IFI27 transcription is an early predictor for COVID-19 outcomes, a multi-cohort observational study.

Purpose: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. Methods: We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients. Results: We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients. Conclusion: These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.

Environmentally persistent free radicals enhance SARS-CoV-2 replication in respiratory epithelium.

Epidemiological evidence links lower air quality with increased incidence and severity of COVID-19; however, mechanistic data have yet to be published. We hypothesized air pollution-induced oxidative stress in the nasal epithelium increased viral replication and inflammation. Nasal epithelial cells (NECs), collected from healthy adults, were grown into a fully differentiated epithelium. NECs were infected with the ancestral strain of SARS-CoV-2. An oxidant combustion by-product found in air pollution, the environmentally persistent free radical (EPFR) DCB230, was used to mimic pollution exposure four hours prior to infection. Some wells were pretreated with antioxidant, astaxanthin, for 24 hours prior to EPFR-DCB230 exposure and/or SARS-CoV-2 infection. Outcomes included viral replication, epithelial integrity, surface receptor expression (ACE2, TMPRSS2), cytokine mRNA expression (TNF-α, IFN-ß), intracellular signaling pathways, and oxidative defense enzymes. SARS-CoV-2 infection induced a mild phenotype in NECs, with some cell death, upregulation of the antiviral cytokine IFN-ß, but had little effect on intracellular pathways or oxidative defense enzymes. Prior exposure to EPFR-DCB230 increased SARS-CoV-2 replication, upregulated TMPRSS2 expression, increased secretion of the proinflammatory cytokine TNF-α, inhibited expression of the mucus producing MUC5AC gene, upregulated expression of p21 (apoptosis pathway), PINK1 (mitophagy pathway), and reduced levels of antioxidant enzymes. Pretreatment with astaxanthin reduced SARS-CoV-2 replication, downregulated ACE2 expression, and prevented most, but not all EPFR-DCB230 effects. Our data suggest that oxidant damage to the respiratory epithelium may underly the link between poor air quality and increased COVID-19. The apparent protection by antioxidants warrants further research.

Environmental Impacts on Infectious Disease: A Literature View of Epidemiological Evidence.

Background: This article summarises a session from the recent Pacific Basin Consortium for Environment and Health Focus meeting on Environmental Impacts on Infectious Disease. Objective: To provide an overview of the literature underpinning the presentations from this session. Methods: References used in developing the presentations were obtained from the presenters. Additional references were obtained from PubMed using key words from the presentations. Findings and Conclusions: The Hokkaido longitudinal children's study has found that exposure to chemicals in early life, such as persistent organic pollutants and per/polyfluorinated compounds, is associated with a range of immunological outcomes such as decreased cord blood IgE, otitis media, wheeze, increased risk of infections and higher risk of food allergy.Epidemiological evidence links exposure to poor air quality to increased severity and mortality of Covid-19 in many parts of the world. Most studies suggest that long-term exposure has a more marked effect than acute exposure.Components of air pollution, such as a newly described combustion product known as environmentally persistent free radicals, induce oxidative stress in exposed individuals. Individuals with genetic variations predisposing them to oxidative stress are at increased risk of adverse health effects from poor air quality.

Ancestral SARS-CoV-2, but not Omicron, replicates less efficiently in primary pediatric nasal epithelial cells.

Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when compared to adults. There is a strong body of evidence that children are also less susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remain to be determined. Here, we use primary nasal epithelial cells (NECs) from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the NECs of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the NECs of children. Importantly, the Delta variant also replicated to significantly lower titers in the NECs of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.

Interference between rhinovirus and other RNA respiratory viruses in the first 2-years of life: A longitudinal community-based birth cohort study.

BACKGROUND: Cross-sectional studies report negative associations between rhinovirus and other RNA respiratory viruses. However, longitudinal studies with frequent, serial sampling are needed to identify the directionality of this relationship and its nature. OBJECTIVE: To investigate the association between rhinovirus and other RNA respiratory viruses detected 1-week apart. METHODS: The Observational Research in Childhood Infectious Diseases cohort study was conducted in Brisbane, Australia (2010-2014). Parents collected nasal swabs weekly from birth until age 2-years. Swabs were analysed by real-time polymerase chain reaction. The association between new rhinovirus detections and five other RNA viruses (influenza, respiratory syncytial virus, parainfluenza viruses, seasonal human coronaviruses, and human metapneumovirus) in paired swabs 1-week apart were investigated. RESULTS: Overall, 157 children provided 8,101 swabs, from which 4,672 paired swabs 1-week apart were analysed. New rhinovirus detections were negatively associated with new pooled RNA respiratory virus detections 1-week later (adjusted odds ratio (aOR) 0.48; 95% confidence interval (CI): 0.13-0.83), as were pooled RNA virus detections with new rhinovirus detections the following week (aOR 0.34; 95%CI: 0.09-0.60). At the individual species level, rhinovirus had the strongest negative association with new seasonal human coronavirus detections in the subsequent week (aOR 0.34; 95%CI: 0.120.95) and respiratory syncytial virus had the strongest negative association with rhinovirus 1-week later (aOR 0.21; 95%CI: 0.050.88). CONCLUSION: A strong, negative bidirectional association was observed between rhinovirus and other RNA viruses in a longitudinal study of a community-based cohort of young Australian children. This suggests within-host interference between RNA respiratory viruses.

