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By Christian Hoffmann &
Bernd S. Kamps

28 August

Virology

Dinnon KH, Leist SR, Schäfer A et al. A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature, August 27, 2020. Full-text: https://doi.org/10.1038/s41586-020-2708-8

Unfortunately, standard laboratory mice do not support infection with SARS-CoV-2 due to incompatibility of the S protein to the murine ortholog (mACE2) of the human receptor, complicating model development. Sometimes it is better to modify the virus (vs the mouse): Kenneth H. Dinnon et al. altered the SARS-CoV-2 receptor binding domain allowing viral entry via mACE, using reverse genetics to remodel the interaction between S and mACE2. This resulted in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged standard lab mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in HFH4-hACE2 transgenic mice. This model may be helpful in studying COVID-19 pathogenesis.

 

Immunology

Takahashi T, Ellingson MK, Wong P, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature August 26, 2020. Full-text: https://doi.org/10.1038/s41586-020-2700-3

This in-depth analysis performed on 137 COVID-19 patients may provide an explanation for the world-wide observed sex biases (more severe courses and deaths among males). Takehiro Takahashi and colleagues revealed that male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. A poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines were associated with worse disease progression in female patients, but not in male patients.

 

Bruchez A, Sha K, Johnson J, et al. MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses. Science  27 Aug 2020. Full-text: https://doi.org/10.1126/science.abb3753

CIITA (the major histocompatibility class II transactivator) is a master regulator of the MHC class II genes which are critical for normal immune function. Anna Bruchez, Ky Sha and colleagues show how proteins such as CIITA are involved in host defense against a range of viruses. They also identified an additional function of these proteins beyond their roles in antigen presentation. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. CD74 p41 can also block the endosomal entry pathway of coronaviruses, including SARS-CoV-2.

 

Diagnostics

Lepak AJ, Chen DJ, Buys A, et al. Utility of Repeat Nasopharyngeal SARS-CoV-2 RT-PCR Testing and Refinement of Diagnostic Stewardship Strategies at a Tertiary Care Academic Center in a low Prevalence Area of the United States. Open Forum Infectious Diseases, August 27, 2020. Full-text:  https://doi.org/10.1093/ofid/ofaa388

The clinical sensitivity of PCR testing may be higher than previously believed. Among a total of 660 patients who had more than one SARS-CoV-2 PCR test performed, the initial test was negative in 638. There were only 6 negative-to-positive conversions (0.9%). All 6 were outpatients undergoing a “person under investigation” work-up 5-17 days after an initial negative result. In > 260 inpatients with repeat testing, the authors found no instances of negative-to-positive conversion including those undergoing PUI or asymptomatic evaluation.

 

Clinical

Hagman K, Hedenstierna M, Gille-Johnson P, et al. SARS-CoV-2 RNA in serum as predictor of severe outcome in COVID-19: a retrospective cohort study. Clinical Infectious Diseases, August 28, 2020. Full-text: https://doi.org/10.1093/cid/ciaa1285

SARS-CoV-2 in serum is unfavorable. In this retrospective study of 167 COVID-19 patients who underwent serum PCR analysis at hospital admission, 3 of 106 serum PCR negative patients and 15 of 61 positive patients died. The hazard ratios for critical disease and all-cause mortality were 7.2 (95% CI 3.0-17) and 8.6 (95% CI 2.4-30) for patients with a positive serum PCR.

 

Comorbidities

Almario CV, Chey WD, Spiegel BMR. Increased Risk of COVID-19 Among Users of Proton Pump Inhibitors. Am J Gastroenterol. 2020 Aug 25. PubMed: https://pubmed.gov/32852340 . Full-text: https://doi.org/10.14309/ajg.0000000000000798

Do PPIs increase the odds for acquiring SARS-CoV-2 infection? Maybe. Using an online survey of 53,130 participants (3,386 with a positive test), Christopher V Almario and colleagues found that individuals using PPIs either once daily (aOR 2.15; 95% CI, 1.90-2.44) or twice daily (aOR 3.67; 95% CI, 2.93-4.60) had significantly increased odds for reporting a positive COVID-19 test when compared with those not taking PPIs. Individuals taking histamine-2 receptor antagonists were not at elevated risk. However, before you stop your PPI: please consider that like all observational studies, this study is very susceptible to confounding (for example, people suffering from other comorbidities may be more likely to take PPIs). Moreover, people participating in this survey were not representative of the general population. Let’s keep an eye out for more data.

 

Treatment

Mather JF, Seip RL, McKay RG. Impact of Famotidine Use on Clinical Outcomes of Hospitalized Patients With COVID-19. Am J Gastroenterol. 2020 Aug 26. PubMed: https://pubmed.gov/32852338 . Full-text: https://journals.lww.com/ajg/Documents/AJG-20-2074_R1.pdf

Another retrospective study reporting on a potential clinical benefit of famotidine. This propensity-matched observational study included 878 consecutive COVID-19-positive patients admitted to Hartford hospital (a tertiary care hospital in Connecticut, USA) between February 24 and May 13 2020. In total, 83 (9.5%) patients received famotidine. These patients were somewhat younger (63.5 vs 67.5 years) but did not differ with respect to baseline demographics or pre-existing comorbidities. Use of famotidine was associated with a decreased risk of in-hospital mortality (odds ratio 0.37, 95% CI 0.16-0.86) and combined death or intubation (odds ratio 0.47, 95% CI 0.23-0.96). Patients receiving famotidine displayed lower levels of serum markers for severe disease including CRP, procalcitonin and ferritin levels. Logistic regression analysis demonstrated that famotidine was an independent predictor of both lower mortality and combined death/intubation.

 

Pediatrics

Dhir SK, Kumar J, Meena J, et al. Clinical Features and Outcome of SARS-CoV-2 Infection in Neonates: A Systematic Review. Journal of Tropical Pediatrics, August 28. Full-text:  https://doi.org/10.1093/tropej/fmaa059

Congenital infection is rare. This comprehensive literature search (up until June 9, 2020) identified 1,992 pregnant women, of which 1,125 (56.5%) gave birth to 1141 neonates. Of these, 58 neonates were reported with SARS-CoV-2 infection. Postpartum acquisition was the commonest mode of infection, and only 4 had a congenital infection.

 

Ma N, Li P, Wang X, et al. Ocular Manifestations and Clinical Characteristics of Children With Laboratory-Confirmed COVID-19 in Wuhan, China. JAMA Ophthalmol, August 26, 2020. Full-text: https://doi.org/10.1001/jamaophthalmol.2020.3690

In this cross-sectional study of 216 children hospitalized with COVID-19 in Wuhan, China, 49 (22.7%) had (mild, self-healing) ocular manifestations, including conjunctival discharge, eye rubbing, and conjunctival congestion. Children with systemic symptoms or cough were more likely to develop ocular symptoms.

 

Sola AM, David AP, Rosbe KW, et al. Prevalence of SARS-CoV-2 Infection in Children Without Symptoms of Coronavirus Disease 2019. JAMA Pediatr. August 25, 2020. Full-text: https://doi.org/10.1001/jamapediatrics.2020.4095

Estimating the epidemic in children. Overall, the prevalence of positive SARS-CoV-2 test results in children without symptoms at 28 children’s hospitals across the US was low (0.65%, 95% CI, 0.47%-0.83%): Only 250 of 33,041 children were PCR positive through 29 May 2020. Of note, there was a strong association between prevalence and contemporaneous weekly incidence of COVID-19 in the general population.