Blog 3. Diagnostic criteria

Research on ME/CFS often refers to diagnostic criteria. These are sets of agreed-upon criteria that physicians and researchers use to determine whether someone has ME/CFS. They are therefore fundamental to both clinical care and scientific research.
But what exactly are diagnostic criteria? Why are there several different sets? And why does it matter which criteria are used in research?

Diagnosing a Disease

When someone becomes ill, a physician’s first task is to determine which disease they have. Once a diagnosis has been established, appropriate care and treatment can be provided. A clear diagnosis also enables researchers to study a disease more effectively.
Researchers often look for measurable characteristics that are associated with a particular disease. Such a characteristic is called a biomarker. A reliable biomarker can help distinguish people who have a disease from those who do not. It can also help rule out other conditions that cause similar symptoms.
For many diseases, diagnosis is based on objective medical tests such as blood analyses, imaging, or other diagnostic procedures. For example, diabetes mellitus can be diagnosed by measuring blood glucose levels.

When No Biomarker Exists

For some diseases, however, no reliable biomarker has yet been identified. This is the case for ME/CFS, but also for conditions such as migraine.
In these situations, diagnosis is based on a person’s symptoms rather than on a laboratory test. Usually, it is not a single symptom but a characteristic combination of symptoms, their duration, and additional clinical requirements that together form the basis for diagnosis. These are known as diagnostic criteria.
For ME/CFS, diagnosis is therefore based on combinations of symptoms such as post-exertional malaise (PEM), persistent fatigue, cognitive impairment, and sleep disturbances.

Diagnostic Criteria Evolve Over Time

Diagnostic criteria rarely emerge all at once. For most diseases, the process begins when clinicians observe that certain symptoms frequently occur together. Based on these observations, the first set of diagnostic criteria is developed. As scientific knowledge advances and researchers gain a better understanding of the underlying biological mechanisms, these criteria may be refined. Additional diagnostic tests, medical imaging, or biomarkers may be incorporated over time.
This process often takes many years—or even decades. That is true not only for ME/CFS, but also for other complex diseases such as multiple sclerosis (MS). In the case of MS, it took many years before researchers identified which symptoms and biological abnormalities were characteristic of the disease and which diagnostic tests could be relied upon.
New insights from biomedical research continue to strengthen the scientific foundation of diagnostic criteria and improve their usefulness for both clinicians and researchers. As a result, diagnostic criteria are regularly reviewed and updated.

Why This Is Particularly Challenging for ME/CFS

The underlying cause of ME/CFS remains unknown. However, there is growing evidence that ME/CFS is a multisystem disease, meaning that it affects multiple systems throughout the body. People with ME/CFS may experience a wide variety of symptoms, many of which also occur in other conditions, including fatigue, pain, and sleep disturbances. This makes it more difficult to distinguish ME/CFS from other illnesses.
In addition, relatively little biomedical and epidemiological research was conducted on ME/CFS for many years. Although research activity has increased substantially in recent years, scientists still do not fully understand which symptoms are most characteristic of the disease or which biological mechanisms underlie it.
As a result, different views still exist regarding which symptoms should be considered central to the diagnosis of ME/CFS.

Different Purposes of Diagnostic Criteria

Diagnostic criteria are not always used for the same purpose. Physicians and researchers have different needs, and therefore apply diagnostic criteria in different ways.

For physicians, diagnostic criteria should be clear, practical, and applicable in everyday clinical care. They use these criteria to establish a diagnosis, determine the most appropriate care, and decide whether additional diagnostic tests are needed. The criteria also need to be suitable for a broad and diverse patient population. In addition to diagnostic criteria, physicians often use clinical guidelines that provide recommendations for diagnosis, further investigations, and treatment.

