Infectious diseases have often played a part in human evolution and experience. In particular, viral epidemics and pandemics have shaped human society as we know it today. A crucial criterion in establishing the etiology and prognosis of a disease is the coinfections associated with the causal organism. A clear understanding of coinfections of a pathogen can have a significant impact on disease severity, decisions related to patient care, and the associated clinical outcomes. For example, coinfections exacerbate the morbidity and mortality rates of respiratory tract infections, which are a global leading cause of death and a major economic burden.
What is a coinfection?
|A coinfection arises when a patient is infected with more than one pathogen at the same time, often as a result of a weakened immune system and pathogens coevolving and adapting, involving an intricate interplay of bacterial, viral, and host factors. For example, according to the World Health Organization, a leading cause of death in people living with HIV is tuberculosis.|
The advent of SARS-CoV-2 and the COVID-19 pandemic has highlighted the importance and susceptibilities of our public health resources in dealing with a novel respiratory pathogen. Even with the unprecedented scientific response to the pandemic, the coinfections that often present with COVID-19 remain to be studied in depth. With the emergence of novel SARS-CoV-2 variants and vaccination drives still underway, understanding the bacterial and viral coinfections that arise alongside SARS-CoV-2 are crucial to understanding the epidemiology and clinical implications of the disease.
Why should we study respiratory coinfections?
Lower respiratory infections are among the top five leading causes of death in humans worldwide. Studying their coinfections is an important field of research as coinfections can act as a reliable predictor for disease prognosis and patient care management.
While it was previously believed that viral respiratory infections are caused by single viruses, recent research has shown that most respiratory infections are caused by multiple bacterial/viral pathogens coinfecting the host. In fact, researchers now believe that during the 1918 influenza pandemic, bacterial coinfections were the leading cause of morbidity and mortality in the patient population.
Several recent studies have now corroborated these findings and concluded that coinfections of respiratory bacterial and viral pathogens result in higher ICU admissions and increased death rates compared to viral infections alone. The recurring annual direct and indirect impacts of respiratory tract coinfections on the economy could be in the tune of billions of dollars.
Coinfections: What have we learned from previous pandemics?
With the ongoing COVID-19 pandemic, it makes sense to turn to what we learned from previous influenza pandemics in terms of coinfections.
A number of bacterial species, like Streptococcus pneumoniae, Hemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, and Streptococcus pyogenes, etc., are part of the normal flora of the upper respiratory tract, but given an opportune environment (e.g., temperature, humidity, and previous or current viral infections), they can become pathogenic.
The 1918 influenza pandemic is considered to be one of the most severe flu pandemics of the recent past, infecting nearly 50 percent of the world’s population. Studies have estimated that approximately 95 percent of the infected individuals also displayed bacterial coinfections, with S. pneumoniae, H. influenzae, and S. aureus being prominent coinfecting bacterial pathogens.
"During the 2009 swine flu pandemic, up to 55 percent of the mortalities displayed bacterial coinfection(s)."
Immunocompromised patients are a subpopulation that is highly susceptible to coinfections, which result in a significant increase in the morbidity associated with the original infection. A previous study has depicted that respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) coinfections led to worsened disease symptoms and greater health care intervention as compared to individual/single viral infections.
Similar outcomes of disease exacerbation have been noted in HIV patients coinfected with tuberculosis or hepatitis B or C virus. Some other notable viral coinfections may include rhinovirus (HRV), HMPV, RSV, and coronaviridae species (non-COVID-19), all manifesting similar symptoms, thus making the accurate diagnosis of the infecting agent important for successful treatment.
What coinfections occur with SARS-CoV-2?
In the last two years, several studies have detailed coinfections in people infected with SARS-CoV-2. A study conducted by researchers at the Stanford University School of Medicine in April 2020 showed that coinfection rates in the SARS-CoV-2-positive population were as high as 20 percent. Likewise, a systematic review and meta-analysis conducted from October 2019 to February 2021 found that 19 percent of patients with COVID-19 had coinfections and that coinfected patients had higher mortality rates than those with single infections.
Another systematic review and meta-analysis was conducted from December 2019 to March 2021 from a total of 31,953 SARS-CoV-2 patients. As part of this literature review, a total of 72 studies were selected that identified and detailed coinfecting pathogens with SARS-CoV-2. Based on these studies, it was estimated that 57.3 percent of reported coinfections were bacterial in nature, 39.5 percent were viral, and 3.2 percent were fungal.
