Absence of Epidermal Antibodies in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Patients but Beware of Single Positive Results.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially life-threatening mucocutaneous blistering diseases that clinically can resemble autoimmune bullous diseases. Moreover, it has been shown that autoantibodies against epidermal proteins are present in SJS/TEN. Objectives: To establish the presence of antibodies against desmosomal and hemidesmosomal proteins in confirmed SJS/TEN patients. Methods: Serum of SJS/TEN patients diagnosed based on clinical criteria, e.g., epidermal detachment with erosions and severe mucosal lesions, (suspicion of) a culprit drug, and matching histologic results was evaluated by various techniques, e.g., indirect immunofluorescence on monkey esophagus, salt split skin and rat bladder, immunoblotting (IB) and immunoprecipitation (IP), ELISAs against desmogleins and BP180, keratinocyte footprint assay, and keratinocyte binding assay. Results: A total of 28 patients were included in this study, 15 men and 13 women with a mean age of 56 years. In most patients, none of the serological tests were positive. In two patients, an elevated DSG3 titer was found suspicious for pemphigus vulgaris. Three patients had elevated NC16a titers, suggesting bullous pemphigoid. However, in all these patients, no other tests were positive and in these patients, the biopsy for direct immunofluorescence showed no evidence for an autoimmune bullous disease. Three patients showed reactivity against rat bladder rat bladder; these were, however, completely negative for A2ML1, envoplakin, and periplakin in the IB as well as the IP. Conclusions: Serological analysis for desmosomal and hemidesmosomal antibodies is reliable to rule an autoimmune bullous disease in patients with suspected SJS/TEN. However, one should not rely on one single test method since false positive results can occur. Moreover, this study also makes it less plausible that antibodies against desmosomal and/or hemidesmosomal components are involved in the pathogenesis of SJS/TEN.

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES: These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS: Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS: These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies.

Paraneoplastic pemphigus: A detailed case series from the Netherlands revealing atypical cases.

BACKGROUND: Paraneoplastic pemphigus (PNP) is an extremely rare life-threatening blistering autoimmune disease that is associated with an underlying neoplasm. There is a set diagnostic criterion for PNP, which is primarily based on a severe stomatitis and the detection of specific antibodies against envoplakin, periplakin and alpha-2-macroglobulin-like protein 1. However, it has become increasingly evident that there are patients with PNP that do not meet all the diagnostic criteria requirements. OBJECTIVES: The aim of this study was to analyse our cohort of Dutch patients and to define the atypical cases that did not meet the diagnostic criteria. METHODS: A retrospective case study of all known Dutch PNP patients of the past 25 years. Patients' clinical and immunological variables were thoroughly analysed and described. RESULTS: Twenty-four patients were included in this study. The results revealed several atypical patient cases that did not completely meet the set diagnostic criteria. Of the 24 patients, two patients presented without stomatitis, in three patients an underlying neoplasm could not be detected, and in two patients the presence of specific autoantibodies could not be demonstrated, although all other criteria for PNP were met. Finally, three of the 24 patients survived the disease. CONCLUSION: Although our findings showed similarities to previous studies and most of the patients met the criteria, there were a few atypical patient cases; highlighting the importance of not strictly adhering to the set criteria when making a diagnosis, as this can lead to a missed or late diagnosis. Thus, it is of crucial importance to combine clinical and elaborate laboratory results to confirm the diagnosis of PNP in suspected patients. Although PNP harbours an unfavourable prognosis in most cases, it might be resolved by timely treatment of the underlying cause.

Insights into clinical and diagnostic findings as well as treatment responses in patients with mucous membrane pemphigoid: A retrospective cohort study.

