A living WHO guideline on drugs for covid-19
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3379 (Published 04 September 2020) Cite this as: BMJ 2020;370:m3379©BMJ Publishing Group Limited.
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Dear Editor
The ‘Global Strategies’ for ‘COVID-19 Pandemic Control’ involve ‘Global Solidarity’ integrating ‘COVID-19 Pharmaceuticals’-‘Non-Pharmaceutical Interventions (NPIs)’. The ‘COVID-19 Pharmaceuticals’ include: Drugs-Antivirals, Monoclonal Antibodies, Convalescent Plasma-Serum and Vaccines. This ‘Communication’ concerns ‘WHO Living Guidelines on COVID-19 Therapeutics’; the ‘12th Version’-‘11th Update’ with the ‘Clinical Question’: ‘The Role of Drugs in the Treatment of COVID-19 Patients’[1]. ‘Living Guidelines’ are developed by continuously dynamically incorporating emerging ‘New-Best Available Research Evidence (BARE)’[2,3] from the over 5000 ‘Registered On-going Clinical Trials’[4] to formulate the ‘Guidelines-Recommendations’. The ‘BARE’ accrues from ‘Systematic Reviews and Meta-Analyses (SRMA)’. The BARE and SRMA have been critically disposed in previous ‘Communications’; not a ‘Sine Qua Non’ to undergird ‘Guidelines-Recommendations Development’[5-16]. Some of the Clinical Trials reportedly did not have ‘Satisfactory Population Diversity’ with under-representation of some ‘Vulnerable Groups’: Immunocompromised Patients at risk for Opportunistic Infections especially where HIV and Tuberculosis are prevalent; ‘SARS-CoV-2 Variants-Subvariants Issues’ too. Also, better evidence is reportedly needed on ‘Patient Values and Preferences’ for ‘COVID-19’. It is, therefore, not surprising that several ‘WHO Living Guidelines’ have ‘Recommendations’ tagged with ‘Uncertainties’[1].
The ‘Guidelines’ dispose the ‘COVID-19 Classification’ (Non-Severe, Severe and Critical Disease) with the ‘Indicated Criteria’ and the ‘Guidelines-Recommendations’ are: ‘Strong, Weak and Conditional’ and they are disposed ‘For or Against’ named/ listed ‘Drugs/ Antivirals’ in defined ‘COVID-19 Severity’[1]. The ‘Recommendations Quality’ reflect considerations of ‘Relative Benefits and Harms’-‘Values and Preferences’-‘Feasibility Issues’-‘Key Outcomes’-‘Equity and Human Rights’-‘Mortality’-‘Mechanical Ventilation’-‘Cost-Benefit Analyses’ etc. For instance, Remdesivir, and in combination with Corticosteroids, Interleukin-6 (IL-6) Receptor Blockers (Tocilizumab and Sarilumab), Janus Kinase (JAK) Inhibitors (Baricitinib), reportedly has ‘Strong Recommendation’ for ‘Severe and Critical Covid-19’ and Remdesivir has ‘Conditional Recommendation’ for ‘Severe COVID-19’ while it has ‘Conditional Recommendation’ against use in ‘Critical COVID-19’[1].The combination of IL-6 Receptor Blockers and JAK Inhibitors with Corticosteroids has ‘Recommendation’ for ‘Severe and Critical COVID-19’ BUT Neutralizing Monoclonal Antibodies (Sotrovimab and Casirivimab-Indevimab) have ‘Strong Recommendations’ against use in ‘COVID-19’ replacing the previous ‘Conditional Recommendation’ for use[1]. There is reportedly ‘Recommendation’ against the following in ‘COVID-19’: Lopinavir-Ritonavir, Convalescent Plasma, Colchicine, Ivermectin, Hydroxychloroquine, Sotrovimab, Casirivimab-Indevimab; some used only in ‘Research Trials’[1].
It is reported that if ‘Neutralizing Monoclonal Antibodies’ have ‘No In-Vitro Activity’, they are not likely to have ‘Clinical Efficacy’ BUT for those with ‘In-Vitro Activity’, RCTs are recommended to confirm ‘Clinical Value’[1]. Also, ‘anti-Coagulation Therapy’ in’COVID-19’ is scheduled for further evaluation in ‘Future Guidelines Update’[1].
Concerning ‘Uncertainties’, the ‘Living Guidelines’ counsel the ‘Treating Clinician’s Perception’ to become ‘Determinant’ for ‘Patient Care Decision-making’. Here lies the imperative to ‘Rekindle’ the ‘Multiparameter-based Medicine (MBM)’ as it recognizes ‘Expert Opinion/ Clinical Experience’ in addition to ‘Other Spheres of Influence’[6, 10-16].The MBM is a ‘Welcome Locus’ on the ‘Evidence-based Medicine (EBM) Improvement Movement’ towards achieving the envisioned ‘Optimal Patient Care’ and in this circumstance: ‘Optimal Treatment of COVID-19 Patients’.
