Severe Respiratory Virus Infection Research Articles

Increased Risk of Acute Aortic Events following COVID-19 and Influenza Respiratory Viral Infections

Acute respiratory viral infections have been associated with an increased incidence of adverse cardiovascular events. However, it is unclear whether severe respiratory viral infections are associated with an increased risk of acute aortic syndromes (AAS). This study was designed to assess whether Coronavirus disease 2019 (COVID-19) and Influenza illnesses are associated with an increased incidence of subsequent AAS in the US population. We used the MarketScan database (2011-2021) to identify patients 18-99years of age without prior diagnosis of aortic pathology who were diagnosed with COVID-19 or Influenza. Identified patients were matched 1:1 by age and sex to control patients without COVID-19 or Influenza. The primary outcome was incidence of AAS (dissection, intramural hematoma, penetrating aortic ulcer, or aneurysm rupture) within 180-days of a viral infection. The association between infection and risk of developing an AAS was analyzed using multivariate Cox proportional hazards models. We identified 1,775,698 patients, including 779,229 (44%) with mild COVID-19, 42,141 (2%) with severe COVID-19, and 66,479 (4%) with Influenza that were matched to 887,849 (50%) control patients without COVID-19 or Influenza illnesses. A total of 164 patients experienced AAS within 6-months after diagnosis, which was highest among those after severe COVID-19. The predicted incidence of AAS was significantly higher among patients after severe COVID-19 (14.1 events/100,000 person-years), mild COVID-19 (13.3 events/100,000), and influenza (13.3 events/100,000) when compared to control patients (2.6 events/100,000). In risk-adjusted Cox regression models, severe COVID-19 (HR:5.4, 95% CI:2.8-10.4; P<0.01), mild COVID-19 (HR:5.1, 95% CI:3.3-7.7; P<0.01) and influenza (HR:5.1, 95% CI:2.6-9.7; P<0.01) diagnoses were associated with a significantly increased risk of AAS within 180-days when compared to matched controls. There is an increased risk of developing acute aortic event in the months following illness with Influenza or COVID-19. These data highlight the need to closely monitor at-risk patients following a viral respiratory infection.

Changes in the etiological structure of severe acute respiratory viral infections in children and adults under the influence of the COVID-19 pandemic

Introduction. The traditional surveillance system for influenza and ARVI provides a general description of epidemics, but does not provide information on the age-related characteristics of the etiology and clinical peculiarities of severe acute respiratory diseases (SARI) in hospitalized patients. Aim. To monitor the etiology of SARI in hospitalized children and adults, assessing the impact of the COVID-19 pandemic on this process. Materials and methods. Standardized clinical and laboratory monitoring of SARI among 18,458 hospitalized patients was carried out in hospitals in three cities of Russia with weekly PCR detection of 11 types of pathogens. Results. According to the investigation of hospitalized patients with SARI for the period from 2018 to 2023, the viral etiology of respiratory diseases was deciphered in 58.3% of cases. Weekly monitoring showed a change in the etiological mosaic of SARI pathogens during the SARS-CoV-2 pandemic with a sharp decrease in the frequency of detection of influenza and respiratory syncytial virus (RSV) during the 2020–2021 season against the background of a significant increase of metapneumovirus and rhinovirus infections in children. During the 2022-2023 season an increase in the proportion of RSV infection in children under 6 years of age (up to 36.2%) was noted against the background of a significant decrease in the frequency of SARS-CoV-2. In the intensive care units (ICU), RSV infection was most often in children during the post-pandemic period (up to 30.1–53.6% of positive cases, p 0.001); in adults, SARS-CoV-2 was mostly detected (76,5–100% of cases, p 0.001). Conclusion. Hospital surveillance data significantly complements the epidemiological information obtained in the traditional surveillance system. Monitoring of infections has shown a continuously changing etiological infrastructure of SARI, with the disappearance of influenza and RSV during the COVID-19 pandemic and their return to circulation in the post-pandemic period.

