Baloxavir marboxil use for critical human infection of avian influenza A H5N6 virus.

BACKGROUND: Recent outbreaks of avian influenza and ongoing virus reassortment have drawn focus on spill-over infections. The increase in human infections with highly pathogenic avian influenza H5N6 virus and its high fatality rate posed a potential threat, necessitating the search for a more effective treatment. METHODS: Longitudinal clinical data and specimens were collected from five H5N6 patients after admission. All patients received antiviral treatment of either sequential monotherapy of oseltamivir and baloxavir or the two drugs in combination. Severity of illness; viral load in sputum, urine, and blood; and cytokine levels in serum and sputum were serially analyzed. FINDINGS: All patients developed acute respiratory distress syndrome (ARDS) and viral sepsis within 1 week after disease onset. When delayed oseltamivir showed poor effects, baloxavir was administered and rapidly decreased viral load. In addition, levels of IL-18, M-CSF, IL-6, and HGF in sputum and Mig and IL-18 in serum that reflected ARDS and sepsis deterioration, respectively, were also reduced with baloxavir usage. However, three patients eventually died from exacerbation of underlying disease and secondary bacterial infection. Nonsurvivors had more severe extrapulmonary organ dysfunction and insufficient H5N6 virus-specific antibody response. CONCLUSIONS: For critical human cases of H5N6 infection, baloxavir demonstrated effects on viral load and pulmonary/extrapulmonary cytokines, even though treatment was delayed. Baloxavir could be regarded as a first-line treatment to limit continued viral propagation, with potential future application in avian influenza human infections and poultry workers exhibiting influenza-like illness. FUNDING: This work was funded by the National Natural Science Foundation of China (81761128014).

The impact of pre-existing influenza antibodies and inflammatory status on the influenza vaccine responses in older adults.

Age-associated immune changes and pre-existing influenza immunity are hypothesized to reduce influenza vaccine effectiveness in older adults, although the contribution of each factor is unknown. Here, we constructed influenza-specific IgG landscapes and determined baseline concentrations of cytokines typically associated with chronic inflammation in older adults (TNF-α, IL-10, IL-6, and IFN-γ) in 30 high and 29 low influenza vaccine responders (HR and LR, respectively). In a background of high H3 antibody titers, vaccine-specific H3, but not H1, antibody titers were boosted in LRs to titers comparable to HRs. Pre-vaccination concentrations of IL-10 were higher in LRs compared with HRs and inversely correlated with titers of pre-existing influenza antibodies. Baseline TNF-α concentrations were positively correlated with fold-increases in antibody titers in HRs. Our findings indicate that baseline inflammatory status is an important determinant for generating post-vaccination hemagglutinin-inhibition antibodies in older adults, and IgG responses can be boosted in the context of high pre-existing immunity.

Real-time assessment of COVID-19 epidemic in Guangdong Province, China using mathematical models.

China government has relaxed the response measures of COVID-19 in early December 2022. In this report, we assessed the number of infections, the number of severe cases based on the current epidemic trend (October 22, 2022 to November 30, 2022) using a transmission dynamics model, called modified susceptible-exposed-infectious-removed (SEIR) to provide valuable information to ensure the medical operation of the healthcare system under the new situation. Our model showed that the present outbreak in Guangdong Province peaked during December 21, 2022 to December 25, 2022 with about 14.98 million new infections (95% CI: 14.23-15.73 million). The cumulative number of infections will reach about 70% of the province's population from December 24, 2022 to December 26, 2022. The number of existing severe cases is expected to peak during January 1, 2023 to January 5, 2023 with a peak number of approximately 101.45 thousand (95% CI: 96.38-106.52 thousand). In addition, the epidemic in Guangzhou which is the capital city of Guangdong Province is expected to have peaked around December 22, 2022 to December 23, 2022 with the number of new infections at the peak being about 2.45 million (95% CI: 2.33-2.57 million). The cumulative number of infected people will reach about 70% of the city's population from December 24, 2022 to December 25, 2022 and the number of existing severe cases is expected to peak around January 4, 2023 to January 6, 2023 with the number of existing severe cases at the peak being about 6.32 thousand (95% CI: 6.00-6.64 thousand). Predicted results enable the government to prepare medically and plan for potential risks in advance.

