Malassezia pachydermatis fungemia in an adult with multibacillary leprosy.

Malassezia pachydermatis is a relatively rare agent of bloodstream infections. We describe an unusual case of Malassezia fungemia in an adult patient hospitalized for Staphylococcus aureus bacteremia who was also found to have multibacillary leprosy. Treatment of the patient required extensive medical management but resulted in a good outcome.

Clinical and histological features of leprosy and human immunodeficiency virus co-infection in Brazil.

BACKGROUND: Both leprosy and human immunodeficiency virus (HIV) are infectious diseases, and are an important global health problem. Patients with leprosy who are co-infected with HIV seem to be at higher risk of developing leprosy reactions. AIM: To examine the histological features of leprosy in patients with HIV and leprosy co-infection, particularly to determine whether the typical leprosy histopathology is present in skin biopsies, and to assess the histological features of leprosy reactions in co-infected patients. METHODS: This was a matched cohort study with 11 co-infected patients and 31 HIV-negative patients with leprosy. A structured protocol for skin-biopsy evaluation was followed, focusing on inflammation of the skin and dermal nerves. RESULTS: Of the 11 HIV-positive patients, 7 (63%) had borderline tuberculoid (BT) leprosy and 5 (70%) of these 7 patients had developed a type 1 reaction. The lesions in these patients were immunologically active, with 100% of biopsies having evidence of compact granulomas, 90% evidence of oedema and 30% evidence of necrosis. CONCLUSIONS: In this study, patients co-infected with HIV and M. leprae had the typical histological lesions of leprosy. There was evidence of immune activation in patients who received combination antiretroviral therapy, and these patients had BT leprosy and leprosy-upgrading reactions.

Clinical and histological features of leprosy and human immunodeficiency virus co-infection in Brazil

BACKGROUND: Both leprosy and human immunodeficiency virus (HIV) are infectious diseases, and are an important global health problem. Patients with leprosy who are co-infected with HIV seem to be at higher risk of developing leprosy reactions. AIM: To examine the histological features of leprosy in patients with HIV and leprosy co-infection, particularly to determine whether the typical leprosy histopathology is present in skin biopsies, and to assess the histological features of leprosy reactions in co-infected patients. METHODS: This was a matched cohort study with 11 co-infected patients and 31 HIV-negative patients with leprosy. A structured protocol for skin-biopsy evaluation was followed, focusing on inflammation of the skin and dermal nerves. RESULTS: Of the 11 HIV-positive patients, 7 (63%) had borderline tuberculoid (BT) leprosy and 5 (70%) of these 7 patients had developed a type 1 reaction. The lesions in these patients were immunologically active, with 100% of biopsies having evidence of compact granulomas, 90% evidence of oedema and 30% evidence of necrosis. CONCLUSIONS: In this study, patients co-infected with HIV and M. leprae had the typical histological lesions of leprosy. There was evidence of immune activation in patients who received combination antiretroviral therapy, and these patients had BT leprosy and leprosy-upgrading reactions.

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.

Leprosy affects the tibial nerves diffusely from the middle of the thigh to the sole of the foot, including skip lesions.

This study investigated where leprosy affects the posterior tibial nerve and whether neurolysis is beneficial. Nine patients with bilateral posterior tibial leprous neuropathy with no sensorimotor recovery were studied. Preoperative sensory-muscle and nerve conduction velocity testing revealed the tarsal tunnel to be the site of a severe lesion in all cases. During surgery, the most proximal site of the nerve lesion was detected by electrically stimulating the spinal roots from the second lumbar nerve to the fourth sacral nerve, evoking efferent mixed nerve compound action potentials that were recorded from the exposed tibial nerve. In all patients, the nerve compound action potentials became normal only proximal to the sciatic nerve bifurcation. Epineuriotomy within these seemingly unaffected segments revealed fibrosis of the interfascicular epineurium. Interfascicular neurolysis was performed on all affected segments. A 2-year follow-up showed an increase in girth of the proximal calf musculature in six of eight patients (the ninth patient had no recordable nerve conduction velocity). It was concluded that (1) leprosy affects the tibial nerves in a scattered way from the sciatic nerve main trunk distally to the exit of the tarsal tunnel; and (2) interfascicular, microsurgical neurolysis is beneficial provided that it is performed on all affected nerve segments.

Vasculitic neuropathy in a patient with inactive treated lepromatous leprosy.

A 46 year old Asian male with previously treated lepromatous leprosy developed a stepwise multifocal sensory disturbance 25 years later. Neurophysiology demonstrated marked deterioration from previous studies. Sural nerve biopsy disclosed a vasculitic process superimposed on inactive lepromatous leprosy. Immunocytochemical stains for mycobacterial antigen showed deposits within nerve and vessel walls. A delayed vasculitic neuropathy precipitated by persisting mycobacterial antigen is proposed.

Comparison of bacillary indexes in slit-skin smears, skin and nerve biopsies; a study from Malawi.

