Figure 1: at the end of this file
Binary logistic regression was used to analyze the mortality association with viral and bacterial co-infections. The mortality rate was 19% (9/48), all of them were critically ill COVID-19 patients admitted to ICU, and two thirds of SARS-CoV-2 critically ill patients who died had co-infection (6/9). We found that viral co-infections (OR=1.78, CI=0.38-8.28) had higher mortality compared to bacterial co-infections (OR=0.44, CI=0.08-2.45) in COVID-19 patients. We observed that there was positive correlation between co-infecting influenza H1N1 virus and mortality (r=0.2). On the other hand, co-infection with Chlamydia pneumoniae (r=-0.17) did not have any correlation with mortality in SARS-CoV-2 infected patients.
In terms of comorbidities, the prevalence of diabetes was 54% (26/48), cardiovascular disease 4% (2/48) and chronic kidney disease (CKD) 10.4% (5/48). Co-infection was present in 20/34 (58.8%) in diabetics, 2/34 (5.9%) in cardiovascular diseases and 4/34 (11.7%) in CKD. There was no significant association of co-infection with diabetes (p=0.25), cardiovascular disease (p=0.24) nor CKD (p=0.7). However, when we used MANOVA test to look at association of death and co-infection with diabetes, cardiovascular disease or CKD, it showed that statistically significant correlation was present between diabetes and death (p=0.02).
We also investigated the importance of different blood markers in COVID-19 patients (Table 1). Specifically, we examined association of d-dimer, lactate dehydrogenase (LDH) and Troponin T with the severity of disease. These markers have been interchangeably used to predict disease severity and the potential of ICU admission. Using linear regression, we found that Troponin T was strongly related (p=0.001) with disease severity compared to LDH (p=0.12) and d-dimer (p=0.25). This finding may imply that Troponin T could be used as a predictor for disease severity.
4. Discussion
In this study, we investigated the presence of co-infections in COVID-19 cases and analyzed their clinical and epidemiological characteristics. Viral and/or bacterial co-infections have been linked to disease severity, both directly, indirectly and through immunological response [20,21]. The occurrence of respiratory co-infections in this study was estimated to be as high as (71%) and two thirds of SARS-CoV-2 critically ill patients who died had co-infection. Influenza A H1N1 was the most common detected among the co-infecting viruses (64%). Several studies have partially reported the prevalence of COVID-19 pneumonia and influenza co-infection [22,23,24]. However, data on clinical significance of influenza A H1N1 co-infections with COVID-19 is limited. The similarity of clinical manifestations between the circulating respiratory viruses such as influenza A H1N1 and SARS-CoV-2 makes the differentiation very difficult [16,25]. Influenza A H1N1 dominance in our study population implies simultaneous outbreaks of two viruses and clearly emphasizes on the importance of screening for other clinically important co-circulating respiratory pathogens. Besides, numerous studies have shown viral co-infections being associated with disease severity, acute respiratory distress syndrome (ARDS) and even death. These studies show higher intensive care admission rates [5,23,26,27]. In this study, influenza A H1N1‐COVID‐19 co-infected patients were more severe and required ICU admission. Our results also showed a high case fatality rate among COVID-19 viral co-infections (r=0.2). The severity and higher case fatality among COVID‐19 viral co-infected patients may be attributed to influenza A H1N1, which is known to induce a strong inflammatory cytokine/chemokine response (cytokine storm). Thus, the H1N1‐COVID‐19 co-infection could accelerate and play a major role in ARDS development. Our data showed that, during pandemics, focusing on the detection of the novel virus may lead to underreporting of other pathogens that could be the etiological agents contributing to disease severity.
