Mapping the burden of onchocercal skin disease.

Onchocerciasis is a neglected tropical disease caused by a nematode parasite, Onchocerca volvulus, and transmitted by bites of Simulium blackflies which breed near fast-flowing rivers. In humans, thousands of microfilariae (immature worms) migrate to the skin and eyes where they cause pathology. Historically, much research was devoted to the serious effect of blindness, from which the disease earns its alternative name of 'river blindness'. Mapping the burden of onchocercal skin disease (OSD) was expedited by the development of a clinical classification and grading system that facilitated comparison of data from different countries. After successful field testing in Nigeria, the classification scheme was used in a multicountry study in seven endemic sites, to estimate the true burden of OSD across Africa. High levels of OSD were found, affecting 28% of the population. A new control programme, the African Programme for Onchocerciasis Control (APOC) was launched in 20 countries using annual doses of ivermectin, donated by Merck & Co., Inc. The multicountry study also found a close correlation between the levels of itching and OSD with the level of endemicity, as determined by the prevalence of onchocercal nodules. This enabled APOC to use Rapid Epidemiological Mapping of Onchocerciasis, which entailed identifying likely vector breeding sites near rivers, then sampling 50 adult males in nearby villages to determine the prevalence of nodules and delineate which villages required treatment. Onchocerciasis is now targeted for elimination in Africa, and the challenge is to complete Onchocerciasis Elimination Mapping of hypoendemic areas using serology.

The 2020 International Alliance for the Control of Scabies Consensus Criteria for the Diagnosis of Scabies.

BACKGROUND: Scabies is a common parasitic skin condition that causes considerable morbidity globally. Clinical and epidemiological research for scabies has been limited by a lack of standardization of diagnostic methods. OBJECTIVES: To develop consensus criteria for the diagnosis of common scabies that could be implemented in a variety of settings. METHODS: Consensus diagnostic criteria were developed through a Delphi study with international experts. Detailed recommendations were collected from the expert panel to define the criteria features and guide their implementation. These comments were then combined with a comprehensive review of the available literature and the opinion of an expanded group of international experts to develop detailed, evidence-based definitions and diagnostic methods. RESULTS: The 2020 International Alliance for the Control of Scabies (IACS) Consensus Criteria for the Diagnosis of Scabies include three levels of diagnostic certainty and eight subcategories. Confirmed scabies (level A) requires direct visualization of the mite or its products. Clinical scabies (level B) and suspected scabies (level C) rely on clinical assessment of signs and symptoms. Evidence-based, consensus methods for microscopy, visualization and clinical symptoms and signs were developed, along with a media library. CONCLUSIONS: The 2020 IACS Criteria represent a pragmatic yet robust set of diagnostic features and methods. The criteria may be implemented in a range of research, public health and clinical settings by selecting the appropriate diagnostic levels and subcategories. These criteria may provide greater consistency and standardization for scabies diagnosis. Validation studies, development of training materials and development of survey methods are now required. What is already known about this topic? The diagnosis of scabies is limited by the lack of accurate, objective tests. Microscopy of skin scrapings can confirm the diagnosis, but it is insensitive, invasive and often impractical. Diagnosis usually relies on clinical assessment, although visualization using dermoscopy is becoming increasingly common. These diagnostic methods have not been standardized, hampering the interpretation of findings from clinical research and epidemiological surveys, and the development of scabies control strategies. What does this study add? International consensus diagnostic criteria for common scabies were developed through a Delphi study with global experts. The 2020 International Alliance for the Control of Scabies (IACS) Criteria categorize diagnosis at three levels of diagnostic certainty (confirmed, clinical and suspected scabies) and eight subcategories, and can be adapted to a range of research and public health settings. Detailed definitions and figures are included to aid training and implementation. The 2020 IACS Criteria may facilitate the standardization of scabies diagnosis.

Onchocerciasis control in the Democratic Republic of Congo (DRC): challenges in a post-war environment.

