Reactive granulomatous dermatitis as a clinically relevant and unifying term: a retrospective review of clinical features, associated systemic diseases, histopathology and treatment for a series of 65 patients at Mayo Clinic.

BACKGROUND: Reactive granulomatous dermatitis (RGD) is an umbrella term used to describe interstitial granulomatous dermatitis (IGD), palisaded neutrophilic and granulomatous dermatitis (PNGD), and interstitial granulomatous drug eruption (IGDR). OBJECTIVE: The aim of this study was to describe systemic associations of RGD, explore possible associations between histopathologic findings and systemic RGD associations and determine clinical relevance of RGD subtypes. METHODS: We retrospectively studied clinical and histopathologic characteristics of patients with RGD from 1990 through 2020. RESULTS: Of 65 patients with RGD (41 women, 24 men; median age at diagnosis, 62 years), 37 had IGD, 26 had PNGD, and 2 had IGDR. Fifty patients (76.9%) had an associated systemic condition; rheumatologic conditions were identified for 34 (52.3%) patients. The associated systemic condition occurred before RGD in approximately 75% of patients. Statistical analyses did not show significant associations between specific subtypes of RGD and systemic diseases or treatment response, and specific histopathologic findings were not predictive of an associated systemic disease. CONCLUSIONS: Although most patients with RGD had an associated systemic condition, subtypes of RGD did not correlate with systemic associations, lending support to the use of the umbrella term RGD.

In Vivo reflectance confocal microscopy of cutaneous acute graft-versus-host disease: concordance with histopathology and interobserver reproducibility of a glossary with representative images.

BACKGROUND: The reliability to non-invasively identify features of inflammatory dermatoses by reflectance confocal microscopy (RCM) remains unknown. Lack of formal training among RCM readers can result in inconsistent assessments, limiting clinical utility. Specific consensus terminology with representative images is necessary to ensure consistent feature-level interpretation among RCM readers. OBJECTIVES: (1) Develop a glossary with representative images of RCM features of cutaneous acute graft-versus-host disease (aGVHD) for consistent interpretation among observers, (2) assess the interobserver reproducibility among RCM readers using the glossary, and (3) determine the concordance between RCM and histopathology for aGVHD features. METHODS: Through an iterative process of refinement and discussion among five international RCM experts, we developed a glossary with representative images of RCM features of aGVHD. From April to November 2018, patients suspected of aGVHD were imaged with RCM and subsequently biopsied. 17 lesions from 12 patients had clinically and pathologically confirmed cutaneous aGVHD. For each of these lesions, four dermatopathologists and four RCM readers independently evaluated the presence of aGVHD features in scanned histopathology slides and 1.5 × 1.5 mm RCM submosaics at 4 depths (blockstacks) respectively. RCM cases were adjudicated by a fifth RCM expert. Interobserver reproducibility was calculated by mean pairwise difference (U statistic). Concordance between modalities was determined by fraction of assignments with agreement. RESULTS: We present a glossary with representative images of 18 aGVHD features by RCM. The average interobserver reproducibility among RCM readers (75%, confidence interval, CI: 71-79%) did not differ significantly from dermatopathologists (80%, 76-85%). The concordance between RCM and histopathology was 59%. CONCLUSIONS: By using the glossary, the interobserver reproducibility among RCM readers was similar to the interobserver reproducibility among dermatopathologists. There was reasonable concordance between RCM and histopathology to visualize aGVHD features. The implementation of RCM can now be advanced in a variety of inflammatory conditions with a validated glossary and representative image set.

Clinical and histopathological features of adult patients with dermatomyositis and melanoma differentiation associated-5 autoantibody seropositivity status, as determined by commercially available testing: a retrospective, single-institution comparative cohort study.