Unfortunately, the topic of co-infection is usually embedded within the characteristics of patients in COVID-19 studies. However, our study investigated the coexistence of a full panel of respiratory viruses and bacteria simultaneously in order to investigate whether viral infection predisposes patients to subsequent bacterial co‐infection or not. Indeed, secondary bacterial co-infection is identified as the main cause of death in patients with viral pneumonia [7,28]. A study of common respiratory pathogens presenting as co-infections with COVID-19 from China revealed that the Mycoplasma pneumoniae and Legionella pneumophila were the most common bacteria detected among COVID-19 patients [29]. In this study, bacterial co-infection was present in 36% of patients and the most common bacterial co-infection among COVID-19 patients was Chlamydia pneumoniae with infection rate of (27%). Our findings appeared to be inconsistent with previous findings from China [29] which could be attributed to the diversity of geographical distribution of circulating respiratory bacteria. Nevertheless, the C. pneumoniae infection is a common cause of acute respiratory infections with seroprevalence of (34.1%) in patients with fatal COVID-19 [30]. However, inverse association was observed between bacterial co-infection and disease severity. This association indicates less likelihood of ICU admission with bacterial co-infection which may be attributed to empirical use of antibiotics during the early onset of COVID-19 disease. It could be argued that COVID-19 patients co-infected with C. pneumoniae who are treated with antibiotics may have suppressed the opportunistic growth of potentially fatal secondary bacterial infections decreasing the likelihood of ICU admission.
Many risk factors including older age, diabetes mellitus, cardiovascular disease, elevated LDH levels, high levels of D‐dimer and elevated inflammatory cytokines/ chemokines have been associated with adverse outcomes in COVID-19. In our study, the prevalence of diabetes was (54%) and significant correlation was present between death and co-infection with diabetes (p=0.02). This is expected as poor glycemic control predisposes to impaired innate and adaptive immunity which might lead to decreased viral clearance [31]. The Troponin complex is a predictor for coronary syndrome and myocardial infarction. The high levels of Troponin are significantly associated with acute myocardial infarction [32]. In this study, high levels of Troponin T were detected among COVID-19 patients. We found that Troponin T was strongly related (p=0.001) with disease severity compared to LDH (p=0.12) and d-dimer (p=0.25). This is explained by presence of ACE-2 receptors on myocardial cells and presence of myocardial injury in SARS-CoV-2 infection [33]. Several studies have revealed that the higher Troponin levels were increased in COVID-19 patients’ ICU admission and in-hospital death [16,34,35]. Our results confirm the important role of Troponin in the COVID-19 severity. We think the Troponin levels can be used as a marker of COVID-19 severity and a predictor of cardiovascular events.
Our study has some limitations. First, only 48 COVID-19 patients were included. Second, our study did not include asymptomatic or pre-symptomatic cases or healthy non- COVID‐19 controls. Third, important data about cardiovascular complications and echocardiography were not included. The impact of a secondary bacterial infections is less clear and cannot be established with the current study design. Future studies to overcome these limitations need to be considered.
In conclusion, the similarity in clinical presentation for both COVID-19 and Influenza makes it difficult to assess their impact on ICU admission and mortality. Our study highlights the importance of screening for co-infecting viruses in COVID-19 patients, given the high prevalence of Influenza viruses. The detection of co-infections in COVID-19 cases shows the importance of flu vaccination and warrants its increased coverage to reduce the hospitalization and associated mortality.
Author Contributions: B.A. contributed to study design, data analysis, results discussion, and manuscript writing and review; M.H. contributed to experimental design and work, and manuscript writing; H.A. conducted the experimental work; A.N. contributed to data analysis and manuscript writing; T.A. contributed to sample and data collection; S.A. performed results discussion and clinical interpretation; A.M. contributed to sample collection and data analysis; A.Z. contributed to Study design, clinical analysis of data, results discussion, manuscript writing and review. All authors read and approved the final manuscript.
Funding: This work was supported by the Research Center at King Fahad Medical city (Grant No 20-066). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.
Acknowledgments: The authors thank the Research Center at King Fahad Medical City for funding this study (Grant No 20-066). Special thanks to Dr. Omar Alhazmi, Mr. Mohammad A Alturkostani, Mr. Abdulaziz A Taleb, and Mr. Saeed Albalawi from the Regional Lab in Medina for their contribution in sample collection.
Conflicts of Interest: The authors declare no conflict of interest.
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