Also, with the ‘Uncertainties’, which are the resultant of the ‘BARE and SRMA Difficulties’, the ‘Attending Treating Clinician’ is cautiously, constantly and carefully ‘Counselled to Take Responsibility’ for the ‘Ultimate Care of the Patient’ and the ‘Responsible Guidelines Development Group (GDG), WHO, BMJ Publishing Group Ltd, MAGICapp, MATCH-IT etc’ depose ‘Not Accepting Any Responsibility’ for ‘Patient Outcomes’ from the ‘Guidelines Use’; WHO encourages ‘Recommendations’-Adaptation’-‘Contextualization’ for ‘Maximized-Impact’. This is tantamount to ‘Corporate Indemnifying Disclaimer’ and is a ‘Clarion Call’ for ‘Measured and Guided Use’ of ‘Published and Disseminated Guidelines’ for the desired ‘Optimal Patient Care’.
In the circumstance that even the ‘12th Updated WHO COVID-19 Therapeutics Living Guidelines’ are replete with ‘Recommendations’ with some tagged with ‘Uncertainties’, the dictum ‘Prevention is Better than Cure’ holds sway and, therefore, the imperative to ‘Prevent COVID-19’ by upholding the ‘Non-Pharmaceutical Interventions (NPIs)’ MUST be urgently rekindled[17-19].
REFERENCES
1. Agarwal A, Rochwerg B, Lamontagne F et al. A living WHO guidelines on drugs for covid-19. BMJ 2020; 370:m3379
2. Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ2020;370:m2980. doi:10.1136/bmj.m2980 pmid:32732190
3. Siemieniuk RAC, Bartoszko JJ, Díaz Martinez JP, et al. Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis. BMJ2021;374:n2231. . doi:10.1136/bmj.n2231 pmid:3455648
4. Maguire BJ, Guérin PJ. A living systematic review protocol for COVID-19 clinical trial registrations. Wellcome Open Res2020;5:60. doi:10.12688/wellcomeopenres.15821.1 pmid:32292826
5. Evidence-based Medicine Working Group Evidence-based Medicine: A new approach to teaching practice of medicine. JAMA 1992; 268 (17):2420-2425
6. Eregie C.O. Beyond Evidence-based Medicine (EBM) as ‘Work In Progress’: An Innovative Proposal for ‘Multiparameter-based Medicine (MBM). https://www.bmj.com/content/366/bmj.l5395/rr of 4th October 2019
7. Sackett DL, Straus SE, Richardson WS et al. Evidence-based Medicine: how to practice and teach Evidence-based Medicine. 2. Edinburgh: Churchill. Livingstone 1992
8. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004; 328 (7454):1490
9. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence-based Medicine: What it is and what it isn’t. BMJ 1996; 312:71-72
10. Eregie C.O. Research Evidence as the Sine Qua Non for Evidence-based Medicine (EBM) as ‘Work In Progress’: How Justified? https://www.bmj.com/content/366/bmj.l5395/rr-0 of 6th October 2019
11. Eregie C.O. Prospective Meta-analysis (PMA) in ‘Evidence-based Medicine (EBM) Movement Improvement’ as ‘Work In Progress’: The Imperative of ‘Parameter-related Pyramids of Evidence’ to address the ‘EBM Interventional Inequity’. https://www.bmj.com/content/367/bmj.l5342/rr of 22nd October 2019
12. Eregie C.O. COVID-19 Pandemic, ‘COVID Phenomenon’ and the politics of the science, facts, research evidence and ‘evidence-based medicine (EBM): the imperative for rekindling the ‘multiparameter-based medicine (MBM)’ in the 21st Century. https://www.bmj.com/content/369/bmj.m1336/rr-20 of 17th April 2020
13. Sibley M. Ockenden report: the refusal of our healthcare service to take patient experience seriously. BMJ 2022; 377:o875
14. Eregie C.O. Best patient care, evidence-based practice and the neglect of patient experience: Reaffirming the imperative to rekindle multiparameter-based medicine (MBM)’. https://www.bmj.com/content/377/bmj.o875/rr-1 of 22nd April 2022
15. Oliver D. Relearning to value expert knowledge. BMJ 2022; 378:o1853
16. Eregie C.O. COVID-19 Pandemic, Disregard for Expert ‘COVID-19 Pandemic Control Advisories’ and Uncomplimentary Outcomes: The Imperative to Rekindle the Relevance of ‘Multiparameter-based Medicine (MBM)’. https://www.bmj.com/content/378/bmj.o1853/rr-1 of 11th August 2022
17. Eregie C.O. Covid-19 Pandemic, Reinfection, Reactivation and COVID-19 Rebound: Efficacy of Covid-19 Pharmaceutical and Non-Pharmaceutical Interventions; The Imperative to Guard Against Interventional Precocity in Downing Guards. https://www.bmj.com/content/377/bmj.o1365/rr of 15th June 2022
18. Eregie C.O. COVID-19 Pandemic, COVID-19 Vaccines and Rapidly Transmuting SARS-CoV-2 Variants/ Sub-variants: The Quest for Pan-Sarbecoviruses Vaccine Variants; A Further Imperative to Guard Against Global Interventional Precocity in Downing Guards. https://www.bmj.com/content/377/bmj.o1257/rr-0 of 17th June 2022
19. Eregie C.O. ‘COVID-19 pandemic, Immunity and Infectivity: evolving facts support the imperative for sustained compliance with non-pharmaceutical interventions’. https://www.bmj.com/content/378/bmj-2020-061402/rr-1 of 23rd July 2022
Professor Charles Osayande Eregie,
MBBS, FWACP, FMCPaed, FRCPCH (UK), Cert. ORT (Oxford), MSc (Religious Education),
Professor of Child Health and Neonatology, University of Benin, Benin City, Nigeria.
