Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

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Hematopoietic cells are instrumental in generating and propagating protective inflammatory responses to infection or injury. However, excessive inflammation contributes to many diseases of the blood, bone marrow, and lymphatic system. We review three clinical categories of hematological inflammatory diseases in which recent clinical and translational advances have been made. The first category are monogenic inflammatory diseases. Genotype-driven research has revealed that previously mysterious diseases with protean manifestations are characterized by mutations which may be germline (e.g. deficiency of ADA2 or GATA2 deficiency) or somatic (e.g. VEXAS syndrome). The second category are the cytokine storm syndromes, including hemophagocytic lymphohistiocytosis and Castleman disease. Cytokine storm syndromes are characterized by excessive production of inflammatory cytokines including interleukin-6 and interferon-gamma, causing end-organ damage and high mortality. Finally, we review disorders associated with monoclonal and polyclonal hypergammaglobulinemia. The serum protein electrophoresis (SPEP) is typically ordered to screen for common diseases such as myeloma and humoral immunodeficiency. However, monoclonal and polyclonal hypergammaglobulinemia on SPEP can also provide important information in rare inflammatory diseases. For example, the autoinflammatory disease Schnitzler syndrome is notoriously difficult to diagnose. While this orphan disease has eluded precise genetic or histological characterization, the presence of a monoclonal paraprotein, typically IgM, is an obligate diagnostic criterion. Likewise, polyclonal hypergammaglobulinemia may be an important early, non-invasive diagnostic clue for patients presenting with rare neoplastic diseases such as Rosai-Dorfman disease and angioimmunoblastic T-cell lymphoma. Applying these three categories to patients with unexplained inflammatory syndromes can facilitate the diagnosis of rare and under-recognized diseases.

Background C1 inhibitor (C1-INH) and complement 4 (C4) have historically been referred to as positive acute phase reactants, however this has never been evaluated in hereditary angioedema (HAE) patients. Low function of C1-INH and low levels of C4 are important in the diagnosis of HAE type 1 and 2. If C1-INH and/or C4 are significant acute phase reactants, their levels may be falsely “normal” in patients with HAE when measured during times of infection or inflammation resulting in missed or delayed diagnosis. Case presentation We present a case series of four HAE patients who had C4, C1-INH, c-reactive protein (CRP) and ferritin measured at baseline and again during a self-reported upper respiratory tract infection (URTI) or flu-like illness. We did not identify any HAE patients who had a significant change in their C1-INH functional level in the context of a mild infection. However, the C4 level did increase into the normal range on three occasions (2 patients, with 1 patient having elevation during two separate illnesses). Conclusions C1 inhibitor may not be a clinically significant acute phase protein and appears to still be a reliable diagnostic marker of hereditary angioedema, even in times of modest acute inflammation, unlike complement C4 which can be elevated in this setting.

Background: Multiple animal antigens, spores and pollens were collected and identified from the Kuwaiti atmosphere. The role for these antigens in mediating allergic rhinitis for Kuwaiti residents needs to be evaluated. Objective: To investigate the causes (both indoors and outdoors) of allergic rhinitis for Kuwaiti residents. Method: This is a retrospective study of all positive skin tests that we obtained in our Allergy clinic in Mubarak Alkabeer Hospital in Kuwait, during the period between May 2013 and December 2015, from patients who presented with allergic rhinitis symptoms and/or signs. They underwent skin prick tests to a battery of common allergens (german cockroach, cat dander, dog dander, house dustmites mix, cladosporium, aspergillus mix, penicillium mix, alternaria, grass pollens mix, Russian thistle pollens, mugwort pollens, rough pigweed pollens, sorrel pollens, compositae pollens, olive pollens, and date palm pollens). A wheal of ≥3 mm was considered a positive skin test. Results: A total of 177 patients with rhinitis (90 females and 87 males) had positive test results to at least one allergen and were considered allergic. 77.9% of the patients had positive results to Russian thistle pollens, 39.9% to cat dander, 29.9% to grass pollens mix, 22.6% to compositae pollens, 22.6% to mugwort pollens, 22% to house dust mites mix, 21.4% to olive pollens, 20.9% to German cockroach, 20.3% to dog dander, 18.1% to rough pigweed pollens, 15.8% to date palm pollens, and 12.4% to sorrel pollens, 14.7% to penicillium, 10.7% to cladosporium, 10.7% to aspergillus mix, and 4% to alternaria. Conclusion: Russian Thistle pollen is the commonest sensitization for Kuwaiti residents with allergic rhinitis. Background: Environmental allergies affect many individuals of all ages. There are several aeroallergens that can trigger allergic reactions, namely allergic rhinitis and allergic asthma. In this study, we aimed to determine the prevalence of various environmental allergies in the Kingston, Ontario region. Methods: A chart review of skin prick test (SPT) results was completed on all patients in the practice of an academic Allergist affiliated with Queen's University. Patients who demonstrated positive SPT (defined as ≥3 mm than the negative control) to one or more allergens were included, and their age, gender and specific positive tests were recorded. Allergens evaluated included dust mites (D. pteronyssinus and D. farinae), dog dander, cat epithelium, tree mixes, birch pollen, other trees, grass mixes, ragweed mixes, short ragweed, other weeds, cockroach and numerous moulds. Of all patients reviewed, 1161 had positive SPT results to one or more allergens. Data analysis was completed with SPSS. Results: Dust mite was the most prevalent allergen (62.6%). The second and third most common were ragweed (52.6%) and cats (51.6%), respectively. The prevalence of other allergens, in order of decreasing frequency, were grass (49.7%), trees (43.1%), birch (34.8%), short ragweed (30.8%), molds (29.7%), other trees (25.6%), dog (...

A young woman with persistent EBV viremia and lymphocytosis had an abnormal CD4‐ T cell population with aberrant loss of CD7. She had a diagnosis of chronic active EBV (CAEBV), a lymphoproliferative disorder for which she ultimately required allogeneic hematopoietic stem cell transplantation.

Cutaneous manifestations are common in monogenic immune disorders, including both infectious and non‐infectious etiologies. We report follow‐up of a case initially published in Pediatric Dermatology in 2001 of a 13‐year‐old boy with a history of inflammatory skin lesions and neutropenia who developed neutrophilic dermatoses precipitated by G‐CSF. Whole exome sequencing performed at 36 years of age revealed a gain‐of‐function mutation in the WAS gene, leading to a diagnosis of X‐linked neutropenia. This case report provides closure on a decades‐long diagnostic odyssey and underscores the importance of genetic sequencing in patients who present with unusual dermatologic findings.