BACKGROUND: Although melanoma differentiation associated (MDA)-5 autoantibodies have been widely explored in dermatomyositis (DM), most studies have relied on MDA-5 autoantibody testing performed in research settings, rather than the now-available commercial laboratory tests. AIM: To characterize the clinical and histopathological data in patients with DM and circulating MDA-5 autoantibodies, as defined by commercially available testing. METHODS: This was a retrospective review of patients with DM who underwent MDA-5 antibody testing. All available skin biopsy slides were reviewed. RESULTS: Cutaneous features more prevalent in MDA-5-positive DM included Raynaud phenomenon (RP) (P < 0.001), cutaneous ulcerations (P = 0.01), mechanic hands (P < 0.02), palmar papules (P < 0.01), oral ulcers (P = 0.024) and alopecia (P = 0.03). Joint and pulmonary involvement were more common in patients with MDA-5-positive DM (both P < 0.001) as was dysphagia (P < 0.01). Myopathy (P = 0.4) and malignancy (P = 0.34) were not statistically different between the cohorts. Vasculopathy was more common in MDA-5-positive DM (P < 0.01), while spongiosis was less common (P < 0.02). CONCLUSION: This study not only confirms some known associations between disease manifestations and MDA-5 autoantibody status, as determined by commercially available tests, but also identifies new associations, including RP and dysphagia.

Differential expression of interferon-induced genes and other tissue-based biomarkers in acute graft-versus-host disease vs. lupus erythematosus in skin.

BACKGROUND: In both acute graft-versus-host disease (GVHD) and lupus erythematosus (LE), the patient's own tissues are subjected to immunological assault via complex mechanisms influenced by interferon (IFN) and other cytokines. Although not typically confused clinically, these entities have overlapping histopathological findings in the skin. AIM: To assess whether GVHD can be differentiated from LE using molecular methods on skin specimens. METHODS: We developed a quantitative reverse transcription PCR assay based on previously identified tissue-based biomarkers of cutaneous GVHD, and compared gene expression in GVHD with that in LE. RESULTS: Both entities showed robust expression of IFN-induced genes and of genes encoding proteins involved in antigen presentation, cell signalling and tissue repair. Levels of gene expression differed significantly in GVHD compared with LE, particularly those of IFN-induced genes such as MX1, OAS3, TAP1 and STAT3 (P < 0.01). Three logistic regression models could differentiate the two entities with a high degree of certainty (receiver operating characteristic area under the curve of 1.0). CONCLUSION: The study demonstrates the feasibility of distinguishing between microscopically similar inflammatory dermatoses using tissue-based molecular techniques.

International Bullous Diseases Group: consensus on diagnostic criteria for epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a complex autoimmune bullous disease disease with variable clinical presentations and multiple possible diagnostic tests, making an international consensus on the diagnosis of EBA essential. OBJECTIVES: To obtain an international consensus on the clinical and diagnostic criteria for EBA. METHODS: The International Bullous Diseases Group (IBDG) met three times to discuss the clinical and diagnostic criteria for EBA. For the final voting exercise, 22 experts from 14 different countries voted on 50 different items. When > 30% disagreed with a proposal, a discussion was held and re-voting carried out. RESULTS: In total, 48 of 50 proposals achieved consensus after discussion. This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed. CONCLUSIONS: This first international consensus conference established generally agreed-upon clinical and laboratory criteria defining the clinical classification of and diagnostic testing for EBA. Holding these voting exercises in person with the possibility of discussion prior to voting has advantages in reaching consensus over Delphi exercises with remote voting.

Underreported use of palliative care and patient-reported outcome measures to address reduced quality of life in patients with calciphylaxis: a systematic review.

Calciphylaxis is associated with significant morbidity and mortality. Palliative care (PC) is a subspecialty that treats the pain and stress of serious illness. To assess whether the role of quality of life (QoL) indices, patient-reported outcome measures and PC have been studied in patients with calciphylaxis, we performed a systematic literature review. Several databases were searched from inception to October 2016 according to modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. We searched for papers on calciphylaxis that mentioned the symptoms and supportive needs of patients, QoL or outcome measures to report symptom severity, and the involvement of PC. Twelve papers met the inclusion criteria. Reported patient symptoms included pain, skin lesion resolution and pruritus, with the first being the most frequently reported. Four papers measured pain using a previously verified patient-reported outcome measure, including the Visual Analogue Scale. One paper used a verified QoL measure, the Dermatology Quality of Life Index. No tool was used consistently. Eight papers reported the use of hospice care or PC in the treatment of calciphylaxis. No outcome measure was used to prompt PC involvement. Overall, QoL indices, patient-reported outcome measures and PC are underreported in the treatment of calciphylaxis. PC may be a resource to assist in symptom management and adaptive coping strategies for patients from the onset of disease.

