A snapshot of pediatric inpatients and outpatients with COVID-19: a point prevalence study from Turkey.

This multi-center point prevalence study evaluated children who were diagnosed as having coronavirus disease 2019 (COVID-19). On February 2nd, 2022, inpatients and outpatients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were included in the study from 12 cities and 24 centers in Turkey. Of 8605 patients on February 2nd, 2022, in participating centers, 706 (8.2%) had COVID-19. The median age of the 706 patients was 92.50 months, 53.4% were female, and 76.7% were inpatients. The three most common symptoms of the patients with COVID-19 were fever (56.6%), cough (41.3%), and fatigue (27.5%). The three most common underlying chronic diseases (UCDs) were asthma (3.4%), neurologic disorders (3.3%), and obesity (2.6%). The SARS-CoV-2-related pneumoniae rate was 10.7%. The COVID-19 vaccination rate was 12.5% in all patients. Among patients aged over 12 years with access to the vaccine given by the Republic of Turkey Ministry of Health, the vaccination rate was 38.7%. Patients with UCDs presented with dyspnea and pneumoniae more frequently than those without UCDs (p < 0.001 for both). The rates of fever, diarrhea, and pneumoniae were higher in patients without COVID-19 vaccinations (p = 0.001, p = 0.012, and p = 0.027).  Conclusion: To lessen the effects of the disease, all eligible children should receive the COVID-19 vaccine. The illness may specifically endanger children with UCDs. What is Known: • Children with COVID-19 mainly present with fever and cough, as in adults. • COVID-19 may specifically threaten children with underlying chronic diseases. What is New: • Children with obesity have a higher vaccination rate against COVID-19 than children without obesity. • Among unvaccinated children, fever and pneumoniae might be seen at a higher ratio than among vaccinated children.

[Analysis of IFN-γR1 (CD119) and IL-12Rß1 (CD212) Deficiency by Flow Cytometry]. / IFN-γR1 (CD119) ve IL-12Rß1 (CD212) Eksikliginin Akan Hücre Ölçer ile Analizi.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare primary immune deficiency (PID). IL-12Rß1 deficiency is the most frequently observed of more than 16 genetic defects that have been identified for MSMD. Genetic and immunological tests are remarkable in the diagnosis of PID. In this study, it was aimed to determine the expression of IFN-γR1 and IL-12Rß1 in patients with MSMD, their relatives, and healthy individuals and to evaluate the importance of flow cytometry as a fast and reliable method in the diagnosis of MSMD. IFN-γR1 and IL-12Rß1 expression levels were analyzed in 32 volunteers including six patients, six relatives, and 20 healthy individuals. The normal range of IFN-γR1 and IL-12Rß1 levels among healthy individuals were determined. IL-12Rß1 expression level in lymphocytes was found to be low in one patient's relative, and less than 1% in three patients and in one patient's relative. It was observed that the IL-12Rß1 expression levels of the patient with STAT1 deficiency were increased compared to the healthy individuals. No difference was found in the expression levels of IFN-γR1 and IL-12Rß1 in one patient, but IFN-γR1 expression was decreased in one patient compared to healthy individuals. Our results show that the determination of IL-12Rß1 and IFN-γR1 deficiencies by flow cytometry can be used as a rapid and reliable method for the diagnosis of MSMD. The use of this method as a screening test will enable early diagnosis especially in patients whose genetic diagnosis has not been confirmed and clinically compatible with MSMD. In addition, it is thought that IL-12Rß1 and IFN-γR1 range data obtained from healthy individuals will be considered as a reference source in routine and research studies to be conducted with MSMD.

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.

[Very rare and life-threatening complications of bocavirus bronchiolitis: pneumomediastinum and bilateral pneumothorax]. / Bokavirus bronsiyolitinin çok nadir ve hayati tehdit eden komplikasyonlari: Pnömomediastinum ve bilateral pnömotoraks.

