Understanding COVID-19 Coinfection

Despite the advances of modern medicine, tuberculosis (TB) – a chronic disease caused by Mycobacterium tuberculosis – is the 13th leading cause of death worldwide (1). TB and COVID-19 share some clinical symptoms, such as a cough and fever, which makes differentiating between them challenging at times – and affects the speed and accuracy of diagnosis and prognosis. This is further complicated by coinfections, which have been reported in previous coronavirus epidemics (2). Coinfection presents a significant threat in the spread of TB and, based on previous cases, highlights the need to understand interactions between M. tuberculosis and SARS-CoV-2 to aid development of therapeutic strategies against the two diseases.

Over the past two years, the scientific community has responded to the ongoing threat of COVID-19 by learning as much as possible about how it spreads, how it affects people and communities, the long-term impact on the body after infection, and the incidence of coinfection with other pathogens. More and more research aims to identify the impact of secondary infection in COVID-19 patients – but, because COVID-19 has a variety of clinical manifestations, it may be challenging to distinguish coinfections such as TB that share clinical features. This is particularly problematic because rapid diagnosis of COVID-19 and TB is critical for identifying coinfection and determining the correct course of treatment.

The complications of coinfections
 

Microbiologists, epidemiologists, virologists, and pathologists have generated a body of research investigating the structure of SARS-CoV-2, its mechanism of infection, the COVID-19 disease pathway, and how it affects individuals differently. These efforts have included studying the long-term effects of COVID-19 and, more recently, tracking mutations that could lead to new viral variants. Coinfection complicates matters because SARS-CoV-2 infection causes an immune response that, in some cases, can become dysfunctional and cause significant lung and systemic pathologies (3). In severe COVID-19 pneumonia, the lung damage and dysregulated immune response puts patients at an increased risk of secondary infections. In addition, infected individuals with pre-existing conditions could be more susceptible to severe COVID-19 disease.

Several factors can complicate the diagnosis and treatment of coinfected patients. For example, secondary infections could be more easily missed in the face of SARS-CoV-2 primary infection, particularly if symptoms overlap. Therefore, diligent testing of COVID-19 patients for other infectious diseases is vital, especially in the intensive care unit (ICU), where patients are at increased risk of nosocomial infections. These patients should be carefully monitored to catch coinfections early and optimize treatment. Testing is also important to identify drug-resistant infections, which are even more challenging to treat.

Though the reported incidence of bacterial and fungal coinfections in hospitalized COVID-19 patients is relatively low (4), such infections can cause severe disease with poorer outcomes. For example, studies have reported a higher incidence of secondary infections in patients admitted to ICU (5,6), and those with secondary infections had lower discharge rates and higher mortality rates than those without (7). However, whether the worse outlook is a result of “longer ICU stay, concomitantly administered medications […], the immunocompromising effects of severe COVID-19 itself, or a combination of factors” is still elusive (8).

Tales of tuberculosis
 

At the start of the pandemic, we predicted that we would see an increase in TB deaths due to disrupted access to diagnostics and treatments, especially in the developing world (9). In addition to health service disruptions, COVID-19 and TB coinfections may be of particular concern because the use of immunomodulators is suspected to lead to the reactivation of latent TB (10). Furthermore, pre-existing TB and underlying lung conditions affect the clinical severity of COVID-19 (10). There is also the potential for drug interactions and a higher risk of additive hepatotoxicity caused by dual treatment with anti-COVID-19 and anti-tubercular drugs (10).

Based on a study of 86 suspected COVID-19 cases from primary care hospitals in Shenyang, China, individuals with co-existing active TB are more likely to develop severe COVID-19 (11). The study, which requires follow-up research due to the small number of participants, implies that latent or active TB increases susceptibility to SARS-CoV-2 infection as well as accelerated and more severe COVID-19 disease progression (11). Based on these findings, the study recommends routine M. tuberculosis screening of COVID-19 patients at admission to hospital.

A review of six studies indicated that TB increases COVID-19 susceptibility and worsens symptoms (12); however, no data appears to exist regarding the influence of SARS-CoV-2 on the progression of TB. Despite these unknowns, an understanding has developed that drug-resistant TB is increasingly prevalent. To help distinguish between different levels of resistance, healthcare professionals use the following characterization:

• Multidrug-resistant TB (MDR-TB) is caused by bacteria that are resistant to at least the two first-line (and most potent) antibiotics, isoniazid and rifampicin. 
• Extensively drug-resistant TB (XDR-TB) is rarer and is defined as MDR plus resistance against fluoroquinolone and either bedaquiline, linezolid, or both. 

Coinfections may increase the risk of potential drug interactions – and MDR-TB treatments may result in adverse side effects, which could be worsened by COVID-19 (13).

Future outlook
 

Early and reliable diagnostics are fundamental for guiding targeted and successful TB treatments. Traditional culture methods are more time-consuming and laborious than molecular diagnostic tests that enable fast TB detection. These assays allow healthcare professionals to detect the M. tuberculosis complex directly from patient specimens. In recent years, resistance to important antibiotic drugs (including isoniazid and rifampicin) has increased (14) and slow conventional antibiotic susceptibility testing for TB can delay appropriate treatment. On the other hand, PCR methods can be used for rapid initial TB screening and identification of resistance to core drugs.

As the pandemic progresses, research has evolved to better understand the challenges of diagnosing and treating coinfections. But this research is still in its infancy, and it remains unclear how coinfections affect clinical outcomes or whether existing infections lead to poorer resilience against the disease. Rapidly identifying secondary pathogens and diagnosing coinfections is therefore critical as the pandemic continues to evolve – and for any future emerging pathogens.