- Email: [email protected]
INTERFERON PRODUCTION IN POSTVIRAL FATIGUE SYNDROME
101
psychiatric upset are being excluded. The greatest challenge facing researchers will be to distinguish fatigue as a symptom of depressive illness, depression as a consequence of chronic fatigue, and depression as an integral part of a new disease entity. Lloyd’s criteria, as they stand, could mean that this issue would remain unexplored. We must keep an open mind on aetiology. Though disordered cell-mediated immunity and persisting viral infection have recently attracted attention they are by no means universal. 5.6 Inclusion of these laboratory findings in a case definition presupposes that immunological dysfunction is of primary aetiological relevance. It is important that immunologists do not deflect attention away from the wider aspects of the chronic fatigue/postviral fatigue syndrome, which is increasingly being seen in primary care settings. ANTHONY S. DAVID SIMON WESSELY ANTHONY J. PELOSI
Institute of Psychiatry,
London SE5 8AF
1. David AS, Wessely S, Pelosi AJ. Postviral fatigue syndrome: Time for a new approach. Br Med J 1988; 296: 696-99. 2. Fegan KG, Behan PO, Bell EJ. Myalgic encephalomyelitis: Report of an epidemic. J R Coll Gen Pract 1983; 33: 335-37. 3. Keighley BD, Bell EJ. Sporadic myalgic encephalomyelitis in a rural practice. J R Coll Gen Pract 1983; 33: 339-41. 4. Ramsay AM. Postviral fatigue syndrome: the saga of Royal Free disease. London: Gower Medical; 1986 5. Behan PO, Behan WMH, Bell EJ. The postviral syndrome: an analysis of the findings in 50 cases. J Infect 1985; 10: 211-22. 6. Yousef GE, Bell EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988; i: 146-50
SIR,-I deplore the suggestion of adding yet another non-specific
long list of those already used to describe the "myalgic encephalomyelitis" syndrome. Recent researchl,2has shown this entity results from persistent enteroviral infection, mainly due to coxsackie and echoviruses. Other fatigue states lacking the cardinal clinical and laboratory features of ME may follow influenza, measles, and chickenpox, for example, or accompany herpesvirus infections such as infectious mononucleosis. The introduction of "chronic fatigue syndrome" to designate ME does nothing to indicate the unique epidemiological, geographical, clinical, and laboratory findings in ME and can only add to the confusion surrounding the diagnosis, therapy, and prognosis of the condition. synonym to the
Microbiology Department, Southend Hospital, Westcliff on-Sea, Essex SS0 0RY
E. G. DOWSETT
1. Yousef GE, Bell
EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988; i: 146-50. 2 Dowsett EG Human enteroviral infections. J Hosp Inf 1988; 11: 103-15.
INTERFERON PRODUCTION IN POSTVIRAL FATIGUE SYNDROME
SIR,-Postviral
fatigue
syndrome
(PVS)
or
myalgic
encephalomyelitis may be due to persistence of a viral pathogen.1 The symptoms in many cases resemble those associated with therapeutic administration of interferon (IFN)2 and chronic stimulation of the endogenous IFN system might explain the fatigue and malaise of PVS. Alternatively symptoms may occur in individuals who respond to viral stimulation by production of more IFN than non-sufferers. Elevated circulating IFN levels have been sought unsuccessfully in affected patients3 but virus-stimulated IFN levels have not been measured. One problem with studies in patients with PVS is the lack of an objective clinical marker to distinguish genuine cases from patients with other complaints such as minor neuropsychiatric disease. In children this is less of a problem. We investigated the in-vitro IFN response of a sample of children from a school in Aberystwyth where an outbreak of PVS among both children and some immediate family members was associated with positive neutralising antibody responses against coxsackie B4 m all cases. Alpha IFN production was measured in response to
production by peripheral blood mononuclear cells. parents of one patient; x children.