Leukocytoclastic vasculitis in children: clinical characteristics, subtypes, causes and direct immunofluorescence findings of 56 biopsy-confirmed cases.

BACKGROUND: Leukocytoclastic vasculitis (LCV) in children is a complex group of conditions. OBJECTIVES: This study presents the demographics, clinical features, direct immunofluorescence (DIF) results and suspected aetiologies of 56 biopsy-confirmed cases of leukocytoclastic vasculitis in children. METHODS: Retrospective review of 56 children seen at Mayo Clinic in Rochester, Minnesota, from 1993 to 2013 with clinical features and cutaneous biopsy consistent with LCV. RESULTS: Twenty-seven (48%) cases were found to be due to IgA vasculitis (Henoch-Schonlein purpura). The remaining cases were found to be due to cutaneous small-vessel vasculitis (n = 19, 34%), urticarial vasculitis (n = 5, 9%), ANCA-associated vasculitis (n = 4, 7%) and acute haemorrhagic oedema of infancy (n = 1, 2%). IgA vasculitis was found to be associated with abdominal pain (P = 0.008), whereas the non-IgA vasculitis group was associated with headache (P = 0.052). Children with IgA vasculitis had palpable purpura (P = <0.001), petechia (P = 0.057), vesicles (P = 0.009) and involvement of the buttock (P = 0.004) more frequently than the non-IgA vasculitis group. On DIF, perivascular IgA was positive in IgA vasculitis compared to non-IgA vasculitis cases (P = <0.001), the other conjugates were similar between the two groups. CONCLUSION: The most common subtype of biopsy-confirmed LCV in children is IgA vasculitis. Clinical features, exam characteristics and DIF results can be helpful in determining the subtype of cutaneous vasculitis in children.

Henoch-Schönlein purpura and systemic disease in children: retrospective study of clinical findings, histopathology and direct immunofluorescence in 34 paediatric patients.

BACKGROUND: Henoch-Schönlein purpura (HSP), an IgA-mediated small vessel vasculitis, is the most common form of vasculitis in children. HSP is commonly associated with systemic involvement of the gastrointestinal tract, joints and kidneys. Renal involvement is the main cause of morbidity and mortality in HSP. OBJECTIVES: To characterize the clinical, histopathological and direct immunofluorescence (DIF) findings, and to correlate the findings with systemic disease in 34 children with HSP seen at our institution. METHODS: This was a retrospective review of paediatric patients with HSP and with available biopsy specimens seen at our institution between 1993 and 2013. RESULTS: Thirty-four paediatric patients were identified (mean age 10·7 years). Renal involvement was found in 17 (50%) patients, gastrointestinal tract involvement in 22 (65%) and joint involvement in 23 (68%). Renal involvement was significantly associated with papillary dermal oedema on histopathology (P < 0·01) and the presence of perivascular C3 on DIF (P = 0·01). The presence of lesions above the waist was significantly associated with gastrointestinal involvement (P = 0·03), as was the presence of clinically apparent oedema (P = 0·01). CONCLUSIONS: This study suggests that in children with HSP, microscopic dermal oedema and C3 on DIF may be predictive of renal involvement. Patients with clinically apparent oedema and lesions above the waist are more likely to have gastrointestinal involvement.

Evidence-based guidelines for laboratory screening for infectious diseases before initiation of systemic immunosuppressive agents in patients with autoimmune bullous dermatoses.

Autoimmune bullous dermatoses (ABD) compromise the skin's innate barrier function for preventing infection. Treating patients with ABD frequently requires systemic immunosuppressive therapy, often with multiple agents. Currently, no pretreatment infection testing guidelines are available for clinicians caring for patients with ABD. We performed a systematic literature review in other medical disciplines that use similar iatrogenic immunosuppressive medications to treat various diseases and conditions and developed infection-testing recommendations for patients with ABD before initiating immunosuppressive therapy. Assessing individual patient risk factors for latent infection and preventable communicable diseases can direct testing for select infections before starting immunosuppressive therapy. Testing patients for hepatitis B virus, hepatitis C virus, and Mycobacterium tuberculosis infection is recommended before initiating rituximab treatment.

