While secondary infections with bacterial, viral, and other pathogens are well-described phenomena in influenza, SARS, MERS, and other respiratory viral illnesses, data regarding superinfections/coinfections in COVID-19 pneumonia are limited and still emerging. The relatively high incidence of severe infection and mortality in COVID-19 is thought in part due to secondary infections, alongside lack of natural immunity and viral replication in the lower respiratory tract leading to severe lung injury and acute respiratory distress syndrome. Notably, there is a desire to avoid invasive diagnostic procedures such as bronchoscopy and radiologic imaging such as computed tomography (CT), in order to minimize aerosol-generating procedures and healthcare worker exposure. This has created a somewhat unique diagnostic challenge in assessing and managing secondary infections in this population relative to other respiratory viral illnesses.
Here we provide a brief review of current knowledge and experience regarding secondary infections in COVID-19, in order to assist providers making critical treatment decisions in hospitalized and/or severely ill patients with SARS-CoV-2 infection.
We will be providing updates as new data and clinical experience become available.
Key Points
While data are limited, still emerging, and primarily from international experience, we note the following trends:
- Secondary infections are reportedly common in hospitalized, severely ill COVID-19 patients, encompassing between ~10%-30% of cases with much greater frequency in the ICU setting.
- Patients with severe illness are much more likely (10x) to have bacterial/fungal secondary infections than viral (2x).
- ICU patients with prolonged illness/intubation have more frequent detection of multidrug-resistant Gram-negative pathogens, likely reflecting hospital-acquired infection.
- Coinfections in COVID-19, particularly with other seasonal respiratory viruses, are extremely common and are reflected in seropositivity rates of up to 80% and PCR positivity of ~20%; these do not appear to be above background levels of respiratory viral infections in non-COVID-19 patients presenting with respiratory symptoms.
- COVID-19 illness in children appears to be less severe, which may reflect underlying differences in immunology or biology; nevertheless, up to 6% of pediatric cases of COVID-19 may be severe/critical.
Definitions
According to the CDC, a superinfection is an "infection following a previous infection especially when caused by microorganisms that are resistant or have become resistant to the antibiotics used earlier," while a coinfection is an infection concurrent with the . The difference is temporal: coinfections occur simultaneously, whereas superinfections develop following the initial infection. While the two terms are used interchangeably in medical literature and clinical practice, and may or may not involve the same sets of pathogens, they are in fact distinct clinical entities.
Superinfections and coinfections are common in respiratory viral illnesses.
Studies have shown that up to 65% of laboratory-confirmed cases of influenza infection are complicated by bacterial co/superinfections with the majority ranging between 11% and . Secondary infections following respiratory viral illnesses most commonly involve the lower respiratory tract, with Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus being the most frequently reported pathogens.
Superinfections and coinfections can augment pathogenesis, increasing the morbidity and mortality of viral infections.
In fact, the majority of deaths associated with the Spanish influenza pandemic of 1918 were not thought to be caused by the H1N1 virus itself, but rather by secondary bacterial pneumonia. Bacterial superinfection was also associated with the higher morbidity and mortality rates seen during the 1957, 1968, and . For instance, during the 2009 swine flu pandemic, bacterial superinfections were identified in 29%-55% of deaths. Cytokine storm, or hypercytokinemia, describes hyperactivation of the immune system that may be provoked or worsened by secondary infections. This can lead to devastating and irreparable destruction of lung tissue as proinflammatory cytokines damage the alveoli, tiny sacs in the lungs responsible for gas exchange and oxygenation.
Superinfections and Coinfections Are Challenging to Diagnose
Diagnosis of secondary bacterial infections typically requires testing of samples obtained by sputum expectoration/induction, nasopharyngeal/oropharyngeal swabs of respiratory passages, bronchoscopy, thoracentesis, and/or lung tissue biopsy. Conventional diagnostic tests have poor sensitivity in identifying the etiologic organisms responsible for respiratory infections. In a review of 5,025 cases of community-acquired bacterial pneumonia from FDA records from 1996-2007, only 44.7% of cases had a pathogen identified. Even when conventional culture-based methods are combined with newer molecular techniques such as multiplex PCR and urine antigen testing, 62% of hospitalized patients with .
Preliminary studies and anecdotal evidence from high-burden COVID-19 areas overseas suggest that superinfections are common, particularly in severe cases. A study analyzing predictors of mortality among 150 COVID-19 cases in Wuhan reported that of 68 deaths, 11/68 (16%) had secondary infections, although further details were not provided. In another Wuhan study of 41 patients, secondary infections (defined as positive respiratory or blood culture along with compatible clinical syndrome) were a reported complication in 31% of ICU patients and 10% of patients overall. A brief report describing characteristics of 3,200 COVID-19-related deaths from numerous regions of Italy reported "" of cases but no further details were provided.
