Preface

Many of the thorough immune panels I've perused on behalf of autism-spectrum
children have pronounced elevations of EBV, CMV, and/or HHV6 (1), suggesting
atypical chronic infection (2). Other immune atypicalities are also presented
in most of those immune panels (1). Chronic active Epstein-Barr virus infection
(CAEBV) illustrates the diagnostic and treatment significance of a thorough
immune panel.

A recently published study by Ohga and colleagues describes "Central nervous
system T-cell lymphoproliferative disorder in a patient with chronic active
Epstein-Barr virus infection." The abstract mentions a young toddler: 
     "CAEBV was diagnosed in a 14-month-old boy with fever, cytopenia,
     hepatosplenomegaly, and abnormal high titers of anti-Epstein-Barr
     virus (EBV) antibodies." 

The abstract makes no mention of pharmaceutical intervention, but reports the
progressive nature of chronic active EBV (CAEBV), even after a long period of
seeming remission:
     "At 8 years of age, he had a splenectomy because of progressive
     disease... After 27 months of clinical remission, muscle weakness and
     paresthesia developed."

At the age of 10, "Magnetic resonance imaging of his brain showed spotty T2
prolongation in left parietal, bilateral frontal, and temporal white matter with
meningeal enhancement." and this included laboratory documentation of infected
lymphocytes that had entered the childs CNS:
     "Brain biopsy revealed the cerebral infiltration of CD3+, CD4+, CD8-,
     CD45RO+, CD56-, and EBV-encoded RNA 1+ cells."

Kenny is a fine looking lad, now 6 years of age, who had an early history of
severe gastroinestinal disturbance, and whose early photos indicate a facial
paralysis on the right side, extending to the mouth, which suggests Bell's Palsy
and a possible involvement of HSV or varicella within certain trigeminal nerves.
He also has language problems, which is also associated with several herpes
class viruses (eg, HSV; 37).  An immune panel purchased by the parents in April
of 1997 revealed several significant items, among many that are instructive:

EBV antibodies:
     anti-EBV-VCA IgG              highly elevated (1280:1)
     anti-EBV-VCA IgM              non-detected
     anti-EBV-early-restricted     elevated (40:1)

HHV6
     anti-HHV6                     elevated (160:1)

NK cells -- ie, cells with CD3- CD16+ CD56+ surface molecule markers
     low percentage                6    ref range (5-20)
     # of NK cells               258    ref range (75-800)
     cytotoxicity                 36    ref range (43-100)

Interleukin 6
     elevated                    113    ref range (0-50)

Tumor necrosis factor alpha 
     elevated                    109    ref range (0-39)


A more complete discussion of Kenny's data will be presented on a subsequent
webpage. For now, we note signs of chronic active Epstein Barr infection,
augmented by decreased NK cell count and by impaired NK function, traits which
have been linked to various causes, including HHV6 and EBV (4-5, 6-7).
Importantly, the child's HSV or varicella related traits (Bell's palsy, with
possible intra-neuronal CNS migration affecting language function) might be
exacerbated by his EBV and HHV6 infections (8-9)

Chronic active EBV infection can lead to lymphoproliferative disorders (10-11),
elevated antibody titres against the EBV early response antigen can be a
significant marker (12); chronic active EBV is known to induce elevations of
TNFa and Interleukin-6 (13, 34); prolonged tonsilitis may have been an early
symptom (34); and other lab-test markers may be instructive, eg:
     "From 6 months of age [yet another child] has had lymphadenopathy,
     low levels of serum uric acid, increased levels of serum lactate
     dehydrogenase and hyper gamma-globulinemia. From the age of 18 months
     he has had persistent Epstein-Barr virus (EBV) infection (target
     cells; B cells), recurrent episodes of thrombocytopenia, anemia and
     hepatosplenomegaly (14)."

Please note that this document presents a very preliminary sketch and does not
present a thorough delineation of all the factors that can alter clinical signs
and outcomes (eg, co-infections, genetic predispositions, etc). Instead, this
document is intended as an initial guide for physicians treating autism-spectrum
children whose thorough immune panels indicate or medical histories suggest the
presence of chronic active infection with Epstein-Barr virus.

Diagnosis in such cases is a complex process that (in my opinion) ought include
data from a thorough immune panel and other medical tests (2b).

Chronic active EBV is not a good companion. EBV's effects can be quite serious
(eg, 12-14); and the virus's persistence quite challenging (eg, 15). The
treatment of a autism-spectrum child with chronic active EBV and/or other co-
infections is not likely to be clear, simple, or fast. With those cavaets as
context, medical literature does provide insights into possible treatments that
may be appropriate in *some* children with documented signs of chronic active
EBV. 

Much of this medical literature is derived from transplantation studies,
because underlying infections (eg, EBV, CMV, etc) can re-activated due to the
immune-impairment induced by immunosuppressant pharmaceuticals needed to
minimize the likelihood of transplant rejection. However, this literature also
mentions treatment of EBV-related lymphoproliferative diseases, which can be
sequelae to chronic active EBV (17a-17g), and anti-EBV strategies have also been
used as preemptive therapy, ie, a therapy intended to minimize EBV and its
sequelae (18, 25-26).

As more parents of autism-spectrum children obtain thorough immune panels and
begin working with physicians willing to utilize medical literature about EBV-
related treatments, we may find that the transplantation studies about EBV- and
CMV-treatments are instructive. And some studies suggest a possible way to
counteract impaired immunity against pathogens with potential gastrointestinal
and/or neurological ramifications -- as might become useful in autism-spectrum
children whose immune-panels reveal impaired responses (ie, no antibodies
levels) against certain vaccinal antigens such as varicella, mumps, tetanus, etc
(10).

A miscellany of citations for anti-EBV, anti-CMV, anti-HHV6, and anti-HepB
treatments is presented (18-36), noting that among the therapies are ivIg,
acyclovir, ganciclovir, famciclovir, foscarnet, and various newer
pharmaceuticals. These citations are but a limited list, intended to illustrate
that treatments seem already in the physician's tool kit -- if and as he or she
begins to work with an autism-spectrum child's thorough immune panel that shows
the possible need for such medications. This is complex stuff! Not nearly as
"easy" as treating strep with an anti-bacterial drug. This webpage is but an
initial step and provides neither diagnostics nor treatment recommendations for
any specific autism-spectrum child.

Evaluating a child via thorough immune panels and other lab-related tests is
complex; and treatments based upon chronic active infections is not easy.
Nonetheless, awareness of medical literature that (for *some* autism spectrum
kids) may suggest possible treatments is worth our continued contemplation.
Chronic active EBV, especially in the presence of NK atypicality, is not to be
brushed off with a phrase like, Well, lot's of kids get these viruses (25).
Instead, these chronic active infections are important.     

That a high percentage of the thorough immune panels of autism-spectrum children
I've perused (n<15) contain such chronic infections is only preliminary data but
is nonetheless highly significant given the potential for neurologic and other
sequelae; and an autism-spectrum child already has symtoms of neurologic
atypicality.

The thorough immune panel (i) is the only way to determine whether or not these
processes are occurring in an autism spectrum child, and (ii) ought become a
mandatory, insurance-paid aspect of autism-spectrum diagnostics and treatments,
including Landau-Kleffner syndrome because of its regressions, the widespread
use of Prednisone, and the increasingly documented link between herpes simplex,
language impairment, and epileptic seizure foci (37).

Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
June 10, 1999

     A series of autism-spectrum research monographs are available by
     links on a web page: http://www.jorsm.com/~binstock/index.htm

References

1. Most of these immune panels contain at least one and sometime several other
immune atypicalities, such as (i) no antibodies against one or more vaccinal
antigens (eg, mumps, varicella, tetanus, and/or diptheria), (ii) atypical immune
cell counts and/or ratios, (iii) alterations in Natural Killer cell count and/or
cytotoxicity, and (iv) atypically elevated antibodies against other pathogens. 

2a. A preliminary discussion of atypical chronic infection:
http://www.jorsm.com/~binstock/chronic1.htm

2b. A thorough immune-panel for autism-spectrum diagnostics:
http://www.jorsm.com/~binstock/tests.htm

3. J Pediatr Hematol Oncol 1999 Jan-Feb;21(1):42-6
Central nervous system T-cell lymphoproliferative disorder in a patient
with chronic active Epstein-Barr virus infection.
Ohga S, Takada H, Honda K, Inamura T, Gondo K, Ohshima K, Yamamoto M, Hara
T
Department of Pediatrics, Faculty of Medicine, Kyushu University, Fukuoka,
Japan.