Post-COVID-19 Fungal Infections: A Case Series

Severe acute respiratory syndrome coronavirus 2-like other viral infections cause temporary immunosuppressive effects. This COVID-19 infection-induced temporary suppression of cellular immunity can predispose to infections like fungal. Furthermore, high-dose corticosteroids used in COVID-19 management can trigger or accelerate fungal infections. This case series presents the clinicomicrobiological profile of a few such admitted cases, as it is very important for all clinicians and clinical microbiologists to keep the new yet recently not-so-uncommon entities in mind while evaluating a patient.

Study protocol: A randomized, double-blind, placebo-controlled trial of isavuconazole prophylaxis for the prevention of covid-19-associated pulmonary aspergillosis

BackgroundDuring the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection. MethodsWe designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants. ResultsDue to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects. ConclusionEnrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections.

Breath Markers of Oxidative Stress in Children with Severe Viral Lower Respiratory Tract Infection.

Severe viral lower respiratory tract infection (LRTI), resulting in both acute and long-term pulmonary disease, constitutes a substantial burden among young children. Viral LRTI triggers local oxidative stress pathways by infection and inflammation, and supportive care in the pediatric intensive care unit may further aggravate oxidative injury. The main goal of this exploratory study was to identify and monitor breath markers linked to oxidative stress in children over the disease course of severe viral LRTI. Exhaled breath was sampled during invasive ventilation, and volatile organic compounds (VOCs) were analyzed using gas chromatography and mass spectrometry. VOCs were selected in an untargeted principal component analysis and assessed for change over time. In addition, identified VOCs were correlated with clinical parameters. Seventy breath samples from 21 patients were analyzed. A total of 15 VOCs were identified that contributed the most to the explained variance of breath markers. Of these 15 VOCs, 10 were previously linked to pathways of oxidative stress. Eight VOCs, including seven alkanes and methyl alkanes, significantly decreased from the initial phase of ventilation to the day of extubation. No correlation was observed with the administered oxygen dose, whereas six VOCs showed a poor to strong positive correlation with driving pressure. In this prospective study of children with severe viral LRTI, the majority of VOCs that were most important for the explained variance mirrored clinical improvement. These breath markers could potentially help monitor the pulmonary oxidative status in these patients, but further research with other objective measures of pulmonary injury is required.

High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity.

Thymic stromal lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1-24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as 'high TSLP' or 'low TSLP' for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflammatory chemokines. These findings present a new paradigm underlying the production of TSLP in the human infant airway epithelium following early life viral exposure and shed light on the long-term impact of viral respiratory illnesses during early infancy and beyond childhood.

Fc-mediated functions and the treatment of severe respiratory viral infections with passive immunotherapy - a balancing act.

Passive immunotherapies have been used to treat severe respiratory infections for over a century, with convalescent blood products from recovered individuals given to patients with influenza-related pneumonia as long ago as the Spanish flu pandemic. However, passive immunotherapy with convalescent plasma or hyperimmune intravenous immunoglobulin (hIVIG) has not provided unequivocal evidence of a clinical benefit for severe respiratory infections including influenza and COVID-19. Efficacy trials, primarily conducted in late-stage disease, have demonstrated inconsistent efficacy and clinical benefit for hIVIG treatment of severe respiratory infections. To date, most serological analyses of convalescent plasma and hIVIG trial samples have focused on the measurement of neutralizing antibody titres. There is, however, increasing evidence that baseline antibody levels and extra-neutralizing antibody functions influence the outcome of passive immunotherapy in humans. In this perspective, findings from convalescent plasma and hIVIG trials for severe influenza, COVID-19 and respiratory syncytial virus (RSV) will be described. Clinical trial results will be discussed in the context of the potential beneficial and deleterious roles of antibodies with Fc-mediated effector functions, with a focus on natural killer cells and antibody-dependent cellular cytotoxicity. Overall, we postulate that treating respiratory viral infections with hIVIG represents a delicate balance between protection and immunopathology.