Culturing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) for Diagnosis and Genome Sequencing.

OBJECTIVE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid detection "re-positive" phenomenon is encountered clinically. The accuracy of a viral nucleic acid test is crucial to prevent reintroduction of the virus into the community. This study evaluated the effect of virus culturing on increasing the sensitivity and specificity of real-time polymerase chain reaction (RT-PCR) detection and viral genomic sequencing. METHODS: A series of tenfold dilutions of a SARS-CoV-2 viral stock were conducted and cultured for either 24 or 48 hours. The viral load of cultured samples was determined by RT-PCR. The cultured and non-cultured samples of 1x 50% tissue culture infectious dose (TCID50) were sequenced using metagenomic next-generation sequencing. The depth and coverage of SARS-CoV-2 genome were measured. RESULTS: The lowest viral load detectable in a sample with RT-PCR was 0.01 TCID50. After a 24-h culture, the viral ORF 1ab and N-gene cycle threshold (CT) values were reduced by 4.4 points and 1 point, respectively. One TCID50 viral load of post 24-h culture revealed the sequence depth reached an average of 752 reads, compared with 0.15 in the nonculture; furthermore, the coverage was 99.99% while 6.42% in the nonculture. CONCLUSION: These results indicate that virus culturing can significantly increase the viral load, which can increase the certainty of true-positive detection of the viral nucleic acids, and improve the quality of virus genomic sequencing.

Containment of SARS-CoV-2 Delta strain in Guangzhou, China by quarantine and social distancing: a modelling study.

China detected the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with Delta variant in May 2021. We assessed control strategies against this variant of concern. We constructed a robust transmission model to assess the effectiveness of interventions against the Delta variant in Guangzhou with initial quarantine/isolation, followed by social distancing. We also assessed the effectiveness of alternative strategies and that against potentially more infectious variants. The effective reproduction number (Rt) fell below 1 when the average daily number of close contacts was reduced to ≤ 7 and quarantine/isolation was implemented on average at the same day of symptom onset in Guangzhou. Simulations showed that the outbreak could still be contained when quarantine is implemented on average 1 day after symptom onset while the average daily number of close contacts was reduced to ≤ 9 per person one week after the outbreak's beginning. Early quarantine and reduction of close contacts were found to be important for containment of the outbreaks. Early implementation of quarantine/isolation along with social distancing measures could effectively suppress spread of the Delta and more infectious variants.

Simultaneous profiling and quantification of 25 eicosanoids in human serum by ultrahigh-performance liquid chromatography coupled to tandem mass spectrometry.

The eicosanoid metabolic pathway is responsible for mediating the production of various inflammatory factors that are closely related to the development and resolution of inflammation. In biological matrices, the major quantifying obstacles were shown to be the oxidation and low quantities of eicosanoids and their metabolites. This study aimed to develop a reliable, sensitive ultrahigh-performance liquid chromatography coupled to a tandem mass spectrometry (UPLC-MS/MS) method to quantify eicosanoids in human serum. Solid-phase extraction (SPE) was used for sample preparation. The approach employed continuous ionization polarity switching. The target eicosanoids showed good linearity over the investigated concentration range (r2 > 0.99). The recovery rates were over 64.5%, and the matrix effects ranged from 73.0 to 128.0%. The limits of quantification were 0.048 ~ 0.44 ng/mL. For the broad concentration range, the CV % for accuracy and precision were less than ± 20%. We successfully applied this method to rapidly analyse 74 serum samples from severe influenza pneumonia, severe bacterial pneumonia and healthy individuals. Eicosanoid-related metabolite concentrations were quantified within a range similar to those of previously published articles. Compared to healthy individuals, our application found that 20-HETE, 14,15-EET and 11,12-EET were upregulated in severe influenza pneumonia patients, while LTB4 was downregulated. 8-HETE and 5-HETE were upregulated in severe bacterial pneumonia patients, while LTE4 was downregulated. This approach provides a means for monitoring the low quantities of eicosanoids in biological matrices, and our finding that different characteristic metabolite profiles may help discriminate the induction of severe pneumonia patients.

