What’s new in human herpesvirus-6? Clinical immunopathology of the HHV-6 infection

Abstract:

Human herpesvirus-6 (HHV-6), formerly known as human B-lymphotropic virus (HBLV), was first isolated in 1986 from patients with lymphoproliferative disorders and AIDS. Antibody prevalence against HHV-6 varies between about 60-80% indicating a widespread latent infection.

Although HHV-6 infects in vivo primarily T-lymphocytes, it is associated with similar diseases as in infection with Epstein-Barr virus (EBV), a clearly B-lymphotropic virus. Reactivation of latent HHV-6 infection in patients with subnormal host defense may cause persistent active infection with so-called postinfectious chronic fatigue syndrome (PICFS) or may contribute to other pathologies such as immune deficiency itself, autoimmune disorders or progressive lymphoproliferation.

Coinfection of CD4 cells by HHV-6 and human immunodeficiency virus (HIV 1) in AIDS patients can aggravate HIV-induced acquired immune deficiency. These characteristics of the only recently detected new virus justify further intense investigation.

 

Source: Krueger GR, Sander C.  What’s new in human herpesvirus-6? Clinical immunopathology of the HHV-6 infection. Pathol Res Pract. 1989 Dec;185(6):915-29. http://www.ncbi.nlm.nih.gov/pubmed/2559396

 

Myalgic encephalomyelitis: postviral fatigue and the heart

Note: This letter appeared in the November 11, 1989 issue of the British Medical Journal.

 

SIR, The controversial subject of myalgic encephalomyelitis has surfaced once more,(1) and I would like to contribute to the debate about its viral origins.

Persistent virus infections impair the specialised functions of cells. These include the synthesis of specific products such as heavy and light myosin chains, melanin, hormones, and immune functions.(2) Evidence of persistent enterovirus infection has been found in both dilated cardiomyopathy,(3-5) an organic disease discussed at a recent symposium,(3) and the more controversial myalgic encephalomyelitis.(6,7)

In murine myocarditis induced by Coxsackie viruses, more severe and lasting disease is associated with immunopathological processes, which include virus specific, cross reactive, and autoimmune reactions.(3, 8, 9) In Coxsackie viral myocarditis and cardiomyopathy of humans the antibodies that cross react with Coxsackie B antigens are reported.(3) Serum samples from patients with.cardiomyopathy may react with cardiac ,B adrenoreceptors, with mitochondrial ADP/ATP carriers, and with cell surface protein of the calcium channel causing calcium overload of myocytes and consequent dysfunction.(3) Thus a complex pattern of pathogenic mechanisms is emerging to explain dilated cardiomyopathy, which was formerly considered to be idiopathic but is now recognised as a late sequel of a proportion of cardiac infections with certain enteroviruses, particularly those of the Coxsackie B group. This does not exclude the possible role of other viruses-for example, arboviruses where these are prevalent-as initiators of such pathogenic processes.

It seems likely that similar immunological and metabolic disturbances in myalgic encephalomyelitis may also result from chronic infection, usually with enteroviruses, providing the organic basis of the postviral fatigue syndrome.(10) This condition is characterised by severe fatiguability and recuperation through rest. The myocardium, however, cannot rest-except terminally. Does “postviral dilated cardiomyopathy” represent the result of postviral fatigue syndrome of the unresting heart?

~NORMAN R GRIST Communicable Diseases (Scotland) Unit, Ruchill Hospital, Glasgow G20 9NB

 

References

1 Harris F, Taitz LS. Damaging diagnoses of myalgic encephalitis in children. BrMedj 1989;299:790. (23 September.)

2 Southern P, Oldstone MBA. Medical consequences of persistent viral infection. N Englj Med 1986;314:359-67.

3 Schultheiss HP, ed. New concepts in viral heart disease. Berlin: Springer, 1988.

4 Bowles NE, Richardson PJ, Olsen EGJ, Archard LC. Detection of Coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1986;i: 1120-3.

5 Kandolf R, Kirschner P, Amies D, et al. Enteroviral heart disease: diagnosis by in situ hybridization. In: Schultheiss HP, ed. New concepts in viral heart disease. Berlin: Springer, 1988:337-48.

6 Yousef GE, Mann GF, Smith DG, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988;i: 146-50.

7 Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatinine kinase. J R Soc Med 1988;81:326-9.

8 Huber SA. The role of immune mechanisms in pathogenesis. In: Bendinelli M, Friedman H, eds. Coxsackieviruses, a general update. New York: Plenum, 1988:103-16.

