key: cord-0770757-6jc379jw
authors: Howard, Leigh M
title: Is there an association between SARS-CoV-2 and Streptococcus pneumoniae?
date: 2020-12-04
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1812
sha: 358017fc390cffa3b18b6a5dd40c19e6d4ae234c
doc_id: 770757
cord_uid: 6jc379jw

nan

A c c e p t e d M a n u s c r i p t

(pneumococcus) have been extensively investigated. Although impactful viral-pneumococcal interactions have been described with common respiratory viruses, including human rhinovirus and respiratory syncytial virus, [1] [2] [3] [4] these interactions have been most widely studied with influenza and pneumococcus, in part prompted by the dramatically increased mortality due to secondary pneumococcal pneumonia during the 1918 influenza A/H1N1 pandemic. [5] [6] [7] [8] [9] [10] [11] [12] It has been hypothesized that respiratory viral infections create favorable conditions in the nasopharyngeal mucosa for colonizing pneumococci to invade, leading to mucosal disease such as pneumonia or otitis media, as well as invasive pneumococcal diseases (IPD), including bacteremia and meningitis.

Several mechanisms for viral facilitation of bacterial colonization have been proposed. Respiratory viruses may alter the integrity of the respiratory epithelia, enhancing conditions for bacterial adherence and translocation, as well as inducing factors required for bacterial adherence and by influencing immunological defenses of the host epithelium. [13] Epidemiological and ecologic observations suggest that co-infection with respiratory viruses such as influenza, human rhinovirus, and respiratory syncytial virus is common in children with pneumococcal pneumonia and IPD, [14, 15] and rates of IPD temporally correlate with periods of high activity of these viruses. [4, 16, 17] Despite the widespread global effects of the novel coronavirus disease pandemic, until now little has been reported regarding the potential bacterial, specifically, pneumococcal interactions with SARS-CoV-2, the virus associated with COVID-19. Several earlier studies using various methods and definitions to identify bacterial coinfections in patients hospitalized with COVID-19 have reported coinfection frequencies ranging from 3.5% for confirmed community-onset bacterial infection [18] to 28% among patients admitted to the ICU, a study which included a multiplex bacterial panel performed on upper respiratory samples in its definition. [19] [20] [21] In one study, while the overall frequency of secondary bacterial infection, defined as bacterial A c c e p t e d M a n u s c r i p t detection in a bronchoalveolar lavage, bronchial, or sputum samples, was 8.5%, 35% of patients with "critical" disease were found to have secondary bacterial infection, compared to only 4% of those with moderate and 9% with "severe" disease. [20] Another study that reported secondary bacterial infection (defined as positive blood or lower respiratory tract culture) frequencies of 15% overall, but frequencies of 50% of non-survivors, compared to 1% of survivors of COVID-19. [21] These important studies, however, have not examined the role of coinfection with specific bacteria, such as pneumococci, on COVID-19-associated clinical course and outcomes.

In this issue, Amin-Chowdhury and coauthors present one of the first examinations of potential interactions that may occur in the setting of pneumococcal and SARS-CoV-2 coinfection.

The authors provide evidence to support a potentially synergistic relationship between SARS-CoV-2 and pneumococci, with markedly higher mortality associated with co-infection and/or secondary Nasopharyngeal pneumococcal colonization, common in children as well as in adults with close contact with children, is typically asymptomatic but represents a critical initial step preceding the development of IPD. The authors" finding that death occurred in nearly half of individuals with SARS-CoV-2 infection within the 3-27 day period after IPD suggests that nasopharyngeal pneumococcal carriage prior to SARS-CoV-2 exposure/infection may modify risk of severe COVID-19 illness. While data are limited, an earlier study conducted by our group among young children in rural Peru has suggested that increases in the density of colonizing nasopharyngeal pneumococci during asymptomatic periods is associated with the subsequent development of acute respiratory illness within four weeks. The illnesses that followed increases in pneumococcal density were typically mild, brief, associated with detection of a respiratory virus, and the great majority resolved without antibiotics. [22, 23] This suggests a contributing role, but not necessarily a primary etiological role, for colonizing pneumococci in the pathogenesis of these mild "cold"-like respiratory illnesses that have typically been considered virus-associated. Whether a similar contributing role exists for A c c e p t e d M a n u s c r i p t pre-existing nasopharyngeal pneumococcal colonization in influencing the symptom course of SARS-CoV-2 infection requires further study.

