Rural and urban exposures shape early life immune development in South African children with atopic dermatitis and nonallergic children.

BACKGROUND: Immunological traits and functions have been consistently associated with environmental exposures and are thought to shape allergic disease susceptibility and protection. In particular, specific exposures in early life may have more significant effects on the developing immune system, with potentially long-term impacts. METHODS: We performed RNA-Seq on peripheral blood mononuclear cells (PBMCs) from 150 children with atopic dermatitis and healthy nonallergic children in rural and urban settings from the same ethnolinguistic AmaXhosa background in South Africa. We measured environmental exposures using questionnaires. RESULTS: A distinct PBMC gene expression pattern was observed in those children with atopic dermatitis (132 differentially expressed genes [DEGs]). However, the predominant influences on the immune cell transcriptome were related to early life exposures including animals, time outdoors, and types of cooking and heating fuels. Sample clustering revealed two rural groups (Rural_1 and Rural_2) that separated from the urban group (3413 and 2647 DEGs, respectively). The most significantly regulated pathways in Rural_1 children were related to innate activation of the immune system (e.g., TLR and cytokine signaling), changes in lymphocyte polarization (e.g., TH17 cells), and immune cell metabolism (i.e., oxidative phosphorylation). The Rural_2 group displayed evidence for ongoing lymphocyte activation (e.g., T cell receptor signaling), with changes in immune cell survival and proliferation (e.g., mTOR signaling, insulin signaling). CONCLUSIONS: This study highlights the importance of the exposome on immune development in early life and identifies potentially protective (e.g., animal) exposures and potentially detrimental (e.g., pollutant) exposures that impact key immunological pathways.

Environment-dependent alterations of immune mediators in urban and rural South African children with atopic dermatitis.

BACKGROUND: In order to improve targeted therapeutic approaches for children with atopic dermatitis (AD), novel insights into the molecular mechanisms and environmental exposures that differentially contribute to disease phenotypes are required. We wished to identify AD immunological endotypes in South African children from rural and urban environments. METHODS: We measured immunological, socio-economic and environmental factors in healthy children (n = 74) and children with AD (n = 78), in rural and urban settings from the same ethno-linguistic AmaXhosa background in South Africa. RESULTS: Circulating eosinophils, monocytes, TARC, MCP-4, IL-16 and allergen-specific IgE levels were elevated, while IL-17A and IL-23 levels were reduced, in children with AD regardless of their location. Independent of AD, children living in a rural environment had the highest levels of TNFα, TNFß, IL-1α, IL-6, IL-8, IL-21, MCP-1, MIP-1α, MIP-1ß, MDC, sICAM1, sVCAM1, VEGFA, VEGFD and Tie2, suggesting a generalized microinflammation or a pattern of trained immunity without any specific TH polarization. In contrast, IL-15, IL-22, Flt1, PIGF and ßFGF were highest in urban children. Rural healthy children had the lowest levels of food allergen-specific IgG4. Early life nutritional factors, medications, animal exposures, indoor environment, sunlight exposure, household size, household income and parental education levels were associated with differences in circulating cytokine levels. CONCLUSIONS: This study highlights the immunological impact of environmental exposures and socio-economic status in the manifestation of immune endotypes in children with AD living in urban and rural areas, which are important in selecting appropriately matched immunological therapies for treatment of AD.

Mechanisms of microbe-immune system dialogue within the skin.

The prevalence and severity of dermatological conditions such as atopic dermatitis have increased dramatically during recent decades. Many of the factors associated with an altered risk of developing inflammatory skin disorders have also been shown to alter the composition and diversity of non-pathogenic microbial communities that inhabit the human host. While the most densely microbial populated organ is the gut, culture and non-culture-based technologies have revealed a dynamic community of bacteria, fungi, viruses and mites that exist on healthy human skin, which change during disease. In this review, we highlight some of the recent findings on the mechanisms through which microbes interact with each other on the skin and the signalling systems that mediate communication between the immune system and skin-associated microbes. In addition, we summarize the ongoing clinical studies that are targeting the microbiome in patients with skin disorders. While significant efforts are still required to decipher the mechanisms underpinning host-microbe communication relevant to skin health, it is likely that disease-related microbial communities, or Dermatypes, will help identify personalized treatments and appropriate microbial reconstitution strategies.

