[Chemotherapy-induced erythema nodosum leprosum: successful treatment with thalidomide]. / Erythema nodosum leprosum unter Chemotherapie. Erfolgreiche Behandlung mit Thalidomid.

The severity and outcome of a chronic granulomatous infection caused by M. leprae depend on the cell-mediated immunity towards the pathogen. The disease classification is based on the host's response to M. leprae ranging from high to low resistance (polar tuberculoid leprosy to polar lepromatous leprosy). The host's position in the spectrum is not stable; leprosy reactions reflecting changed immune status may occur spontaneously or during chemotherapy. The type II reaction or erythema nodosum leprosum can most often be seen in patients with lepromatous leprosy, a multiorgan disease characterized by an unrestricted bacillary replication. Clinically, this reaction is characterized by crops of painful bright pink, dermal and subcutaneous nodules arising in clinically normal skin, in association with fever, malaise, glomerulonephritis and arthralgias. Therefore, prompt institution of immunosuppressive therapy with corticosteroids or thalidomide is recommended. This case report describes the development of erythema nodosum leprosum during chemotherapy treated successfully with thalidomide. Furthermore, immunologic effects and potential side effects of this drug are discussed.

Anti-tuberculosis drug resistance surveillance in Uganda 1996-1997.

SETTING: Drug resistance surveillance conducted by the National Tuberculosis and Leprosy Control Programme (NTLP) Uganda from 1996-1997 in collaboration with the Armauer Hansen Institute/German Leprosy Relief Association (GLRA), Germany, for the WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. OBJECTIVE: To determine the prevalence of primary and acquired anti-tuberculosis drug resistance in Uganda. DESIGN: The survey area covered three GLRA-supported operational NTLP zones, corresponding to 50% of the Ugandan population. A representative random sampling of individual patients was chosen as sampling procedure. Altogether 586 smear-positive TB patients (537 new cases and 49 previously treated cases) were included in the survey. RESULTS: For primary resistance the results were as follows: isoniazid (H) 6.7%, rifampicin (R) 0.8%, ethambutol (E) 6.1%, streptomycin (S) 13.4%, thioacetazone (T) 3.2%, pyrazinamide (Z) 0%, multidrug resistance (MDR) 0.5%; for acquired resistance they were: H 37.8%, R 4.4%, S 22.2%, E 11.1%, T 20.0%, Z 0%, and MDR 4.4%. CONCLUSION: According to these data the NTLP Uganda has been effective in preventing high levels of primary drug resistance. If it is assumed that the sampling process reflects the distribution of new patients and previously treated patients in the study areas, the amount of acquired resistance (any resistance) in the community of smear-positive patients is approximately 5%. To further monitor programme performance the NTLP will embark on a nationwide survey in 1998/1999.

Universal pattern of RpoB gene mutations among multidrug-resistant isolates of Mycobacterium tuberculosis complex from Africa.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) presents an increasing burden in Southern Africa. Rapid diagnostic tests for drug resistance to rifampicin have been developed based on mutation analysis of the rpoB gene. However, geographic differences of underlying mutations have recently been suggested. OBJECTIVE: Drug-resistant strains of Mycobacterium tuberculosis complex from Africa were analysed for geographic differences in frequency and location of rpoB mutations. DESIGN: A random sample of rifampicin-resistant strains was collected from 87 patients with pulmonary MDR-TB treated in 12 hospitals from six different regions of South Africa. In addition, 18 isolates of M. tuberculosis complex from Namibia, Sierra Leone, and Uganda, including 13 isolates of M. africanum, were analyzed. Point mutations were detected by direct sequence analysis of the rpoB gene. RESULTS: Missense mutations were identified for 91 isolates (87%). Double mutations were present in eight (8%) MDR-TB isolates, two of which carried one mutation outside a previously described diagnostic region. We found no geographic differences regarding the frequency and pattern of single rpoB gene mutations. CONCLUSION: Our results confirm that molecular genetic analysis of rifampicin resistance based on a core region within the rpoB gene is universally applicable to strains of M. tuberculosis complex from different geographic regions.