PURPOSE: Central nervous system (CNS)-T cell lymphoproliferative disorder
(T-LPD) developing during the course of chronic active Epstein-Barr virus
(CAEBV) infection is reported. PATIENTS AND METHODS: CAEBV was diagnosed in
a 14-month-old boy with fever, cytopenia, hepatosplenomegaly, and abnormal
high titers of anti-Epstein-Barr virus (EBV) antibodies. At 8 years of age,
he had a splenectomy because of progressive disease. RESULTS: After 27
months of clinical remission, muscle weakness and paresthesia developed.
Magnetic resonance imaging of his brain showed spotty T2 prolongation in
left parietal, bilateral frontal, and temporal white matter with meningeal
enhancement. Brain biopsy revealed the cerebral infiltration of CD3+, CD4+,
CD8-, CD45RO+, CD56-, and EBV-encoded RNA 1+ cells. CONCLUSIONS: The CNS
involvement of EBV-associated T-LPD is a rare but serious complication in
CAEBV without known underlying immunodeficiency.
PMID: 10029811, UI: 99154073

4. Nature 1993 Apr 1;362(6419):458-62 
Infection of natural killer cells by human herpesvirus 6.
Lusso P, Malnati MS, Garzino-Demo A, Crowley RW, Long EO, Gallo RC
Laboratory of Tumor Cell Biology, National Cancer Institute, National
Institutes of Health, Bethesda, Maryland 20892.

Natural killer (NK) cells are a functionally defined subset of non-T, non-B
lymphocytes of bone marrow origin, which induce lysis of selected target cells,
including neoplastic and virus-infected cells. The NK cell function provides an
important mechanism of primary defence against viruses in vivo, as demonstrated
by the occurrence of multiple herpesvirus infections in patients congenitally
lacking NK cells. Here we show that functionally competent CD3- NK clones can
be productively infected by human herpesvirus 6 (HHV-6), a T-lymphotropic DNA
virus that may play a role in the acquired immunodeficiency syndrome (AIDS) and
in the chronic fatigue syndrome, two disorders associated with a defective NK
cell activity. The infection is cytopathic and induces de novo expression of
CD4, an antigen not expressed within the NK lineage, thereby predisposing NK
cells to infection by human immunodeficiency virus type 1 (HIV-1). These
results provide evidence that a herpesvirus can directly target and kill NK
cells, a potential strategy to suppress the natural anti-viral immunity of the
host.
PMID: 7681936, UI: 93218722

5. Pediatr Infect Dis J 1992 May;11(5):369-73 
Interferon and natural killer cell activity in patients with exanthem subitum.
Takahashi K, Segal E, Kondo T, Mukai T, Moriyama M, Takahashi M, Yamanishi K
Department of Virology, Osaka University, Japan.

Early immune response was studied by assessing interferon (IFN) and natural
killer cell activity in 13 patients with exanthem subitum associated with human
herpesvirus 6 infection during the acute and convalescent phases. Only
IFN-alpha showed a significant increase in the plasma of patients during the
acute febrile phase compared with the convalescent period. The inhibitory
effect of IFN-alpha and IFN-beta on human herpesvirus 6 replication was
demonstrated in vitro with cord blood mononuclear cells. Natural killer cell
activity was also significantly augmented in the acute phase, especially in the
exanthem period, rather than in the convalescent phase (P less than 0.01).
These results suggest that the enhanced IFN-alpha response and natural killer
cell activity in the acute early phase of the disease may play pivotal roles in
the recovery from exanthem subitum.

6. J Clin Immunol 1985 Jan;5(1):46-54 
Immune function in chronic active Epstein-Barr virus infection.
Kibler R, Lucas DO, Hicks MJ, Poulos BT, Jones JF

The spectrum of illness attributed to Epstein-Barr virus (EBV) includes
patients with symptoms persisting for more than 1 year without any other
obvious underlying disease. High titers of antibodies to EBV, either IgG
antiviral capsid antigen or anti-early antigen, can be demonstrated. In this
study, 13 patients diagnosed as having chronic active EBV infection were
examined to determine aspects of their immunologic status. Morphological
examination and fluorescent antibody analysis revealed no abnormalities in the
phenotypes of peripheral blood white cells present in these patients. Compared
to those from healthy control individuals, mononuclear cells from the patients
showed a markedly depressed ability to produce both interleukin-2 and
interferon after stimulation with mitogen and a phorbol ester. Studies of
natural killer (NK) cell activity revealed that unfractionated mononuclear
cells from patients with chronic active EBV infection were significantly lower
in killing activity compared to the control group. Fractionation procedures to
enrich for large granular lymphocytes resulted in an increase in NK activity
for all individuals, but killing activity still remained slightly lower in the
patients than in the control group. The dysfunctions which were found in
patients with chronic active EBV infection may reflect a primary defect in
natural immune functions of the patients predisposing them to a chronic or
intermittent clinical disease rather than a self-limiting illness.
Alternatively, the abnormalities detected in these experiments may be a result
of the viral infection itself.
PMID: 2579970, UI: 85158110

7. J Med Virol 1989 Jun;28(2):110-7 
Brief report: killer cell defect and persistent immunological abnormalities in
two patients with chronic active Epstein-Barr virus infection.
Joncas J, Monczak Y, Ghibu F, Alfieri C, Bonin A, Ahronheim G, Rivard G
Department of Microbiology, Hopital Sainte-Justine, Montreal, Quebec, Canada.
 
Two members of a family have manifested a syndrome of chronic active
Epstein-Barr virus (EBV) infection. A father and his daughter suffered
prolonged or recurrent mononucleosis, with splenomegaly, anemia, and
intermittent fever; persistent immunological abnormalities included defective
natural killer (NK) cytotoxicity, inverted CD4/CD8 ratios, hyper IgG1, high EBV
viral capsid antigen (VCA) and early antigen (EA) antibodies, and low or
undetectable EBV nuclear antigen (EBNA) antibody titers. The EBV seronegative
member of the family was free of these abnormalities. However, NK activity in
the seronegative individual was low-normal and its EBV-specific
antibody-dependent K-cell cytotoxicity (EBV-ADCC) was abnormally low,
suggesting that this K-NK cell defect may be primary. The father, who suffered
from the syndrome for more than 15 years, lacked (or lost) antibodies to
EBV-envelope and infected cell membranes, such as antibody-dependent cellular
cytotoxicity (ADCC), neutralizing (NT), and gp 350/220 antibodies. Slow
improvement over a period of years was heralded by rising NK cytotoxicity.
PMID: 2544675, UI: 89293103

8. J Virol 1993 Nov;67(11):6768-77 
Activation of the Epstein-Barr virus replicative cycle by human herpesvirus 6.
Flamand L, Stefanescu I, Ablashi DV, Menezes J
Laboratory of Immunovirology, Ste-Justine Hospital, Montreal, Canada.

One common attribute of herpesviruses is the ability to establish latent,
life-long infections. The role of virus-virus interaction in viral reactivation
between or among herpesviruses has not been studied. Preliminary experiments in
our laboratory had indicated that infection of Epstein-Barr virus (EBV)
genome-positive human lymphoid cell lines with human herpesvirus 6 (HHV-6)
results in EBV reactivation in these cells. To further our knowledge of this
complex phenomenon, we investigated the effect of HHV-6 infection on expression
of the viral lytic cycle proteins of EBV. Our results indicate that HHV-6
upregulates, by up to 10-fold, expression of the immediate-early Zebra antigen
and the diffuse and restricted (85 kDa) early antigens (EA-D and EA-R,
respectively) in both EBV producer and nonproducer cell lines (i.e., P3HR1,
Akata, and Raji). Maximal EA-D induction was observed at 72 h post-HHV-6
infection. Furthermore, expression of late EBV gene products, namely, the viral
capsid antigen (125 kDa) and viral membrane glycoprotein gp350, was also
increased in EBV producer cells (P3HR1 and Akata) following infection by HHV-6.
By using dual-color membrane immunofluorescence, it was found that most of the
cells expressing viral membrane glycoprotein gp350 were also positive for HHV-6
antigens, suggesting a direct effect of HHV-6 replication on induction of the
EBV replicative cycle. No expression of late EBV antigens was observed in Raji
cells following infection by HHV-6, implying a lack of functional
complementation between the deleted form of EBV found in Raji cells and the
superinfecting HHV-6. The susceptibility of the cell lines to infection by
HHV-6 correlated with increased expression of various EBV proteins in that
B95-8 cells, which are not susceptible to HHV-6 infection, did not show an
increase in expression of EBV antigens following treatment with HHV-6.
Moreover, UV light-irradiated or heat-inactivated HHV-6 had no upregulating
effect on the Zebra antigen or EA-D in Raji cells, indicating that infectious
virus is required for the observed effects of HHV-6 on these EBV products.
These results show that HHV-6, another lymphotropic human herpesvirus, can
activate EBV replication and may thus contribute to the pathogenesis of
EBV-associated diseases.

9. Res Virol 1990 Jan-Feb;141(1):17-30 
Herpes simplex type 1 activation by Epstein-Barr virus nuclear antigen 1.
Machuca I, Michal Y, Epstein A, LiVigni R, Lenoir G, Jacquemont B
INSERM, Ecole Normale Superieure, Lyon, France.