Associations between Environmental dust composition and Atopic Dermatitis in urban and rural settings.

BACKGROUND: Environmental exposures are involved in the pathogenesis of the allergic phenotype and in determining which individual triggers a person becomes sensitized to. Atopic dermatitis (AD) may modulate these effects through increased penetration through the skin modifying the immune system and AD may be triggered or intensified by environmental exposures. These exposures and immune-modulating factors may differ in urban and rural environments. OBJECTIVES: To compare house dust composition in urban and rural settings and correlate them with AD outcomes. METHODS: Dust samples were collected from the beds of 156 children aged 6 months to 3 years. 42% of participants had atopic dermatitis. Samples were analyzed for bacterial endotoxin, fungal (ß-1,3-glucan) levels, and house dust mite, cockroach, dog, cat, mouse, and peanut allergen. Exposures were compared in urban and rural environments and in participants with and without AD. RESULTS: Endotoxin but not fungal ß-glucan exposure is higher in the environment of healthy controls than children with AD in both urban and rural settings. House dust mite allergen exposure is high in urban and rural settings with Dermatophagoides detected in 100% of samples. Cat and dog allergen exposure mirrors pet ownership patterns which differ slightly between groups and environments. Mouse allergen exposure is higher in urban homes. CONCLUSION: Environmental endotoxin may be protective against AD in both urban and rural settings. There are marked differences in allergen exposure in urban and rural settings, but these are unlikely to be important protective or risk factors.

House dust microbiota and atopic dermatitis; effect of urbanization.

BACKGROUND: Previous studies have shown that a child's risk of developing atopic disease is impacted by both genetic and environmental factors. Because small children spend the majority of their time in their homes, exposure to microbial factors in their home environment may be protective or risk factors for development of atopic diseases, such as atopic dermatitis. METHODS: Dust samples from the homes of 86 Black South African children 12 to 36 months old were collected for analysis of the bacterial microbiome. This case-control study design included children with and without atopic dermatitis from rural and urban environments. RESULTS: Significant differences in bacterial composition and diversity were found when comparing children with and without atopic dermatitis. Furthermore, house dust microbiota was significantly different in rural and urban areas. Differences were best accounted for by higher relative abundance of Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae families in rural compared with urban houses. Levels of Ruminococcaceae were also found to be significantly depleted in the house dust of rural children with atopic dermatitis as compared to control children. CONCLUSIONS: House dust composition may be an important risk factor for the development of atopic disease, and this association may be driven in part by the gut microbiome. Low levels of the Ruminococcaceae family from Clostridia class in particular may explain the association between urban living and atopy. However, further research is needed to elucidate these links.

Molecular IgE sensitization profiles of urban and rural children in South Africa.

BACKGROUND: Allergens can act as disease-triggering factors in atopic dermatitis (AD) patients. The aim of the study was to elucidate the molecular IgE sensitization profile in children with and without AD living in urban and rural areas of South Africa. METHODS: Specific IgE reactivity was assessed in 166 Black South African children aged 9-38 months using a comprehensive panel of microarrayed allergens. According to clinical characterization children fell in four groups, urban AD cases (n = 32), urban controls (non-AD, n = 40), rural cases (n = 49) and rural controls (non-AD, n = 45). RESULTS: IgE reactivity to at least one of the allergens was detected in 94% of urban and 86% of rural AD children. House dust mite (HDM; 81% urban, 74% rural AD) and animal-derived allergens (50% urban, 31% rural AD) were the most frequently recognized respiratory allergens, whereas IgE to pollen allergens was almost absent. Urban AD children showed significantly higher frequency of IgE reactivity (50%) to mouse lipocalin, Mus m 1, than rural AD children (12%). The most frequently recognized food allergens were from egg (63% urban, 43% rural AD), peanut (31% vs 41%), and soybean (22% vs 27%), whereas milk sensitization was rare. α-gal-specific IgE almost exclusively occurred in rural children (AD: 14%, non-AD: 49%). CONCLUSION: Molecular allergy diagnosis detects frequent IgE sensitization to HDM, animal but not pollen allergens and to egg, peanut, and soy, but not milk allergens in African AD children. Urban AD children reacted more often to Mus m 1, whereas α-gal sensitization is more common in rural children likely due to parasite exposure.

