Pediatric Annals

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Update on Chronic Fatigue Syndrome and Epstein-Barr Virus

Ben Z Katz, MD

Abstract

Since 1994, chronic fatigue syndrome (CFS) has been defined for adults in the United States as clinically evaluated, unexplained, persistent, or relapsing fatigue that is of new or definite onset. The fatigue cannot be the result of ongoing exertion, cannot substantially be alleviated by rest, and must result in substantial reduction in previous levels of occupational, educational, social, or personal activities. In addition, four or more of the following need to be present: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; myalgia; arthralgia; headache; unrefreshed sleep; and postexertional malaise lasting more than 24 hours. These symptoms need to have persisted or recurred during 6 or more consecutive months and must not have predated the fatigue.1

The clinical evaluation necessary to diagnose CFS includes a complete history and physical examination and normal screening laboratory tests (including complete blood count, erythrocyte sedimentation rate, alanine aminotransferase, alkaline phosphatase, total protein, albumin, globulin, calcium, phosphorous, glucose, blood urea nitrogen, creatinine, electrolytes, thyroid stimulating hormone, and urinalysis). Any active medical condition, any medical condition that may relapse or not completely resolve with therapy, any past or current major psychiatric disorder, any substance abuse within 2 years of onset, or severe obesity excludes the diagnosis of CFS.1

Chronic fatigue is a common complaint for which individuals seek medical attention, and CFS is a debilitating illness. The prevalence of CFS has been estimated by the Centers for Disease Control and Prevention (CDC) to be between 2.0 to 7.3 cases per 100 000 in the United States, although these studies have generally made use of passive physician referrals.2 When active surveillance is used, the prevalence in adults may be as high as 0.4%.3 Symptoms of fatigue are common among adolescents but not younger children; in one British study, CFS was the most common cause of prolonged medical leave from school in adolescence.4 In a recent prevalence study that my colleagues and I conducted, CFS was not diagnosed in any child younger than 12 years. In adolescents older than 12 years, the prevalence of CFS was almost 0.15%.5

The etiology of CFS is unknown. Many patients recall a viral infection that seems to have triggered their chronic fatigue. In many instances that viral illness is mononucleosislike or frank infectious mononucleosis. Although most primary Epstein-Barr virus (EBV) infections are asymptomatic, the most common cause of infectious mononucleosis, by far, is EBV. Once infected with EBV, the virus lingers in the host as a lifelong, latent infection that can occasionally reactivate, usually in the setting of immunosuppression. Thus, the idea that EBV could be a cause of CFS is appealing. In 1985, back-to-back articles published in the Annals of Internal Medicine implying that patients with CFS had abnormal serologic responses to EBV gave additional objective credence to this concept.6-7

In 1988, Dr. Warren Andiman and I wrote a review article summarizing the data linking CFS to EBV and found it wanting.8 The main argument against the linkage was that the serologic and immunologic data upon which it was based did not stand up to close scrutiny. Furthermore, a placebo-controlled trial of acyclovir was performed by Straus and colleagues at the National Institutes of Health in two groups of patients suffering from CFS (one group with and one without serologic evidence of an active EBV infection). Both groups had a mean of 7 years of fatigue, and the same (70%) response rate was found in the placebo and the acyclovir groups.9 Finally, in 1991, Matthews et al. demonstrated mat EBV serologies were, by and large, not able to distinguish patients with CFS and "chronic mononucleosis" (defined as patients…

Since 1994, chronic fatigue syndrome (CFS) has been defined for adults in the United States as clinically evaluated, unexplained, persistent, or relapsing fatigue that is of new or definite onset. The fatigue cannot be the result of ongoing exertion, cannot substantially be alleviated by rest, and must result in substantial reduction in previous levels of occupational, educational, social, or personal activities. In addition, four or more of the following need to be present: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; myalgia; arthralgia; headache; unrefreshed sleep; and postexertional malaise lasting more than 24 hours. These symptoms need to have persisted or recurred during 6 or more consecutive months and must not have predated the fatigue.1