We have investigated the effect of Epstein-Barr virus nuclear antigen 1
(EBNA-1), a nuclear protein encoded by EBV, on herpes simplex virus type 1
(HSV-1) infection either in cells constitutively expressing EBNA-1 or in
transient expression assays. Rat-1 cells and rat embryo fibroblasts (REF)
immortalized by c-myc or E1A were transfected with a specific EBV DNA fragment
coding for EBNA-1. Cloned cell lines which constitutively expressed this
antigen were infected with HSV-1. Our results indicate that in
EBNA-1-expressing cells, virus growth was higher than in control cells for
different virus strains or rodent cell lines. This increase was maximal when
cells were infected at low multiplicity, as determined by virus growth, and
correlated with the stimulation of viral DNA synthesis. REF + c-myc and Vero
cells were cotransfected by an EBNA-1 expression vector driven by Moloney
murine leukaemia virus LTR and HSV-1 immediate-early (alpha 0) or early
thymidine kinase upstream promoter regulatory regions linked to chloramphenicol
acetyltransferase (CAT) coding sequences as effectors. In both cell lines,
stimulation of CAT expression by EBNA-1 was observed only with the
immediate-early promoter. These results suggest that EBNA-1 can transactivate
immediate-early HSV-1 expression.

10. In Vivo 1994 Jul-Aug;8(4):533-42 
Demonstration of active and latent Epstein-Barr virus and human herpevirus-6
infections in bone marrow cells of patients with myelodysplasia and chronic
myeloproliferative diseases.
Krueger GR, Kudlimay D, Ramon A, Klueppelberg U, Schumacher K
Laboratory of Immunopathology, University of Cologne, Germany.

After previous serological screening for Epstein-Barr virus (EBV), human
herpesvirus-6 (HHV-6) and human cytomegalovirus (HCMV) showed elevated antibody
titers against EBV and HHV-6 in more than 50% of patients with myelodysplasia
and chronic myeloproliferative diseases, the present study was carried out in
order to investigate viral antigen expression and distribution in bone marrow
cells of these patients. Trephine biopsies were studied from 60 patients with
myelodysplasia (MDS), 36 patients with chronic myelogenous leukemia (CML) and
18 patients with osteomyelofibrosis (PMF). Elevated anti-EBV EA titers were
found in 62% of the MDS cases, in 33% of the CMLs and in 62% of the OMF
patients. HHV-6 titers were elevated in 18% of the MDS cases, but in only one
case each of CML and OMF. Antigen expression in bone marrow cells was even more
frequent: EBV-EA was 76% in MDS cases, 77% in CML and 40% in OMF. HHV-6 p41 was
observed in 47% of the MDS cases, in 54% of the CML cases and in 20% of the
OMFs. In comparing these data with those from the literature and with our own
studies in Hodgkin's disease, it is hypothesized that the reactivated
herpesviruses may contribute to the pathogenesis of these hematopoietic
disorders by interfering with the cytokine regulation of cell proliferation and
differentiation.


11. Am J Hematol 1999 May;61(1):26-33
Restricted diversification of T-cells in chronic active Epstein-Barr virus
infection: potential inclination to T-lymphoproliferative disease.
Ohga S, Kimura N, Takada H, Nagano M, Ohshima K, Nomura A, Muraoka K, Take
H, Yamamori S, Hara T
Department of Pediatrics, Faculty of Medicine, Kyushu University, Fukuoka,
Japan. ohgas@mailserver.med.kyushu-u.ac.jp

To assess the abnormal T-cell expansion in chronic active Epstein-Barr
virus infection (CAEBV), T-cell antigen receptor (TCR) repertoire was
analyzed in four patients with the disease. All fulfilled the diagnostic
criteria of CAEBV, presenting with fever, hepatosplenomegaly, cytopenia,
abnormal high titers of anti EBV-antibodies, and positive EBV genome of
unknown cause. Southern blotting probed with EBV-terminal repeats and TCR
Cbeta gene indicated clonal expansion of the infected cells in 3 and 2
patients, respectively. The number of CD4+ HLA-DR+ cells appreciably
increased in patients 1 (59%) and 2 (24%), who had a coronary aneurysm and
central nervous system involvement, respectively. TCR gene expression
examined by the inverse polymerase chain reaction methods revealed that
Vbeta gene usages were preferential in all patients (Vbeta7 and Vbeta12:
patient 1, Vbeta4: patient 2, Vbeta13: patients 3 and 4), compared with
those in healthy controls. Valpha18 gene expression was remarkably high in
patients 1 and 2. Moreover, Jbeta gene expression was skewing in the
reigning Vbeta clones in all patients. Vbeta4-Jbeta1.5 and Vbeta13-Jbeta1.5
genes were clonally expressed in patients 2 and 4, respectively. These
results suggest that CAEBV is associated with the restricted diversity of
T-cells, which may stem from the sustained expansion of oligoclonal T-cells
possibly driven by conventional viral antigens, but not, superantigens.
Although the study is limited by the small number of patients, the
unbalanced T-cell repertoire might contribute to the evolution of
T-lymphoproliferative disease, otherwise, imply the innate defective
immunity to EBV in CAEBV patients.

12. Acta Haematol 1996;96(3):140-5
In situ hybridization studies of cytomegalovirus and Epstein-Barr virus in
reactive histiocytic hyperplasia with hemophagocytosis.
Han K, Kim Y, Kahng J, Lee J, Moon Y, Kang C, Shim S
Department of Clinical Pathology, Catholic University Medical College,
Seoul, South Korea.

We studied 14 adult patients presenting with fever and cytopenia of the
peripheral blood and histiocytic hyperplasia with hemophagocytosis (HHH) in
the bone marrow regarding an association of cytomegalovirus (CMV) and
Epstein-Barr virus (EBV) by using in situ hybridization (ISH) and also
evaluated the clinical and laboratory findings according to the encountered
organisms. ISH using a CMV RNA probe demonstrated infected cells in 6 out
of 14 cases (43%), and ISH using an EBV EBER RNA probe demonstrated
infected nuclei in 5 out of the same 14 cases (36%) of HHH. No cases showed
a positive reaction with both probes. Three cases showed a negative
reaction with both probes. The mean age of all patients was 29 years; and
that of the CMV-positive patients was 27 years and that of the EBV-positive
patients was 36 years. Organomegaly was found in 3 out of 6 CMV-positive
patients (1 hepatomegaly, 1 splenomegaly, 1 hepatosplenomegaly), and 4 out
of 5 EBV-positive patients (lymphadenopathy in all 4 cases,
hepatosplenomegaly in 2 cases). One of the CMV-positive case had acute
myeloblastic leukemia, and 2 EBV-positive cases had underlying malignancy
(1 Hodgkin's disease, 1 non-Hodgkin's lymphoma). Seven out of the 14 HHH
cases (50%) died within several months after diagnosis. Nucleic acid
hybridization methods can be used for the routine examination of the
association of CMV or EBV.

13. Acta Paediatr Jpn 1998 Aug;40(4):362-6
Recurrent hepatosplenomegaly and peripheral blood cytopenia, persistent
Epstein-Barr virus infection and central nervous system manifestation in a
patient with lymphadenopathy and low serum uric acid.
Sugita K, Hagisawa S, Satoh Y, Eguchi M, Furukawa T
Second Department of Pediatrics, Dokkyo University School of Medicine,
Tochigi, Japan.

We describe a 27-month-old boy who was first admitted to our hospital on 7
January 1995 with nasal bleeding. From 6 months of age he has had
lymphadenopathy, low levels of serum uric acid, increased levels of serum
lactate dehydrogenase and hyper gamma-globulinemia. From the age of 18
months he has had persistent Epstein-Barr virus (EBV) infection (target
cells; B cells), recurrent episodes of thrombocytopenia, anemia and
hepatosplenomegaly. Dysmobility of the left leg and arm from a central
nervous system complication during a relapse with pancytopenia on March
1995, was also observed. Relapses of thrombocytopenia with increases of
platelet-associated immunoglobulin G and hepatosplenomegaly have been
observed approximately every 2 months, and two relapses of pancytopenia
were accompanied with weak positivity of Coombs test and low level of
haptoglobin.
     [comment: The authors of this citation report using a steroid
     pharmaceucial. As a non-MD researcher, I have *extreme* doubts about
     using steroids in autism-spectrum children *unless* underlying
     chronic infections are ruled out or concurrently treated (#6).]
These recurrent episodes were improved with prednisolone. However, now in June
1997 we have not been able to diagnose what underlies the above clinical
symptoms, except that the patient has a persistent EBV infection.

14. Leuk Lymphoma 1995 Nov;19(5-6):401-6
Hemophagocytic syndrome in Epstein-Barr virus-associated
T-lymphoproliferative disorders: disease spectrum, pathogenesis, and
management.
Su IJ, Wang CH, Cheng AL, Chen RL
Department of Pathology, National Taiwan University Hospital, Taipei,
Republic of China.

