Critical Reflections on the Cochrane Review of Long Covid Research

Where Is the Line Between Scientific Discourse and Prejudice?

We are writing to present a detailed critique of the recent Cochrane review evaluating Long Covid research conducted by Resia Pretorius, Douglas Kell, and their collaborators.

The Cochrane review uses a set of criteria to evaluate five articles from the Pretorius research group. However, the suitability and appropriateness of the Cochrane framework for evaluating these specific pieces of research are questionable. The Cochrane framework is generally employed to consolidate and evaluate a wide range of studies on a given topic to minimize bias. Yet, this review focuses solely on early-stage research from a single group, which makes it difficult to avoid a narrow perspective.

The authors' decision to conduct a systematic review—despite the early-stage nature of the research and the potential for perceived bias—prompts significant inquiry. It calls into question whether a systematic review, typically used to synthesize mature research, was the most appropriate methodology to evaluate such nascent studies.

Several instances in the review evoke concerns over its objectivity. Remarkably, the review seems to place undue emphasis on the microscopy images presented in the studies. However, the main thrust of these studies was not centred on microscopy; the images served merely as supportive data. Therefore, it is peculiar that the review overlooks critical findings and statistical analyses derived from proteomics - notably, the discovery of a significant increase in α(2)-antiplasmin, as evidenced in the Pretorius 2021 and Kruger 2022 studies.

The review critiques the staining methodology and the fluorescence microscopy techniques as not being clearly described and questions the repeatability of the studies. However, several international teams have had no difficulty following and repeating the methodology, achieving the same outcomes - an aspect blatantly ignored by the review. This selective focus and critique raise questions about the balance and thoroughness of the review's examination. Furthermore, contrary to the review's claim that the data is inaccessible, the data can indeed be accessed via links provided in the journal articles or by contacting the authors directly. The review also criticizes the sample sizes and selection criteria, seemingly without acknowledging the unprecedented context of a pandemic in which these studies were conducted. Additionally, the review fails to consider that there are still no standardised guidelines for accurately diagnosing patients with Long Covid.

The Cochrane review also draws certain connections that aren't present in the original articles - such as the association with plasmapheresis - raising further questions about its purpose. Furthermore, the authors seem to conflate plasmapheresis with H.E.L.P. apheresis.

Whilst H.E.L.P. apheresis has indeed been mooted as a potential treatment for Long Covid, plasmapheresis, on the contrary, has not. This again calls into question the thoroughness and accuracy of the review.

Early research papers by Pretorius, Kell and their team were among the earliest to provide peer-reviewed data on Long Covid. Conducted during lockdown amidst the profound uncertainties of a pandemic, these studies could have been kept under wraps until more mature datasets were available. However, in the spirit of scientific progress and openness the team opted to share their findings promptly, encouraging further investigation by other researchers. Why do the authors of the review not recognize the strategic decision to publish these studies early to catalyse further research—an approach that numerous other research groups have adopted?

In essence, this Cochrane review can be seen as an academic reinterpretation of an opinion commissioned by the BMJ; an opinion which one of its co-authors (Robert AS Ariëns) has now disclosed he published in his capacity as editor.

When the authors of the review express concerns about bias whilst there is clear evidence of potential bias within their own ranks, it appears to be a clear instance of the critic failing to apply the same scrutiny to themselves.

Paul Garner, a co-creator of the Cochrane Reports, has been open about his personal journey of recovery from Long Covid, attributing his recovery to psychological rather than biomedical factors. He has shared his experience in detail and promoted this perspective publicly.

While Garner's personal story is certainly valuable as an anecdote, it must be considered in the context of his professional role. As a co-author of the Cochrane Review, the potential influence of his personal experience on the interpretation of research findings cannot be ignored. Transparency, especially regarding potential conflicts of interest, is critical in maintaining the credibility of scientific review processes. This point becomes even more salient considering that, besides Garner, at least two other authors, as well as some of the reviewers, also have affiliations with Cochrane.

Another potential source of bias could stem from the choice of reviewers. The Cochrane review appointed a neuropsychiatrist (Alan J Carson) and a systematic reviews expert (Ingeborg Welters) as 'independent' peer reviewers. However, their professional affiliations and research perspectives should also be scrutinized for potential alignment with the views of the report's authors, which could inadvertently influence the objectivity of the review. While the peer review process is designed to ensure rigor and validity, the independence of reviewers is paramount to avoid any inclination towards confirmation bias.

One may question whether the review's purpose is an attempt to discredit microclot research, potentially stalling or blocking necessary clinical trials. Of utmost importance, however, is the question: how does this review contribute to the understanding and treatment of Long Covid?

In our view, true researchers must fall into da Vinci's category of 'those who see', ever seeking to push boundaries and expand understanding. As we navigate the complex challenges of Long Covid, it is the duty of the scientific community to conduct and evaluate research with the utmost transparency, rigor, and objectivity. To quote Albert Einstein, 'The right to search for truth also implies a duty; one must not conceal any part of what one has recognized to be true’.

About the authors

Nico Pretorius is an entrepreneur and engineer and the husband of Resia Pretorius and has a personal connection to this work.

Dr M Asad Khan is a Consultant Respiratory Physician in Manchester in the United Kingdom. He has Long Covid and has been demonstrated to have microclots using Pretorius’ techniques on multiple occasions. He has undergone anticoagulation and HELP apheresis with clinical benefit.

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