PD-1 Impairs CD8+ T Cell Granzyme B Production in Aged Mice during Acute Viral Respiratory Infection.

CD8+ T cell dysfunction contributes to severe respiratory viral infection outcomes in older adults. CD8+ T cells are the primary cell type responsible for viral clearance. With increasing age, CD8+ T cell function declines in conjunction with an accumulation of cytotoxic tissue-resident memory (TRM) CD8+ T cells. We sought to elucidate the role of PD-1 signaling on aged CD8+ T cell function and accumulation of CD8+ TRM cells during acute viral respiratory tract infection, given the importance of PD-1 regulating CD8+ T cells during acute and chronic infections. PD-1 blockade or genetic ablation in aged mice yielded improved CD8+ T cell granzyme B production comparable to that in young mice during human metapneumovirus and influenza viral infections. Syngeneic transplant and adoptive transfer strategies revealed that improved granzyme B production in aged Pdcd1-/- CD8+ T cells was primarily cell intrinsic because aged wild-type CD8+ T cells did not have increased granzyme B production when transplanted into a young host. PD-1 signaling promoted accumulation of cytotoxic CD8+ TRM cells in aged mice. PD-1 blockade of aged mice during rechallenge infection resulted in improved clinical outcomes that paralleled reduced accumulation of CD8+ TRM cells. These findings suggest that PD-1 signaling impaired CD8+ T cell granzyme B production and contributed to CD8+ TRM cell accumulation in the aged lung. These findings have implications for future research investigating PD-1 checkpoint inhibitors as a potential therapeutic option for elderly patients with severe respiratory viral infections.

Severe viral lower respiratory tract infections in Brazilian children: Clinical features of a national cohort

BackgroundThe accurate etiological diagnosis of lower respiratory tract infections (LRTI) is essential for their effective clinical management. The extensive use of molecular methods during the COVID-19 pandemic has enabled massive data acquisition on viral lower respiratory tract infections. The current study aims to identify clinical features associated with eight viral agents among children presenting severe LRTI. Methodsretrospective cohort study of data from the Brazilian Influenza Epidemiological Surveillance Information System. Patients under 20 years-old who had severe LRTI with etiological confirmation through RT-PCR between 2020 and 2022 were included. Binary logistic regressions were used to examine associations between pathogens and symptoms. Results60,657 cases were assessed. The main viral agents detected were Sars-CoV-2 (COV2) (41.2%), Respiratory Syncytial Virus (29.1%), Human Rhinovirus (HRV) (12.1%), and Influenza (FLU) (5.5%). A general mortality rate of 4.3% was observed. The multivariate analysis evidenced that COV2 less likely presented with cough (OR: 0.34; 95%CI: 0.32–0.36), respiratory discomfort (Adjusted Odds Ratio (aOR): 0.61; 95%Confidence Interval (CI): 0.59–0.64), and desaturation (aOR: 0.71; 95%CI: 0.69–0.75). RSV strongly associated with cough (aOR: 2.59; 95%CI: 2.45–2.75) and respiratory discomfort (aOR: 1.54; 95%CI: 1.46–1.62), whereas FLU was linked to fever (aOR: 2.27; 95%CI: 2.06–2.50) and sore throat (aOR: 1.48; 95%CI: 1.34–1.64). ConclusionsThe viral agents responsible for severe LRTI have distinct associations with clinical features in children.

