Geographic determinants of leprosy in Karonga District, Northern Malawi.

BACKGROUND: Geographical differences in leprosy risk are not understood, but may provide clues about the natural history of the disease. We report an analysis of the geographical distribution of leprosy in Karonga District, a rural area of Northern Malawi, between 1979 and 1989. METHODS: Cohort study of the incidence of leprosy based on two total population surveys. Area of residence was determined using aerial photographs, which allowed identification of households, as well as location of roads, rivers and the lake shore. RESULTS: Incidence rates were between two and three times higher in the north compared to the south of the district, and lowest in the semi-urban district capital. The most obvious environmental difference between these regions is the north's higher rainfall and more fertile soil. There was no overall association between leprosy incidence and population density, although highest rates were observed in the least densely populated areas. Looking at the entire district, incidence rates increased with increasing distance from a main road, but declined with increasing distance from a river or from the shore of Lake Malawi. The negative association with proximity to rivers may reflect the larger number of rivers in the north of the district. Apparent differences in incidence rates between groups speaking different languages reflected confounding by area of residence. CONCLUSIONS: There is a marked variation, not explained by socioeconomic or cultural factors, in the incidence of leprosy within Karonga District. Our results are consistent with a theme in the literature associating the environment, particularly proximity to water, with leprosy.

PIP: Researchers do not understand how geographical differences relate to the risk of contracting leprosy. The study of such differences, however, may provide clues about the natural history of the disease. The authors report findings from an analysis of the geographical distribution of leprosy in Karonga District, a rural area in Northern Malawi, between 1979 and 1989. Findings are based data from two total population surveys. The areas of residence were determined using aerial photographs, which allowed the identification of households, roads, rivers, and the lake shore. Analysis revealed that incidence rates were 2-3 times higher in the north compared to the south of the district, and lowest in the semi-urban district capital. The north has higher rainfall and more fertile soil. There was no overall association between the incidence of leprosy and population density, although the highest rates were observed in the least densely populated areas. Considering the entire district, incidence rates increased with increasing distance from a main road, but declined with increasing distance from a river or from the shore of Lake Malawi. This negative association with proximity to rivers may reflect the larger number of rivers in the north of the district. Apparent differences in incidence rates between groups speaking different languages reflected confounding by area of residence. The authors conclude that there is a marked variation, not explained by socioeconomic or cultural factors, in the incidence of leprosy within Karonga District. These results are consistent with literature which associates the environment, especially proximity to water, with leprosy.

Delayed-type hypersensitivity to Mycobacterium leprae soluble antigens as a test for infection with the leprosy bacillus.

BACKGROUND: Mycobacterium leprae (M. leprae) soluble antigen (MLSA) reagents have been developed with the aim of finding a reagent, comparable to tuberculin, which could identify individuals infected with the leprosy bacillus. They have yet to be evaluated fully in human populations. METHODS: More than 15000 individuals living in a leprosy endemic area of northern Malawi were skin tested with one of five batches of MLSA prepared using two different protocols. The main difference in preparation was the introduction of a high G centrifugation step in the preparation of the last three ('second-generation') batches. RESULTS: The prevalence of skin-test positivity (delayed-type hypersensitivity (DTH)) and association with the presence of a BCG scar were greater for first (batches A6, A22) than second (batches AB53, CD5, CD19) generation reagents. The association of positivity with M. leprae infection was investigated by comparing results among known (household) contacts of leprosy cases, and among newly diagnosed leprosy patients with those in the general population. While positivity to 'first-generation' antigens appeared to be associated with M. leprae infection, positivity to later antigens was unrelated either to exposure to leprosy cases or presence of leprosy disease. There were geographical differences in the prevalence of DTH to the various batches, probably reflecting exposure to various mycobacteria in the environment. CONCLUSIONS: Our results suggest that the 'second-generation' batches have lost antigens that can detect M. leprae infections, but that they retain one or more antigens which are shared between M. leprae and environmental mycobacteria. Natural exposure to these both sensitizes individuals and provides natural protection against M. leprae infection or disease. Identification of antigens present in these groups of skin test reagents may assist in production of improved skin test reagents.

Tuberculin sensitivity: conversions and reversions in a rural African population.

