Sequential monitoring of 724 sera for antibodies to a neoantigen based on phenolic glycolipid-I (PGL-I) and native lipoarabinomannan (LAM) in 90 leprosy patients undergoing therapy in San Francisco was conducted. Untreated lepromatous patients frequently (91%) had significant antibodies to both moieties. Antibodies were less frequently found in tuberculoid patients (74% to neoantigen and 37% to LAM). In the first 3 years of treatment, average serum antibodies to both moieties fell significantly. Antibodies to LAM fell during each of the first 4 years of therapy, but decreasing antibody levels to the PGL-I neoantigen did not appear to fall consistently after the third year of treatment. A wide variation in the rate of fall of serum antibodies was noted. Sequential changes in the amounts of serum antibodies to the neoantigen and LAM in general paralleled one another but were at times discrepant. Both in San Francisco and Malaysia, skin-smear negative, long-term treated, lepromatous leprosy patients frequently harbored significant antibodies to both PGL-I and LAM.
A detailed account and definition is given of the previously inadequately described "giant reactions" to tuberculin occasionally seen in leprosy patients. The reaction is an accelerated and exaggerated response to species-specific antigens of Mycobacterium tuberculosis found in both PPD and New tuberculin. Our studies were performed in Malaysia, Uganda, Spain, and England. There was a significantly higher incidence of the phenomenon in Malaysia than in the other centers, but this may have been because there alone previously untreated lepromatous (LL and BL) patients were serially tested for up to three years after starting chemotherapy. Of the 28 patients exhibiting giant reactions, 27 occurred among lepromatous patients (24 LL and 3 BL), of which only 3 (1 LL and 2 BL) were untreated. One treated BL patient had developed, and one untreated BL patient was a family contact of, active tuberculosis. Giant reactions are uncommon in untreated and in very long-term treated LL patients, but may occur in up to a fifth of those receiving their first 1-3 years of chemotherapy. Although the mechanism is not yet understood, it appears to be a coincidence of delayed hypersensitivity of the tuberculin type and a less-delayed phenomenon of excessive local edema associated with local lymphadenopathy and short-lasting symptoms of malaise and pyrexia. It is suggested that the majority of giant reactions occur during a period of temporary lack of immune regulation associated with changing levels of antigenic load.
The findings of autopsies performed on 35 leprosy subjects in the University Hospital, Kuala Lumpur, between January 1981 and December 1985 are presented. This is the first report based on autopsy findings from Malaysia. The patients were elderly subjects with a mean age of 74 years. Sixty-six percent had lepromatous leprosy. None had active skin lesions. The most common cause of death was pyogenic infection, particularly bronchopneumonia. Tuberculosis was noted in 25% of the cases. The other important causes of death included cardiac and renal failure. Renal lesions were evident in 71% of the cases, and the most common pathology was interstitial nephritis. Generalized amyloidosis complicated six (17%) patients.
Skin biopsies from 100 patients with untreated lepromatous leprosy from Malaysia, India, Africa, and South America were examined with particular regard to pathological changes in intima, media, or adventitia of blood vessels and to the presence of leprosy bacilli in these layers. Bacilli were found in capillaries, venules, or arterioles in all cases, and in many instances they were present in endothelial lining cells or smooth muscle in large masses (globi). In several cases, solid-staining bacilli in endothelial lining cells were especially prominent. The findings are discussed in relation to a) the continuous bacteremia of lepromatous leprosy, b) the role of endothelial cells in phagocytosis, c) smooth muscle cells of the media as a site in which bacilli may persist, and d) the transmission of human leprosy by biting arthropods.
Fifteen patients with pure lepromatous leprosy were treated for 12 months with DDS at 50 mgm. twice weekly. The drug was fully effective in this dose, and the incidence and severity of ENL were not less than on larger doses
Proof that a patient is suffering from sulfone-resistant leprosy depends on demonstrating that his bacilli can multiply in the mouse foot pad even when the mice are fed sulfone in the diet. Hitherto the maximal dose of DDS tolerated by the mouse has been used in such tests. This paper concerns a patient whose bacilli multiplied in mice fed lower doses of DDS, but were inhibited when the maximal dose was used . His clinical features are distinctive and probably characteristic of this type of "partial" resistance. It is likely that more cases of this type will be found . Recommendations are made concerning the investigation of possible DDS-resistant leprosy patients and their treatment.
