The changing epidemiology of human leishmaniasis in the non-endemic country of Austria between 2000 to 2021, including a congenital case.

BACKGROUND: Leishmaniasis is caused by infection with intracellular protozoans of the genus Leishmania. Transmission occurs predominantly by the bite of phlebotomine sandflies, other routes, including congenital transmission, are rare. The disease manifests as either cutaneous, visceral or mucosal/mucocutaneous leishmaniasis. In recent years, changes in the epidemiological pattern have been reported from Europe. PRINCIPAL FINDINGS: A total of 311 new and 29 published leishmaniasis cases occurring between 01/01/2000 and 12/31/2021 in Austria were collected and analyzed. These encompassed 146 cutaneous (CL), 14 visceral (VL), 4 mucosal, and 3 cases with concurrent VL and CL. In addition, asymptomatic infections, comprising 11 unspecified cases with Leishmania DNA detectable only in the blood and 162 cases with anti-Leishmania antibodies were reported. Particularly since 2016, the incidence of leishmaniasis has steadily risen, mainly attributable to increasing numbers of CL and cases with positive serology against Leishmania species, whereas the incidence of VL has slowly decreased. Analysis revealed that a shift in the causative species spectrum had occurred and that a substantial number of CL cases were caused by members of the Leishmania donovani/infantum complex. Simultaneous occurrence of VL and CL was identified in immunocompromised individuals, but also in a not yet reported case of an immunocompetent child after vertical transmission. CONCLUSIONS: The incidence of leishmaniasis has risen in the recent years. The numbers are anticipated to keep rising due to increasing human mobility, including travel and forced migration, growing reservoir host populations as well as expansion and dispersal of vector species caused by climate and habitat changes, urbanization and globalization. Hence, elevated awareness for the disease, including possible transmission in previously non-endemic regions and non-vector transmission modes, support of sandfly surveillance efforts and implementation and establishment of public health interventions in a One Health approach are pivotal in the global efforts to control and reduce leishmaniasis.

Human dirofilariosis in Austria: the past, the present, the future.

BACKGROUND: Dirofilariosis is a vector-borne parasitosis caused by filarial nematodes of the genus Dirofilaria. In humans, who represent accidental hosts, dirofilariosis is mostly caused by Dirofilaria repens and Dirofilaria immitis. In Austria, the first reported case occurred in 1978. Since then, several (case) reports have been published. METHODS: A systematic and retrospective review of collected published cases and new, unpublished confirmed cases of human dirofilariosis occurring in Austria was performed. A nematode was extracted from the eyelid of a previously unreported case and subsequently characterized histologically and using molecular biology techniques. RESULTS: Data on a total of 39 cases of human dirofilariosis in Austria occurring between 1978 and 2020 are summarized. Over the past four decades the incidence has markedly increased, in particular after 1998. Of the 39 patients, men and women were equally affected, and the mean age was 47.1 years. The area most frequently affected was the head (38.5% of cases). Confined ocular involvement was observed in 23.1% of cases, and nematodes were isolated from the neck/trunk, extremities and the genito-inguinal area in 25.6, 15.4 and 15.4% of patients, respectively. Microfilariae were detected in two cases. Of the 39 patients, only 73.9% tested positive for anti-filarial antibodies and 56.3% for eosinophilia, despite successful isolation of a nematode; consequently, these measures did not represent reliable markers for dirofilariosis. Most patients had a travel history to countries endemic for Dirofilaria species. One patient who had not traveled abroad represented the only autochthonous case recorded to date. Dirofilaria repens was the predominant species, identified in 89.7% of cases. In the newly reported case of subcutaneous dirofilariosis, a live non-gravid Dirofilaria repens adult female of 12 cm length was isolated from the eyelid of the patient, and a video of the extraction is provided. CONCLUSIONS: The incidence of human dirofilariosis cases has increased strikingly over the last four decades in Austria. More cases can be expected in the foreseeable future due to changes in human behavior and (travel) activities as well as climate changes and the associated alterations in the availability of the natural reservoir, the vectors and the intrinsic characteristics of the parasite.

Hypopyon sign as an unusual complication of varicella infection in a girl with atopic dermatitis.

