patients and achieved faster clearance of bacilli assessed by mouse footpad and bacillary adenosine triphosphate content.
Repeated immunotherapy with BCG until the development of a papulonodule at the injected site (an indicator that the cutaneous reactivity has been restored) in combination with chemotherapy was effective in these patients achieving faster killing of bacteria as evidenced by the fall in the MI to zero and clearance of bacilli (evidenced by the fall in the BI), thus reducing disease morbidity (relapses and reactions). Mantoux testing prior to administration of BCG may serve as a simple guide to the immune status of the patient. Subsequent conversion of the Mantoux to positive following BCG could be as a result of the immunostimulant action of BCG. In all three cases, the MI became zero following one-four injections of BCG. The increase in BI after Injection BCG was administered in the third case is possibly due to the live solid bacilli being converted into granular forms as a result of effective bacterial killing following stimulation of the immunity. However, the MI in the third patient was 6% and became zero after administration of BCG.
Fragmentation of bacilli in severe type 2 reaction also may cause an increase in BI as was the case in the second patient.
Immunotherapy (Injection BCG) combined with chemotherapy would be able to achieve effective killing and faster clearance of bacilli decreasing disease morbidity. Mantoux testing would serve as a simple guide to evaluate the level of immunity, especially where facilities for more sophisticated assays do not exist. These case reports would lead to the trend in combination therapy for recalcitrant cases of leprosy and help lower the tendency for inappropriate diagnosis of drug-resistant leprosy.