Molecular epidemiology of Staphylococcus aureus in African children from rural and urban communities with atopic dermatitis.

BACKGROUND: Staphylococcus aureus has been associated with the exacerbation and severity of atopic dermatitis (AD). Studies have not investigated the colonisation dynamics of S. aureus lineages in African toddlers with AD. We determined the prevalence and population structure of S. aureus in toddlers with and without AD from rural and urban South African settings. METHODS: We conducted a study of AD-affected and non-atopic AmaXhosa toddlers from rural Umtata and urban Cape Town, South Africa. S. aureus was screened from skin and nasal specimens using established microbiological methods and clonal lineages were determined by spa typing. Logistic regression analyses were employed to assess risk factors associated with S. aureus colonisation. RESULTS: S. aureus colonisation was higher in cases compared to controls independent of geographic location (54% vs. 13%, p < 0.001 and 70% vs. 35%, p = 0.005 in Umtata [rural] and Cape Town [urban], respectively). Severe AD was associated with higher colonisation compared with moderate AD (86% vs. 52%, p = 0.015) among urban cases. Having AD was associated with colonisation in both rural (odds ratio [OR] 7.54, 95% CI 2.92-19.47) and urban (OR 4.2, 95% CI 1.57-11.2) toddlers. In rural toddlers, living in an electrified house that uses gas (OR 4.08, 95% CI 1.59-10.44) or utilises kerosene and paraffin (OR 2.88, 95% CI 1.22-6.77) for heating and cooking were associated with increased S. aureus colonisation. However, exposure to farm animals (OR 0.3, 95% CI 0.11-0.83) as well as living in a house that uses wood and coal (OR 0.14, 95% CI 0.04-0.49) or outdoor fire (OR 0.31, 95% CI 0.13-0.73) were protective. Spa types t174 and t1476, and t272 and t1476 were dominant among urban and rural cases, respectively, but no main spa type was observed among controls, independent of geographic location. In urban cases, spa type t002 and t442 isolates were only identified in severe AD, t174 was more frequent in moderate AD, and t1476 in severe AD. CONCLUSION: The strain genotype of S. aureus differed by AD phenotypes and rural-urban settings. Continued surveillance of colonising S. aureus lineages is key in understanding alterations in skin microbial composition associated with AD pathogenesis and exacerbation.

Deep forehead lipomas in children-A series and review.

Deep forehead lipomas are rare in children and may be confused with other more concerning soft tissue masses. We describe four children with deep forehead lipomas, diagnosed between 2 months and 1 year of age, three of them congenital. Notable findings included association with intracranial lipoma and seizures in one patient and the development of marked alopecia overlying the lipoma in another. While deep forehead lipomas may become less visible over time, alopecia and non-syndromic extracutaneous involvement may be important associations.

The prevalence of human T-lymphotropic virus type 1 & 2 (HTLV-1/2) in South African blood donors.