The Epstein-Barr virus (EBV) has been shown to infect T lymphocytes and is
associated with two recently recognized human T-lymphoproliferative
disorders: childhood EBV-associated hemophagocytic syndrome (VAHS)
representing a primary or active EBV infection of T cells in young
children, and the EBV-containing T cell lymphoma in adults predominantly
affecting the nose, skin and gastrointestinal tract...  The
patients developing HS share common clinicopathologic features such as
fever, skin lesions, lung infiltrates, hepatosplenomegaly with jaundice,
cytopenias, and coagulopathy. The liver, spleen, lymph nodes, and bone
marrow usually show florid histiocytic proliferation with hemophagocytosis
in addition to the proliferation of atypical T lymphocytes or immunoblasts.
The HS in T cell lymphoma may develop simultaneously with initial lymphoma
presentation, at tumor relapse, or even during remission. The cytokines, in
particular tumor necrosis factor-alpha, released from the EBV-infected T
lymphocytes are presumed to cause the histiocytic activation and the
subsequent hemophagocytic process. Chemotherapy or antiviral agents fail to
arrest the hemophagocytic process in both diseases. Immunomodulatory
treatment incorporating etoposide and intravenous immunoglobulin, however,
has been effective in the control of the progression of the hemophagocytic
process in a substantial number of VAHS patients. Preliminary data suggest
that bone marrow transplantation may be a promising way for eliminating
both the virus and the proliferating T cells. Further investigations are
mandatory for combating this aggressive hemophagocytic process in
EBV-associated T lymphoproliferative disorders.

15. J Pediatr Hematol Oncol 1998 Jul-Aug;20(4):342-6
Interferon-alpha therapy for chronic active Epstein-Barr virus infection:
potential effect on the development of T-lymphoproliferative disease.
Sakai Y, Ohga S, Tonegawa Y, Takada H, Nakao F, Nakayama H, Aoki T,
Yamamori S, Hara T
Department of Pediatrics, Faculty of Medicine, Kyushu University, Fukuoka,
Japan.

PURPOSE: A patient with aggressive chronic active Epstein-Barr virus
(CAEBV) infection is described whose disease activity subsided after
interferon (IFN)-alpha therapy. PATIENT AND METHODS: The patient had
intermittent fever, cytopenia, liver dysfunction, hepatosplenomegaly,
abnormal titers of EBV-associated antibodies, and positive EBV genomes.
RESULTS: Despite repeated trials of the antiviral agents prednisolone and
gamma-globulin, his condition deteriorated. The administration of IFN-alpha
(1 x 10(5) U/kg subcutaneously 3 times per week) led to a dramatic clinical
improvement. During the IFN-alpha therapy, the rearrangement bands of
T-cell antigen receptor genes disappeared assessed by Southern blotting
with a decrease in the number of activated T cells, although the EBV-genome
remained evident. CONCLUSIONS: These observations suggest that IFN-alpha is
useful in managing CAEBV, possibly restraining the clonal development of
T-lymphoproliferative disease (LPD) and EBV-associated B-LPD, although it
does not eradicate the proliferation of EBV.

16. A preliminary discussion of contraindications to steroid therapy in autism-
spectrum children:
http://www.jorsm.com/~binstock/steroid1.htm

17a. Transplantation 1999 Apr 15;67(7):990-8 
Lymphoproliferative disorders after organ transplantation in children.
Dror Y, Greenberg M, Taylor G, Superina R, Hebert D, West L, Connolly B, Sena
L, Allen U, Weitzman S
Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario,
Canada.

BACKGROUND: After organ transplant, patients are at risk of posttransplant
lymphoproliferative disorders (PTLD). The purpose of this study was to analyze
26 pediatric cases of PTLD observed at our institution between 1988 and 1996,
and to evaluate the validity of the Society for Hematopathology Workshop (SHPW)
1997 classification in our patient population. METHODS: Charts were reviewed
for analysis of incidence, clinical course, and outcome. Tissue samples were
classified by a pathologist according to SHPW recommendations. RESULTS: By
morphology, 20 were monomorphic, 5 polymorphic, and 1 hyperplastic. Assessment
of lineage by morphology, molecular studies, and immunophenotyping did not
correlate in six cases. By immunophenotyping, 12 were B cell, 4 T cell, 8 mixed
B/T cells, and 2 undetermined. The 20 patients evaluable for treatment efficacy
were treated with various therapeutic combinations, including immunosuppressive
drug reduction, acyclovir/ganciclovir, interferon-alpha, immunoglobulins,
surgery, and local irradiation. No patient received systemic chemotherapy.
Thirteen patients achieved complete remission and 3, partial; 1 died 5 days
after starting therapy, and 3 of progressive disease. Adverse prognostic
factors included low platelet or neutrophil counts; stage III-IV and SHPW
morphology were marginally significant. CONCLUSIONS: The majority of patients
eligible for treatment can be cured with immunosuppressive drug reduction and
antiviral drugs, along with surgery and irradiation when indicated. Systemic
chemotherapy or innovative approaches may have a role in unresponsive cases.
Morphologic SHPW grouping is feasible and seems to have clinical relevance.
However, correlation with clonality and immunophenotyping is not always
possible, necessitating modifications including segregation of descriptive
morphology from clonality and cell origin.

17b. Transplantation 1999 Mar 15;67(5):765-7 
Treatment of Epstein-Barr virus-induced posttransplantation lymphoproliferative
disorder with foscarnet alone in an adult after simultaneous heart and renal
transplantation.
Oertel SH, Ruhnke MS, Anagnostopoulos I, Kahl AA, Frewer AF, Bechstein WO,
Hummel MW, Riess HB
Department of Haematology and Oncology, Charite-Campus Virchow, Medizinische
Fakultat der Humboldt Unversitat, Berlin, Germany.

BACKGROUND: The kind and intensity of immunosuppression as well as Epstein-Barr
virus, a transforming herpes virus that selectively infects B lymphocytes and
causes infectious mononucleosis, have been implicated in the development of
posttransplantation lymph-proliferative disorders (PT-LPD), a life-threatening
complication of solid organ transplantation. The morphologic spectrum of PT-LPD
ranges from polymorphous hyperplasia to monomorphous B-non-Hodgkin lymphomas.
Among different modalities of treatment, reduction of immunosuppression with or
without co-administration of antiviral agents may result in PT-LPD regression
especially in mononucleosis-like disease. METHODS: Nonmononucleosis-like PT-LPD
in a simultaneous heart and renal recipient was treated with Foscarnet, a
potent inhibitor of different herpes viruses with a low profile of toxicity,
although intensive immunosuppression therapy was maintained. RESULTS AND
CONCLUSIONS: A 4-week course of Foscarnet resulted in relapse-free complete
remission (follow-up 10+ months). Thus, antiviral treatment with Foscarnet, may
induce prolonged remission in nonmononucleosis-like PT-LPD without reduction of
immunosuppression.

17c. Springer Semin Immunopathol 1998;20(3-4):437-53 
The antiviral prophylaxis of post-transplant lymphoproliferative disorder.
Davis CL
Division of Nephrology and Transplantation Services, University of Washington
Medical Center, Seattle 98195-6174, USA.

17d. Antimicrob Agents Chemother 1998 Nov;42(11):2923-31 
The Epstein-Barr virus thymidine kinase does not phosphorylate ganciclovir or
acyclovir and demonstrates a narrow substrate specificity compared to the
herpes simplex virus type 1 thymidine kinase.
Gustafson EA, Chillemi AC, Sage DR, Fingeroth JD
Division of Infectious Disease, Dana-Farber Cancer Institute, Boston,
Massachusetts, USA.

The Epstein-Barr virus (EBV) thymidine kinase (TK) was expressed in mammalian
143B TK- cells to investigate its substrate specificity. The herpes simplex
virus type 1 (HSV-1) TK was similarly expressed for comparison. Both viral TKs
conferred a TK+ phenotype on 143B TK- cells. The nucleoside analog ganciclovir
(GCV) did not affect the growth of 143B EBV TK or 143B TK- cells but
effectively killed 143B HSV-1 TK cells. Furthermore, lysates of 143B EBV TK
cells could not phosphorylate GCV, which was confirmed by high-performance
liquid chromatography. EBV TK, HSV-1 TK, and EBV TK N-, a truncated EBV TK
missing 243 N-terminal amino acids, were purified as fusion proteins expressed
in bacteria, and all had TK activity. In addition, EBV TK was observed to have
a thymidylate kinase activity but could not phosphorylate GCV, acyclovir, or
2'-deoxycytidine. In competition assays, only nucleoside analogs of thymidine
significantly inhibited thymidine phosphorylation by EBV TK, with the following
rank order: 5-bromodeoxyuridine > zidovudine > stavudine > sorivudine. These
results demonstrate that EBV TK substrate specificity is narrower than those of
alphaherpesvirus TKs and that thymidine analogs may be the most suitable
nucleoside antivirals to target the enzyme. Clinical implications for
gammaherpesviruses are discussed.