SETTING: Karonga District, northern Malawi, 1980-1989. OBJECTIVE: To measure and interpret incidence and prevalence of tuberculin sensitivity. DESIGN: Tuberculin testing carried out within two total population surveys. Tuberculin 'positivity' and 'conversion' were defined using criteria recommended by the Tuberculosis Surveillance Research Unit and the American Thoracic Society, respectively. RESULTS: Data on 64,225 tests were available for analysis, including paired results on 6991 individuals tested in both surveys. Frequency distributions of induration varied by age, sex, BCG scar status and zone within the district. The prevalence of 'positivity' was similar in males and females until age 15, then higher among males, and was consistently higher among individuals with than among those without a BCG scar. Tuberculin 'conversion' rates estimated from cross-sectional data ranged from 0.34 to 1.15 per cent per annum. Conversion rates derived from longitudinal data were found to increase linearly with age, and the reversion rates declined rapidly with age among younger individuals. Such trends, which have been reported in other populations, are shown here to arise as an artefact of test instability. Prospective follow-up of observed converters showed greatly increased risks of tuberculosis, in particular during the two years following the second ('converted') test (relative risk > 10). CONCLUSION: Estimation of a convincing 'true' annual risk of infection from tuberculin survey data is not possible from either cross-sectional or longitudinal data, due to misclassifications and the instability of delayed type hypersensitivity over time. An apparent increase in infection risk with age can arise as an artefact of test instability. BCG-induced tuberculin sensitivity declines rapidly in this population in most individuals. It is necessary to consider tuberculin reversions, whether real or apparent, when interpreting tuberculin data on individuals or populations.

Trends in antituberculosis drug resistance in Karonga District, Malawi, 1986-1998.

SETTING: Karonga District, Malawi. OBJECTIVES: To examine long term trends in initial and acquired resistance to antituberculosis drugs in a rural area of Africa. DESIGN: Monitoring of all patients with culture-confirmed tuberculosis 1986-1998. RESULTS: Initial drug resistance results were available for 1121 patients. The proportion resistant to any of the first line drugs (streptomycin, isoniazid, rifampicin or ethambutol) was 9.6%, and to isoniazid 7.2%. Initial resistance to at least isoniazid and rifampicin (multidrug resistance) was seen in only six patients. No initial resistance to ethambutol was found. There was no significant change in initial drug resistance over time. Overall, 22/120 (18%) patients with previous treatment were resistant to at least one drug; only one had multidrug resistance. Acquired resistance decreased over the period of the study. There were no associations between age, sex or human immunodeficiency virus (HIV) status and initial or acquired drug resistance. CONCLUSIONS: Changes in acquired resistance may reflect the recent performance of a control programme more quickly than those in initial resistance. It is encouraging that acquired resistance decreased and levels of multidrug resistance were low despite more than a decade of use of rifampicin. The lack of association between HIV and drug resistance confirms findings elsewhere in Africa.

BCG scars in northern Malawi: sensitivity and repeatability of scar reading, and factors affecting scar size.

SETTING: Karonga district, northern Malawi. OBJECTIVE: To assess the sensitivity and repeatability of BCG scar reading, and factors affecting scar size. DESIGN: Follow-up of individuals aged > 3 months who were recruited into a BCG vaccine trial (1986-1989), and of infants vaccinated in health centres (1989-1991), who were examined for presence and size of BCG scars in subsequent years. All examinations were carried out blind of information on true vaccination status or the results of previous examinations. RESULTS: For trial individuals who were considered scar negative at recruitment and received BCG, the sensitivity of scar reading was > or = 93%, repeatability was > or = 94% for those < 60 years old at vaccination, and only around 1% were assessed as having > 1 BCG scar post-vaccination. For infants vaccinated when < 1 month old in health centres, the proportion who still had recognisable scars 4 years later was < 80%. Scars were larger in individuals with a prior BCG vaccination, and for those aged 15-59 at vaccination the scars were approximately 1 mm larger for males than for females. CONCLUSIONS: A BCG scar is a highly sensitive and repeatable indicator of vaccination status when the vaccine is properly handled, delivered appropriately, and given at over 3 months of age, but not for vaccinations given within 1 month of birth. Given that most vaccinations in the world are given soon after birth, this low sensitivity will lead to both vaccine coverage and vaccine efficacy being underestimated in studies in which vaccination status is inferred from the presence/absence of a distinctive BCG scar. Age-sex patterns identified for scar size show important similarities to those found with skin test responses to tuberculin.

Leprosy in Malawi. 1. Sensitivity and specificity of the diagnosis and the search for risk factors for leprosy.