Interferon o
=
=
Sendai virus.4 Briefly peripheral blood mononuclear cells were isolated by ’Ficoll/Hypaque’ density centrifugation, washed with RPMI (Flow) and resuspended in the same medium with 10% fetal calf serum and 100 haemagglutinating units/ml of Sendai virus. 24 h later the supernatants were tested for alpha IFN production by immunoradiometric assay (Boots Celltech). Eight affected children were tested, four with ongoing symptoms of at least 3 months’ duration and four who had recovered after a minimum of 5 months’ illness. The affected parents of one child were also tested. The symptoms were typical of PVS (profound malaise and easy fatiguability). Individuals complained of chest pain or sore throats, one had a grand mal convulsion and heart arrhythmias, another had transient diplopia; and lymphadenopathy was detected in some patients. A control group of four age-matched classmates was also tested, two of whom had positive neutralising titres to coxsackie B4. The results are shown in the figure. Affected children assessed with or without their parents produced significantly more alpha IFN in vitro than controls. Children with symptoms and recovered children did not differ significantly in their ability to produce alpha IFN. Although the numbers are small this finding is consistent with these individuals having an excessive IFN response to viral stimulation either as a result of persistent infection or as a genetic characteristic. It is also consistent with the clinical observation in the children that intercurrent viral infections led to exacerbation of their symptoms. We thank the Public Health Laboratories the serological assays.
Departments of Infectious Diseases and Virology, Royal Free Hospital, London NW3 2QC: and Department of Paediatrics, Bronglais Hospital, Aberystwyth
at
Epsom and Cardiff for doing A. M. L. LEVER* D. M. LEWIS B. A. BANNISTER M. FRY N. BERRY
*Present address: Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. 1. Yousef
GE, Bell EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988, i: 146-49 2. McDonald EM, Mann AH, Thomas HC. Interferons and mediators of psychiatric morbidity: an investigation in a trial of recombinant alpha interferon in hepatitis B Lancet 1987; ii: 1175-78. Wakefield D. Interferon and myalgic encephalomyelitis. Lancet 1988, i. 471 4. Ikeda T, Lever AML, Thomas HC. Evidence for a deficiency of interferon production in patients with chronic hepatitis B virus infection acquired in adult life. Hepatology 1986; 6: 962-65. carriers.
3.
Lloyd A, AbiHanna D,
psychiatric upset are being excluded. The greatest challenge facing researchers will be to distinguish fatigue as a symptom of depressive illness, depression as a consequence of chronic fatigue, and depression as an integral part of a new disease entity. Lloyd’s criteria, as they stand, could mean that this issue would remain unexplored. We must keep an open mind on aetiology. Though disordered cell-mediated immunity and persisting viral infection have recently attracted attention they are by no means universal. 5.6 Inclusion of these laboratory findings in a case definition presupposes that immunological dysfunction is of primary aetiological relevance. It is important that immunologists do not deflect attention away from the wider aspects of the chronic fatigue/postviral fatigue syndrome, which is increasingly being seen in primary care settings. ANTHONY S. DAVID SIMON WESSELY ANTHONY J. PELOSI
Institute of Psychiatry,
London SE5 8AF
1. David AS, Wessely S, Pelosi AJ. Postviral fatigue syndrome: Time for a new approach. Br Med J 1988; 296: 696-99. 2. Fegan KG, Behan PO, Bell EJ. Myalgic encephalomyelitis: Report of an epidemic. J R Coll Gen Pract 1983; 33: 335-37. 3. Keighley BD, Bell EJ. Sporadic myalgic encephalomyelitis in a rural practice. J R Coll Gen Pract 1983; 33: 339-41. 4. Ramsay AM. Postviral fatigue syndrome: the saga of Royal Free disease. London: Gower Medical; 1986 5. Behan PO, Behan WMH, Bell EJ. The postviral syndrome: an analysis of the findings in 50 cases. J Infect 1985; 10: 211-22. 6. Yousef GE, Bell EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988; i: 146-50
SIR,-I deplore the suggestion of adding yet another non-specific
long list of those already used to describe the "myalgic encephalomyelitis" syndrome. Recent researchl,2has shown this entity results from persistent enteroviral infection, mainly due to coxsackie and echoviruses. Other fatigue states lacking the cardinal clinical and laboratory features of ME may follow influenza, measles, and chickenpox, for example, or accompany herpesvirus infections such as infectious mononucleosis. The introduction of "chronic fatigue syndrome" to designate ME does nothing to indicate the unique epidemiological, geographical, clinical, and laboratory findings in ME and can only add to the confusion surrounding the diagnosis, therapy, and prognosis of the condition. synonym to the
Microbiology Department, Southend Hospital, Westcliff on-Sea, Essex SS0 0RY
E. G. DOWSETT
1. Yousef GE, Bell
EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988; i: 146-50. 2 Dowsett EG Human enteroviral infections. J Hosp Inf 1988; 11: 103-15.