Varicella-zoster virus (VZV) infection, also known as chickenpox, is a common childhood affliction. Generalized small itchy single-standing vesicles on erythematous skin are typical. Both cutaneous and systemic complications of the VZV infection may commonly occur. A three-year-old girl with a previous history of mild atopic dermatitis presented in our Pediatric Dermatology Clinic in poor general condition, with a skin rash predominantly consisting of generalized large blisters with hypopyon sign and erosions. On a closer look, scattered erythematous papules and vesicles were also visible. A positive Tzanck smear from an intact pinhead-sized vesicle and VZV PCR confirmed the clinical diagnosis of chickenpox. Cultures from hypopyon material revealed Staphylococcus aureus superinfection. We report an exceptional, not-yet described complication of chickenpox with hypopyon-forming superinfection in an atopic child. In addition, our case nicely underscores the necessity of early VZV vaccination, which has been available and recommended now for more than 10 years in pediatric vaccination programs to avoid severe complications.

Kombinierte Hoch-/Niedrig-Dosis-Therapie mit systemischen Glukokor-tikoiden bei schweren Verlaufsformen der Alopecia areata im Kindesalter.

HINTERGRUND: Schwere Verlaufsformen der Alopecia areata (AA) im Kindesalter sind aufgrund limitierter Optionen therapeutisch herausfordernd. Systemische, hochdosierte Glukokortikoide weisen die schnellste Ansprechrate auf, nach dem Absetzen kommt es allerdings zu Rezidiven. Eine längerfristige Hochdosis-Anwendung ist aufgrund der zu erwartenden Nebenwirkungen nicht empfehlenswert. Eine dauerhafte Steroiderhaltungstherapie unterhalb der Cushing-Schwellen-Dosis nach Bolustherapie könnte die Krankheitsaktivität ohne Nebenwirkungen längerfristig unterdrücken. PATIENTEN UND METHODIK: Im Rahmen einer offenen Anwendungsbeobachtung wurden 13 Kinder mit schweren Formen der AA in diese Studie eingeschlossen. Bei sieben Kindern lag eine AA totalis/universalis vor, bei sechs eine multifokale AA mit Befall von mehr als 50 % der Kopfhaut. Das Therapieregime sah eine initiale Prednisolon-Dosierung von 2 mg/kg Körpergeweicht (KG) vor und wurde innerhalb von neun Wochen auf eine Erhaltungsdosierung unter der individuellen Cushing-Schwelle reduziert. Der Nachbeobachtungszeitraum betrug ein bis drei Jahre. ERGEBNISSE: Wir beobachteten in 62 % aller Fälle ein komplettes Nachwachsen der Haare. Die mittlere Dauer bis zum Ansprechen lag bei 6,6 Wochen und konnte mit der Erhaltungstherapie über den gesamten Beobachtungszeitraum aufrechterhalten werden. An Nebenwirkungen wurden ausschließlich eine Gewichtszunahme (1-3 kg) bei allen Behandelten sowie eine milde Steroidakne in 23 % der Fälle beobachtet. SCHLUSSFOLGERUNGEN: Die kombinierte Hoch-/Niedrig-Dosis-Therapie mit systemischen Glukokortikoiden mittels Prednisolon zeigte eine hohe, dauerhafte Ansprechrate ohne signifikante Nebenwirkungen.

Sequential high- and low-dose systemic corticosteroid therapy for severe childhood alopecia areata.

BACKGROUND: Given the limited number of therapeutic options, severe childhood alopecia areata (AA) poses a clinical challenge. The best and most rapid response rates can be achieved with high-dose systemic corticosteroids, however, relapse following treatment discontinuation is inevitable. Due to systemic side effects, long-term high-dose corticosteroid regimens are not feasible. Following initial pulse therapy, continuation of corticosteroid therapy at a dose below the Cushing threshold might be able to suppress disease activity without causing severe side effects. PATIENTS AND METHODS: Thirteen children with severe AA were enrolled in our open observational study. Seven had alopecia totalis or universalis; the remaining six children had multifocal alopecia affecting more than 50 % of the scalp. The treatment regimen consisted of initial pulse therapy with prednisolone 2 mg/kg PO, which was subsequently tapered to a maintenance dose below the individual Cushing threshold within nine weeks. Children were followed-up for one to three years. RESULTS: Sixty-two percent of individuals showed complete hair regrowth. The mean time to response was 6.6 weeks. Said response was sustained with maintenance therapy for the entire follow-up period. Noticeable side effects included weight gain (1-3 kg), which was observed in all children, and mild steroid acne in 23 % of cases. CONCLUSIONS: Sequential high- and low-dose prednisolone therapy is an effective and safe therapeutic option for childhood AA.

T cells co-producing Mycobacterium tuberculosis-specific type 1 cytokines for the diagnosis of latent tuberculosis.