BACKGROUND: The variable clinical severity of mucous membrane pemphigoid (MMP) often leads to diagnostic and therapeutic delays. OBJECTIVE: To describe the characteristics of a large cohort of patients with MMP. METHODS: A retrospective review of clinical and diagnostic characteristics as well as treatment responses in 145 patients with MMP. RESULTS: Monosite involvement was seen in 41.4% and multisite involvement in 58.6% of the patients. The oral mucosa was affected in 86.9% of the patients, followed by the ocular mucosa (30.3%), skin (26.2%), genital mucosa (25.5%), nasal mucosa (23.4%), and pharyngeal and/or laryngeal mucosa (17.2%). Ocular disease developed during the disease course in 41.7% of patients with initially other mucosal site involvement. The malignancy rate was significantly higher in patients with autoantibodies against laminin-332 than in patients with MMP without laminin-332 autoantibodies (35.3% vs 10.9%, respectively; P = .007). Systemic immunosuppressive or immunomodulatory therapy was administered to 77.1% of the patients, mainly to patients with multisite (P < .001), ocular (P < .001), and pharyngeal and laryngeal involvement (P = .002). The remaining patients (22.9%) received topical therapy. Adverse events were frequently reported. LIMITATIONS: Retrospective design. CONCLUSION: Patients with MMP present with a heterogeneous clinical presentation, and new symptoms may develop during the disease course. Cancer screening should be considered for patients with MMP and, in particular, for those with autoantibodies against laminin-332.

Use of Convolutional Neural Networks for the Detection of u-Serrated Patterns in Direct Immunofluorescence Images to Facilitate the Diagnosis of Epidermolysis Bullosa Acquisita.

The u-serrated immunodeposition pattern in direct immunofluorescence (DIF) microscopy is a recognizable feature and confirmative for the diagnosis of epidermolysis bullosa acquisita (EBA). Due to unfamiliarity with serrated patterns, serration pattern recognition is still of limited use in routine DIF microscopy. The objective of this study was to investigate the feasibility of using convolutional neural networks (CNNs) for the recognition of u-serrated patterns that can assist in the diagnosis of EBA. The nine most commonly used CNNs were trained and validated by using 220,800 manually delineated DIF image patches from 106 images of 46 different patients. The data set was split into 10 subsets: nine training subsets from 42 patients to train CNNs and the last subset from the remaining four patients for a validation data set of diagnostic accuracy. This process was repeated 10 times with a different subset used for validation. The best-performing CNN achieved a specificity of 89.3% and a corresponding sensitivity of 89.3% in the classification of u-serrated DIF image patches, an expert level of diagnostic accuracy. Experiments and results show the effectiveness of CNN approaches for u-serrated pattern recognition with a high accuracy. The proposed approach can assist clinicians and pathologists in recognition of u-serrated patterns in DIF images and facilitate the diagnosis of EBA.

Assessment of Diagnostic Strategy for Mucous Membrane Pemphigoid.

IMPORTANCE: An accurate diagnosis of mucous membrane pemphigoid (MMP) is essential to reduce diagnostic and therapeutic delay. OBJECTIVE: To assess the diagnostic accuracy of direct immunofluorescence microscopy on mucosal biopsy specimens and immunoserology in a large cohort of patients with suspected MMP. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was carried out in a single tertiary care center for blistering diseases between January 2002 and March 2019. Eligible participants were patients with suspected MMP and paired data on at least a mucosal biopsy specimen for direct immunofluorescence microscopy (DIF) and indirect immunofluorescence microscopy (IIF) on a human salt-split skin substrate (SSS). In addition, an optional DIF test on a skin biopsy specimen and one or more performed routine immunoserologic tests were analyzed. Data analysis was conducted from April 2019, to June 2020. MAIN OUTCOMES AND MEASURES: Diagnostic accuracy of DIF, IIF SSS, and immunoblot for BP180 and BP230. RESULTS: Of the 787 participants, 121 (15.4%) received the diagnosis of MMP (50 men [41.3%], 71 women [58.7%]; mean [SD] age at diagnosis, 60.1 [17.7] years). Sixty-seven of the patients with MMP (55.4%) had monosite involvement, of which oral site was the most frequently affected (51 [42.1%]). No significant difference was found between the sensitivity of DIF on a perilesional buccal biopsy and a normal buccal biopsy (89.3% vs 76.7%). Three patients with solitary ocular involvement showed a positive DIF of only the oral mucosa. In 6 patients with a negative mucosal DIF, a skin biopsy confirmed diagnosis of MMP. Overall, IIF SSS was less sensitive (44.6%), but highly specific (98.9%). The sensitivity of immunoblot (66.1%) was higher compared to SSS, but with lower specificity (91.3%). CONCLUSIONS AND RELEVANCE: This comparative diagnostic accuracy study of a cohort of 787 patients found a high sensitivity of a mucosal DIF biopsy for diagnosis of MMP, and lower sensitivity of serologic analysis. A biopsy can be taken from either perilesional or normal buccal mucosa. An additional DIF biopsy of another mucosal site or of affected or unaffected skin may increase the diagnostic yield and is recommended in patients with negative DIF results and high clinical suspicion.