The response to lepromin and Kveim antigens was compared and studied in 15 leprosy patients who were tuberculin negative. Of the 11 lepromin positive tuberculoid patients, 4 were Kveim positive, 1 was equivocal, and the rest were negative. Of the four lepromin negative lepromatous patients, one gave a positive Kveim test while the other three were negative. It has been shown that false-positive Kveim reactions are found in a higher percentage of South Indian leprosy patients than in those of other backgrounds, such as Japanese and Malaysian Chinese patients. It is also suggested that no definite relationship exists between the reaction of leprosy patients to lepromin and Kveim antigens. We further suggest that the anergy exhibited by lepromatous patients to the antigen of M. leprae is specific, as evidenced by the positive Kveim response in one lepromatous patient.
Using a trial design previously evolved at Sungei Buloh Leprosarium, a pilot trial was performed of B.663, in the dosage of 100 mgm. twice weekly, in eight patients with previously untreated lepromatous leprosy. The therapeutic results, as measured by clinical, bacteriologic and histologic assessment, and especially by the rate of fall of the morphologic index, were similar to those obtained with sulfone therapy or with 0.663 in the dosage of 300 mgm. daily. Although B.663 pigmentation was produced in all eight patients, it developed more slowly and was less intense than with standard dosage. Difficulties resulting from skin discoloration in assessing the clinical progress of patients on B.663 are discussed.
Kveim tests using a validated material have been undertaken in Malaysia on 39 patients (32 Chinese; 4 Malay and 3 Aboriginal) with lepromatous or tuberculoid leprosy. All the patients had been treated for leprosy, most for two or more years. The tests were read microscopically. Of the 21 lepromatous patients one gave a weak positive and two an equivocal Kveim test whereas four of the nine tuberculoid patients gave equivocal or weak Kveim positivity. Only the tuberculoid form elicits a higher proportion of granulomas than might be expected in a comparable normal population. Of nine patients (8 lepromatous; 1 tuberculoid ) who failed to sensitize well to tuberculin
following two BCG vaccinations, two gave equivocal Kveim tests similar in appearance to those in the other groups.
From an extensive search of one of the largest inpatient leprosaria in the world, at Sungei Buloh, Malaysia, nine patients with lepromatous leprosy were discovered who gave prima facie evidence of sulfone resistance. The evidence was based on a failure to show clinical improvement over at least five years despite treatment with sulfones and an absence of a satisfactory fall in the bacteriologic (BI) or the morphologic (MI) index. The selected patients were admitted to our Research Unit for (a) a further six month, rigorously controlled, trial period on DDS (as injectable sulfone, 300 mgm. twice weekly) and (b) DDS sensitivity tests, based on use of the foot pad infection in mice with bacilli obtained from skin biopsies. The response of the nine patients to the six month trial period on DDS was assessed clinically, bacteriologically and histologically, and revealed that only four of the patients failed to respond satisfactorily. Furthermore, the sensitivity tests in the mouse foot pad infection showed that only the strains of M. leprae from the four patients who failed to improve were insensitive to DDS. Thus there was a good correlation between the results of the clinical and experimental studies and for the first time direct proof for the existence of DDS resistant strain s of M. leprae. The MI proved to be the most sensitive of the assessments used to determine the response of the selected patients to a trial period on DDS. The histology of patients with drug resistance is essentially that of relapsing or very acute leprosy. Its features have much in common with those of "histoid" lesions, the latter being distinguished mainly by the absence of cytologic maturation. Classification is complicated by the presence of borderline features in otherwise lepromatous lesions.
The first three patients with proven DDS-resistant leprosy infections were treated for one year with the riminophenazine
derivative B.663 (300 mgm. daily for six days a week). All of them showed satisfactory clinical, bacteriologic and histologic
improvement, which at the time of writing has been maintained for a total period of 28 months. The results show that
active leprosy resulting from resistance to one drug can still respond satisfactorily to a different type of drug, as is the case with drug resistance in other bacterial infections. In this limited study B.663 showed no toxicity, but the degree of skin discoloration was disconcerting to Chinese patients.