Patients treated with tumor necrosis factor (TNF)-alpha-antagonizing medication are at increased risk of developing active tuberculosis (TB), brought about mainly by reactivation of latent infection. Thus, screening for latent TB infection (LTBI) prior to administration of anti-TNF-alpha-therapy is required. For a long time, the tuberculin skin test (TST) was the only means of diagnosing LTBI, however, interferon-gamma-release assays (IGRAs), are promising new tools. Fifty two patients with dermatological disorders were included prior to implementation of anti-TNF-alpha therapy. Mycobacterium tuberculosis (MTB)-specific cytokine production, including interferon (IFN)-gamma, TNF-alpha, interleukin (IL)-2 and IL-10, was measured in CD4+ and CD8+ T cells by cytokine flow cytometry following stimulation of peripheral blood mononuclear cells (PBMC) with purified protein derivative (PPD) and early secretion antigenic target (ESAT)-6. Simultaneously, a TST was administered and 11 were TST-positive. Generally, MTB-specific IFN-gamma produced by CD4+ T cells correlated well with TST results. CD4+ T cells co-producing specific IFN-gamma and TNF-alpha after ESAT-6 stimulation showed the highest overall agreement with the TST (Kappa [kappa] = 0.87). Each single cytokine displayed individual patterns, the expression of IFN-gamma, however, showed the highest concordance with the TST (kappa = 0.82). This suggests that the enumeration of MTB-specific CD4+ T cells might introduce greater specificity for the diagnosis of latent TB, compared to the TST.

De novo tuberculosis during infliximab therapy in a patient with Behçet disease.

A woman with oculocutaneous Behçet disease developed primary tuberculosis while being treated with infliximab. A latent tuberculosis infection had been excluded before therapy. After more than 80 weeks of treatment, the patient complained of fevers, night sweats, shivering and vigorous cough. The chest x-ray showed miliary shadowing. Mycobacterium tuberculosis was identified. The history revealed recent contact to an individual with smear-positive tuberculosis. This constellation speaks in favor of a de novo tuberculosis infection with a fulminant course.

Fatal paraneoplastic pemphigus associated with a mediastinal tumor.

Paraneoplastic pemphigus (PNP) is a rare life-threatening autoimmune bullous skin disease which is an obligate paraneoplasma. A 34-year-old woman presented with recalcitrant stomatitis and a generalized lichenoid rash. A diagnosis of PNP was established based on clinical findings, immunofluorescence, histopathology and biochemistry. A localized mediastinal mass was found with CT imaging and excised. The histologic diagnosis was dendritic cell sarcoma. Despite removal of tumor and immunosuppressive therapy, the PNP progressed rapidly and the patient died of septic multiorgan failure.

Autoantibodies to the translational suppressors T cell intracytoplasmic antigen 1 and T cell intracytoplasmic antigen 1-related protein in patients with rheumatic diseases: increased prevalence in systemic lupus erythematosus and systemic sclerosis and correlation with clinical features.

OBJECTIVE: T cell intracytoplasmic antigen 1 (TIA-1) and TIA-1-related protein (TIAR) are involved in posttranscriptional regulation of the expression of tumor necrosis factor alpha (TNFalpha) and other proteins. Given the pivotal role of TNFalpha in chronic inflammatory diseases, this study was undertaken to analyze sera from patients with systemic autoimmune diseases for the presence of autoantibodies to TIA proteins and to investigate the expression of these proteins in inflamed tissue. METHODS: The presence of autoantibodies to TIA proteins in sera from 385 patients with rheumatic diseases and healthy controls was determined by immunoblotting using recombinant antigens. Expression of TIA proteins in skin and kidney tissue was analyzed by immunohistochemistry. Serum levels of TNFalpha were measured by enzyme-linked immunosorbent assay. RESULTS: Autoantibodies to TIA-1 and/or TIAR were detected in 61% of patients with systemic lupus erythematosus (SLE), 42% of patients with systemic sclerosis (SSc), 15-31% of patients with other rheumatic diseases, and 6% of healthy controls. Compared with patients negative for anti-TIA antibody, anti-TIA antibody-positive SLE patients had higher disease activity (P = 0.01), elevated antibodies to double-stranded DNA (P = 0.0003), and increased serum TNFalpha levels (P = 0.018). In SLE patients, anti-TIAR antibodies were associated with lupus nephritis (P = 0.02), while in patients with SSc, anti-TIA-1 was associated with lung involvement (P = 0.02). Immunohistochemical analysis of skin and kidney tissue revealed aberrant expression of TIA proteins in skin lesions from SLE and SSc patients, as well as in glomerular cells from SLE patients. CONCLUSION: Aberrant expression of TIA proteins in inflammatory tissue may lead to systemic autoantibody responses, particularly in SLE and SSc. Increased occurrence of anti-TIA autoantibodies in patients with severe organ involvement may point to a possible pathogenetic role.