An Unexpected Case of Late Fatal Central Venous Catheter Sepsis: A Case Report.

Introduction Central venous catheters (CVC) are associated with risks and complications. Complications like vessel perforation, thrombosis, infection with significant morbidity and mortality, knotting, and ventricular perforation have been described. Another less-frequent complication is retained CVC fragments. We present a case of a very late but fatal complication after a CVC placement. This report is written in line with the consensus-based surgical case report guidelines (SCARE). Case A 46-year-old male presented to the emergency department in a critical (septic) shock. The patients' medical history featured a long-intensive care admission 28 years ago. The cause of this sepsis was not evident until a computed tomography scan was performed to exclude a pulmonary embolism, revealing a remnant of a central catheter in both pulmonary arteries. Despite extensive resuscitation, the patient died within 24 hours after admission. An autopsy was performed confirming that the catheter remnant was the only possible cause of the fatal sepsis. Discussion CVC's are associated with (fatal) complications; however, retainment of remnants are described unfrequently but do occur in almost 2% of the cases. Endovascular removal of these remnants has been performed successfully and should be the first treatment of choice if removal is considered. No evidence is available that suggests that routine removal has to be attempted but some longer term complications can be expected, so awareness of possible remnants after CVC removal should exist. Conclusion Retained fragments of CVC's are rare but are described after prolonged use. This case shows that these retained intravascular fragments can cause fatal complications on the long-term. Upon removal of CVC's, there should be awareness that retainment of fragments can occur.

Oral Lesions in Autoimmune Bullous Diseases: An Overview of Clinical Characteristics and Diagnostic Algorithm.

Autoimmune bullous diseases are a group of chronic inflammatory disorders caused by autoantibodies targeted against structural proteins of the desmosomal and hemidesmosomal plaques in the skin and mucosa, leading to intra-epithelial or subepithelial blistering. The oral mucosa is frequently affected in these diseases, in particular, in mucous membrane pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus. The clinical symptoms are heterogeneous and may present with erythema, blisters, erosions, and ulcers localized anywhere on the oral mucosa, and lead to severe complaints for the patients including pain, dysphagia, and foetor. Therefore, a quick and proper diagnosis with adequate treatment is needed. Clinical presentations of autoimmune bullous diseases often overlap and diagnosis cannot be made based on clinical features alone. Immunodiagnostic tests are of great importance in differentiating between the different diseases. Direct immunofluorescence microscopy shows depositions of autoantibodies along the epithelial basement membrane zone in mucous membrane pemphigoid subtypes, or depositions on the epithelial cell surface in pemphigus variants. Additional immunoserological tests are useful to discriminate between the different subtypes of pemphigoid, and are essential to differentiate between pemphigus and paraneoplastic pemphigus. This review gives an overview of the clinical characteristics of oral lesions and the diagnostic procedures in autoimmune blistering diseases, and provides a diagnostic algorithm for daily practice.

Nonbullous pemphigoid: Insights in clinical and diagnostic findings, treatment responses, and prognosis.

BACKGROUND: Nonbullous pemphigoid is an under-recognized phenotype of the autoimmune bullous disease pemphigoid, characterized by the absence of blisters. Several disease aspects have not been studied previously. OBJECTIVE: To describe the characteristics of nonbullous pemphigoid. METHODS: A retrospective review study of medical records. The diagnosis of pemphigoid was based on meeting 2 of the following 3 criteria: (1) pruritus, (2) positive direct immunofluorescence microscopy, or (3) positive indirect immunofluorescence microscopy on salt-split skin. RESULTS: The review included 69 patients. The mean delay in diagnosis was 29 months. Skin examination most often showed pruritic papules/nodules (37%) or pruritus without primary skin lesions (22%). Histopathologic findings were mainly nonspecific. Results of direct and indirect immunofluorescence microscopy were positive in 60% and 69%, respectively. During follow-up, blisters formed in 17%, which was associated with a positive indirect immunofluorescence microscopy (P = .014) and a positive BP180 immunoblot result (P = .032). The Kaplan-Meier estimates of mortality at 1, 2, and 3 years were 14%, 34%, and 46%, respectively, with an 8.6-fold increased all-cause mortality risk. LIMITATIONS: The retrospective study design. CONCLUSIONS: Nonbullous pemphigoid presented with heterogeneous pruritic skin lesions, resulting in delayed diagnosis. Direct and indirect immunofluorescence microscopy are essential to diagnose nonbullous pemphigoid, in contrast to histopathology, mainly showing nonspecific findings. An increased all-cause mortality risk was observed during follow-up.

