Essay: The Significance of Coinfections in Medical Research and Diagnostics

Abstract
Coinfections are increasingly becoming a point of interest for research and medical diagnostics due to their global prevalence. Studies of coinfections have shown that they can accelerate disease progression and lead to higher mortality rates. During the current COVID-19 pandemic, coinfections have special significance because of the role they have been reported to play in increasing the susceptibility of individuals to opportunistic pathogens. Increased testing for coinfections can contribute greatly to understanding pathogen-pathogen interactions in coinfections and lead to improved treatments for patients with coinfections.
Introduction
Historically, microbial research has been focused around isolating individual pathogens to understand their mechanisms of infection. However, this ignores the very important health effects that can arise as a result of the interactions between various pathogens. It is increasingly becoming clear that rather than being the exception, coinfections are the rule. Due to advances in medical diagnostic techniques, coinfections are being detected in clinical settings more and more. However, their significance is not well understood due to a lack of research on the nature and consequences of many coinfections. Much more information is needed on the circumstances and mechanisms of pathogen-pathogen interactions in coinfections.
Understanding Coinfection
Coinfections are the infection of a cell or organism by more than one type of pathogen at a time. For the purposes of this paper, this includes secondary infections in cases when the primary pathogen is still present in the host. Coinfections often involve an opportunistic pathogen taking advantage of the immunosuppression caused by a primary pathogen. Some very well studied cases of coinfection are those that occur with Human Immunodeficiency Virus (HIV), due to the immunodeficiency caused by chronic HIV infection. One particular area of focus is HIV-Tuberculosis (TB) coinfections. As stated by the World Health Organization (2018), TB is one of the leading causes of death for people with HIV. Research has shown that Mycobacterium tuberculosis and HIV act as a syndemic: immunosuppression due to HIV infection increases the susceptibility of individuals to reactivation of latent TB or even primary infection by M. tuberculosis (Collins et al. 2002; Bruchfeld et al. 2015). In turn, TB expedites the advance of HIV infection to Acquired Immunodeficiency Syndrome (AIDS) (Collins et al. 2002; Bruchfeld et al. 2015).
Other well studied coinfections include those involving influenza. Due to constant evolution, influenza viruses repeatedly cause seasonal epidemics and sometimes pandemics. Studies have shown that coinfections with influenza viruses are common and often lead to more severe health impacts (Liu et al. 2010; Szymański et al. 2017). In 2008, Brundage and Shanks proposed a hypothesis that the majority of the deaths during the 1918-1919 influenza pandemic were caused by bacterial coinfections rather than the influenza virus. This hypothesis is well supported by reviews from that time, which concur that infection by the influenza virus weakened patients’ immune systems and pulmonary tissues, allowing opportunistic pathogens to invade (Jordan et al. 1919; Vaughan 1921). This brings up an important question: Do coinfections always have greater health impacts than single infections?
