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The risk of methicillin-resistant Staphylococcus aureus infection following COVID-19 and influenza: A retrospective cohort study from the TriNetX network
Dear Editor,
We read with great interest that several studies reported the co- and secondary bacterial infections following severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection, especially for patients with severe-to-critical coronavirus disease 2019 (COVID-19).1, 2, 3 However, the reported incidences of secondary infection post COVID-19 were inconsistent in different studies.4,5 Therefore, continuing surveillance investigation of the pathogens, especially multidrug-resistant organisms causing secondary infections following COVID-19 is needed to provide the epidemiologic information and further guide the appropriate use of antimicrobials for the patients with SARS-CoV-2 infection.6 Although it is well known that Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) could be the common pathogens causing secondary infection following influenza,7 it is unclear whether the incidence of MRSA secondary infection in patients with COVID-19 could be as high as that in patients with influenza. We, therefore, examined a large dataset of global healthcare records to determine the incidence of MRSA infection within one month after COVID-19 infection, and compare these risks with the matched patients following infection with influenza.
This retrospective cohort study was conducted using the TriNetX health records network with 73 healthcare organizations worldwide. COVID-19 was defined by the ICD-10 codes (U07.1-U07.2, B97.29, B34.2, J12.81) or positive laboratory results (TNX:LAB:9008-SARS coronavirus 2 and related RNA), and influenza was defined by ICD-10 codes (J09-J11). Cases who were 18 or older were included between March 1, 2020 and September 30, 2022. To avoid contamination between cohorts, the control influenza cohort excluded cases who had COVID-19 within 3 months, and the influenza cases were excluded in the COVID-19 cohort at any point in time. Primary outcome was the risk of secondary MRSA infection (B95.62, A49.02, J15.212) after the 48 h of the index event. Secondary outcome was the risk of MRSA bacteremia (R78.81).
Propensity score with 1:1 matching method was used to identify matched cohorts. Any characteristic with a standardized mean difference between cohorts lower than 0.1 was considered well matched. Hazard ratios (HRs) with 95% confidence intervals were calculated using the Cox model and the null hypothesis of no difference between cohorts was tested using log-rank tests. The Kaplan-Meier estimator was used to estimate the incidence of the outcomes.
Initial, 3,004,268 patients with COVID-19 and 128,393 patients with influenza were identified and then, each 128,392 cases remained in the both cohorts after propensity score matching (Table 1). Compared with the influenza cohort, the COVID-19 cohort was associated with the higher risk of secondary MRSA infection (HR, 1.52; 95% CI, 1.19-1.94) within one month. The higher risk of MRSA infection following SARS-CoV-2 infection than influenza cohort remained unchanged in different time frames (2-5 days: HR, 1.78; 95% CI, 1.20-2.64; 2-10 days: HR, 1.63; 95% CI, 1.90-2.24; 2-15 days: HR, 1.65; 95% CI, 1.24-2.20; 2-20 days: HR, 1.56; 95% CI, 1.20-2.04 and 2-30 days: HR, 1.52; 95% CI, 1.19-1.94). In addition, COVID-19 patients also had higher risk of MRSA bacteremia than patients with influenza in one month (HR, 1.43; 95% CI, 1.16-1.75). The higher risk of MRSA bacteremia remained consistent across different time periods (2-5 days: HR, 1.30; 95% CI, 0.94-1.79; 2-10 days: HR, 1.46; 95% CI, 1.12-1.91; 2-15 days: HR, 1.49; 95% CI, 1.18-1.90; 2-20 days: HR, 1.55; 95% CI, 1.24-1.93 and 2-30 days: HR, 1.43; 95% CI, 1.16-1.75). Further Kaplan-Meier estimation showed a similar finding that the incidence of MRSA infection for COVID-19 patients was higher than those with influenza (Log rank p < 0.05) (Fig. 1).
Table 1
Baseline characteristics for COVID-19 and influenza cohorts before and after matching.