17e. Blood Cells Mol Dis 1998 Jun;24(2):114-23 
Arginine butyrate-induced susceptibility to ganciclovir in an
Epstein-Barr-virus-associated lymphoma.
Mentzer SJ, Fingeroth J, Reilly JJ, Perrine SP, Faller DV
Department of Surgery and Medicine, Brigham and Women's Hospital, Boston, MA
02115, USA.

Lymphoproliferative disorders associated with Epstein-Barr virus (EBV)
infections can occur in the setting of immunosuppression. In some patients, the
lymphoproliferative disorder can resemble an aggressive monoclonal non-Hodgkins
lymphoma (NHL). These NHL are poorly responsive to conventional therapy.
Similarly, antiviral therapy with synthetic nucleosides such as ganciclovir are
ineffective because the genes that render the virus susceptible to therapy are
not expressed in EBV+ lymphomas. Using a cell line derived from a lung
transplant recipient with an EBV+ immunoblastic NHL, we studied the ability of
arginine butyrate to induce the expression of EBV thymidine kinase. Arginine
butyrate was not only effective in inducing EBV thymidine kinase transcription,
but also acted synergistically with the antiviral agent ganciclovir to inhibit
cell proliferation and decrease cell viability. Based on these findings, the
patient from whom the cell line was derived was treated with arginine
butyrate/ganciclovir as well as conventional cytotoxic chemotherapy. No
additional toxicity was observed with the arginine butyrate/ganciclovir
therapy. Histologic examination of the tumor showed substantial necrosis. These
observations suggest the feasibility of arginine butyrate induction of
ganciclovir susceptibility in patients with EBV-associated lymphomas.

17f. Ned Tijdschr Geneeskd 1998 Mar 21;142(12):650-4 
[Meningo-encephalitis and hydrocephalus caused by Epstein-Barr virus].
[Article in Dutch]
van der Klooster JM, van Saase JL, Grootendorst AF, Sinnige HA
Afd. Interne Geneeskunde en Intensive-caregeneeskunde, Sint Clara Ziekenhuis,
Rotterdam.

In a 35-year-old woman who presented with acute somnolence, confusion and slow
irregular breathing, Epstein-Barr virus (EBV) meningoencephalitis was diagnosed
after serological testing and a polymerase chain reaction of the cerebrospinal
fluid. She developed papilloedema and bilateral nervus abducens paresis. A CT
scan showed generalized oedema of the brain and triventricular hydrocephalus.
Treatment with a ventriculoperitoneal shunt and ganciclovir led to complete
recovery. Meningoencephalitis is a not uncommon, yet rarely reported
complication of infectious mononucleosis. It usually runs a mild course with
spontaneous and full recovery. Hydrocephalus secondary to aqueduct stenosis is
a complication of Epstein-Barr virus (EBV) meningoencephalitis which has not
been reported in adults before. The disease should be considered whenever the
clinical condition deteriorates or neurological symptoms increase.

17g. Clin Infect Dis 1997 Dec;25(6):1344-9 
Comparison of intravenous ganciclovir followed by oral acyclovir with
intravenous ganciclovir alone for prevention of cytomegalovirus and
Epstein-Barr virus disease after liver transplantation in children.
Green M, Kaufmann M, Wilson J, Reyes J
Department of Pediatrics, University of Pittsburgh School of Medicine,
Children's Hospital of Pittsburgh, Pennsylvania 15213, USA.

A randomized trial was performed to compare the sequential use of 2 weeks of
intravenous ganciclovir (10 mg/[kg.d]) followed by 50 weeks of high-dose oral
acyclovir (800 mg/m2 four times daily) with 2 weeks of intravenous ganciclovir
alone as prophylaxis for cytomegalovirus (CMV) and Epstein-Barr virus (EBV)
disease after pediatric liver transplantation. CMV disease was diagnosed for
seven of 24 patients treated with ganciclovir followed by high-dose oral
acyclovir compared with two of 24 children treated with ganciclovir alone (P =
.048). Similarly, the rate of CMV disease among high-risk patients
(CMV-positive donor/CMV-negative recipient) treated with the combination
regimen was higher than that among high-risk patients treated with ganciclovir
alone (four [57%] of seven vs. zero of five, respectively; vs P < .05). The
rate of EBV disease among patients treated with the combination regimen (eight
[33%] of 24) was similar to that among patients treated with ganciclovir alone
(five [21%] of 24; P = not significant). We conclude that sequential
prophylaxis with 2 weeks of intravenous ganciclovir followed by 50 weeks of
high-dose oral acyclovir did not decrease the frequency of CMV or EBV disease
after pediatric liver transplantation when compared with 2 weeks of intravenous
ganciclovir alone.

18. Transplantation 1997 Sep 27;64(6):848-52 
Reduced incidence of Epstein-Barr virus-associated posttransplant
lymphoproliferative disorder using preemptive antiviral therapy.
Darenkov IA, Marcarelli MA, Basadonna GP, Friedman AL, Lorber KM, Howe JG,
Crouch J, Bia MJ, Kliger AS, Lorber MI
Department of Surgery, Yale University School of Medicine, New Haven,
Connecticut 06520-8062, USA.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) has been
observed with increasing frequency consequent to the availability of more
effective and potent immunosuppression. Prior work suggested that a peripheral
blood monitoring strategy detecting peripheral B lymphoproliferation was
effective in the early diagnosis of PTLD among 7 of 179 (3.9%) consecutive
transplant recipients. Each of those seven patients received at least one
course of antithymocyte globulin, Minnesota antilymphocyte globulin, or OKT3
before developing PTLD. METHODS: To determine whether antiviral prophylaxis
might reduce the incidence of PTLD, a subsequent group of 198 consecutive
recipients received either ganciclovir or acyclovir during antilymphocyte
antibody administration. When the donor or recipient were
cytomegalovirus-seropositive, ganciclovir was given; acyclovir was used when
both were cytomegalovirus-seronegative. Baseline and protocol posttransplant
cell surface profiles were obtained using immunofluorescence and flow cytometry
to detect T cells, lymphocyte activation markers, and the CD19 B cell antigen.
RESULTS: Demographic factors, including the incidence of recipients more than
50 years of age, non-Caucasians, previous transplantation, and diabetes
mellitus, were similar in both groups. Additionally, the number of patients
receiving antilymphocyte preparations was similar. However, only one patient
(0.5%) from the latter group who received preemptive antiviral therapy
developed PTLD. Although elevations in CD19+ B cells preceded clinical PTLD
among each of the seven earlier patients, evidence of peripheral B cell
proliferation was not demonstrated for the sole patient from the latter group,
which suggests a possible effect of antiviral therapy. CONCLUSIONS:
Prophylactic antiviral therapy may reduce the sensitivity of peripheral
monitoring for B lymphoproliferation, but the dramatic reduction in PTLD
incidence strongly supports its use among transplant recipients at risk.

19. Exp Mol Pathol 1999 Apr;66(1):19-30 
Stealth virus epidemic in the mohave valley: severe vacuolating encephalopathy
in a child presenting with a behavioral disorder.
Martin WJ, Anderson D
Center for Complex Infectious Diseases, Rosemead, 91770, California.
[Medline record in process]

An infectious illness, attributed to atypically structured cytopathic "stealth"
viruses, occurred in 1996 in the Mohave Valley region of the United States. A
stealth virus-infected child from this region has developed a severe
noninflammatory, vacuolating (spongiform) en cephalopathy. The illness
initially presented as a behavioral problem without overt neurological signs.
Extensive investigations, including repeated magnetic resonance imaging, two
brain biopsies, and stealth virus cultures, have helped define the disease
process occurring in this child. Significant clinical benefit with apparent
retardation of disease progression occurred during a 6-week course of
ganciclovir therapy. The potential contributing role of stealth virus
infections in children presenting with behavioral problems needs to be
addressed.

20. J Gastroenterol Hepatol 1999 Mar;14(3):262-8 
Histological changes during clearance of chronic hepatitis B virus infection by
adoptive immunity transfer.
Lau GK, Yuen ST, Au WY, Wu PC, Liang R
Department of Medicine, Queen Mary Hospital, Hong Kong, China.
gkklau@hkstar.com

BACKGROUND: Serological clearance of hepatitis B surface antigen (HBsAg) has
been described after reception of hepatitis B surface antibody positive marrow,
via allogeneic bone marrow transplantation (BMT). Histological changes during
the clearance of HBsAg are unknown. METHODS AND RESULTS: We described two
chronic hepatitis B carriers (both hepatitis B e antigen negative), who cleared
HBsAg after allogeneic bone marrow transplantation. Both received hepatitis B
surface and core antibody positive human leucocyte antigen identical donors'
marrow and had serological clearance of HBsAg 15 and 7 weeks after allogeneic
BMT, respectively. Both events were preceded by hepatic flare. Both patients
were also treated with famciclovir for the prevention of hepatitis B
reactivation after BMT. Histological examination during the flare showed only
mild necroinflammatory activity with multiple foci of confluent necrosis,
associated with moderate lymphocytic infiltration. The majority of these
lymphocytes were cluster of differentiation (CD) 8 positive. Using
immunohistochemistry, there was no detectable hepatic expression of hepatitis
B core antigen. However, HBsAg was positive, mainly in the area of confluent
necrosis. Using in situ hybridization, hepatitis B virus (HBV) DNA was detected
in the nucleus of 5% of hepatocytes, but not in the cytoplasm. CONCLUSIONS: At
their last follow up, 22 and 16 months after BMT, the serum of both patients
remained HBsAg negative, hepatitis B surface antibody positive and HBV-DNA
negative by branched DNA assay.