Tuberculosis chemotherapy and sputum conversion among HIV-seropositive and HIV-seronegative patients in south-eastern Uganda.

OBJECTIVE: To investigate if there is a difference in response to tuberculosis treatment between HIV seronegative and HIV seropositive patients following two months of intensive phase tuberculosis treatment. DESIGN: Prospective cohort study. SETTING: St. Francis Leprosy Centre, south-east Uganda. SUBJECTS: Four hundred fifty seven patients with never previously treated sputum smear-positive tuberculosis admitted during a two-year period in 1991/1993. INTERVENTION: Intensive phase treatment with streptomycin, isoniazid, rifampicin and pyrazinamide. MAIN OUTCOME MEASURES: Sputum conversion from a positive to a negative smear at eight weeks of treatment. RESULTS: HIV seropositivity prevalence was 28%. Among HIV seronegative patients, conversion to a negative smear status occurred in 76% persons compared to 78% in HIV seropositive patients. This difference was not statistically significant (OR = 0.9; 95% CI, 0.6-1.5). HIV seropositive patients, however, were more likely to die (p = 0.017). A high prevalence of resistance to isoniazid and streptomycin was found. Isoniazid resistance was more likely in HIV seronegative patients with M. tuberculosis strains compared to HIV seropositive persons (p < 0.005). Initial resistance to antituberculosis drugs did not have a significant effect on smear conversion. CONCLUSION: This study demonstrates that HIV-seropositive status is not a principal factor in delaying sputum conversion among patients receiving intensive phase tuberculosis treatment.

PIP: A prospective cohort study was undertaken to investigate the response of HIV-seropositive and -seronegative patients at St. Francis Leprosy Center, southeastern Uganda, to tuberculosis chemotherapy. The study population included 457 patients without a history of prior tuberculosis therapy between 1991 and 1993. The subjects were exposed to an intensive phase therapy of rifampicin, streptomycin, isoniazid, and pyrazinamide. After the treatment, sputum culture and sensitivity tests were conducted. Findings showed that 77% of the patients who never received tuberculosis treatment in the past converted to a negative smear status after the 8-week treatment. There was no significant difference in sputum conversion rates between HIV-seropositive and -seronegative patients. The study also revealed that HIV seropositivity prevalence was 28%. Among HIV-seronegative patients, conversion to a negative smear status occurred in 76% compared to 78% HIV-seropositive patients. Moreover, a significant number of HIV-seronegative patients died during the initial course of the therapy. Also, a high prevalence of isoniazid and streptomycin resistance was noted; however, this result never affected the conversions of smears. In conclusion, the study clearly demonstrates that other factors outside the seropositive status may be the principal causes of the delay in sputum conversion among patients receiving intensive tuberculosis chemotherapy.

Tuberculosis chemotherapy and sputum conversion among HIV-seropositive and HIV-seronegative patients in South-Eastern Uganda

Objective: To investigate if there is a difference in response to tuberculosis treatment between HIV-Seropositive and HIV-seronegative patients in South-Eastern Uganda. Design: Prospective cohort study. Setting: St. Francis Leprosy Centre; south-East Uganda. Subjects: four hundred fifty seven patients with never previously treated sputum smear-positive tuberculosis admitted during a two-year period in 1991/1993. Intervention: Intensive phase treatment with streptomycin; isoniazid; rifampicin and pyrazinamide. Main outcome measures: Sputum conversion from a positive to a negative smear at eight weeks of treatment. Results: HIV seropositivity prevalence was 28among HIV seronegative patients; conversion to a negative smear status occurred in 76 persons compared to 78 in HIV seropositive patients.This difference was not statistically significant (OR=0.9; 95CI; 0.6-1.5). HIV seropositive patients; however; were more likely to die (p=0.017). A high prevalence or resistance to isoniazid and streptomycin was found. Isoniazid restance was more likely in HIV seronegative patients with M.tuberculois strains compared to HIV seropositive persons (p0.005). Initial resistance to antituberculosis drugs did not have a significant effect on smear conversion. Conclusion : This study demonstrates that HIV-seropositive status is not a principal factor in delaying sputum conversion among patients receiving intensive phase tuberculosis treatment

Molecular analysis of katG gene mutations in strains of Mycobacterium tuberculosis complex from Africa.