9 Beisel KW, Rose NR. Relationship of coxsackievirus to cardiac autoimmnunity. In: Bendinelli M, Friedmann H, eds. Coxsackievinruses, a general update. New York: Plenum, 1988:271-92.

10 Behan PO, Behan WMH, Bell EJ. The post-viral fatigue syndrome-an analysis of the findings in 50 cases. J Infect 1985;10:21 1-22.

 

Source:  N. R. Grist. Myalgic encephalomyelitis: postviral fatigue and the heart. BMJ. 1989 Nov 11; 299(6709): 1219. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1838100/pdf/bmj00258-0049b.pdf

 

The chronic fatigue syndrome: definition, current studies and lessons for fibromyalgia research

Abstract:

Chronic fatigue syndrome (CFS) is characterized by chronic, debilitating fatigue lasting greater than 6 months. Frequent chronic and recurrent findings include fever, pharyngitis, myalgias, adenopathy, arthralgias, difficulties in cognition and disorders of mood. In the majority of patients, the illness starts suddenly with an acute, “flu-like” illness.

The following laboratory abnormalities are seen with some frequency, although none are seen in all patients: lymphocytosis, atypical lymphocytosis, monocytosis, elevation of hepatocellular enzymes, low levels of antinuclear antibodies, varying levels of antithyroid antibodies, partial hypergammaglobulinemia, elevated CD4:CD8 ratio, decreased cytolytic activity of natural killer cells, and low levels of immune complexes. Clinical and serologic studies suggest an association of CFS with all of the human herpesviruses, particularly Epstein-Barr virus (EBV) and the recently discovered human B lymphotropic virus (HBLV) or human herpesvirus 6; neither EBV nor HBLV has yet been shown to play a causal role in the illness.

Preliminary evidence suggests that many of these features of CFS also are seen in patients with fibromyalgia.

 

Source: Komaroff AL, Goldenberg D. The chronic fatigue syndrome: definition, current studies and lessons for fibromyalgia research. J Rheumatol Suppl. 1989 Nov;19:23-7. http://www.ncbi.nlm.nih.gov/pubmed/2691680

 

Nonrestorative sleep and symptoms after a febrile illness in patients with fibrositis and chronic fatigue syndromes

Abstract:

This review summarizes the physiologic and clinical evidence that shows nonrestorative sleep to be associated with chronic fatigue and diffuse myalgia after a flulike illness. Such a febrile illness may trigger alteration in sleep-wake brain and immune functions in patients with fibrositis or chronic fatigue syndromes.

 

Source: Moldofsky H. Nonrestorative sleep and symptoms after a febrile illness in patients with fibrositis and chronic fatigue syndromes. J Rheumatol Suppl. 1989 Nov;19:150-3. http://www.ncbi.nlm.nih.gov/pubmed/2691676

 

Liver extract-folic acid-cyanocobalamin vs placebo for chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome is a recently defined entity for which clinical criteria were proposed by the Centers for Disease Control, Atlanta, Ga. A frequently advocated treatment in Southern California is an injectable solution of bovine liver extract containing folic acid and cyanocobalamin (LEFAC).

We conducted a double-blind, placebo-controlled, crossover trial of intramuscular LEFAC in 15 patients who met the Centers for Disease Control criteria for chronic fatigue syndrome. Although patients responded to placebo and LEFAC by several criteria of functional status, no significant difference was apparent between response to placebo and that to LEFAC. The placebo response appeared to be strong.

 

Source: Kaslow JE, Rucker L, Onishi R. Liver extract-folic acid-cyanocobalamin vs placebo for chronic fatigue syndrome. Arch Intern Med. 1989 Nov;149(11):2501-3. http://www.ncbi.nlm.nih.gov/pubmed/2684076

 

Fibromyalgia and its relation to chronic fatigue syndrome, viral illness and immune abnormalities

Abstract:

Fibromyalgia and chronic fatigue syndrome have similar clinical and demographic features. We found that most patients with chronic fatigue syndrome have a tender point examination similar to patients with fibromyalgia. Similar pathophysiologic mechanisms are also being explored in each syndrome, including a potential role for viral induced immune dysfunction.

 

Source: Goldenberg DL. Fibromyalgia and its relation to chronic fatigue syndrome, viral illness and immune abnormalities. J Rheumatol Suppl. 1989 Nov;19:91-3. http://www.ncbi.nlm.nih.gov/pubmed/2607516

 

Chronic fatigue syndrome: review of the literature

Abstract:

Chronic fatigue syndrome, previously known as chronic mononucleosis or post-infectious fatigue, is a poorly understood illness characterized by chronic debilitating fatigue, recurrent flu-like symptoms, and few clinical or laboratory abnormalities. Attention was briefly focused on the Epstein-Barr virus (EBV) as a causal agent, but that hypothesis is now in serious doubt. While a significant incidence of psychiatric illness has been demonstrated among patients with the chronic fatigue syndrome, there is also evidence of subtle immune system abnormalities, leading some researchers to postulate a multi-factorial psycho-immune cause.