21. Curr Opin Pediatr 1999 Feb;11(1):21-7 
Advances in antiviral therapy.
Zerr DM, Frenkel LM
Department of Pediatrics, University of Washington, Children's Hospital and
Regional Medical Center, Seattle 98105, USA.

Multiple agents for the treatment and prevention of viral illnesses have been
developed during the past few years. While in many cases this has been in
direct response to the human immunodeficiency virus type 1 epidemic, a number
of new antiviral agents are relevant to the practice of general pediatrics.
This article reviews recent advances in the therapy of some common and a few
unusual viral illnesses of children. The indication and efficacy of the newly
developed agents valacyclovir, famciclovir, cidofovir, oral and intraocular
ganciclovir, adefovir, respiratory syncytial virus immune globulin,
palivizumab, and imiquimod are discussed, as well new uses of acyclovir,
lamivudine, and ribavirin. Many of the antivirals discussed, including
valacyclovir and cidofovir, have not yet been studied in children, but they
hold promise for improving the treatment of pediatric viral infections.

22. Clin Obstet Gynecol 1999 Mar;42(1):134-48; quiz 174-5 
Prevention of perinatal herpes: prophylactic antiviral therapy?
Scott LL
University of Miami School of Medicine, Department of Obstetrics and
Gynecology, Plantation, FL 33324, USA. LLScottMD@aol.com

ab: "...Use of acyclovir in infants, even in those that are premature, is very
well tolerated, with a wide margin of safety..." 

23. Transplantation 1999 Jan 27;67(2):315-20 
Efficacy and cost effectiveness of oral ganciclovir in the prevention of
cytomegalovirus disease after lung transplantation.
Speich R, Thurnheer R, Gaspert A, Weder W, Boehler A
Department of Internal Medicine, Zurich University Hospital, Switzerland.
klinspr@usz.unizh.ch

BACKGROUND: Cytomegalovirus is the single most frequent pulmonary pathogen in
lung transplant recipients who survive at least 2 weeks. Patients at increased
risk are either seropositive or have received an allograft from a donor with
latent infection...  The only adverse effect was a
subclavian vein thrombosis in the intravenous ganciclovir group. CONCLUSIONS:
In lung transplant recipients, ganciclovir prophylaxis, either intravenous or
oral, is safe, well tolerated, and effective in preventing cytomegalovirus
disease. Moreover, ganciclovir prophylaxis seems likely to reduce the incidence
of bronchiolitis obliterans syndrome. The oral formulation might be preferable
because its convenience and possibly lower costs."

24. Pediatrics 1999 Jan;103(1):E10 
Intractable diarrhea from cytomegalovirus enterocolitis in an immunocompetent
infant.
Fox LM, Gerber MA, Penix L, Ricci A Jr, Hyams JS
University of Connecticut School of Medicine, University of Connecticut Health
Center, Farmington, Connecticut, USA.

Infection with cytomegalovirus (CMV) in infants can be congenital or perinatal.
Infected infants may be asymptomatic or present with pneumonia, rash,
hepatosplenomegaly, or encephalitis.1 In the presence of an immunodeficiency,
severe and sometimes fatal disease may occur. To our knowledge, CMV has not
been identified previously as a cause of intractable diarrhea of infancy. We
report the case of a 5-week-old immunocompetent infant with intractable
diarrhea attributable to CMV-induced enterocolitis. Recognition of this
infection and initiation of ganciclovir therapy was associated with a rapid
improvement and resolution of the diarrhea.

25. Transplantation 1998 Dec 27;66(12):1780-6 
Effect of oral acyclovir or ganciclovir therapy after preemptive intravenous
ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus
seropositive renal and liver transplant recipients receiving antilymphocyte
antibody therapy.
Turgeon N, Fishman JA, Basgoz N, Tolkoff-Rubin NE, Doran M, Cosimi AB, Rubin RH
Transplantation and Infectious Disease Units, Massachusetts General Hospital,
Boston 02114, USA.

BACKGROUND: Organ transplant recipients who are seropositive for
cytomegalovirus (CMV) and who are treated with antilymphocyte antibody (ALA)
therapy have a high rate of symptomatic CMV disease. The intravenous
administration of ganciclovir therapy once daily during ALA therapy decreased
the incidence from 24% to 10% in patients receiving ALA as an induction therapy
and from 64% to 22% in those treated for rejection. The present study was
undertaken to determine whether a more intensive and sustained antiviral
regimen could be more effective. METHODS: From April 1995 to December 1997, all
CMV seropositive renal and liver transplant recipients who received ALA therapy
were treated with intravenously administered ganciclovir (5 mg/kg/day with dose
adjusted for renal dysfunction) for the length of ALA therapy and then with
orally administered acyclovir (400 mg three times/day) or ganciclovir (1 gm
twice/day) for 3 to 4 months. The incidence of CMV viremia and of CMV disease
was determined during the 6 months after completion of ALA therapy. RESULTS:
Forty-one patients (35 renal and 6 liver transplant recipients) were studied.
CMV disease occurred in 2 patients (4.9%), both of whom were treated for
rejection; it occurred in 1 of 21 patients (4.8%) treated with orally
administered acyclovir, and in 1 of 20 patients (5%) treated with orally
administered ganciclovir. The only patient who developed CMV disease in the
ganciclovir group had received only 26 days of oral antiviral therapy. No CMV
disease was documented in the group of patients receiving ALA therapy as
induction therapy. CMV viremia occurred in three patients in the acyclovir
group (14.3%) and in one patient in the ganciclovir group (5%). Among renal
transplant recipients only, 1 of 35 patients developed CMV disease (2.9%) and
no case of CMV disease was documented in patients treated with orally
administered ganciclovir. All six patients receiving two courses of ALA therapy
each were free of CMV disease. Toxicity of the regimen was minimal, and
antiviral resistance did not develop. CONCLUSIONS: Preemptive antiviral therapy
with intravenously administered ganciclovir during ALA therapy and then orally
administered ganciclovir for 3 to 4 months provides virtually complete
protection against the excessive rate of CMV disease that occurs in CMV
seropositive allograft recipients receiving ALA therapy.

26. Transplantation 1998 Dec 27;66(12):1604-11 
Prevention and preemptive therapy of postransplant lymphoproliferative disease
in pediatric liver recipients.
McDiarmid SV, Jordan S, Lee GS, Toyoda M, Goss JA, Vargas JH, Martin MG, Bahar
R, Maxfield AL, Ament ME, Busuttil RW
Department of Surgery, UCLA Medical Center, Los Angeles, California, USA.

BACKGROUND: We have previously reported a 10% incidence of posttransplant
lymphoproliferative disease (PTLD) in pediatric patients receiving first liver
grafts and primarily immunosuppressed with tacrolimus. To decrease the
incidence of PTLD, we developed a protocol utilizing preemptive intravenous
ganciclovir in high-risk recipients (i.e., donor (D)+, recipient (R)-),
combined with serial monitoring of peripheral blood for Epstein Barr virus
(EBV) by polymerase chain reaction (PCR). METHODS: Consecutive pediatric
recipients of a first liver graft were immunosuppressed with oral tacrolimus
(both induction and maintenance), and low-dose prednisone. EBV serologies were
obtained at the time of orthotopic liver transplant in recipients and donors.
Recipients were divided into groups: group 1, high-risk (D+R-), and group 2,
low-risk (D+R+; D-R-; D-R+). In group 1 (high-risk), all patients received a
minimum of 100 days of intravenous ganciclovir (6-10 mg/kg/day), while, in
group 2 (low-risk), patients received intravenous ganciclovir during their
initial hospitalization and then were converted to oral acyclovir (40
mg/kg/day) at discharge. Semiquantitative EBV-PCR determinations were made at
1-2-month intervals. In both groups, patients with an increasing viral copy
number by EBV-PCR had tacrolimus levels decreased to 2-5 ng/ml. Tacrolimus was
stopped, and intravenous ganciclovir reinstituted for PTLD. A positive EBV-PCR
with symptoms, but negative histology, was defined as EBV disease; PTLD was
defined as histologic evidence of polyclonal or monoclonal B cell
proliferation. RESULTS: Forty children who had survived greater than 2 months
were enrolled. There were 18 children in group 1 (high-risk; mean age of
14+/-15 months and mean follow-up time of 243+/-149 days) and 22 children in
group 2 (low-risk; mean age of 64+/-65 months and follow-up time of 275+/-130
days). In group 1 (high-risk), there was no PTLD and one case of EBV disease
(mononucleosis-like syndrome), which resolved. In group 2 (low-risk), there
were two cases of PTLD; both resolved when tacrolimus was stopped. Both
children were 8 months old at time of transplant. Neither received OKT3, and
they had one and two episodes of steroid-sensitive rejection, respectively. One
child had EBV disease (mild hepatitis), which resolved. CONCLUSIONS: Since
instituting this protocol, the overall incidence of PTLD has fallen from 10% to
5% for children receiving primary tacrolimus therapy after OLT. No high-risk
pediatric liver recipient treated preemptively with intravenous ganciclovir
developed PTLD. Both children with PTLD were less than 1 year at OLT and
considered low-risk. However, their positive EBV antibody titers may have been
maternal in origin and not have offered long-term protection. Serial monitoring
of EBV-PCR after pediatric OLT is recommended to decrease the risk of PTLD by
allowing early detection of EBV infection, which is then managed by decreasing
immunosuppression and continuing intravenous ganciclovir.
     [comment: we note that transplant survival often necessitates using
     Prednisone as an immunosuppressant, along with the appropriate anti-
     viral treatment to counter a chronic infection that could become
     reactivated.]

