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Prevalence and Clinical Disease Severity of Respiratory Coinfections During the Coronavirus Disease 2019 Pandemic

Published:August 09, 2022DOI:https://doi.org/10.1016/j.yamp.2022.07.003

      Keywords

      Key points

      • An increased use of multiplex polymerase chain reaction–based assays has challenged the notion of a single respiratory pathogen always being responsible for a given disease.
      • Rates of coinfection between severe acute respiratory syndrome coronavirus 2 and other respiratory viruses is highly variable based on etiology and patient population.
      • Rates of coinfection or superinfection with bacteria are generally lower in patients with coronavirus disease 2019 than for those with influenza or respiratory syncytial virus.
      • Higher rates of bacterial and fungal pneumonia in ventilated patients with coronavirus disease 2019 in the intensive care unit warrants increased diagnostic testing and empirical antibiotic therapy.
      • Low rates of community-acquired respiratory coinfections, and higher rates of antimicrobial resistance, warrant greater antibiotic stewardship for patients with nonsevere coronavirus disease 2019.

      Introduction

      Respiratory tract infections represent a major global health concern. Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 470 million confirmed cases and approximately 6 million deaths worldwide [
      • World Health Organization Coronavirus
      COVID-19) Dashboard.
      ]. Since the beginning of COVID-19 pandemic, the presence of more than 1 pathogenic organism in the respiratory tract of patients with COVID-19 has been widely recognized owing to the availability of advanced molecular detection technologies, such as multiplex polymerase chain reaction (PCR) and next-generation sequencing. However, the association between the occurrence of multiple pathogen infections and clinical disease severity remains unclear. In the study of disease evolution, multiple infections fall into 2 broad categories: coinfection and superinfection. Coinfection occurs when a person is found to be infected by two or more micro-organisms, but which infection was established first cannot be clearly determined, while superinfection is an infection arising when one or more infections is already present. A substantial number of patients with COVID-19 were also coinfected with various pathogens, including other respiratory viruses, bacteria, and fungi, which can influence infectious disease dynamics. This review presents an overview of the prevalence and clinical disease severity of respiratory coinfections and superinfections (Table 1) and discusses possible mechanisms of the interactions between viral infections, including SARS-CoV-2, and bacterial infections during the COVID-19 pandemic.
      Table 1Prevalence of common coinfections in patients with COVID-19
      CoinfectionsGeographyPatient PopulationDiagnostic Method for Coinfected AgentsNo. of PatientsNo. of Coinfected CaseCoinfection RateReference
      References included in the review are arranged alphabetiacally within each type of coinfection.
      Viral coinfection
       SARS-CoV-2 coinfected with influenza A/BChinaAged ≥ 50 yIgM serology2139745.5%Cheng et al,
      • Cheng Y.
      • Ma J.
      • Wang H.
      • et al.
      Co-infection of influenza A virus and SARS-CoV-2: a retrospective cohort study.
      2021
      SpainAdultsNAAT25572%–8%Garcia-Vidal et al,
      • Garcia-Vidal C.
      • Sanjuan G.
      • Moreno-García E.
      • et al.
      Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study.
      2021
      JapanAdultsNAAT298289.4%Ishiguro et al,
      • Ishiguro T.
      • Kobayashi Y.
      • Shimizu Y.
      • et al.
      Frequency and Significance of Coinfection in Patients with COVID-19 at Hospital Admission.
      2021
      USAAdultsNAAT11610.9%Kim et al,
      • Kim D.
      • Quinn J.
      • Pinsky B.
      • et al.
      Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens.
      2020
      TurkeyAdultsDirect fluorescent antibody110360.5%Ozaras et al,
      • Ozaras R.
      • Cirpin R.
      • Duran A.
      • et al.
      Influenza and COVID-19 coinfection: report of six cases and review of the literature.
      2020
      USAAdultsNAAT2555822.8%Rizzo et al,
      • Rizzo K.R.
      • Hoover C.
      • Jain S.
      • et al.
      Influenza and SARS-CoV-2 Co-infections in California, USA, September 2020-April 2021.
      2021
      ChinaChildrenNAAT3412.9%Wu et al,
      • Wu Q.
      • Xing Y.
      • Shi L.
      • et al.
      Coinfection and Other Clinical Characteristics of COVID-19 in Children.
      2020
      ChinaAdultsNAAT14521.4%Xiang et al,
      • Xiang X.
      • Wang Z.H.
      • Ye L.L.
      • et al.
      Co-infection of SARS-COV-2 and influenza A virus: a case series and fast review.
      2021
      ChinaAdultsIgM serology30717657.3%Yue et al,
      • Yue H.
      • Zhang M.
      • Xing L.
      • et al.
      The epidemiology and clinical characteristics of co-infection of SARS-CoV-2 and influenza viruses in patients during COVID-19 outbreak.
      2020
       SARS-CoV-2 coinfected with RSVSpainAdultsNAAT25610.4%Garcia-Vidal et al,
      • Garcia-Vidal C.
      • Sanjuan G.
      • Moreno-García E.
      • et al.
      Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study.
      2021
      USAAdultsNAAT11665.2%Kim et al,
      • Kim D.
      • Quinn J.
      • Pinsky B.
      • et al.
      Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens.
      2020
      USAChildrenNAAT7137510.5%Wanga et al,
      • Wanga V.
      • Gerdes M.E.
      • Shi D.S.
      • et al.
      Characteristics and clinical outcomes of children and adolescents aged <18 years hospitalized with COVID-19 - six hospitals, United States, July-August 2021 [published correction appears in MMWR Morb Mortal Wkly Rep. 2022 Feb 04;71(5):185].
      2021
      ChinaChildrenNAAT3438.8%Wu et al,
      • Wu Q.
      • Xing Y.
      • Shi L.
      • et al.
      Coinfection and Other Clinical Characteristics of COVID-19 in Children.
      2020
      Bacterial coinfection
       Community-acquired coinfectionsSpainAdultsCulture989252.5%Garcia-Vidal et al,
      • Garcia-Vidal C.
      • Sanjuan G.
      • Moreno-García E.
      • et al.
      Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study.
      2021
      SwedenAdultsCulture, NAAT antigen1243464.0%Hedberg et al,
      • Hedberg P.
      • Johansson N.
      • Ternhag A.
      • et al.
      Bacterial co-infections in community-acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus.
      2022
      USAAdultsCulture, NAAT antigen1705593.5%Vaughn et al,
      • Vaughn V.M.
      • Gandhi T.N.
      • Petty L.A.
      • et al.
      Empiric antibacterial therapy and community-onset bacterial coinfection in patients hospitalized with coronavirus disease 2019 (COVID-19): a multi-hospital cohort study.
      2021
       Community-acquired coinfections (72 h)USAAdultsCulture30281836.0%Kubin et al,
      • Kubin C.J.
      • McConville T.H.
      • Dietz D.
      • et al.
      Characterization of Bacterial and Fungal Infections in Hospitalized Patients With Coronavirus Disease 2019 and Factors Associated With Health Care-Associated Infections.
      2021
       Community-acquired pneumoniaUSAAdultsCulture, NAAT antigen1705261.7%Vaughn et al,
      • Vaughn V.M.
      • Gandhi T.N.
      • Petty L.A.
      • et al.
      Empiric antibacterial therapy and community-onset bacterial coinfection in patients hospitalized with coronavirus disease 2019 (COVID-19): a multi-hospital cohort study.
      2021
      USAAdultsCulture3796350.9%Weidmann et al,
      • Weidmann M.D.
      • Berry G.J.
      • Zucker J.E.
      • et al.
      Bacterial Pneumonia and Respiratory Culture Utilization among Hospitalized Patients with and without COVID-19 in New York City.
      2022
       Health care–associated superinfections (>72 h)USAAdultsCulture302835011.6%Kubin et al,
      • Kubin C.J.
      • McConville T.H.
      • Dietz D.
      • et al.
      Characterization of Bacterial and Fungal Infections in Hospitalized Patients With Coronavirus Disease 2019 and Factors Associated With Health Care-Associated Infections.
      2021
       Hospital-acquired superinfectionsSpainAdultsCulture989383.8%Garcia-Vidal et al,
      • Garcia-Vidal C.
      • Sanjuan G.
      • Moreno-García E.
      • et al.
      Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study.
      2021
       Ventilator-associated lower respiratory tract superinfectionsSwedenIntubated AdultsCulture42612929.4%Hedberg et al,
      • Hedberg P.
      • Ternhag A.
      • Giske C.G.
      • et al.
      Ventilator-Associated Lower Respiratory Tract Bacterial Infections in COVID-19 Compared With Non-COVID-19 Patients.
      2022
       Ventilator-associated pneumoniaUSAIntubated AdultsCulture63124639.0%Weidmann et al,
      • Weidmann M.D.
      • Berry G.J.
      • Zucker J.E.
      • et al.
      Bacterial Pneumonia and Respiratory Culture Utilization among Hospitalized Patients with and without COVID-19 in New York City.
      2022
      Abbreviation: NAAT, nucleic acid amplification test.
      a References included in the review are arranged alphabetiacally within each type of coinfection.