 

Source: Turgeon SA. Chronic fatigue syndrome: review of the literature. Can Fam Physician. 1989 Oct;35:2061-5. http://www.ncbi.nlm.nih.gov/pubmed/21249084

Note: You can read the full article here:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2280912/

 

Immunological abnormalities in the chronic fatigue syndrome

Abstract:

The chronic fatigue syndrome is a disorder of unknown aetiology which is characterized by debilitating fatigue. Recent evidence has suggested that viruses may persist in the tissues of patients with chronic fatigue syndrome. A concurrent immunological disturbance is likely to be associated with the persistence of viral antigens.

Therefore, the humoral and cellular immunity of 100 patients who were suffering from chronic fatigue syndrome and that of 100 healthy, age- and sex-matched control subjects were compared. This study documents the frequent occurrence of abnormalities within the cellular and humoral immune systems of patients with well-defined chronic fatigue syndrome. Disordered immunity may be central to the pathogenesis of chronic fatigue syndrome.

In patients with chronic fatigue syndrome, a significant (P less than 0.01) reduction was found in the absolute number of peripheral blood lymphocytes in the total T-cell (CD2), the helper/inducer T-cell (CD4) and the suppressor/cytotoxic T-cell (CD8) subsets. A significant (P less than 0.001) reduction also was found in T-cell function, which was measured: in vivo by delayed-type hypersensitivity skin-testing (reduced responses were recorded in 50 [88%] of 57 patients); and in vitro by phytohaemagglutinin stimulation. Reduced immunoglobulin (Ig) levels were common (56% of patients), with the levels of serum IgG3- and IgG1-subclasses particularly (P less than 0.05) affected.

 

Source: Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Immunological abnormalities in the chronic fatigue syndrome. Med J Aust. 1989 Aug 7;151(3):122-4. http://www.ncbi.nlm.nih.gov/pubmed/2787888

 

Chronic fatigue syndrome

Note: This letter appeared in the February 15, 1989 edition of the Canadian Medical Association Journal in response to Dr. Ray Holland’s letter of August 1, 1988 . You can read Dr. Holland’s letter as well as Dr. Salit’s response here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268060/?page=1 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268061/

 

A useful supplement to the letters about chronic fatigue syndrome from Drs. Ray G.L. Holland (Can Med Assoc J 1988; 139: 198-199) and Irving E. Salit (ibid: 199) might be the working case definition of this syndrome proposed by Holmes and colleagues,(1) of the US Centers for Disease Control.

Holmes and colleagues have suggested that a case of chronic fatigue syndrome must fulfill two major criteria: that it consist of persistent or relapsing debilitating fatigue of new onset that has reduced the patient’s activity level to below 50% of normal for at least 6 months and that other clinical conditions that may produce similar symptoms have been excluded by thorough evaluation.

In addition, there must be 6 or more of 11 minor features (mild fever, sore throat, painful neck or axillary lymph nodes, generalized muscle weakness, myalgia, easy fatigability, headaches, migratory arthralgia, neuropsychologic complaints, sleep disturbances and rapid onset of the main symptom complex), along with 2 or more of 3 physical findings (low-grade fever, nonexudative pharyngitis, and palpable or tender neck or axillary lymph nodes).

We have found that many people with this clinical picture have concomitant food and chemical sensitivities and may have an intracellular magnesium deficiency in spite of normal serum levels.(2) This is probably the result of the inordinate amount of this essential mineral that they spill in their urine. The generalized aching and muscle tightness these patients experience can frequently be eased by appropriate magnesium (and calcium) supplementation, presumably because of the reduction of neuromuscular irritability.

We were therefore greatly surprised to learn in a later letter from Dr. Holland (ibid: 706) that “it would be nontherapeutic to offer such a patient empathy” and that we must not condone a belief in a “nonexistent disease”.

These statements are difficult to reconcile with the immunologic abnormalities,(3,5) disorders of muscle metabolism (5) and abnormal results of muscle biopsy (5) found in such patients. Specific flow cytometric measurements of lymphocyte dysfunction may prove to be a means of characterizing and diagnosing this syndrome.(6)

Holland, who reminds us of the dictum “Primum non nocere”, should take his own advice to heart. We are only beginning to unravel the secrets of this debilitating condition, which is very likely caused by a combination of triggering factors, including infective and environmental influences.