What happened to home HIV test collection kits? Intent to use kits, actual use, and barriers to use among persons at risk for HIV infection.

Through sequential cross-sectional surveys, we examined intent to use home HIV test collection kits, actual use and barriers to use among persons at high risk for HIV infection. Interest in kits was assessed in the 1995-96 HIV Testing Survey (HITS, n=1683). Kit use, knowledge of kits and barriers to use were assessed in the 1998-99 HITS (n=1788), after kits had become widely available. When asked to choose among future testing options, 19% of 1995-96 participants intended to use kits. Untested participants were more likely than previously tested HIV-negative participants to choose kits for their next HIV test (p < 0.001). Among 1998-99 participants, only 24 (1%) had used kits; 46% had never heard of kits. Predictors of not knowing about kits included never having been HIV tested and black or Latino race. Common reasons for not using kits among participants aware of home test kits were concerns about accuracy, lack of in-person counselling and cost. Despite high rates of anticipated use, kits have had minimal impact on the testing behaviour of persons at high risk for HIV infection. Increasing awareness of kits, reducing price and addressing concerns about kit testing procedures may increase kit use, leading to more HIV testing by at-risk individuals.

Relationships Between Blueberry Flower Age, Pollination, and Conidial Infection by Monilinia vaccinii-corymbosi.

ABSTRACT Monilinia vaccinii-corymbosi infects open blueberry flowers via the gynoecial pathway, leading to mummification of the developing fruit. To determine the effect of flower age on infection, stigmata were inoculated with conidia of M. vaccinii-corymbosi between 0 and 5 days after anthesis, fungal growth rates through the stylar canal were measured in detached flowers in the laboratory, and fruit disease incidence was determined in plants grown in the greenhouse. Hyphal growth rates were greatest in flowers inoculated on the day of anthesis, declined linearly with increasing flower age at inoculation (r = 0.921; P < 0.0001; n = 12), and were unaffected by the presence or absence of pollen applied at the time of inoculation. In greenhouse-grown plants, the percentage of infected fruit decreased exponentially with increasing flower age at inoculation (R = 0.878; P = 0.0057; n = 10), with disease incidence ranging from 76.4% for flowers inoculated on the day of anthesis to 15.5% for those inoculated 4 days later. Fruit disease incidence in the greenhouse was linearly correlated with hyphal growth rates in detached flowers (r = 0.985; P < 0.0001; n = 9), justifying the use of detached flowers when investigating gynoecial infection by M. vaccinii-corymbosi. In separate experiments, the effects of timing and sequence of pollination and inoculation on hyphal growth rates through the stylar canal and on disease incidence were investigated. Application of pollen to detached flowers 1 or 2 days before inoculation reduced hyphal growth rates by between 14.0 and 42.9% compared with flowers that received pollen and conidia simultaneously. Similarly, reductions in fruit disease incidence by between 9.5 and 18.3% were observed on greenhouse-grown plants for pollination-to-inoculation intervals ranging from 1 to 4 days. These results document that newly opened flowers are most susceptible to infection by M. vaccinii-corymbosi and that fruit disease incidence is reduced if pollination occurs at least 1 day before inoculation. Strategies that lead to early pollination of newly opened flowers may be useful for managing mummy berry disease in the field.

Does HIV reporting by name deter testing? MESH Study Group.

OBJECTIVE: Name-based HIV reporting is controversial in the United States because of concerns that it may deter high-risk persons from being tested. We sought to determine whether persons at risk of HIV infection knew their state's HIV reporting policy and whether they had delayed or avoided testing because of it. DESIGN: A cross-sectional anonymous survey. METHODS: We interviewed 2404 participants in one of three high-risk groups: men who have sex with men (MSM), heterosexuals attending a sexually transmitted disease (STD) clinic, and street-recruited injection drug users (IDU). Participants were asked standardized questions about their knowledge of reporting policies and reasons for having delayed or avoided testing. We recruited in eight US states: four with name-based reporting and four without; all offered anonymous testing at certain sites. RESULTS: Fewer than 25% correctly identified their state's HIV reporting policy. Over 50% stated they did not know whether their state used name-based reporting. Of the total, 480 participants (20%) had never been tested. Of these, 17% from states with name-based reporting selected concern about reporting as a reason for not testing compared with 14% from states without name-based reporting (P = 0.5). Comparing previously tested participants from states with name-based reporting to those from states without, concern about HIV reporting was given as a reason for delaying testing by 26% compared with 13% of IDU (P < 0.001), and for 26% compared with 19% of MSM (P = 0.06). CONCLUSION: Most participants did not know their state's HIV reporting policy. Name-based reporting policies were not associated with avoiding HIV testing because of worry about reporting, although they may have contributed to delays in testing among some IDU.