While compelling, the findings presented by Amin-Chowdhury et al should be interpreted in the context of several important considerations. The authors acknowledge that very little community testing was performed during the initial phase of the SARS-CoV-2 pandemic, resulting in the majority of testing occurring in symptomatic patients presenting to the hospital for care. Therefore, IPD occurring in the 3-27 day period following mild SARS-CoV-2 infection that was managed in the outpatient setting would have remained undetected as such. Additionally, it is not possible to determine the sequence of infection in co-infection cases. Thus, while few secondary cases of IPD were observed, the incidence of secondary IPD cases following COVID-19 may be underestimated.

Furthermore, a number of the SARS-CoV-2 infections were acquired during the 3-14 day period after IPD diagnosis among patients with a negative SARS-CoV-2 test at hospital admission, suggesting the possibility of nosocomial acquisition among this vulnerable group. Additionally, from available data it is difficult to estimate whether co-infection with SARS-CoV-2 and pneumococci occurred at a rate that is greater than that expected by chance, given the dynamic patterns of SARS-CoV-2 circulation and detection throughout the early and later phases of the pandemic, as well as the national lockdown, which may have resulted in unpredictable transmission patterns for both pathogens differentially across specific subpopulations. Finally, while the significantly higher mortality observed in patients with co-infection or subsequent SARS-CoV-2 infection within 28 days after IPD is compelling, the authors note that most deaths occurred in the elderly and among those with multiple comorbidities.

Patients who are more medically frail and/or exhibit certain comorbidities may be more likely to be exposed to and/or exhibit severe manifestations of pneumococcal and SARS-CoV-2 infection. [20, 21, insights into a potential synergistic interaction between SARS-CoV-2 and pneumococcal infection, findings that may contribute improved insight into the pathogenesis of SARS-CoV-2. Future studies that employ longitudinal assessments, taking into account pneumococcal colonization and density patterns before, during, and after SARS-CoV-2 infection, will further elucidate the contributions of these potential interactions to SARS-CoV-2 pathogenesis and ultimately enhance response efforts to this global threat.

The author has no potential conflicts of interest to disclose.

Nasopharyngeal Pneumococcal Density and Evolution of Acute Respiratory Illnesses in Young Children

Nasopharyngeal Pneumococcal Density Is Associated With Viral Activity but Not With Use of Improved Stoves Among Young Andean Children

Nasopharyngeal Pneumococcal Carriage During Childhood Community-Acquired Alveolar Pneumonia: Relationship Between Specific Serotypes and Coinfecting Viruses

Association between respiratory syncytial virus activity and pneumococcal disease in infants: a time series analysis of US hospitalization data

Identifying the interaction between influenza and pneumococcal pneumonia using incidence data

Influenza A virus facilitates Streptococcus pneumoniae transmission and disease

Streptococcus pneumoniae in ferrets

Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source

Live attenuated influenza vaccine enhances colonization of Streptococcus pneumoniae and Staphylococcus aureus in mice

Seasonality of invasive pneumococcal disease: temporal relation to documented influenza and respiratory syncytial viral circulation

Insights into the interaction between influenza virus and pneumococcus

Viral and bacterial interactions in the upper respiratory tract

High nasopharyngeal pneumococcal density, increased by viral coinfection, is associated with invasive pneumococcal pneumonia

Viral coinfections in children with invasive pneumococcal disease

Temporal association between rhinovirus circulation in the community and invasive pneumococcal disease in children

Seasonal drivers of pneumococcal disease incidence: impact of bacterial carriage and viral activity

Empiric Antibacterial Therapy and Community-onset Bacterial Co-infection in Patients Hospitalized with COVID-19: A Multi-Hospital Cohort Study

Bacterial and viral co-infections in patients with severe SARS-CoV-2 pneumonia admitted to a French ICU

COVID-19 with Different Severities: A Multicenter Study of Clinical Features

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

Nasopharyngeal Pneumococcal Density during Asymptomatic Respiratory Virus Infection and Risk for Subsequent Acute Respiratory Illness

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