A sample of 124 isoniazid (INH)-resistant and 88 susceptible strains of Mycobacterium tuberculosis complex from south, central, and west Africa was analyzed by direct sequence analysis and PCR-restriction fragment length polymorphism analysis of their catalase-peroxidase (katG) genes. Point mutations at codon 315 were found in the genomes of 64% of INH-resistant strains, but no complete deletions were identified. Mutations at codon 463 were independent of INH resistance and were linked to the geographic origins of the strains.

[Current aspects of leprosy]. / Aktuelle Aspekte der Lepra.

About 95% of individuals who come in contact with M. leprae do not develop overt disease. The clinical form of the disease correlates with the T-cell mediated immune response of the host rather the direct damage caused by bacilli. We review the current aspects of epidemiology, transmission, bacteriology, clinical features, reactions, diagnosis, chemotherapy and treatment of reactions.

Comparison of DNA fingerprint patterns of isolates of Mycobacterium africanum from east and west Africa.

Mycobacterium africanum is a pathogen found in tuberculosis patients in certain parts of Africa and is a member of the Mycobacterium tuberculosis complex. Biochemically, strains of M. africanum exhibit a high degree of variability, with some tendency to cluster according to their geographical origin. To investigate whether this phenotypic variability is reflected at the genetic level, we performed DNA fingerprint analysis of strains isolated from patients with pulmonary tuberculosis in Uganda and Sierra Leone. IS6110 DNA fingerprinting was carried out by the mixed-linker PCR method. A total of 138 strains of M. africanum were analyzed: 42 isolates from Uganda and 96 isolates from Sierra Leone. With few exceptions, the resulting DNA fingerprint patterns grouped together according to their country of origin. A striking lack of variability of DNA fingerprints was found for strains from Sierra Leone, where 70 of 96 isolates (61.5%) fell into clusters. The two largest clusters accounted for 41.7% of all isolates and differed by only one band, as confirmed by standard DNA fingerprinting. In contrast, only two clusters (7.1%) with two and three isolates, respectively, were found for M. africanum isolates collected in Uganda, and three of the DNA fingerprints contained fewer than seven bands. Strains of M. tuberculosis collected and processed during the same time period were highly variable in both countries. Our results support the concept of geographically defined subtypes of M. africanum. In addition, they demonstrate that natural geographic differences in the variability of IS6110 DNA fingerprints within the M. tuberculosis complex must be considered if this technique is used for epidemiologic studies.

[Initial manifestation of tuberculoid leprosy in pregnancy. Guidelines for diagnosis and therapy]. / Erstmanifestation einer tuberkuloiden Lepra in der Schwangerschaft. Leitlinien zur Diagnostik und Therapie.

Pregnancy has long been associated with the first presentation of clinical leprosy or aggravation of the existing disease. In Germany leprosy has been diagnosed in 107 patients since 1980. A 27-year-old Singhalese female, gravida 2 at 14 weeks' gestation was admitted with well defined, elevated, erythematous lesions on her cheeks and nose. Clinical examination revealed central anaesthesia in the lesions. No further signs of leprosy in the skin, the mucosae and the peripheral nerves were found. Fite-Faraco staining of the skin biopsy showed sporadic acid-fast bacilli and confirmed an active subpolar tuberculoid leprosy (TTs). Outpatient treatment was immediately initiated with oral rifampin 600 mg monthly and dapsone 100 mg daily. During the 4-month treatment cycle the skin lesions vanished completely. Additional leprosy reactions did not occur and the medication was well tolerated. However, in the 32nd gestational week the patient was readmitted with premature labour and 3 weeks later Caesarean section was performed because of cardiotocographic pathology. Polymerase chain reaction (PCR) for M. leprae of placental tissue was negative. Antibodies against phenolic glycolipid 1 (PGL 1) of M. leprae (IgM-Elisa and Dot-Elisa) from cord blood, maternal and newborn blood were not found. On the fifth postpartal day the healthy mother and her baby were discharged. In conclusion, leprosy in pregnancy can be treated safely and successfully by combined drug therapy.