Researchers have different objectives. In scientific studies, it is important to define participants’ characteristics as accurately as possible so that these can be related to the disease being studied. Researchers may investigate symptoms, co-existing medical conditions (comorbidities), genetic factors, biomarkers, or other clinical characteristics. Depending on the research question, different inclusion criteria may be appropriate.
Some studies use stricter or more specific diagnostic criteria to create relatively homogeneous groups of participants, making it easier to detect biological differences. Other studies intentionally include a broader and more diverse group of participants to better understand the variation that exists within the ME/CFS population.
Researchers also study the diagnostic process itself. For example, they investigate which symptoms are most characteristic of ME/CFS or evaluate whether new combinations of diagnostic criteria improve diagnostic accuracy.

Different Sets of Diagnostic Criteria

Because diagnostic criteria serve different purposes and scientific knowledge has evolved over time, several sets of diagnostic criteria have been developed for ME/CFS. Today, four sets are used most frequently:

• Fukuda criteria

• Canadian Consensus Criteria (CCC)

• International Consensus Criteria (ICC)

• Institute of Medicine criteria (IOM)

These diagnostic criteria differ in several respects, including how strict they are and which symptoms they consider most important. The Fukuda Criteria are generally regarded as broader and more inclusive. The CCC, ICC, and IOM Criteria place greater emphasis on specific symptoms, particularly post-exertional malaise (PEM). The different criteria also reflect differences in terminology. Some refer to Chronic Fatigue Syndrome (CFS), while others use Myalgic Encephalomyelitis (ME) or ME/CFS. Having multiple diagnostic criteria has both advantages and disadvantages. Different criteria may identify different groups of patients, leading to different scientific insights. At the same time, this makes it more difficult to compare findings across studies.
Within the Dutch ZonMw ME/CFS Research Programme, one or more of these diagnostic criteria are used across the various research projects. Researchers also examine similarities and differences between participants who meet different sets of criteria.

The grey area

Because no definitive cause or reliable biomarker for ME/CFS has yet been identified, and because patients can experience a wide variety of symptoms, there is an inevitable grey area in diagnosis. In some cases, it is not entirely clear whether a person does or does not have ME/CFS.
When researchers use broader diagnostic criteria, they are likely to include more people who genuinely have ME/CFS. However, this also increases the possibility that participants with other conditions presenting similar symptoms are included in the study.
Conversely, when stricter diagnostic criteria are applied, the study population is likely to be more homogeneous. This can make underlying biological differences easier to detect. However, it may also exclude people with ME/CFS who have co-existing medical conditions, even though studying these individuals may provide valuable insights into shared biological mechanisms. For this reason, comparing studies remains challenging, and it is not always straightforward to determine how well the results apply to the wider ME/CFS population.

Comparing Research Findings

Researchers aim to compare new findings with previous studies whenever possible. Sometimes they even combine data from multiple studies to create larger datasets, increasing the statistical power and reliability of their analyses.
It is equally important that scientific studies can be replicated. When multiple independent studies produce similar findings, confidence in those results grows. For this reason, researchers should always describe clearly which diagnostic criteria they have used. Without this information, comparing studies becomes difficult.
Many older studies used relatively broad diagnostic criteria, whereas more recent research increasingly applies stricter definitions. This makes comparisons between older and newer studies more complicated and raises ongoing questions about which approach is most appropriate. Within the Dutch ZonMw ME/CFS Research Programme, the participating consortia align their methodologies and participant inclusion criteria as much as possible. This improves comparability between studies and enables the different research projects to complement one another.

The Search for a Biomarker

As long as the diagnosis of ME/CFS is based on symptoms rather than objective laboratory tests, the search for better diagnostic criteria remains essential. Researchers around the world are working to identify reliable biomarkers for ME/CFS. The Dutch research consortia participating in the ZonMw ME/CFS Research Programme are also contributing to this effort.
If a reliable biomarker is identified in the future, it will become possible to determine more accurately who does and does not have ME/CFS. This would allow researchers to conduct more targeted studies and help healthcare professionals provide patients with more appropriate care.
At the same time, the history of many other diseases shows that developing robust diagnostic criteria is often a lengthy process. As scientific knowledge advances, diagnostic criteria will continue to evolve and improve.