Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.

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.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.

Background: We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. 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 ), in analyses restricted to 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 ). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P= 3.4×10 -3 ). When these 14 loci and TLR7 were considered, all individuals hemizygous ( n =20) or homozygous ( n =5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P =4.7×10 -7 ), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P =0.02). Finally, the patients with pLOF or 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.

The efficacy of omalizumab treatment in patients with nonatopic severe asthma.

INTRODUCTION: Nonatopic asthmatic patients generally have more severe clinical manifestations, frequently accompanied by chronic sinusitis and nasal polyps, with more limited therapeutic options as compared to atopic asthmatic patients. This has led to a search for novel therapeutic approaches, including omalizumab, for nonatopic asthmatic patients who are not adequately controlled with current therapies. MATERIALS AND METHODS: In this retrospective study undertaken between August 1, 2020, and December 31, 2021, at a tertiary allergy clinic, data from 61 patients with nonatopic asthma inadequately controlled with optimum therapy was examined. RESULTS: A total of 61 patients with severe asthma were included in the study [Female: 48 (78.7%), male: 13 (21.3%, mean age: 49 (18-71) years]. The mean duration of asthma was 60 (18-160) months. A statistically significant increase in Forced expiratory volume (FEV1per second), forced vital capacity (FVC), and asthma control test (ACT) scores were found after 1 year of omalizumab treatment (p ˂ 0.001, for all parameters). Omalizumab treatment was associated with a significant decrease in the number of asthma exacerbations, asthma-related hospitalizations, duration of hospitalizations, and several unplanned emergency room visits after 1 year (p ˂ 0.001, for all parameters). A 1-year treatment with omalizumab led to significant changes in eosinophil counts and serum IgE levels (p ˂ 0.001 and ˂ 0.001, respectively). CONCLUSION: In the severe atopic asthma patient group, omalizumab treatment provided similar clinical benefits to those observed in patients with severe atopic asthma, suggesting that it may be a useful therapeutic option in patients with nonatopic asthma who failed to benefit from treatments with steps 4 and 5.

A Single Center Experience of Super-Responders Among Severe Asthma Patients Receiving Treatment with Mepolizumab.

OBJECTIVE: Anecdotal reports among clinicians treating severe asthma patients with novel add-on treatments such as mepolizumab suggest that a fraction of these patients may experience a much more dramatic benefit from these agents than reported in large, randomized controlled studies. Although these patients have been referred to as super-responders in some studies, currently, there is no consensus regarding the nomenclature. Therefore, our aim was to assess the real-life data among patients receiving mepolizumab treatment due to severe eosinophilic asthma, in an effort to determine potential clinical and laboratory differences between super-responders and other group of patients. MATERIAL AND METHODS: Data from adult patients who received at least four doses of mepolizumab due to persistent severe asthma between Janury 1, 2020, and December 31, 2021, in a Tertiary Allergy Clinic were evaluated in a retrospective manner. RESULTS: A total of 57 patients with severe asthma receiving mepolizumab treatment were included [female: 38, male: 19]. At 4th- and 12th-month after initiation of mepolizumab treatment, significant differences in forced expiratory volume in 1 second, forced vital capacity, forced expiratory volume in 1 second/forced vital capacity, blood eosinophil count, and serum immunoglobulin E level were detected as compared to baseline (P < .001, P < 0.001, P =.027, P < .001, and P =.035). Also, at the 12th-month of treatment with mepolizumab, there were significant differences compared to baseline in asthma control test scores, number of asthma exacerbations, non-planned emergency room visits, hospitalizations, and daily need for oral corticosteroids (P <.001, for all parameters). Also, there was not a statistically significant difference between super-responders and responders groups in regard to age, gender, duration of disease, duration of mepolizumab treatment, allergen sensitivities, and comorbid conditions (chronic rhinosinusitis, nasal polyps, and aspirin sensitivity). CONCLUSION: Our results suggest that mepolizumab may be an effective therapeutic option in patients with severe asthma. On the other hand, patients who were considered to be super-responders to mepolizumab treatment were not significantly different from the remaining group of patients (responders). Obviously, further studies are warranted to better define the super-responders among patients with severe asthma who receive mepolizumab treatment.

Evaluation of malnutrition risk and nutrition status in adult patients with common variable immunodeficiency.