BACKGROUND AND OBJECTIVES: Donated blood is not currently screened for human T-cell lymphotropic virus (HTLV) in South Africa. Several small studies have detected HTLV-1 in South Africa, but prevalence by geographic region or population group is unavailable. MATERIALS AND METHODS: We performed a large seroprevalence study of South African blood donors during 3 months in 2013. All geographic regions except the Western Cape were included, and Black and Coloured (local term for mixed race) donors were oversampled. Identity-unlinked plasma samples were screened with the Abbott Prism HTLV-1/2 assay, and repeatedly reactive samples were tested by the Inno-LIA HTLV-1/2 Score confirmatory assay. Odds ratios were calculated with multivariable logistic regression. RESULTS: Of 46 752 donors tested, 133 (0·28%) were initially reactive, 111 (0·24%) repeatedly reactive and 57 (0·12%) confirmed positive for HTLV-1; none were HTLV-2 positive. Prevalence was 0·062% weighted to annual blood donations but highly concentrated in the Black population group (OR = 20·24 CI: 2·77-147·88); higher in females than males (OR = 1·81 CI: 1·06-3·08); and in donors aged >50 years compared to ages 16-19 (OR = 6·4 CI: 2·95-13·86). After controlling for age, sex and population group, there was no difference in prevalence between new and repeat blood donors or among geographic regions within South Africa. CONCLUSIONS: We conclude that HTLV-1 infection is widespread among the Black population of South Africa and its epidemiology is similar to other endemic areas. Because South Africa is increasing its recruitment of Black blood donors, the implications for blood screening require further consideration.

Focus on the Top Ten Diagnoses Could Reduce Pediatric Dermatology Referrals.

There is a sense that many patients seen at referral centers could be managed at a primary health care level. The objective of the current study was to examine the range of diagnoses among consultations at the Red Cross Children's Hospital in Cape Town, South Africa, to help develop a strategy for targeted education of primary health care personnel. This was a retrospective review of data for children seen at a pediatric dermatology clinic from 2005 to 2010, recorded according to International Classification of Diseases coding and compared with published data from similar clinical settings. There were 13,253 clinic visits, with 4,789 patients seen (median age 4.8 yrs, range 2 days to 18.6 yrs). The top 10 diagnoses accounted for 88.5% of consultations (59.5% atopic eczema [AE], 7.1% seborrheic dermatitis [SD], 4.2% superficial mycoses, 3.1% molluscum contagiosum, 2.8% vitiligo, 2.7% viral warts, 2.4% prurigo or scabies, 2.3% psoriasis, 2.3% hemangioma, 2.1% impetigo). Disease prevalence was somewhat different during the first year of life (AE 43.7%, SD 18.6%, hemangiomas 13.4%). Inflammatory dermatoses (76.6%) were more prevalent than infections and infestations (14.5%). The disease spectrum was similar to that in developed countries, although AE prevalence was higher in this study (followed by London 36%, Greece 35%, and Hong Kong 33%) than in 19 published studies. The top 10 diagnoses accounted for more than 70% of diagnoses in 12 studies. The retrospective nature and setting at a specialist clinic increased bias and limited generalizability. Focused education on the optimal care of common diseases, especially AE, could reduce referrals, improve access, and allow specialists at tertiary centers more time to manage complex and uncommon dermatoses.

Strongyloidiasis and infective dermatitis alter human T lymphotropic virus-1 clonality in vivo.

