Chronic Active Human Herpesvirus-6 (HHV-6) Infection: A New Disease Paradigm
by Joseph H. Brewer, M.D.

Introduction

Human herpesvirus-6 was discovered in 1986. Since then, a considerable amount of research information has been published regarding this fascinating virus. The role of this relatively new member of the herpes family in human disease continues to be defined. It is now widely accepted that primary infection results in roseola (erythema subitum). The virus can also cause a mononucleosis-like syndrome in older children and adults. HHV-6 has now been associated with a variety of potentially life-threatening infectious complications in the immune compromised host. Numerous serious neurologic conditions have been described in both the normal host (children and adults), and the immune compromised host. The virus is clearly neurotropic and immunotropic. Recent evidence also suggests tropism and infection of endothelial cells.

Our group has been intensely interested in HHV-6 infection for the past two years. We have been studying a variety of disease associations, especially in the previously healthy adult who has developed new onset disease (examples: multiple sclerosis, chronic fatigue syndrome, fibromyalgia). Based on the studies and observations in our own patient population, as well as an extensive review of the medical literature, it is our belief that this virus can establish a chronic active infection in certain patient populations and lead to chronic diseases via several different postulated mechanisms. We believe this represents an evolving understanding of a "New Paradigm" of human diseases related to the chronic active HHV-6 infection. In working with these concepts for over two years, it has become clear that this is a very complicated pathophysiological and clinical puzzle. Herein, we present this new paradigm and begin to "piece together" some of this intriguing puzzle. The process of "piecing together" the puzzle of newly described microbial pathogens is indeed not new to those of us who have spent our medical careers in the field of infectious diseases.

In this era of global communication and rapid access to a massive amount of information on the Internet, we believe it is important to share our observations and ideas about this new paradigm with the health care community and the interested public in a time efficient fashion. Putting forth these new disease concepts in the venue of the "information highway" is somewhat non-traditional. However, our goal is to stimulate interest, generate new ideas from others, further research interests, and share current information in a rapid, global format. In the end, we hope that our small addition to the information network will help lead to better care and treatments for our patients and improve the lives of mankind.

 

Chronic Active Human Herpesvirus-6 (HHV-6) Infection: A New Disease Paradigm
by Joseph H. Brewer, M.D.

Chronic Active Human Herpesvirus-6 (HHV-6) Infection: A New Disease Paradigm
by Joseph H. Brewer, M.D.

 

Comments

I. TRIGGERING EVENT
Transient immune dysfunction results in loss of viral containment of HHV-6 latency and thus reactivation. The immune dysfunction presumably relates to cell mediated immunity (CMI) and natural killer (NK) cell dysfunction. CMI (T cell immunity) entails antigen specific immunity and is major histocompatibility complex (MHC) restricted. In the genetically predisposed individual (see below – Genetic predisposition), MHC restricted antigen presentation and/or recognition may be ineffective in controlling the activated HHV-6. With altered T cell function for the virus, NK function becomes very important as a primary control mechanism for containing the activated virus. Thus, loss of NK function, coupled with T cell abnormalities, result in a major problem in containment of the virus for these individuals. This initial "loss of containment", may then lead to active HHV-6 infection. Examples of possible events, that may trigger transient immune dysfunction (thus viral reactivation) are: acute viral infection (mononucleosis – EBV or CMV, Hepatitis C, parvovirus, etc.), vaccination (post-vaccination neurologic syndromes, Gulf War syndrome), pregnancy, trauma, surgery, extreme stress, chemical immune suppression (chemotherapy, corticosteroids), HIV infection, Lyme disease, and leakage from silicone implants (1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17).
[See References – Group I]

II. GENETIC PREDISPOSITION
Genetics, particularly the specific MHC Class I and Class II determinants expressed by cells for any given individual, are associated with the effectiveness of the immune response for infections (18). Several reports have shown that viral infections, for which CMI (T cell response) is important, can vary widely in disease severity and clinical spectrum based on MHC type (18). Highly variable immune responses to infection related to MHC differences has been reported with a number of viruses including Herpes simplex virus (HSV), Varicella zoster virus (VZV), cytomegalovirus (CMV), Epstien-Barr virus (EBV), and Hepatitis C virus (HCV) (18, 19, 20). The same type of MHC dependent variation in response to infection likely occurs with HHV-6, as well. Genetically predisposed individuals presumably have inadequate or "lethargic" control and containment of either primary HHV-6 infection or reactivation. Genetic and epidemiologic data strongly suggests a genetic predisposition, especially with the prototypic example of multiple sclerosis (MS) (21, 22, 23). Clinical experience with both chronic fatigue syndrome (CFS) and fibromyalgia (FM) patients has suggested similar epidemiologic trends. We have observational data on patients with MS and CFS who have active HHV-6 viremia, in which we have done MHC Class II typing. The incidence of MHC Class II type DR 15, DQ 6 is approximately 65% (unpublished data). This is similar to what is reported in the MS genetic studies, which is significantly higher than the general population (22). There are likely problems involved with processing, presentation, or recognition of viral peptides. Certain MHC types (e.g. MHC Class II type DR 15 and DQ 6 in MS patients) may have a problem with MHC restricted antigen presentation and subsequent recognition by T cells. These problems with antigen presentation and/or recognition result in an inadequate CMI response for HHV-6.
[See References – Group II]

