Post by Nadica (She/Her) on Nov 24, 2024 4:11:36 GMT
On the Prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome after a SARS-CoV-2 infection - Published Nov 15, 2024
There is an increasing body of evidence connecting the post-acute SARS-CoV-2 condition (PASC, commonly known as long COVID) to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating disease of unknown cause characterized by persistent and unexplained fatigue, post-exertional malaise (PEM), among other symptoms.1,2 This connection implies that, in the clinic, some PASC cases comply with the official case definitions of ME/CFS. As such, there is a necessity to quantify the burden of ME/CFS among the PASC population in order to delineate effective healthcare interventions for the benefit of these patients who are often neglected or, in some extreme cases, stigmatized by medical staff and society.3
To answer this urgent research question, Dehlia and Guthridge4 performed a systematic review and meta-analysis of recent data on PASC adults and reported an ME/CFS prevalence estimate of 51% (95% CI, 42%-60%); this systematic review and meta-analysis will be referred to as PASC-ME/CFS study. In the present Letter to Editor, we aimed to discuss the reliability of this estimate using the research protocol from the European Network on ME/CFS (EUROMENE) for systematic reviews and meta-analysis on the epidemiology burden of ME/CFS in Europe.5,6
According to the EUROMENE protocol for studies on adults only, there are essentially two inclusion conditions: (1) studies reporting prevalence or incidence of ME/CFS whose disease diagnosis was based on the 1994 Centre for Disease Control Control criteria, the Canadian Consensus Criteria, the London Criteria International Consensus Criteria or the Institute of Medicine criteria; (2) studies conducted in community or primary care settings. The protocol considers a third condition related to the European origin of the studies. This condition is not relevant for this letter given that the PASC-ME/CFS study focused on both European and non-European studies.
With respect to the exclusion criteria, the EUROMENE protocol considers the following four conditions: (1) studies without primary data; (2) studies conducted in biased samples or based on self-report of the diagnosis of ME/CFS; (3) studies with an inappropriate case definition (e.g., CFS-like illness or other clinical criteria, such as the Oxford criteria due to lack of specificity); (4) duplicate reports (when data from multiple studies overlaps, the study with the largest sample size should be selected). As in the inclusion criteria, there is an additional exclusion condition related to non-European origin of the studies (not relevant to the present letter).
When we compared the EUROMENE inclusion and exclusion conditions with the ones specified by PASC-ME/CFS study, we found three remarkable differences. The first one is that the PASC-ME/CFS study considered the DePaul Symptom Questionnaire (DSQ) as an eventual ME/CFS diagnostic criteria, besides the ones in the EUROMENE protocol. This additional inclusion condition is surprising given that DSQ is simply a questionnaire that allows testing different case definitions in the same individual.7 As such, studies using DSQ for ME/CFS diagnosis are yet required to disclose the respective case definition. The second difference is that the PASC-ME/CFS study did not include an exclusion condition related to biased studies, such as the ones based on the recruitment of participants from PASC support groups or from clinics specialized in ME/CFS diagnosis. Focusing only on random samples from the general population is in fact the recommended approach by the critical appraisal checklist from the Joanna Briggs Institute for prevalence (or incidence) systematic reviews. The third difference is that the PASC-ME/CFS study did not specify an exclusion condition concerning duplicated or overlapping data as the EUROMENE protocol did.
We then re-assessed the 13 studies selected by the PASC-ME/CFS study for the meta-analysis stage but now under the scope of the EUROMENE research protocol (Table 1). We found that all of these studies satisfied at least one of the exclusion conditions of that protocol: no primary care or community data (n=9); biased samples (n=12); unclear information on ME/CFS case definition (n=1); no application of an ME/CFS case definition (n=1); and studies with overlapping data (n=3). The most important implication is that the pooled prevalence estimates of around 50% reported by the PASC-ME/CFS study can be simply explained by high biased data from PASC cases recruited from PASC support groups who probably had more symptoms, biased data from PASC patients who were already suspected to comply with a ME/CFS diagnosis, and duplicated data.
Our final remark is related to the search query of the PASC-ME/CFS study, which did not account for CFS/ME as an alternative acronym for the disease name. That might explain the exclusion of the study of Simani et al.8 from the meta-analysis when it seems to satisfy the inclusion criteria of the PASC-ME/CFS study. This alternative acronym was specified in the query included in the EUROMENE search strategy.
In conclusion, the prevalence reported in the PASC-ME/CFS study is likely to be an overestimation due to biased samples towards suspected ME/CFS cases and data duplication. It might also be based on incomplete data due to a limited search strategy. As a consequence, the prevalence of ME/CFS among the PASC population remains an important open question, best answered through population studies that prioritize random sampling from the community and primary care settings. We recognize that conducting these studies can be challenging, particularly due to variability in healthcare resources and the complexity of diagnosing ME/CFS without an objective biomarker. This challenge is illustrated by the scarcity of high-quality epidemiological studies of the disease.6,9 Notwithstanding this challenge, future research would benefit from adhering to standardized protocols to improve consistency and comparability of findings. In fact, the publication of the EUROMENE protocol was exactly with the purpose of providing a high-quality research template for researcher community. More importantly, an accurate prevalence estimate of the disease is critical to inform healthcare interventions, allocate resources, and develop specialized programs for patients, many of whom face challenges accessing appropriate care. Such a crucial epidemiological information is also critical to raise awareness of the condition within the medical community, reduce stigma, and attract investment in much-needed treatment research.