Human T-lymphotropic Virus-1 (HTLV-1) is a retrovirus that persists lifelong by driving clonal proliferation of infected T-cells. HTLV-1 causes a neuroinflammatory disease and adult T-cell leukemia/lymphoma. Strongyloidiasis, a gastrointestinal infection by the helminth Strongyloides stercoralis, and Infective Dermatitis associated with HTLV-1 (IDH), appear to be risk factors for the development of HTLV-1 related diseases. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the HTLV-1-infected T-cell population (i.e. the number of distinct clones and abundance of each clone). A newly developed biodiversity estimator called "DivE" was used to estimate the total number of clones in the blood. We found that the major determinant of proviral load in all subjects without leukemia/lymphoma was the total number of HTLV-1-infected clones. Nevertheless, the significantly higher proviral load in patients with strongyloidiasis or IDH was due to an increase in the mean clone abundance, not to an increase in the number of infected clones. These patients appear to be less capable of restricting clone abundance than those with HTLV-1 alone. In patients co-infected with Strongyloides there was an increased degree of oligoclonal expansion and a higher rate of turnover (i.e. appearance and disappearance) of HTLV-1-infected clones. In Strongyloides co-infected patients and those with IDH, proliferation of the most abundant HTLV-1⁺ T-cell clones is independent of the genomic environment of the provirus, in sharp contrast to patients with HTLV-1 infection alone. This implies that new selection forces are driving oligoclonal proliferation in Strongyloides co-infection and IDH. We conclude that strongyloidiasis and IDH increase the risk of development of HTLV-1-associated diseases by increasing the rate of infection of new clones and the abundance of existing HTLV-1⁺ clones.

The South African Food Sensitisation and Food Allergy population-based study of IgE-mediated food allergy: validity, safety, and acceptability.

BACKGROUND: Few studies exist on food sensitization and challenge-proven food allergy in low- and middle-income countries. OBJECTIVE: To describe the study design and methodology to recruit infants from an African population for skin prick testing and oral food challenges and the use of preliminary data to investigate the extent to which the study sample is representative of the target population. METHODS: Children 12 to 36 months old were recruited from childcare education facilities in Cape Town. Children underwent skin prick testing to foods. Those with a reactive wheal of at least 1 mm larger than the negative control and not clearly tolerant according to history to a full age-appropriate portion to at least 1 food underwent oral food challenges. Parents who chose not to participate completed a nonparticipant questionnaire. Interim analysis of at least 500 respondents was performed. Demographic features of participating children were compared with those of nonparticipants and the population demographics of the most recent Cape Town census data. RESULTS: The response rate was 60.1%, with high participation and completion rates of 96.5% and 97.5%, respectively. Demographics of the completed participant sample were similar to those of the Cape Town census. Use of a nonrespondent questionnaire indicated no selection bias in favor of increased participation of participants with allergy. No ethnic differences in sensitization or food allergy were evident. CONCLUSION: The study was safe and feasible and the recruitment was effective and representative of the target population. Future studies will aim to increase the precision of the prevalence of food sensitization and allergy, describe environmental risk factors, and include a rural black African cohort.

A Review and Proposed Approach to the Neutrophilic Dermatoses of Childhood.

Neutrophilic dermatoses (NDs) are inflammatory skin conditions that are not associated with infection. The classification and clinical approach to these conditions in children is poorly described. This review classifies these conditions into five nosological subtypes: Sweet's syndrome, pyoderma gangrenosum, aseptic pustules, neutrophilic urticarial dermatoses, and Marshall's syndrome. In addition, we review the various secondary diseases that need to be excluded in the clinical management of the NDs of childhood, with a focus on the autoinflammatory conditions that the reader may not be familiar with. We propose a practical clinical approach to these disorders.

Scurvy masquerading as IgA vasculitis.

BACKGROUND: Vitamin C deficiency, or scurvy, is rare but poses risks for children with poor diets, limited resources, or malabsorption issues. It may also be common in children with restrictive or selective dietary habits in children with global developmental delay, autism spectrum disorder, and physical disabilities. Symptoms include fatigue, irritability, joint and muscle pain, joint swellings, edema, swollen gums, easy bruising, and delayed wound healing. Early recognition and prompt intervention are essential to prevent the progression of symptomatic vitamin C deficiency in children. CASE PRESENTATION: We present a case of a 13-year-old boy with developmental delay secondary to Lennox Gastaut syndrome referred for suspected recurrent, severe, and atypical IgA vasculitis. He presented with irritability, loss of appetite, petechial and ecchymotic lower limb lesions, unilateral gum swelling, severe arthritis, peripheral oedema, severe weight loss, anaemia, and raised inflammatory markers. Multiple investigations were performed before the diagnosis of scurvy was made. A surgical finding of friable gingival tissue with multiple loose teeth, a skin biopsy with follicular hyperkeratosis and extravasated perifollicular red blood cells, and a typical X-ray finding led to the diagnosis of scurvy. CONCLUSION: Scurvy should be given careful consideration as a differential diagnosis in patients presenting with musculoskeletal issues, mucocutaneous complaints, and constitutional symptoms such as malaise, asthenia, irritability, and loss of appetite. A focused and detailed dietary history looking for a lack of good sources of vitamin C can be an easy indicator of this differential. Imaging studies revealing the typical features can also help make the diagnosis. Pathology of the skin revealing pathognomonic features can add to the certainty of the diagnosis. In the absence of all else, the rapid response to treatment with an appropriate dose of vitamin C has a diagnostic and therapeutic role.