The genetic characterization of hemagglutinin (HA), neuraminidase (NA) and polymerase acidic (PA) genes of H3N2 influenza viruses circulated in Guangdong Province of China during 2019-2020.

The evolution of seasonal influenza viruses, which can cause virus antigenic drift to escape human herd immunity, is a significant public health problem. Here, we obtained hemagglutinin (HA), neuraminidase (NA), and polymerase acidic protein (PA) the gene sequences of 84 influenza virus isolates collected in Guangdong Province during the 2019-2020 influenza season. Phylogenetic analyses revealed all these isolates were genetically similar to the viruses of clade 3C2a A1b, specifically those within subclades of A1b 137F (59 cases), A1b 186D (19 cases), and A1b 94 N (6 cases). The influenza virus isolates were distinct from the World Health Organization recommended influenza A vaccine virus for the 2019-2020 Northern Hemisphere season (A/Kansas/14/2017; H3N2). Phylogenies inferred from the individual gene segment sequences revealed that one reassortment event occurred among these clades. The genetic variation involved mutations within viral antigenic epitopes and two N-glycosylation site alterations. The novel mutation sites of G202D and D206N in the HA gene, E344K in the NA gene, and K626R in the PA gene which may affect the spread of the virus were observed. We investigated the evolution of these genes and found that the HA and NA genes were under greater pressure than PA gene. Mutations associated with conferring resistance to NA inhibitors or baloxavir acid were not found. Our results suggest that a rapid evolution of the H3N2 influenza virus occurred, thus continuous monitoring is critical for establishing appropriate vaccine formulations or drug delivery for targeting influenza.

Using discrete event simulation to optimize nucleic acid testing process for coronavirus disease 2019 (COVID-19).

Background: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory coronavirus-2 (SARS-CoV-2) has placed enormous diagnostic burden on hospitals and testing laboratories. It is thus critical for such facilities to optimize the diagnostic process to enable maximum testing on minimum resources. The current standard of diagnosis is the detection of the viral nucleic acid in clinical specimens. Methods: In order to optimize the laboratory's nucleic acid testing system for COVID-19, we performed a Discrete-Event-Simulation using the Arena Simulation Software to model the detection process based on the data obtained from the First Affiliated Hospital of Guangzhou Medical University (FAHGMU). The maximum of total time that specimens spent and the equipment consumption was compared under different scenarios in the model. Results: Seven scenarios were performed to simulate actual situation and improved situations. We analyzed conditions that adding a new nucleic acid extraction system (NAES), shifting a member from night duty to morning duty, using specimen tubes containing guanidine isothiocyanate (GITC), then tested the maximum testing capacity in the current number of technicians. In addition, the costs including personal protective equipment (PPE) and testing kits was calculated. Conclusions: A work schedule based on specimen-load improves efficiency without incurring additional costs, while using the specimen tubes containing GITC could reduce testing time by 30 min. In contrast, adding new NAESs or polymerase chain reaction (PCR) instruments has minimal impact on testing efficiency.

Crucial control measures to contain China's first Delta variant outbreak.

The SARS-CoV-2 B.1.617.2 (Delta) variant flared up in late May in Guangzhou, China. Transmission characteristics of Delta variant were analysed for 153 confirmed cases and two complete transmission chains with seven generations were fully presented. A rapid transmission occurred in five generations within 10 days. The basic reproduction number (R0) was 3.60 (95% confidence interval: 2.50-5.30). After redefining the concept of close contact, the proportion of confirmed cases discovered from close contacts increased from 43% to 100%. With the usage of a yellow health code, the potential exposed individuals were self-motivated to take a nucleic acid test and regained public access with a negative testing result. Facing the massive requirement of screening, novel facilities like makeshift inflatable laboratories were promptly set up as a vital supplement and 17 cases were found, with 1 pre-symptomatic. The dynamic adjustment of these three interventions resulted in the decline of Rt from 5.00 to 1.00 within 9 days. By breaking the transmission chain and eliminating the transmission source through extending the scope of the close-contact tracing, health-code usage and mass testing, the Guangzhou Delta epidemic was effectively contained.