There is an increasing body of evidence connecting the post-acute SARS-CoV-2 condition (PASC, commonly known as long COVID) to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating disease of unknown cause characterized by persistent and unexplained fatigue, post-exertional malaise (PEM), among other symptoms.1,2 This connection implies that, in the clinic, some PASC cases comply with the official case definitions of ME/CFS. As such, there is a necessity to quantify the burden of ME/CFS among the PASC population in order to delineate effective healthcare interventions for the benefit of these patients who are often neglected or, in some extreme cases, stigmatized by medical staff and society.3
To answer this urgent research question, Dehlia and Guthridge4 performed a systematic review and meta-analysis of recent data on PASC adults and reported an ME/CFS prevalence estimate of 51% (95% CI, 42%-60%); this systematic review and meta-analysis will be referred to as PASC-ME/CFS study. In the present Letter to Editor, we aimed to discuss the reliability of this estimate using the research protocol from the European Network on ME/CFS (EUROMENE) for systematic reviews and meta-analysis on the epidemiology burden of ME/CFS in Europe.5,6
According to the EUROMENE protocol for studies on adults only, there are essentially two inclusion conditions: (1) studies reporting prevalence or incidence of ME/CFS whose disease diagnosis was based on the 1994 Centre for Disease Control Control criteria, the Canadian Consensus Criteria, the London Criteria International Consensus Criteria or the Institute of Medicine criteria; (2) studies conducted in community or primary care settings. The protocol considers a third condition related to the European origin of the studies. This condition is not relevant for this letter given that the PASC-ME/CFS study focused on both European and non-European studies.
With respect to the exclusion criteria, the EUROMENE protocol considers the following four conditions: (1) studies without primary data; (2) studies conducted in biased samples or based on self-report of the diagnosis of ME/CFS; (3) studies with an inappropriate case definition (e.g., CFS-like illness or other clinical criteria, such as the Oxford criteria due to lack of specificity); (4) duplicate reports (when data from multiple studies overlaps, the study with the largest sample size should be selected). As in the inclusion criteria, there is an additional exclusion condition related to non-European origin of the studies (not relevant to the present letter).
When we compared the EUROMENE inclusion and exclusion conditions with the ones specified by PASC-ME/CFS study, we found three remarkable differences. The first one is that the PASC-ME/CFS study considered the DePaul Symptom Questionnaire (DSQ) as an eventual ME/CFS diagnostic criteria, besides the ones in the EUROMENE protocol. This additional inclusion condition is surprising given that DSQ is simply a questionnaire that allows testing different case definitions in the same individual.7 As such, studies using DSQ for ME/CFS diagnosis are yet required to disclose the respective case definition. The second difference is that the PASC-ME/CFS study did not include an exclusion condition related to biased studies, such as the ones based on the recruitment of participants from PASC support groups or from clinics specialized in ME/CFS diagnosis. Focusing only on random samples from the general population is in fact the recommended approach by the critical appraisal checklist from the Joanna Briggs Institute for prevalence (or incidence) systematic reviews. The third difference is that the PASC-ME/CFS study did not specify an exclusion condition concerning duplicated or overlapping data as the EUROMENE protocol did.
We then re-assessed the 13 studies selected by the PASC-ME/CFS study for the meta-analysis stage but now under the scope of the EUROMENE research protocol (Table 1). We found that all of these studies satisfied at least one of the exclusion conditions of that protocol: no primary care or community data (n=9); biased samples (n=12); unclear information on ME/CFS case definition (n=1); no application of an ME/CFS case definition (n=1); and studies with overlapping data (n=3). The most important implication is that the pooled prevalence estimates of around 50% reported by the PASC-ME/CFS study can be simply explained by high biased data from PASC cases recruited from PASC support groups who probably had more symptoms, biased data from PASC patients who were already suspected to comply with a ME/CFS diagnosis, and duplicated data.
Our final remark is related to the search query of the PASC-ME/CFS study, which did not account for CFS/ME as an alternative acronym for the disease name. That might explain the exclusion of the study of Simani et al.8 from the meta-analysis when it seems to satisfy the inclusion criteria of the PASC-ME/CFS study. This alternative acronym was specified in the query included in the EUROMENE search strategy.
In conclusion, the prevalence reported in the PASC-ME/CFS study is likely to be an overestimation due to biased samples towards suspected ME/CFS cases and data duplication. It might also be based on incomplete data due to a limited search strategy. As a consequence, the prevalence of ME/CFS among the PASC population remains an important open question, best answered through population studies that prioritize random sampling from the community and primary care settings. We recognize that conducting these studies can be challenging, particularly due to variability in healthcare resources and the complexity of diagnosing ME/CFS without an objective biomarker. This challenge is illustrated by the scarcity of high-quality epidemiological studies of the disease.6,9 Notwithstanding this challenge, future research would benefit from adhering to standardized protocols to improve consistency and comparability of findings. In fact, the publication of the EUROMENE protocol was exactly with the purpose of providing a high-quality research template for researcher community. More importantly, an accurate prevalence estimate of the disease is critical to inform healthcare interventions, allocate resources, and develop specialized programs for patients, many of whom face challenges accessing appropriate care. Such a crucial epidemiological information is also critical to raise awareness of the condition within the medical community, reduce stigma, and attract investment in much-needed treatment research.