OBJECTIVE: To evaluate onchocerciasis control activities in the Democratic Republic of Congo (DRC) in the first 12 years of community-directed treatment with ivermectin (CDTI). METHODS: Data from the National Programme for Onchocerciasis (NPO) provided by the National Onchocerciasis Task Force (NOTF) through the annual reports of the 21 CDTI projects for the years 2001-2012 were reviewed retrospectively. A hypothetical-inputs-process-outputs-outcomes table was constructed. RESULTS: Community-directed treatment with ivermectin expanded from 1968 communities in 2001 to 39 100 communities by 2012 while the number of community-directed distributors (CDD) and health workers (HW) multiplied. By 2012, there were ratios of 1 CDD per 262 persons and 1 HW per 2318 persons at risk. More than 80% of the funding came from the fiduciary funds of the African Programme for Onchocerciasis Control. The cost of treatment per person treated fell from US$ 1.1 in 2001 to US$ 0.1 in 2012. The therapeutic coverage increased from 2.7% (2001) to 74.2% (2012); the geographical coverage, from 4.7% (2001) to 93.9% (2012). Geographical coverage fell in 2005 due to deaths in loiasis co-endemic areas, and the therapeutic coverage fell in 2008 due to insecurity. CONCLUSIONS: Challenges to CDTI in DRC have been serious adverse reactions to ivermectin in loiasis co-endemic areas and political conflict. Targets for personnel or therapeutic and geographical coverages were not met. Longer term funding and renewed efforts are required to achieve control and elimination of onchocerciasis in DRC.

The African Programme for Onchocerciasis Control: impact on onchocercal skin disease.

OBJECTIVES: To assess the long-term impact of the African Programme for Onchocerciasis Control on itching and onchocercal skin disease (OSD). METHODS: Seven study sites in Cameroon, Sudan, Nigeria and Uganda participated. Two cross-sectional surveys were conducted of communities meso- and hyper-endemic for onchocerciasis before and after 5 or 6 years of community-directed treatment with ivermectin (CDTI). Individuals were asked about any general health symptoms including itching and underwent full cutaneous examinations. Onchocercal skin lesions were documented according to a standard classification. RESULTS: Five thousand one hundred and ninety three people were examined in phase I and 5,180 people in phase II. The presence of onchocercal nodules was a strongly significant (P < 0·001) risk factor for all forms of onchocercal skin disease: APOD (OR 1·66); CPOD (OR 2·84); LOD (OR 2·68); reactive skin lesions (OR 2·38) and depigmentation (OR 3·36). The effect of community-directed treatment with ivermectin was profound. At phase II, there were significant (P < 0·001) reductions in the odds of itching (OR 0·32), APOD (OR 0·28); CPOD (OR 0·34); reactive skin lesions (OR 0·33); depigmentation (OR 0·31) and nodules (OR 0·37). Reduction in the odds of LOD was also significant (OR 0.54, P < 0.03). CONCLUSIONS: This first multi-country report of the long-term impact of CDTI reveals a substantial reduction in itching and OSD. APOC operations are having a major effect in improving skin health in poor rural populations in Africa.

A case of cutaneous extravascular necrotizing granuloma without systemic manifestations.

Cutaneous extravascular necrotizing granuloma, an unusual palisading dermal granuloma, was first described by Churg and Strauss in 1951 in association with the syndrome of allergic granulomatosis (Churg-Strauss syndrome), for which it was though to be pathognomonic. It has subsequently been described in association with a number of autoimmune and immunoreactive diseases, and is regarded as a cutaneous marker of systemic pathology. To our knowledge, only one patient has been reported with clinical features confined to the skin. We report a 46-year-old woman with recurrent cutaneous lesions over a 10-year period and the classic histopathological pattern, but no underlying systemic disease.

Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability.

Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted.

Onchocerciasis: the clinical and epidemiological burden of skin disease in Africa.