Chinese expert consensus on immunoprophylaxis of common respiratory pathogens in children (2021 edition).

Respiratory tract infections are infectious diseases involving the respiratory tract (such as the sinuses, throat, airways or lungs), which are the common respiratory disorders in children. With the development of society and the improvement of economic conditions, great progress has been made in China in the prevention of common respiratory pathogens in children. As a result, the incidence and mortality of respiratory tract infections in children have dropped sharply in the past decades. However, there is still a certain gap compared with the international leading levels, which can be partly attribute to insufficient public awareness of vaccination, uneven vaccination services of vaccinators, and so on. On the basis of comprehensive analysis of the clinical evidence of immunoprophylaxis of common respiratory pathogens among children in China and abroad, combined with the clinical situation and the experience of experts, the consensus focuses on the characteristics of transmission, clinical manifestations and immunoprophylaxis of common respiratory pathogens in children, so as to provide reference for clinical practice. This consensus document applies to all Centers for Disease Control and Prevention (CDC) staff levels engaged in the prevention and control of related pathogens, vaccinators at vaccination sites, and medical staff in pediatric, respiratory, and infectious diseases departments at all levels in medical institutions.

Co-infecting pathogens can contribute to inflammatory responses and severe symptoms in COVID-19.

Background: The current COVID-19 pandemic is posing a major challenge to public health on a global scale. While it is generally believed that severe COVID-19 results from over-expression of inflammatory mediators (i.e., a "cytokine storm"), it is still unclear whether and how co-infecting pathogens contribute to disease pathogenesis. To address this, we followed the entire course of the disease in cases with severe or critical COVID-19 to determine the presence and abundance of all potential pathogens present-the total "infectome"-and how they interact with the host immune system in the context of severe COVID-19. Methods: We examined one severe and three critical cases of COVID-19, as well as a set of healthy controls, with longitudinal samples (throat swab, whole blood, and serum) collected from each case. Total RNA sequencing (meta-transcriptomics) was performed to simultaneously investigate pathogen diversity and abundance, as well as host immune responses, in each sample. A Bio-Plex method was used to measure serum cytokine and chemokine levels. Results: Eight pathogens, SARS-CoV-2, Aspergillus fumigatus (A. fumigatus), Mycoplasma orale (M. orale), Myroides odoratus (M. odoratus), Acinetobacter baumannii (A. baumannii), Candida tropicalis, herpes simplex virus (HSV) and human cytomegalovirus (CMV), identified in patients with COVID-19 appeared at different stages of the disease. The dynamics of inflammatory mediators in serum and the respiratory tract were more strongly associated with the dynamics of the infectome compared with SARS-CoV-2 alone. Correlation analysis revealed that pulmonary injury was directly associated with cytokine levels, which in turn were associated with the proliferation of SARS-CoV-2 and co-infecting pathogens. Conclusions: For each patient, the cytokine storm that resulted in acute lung injury and death involved a dynamic and highly complex infectome, of which SARS-CoV-2 was a component. These results indicate the need for a precision medicine approach to investigate both the infection and host response as a standard means of infectious disease characterization.

How fast and how well the Omicron epidemic was curtailed. A Guangzhou experience to share.

Introduction: SARS-CoV-2 has ravaged the world and undergone multiple mutations during the course of the COVID-19 pandemic. On 7 April 2022, an epidemic caused by SARS-CoV-2 Omicron (BA.2) variant broke out in Guangzhou, China, one of the largest transportation and logistical hubs of the country. Methods: To fast curtained the Omicron epidemic, based on the routine surveillance on the risk population of SARS-CoV-2 infection, we identify key places of the epidemic and implement enhanced control measures against Omicron. Results: Transmission characteristics of the Omicron variant were analyzed for 273 confirmed cases, and key places involved in this epidemic were fully presented. The median incubation time and the generation time were 3 days, and the reproduction number Rt was sharply increased with a peak of 4.20 within 2 days. We tried an all-out effort to tackle the epidemic in key places, and the proportion of confirmed cases increased from 61.17% at Stage 2 to 88.89% at Stage 4. Through delimited risk area management, 99 cases were found, and the cases were isolated in advance for 2.61 ± 2.76 days in a lockdown zone, 0.44 ± 1.08 days in a controlled zone, and 0.27 ± 0.62 days in a precautionary zone. People assigned with yellow code accounted for 30.32% (84/277) of confirmed COVID-19 cases, and 83.33% of them were detected positive over 3 days since code assignment. For the districts outside the epicenter, the implementation duration of NPIs was much shorter compared with the Delta epidemic last year. Conclusion: By blocking out transmission risks and adjusting measures to local epidemic conditions through the all-out effort to tackle the epidemic in key places, by delimiting risk area management, and by conducting health code management of the at-risk population, the Omicron epidemic could be contained quickly.

