+++ Treatment +++
* * * Next update: 24 November. In the meantime, find the global updates at 7 Days. * * *
Schwaiger J, Karbiener M, Aberham C, Farcet MR, Kreil TR. No SARS-CoV-2 Neutralization by Intravenous Immunoglobulins Produced From Plasma Collected Before the 2020 Pandemic. J Infect Dis. 2020 Nov 13;222(12):1960-1964. PubMed: https://pubmed.gov/32941626. Full-text: https://doi.org/10.1093/infdis/jiaa593
Julia Schwaiger and colleagues from Baxter AG tested 54 intravenous immunoglobulin preparations, produced from plasma collected in Europe and the US. Although highly potent neutralization of a seasonal coronavirus HCoV-229E was seen, there was no cross-neutralization of the new SARS-CoV-2.
Hueso T, Pouderoux C, Péré H, et al. Convalescent plasma therapy for B-cell–depleted patients with protracted COVID-19. Blood 136 (20): 2290–2295. Full-text: https://doi.org/10.1182/blood.2020008423
The secondary humoral deficiency induced by anti-CD20 monoclonal antibodies such as rituximab may prevent the elicitation of a specific SARS-CoV-2 antibody response. Thomas Hueso and colleagues from France report on 17 consecutive patients with profound B cell lymphopenia and prolonged COVID-19 symptoms, negative SARS-CoV-2 serology, and positive RNAemia who were treated with four units of convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Of note, SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. This small series indicates that convalescent plasma could be promising at least in patients unable to mount a specific humoral response.
Mehew J, Johnson R, Roberts D, et al. Convalescent plasma for COVID-19: male gender, older age and hospitalisation associated with high neutralising antibody levels, England, 22 April to 12 May 2020. Euro Surveill. 2020;25(45):pii=2001754. Full-text: https://doi.org/10.2807/1560-7917.ES.2020.25.45.2001754
How to select donors of convalescent plasma (CP)? The answer: take older males with blood group AB and with severe disease – and don’t wait too long. In this study from the UK, 275/330 donors had detectable neutralizing antibodies against SARS-CoV-2. For these 275 donors, median levels of neutralizing antibodies were higher in men compared with women, in those hospitalized compared with non-hospitalized, in those with blood group AB compared with other groups. Neutralizing antibody levels decreased as the time between SARS-CoV-2 diagnosis and donation increased. According to the authors, their data will be of value in the timely recruitment of CP donors most likely to have high levels of neutralizing antibodies for ongoing studies investigating its effectiveness.
Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19A Randomized Clinical Trial. JAMA 2020, published 12 November. Full-text: https://doi.org/10.1001/jama.2020.22760
Fluvoxamine (a potent agonist of the sigma-1 receptor (σ1R)), is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. In this small randomized trial that included 152 adult outpatients with COVID-19 and symptom onset within 7 days, Eric Lenze et al. found that clinical deterioration occurred in 0 patients treated with fluvoxamine vs 6 (8.3%) patients treated with placebo over 15 days. The authors acknowledge the limitations of their study: a small number of endpoint events, which makes the findings fragile; 20% of study participants stopped responding to surveys during the 15-day trial; the follow-up duration was short and did not measure the effect of fluvoxamine on persistent symptoms or late deterioration. The potential advantages of fluvoxamine for outpatient treatment of COVID-19 would include its safety, widespread availability, low cost, and oral administration. Note that fluvoxamine can cause drug-drug interactions, particularly via inhibition of cytochromes P450 1A2 and 2C19. Eagerly awaiting data from larger trials. See also the comment by SeymourCW, Bauchner H, Golub RM. COVID-19 Infection—Preventing Clinical Deterioration. JAMA 2020, published 12 November. Full-text: https://doi.org/10.1001/jama.2020.21720
Monk PD, Marsden R, Tear VJ, et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med 2020, published 12 November. Full-text: https://doi.org/10.1016/S2213-2600(20)30511-7
SNG001 is a formulation of recombinant interferon beta for inhaled delivery by nebuliser that is in development for the treatment of virus-induced lower respiratory tract illnesses. In this pilot trial, Tom Wilkinson, Phillip Monk and colleagues show that patients randomly assigned to SNG001 (n = 48) had greater odds of improvement versus placebo on the WHO Ordinal Scale for Clinical Improvement (OSCI) and more rapid recovery to a point where patients were no longer limited in their activity, with a greater proportion of patients recovering during the 28-day study period. Note that there was no significant difference between treatment groups in the odds of hospital discharge by day 28 – so await results from larger trials before drawing any conclusions.