      Respiratory viral coinfections

      In late 2019, an acute respiratory disease, COVID-19, emerged in humans caused by a novel coronavirus, SARS-CoV-2. Unlike previously known coronaviruses, SARS-CoV-2 combines greater pathogenicity with high transmissibility during the presymptomatic or asymptomatic period [
      • Tan J.
      • Liu S.
      • Zhuang L.
      • et al.
      Transmission and clinical characteristics of asymptomatic patients with SARS-CoV-2 infection.
      ]. COVID-19 has spread rapidly across the globe and has become a major pandemic disease. The increasing number of infections prompt the need to use rapid antigen-based assays and real-time reverse transcription PCR technology to rapidly detect SARS-CoV-2 RNA and confirm the clinical diagnosis of COVID-19 [
      • Wang W.
      • Xu Y.
      • Gao R.
      • et al.
      Detection of SARS-CoV-2 in Different Types of Clinical Specimens.
      ].
      Respiratory virus infections are associated with a wide spectrum of clinical symptoms. This classical thinking that a single virus is associated with clinical symptoms has been challenged by the more advanced multiplexed PCR-based assays, which may simultaneously identify multiple pathogens associated with one clinical syndrome [
      • Ramanan P.
      • Bryson A.L.
      • Binnicker M.J.
      • et al.
      Syndromic Panel-Based Testing in Clinical Microbiology.
      ]. Broad respiratory syndromic testing is widely used to identify viral pathogens that cocirculate with SARS-CoV-2. Coinfections involving viruses are recognized to influence the disease dynamics that occur relative to a single infection [
      • Kumar N.
      • Sharma S.
      • Barua S.
      • et al.
      Virological and Immunological Outcomes of Coinfections.
      ].

      Prevalence of respiratory viral coinfections

      Respiratory viral coinfection with SARS-CoV-2 refers to the simultaneous infection of other respiratory viruses at the time of COVID-19 diagnosis. Previous reports have shown viral coinfection and superinfection are rare [
      • Musuuza J.S.
      • Watson L.
      • Parmasad V.
      • et al.
      Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: a systematic review and meta-analysis.
      ]. This article focuses on the prevalence and outcome of viral coinfection.

      Viral coinfection in adults

      The overall rate of coinfection of SARS-CoV-2 and other respiratory viruses in adults is considerably variable as reported. The rate of viral coinfection depends on the cocirculation of respiratory viruses in the specific time of the year and the geographic region where the study was conducted. In the beginning of COVID-19 pandemic, Yue and colleagues [
      • Yue H.
      • Zhang M.
      • Xing L.
      • et al.
      The epidemiology and clinical characteristics of co-infection of SARS-CoV-2 and influenza viruses in patients during COVID-19 outbreak.
      ] carried out an epidemiologic study in Wuhan, China, between January 12 and February 21, 2020, and reported that the prevalence of SARS-CoV-2 and influenza coinfections was as high as 57.3% (176/307 cases), although the diagnosis of influenza was based on IgM serologic testing alone. From March 3 through 25, 2020, Kim and colleagues [
      • Kim D.
      • Quinn J.
      • Pinsky B.
      • et al.
      Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens.
      ] conducted a study to assess the prevalence of coinfections in Northern California.. A total of 1217 nasopharyngeal swabs of symptomatic adult patients were tested by multiplex real-time reverse transcription PCR assays for SARS-CoV-2 and other respiratory pathogens. Of the 116 specimens positive for SARS-CoV-2, 24 were positive for 1 or more additional pathogens including influenza, rhinovirus, enterovirus, respiratory syncytial virus (RSV), and non–SARS-CoV-2 coronaviridae. The rates of coinfection between SARS-CoV-2 and other respiratory pathogens were 20.7%.
      When the California Department of Public Health assessed influenza activity in California during the 2020 to 2021 influenza season, their analyses revealed that, among the 255 positive influenza cases, 58 persons were coinfected with SARS-CoV-2. The occurrence of influenza and SARS-CoV-2 coinfections was 23%, with influenza B being the predominant type (39/58 [67%]) [
      • Rizzo K.R.
      • Hoover C.
      • Jain S.
      • et al.
      Influenza and SARS-CoV-2 Co-infections in California, USA, September 2020-April 2021.
      ]. The report indicated that SARS-CoV-2 testing was prioritized over influenza virus testing and infrequent influenza testing might have contributed to underestimates of influenza transmission [
      • Rizzo K.R.
      • Hoover C.
      • Jain S.
      • et al.
      Influenza and SARS-CoV-2 Co-infections in California, USA, September 2020-April 2021.
      ]. Since the highly transmissible SARS-CoV-2 virus became the predominant circulating respiratory virus in humans, its impact on the circulation of other respiratory viruses has been evaluated [
      • Uhteg K.
      • Amadi A.
      • Forman M.
      • et al.
      Circulation of Non-SARS-CoV-2 Respiratory Pathogens and Coinfection with SARS-CoV-2 Amid the COVID-19 Pandemic.
      ]. The majority of cocirculating respiratory viruses seem to be less prevalent since the onset of the COVID-19 pandemic. This finding might be attributable to both intrinsic viral characteristics and viral interference [
      • Uhteg K.
      • Amadi A.
      • Forman M.
      • et al.
      Circulation of Non-SARS-CoV-2 Respiratory Pathogens and Coinfection with SARS-CoV-2 Amid the COVID-19 Pandemic.
      ].