Human bocavirus (HBoV), that was first identified in 2005 and classified in Parvoviridae family, is a small, non-enveloped, single-stranded DNA virus, responsible for upper and lower respiratory tract infections, especially in young children. Although HBoV generally causes self-limited influenza-like illness, it may also lead to pneumonia, bronchiolitis, croup and asthma attacks. In this report, a case of acute bronchiolitis complicated with pneumomediastinum and bilateral pneumothorax caused by HBoV has been presented. A three-year-old boy was referred to our pediatric intensive care unit with a two day history of fever, tachypnea, hypoxia and respiratory failure. On auscultation, there were widespread expiratory wheezing and inspiratory crackles. The chest radiography yielded paracardiac infiltration and air trapping on the right lung and infiltration on the left lung. The patient had leukocytosis and elevated C-reactive protein level. On the second day of admission, respiratory distress worsened and chest radiography revealed right pneumothorax and subcutaneous emphysema in bilateral cervical region and left chest wall. He was intubated because of respiratory failure. In the thorax computed tomography, pneumomediastinum and bilateral pneumothorax were detected and right chest tube was inserted. Repetitive blood and tracheal aspirate cultures were negative. A nasopharyngeal swab sample was analyzed by multiplex real-time polymerase chain reaction method with the use of viral respiratory panel (FTD(®) Respiratory Pathogens 21 Kit, Fast-Track Diagnostics), and positive result was detected for only HBoV. On the ninth day of admission, pneumomediastinum and bilateral pneumothorax improved completely and he was discharged with cure. In conclusion, HBoV bronchiolitis may progress rare but severe complications, it should be kept in mind as an etiological agent of the respiratory tract infections especially children younger than five years old.

[A case of bronchiolitis obliterans secondary to human metapneumovirus bronchiolitis]. / Insan metapnömovirus bronsiyolitine ikincil gelisen bronsiyolitis obliterans olgusu.

Human metapneumovirus (hMPV), formerly classified in Paramyxoviridae family is now moved into Pneumoviridae, which was described as a novel family. It causes upper and lower respiratory tract infections (LRTIs) usually in children younger than five years old. The recent epidemiological studies indicated that hMPV is the second most frequently detected virus in LRTIs of young children, following the respiratory syncytial virus (RSV). Bronchiolitis obliterans (BO) is a chronic obstructive lung disease characterized by fibrosis of the distal respiratory airways. It is usually a result of an inflammatory process triggered by a LRTI related to adenovirus, RSV, Mycoplasma pneumoniae, measles virus, Legionella pneumophila, influenza virus or Bordetella pertussis as a causative agent. In this report, a case of hMPV bronchiolitis complicated with BO has been reported to point out the complications and severity of the clinical progress belongs to this virus. A three-month-old female patient has admitted to our pediatric intensive care unit with the diagnosis of acute bronchiolitis and respiratory failure. She was born at term, weighing 2950 gram and had been hospitalized in newborn intensive care unit for 11 days with the diagnosis of transient tachypnea of the newborn and neonatal sepsis. On auscultation, there were bilateral crepitant rales, wheezing and prolonged expirium. Her oxygen saturation was 97-98% while respiratory support was given with a non-rebreathing reservoir mask. Complete blood count, procalcitonin and C-reactive protein levels were in normal ranges. The chest radiography yielded right middle lobe atalectasia, left paracardiac infiltration and bilateral air trapping. A nasopharyngeal swab sample was analyzed by a commercial multiplex real-time reverse transcriptase-polymerase chain reaction (Thermo Fisher Scientific®, USA) developed for the detection of 15 respiratory viruses. Her sample yielded positive result for only hMPV. On the 4th day of hospitalization, the patient was intubated because of respiratory failure and carbon dioxide retention. She was extubated on the 19th day but could not tolerate. In the thorax computed tomography (CT), bilateral hyperinflation, patchy infiltration, mosaic perfusion and atelectasis especially bilateral posterior areas were detected. Bronchoscopy was normal except mild bronchomalacia in right middle lobe bronchus. The patient was diagnosed as BO secondary to hMPV bronchiolitis, according to the clinical, virological, bronchoscopic and thorax CT results. On the 76th day of admission, she was discharged with respiratory support with home ventilation via a tracheostomy cannula and medical treatments of oral metilprednisolone, nebulized salbutamol and budesonide. In conclusion, hMPV should not be undervalued especially in infants with severe LRTI that can be complicated with BO.

Tiny hair tuft: a clue for occipital cephalocele.

Recurrent meningitis is a rare problem and can be due to alterations in immune system, or craniospinal defect. Any clue either in patient's history or physical examination would be helpful for avoiding unnecessary and tiring tests. Here we present the case of a child with recurrent bacterial meningitis who had an unnoticed hair tuft on the occipital region. The final diagnosis was occipital cephalocele with a rare presentation of a tiny tuft of hair.

