Delayed resolution versus treatment failure in paucibacillary leprosy patients under six months fixed duration multidrug therapy.

Thirty paucibacillary (PB) patients were given multidrug therapy (MDT) PB regimen for six months and were examined clinically and histopathologically before therapy, at six months and 12 months after therapy; and in four patients, at 18 to 23 months after MDT. Histopathological activity was present in 50% and 25% of patients after six months and 12 months respectively after MDT. At 18 to 23 months, the four patients continued to have active lesions both clinically and histopathologically. On the basis of this study it is found that fixed duration of MDT is effective in a large majority of patients especially those with indeterminate leprosy. However, there is "delayed resolution" in a significant number of patients which in a few instances may turn out to be "treatment failures". Therefore, a regular follow up of high risk patients for at least two years and if possible, five years, with freedom to intervene with additional anti-inflammatory or antileprosy therapy as desired, is recommended.

Pathologic changes in a tibial nerve with surviving M. leprae in a healed tuberculoid leprosy patient.

A tibial nerve from a disease-arrested borderline tuberculoid (BT) leprosy patient was dissected out and examined almost in its entirety using hematoxylin and eosin staining, a modified Fite's stain for acid-fast bacilli (AFB), solochrome cyanin stain for myelin, and van Gieson's stain for fibrous tissue. Fibrosis of the perineurium and epineurium and fibrous replacement of the nerve parenchyma, which was maximum at the ankle joint area, were seen. In focal areas inflammation was present, especially in the epineurium around blood and lymph vessels. Even 21 years after adequate antileprosy therapy, AFB were present in the endoneurium in all except 2 of the 10 segments of the nerve, evoking hardly an inflammatory reaction or other ill effects. It is pointed out that BT leprosy should also be considered a generalized disease, especially when there is peripheral nerve trunk involvement and, in such cases, a longer duration of currently available antileprosy therapy is advisable. Trauma to nerve trunk plays a major role in producing nerve destruction and paralysis.

Histopathologic evidence to show that indeterminate leprosy may be a primary lesion of the disease.

Five biopsies of patients with indeterminate leprosy and five with skin lesions of nonspecific chronic inflammation were chosen. Histopathologic changes in the presence of acid-fast bacilli (AFB) in an average number of 145 serial sections from the entire paraffin block from each were evaluated. In all five indeterminate lesions AFB were found in the dermis, but intraneural AFB were present in only two cases. Mainly, lymphocytic infiltrate was present in two and early, poorly formed granulomas were seen in three. It is suggested that nonspecific chronic inflammation of the skin could precede indeterminate disease and that AFB, before they entered the dermal nerves, may be found in other dermal tissues. In most if not all early lesions of indeterminate leprosy Mycobacterium leprae would be found if an adequate number of sections stained for AFB were examined. The histopathologic and immunologic features of indeterminate disease were in favor of it being a primary lesion in leprosy.

Viability of Mycobacterium leprae in skin and peripheral nerves and persistence of nerve destruction in multibacillary patients after 2 years of multidrug therapy.

The pathological changes, bacterial load, and viability of Mycobacterium leprae in the skin and nerves of nine lepromatous leprosy patients who had undergone 2 years of multidrug therapy (MDT) were studied. M. leprae and varying amounts of their remnants were present in the nerves and skin of all but one patient. M. leprae isolated from skin biopsies of six patients and nerve biopsies of nine patients were inoculated into mouse foot pads. No growth was obtained from any one of them. During the electron-microscopic examination of three nerve biopsies, only one specimen showed a small number of solid-staining M. leprae. These findings would explain the low relapse rate in patients treated with 2 years of fix-duration MDT. Results of a long-term follow up of patients is awaited with interest. The possibility of nerve paralysis due to intraneural microreaction and fibrosis consequent to the continued presence of dead bacterial remnants should be seriously considered.

Viability of Mycobacterium leprae in lepromatous patients after five years of dapsone monotherapy supplemented with two years of multidrug therapy.