27. Bone Marrow Transplant 1998 Nov;22(9):899-904 
Cytomegalovirus pp65 antigenemia-guided pre-emptive treatment with ganciclovir
after allogeneic stem transplantation: a single-center experience.
Manteiga R, Martino R, Sureda A, Labeaga R, Brunet S, Sierra J, Rabella N
Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Barcelona,
Spain.

The optimal prophylactic strategy for cytomegalovirus (CMV) disease after
allogeneic hematopoietic stem cell transplantation has not yet been
established. The aim of this study was to analyze our single-center experience
with a uniform protocol of CMV antigenemia-guided pre-emptive treatment with
ganciclovir (GCV) after allografting. Fifty-two consecutive adult patients, 48
of them transplanted from HLA-identical matched related donors were included.
T cell-depleted marrow or peripheral blood were used in 21 cases. After
engraftment, weekly blood samples were tested for CMV pp65 antigenemia and
viremia (conventional cultures) until day +100. GCV was started if CMV
antigenemia and/or CMV viremia were detected. CMV infection (CMV-I) was found
in 19 patients (37%). Seven patients suffered from CMV disease (CMV-D), three
colitis and four pneumonias. There was one death directly related to CMV-D and
three further cases died from refractory GVHD with CMV-D. Only one patient
developed CMV pneumonia without any previous positive antigenemia and/or
viremia. Multivariate analysis identified grades II-IV acute GVHD (P = 0.02)
and peripheral blood stem cell transplantation (P = 0.03) to be risk factors
for developing CMV-I. In conclusion, this monitoring protocol allowed early
treatment of CMV-I without progression to CMV-D. Pre-emptive therapy had the
additional advantage of avoiding GCV administration in most of our allograft
recipients.

28. Clin Infect Dis 1998 Sep;27(3):653-4 
Successful treatment of human herpesvirus 6 encephalitis in a bone marrow
transplant recipient.
Cole PD, Stiles J, Boulad F, Small TN, O'Reilly RJ, George D, Szabolcs P, Kiehn
TE, Kernan NA
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New
York, USA.

29. Infection 1998 Jul-Aug;26(4):234-5 
Postural epigastric pain: a unique symptom of primary cytomegalovirus
gastritis?
Giladi M, Lembo A, Johnson BL Jr
Div. of Infectious Diseases, UCLA School of Medicine, USA.

Cytomegalovirus (CMV) gastritis has been reported in transplant patients.
Symptoms are considered nonspecific, and gastroscopy with biopsy is usually
performed to establish the diagnosis. Three patients are described here 1 to 3
months after solid organ transplantation, with primary CMV gastritis, confirmed
by gastroscopy, histopathologic examination and cultures. The clinical
presentation in all three cases was sharp epigastric pain that decreased in a
supine position, increased while sitting and further increased when standing or
walking. The epigastric pain completely resolved after treatment with
ganciclovir. To the best of our knowledge, such postural epigastric pain has
not been described as a specific symptom in any other clinical entity and may
be a unique sign of primary CMV gastritis.
PMID: 9717682, UI: 98383427

30. Bone Marrow Transplant 1998 Jul;22(2):175-80 
Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after
allogeneic hemopoietic stem cell transplantation (HSCT): a randomised study.
Moretti S, Zikos P, Van Lint MT, Tedone E, Occhini D, Gualandi F, Lamparelli T,
Mordini N, Berisso G, Bregante S, Bruno B, Bacigalupo A
Divisione Ematologia II, Ospedale San Martino, Genova, Italy.

This trial was designed to compare foscarnet with ganciclovir as pre-emptive
therapy for CMV infection in patients undergoing allogeneic hemopoietic stem
cell transplant (HSCT). Thirty-nine patients were randomized to receive
foscarnet 90 mg/kg every 12 h (n = 20) or ganciclovir 5 mg/kg every 12 h (n =
19) for 15 days at the time of development of CMVAg-emia. Primary-end points of
the study were (1) outcome of CMVAg-emia; (2) progression to CMV disease; and
(3) side-effects of treatment. The secondary end-point was transplant-related
mortality (TRM). The two groups were comparable for diagnosis, status of
disease, donor type, acute graft-versus-host (aGVHD) prophylaxis, interval
between HSCT and CMVAg-emia and number of CMVAg positive cells; the donor and
recipient age were borderline older in the foscarnet group. Increments of serum
creatinine in the foscarnet group, and cytopenia in the ganciclovir group were
controlled by reducing the administered dose: in the first 15 days of therapy
9/20 foscarnet and 10/19 ganciclovir patients had a dose reduction greater than
20% (P = 0.43). Clearance of CMVAg-emia was faster in the foscarnet group
although with borderline statistical significance. Failures of treatment
occurred in 3/20 patients in foscarnet group vs 8/19 patients in ganciclovir
group (P= 0.06): causes of failure were the need for combination therapy to
control antigenemia (1/20 vs 5/19), and reactivation during treatment for 2 vs
3 patients, respectively. CMV disease was diagnosed in 1 vs 2 patients (P =
0.5) who subsequently died. The actuarial 1-year TRM was 25 vs 12%,
respectively (P = 0.3). This study suggests that foscarnet and ganciclovir are
both effective for pre-emptive therapy of CMVAg-emia, although the number of
failures would seem to be slightly higher in the ganciclovir patients.
Side-effects are seen in both groups and can be managed with appropriate dose
reduction.

31. Transpl Int 1998;11 Suppl 1:S130-4 
Acyclovir plus CMV immunoglobulin prophylaxis and early therapy with
ganciclovir are effective and safe in CMV high-risk renal transplant pediatric
recipients.
Ginevri F, Losurdo G, Fontana I, Rabagliati AM, Bonatto L, Valente R, Venzano
P, Nocera A, Basile GC, Valente U, Gusmano R
Department of Nephrology, G. Gaslini Institute, Genoa, Italy.

Cytomegalovirus (CMV) infection is still a major cause of morbidity in
high-risk renal transplant recipients. In the present report, we have reviewed
our records of renal transplant pediatric recipients (RTPR; mean age 14.1 +/-
4.9 years) since 1991, when we started a policy of CMV prophylaxis constituting
high-dose oral acyclovir plus CMV hyperimmune immunoglobulins (HIg) followed by
early i.v. ganciclovir therapy in high-risk patients (i.e., CMV
donor+/recipient-). Four patients received a kidney from a living relative
(LR), 2 patients had one previous transplant, and 1 had a combined liver-kidney
transplant. Thirty-three patients who were negative for CMV antibodies (ab)
before transplantation received a kidney from CMV ab positive donors. The
immunosuppressive regimen included cyclosporine A and steroids, with the
addition of azathioprine in the 4 patients who received an LR kidney. Serial
assessments for CMV antigenemia (pp 65) were routinely performed for 6 months
after transplantation to define CMV infection. Among the 33 CMV seronegative
recipients (R-) who received the graft from a CMV seropositive donor (D+), 18
(54.5%) experienced CMV infection, whereas among the 28 CMV R+, who received a
graft from a CMV D+, 11 (39.3%) experienced CMV infection. With regard to CMV-
related symptoms, only 2 patients suffered from a CMV syndrome (fever and
leukopenia in 1 patient, fever and arthralgia in the other). In no case did the
spectrum of CMV disease occur; only minor symptoms were present in 7 of the
remaining CMV-infected patients (fever in 6 and leukopenia in 1). Rejection
episodes and renal function did not differ between CMV-infected and
non-CMV-infected patients. Our experiences support the use of prophylactic
acyclovir plus CMV HIg followed by early therapy with i.v. ganciclovir to
combat the risk of increased morbidity in high risk RTPR.