See also the comment by Peiffer-Smadja N, Yazdanpanah Y. Nebulised interferon beta-1a for patients with COVID-19. Lancet Respir Med 2020, published 12 November. Full-text: https://doi.org/10.1016/S2213-2600(20)30523-3
D’Alessio A, Del Poggio P, Bracchi F, et al. Low-dose ruxolitinib plus steroid in severe SARS-CoV-2 pneumonia. Leukemia (2020). https://doi.org/10.1038/s41375-020-01087-z
Results from a small non-randomized study might suggest a benefit from ruxolitinib in patients with severe COVID-19 pneumonia not requiring mechanical ventilation at baseline. D’Alessio et al. report an analysis of 32 patients (Group A) who received ruxolitinib, a JAK 1/2 (Janus Kinase) inhibitor, and 43 patients who served as a control group (Group B). Ruxolitinib was administered orally at a dose of 5 mg twice daily for 7 days and then tapered to 5 mg daily to complete a 10-day course of treatment. All patients received methylprednisolone. Concomitant administration of hydroxychloroquine, lopinavir/ritonavir or remdesivir was not permitted during treatment with ruxolitinib. Kaplan–Meier estimates of the percentage of patients who were alive and clinically recovered at the end of follow-up were 89% for group A and 57% for group B (SE ± 6.1). As always: to be confirmed in larger trials.
Hoang TN, Pino M, Boddapati AK. Baricitinib treatment resolves lower airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell November 09, 2020.ft https://doi.org/10.1016/j.cell.2020.11.007
Timothy Hoang and colleagues investigated the immunologic and virologic efficacy of baricitinib (approved JAK1/2 inhibitor) in rhesus macaques. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was NOT reduced with baricitinib and type I IFN antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. However, animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment.
Self WH, Semler MW, Leither LM. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19 – A Randomized Clinical Trial. JAMA. November 9, 2020. Full-text: https://doi.org/10.1001/jama.2020.22240
No, there was no effect of HCQ in this RCT among 479 adults hospitalized with respiratory illness from COVID-19. Do we need more clinical studies?
Saag MS. Misguided Use of Hydroxychloroquine for COVID-19. The Infusion of Politics Into Science. JAMA. November 9, 2020. Full-text: https://doi.org/10.1001/jama.2020.22389
Nice comment on the HCQ story. According to Michael Saag, the clear, unambiguous, and compelling lesson from the hydroxychloroquine story for the medical community and the public is that science and politics do not mix.
Tsai A, Diaware O, Nahass RG, et al. Impact of tocilizumab administration on mortality in severe COVID-19. Sci Rep 10, 19131 (2020). Full-text: https://doi.org/10.1038/s41598-020-76187-y
Another study that does not support the use of tocilizumab for the management of cytokine storm in patients with COVID-19. In this single-center propensity-score matched cohort study, 132 patients were included in the matched dataset (tocilizumab = 66; no tocilizumab = 66). Approximately 73% of the patients were male. Hypertension (55%), diabetes mellitus (31%), and chronic pulmonary disease (15%) were the most common comorbidities present. There were 18 deaths (27.3%) in the tocilizumab group and 18 deaths (27.3%) in the no tocilizumab group.