Susceptibility of severe combined immunodeficient mice to Mycobacterium leprae.

The susceptibility of severe combined immunodeficient (SCID) mice to human leprosy bacilli was investigated. Nude mice were used as controls. SCID mice were found to be highly susceptible to Mycobacterium leprae and the progress of infection was comparatively 2-3 months earlier than observed in the nude mice. After reaching a maximum of approximately 1 x 10(9) acid fast bacilli/foot pad at about 8 months postinfection the number of bacilli gradually decreased. The progress of infection in nude mice was different from that found in SCID mice. The multiplication of M. leprae in the foot pads of nude mice continued and reached approximately 2.0 x 10(10) bacilli/foot pad and then nearly remained the same. The results indicate that SCID mice can be used as a suitable model for screening antileprosy drugs while nude mice should be involved in the production of M. leprae for use in other fields of leprosy research.

[Leprosy--current aspects of a disease from biblical times]. / Lepra--aktuelle Aspekte einer Erkrankung aus biblischer Zeit.

95% of individuals who come in contact with M. leprae do not develop an overt disease. It begins as an indeterminate form that may undergo spontaneous cure or may progress to different forms of leprosy (TT, BT, unstable form of BB, BL, or LL). The clinical form of the disease correlates with the T cell mediated immune response rather than to the direct damage caused by the bacilli. The lack of cellular immunity in lepromatous patients relates specifically to M. leprae. Current aspects of etiology, transmission, epidemiology, classification, clinical features, immunopathology, chemotherapy, treatment of reactions, immunotherapy and vaccination are elucidated and discussed.

Characterization of rifampin-resistance in pathogenic mycobacteria.

The emergence of rifampin-resistant strains of pathogenic mycobacteria has threatened the usefulness of this drug in treating mycobacterial diseases. Critical to the treatment of individuals infected with resistant strains is the rapid identification of these strains directly from clinical specimens. It has been shown that resistance to rifampin in Mycobacterium tuberculosis and Mycobacterium leprae apparently involves mutations in the rpoB gene encoding the beta-subunit of the RNA polymerases of these species. DNA sequences were obtained from a 305-bp fragment of the rpoB gene from 110 rifampin-resistant and 10 rifampin-susceptible strains of M. tuberculosis from diverse geographical regions throughout the world. In 102 of 110 rifampin-resistant strains 16 mutations affecting 13 amino acids were observed. No mutations were observed in rifampin-susceptible strains. No association was found between particular mutations in the rpoB gene and drug susceptibility patterns of multidrug-resistant M. tuberculosis strains. Drug-resistant M. tuberculosis strains from the same outbreak and exhibiting the same IS6110 DNA fingerprint and drug susceptibility pattern contained the same mutation in the rpoB gene. However, mutations are not correlated with IS6110 profiling outside of epidemics. The evolution of rifampin resistance as a consequence of mutations in the rpoB gene was documented in a patient who developed rifampin resistance during the course of treatment. Rifampin-resistant strains of M. leprae, Mycobacterium avium, and Mycobacterium africanum contained mutations in the rpoB gene similar to that documented for M. tuberculosis. This information served as the basis for developing a rapid DNA diagnostic assay (PCR-heteroduplex formation) for the detection of rifampin susceptibility of M. tuberculosis.

Alpha-ketoglutarate dehydrogenase in the in vitro-grown Mycobacterium lepraemurium.

The Hawaiian and Kumato strains of Mycobacterium lepraemurium were cultivated on Ogawa egg-yolk medium, and the alpha-ketoglutarate dehydrogenase activity was investigated in cell-free preparations of this mycobacterium. The enzymatic activity was mainly localized in the particulate fraction (150,000 x g pellet), and extremely low activity was found in the soluble fraction (150,000 x g supernatant). alpha-Ketoglutarate dehydrogenase was not stable; the activity was lost completely when the enzyme was kept at 45 degrees C for 1 hr or stored at -70 degrees C. The enzyme reduced only NAD+ but not NADP+ by alpha-ketoglutarate, indicating the presence of NAD(+)-dependent alpha-ketoglutarate dehydrogenase in cultivated M. lepraemurium.