III. ACTIVE HHV-6 INFECTION
There is a growing body of information demonstrating active HHV-6 infection in patients with MS and CFS (24, 25, 26, 27, 28, 29). Albeit, virtually the entire population harbors latent HHV-6 (especially the B variant), it is very rare for the normal healthy individual to have active HHV-6 infection. Accurately differentiating between latent infection and active infection by laboratory testing has been a significant obstacle, however, newer methods have improved testing sensitivity and specificity for active infection (see HHV-6 Diagnosis). Until recently, the demonstration of HHV-6 reactivation has been predominately in the immune compromised host (30). However, studies using rapid viral culture or PCR detection (especially in the serum), have shown active HHV-6 infection in the bloodstream of both MS and CFS patients (26, 27, 28, 29). Such infection in these patients could be reactivation (usually the HHV-6B variant) or primary infection (usually the HHV-6A variant). Additionally, we have some limited but intriguing observational data demonstrating active HHV-6 viremia in FM, "post-Lyme disease" patients, certain syndromes in HIV patients (encephalopathy, FM, etc.) and Gulf War Syndrome (unpublished data).
[See References – Group III]

IV. IMMUNE DYSFUNCTION AS A RESULT OF CHRONIC ACTIVE HHV-6 INFECTION
Viral induced immune suppression has been documented with numerous viruses including virtually all of the members of the herpes virus family (31). The mechanisms of herpes virus induced immune suppression include: down regulation of MHC protein expression of both Class I and Class II proteins, altered cytokine production and activity, altered T cell recognition, and impaired NK function (31, 32). HHV-6 is immune suppressive, once activated (33). Cells involved in CMI (CD4, CD8 cytotoxic cells, NK cells) are affected either directly or indirectly by HHV-6 (33, 34). Laboratory analysis of immune function in MS and CFS patients has shown abnormal but variable results (35, 36, 37, 38, 39). In the literature, profound abnormality of NK function has been consistently demonstrated in both groups of patients(35, 36, 37, 38, 39). Furthermore, low NK function is inversely correlated with increased disease activity and severity (36, 39). Our group has shown severe NK dysfunction in both CFS and MS patients with active HHV-6 viremia (40). Reports of patients who have low or absent numbers of NK cells clearly demonstrate that these cells are very important for control of herpes virus infections, in that, these patients had severe, recurrent infections with several different herpes viruses (41). With chronic active HHV-6 infection, loss of NK cell activity results in lack of direct viral killing, loss of up regulation of MHC ClassII expression, diminished interferon gamma production, and loss of up regulation of CD4 cells and CD8 cytotoxic cells (34, 35). Thus, the HHV-6 induced immune suppression, of which the most consistent abnormality is marked decrease in NK function, gives rise to chronic ongoing HHV-6 reactivations.
[See References – Group IV]

V. IMMUNE CELL TROPISM
HHV-6 can infect and complete its replication in several different immune cells (42, 43). The virus is cytopathic for both T cells and NK cells (42, 43). Altered cytokine production by HHV-6 infected cells has also been demonstrated (44). As noted above in #4, immune dysfunction has been demonstrated in patients with active HHV-6 infection, and in clinical MS and CFS (particularly NK dysfunction). HHV-6 is then allowed to chronically reactivate. The resultant impairment of immune function, in turn, may lead to reactivation or emergence of other micro-organisms that persist chronically or in a latent state; in effect, opportunists (45, 46, 47, 48, 49). The most obvious example is reactivation of EBV, which has been reported in studies of CFS patients (45, 46). Since EBV is also immune suppressive, it may be playing an additional role in the immune effects on T cell function and NK function (10). Other persistent organisms that could potentially activate in the setting of defective immune functions (NK cell) are chlamydia, mycoplasma, Borrelia burgdorferi, and babesia, among others. Experimental studies have shown the importance of NK cells in immune control of several of these organisms (7, 47, 48, 49). Thus active HHV-6 and the related immune dysfunction may well be associated with "co-activations" of other persistent or latent organisms. The role of these co-infections in symptom production is not clear but raises some interesting questions.
[See References – Group V]