Consultant Paediatrician and Neonatologist, University of Benin Teaching Hospital, Benin City, Nigeria.
UNICEF-Trained BFHI Master Trainer,
ICDC-Trained in Code Implementation,
*Technical Expert/ Consultant on the FMOH-UNICEF-NAFDAC Code Implementation Project in Nigeria,
*No Competing Interests.
Competing interests: No competing interests
Dear Editor,
When I‘m reading the article, it was found that the dose recommendation for Nirmatrelvir and ritonavir in renal insufficiency GFR 30-59 ml/min patients was inconsistent with the drug Instructions and WHO guidelines. Is it a citation error or other evidence-based evidence?
WHO recommend：In renal insufficiency (GFR 30–59 mL/min) the dose reduction is 150 mg of nirmatrelvir and 100 mg of ritonavir every 12 hours daily for 5 days；
The article recommend： With renal insufficiency GFR 30-59ml/min, 150 mg of nirmatrelvir and 50 mg of ritonavir every 12 hours daily for 5 days;
FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR PAXLOVIDTM(12/2021) : Dose reduction for moderate renal impairment (eGFR ≥30 to <60 mL/min): 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet tablet), with both tablets taken together twice daily for 5 days.
Competing interests: No competing interests
Dear Editor
April 22, 2022, WHO made a strong recommendation for nirmatrelvir and ritonavir, sold under the name Paxlovid, for mild and moderate COVID-19 patients at highest risk of hospital admission, calling it the best therapeutic choice for high-risk patients to date. However, availability, lack of price transparency in bilateral deals made by the producer, and the need for prompt and accurate testing before administering it, are turning this life-saving medicine into a major challenge for low- and middle-income countries.
Pfizer’s oral antiviral drug (a combination of nirmatrelvir and ritonavir tablets) is strongly recommended for patients with non-severe COVID-19 who are at highest risk of developing severe disease and hospitalization, such as unvaccinated, older, or immunosuppressed patients.
This recommendation is based on new data from two randomized controlled trials involving 3078 patients. The data show that the risk of hospitalization is reduced by 85% following this treatment. In a high-risk group (over 10% risk of hospitalization), that means 84 fewer hospitalizations per 1000 patients.
WHO suggests against its use in patients at lower risk, as the benefits were found to be negligible.
One obstacle for low- and middle-income countries is that the medicine can only be administered while the disease is at its early stages; prompt and accurate testing is therefore essential for a successful outcome with this therapy.
Update to living WHO guideline on drugs for covid-19. BMJ. 2022 Mar 2;376:o534. doi: 10.1136/bmj.o534. PMID: 35236655.
Competing interests: No competing interests
Dear Editor
On 23 December last year, the US Food and Drug Administration (FDA) granted emergency approval for Merck's (MSD's in Japan) molnupiravir. The following day, the Japanese Ministry of Health, Labour and Welfare (MHLW)'s Pharmaceutical Evaluation and Control Division issued a "Report on the Deliberation Results" (1) and granted "special approval". This report presents the basic data of the clinical trial for the approval of molnupiravir. Similar data have been reported by Bernal et al. in the NEJM (2).
The data reported in the Japanese "Report on the Deliberation Results" and by Bernal et al. are very concerning, and highlight the major unknowns that still surround using molnupiravir.
The first problem is efficacy estimates that change substantially over time. In the interim analysis, the relative risk (RR) for “hospitalization for any cause or death through day 29” was 0.52 (95% CI, 0.34 to 0.80). However, in the final analysis the effect was less strong: the RR was 0.70 with a wide 95% confidence interval of 0.49 to 0.99, which means that a single increase or decrease in "hospitalization or death" with either the study drug or placebo could render the result not statistically significant.
A bigger problem is that the RR after interim analysis was 1.33 (95% CI, 0.69 to 2.54). (This is also shown by the FDA data in the text by Owen Dyer in the BMJ (3).) In these data, the 95% confidence intervals for the pre- and post-interim RRs overlap only slightly, and a significant difference between them cannot be ruled out. Moreover, the direction of the effect is different before and after the interim analysis. In the interim analysis, molnupiravir reduced the primary outcome, but afterwards it tended to increase it. The Japanese "Report on the Deliberation" also takes issue with this, but does not call for further analysis and states that it "does not negate the effectiveness of molnupiravir”.