An attempt was made to assess the true public-health importance of onchocercal skin disease throughout the African region and hence provide an objective basis for the rational planning of onchocerciasis control in the area. The seven collaborative centres that participated in the study (three in Nigeria and one each in Ghana, Cameroon, Tanzania and Uganda) were all in areas of rainforest or savannah-forest mosaic where onchocercal blindness is not common. A cross-sectional dermatological survey was undertaken at each site following a standard protocol. At each site, the aim was to examine at least 750 individuals aged 5 years and living in highly endemic communities and 220-250 individuals aged 5 years and living in a hypo-endemic (control) community. Overall, there were 5459 and 1451 subjects from hyper-and hypo-endemic communities, respectively. In the highly endemic communities, the prevalence of itching increased with age until 20 years and then plateaued, affecting 42% of the population aged 20 years. There was a strong correlation between the prevalence of itching and the level of endemicity (as measured by the prevalence of nodules; r=0.75; P<0.001). The results of a multivariate logistic regression analysis showed that, at the individual level, the presence of onchocercal reactive skin lesions (acute papular onchodermatitis, chronic papular onchodermatitis and/or lichenified onchodermatitis) was the most important risk factor for pruritus, with an odds ratio (OR) of 18.3 and 95% confidence interval (CI) of 15.19-22.04, followed by the presence of palpable onchocercal nodules (OR=4.63; CI=4.05-5.29). In contrast, non-onchocercal skin disease contributed very little to pruritus in the study communities (OR=1.29; CI=1.1-1.51). Onchocercal skin lesions affected 28% of the population in the endemic villages. The commonest type was chronic papular onchodermatitis (13%), followed by depigmentation (10%) and acute papular onchodermatitis (7%). The highest correlation with endemicity was seen for the prevalence of any onchocercal skin lesion and/or pruritus combined (r=0.8; P<0.001). Cutaneous onchocerciasis was found to be a common problem in many endemic areas in Africa which do not have high levels of onchocercal blindness. These findings, together with recent observations that onchocercal skin disease can have major, adverse, psycho-social and socio-economic effects, justify the inclusion of regions with onchocercal skin disease in control programmes based on ivermectin distribution. On the basis of these findings, the World Health Organization launched a control programme for onchocerciasis, the African Programme for Onchocerciasis Control (APOC), that covers 17 endemic countries in Africa.

Geographic variation in the calls of wild chimpanzees: a reassessment.

Male chimpanzees produce a species-typical call, the pant hoot, to communicate to conspecifics over long-distances. Calls given by males from the well-known Gombe and Mahale populations typically consist of four different phases: an introduction, build-up, climax, and let-down. Recent observations suggest that chimpanzees living in the Kibale National Park, Uganda, consistently give calls that lack a build-up and are thus qualitatively distinguishable acoustically from those made by other East African conspecifics. We analyzed additional recordings from Mahale and Kibale to re-examine geographic variation in chimpanzee calls. Results indicate that males from both sites produce pant hoots containing all four parts of the call. Calls made by chimpanzees from the two populations, however, differ in quantitative acoustic measures. Specifically, males at Kibale initiate their calls with significantly longer elements and build-up over briefer periods at slower rates than individuals from Mahale. Kibale males also deliver acoustically less variable calls than chimpanzees at Mahale. Although climax elements do not differ between populations in any single acoustic feature, discriminant function analysis reveals that acoustic variables can be used in combination to assign calls to the correct population at rates higher than that expected by chance. Ecological factors related to differences in habitat acoustics, the sound environment of the local biota, and body size are likely to account for these observed macrogeographic variations in chimpanzee calls.

HLA-DQ alleles associate with cutaneous features of onchocerciasis. The Kaduna-London-Manchester Collaboration for Research on Onchocerciasis.

Onchocerciasis is associated with a spectrum of cutaneous changes, ranging from clinically normal skin to acute and chronic pathology. An important aspect of disease expression may be the level of immune response to parasite antigens, which is likely to be regulated by MHC-encoded molecules. We therefore investigated HLA class I and class II phenotypes in Nigerian residents of an area endemic for onchocerciasis. All study subjects were carefully characterized for parasite load and skin pathology. Individuals with depigmentation had increased frequencies of DQA1*0501 and DQB1*0301 compared with persons with normal skin and high microfilarial load (NSHMF) (Odds Ratios 3.6 (95% CI 1.0 to 13.2) and 3.8 (1.0 to 15.2), respectively). Conversely, individuals with depigmentation had a decreased frequency of DQA1*0101 and Cw6 compared with NSHMF (Odds Ratios 0.2 (0.1 to 0.9) and 0.1 (0.02 to 0.8), respectively). When NSHMF subjects were examined by age, a further decrease in DQA1*0501 frequency and increase in DQA1*0101 frequency were observed in older NSHMF individuals. These results strongly suggest that there is an immunogenetic basis for the spectrum of cutaneous presentations in onchocerciasis and that HLA-DQ molecules are associated with the level of immune response to parasite antigens.

Human onchocerciasis in Nigeria: isotypic responses and antigen recognition in individuals with defined cutaneous pathology.