VI. ENDOTHELIAL CELL TROPISM / VASCULOPATHY
HHV-6 has been shown to infect endothelial cells and can establish chronic infection in these cells (50, 51). The infection of the cells can likely alter function of the endothelial cell and the cell surface, thus leading to activation of the coagulation pathways. Several members of the herpes family of viruses, particularly CMV, can infect endothelial cells and induce procoagulant activity (52, 53, 54). Presumably, the same applies to HHV-6, resulting in a hypercoaguable state. A hypercouaguable state has been clearly demonstrated by laboratory analysis of patients with a clinical diagnosis of CFS (55). Several of these patients also had antiphospholipid antibodies present (mainly anti-beta 2 GPI antibodies) (55). This is a curious finding since the antiphospholipid syndrome can be indistinguishable from MS in terms of neurological symptoms and clinical features (e.g. MRI scans) (56). Fibrin deposition, with or without thrombus formation, in turn, leads to various consequences. The resultant vasculopathy and coagulopathy can likely be either diffuse or focal, in terms of vessel involvement. Vascular stasis and impaired flow in the arterial circulation and the capillary bed result in decreased oxygen delivery and focal ischemia. Another consequence of fibrin deposition may be alteration in red blood cell (RBC) morphology and shape (nondiscocitic erythrocytes). Several studies have shown abnormal RBC morphologic changes in patients with CFS (57, 58). These changes are consistent with RBC surface alteration that may have been induced by flow through vessels in which fibrin has been deposited. The altered RBCs also have impaired oxygen carrying capacity and thus can accentuate impaired oxygen delivery (59). Another phenomenon that is commonly seen in CFS patients is a low erythrocyte sedimentation rate (ESR) (60). This may be the result of the fibrin formation and altered RBC surface changes, thereby slowing the rate of sedimentation of the erythrocytes. The endothelial cell involvement and vasculopathy may also give rise to focal vasospasm. Impaired oxygen delivery to tissues has been demonstrated by numerous studies in the CFS and FM literature (61, 62, 63). Muscle ischemia and impaired muscle oxygenation has been reported in several studies in both groups of patients (61, 62, 63). This could give rise to the symptoms of fatigue, decreased activity tolerance, increased symptoms after activity, and muscle pain (excess lactate production). Focal hypoperfusion demonstrated by SPECT scanning of the central nervous system (CNS) has been reported in CFS and FM (64, 65, 66). The diminished CNS perfusion could certainly relate to some of the neurologic and cognitive symptoms commonly reported by CFS and FM patients. Thus, there is ample clinical evidence of impaired oxygen delivery and focal hypoferfusion in these patients. In the venous circulation, the coagulopathy may give rise to venous pooling, stasis, and thrombosis. Clinically, venous flow abnormalities and increased thrombosis is seen with CFS patients (unpublished data). Hereditary coagulation abnormalities may also be involved in a subset of these patients. Several of the hereditary thrombophilias or hypofibrinolysis traits have been found in CFS patients (55). Lastly, it is interesting that vasculitis is one of the early histopathologic changes in the involved CNS tissue of MS patients (67). This entire process (vasculopathy, a hypercoaguable state, impaired oxygen delivery, and venous pooling) may be major factors in symptom production in the patients with the diseases described herein.
[See References – Group VI]

VII. NEUROTROPISM
HHV-6 is probably the most neurotropic of all the herpes viruses (33, 68). HHV-6 infects the CNS during primary infection in childhood (roseola) (68). The virus has been described in numerous reports of encephalitis in the literature (primary infection in children, immune compromised hosts, and individuals with a normal immune system) (69, 70, 71, 72). Several of these infections were fatal (70, 71, 72). Autopsy studies have shown HHV-6 infection in the CNS tissues of patients with MS (73, 74, 75, 76,). HHV-6 can infect oligodendrocytes and microglial cells (77). The virus may have a direct cytopathic effect on the cell or could cause damage by an immunopathogenic mechanism. Activated T cells directed at HHV-6 peptides could give rise to cellular damage and resultant demyelination. There may be a molecular mimicry mechanism involved as well (78). With any of the mechanisms, the associated inflammation and cytokine production probably plays an important role in the pathogenesis of tissue damage (i.e. demyelination) and the clinical consequences. Active HHV-6 infection of the CNS (either seeding from the periphery or reactivation in the CNS) may indeed be very important in MS, whether via a direct effect, an immune mechanism or both.

Possible Disease Associations*

Diagnosis

Serologic assays (IgG antibodies) can be used to establish evidence of latent HHV-6 infection (past exposure) (31). IgM antibodies may be useful in the diagnosis of primary infection (31). The use of IgM serology to detect reactivation has shown variable results and probably lacks in sensitivity and specificity. The detection of active HHV-6 infection is more difficult (28, 31). Traditional viral cultures to assess for cytopathic effect are cumbersome and not rapid enough for routine clinical use (28). A rapid viral culture technique has been developed, in which the patient’s leukocytes are co-cultured with fibroblasts. Active infection is determined by staining the fibroblast layer with a monoclonal stain specific for an immediate early antigen, thus looking for cross infection of the fibroblasts. This method has sensitivity in the range of 80-85%, with specificity of nearly 100% (28). DNA detection by PCR methodology on cellular specimens (PBMC) cannot always reliably differentiate between latent and active infection. DNA detection on acellular specimens (serum, plasma, CSF), is probably more reliable for active infection, however the presence of "inhibitors" create problems with false negative results (decreased sensitivity). Reverse transcriptase PCR assays (messenger RNA detection) appear to be very promising for detection of active HHV-6 infection with excellent sensitivity and specificity (76). However, such assays are not commercially available at present. In the studies with our patient populations described herein, we used the rapid culture to reliably assess active HHV-6 infection. This test, in our opinion, is the best current assay system for active infection, particularly in view of the high degree of specificity. Accurately differentiating between latent infection and active / productive infection is of paramount importance in defining this disease process as well as clinical diagnosis. At present, there are not commercially available methods to distinguish HHV-6 variant A from variant B by these laboratory tests. Hopefully, accurate testing to separate out which variant is present will be forthcoming.

