Coronavirus disease 2019 (COVID-19), caused by a novel beta-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide since December 2019, causing significant global public health and economic problems (1, 2). The World Health Organization declared COVID-19 a pandemic on March 11, 2020 (2). As of December 19, 2020, there have been over 75.7 million cases and 1.68 million deaths associated with COVID-19 worldwide (3). Nearly half of these cases involved four COVID-19 high-burden countries, including the United States (23.1%), India (13.2%), Brazil (9.5%), and Russia (3.7%) (3). Evidence to date suggests that COVID-19 patients with preexisting comorbidities such as hypertension, diabetes, and cardiovascular disease are at greater risk of death, but few studies have involved COVID-19 patients coinfected with other respiratory infectious diseases (4).

The initial signs and symptoms of COVID-19 are similar to other respiratory infections, such as tuberculosis (TB) and influenza. However, coinfections with common viral, bacterial, and fungal pathogens among COVID-19 patients are not unusual (5–7), which can interfere with the diagnosis and treatment of COVID-19. Before the COVID-19 outbreak, TB had been the most fatal infectious disease in the world for many years (8). Globally, an estimated 10 million people contracted TB and 1.4 million died from TB in 2019 (8). At present, evidence suggests that the main transmission route of both COVID-19 and TB is via respiratory droplets, and their main target are the lungs, which can lead to a worse outcome among COVID-19 and TB coinfection patients (aptly abbreviated COVID-TB) (7, 8). Therefore, due to the high prevalence of both of these infectious diseases and the potential worse prognosis of coinfection, an intensive investigation of COVID-TB cases may be of great clinical significance (3, 4, 8). However, few studies have focused on COVID-TB cases to date, and most of these are case reports involving only one patient, thus precluding systematic summaries of the clinical characteristics of coinfection cases (7, 9, 10). In addition, it is unclear whether COVID-TB patients have a worse prognosis or are more likely to develop severe disease, thus necessitating further study.

In this study, we aimed to more fully assess the impact of TB coinfection on COVID-19 patients using the following approach: (1) we present an overview of COVID-TB case reports or case series published through December 18, 2020 and describe the demographic characteristics, clinical symptoms, comorbidities, imaging features, laboratory indicators, type of TB coinfection, and treatment strategies for both COVID-TB survivors and non-survivors; (2) we performed a pooled analysis of published data regarding the odds ratios (ORs) of death or severe disease, comparing the COVID-TB and non-TB groups; and (3) we assessed the quality of outcomes using GRADEpro.

This meta-analysis of 36 studies provided a summary of demographic, radiological, and laboratory characteristics as well as symptoms at admission, comorbidities, therapy, and outcomes of COVID-TB cases and investigated the impact of TB on the prognosis of COVID-19 patients. Our study showed that non-survivors were older and had more complications associated with hypertension, hepatitis, and cancer, had more symptoms of dyspnea, and were more likely to have CT imaging features of bilateral lesions, infiltrates, tree in bud, and higher leucocyte count than survivors. We also found a moderate level of evidence indicating that COVID-TB patients are at higher risk of death or serious illness than COVID-19 patients without TB.

Older age, especially >65 years, may be a risk factor for death from COVID-TB, consistent with previous findings indicating that the mortality rate from COVID-19 increases exponentially with age (50, 51). According to a model-based analysis, the estimated overall death rate for COVID-19 was 0.66%, but increasing to 7.8% among patients aged >80 years and decreasing to 0.0016% among children aged <9 years (52). There are several primary reasons for these differences, including more preexisting comorbidities, dysregulation in the immune response, and chronic subclinical systemic inflammation (inflammaging) among older adults than younger persons (53). Thus, the elderly should be the primary focus of both COVID-19 and COVID-TB mitigation efforts due to its much higher mortality risk in that group.

COVID-TB patients had a much higher rate of comorbidities than COVID-19 patients (56.41 vs. 25.1%) (54). The most prevalent comorbidities among COVID-19 patients were hypertension (21.1, 95% CI: 13.0–27.2%), diabetes (9.7%, 95 CI: 7.2–12.2%), cardiovascular disease (8.4%, 95% CI: 3.8–13.8%), and respiratory system disease (1.5%, 95% CI: 0.9–2.1%), whereas the most common comorbidities among COVID-TB patients were diabetes (24.36%), hypertension (17.95%), HIV infection (6.41%), hepatitis (3.85%), epilepsy (3.85%), and cancer (2.56%) (54). Indeed, both HIV infection and diabetes are important risk factors for TB infection (55). Interestingly, we found that COVID-TB patients who died had a much higher proportion of hypertension (47.06 vs. 9.84%) and cancer (11.76 vs. 0%) than those who survived. A previous study also indicated that underlying diseases such as hypertension (OR = 2.72, 95% CI: 1.60, 4.64) and diabetes (OR = 3.68, 95% CI: 2.68, 5.03) are risk factors for critical disease/mortality (56). Early publications reported a “harmful hypothesis” that SARS-CoV-2 binds to target cells via angiotensin-converting enzyme 2 (ACE2), and patients with hypertension usually have increased expression of ACE2 due to the use of renin angiotensin system inhibitors (57). Although some studies indicated that ACE inhibitors (angiotensin converting enzyme inhibitors) and ARB (angiotensin-receptor blockers) therapy was harmful in COVID-19 patients, an updated meta-analysis concluded that ACEI/ARB therapy does not contribute to increased risk of mortality or severe manifestations among COVID-19 patients (58, 59). It was recommended that ACEI/ARB therapy be continued among patients with coexisting hypertension (60). However, whether the guidelines regarding ACEI/ARB therapy among COVID-19 patients are equally applicable to COVID-TB patients remains to be determined.

