Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.

Deciphering Unexpected Vascular Locations of Scedosporium spp. and Lomentospora prolificans Fungal Infections, France.

Scedosporium spp. and Lomentospora prolificans are emerging non-Aspergillus filamentous fungi. The Scedosporiosis/lomentosporiosis Observational Study we previously conducted reported frequent fungal vascular involvement, including aortitis and peripheral arteritis. For this article, we reviewed 7 cases of Scedosporium spp. and L. prolificans arteritis from the Scedosporiosis/lomentosporiosis Observational Study and 13 cases from published literature. Underlying immunosuppression was reported in 70% (14/20) of case-patients, mainly those who had solid organ transplants (10/14). Osteoarticular localization of infection was observed in 50% (10/20) of cases; infections were frequently (7/10) contiguous with vascular infection sites. Scedosporium spp./Lomentospora prolificans infections were diagnosed in 9 of 20 patients ≈3 months after completing treatment for nonvascular scedosporiosis/lomentosporiosis. Aneurysms were found in 8/11 aortitis and 6/10 peripheral arteritis cases. Invasive fungal disease--related deaths were high (12/18 [67%]). The vascular tropism of Scedosporium spp. and L. prolificans indicates vascular imaging, such as computed tomography angiography, is needed to manage infections, especially for osteoarticular locations.

Tezepelumab for refractory eosinophilic granulomatosis with polyangiitis-related asthma.

Conventional immunosuppressants are ineffective for the management of EGPA-related asthma. Tezepelumab is a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TLSP) that has proven efficacy in several phase 3 studies for the treatment of asthma. We treated with off-label tezepelumab the first two patients with severe refractory EPGA-related asthma. These preliminary findings suggest that targeting upstream signaling of the T2 inflammatory pathway can improve symptoms, reduce BVAS and increase Asthma Control Test scores, even in patients with refractory asthma who have failed several previous lines of treatment. Nevertheless, by analogy with dupilumab-induced IL-4/13 blockade, the persistence of sputum eosinophilia (reported in both patients) raises questions as to whether TSLP inhibition could lead to a rebound of eosinophilia and potentially to eosinophil-related symptoms in patients with EGPA.

STAT3 mutation-associated airway epithelial defects in Job syndrome.

BACKGROUND: Job syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway infections. OBJECTIVES: Airway epithelial cells play a central role as the first line of defense against pathogenic infection and express high levels of STAT3. This study thus interrogates how AD-HIES STAT3 mutations impact the physiological functions of airway epithelial cells. METHODS: This study created human airway basal cells expressing 4 common AD-HIES STAT3 mutants (R382W, V463del, V637M, and Y657S). In addition, primary airway epithelial cells were isolated from a patient with Job syndrome who was harboring a STAT3-S560del mutation and from mice harboring a STAT3-V463del mutation. Cell proliferation, differentiation, barrier function, bacterial elimination, and innate immune responses to pathogenic infection were quantitatively analyzed. RESULTS: STAT3 mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells. As a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, AD-HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration in response to an experimental model of Pseudomonas aeruginosa infection. CONCLUSIONS: AD-HIES STAT3 mutations confer numerous abnormalities to airway epithelial cells in cell differentiation and host innate immunity, emphasizing their involvement in the pathogenesis of lung complications in Job syndrome. Therefore, therapies must address the epithelial defects as well as the previously noted immune cell defects to alleviate chronic infections in patients with Job syndrome.

Primary immunodeficiency diseases of adults: a review of pulmonary complication imaging findings.

