Lethal synergy between SARS-CoV-2 and Streptococcus pneumoniae in hACE2 mice and protective efficacy of vaccination.

Secondary infections are frequent complications of viral respiratory infections, but the potential consequence of SARS-CoV-2 coinfection with common pulmonary pathogens is poorly understood. We report that coinfection of human ACE2-transgenic mice with sublethal doses of SARS-CoV-2 and Streptococcus pneumoniae results in synergistic lung inflammation and lethality. Mortality was observed regardless of whether SARS-CoV-2 challenge occurred before or after establishment of sublethal pneumococcal infection. Increased bacterial levels following coinfection were associated with alveolar macrophage depletion, and treatment with murine GM-CSF reduced numbers of lung bacteria and pathology and partially protected from death. However, therapeutic targeting of IFNs, an approach that is effective against influenza coinfections, failed to increase survival. Combined vaccination against both SARS-CoV-2 and pneumococci resulted in 100% protection against subsequent coinfection. The results indicate that when seasonal respiratory infections return to prepandemic levels, they could lead to an increased incidence of lethal COVID-19 superinfections, especially among the unvaccinated population.

Disease Tolerance during Viral-Bacterial Co-Infections.

Disease tolerance has emerged as an alternative way, in addition to host resistance, to survive viral-bacterial co-infections. Disease tolerance plays an important role not in reducing pathogen burden, but in maintaining tissue integrity and controlling organ damage. A common co-infection is the synergy observed between influenza virus and Streptococcus pneumoniae that results in superinfection and lethality. Several host cytokines and cells have shown promise in promoting tissue protection and damage control while others induce severe immunopathology leading to high levels of morbidity and mortality. The focus of this review is to describe the host cytokines and innate immune cells that mediate disease tolerance and lead to a return to host homeostasis and ultimately, survival during viral-bacterial co-infection.

Viral Culture in Hospitalized Congregate Care Patients With Prolonged SARS-CoV-2 Viral RNA Detection

Prolonged detection of SARS-CoV-2 viral RNA has been observed in hospitalized congregate care patients following resolution of clinical symptoms. It is unknown whether patients with persistent PCR positivity pose a risk for COVID-19 transmission. The purpose of this study was to examine the results of serial PCR testing, viral load, and viral culture in patients awaiting discharge prior to a negative PCR test. We sampled 14 patients who were admitted from skilled nursing and/or rehabilitation facilities to a large academic medical center, had clinical signs and symptoms of COVID-19, and had multiple PCR-positive tests separated by at least 14 days. PCR-positive nasopharyngeal swabs were obtained from each patient for viral load quantification and viral culture. The mean age of patients was 72.5 years (55 – 92), with a mean peak SOFA score of 5.6 (1 – 11). Patients were hospitalized for a mean of 37.0 days (25 – 60). RNA was detected by PCR for a mean of 32.9 days (19 – 47). Mean viral load for the first PCR-positive nasopharyngeal swab collected at our hospital was 5.81 genomic copies/mL (2.12 – 9.72). Viral load decreased significantly with days from clinical symptom onset (R = -0.69, 95% CI, -0.80 – -0.55). Four out of 28 samples grew active virus via culture, with no active virus isolates after 2 days of symptom onset. Our viral culture data suggests that persistent PCR positivity may not correlate with infectivity, which has important implications for COVID-19 infection control precautions among older congregate care patients.

Lack of active SARS-CoV-2 virus in a subset of PCR-positive COVID-19 congregate care patients.

Highly sensitive nucleic acid amplification tests (NAATs) designed to detect SARS-CoV-2 RNA are the standard of care for the diagnosis of COVID-19. However, the accuracy of these methods for the quantitation of active virus rather than non-infectious RNA fragments that can persist for extended periods of time has been unclear. This issue is particularly relevant for congregate care patients who are unable to return to their home residence until fully negative by NAATs. We tested paired samples from individual patients for the presence of virus at both early and later stages of disease. Culture of nasopharyngeal swab samples for 10 days in Vero E6 cells revealed active virus in only 4 out of 14 (28.6%) patients. The ability to isolate viral plaque-forming units (PFU) correlated with viral RNA loads of >6.79 log genomic copies/ml and only occurred in samples collected from patients early after symptom onset and before development of antibody. Culture in Vero E6 cells lacking the STAT1-dependent interferon signaling pathway increased the numbers of viral PFU detected but did not affect the incidence of positive cultures. We conclude that culturable virus is correlated with SARS-CoV-2 NAATs detection only during early symptom onset and with high viral titers/low antibody titers in non-immunosuppressed patients.