The sensitivity and specificity of the diagnosis of leprosy in the context of a total population survey are examined. It is apparent that diagnostic tools are unsatisfactory with regard to reaching a highly sensitive and specific case definition of paucibacillary leprosy, particularly in actively found suspects. Histopathological examination of 4 mm punch biopsy specimens contributed appreciably to both the sensitivity and specificity of the diagnosis of leprosy, though there was evidence for false positive and false negative histopathology results. The needs for high sensitivity during the intake phase of a vaccine trial and for high specificity during follow-up surveys for risk factors are discussed.

Leprosy in Malawi. 2. Background, design and prospects of the Karonga Prevention Trial, a leprosy vaccine trial in northern Malawi.

The Karonga Prevention Trial is the largest vaccine trial ever mounted in Africa. It is designed to test two hypotheses: (i) whether the addition of killed Mycobacterium leprae can increase the protection against leprosy (and tuberculosis) imparted by BCG alone; and (ii) whether repeating a BCG vaccination can increase upon the protection provided by an initial dose. The rationale and design of the trial are discussed in relation to the history of vaccination against leprosy and to several contending arguments which determined the ultimate protocol. The potential of the trial to reveal statistically significant differences between the vaccines being compared is discussed, as are the implications of possible results for future research and control of leprosy.

Two cases of cutaneous leishmaniasis in Malawi.

Leishmaniasis is rarely encountered in southern Africa. Two cases were diagnosed by histopathology in northern Malawi in one year. One was an 18 months old child with negative human immunodeficiency virus 1 (HIV-1) serology and widespread skin lesions; the other an HIV-1 positive adult with 2 skin lesions. The Leishmania species responsible could not be identified, but the infection may be more prevalent in this region than previously thought.

Tuberculosis: associations with HIV and socioeconomic status in rural Malawi.

Tuberculosis (TB) is associated with human immunodeficiency virus (HIV) infection, increasing age and male sex, but less is known about other risk factors in developing countries. As part of the Karonga Prevention Study in northern Malawi, we conducted a retrospective cohort study in the general population to assess risk factors for the development of TB. Individuals were identified in 1986-89 and TB cases diagnosed up to 1996 were included. TB was confirmed in 62/11,059 (0.56%) HIV negative individuals and 7/182 (3.9%) HIV positive individuals (relative risk 7.1, 95% confidence interval 3.2-15.7). This association was little altered by adjustment for age, sex or socioeconomic factors. The risk of TB was higher in those aged over 30 years than in younger individuals, in men than in women, in those engaged in occupations other than farming than in subsistence farmers, in those living in households with burnt brick dwellings than in those with less well built dwellings, and in those with some schooling than in those with none. These associations persisted after adjusting for age, sex, HIV status and population density. The absolute risks of TB were low in this study due to the passive follow-up and strict diagnostic criteria. The relative risk with HIV was of a similar magnitude to that measured elsewhere. Increased risks of TB with age and in men are expected. Associations with measures of higher socioeconomic status were unexpected. They may reflect a greater likelihood of diagnosis in this group.

Human immunodeficiency virus: GACPAT and GACELISA as diagnostic tests for antibodies in urine.

Testing for antibodies to human immunodeficiency virus (HIV) in urine may be of use in epidemiological studies. We collected 336 paired urine and serum samples from subjects in Karonga District, northern Malawi: 86 (25.6%) of the serum samples were HIV positive. Serum results were compared with those from immunoglobulin (Ig) G antibody-capture particle adherence tests (GACPAT) and IgG antibody-capture enzyme-linked immunosorbent assay (GACELISA) on the corresponding urine samples performed independently in 2 laboratories. The minimum observed relative sensitivity and specificity of GACPAT were 96.5% and 98.8% respectively; the specificity could be raised by using a protocol involving re-testing of reactive samples to determine end-point titre. For GACELISA, the observed relative sensitivity and specificity were 98.8% and 99.2% respectively. Such assays may be useful either as a primary screen in populations where urine samples are considerably easier to obtain than serum samples, or as an alternative test for individuals unwilling to provide a serum sample.

Leprosy. The beginning of an end to a public health problem?

Incidence rates of leprosy seem to be falling in most countries around the world, despite the HIV epidemic. Among the reasons for the declining rates are changing socioeconomic conditions and high BCG vaccination coverage. The numbers of people disabled by leprosy, however, are more important than incidence rates of leprosy per se. The issue of the disabled will remain a public health problem for many decades to come.