The ratio of "hospitalization or death" for placebo is different between the two, 53/377 for that in the interim analysis and 15/322 after the interim analysis, RR = 3.02 (95% CI, 1.74 to 5.25). This alone indicates that the difference is most likely due to the very different demographics of the two groups of participants. As such, the situation is somewhat like what can occur with but in the case of multiple RCTs, “if there is considerable variation in the result, and particularly if there is inconsistency in the direction of effect, it may be misleading to quote an average value for the intervention effect” (4), and it is recommended not to subject such results to meta-analysis. In this case, the background of the participants in the RCT, rather than a meta-analysis, should be taken into account when considering the indications for treatment.
Bernal et al. also suggest that the difference in RR before and after the interim analysis is due to differences in the background of the participants. If this is the case, then instead of combining the pre- and post-interim analyses, we should analyse the differences in background and identify the groups that benefit and those that are harmed. The latter group should then be excluded from the indication for molnupiravir. However, Bernal et al. have not done these tasks. For the trial subjects after the interim analysis, molnupiravir might increase "hospitalization or death" by about 30%, making it a "poison" rather than a "medicine".
A review is needed, with disclosure of the original data from the trials that produced these results.
1) https://www.pmda.go.jp/files/000245005.pdf
2) https://doi.org/10.1056/NEJMoa2116044
3) BMJ 2021;375:n2984. https://doi.org/10.1136/bmj.n2984
4) Jonathan J Deeks et al.ed. “9 Analysis data and undertaking meta-analyses”, Julian PT Higgins and Sally Green ed. Cochrane Handbook for Systematic Reviews of Interventions. (Wiley-Blackwell 2008). P.279.
Competing interests: No competing interests
Dear Editor;
I read with interest these WHO guidelines for therapeutics for COVID-19. The guidelines are very useful for practicing clinicians. However, in the update, the authors should also evaluate the effectiveness of fluvoxamine (1) and inhaled budesonide (2) and ciclesonide (3) for early/mild COVID-19 as these therapeutics have strong evidence for disease mitigation.
1. Reis G, Dos Santos Moreira-Silva EA, et al. Lancet Glob Health. 2022 Jan;10(1):e42-e51. doi: 10.1016/S2214-109X(21)00448-4.
2. Yu LM, Bafadhel M, Dorward J, et al. Lancet. 2021 Sep 4;398(10303):843-855. doi: 10.1016/S0140-6736(21)01744-X.
3. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. JAMA Intern Med. 2022 Jan 1;182(1):42-49. doi: 10.1001/jamainternmed.2021.6759.
Competing interests: I have received honorarium for speaking engagements from AstraZeneca, makers of inhaled corticosteroids.
Dear Editor
SARS-CoV-2 and the potential use of nicotine related agents in treatment & prevention.
Our Team first suggested that urgent research was required into the potential use of Nicotine for the treatment of SARS-CoV-2 in March 2020 at the beginning of the Pandemic (1). Soon afterwards other researchers across the world showed interest in its potential use (2,3,4)
At the time there was much media interest in this issue but the medical establishment appeared to dismiss the possibility perhaps for fear of inadvertently propagating an adverse public health message that smoking could be beneficial in some way. Clearly, this is not the case and 2 years on there will be no Nobel Prizes awarded in 2022 for proclaiming that smoking is dangerous and extremely ill advised. That much is accepted.
However, in scientific terms it is a recognised fact that the SARS-CoV-2 virus uses the ACE-2 receptor (a nicotinic receptor) for cell entry. This is a fundamental aspect of the pathogenesis of infection in this disease. It is also physiologically accepted that nicotinic receptors and pathways are ubiquitous throughout the body. Importantly, nicotinic pathways are important in neuroimunomodulation.
Despite assembling a pan-professorial team with expertise in Intensive Care Treatment, Biochemistry, Respiratory Medicine and Statistics we were unable to secure any grant for even limited funding into the possible roll of nicotine in the prevention or treatment of this disease.
Nevertheless, undeterred we were able to some extent tag our research onto a Public Health Wales Study of SARS-CoV-2 levels in factory workers during the ‘second wave’. One thousand workers were studied. We simply asked the question as to whether or not the workers were smokers and collated the subsequent responses with the antibody levels which were measured. Our results were dependently corroborated by statisticians from the University of the West of England. Our Study showed over 80% protection against disease in smokers (as deduced from the presence of SARS Covid-2 antibodies; Fisher’s Exact Test P<0.005)
A reasonable hypothesis would seem that in terms of prevention nicotine may competitively bind to ACE-2 receptors therefore inhibiting viral binding, cell entry and consequential pathogenesis of disease.
A further plausible hypothesis would seem that the virus interrupts neuroimmunomodulation pathways. Indeed, perhaps this may the explanation for the so called “cytokine storm” which is common in patients who are severely ill. Furthermore one might expect that in smokers chronic exposure to nicotine may damage these pathways which would explain the observation that whilst smokers seem less likely to develop this disease those that do so often do much worse.