This condition, called myalgic encephalomyelitis in Britain, is most certainly not psychosomatic, in spite of the frequently associated emotional turmoil.

Most normal healthy people will react “emotionally” when their finances, lifestyle and health are shattered by a debilitating condition, and they may well respond to a sympathetic approach to their total well-being.

~Gerald H. Ross, MD, CCFP, Fellow in environmental medicine

~Jean A. Monro, MB, BS, LRCP, MRCS, Medical director Breakspear Hospital for Allergy and Environmental Medicine Abbots Langley, England

 

References

  1. Holmes GP, Kaplan JE, Gantz NM et al: Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108: 387-389
  2. Rea WJ, Johnson AR, Smiley RE et al: Magnesium deficiency in patients with chemical sensitivity. Clin Ecol 1986; 4:17-20
  3. Tosato G, Straus SE, Werner H et al: Characteristic T cell dysfunction in patients with chronic active EpsteinBarr virus infection (chronic infectious mononucleosis). J Immunol 1985; 134:3082-3088
  4. Kuis W, Roord JJ, Zegers BJM et al: Heterogeneity of immune defects in three children with a chronic active Epstein-Barr virus infection. J Clin Immunol 1985; 5: 377-385
  5. Behan PO, Behan WMH, Bell EJ: The postviral fatigue syndrome – an analysis of the findings in 50 cases. J Infect 1985; 10: 211-222
  6. Johnson TS, Gratzner HG, Steinbach T et al: Flow cytometric measurement of lymphocyte immune function in chronic fatigue syndrome patients. Presented at 22nd scientific session, American Academy of Environmental Medicine, Lake Tahoe, Nev, Oct 22-25, 1988

Source: Gerald H. Ross and Jean A. Monro. Chronic fatigue syndrome. CMAJ. 1989 Feb 15; 140(4): 361. PMCID: PMC1268650 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268650/?page=1

 

“Virus of the year”?

Note: This letter by Dr. Ray Holland, published in the Canadian Medical Association Journal on August 1, 1988, generated several responses. Dr. Salit’s response appears below. 

 

There appears to be a scarcity of information in medical and psychiatric journals (although not in the lay press) on what was initially termed the Epstein-Barr syndrome but was later renamed chronic fatigue syndrome because it can be caused by infective agents other than the Epstein-Barr virus (EBV). For example, the last article on the subject in CMAJ appeared in 1985.(1) There the syndrome, consisting of fatigue, depression, myalgia, muscle weakness, headaches and paresthesia, was named sporadic postinfectious neuromyasthenia (PIN), a term preferable to chronic fatigue syndrome because it is not ambiguous and because the condition can be of both infectious and psychologic origin.

Presumably the condition was named chronic fatigue syndrome because fatigue is the main presenting symptom, but in psychologic depression fatigue can also be the main manifestation. It is unfortunate, therefore, that the American Medical Association appears to have adopted such an ambiguous term while lamenting that the lack of a definitive diagnosis leaves both patients and health care providers frustrated.(2)

To confuse matters further, the media have labelled the condition chronic fatigue in overachievers or Yuppie flu. In fact, traditional psychiatrists have for some timed called chronic fatigue in overachievers anhedonia (inability to experience pleasure), which, if untreated, may lead to fatigue, depression and the other symptoms mentioned.

While the clinical picture may be ambiguous, the serologic findings may be more so, even when interpreted along with the clinical findings, because those exposed to EBV may have positive serologic results but no chronic sequelae, in much the same way as most people exposed to tuberculosis have subclinical infection. How high does the antibody titre have to be for a definite diagnosis of chronic fatigue syndrome in those who were apparently well before the acute viral attack, even if one excludes those with a previous psychiatric history, as Salit did? One must suspect that a high antibody titre that does not correlate with the clinical findings implies a psychologic origin, as does a low antibody titre. However, it appears that many patients who are told that they have positive but inconclusive serologic results of testing for EBV are choosing to believe that they have the disease. The local medical laboratory has informed me that there is not even a range of titres for EBV but that patients must find their own range by correlating values with how they feel! The media seem to infer that cases with negative results of EBV testing either have not been diagnosed because of lack of the necessary technology or have been misdiagnosed, because there is no mention that the cause may be psychologic.

Such a state of affairs is only too likely in today’s society, in which people are actually healthier than ever before but are more disease conscious and in which the media have a lively interest in medical matters. Rather than an epidemic of the disease, there appears to be an epidemic of the diagnosis, such that EBV should be named “virus of the year”.