Seroprevalence of Antibodies to SARS-CoV-2 in Guangdong Province, China between March to June 2020.

Guangdong province, located in South China, is an important economic hub with a large domestic migrant population and was among the earliest areas to report COVID-19 cases outside of Wuhan. We conducted a cross-sectional, age-stratified serosurvey to determine the seroprevalence of antibodies against SARS-CoV-2 after the emergence of COVID-19 in Guangdong. We tested 14,629 residual serum samples that were submitted for clinical testing from 21 prefectures between March and June 2020 for SARS-CoV-2 antibodies using a magnetic particle based chemiluminescent enzyme immunoassay and validated the results using a pseudovirus neutralization assay. We found 21 samples positive for SARS-CoV-2 IgG, resulting in an estimated age- and sex-weighted seroprevalence of 0.15% (95% CI: 0.06-0.24%). The overall age-specific seroprevalence was 0.07% (95% CI: 0.01-0.24%) in persons up to 9 years old, 0.22% (95% CI: 0.03-0.79%) in persons aged 10-19, 0.16% (95% CI: 0.07-0.33%) in persons aged 20-39, 0.13% (95% CI: 0.03-0.33%) in persons aged 40-59 and 0.18% (95% CI: 0.07-0.40%) in persons ≥60 years old. Fourteen (67%) samples had pseudovirus neutralization titers to S-protein, suggesting most of the IgG-positive samples were true-positives. Seroprevalence of antibodies to SARS-CoV-2 was low, indicating that there were no hidden epidemics during this period. Vaccination is urgently needed to increase population immunity to SARS-CoV-2.

Clinical impact of nosocomial infection with pandemic influenza A (H1N1) 2009 in a respiratory ward in Guangzhou.

BACKGROUND: Nosocomial outbreaks of pandemic influenza A (H1N1) 2009 virus [A(H1N1)pdm09] easily develop due to its high transmissibility. This study aimed to investigate the clinical impacts of a nosocomial outbreak of A(H1N1)pdm09 between 21 January and 17 February 2016. METHODS: Patients who developed influenza-like illness (ILI) more than 48 hours after hospitalization in the index ward were enrolled as suspected patients, defined as group A and quarantined. Patients in other wards were defined as group B. A phylogenetic tree was constructed to determine the origins of the hemagglutinin and neuraminidase genes. RESULTS: After the implementation of an infection control measure bundle, the outbreak was limited to eight patients with ILIs in group A. Nasal swabs from seven patients were positive for A(H1N1)pdm09. All the patients recovered after treatment. Prolonged viral shedding was observed in a patient with bronchiectasis and Penicillium marneffei infection. Compared to the expected duration of hospitalization in patients without fever, those with fever had a median 7-day delay in discharge and a mean excess cost of 3,358 RMB. The four influenza strains identified were genetically identical to the A/California/115/2015 strain. Six of the 54 patients in group B who underwent bronchoscopy developed transient fever. These patients were hospitalized in various wards of the hospital and recovered after a short-term course of empirical antibiotics. CONCLUSIONS: After the implementation of infection control measures, the nosocomial A(H1N1)pdm09 outbreak was rapidly contained; infected patients had a delay in discharge and excess costs, but no deaths occurred.

Multiple basic amino acids in the cleavage site of H7N9 hemagglutinin contribute to high virulence in mice.