Data analyzed in this paper were collected within the framework of the Lepra Evaluation Project, an epidemiological study of leprosy in Karonga District, northern Malawi. For 212 patients information on the number of skin lesions, slit-skin smear and skin biopsy results were available. Among 61 patients with a single lesion none were slit-skin-smear positive and two had bacilli detected in skin biopsies. In contrast, among 119 patients with four or more lesions 34 (28.6%) versus 59 (49.6%) had bacilli detectable in slit-skin smears or skin biopsies, respectively. In a further 47 patients skin biopsy results could be compared with split-nerve biopsy results. In 20 of 47 patients the bacterial indexes (BIs) were identical in skin and nerve biopsies, while in 26 of 47 patients the BIs were higher in nerve than in skin biopsies. This difference, which is consistent with several other studies in the literature, provides an insight into the pathogenesis of leprosy.

Erythema nodosum leprosum is associated with up-regulation of polyclonal IgG1 antibody synthesis.

Erythema nodosum leprosum (ENL) is a serious complication of lepromatous (L) disease in leprosy. We have previously shown that of the four IgG subclasses, IgG1 and IgG3 Mycobacterium leprae-specific antibodies are significantly lower in leprosy patients during ENL reaction compared with untreated L patients. To see if this decrease results from a down-regulation of antibody synthesis during ENL, the frequency of antibody-secreting B cells (ABSC) in the blood compartment was determined by ELISPOT and related to serum immunoglobulin concentrations (microgram/ABSC). Control groups consisted of 16 patients with stable L disease and 32 healthy endemic controls (EC). Paired samples were analysed during acute ENLS (n = 13) and after the reaction had subsided to identify changes associated with ENL. Polyclonal (PC) IgG1 was elevated in L patients compared with EC (325 micrograms versus 180 micrograms). Interestingly, patients during acute ENL showed concentrations higher than L patients (419 micrograms), which decreased after the reaction had subsided (260 micrograms), indicating the transient nature of the antibody response. IgG2 antibodies showed the reverse trend and were lower during ENL and increased after the reaction had subsided. The mean concentrations for PC IgG3 and IgG4 antibodies were similar during ENL and after the reaction had subsided. Thus, decrease in M. leprae-specific IgG1 and IgG3 antibodies is not related to down-regulation of B cell responses. Identification of factors which regulate PC IgG1 antibody synthesis may provide additional insights into determinants of ENL reactions.

Induction of Th1 cytokine responses by mycobacterial antigens in leprosy.

Twelve mycobacterial antigens were compared for induction of gamma interferon (IFN-gamma) secretion by human blood mononuclear cells of patients with leprosy. Fractionated Mycobacterium leprae antigens containing cell wall proteins or cytosolic and membrane proteins induced good IFN-gamma responses in tuberculoid leprosy patients. Lipoarabinomannan from M. tuberculosis Erdman and M. leprae mycolylarabinogalactan peptidoglycan were the poorest IFN-gamma inducers.

Immunohistochemical study of cutaneous neuritis in positive lepromin reactions.

Sixty skin biopsies taken from positive tuberculoid and borderline-tuberculoid late lepromin reaction were studied using histological techniques. The distribution of mycobacterial antigen and nerves was demonstrated using immunochemical methods. A total of 557 nerve bundles was observed in 51 biopsies; 9 were devoid of nerves in the sections examined; 475 nerve bundles showed some relationship to the inflammatory infiltrate (85%); perineuritis being seen in 144 (30%) and endoneuritis in 5 (0.9%). Mycobacterial antigens inside the granuloma were detected in 59 of the 60 biopsies (98%). Only one specimen, showing a strong tuberculoid reaction, failed to show these antigens. On the contrary, mycobacterial antigen was absent in almost all nerves. Small deposits were detected in the perineurium of one nerve with perineuritis, and inside a Schwann cell of another, the latter belonging to a previously multibacillary patient. The neurotropic tendency of the granuloma does not seem to be stimulated by the presence of mycobacterial antigens inside the nerves, as normally these antigens do not penetrate them. The hypothesis of some antigenic fraction of the neural tissue which cross-reacts with Mycobacterium leprae antigens, thus eliciting a perineural or near-perineural inflammatory reaction is put forward, but needs further investigation.

Testing for antibody to human immunodeficiency virus type 1 in a population in which mycobacterial diseases are endemic.

During a large epidemiologic study in the Karonga District of northern Malawi, serum samples from 139 patients with incident leprosy, 124 with newly diagnosed leprosy, 277 patients with incident tuberculosis, and 2296 controls were tested for antibodies to human immunodeficiency virus. Sera were tested according to a four-test protocol using two ELISAs and two particle agglutination assays. Overall, 188 samples were considered positive, 2634 were considered negative, and 14 were indeterminate. All 18 available positive specimens from leprosy patients, a random sample of 14 positive specimens from tuberculosis patients, and 15 positive specimens from controls were tested by Western blot. There was no evidence of substantial numbers of ELISA false-positives in any patient group or among controls.

Clinical and histological discrepancies in diagnosis of ENL reactions classified by assessment of acute phase proteins SAA and CRP.