| Before matching | After matching | |||||
|---|---|---|---|---|---|---|
| COVID-19 | Influenza | SMD | COVID-19 | Influenza | SMD | |
| Number | 3,004,268 | 128,393 | 128,392 | 128,392 | ||
| Age; mean ± SD, year | 47.3±17.7 | 47.5±19.3 | 0.781 | 47.4±19.2 | 47.5±19.3 | 0.004 |
| Sex; n (%) | ||||||
| Female | 1,678,280 (55.9) | 75,617 (58.9) | 0.061 | 75,641 (58.9%) | 75,616 (58.9%) | <0.001 |
| Male | 1,288,549 (42.9) | 51,780 (40.3) | 0.052 | 51,763 (40.3%) | 51,780 (40.3%) | <0.001 |
| Race; n (%) | ||||||
| White | 1,603,957 (53.3) | 488,603 (60.3) | 0.141 | 84,667 (65.9%) | 83,796 (65.3%) | 0.014 |
| Black or African American | 402,873 (13.4) | 17,012 (13.2) | 0.005 | 17,005 (13.2) | 17,012 (13.2) | <0.001 |
| Hispanic or Latino | 234,190 (7.8) | 9,562 (7.4) | 0.013 | 9,280 (7.2) | 9,562 (7.4) | 0.008 |
| Comorbidities; n (%) | ||||||
| Disease of respiratory system | 852,444 (28.4) | 66,991 (52.2) | 0.500 | 66,952 (52.1) | 66,990 (52.2) | 0.001 |
| Disease of circulatory system | 829,730 (27.6) | 59,017 (46.0) | 0.388 | 58,991 (45.9) | 59,016 (46.0) | <0.001 |
| Hypertensive disease | 623,360 (20.7) | 44,753 (34.9) | 0.319 | 44,906 (35.0) | 44,752 (34.9) | 0.003 |
| Neoplasms | 409,135 (13.6) | 35,981 (28.0) | 0.361 | 35,558 (27.7) | 35,980 (28.0) | 0.007 |
| Chronic lower respiratory disease | 313,002 (10.4) | 26,912 (21.0) | 0.251 | 26,470 (20.6) | 26,912 (21.0) | 0.008 |
| Diabetes mellitus | 301,326 (10.0) | 24,521 (19.1) | 0.259 | 24,308 (18.9) | 24,520 (19.1) | 0.004 |
| Asthma | 194,640 (6.5) | 16,751 (13.0) | 0.223 | 16,425 (12.8) | 16,751 (13.0) | 0.008 |
| Chronic kidney disease | 150,798 (5.0) | 16,864 (13.1) | 0.285 | 16,659 (13.0) | 16,863 (13.1) | 0.005 |
| Overweight, obesity and other hyperalimentation | 358,122 (11.9) | 23,370 (18.2) | 0.176 | 23,096 (18.0) | 23,370 (18.2) | 0.006 |
SD, standard deviation; SMD, Standardized mean difference
The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection in COVID-19 and influenza cohorts.
In summary, this retrospective cohort study demonstrated that COVID-19 patients would carry a significantly higher risk of MRSA infections, including MRSA bacteremia, than patients with influenza. The causes of higher risk of MRSA infection and bacteremia in COVID-19 patients than patients with influenza could be multifactorial. In contrast to influenza, systematic corticosteroid and interleukin-6 blockade are recommended for hospitalized patients with severe COVID-19. However, the use of these anti-inflammatory agents may increase the risk of secondary infection. In addition, infection prevention and control measures may not be strictly executed during COVID-19 pandemic. Thus, the incidence of nosocomial infections including MRSA infection could be higher than usual. Finally, the immune status following SARS-CoV-2 infection could be different from those after influenza. However, further investigation is warranted to clarify these mechanisms and validate our findings. Overall, the finding of the present study is consistent with several observational studies which reported that MRSA could be a frequent pathogen causing superinfection following SARS-CoV-2 infections.8,9 In one review on the epidemiology of MRSA lung infection in patients with COVID-19,10 the relative prevalence among all identified bacteria could range from 2% to 29%. All these findings indicated the critical role of MRSA among patients with COVID-19 and suggestd that clinicians keep alert the possible MRSA secondary infection following SARS-CoV-2 infections. Because inappropriate empirical antibiotic would be associated with poor outcome of patient with sepsis, empirical use of anti-MRSA agents for COVID-19 patients with secondary infection should be considered, especially for those with risk of MRSA infection.
This study had several limitations. First, although we matched the baseline characteristics of COVID-19 and influenza cohorts using propensity score method, some residual confounding factors, such as the disease severity, the use of anti-inflammatory agents, and the vaccine effect still existed. Second, SARS-CoV-2 infection could present as asymptomatic, so the influenza cohort might include patients without identified COVID-19. To avoid this confounding, the cases in the influenza cohort in this study was identified before 2020, when there was no COVID-19.
In conclusion, patients with COVID-19 would be associated with a higher risk of secondary MRSA infection than those with influenza. During this pandemic, clinicians should consider MRSA as potential pathogens causing secondary infection following SARS-CoV-2 infection.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.