Recommendations for the use of rituximab (anti-CD20 antibody) in the treatment of autoimmune bullous skin diseases.

Autoimmune bullous skin disorders are induced by autoantibodies against distinct adhesion complexes of the epidermal and dermal-epidermal junction. Since most of these disorders are characterized by a severe, potentially lethal course,they require long-term immunosuppressive treatment to reduce the de novo synthesis of pathogenic autoantibodies by B lymphocytes. Rituximab, a chimeric monoclonal antibody against CD20 on B lymphocytes, has shown promise in several case reports or cohort studies in the treatment of paraneo-plastic pemphigus,refractory cases of pemphigus vulgaris and foliaceus and in other autoimmune bullous disorders. Treatment with rituximab leads to depletion of pathogenic B-cells which may last up to 12 months resulting in a reduction of plasma cells secreting pathogenic autoantibodies. Rituximab is usually administered in an adjuvant setting at a dose of 375 mg/m(2) i.v.in weekly intervals for four consecutive weeks in addition to the standard immunosuppressive treatment. The present consensus statement of German-speaking dermatologists, rheumatologists and oncologists summarizes and evaluates the current evidence for the use and mode of application of rituximab in autoimmune bullous skin disorders.

Combination of an EGFR blocker and a COX-2 inhibitor for the treatment of advanced cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers worldwide. Epidermal growth factor receptor (EGFR) is expressed at the cell surface by more than 90% of SCCs and its activation is responsible for cell cycle progression, proliferation, survival, angiogenesis and metastasis. Cyclooxygenase-2 (COX-2) is an enzyme up-regulated through EGFR signaling and responsible for some of the EGFR-dependent biological effects. An 88-year-old man presented with a recurrent, locoregionally meta-static SCC of the right parietal region, which was resistant to radiotherapy. With a combination therapy of an EGFR blocker (cetuximab) and a COX-2 inhibitor (celecoxib), the tumor regressed partially and the patient's Karnofsky index improved. We speculate that the combined use of cetuximab and COX-2 inhibitors can be a new and effective therapy for advanced and recurrent cutaneous SCCs.

Recommendations for the use of immunoapheresis in the treatment of autoimmune bullous diseases.

Despite the use of high-dose systemic corticosteroids in combination with other immunosuppressants, in some patients with autoimmune bullous diseases only insufficient improvement is achieved. In these cases and in acute severe disease, adjuvant immunoapheresis has been increasingly used. A consensus meeting was held in mid-2005 in Hamburg, aiming at developing guidelines for the use of immunoapheresis in the treatment of autoimmune bullous diseases. This paper summarizes the experts' recommendations.

Soluble FAS ligand: a discriminating feature between drug-induced skin eruptions and viral exanthemas.

The clinical spectrum of cutaneous eruptions comprises benign variants like maculopapular rashes (MPRs) and potentially life-threatening events such as toxic epidermal necrolysis (TEN). Apoptosis of keratinocytes is a common histopathological feature of all these drug eruptions. As in skin lesions of TEN and Stevens-Johnson syndrome patients, apoptosis of keratinocytes is often accompanied by an only sparse cellular infiltrate, a soluble fatty acid synthetase ligand (sFASL)-mediated mechanism of keratinocyte cell death is postulated. In MPR patients, evidence for the occurrence of a similar process could not be established so far. We therefore examined sera and lesional skin sections from patients with clinical variants of drug eruptions for FASL expression using a sandwich ELISA and immunohistochemistry, respectively. As controls, healthy persons and patients with other inflammatory skin diseases such as viral exanthema were analyzed. Elevated levels of FASL were detected not only in TEN patients but also in sera and lesional skin of patients with MPR. In contrast, sFASL was repeatedly negative in all viral exanthemas and healthy controls tested. Thus, determination of sFASL serum concentration may represent a discriminating tool between drug rashes and viral exanthemas.

IgA pemphigus--occurrence of anti-desmocollin 1 and anti-desmoglein 1 antibody reactivity in an individual patient.