Variation and Heritability of Phenology in the Fungus Monilinia vaccinii-corymbosi on Blueberry.

ABSTRACT The germination of field-collected pseudosclerotia and the development of apothecia from eight New Jersey populations of the mummy berry fungus Monilinia vaccinii-corymbosi were evaluated under controlled conditions in the greenhouse. Development data for apothecia were used to describe the timing of apothecium formation and to estimate broad- and narrow-sense heritabilities of fungal phenology. Mean development times for the formation of apothecia ranged from 35.4 to 54.7 days. The mean development times for populations collected from early-season cv. Weymouth ranged from 35.4 to 39.6 days and were significantly shorter than the development times for three of the four populations collected from late-season cv. Jersey (46.9 to 54.7 days) or for the population collected from mixed stands of cultivated blueberries (42.7 days). The development of populations from late cultivars planted in very close proximity to early cv. Weymouth was early (36.5 to 39.0 days) and not significantly different from the development of populations collected from cv. Weymouth. Phenotypic and genetic variances of apothecium development for individual populations ranged from 18.9 to 44.8 and 7.2 to 30.9, respectively. Broad-sense heritabilities of apothecia development for each fungal population, calculated by partitioning phenotypic variation into genetic and environmental components, ranged from 0.31 to 0.78. Narrow-sense heritabilities of apothecia development, based on parent-offspring regression, ranged from 0.58 to 0.78. These results indicate that populations of M. vaccinii-corymbosi differ in phenology and that a significant portion of the phenological variation within populations is genetic. Thus, it is plausible to propose that the phenology of apothecium development is a component of fungal fitness and that host phenology can influence the timing of pathogen development.

Name-based surveillance and public health interventions for persons with HIV infection. Multistate Evaluation of Surveillance for HIV Study Group.

Name-based surveillance of HIV infection is the law in 31 U.S. states but remains controversial. This policy can be advocated solely to support surveillance of the epidemic, but a frequent argument is that it also provides a public health benefit by allowing follow-up of HIV-infected persons. These persons can then receive timely medical care and can be assisted with notifying sex and needle-sharing partners. Few comparative data are available to evaluate the outcomes of these interventions. In five states with name-based surveillance of HIV infection, the Multistate Evaluation of Surveillance for HIV Study Group surveyed a cross-sectional probability sample of persons with AIDS who tested positive for HIV before the date of their AIDS diagnosis. Health department follow-up of a reported HIV infection was not associated with more timely receipt of medical care after a positive HIV test result. Only 8.6% of persons who delayed medical care after their first positive HIV test result gave concern about being reported by name as a reason; no person gave it as the main reason. Persons who were tested anonymously and those who were tested confidentially did not differ in the mean number of sex and needle-sharing partners notified: Those tested anonymously reported personally notifying 3.85 sex and needle-sharing partners, and those tested confidentially reported notifying-personally and through the health department-3.80 partners. Many researchers and policymakers believe that name-based surveillance of HIV infection will have positive or negative effects on partner notification and access to health care. These results suggest that the potential for such effects has been exaggerated.

Multistate evaluation of anonymous HIV testing and access to medical care. Multistate Evaluation of Surveillance of HIV (MESH) Study Group.

