Trial By Error: New JAMA Article Seeks to Revive the Zombie Case Definition for CFS from 1994

By David Tuller, DrPH

The long Covid narrative seems to bounce back and forth with each new study or review documenting contrasting findings—evidence of serious pathophysiological anomalies among sub-sets of patients followed by data that appear to implicate psychological and/or emotional factors in the generation of reported symptoms. A new study in JAMA Network Open falls in the latter camp and has promptly been touted by some as indicating that, when it comes to long Covid, there might be a lot less than meets the eye.

I recently wrote about the effort of the Collaborative on Fatigue Following Infection (COFFI) to revive a discredited 1991 definition for chronic fatigue syndrome (CFS), known as the Oxford criteria, as the basis for promoting their construct of post-infective fatigue syndrome (PIFS) in the context of long Covid. The JAMA Network Open article, whose authors include key members of COFFI, is a related attempt to rehabilitate a similarly obsolete 1994 set of criteria known as the Fukuda definition. In the article, they declare that “studies of PIFS have benefitted from an international case definition that is centered around the symptom of fatigue”–with Fukuda cited as the source.

The 1991 and 1994 case definitions for CFS rely on fatigue as their core construct; in fact, the 1991 definition requires no other symptoms. Neither definition requires the symptoms known as post-exertional malaise, which is now regarded as a distinguishing feature of the illness or cluster of illnesses variously called myalgic encephalomyelitis (ME), ME/CFS, CFS/ME, and other iterations. Very few investigators, if any, still use these ancient case definitions. Now the COFFI crew wants to revive and rebrand them as definitions not for CFS but for PIFS–to serve as the template for addressing long Covid.

It’s like these people haven’t had a new idea since the 1990s.

I have previously criticized two of the JAMA Network Open authors—senior author Professor Vegard Wyller of Norway and Professor Andrew Lloyd of Australia—for flawed claims and/or inaccurate statements. In this study of 12- to 25-year-olds, they and colleagues compared 382 participants with SARS-CoV-2 infection confirmed by PCR and 85 who were PCR-negative. At six months, they assessed whether participants in each group met the definition for post-Covid-19 condition (PCC), per a 2021 consensus definition from the World Health Organization (WHO). At that point, there were no statistically significant differences in PCC prevalence, with almost half of the participants in each group reporting symptoms consistent with the diagnosis. Much smaller percentages in both groups met their definition for post-infective fatigue syndrome—that is, the Fukuda definition.

This study has now been tweeted thither and yon as bolstering the argument that long Covid is, you know, overblown and essentially unrelated to coronavirus infection. This is an unfortunate and unwarranted conclusion.

The WHO definition is designed for clinical care. Clinical case definitions are by nature broad in order to identify all patients who might possibly need treatment. In contrast, research case definitions are drawn more narrowly to limit the possibility that people without the condition in question will be included in studies and confound the findings.

According to the WHO clinical definition, “post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.” Furthermore, per the definition, “there is no minimum number of symptoms required for the diagnosis.” In other words, a couple of months of fatigue alone—or another symptom—would mean that someone would qualify as having PCC.

That’s a fairly low bar. It is self-evident that a definition this expansive is going to sweep in many people with any kind of symptoms, or even a single symptom, related to pretty much anything. Further confusing the analysis is the manner in which controls were selected. Some were “asymptomatic close contacts” of the positive cases, but “some individuals in the SARS-CoV-2–negative group had been tested because of acute infectious symptoms.” PCR testing is not infallible; depending upon when the test is done and other factors, it can yield false negatives. Moreover, it seems that some of these control group members were likely suffering from an acute viral illness other than Covid-19. If so, it wouldn’t be surprising if some were experiencing prolonged recoveries as well, as can happen with all kinds of infectious disease.

The JAMA Network Open article reports that symptom severity and “emotional maladjustment” at baseline were both risk factors for PCC and PIFS at six months. The authors appear to assume that this reported emotional maladjustment is a causal factor in both the reported severity of the initial symptoms and in the development of PCC or PIFS. Here’s the problem: It is understandable that patients experiencing an acute viral illness would also experience anxiety, depression or related mood disturbances, so any such association should be expected. Unfortunately, some researchers in this field routinely interpret associations as causal in the direction of their own pet theories—even when logic would dictate otherwise.


An effort to push non-pharmacological interventions

Here’s some key background. In a well-known study published in 2006, Australian researchers reported that 11% of patients with one of three infectious diseases—two viral, one bacterial–met the Fukuda criteria for chronic fatigue syndrome six months after the infection. The main risk factor they identified was the severity of the initial illness. Other studies of prolonged post-infectious symptoms have reported similar rates, which represent significant minorities of patients but nowhere near the almost half reported for PCC in the new article.

This phenomenon has long been well-known among those interested in post-viral illnesses—including many patients diagnosed with ME and its siblings. Most people recover from most viral illnesses–but some inevitably do not. That’s why everyone involved in this field—scientists, clinicians, and advocates as well as patients—knew immediately that the pandemic would be accompanied by a wave of post-acute symptoms, that many of these symptoms would be non-specific, and that many experts would attribute them to psychological factors.

That has all come to pass.

Even though most people with Covid-19 recover, a significant proportion seem to remain disabled. And when you’re dealing with a pandemic, even a small minority is going to yield enormous numbers. In this case, however, the authors have calculated maximal estimates from operationalizing very loose criteria, generated further confusion with a problematic comparison group, and then argued that fears of prolonged disability are overblown. While doing so, they have also brought back zombie case definitions from three decades ago without mentioning that they have been widely rejected as inadequate.

Here’s one of the study’s conclusions: “These findings suggest that persistent symptoms in this age group are related to factors other than SARS-CoV-2 infection.” No. This study suggests that when you use a very open-ended clinical definition of long Covid for research in this manner, you get results that are likely to be inflated and therefore essentially meaningless. The study’s main finding seems to be that the WHO case definition is not helpful for calculating prevalence rates—at least in this young population. The authors, to their credit, point out these shortcomings of the PCC definition.

But they also reveal their agenda with this statement: “The results do suggest that nonpharmacological interventions may be beneficial and should be investigated in future studies, in line with experiences from PIFS following other infections.” Uh, oh! That presumably means variations of graded exercise therapy and cognitive behavior therapy.

In fact, as we all know from re-analyses of the PACE trial and the new guidelines for ME/CFS from the UK’s National Institute for Health and Care Excellence, the evidence of benefits from such non-pharmacological interventions is poor to non-existent. These COFFI members are seeking to resuscitate a paradigm that has already been abandoned by major health agencies in the US, the UK and around the world. It is a dispiriting spectacle to watch.

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