Treatment

Treatment of HHV-6 infection has not received much attention in the literature. The obvious initial consideration for a treatment strategy would be antiviral therapy. Several antiviral agents are now available for the prevention and treatment of the herpes viruses (HSV 1 and 2, VZV, and CMV) (82). The role of these agents in the treatment of HHV-6 infections is not well established due to limited data. In vitro studies with HHV-6 have shown that the virus is resistant to acyclovir (Zovirax) at achievable serum levels (83, 84, 85). Although not specifically studied, the other oral agents, famciclovir (Famvir) and valacyclovir (Valtrex) are likely to be ineffective as well. The parenteral antiviral drugs that have activity against cytomegalovirus (CMV) have been studied in vitro against HHV-6, with conflicting results (83, 84, 85). Albiet HHV-6 has been sensitive to ganciclovir (Cytovene) and foscarnet (Foscavir), some studies have shown resistance, especially with ganciclovir and the HHV-6A variant (85). Resistance may be strain dependent. Both agents have been used successfully to treat life threatening HHV-6 infections in transplant patients, including encephalitis (86, 87). Cidofovir (Visitide) would be an attractive consideration, given its broad antiviral activity, however it has not been studied with HHV-6. The toxicity of cidofovir may also be a problem, especially with more prolonged use. In acute HHV-6 infections, as is the case in the transplant patients, the anti-CMV agents may be very useful (86, 87). The role of the parenteral agents currently used for CMV infections in chronic active HHV-6 infection may be more limited. The reasons for this include: inconvenient route for chronic administration (intravenous), risk of catheter complications with chronic use, toxicity (particularly cumulative toxicity over time), and relapse of infection when therapy is discontinued. We have administered IV ganciclovir to several selected patients with MS or severe unrelenting CFS in which there was ongoing active HHV-6 infection of the bloodstream documented by repeatedly positive blood cultures. Analysis of this data has lead to several preliminary observations. The clinical and virologic responses have been variable. A subset of patients with both MS and CFS clearly seemed to respond to ganciclovir. In the "responders", there appeared to be diminished viral activity (decreased number of positive viral blood cultures) but we rarely saw complete clearance of viremia. These patients also showed evidence of a clinical response (an example, is an MS case that we have previously reported, who had a marked decrease in MS relapses on therapy) (27). Also, in the group of patients who "responded" clinically and virologically, there was a tendency to relapse when antiviral therapy was discontinued (even after 6 months or more of therapy). Immune function (low NK function) did not improve on ganciclovir therapy, which may partially explain the tendency to relapse. There was another group of patients that did not respond to the ganciclovir. Although the reason for this is unknown, we would postulate strain specific resistance as a likely explanation. We found that ganciclovir was well tolerated in these patients. One study of CFS patients treated with IV ganciclovir (for 30 days) has been reported in the literature (88). Using functional status, there was improvement in 13 of 18 patients at 24 weeks after ganciclovir. The remainder of patients failed to improve. HHV-6 was not addressed in this study and long term follow up data was not provided. This type of data, at 24 weeks, would be generally consistent with our observations. We have given IV foscarnet to two patients with active HHV-6 infection. In both, therapy was discontinued by the fourth week due to toxicity. Oral antiviral therapy may be more practical and amenable to long term maintenance therapy. Unfortunately, as noted above, none of the currently available agents appear to be particularly attractive based on their in vitro activity. Acyclovir (or valacyclovir) may have some limited, strain dependent activity. One study showed that acyclovir reduced the frequency of disease exacerbations in MS patients. Valganciclovir, an oral form of ganciclovir with serum levels similar to the IV formulation, is currently being evaluated in clinical trials of patients with CMV infections. Several drugs that have a very broad antiviral spectrum (including herpes viruses) are being evaluated as potential antiviral agents. Some of these agents (e.g. PMPA) may surface in the future as effective agents for HHV-6.