Detection of HHV-8 DNA in a German patient with classical Kaposi's sarcoma may allow an estimation of the incubation period.

DNA of HHV-8 (Kaposi's sarcoma-associated Herpes virus [KSHV]) was detected in a biopsy of a Kaposi's sarcoma in an elderly male patient from Saxony (East Germany). The diagnosis of classical Kaposi's sarcoma was first made in 1986. During World War II, the patient had been on active service on the Greek Islands of Crete and Rhodes only, he did not travel outside East Germany after the war. It is assumed that the patient was infected during his stay on the islands of Crete or Rhodes, where classical Kaposi's sarcoma is endemic. If so, the incubation period of classical Kaposi's sarcoma could be as long as 40 years.

Does the introduction of WHO-MDT influence trends in the incidence of leprosy?--the Malawian experience.

There has been an average annual decline in detection rates of all types of leprosy in Malawi of around 11.6% between 1977 and 1991. There was no obvious acceleration or slowing down of this decline following the introduction of WHO/MDT in 1983-84. Disability ratios stayed at the same level of about 11% during the 15 years covered by this paper suggesting that patients did not self-report earlier after 1983-84 which might have masked an underlying accelerated decline in detection rates. Thus it is concluded that the influence of WHO/MDT on the pattern of leprosy over a period of time, in a country like Malawi, is so far not noticeably different from any influence dapsone monotherapy might have had.

A comparison of sensory loss tests and histopathology in the diagnosis of leprosy.

Three different sensory loss tests, for anaesthesia to light touch, for diminished pain sensation and for loss of thermosensation, were compared with histopathological examination results in the diagnosis of suspected tuberculoid leprosy in 120 individuals with 126 lesions. Though none of the 3 tests used in this study was found to be strikingly superior to any of the others, the results indicate potentially important differences in their usefulness in different subgroups of suspected patients. The methodological problems inherent in such studies are discussed.

The anatomical distribution of single leprosy lesions in an African population, and its implications for the pathogenesis of leprosy.

Data on the anatomical sites of single leprosy lesions found in 635 newly diagnosed and biopsy-confirmed leprosy patients are presented. These patients were found during total population surveys carried out by the Lepra Evaluation Project, a prospective longitudinal study of the epidemiology of leprosy in Karonga District, Northern Malawi. There was a striking excess of single lesions on the face and the back of the arms, compared to the distribution of skin surface area, and a deficit on the legs, regardless of age. There is some evidence for a sex difference in lesion distribution among adults, with facial and arm lesions being relatively more common in females and back lesions being more common in males. The excess of lesions on the face compared to the lower limbs is similar to data from Uganda, but very unlike data from Burma and elsewhere in Asia. Overall, the distribution of lesions does not suggest a pattern reflecting entry of Mycobacterium leprae, nor does it suggest an association with anatomical distribution of the nervous or vascular system. It is argued that the distribution reflects the influence of some 'local' environmental or behavioural factors.

Long-term active surveillance of leprosy suspects--what are the likely returns?

Data are presented from the Karonga District in Northern Malawi on the long-term follow up of 277 leprosy suspects who were not given antileprosy treatment or kept on active surveillance. Individuals who were started on antileprosy treatment within a year after leprosy was first suspected, usually on the basis of histopathology results, are excluded from this analysis, because their active surveillance would not usually cause an organizational or financial problem for leprosy control projects. After an average follow-up period of 4.5 years 35 of the 277 suspects included in the analysis (13%) were diagnosed with what we consider to be 'unequivocal' leprosy, and 3 of the 35 had developed disabilities. In 211/277 (76%) all signs of leprosy had disappeared completely. Comparing clinical certainties at first and last examinations and comparing clinical with histopathological certainties at last examinations it is estimated that up to 50% of the 35 cases of unequivocal leprosy which 'arose' in this group were attributable to misdiagnosis at the 1st or 2nd examination rather than to genuine progression of the disease. This estimate is compatible with an overall sensitivity of 90% and an overall specificity of 95% at each examination. Leprosy suspects with 1 cardinal sign of leprosy, either a typical lesion without loss of sensation, or loss of sensation in an otherwise untypical lesion, should be considered a high-risk group in that approximately 25% of such suspects (19/78) were later found with unequivocal leprosy. Policies towards such suspects should be formulated by leprosy control projects.