Concomitant infections in children with allergic pathology in the Kaliningrad region

The aim of our work was to study the structure and prevalence of the infectious syndrome in children from Kaliningrad Region with moderate-to-severe allergic pathology, with a complex manifestations of allergic reactions, both on skin and on the mucous membranes of the digestive and respiratory tract.&#x0D; Ninety children from 0 to 18 years old with various symptoms of allergic pathology were examined and included in the study group using standard clinical, objective and laboratory criteria. The severity of clinical course was associated with the severe and long-lasting symptoms, as well as with frequent bacterial and bacterial-fungal complications, with impaired quality of life and night sleep. The children were consulted by the specialists in otorhinolaryngology, hematology, pulmonology, surgery, ophthalmology, infectology, endocrinology, cardiology. Diagnoses according to nosological forms were made in accordance with the current clinical recommendations of Russian Ministry of Health. Our article presents data on concomitant infectious diseases and their impact on general condition and severity of hypersensitive responses. The average age of allergic manifestations in the group of children was 3.12±2.72 years. The average duration of the disease in the observed group was 7.5±0.88 years. The number of boys in our group prevailed (n = 56) by 1.6 times. Complicated heredity factors were reported by 15% of the patients’ parents. However, with careful collection of medical history taking, upon dynamic observation, the aggravated heredity on the mother’s side was detected in 45.56% (n = 41), and on the father’s side, in 31.1% of cases (n = 28). In eight families, both parents suffered from allergic pathology, in siblings, 21.1% (n = 19) of the examined children had allergies. In the families, including grandparents, allergic pathology was reported in 56 cases (62.2%).&#x0D; Almost all patients had problems with nasal breathing, 77 (85.6%) children with adenoid hypertrophy had a habit of breathing through the mouth. Postnasal drip syndrome was found in 78 cases. Allergic rhinitis with adenoid hypertrophy is, generally, accompanied by postnasal leakage, which can provoke aspiration bronchitis and pneumonia, especially if pathogenic or opportunistic flora is transferred to the nasal cavity and/or to the pharynx.&#x0D; Conclusions: 1. Identification and rehabilitation of chronic foci of infection, bacterial, fungal, should be a necessary component of the personalized therapy of allergic pathology in children. 2. In cases of recurrent sowing or finding of pathogenic flora (iodophilic flora, fungi, coccal flora) in the coprogram, one should exclude not only transient lactase deficiency, but also congenital lactase deficiency, thus preventing development of enterocolitis in the future like as worsening of skin status and respiratory manifestations. 3. In case of severe respiratory viral infections in children during the period of adaptation for pre-school institutions, one should exclude sensitization to allergens of house dust mites and epidermal allergens of domestic animals. 4. A comprehensive and personalized approach to the diagnosis of allergic disorders and comorbid conditions enables us to create conditions for stable remission, making it possible to conduct allergen-specific immunotherapy, which may provide a disease-modifying effect upon the hyperreactive states in our patients.

Risk factors for severity in seasonal respiratory viral infections and how they guide management in hematopoietic cell transplant recipients.

Seasonal respiratory virus infections (RVIs) often progress to severe diseases in hematopoietic cell transplant (HCT) recipients. This review summarizes the current evidence on risk factors for the severity of RVIs in this high-risk population and provides clinical management. The likelihood of the respiratory viral disease progression depends on the immune status of the host and the type of virus. Conventional host factors, such as the immunodeficiency scoring index and the severe immunodeficiency criteria, have been utilized to estimate the risk of progression to severe disease, including mortality. Recent reports have suggested nonconventional risk factors, such as hyperglycemia, hypoalbuminemia, prior use of antibiotics with broad anaerobic activity, posttransplant cyclophosphamide, and pulmonary impairment after RVIs. Identifying novel and modifiable risk factors is important with the advances of novel therapeutic and preventive interventions for RVIs. Validation of recently identified risk factors for severe RVIs in HCT recipients is required. The development of innovative interventions along with appropriate risk stratification is critical to improve outcomes in this vulnerable population.

