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Many people are saying...


...bacterial superinfection is a driver of mortality in viral pneumonia such as influenza and COVID-19.
This piece is courtesy of Dr. Alison Castle and the FLARE team with advisory review by Dr. Emily Hyle, Dr. Sarah Turbett, and Dr. Alyssa Letourneau.
The FLARE Four:
  1. Secondary bacterial infection has been reported to be a major cause of mortality in viral respiratory infections prior to COVID-19. 
  2. Available data on secondary infections in COVID-19 are limited but do indicate that nosocomial infections are associated with increased COVID-19 severity and death.
  3. Risk factors for secondary bacterial and fungal infections include invasive devices (central venous catheters), diabetes, combination antibiotic therapy, and glucocorticoid treatment.
  4. Given long ICU stays associated with COVID-19, it is likely that rates of secondary bacterial infection will reflect, in part, nosocomial infections that are common in critical illness.
Introduction
Although SARS-CoV-2 infection is responsible for COVID-19, it remains unclear whether viral-induced cell death per se is ultimately fully responsible for the clinical syndrome following infection. Prior FLAREs have discussed the possibility of “dysregulated immunity” as a potential contributor, but another important potential source of morbidity is co-infection with other pathogens - bacterial, fungal, and viral alike. Indeed, Fauci and colleagues (yes, that Fauci) noted that most patients who died during the 1918 influenza pandemic had autopsy evidence of bacterial pneumonia (Morens, Taubenberger, and Fauci 2008), a finding recognized even by contemporary physicians - one of whom noted in 1919, “If grippe (influenza) condemns, the secondary infections execute” (Cruveilhier 1919).
 
Multiple reports have identified co-infections in COVID-19 patients, but the epidemiology and pathological consequences of these remain ill-defined. In addition, many such infections might simply reflect prolonged hospitalizations and its attendant risks rather than factors unique to the virology of SARS-CoV-2. In this FLARE, we explore the risk factors associated with secondary infection, the role of prophylactic antimicrobial therapy, and approaches to mitigating nosocomial infections in patients with COVID-19.
Why are people so concerned about bacterial infections if COVID-19 is a viral illness?
Laboratory models have established that viral infection may disrupt host mucociliary clearance and immune response, decreasing the threshold for bacterial infection (Hendaus, Jomha, and Alhammadi 2015). Furthermore, observations such as those by Fauci and colleagues have led many to posit that secondary infection is a major driver of morbidity and mortality in viral respiratory disease. In addition to data from the 1918 influenza pandemic, bacterial superinfection was reported to be associated with poor outcome in the 1957 H2N2 and the 1968 H3N2 influenza pandemics (Kash and Taubenberger 2015). This association persists even in the modern antibiotic era. During the 2009 outbreak of severe respiratory failure secondary to H1N1 influenza (Rice et al. 2012), 30% of critically ill patients were diagnosed with bacteremia or bacterial pneumonia within 72 hours of ICU presentation - an observation consistent with the idea that bacterial superinfection was a significant driver of severe disease. Indeed, compared to patients who were not diagnosed with bacterial infection, these patients were more likely to develop shock, require extended ICU care, mechanical ventilation, and die.
Lessons from pediatric respiratory failure
The published data about viral co-infection in COVID-19 patients suffer from inconsistencies. One report from the San Francisco Bay area examined symptomatic patients with likely respiratory viral illness and identified just ~10% (total 116) positive for SARS-CoV-2, of which 20% were also PCR positive for another pathogen. These data suggested a substantial incidence of viral co-infection among COVID-19 patients (Kim et al. 2020). However, another study from the same region at the same time tested 166 hospitalized COVID-19 patients for influenza/RSV and found that none were positive for these pathogens (Myers et al. 2020). Similarly, a Wuhan cohort of 99 inpatients revealed zero viral co-infections (Chen et al. 2020). How can we reconcile these data? One possible explanation might lie in the now well-recognized rate of asymptomatic SARS-CoV-2 infection, such that many positive tests in non-hospitalized individuals in the first study (Kim et al. 2020) may represent incidental findings rather than drivers of URI symptoms.
 
Much more granular data are available regarding bacterial co-infection, particularly in patients hospitalized with moderate to severe COVID-19 (Ruan et al. 2020; X. Yang et al. 2020; Wang et al. 2020; Zhang et al. 2020; Chen et al. 2020). A retrospective study of 918 COVID-19 patients from Wuhan, China found that 7.1% had a bacterial or fungal co-infection (He et al. 2020). The most common types were pneumonia (32.3%), bacteremia (24.6%) and urinary tract infection (21.5%). Two smaller cohort studies have reported similar nosocomial infection rates (8% of 150 hospitalized patients (Ruan et al. 2020) and 13.5% of 52 mechanically ventilated patients (X. Yang et al. 2020). In contrast, one study of 339 COVID-19 patients over 60 years of age with severe and critical disease were found to have bacterial secondary infection in 42.8% of cases (Wang et al. 2020). The table below summarizes these and related data.
Table. Comparison of major studies reporting bacterial and fungal infections in patients with SARS-CoV-2 infection. Readers should note that some hospital systems utilize a respiratory virus panel which includes PCR testing for two bacterial pathogens, C. pneumoniae and M. pneumoniae. The individual pathogens tested for in these panels are not consistently described by authors across these studies.
What are the organisms?
Specific organisms have not been typically reported (see Table). Fungal pathogens such as Candida albicans, Aspergillus species, Pneumocystis jirovecii, and Mucor species have been described in a small subset of patients and case reports (He et al. 2020; X. Yang et al. 2020; Wang et al. 2020; Zhang et al. 2020; Chen et al. 2020).
 