32. Bone Marrow Transplant 1998 May;21(10):1063-6 
Primary human herpes virus 6 infection transmitted from donor to recipient
through bone marrow infusion.
Lau YL, Peiris M, Chan GC, Chan AC, Chiu D, Ha SY
Department of Paediatrics, The University of Hong Kong, Queen Mary Hospital,
Pokfulam.

An 8.5-month-old boy with Wiskott-Aldrich syndrome received a sibling matched
bone marrow transplant from his healthy non-identical twin brother. The donor
had primary human herpes virus 6 (HHV-6) infection around the time of bone
marrow donation. The recipient had hepatitis in the first week and then
developed fever and rash on day 18. Skin biopsy was shown to have HHV-6 antigen
and his peripheral blood leukocytes were HHV-6 DNA positive. He engrafted on
day 18 but the ANC dropped from 5.5 x 10(9)/l (day 23) to 0.48 x 10(9)/l (day
34) with persistent HHV-6 DNAemia. Bone marrow on day 35 was positive for HHV-6
DNA. He was treated with G-CSF and ganciclovir with good response. He later had
pneumonitis which was treated empirically with foscarnet, ceftazidime and
clarithromycin.

33. Clin Infect Dis 1997 Dec;25(6):1344-9 
Comparison of intravenous ganciclovir followed by oral acyclovir with
intravenous ganciclovir alone for prevention of cytomegalovirus and
Epstein-Barr virus disease after liver transplantation in children.
Green M, Kaufmann M, Wilson J, Reyes J
Department of Pediatrics, University of Pittsburgh School of Medicine,
Children's Hospital of Pittsburgh, Pennsylvania 15213, USA.

A randomized trial was performed to compare the sequential use of 2 weeks of
intravenous ganciclovir (10 mg/[kg.d]) followed by 50 weeks of high-dose oral
acyclovir (800 mg/m2 four times daily) with 2 weeks of intravenous ganciclovir
alone as prophylaxis for cytomegalovirus (CMV) and Epstein-Barr virus (EBV)
disease after pediatric liver transplantation. CMV disease was diagnosed for
seven of 24 patients treated with ganciclovir followed by high-dose oral
acyclovir compared with two of 24 children treated with ganciclovir alone (P =
.048). Similarly, the rate of CMV disease among high-risk patients
(CMV-positive donor/CMV-negative recipient) treated with the combination
regimen was higher than that among high-risk patients treated with ganciclovir
alone (four [57%] of seven vs. zero of five, respectively; vs P < .05). The
rate of EBV disease among patients treated with the combination regimen (eight
[33%] of 24) was similar to that among patients treated with ganciclovir alone
(five [21%] of 24; P = not significant). We conclude that sequential
prophylaxis with 2 weeks of intravenous ganciclovir followed by 50 weeks of
high-dose oral acyclovir did not decrease the frequency of CMV or EBV disease
after pediatric liver transplantation when compared with 2 weeks of intravenous
ganciclovir alone.

34. Scand J Infect Dis Suppl 1996;100:72-82 
Clinical and immunological considerations in Epstein-Barr virus-associated
diseases.
Andersson J
Department of Infectious Diseases, Karolinska Institute, Huddinge University
Hospital, Huddinge, Sweden.

Despite the fact that nucleoside analogues, such as aciclovir and ganciclovir,
and DNA-polymerase inhibitors, such as foscarnet, have a proven antiviral
effect on oropharyngeal-Epstein-Barr virus (EBV) replication, they have been
unable to show any effect on the severity or duration of infectious
mononucleosis (IM), a condition for which there is currently no established
treatment. Clinical symptoms may be due to an EBV-induced polyclonal humoral,
as well as cellular, immunoreactivity with limited pathology caused by viral
replication itself. However, despite an extensive immune response, 90% of
tested IM patients (n = 36) had a spontaneous outgrowth of in vivo EBV-infected
B-lymphocytes at onset of disease, indicating lack of specific EBV-restricted
cellular cytotoxicity at this time. Establishment of an EBV-specific
T-lymphocyte response occurred 90-180 days after onset of disease (human
leukocyte antigen-restricted cytotoxicity against EBV-infected B-cells). Thus,
development of a specific cytotoxic response was a gradual and slow process.
Assessment of cytokine pattern, at the single cell level, was performed by
immunocytochemical technique and by enzyme-linked immunosorbent assay. This
revealed an increased production of interleukin (IL)-2, interferon (IFN)-gamma,
IL-6 and tumour necrosis factor (TNF) beta in all IM patients. Those with
disseminated disease were characterized by lack of IFN-gamma production. This
loss was selective since in vitro stimulation with superantigen, such as
streptococcal pyrogenic exotoxin A, induced a normal response. These patients
lacked signs of EBV-specific T-cell cytotoxicity in vitro. Treatment with
intravenous or subcutaneous IFN-gamma, 1.5 MU every second day, in combination
with intravenous immunoglobulin G (0.5 g/kg three times per week) and oral
aciclovir, 800 mg 5 times daily, has shown promising results in some patients.
Cytokine production in tonsil tissue in 4 patients with fulminant IM and
respiratory tract obstruction showed a concomitant expression of IL-2,
IFN-gamma, IL-6, TNF beta, transforming growth factor (TGF) beta 1-3,
granulocyte colony stimulating factor, granulocyte macrophage colony
stimulating factor, IL-4 IL-1alpha, IL-beta and TNF alpha. The number of IL-2,
IFN-gamma, IL-6 and TNF beta producing cells was significantly higher compared
to tonsil tissue obtained from children with tonsillar hypertrophy. Thus, IM is
associated with extensive local cytokine production. It is suggested that this
extensive cytokine production is closely involved in the pathology of IM and
that patients with atypical IM have a dysregulation in the cytokine network.
However, the mechanism by which EBV-infected B-lymphocytes triggers this
cytokine cascade is still unknown. These findings show the need for evaluation
of patients with immunodeficiency and EBV-induced lymphoproliferative disorders
and perhaps the introduction of new immunoregulatory treatment strategies.

35. Eur J Pediatr 1994 Dec;153(12):894-7 
CD3-negative lymphoproliferative disease of granular lymphocytes in a girl with
an unusual pattern of anti-Epstein-Barr virus antibodies.
Fukunaga Y, Asano T, Takehana J, Ambo K, Matsuoka K, Yamamoto M
Department of Paediatrics, Nippon Medical School, Tokyo, Japan.

We describe an 11-year-old girl who initially had mild hepatosplenomegaly and
then presented with abnormal expansion of CD3-negative granular lymphocytes in
peripheral blood and Epstein-Barr virus (EBV) genome in the DNA obtained from
the peripheral blood mononuclear cells (PBMNC). After approximately 3 years,
she developed oedema, ascites, marked hepatosplenomegaly, and pancytopenia, and
showed both a profile of anti-EBV antibodies of reactivated infection and a
high titre of anti-cytomegalovirus antibody. Although she was treated with
antibiotics, ganciclovir, and prednisolone, she died of hepatic failure.
CONCLUSION: Careful clinical observation, periodic examination of anti-EBV
antibodies, and the analysis of EBV genome from PBMNC are needed in young
patients with CD3-negative lymphoproliferative disease of granular lymphocytes.

36. J Clin Pharmacol 1994 Dec;34(12):1199-207 
Pharmacokinetics of famciclovir in subjects with chronic hepatic disease.
Boike SC, Pue M, Audet PR, Freed MI, Fairless A, Ilson BE, Zariffa N, Jorkasky
DK
Department of Clinical Pharmacology, SmithKline Beecham Pharmaceuticals,
Philadelphia, Pennsylvania 19104.

The pharmacokinetic profile of penciclovir was determined after a single 500-mg
dose of its oral precursor, famciclovir, in 9 healthy volunteers and in 14
patients with chronic hepatic disease. Plasma and urine samples were analyzed
for concentrations of penciclovir and 6-deoxy-penciclovir using a reverse-phase
high-performance liquid chromatography (HPLC) method. Famciclovir was not
quantifiable in patients with hepatic disease, and 6-deoxy-penciclovir was
quantifiable in only a limited number of specimens. The extent of systemic
availability of penciclovir, as measured by AUC0-infinity, was similar in
patients with hepatic disease and in healthy subjects. In contrast, Cmax was
significantly lower (average decrease of 43%) in subjects with hepatic disease
relative to healthy normal subjects. Median Tmax for subjects with hepatic
disease was significantly increased (by 0.75 hours) compared with subjects with
normal liver function. These data suggest a decrease in the rate, but not the
extent, of systemic availability of penciclovir in patients with hepatic
disease. It should be unnecessary to modify the dose of famciclovir for
subjects with compensated hepatic disease and normal renal function.

37. A preliminary discussin of LKS and HSV:
http://www.jorsm.com/~binstock/lks-hsv.htm