May primum non nocere prevail as high-tech medicine continues to advance, at an alarming rate.

~Ray G.L. Holland, MD, FRCPC Box 458 Port Colbome, Ont.

References

  1. Salit IE: Sporadic postinfectious neuromyasthenia. Can Med Assoc J 1985; 133: 659-663
  2. Straus SE: EB or not EB – that is the question [E]. JAMA 1987; 257: 2335- 2336

 

[Dr. Salit responds:]

I too believe that the lack of information in medical journals on PIN [postinfectious neuromyasthenia] is a problem. There appears to be confusion about the condition among physicians, granting agencies and medical journals; they are unable to neatly classify the ailment into a nosologic category. The comment has been that the illness is “too vague” or “ill-defined”. This translates into an inability to have studies related to this subject published. Indeed, last year CMAJ rejected my article on immunologic aberrations in PIN, citing similar reasons.

The term chronic fatigue syndrome (1) was probably chosen by US investigators because it is a generic term. In 1985 these investigators thought that the illness was due to EBV; hence the common designation chronic EBV infection.(2) At that time I felt that the illness was induced by many etiologic agents, so I used the term PIN.(3) Most investigators in this area have come around to this way of thinking but have chosen not to use the term PIN.

Dr. Holland indicates that this disease has been acknowledged by psychiatrists in the past under other designations. Indeed, very similar illnesses have been known to different specialists by different names for decades. I have suggested a unifying hypothesis concerning a common pathophysiologic mechanism.(4)

EBV serologic findings have been the most confusing diagnostic aspect of this illness. Some patients after typical acute infectious mononucleosis have a form of chronic mononucleosis that symptomatically resembles PIN.(5) The serologic findings strongly suggest chronic active EBV infection. However, in most cases of PIN the illness probably did not start with acute infectious mononucleosis, and the patients probably do not have continuing active EBV infection. Using a sensitive DNA probe we found that PIN patients were not excreting EBV.(6) Furthermore, there is such extensive overlap between PIN patients and healthy controls that EBV serologic findings cannot be used to make the diagnosis.(7) It is also likely that such patients have moderately elevated titres of antibodies to a variety of other antigens. Most adults in Canada have EBV antibodies from a prior infection. Too often a diagnosis of chronic EBV infection is made on the basis of certain symptoms and the findings of any EBV antibody. This is inappropriate.

Holland says that “there appears to be an epidemic of the diagnosis”. What has become very apparent to me is that there are a large number of people in the community with illnesses that might be included under the rubric PIN. Physicians argue about the existence of this disease, but it is clear to me that PIN patients have an illness (or a deviation from a normal state of health). Despite the fact that we do not understand the disease process that results in this illness, the patients still require appropriate medical care, consisting of empathy, an acknowledgement that they are ill, reassurance that there is an absence of a more severe disease and, finally, guidelines on how best to manage the condition.(4’8’9)

I do not think that primum non nocere should prevail, although I can accept secundum non nocere. First we should show some understanding and compassion.

~ Irving E. Salit, MD, FRCPC Division of Infectious Diseases Toronto General Hospital Toronto, Ont.

References

  1. Holmes GP, Kaplan JE, Gantz NM et al: Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108: 387-389
  2. Jones JF, Ray CG, Minnich LL et al: Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated antiearly antigen antibodies. Ann Intern Med 1985; 102: 1-7 3. Salit IE: Sporadic postinfectious neuromyasthenia. Can Med Assoc J 1985; 133: 659-663
  3. Idem: Chronic EBV infections (postinfectious neuromyasthenia). Med North Am 1987; 10: 1944-1950
  4. Straus SE: The chronic mononucleosis syndrome. J Infect Dis 1988; 157: 405- 412
  5. Salit IE, Diaz-Mitoma F, Walmsley S et al: Absence of Epstein-Barr virus excretion in post-infectious neuromyopathies. Presented at the American Society for Microbiology annual meeting, Miami Beach, May 9, 1988
  6. Buchwald D, Sullivan JL, Komaroff AL: Frequency of “chronic active Epstein-Barr virus infection” in a general medical practice. JAMA 1987; 257: 2303-2307
  7. Salit IE: Post-infectious fatigue. Can Fam Physician 1987; 133: 1217-1219 9. Taerk GS, Toner B, Salit IE et al: Depression in patients with neuromyasthemia. Int J Psychiatry Med 1987; 17: 49-56

 

Source: R G Holland. “Virus of the year”? CMAJ. 1988 Aug 1; 139(3): 198–199. PMCID: PMC1268060 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268060/?page=1 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1268061/