Cyclic-di-GMP Induces STING-Dependent ILC2 to ILC1 Shift During Innate Type 2 Lung Inflammation.

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during Alternaria and IL-33 exposure. Further, CD127-ST2-Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either Alternaria or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.

Alternaria alternata Accelerates Loss of Alveolar Macrophages and Promotes Lethal Influenza A Infection.

Chronic inhalation of fungi and fungal components has been linked to the development of respiratory disorders, although their role with respect to the pathogenesis of acute respiratory virus infection remains unclear. Here, we evaluate inflammatory pathology induced by repetitive administration of a filtrate of the ubiquitous fungus, Alternaria alternata, and its impact on susceptibility to infection with influenza A. We showed previously that A. alternata at the nasal mucosae resulted in increased susceptibility to an otherwise sublethal inoculum of influenza A in wild-type mice. Here we demonstrate that A. alternata-induced potentiation of influenza A infection was not dependent on fungal serine protease or ribonuclease activity. Repetitive challenge with A. alternata prior to virus infection resulted proinflammatory cytokines, neutrophil recruitment, and loss of alveolar macrophages to a degree that substantially exceeded that observed in response to influenza A infection alone. Concomitant administration of immunomodulatory Lactobacillus plantarum, a strategy shown previously to limit virus-induced inflammation in the airways, blocked the exaggerated lethal response. These observations promote an improved understanding of severe influenza infection with potential clinical relevance for individuals subjected to continuous exposure to molds and fungi.

Onset of disseminated cutaneous nodules following toe amputation in heart transplant patient.

Alternaria spp. infections are rare, but organ transplant recipients and immunosuppressed patients are particularly at risk of developing cutaneous alternariosis. Although cutaneous alternariosis is well-defined, instances of disseminated infection are exceedingly rare. We report a case of disseminated Alternaria infection in an immunocompromised patient from a primary focus of ungual phaeohyphomycosis.

Iatrogenic immunosuppression may favour Alternaria skin lesion flares.

Alternaria spp may cause opportunistic mycoses in the skin after cutaneous inoculation or through blood dissemination in immune-suppressed patients. Here, we describe a case of cutaneous infection with Alternaria spp in a 62-year-old man, presenting with multifocal papules and erythematous nodules involving distal limbs bilaterally. The absence of inflammatory bowel disease was confirmed by a gastroenterologist. The patient was under treatment for uveitis of unknown origin with immunosuppressive doses of cyclosporin and prednisolone for approximately 3 months. The diagnosis was based on clinical signs, demonstration of fungal elements in skin biopsies and deep fungal culture. Complete clinical remission was achieved by oral and systemic treatment with antifungal drugs. However, because cessation of the immunosuppressive medication was not possible, his clinical history was characterised by multiple flares requiring each time oral and intravenous antifungal treatment.

[A case of pulmonary alternariosis complicated with aspergillosis].

A 61-year-old woman with pulmonary alternariosis and aspergillosis was reported. The patient presented with recurrent hemoptysis and cough for 3 years. Alternaria was identified by fungal culture. Biopsy specimen showed pulmonary aspergillosis. The patient had been treated with voriconazole at 400 mg/d through intravenous guttae for 7 days, and then switched amphotericin B at 25 mg/d through intravenous guttae for 11 days. The patient was treated with voriconazole at 400 mg through oral when she was discharged from hospital. After the treatment, the clinical symptoms of hemoptysis and cough were recovered, and the lung CT examinations showed normal.

Molecular Identification of Cutaneous Alternariosis in a Renal Transplant Patient.

Cutaneous alternariosis is a rare condition, caused by an uncommon opportunistic pathogen. The most frequently affected individuals are immunosuppressed patients, e.g., organ transplant patients on immunosuppressive therapy. Clinical manifestations range from local skin lesions to disseminated disease. We present a case report of cutaneous alternariosis in a renal transplant recipient, confirmed by histological examination and molecular means. In addition, a review of the literature was performed.

Tzanck smear as an accurate and rapid diagnostic tool for cutaneous alternariosis in a renal transplant recipient.

Alternaria species are becoming increasingly important opportunistic pathogens in recipients of solid organ transplant, as it has been shown that dissemination with systemic involvement is not as rare as previously reported. Therefore, rapid and accurate diagnosis is necessary for appropriate patient management. We report a patient with renal transplant who developed recurrent cutaneous alternariosis. Tzanck smear successfully and very rapidly revealed hyphae and spores in both the primary and subsequent lesions. Furthermore, Tzanck smear provided guidance for histopathological examination of the second lesion, which failed to disclose the fungal elements until additional deeper serial sections were performed. The present case emphasizes that the Tzanck smear is a useful clinical tool leading to the immediate correct diagnosis even in deep fungal infections.

[Sinonasal fungal infections are not exclusively due to mucorales and Aspergillus!]. / Les infections fongiques nasosinusiennes ne sont pas uniquement liées aux mucorales et aux Aspergillus !

