One of the most perplexing dilemmas in modern science is chronic fatigue syndrome (CFS). Even though the illness was recognized at the beginning of the 20th century, the pathogenicity and etiology of the disease remain unknown. We describe an open-inquiry case study on CFS that we have used in our biology classrooms to increase students' critical-thinking skills and understanding of scientific method. Three general categories of potential pathogens – virus, vaccine, and microbiome – are discussed during multiple classroom sessions. We found that our students were more proactive than expected. They researched credible references from the most recent publications and formulated arguments on the medical issue. They applied knowledge of human body systems to explain the complexity of the disease. Students were capable of distinguishing “correlation” and “cause” relations between the disease and pathogens. We observed a high level of student participation and involvement, which not only increased their knowledge of scientific approaches but also strengthened their interaction and communication skills. The case study is suitable for biology courses in both high school and college.

## Introduction

The study of chronic fatigue syndrome (CFS) is a matter of significant controversy in modern science. Even though the illness was recognized at the beginning of the 20th century and millions of dollars were poured into studies of it, we still don't know, at this late date, much about its etiology or pathogenicity. As debates and discussions continue, one of the researchers has claimed, “We don't have agreement on almost anything” (Kaiser, 2010). It is a disease doctors refuse to see; they aren't persuaded by the scientific evidence (Rehmeyer, 2015).

Taking into consideration the vast amount of theoretical topics and applied approaches covered in those debates, as college biology professors, we recognize the value and relevance of this enigmatic disease as a subject in our lectures (Zaitsev, 2009b; Zaitsev et al., 2013). It not only helps us review some of the topics of biochemistry, but also enhances coverage of the unit on the human body system. Implementation of some research conjectures demonstrates the tentative nature of science and induces students to think analytically and critically (Zaitsev, 2009a, 2010). This article will provide information on the peculiarity of the enigmatic disease and the controversy surrounding it so that it can be introduced to biology classes in both high schools and colleges.

## Background on CFS: Being Sick & Tired

When most people become tired, rest or sleep will usually rejuvenate them. In people with CFS, fatigue is resistant and excessive and does not improve with either rest or sleep. It may be aggravated by physical or mental activity (CDC, 2012), causing extreme exhaustion. Other common signs and symptoms include unexplained muscle and joint pain, atypical headache, enlarged lymph nodes, mild fever, a wide range of gastrointestinal difficulties, and inability to sleep or to sleep deeply. These nonspecific signs and symptoms are similar to those of many other illnesses such as anemia, hypothyroidism, Lyme disease, depression, and others. Many psychiatrists speculate that the condition is the product of profoundly psychological or behavioral causes (Prins et al., 2006; Deary & Chalder, 2010). A survey of 811 physicians revealed that 44% did not feel confident making the diagnosis of CFS (Bowen et al., 2005).

## The Controversy

Lately, more evidence has accumulated demonstrating that CFS is a serious physical disability that is not caused by psychosis but is a result of complex pathophysiological processes in the human body. It is deemed more appropriate to use the term myalgic encephalomyelitis (ME) since it indicates an underlying pathophysiology (Carruthers et al., 2011), which might cause neurological changes (Tirelli et al., 1998; Chen et al., 2008), cardiovascular abnormalities (Peckerman et al., 2003; Hollingsworth et al., 2010), endocrine dysfunction (Hyde, 2007), and immunopathology (Lorusso et al., 2009; Broderick et al., 2010), among many other pathologies.

Some researchers differentiate between CFS and ME, specifying that the latter is an acute illness that often becomes chronic (Jason et al., 2012), but in mainstream usage these terms are interchangeable. It is characteristic of CFS/ME that signs and symptoms come and go (fluctuate). The disease affects both sexes and all racial, age, and socioeconomic groups (Jason et al., 1999). It may exhibit a sudden onset or come on gradually. Some patients improve spontaneously, but many others experience a prolonged course of the disease with periods of remission and exacerbation (U.S. Food and Drug Administration, 2013). Diagnostics are based purely on clinical symptoms using nothing but self-report questionnaires (Morris & Maes, 2013), and there are no explicit testing methods to pinpoint this illness specifically. There are also no common agreements on the diagnosis; different scientists and health organizations use different core symptoms to diagnose CFS/ME (reviewed by Jason et al., 2012). Some take post-exertional malaise as a hallmark for diagnosis (“London,” Hyde, and Goudsmit criteria) while others rely on fatigue that does not get resolved with bed rest (Holmes et al., U.S. Centers for Disease Control and Prevention [CDC], and Canadian criteria) (Table 1). Understandably, the latter three, especially the recent CDC empiric criteria (Reeves et al., 2005), have expanded the pool of CFS/ME patients. The Fukuda criteria, which require four out of eight symptoms (Table 1), constitute the most widely used definition in CFS/ME research, but many limitations and challenges remain with regard to these polythetic criteria. The time period required for diagnosis varies among the different criteria. The Goudsmit criteria require the major symptom to be present for three months, whereas most of the others require six months. However, the Hyde criteria do not suggest a specific time period. More recently, Carruthers et al. (2011) proposed new hallmarks for the definition of CFS/ME – referred to as International Consensus Criteria – that require the patient to have post-exertional neuroimmune exhaustion plus one symptom from each of three categories (Table 2). Shortly after the latter criteria were published, the Morris-Maes criteria appeared in the journal Neuroendocrinology Letters (Morris & Maes, 2013). Morris and Maes criticized the International Consensus Criteria and proposed the use of neuroimmune biomarkers in CFS/ME diagnosis. The historical development of the different criteria purporting to select patients with CFS/ME is described in detail by Jason et al. (2012), Morris and Maes (2013), and Sunnquist et al. (2017).