      Viral coinfection in children

      The prevalence of viral coinfections is significantly higher in children than adults. A study from 6 US children’s hospitals located in areas with high COVID-19 incidence during July and August 2021 found viral coinfections with SARS-COV-2 was common (113/713 [16%]) in pediatric patients aged less than 18 years. The coinfection rate was even higher among infants (32.4%) and young children aged 1 to 4 years (36.1%). The predominant (>65%) viral coinfections were caused by RSV [
      • Wanga V.
      • Gerdes M.E.
      • Shi D.S.
      • et al.
      Characteristics and clinical outcomes of children and adolescents aged <18 years hospitalized with COVID-19 - six hospitals, United States, July-August 2021 [published correction appears in MMWR Morb Mortal Wkly Rep. 2022 Feb 04;71(5):185].
      ].
      Children with COVID-19 present with distinct epidemiologic and clinical characteristics that differ from adults. They may be asymptomatic or symptomatic with generalized clinical manifestations, like fever, cough, and nasal congestion. This pattern of symptoms makes it difficult to distinguish children with COVID-19 from those with infection of other common respiratory viruses. A retrospective study of previous healthy children exposed to SARS-COV-2 in their household, who subsequently tested positive for SARS-COV-2, reported 19 of 34 children (51%) coinfected with other respiratory pathogens [
      • Wu Q.
      • Xing Y.
      • Shi L.
      • et al.
      Coinfection and Other Clinical Characteristics of COVID-19 in Children.
      ].

      Clinical outcomes of respiratory viral coinfections

      The COVID-19 pandemic has caused great challenges for health care systems globally. Viral coinfections are commonly seen in hospitalized patients [
      • Garcia-Vidal C.
      • Sanjuan G.
      • Moreno-García E.
      • et al.
      Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study.
      ]. A retrospective study found that, even though viral coinfection was common at 30.5% in patients hospitalized with COVID, coinfection was not an independent risk factor for the severity of hospital admission, need for high-flow oxygen therapy or mechanical ventilation, or mortality [
      • Ishiguro T.
      • Kobayashi Y.
      • Shimizu Y.
      • et al.
      Frequency and Significance of Coinfection in Patients with COVID-19 at Hospital Admission.
      ]. Another study analyzed inpatient data and revealed that patients positive for SARS-CoV-2 had a lower rate of coinfection with other respiratory viruses compared with those positive for other respiratory viruses (1.4% vs 4.8%). Patients with COVID-19 testing positive for other viruses including rhinovirus, parainfluenza, and seasonal coronavirus presented with mild disease and did not progress to pneumonia [
      • Wee L.E.
      • Ko K.K.K.
      • Ho W.Q.
      • et al.
      Community-acquired viral respiratory infections amongst hospitalized inpatients during a COVID-19 outbreak in Singapore: co-infection and clinical outcomes.
      ]. The proportion of SARS-COV-2 coinfected patients requiring care in the intensive care unit (ICU) (4/21 [19%]) was significantly lower than the proportion of those infected with SARS-CoV-2 alone (113/280 [47%]), indicating that coinfection with other respiratory viruses might not worsen the outcome of SARS-CoV-2–associated respiratory disease [
      • Burrel S.
      • Hausfater P.
      • Dres M.
      • et al.
      Co-infection of SARS-CoV-2 with other respiratory viruses and performance of lower respiratory tract samples for the diagnosis of COVID-19.
      ].
      The clinical disease severity of respiratory viral coinfections in patients with COVID-19 could be impacted by the specific organism(s) causing of coinfection.

      Coinfection with influenza

      Influenza virus is a frequent cause of community-acquired pneumonia (CAP). Coinfection with SARS-CoV-2 may worsen COVID-19 symptoms and increase mortality, especially for the elderly [
      • Rizzo K.R.
      • Hoover C.
      • Jain S.
      • et al.
      Influenza and SARS-CoV-2 Co-infections in California, USA, September 2020-April 2021.
      ]. Patients coinfected with SARS-CoV-2 and influenza B virus have presented with symptoms of fatigue (13%), abnormalities on a computed tomography scan of the chest (100%) or decreased lymphocytes and poor prognosis compared with SARS-CoV-2 single positive patients [
      • Yue H.
      • Zhang M.
      • Xing L.
      • et al.
      The epidemiology and clinical characteristics of co-infection of SARS-CoV-2 and influenza viruses in patients during COVID-19 outbreak.
      ]. Ozaras and colleagues [
      • Ozaras R.
      • Cirpin R.
      • Duran A.
      • et al.
      Influenza and COVID-19 coinfection: report of six cases and review of the literature.
      ] reported 6 patients with COVID-19 who were coinfected with influenza and suffered from pneumonia. A thoracic computed tomography scan showed multiple lesions in the lung in 2 cases, bilateral lung lesions in 3 cases, and a single central lesion in 1 case [
      • Ozaras R.
      • Cirpin R.
      • Duran A.
      • et al.
      Influenza and COVID-19 coinfection: report of six cases and review of the literature.
      ]. A recent research study using an animal model for SARS-CoV-2 infection demonstrated that coinfection with influenza A virus causes more severe and prolonged pneumonia in SARS-CoV-2–infected hamsters [
      • Kinoshita T.
      • Watanabe K.
      • Sakurai Y.
      • et al.
      Co-infection of SARS-CoV-2 and influenza virus causes more severe and prolonged pneumonia in hamsters.
      ]. The research team examined the respiratory organs of coinfected hamsters using immunohistochemical stain and found the infected regions were clearly divided into SARS-CoV-2–patterned and influenza–patterned areas and both viruses never coexisted at the same site in these organs, indicating that each virus may have distinct cell tropism and can efficiently spread in the respiratory organ without interference with the other [
      • Kinoshita T.
      • Watanabe K.
      • Sakurai Y.
      • et al.
      Co-infection of SARS-CoV-2 and influenza virus causes more severe and prolonged pneumonia in hamsters.
      ].