The clinical evaluation necessary to diagnose CFS includes a complete history and physical examination and normal screening laboratory tests (including complete blood count, erythrocyte sedimentation rate, alanine aminotransferase, alkaline phosphatase, total protein, albumin, globulin, calcium, phosphorous, glucose, blood urea nitrogen, creatinine, electrolytes, thyroid stimulating hormone, and urinalysis). Any active medical condition, any medical condition that may relapse or not completely resolve with therapy, any past or current major psychiatric disorder, any substance abuse within 2 years of onset, or severe obesity excludes the diagnosis of CFS.1

Chronic fatigue is a common complaint for which individuals seek medical attention, and CFS is a debilitating illness. The prevalence of CFS has been estimated by the Centers for Disease Control and Prevention (CDC) to be between 2.0 to 7.3 cases per 100 000 in the United States, although these studies have generally made use of passive physician referrals.2 When active surveillance is used, the prevalence in adults may be as high as 0.4%.3 Symptoms of fatigue are common among adolescents but not younger children; in one British study, CFS was the most common cause of prolonged medical leave from school in adolescence.4 In a recent prevalence study that my colleagues and I conducted, CFS was not diagnosed in any child younger than 12 years. In adolescents older than 12 years, the prevalence of CFS was almost 0.15%.5

The etiology of CFS is unknown. Many patients recall a viral infection that seems to have triggered their chronic fatigue. In many instances that viral illness is mononucleosislike or frank infectious mononucleosis. Although most primary Epstein-Barr virus (EBV) infections are asymptomatic, the most common cause of infectious mononucleosis, by far, is EBV. Once infected with EBV, the virus lingers in the host as a lifelong, latent infection that can occasionally reactivate, usually in the setting of immunosuppression. Thus, the idea that EBV could be a cause of CFS is appealing. In 1985, back-to-back articles published in the Annals of Internal Medicine implying that patients with CFS had abnormal serologic responses to EBV gave additional objective credence to this concept.6-7

In 1988, Dr. Warren Andiman and I wrote a review article summarizing the data linking CFS to EBV and found it wanting.8 The main argument against the linkage was that the serologic and immunologic data upon which it was based did not stand up to close scrutiny. Furthermore, a placebo-controlled trial of acyclovir was performed by Straus and colleagues at the National Institutes of Health in two groups of patients suffering from CFS (one group with and one without serologic evidence of an active EBV infection). Both groups had a mean of 7 years of fatigue, and the same (70%) response rate was found in the placebo and the acyclovir groups.9 Finally, in 1991, Matthews et al. demonstrated mat EBV serologies were, by and large, not able to distinguish patients with CFS and "chronic mononucleosis" (defined as patients with CFS and EBV serologic abnormalities or patients with CFS whose illness was documented to have begun after heterophile-positive infectious mononucleosis) from those with CFS alone. Matthews et al. found a high degree of psychiatric morbidity in both groups they studied;10 the 70% placebo-response rate in the group studied by Straus et al.9 was also consistent with the concept of CFS having a psychological component. Because of these data, the terms "chronic mononucleosis" and "chronic Epstein-Barr virus infection" are no longer used by the CDC, and serologic testing for EBV is not one of the tests required to rule in or rule out a diagnosis of CFS.1

Nevertheless, the relationship among EBV, psychiatric comorbidity, and CFS remains controversial for several reasons: We and Matthews recognized that there are rare patients with what is termed "severe" or "chronic active" EBV infection, who suffer from dramatic clinical illnesses (eg, pneumonia, hepatitis, or uveitis) with cytopenias and grossly elevated EBV serologies. And, in a Matthews et al. study,10 there were more patients in the "chronic mononucleosis" group whose fatiguing illness began after an "influenza-like" episode and who met the diagnostic criteria for CFS (ie, they were less likely to be excluded due to a psychiatric comorbidity than patients not in the "chronic mononucleosis" group).