To date, efforts to combat the spread of this disease have focused upon public health measures and the development of vaccinations. We applaud these incredible efforts but feel that in science open mindedness is vital, particularly in this instance where a counter intuitive observation has been made.
Whilst huge investments have been made towards the development of vaccines it is clear that in this particular disease vaccination is problematic both because of short lived immunity derivation and also because of the mutagenic nature of this virus which partially or potentially may completely render generations of vaccines ineffective as indeed we are already observing to some extent. It is hoped that gradual virus attenuation, perhaps evidenced by the current wave of Omicron B infections, may mean that in the future the disease will become mild and manageable. However, there is no guarantee of this.
It would seem likely that whilst mutations could reduce the effectiveness of vaccines against various strains SARS Cov-2, this family of viruses is unlikely to stop using the ACE-2 receptor for cell entry any time soon.
In addition, we feel that it is very important to understand that research will also have the benefit of understanding reports that nicotine may be helpful in the treatment of Ulcerative Colitis and Parkinson’s disease which might be explained by its effects on nicotinic pathways and neuroimmunomodulatary damage caused by nicotine exposure (5,6). It may well be that conditions such as ARDS maybe a neuroimmunologically mediated (7). Research funding and understanding of neuroimmunomodulation in such diseases would be extremely beneficial.
Once again, we urge Scientific and Political communities to adopt a pragmatic and open minded stance with regard to the use of nicotine and related agents for the possible prevention & treatment of this worrying disease.
We appeal for further modest funding and attention to the understanding of SARS CoV - 2 as a nicotinic virus.
Mr. J.P. Davies MB BCh FRCS FRCS (ORTH)
Consultant Orthopaedic Surgeon &
Honorary Lecturer at the University of Wales College of Medicine.
1. Response to the Emerging Coronavirus Outbreak. Davies J P, Davies R, Conway N. BMJ 2020:368 doi https://doi.org.1136/bmj.m406.
2. Cytokine Release Syndrome (CRS) and Nicotine in COVID-19 Patients: Trying to Calm the Storm. Gonzalez-Rubio, Navarro-lopez C, Lopez-Najera E et al Frontiers in Immunology, 11, 1359. https://doi.org/10.3389/fimmu.2020.0135914.
3. A Nicotinic Hypothesis for Covid-19 with Preventative and Therapeutic Implications. Changeux J P, Amoura Z, Rey F A et al. C R Biol. 2020 Jun 5;343(1):33-39. doi: 10.5802/crbiol.8.
4. Editorial: Nicotine and SARS-Cov-2:COVID-19 may be a disease of the nicotinic cholinergic system.Farsalinos K, Niaura R, Houezec J L et al. Toxicol Rep. 2020; 7: 658–663 doi: 10.1016/j.toxrep.2020.04.012
5. Nicotine Treatment for Ulcerative Colitis. Guslandi M. British Journal of Clinical Pharmacolgy. 1999 Oct; 48(4): 481–484.
6. Nicotine promotes neuron survival and partially protects from Parkinson’s disease by suppressing SIRT6. Nicholatos J.W, Francisco A B, Bender C A et al. Acta Neuropathol Commun 6, 120 (2018). https://doi.org/10.1186/s40478-018-0625-y
7. Nicotine exerts and an anti-inflammatory effect in a murine model of acute lung injury. Mabley J, Gordon S, Pacher P. Inflammation 2011;34(4):231-7.
Competing interests: No competing interests
Dear Editor:
Response to the WHO recommendation on convalescent plasma use in Covid-19 from the US National CCPP19 Convalescent Plasma Project Leadership Team
On December 6, the World Health Organization (WHO) updated its recommendations on COVID-19 management and recommended against the use of COVID-19 convalescent plasma (CCP) in treating any stage of COVID-19 disease. This recommendation was based on an analysis of aggregated randomized trial (RCT) data that, in the view of the WHO, did not show clear clinical benefits of CCP, although the recommendations did acknowledge evidence that CCP was effective in reducing the viral load in treated patients.
As a mechanical and largely statistical exercise in which the results of all RCTs are simply tabulated and summarized, the WHO analysis is exemplary. But as a scientific examination and assessment of these RCTs, an exercise that requires digging below the surface to ask critical questions, the WHO recommendations are seriously wanting. Most importantly, the WHO recommendation ignores patient groups who may derive substantial benefit from CCP.
In every RCT, the first issue to address is whether the core hypothesis motivating the RCT was in fact appropriately tested. Had the WHO dug deeper into the RCTs it would have discovered that most RCTs did not test CCP appropriately. Decades of experience have shown conclusively that for convalescent plasma to work, it must be provided early in the course of illness and with sufficient antibody content, , a principle that is supported by robust biological evidence and animal models (1).
