The histological diagnosis of leprosy type 1 reactions: identification of key variables and an analysis of the process of histological diagnosis.

BACKGROUND: Type 1 leprosy reactions (T1R) are a major inflammatory complication of leprosy affecting 30% of patients with borderline leprosy, but there has been no diagnostic evaluation of the histological diagnosis of this entity. METHODS: In a prospective study based in India, skin biopsies were taken from 99 patients with clinically diagnosed T1R and 52 non-reactional controls. These were assessed histologically by four histopathologists whose assessments were then compared. RESULTS: Reactions were under-diagnosed, with 32-62% of clinically diagnosed reactions being given a histological diagnosis. The pathologists showed good specificities (range 72% to 93%) but much poorer sensitivities (range 42% to 78%). The most commonly reported histological features of TIR were cell maturity, oedema and giant cells. Five key variables were identified that the pathologists used in diagnosing a reaction: intra-granuloma oedema, giant cell size, giant cell numbers, dermal oedema and HLA-DR expression. A predictive model for the diagnosis of T1R was developed using stepwise logistic regression analysis, with clinical diagnosis of reaction as an outcome, and then identification of the key variables that each pathologist used in making the diagnosis of T1R. 34-53% of the variation between pathologists could be accounted for. The four pathologists used a similar diagnostic model and for all of them their estimations of epithelioid cell granuloma oedema, dermal oedema, plasma cells and granuloma fraction were significant variables in the diagnosis of T1R. Each pathologist then added in variables that were specific to themselves. CONCLUSIONS: This study has identified T1R as being under-diagnosed in comparison with clinical assessments. Key variables for diagnosing T1R were established. This comparative masked study highlights the need for such studies in other inflammatory conditions.

Observations on reactions of leprosy in the field.

In order to assess the incidence of reaction in leprosy, it would be necessary to examine the data from a field control unit. In this study, it was found, at a fully monitored control unit, that Type I reaction occurred in 3.9% of borderline cases and Type II in 23.7% of LL and BL cases. Even so, the load of reaction is not high since reaction of Type I and Type II together are seen only in 3.7% of all types of cases. A majority of them are of mild or moderate degree and could be treated as out-patients. Of the borderline cases, the BB type showed maximum rate of reaction. The BL type can present with both Type I and Type II reactions with a total incidence of 12.8%. While the BT type constituted 74% of total cases, reaction of Type I occurred in 3.1% of cases. Reaction also occurred in 0.8% of RFT cases.

Indeterminate leprosy in an infant.

An infant, 8 months old having histologically confirmed indeterminate leprosy is reported. The source of infection and possible mode of transmission are discussed.

The INFIR Cohort Study: investigating prediction, detection and pathogenesis of neuropathy and reactions in leprosy. Methods and baseline results of a cohort of multibacillary leprosy patients in north India.

The aim of this study was to find predictors of neuropathy and reactions, determine the most sensitive methods for detecting peripheral neuropathy, study the pathogenesis of neuropathy and reactions and create a bank of specimen, backed up by detailed clinical documentation. A multi-centre cohort study of 303 multibacillary leprosy patients in Northern India was followed for 2 years. All newly registered MB patients requiring a full course of MDT, who were smear positive and/or had six or more skin lesions and/or had two or more nerve trunks involved, were eligible. A detailed history was taken and physical and neurological examinations were performed. Nerve function was assessed at each visit with nerve conduction testing, warm and cold detection thresholds, vibrometry, dynamometry, monofilaments and voluntary muscle testing. Because the latter two are widely used in leprosy clinics, they were used as 'gold standard' for sensory and motor impairment. Other outcome events were type 1 and 2 reactions and neuritis. All subjects had a skin biopsy at registration, repeated at the time of an outcome event, along with a nerve biopsy. These were examined using a variety of immunohistological techniques. Blood sampling for serological testing was done at every 4-weekly clinic visit. At diagnosis, 115 patients had an outcome event of recent onset. Many people had skin lesions overlying a major nerve trunk, which were shown to be significantly associated with an increased of sensory or motor impairment. The most important adjusted odds ratios for motor impairment were, facial 4.5 (1.3-16) and ulnar 3.5 (1.0-8.5); for sensory impairment they were, ulnar 2.9 (1.3-6.5), median 3.6 (1.1-12) and posterior tibial 4.0 (1.8-8.7). Nerve enlargement was found in 94% of patients, while only 24% and 3% had paraesthesia and nerve tenderness on palpation, respectively. These increased the risk of reactions only marginally. Seven subjects had abnormal tendon reflexes and seven abnormal joint position sense. In all but one case, these impairments were accompanied by abnormalities in two or more other nerve function tests and thus seemed to indicate more severe neuropathy. At diagnosis, 38% of a cohort of newly diagnosed MB leprosy patients had recent or new reactions or nerve damage at the time of intake into the study. The main risk factor for neuropathy found in this baseline analysis was the presence of skin lesions overlying nerve trunks. They increased the risk of sensory or motor impairment in the concerned nerve by 3-4 times. For some nerves, reactional signs in the lesions further increased this risk to 6-8 times the risk of those without such lesions. Patients with skin lesions overlying peripheral nerve trunks should be carefully monitored for development of sensory or motor impairment.

Initial experiences of implementation of functional integration (FI) in LEPRA India projects in Orissa.