Given the immune deficiency that results from chronic active HHV-6 infection, immune modulation is another attractive avenue for consideration. Beta interferon has been shown to decrease MS relapses and decrease the number of active lesions on MRI head scans in controlled studies (both Beta 1a and Beta 1b types) (89). The proposed mechanism is an immune regulatory role (down regulation of CMI) by the interferon. Since interferon has known anti-viral properties, another explanation for the positive results could be an anti-viral effect on HHV-6. In our observations of MS patients with HHV-6 viremia, we have not seen a lower rate of positive HHV-6 blood cultures or higher NK function assay results in patients on either of the beta interferon preparations (unpublished data). However, this would not rule out an anti-viral effect of interferon, particularly a partial effect. Since the beta interferon studies included large numbers of patients, our observations in a small number of patients is likely too small of a sample to see a statistically significant difference. The anti-viral effects of the interferon preparations on HHV-6 have not been studied. Defining the effect of interferon on HHV-6 will be an important area of research. Intravenous gamma globulin has been given to both MS and CFS patients with improvement in clinical parameters, but results in the literature have varied (90, 91). Other immune modulators such as G-CSF and GM-CSF have not been studied.

Another immune modulator that may have substantial promise is transfer factor (TF). There are several reasons to consider TF. TF has consistently shown efficacy in the prevention and treatment of viral infections. Studies reporting efficacy of specific TF have been reported with HSV 1 and 2, VZV, EBV, and CMV (93, 94, 95, 96). TF has proven to be extremely safe with virtually no significant adverse effects (96). Since TF acts on CMI, this type of agent may improve the immune dysfunction that is a key feature of chronic active HHV-6 infection (97). Recent techniques obtaining TF from bovine colostrum provides a way to recover TF in large enough amounts for commercial preparation (98). We have done some preliminary studies in patients with CFS and chronic active HHV-6 infection using a TF preparation derived from bovine colostrum that has activity for HHV-6 included in its scope of TF activities. Albeit the data is still preliminary, this type of immune modulation appears to be very promising. We have seen significant symptom improvement, consistently negative HHV-6 blood cultures and marked improvement in NK function in patients taking this particular TF (unpublished data).

Another interesting treatment concept involves the use of anti-coagulants. Given the issue of activated coagulation pathways in these patients (endothelial cell tropism and vasculopathy), anti-coagulation may improve oxygen delivery and help with the symptoms that have been caused by a hypercoaguable state and fibrin deposition (99). One study has demonstrated symptom improvements in CFS patients treated with heparin (99). Several studies have shown that herpes viruses attach to cell surfaces via heparan sulfate receptors and that exogenous heparin can block this interaction and viral infectivity (100, 101). Thus, heparin may have some antiviral properties for herpes viruses. Patients with hereditary hypercoaguable syndromes (thrombophilia or hypofibrinolysis) may be at further risk for substantial hypercoaguable related problems and require anticoagulation. One evolving concept involves blocking viral activation (antiviral agents or immune modulation such as TF) combined with anticoagulants (heparin or coumadin). A model for a hypercoaguable state in patients with active HHV-6 infection and possible management strategies of the patient with a hypercoaguable state and associated active HHV-6 infection are outlined in Table 2 and 3.

 

References: Comments Section

I. GROUP 1: TRIGGERING EVENT

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3.	Dinerman H and Steere AC. Lyme disease associated with fibromyalgia. Ann Intern Med 1992;117:281-285.
4.	Buskila D, Shnaider A, Neurmann L et al. Fibromyalgia in hepatitis C infection. Arch Intern Med 1997;157:2947-2500.
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6.	Siber WJ, Rodin J, Larson L et al. Modulation of human natural killer cell activity by exposure to uncontrollable stress. Brain Behav Immun 1992;6:141-156.
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8.	Welsh RM. Regulation of virus infections by natural killer cells. Nat Immun Cell Growth Regul 1986;5:169-199.
9.	Malanti MS, Lusso P, Ciccone E et al. Recognition of virus-infected cells by natural killer cell clones is controlled by polymorphic target cell elements. J Exp Med 1993;178:961-969.
10.	Hsu D-H, deWaal Malefyt R, Florentino et al. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF 1. Science 1990;250:830-832.
11.	Schrier RD, Rice GPA and Goldstone MBA. Suppression of natural killer activity and T cell proliferation by fresh viral isolates of human cytomegalovirus. J Infect Dis 1986;153:1084-1091.
12.	Walter R, Hartman K, Fleisch et al. Reactivation of herpesvirus infections after vaccinations? Lancet 1999;353:810.
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14.	Golightly M, Thomas J, Volkman D et al. Modulation of natural killer cell activity by Borrelia burgdorferi. Ann NY Acad Sci 1988;539:103-111.
15.	Rouas-Freiss N, Goncalves RM, Menier C et al. Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc Natl Acad Sci 1997;94:11520-11525.
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17.	Vojdani A, Campbell A and Brautbar N. Immune functional impairment in patients with clinical abnormalities and silicone breast implants. Toxicol Ind Health 1992;8:415-429.

