New comparative analysis finds significant global variation in national COVID-19 treatment guidelines

National clinical guidelines for the treatment of COVID-19 vary significantly around the world, with under-resourced countries the most likely to diverge from World Health Organization (WHO) treatment recommendations, finds a new publication in the journal BMJ Global Health.

The analysis, led by researchers at the Infectious Diseases Data Observatory (IDDO) and the Mahidol Oxford Tropical Medicine Research Unit (MORU), found that a large number of national guidelines recommend at least one treatment proven not to work.

There is clearly more variation in national guidelines for COVID-19 therapeutics than there should be to ensure optimum treatment - Philippe Guerin

"In the fog of war on COVID-19, countries clearly felt the need to do something, even if it was based on very little evidence, and the WHO treatment guidelines were not systematically used and disseminated”, said IDDO Director Professor Philippe Guerin, one of the study leads. “But why many of these unproven remedies continued to be recommended as evidence of their ineffectiveness accrued is much less clear,” 

“The formalisation of processes in the development of national guidelines for COVID-19 and other infectious diseases is essential for ensuring that these guidelines are grounded in the best available evidence,” said MORU’s Professor Nick White, who co-led the study. “A systematic and structured approach would not only enhance the credibility of the guidelines but could also contribute to their effectiveness in guiding public health interventions, especially in a pandemic setting.”

The analysis

Significant variations in national COVID-19 treatment recommendations have been suspected since the advent of the pandemic, but these haven’t been formally quantified or studied in depth, note the researchers. 

While COVID-19 infection is no longer taking the toll on lives and health that it once did, the virus is still evolving and active around the globe with significant mortality for the most vulnerable populations without adequate treatment, with the WHO declaring it to no longer public health emergency only in April 2023.

To assess how well national clinical practice followed WHO recommendations (regarded as the gold standard) for COVID-19 treatment, the researchers analysed all 194 WHO member states’ most recent and available national guidelines at the end of 2022. 

They scored each set of guidelines according to how closely they aligned with the WHO recommendations, with extra points awarded for those that were updated within the last 6 months, those that made recommendations in line with the strength of evidence, and those that included assessments of the effectiveness of treatments and their side effects.

The wealth and resources of each country were then compared using per capita World Bank gross domestic product (GDP) in US dollars for 2021, the Human Development Index 2021, and the Global Health Security Index (GHSI) 2021.

Of the 194 countries, 72 guidelines could not be retrieved. Of the remaining 122, 9 had no formal guidelines or guidelines couldn’t be accessed, and a further 4 didn’t recommend any treatments. These were therefore excluded, leaving a total of 109 analysable guidelines.

Key findings

The countries for which guidelines weren’t obtained had, on average, smaller populations, lower GDP per head, and a lower GHSI, indicative of greater economic challenges and less ability to respond to health emergencies.

Important findings include:

• Inconsistent definition of disease severity: the 11th iteration of the WHO guidelines categorises disease severity, but most of the reviewed guidelines (84%;92) didn’t define COVID-19 severity in the same way, and some didn’t define severity at all (6.5%;7). Only 10 guidelines (9%;10) used disease severity definitions that were comparable with those of the WHO.
• No assessment of certainty of therapeutic recommendations: most (77%; 84) national guidelines didn’t include an assessment of the strength or certainty of the therapeutic recommendation. 
• A wider range of recommended drugs: the range of recommended drugs, irrespective of severity, varied from 1 to 22. The WHO guidelines recommend a total of 10.
• Mismatch with WHO guidance: in all, 105 guidelines included at least one treatment recommended by the WHO, but 4 didn’t recommend any.  Countries in the African region had a significantly lower proportion of therapies recommended by the WHO, compared with countries in Europe and South East Asia.

Recommended medications

 The most commonly recommended drugs were corticosteroids (92%;100), with 80% (88) of guidelines recommending them for the same disease severity as the WHO. But corticosteroids weren’t recommended in severe disease in nearly 1 in 10 guidelines despite overwhelming evidence of their benefit. National Guidelines from countries with low-resource settings showed the greatest divergence when stratified by gross domestic product per year, Human DevelopmentIndex and the Global Health Security Index.

Remdesivir was recommended for severe or critical disease in half the guidelines (51%;72); the WHO guidelines only indicate remdesivir conditionally for mild disease in patients at highest risk of hospital admission.

In late 2022, many guidelines continued to recommend treatments that the WHO has advised against, including chloroquine, lopinavir–ritonavir, azithromycin; vitamins and/or zinc.

One in three guidelines (36; 33%) recommended at least one neutralising monoclonal antibody directed against SARS-CoV-2, the virus responsible for COVID-19 infection. And these guidelines were issued by wealthier countries. But 2 of these monoclonal antibodies—bamlanivimab±etesivamab and regdanivimab—appeared consistently in clinical guidelines, despite not being recommended by the WHO. 

Doses of the most commonly recommended drugs also varied. And many guidelines had not been updated for more than 6 months.

Guidelines from countries with low resources settings showed the greatest divergence from the WHO recommendations, when stratified by annual GDP, the Human Development Index and the Global Health Security Index.

Underlying causes

The researchers acknowledge several limitations to their findings, including the scoring used to assess the guidelines, which has not been validated by other studies, and the inability to assess all national guidelines.

But they nevertheless ask: “Why do [national guidelines] differ so much in their treatment guidance for such a widespread and potentially serious infection when all have access to the same information?” 

“Apart from the prohibitive cost of some medications for low-resource settings, we do not have a satisfactory explanation.” 

They suggest some possible reasons for the discrepancies, including variations in how the severity of, and therefore the most appropriate treatment for, COVID-19 infection is defined; the evolution of the evidence; and the research chaos and confusion of the early stages of the pandemic, leading to claims and counter claims, compounded by intense political and media interest.

Global health inequalities clearly have a part to play, leading to the recommendation of ineffective, unaffordable and unavailable therapies, they suggest.

Read the full study.

With thanks to BMJ Global for text adapted here.