Formation of Calprotectin-Derived Peptides in the Airways of Children with Cystic Fibrosis.

Calprotectin is released by activated neutrophils along with myeloperoxidase (MPO) and proteases. It plays numerous roles in inflammation and infection, and is used as an inflammatory biomarker. However, calprotectin is readily oxidized by MPO-derived hypohalous acids to form covalent dimers of its S100A8 and S100A9 subunits. The dimers are susceptible to degradation by proteases. We show that detection of human calprotectin by ELISA declines markedly because of its oxidation by hypochlorous acid and subsequent degradation. Also, proteolysis liberates specific peptides from oxidized calprotectin that is present at inflammatory sites. We identified six calprotectin-derived peptides by mass spectrometry and detected them in the bronchoalveolar lavage fluid of children with cystic fibrosis (CF). We assessed the peptides as biomarkers of neutrophilic inflammation and infection. The content of the calprotectin peptide ILVI was related to calprotectin (r = 0.72, p = 0.01, n = 10). Four of the peptides were correlated with the concentration of MPO (r > 0.7, p ≤ 0.01, n = 21), while three were higher (p < 0.05) in neutrophil elastase-positive (n = 14) than -negative samples (n = 7). Also, five of the peptides were higher (p < 0.05) in the bronchoalveolar lavage fluid from children with CF with infections (n = 21) than from non-CF children without infections (n = 6). The specific peptides liberated from calprotectin will signal uncontrolled activity of proteases and MPO during inflammation. They may prove useful in tracking inflammation in respiratory diseases dominated by neutrophils, including coronavirus disease 2019.

Health consequences of disinfection against SARS-CoV-2: Exploring oxidative stress damage using a biomonitoring approach.

Individuals who get involved in the disinfection of public settings using sodium hypochlorite might suffer adverse health effects. However, scarce information is available on the potential oxidative stress damage caused at low concentrations typically used for disinfection. We aimed to assess whether exposure to sodium hypochlorite during the COVID-19 pandemic causes oxidative stress damage in workers engaged in disinfection tasks. 75 operators engaged in the disinfection of public places were recruited as the case group, and 60 individuals who were not exposed to disinfectant were chosen as the control group. Spot urine samples were collected before (BE) and after exposure (AE) to disinfectants in the case group. Likewise, controls provided two spot urine samples in the same way as the case group. Urinary malondialdehyde (MDA) levels were quantified by forming thiobarbituric acid reactive substances in the urine. In addition, the concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the urine was determined using an ELISA kit. Results showed significant differences in the urinary levels of oxidative stress markers, where median 8-OHdG (AE case: 3.84 ± 2.89 µg/g creatinine vs AE control 2.54 ± 1.21 µg/g creatinine) and MDA (AE case: 169 ± 89 µg/g creatinine vs AE control 121 ± 47 µg/g creatinine) levels in case group AE samples were 1.55 and 1.35-times higher than the control group AE samples (P < 0.05), respectively. Besides, urinary levels of oxidative stress markers in AE samples of the case group were significantly higher than in BE samples (8-OHdG BE 3.40 ± 1.95 µg/g creatinine, MDA BE 136 ± 51.3 µg/g creatinine, P < 0.05). Our results indicated that exposure to even low levels of sodium hypochlorite used in disinfection practices might cause oxidative stress related damage. With this in mind, implementing robust protective measures, such as specific respirators, is crucial to reduce the health burdens of exposure to disinfectants.

The interplay between environmental exposures and COVID-19 risks in the health of children.

BACKGROUND: An unusual feature of SARS-Cov-2 infection and the COVID-19 pandemic is that children are less severely affected than adults. This is especially paradoxical given the epidemiological links between poor air quality and increased COVID-19 severity in adults and that children are generally more vulnerable than adults to the adverse consequences of air pollution. OBJECTIVES: To identify gaps in knowledge about the factors that protect children from severe SARS-Cov-2 infection even in the face of air pollution, and to develop a transdisciplinary research strategy to address these gaps. METHODS: An international group of researchers interested in children's environmental health was invited to identify knowledge gaps and to develop research questions to close these gaps. DISCUSSION: Key research questions identified include: what are the effects of SAR-Cov-2 infection during pregnancy on the developing fetus and child; what is the impact of age at infection and genetic susceptibility on disease severity; why do some children with COVID-19 infection develop toxic shock and Kawasaki-like symptoms; what are the impacts of toxic environmental exposures including poor air quality, chemical and metal exposures on innate immunity, especially in the respiratory epithelium; what is the possible role of a "dirty" environment in conveying protection - an example of the "hygiene hypothesis"; and what are the long term health effects of SARS-Cov-2 infection in early life. CONCLUSION: A concerted research effort by a multidisciplinary team of scientists is needed to understand the links between environmental exposures, especially air pollution and COVID-19. We call for specific research funding to encourage basic and clinical research to understand if/why exposure to environmental factors is associated with more severe disease, why children appear to be protected, and how innate immune responses may be involved. Lessons learned about SARS-Cov-2 infection in our children will help us to understand and reduce disease severity in adults, the opposite of the usual scenario.