Table 1.
Criteria and core symptoms used in CFS/ME diagnosis (reviewed by Jason et al., 2012).
CriteriaSymptoms
Fatigue Not Resolved with Bed RestPost-exertional MalaiseMemory and Concentration Impairment Plus Disturbed SleepVascular Damage in the Central Nervous SystemCirculatory ImpairmentCardiac IrregularityEndocrine DysfunctionPresence of Viral IllnessFluctuation of Symptoms≥3 Months≥6 Months
“London” ME criteria  + +  +   + +  +
Hyde ME criteria  +  + + + +
Goudsmit ME criteria  +        +
Holmes et al. CFS criteria +          +
CDC CFS criteria + +         +
Canadian ME/CFS criteria +  +        +
Fukuda CFS criteria Four symptoms out of the following eight: impaired memory or concentration; sore throat; tender cervical or axillary lymph nodes; muscle pain; multi-joint pain; new headaches; unrefreshing sleep; post-exertion malaise. +
CriteriaSymptoms
Fatigue Not Resolved with Bed RestPost-exertional MalaiseMemory and Concentration Impairment Plus Disturbed SleepVascular Damage in the Central Nervous SystemCirculatory ImpairmentCardiac IrregularityEndocrine DysfunctionPresence of Viral IllnessFluctuation of Symptoms≥3 Months≥6 Months
“London” ME criteria  + +  +   + +  +
Hyde ME criteria  +  + + + +
Goudsmit ME criteria  +        +
Holmes et al. CFS criteria +          +
CDC CFS criteria + +         +
Canadian ME/CFS criteria +  +        +
Fukuda CFS criteria Four symptoms out of the following eight: impaired memory or concentration; sore throat; tender cervical or axillary lymph nodes; muscle pain; multi-joint pain; new headaches; unrefreshing sleep; post-exertion malaise. +
Table 2.
The International Consensus Criteria (Carruthers et al., 2011) require one symptom from each of the three categories shown here, in addition to post-exertional neuroimmune exhaustion, for CFS/ME diagnosis.
Neurological ImpairmentsImmune, Gastrointestinal & Genitourinary ImpairmentsEnergy Production/Transportation Impairments
Neurocognitive impairments (difficulty processing information and short-term memory loss) Often flu-like symptoms Cardiovascular abnormalities
Pain (abdominal pain, headaches, myalgias, arthralgias) Often viral infections with prolonged recovery periods Respiratory symptoms (fatigue of chest wall muscles, air hunger, etc.)
Sleep disturbance (disturbed sleep patterns or unrefreshing sleep) Gastrointestinal tract disturbances (irritable bowel syndrome, bloating, nausea) Loss of thermostatic stability (cold extremities, sweating episodes, etc.)
Neurosensory, perceptual, and motor disturbances Genitourinary problems (nocturia, urinary urgency) Intolerance to extremes of temperature
Sensitivities to foods, medications, odors, or chemicals
Neurological ImpairmentsImmune, Gastrointestinal & Genitourinary ImpairmentsEnergy Production/Transportation Impairments
Neurocognitive impairments (difficulty processing information and short-term memory loss) Often flu-like symptoms Cardiovascular abnormalities
Pain (abdominal pain, headaches, myalgias, arthralgias) Often viral infections with prolonged recovery periods Respiratory symptoms (fatigue of chest wall muscles, air hunger, etc.)
Sleep disturbance (disturbed sleep patterns or unrefreshing sleep) Gastrointestinal tract disturbances (irritable bowel syndrome, bloating, nausea) Loss of thermostatic stability (cold extremities, sweating episodes, etc.)
Neurosensory, perceptual, and motor disturbances Genitourinary problems (nocturia, urinary urgency) Intolerance to extremes of temperature
Sensitivities to foods, medications, odors, or chemicals

## Second Session: Simmering Controversy

Students were more proactive than we anticipated. They found many new references that are not listed in the case study, including some recent research studies. They also found that there was a recent attempt to rename CFS/ME as “systemic exertion intolerance disease.” Some students appeared to be skeptical about this endeavor, since researchers could not agree upon the various definitions of the disease and there were no definitive medical tests that could be used for diagnosis.