Since publication of the revised CDC criteria for CFS, three somewhat conflicting studies have been published attempting to sort out the relationships (if any) among EBV, psychological comorbidity, and CFS. Buchwald et al. followed a population-based cohort of patients greater than 16 years old without chronic medical conditions for 6 months after serologically confirmed infectious mononucleosis to determine how commonly patients failed to recover and whether there were any demographic, clinical, or psychological factors associated with delayed recovery. At 6 months, 12% of patients had not fully recovered; these individuals often reported fatigue and impaired functioning, and thus resembled patients with CFS. The only factors that correlated with failure to recover completely were being female, having better family support, and having more previous threatening life events.11 The authors speculated that having a more supportive environment might have allowed the patient to maintain a sick role for a longer period of time. The fact that patients who failed to recover had had more previous threatening life events seemed to correlate with older literature showing that patients with "poor ego strength" took longer to recover from infectious mononucleosis.12

White and colleagues assessed patients 16 to 65 years of age with either glandular fever (the British term for infectious mononucleosis) or an upper respiratory tract infection (URI) for the development of fatigue. Almost half of their patients with glandular fever were EBV seronegative. The major causes of glandular fever other than EBV were hepatitis A, influenza B, adenovirus, and Streptococcus. All interviews were conducted blinded to the patient's cohort. Nine percent of subjects with glandular fever, whether caused by EBV or a different etiologic agent, were fatigued and complained of excessive sleeping at 6 months, compared to none in the URI group, and symptoms appeared to be worse in the EBV-associated glandular fever group. While there was no difference in the number of stressful life events in the previous 6 months among the three groups (glandular fever associated with EBV, glandular fever not associated with EBV, and URI), the authors did not report if this was the case with those who went on to develop fatigue. There was an association with fatigue at 6 months and the development of depression in patients who had EBV-associated glandular fever.

Although there was no difference in psychological morbidity at onset among the three groups, again the authors did not report whether those who went on to develop fatigue had demonstrated greater psychological morbidity at the onset of illness. The authors concluded that postinfectious fatigue was a demonstrable entity following glandular fever and that it was associated with depression.13 Additional data from these three cohorts, recently reported, show that a history of mood disorders, spending a lot of time in bed at disease onset, and decreased physical fitness were also predictors of CFS. The authors noted that because physical deconditioning was a predictor of CFS, an early return to physical activity might be beneficial.14

Wessley et al. performed a cohort study of patients 18 to 45 years of age who visited their doctor either for a systemic infection or for some other reason; they did not specifically search for EBV as the etiologic agent for any of the systemic infections. There was no greater fatigue at onset or after 6 months in either cohort, but those who complained of fatigue at 6 months were more likely to have had fatigue at onset and psychological distress before presentation. Thus, these authors could not document a postinfectious fatigue syndrome following systemic infection in general.15

In summary, whether EBV infection can cause CFS is still controversial. There is no confirmed evidence of an abnormal infection with or immunologic response to EBV in patients with CFS.810 Wessley et al. could not document a "postsystemic infection" fatigue syndrome, but Buchwald et al. and White et al. were able to do so when the inciting illness was EBV-related.11'1315 One reasonable explanation for this discrepancy is that most of the systemically infected patients in the study of Wessley et al. did not have evidence of EBV infection, but rather influenza-like illnesses or mere URIs; thus, finding an increased prevalence of CFS among that population would not have been expected, especially in view of the fact that patients with URIs formed the control group for the study of White et al. where CFS was not found.