Had the WHO dug deeper into the RCTs it would have noted that nearly all RCTs were conducted in heterogenous hospitalized patient populations, often including patients who had already progressed from the viral to the inflammatory phase of COVID-19, manifested by prolonged duration of symptoms and/or a requirement for invasive oxygen supplementation. Had the WHO dug deeper into the RCTs, it also would have noted that some RCTs used CCP with an insufficient amount of antibody.
Unfortunately, many CCP RCTs did not, and by virtue of their study designs could not, test the hypothesis that CCP works if provided early and in a sufficient dose. Given the catastrophic conditions caused by a global pandemic, the drive to focus treatments on the sickest of hospitalized patients was understandable, but it has been known for decades that most such patients do not benefit from convalescent plasma.
The WHO ignored multiple signals of CCP efficacy found in subgroups of patients in the RCTs who were treated early or in less severe stages of illness and received high titer CCP (2). The WHO ignored multiple observational studies, some much larger than any published randomized RCT (3), in which careful propensity matching was employed, and CCP efficacy was demonstrated (4, 5). The WHO ignored studies that showed the particular value of CCP in immunosuppressed patients (6,7).
The WHO ignored a carefully conducted randomized RCT of CCP from Argentina, conducted in elderly outpatients shortly after their diagnosis, that reduced progression of disease by half (8). This finding has just now been replicated in another out-patient RCT in the United States (Sullivan et al), although we recognize that this finding was not available to the WHO on December 6.
A most unfortunate consequence of the WHO recommendation on CCP is that it discourages use of CCP, including in low and middle-income countries (LMIC), where it may be the only antiviral available. In comparison to all other drug or in-patient therapies, CCP is safe, relatively inexpensive and widely available, well worth the investment in making it accessible in resource-limited settings. In addition, convalescent plasma is the only treatment that can be employed rapidly in any new epidemic situation as soon as there are survivors. Its success in this setting for COVID-19 has recently been demonstrated in a large RCT (9). We urge the WHO to revisit its recommendation on CCP by reviewing the totality and consistency of the evidence supporting its benefit, taking account of the pandemic conditions and the features of RCT design that affected the findings of most large RCTs. The first step should be to examine in detail the RCTs that replicated the circumstances under which convalescent plasma has worked effectively in the past. This means focusing on RCTs that administered high titer CCP early in the disease course. Such trials are consistent with both the historical use of convalescent serum and the contemporary employment of monoclonal antibodies in COVID-19. They are the most appropriate RCTs upon which any recommendation for CCP use should be based.
Nigel Paneth (paneth@msu.edu)
Arturo Casadevall
Liise-anne Pirofski
Jeffrey H. Henderson
Brenda Grossman
Shmuel Shoham
Michael J Joyner
For CCPP19.org
REFERENCES
1. Casadevall A, Pirofski LA, and Joyner MJ: The Principles of Antibody Therapy for Infectious Diseases with Relevance for COVID-19. mBio. 2021;12(2).
2. Focosi D, Franchini M, Pirofski L-a et al: COVID-19 convalescent plasma and randomized clinical trials: rebuilding confidence by explaining failures and finding signals of efficacy. medRxiv. 2021; 09.07.21263194.
3. Arnold Egloff SA, Junglen A, Restivo JS et al: Convalescent plasma associates with reduced mortality and improved clinical trajectory in patients hospitalized with COVID-19. The Journal of Clinical Investigation. 2021; Oct 15;131(20):e151788
4. Klassen SA, Senefeld JW, Senese KA et al: Convalescent Plasma Therapy for COVID-19: A Graphical Mosaic of the Worldwide Evidence. Frontiers in Medicine (Lausanne). 2021; Jun 7;8:684151
5. Klassen SA, Senefeld JW, Johnson PW et al: The Effect of Convalescent Plasma Therapy on Mortality Among Patients with COVID-19: Systematic Review and Meta-analysis. Mayo Clinic Proceedings. 2021; May;96(5):1262-1275
6. Senefeld JW, Klassen SA, Ford SK et al: Use of convalescent plasma in COVID-19 patients with immunosuppression. Transfusion. 2021; Aug;61(8):2503-2511
7. Thompson MA, Henderson JP, Shah PK et al: Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19. JAMA Oncol. 2021; Jun 17; 7(8): 1167-75
8. Libster R, Pérez Marc G, Wappner D et al: Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021; Feb 18;384(7):610-618.
9. Ortigoza MB, Yoon H, Goldfeld KS et al: Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial. JAMA Internal Medicine. 2021; Dec 13; doi: 10.1001/jamainternmed.2021.6850. Online ahead of print.
Competing interests: No competing interests
COVID-19 convalescent plasma should be further investigated!
Dear Editor,
on December 7th, WHO updated its living guideline on COVID-19 therapeutics, including convalescent plasma (CCP). This led to their recommendation against the use of CCP for COVID-19 patients, adding that it should only be used within clinical trials for severely and critically ill COVID-19 patients. In addition to their recommendation, WHO has stated that even though the evidence surrounding CCP’s benefit for severely ill patients is uncertain, they do recommend that trials focusing on subgroups of severe and critically ill patients should continue.
