key: cord-0761608-xt155i8o
authors: Singh, Vijay; Upadhyay, Pallavi; Reddy, Jairus; Granger, John
title: SARS-CoV-2 Respiratory Co-Infections: Incidence of Viral and Bacterial Co-Pathogens
date: 2021-02-25
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.02.087
sha: 5e5fa055c610d55c0e234f8d05afd470e4721ab7
doc_id: 761608
cord_uid: xt155i8o

The COVID-19 global pandemic, caused by the SARS-CoV-2 virus, has created an unprecedented challenge to our healthcare system. Secondary and concurrent bacterial and viral co-infections are well documented for other viral respiratory pathogens however our knowledge regarding co-infections in COVID-19 remains limited. The present study encompasses concurrent testing of 50,419 individual samples for the presence of SARS-CoV-2 and other bacterial and viral respiratory pathogens between March and August 2020. Overall a lower rate of viral co-infection was observed in the SARS-CoV-2 positive population when compared to the population testing negative for the virus. Significant levels of Staphylococcus aureus and Epstein-Barr virus co-infections were detected in the SARS-CoV-2 positive population. This is one of the largest surveys looking into the co-infection patterns of SARS-CoV-2 infection in the United States. Data from the present study will enhance our understanding of the current pandemic and will assist clinicians in making better patient care decisions especially with respect to anti-microbial therapy.

The COVID-19 pandemic caused by SARS-CoV-2, a novel coronavirus, has resulted in the largest mobilization of public health resources and policy in recent memory. At the time of writing this report the pandemic has infected 92.3 million people resulting in over 1.98 million deaths globally. The United States, representing 4.25% of the world population, has been disproportionately affected by the pandemic. The total SARS-CoV-2 positive cases in the United States stands at 23.1 million with 384,000 fatalities which represents 20% of the world tally (cdc.gov/coronavirus/2019-ncov). Co-evolution of viral and bacterial respiratory pathogens has created an environment wherein a viral infection allows concurrent or secondary bacterial co-J o u r n a l P r e -p r o o f infections which lead to enhanced morbidity and mortality associated with respiratory viral infections, greatly enhancing the disease burden on society (Mc Cullers, 2014; Gupta et al., 2008) . Although viral-bacterial co-infections are well researched, studies detailing their impact during the COVID-19 pandemic remain sparse. With mass vaccination efforts against SARS-CoV-2 still in their initial stages, underlying co-infections and their treatment can have a significant impact on disease morbidity and associated patient care (Cox et al., 2020; Kim et al., 2020) . In the present paper we report the rates of respiratory bacterial and viral co-infections in SARS-CoV-2 infected patients in the United States.

Nasal, oropharyngeal and sputum swabs were received and tested by HealthtrackRX in our laboratory located at Denton, Texas, USA. Nucleic acid extraction and real-time PCR on the Open Array TM platform (Thermo Fisher Scientific, California, USA) were performed as previously described (Singh et al., 2019) . The following microbial pathogens were tested for: (1) 

Between 03/16/20 and 08/01/2020, a total of 50,419 respiratory samples (nasopharyngeal, oro-pharyngeal, and sputum swabs) were collected and concurrently tested for the presence of SARS-CoV-2 and other respiratory pathogens.

SARS-CoV-2+ patients (n=4,259) represented 8.44% (95% confidence interval [CI] 0.082 to 0.087; p=0.084) of the total samples analyzed in this study. Gender distribution of SARS-CoV-2+ population (55.5% female and 44.4% male) was similar to that of the total population (55.3% female and 44.6% male). The average age of the SARS-CoV-2+ patients was 45.21±20.43 years. Distribution of the SARS-CoV-2+ population over an age range revealed higher incidences of infections in the younger age groups (20-49 years) which comprised approximately 50% of the total positive cases ( Figure 1 ). Early reporting had demonstrated higher rates of SARS-CoV-2 infection in the older population (Stokes et al., 2020) . However, latest trends of the COVID-19 pandemic in the United States (Boehmer et al., 2020) are in agreement with our data that show higher infection rates in the younger population.