Sixteen out of 45 (36%) leprosy patients with clinical features of acute erythema nodosum leprosum (ENL) did not show the characteristic presence of neutrophils (polymorphs) in histology of the ENL lesion. The acute-phase reactants, serum amyloid A (SAA) and C-reactive protein (CRP) which are systemic markers of inflammation, and IgM and IgG antibody to Mycobacterium leprae were determined in these patients in order to understand the differences in histological diagnosis. Both SAA and CRP were elevated in ENL patients, irrespective of the presence of polymorph infiltrates, as compared to nonreactional lepromatous patients, patients with histologically confirmed reversal reactions and endemic controls, indicating that all clinically diagnosed ENL patients had ongoing inflammatory reactions. On the other hand, IgM and IgG antibodies were significantly lower (> 70%) in ENL patients as compared to nonreactional lepromatous patients. When the two ENL groups [ENL-PMN+ve (positive for neutrophils) and ENL-PMN-ve (negative for neutrophils)] were compared, there were no significant differences in the mean SAA, IgM or IgG antibody concentrations, but CRP was eightfold lower in ENL-PMN-ve as compared to the ENL-PMN+ve group. This may indicate that the timing or modulation of the reaction was different in the two ENL groups. Thus, measurement of the acute-phase response and the ratio of SAA/CRP in particular are helpful in the clinical diagnosis of ENL reactions in leprosy.

Reactions in leprosy: an epidemiological study of 386 patients in west Nepal.

This paper presents epidemiological data on reversal reaction (RR) and erythema nodosum leprosum reaction (ENL) from a retrospective study of 386 leprosy patients newly registered at Green Pastures Hospital, Pokhara, West Nepal. The average follow-up time was 21 months. The prevalence of RR at first examination was 28% (23-32), and the prevalence of ENL reaction was 5.7% (2.3-9.2). The overall incidence rates among the 335 patients that were available for follow-up were 8.7 (6.5-12)/100 person years at risk (PYAR) for RR and 3.2 (1.5-6.7)/100 PYAR for ENL. Relapse of RR was common (1.4/patient). In all, 52% of RR were complicated by new nerve function impairment, against 59% of ENL reactions. The finding of other investigators that most RRs occur during the first year of treatment was confirmed by this study. The most significant risk factor for RR was extent of clinical disease measured by a count of body areas with clinical signs of leprosy. The risk of developing a RR for patients with 'extensive disease' (3 or more out of 9 body areas involved) was 10 times that of patients with limited disease (Rate Ratio 10 (1.3-76), p = 0.026). The study indicated that the following categories of patients in Nepal are at high or increased risk of developing a RR: 1, borderline patients during their first year of MDT; and 2, patients with more extensive clinical disease as described above.

A case control study on human immunodeficiency virus-1 (HIV-1) infection as a risk factor for tuberculosis and leprosy in western Kenya.

A case control study was undertaken in Western Kenya from April 1989 to August 1990 to evaluate HIV-1 infection as a risk factor for tuberculosis and leprosy. The study involved 144 newly diagnosed sputum smear positive tuberculosis cases with 432 age, sex and neighbourhood-matched controls, and 132 diagnosed leprosy cases with 384 matched controls. Odds ratios obtained by conditional logistic regression (matched) analysis were 4.9 (95% CI 2.6, 6.8), and 1.8 (95% CI 0.9, 3.2), for the association between HIV-1 and tuberculosis and leprosy respectively. Approximately 31% of tuberculosis cases among males, and 11% of cases among females, were attributable to HIV infection.

PIP: Between April, 1989, and August 1990. in Busia, Siaya, Kisumu, and South Nyanza districts of Western Kenya, health workers recruited 144 sputum smear positive tuberculosis (TB) cases and 432 age, sex, and neighborhood matched controls. They also recruited 132 newly detected leprosy cases and 384 matched controls. Researchers wanted to determine the association between HIV-1 and TB and between HIV-1 and leprosy. TB cases were more likely to be HIV-1 seropositive than were their controls, regardless of age (odds ratio = 4.9). Less than 30-year-old female TB patients were less likely to be HIV-1 seropositive than were less than 30-year-old male TB patients (OR, 2.8 vs. 8.1), while the opposite was true for older TB patients (OR, 19.6 vs. 2.6). Though not statistically different, the OR was greater for certain TB cases than for possible TB cases (13.7 vs. 3.5) and for BCG negative cases than for BCG positive cases (16.5 vs. 3.1). Etiologic fractions indicated that HIV infection was responsible for 31% of TB cases among males and 11% of TB cases among females. Overall, leprosy cases and controls had lower HIV seropositivity rates than did their TB counterparts (OR, 1.8 vs. 4.9). Even though none of the ORs for the association between HIV infection and leprosy were statistically significant from unity, the fact that ORs were greater than unity in all (1.4-2.4) but 1 group (5-29 year old females, OR = 0.5) indicated a possible trend towards positive association. Though not statistically different, polar lepromatous type of leprosy and the leprosy category of histopathologically confirmed cases had the highest ORs (3.7 and 1.9, respectively). Multibacillary leprosy cases had a higher OR than did paucibacillary leprosy (2 vs. 1.6).