BACKGROUND: IgA pemphigus is a rare pustular autoimmune disease with exclusive IgA anti-keratinocyte cell surface antibody reactivity. Two subtypes have been discerned: in the subcorneal pustular dermatosis type, desmocollin 1 has been identified as a targeted autoantigen, while in few cases of the intraepidermal neutrophilic type, IgA anti-desmoglein 1 or IgA anti-desmoglein 3 reactivity has been demonstrated. PATIENTS AND METHODS: A 48-year-old white male presented with generalized large confluent pustules. Skin pathology was assessed by histology and direct immunofluorescence analysis. IgG/IgA autoantibodies against desmoglein 1/3 and desmocollin 1 were measured by ELISA and indirect immunofluorescence using desmocollin 1 cDNA-transfected COS7 cells, respectively. RESULTS: Histopathology revealed subcorneal pustules and direct immunofluorescence microscopy exclusively showed in vivo bound IgA with an intercellular pattern in the epidermis. Desmocollin 1 was identified as a target of IgA autoantibodies by indirect immunofluorescence microscopy utilizing desmocollin 1 cDNA-transfected COS7 cells. In addition, IgA anti-desmoglein 1 reactivity was demonstrated by ELISA. Neither IgA anti-desmoglein 3 nor IgG anti-desmoglein 1/3 autoantibodies were present. CONCLUSIONS: Both desmocollin 1 and desmoglein 1 were autoantigens in this patient with IgA pemphigus and a distinct clinical presentation. To our knowledge, this is the first IgA pemphigus case with dual autoantibody reactivity.

Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants.

De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection and tumor metastasis. The cellular mechanisms of lymphangiogenesis in human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation. Donor-derived cells were detected by in situ hybridization of the Y chromosome. We compared these tissues with biopsies of essentially normal skin and intestine, and two rare carcinomas with low rates of lymphatic endothelial proliferation that were derived from individuals with gender-mismatched bone marrow transplants. Here, we provide evidence for the participation of recipient-derived lymphatic progenitor cells in renal transplants. In contrast, lymphatic vessels of normal tissues and those around post-transplant carcinomas did not incorporate donor-derived progenitors. This indicates a stepwise mechanism of inflammation-associated de novo lymphangiogenesis, implying that potential lymphatic progenitor cells derive from the circulation, transmigrate through the connective tissue stroma, presumably in the form of macrophages, and finally incorporate into the growing lymphatic vessel.

Transglutaminases as diagnostically relevant autoantigens in patients with gluten sensitivity.

BACKGROUND: Patients with gluten sensitivity, i. e. celiac disease and dermatitis herpetiformis have anti-endomysial antibodies recognizing transglutaminases, which are usually detected on appropriate tissue sections. It would be desirable to have available a reliable, tissue-independent serological diagnostic tool. We compared disease-specificity and sensitivity of tTG versus eTG-based detection systems for the diagnosis of anti-endomysial IgA-antibodies. PATIENTS AND METHODS: We examined 204 serum samples in duplicates with commercial human ELISA-kits: 54 healthy blood donors, 20 celiac disease, 29 dermatitis herpetiformis and 101 with other autoimmune dermatoses. RESULTS: The tTG-based ELISA proved to be very disease-specific (100 %) and sensitive for the diagnosis of gluten sensitivity (95 % celiac disease; 96.6 % dermatitis herpetiformis). The eTG-based ELISA was also perfectly specific (100 %), but only 15 % of celiac disease-sera and 44.8 % of dermatitis herpetiformis-sera yielded positive results. CONCLUSIONS: The human tTG-ELISA fulfills all criteria of a screening test and, because of being investigator-independent, inexpensive and highly reproducible, compares favorably with the current diagnostic gold standard (indirect immunofluorescence and biopsy) of celiac disease and dermatitis herpetiformis. The low sensitivity of the eTG-ELISA may have technical reasons, but could theoretically also be linked to disease activity or indicate the existence of an as yet undefined disease subset. Studies are currently under way to address these issues.

Unusual clinical manifestation of linear IgA dermatosis: a report of two cases.

Linear IgA dermatosis is a rare autoimmune bullous skin disease with subepidermal blister formation and linear IgA deposits along the basement membrane zone. We describe two female patients showing erythematous annular plaques with scaling at the margin, strictly localized to the palms in one patient, and also found on the soles and buttocks in the second patient. Histology showed numerous neutrophils in the dermis with an admixture of eosinophils, some subepidermal clefting, and occasional papillary microabscesses. Direct immunofluorescence and immunoelectron microscopy revealed in vivo IgA deposition along the basement membrane zone. One patient cleared after treatment with dapsone. The second patient did not respond to dapsone alone and various immunosuppressive treatment regimens. Considerable improvement was achieved with intravenous immunoglobulin therapy combined with corticosteroid and dapsone.