Epidemiology of acute respiratory viral infections of children with cancer before the COVID-19 pandemic

Children with cancer became a major high-risk group during the COVID-19 pandemic. It has become difficult for patients to reach practical and safe care and treatment all over the world. The late diagnosis of many childhood cancers was driven by limited access to healthcare due to the pandemic and fears of COVID-19 that prevented parents from making an early medical assessment of their child's symptoms. Acute respiratory diseases are an important cause of morbidity and mortality in children with cancer, regardless of the COVID-19 pandemic and were seen less frequently in the pandemic during the lockdown and distant education period in comparison to the time before the pandemic in children with cancer. Acute respiratory viral infections frequently cause febrile neutropenia attacks in children under five years of age. A three year retrospective cross-sectional study was performed in a tertiary care university hospital. Children with cancer who presented to the Department of Pediatric Hematology and Oncology with the diagnosis of acute respiratory viral infection were included in the study if they had available results of multiplex polymerase chain reaction (PCR) of nasopharyngeal aspirate samples. The qualitative detection of 18 respiratory viruses and four bacterias were detected by the real-time multiplex polymerase chain reaction. Sixty-six patients with 93 acute respiratory viral infection were included in this study. Seventy of 93 (75%) samples were positive for at least one pathogen. The most common three viruses were HRV, Influenza H1N1, and Influenza H1N3, respectively. Other than COVID-19, the risk of severe acute respiratory viral infections are always important in children with cancer and during the pandemic, hygiene measures and social restrictions caused a reduction in the number of acute respiratory viral infection. This study is critical because it shows the distribution of agents in children with cancer who had acute viral upper respiratory tract infections in the near term before the pandemic.

Molecular consequences of peripheral Influenza A infection on cell populations in the murine hypothalamus

Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite, and excessive sleepiness. These responses, mediated by the brain, will normally disappear once the virus is cleared from the system, but a severe respiratory virus infection may cause long-lasting neurological disturbances. These include encephalitis lethargica and narcolepsy. The mechanisms behind such long lasting changes are unknown. The hypothalamus is a central regulator of the homeostatic response during a viral challenge. To gain insight into the neuronal and non-neuronal molecular changes during an IAV infection, we intranasally infected mice with an H1N1 virus and extracted the brain at different time points. Using single-nucleus RNA sequencing (snRNA-seq) of the hypothalamus, we identify transcriptional effects in all identified cell populations. The snRNA-seq data showed the most pronounced transcriptional response at 3 days past infection, with a strong downregulation of genes across all cell types. General immune processes were mainly impacted in microglia, the brain resident immune cells, where we found increased numbers of cells expressing pro-inflammatory gene networks. In addition, we found that most neuronal cell populations downregulated genes contributing to the energy homeostasis in mitochondria and protein translation in the cytosol, indicating potential reduced cellular and neuronal activity. This might be a preventive mechanism in neuronal cells to avoid intracellular viral replication and attack by phagocytosing cells. The change of microglia gene activity suggest that this is complemented by a shift in microglia activity to provide increased surveillance of their surroundings.

Molecular consequences of peripheral Influenza A infection on cell populations in the murine hypothalamus.

Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite, and excessive sleepiness. These responses, mediated by the brain, will normally disappear once the virus is cleared from the system, but a severe respiratory virus infection may cause long-lasting neurological disturbances. These include encephalitis lethargica and narcolepsy. The mechanisms behind such long lasting changes are unknown. The hypothalamus is a central regulator of the homeostatic response during a viral challenge. To gain insight into the neuronal and non-neuronal molecular changes during an IAV infection, we intranasally infected mice with an H1N1 virus and extracted the brain at different time points. Using single-nucleus RNA sequencing (snRNA-seq) of the hypothalamus, we identify transcriptional effects in all identified cell populations. The snRNA-seq data showed the most pronounced transcriptional response at 3 days past infection, with a strong downregulation of genes across all cell types. General immune processes were mainly impacted in microglia, the brain resident immune cells, where we found increased numbers of cells expressing pro-inflammatory gene networks. In addition, we found that most neuronal cell populations downregulated genes contributing to the energy homeostasis in mitochondria and protein translation in the cytosol, indicating potential reduced cellular and neuronal activity. This might be a preventive mechanism in neuronal cells to avoid intracellular viral replication and attack by phagocytosing cells. The change of microglia gene activity suggest that this is complemented by a shift in microglia activity to provide increased surveillance of their surroundings.