      Coinfection with Respiratory Syncytial Virus

      RSV is the most common cause of bronchiolitis and pneumonia in children younger than 1 year of age. Patients coinfected with SARS-Cov-2 have been reported and hospitalized [
      • Wanga V.
      • Gerdes M.E.
      • Shi D.S.
      • et al.
      Characteristics and clinical outcomes of children and adolescents aged <18 years hospitalized with COVID-19 - six hospitals, United States, July-August 2021 [published correction appears in MMWR Morb Mortal Wkly Rep. 2022 Feb 04;71(5):185].
      ]. A retrospectively study found that 6 of 32 hospitalized children (18.7%) less than 24 months of age coinfected with SARS-CoV-2 and RSV, and had a significantly longer length of stay (7 days vs 3 days) than those without [
      • Alvares P.A.
      SARS-CoV-2 and respiratory syncytial virus coinfection in hospitalized pediatric patients.
      ]. However, there was no difference in the need for intensive care or mechanical ventilation or mortality [
      • Alvares P.A.
      SARS-CoV-2 and respiratory syncytial virus coinfection in hospitalized pediatric patients.
      ]. Similar findings were presented by Giannattasio and colleagues [
      • Giannattasio A.
      • Maglione M.
      • D'Anna C.
      • et al.
      Silent RSV in infants with SARS-CoV-2 infection: a case series.
      ] among 6 infants aged 18 days to 9 months coinfected with both SARS-CoV-2 and RSV. The infants experienced mild fever and respiratory symptoms with an uncomplicated resolution [
      • Giannattasio A.
      • Maglione M.
      • D'Anna C.
      • et al.
      Silent RSV in infants with SARS-CoV-2 infection: a case series.
      ]. RSV, which can cause more severe disease in infants, caused relatively mild disease in coinfected infants in this study of limited size. The authors speculate that this finding could be due to increased infectivity and replication of SARS-CoV-2, which may suppress RSV replication and clinical expression [
      • Giannattasio A.
      • Maglione M.
      • D'Anna C.
      • et al.
      Silent RSV in infants with SARS-CoV-2 infection: a case series.
      ].

      Virological mechanisms that determine viral persistence or exclusion during coinfections

      Viral competition for resources in the respiratory tract

      Molecular methods of viral detection and their increased sensitivity over culture have led to increased diagnoses of viral respiratory infections. This increase has also led to a greater frequency of viral coinfections being detected. When looking at the interactions between individual viruses during viral–viral respiratory coinfections, there seem to be both cases of inhibition and enhancement of one virus over another.
      In the case of inhibition, it has been demonstrated through mathematical modeling that one virus can block infection with another virus by being the first to infect a cell [
      • Pinky L.
      • Dobrovolny H.M.
      Coinfections of the respiratory tract: viral competition for resources.
      ]. In addition, the replication speed of the virus played a role with a rapidly replicating virus, such as rhinovirus, decreasing the replication of other viruses and a slow-growing virus, such as parainfluenza virus, being out-competed and subsequently suppressed in a viral–viral coinfection model [
      • Pinky L.
      • Dobrovolny H.M.
      Coinfections of the respiratory tract: viral competition for resources.
      ]. This pattern is consistent with reports of viral coinfections seen during the pandemic, with 1 study reporting 8% of cases as coinfected, with rhinovirus comprising 6% and influenza virus comprising 2% of SARS-CoV-2 coinfections [
      • Kim K.W.
      • Deveson I.W.
      • Pang C.N.I.
      • et al.
      Respiratory viral co-infections among SARS-CoV-2 cases confirmed by virome capture sequencing.
      ].
      Ferret models of SARS-CoV-2 and influenza A virus coinfection showed that influenza A outcompeted SAR-CoV-2 in both viral titers and infectivity when coinfected ferrets were cohoused with uninfected ferrets [
      • Huang Y.
      • Skarlupka A.L.
      • Jang H.
      • et al.
      SARS-CoV-2 and Influenza A Virus Coinfections in Ferrets.
      ]. Additional animal studies in murine models also showed increased influenza viral loads in coinfections and increased mortality, which could be ameliorated by prior immunity to influenza [
      • Achdout H.
      • Vitner E.B.
      • Politi B.
      • et al.
      Increased lethality in influenza and SARS-CoV-2 coinfection is prevented by influenza immunity but not SARS-CoV-2 immunity.
      ].
      Studies in humans have been more ambiguous, with some studies showing similar clinical outcomes in patients infected with SARS-CoV-2 alone versus with a viral coinfection [
      • Cheng Y.
      • Ma J.
      • Wang H.
      • et al.
      Co-infection of influenza A virus and SARS-CoV-2: a retrospective cohort study.
      ] and others showing higher rates of viral–viral coinfections in patients with severe cases of COVID-19 [
      • Yue H.
      • Zhang M.
      • Xing L.
      • et al.
      The epidemiology and clinical characteristics of co-infection of SARS-CoV-2 and influenza viruses in patients during COVID-19 outbreak.
      ,
      • Xiang X.
      • Wang Z.H.
      • Ye L.L.
      • et al.
      Co-infection of SARS-COV-2 and influenza A virus: a case series and fast review.
      ,
      • Stowe J.
      • Tessier E.
      • Zhao H.
      • et al.
      Interactions between SARS-CoV-2 and influenza, and the impact of coinfection on disease severity: a test-negative design.
      ] or who had died [
      • Hashemi S.A.
      • Safamanesh S.
      • Ghasemzadeh-Moghaddam H.
      • et al.
      High prevalence of SARS-CoV-2 and influenza A virus (H1N1) coinfection in dead patients in Northeastern Iran.
      ]. Data published before the pandemic looking at influenza viral coinfections suggested that detection of more than 1 virus correlated with less severe disease [
      • Martin E.T.
      • Kuypers J.
      • Wald A.
      • et al.
      Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children.
      ] or had no difference in clinical disease severity [
      • Asner S.A.
      • Science M.E.
      • Tran D.
      • et al.
      Clinical disease severity of respiratory viral co-infection versus single viral infection: a systematic review and meta-analysis.
      ]. This finding will need to be investigated in the context of SARS-CoV-2 coinfections. One large observational study in more than 21,000 positive specimens found that, although viral coinfection was not associated with an increase in viral load when compared with single-virus infections, there was evidence of viral competition that decreased the viral load [
      • Burstein R.
      • Althouse B.M.
      • Adler A.
      • et al.
      Interactions among 17 respiratory pathogens: a cross-sectional study using clinical and community surveillance data.
      ].

