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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