INTERFERON PRODUCTION IN POSTVIRAL FATIGUE SYNDROME
SIR,-Postviral
fatigue
syndrome
(PVS)
or
myalgic
encephalomyelitis may be due to persistence of a viral pathogen.1 The symptoms in many cases resemble those associated with therapeutic administration of interferon (IFN)2 and chronic stimulation of the endogenous IFN system might explain the fatigue and malaise of PVS. Alternatively symptoms may occur in individuals who respond to viral stimulation by production of more IFN than non-sufferers. Elevated circulating IFN levels have been sought unsuccessfully in affected patients3 but virus-stimulated IFN levels have not been measured. One problem with studies in patients with PVS is the lack of an objective clinical marker to distinguish genuine cases from patients with other complaints such as minor neuropsychiatric disease. In children this is less of a problem. We investigated the in-vitro IFN response of a sample of children from a school in Aberystwyth where an outbreak of PVS among both children and some immediate family members was associated with positive neutralising antibody responses against coxsackie B4 m all cases. Alpha IFN production was measured in response to
production by peripheral blood mononuclear cells. parents of one patient; x children.
Interferon o
=
=
Sendai virus.4 Briefly peripheral blood mononuclear cells were isolated by ’Ficoll/Hypaque’ density centrifugation, washed with RPMI (Flow) and resuspended in the same medium with 10% fetal calf serum and 100 haemagglutinating units/ml of Sendai virus. 24 h later the supernatants were tested for alpha IFN production by immunoradiometric assay (Boots Celltech). Eight affected children were tested, four with ongoing symptoms of at least 3 months’ duration and four who had recovered after a minimum of 5 months’ illness. The affected parents of one child were also tested. The symptoms were typical of PVS (profound malaise and easy fatiguability). Individuals complained of chest pain or sore throats, one had a grand mal convulsion and heart arrhythmias, another had transient diplopia; and lymphadenopathy was detected in some patients. A control group of four age-matched classmates was also tested, two of whom had positive neutralising titres to coxsackie B4. The results are shown in the figure. Affected children assessed with or without their parents produced significantly more alpha IFN in vitro than controls. Children with symptoms and recovered children did not differ significantly in their ability to produce alpha IFN. Although the numbers are small this finding is consistent with these individuals having an excessive IFN response to viral stimulation either as a result of persistent infection or as a genetic characteristic. It is also consistent with the clinical observation in the children that intercurrent viral infections led to exacerbation of their symptoms. We thank the Public Health Laboratories the serological assays.
Departments of Infectious Diseases and Virology, Royal Free Hospital, London NW3 2QC: and Department of Paediatrics, Bronglais Hospital, Aberystwyth
at
Epsom and Cardiff for doing A. M. L. LEVER* D. M. LEWIS B. A. BANNISTER M. FRY N. BERRY
*Present address: Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. 1. Yousef
GE, Bell EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988, i: 146-49 2. McDonald EM, Mann AH, Thomas HC. Interferons and mediators of psychiatric morbidity: an investigation in a trial of recombinant alpha interferon in hepatitis B Lancet 1987; ii: 1175-78. Wakefield D. Interferon and myalgic encephalomyelitis. Lancet 1988, i. 471 4. Ikeda T, Lever AML, Thomas HC. Evidence for a deficiency of interferon production in patients with chronic hepatitis B virus infection acquired in adult life. Hepatology 1986; 6: 962-65. carriers.
3.
Lloyd A, AbiHanna D,