BACKGROUND: The aim of this study is to determine the prevalence of malnutrition in outpatients with common variable immunodeficiency (CVID) and the utility of nutrition screening tools to detect malnutrition in these patients. METHODS: Fifty outpatients with CVID were included in the study. Nutrition risk for each patient was evaluated using four nutrition screening tools: Malnutrition Screening Tool (MST), Malnutrition Universal Screening Tool (MUST), Short Nutritional Assessment Questionnaire (SNAQ), and Nutritional Risk Screening 2002 (NRS-2002). RESULTS: According to MUST, MST, SNAQ, and NRS-2002, malnutrition risk was determined to be 48% (n = 24), 26% (n = 13), 20% (n = 10), and 20% (n = 10), respectively. Malnutrition was detected in 54% (n = 27) of the patients. It was found that MUST showed a better correlation in detecting malnutrition in outpatients with CVID (κ = 0.482, P = 0.001). MUST has a higher positive and negative predictive value than other nutrition screening tools (79% and 70%, respectively). In the multivariate logistic regression analysis, it was found that low serum immunoglobulin A (IgA) levels at diagnosis increased the risk of malnutrition by ∼15 times, and low CD19+ B-cell counts increased the risk by approximately eight times. CONCLUSION: The prevalence of malnutrition in patients with CVID was found to be quite high, and there was a strong correlation between malnutrition and low CD19+ B-cell counts and low serum IgA levels. Given the high rate of malnutrition in patients with CVID, nutrition assessment is recommended rather than starting with nutrition screening.

Relationship between Selective IgA Deficiency and COVID-19 Prognosis.

The prevalence and mortality rates of coronavirus disease 2019 (COVID-19) widely vary among populations. Mucosal immunity is the first barrier to the pathogen's entry into the body. Immunoglobulin A (IgA) is the primary antibody responsible for mucosal immunity. We explored the relationship between selective IgA deficiency (SIgAD) and COVID-19 severity. We included 424 patients (203 women) with COVID-19. Eleven patients had SIgAD. Laboratory data of patients with SIgAD and normal IgA levels were compared. The relationship between SIgAD and severe COVID-19 infection was explored using logistic regression analysis. In the univariate logistic regression analysis, the risk of severe COVID-19 disease in patients with SIgAD was approximately 7.7-fold higher than that in other patients (odds ratio [OR], 7.789; 95% confidence interval [CI], 1.665-36.690, P = 0.008), while it was 4-fold (OR, 4.053; 95% CI, 1.182-13.903, P = 0.026) higher in the multivariate logistic regression analysis. Serum IgA levels were positively correlated with total lymphocyte counts and negatively correlated with C-reactive protein levels, which was a risk factor for severe COVID-19. In patients with SIgAD, the number of severe acute respiratory coronaviruses 2 that pass through mucosal membranes may be increased, leading to complications such as cytokine storm syndrome and acute respiratory distress syndrome.

Memory B cells and serum immunoglobulins are associated with disease severity and mortality in patients with COVID-19.

PURPOSE OF THE STUDY: The aim of this study was to investigate the relationship of B cell-mediated immunity with disease severity and mortality in patients with COVID-19. STUDY DESIGN: In this retrospective cohort and single-centre study, 208 patients with laboratory-confirmed COVID-19 were recruited. A COVID-19 severity score, ranging from 0 to 10, was used to evaluate associations between various factors. Serum immunoglobulin levels and the number of cells in B lymphocyte subsets were measured and their association with disease severity and mortality in patients with COVID-19 examined. RESULTS: The median age of the patients was 50 (35-63) years and 88 (42%) were female. The number of deceased patients was 17. The median COVID-19 severity score was 8 (6-8) in deceased patients and 1 (0-2) in survivors. Deceased patients had significantly lower levels of total B lymphocytes, naive B cells, switched memory B cells, and serum IgA, IgG, IgG1 and IgG2 than recovered patients (all p<0.05). In addition, a significant negative correlation was found between the number of these parameters and COVID-19 severity scores. Decrease in the number of total B cells and switched memory B cells as well as lower serum IgA, IgG and IgG1 levels were independent risk factors for mortality in patients with COVID-19. CONCLUSION: In the present study, the prognosis of patients with COVID-19 was shown to be associated with the B cell subset and serum immunoglobulin levels.

An association between immune status and chest CT scores in COVID-19 patients.