Bacterial coinfections among COVID-19 patients
Viral infections like SARS-CoV-2 result in physical modifications of the respiratory passage that allow for subsequent or concurrent bacterial infections. In an early rapid review and meta-analysis in July 2020, compiled data from 24 studies with a total of 3,338 COVID-19 patients showed that the most common coinfections were bacterial in nature, including S. aureus, S. pneumoniae, Mycoplasma pneumoniae, and H. influenzae. However, overall, only 6.9 percent of COVID-19 patients were found to have bacterial coinfections. At the time, the authors concluded that there was not enough evidence to support widespread use of antibiotics in hospitalized COVID-19 patients.
"Coinfections of SARS-CoV-2 have been reported for all age groups, however, advanced age appears to be a significant factor in higher rates of coinfections."
S. aureus is a serious pathogen of the human respiratory tract with infections often leading to fatal outcomes. In a coinfection study conducted by HealthTrackRX between March and August 2020 on 50,419 SARS-CoV-2 samples, a significantly higher proportion of the SARS-CoV-2-positive population demonstrated S. aureus and Epstein-Barr virus coinfections compared to the SARS-CoV-2-negative population.
Similar findings were noted by another US-based research group, where COVID-19 positive patients also had higher rates of S. aureus, as well as Klebsiella pneumoniae and M. catarrhalis, coinfections compared to the SARS-CoV-2-negative population.
Coinfections of SARS-CoV-2 have been reported for all age groups, however, advanced age appears to be a significant factor in higher rates of coinfections and the associated morbidities of COVID-19. Age-related impairment of the immune system could be responsible for the adverse outcomes of SARS-CoV-2 infections in elderly patients.
A number of studies have now been published in the span of two years indicating that bacterial coinfections in COVID-19 patients can lead to complications in patient care management and treatment. However, coinfection characterizations are still in progress and researchers speculate that multidrug resistant bacteria are among the coinfecting pathogens exacerbating the infection spread.
Viral coinfections among COVID-19 patients
Noted viral coinfections in SARS-CoV-2 patients, both in the US and worldwide, include known respiratory viral pathogens such as adenovirus, HMPV, and coronaviridae species (non-COVID-19). Interestingly, researchers have also detected significant coinfection rates with the herpes virus family, including HHV3, 4, 6, and 7.
Virologists speculate that the unregulated expression of cytokines or “cytokine storms” observed in COVID-19 patients is responsible for the reactivation of these viral pathogens. However, some studies have found that the overall viral coinfection rate was lower in SARS-CoV-2-positive patients. This may be attributed to viral interference, where host defense responses triggered by a previous viral infection prevent or delay concurrent or subsequent infections by another viral species.
Detecting SARS-CoV-2 coinfections
Non-pharmaceutical intervention (social distancing, mask wearing, increased personal hygiene, and travel restrictions) had an unprecedented impact on the circulation of several other respiratory viruses like influenza and RSV, which had infections rates approach 0 percent in the northern hemisphere during their regular season in 2020. With the easing of non-pharmaceutical interventions and the onset of winter, there has been a spike in reports of influenza cases since the beginning of November 2021.
"The CDC has updated its testing guidelines to co-test for influenza A/B along with SARS-CoV-2."
Nucleic acid-amplification techniques (NAAT), especially multiplex PCR assays and next-generation sequencing (NGS), have greatly enhanced our ability to rapidly detect coinfections. NGS has further transformed disease diagnostics and microbiological investigations, especially for novel pathogen identification, due to high scalability and throughput.
Diagnosing coinfections helps support antimicrobial stewardship
COVID-19 may no longer be an emerging infectious disease; however, the emergence of novel SARS-CoV-2 variants continues to prolong the pandemic. Each new variant raises new questions about its infectivity and impact on vaccine efficacy, raising fears of a new wave of infections.
Studying SARS-CoV-2 coinfections to detect additional pathogens that contribute to patient outcomes can help clinicians design more precise and personalized treatment plans for patients, such as prescribing targeted antibiotics. Having a precise diagnosis of any coinfections can also help reduce the unnecessary or excessive use of antiviral and antibacterial treatments, supporting antimicrobial stewardship efforts.