The relationship between bifidobacteria and allergic asthma and/or allergic dermatitis: a prospective study of 0-3 years-old children in Turkey.

Bifidobacteria are beneficial bacteria for humans. These bacteria are particularly effective at protecting against infectious diseases and modulating the immune response. It was shown that in newborns, the fecal distribution of the colonizing Bifidobacterium species influences the prevalence of allergic diseases. This study aimed to compare the faecal Bifidobacterium species of allergic children to those of healthy children to detect species level differences in faecal distribution. Stool samples were obtained from 99 children between 0 and 3 years of age whose clinical symptoms and laboratory reports were compatible with atopic dermatitis and allergic asthma. Samples were also obtained from 102 healthy children who were similar to the case group with respect to age and sex. Bifidobacteria were isolated by culture and identified at the genus level by API 20 A. In addition, 7 unique species-specific primers were used for the molecular characterization of bifidobacteria. The McNemar test was used for statistical analyses, and p < 0.05 was accepted as significant. Bifidobacterium longum was detected in 11 (11.1%) of the allergic children and in 31 (30.3%) of the healthy children. Statistical analysis revealed a significant difference in the prevalence of B. longum between these two groups (X(2): 11.2, p < 0.001). However, no significant differences in the prevalence of other Bifidobacterium species were found between faecal samples from healthy and allergic children. (p > 0.05). The significant difference in the isolation of B. longum from our study groups suggests that this species favors the host by preventing the development of asthma and allergic dermatitis. Based on these results, we propose that the production of probiotics in accordance with country-specific Bifidobacterium species densities would improve public health. Thus, country-specific prospective case-control studies that collect broad data sets are needed.

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.

The epidemiology and economic impact of varicella-related hospitalizations in Turkey from 2008 to 2010: a nationwide survey during the pre-vaccine era (VARICOMP study).

Varicella can cause complications that are potentially serious and require hospitalization. Our current understanding of the causes and incidence of varicella-related hospitalization in Turkey is limited and sufficiently accurate epidemiological and economical information is lacking. The aim of this study was to estimate the annual incidence of varicella-related hospitalizations, describe the complications, and estimate the annual mortality and cost of varicella in children. VARICOMP is a multi-center study that was performed to provide epidemiological and economic data on hospitalization for varicella in children between 0 and 15 years of age from October 2008 to September 2010 in Turkey. According to medical records from 27 health care centers in 14 cities (representing 49.3% of the childhood population in Turkey), 824 children (73% previously healthy) were hospitalized for varicella over the 2-year period. Most cases occurred in the spring and early summer months. Most cases were in children under 5 years of age, and 29.5% were in children under 1 year of age. The estimated incidence of varicella-related hospitalization was 5.29-6.89 per 100,000 in all children between 0-15 years of age in Turkey, 21.7 to 28 per 100,000 children under 1 year of age, 9.8-13.8 per 100,000 children under 5 years of age, 3.96-6.52 per 100,000 children between 5 and 10 years of age and 0.42 to 0.71 per 100,000 children between 10 and 15 years of age. Among the 824 children, 212 (25.7%) were hospitalized because of primary varicella infection. The most common complications in children were secondary bacterial infection (23%), neurological (19.1%), and respiratory (17.5%) complications. Secondary bacterial infections (p < 0.001) and neurological complications (p < 0.001) were significantly more common in previously healthy children, whereas hematological complications (p < 0.001) were more commonly observed in children with underlying conditions. The median length of the hospital stay was 6 days, and it was longer in children with underlying conditions (<0.001). The median cost of hospitalization per patient was $338 and was significantly higher in children with underlying conditions (p < 0.001). The estimated direct annual cost (not including the loss of parental work time and school absence) of varicella-related hospitalization in children under the age of 15 years in Turkey was $856,190 to $1,407,006. According to our estimates, 882 to 1,450 children are hospitalized for varicella each year, reflecting a population-wide occurrence of 466-768 varicella cases per 100,000 children. In conclusion, this study confirms that varicella-related hospitalizations are not uncommon in children, and two thirds of these children are otherwise healthy. The annual cost of hospitalization for varicella reflects only a small part of the overall cost of this disease, as only a very few cases require hospital admission. The incidence of this disease was higher in children <1 year of age, and there are no prevention strategies for these children other than population-wide vaccination. Universal vaccination is therefore the only realistic option for the prevention of severe complications and deaths. The surveillance of varicella-associated complications is essential for monitoring of the impact of varicella immunization.