      Epithelial and organ damage

      Although the significance of viral coinfection is unknown, the mechanisms of coinfection include virus-induced airway damage, decreased mucociliary clearance, and damage to the immune system [
      • Vareille M.
      • Kieninger E.
      • Edwards M.R.
      • et al.
      The airway epithelium: soldier in the fight against respiratory viruses.
      ].
      Animal models of SARS-CoV-2 and influenza A virus coinfection led to significantly more weight loss and more severe inflammation in both the nose and lungs when compared with animals singly infected with each virus [
      • Huang Y.
      • Skarlupka A.L.
      • Jang H.
      • et al.
      SARS-CoV-2 and Influenza A Virus Coinfections in Ferrets.
      ,
      • Zhang A.J.
      • Lee A.C.
      • Chan J.F.
      • et al.
      Coinfection by Severe Acute Respiratory Syndrome Coronavirus 2 and Influenza A(H1N1)pdm09 Virus Enhances the Severity of Pneumonia in Golden Syrian Hamsters.
      ]. In addition, influenza A virus preinfection led to an increase in SARS-CoV-2 infectivity in cell-based models and also led to more lung damage and higher viral loads in mouse models [
      • Bai L.
      • Zhao Y.
      • Dong J.
      • et al.
      Coinfection with influenza A virus enhances SARS-CoV-2 infectivity.
      ]. Other models of epithelial, endothelial, and mononuclear cells have also shown infectivity with high viral loads, leading to cell damage and deterioration of barrier function [
      • Deinhardt-Emmer S.
      • Böttcher S.
      • Häring C.
      • et al.
      SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction [published online ahead of print, 2021 Feb 26].
      ].

      Impact on the pattern of immune responsiveness

      Because of the damage to the immune system caused by the coinfection, the presentation of patients who are positive for both SARS-CoV-2 and other viruses may be more severe [
      • Tay M.Z.
      • Poh C.M.
      • Rénia L.
      • et al.
      The trinity of COVID-19: immunity, inflammation and intervention.
      ]. It has been shown that SARS-CoV-2 infection leads to epithelial cell damage and the release of interferon [
      • Deinhardt-Emmer S.
      • Böttcher S.
      • Häring C.
      • et al.
      SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction [published online ahead of print, 2021 Feb 26].
      ]. Increases in proinflammatory cytokine levels early in infections have been linked to worse outcomes, with severe COVID-19 being linked with an increased cytokine response throughout disease progression [
      • Lucas C.
      • Wong P.
      • Klein J.
      • et al.
      Longitudinal analyses reveal immunological misfiring in severe COVID-19.
      ].
      When looking at influenza A and SARS-CoV-2 coinfection, one study showed an increase in serum cytokines (interleukin-2R [IL-2R], IL-6, IL-8, and tumor necrosis factor-α), cardiac troponin I, and a higher incidence of lymphadenopathy in patients solely infected with SARS-CoV-2 [
      • Cheng Y.
      • Ma J.
      • Wang H.
      • et al.
      Co-infection of influenza A virus and SARS-CoV-2: a retrospective cohort study.
      ]. A hamster model of SARS-CoV-2 and influenza coinfection also showed a higher histology score for pulmonary edema, vasculitis, and inflammatory cell infiltration than single-virus infected animals [
      • Zhang A.J.
      • Lee A.C.
      • Chan J.F.
      • et al.
      Coinfection by Severe Acute Respiratory Syndrome Coronavirus 2 and Influenza A(H1N1)pdm09 Virus Enhances the Severity of Pneumonia in Golden Syrian Hamsters.
      ]. Additionally, looking at the impact of influenza A and SARS-CoV-2 coinfections in adult inpatients showed that coinfection led to an increased odds of acute heart failure, multilobar infiltrates, acute kidney injury, secondary bacterial infection, and ICU admission. Coinfected patients also had a relatively higher SARS-CoV-2 viral load based on relative cycle threshold values than patients singly infected with SARS-CoV-2, which significantly correlated with acute kidney injury and acute respiratory distress syndrome [
      • Zheng J.
      • Chen F.
      • Wu K.
      • et al.
      Clinical and virological impact of single and dual infections with influenza A (H1N1) and SARS-CoV-2 in adult inpatients.
      ].

      Bacterial coinfection in the setting of respiratory viral illness

      Respiratory viral infection may predispose hosts to bacterial pneumonia, but the degree to which this occurs varies widely based on the viral pathogen. We will examine 3 commonly occurring respiratory viral pathogens—influenza virus, RSV, and SARS-CoV-2—to understand how each affects risk for bacterial coinfection, outcomes associated with coinfection, and the mechanisms underlying these associations.