Assessment of Diagnostic Strategy for Early Recognition of Bullous and Nonbullous Variants of Pemphigoid.

Importance: A substantial number of patients with bullous pemphigoid do not develop skin blisters and may not have received the correct diagnosis. Diagnostic criteria and an optimal diagnostic strategy are needed for early recognition and trials. Objectives: To assess the minimal requirements for diagnosis of bullous and nonbullous forms of pemphigoid and to evaluate the optimal diagnostic strategy. Design, Setting, and Participants: This paired, multivariable, diagnostic accuracy study analyzed data from 1125 consecutive patients with suspected pemphigoid who were referred to the Groningen Center for Blistering Diseases from secondary and tertiary care hospitals throughout the Netherlands. Eligible participants were patients with paired data on at least (1) a skin biopsy specimen for the direct immunofluorescence (DIF) microscopy test; (2) indirect immunofluorescence on a human salt-split skin substrate (IIF SSS) test; and (3) 1 or more routine immunoserologic tests administered between January 1, 2002, and May 1, 2015. Samples were taken from patients at the time of first diagnosis, before introduction of immunosuppressive therapy, and within an inclusion window of a maximum of 4 weeks. Data analysis was conducted from October 1, 2015, to December 1, 2017. Main Outcomes and Measures: Pairwise DIF, IIF SSS, IIF on monkey esophagus, BP180 and BP230 enzyme-linked immunosorbent assays, and immunoblot for BP180 and BP230 tests were performed. The results were reported in accordance with 2015 version of the Standards for Reporting Diagnostic Accuracy. Results: Of the 1125 patients analyzed, 653 (58.0%) were women and 472 (42.0%) were men, with a mean (SD) age of 63.2 (19.9) years. In total, 343 participants received a pemphigoid diagnosis, with 782 controls. Of the 343 patients, 74 (21.6%, or 1 in 5) presented with nonbullous pemphigoid. The DIF microscopy was the most sensitive diagnostic test (88.3% [n = 303]; 95% CI, 84.5%-91.3%), whereas IIF SSS was less sensitive (77.0% [n = 263]; 95% CI, 72.2%-81.1%) but was highly specific (99.9%; 95% CI, 99.3%-100%) and complemented most cases with negative DIF findings. Results of the BP180 NC16A enzyme-linked immunosorbent assay did not add diagnostic value for initial diagnosis in multivariable logistic regression analysis of combined tests. These findings lead to the proposed minimal criteria for diagnosing pemphigoid: (1) pruritus and/or predominant cutaneous blisters, (2) linear IgG and/or C3c deposits (in an n-serrated pattern) by DIF on a skin biopsy specimen, and (3) positive epidermal side staining of IgG by IIF SSS on a serum sample; this proposal extends bullous pemphigoid with the unrecognized nonbullous form. Conclusions and Relevance: Both DIF and IIF SSS tests should be performed for diagnosis of the bullous and nonbullous variants of pemphigoid, and the BP180 NC16A enzyme-linked immunosorbent assay is recommended as an add-on test for disease activity monitoring.

Detection of u-serrated patterns in direct immunofluorescence images of autoimmune bullous diseases by inhibition-augmented COSFIRE filters.

Direct immunofluorescence (DIF) microscopy of a skin biopsy is used by physicians and pathologists to diagnose autoimmune bullous dermatoses (AIBD). This technique is the reference standard for diagnosis of AIBD, which is used worldwide in medical laboratories. For diagnosis of subepidermal AIBD (sAIBD), two different types of serrated pattern of immunodepositions can be recognized from DIF images, namely n- and u-serrated patterns. The n-serrated pattern is typically found in the most common sAIBD bullous pemphigoid. Presence of the u-serrated pattern indicates the sAIBD subtype epidermolysis bullosa acquisita (EBA), which has a different prognosis and requires a different treatment. The manual identification of these serrated patterns is learnable but challenging. We propose an automatic technique that is able to localize u-serrated patterns for automated computer-assisted diagnosis of EBA. The distinctive feature of u-serrated patterns as compared to n-serrated patterns is the presence of ridge-endings. We introduce a novel ridge-ending detector which uses inhibition-augmented trainable COSFIRE filters. Then, we apply a hierarchical clustering approach to detect the suspicious u-serrated patterns from the detected ridge-endings. For each detected u-serrated pattern we provide a score that indicates the reliability of its detection. In order to evaluate the proposed approach, we created a data set with 180 DIF images for serration pattern analysis. This data set consists of seven subsets which were obtained from various biopsy samples under different conditions. We achieve an average recognition rate of 82.2% of the u-serrated pattern on these 180 DIF images, which is comparable to the recognition rate achieved by experienced medical doctors and pathologists.