BACKGROUND: The characteristic features of the immune responses of COVID-19 patients and how they reflect lung involvement have not been clearly elucidated. AIM: The aim of this study was to examine the immune status and the correlations thereof with chest CT scores and lung involvement of patients with COVID-19. METHODS: In this retrospective and single-center study, 72 patients with laboratory-confirmed COVID-19 were recruited. The counts of peripheral lymphocyte subsets (CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells and CD16+ 56+ NK cells) and those of serum immunoglobulins (IgA, IgG, IgM) were measured and their associations with chest CT scores analysed. RESULTS: The proportions of lymphopenia in patients with extensive lung involvement were twice that in the general study population. In the severe disease group, the levels of total lymphocytes, T cells, B cells, NK cells; and serum IgA levels, were significantly lower than in the mild disease group (all P < .05). We found that the numbers of lymphocyte subsets and the IgA level negatively correlated with the chest CT scores. On multivariate regression analysis, pretreatment decreases in total lymphocytes, CD3+ T cells, CD4+ T cells, and CD19+ B cells, and serum IgA levels, were independent predictors of severe lung involvement. CONCLUSIONS: The cell numbers of peripheral lymphocyte subsets and the serum IgA level were negatively correlated with the chest CT scores in COVID-19 patients. These parameters tended to independently predict severe lung involvement in such patients.

Allergic diseases in the elderly population: a single-center experience.

BACKGROUND: Although allergic diseases are generally considered to be diseases of childhood and youth, the first symptoms of allergic diseases can be seen in old age sometimes. The aim of this study was to determine the prevalence and characteristics of allergic diseases in the elderly population admitted to the allergy unit on an outpatient basis. METHODS: The files of the patients who applied to our clinic's allergy unit during the 8-year period were retrospectively analyzed. The data of patients aged ≥ 65 years were obtained from the files of our allergy unit archive. RESULTS: A total of 1272 patients aged ≥ 65 years old were included in the study. The mean age was 70 years (range: 65-97 years). Most of the patients were female (n = 704, 55.3%). Of the patients, 887 (69.8%) presented with cutaneous symptoms, and urticaria was identified in 500 of them (56.3%). Drug hypersensitivity reactions were detected in 175 (13.7%) patients. A total of 71 (5.6%) patients had asthma, 65 (5.1%) had anaphylaxis, 48 (3.8%) had allergic rhinitis, 24 (1.9%) had hymenoptera venom allergy, and 18 (1.4%) had food allergies. Atopy history (OR = 2.323, 95% CI = 1.590-3.393, p < 0.001) and comorbidity (OR = 1.631, 95% CI = 1.050-2.533, p = 0.029) were found to be risk factors for drug hypersensitivity reactions. Male sex (OR = 3.462, 95% CI = 1.097-10.933, p = 0.034) and atopy history (OR = 14.877, 95% CI = 6.081-36.393, p < 0.001) were found to be risk factors for hymenoptera venom allergy. DISCUSSION: Diagnosis becomes difficult due to the perception that allergic diseases mainly affect young people. Clinical symptoms are not evident in the elderly and age-related difficulties are encountered in diagnostic tests. There is a need to develop specific guidelines for the diagnosis of allergic diseases in the elderly.

Nephrological factors may cause kidney dysfunction in patients with common variable immunodeficiency

Background/aim: Common variable immunodeficiency (CVID) is a heterogeneous primary deficiency characterized by hypogammaglobulinemia, recurrent infections, an increased risk of autoimmune disease, malignancy, and chronic inflammation. Proteinuria is one of the most important prognostic factors causing progression in kidney disease. Proteinuria causes tubulotoxicity, activates inflammatory markers that cause fibrosis, and consequently nephropathy progression. The data is scant in the literature regarding the inflammation and nephropathy in CVID. Hence, in the present study, we aimed to investigate the relationship between tubular dysfunction, proteinuria, and inflammation in patients with CVID. Materials and methods: This was a cross-sectional study involving 27 patients with CVID (15 females, 12 males; mean age, 39.88 ± 13.47 years) and 18 control subjects (10 females, 8 males; mean age, 33.83 ± 7.97 years). Patients were evaluated for kidney functions including glomerular filtration rate, fractional excretion of sodium, metabolic acidosis, serum/urine anion gap, 24-h urine proteinuria and, were grouped in terms of proteinuria. Blood samples obtained from the patients with CVID were taken into 2 mL EDTA tube to evaluate peripheral NK cell subgroups according to CD56 and CD16 expression and CD3, CD4, CD 8 expression to determine subtypes T cells. These cells were evaluated by flow cytometry technique. Results: Urinary density, fractional excretion of sodium, proteinuria, and metabolic acidosis are found to be higher in patients with CVID when compared to healthy controls. In the bivariate correlation analysis, proteinuria was positively correlated with age (r = 0.496, p = < 0.001), CD8+T cells percentage (r = 0.427, p = 0.02). Albumin, CRP, and CD8+T cell percentage were found to be independent variables of proteinuria. Conclusion: Increased chronic ongoing inflammation was found to be associated with proteinuria in patients with CVID. Hence, in routine outpatient clinics, proteinuria should not be overlooked in this group of patients.