      Influenza-associated bacterial coinfection

      As a long-known cause of seasonal epidemics and occasional pandemics, the association of influenza with bacterial superinfection has long been established, with review of autopsy findings from the 1918 Spanish Flu pandemic displaying that bacterial superinfection was likely a central risk factor for mortality [
      • Morens D.M.
      • Taubenberger J.K.
      • Fauci A.S.
      Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness.
      ]. A variety of studies have attempted to characterize the rates of bacterial coinfection or superinfection in the setting of influenza, yet many of these have been limited to a single influenza season [
      • Shah N.S.
      • Greenberg J.A.
      • McNulty M.C.
      • et al.
      Bacterial and viral co-infections complicating severe influenza: incidence and impact among 507 U.S. patients, 2013-14.
      ,
      • MacIntyre C.R.
      • Chughtai A.A.
      • Barnes M.
      • et al.
      The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09.
      ]. A metanalysis found rates varying from 2% to 65%; however, when the studies contributing the majority of heterogeneity were removed the range was 11% to 35% [
      • Klein E.Y.
      • Monteforte B.
      • Gupta A.
      • et al.
      The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis.
      ]. More recently, a prospective multicenter study from Spain has assessed rates of bacterial pneumonia from 2009 to 2015, including years of both pandemic and seasonal epidemic influenza [
      • Martin-Loeches I.
      • JS M.
      • Vincent J.L.
      • et al.
      Increased incidence of co-infection in critically ill patients with influenza.
      ]. These authors found lower rates of bacterial coinfection during 2009 (11.4%), associated with the H1N1 pandemic during that year, relative to increased rates in subsequent years (17.3%–23.4%) [
      • Martin-Loeches I.
      • JS M.
      • Vincent J.L.
      • et al.
      Increased incidence of co-infection in critically ill patients with influenza.
      ]. A metanalysis focusing on pandemic H1N1 influenza during 2009 found that 19% of hospitalized patients were found to have secondary bacterial pneumonia and that this rate increased to 23% when looking at autopsy specimens from fatal influenza cases [
      • MacIntyre C.R.
      • Chughtai A.A.
      • Barnes M.
      • et al.
      The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09.
      ].
      Outcomes in patients with influenza have been found to be consistently worse in the setting of bacterial coinfection. Authors of the 2009 to 2015 Spanish study finding an adjusted odds ratio (OR) of 1.9 (95% CI, 1.5–2.5) for hospital mortality, whereas another retrospective study of 209 patients hospitalized with influenza from the Netherlands, 41 of whom had community-acquired bacterial coinfection (19.6%), found an adjusted hazard ratio of 2.6 (95% confidence interval [CI], 1.252–5.480) for mortality associated with bacterial coinfection [
      • Teng F.
      • Liu X.
      • Guo S.B.
      • et al.
      Community-acquired bacterial co-infection predicts severity and mortality in influenza-associated pneumonia admitted patients.
      ]. Of note, this latter study found a large difference in mortality by bacterial species responsible for coinfection, with Staphylococcus aureus producing a mortality (adjusted hazard ratio) of 6.267 (95% CI, 2.679–14.662). A smaller study comparing mortality rates in patients with bacterial pneumonia in the setting of influenza (VI; n = 57) or other types of respiratory viral illness (NI; n = 77), they found that VI patients had lower rates of bacterial pneumonia than NI patients (23% vs 44%), as well as overall lower length of hospital and ICU stay, but no significant trends associated with bacterial pneumonia status [
      • Manna S.
      • Baindara P.
      • Mandal S.M.
      Molecular pathogenesis of secondary bacterial infection associated to viral infections including SARS-CoV-2.
      ].
      A large portion of bacterial pneumonia in the setting of influenza has been found to be community acquired. One study involving 4313 patients with influenza hospitalized between 2010 and 2015 at 179 US hospitals found a CAP rate of 10.6%, with S aureus presenting as the most common etiology, and a mortality adjusted OR of 3.00 (95% CI, 2.17–4.16) [
      • Bartley P.S.
      • Deshpande A.
      • Yu P.C.
      • et al.
      Bacterial coinfection in influenza pneumonia: rates, pathogens, and outcomes.
      ]. Bacterial isolates identified were also more consistent with CAP, with the largest study of all types of bacterial pneumonia in patients with influenza identifying Streptococcus pneumoniae as the most common etiology (51.0%) by a large margin [
      • Martin-Loeches I.
      • JS M.
      • Vincent J.L.
      • et al.
      Increased incidence of co-infection in critically ill patients with influenza.
      ], and the most comprehensive meta-analysis of this subject has also found S pneumoniae as the most common etiology (35%), although S aureus made a more significant contribution (28%) [
      • Klein E.Y.
      • Monteforte B.
      • Gupta A.
      • et al.
      The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis.
      ].
      There are a number of pathways by which influenza has been identified in both animal and human studies to increase susceptibility to bacterial pneumonia, including (1) depletion of alveolar macrophages by 90% during the first week of influenza infection in mice [
      • Ghoneim H.E.
      • Thomas P.G.
      • McCullers J.A.
      Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections.
      ], (2) inhibition of the phagocytic activity of macrophages and neutrophils through induction of type 1 IFN responses [
      • Sun K.
      • Metzger D.W.
      Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection.
      ,
      • Tian X.
      • Xu F.
      • Lung W.Y.
      • et al.
      Poly I:C enhances susceptibility to secondary pulmonary infections by gram-positive bacteria.
      ], (3) inhibition of Th17 T cells that modulate the immune surveillance of pathogenic bacteria via type 1 IFN signaling, as well as (4) an increase in bacterial binding sites in the upper and lower respiratory tract produced by neuraminidase cleavage of sialic acid [
      • Foster T.J.
      • Hook M.
      Surface protein adhesins of Staphylococcus aureus.
      ], and upregulation of surface receptors recognized by bacteria from the host inflammatory response and wound healing [
      • Bucior I.
      • Pielage J.F.
      • Engel J.N.
      Pseudomonas aeruginosa Pili and Flagella Mediate Distinct Binding and Signaling Events at the Apical and Basolateral Surface of Airway Epithelium.
      ,
      • Davison V.E.
      • Sanford B.A.
      Adherence of Staphylococcus-Aureus to Influenza-a Virus-Infected Madin-Darby Canine Kidney-Cell-Cultures.
      ]. Interestingly, the mortality rates for influenza with bacterial pneumonia have been found to be highest in animal studies when bacterial infection occurs during the first week of viral infection [
      • Jamieson A.M.
      • Pasman L.
      • Yu S.
      • et al.
      Role of tissue protection in lethal respiratory viral-bacterial coinfection.
      ], which in conjunction with high rates of CAP and the mechanisms listed elsewhere in this article, suggest that viral and bacterial infection act synergistically to decrease pulmonary function and inhibit host responses.