Does vitamin D supplementation reduce the frequency or severity of respiratory viral infections in adults?

University of Chicago (NorthShore) Family Medicine Residency, Glenbrook, IL The corresponding author is Joseph Gibes; [email protected]. The authors declare no conflicts of interest.

The global epidemic trend analysis of influenza type B drug resistance sites from 2006 to 2018.

Influenza is a severe respiratory viral infection that causes significant morbidity and mortality, due to annual epidemics and unpredictable pandemics. With the extensive use of neuraminidase inhibitor (NAI) drugs, the influenza B virus has carried different drug-resistant mutations. Thus, this study aimed to analyze the prevalence of drug-resistant mutations of the influenza B virus. Near full-length sequences of the neuraminidase (NA) region of all influenza B viruses from January 1, 2006, to December 31, 2018, were downloaded from public databases GISAID and NCBI. Multiple sequence alignments were performed using Clustal Omega 1.2.4 software. Subsequently, phylogenetic trees were constructed by FastTree 2.1.11 and clustered by ClusterPickergui_1.2.3.JAR. Then, the major drug resistance sites and surrounding auxiliary sites were analyzed by Mega-X and Weblogo tools. Among the amino acid sequences of NA from 2006 to 2018, only Clust04 in 2018 carried a D197N mutation of the NA active site, while other drug resistance sites were conserved without mutation. According to the Weblogo analysis, a large number of N198, S295, K373, and K375 mutations were found in the amino acid residues at the auxiliary sites surrounding D197, N294, and R374. We found the D197N mutation in Clust04 of the 2018 influenza B virus, with a large number of N198, S295, K373, and K375 mutations in the helper sites around N197, N294, and R374 from 2006 to 2018. NA inhibitors are currently the only kind of specific antiviral agent for the influenza B virus, although these mutations cause mild NAIs resistance.

Severe respiratory viral infections: T-cell functions diverging from immunity to inflammation.

Respiratory viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) trigger distinct clinical outcomes defined by immunity-based viral clearance or disease associated with exaggerated and prolonged inflammation. The important role of T cells in shaping both antiviral immunity and inflammation has revived interest in understanding the host-pathogen interactions that lead to the diverse functions of T cells in respiratory viral infections. Inborn deficiencies and acquired insufficiency in immunity can prolong infection and shift the immune response towards exacerbated inflammation, which results from persistent innate immune activation and bystander T-cell activation that is nonspecific to the pathogen but is often driven by cytokines. This review discusses how virus variants, exposure doses, routes of infection, host genetics, and immune history can modulate the activation and function of T cells, thus influencing clinical outcomes. Knowledge of virus-host interaction can inform strategies to prevent immune dysfunction in respiratory viral infection and help in the treatment of associated diseases.

IFIH1 deficiency causing neonatal herpes simplex virus encephalitis and recurrent retinitis