II. GROUP 2: GENETIC PREDISPOSITION

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19.	Lekstrom-Himes JA, Hohman P, Warren T et al. Association of major histocompatibility complex determinants with the development of symptomatic and asymptomatic genital herpes simplex virus type 2 infections. J Infect Dis 1999;179:1077-1085.
20.	Minton EJ, Smillie D, Neal KR et al. Association between MHC Class II alleles and clearance of circulating hepatitis C virus. J Infect Dis 1998;178:39-44.
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23.	Kurtzke JF. Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev 1993;6:382-427.

III. GROUP 3: ACTIVE HHV-6 INFECTION

24.	Buchwald D, Cheney PR, Peterson DL et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med 1992;116:103-113.
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27.	Knox KK, Brewer JH, Henry JM et al. Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease. Clin Infect Dis 2000;31:894-903.
28.	Knox KK, Brewer JH, and Carrigan DR. Persistent active human herpesvirus six (HHV-6) infections in patients with chronic fatigue syndrome. J Chron Fatigue Syndr 1999;5:245-246.
29.	Brewer JH, Know KK and Carrigan DR. Longitudinal study of chronic active human herpesvirus 6 (HHV-6) viremia in patients with chronic fatigue syndrome. Abstract. IDSA. 37th Annual Meeting. Nov. 18-21, 1999. Philadelphia, Pennsylvania.
30.	Singh N and Carrigan DR. Human herpesvirus-6 in transplantation: an emerging pathogen. Ann Intern Med 1996;124:1065-1071.

IV. GROUP 4: ACTIVE HHV-6 INDUCED IMMUNE DEFICIENCY

31.	Banks TA and Rouse BT. Herpesviruses – Immune escape artists? Clin Infect Dis 1992;14:933-941.
32.	Reyburn HT, Mandleboim O, Vales-Gomez M et al. The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 1997;386:514-517.
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34.	Yakushijin Y, Yasukawa M and Kobayashi Y. Establishment and functional characterization of human herpesvirus 6-specific CD4+ human T cell clones. L Virol 1992;66:2773-2779.
35.	Klimas NG, Salvato F, Morgan R et al. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990;28;1403-1410.
36.	Ojo-Amaize EA, Conley EJ and Peter JB. Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome. Clin Infect Dis 1994;18 (Suppl 1):S157-S159.
37.	Caliguri M, Murray C, Buchwald et al. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol 1987;139:3306-3313.
38.	Whiteside TL and Friberg D. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. Am J Med 1998;105:27S-34S.
39.	Kastrukoff LK, Morgan NG, Zecchini D et al. A role for natural killer cells in the immunopathogenesis of multiple sclerosis. J Neuroimmonol 1998;86:123-133.
40.	Brewer JH, Knox KK, and Carrigan DR. Severe dysfunction of natural killer (NK) cells associated with chronic active human herpesvirus-6 (HHV-6) viremia in patients with chronic fatigue syndrome. Abstract. IDSA. 37th Annual Meeting. Nov. 18-21, 1999. Philadelphia, Pennsylvania.
41.	Biron CA, Byron KS and Sullivan JL. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 1989;26:1731-1735.

V. GROUP 5: IMMUNE CELL TROPISM

42.	Lusso P, Malnati M, De Maria A et al. Productive infection of CD4+ and CD8+ mature human T cell populations and clones by human herpesvirus 6. J Clin Microbiol 1991;147:685-691.
43.	Lusso P, Malnati M, Garzino-Demo A et al. Infection of natural killer cells by human herpesvirus 6. Nature 1993;362:458-462.
44.	Flamand L, Gosselin J, D’Addario M et al. Human herpesvirus 6 induces interleukin 1 beta and tumor necrosis factor alpha, but not interleulin-6, in peripheral blood mononuclear cell cultures. J Virol 1991;65:5105-5110.
45.	Strauss SE, Tosato G, Armstrong G et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 1985;102:7-16.
46.	Buchwald D, Goldenberg DL, Sullivan et al. The "chronic, active Epstein-Barr virus infection" syndrome and primary fibromyalgia. Arthritis Rheum 1987;10:1132-1136.
47.	Golightly M, Thomas J, Volkman D et al. Modulation of natural killer cell activity by Borrelia burgdorferi. Ann NY Acad Sci 1988;539:103-111.
48.	Tseng CT and Rank RG. Role of NK cells in early host response to chlamydial genital infection. Infect Immun 1998;66:5867-5875.
49.	Lai WC, Bennett M, Pakes SP et al. Resistance to Mycoplasma pulmonis mediated by activated natural killer cells. J Infect Dis 1990;161:1269-1275.