      RSV-associated bacterial coinfection

      Before the COVID-19 pandemic, RSV represented the leading cause of lower respiratory tract infection in children, with an estimated 2.7 to 3.8 million cases in 2015, causing higher rates of hospitalization and mortality relative to influenza in children under 5 years [
      • Shi T.
      • McAllister D.A.
      • O'Brien K.L.
      • et al.
      Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.
      ]. A wide range of bacterial coinfection rates is associated with RSV. One study of children with bronchopulmonary RSV found that 43.6% had a concurrent respiratory culture positive for pathogenic bacteria [
      • Hishiki H.
      • Ishiwada N.
      • Fukasawa C.
      • et al.
      Incidence of bacterial coinfection with respiratory syncytial virus bronchopulmonary infection in pediatric inpatients.
      ], with the most common pathogens being Haemophilus influenzae (43.9%), S pneumoniae (36.6%), and Moraxella catarrhalis (29.3%). A larger study of children with RSV pneumonia between 2010 and 2019 found that 32.4% had a concurrent respiratory bacterial infection, the most common etiologies of which were S pneumonia (40.8%), S aureus (40.8%), and H influenzae (25.4%) [
      • Lin H.C.
      • Liu Y.C.
      • Hsing T.Y.
      • et al.
      RSV pneumonia with or without bacterial co-infection among healthy children.
      ]. This study also assessed the effect of bacterial coinfection on clinical outcomes in children with bacterial coinfection compared with RSV alone, finding significantly higher rates of invasive ventilation (3.0% vs 0.0%) and ICU care (11.9% vs 6.4%), although mortality was not reported. One study focusing on 165 patients with RSV who were intubated and treated in the ICU found similarly high rates of respiratory culture positivity (42.6%); however, they used quantitative culture to separate bacterial coinfection (21.8%) and low bacterial growth or possible coinfection (20.8%) based on whether their cultures grew greater or less than 105 CFU/mL, respectively [
      • Thorburn K.
      • Harigopal S.
      • Reddy V.
      • et al.
      High incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (RSV) bronchiolitis.
      ]. Although there was no significant difference in mortality rates, this study found a small but significant increase in length of mechanical ventilation in the bacterial coinfection group (6 days vs 4 days).
      Interestingly, a retrospective cohort study concluding within the past year has directly compared rates of CAP in admitted adult patients testing positive for Influenza, RSV, or SARS-CoV-2 [
      • Hedberg P.
      • Johansson N.
      • Ternhag A.
      • et al.
      Bacterial co-infections in community-acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus.
      ]. Hedberg and colleagues (2022) [
      • Hedberg P.
      • Johansson N.
      • Ternhag A.
      • et al.
      Bacterial co-infections in community-acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus.
      ] found that roughly similar proportions of adults with influenza or RSV had concurrent CAP, 27% and 29% respectively, whereas only 4% of patients with SARS-CoV-2 had CAP. For all 3 viral infections, no significant differences in length of stay, ICU admission, or 30-day mortality between patients with or without CAP were seen, except a lower adjusted hazard ratio of being discharged alive for patients with influenza and CAP relative to those without CAP (0.76; 95% CI, 0.64–0.90). Of note, this study assessed only adult patients, whereas most studies of coinfection in the setting of RSV have focused on pediatric patients. Therefore, in adults, RSV infection involves high rates of bacterial pneumonia, similar to or increased in prevalence compared with influenza coinfection; however, exacerbation of outcomes by coinfection in pediatric populations is modest in comparison with that of influenza.