Sokolowska, M. Outsmarting SARS-CoV-2 by empowering a decoy ACE2. Sig Transduct Target Ther 5, 260 (2020), published 3 November. Full-text: https://doi.org/10.1038/s41392-020-00370-w
There are currently a few therapeutic approaches which focus on blocking SARS-CoV-2 binding to its key receptor, an angiotensin-converting enzyme 2 (ACE2), or on inhibition of virus spike cleavage. Milena Sokolowska discusses soluble recombinant human ACE2 (rhACE2) and a paper we presented on August 4: Chan KK, Dorosky D, Sharma P, et al. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science 2020, published 4 August. Full-text: https://science.sciencemag.org/content/early/2020/08/03/science.abc0870
Mattay MA, Thompson BT. Dexamethasone in hospitalised patients with COVID-19: addressing uncertainties. Lancet Resp Med October 29, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30503-8
An important comment on unanswered questions regarding the use of dexamethasone. Michael Matthay and Taylor Thompson discuss the limitations of the pragmatic RECOVERY trial (huge number of excluded patients, no data on oxygen support, no use of remdesivir, no data on viral clearance etc). They also discuss the steps need to be taken to learn more about the effects of dexamethasone in hospitalised patients with COVID-19.
Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 2020, published 28 October. Full-text: https://doi.org/10.1056/NEJMoa2029849
Bamlanivimab (LY-CoV555) is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. In this interim analysis, the patients who received LY-CoV555 had fewer hospitalizations and a lower symptom burden than those who received placebo, with the most pronounced effects observed in high-risk cohorts. Be prepared: the results are not spectacular.
Ledford H. The race to make COVID antibody therapies cheaper and more potent. Nature 2020, published 23 October. Full-text: https://www.nature.com/articles/d41586-020-02965-3
Injections of antibodies might prevent mild COVID-19 from becoming severe, but the treatments are expensive and difficult to make.
Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P; PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020 Oct 22;371:m3939. PubMed: https://pubmed.gov/33093056. Full-text: https://doi.org/10.1136/bmj.m3939
Convalescent plasma (giving neutralizing antibodies of people who made it through SARS-CoV-2 infection) has been one of the biggest hopes. This open label randomized controlled trial (RCT; the largest to date with results) investigated the effectiveness of CP in adults with moderate COVID-19 in 39 public and private hospitals across India. In total, 235 patients were assigned to two doses of 200 mL CP and 229 to best standard of care only (control arm). Progression to severe disease or all-cause mortality at 28 days after enrolment occurred in 44 (19%) participants receiving CP and in 41 (18%) in the control arm. Moreover, CP treatment did not show anti-inflammatory properties and there were no difference between patients with or without neutralizing antibodies at baseline (who had produced their own antibodies or not). The main limitation: The authors did not measure the antibody titers in CP before transfusion because validated, reliable commercial tests were not available when the trial started. Let’s hope that low antibody titers were the reason for the lack of efficacy.
Pathak EB. Convalescent plasma is ineffective for covid-19. BMJ. 2020 Oct 22;371:m4072. PubMed: https://pubmed.gov/33093025. Full-text: https://doi.org/10.1136/bmj.m4072
A strong statement, after all (and some thoughts on how to deal with the bad results of the PLACID trial).
Chowdhury JF, Moores LK, Connors JM. Anticoagulation in Hospitalized Patients with Covid-19. N Engl J Med. 2020 Oct 22;383(17):1675-1678. PubMed: https://pubmed.gov/33085867. Full-text: https://doi.org/10.1056/NEJMclde2028217
The case of a 78-year-old man with hypertension and hyperlipidemia who was brought to the emergency department 48 hours ago. Now that the patient’s condition has worsened, with progressive hypoxemia, elevated inflammatory markers, and an increase in d-dimer level, it is to decide whether a) the prophylactic doses of anticoagulants should be maintained or whether b) they should be replaced by an increased dose (and if so, what agent). Lisa Moores says a), Jean Connors says b). Both have good arguments. This is bad news, because after 9 months, we still don’t know what to do.