Homozygous loss-of-function variants in Interferon induced with helicase C domain 1 (IFIH1) leads to immunodeficiency with early onset recurrent and severe viral respiratory infections (Immunodeficiency 95; MIM 619773). Severe respiratory infections with RNA viruses such as rhinovirus and respiratory syncytial virus (RSV) are most characteristic of IFIH1 deficiency. IFIH1 encodes melanoma differentiation-associated protein 5 (MDA5), an intracellular sensor of mainly long double-stranded RNA (ds-RNA), a viral replication intermediate. When activated, MDA5 triggers antiviral pathways including increased transcription of Type 1-interferon. The antiviral role of MDA5 is best described for positive (+) RNA viruses such as Picornavirus family which produce long ds-RNA as a replication intermediate. We present a patient with neonatal herpes simplex virus (HSV) encephalitis and recurrent retinitis with homozygous variant of unknown significance (VUS) in IFIH1, c.2062A>G (p.Lys688Glu).Patient is a 10-year-old male, born of consanguineous parents from the United Arab Emirates. Past medical history is notable for neonatal HSV encephalitis, grade 3 intraventricular hemorrhage, cerebral palsy, epilepsy, optic atrophy and recurrent HSV retinitis. Patient has no additional history of severe or recurrent infections. No family history of recurrent or severe infections, malignancy, autoimmunity or autoinflammation.Immune evaluation demonstrated anemia with elevated mean corpuscular volume and mild elevation of platelets and monocytes. Patient had normal lymphocyte subsets, normal T and B cell subset distributions, protective vaccine titers and normal immunoglobins apart from mildly elevated immunoglobulin G. An Invitae primary immunodeficiency panel demonstrated homozygous VUS in IFIH1, c.2062A>G (p.Lys688Glu). This variant is not found in gnomAD or ClinVar and has a Combined Annotation Dependent Depletion score of 22.6. Functional testing demonstrated decreased interferon induction after stimulation with intracellular RNA, intracellular DNA and agonists of both Toll-like receptor 7 and 9. These findings are consistent with MDA5 deficiency given decreased interferon response with known MDA5 agonists.In summary, we describe a patient with recurrent and severe infections with a DNA virus and no known infections with respiratory RNA viruses. Both DNA and RNA viruses produce long ds-RNA as replication intermediates, an MDA5 agonist. This patient highlights the anti-viral role of MDA5 for both DNA and RNA viruses.

Neuregulin-1 reduces vascular leak and airway epithelium permeability caused by respiratory viral infection

Abstract Respiratory viruses, such as Respiratory Syncytial Virus (RSV), are associated with significant morbidity and mortality. Mice with pre-existing atopy are protected from mortality to Sendai virus (SeV), a rodent virus related to RSV. We found that lungs of atopic mice had increased levels of neuregulin-1(NRG1), and hypothesized that SeV induces death via lung vascular leak, and that NRG1 might inhibit vascular leakage. Non-atopic C57Bl/6 mice were treated with NRG1 (500ng/30 mcl, i.n) or PBS for five days before infection with SeV (2×10 5pfu) or UV-inactivated SeV (UV-SeV) and 8 days post viral inoculation, Evan’s Blue Dye (EBD) was injected i.v with EBD concentration determined spectrophotometrically one hour later in homogenized lungs. Vascular leak in SeV-infected mice was 65.25% and 46.62% more than in UV-SeV-treated or SeV-infected mice pre-treated with NRG1, respectively. We also found that RSV infection of well-differentiated human bronchial epithelial cells (hBEC) grown at the air-liquid interface caused 70KDa FITC-Dextran leakage 8 days post-inoculation. NRG1 pretreatment for 5 days before RSV inoculation reduced epithelial leakage 8 days post-inoculation by 2.5 fold (p&amp;lt;0.001). These results suggest NRG1 has the potential to improve epithelial barrier function in rodent and human systems and may explain the increased survival following a severe respiratory viral infection. Abigail Wexner Research Institute at Nationwide Children’s Hospital, Start-up fund to MHG

A 4-year-old with life-threatening respiratory and neuro-invasive viral infections, and Burkitt lymphoma

We report a novel, homozygous c.745C>T (p.R249*) mutation in TYK2, resulting in autosomal recessive, complete TYK2 deficiency, causing susceptibility to repeated, severe respiratory viral infections, EBV-driven Burkitt lymphoma, and debilitating Jamestown Canyon viral encephalitis. The mutation causes loss of protein expression, resulting in loss of kinase and scaffolding function, with cellular loss of responsiveness to IFN-α, IFN-β, IL-10, IL-12 and IL-23. This case expands the mutation repertoire of TYK2 deficiency, as well as the potential spectrum of associated viral disease.