Pathogen-Pathogen Interactions
There are a variety of factors that influence coinfection severity, including which pathogens can be involved, the nature of those pathogens and the nature of pathogen-pathogen interactions. Coinfections can occur with any pathogenic species including parasites and fungi. Pathogens can interact either directly with each other, or indirectly through the host’s defense mechanisms and resources (Griffiths et al. 2011). In-host interactions between pathogens can result in microbial cooperation, interference or neutrality, depending on the relatedness of the pathogens (Kinnula et al. 2017). Pathogens that are more genetically related are likely to interact cooperatively to augment their transmission. This can lead to decreased virulence if they work together to use host resources economically (Buckling and Brockhurst 2008) or to increased virulence if the pathogens promote each other’s growth (Brown et al. 2002). Correspondingly, remotely related pathogens are likely to interfere with each other, which can lead to increased virulence due to competition for resources (Bremermann and Pickering 1983), or decreased virulence due to suppression of one pathogen by the other (Hibbing et al. 2010). In neutral coinfections, infection by one pathogen does not interact whatsoever with infection by another pathogen. In cases of virus-virus coinfection, recombination can occur and increase offspring fitness, thus exacerbating negative impacts on host health. Studies have also shown that direct interactions between viruses and bacteria can promote infection by multiple other viruses and bacteria (Erickson et al. 2018; Rowe et al. 2019; Neu and Mainou 2020). This is especially relevant to today’s circumstances of dealing with the devastating coronavirus disease 2019 (COVID-19), a global pandemic, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Coinfections with SARS-CoV-2
A novel ß coronavirus, SARS-CoV-2 is thought to be primarily transmitted via respiratory droplets through the air or through contact (Somsen et al. 2020). New research suggests that it may be possible for SARS-CoV-2 to also spread through aerosol transmission despite masks and other personal protective equipment (Goldberg et al. 2021). A highly pathogenic virus, SARS-CoV-2 has particularly severe effects on immunocompromised individuals, individuals with comorbidities, and older people (N. Chen et al. 2020). However, the disease effects are not limited to these at-risk groups. Therefore, it is crucial to understand the effects of SARS-CoV-2 infection and the role coinfections might play in the presentation of COVID-19. The first step towards this is detecting coinfections.
Classical techniques of coinfection diagnosis involve serology and pathogen isolation. Unfortunately, these techniques can be prone to error due to a limit of sensitivity or specificity. Real-time multiplex polymerase chain reaction (PCR) can help with misdiagnoses. However, it is not a perfect solution as it requires the sequence of the target genomes, making it difficult to identify unknown pathogens. Next Generation Sequencing (NGS) has been a great boon to clinical diagnostics, as it is capable of detecting almost all potential genomes present in a sample. Thus, NGS can be utilized as a screening tool to detect coinfections. Widespread NGS is particularly crucial in this pandemic for identifying coinfections and understanding the outcomes of pathogen–SARS-CoV-2 interactions. As it is quite difficult to isolate multiple viruses in purified form, improved tools such as cocultured cells and transgenic cell lines can be used for simultaneous isolation of multiple viruses (Kumar et al. 2018).
However, due to the current pandemic, public health labs are overwhelmed with the sheer number of samples that need to be tested for SARS-CoV-2 alone. Tests of choice for detecting SARS-CoV-2 revolve around nucleic acid amplification techniques, such as real-time reverse transcription PCR (rRT-PCR), and focus primarily on identifying the presence/absence of SARS-CoV-2 in the sample (CPHLN 2020). Since both the personnel qualified and the resources required to perform virus isolation tests for coinfection detection are in shortage, only a limited amount of coinfection monitoring occurs, as the lab capacity permits (Binnicker 2020; CPHLN 2020).
Despite these limitations, studies are being conducted on SARS-CoV-2–pathogen coinfections. Sharifipour et al.’s (2020) study examined bacterial coinfections in the respiratory tract of COVID-19 patients in the intensive care unit of a hospital in Iraq. In a sample of 19 people, all tested positive for bacterial coinfection. Out of these, 17 individuals were infected by antibiotic resistant Acinetobacter baumannii and 1 individual was infected by methicillin resistant Staphylococcus aureus (S. aureus). The only surviving individual was infected by methicillin susceptible S. aureus, which may have been a contributing factor to his recovery since his infection was able to be treated via antibiotics.
As this study and many others highlight, coinfections with SARS-CoV-2 can greatly increase the disease severity and mortality of patients (X. Chen et al. 2020; Tay et al. 2020; Yang et al. 2020). Individuals with comorbidities and immune system alterations are at much higher risk for experiencing negative outcomes of coinfections with SARS-CoV-2 (Martins-Filho et al. 2020). Increased testing for coinfection identification can contribute to the knowledge database on the identities of the predominant pathogens involved in and their mechanisms of interaction in coinfections with SARS-CoV-2. It will also lead to more accurate diagnoses and allow physicians to design more appropriate treatments that can help eliminate the coinfection and improve the overall outcome of the patients.