BACKGROUND: Avian influenza A (H7N9) virus has caused more than 1,500 cases of human infection since its emergence in early 2013. Displaying little or no pathogenicity in poultry, but a 40% case-fatality rate in humans, five waves of H7N9 human infections occurred in China during 2013-2017, caused solely by a low pathogenicity strain. However, avian isolates possessing a polybasic connecting peptide in the hemagglutinin (HA) protein were detected in mid-2016, indicating that a highly pathogenic virus had emerged and was co-circulating with the low pathogenicity strains. METHODS: Here we characterize the pathogenicity of a newly emerged human H7N9 variant with a PEVPKRKRTAR/GLF insertion motif at the cleavage site of the HA protein in vitro and in vivo. RESULTS: This variant replicates in MDCK cells independently of TPCK-trypsin, which is indicative of high pathogenicity in chickens. The 50% mouse lethal dose (MLD50) of this novel isolate was less than 10 plaque forming units (PFU), compared with 3.16×104 for an identical virus lacking the polybasic insertion, indicating a high virulence phenotype. CONCLUSIONS: Our results demonstrate that the multiple basic amino acid insertion in the HA protein of the H7N9 variant confers high virulence in mammals, highlighting a potential risk to humans. Continuous viral surveillance is therefore necessary in the China region to improve pandemic preparedness.

Antigenic Drift of the Hemagglutinin from an Influenza A (H1N1) pdm09 Clinical Isolate Increases its Pathogenicity In Vitro.

The influenza A (H1N1) pdm09 virus emerged in 2009 and has been continuously circulating in humans for over ten years. Here, we analyzed a clinical influenza A (H1N1) pdm09-infected patient case hospitalized for two months in Guangdong (from December 14, 2019 to February 15, 2020). This isolate, named A/Guangdong/LCF/2019 (LCF/19), was genetically sequenced, rescued by reverse genetics, and phylogenetically analyzed in the context of other relevant pdm09 isolates. Compared with earlier isolates, this pdm09 virus's genetic sequence contains four substitutions, S186P, T188I, D190A, and Q192E, of the hemagglutinin (HA) segment at position 186-192 (H3 numbering) in the epitope Sb, and two of which are located at the 190-helix. Phylogenetic analysis indicated that the epitope Sb started undergoing a rapid antigenic change in 2018. To characterize the pathogenicity of this novel substitution motif, a panel of reassortant viruses containing the LCF/2019 HA segment or the chimeric HA segment with the four substitutions were rescued. Kinetic growth data revealed that the reassortant viruses, including the LCF/2019 with the PTIAAQE substitution, propagated faster than those rescued ones having the STTADQQ motif in the epitope Sb in Madin-Darby Canine Kidney (MDCK) cells. The HI test showed that the binding activity of escape mutant to 2018 pdm09 sera was weaker than GLW/2018, suggesting that old vaccines might not effectively protect people from infection. Due to the difference in the selection of vaccine strains, people vaccinated in the southern hemisphere could still suffer a severe infection if infected with this antigenic drift pdm09 virus.

Different Circulation Pattern of Multiple Respiratory Viruses in Southern China During the COVID-19 Pandemic.

China implemented stringent non-pharmaceutical interventions (NPIs) in spring 2020, which has effectively suppressed SARS-CoV-2. In this study, we utilized data from routine respiratory virus testing requests from physicians and examined circulation of 11 other respiratory viruses in Southern China, from January 1, 2018 to December 31, 2020. A total of 58,169 throat swabs from patients with acute respiratory tract infections (ARTIs) were collected and tested. We found that while the overall activity of respiratory viruses was lower during the period with stringent NPIs, virus activity rebounded shortly after the NPIs were relaxed and social activities resumed. Only influenza was effectively suppressed with very low circulation which extended to the end of 2020. Circulation of other respiratory viruses in the community was maintained even during the period of stringent interventions, especially for rhinovirus. Our study shows that NPIs against COVID-19 have different impacts on respiratory viruses.

Publisher Correction: Exuberant fibroblast activity compromises lung function via ADAMTS4.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Exuberant fibroblast activity compromises lung function via ADAMTS4.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.