Notably, many infections reported in those with COVID-19 are caused by drug-resistant organisms. These include Pseudomonas aeruginosa, ESBL Klebsiella pneumoniae, multidrug resistant E. coli, Acinetobacter, and Enterococcus (He et al. 2020; X. Yang et al. 2020; Wang et al. 2020; Zhang et al. 2020; Chen et al. 2020).
What risk factors might account for secondary infection?
In a single center study of 65 COVID-19 patients who developed a nosocomial infection, invasive devices (OR 4.28, 95% CI: 2.47–8.61), diabetes (OR 3.06, 95% CI: 1.41–7.22), and use of more than one class of antibiotic (OR 1.84, 95% CI: 1.31–4.59) were significant predictors of nosocomial infection (He et al. 2020). In this study, glucocorticoid use was also positively associated with secondary infection with 38%  of patients exposed to glucocorticoids. Interestingly, 75.4% of patients who developed secondary bacterial and/or fungal infection were receiving prophylactic antibiotics. A disproportionately high use of antibiotics has been reported in people with COVID-19, even with an overall low incidence of known bacterial infections (Zhou et al. 2020). 
 
In a meta-analysis of 5270 patients with coronaviruses, including SARS-CoV-1, MERS-CoV and SARS-CoV-2, treatment with corticosteroids was strongly associated with bacterial infection (RR = 2.08, 95% CI 1.54-2.81, p <0.001), though this only examined patients from two studies where occurrence of bacterial infection was reported (Z. Yang et al. 2020). Pooled mortality from these studies indicated an increased risk of death in association with steroids (RR = 2.11, 95%CI = 1.13–3.94, P = 0.019), though patients with severe disease were also more likely to receive corticosteroids. 
 
In the pre COVID-19 era, there are differing reports of the effect of corticosteroids on rates of infection in large patient cohorts. In the CORTICUS trial, a randomized trial of hydrocortisone for relative adrenal insufficiency in septic shock, there was a statistically significant increase (odds ratio 1.37 (95% CI, 1.05 to 1.79) in superinfection after receiving hydrocortisone (Sprung et al. 2008). However, in the ADRENAL trial, 2800 patients were randomized to hydrocortisone or placebo for septic shock. There was no difference in the occurrence of new bacteremia or fungemia between groups (14.1% in both groups) (Venkatesh et al. 2018). Thus the data are mixed as to the effect of steroids on the risk of infection and may be pathogen-dependent.
What is the role of typical hospital acquired infections?
Some bacterial infections may be more related to long hospitalization rather than a complication of bacterial pneumonia per se. There is a strong association between nosocomial infection and mortality (He et al. 2020; Wang et al. 2020). In a pre-print, non-peer reviewed study, Zhang et al. evaluated the differences in secondary infection between those with non-severe COVID-19 and those with severe disease (Zhang et al. 2020). As expected, patients with severe COVID-19 suffered a significantly higher rate of secondary infection (see Table above). Another study showed a (perhaps predictable) association between indwelling catheters and nosocomial infection with an odds ratio of 4.28 (CI: 2.47-8.61) (He et al. 2020). In this study, the most common pathogen reported was coagulase-negative Staphylococcus.
Are empiric antibiotics or antifungal treatments something we should consider?
COVID-19 patients with secondary infection have poor outcomes with higher risk of mortality. However as highlighted above (He et al. 2020), 75.4% of patients who developed secondary bacterial or fungal infections were already receiving prophylactic antibiotics. Regimens included fluoroquinolones (61.5%), combination of antibiotics (not otherwise defined, 10.8%) and cephalosporins (9.2%). This suggests that prophylactic agents may not prevent the hospital-acquired infections and risk selecting for more drug-resistant pathogens.
 
Others have postulated that critically ill COVID-19 patients are at risk for invasive fungal diseases based on a previously described association between influenza and invasive aspergillosis (Gangneux et al. 2020; Vanderbeke et al. 2018). The theoretical pathophysiology is thought to be twofold: 1. viral destruction of bronchial epithelium allowing an opportunity for the colonizing fungi to cause invasive disease and 2. SARS-CoV-2 induced lymphopenia. More data are needed to investigate how this immune dysregulation influences the risk for secondary bacterial and fungal infections.
Conclusions
The secondary infections observed in COVID-19 patients are a consequence of viral pneumonia but also prolonged hospital exposure and critical illness. Nosocomial infections related to long hospital course impact severity of COVID-19 and increase mortality. Indwelling devices, diabetes, prophylactic antibiotics, and glucocorticoids have been associated with increased secondary infection risk. Many of the pathogenic organisms are multidrug-resistant, hospital-acquired infections; therefore, we recommend a low threshold to obtain culture data in COVID-19 patients and the use of appropriately targeted antibiotic therapy for this population.
FLARE is a collaborative effort within the Pulmonary and Critical Care Division and the Department of Medicine at Massachusetts General Hospital. Its mission is to appraise the rapidly evolving literature on SARS-CoV-2 with a focus on critical care issues.

All prior FLAREs are available here: massgeneral.org/FLARE.
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References:
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