Some studies suggest that secondary infection is a risk factor for death of viral pneumonia. Our study retrospectively analyzed the clinical characteristics of 165 patients diagnosed with severe and critical COVID-19, and focused on the risk factors of secondary infection and prognosis. Herein, the critical subtype had a higher incidence of secondary infection than the severe subtype (47.1% v.s. 5.2%). In the critical subtype, non-infected group had a higher improved rate after 28 days from onset than the infected group, suggesting secondary infection is associated with disease severity and prognosis. In our study, the secondary infections were mainly lung infections, accounting for about 90%, and pathogens were mainly Gram-negative bacteria, principally Burkholderia multivorans, Stenotrophomonas maltophilia, Acinetobacter baumannii, Klebsiella pneumoniae followed by Candida albicans and Aspergillus flavus, which is similar to the previoys report[2, 14].
The pathogenesis of SARS-CoV-2 combined with bacterial and fungal infections is complex that involving interreaction between viruses, bacterial virulence factors and host immune system which damages to all organs, especially the respiratory system. The possible mechanisms of secondary pulmonary infection of COVID-19 are as follows: First, like other SARS coronaviruses, SARS-COV-2 targets the invasion of alveolar epithelial cells and type II alveolar cells by binding the SARS spike protein to the angiotensin-converting enzyme 2(ACE2) receptor. Second, we found that those with no improvement after 28 days from illness onset had lower CD4(+) T cells and CD8(+) T cells, and the higher incidence of respiratory distress syndrome (RDS) and secondary infection, suggesting that T lymphocyte injury is the negative factor leading to the exacerbations of the patient, which is consistent with previous reports2. Lymphocytopenia is the typical feature of severe patients with SARS-CoV and MERS-CoV because coronavirus consumes many immune cells and inhibits the body's cellular immune function[]. And the early rapid replication of the virus leads to many epithelial and endothelial cells apoptosis and vascular leakage, which triggers the release of numerous pro-inflammatory cytokines and chemokines, such as IL-2R、IL-6、IL-10、TNF-α, induces a cytokine storm in the body, generates a series of immune responses and causes changes in peripheral white blood cells and immune cells such as lymphocytes. Third, the release of risk-related molecular patterns (DAMps), which serve as endogenous danger signals to promote and exacerbate immune and inflammatory responses that lead to lung injury, and the DAMP/ receptor axis of late glycosylation end-products have been found to integrate with toll-like receptors (TLRs), amplifying bacterial fungal inflammatory responses[15, 16].
Previous studies have suggested that secondary infection, especially Gram-negative bacteria infection, may be associated with hormone use, severe basic diseases, and frequent invasive operations. Most of severe and critical patients are male middle-aged and elderly population which may be associated with chronic basic diseases and weakened immune system. If infected with SARS-CoV-2, elderly male patients with chronic basic diseases, such as cardio-cerebrovascular diseases, are more likely to develop into critical subtype and have a higher risk of death4. According to one study, the fatality rate of COVID-19 in diabetic patients is 35.4%. Diabetic patients are more likely to suffer from multiple organ dysfunction, secondary infection and poor prognosis. Moreover, We found that the utilization of invasive ventilator, deep vein catheterization, catheter indwelling and ECMO in the infected group were significantly higher than those in the non-infected group, identifying the invasive operation is related to secondary infection. Using invasive ventilator for long time leads the upper respiratory tract to lose the filtration and humidification of the inhaled air, destroys upper respiratory barrier function and airway mucosa. Plus, the mechanical ventilation makes it easy for pathogens to multiply in the respiratory tract, suppresses the ciliary system of the lower respiratory tract, impacts the fluent respiratory tract and clearance function, thus which increased frequency of sputum aspiration, resulting in damage to the airway mucosa. Because the patients' physiological reflexes such as swallowing and coughing, protease, complement and inflammatory factors can be released to increase the permeability of pulmonary capillaries, aggravate the diffusion of inflammation and tissue damage, and eventually cause pulmonary infection. Therefore, timely assessment of the necessity of mechanical ventilation, prompt removal of the ventilator, and tracheotomy for the long-term ventilator-dependent patient, reduce the incidence of ventilator-related lung infection. Studies have shown that prolonged arteriovenous catheterization is a risk factor for catheter-related bloodstream infections. Our study had only one case of bloodstream infection, which may be related to the early usage of antibiotics therapy and strict aseptic operation, or small samples and the short follow-up time.
As shown in the A brief case of secondary infection, it is of great importance for the improvement of the prognosis and survival rate to detect the secondary infection as early as possible and to select appropriate antimicrobial agents in combination with drug sensitivity results in time.
Our study focused on the effect of secondary bacterial and fungal infection on the prognosis of SARS-CoV-2 infection and analyzed infection-related risk factors to reduce COVID-19 mortality and improve disease outcomes. We suggest that preventive measures for co-infection include strict aseptic operation, less number of invasive operations, shortening the time of the indwelling catheter, early appropriate empirical antibiotic therapy and so on.
Our study has some limitations. The incidence of secondary infections may be underestimated due to the usage of the empirical antibiotic therapy and uncertainty of sensitivity and specificity of specimen culture. Besides, some cases didn’t undertake different parts of the pathogen culture. According to clinical manifestations, laboratory examination and radiography cannot completely distinguish viral infection from secondary infection. Due to small samples, it was not possible to assess the independent correlation of risk factors for secondary infection. What’s more, we did not focus on the details of antibiotic therapy because different drugs may also affect prognosis.