      SARS-CoV-2–associated bacterial coinfection

      The literature to date on bacterial coinfection in the setting of SARS-CoV-2 has shown significant differences from influenza or RSV coinfection. One study of 4267 patients hospitalized with COVID-19 in New York City found that only 2.1% had positive respiratory cultures and 1.9% had positive blood cultures, although 71% received at least 1 dose of an antibiotic [
      • Nori P.
      • Cowman K.
      • Chen V.
      • et al.
      Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge.
      ]. Whereas Hedberg, Johansson, and colleagues [
      • Hedberg P.
      • Johansson N.
      • Ternhag A.
      • et al.
      Bacterial co-infections in community-acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus.
      ] reported a CAP coinfection rate of 4% with SARS-CoV-2, other studies assessing CAP have found significantly lower rates. A multicenter study of 1705 patients hospitalized with COVID-19 in Michigan found that only 1.5% qualified as having CAP (defined as positive culture <3 days from admission). Another study of 3796 hospitalized patients with COVID-19 in New York City found that only 0.9% of patients with COVID-19 had CAP (defined as positive culture <2 days from admission), which only represented 12.2% of bacterial pneumonia cases in patients with COVID-19, whereas the large majority of cases were due to ventilator-associated pneumonia (VAP, 85.7%) [
      • Weidmann M.D.
      • Berry G.J.
      • Zucker J.E.
      • et al.
      Bacterial Pneumonia and Respiratory Culture Utilization among Hospitalized Patients with and without COVID-19 in New York City.
      ]. This study also found that a significantly higher proportion of bacterial pneumonia in patients with COVID-19 was ventilator-associated relative to patients who did not have COVID. Rates of bacterial pneumonia among ventilated patients were also found to be significantly higher for those testing positive for SARS-CoV-2, was also seen in an independent study of a large cohort in Sweden [
      • Hedberg P.
      • Ternhag A.
      • Giske C.G.
      • et al.
      Ventilator-Associated Lower Respiratory Tract Bacterial Infections in COVID-19 Compared With Non-COVID-19 Patients.
      ]. Although meta-analyses have only looked at overall rates of bacterial coinfection in the setting of SARS-CoV-2, the largest of these found considerable heterogeneity between studies, with subgroup analyses showing rates of 4% in all hospitalized patients and 14% for ICU patients alone, consistent with the largest individual studies described elsewhere in this article [
      • Nori P.
      • Cowman K.
      • Chen V.
      • et al.
      Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge.
      ,
      • Lansbury L.
      • Lim B.
      • Baskaran V.
      • et al.
      Co-infections in people with COVID-19: a systematic review and meta-analysis.
      ,
      • Vaughn V.M.
      • Gandhi T.N.
      • Petty L.A.
      • et al.
      Empiric antibacterial therapy and community-onset bacterial coinfection in patients hospitalized with coronavirus disease 2019 (COVID-19): a multi-hospital cohort study.
      ].
      Although Hedberg and colleagues did not report significant differences in the risk of ICU admission or 30-day mortality for patients with COVID-19 with CAP relative to those without, another large observational study looking specifically at clinically confirmed CAP found significantly increased rates of ICU admission (rate ratio = 4.45), mechanical ventilation (rate ratio = 6.74), higher rates of septic shock (rate ratio = 4.60), longer length of stay (mean 7 vs 5 days) and greater mortality (47.5% vs 18.0%) for patients with CAP [
      • Vaughn V.M.
      • Gandhi T.N.
      • Petty L.A.
      • et al.
      Empiric antibacterial therapy and community-onset bacterial coinfection in patients hospitalized with coronavirus disease 2019 (COVID-19): a multi-hospital cohort study.
      ]. A study specifically assessing hospital-acquired respiratory coinfections with bacterial or fungal pathogens found that that they occurred in 6.8% of patients with COVID-19, and more than 10-fold as many positive respiratory cultures relative to community-acquired infections [
      • Kubin C.J.
      • McConville T.H.
      • Dietz D.
      • et al.
      Characterization of Bacterial and Fungal Infections in Hospitalized Patients With Coronavirus Disease 2019 and Factors Associated With Health Care-Associated Infections.
      ]. For both hospital- and community-acquired infections, the vast majority were associated with bacterial etiologies, with only 4% of community-acquired and 2% of health care–associated pathogens involving fungal isolates (Aspergillus). Few other studies have directly assessed the rate of fungal respiratory infection in the setting of hospitalized patients with COVID-19. Of these, Nori and colleagues [
      • Nori P.
      • Cowman K.
      • Chen V.
      • et al.
      Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge.
      ] represents the largest and also found low rates of coinfection with fungal pathogens, with 3 of 112 (2.7%) positive respiratory isolates of fungal etiology (Candida and Aspergillus spp). However, high rates of pulmonary aspergillosis have been demonstrated among patients with COVID-19 admitted to an ICU, with 1 meta-analysis of 30 studies covering 3441 patients demonstrating a pooled incidence rate of 14% (95% CI, 11%–17%) with a case fatality rate of 52% (95% CI, 47%–56%) [
      • Chen W.
      • Yin C.
      • Zhong M.
      • et al.
      Incidence and outcomes of patients with COVID-19 associated pulmonary aspergillosis (CAPA) in intensive care units: a systematic review and meta-analysis of 31 cohort studies.
      ].
      The etiologies of bacterial respiratory infections also reflect a relatively high proportion of health care–associated and/or ventilator-associated pathogens in patients with COVID-19, relative to pathogens found in patients with influenza. Although S pneumoniae represented the most common bacterial pneumonia pathogen for patients with influenza, Staphylococcus, Pseudomonas, and Enterobacterales spp (such as Klebsiella) represented the most common etiologies in patients with COVID-19 found by studies looking at both community-acquired and health care–associated pneumonia [
      • Nori P.
      • Cowman K.
      • Chen V.
      • et al.
      Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge.
      ,
      • Weidmann M.D.
      • Berry G.J.
      • Zucker J.E.
      • et al.
      Bacterial Pneumonia and Respiratory Culture Utilization among Hospitalized Patients with and without COVID-19 in New York City.
      ,
      • Kubin C.J.
      • McConville T.H.
      • Dietz D.
      • et al.
      Characterization of Bacterial and Fungal Infections in Hospitalized Patients With Coronavirus Disease 2019 and Factors Associated With Health Care-Associated Infections.
      ]. In a large observational study looking specifically at CAP in patients with COVID-19, bacterial pathogen profiles were more similar to that of patients with influenza, with the most common pathogen being S pneumoniae (28%), albeit far lower than coinfection in patients with influenza (56%), and with patients with COVID-19 with CAP having a higher proportion of S aureus as the second-most common pathogen (26% vs 19%) [
      • Hedberg P.
      • Johansson N.
      • Ternhag A.
      • et al.
      Bacterial co-infections in community-acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus.
      ].
      Despite the lower rates of bacterial respiratory coinfection in patients with COVID-19 relative to patients with influenza and RSV, high rates of early antibiotic therapy have been observed in these patient populations. The 3 largest such studies, including 4267, 3028, and 1705 patients with COVID-19 from Spring 2020, respectively, found that 71%, 67%, and 57% of patients received some form of antibiotic therapy during their treatment [
      • Nori P.
      • Cowman K.
      • Chen V.
      • et al.
      Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge.
      ,
      • Vaughn V.M.
      • Gandhi T.N.
      • Petty L.A.
      • et al.
      Empiric antibacterial therapy and community-onset bacterial coinfection in patients hospitalized with coronavirus disease 2019 (COVID-19): a multi-hospital cohort study.
      ,
      • Kubin C.J.
      • McConville T.H.
      • Dietz D.
      • et al.
      Characterization of Bacterial and Fungal Infections in Hospitalized Patients With Coronavirus Disease 2019 and Factors Associated With Health Care-Associated Infections.
      ]. Interestingly, the smallest of these studies found that 54% of those patients with COVID-19 started on early antimicrobial therapy had it discontinued within 1 day after SARS-CoV-2 tests returned positive, but of those remaining on antimicrobial therapy, only 7.4% had a community-onset bacterial infection confirmed [
      • Vaughn V.M.
      • Gandhi T.N.
      • Petty L.A.
      • et al.
      Empiric antibacterial therapy and community-onset bacterial coinfection in patients hospitalized with coronavirus disease 2019 (COVID-19): a multi-hospital cohort study.
      ]. Another meta-analysis of 24 studies including 3338 patients also found that 72% of patients received antibiotics (95% CI, 56%–88%). However, most of the studies have looked at cases dating from the first or second wave of the COVID-19 pandemic in 2020, when effective antivirals were not available, and it remains to be seen whether such high rates of antibiotic therapy have continued into 2021 to 2022.
      Nori and colleagues (2021) [
      • Nori P.
      • Cowman K.
      • Chen V.
      • et al.
      Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge.
      ] also assessed antibiotic use in health care–associated infections, finding that 79% of patients who had a positive bacterial culture (blood or respiratory) had received antibiotics in the 30 days before positive culture, and all 21 patients with multi-drug resistant pathogens were in this group. Kubin and colleagues (2021) [
      • Kubin C.J.
      • McConville T.H.
      • Dietz D.
      • et al.
      Characterization of Bacterial and Fungal Infections in Hospitalized Patients With Coronavirus Disease 2019 and Factors Associated With Health Care-Associated Infections.
      ] found increasing rates of antimicrobial resistance in isolates recovered later in patients’ hospital stay, 33% of S aureus isolates were methicillin resistant, 76% of which were respiratory isolates, 42% of Enterobacterales were cephalosporin resistant and 7% were carbapenem resistant (the majority of which were respiratory isolates). However, a study from the same institution comparing rates of antimicrobial resistance for bacterial respiratory isolates in patients with and without COVID-19 found no significant increase in any of these categories except for patients with COVID-19 with methicillin-resistant S aureus and overall resistance to penicillin class antibiotics [
      • Weidmann M.D.
      • Berry G.J.
      • Zucker J.E.
      • et al.
      Bacterial Pneumonia and Respiratory Culture Utilization among Hospitalized Patients with and without COVID-19 in New York City.
      ]. Thus, antimicrobial resistance rates seemed comparable for COVID-19 and patient populations without COVID-19, with the exception of methicillin-resistant S aureus, but increasing risk of resistance with hospital stay further highlights the need for stewardship in early antibiotic treatment, particularly for nonintubated patients. This finding is corroborated by health care–associated infection risk factors assessed in Kubin and colleagues (2021), the leading of which were invasive mechanical ventilation (OR, 6.0; 95% CI, 3.7–10.0), ICU care (OR, 4.1; 95% CI, 2.5–6.8), and steroid treatment (OR, 1.9; 95% CI, 1.4–2.6).
      Although there are a host of mechanisms by which influenza has been found to predispose human epithelia to bacterial coinfection, with high rates of CAP to support the manifestation of these mechanisms in real-world settings, there is a paucity of research into which of these mechanisms may also operate in the setting of SARS-CoV-2 infection. However, observational studies have found far lower rates of CAP in SARS-CoV-2 relative to patients with influenza, and instead prolonged exposure to health care settings and particularly mechanical ventilation seem to be driving the majority of bacterial and fungal pneumonia cases seen in patients with COVID-19. Respiratory culture ordering and antibiotic use should, therefore, be primarily considered in severe COVID-19 disease requiring ICU-level care and invasive mechanical ventilation.

      Disclosure

      The authors have nothing to disclose.

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