In 2000, the Government of the State of Orissa (population 37 million) in India decided to introduce functional integration for the control of leprosy, in place of the long-established vertical programme, using the general health services and the primary health care system. This paper describes the initial (9 months) experience of implementing this strategy in two projects run by LEPRA India. One of these, in the district of Koraput, was established in 1991 and covers a population of 1.5 million people. The other, in Kalahandi district, started in 1997 and covers a population of 600,000. Both projects operate under difficult conditions with regard to terrain, the use of numerous tribal languages, illiteracy, water shortage, poor roads and communications. The preparatory phase included intensive health education of the public on leprosy, using a wide range of educational media and techniques. At the same time, LEPRA India supported the Government in the training and orientation of trainers, medical officers, primary health care staff and female health workers at village level. In all, over 2000 were trained. This paper describes all aspects of the implementation of functional integration in these two areas. In the 9-month period, 4207 suspect cases were referred to medical officers by health workers, but only 256 (6%) were confirmed as having leprosy. There were 169 confirmed self-reporting cases. Despite the clearly understood intention to involve primary health staff in case detection, 67% of all cases were in fact detected by LEPRA India, possibly due to overlapping attendance at clinics by vertical and general staff. There is obviously a need for further training of the general staff since only 6% of cases referred by them were confirmed as having leprosy. Steps must also be taken to ensure that the emphasis on case detection, confirmation and treatment shifts from the vertical to the general health staff. The supply of anti-leprosy drugs and steroids to primary health centers needs improvement. Appropriate teaching and learning material is urgently needed for both field staff and medical officers.

Reactions in borderline leprosy.

This is a retrospective study of 276 patients consisting of 157 active and 119 reactive patients of borderline leprosy. They were followed up for 10 years after sulphone monotherapy. The presenting symptoms were carefully examined from the records and systematically presented. Frequency of reactions was least in BT cases and most in BL cases. Risk factors of reaction appear to be the type of leprosy, multiplicity of lesions, high BI and, possibly, psychological stress. Biopsy of skin lesions was performed in all cases initially, and at the subsidence of the disease. Histological findings closely correlated with clinical classification. While all the cases showed clinical subsidence, histological subsidence was found in 200 (73%) cases, and the condition was static in 36 cases (13%). Immunological upgrading was seen in 110%, while 4% showed downgrading. Bacteriological status and lepromin reaction of active and reactive cases were compared. All these factors need to be taken into consideration for instituting prompt and proper treatment.

Cytodiagnosis of histoid leprosy.

This paper presents cytomorphological features of the histoid variety of lepromatous leprosy. Fine needle aspiration of a lepromatous nodule showed cytological features consistent with those of histoid leprosy. Simultaneously, a biopsy of the nodule was also performed and the case confirmed as histoid leprosy. The advantages of the fine needle aspiration technique are that it is simple, quickly reportable, and less traumatizing. Multiple aspirations from different sites may be obtained, which would add to the value of sampling. The need to differentiate a histoid nodule from a conventional lepromatous nodule is explained.

Correlation of clinical, histological and immunological features across the leprosy spectrum.

The Ridley-Jopling system of classification of the variegated clinical pattern of leprosy is based on the specific cell-mediated immunity observed in the histopathology of skin lesions conforming to a spectrum from TT at one end to LL at the other. In this study a fairly large sample of 90 patients was classified on clinical grounds; the histopathology of the skin lesions was studied blind. There was an overall concordance of 90% between the clinical and histological classifications. In addition, the systemic cell-mediated and humoral immune responses were studied. The in vivo cell-mediated immune response, namely the Mitsuda skin response, mostly conformed to the clinical classification. While the in vitro lymphoproliferative responses to BCG and its sonicate were high, the lymphoproliferative responses to Dharmendra lepromin were surprisingly poor. Humoral responses to 35 kDA protein of M. leprae and PGL-1 were good in most LL, BL patients and tapered off towards TT. IgG antibodies to recombinant ML 65 kDa proteins denoted mycobacterial presence.

Poor correlation of systemic immunological parameters with clinical features in macular leprosy.

On the basis of clinical features and bacteriological status, macular skin lesions of nine cases of leprosy were classified as falling within a spectrum between the tuberculoid at one end and the lepromatous at the other. While histologic correlation was seen in 60% of cases, humoral and cellular systemic immunologic features were found to be uncharacteristic. It is suggested that macular lesions form an early stage in the development of leprosy where the systemic immunological response is yet to set in fully.

Modified leprosy elimination campaign (MLEC) for case detection in a remote tribal area in the State of Orissa, India.

A leprosy project was established in a difficult to reach area under guidelines of Government of India. The leprosy services were provided by Koraput Leprosy Eradication Project (KORALEP) and general health services by Primary Health Care (PHC). Leprosy elimination campaigns (LECs) were suggested by WHO to detect more cases in the community. A modified leprosy elimination campaign (MLEC), carried out utilizing the services of primary health care workers is discussed in this paper. Apart from the trained health workers, Anganwadi workers along with some literate people from the district were also included in the search teams. In all, 1543 cases were shortlisted from the suspects identified and on re-examination 576 cases were confirmed as active cases. Sixty percent of the cases detected were very early cases with two to three skin lesions. This could be achieved with a very brief training of health workers and involving village voluntary workers. MLEC was found to be a useful tool for case finding in such areas.