As the SUPPORT-E Consortium* we wish to respond to these recommendations.
In line with the recommendations from WHO, we agree that there is no firm evidence that CCP is a beneficial therapeutic treatment for COVID-19 patients, but we firmly believe that, given the rate of SARS-CoV-2 infection in Europe, as well as the existing therapeutic means and treatments, CCP is still worth investigating, in particular within specific patient groups.
There is no evidence that randomized clinical trials should focus only on severely ill COVID-19 patients: in fact the strongest data suggest efficacy of CCP in early intervention [1-3] among seronegative patients and immunosuppressed patients [4;5] Also, a significant antibody dose response has been reported [3;6-8]. A large number of earlier trials relied on “low titre” CCP, this is very different to CCP currently collected from vaccinated convalescent donors that have ten times higher titres, and broad “cross-variants” viral neutralization [9-12].
Moreover, the polyclonal antibody content of convalescent plasma could make this product an ideal source for hyperimmune immunoglobulin preparation, which require pooling large numbers of units of donor plasma, so standardizing the dose of high titre polyclonal specific antibodies. Although studies pertaining to the use of hyperimmune globulin have yet to be published, it is clear that CCP availability is a prerequisite in case of need for specific Ig preparation.
Other treatment options, notably recombinant monoclonal antibodies (MoAb) are not always available, especially in low and middle-income countries. These are expensive and prone to potential reduced efficacy against variants of concern.
The recent introduction of the Omicron variant with a high number of mutations in the Spike protein lead to viral escape and challenge existing MoAb [13]. Conversely, CCP collected among recently infected donors would contain Ig produced after infection with current variants. Additionally, this treatment would also be available in low-income countries.
WHO guidance does not present evidence against the use of CCP in people who do not have severe COVID-19 [14]. For non-severe COVID-19 it is based inter alia on the RECOVERY trial [15] which only provides good evidence for severely or critically ill patients, or on the PLACID trial which assessed CCP with low to undetectable levels of anti-SARS-CoV-2 antibodies to those randomised to receive convalescent plasma [16]. Among the participants, 99% were enrolled from inpatient settings [14], i.e., the significant subgroup of non-hospitalized, vulnerable patients at risk of hospitalization were not adequately represented in this analysis. Positive signals of CCP efficacy were detected in subgroup analyses of some negative RCTs. For instance, in patients with immunodeficiency enrolled in the REMAP-CAP trial [17], or in patients with milder COVID-19 in the recently published TSUNAMI trial [18]. The WHO provides recommendations for the whole spectrum of COVID-19 disease, while the available evidence is limited. Knowledge gaps must be clearly identified and investigated in further trials, e.g., very early treatment in non-hospitalized patients, immunocompromised patients, antibody-negative patients.
WHO latest guidance on CCP also refers to potential harm of transfusion, whilst also stating that there is no evidence of an increase of risks of transfusion-associated complications. The SUPPORT-E Consortium is therefore questioning the three-times repeated assertion of CCP associated to transfusion harm and its evidence. A recent meta-analysis on 30 randomized and non-randomized trials documented the safety of CCP compared to standard therapy, even when thromboembolic complications were considered [19].
On the mobilization of resources dedicated to collect CCP, it should be noted that there is no waste or overuse of human resources. Research on CCP allowed blood establishments to increase their collection of plasma that, if not used for treating COVID-19 patients, is nevertheless kept and stored for future usage, for regular (non-COVID-19 related) transfusion or to produce plasma derived medicinal products (PDMPs).
The SUPPORT-E Consortium notes that the WHO guidance on CCP highlights high cost and limited availability, when for monoclonals (or antivirals) these logistic arguments are not emphasized in the same manner. In particular, the conclusion drawn from these practical issues is peculiar since it is presented as if the above practical issues contribute to the recommendation not to administer CCP while it leads to recommending monoclonals – despite the even higher cost and very limited availability, and the increased risk that monoclonals lose their activity against newly emerging variants.
In Europe, a big part of research on CCP is based on data collected and shared through the SUPPORT-E EU CCP database [20] containing data on 153,000 CCP donations; analysing the data and drawing conclusions from them is ongoing and results will be presented at the end of the project. It therefore seems premature to draw firm conclusions on the use of CCP, at this stage.
We believe that research on CCP use should only stop or be discouraged in either of two situations: (i) when a therapy is showing harm to the patients or (ii) when the question explored is no longer pertinent or worth exploring. We do not think that this is the case.
We further wish to underline the importance of the scientific community to keep exploring the potential of CCP. It still is a promising, inexpensive, and well tolerated therapy that actively involves communities to care for those who suffer from acute infection by those who have recovered thus valuing the contribution of donors in this fight against a pandemic.
The SUPPORT-E Consortium is very much grateful for the ongoing financial support of the European Commission funding this research.