VI. GROUP 6: ENDOTHELIAL CELL TROPISM / VASCULOPATHY

50.	Wu CA and Shanley JD. Chronic infection of human umbilical vein endothelial cells by human herpesvirus-6. J Gen Virol 1998;79:1247-1256.
51.	Ueda T, Miyake Y, Imoto K et al. Distribution of human herpesvirus 6 and varicella-zoster virus in organs of a fatal case with exanthem subitum and varicella. Acta Paediatr Jpn 1996;38:590-595.
52.	Bruggerman CA, Debie WM, Grauls G et al. Cytomegalovirus infection of rat endothelial cells in vitro. Arch Virol 1986;87:265-272.
53.	Van Dam-Mieraras MC, Bruggman CA, Muller AD et al. Induction of endothelial cell procoagulant activity by cytomegalovirus infection. Thromb Res 1987;47:69-75.
54.	Van Dam-Mieras MC, Muller AD, Van Hinsbergh VW et al. The procoagulant response of cytomegalovirus infected endothelial cells. Thromb Haemost 1992;68:364-370.
55.	Berg D, Berg LH and Couvarars J. Is CFS/FM with an undefined hypercoaguable state brought on by immune activation of coagulation? J Chron Fatigue Syndr 1999;3/4:113-114.
56.	Cuadrado MJ, Khamashta MA, Ballesteros A et al. Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Medicine 2000;79:57-68.
57.	Simpson LO, Murdoch JC and Herbison GP. Red cell shape changes following trigger finger fatigue in subjects with chronic tiredness and healthy controls. N Z Men J 1993;106:104-107.
58.	Simpson LO. Nondiscocytic erythrocytes in myalgic encephalitis. N Z Med J 1989;102:126-127.
59.	Vandergriff KD and Olson JS. Morphologic and physiological factors affecting oxygen uptake and release by red blood cells. J Biol Chem 1984;259:12619-12627.
60.	Buchwald D and Kamaroff AL. Review of laboratory findings for patients with chronic fatigue syndrome. Rev Infect Dis 1991;13(Suppl 1):S12-18.
61.	Arnold DL, Bore PJ, Radda GK et al. Excessive intracellular acidosis of skeletal muscle on exercise in a patient with post-viral exhaustion/fatigue syndrome. A 31P nuclear magnetic resonance study. Lancet 1984;1:1367-1369.
62.	Lund N, Bengtsson A and Thorberg P. Muscle tissue oxygen pressure in primary fibromyalgia. Scand J Rheumatol 1986;15:165-173.
63.	Riley MS, O’Brien CJ, McCluskey DR et al. Aerobic work capacity in patients with chronic fatigue syndrome. Br Med J 1990;1:953-956.
64.	Goldstein JA, Mena I, Yunus MB et al. Regional cerebral blood flow by SPECT in chronic fatigue syndrome with and without fibromyalgia (abstract). Arthritis Rheum 1993;36:S222.
65.	Mountz JM, Bradley LA, Modell JG et al. Fibromyalgia in women. Abnormalities of regional cerebral blood flow in the thalamus and caudate nucleus and associated with low pain threshold levels. Arthritis Rheum 1995;38:926-938.
66.	Lange G, Wang S, DeLuca J et al. Neuroimaging in chronic fatigue syndrome. Am J Med 1998;105:S50-S53.
67.	Adams CWM, Poston RN, Buk SJ et al. Inflammatory vasculitis in multiple sclerosis. J Neurol Sci 1985;69:269-283.

VII. GROUP 7: NEUOTROPISM

68.	Caserta MT, Hall CB, Schnabel K et al. Neuroinvasion and persistence of human herpesvirus-6 in children. J Infect Dis 1994;170:1585-1589.
69.	Kamei A, Fujiwara T, Hiraga S et al. Acute disseminated demyelination due to primary human herpesvirue-6 infection. Eu J Pediatr 1997;156:709-712.
70.	Knox KK and Carrigan DR. Active human herpesvirus six (HHV-6) infection of the central nervous system in the patients with AIDS. J Acq Immune Defic Syndr and Hum Retrovir 1995;9:69-73.
71.	Drobyski WR, Knox KK, Majewski D et al. Fatal encephalitis due to variant B human herpesvirus-6 infection in a bone marrow transplant recipient. N Engl J Med 1994;330:1356-1360.
72.	Novoa LJ, Nagra RM, Nakawatase T et al. Fulminate demyelinating encephalomyelitis associated with productive HHV-6 infection in an immunocompetent adult. J Med Virol 1997;52:308-310.
73.	Challoner PB, Smith KT, Parker JD et al. Plaque associated expression of human herpesvirus-6 in multiple sclerosis. Proc Natl Acad Sci 1995;92:7440-7444.
74.	Carrigan DR, Harrington D and Knox KK. Subacute leukoencephalitis caused by CNS infection with human herpesvirus six manifesting as acute multiple sclerosis. Neurology 1996;47:145-148.
75.	Carrigan DR and Knox KK. Human herpesvirus six and multiple sclerosis. Multiple Sclerosis 1997;4(5):390-394.
76.	Brewer JH, Knox and Carrigan DR. Active human herpesvirus-6 infections are present in the CNS, lymphoid tissues and peripheral blood of patients with multiple sclerosis. Abstract 57. IDSA 36th Annual Meeting. Nov. 12-15. Denver, Colorado.
77.	Albright AV, Lavi E, Black et al. The effect of human herpesvirus-6 (HHV-6) on cultured human neural cells: oligodendrocytes and microglia. J Neurovirol 1998;4(5):486-494.
78.	Albert LJ and Inman RD. Molecular mimicry and autoimmunity. N Engl J Med1999;341:2068-2074.