Rhino-sinusal infections are serious diseases and possibly lethal. When they are invasive, we easily discuss apergilloses and mucormycoses. The confirmation of the diagnosis of mucormycosis need an extensive surgery for precise histopathological and mycological evaluation. The pathologist may be faced to other rare mycoses such as phaeohyphomycoses, which present different morphological features than mucormycoses and Aspergillus. Once the diagnosis is established, an appropriate antifungal treatment is quickly started. The aim of our work is to report two observations of phaeohyphomycoses, to describe their histopathological features, to discuss complementary diagnostic methods and to present the main differential diagnoses.

Cutaneous alternariosis in an immunocompetent patient.

Alternaria species are a type of dematiaceous fungi that cause a wide spectrum of disease with cutaneous infections being the most common. These infections are most common in immunocompromised individuals. However, only a few cases of primary cutaneous alternariosis have been reported in immunocompetent patients. We present a case of an otherwise healthy 13-year-old male who presented with primary cutaneous alternariosis on his left ankle that responded to the use of topical econazole and oral itraconazole. We also provide a review of previously described cases of primary cutaneous alternariosis in the literature.

Unusual fungal sepsis of Alternaria alternata in acute lymphoblastic leukaemia in an adult patient.

We report a case of unusual fungal sepsis of Alternaria alternata in a patient of acute lymphoblastic leukaemia in 62-year-old male who presented with complaints of 'off and on' fever with decreased oral intake. On evaluation, haemogram showed low platelet count and 68% blast cells in peripheral blood. On flow cytometry of peripheral blood, the gated blasts (approximately 55%) highly express CD45, CD10, CD19, CD22 and condition was diagnosed as acute lymphoblastic leukaemia. He was started on standard induction treatment along with supportive therapies. During the course of treatment, two sets of paired blood cultures were sent 48 h apart. All of blood cultures were done on Bac-T alert 3D system. All of them yielded fungus. The fungus was then grown on Sabouraud's Dextrose agar media. It was identified as A. alternata. The patient condition worsened and later had cardiac arrest in ICU and could not be revived.

Cutaneous alternariosis in a renal transplant recipient: a case report and literature review.

Organ transplant recipients under immunosuppressive therapy have a highly increased risk of acquiring unusual opportunistic infections. Diagnosis of the etiology of infection may be difficult in clinical manifestations, which need further histological and biological investigations. We recently treated a male renal transplant recipient with a cutaneous phaeohyphomycosis due to Alternaria species. The diagnosis was based on microscopy and culture of the skin lesions. Treatment with oral itraconazole for 5 weeks was ineffective, then clinical improvement was achieved by combination of amphotericin B wet-packing and systemic antifungal therapy with oral voriconazole. Alternaria species are ubiquitous plant-inhabiting saprobes, which are increasingly associated with opportunistic phaeohyphomycosis in immunocompromised individuals. To the best of our knowledge, this is the second case report noting sporotrichoid pattern as the manifestation of cutaneous alternariosis. In this context, we reviewed recent renal-transplant-related cutaneous alternariosis reported in the English-language literature during 1995 to 2011 to summarize its clinical features and outcomes, and to guide clinicians in the care of kidney transplant patients with cutaneous alternariosis.

Alternaria alternata in a case of mass in the lung.

A 50-year-old woman, an agriculture worker with diabetes and asthma presented to us with complaints of fever with chills, cough with scanty, mucopurulent sputum and dull aching chest pain in right mammary area radiating to axilla. Chest X-ray and computed tomography scan revealed mass in the right lung. Ultrasound guided fine-needle aspiration cytology was done and the greenish fluid on direct wet mount and inoculation on Sabouraud's dextrose agar isolated Alternaria species. Serum specimen was evaluated for immunoglobulin E specific titres for Alternaria species which was high. Patient was treated with fluconazole for 6 weeks after which the symptoms disappeared and chest X-ray was normal.

A rare case of allergic bronchopulmonary mycosis caused by Alternaria alternata.

A rare case of allergic bronchopulmonary mycosis (ABPM), caused by Alternaria alternata, is reported in an immunocompetent resident of Delhi. Her complaints included a generalized, urticarial skin rash and occasional pain in the right lower chest. Her differential count showed eosinophils, 22%; absolute eosinophil count (AEC), 2400 cells/µl; and total IgE, 4007 IU/ml. The computerised tomogram (CT) scan of her thorax showed an enhancing lesion with surrounding ground glass haziness in the right lower lobe. Histopathologic examination of the resected lung revealed a necrotizing granulomatous inflammation, parenchymal infiltration by eosinophils, lymphocytes, neutrophils, plasma cells and some exudative bronchiolitis suggestive of ABPM. Observation of KOH wet mounts of repeat sputum and BAL samples demonstrated the presence of septate, brownish hyphae and cultures of these specimens yielded A. alternata (identified by sequencing of the ITS region). Her serum showed a three-fold higher specific IgE to A. alternata antigens than control levels, and the type I cutaneous hypersensitivity response to antigens of A. alternata was strongly positive. She was treated successfully with oral glucocorticoids and itraconazole. To our knowledge, ABPM due to Alternaria alternata has not been reported previously.