Introducing high-flow nasal cannula oxygen therapy at the intermediate care unit: expanding the range of supportive pulmonary care.

BACKGROUND: Non-invasive respiratory support is a frequent indication for intermediate care unit (IMCU) admission. Extending the possibilities of respiratory support at the IMCU with high-flow nasal cannula oxygen therapy (HFNC) may prevent intensive care unit (ICU) transfer and invasive ventilation. However, the safety and limitations of HFNC administration in the stand-alone IMCU setting are not yet studied. This study therefore aims to investigate to what extent and in which patients HFNC can safely be administered at a stand-alone mixed surgical IMCU. METHODS: A case series, using retrospectively collected data, was performed after the first year of introducing HFNC at a stand-alone IMCU. The following variables were collected: indication to start HFNC, vital parameters and arterial blood gas measurements. Primary outcome was 30-day mortality. Secondary outcome was transfer to the ICU. RESULTS: A total of 96 admissions were included. The indications to start HFNC at the IMCU were predominantly pathologies of pulmonary origin (n=67, 69.8%). Less frequent indications were prolonged support postweaning (n=15), non-pulmonary sepsis (n=7) and post-trauma resuscitation (n=6). The average PaO2/FiO2ratio at start of HFNC was 152 (95% CI 139 to 165). 30-day mortality was 7, of which 5 were admitted with treatment restrictions (no ICU policy) and 2 deaths were unrelated to HFNC. Transfer to the ICU occurred in 18 (18.8%) admissions, of which 12 received invasive mechanical ventilation. Reason for ICU transfer was mainly PaO2/FiO2 ratio<100 under maximum non-invasive treatment (n=12, 66.7%). Application of HFNC at the IMCU prevented 162 days of ICU admission. DISCUSSION: Administration of HFNC at a stand-alone surgical IMCU may be safe as it expands the range of supportive possibilities and thereby reduces the need for ICU admissions. Pulmonary indications to start HFNC increase the risk of ICU transfer and mechanical ventilation. LEVEL OF EVIDENCE: Level VI.

Allergic contact dermatitis caused by dimethylthiocarbamylbenzothiazole sulfide (DMTBS) in canvas shoes: in search of the culprit allergen.

BACKGROUND: During rubber vulcanization, new compounds can be formed. OBJECTIVES: To report a case of allergic shoe dermatitis in which the search for the allergen ultimately led to the identification of dimethylthiocarbamylbenzothiazole sulfide (DMTBS). METHODS: A female presented with eczema on her feet after wearing Sperry Top Sider® canvas sneakers. Patch testing was performed with the European baseline series, additional series, shoe materials, and extracts of shoe materials. Thin-layer chromatography (TLC) was performed for additional patch testing, and high-performance liquid chromatography and gas chromatography-mass spectometry were used for chemical analysis. RESULTS: Positive reactions were found to thiuram mix (+), tetramethylthiuram monosulfide (TMTM) (+), shoe material (+), and shoe extracts in eth. (++) and acetone (+). The extracts did not contain TMTM or other components of thiuram mix. TLC strips yielded a positive reaction (+) to one spot, whereas chemical analysis gave a negative result. Thereafter, a similar sneaker from another patient with shoe dermatitis was analysed, and DMBTS was identified. New extracts of the shoe of our first patient were then also shown to contain DMTBS. DMTBS as culprit allergen was confirmed by positive patch testing with a dilution series with DMTBS. CONCLUSION: DMBTS was identified as the culprit allergen in shoe dermatitis, giving rise to compound allergy. The positive reaction to TMTM was considered to represent cross-reactivity.