Students applied their course knowledge to describe symptoms of CFS/ME affecting various body systems, such as the immune system and nervous system. The case study reinforced concepts learned in the lecture. For example, the group focusing on vaccination applied the mechanism of immune response. During their presentation, students explained (1) what a vaccination is, (2) how it impacts the immune system in humans, (3) which cells are triggered by immune responses, and (4) how antibodies are generated. They even found a court case in the United States in which a young patient won \$250,000 compensation for having developed CFS/ME after being given a hepatitis B vaccination. They also brought up relevant data from the the Canadian Laboratory Center for Disease Control that show no evidence to support that finding of causation.

Students who focused on CFS/ME treatment elaborated on neurotransmitters, on antidepressant medications given to CFS/ME patients, and on the role of antioxidants in improving patients' condition. Students were also aware of the challenges of treatment. For instance, antidepressants could give a patient suicidal thoughts. Some students knew about side effects of these medications from their own life experience and brought valuable arguments to the classroom. There was an exciting discussion on this topic.

Most students realized that there might be a correlation between CFS/ME and the proposed “pathogenic agents.” In the classroom, students inquired why some people who have been infected with the same viruses or who have received the same types of vaccine do not have CFS while others do. They were confident in articulating their opinions. For example, they argued that those agents themselves might not cause the disease; the patient might have other underlying, contributing medical conditions, such as HIV, or a combination of various agents might trigger the disease. They cited relevant research to demonstrate their findings. Students distinguished between “correlation” and “cause,” indicating that they comprehended fundamental aspects of pathology in medicine. However, students usually were unsure how to further their discussion.

The group assigned the last topic – on future directions of CFS/ME research – did not fully understand their challenge. They mostly gave an overview of CFS/ME research rather than offering possible perspectives. It was a difficult topic to present, since the students were not experts on CFS/ME; however, they did find some useful information in research on CFS/ME. For example, they found that there is 200× more funding for HIV than for CFS/ME. They explained that this is due to the lack of definite explanations of the nature of CFS/ME. Students advocated for more patient sample analysis and the search for biomarkers.

Students showed that they were capable of conducting independent research using credible resources such as peer-reviewed research articles, patient pictures, court cases, and others. All groups included figures and graphs from such reference materials in their presentations. In presenting these scientific analyses, students demonstrated their critical-thinking skills.

When given the case study, students started with an uncertainty about CFS/ME. To them, a person with this syndrome seemed more or less like a person who does not want to work, who just feels tired all the time. However, after their own research on CFS/ME, many of the students had revised their opinions on the disease. In the end, students were asked in a survey whether they believed that CFS/ME is an actual physical disease or rather a psychological problem. Half of the class believed that it is a real disease and the others did not.

Interestingly, we also found that students justified their opinions using anthropology and sociology studies from other disciplines. For example, to explain why most of the patients diagnosed were white women in the United States, some students suggested that women are more outspoken than most men. Meanwhile, the white population has more access to good health care than minority populations. However, that does not mean that CFS/ME does not exist in minority populations. Approximately 3.9 million minority individuals were potential CFS/ME patients, based on the students' findings.

The painting reproduced here as Figure 1 captures the frustration and despair of a CFS/ME patient, putting a human face on the problem. Our college has an Arts Across the Curriculum program that has been successful for many years. Connections between the arts and sciences are important to attract students' attention to problems they might not experience themselves. As some students indicated, socioeconomic factors should be taken into consideration when statistics are used in clinical studies.

Figure 1.

Defeated, an oil painting on canvas by Igor V. Zaitsev. This painting was created for the May 12th International Awareness Day for Chronic Immunological and Neurological Diseases: Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, Fibromyalgia, Gulf War Syndrome, and Multiple Chemical Sensitivity. These diseases affect both men and women, regardless of their race, nationality, and age.

Figure 1.

Defeated, an oil painting on canvas by Igor V. Zaitsev. This painting was created for the May 12th International Awareness Day for Chronic Immunological and Neurological Diseases: Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, Fibromyalgia, Gulf War Syndrome, and Multiple Chemical Sensitivity. These diseases affect both men and women, regardless of their race, nationality, and age.

## Conclusion

The case study presented here uses a controversial human disease as an example to enhance students' learning in human body systems, symptoms of a disease, complexity of diagnosis, and the scientific method. It provides opportunities for students to build critical-thinking skills and interests in medical research studies. We introduced the case study to students who intended to pursue careers in health-related fields and they found it interesting and engaging. As shown in an earlier article (Zaitsev, 2009b), during such discussions we observed a high level of student participation and involvement, which not only increased their knowledge on the scientific approaches but also improved their skills of interaction and communication with each other. However, in the future we would modify the case study on the basis of feedback from students. As noted above, at the end of the activities half of our students believed that CFS/ME is a real disease while the others did not. Therefore, it is a great case study for creating a debate in the classroom. The debate should take place after the students' presentations. Alternatively, an essay on whether CFS/ME is a real disease could be assigned to each student. Perhaps those modifications may improve students' comprehension of the material.

The authors would like to express their gratitude to Gordon Stumpo and Dr. Joseph Lieberman for their valuable advice during the development of this paper. The header images are modified from CDC and NIH image collections.

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