Copy-editor: Rob Camp
Paper of the Day
Rubin EJ, Longo DL, Baden LR. Interleukin-6 Receptor Inhibition in Covid-19 – Cooling the Inflammatory Soup. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631064. Full-text: https://doi.org/10.1056/NEJMe2103108
In their nice editorial, Eric Rubin, Dan Longo, and Lindsey Baden discuss how we can make sense of these disparate results between COVACTA and the REMAP-CAP data. Differences among the trials (enrolment criteria, timing of therapy, primary outcome, and background care, especially steroid use) may account for the discrepancy. In addition, inflammation may not be the same: patients with severe disease at initial presentation may have a different pathogenesis than those in whom inflammatory disease develops later, which suggests that the timing of treatment may be crucial in understanding responses. However, according to the authors, these points raise thorny issues. Is the value of interleukin-6 inhibition dependent on the timing of treatment, being beneficial only if proximate to an acute late inflammatory decompensation event? We rely on clinical trials to either endorse or reject possible interventions. But what if the results of trials change as the underlying therapies improve, a particular problem with platform trials, which always need to include contemporaneous controls? For now, we are left with evidence of benefit from interleukin-6 inhibitors, but how to best use them remains unclear.
Marcus JE, Frankel DN, Pawlak MT, et al. Risk Factors Associated With COVID-19 Transmission Among US Air Force Trainees in a Congregant Setting. JAMA Netw Open. 2021 Feb 1;4(2):e210202. PubMed: https://pubmed.gov/33630090. Full-text: https://doi.org/10.1001/jamanetworkopen.2021.0202
Basic military training is the first step in the transition of a civilian to an enlisted member of the US Air Force. It brings together more than 39,000 trainees every year from around the US and represents an “ideal” setting to assess symptoms and lab values of a young, healthy population living in congregant-setting cohorts in a controlled environment. Among 10,613 US Air Force basic trainees in 263 cohorts, 403 trainees (3%) received a COVID-19 diagnosis in 129 cohorts (49%). Of these, 204 (51%) were symptomatic, and 199 (49%) were asymptomatic. Median cycle threshold values were lower in symptomatic trainees compared with asymptomatic trainees (21.2 vs 34.8). Cohorts with infection clusters were predominantly men, had more symptomatic trainees, and had more symptoms per patient compared with cohorts without clusters.
Zhou S, Butler-Laporte G, Nakanishi T, et al. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity. Nat Medicine February 25, 2021. https://www.nature.com/articles/s41591-021-01281-1
OAS proteins are part of the innate immune response against RNA viruses. They are induced by interferons and activate latent RNase L, resulting in direct viral and endogenous RNA destruction, as demonstrated in in vitro studies. In this large-scale study of 931 proteins assessed for COVID-19 outcomes in > 14,000 cases and 1.2 million controls of European ancestry, Sirui Zhou and colleagues from Montreal, Canada provide evidence that increased OAS1 levels in the non-infectious state are strongly associated with reduced risks (22-46%) of severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection.
Prendecki M, Clarke C, Brown J, et al. Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine. Lancet February 25, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00502-X/fulltext
Early evidence for vaccine responses following previous natural infection. Maria Prendecki and colleagues looked at 72 HCWs from Imperial College Healthcare NHS Trust in London who were vaccinated, among them 21 (29%) participants with evidence of previous SARS-CoV-2 infection. Immune responses were analyzed 21-25 days after the first shot. In almost all individuals with previous SARS-CoV-2 infection, strong humoral and cellular responses to one dose of BNT162b2 vaccine, with evidence of high titers of virus neutralization were seen. In contrast, most infection-naive individuals generated only weak T cell responses and low titers of neutralizing antibodies.
Manisty C, Otter AD, Treibel TA, et al. Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet February 25, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00501-8/fulltext
Same direction: in this nested case-control analysis of 51 participants of COVIDsortium (24 seropositive) seronegative individuals had anti-S titers after one dose of vaccine comparable to peak anti-S titers in individuals with a previous natural infection who had not yet been vaccinated. Among those with a previous SARS-CoV-2 infection, vaccination increased anti-S titers more than 140-fold from peak pre-vaccine levels. This increase appears to be at least one order of magnitude greater than reported after a conventional prime-boost vaccine strategy in previously uninfected individuals.
Ozonoff A, Nanishi E, Levy O. Bell’s palsy and SARS-CoV-2 vaccines. The Lancet Infectious Diseases, February 24, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00076-1/fulltext
Bell’s palsy is a type of facial paralysis that results in a temporary inability to control the facial muscles on the affected side of the face. Al Ozonoff and colleagues say that observed incidence of Bell’s palsy following mRNA vaccination is 3-7 times higher than would be expected in the general population. According to their comment, this signals a potential safety phenomenon and suggests inaccurate reporting to the public. However, it is also noted that Bell’s palsy usually self-resolves and that the mRNA vaccines offer a substantial net benefit to public health.
Kwan JY, Lin LT, Bell R, et al. Elevation in viral entry genes and innate immunity compromise underlying increased infectivity and severity of COVID-19 in cancer patients. Sci Rep 11, 4533 (2021). https://doi.org/10.1038/s41598-021-83366-y
What is the potential biological rationale behind the enhanced risk of COVID-19 among cancer patients? Jennifer Yin Yee Kwan from Toronto and colleagues suggest an increased expression of SARS-CoV-2 viral entry genes in the cancer state, particularly in respiratory, gastrointestinal, and genitourinary tract tissues. Elevation of ACE2, TMPRSS2, and CTSL in cancer vs. normal tissue was observed in many of the tissues examined. Moreover, it appeared that some entry genes have transient elevation with radiotherapy or chemotherapies.
REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631065. Full-text: https://doi.org/10.1056/NEJMoa2100433
Two weeks ago, encouraging (but not peer-reviewed) results from the RECOVERY trial revitalized the strategy of blocking interleukin-6 in patients with severe COVID-19 (https://www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19). Now we are getting some more evidence, provided by REMAP-CAP. REMAP-CAP is an international, adaptive platform trial designed to determine effective treatment strategies for patients with severe pneumonia in both pandemic and non-pandemic settings. Patients eligible for the platform are assessed for eligibility to potentially undergo randomization to multiple interventions across multiple domains. Adult patients with COVID-19, within 24 hours after starting organ support in the ICU, were randomly assigned to receive tocilizumab (8 mg per kg of body weight), sarilumab (400 mg), or standard care (control). Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support–free days was 10 in the tocilizumab group, 11 (0 to 16) in the sarilumab group, and 0 in the control group. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08).
Rosas IO, Bräu N, Waters M, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631066. Full-text: https://doi.org/10.1056/NEJMoa2028700
But can we trust these platform data? In COVACTA, a large randomized Phase III trial, 438 patients who were hospitalized with severe pneumonia were randomized 2:1 to receive TCZ or placebo, the use of TCZ did not result in significantly better clinical status or lower mortality (19.7% versus 19.4%) at 28 days.
Cheong RCT, Jephson C, Frauenfelder C, et al. Otolaryngologic Manifestations in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With COVID-19. JAMA Otolaryngol Head Neck Surg. 2021 Feb 25. PubMed: https://pubmed.gov/33630068. Full-text: https://doi.org/10.1001/jamaoto.2020.5698
Single-center exploratory observational cohort study focusing on otolaryngologic manifestations of 50 children 18 years or younger presenting with PIMS-TS. Elevated rates of otolaryngology manifestations, such as dysphonia, dysphagia, and anosmia/hyposmia that persisted for longer than 6 weeks.