Our objective in this review is to familiarize radiologists with the spectrum of initial and progressive CT manifestations of pulmonary complications observed in adult patients with primary immunodeficiency diseases, including primary antibody deficiency (PAD), hyper-IgE syndrome (HIES), and chronic granulomatous disease (CGD). In patients with PAD, recurrent pulmonary infections may lead to airway remodeling with bronchial wall-thickening, bronchiectasis, mucus-plugging, mosaic perfusion, and expiratory air-trapping. Interstitial lung disease associates pulmonary lymphoid hyperplasia, granulomatous inflammation, and organizing pneumonia and is called granulomatous-lymphocytic interstitial lung disease (GLILD). The CT features of GLILD are solid and semi-solid pulmonary nodules and areas of air space consolidation, reticular opacities, and lymphadenopathy. These features may overlap those of mucosa-associated lymphoid tissue (MALT) lymphoma, justifying biopsies. In patients with HIES, particularly the autosomal dominant type (Job syndrome), recurrent pyogenic infections lead to permanent lung damage. Secondary infections with aspergillus species develop in pre-existing pneumatocele and bronchiectasis areas, leading to chronic airway infection. The complete spectrum of CT pulmonary aspergillosis may be seen including aspergillomas, chronic cavitary pulmonary aspergillosis, allergic bronchopulmonary aspergillosis (ABPA)-like pattern, mixed pattern, and invasive. Patients with CGD present with recurrent bacterial and fungal infections leading to parenchymal scarring, traction bronchiectasis, cicatricial emphysema, airway remodeling, and mosaicism. Invasive aspergillosis, the major cause of mortality, manifests as single or multiple nodules, areas of airspace consolidation that may be complicated by abscess, empyema, or contiguous extension to the pleura or chest wall. CLINICAL RELEVANCE STATEMENT: Awareness of the imaging findings spectrum of pulmonary complications that can occur in adult patients with primary immunodeficiency diseases is important to minimize diagnostic delay and improve patient outcomes. KEY POINTS: • Unexplained bronchiectasis, associated or not with CT findings of obliterative bronchiolitis, should evoke a potential diagnosis of primary autoantibody deficiency. • The CT evidence of various patterns of aspergillosis developed in severe bronchiectasis or pneumatocele in a young adult characterizes the pulmonary complications of hyper-IgE syndrome. • In patients with chronic granulomatous disease, invasive aspergillosis is relatively frequent, often asymptomatic, and sometimes mimicking or associated with non-infectious inflammatory pulmonary lesions.

Rapid identification of fungi from respiratory samples by Bruker Biotyper matrix-assisted laser desorption/ionisation time-of-flight using ID-FUNGI plates.

Identification of moulds is crucial for the clinical management of patients. The goal of this study was to evaluate the new ID-FUNGI plate (IDFP) for the identification of moulds by MALDI Biotyper. IDFP was compared with Sabouraud with gentamicin and chloramphenicol plate (SAB) for the identification of 80 moulds from respiratory samples and eight reference strains. With the direct transfer method, species identification rose from 6% with SAB to 68% with IDFP using score cut-off 2 and from 20 to 75% using cut-off 1.7 (p < 0.001). Our study highlights that the new IDFP improves mycological diagnostic and workflow in laboratories.

Chloroquine Inhibits the Release of Inflammatory Cytokines by Human Lung Explants.

On human lung parenchymal explants, chloroquine concentration clinically achievable in the lung (100 µM) inhibited the lipopolysaccharide-induced release of TNF-ɑ (by 76%), IL-6 (by 68%), CCL2 (by 72%), and CCL3 (by 67%). Besides its antiviral activity, chloroquine might also mitigate the cytokine storm associated with severe pneumonia caused by coronaviruses.

Correction to: A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

The original version of the article contained error regarding the presentation of the institutional authors in the PDF and html versions.

Efficacy of immunoglobulin replacement therapy and azithromycin in severe asthma with antibody deficiency.

BACKGROUND: Although antibody deficiency (AD) is a well-known cause of recurrent respiratory infections, there are few data on its impact in adults with asthma. The objective of the present study was to assess outcomes in adults with severe asthma and AD after treatment with either azithromycin or subcutaneous immunoglobulins (SCIg). METHODS: We performed a 5-year, prospective, observational, two-centre study of adults with severe asthma and AD in France. Bronchiectasis was ruled out by high-resolution computed tomography. Patients were treated for one year with either azithromycin (250 mg every other day) or SCIg (0.4-0.6 g/kg/months, weekly). All patients were evaluated for exacerbations, asthma control and lung function at baseline and then one year after treatment initiation. RESULTS: Thirty-nine patients with severe asthma were included in the study: 14 had been treated with azithromycin and 25 had been treated with SCIg. Before the initiation of treatment for AD, all patients had an Asthma Control Questionnaire (ACQ-7) score > 1.5 (mean ± SD: 2.71 ± 0.53) despite treatment at GINA step 4 or 5, and had a high exacerbation rate requiring oral corticosteroids and/or rescue antibiotics (∼7.2 ± 2.1/patient/year). One year after treatment initiation, we observed a significantly higher FEV1 (mean: 0.18 ± 0.22 L) and ACQ-7 score (1.26 ± 0.68), and a significantly lower exacerbation rate (1.63 ± 1.24/patient/year). CONCLUSIONS: Treatment of AD dramatically improved asthma outcomes - suggesting that adults with severe asthma and recurrent respiratory infections should be screened and (if appropriate) treated for AD.

Aspergillus felis in Patient with Chronic Granulomatous Disease.

We report a case of Aspergillus felis infection in a patient with chronic granulomatous disease who had overlapping features of invasive pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Identifying the species responsible for aspergillosis by molecular methods can be crucial for directing patient management and selection of appropriate antifungal agents.