Risk factors for community-acquired urinary tract infection caused by ESBL-producing bacteria in children.

BACKGROUND: The aim of the present study was to investigate the risk factors of antimicrobial resistance in children with urinary tract infection caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria. METHODS: A total of 344 patients diagnosed with urinary tract infection (UTI) between January 2008 and December 2009 were enrolled in this retrospective study. Causative microorganisms were ESBL-producing bacteria in 148 patients and non-ESBL-producing bacteria in 196 patients. There was no difference between the two groups regarding distribution of age, sex and length of follow up. RESULTS: The most frequent causative agent was Escherichia coli, of which 41.4% were ESBL producing. Among Klebsiella species, 53.2% were ESBL producing. The proportion of ESBL-producing bacteria that were resistant to antibiotics was 83.1% for trimethoprim/sulfamethoxazole, 18.2% for nitrofurantoin, 47.3% for quinolones, and 39.9% for aminoglycosides. For non-ESBL-producing bacteria, the resistance rate was 62.2% for trimethoprim/sulfamethoxazole, 4.6% for nitrofurantoin, 9.7% for quinolones, and 9.7% for aminoglycosides. Age <1 year, high UTI recurrence rate, long duration of prophylaxis, use of cephalosporins for prophylaxis, hospitalization within the previous 3 months and clean intermittent catheterization were found to be significant risk factors for ESBL-producing bacteria (P < 0.05). Logistic regression analysis identified age <1 year and high recurrence UTI rate to be independent risk factors, increasing the risk 1.74-fold and 2.25-fold, respectively. CONCLUSIONS: Recognition of the risk factors for ESBL-producing bacteria may be helpful to determine new policies in the management of UTI. Recurrence of UTI should be prevented especially in the first year of life, and prophylactic cephalosporins should be avoided.

Preseptal and Orbital Cellulitis: Analysis of Clinical, Laboratory and Imaging Findings of 123 Pediatric Cases From Turkey.

BACKGROUND: We aimed to compare the clinical and laboratory characteristics and imaging methods of patients diagnosed with preseptal cellulitis and orbital cellulitis in the pediatric age group. METHODS: The study was designed retrospectively, and the medical records of all patients who were hospitalized with the diagnosis of preseptal cellulitis and orbital cellulitis were reviewed. The findings of preseptal cellulitis and orbital cellulitis groups were compared. The risk factors for the development of orbital involvement were analyzed. RESULTS: A total of 123 patients were included, 90.2% with preseptal cellulitis and 9.8% with cellulitis. The male gender ratio was 60.2%, and the mean age was 72 ± 43 months. While all patients had eyelid swelling and redness, 20.3% had fever. Ocular involvement was 51.2% in the right eye and 4.9% in both eyes. The most common predisposing factor was rhinosinusitis (56.1%). Radiologic imaging (computed tomography/magnetic resonance imaging) was performed in 83.7% of the patients. Subperiostal abscess was detected in 7 cases (5.6%) in which three of the cases were managed surgically and four were treated with medically. The levels of C-reactive protein were significantly higher in patients with orbital involvement (P = 0.033), but there was no difference between the presence of fever, leukocyte and platelet values. CONCLUSIONS: Rhinosinusitis was the most common predisposing factor in the development of preseptal cellulitis and orbital cellulitis. Orbital involvement was present in 9.8% of the patients. It was determined that high C-reactive protein value could be used to predict orbital involvement.

DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling.

Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo is not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1. The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice. Similarly, dpp9 deficiency was partially rescued by the inactivation of asc, an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish. These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1ß signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in two animal models of the disease.

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia.

Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs.

Life-threatening 'breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-ß. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

Evaluation of vaccination status of health care workers for recommended vaccines and their acceptance of SARS-CoV-2 vaccines.