A comprehensive review of 221 patients with SARS-CoV-2 pneumonia admitted to Zhongnan Hospital, Wuhan, provides insightful, but somewhat unclear, information. In our interpretation, 57/221 (25.8%) patients were reported to have coinfections, which we presume includes secondary infections that were present on admission. The majority of these were viral (57.9% or 33/57) as opposed to bacterial (29.8% or 17/57) or fungal (12.3% or 7/57) as shown in Figure 1. Nineteen patients (8.6%) reportedly developed nosocomial infections during hospitalization. The series included 55 severe/166 non-severe cases. Notably, patients with severe illness were 10 times more likely to have superinfections with bacteria or fungi than non-severe cases, and
Notably, among COVID-19 ICU cases in Zhongnan Hospital, there was a high reported frequency of secondary infections with carbapenem-resistant Acinetobacter baumannii, particularly among ICU deaths (55.6% or 5/9) versus ICU patients ultimately transferred to the ward (17.4% or 4/23). A single case of secondary infection with both A. baumannii and Klebsiella pneumoniae was also reported in a review of admitted to Wuhan Jinyintan Hospital. A similar finding was reported in a small series of five cases admitted to French hospitals, all of whom were visitors from China, where a single case of severe disease with A. baumannii and Aspergillus flavus endotracheal cultures. While sample sizes were limited, these findings suggest nosocomial transmission of hospital organisms in critically ill ventilated patients, and/or endogenous colonization with flora harboring antimicrobial resistance. This is consistent with reports of heavily multidrug-resistant organisms circulating in South and Southeast Asia. Providers concerned about secondary infections in severe COVID-19 cases should consult institutional antibiograms and/or consider local drug resistance and hospital epidemiologic patterns when selecting empiric regimens, particularly targeting gram-negative, nosocomial, and/or opportunistic pathogens.
Recent limited observations suggest that coinfections in COVID-19 patients are more frequently viral than bacterial, and rates of viral coinfections in COVID-19 illness are consistent with what is seen with other respiratory viral illnesses.
A study of 30 COVID-19 patients in Qingdao (Shandong province, northeast China) suggested a high proportion of coinfections with other respiratory pathogens based on serum IgM antibody detection. Of note, this antibody panel was limited to nine respiratory pathogens (including influenza A/B, parainfluenza virus, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila), and the window of IgM positivity with respect to each of these pathogens was not defined, possibly reflecting infection in the recent past. Provided these limitations, 24 (80%) of these patients showed evidence of coinfection with at least one respiratory pathogen; the co-pathogens were influenza A (60%) and influenza B (53%), followed by M. pneumoniae (23%) and L. pneumophila (20%).
Recent data from our hospital at Stanford of coinfection among COVID-19 patients in Northern California. Out of 1,217 samples from symptomatic patients from multiple Northern California locations tested for SARS-CoV-2 and other respiratory pathogens:
- 116 (9.5%) tested positive for SARS-CoV-2 and 1,101 (90.5%) tested negative
- 318 (26.1%) were positive for other respiratory viruses by multiplex PCR testing
- 24/116 (20.7%) of SARS-CoV-2-positive cases had a respiratory coinfection, compared with 294/1,101 (26.7%) of SARS-CoV-2-negative cases
Statistically, there was no difference in the rates of respiratory coinfections comparing SARS-CoV-2 and non-SARS-CoV-2 cases.
In contrast, a letter describing clinical experience in Shenzhen (Guangdong province, southeast China) noted that in a group of 186 symptomatic patients admitted to Shenzhen Hospital, 92 patients tested positive for SARS-COV-2 and of these, only 3.2% were by multiplex PCR testing of respiratory samples.
While it is difficult to determine reliable coinfection estimates, most available data have consistently shown that viral respiratory coinfections with SARS-CoV-2 are common and are more prevalent than bacterial or fungal coinfections, which is expected given the magnitude of co-circulating seasonal respiratory pathogens during the current COVID-19 pandemic.
Pediatric Patients
Historically, children have been vulnerable populations during pandemics such as H1N1 influenza. However, emerging evidence suggests that children have lower rates of SARS-CoV-2 infection and tend to experience less severe illness, despite having high rates of respiratory coinfections. A study of 20 pediatric inpatients in Wuhan reported that 40% had respiratory coinfections. Notably, the were Mycoplasma (20%), followed by influenza B (10%) and influenza A, respiratory syncytial virus, and cytomegalovirus (each 5%).
Despite having high rates of respiratory coinfections, children with COVID-19 tend to experience mild or no symptoms. The CDC recently reported data from 2,572 laboratory-confirmed COVID-19 cases in children <18 years, noting lower rates of symptomatic disease compared with adults (73% vs 93%), as well as lower rates of hospitalization (5.7% vs 10%). Nevertheless, it should be emphasized that serious and/or in this age group.
These findings are consistent with a study of over 2,000 pediatric patients from multiple regions of China, including 731 laboratory-confirmed cases of SARS-CoV-2 and 1,412 suspected cases, where over 90% of patients were classified as having asymptomatic, mild, or moderate illness. Only 6% of cases were deemed severe or critical, of adult cases.
"There could be a number of reasons," said Bonnie Maldonado, MD, professor of pediatric infectious diseases at Stanford and chair of the American Association of Pediatrics' Committee on Infectious Diseases, in reference to why children experience less severe symptoms. "It's possible that the receptor for the virus may not be in the same configuration in children as adults. It's possible that there were just more adults who were tested because that has been the focus. However, there have been other studies of who did not have as severe disease."
Another potential explanation is immunologic, according to Zhengde Xie, a clinician at China's National Clinical Research Center for Respiratory Diseases. The immature immune systems of children may not mount as robust or severe a response to SARS-CoV-2 infection as adults. This phenomena may mimic primary Epstein-Barr virus infection, which typically causes dramatic and prolonged illness (infectious mononucleosis) in older children and young adults, but in immunocompetent young children.
We would appreciate your sharing your comments and clinical experiences/impressions below.
Woo Joo Kwon, Gabrielle Li, Matthew Zheng, Harleen Kaur, and Noah Magbual are medical students at Stanford University., is a physician-scientist specializing in infectious diseases at Stanford and the Palo Alto Medical Foundation, and serves as medical director at , developing genome-based diagnostics for infectious diseases.