CONTEXT: Infection with the human immunodeficiency virus (HIV) is the only infectious disease for which anonymous testing is publicly funded, an exception that has been controversial. OBJECTIVE: To assess whether anonymous HIV testing was associated with earlier HIV testing and HIV-related medical care than confidential HIV testing. DESIGN: Retrospective cohort. SETTING: Arizona, Colorado, Missouri, New Mexico, North Carolina, Oregon, and Texas. PARTICIPANTS: Probability sample of 835 new acquired immunodeficiency syndrome (AIDS) cases reported to the state health department's HIV/AIDS Reporting System from May 1995 through December 1996. All had responded to the AIDS Patient Survey; 643 had been tested confidentially for HIV, and 192 had been tested anonymously. MAIN OUTCOME MEASURES: First CD4+ cell count; number of days from HIV-positive test result to first HIV-related medical care, from first HIV-related medical care to AIDS, and from first HIV-positive test result to AIDS. RESULTS: Persons tested anonymously sought testing and medical care earlier in the course of HIV disease than did persons tested confidentially. Mean first CD4+ cell count was 0.427x 10(9)/L in persons tested anonymously vs 0.267x 10(9)/L in persons tested confidentially. Persons tested anonymously experienced an average of 918 days in HIV-related medical care before an AIDS diagnosis vs 531 days for persons tested confidentially. The mean time from learning they were HIV positive to the diagnosis of AIDS was 1246 days for persons tested anonymously vs 718 days for persons tested confidentially. After adjustment for the subject's age, sex, race/ethnicity, education, income, insurance status, HIV exposure group, whether the respondent had a regular source of care or symptoms at the time of the HIV test, and state residence, anonymous testing remained significantly associated with earlier entry into medical care (P<.001). CONCLUSION: Anonymous testing contributes to early HIV testing and medical care.

Selection of Populations of Puccinia recondita f. sp. tritici for Shortened Latent Period on a Partially Resistant Wheat Cultivar.

ABSTRACT Wild-type fungal population 851-WT was selected for shortened latent period on cv. CI 13227 for five uredinial generations to study the adaptation of Puccinia recondita f. sp. tritici to partially resistant wheat cultivars. Differences among wild-type and selected populations for traits contributing to parasitic fitness (i.e., latent period, infection frequency, and uredinium area and growth rate) were assessed in monocyclic infection experiments on susceptible cv. Monon and partially resistant cvs. Suwon 85, Sw 72469-6, L-574-1, and CI 13227. Differences were greatest among fungal populations on cv. CI 13227. The mean latent period of selected population 851-C5 was 2 days shorter (~20%) than that of wild-type population 851-WT. In addition, uredinia of population 851-C5 expanded 40% faster and produced ~75% more urediniospores. On cv. L-574-1, the selected population was also more fit than the wild-type progenitor for initial uredinium area and growth rate and cumulative urediniospore production. In contrast to wild-type and selected populations on cvs. CI 13227 and L-574-1, selected population 851-C5 on cv. Monon produced slower expanding uredinia with fewer urediniospores than did population 851-WT on Monon. These results show that variation in the latent period of P. recondita f. sp. tritici populations is partially under genetic control and wild-type P. recondita f. sp. tritici populations contain members reproductively more fit on partially resistant wheat cultivars but not necessarily on susceptible cultivars. Such members are capable of partially overcoming quantitative host resistance.

Phenology of Apothecium Production in Populations of Monilinia vaccinii-corymbosi from Early- and Late-Maturing Blueberry Cultivars.

ABSTRACT Pseudosclerotia were evaluated for differences in timing of apothecium development in four controlled experiments conducted over a 2-year period. In a separate experiment, conidia from 10 randomly selected isolates from both of the fungal populations were used to inoculate open flowers. Germination of pseudosclerotia produced from these artificial inoculations also was evaluated. The timing and rate of shoot elongation for cvs. Weymouth and Jersey were assessed in one greenhouse and two field experiments. Average development times for the fungal population from cv. Weymouth were 8 to 15 days earlier or 33 to 42% less than those for the population from cv. Jersey. The fungal population from Weymouth also exhibited less variation in development times for each developmental stage measured. Similarly, germination of pseudosclerotia produced in artificial inoculations differed between populations. On average, pseudosclerotia derived from the Weymouth population produced apothecia 16 days earlier. During spring 1995 and 1996, vegetative and truss buds on cv. Weymouth developed 4 to 16 days earlier than those on cv. Jersey. These results demonstrate that M. vaccinii-corymbosi exhibits variation in timing of pseudosclerotia germination and apothecium development within and between populations. We hypothesize that differences observed in the timing of apothecium development are related to the fitness of the populations on their original host cultivars and were selected by host phenology.