The most common clinical manifestations of COVID-TB are fever, cough, dyspnea, weight loss, fatigue, and expectoration (13, 61). Existing evidence indicates that the features of lung imaging among COVID-19 patients include bilateral involvement, peripheral distribution, mixed ground-glass opacity and consolidation, and vascular thickening (62), whereas the most common CT findings of COVID-TB include bilateral lesions, cavities, infiltrates, ground-glass opacity, nodules, pleural effusion, and fibrosis. Thus, clinicians should take COVID-TB coinfection into consideration upon encountering the above CT imaging features in the future instead of just focusing on one disease. The increased prevalence of dyspnea and CT findings including bilateral lesions, infiltrates, and tree in bud among COVID-TB patients who died suggests that they may be good predictors of disease severity, in line with the findings of previous studies (13, 61).

Markedly elevated levels of inflammatory markers, including CRP, ESR, PCT, FER, and LDH, slightly increased neutrophil count and D-dimer level, and decreased lymphocyte count and hemoglobin level were observed in COVID-TB patients. However, we did not find any significant differences in these indexes (except the leucocyte count) between the survivors and non-survivors, which was inconsistent with previous findings that inflammatory markers were elevated in severe disease and critically ill groups (63, 64). The findings regarding the characteristics of COVID-TB biomarkers may provide references for conventional hematological and inflammatory examinations for disease severity classification, and early warning of progression (65).

According to the COVID-19 treatment guidelines, the main treatments include antiviral therapy, immune-based therapy, and adjunctive therapy (66). Antiviral therapies may have a greater effect in the early course of COVID-19, whereas immunosuppressive/anti-inflammatory therapies will be more beneficial in the later stages (66, 67). Although previous studies indicated that corticosteroids are associated with a reduction in short-term mortality and the need for mechanical ventilation in COVID-19 patients, whether immunosuppressive therapies such as dexamethasone, a corticosteroid, can be used in COVID-TB patients as well has not been investigated (68). In our study, although there was no statistically significant difference in the proportion of corticosteroid therapy among COVID-TB survivors and non-survivors, we still recommend a more cautious use of corticosteroids in COVID-TB patients because of the potential increased risk of active or severe TB infection associated with corticosteroid use. Studies involving larger samples are needed to explore the impact of corticosteroid therapy on the prognosis of COVID-TB patients (69). It is also worthwhile to explore whether COVID-19 patients with active TB, LTBI, or previous TB should receive standard anti-TB treatment.

Based on this meta-analysis, we found that COVID-TB patients were 2.21 and 2.27 times more likely to die or develop severe COVID-19, respectively. In many countries, the ongoing COVID-19 pandemic coincides with other major public health problems, especially TB, and the impact of the COVID-19 pandemic may be ameliorated if we continue to implement health-care services and key prevention measures (70, 71). COVID-TB infection is a novel disease that remains to be further explored and needs more attention in high-TB burden countries such as India, Indonesia, and China (8). Encouragingly, it has been reported that use of the GeneXpert MTB/RIF platform for the surveillance of COVID-19 is relevant and achievable, especially in low-income and middle-income countries without sufficient classical real-time PCR capabilities but with an already existing GeneXpert MTB/RIF network (72).

Our study has some strengths. First, detailed information was collected in our study, including data regarding demographic characteristics, imaging findings, symptoms at admission, comorbidities, therapies, and outcomes, and the synthesis of these characteristics may provide further guidance for clinicians in terms of diagnosis and treatment of COVID-TB. Second, a comprehensive literature search of both Chinese and English language databases were performed, resulting in a more accurate evaluation of summary estimates with higher precision. Third, the studies included in our meta-analysis had relatively low levels of heterogeneity.

Our study also has several limitations. First, although we performed an extensive search of the literature, most of the eligible studies included in the Forest plots were Chinese. Second, some detailed patient information was not available due to publication bias or no relevant laboratory tests having been performed. Finally, the sample size of our case overview was still limited; thus, further large cohort studies of COVID-TB are needed.

In summary, older age, complications including hypertension, hepatitis, cancer, symptoms of dyspnea at admission, CT imaging features of bilateral lesions, infiltrates, tree in bud, and higher leucocyte count may be predictors for poor prognosis of COVID-TB patients. Furthermore, a moderate level of evidence suggests that people with COVID-TB are 2.21 and 2.27 times more likely to die or develop severe disease, respectively, than COVID-19 patients. Finally, routine screening for Mycobacterium tuberculosis is recommended among suspected or confirmed cases of COVID-19 in high–TB burden countries due to the worse prognosis of COVID-TB and the confounding clinical symptoms of these two diseases.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

H-cL, W-mS, and Y-fL conceived and designed the study. H-cL, X-hZ, Q-qA, S-qL, and YL directed its implementation including the data analysis and writing of the paper. W-mS and Y-fL analyzed the data. W-mS, YL, Q-yZ, J-yL, T-tX, S-jL, X-hZ, and N-nT contributed to data collection, materials, and analytic tools. W-mS and H-cL wrote and revised the manuscript. All authors revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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