Human T cell lymphotropic virus type 1- associated infective dermatitis in KwaZulu Natal, South Africa.

BACKGROUND: The Human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis (IDH), is a chronic relapsing dermatitis which usually presents in children older than 2 years. A total of 300 cases have been reported worldwide (Latin America, the Caribbean and only 5 from Senegal). Neither IDH, nor its complications have been reported from the rest of Africa. We aimed to examine the clinical and aetiological characteristics of IDH in a cohort of South African children. METHODS: Attendees at the dermatology clinic at King Edward VIII Hospital, Durban underwent clinical examination. After obtaining consent those suspected of IDH had specimens taken for blood counts, immunoglobulins, serum protein electrophoresis, viral studies (including genotyping), skin swabs and stool examinations. RESULTS: Nineteen of 60 suspected cases recruited over 3 years met the diagnostic criteria for IDH. The male-to-female ratio was 1:2; mean age 8 years (range 0.7 to 15). Dermatitis mostly affected the scalp (78.9%) and axilla (73.7%); fewer children had nasal crusting (47.4%). Mean Ig A, IgG and IgM were raised, at 3.52 g/l, 22.6 g/l and 1.38 g/l, respectively. The median CD4 cell count was 1958 cells/mm3. Viral genotyping of all tested samples were positive for the Cosmopolitan, Subtype A (HTLV-1a). CONCLUSIONS: IDH is a distinct entity which also affects South Africans. Our patients were older at presentation and the majority did not present with nasal crusting as has been described in other countries.

Skin and nasal colonization of coagulase-negative staphylococci are associated with atopic dermatitis among South African toddlers.

BACKGROUND: Skin colonization with coagulase-negative staphylococci (CoNS) is generally beneficial, but recent investigations suggest its association with flares and atopic dermatitis (AD) severity. However, this relationship remains unclear. OBJECTIVE: To assess patterns of staphylococcal colonization and biofilm formation in toddlers with and without AD from rural and urban South African settings. METHODS: We conducted a cross-sectional study of AD-affected and non-atopic AmaXhosa toddlers from rural Umtata and urban Cape Town, South Africa. CoNS isolates were recovered from lesional, nonlesional skin samples and the anterior nares of participants. Identification of the staphylococci was achieved by MALDI-TOF mass spectrometry. The microtiter plate assay assessed in-vitro biofilm formation. RESULTS: CoNS and S. aureus commonly co-colonized nonlesional skin among cases (urban: 24% vs. 3%, p = 0.037 and rural 21% vs. 6%, p<0.001), and anterior nares in urban cases (24% vs. 0%, p = 0.002) than the control group. S. capitis colonization on nonlesional skin and anterior nares was positively associated with more severe disease in rural (48.3±10.8 vs. 39.7±11.5, P = 0.045) and urban cases (74.9±10.3 vs. 38.4±13, P = 0.004), respectively. Biofilm formation was similar between cases and controls, independent of rural-urban living. CONCLUSION: CoNS colonization is associated with AD and disease severity and may be implicated in AD exacerbations. Studies are needed to understand their underlying pathological contribution in AD pathogenesis.