Both bacterial and viral respiratory co-infections can be secondary or concurrent. A variety of synergistic biologic interactions between viruses and bacteria have been reported, leading to an increased risk of bacterial infections (where a primary viral infection is present), J o u r n a l P r e -p r o o f and vice versa. (Lee et al., 2016) In the case of SARS-CoV-2, this is substantiated by our current study's co-infection data, by the data of Massey and co-workers (2020), and our previous work on co-infections present in "influenza-like-illnesses" (Singh et al., 2019) .

It is now widely accepted that in all the influenza pandemics of the last century the leading cause of mortality were secondary or concurrent bacterial co-infections including S. pneumoniae, S. aureus and H. influenzae (Gupta et al., 2008 ). An initial study originating from Wuhan, China reported bacterial co-infections in 50% of the patients that did not survive COVID-19 . A review of 13 studies reporting SARS-CoV-2 co-infection rates, disclosed co-infection and secondary infection rates ranging from 0.6-45.0% (Lai et al., 2020) .

In the present study significant bacterial and viral co-infections were observed in both SARS-CoV-2+ and SARS-CoV-2-population. In general, the SARS-CoV-2+ patients had lower incidences of co-infections as opposed to the SARS-CoV-2-patients ( Figure 2 ). This trend is similar to previously reported Stanford University data (Kim et al., 2020) , and differs from the data of Massey and coworkers (Massey et al., 2020) . However, the bacterial co-infections were comparable (33.17% SARS-CoV-2+, 35.45% SARS-CoV-2-). The viral co-infection rate was significantly lower in the SARS-CoV-2+ patients (3.42%) in comparison to SARS-CoV-2patients (8.66%). A detailed analysis of the co-infecting pathogens (Table 1) A similar trend was observed with viral co-infections, wherein the SARS-CoV-2+ patients had lower incidences of co-infections for all the viral targets when compared to the SARS-CoV-2patients, congruent to the study conducted by Kim and coworkers (2020) . All the viral co-infections were reported at less than 1% incidence rate apart from EBV. A possible explanation of the lower viral co-infection rate could be the time frame in which the study was Distribution of all co-infections (bacterial and viral) in the SARS-CoV-2+ population suggests a positive correlation with age ( Figure 3) . Even though the overall median age of the SARS-CoV-2+ patients was 45 years, the co-infections were significantly higher in the older age J o u r n a l P r e -p r o o f group (60+ years) as opposed to any other age group. Detailed analyses of the COVID-19 pandemic assert that the most severe outcome of the disease is observed in older patients (Wu et al., 2020) and our results may provide a possible explanation to this observation.

The present study, to our knowledge, is the largest such study related to the co-infections of SARS-CoV-2. Our observations provide significant insight into the potential risks and clinical outcomes for COVID-19 patients, especially in the susceptible older age group. While SARS-CoV-2 has a higher mortality rate than most other respiratory viruses, even without a bacterial coinfection, 33% of CoV-2 (+) cases in our study had a concurrent bacterial infection and could have benefitted from an antibiotic. Novel existing therapies, such as remdesivir and dexamethasone, were used for treatment of hospitalized SARS-CoV-2 patients, but like all other respiratory viruses, bacterial coinfections cannot be ignored. It is widely known that a variety of bacteria can both colonize, and under appropriate conditions cause infections of, the entire respiratory tract. Examples include S. pneumoniae, S. aureus and H. influenzae amongst others.

At the current time, immune system gene expression analysis is not in widespread use. Such analysis, once a consensus validation of the clinical utility has been completed, could be instrumental in determining whether a given detected microbial population represents an infection or a colonization. Meanwhile, clinicians must rely upon a given patient's signs and symptoms, in determining whether an infection exists. This is a potential microbiologic-test interpretative limitation for both classic culture-based and current molecular-diagnostic tests.

The main limitation of the study was that the patient records of hospitalization, recovery and treatment were not available which do not allow us to make further assessment of the impact of co-infections during SARS-CoV-2 infection. As a future endeavor, data will be collected J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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SARS-CoV-2 as possible inducer of viral reactivations

Co-infections: potentially lethal and unexplored in COVID-19

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Co-infections among patients with COVID-19: The need for combination therapy with non-anti-SARS-CoV-2 agents?

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Staphylococcus aureus and influenza A virus: Partners in coinfection

A Survey of Viral-bacterial Co-infection in Respiratory Samples Using Multiplex Real Time-PCR

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Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Instances of viral co-infections in the SARS-CoV-2+ population were found to be significantly lower than the SARS-CoV-2-population (p<0.05)