Hubert Schrezenmeier
Vincenzo de Angelis
Stéphane Bégué
Livia Cannata
Christian Erikstrup
Lise Escourt
Hendrik Feys
Catherine Hartmann
Marcello Lembo
Gaia Mori
David Roberts
Ellen van der Schoot
Daphne Thijssen-Timmer
Pierre Tiberghien
On behalf of the SUPPORT-E Consortium: * SUPPORT-E is an EU funded project dedicated to research on COVID19 convalescent plasma; https://www.support-e.eu/
Reference List
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(2) de Candia P., Prattichizzo F, Garavelli S, La GR, De RA, Pontarelli A et al. Effect of time and titer in convalescent plasma therapy for COVID-19. iScience 2021; 24(8):102898.
(3) Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med 2021; 384(11):1015-1027.
(4) Senefeld JW, Klassen SA, Ford SK, Senese KA, Wiggins CC, Bostrom BC et al. Use of convalescent plasma in COVID-19 patients with immunosuppression. Transfusion 2021.
(5) Thompson MA, Henderson JP, Shah PK, Rubinstein SM, Joyner MJ, Choueiri TK et al. Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19. JAMA Oncol 2021.
(6) Körper S, Weiss M, Zickler D, Wiesmann T, Zacharowski K, Corman VM et al. Results of the CAPSID randomized trial for high-dose convalescent plasma in patients with severe COVID-19. J Clin Invest 2021; 131(20).
(7) O`Donnell MR, Grinsztejn B, Cummings MJ, Justman J, Lamb MR, Eckhardt CM et al. A randomized, double-blind, controlled trial of convalescent plasma in adults with severe COVID-19. medRxiv 2021;2021.
(8) Salazar E, Christensen PA, Graviss EA, Nguyen DT, Castillo B, Chen J et al. Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG. Am J Pathol 2021; 191(1):90-107.
(9) Wang Z, Muecksch F, Schaefer-Babajew D, Finkin S, Viant C, Gaebler C et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature 2021.
(10) Lustig Y, Nemet I, Kliker L, Zuckerman N, Yishai R, Alroy-Preis S et al. Neutralizing Response against Variants after SARS-CoV-2 Infection and One Dose of BNT162b2. N Engl J Med 2021.
(11) Stamatatos L, Czartoski J, Wan YH, Homad LJ, Rubin V, Glantz H et al. mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection. Science 2021.
(12) Jahrsdörfer B, Fabricius D, Scholz J, Ludwig C, Grempels A, Lotfi R et al. BNT162b2 Vaccination Elicits Strong Serological Immune Responses Against SARS-CoV-2 Including Variants of Concern in Elderly Convalescents. Front Immunol 2021; 12:743422. doi: 10.3389/fimmu.2021.743422. eCollection;%2021.:743422.
(13) Wilhelm A, Widera M, Grikscheit K, Toptan T, Schenk B, Pallas C et al. Reduced Neutralization of SARS-CoV-2 Omicron Variant by Vaccine Sera and monoclonal antibodies. medRxiv 2021;2021.
(14) Siemieniuk RA, Bartoszko JJ, Diaz Martinez JP, Kum E, Qasim A, Zeraatkar D et al. Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis. BMJ 2021; 374:n2231.
(15) RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet 2021; 397(10289):2049-2059.
(16) Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P. 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; 371:m3939. doi: 10.1136/bmj.m3939.:m3939.
(17) Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D et al. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA 2021; 326(17):1690-1702.
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(20) DG SANTE: EU CCP Database. 10-12-2021.
https://ec.europa.eu/health/blood_tissues_organs/covid-19_en
Competing interests: all authors are involved in the SUPPORT-E consortium, funded by the European Commission, and involved in reasearch on collection, characterization and use of convalescent plasma
Dear Editor,
You are clearly writing these information blurbs for lay individuals without medical backgrounds. Part of the psychology of COVID and the overrun of the hospitals is the unknown which is not addressed here though mild cases are listed. In many countries, including the US, communication to the lay public on what to actually do if you get COVID and have mild clinical signs is exceptionally poor and this publication Does Not Help.
I am not talking about drugs that doctors might administer. Much more basic.
What do people at home do to self treat?
NSAID e.g. ibuprofen - possibly combined with other e.g. paracetamol
Expectorant over the counter
Fluids - ie stay well hydrated
Monitor with an O2 sat finger cuff. Present to the hospital if <93% (For ALL age groups)
Other
This is the regimen that the medical staff working the Apache nation implemented that resulted in the lowest mortality of all of the tribes in the US. Most importantly, it was well outreached and communicated, and people knew the plan. They were not spinning in a what do I do now? frenzy. And with this plan people with mild symptoms felt better.
Obviously this could be modified but THIS IS WHAT PEOPLE NEED. If they are not afraid, unneeded hospital visits are minimized.
Thank you for considering this recommendation.
Competing interests: No competing interests
Re: A living WHO guideline on drugs for covid-19
Dear Editor
How do these recommendations (paxlovid) for medium risk interface with UK NHS guidelines NOT to test anyone except high risk?
Please could someone from public health answer and also advise how 65 year olds get their medication within UK (England) health care system
Competing interests: I am over 65