Even if EBV can cause a fatigue syndrome 6 months following infection, it is unclear whether this represents CFS as it is commonly thought of (a debilitating disease that persists for years) or whether this simply represents a patient who takes somewhat longer than usual to recover from infectious mononucleosis; this sort of fatigue syndrome, although meeting CDC criteria, would likely then represent only a minor subset of CFS, likely to resolve spontaneously in a relatively shorter period of time. The fact that White and colleagues did not find a relationship between patients fatigued after glandular fever and psychological disorders, in contrast to many other studies of CFS where such a correlation has been demonstrated,16 might also argue that fatigue following infectious mononucleosis is distinct from other cases of CFS. It is also interesting to note that, even though substantial impairment in short-term memory or concentration is part of the CDC definition of CFS,1 when tested, patients with postglandular fever fatigue did not have particular difficulty processing information. Thus it is the perception of poor effort and ability to concentrate that is being reported, rather than any true decreased ability.17 This might also imply either that CFS following infectious mononucleosis is different from CFS in general, or bolster the importance of psychological issues in the pathophysiology of CFS. Clearly, longer follow-up of patients recovering from infectious mononucleosis is necessary to resolve these issues.

Finally, there has been no study of the outcome of EBV infection in adolescents, with an emphasis on identifying those at risk for developing CFS. Adolescence is a time of rapid change in the individual's growth, sleep patterns, and sexual, hormonal, and psychological development. It is likely that the reason CFS is recognized in adolescents but not younger children is that one of these developmental processes can go awry, leading to CFS. Studying adolescents following EBV infection undoubtedly will prove important for delineating the pathophysiology of both infectious mononucleosis and CFS. More research will clearly be needed before the relationship of CFS and EBV infection is sorted out.

REFERENCES

1. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994;121:953-959.

2. Gunn WJ, Connell DB, Randall B. Epidemiology of chronic fatigue syndrome: The Centers for Disease Control study. In: Bock G, Whelan J, eds. Chronic Fatigue Syndrome. N.Y. Wiley 1993; pp. 83-101.

3. Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159:2129-2137.

4. Dowsett EG, Colby J. Long-term absence due to ME/CFS in UK schools. Journal of Chronic Fatigue Syndrome. 1997;3:29-42.

5. Jordan KM, Mears CJ, Katz BZ, et al. Prevalence of pediatric chronic fatigue syndrome in a communitybased sample. Ms. submitted.

6. Jones JF, Ray G, Minnich LL, et al. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med. 1985;102:1-6.

7. Straus SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of EpsteinBarr virus infection. Ann Intern Med. 1985;102:7-16.

8. Katz BZ, Andiman WA. Chronic fatigue syndrome. J Pediatr. 1988;113:944-947.

9. Straus SE, Dale JK, Tobi M, et al. Acyclovir treatment of the chronic fatigue syndrome: lack of efficacy in a placebo-controlled trial. N Engl J Med. 1988;319:1692-1698.

10. Matthews DA, Lane TJ, Manu P. Antibodies to Epstein-Barr virus in patients with chronic fatigue. South Med J. 1991;84:832-840.

11. Buchwald DS, Rea TD, Katon WJ, Russo JE, Ashley RL. Acute infectious mononucleosis: characteristics of patients who report failure to recover. Am J Med. 2000;109:531-537.

12. Greenfield NS, Roessler R, Crosley AP. Ego strength and length of recovery from infectious mononucleosis. J Nerv Ment Dis. 1959;128:125-128.

13. White PD, Thomas JM, Amess J, et al. Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever. Br J Psychiatr. 1998;173:475-481.

14. White PD, Thomas JM, Kangro HO, et al. Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet. 2001 ;358: 1946-1954.

15. Wessely S, Chalder T, Hirsch S, Pawlikowska T, Wallace P, Wright DJM. Postinfectious fatigue: prospective cohort study in primary care. Lancet. 1995;345:1333-1338.

16. White PD, Grover SA, Kangro HO, Thomas JM, Amess J, Clare AW. The validity and reliability of the fatigue syndrome that follows glandular fever. Psychol Med. 1995;25:917-924.

17. White PD, Dash AR, Thomas JM. Poor concentration and the ability to process information after glandular fever. J Psychosom Res. 1998;44:269-278.

10.3928/0090-4481-20021101-10

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