Knee muscle strength in multiple sclerosis: relationship with gait characteristics.

[Purpose] To investigate the relationship between isokinetic knee muscle strength and kinematic, kinetic and spatiotemporal gait parameters of patients with multiple sclerosis (MS). [Subjects and Methods] Twenty-nine MS patients (mean age 31.5±6.5) were investigated in this study. The isokinetic knee muscle strength and gait parameters of MS patients with moderate and severe disability, as determined by the expanded disability status scale (EDSS): EDSS=1-4.5 (n=22, moderate disability) and EDSS>4.5 (n=7, severe disability) were measured. [Results] Isokinetic knee muscle strength, kinematic, kinetic and spatiotemporal gait parameters differed between moderate (EDSS=1-4.5, n=22) and severe disability (EDSS>4.5, n=7). The correlation between each of gait speed, stride length, total range of knee joint movement and the four strength parameters (minimum and maximum quadriceps and hamstring muscle strengths) were significant for the MS group as a whole. Within subgroups, the correlation between minimum hamstring strength and total range of knee movement was significant only in group EDSS>4.5; minimum hamstring correlated with peak knee extensor moment in group EDSS=1-4.5, but at a reduced level of significance. [Conclusion] The present study revealed significant correlations between gait characteristics and isokinetic strength parameters of the quadriceps and hamstring muscles. Our study suggests that rehabilitation protocols for MS patients should include a critical strength training programme particularly for the hamstring and quadriceps muscles.

Mean platelet volume in the diagnosis and prognosis of Crimean-Congo hemorrhagic fever.

INTRODUCTION: Crimean-Congo hemorrhagic fever (CCHF) is a viral tick-borne zoonosis, which is a severe illness, causing hemorrhages in humans. Mean platelet volume (MPV) is used as a surrogate marker of platelet function and has been shown to be a sign of inflammation. The objective of the present study is to examine the association between MPV and CCHF. We also aimed to investigate the association between MPV and coagulopathy markers in the mortality rates and prognosis of patients with CCHF. PATIENTS AND METHODS: Ninety-three patients with CCHF were enrolled retrospectively into the study and 15 of them were excluded according to the exclusion criteria. Twenty-five healthy individuals were included as a control group which was age and gender matched with CCHF patients. We compared the levels of MPV between the patient and the control groups. We also compared the coagulopathy markers of fatal CCHF patients (n = 9) with nonfatal cases (n = 69). RESULTS: Platelet counts were significantly lower in the CCHF group. Levels of international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) were significantly higher in CCHF group (P < .001, <.001, <.001, respectively). A statistically significant increase in MPV was observed in patients with CCHF compared with healthy controls (8.63 ± 1.23 fL vs 7.65 ± 0.42 fL, P < .001). Receiver-operating characteristic curve analysis suggested that the optimum MPV level cutoff points for patients with CCHF was 8.15 fL, with a sensitivity and specificity of 65% and 88%, respectively. The MPV levels were not significantly different between group 2 (nonsurvivor) and group 1 (survivor). However, platelet count, D-dimer, INR, PT, and aPTT were also positively correlated with the mortality rates (P = .008, <.001, <.001, <.001, and <.001, respectively). Multivariable logistic regression model showed an independent correlation between MPV and mortality rate (P < .001). CONCLUSION: In conclusion, MPV may be a beneficial marker in the diagnosis of CCHF, especially in cases with thrombocytopenia, the MPV levels are high. We also conclude that MPV may independently predict the prognosis of patients with CCHF.