Antigen (Ag)-specific isotype responses to Onchocerca volvulus Ag (OvAg) were assessed by enzyme-linked immunosorbent assay and immunoblot in 123 residents of a mesoendemic area in northern Nigeria and 16 Nigerians from a nonendemic area. Individuals from an endemic area were divided into six groups on the basis of cutaneous onchocercal pathology: acute papular onchodermatitis (APOD), chronic papular onchodermatitis (CPOD), lichenified onchodermatitis (LOD), atrophy (ATR), depigmentation (DPM) and normal skin, high microfilarial load (NSHMF). Immunoglobulin (Ig)G1-4 levels were all significantly associated with residence in an endemic area after controlling for age and sex (all P values = 0.0001). Both IgG1 and IgG3 were significantly associated with onchocercal clinical category after controlling for age, sex, and microfilarial load (P = 0.0031 and 0.0035, respectively). The IgG1 and IgG3 responses were both highest in LOD and lowest in NSHMF and ATR, respectively. A significant inverse association was found between IgG1 levels and microfilarial load after controlling for age, sex, and clinical category (P = 0.0061). On immunoblotting, 20 (44.4%) of 45 individual onchocerciasis sera contained IgG4 antibodies against a band of 29-31 kD, which was not recognized by pooled sera from individuals with other filarial infections. There was heterogeneity of antigen recognition within each of the onchocercal clinical groups, which together with the small numbers examined by immunoblotting, limits interpretation. Nevertheless, some differences in patterns of antigen recognition were found between the onchocercal groups. The LOD group demonstrated prominent immunoreactivity in IgG1 and IgG3 while a general paucity of low molecular weight reactivity was seen with NSHMF in IgG1-3 subclasses, but there was no specific banding pattern that differentiated NSHMF from those with pathology. Comparison of microfilariae-positive (mf+) and mf- individuals with onchocercal skin disease revealed significantly higher levels of all IgG subclasses and higher overall scores on semiquantitative assessment of immunoblots for IgG1, IgG2, and IgG4 for mf+ individuals. Differing isotypic responses may play a role in the pathogenesis of the clinical spectrum of cutaneous onchocerciasis.

A clinical classification and grading system of the cutaneous changes in onchocerciasis.

Although onchocerciasis is one of the most important diseases of the skin and eye in the tropical world, to date there has been no formal consensus regarding the description and terminology of skin lesions. Furthermore, the contribution of cutaneous pathology to the morbidity and socio-economic effects of the disease has been largely neglected. We present a clinical classification and grading system for recording the cutaneous changes of onchocerciasis, and propose that this system be used as a standard method of description to convey clinical information between workers in all endemic areas to assist local and comparative research.

Lichen planus pemphigoides: its relationship to bullous pemphigoid.

Clinical and immunopathological studies of three patients with lichen planus pemphigoides (LPP) were carried out to investigate the relationship between LPP and bullous pemphigoid (BP) and to determine whether the antigen in LPP is the classical BP antigen. LPP is usually considered to be the coexistence of lichen planus with BP. The bullae in LPP were subepidermal and indistinguishable from BP. Indirect immunofluorescence demonstrated antibody binding to the epidermal surface of 1 M NaCl-split skin and mucosae, as in BP. The tissue distribution of the LPP antigen mirrored the distribution of BP in stratified squamous epithelia but was absent from transitional epithelia (pig bladder). Immunoelectron microscopy, both direct (two cases) and indirect (one case), showed binding to the lamina lucida as with BP antigen. Western blotting of epidermal extracts using the patients' sera showed that instead of reacting with the classical bullous pemphigoid antigen (220 kDa in our series), the antisera reacted with a unique band of 200 kDa in addition to the band of 180 kDa found as a minor antigen in bullous pemphigoid, but more commonly in pemphigoid gestationis. The relationship between these antigens awaits molecular characterization. These findings suggest that the target antigen in LPP may be unique.

Ichthyosis bullosa of Siemens and bullous ichthyosiform erythroderma--variants of the same disease?

A patient is described with features of both bullous ichthyosiform erythroderma (BIE) and ichthyosis bullosa--a separate entity first described in 1937 by Siemens. This combination of characteristics has not been previously reported. Bullous ichthyosiform erythroderma and ichthyosis bullosa of Siemens, occurring together in this patient may best be regarded as varying expressions of a single genodermatosis.

Sporotrichoid spread of cutaneous Mycobacterium chelonei infection.

Atypical mycobacterial infections of the skin have increased in frequency in immunocompromised individuals in recent years. Such patients may follow a different clinical pattern from immunocompetent patients, often lacking a history of preceding trauma and presenting with multiple suppurating subcutaneous nodules. A sporotrichoid pattern of spread may occur with the species Mycobacterium kansasii and M. marinum but is rare with M. chelonei.