INTRODUCTION: Health care workers (HCWs) are disproportionately exposed to infectious diseases and play a role in nosocomial transmission, making them a key demographic for vaccination. HCW vaccination rates are not optimal in many countries; hence, compulsory vaccination policies have been implemented in some countries. Although these policies are effective and necessary under certain conditions, resolving HCWs' hesitancies and misconceptions about vaccines is crucial. HCWs have the advantage of direct contact with patients; hence, they can respond to safety concerns, explain the benefits of vaccination, and counter antivaccine campaigns that escalate during pandemics, as has been observed with COVID-19. METHOD: A short survey was carried out in May-June 2020 on the vaccination status of HCWs working with pediatric patients with COVID-19. The survey inquired about their vaccination status (mumps/measles/rubella [MMR], varicella, influenza, and diphtheria/tetanus [dT]) and willingness to receive hypothetical future COVID-19 vaccines. The respondents were grouped according to gender, age, occupation, and region. RESULTS: In total, 4927 HCWs responded to the survey. Most were young, healthy adults. The overall vaccination rates were 57.8% for dT in the past 10 years, 44.5% for MMR, 33.2% for varicella, and 13.5% for influenza. Vaccination rates were the highest among physicians. The majority of HCWs (81%) stated that they would be willing to receive COVID-19 vaccines. CONCLUSION: Although vaccination rates for well-established vaccines were low, a majority of HCWs were willing to receive COVID-19 vaccines when available. Education and administrative trust should be enhanced to increase vaccination rates among HCWs.

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.

Viral etiology in hospitalized children with acute lower respiratory tract infection.

This study was performed to investigate the viral etiological agents, age distribution and clinical manifestations of lower respiratory tract infection (LRTI) in hospitalized children. The viral etiology and clinical findings in 147 children (1 month to 5 years of age) hospitalized with acute LRTI were evaluated. Cell culture was used for isolation of influenza viruses and direct fluorescent antibody assay for parainfluenza viruses (PIVs), respiratory syncytial virus (RSV) and adenoviruses (ADVs). Reverse-transcriptase polymerase chain reaction was employed for human metapneumovirus (hMPV). One hundred and six of all patients (72.1%) were male, and 116 children (79.8%) were < or = 2 years. A viral etiology was detected in 54 patients (36.7%). RSV was the most frequently isolated (30 patients, 55.6%), and PIV (27.8%), hMPV (13%), influenza-A (9.3%), and ADV (5.6%) were also shown. Dual infection was detected in six patients. There were no statistically significant differences between the two groups (with isolated virus or no known viral etiology) with respect to symptoms, clinical findings, laboratory work-up, or radiological data. Length of hospital stay was also not different. Determination of the etiology of acute LRTI in children less than 5 years of age seems impossible without performing virological work-up, whether viral or nonviral in origin.

Imaging of Multisystem Inflammatory Disease in Children (MIS-C) Associated With COVID-19.

RATIONALE AND OBJECTIVES: To retrospectively evaluate imaging findings in multisystem inflammatory disease in children associated with COVID-19 (MIS-C). MATERIALS AND METHODS: The radiological imaging findings of 45 pediatric patients aged between 52 days and 16 years, who were diagnosed with MIS-C according to the World Health Organization (WHO) criteria, were evaluated. All the patients underwent chest X-ray and echocardiography. The findings obtained from 25 abdominal radiographs, 24 abdominal US, 7 abdominal CT, 16 thorax CT, 21 cranial MRI and one spinal MRI, MR cholangiography (MRCP) and cardiac MRI examinations were categorized and evaluated according to the affected systems. RESULTS: While the most common findings in chest X-ray were perihilar opacity and peribronchial thickening, pleural effusion was the most finding in thorax CT. Echocardiography findings of myocarditis were observed in 31% of the cases. The most common findings in abdominal radiological evaluation were hepatomegaly and splenomegaly, edema in the gallbladder wall and periportal area, mesenteric lymph nodes in the right lower quadrant, thickening of the intestinal walls, and free fluid. Reversible splenial lesion syndrome (RESLES) was the most common neurological finding. Acute disseminated encephalomyelitis (ADEM)-like lesions, acute hemorrhagic necrotizing encephalomyelitis, and radiological findings consistent with Guillain-Barré syndrome were found in one case each. CONCLUSION: Radiological findings seen in MIS-C in pediatric cases are correlated with the affected system. According to the system involved, there is no specific finding for this disease. Radiological findings are not the primary diagnostic tool but can assist in the evaluation of the affected systems and to guide treatment.

Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance.

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.