Eleven lepromatous leprosy (LL) patients with a bacterial index (BI) of three and above who had undergone two years of multidrug therapy (MDT) and yet had positive skin smears at the end of treatment were chosen for this study. Biopsies from the skin and lymphnodes were histopathologically evaluated for the presence of granulomas and M. leprae. M. leprae isolated from the skin and lymphnodes were inoculated into the foot-pads of normal mice to test their viability. On histopathological examination of the biopsy specimens, it was found that granulomas and M. leprae were present in the skin and lymphnode biopsies of all patients except two, in whom, although granulomas persisted, M. leprae were not found in skin biopsy specimens. No growth was obtained in the foot-pads of mice inoculated with organisms isolated from skin and lymphnode biopsies of all 11 patients indicating a near complete bacterial kill. That would account for the extremely low relapse rates reported until now in LL patients who had undergne two years of MDT.

Influence of acetylator phenotype of the leprosy patient on the emergence of dapsone resistant leprosy.

The half time of disappearance of dapsone and monoacetyl dapsone and the acetylator phenotype of the leprosy patients who harboured dapsone sensitive and dapsone resistant M. leprae was assessed in 27 subjects. Sixteen patients were rapid acetylators, five were slow and six were intermediate acetylators. The mean T 1 1/2 lives of dapsone (30.26 +/- 11.0) and monoacetyl dapsone (31.11 +/- 12.0) were also studied in the above patients. The percentage of different acetylators in both resistant and sensitive groups were similar showing no correlation between the emergence of drug resistance and the phenotype of the patient. The mean time of disappearance of DDS and MAD in the different acetylators did not show significant difference. The ratios of MAD/DDS in an individual at 3, 6 or 24 hours after the dose were similar. The mean T 1 1/2 lives of DDS and MAD in resistant and sensitive patients also showed no difference. Neither T 1 1/2 lives of DDS or MAD nor the acetylator phenotype seem to influence the emergence of dapsone resistance.

Certain aspects of dapsone metabolism in leprosy patients as studied by high performance liquid chromatography (HPLC) and qualitative screening tests.

Dapsone (DDS) in urine of 250 leprosy patients collected on surprise visits were screened by simple paper spot, tile tests and sensitive Enzyme linked immunosorbent assay (ELISA) and Haemagglutination inhibition (HI) tests. The urinary DDS concentration as well as DDS/C ratios were also studied. Simultaneously, 50 microliter of blood was collected from each of these patients and its dapsone content was estimated by HPLC. Urine samples with means of 25 to 30 micrograms/ml DDS and 55-64 micrograms/mg DDS/C ratios were found to give positive tests by any of the above screening procedures, while their mean blood DDS concentration was found to be 0.91 microgram/ml. The corresponding values for those specimens giving negative tests were 3.8 to 5.7 micrograms DDS per ml and 9 to 13 micrograms/mg DDS/C ratio. The blood DDS concentration in this group was ranging from 0.16 to 0.18 micrograms/ml. The findings are discussed in relation to their metabolic significance and their application in a leprosy control programme.

Secondary and primary dapsone resistant leprosy: an analysis of 199 patients from St. Thomas Hospital and leprosy project, Chettupattu, South India.

The occurrence of secondary and primary dapsone resistance in 199 patients in our control area and the influence of certain variables such as age, initial bacteriological and morphological indices, duration of regular dapsone monotherapy, on the emergence of dapsone resistance was investigated. Ninety one of 122 patients and 29 out of 77 showed secondary (SDR) and primary (PDR) resistance to dapsone respectively. Very low BI (BI:2.5) group also showed both SDR (60%) and PDR (40%). Low or high MI group exhibited the same degree of resistance. Multiplication of M. leprae was obtained even when the MI of the inocula was zero. Even in the group who had 1 to 5 years duration of regular dapsone treatment, 85% patients showed SDR. Significance of such results are discussed in relation to chemotherapy. The overall minimum prevalence of SDR was found to be 5.6% and 21% in the case of PDR in our control area.