In this case-control study, we identified several risk factors of secondary infections in severe and critical patients hospitalized with COVID-19. Significant risk factors were male, age 65 or older, heart diseases, hypoproteinemia, corticosteroids and PPI.
As previously covered risk factors for hospital acquired pneumonia (HAP), male, age 65 or older were risk factors of secondary infection [13, 17]. Recent studies related to COVID-19 reported that male was a risk factor associated with disease severity status, and age 65 or older was a risk factor related to death [7, 15, 18, 19].
In multivariate regression model, heart disease was the only underlying comorbidity associated with secondary infections. It had been uncovered that, acute cardiac events and poor prognosis appeared on patients with coronary heart disease were related to influenza and lower respiratory tract virus infection . Previous report indicated that MERS-CoV would damage the heart muscle, when COVID-19 appeared, some researchers also confirmed its heart damage effect . So what was the relationships between heart diseases and secondary infections in patients with COVID-19? We speculated that patients with heart disease once infected with COVID-19 were more likely to develop into severe illness, thus exposing inpatients to invasive devices such as mechanical ventilation and central venous catheterization.
Diabetes was generally considered as a risk factor for infections , but in our study, there was no statistically significant difference between cases and controls. Previous risk factors of pneumonia reported chronic obstructive pulmonary disease (COPD) to be one risk factor associated with secondary infection .We also found the proportion of COPD in the cases was more than three times that in the controls. Unfortunately, we did not record enough patients with COPD in the two groups. Despite the incidence of anemia between cases and controls were notable difference, there were only 3 patients in each group. Therefore anemia couldn't be included in univariable regression.
In a sepsis study, albumin could be used as a predictor of disease severity . Hypoproteinemia was a risk factor of carbapenem-resistant Klebsiella pneumoniae bacteremia in non-transplant patients . In our study, we found that hypoproteinemia was also a key risk factor of secondary infections. Report showed COVID-19 attacked the body's immune and disrupted immune response . Besides, hypoproteinemia would weaken immunity to be susceptible to infections, and systemic edema, ascites and pleural effusion caused by hypoproteinemia might cause infections.
Among factors identified by multivariate regression, corticosteroids' risk ratio was notable. Corticosteroids could suppress the immune system if taken for long time or large doses. A research of BSI in ICU reported immunosuppressants were associated with BSI . One possible cause of hospital-acquired pneumonia (HAP) was that diseases on admission destroyed patients' immune system, thus making patients be susceptible to infections . In addition, COVID-19 attacked the human immune system and made corticosteroids' influences more prominent . Therefore, the use of corticosteroids to treat inflammation was a double-edged sword. It was necessary to comprehensively evaluate the patient's condition before rationally using corticosteroids in the short term.
Taking proton pump inhibitors (PPI) increased the risk of secondary infections in patients hospitalized with COVID-19. Herzig SJ et al. reported acid-suppressive medication use was associated with 30% increased odds of hospital-acquired pneumonia. Statistically significant risk was demonstrated only for use of PPI .
Undoubtedly, risk factors associated with secondary infections were severity of illness on admission, ICU admission, ventilator, central venous catheterization. Disease severity status on admission was a leading cause for secondary infections. Critical illness of patients usually had decreased level of consciousness and needed to be admitted to the ICU. Once it happened, invasive devices such as ventilator and central venous catheterization were required. These were the major risk factors of secondary infections confirmed in many previous studies [26–30].
Unfortunately, of the same pathogens from sputum and blood culture 4 inpatients all died. We speculated prolonged pneumonia or bloodstream infections could cause another infection.
In recent years, scholars reported gastric catheterization and urinary catheterization were risk factors of nosocomial infections [14, 19, 31]. Intravenous sedatives were typically used to enhance inpatients comfort and patient-ventilator synchrony. A systematic review about the relationship between sedatives and healthcare-associated infection reported that, the three most common sedatives (benzodiazepines, propofol, and dexmedetomidine) for mechanically ventilation patients had different pharmacologic and immunomodulatory effects, which might impact infection risk.32Further observations were demanded to confirm the relationship between gastric catheterization, urinary catheterization, and sedatives with secondary infections.
However, our study has several limitations. Firstly, control group could not include enough critical inpatients due to the characteristics of pneumonia caused by COVID-19. Almost none of these phenomena were observed in the controls (severity of illness on admission, ICU admission, ventilator, central venous catheterization, gastric catheterization, urinary catheterization, and sedatives). More prospective studies were needed to quantify the odds of secondary infections increased by these factors. Secondly, due to the lack of certain records on admission, some factors that might be related to secondary infections could not be explored, e.g. smoking history and BMI (body mass index). Finally, limited by the number of inpatients enrolled in case group, some variables could not be included in the multivariate regression model simultaneously.
To the best of our knowledge, this is the first report of risk factors for secondary infections in severe and critical patients hospitalized with COVID-19. Severe and critical inpatients with male, age (≥ 65 years), heart diseases, hypoproteinemia, treated with corticosteroids, and PPI need to be observed carefully and to be intervened with drugs to prevent the occurrence of secondary infections as early as possible. In particular, inpatients needing ICU admission and invasive devices also need to be given optimal cares and to be minimized the duration.