Setting up HIV serology for the Karonga leprosy vaccine trial in Malawi.

As part of the leprosy vaccine trial taking place in Karonga District, Northern Malawi, it is essential to establish whether the presence of HIV infection in the population is affecting the incidence rate or clinical presentation of leprosy or the effectiveness of the trial vaccines. To obtain the appropriate information, a rapid and economical HIV testing protocol, which could be performed in a rural laboratory and would be robust under variable environmental conditions, had to be developed. This paper reports on the development/evaluation phase of a multitest protocol based on commercially available particle agglutination and ELISA anti-HIV antibody detection kits. The protocol was devised by first evaluating a range of kits in London using a battery of African and non-African sera and then field testing 1455 sera in Malawi, which included 184 sera from leprosy patients and 60 sera from syphilis patients to check for cross-reactivity. According to the protocol developed, all sera are screened initially both by indirect ELISA (Organon) and using a rapid and economical modification of the Serodia particle agglutination test. Positives are retested using both a competitive ELISA (Wellcome or Behring) and the standard Serodia particle agglutination test. The validity of this multitest protocol was confirmed by Western blotting a large sample of the positive and negative Malawian sera in London. Factors affecting kit selection, and problems associated with individual kits, are discussed. While the specific multitest protocol developed for Malawi might not be suitable for every project, the principle of developing economical alternatives to Western blotting is an important consideration for any field investigation of HIV.

Disabilities in leprosy patients ascertained in a total population survey in Karonga District, northern Malawi.

This paper describes the pattern of disability among 1654 leprosy patients ascertained between 1973 and 1987 in Karonga District, Northern Malawi. Approximately 20% of patients identified prior to 1980 had some disability at registration, but this percentage fell to approximately 10% with the introduction of total population surveys in the Lepra Evaluation Project. The proportion of patients with disabilities at registration increased with age, was higher among males than females, was higher among borderline and lepromatous than tuberculoid patients, and was higher for passively than for actively detected patients. The risk of developing disabilities among patients without any disabilities at registration was approximately 5 per 1000 person years, and appeared to be slightly higher after the completion of treatment than during treatment.

The Karonga Prevention Trial: a leprosy and tuberculosis vaccine trial in northern Malawi. I. Methods of the vaccination phase.

In this report the methods of the Karonga Prevention Trial, a double-blind leprosy and tuberculosis vaccine trial in Karonga District, Northern Malawi, are described in detail. During a total population house-to-house survey, which lasted from November 1985 until August 1989, 121,008 people (57,892 males and 63,116 females) were vaccinated. A further 5835 people refused vaccination and 5757 were ineligible for vaccination, 2652 of them because they had a history or signs of leprosy, or because they were suspected to have early leprosy. A total of 66,145 individuals, without evidence of prior BCG vaccination, received one of the following: BCG, BCG + 5 x 10(7) killed Mycobacterium leprae, or BCG + 6 x 10(8) killed M. leprae; 54,863 individuals found with a typical or a doubtful BCG scar received either placebo or BCG, or (from mid-1987 onwards) BCG + 6 x 10(8) killed M. leprae. Side-effects were not looked for systematically, but 4 individuals self-reported with glandular abscesses, 9 with large post-vaccination ulcers (> 25 mm in diameter) and 2 with ulcers which persisted for more than 1 year. BCG vials collected from paraffin refrigerators in the field showed satisfactory concentrations of viable BCG throughout the trial. Post-vaccination skin test (RT23 and M. leprae soluble antigen) results and post-vaccination ulcer rates indicate that few mistakes were made in the field when recording the vaccine codes.

Epidemiological aspects of relapses in leprosy.

Life table methods in which the cumulative probability of relapse in successive periods is calculated are preferable to the presentation of overall relapse rates. Their use facilitates the comparison of relapse rates and trends from different studies independent of duration of follow-up. Results from various studies including data from Malawi indicate that, (1) unlike after dapsone monotherapy, the cumulative probability of relapse in multibacillary patients is near to zero after WHO/MDT if strict definitions of relapse are used and, (2) the cumulative probability of relapse may approach 5% in paucibacillary patients 10 years after completion of WHO/MDT. On the whole, the epidemiological relevance of relapses is insignificant and future treatment regimens should be evaluated concerning their efficacy in preventing disabilities rather than relapses.