References: Diagnosis and Treatment Sections

79.	Norton R, Caserta MT, Breese Hall C et al. Detection of human herpesvirus 6 by reverse trancsription-PCR. J Clin Microbiol 1999;37:3672-3675.
80.	Balfour H. Antiviral drugs. N Engl J Med 1999;340:1255-1268.
81.	Russler SK, Tapper MA, and Carrigan DR. Susceptibility of human herpesvirus 6 to acyclovir and ganciclovir. Lancet 1989; 2:382.
82.	Burns WH and Sanford GR. Susceptibility of human herpesvirus 6 to antivirals in vitro. J Infect Dis 1990; 162:634-637.
83.	Reyman D, Naesens L, Balzarini J et al. Antiviral activity of selected nucleoside analogues against human herpesvirus-6. Antiviral Res 1995;28:343-357.
84.	Mookerjee BP and Vogelsang G. Human herpes virus 6 encephalitis after bone marrow transplantation: successful treatment with ganciclovir. Bone Marrow Transpl 1997; 20:905-906.
85.	Cole PD, Stiles J, Boulad F et al. Successful treatment of human herpesvirus 6 encephalitis in a bone marrow transplant recipient. Clin Infect Dis 1998;27:653-654.
86.	Lerner MA, Zervos M, Dworkin HJ et al. New cardiomyopathy: Pilot study of intravenous ganciclovir in a subset of the chronic fatigue syndrome. Infect Dis Clin Pract 1997;6:110-117.
87.	Rudick RA, Cohen JA, Weinstock-Guttman B et al. Management of multiple sclerosis. N Engl J Med 1997;337:1604-1611.
88.	Sorenson PS, Wanscher B, Jensen CV et al. Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 1998;50:1273-1281.
89.	Lloyd A, Kickie I, Wakefield D et al. A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med 1990;89:561-568.
90.	Dwyer JM. The use of antigen-specific transfer factor in the management of infections with herpes viruses. In: Kirkpatrick CH, Burger DR and Lawrence HS eds. Immunobiology of transfer factor. New York Academic Press 1983:233-243.
91.	Jones JF, Jeter WS, Fulginiti VA et al. Treatment of childhood combined Epstein-Barr virus/cytomegalovirus infection with oral bovine transfer factor. Lancet 1981;2:122-124.
92.	Steele RW, Myers MG and Monroe VM. Transfer factor for the prevention of varicella-zoster infection in childhood. N Engl J Med 1980;303:355-359.
93.	Viza D, Vich JM, Phillips J et al. Orally administered specific transfer factor for the treatment of herpesvirus infections. Lymphok Res 1985;4:27-30.
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95.	Lang I, Nekam H, Gergely P et al. Effect of in vivo and in vitro treatment with dialyzable leukocyte extracts on human natural killer cell activity. Clin Immunol and Immunopathol 1982;25:139-144.
96.	Wilson GB and Paddock GV. Process of obtaining transfer factor from colostrum; transfer factor so obtained and use thereof. U.S. Patent 4,816,563 (1989).
97.	Berg D, Berg LH, and Couvaras J. Does adding anticoagulant therapy improve CFS patients symptoms, since there appears to be a correlation between a hypercoaguable state from immune activation? J Chronic Fatigue Syndr 1999;3/4:114-115.
98.	Immergluck LC, Domowicz MS, Schwartz NB et al. Viral and cellular requirements for entry of herpes simplex virus type 1 into primary neuronal cells. J Gen Virol 1998;79:549-559.
99.	Compton T, Nowlin DM and Cooper NR. Initiation of human cytomegalovirus infection requires initial interaction with cell surface heparan sulfate. Virology 1993;193:834-841.

 

Plaza Internal Medicine Infectious Diseases. P.C.

Joseph H. Brewer, M.D., Robert E. Neihart, M.D., Paul M. Jost, M.D., Curtis Fitzsimmons, M.D.

Our Medical practice specializes in Internal Medicine (diagnosis and treatment of diseases of adults) and Infectious Diseases (diagnosis and management of diseases related to infections). All of our physicians are Infectious Diseases specialists. Thus, the major focus of the practice is Infectious Diseases.

All of our physicians are on the medical staff and hospitalize at St. Luke’s Hospital of Kansas City. St. Luke’s Hospital is a teaching institution (affiliated with the University of Missouri - Kansas City medical school) and is actively involved in scientific and medical research.

All patients are seen by appointment only. Appointments are made through the main telephone number during regular business hours.

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