Ruther et al document HSV as a significant participant in IBD and describe
how IFN-alpha treatment was very helpful (1). Becker presents citations
implicating HSV (nasal-olfactory-amygdala) and its migration into areas
affected in autism (2) -- eg, amygdala and hippocampus. Chonmaitree found
CMV and/or HSV in 2-4% of 271 kid with acute otitis (3). RM Gesser et al
documented that HSV can migrate from the gastroinestinal tract into the CNS,
including into the amygdala (4-6). IFN-alpha, helpful in HSV-related IBD (1),
is also helpful in HSV within the CNS, especially in conjunction with acyclovir
(7).
Cytokine-induced viral purging can occur with cell destruction (8), which would
be extremely important in cases of persisting CNS infection.
Comments: Given the correspondence between autism symptoms and HSV literature,
that some autism-spectrum children are acyclovir-responders is not surprising.
Should
IFN-alpha be researched as a therapy useful in a subgroup of autism-spectrum
children? In my opinion, the answer clearly is Yes.
Teresa
1. Hepatogastroenterology 1998 May-Jun;45(21):691-9
Interferon alpha (IFN alpha 2a) therapy for herpes virus-associated
inflammatory bowel disease (ulcerative colitis and Crohn's disease).
Ruther U, Nunnensiek C, Muller HA, Bader H, May U, Jipp P
BACKGROUND/AIMS: The etiology and pathogenesis of ulcerative colitis and
Crohn's disease remain unclear, so that exact causal therapy is not yet
possible. In our UC and CD patients, viral infections, particularly of the
upper respiratory tract, aggravated the underlying disease. This had led us
to use in-situ hybridization to investigate intestinal mucosa for viral agents
such as HSV I + II- and Epstein-Barr virus DNA. We found these DNA in the
cell nuclei in the surface and glandular epithelia of the affected mucosa of the
small intestine and the colon. These findings indicated that viruses may
exacerbate these inflammatory bowel diseases.
METHODOLOGY: Over a period of 1-4.7 years, we treated 16 patients
aged 25-65 with Crohn's disease (12 patients) or ulcerative colitis (four
patients).
In 14 patients, inflammatory bowel disease had been diagnosed years before
(mean, 15.3 years). When we started therapy, 75% of the patients with Crohn's
disease had extra-intestinal manifestations; and the CDAI after Best averaged
considerably above 150.
All patients had been taking either prednisone or prednisolone and/or 5-ASA or
SASP and/or azathioprine or metronidazole for many years. Using PCR, mucosal
specimens of the small intestine and/or the colon were tested for EBV-, HSV
I + II, HHV6- and CMV DNA. In 12 of the 16 patients. EBV- and/or HHV6 DNA were
found in the affected mucosa. Since interferon alpha administration has
proven effective in chronic hepatitis-B therapy, we decided to administer
interferon alpha 2a (13,46,47,55). After stopping the above-mentioned basic
therapies,
we commenced treatment with 6 million units of interferon alpha 2a
subcutaneously
3 times per week for at least six months. Four of the patients showed no signs
of improvement, and their therapy was stopped after three months. For the
others, therapy was continued until patients were clinically symptom-free
and viral DNA could no longer be traced in their mucosal biopsies.
RESULTS: With interferon therapy, 12 of the 16 patients showed slow but
continual
improvement. Particularly impressive was the remission of the extra-intestinal
manifestations, which did not recur in any patient during interferon therapy.
Four patients did not show any improvement, and the clinical symptom of
diarrhea continued. Two patients with ulcerative colitis suffered relapses
three and four years later, after severe bouts of para-influenza of the
upper respiratory tract. In these two patients, EBV- and HHV6 DNA was found in
the inflamed mucosa of the colon. Renewed therapy with interferon alpha 2a
successfully cleared up the inflammation. The patient group needed an
average of eight weeks to become clinically symptom-free, and an average of six
months to achieve complete virus elimination in the pathologically altered
mucosa.
CONCLUSIONS: For herpesvirus-associated ulcerative colitis and Crohn's
disease,interferon alpha 2a treatment should be started as early as possible to
prevent disease becoming chronic. Whether this kind of antiviral treatment will
be as
effective in the long term, and whether malignant transformation (herpes
viruses are potential tumor inducers) will be delayed or prevented, are
questions that can be answered only by future long-term studies.
2. Virus Genes 1995;10(3):217-26
HSV-1 brain infection by the olfactory nerve route and virus
latency and reactivation may cause learning and behavioral
deficiencies and violence in children and adults: a point of view.
Becker Y
Department of Molecular Virology, Faculty of Medicine, Hebrew University of
Jerusalem, Israel.
Two recent studies provided new evidence on the latency of HSV-1 DNA in 15.5% of
olfactory bulbs
and in 72.5% of trigeminal nerves from human corpses at forensic postmortems (1)
and in 35% of 40
autopsied human brains (2). In the latter brains, latent HSV-1 DNA was found in
the olfactory bulbs,
amygdala, hippocampus, brain stem, and trigeminal ganglia. Although in these
studies it is not known by
which route HSV-1 entered the olfactory bulbs and brain, experimental studies in
mice (3) revealed that
injection of HSV-1 into the olfactory bulbs leads to virus migration into the
brain amygdala and
hippocampus via the olfactory nerve and locus coeruleus. If the olfactory
ciliary nerve epithelium is the
port of entry of HSV-1 into the olfactory bulbs and brain in humans as well,
protection of the nose
against HSV-1 infection may be needed to prevent virus latency in neurons in the
amygdala and
hippocampus (3). Infection of humans by HSV-1 was estimated to increase from
18.2% in the 0-20 year
population group to 100% in persons older than 60 years (1), indicating that
worldwide human
populations at all ages are at risk of brain infection by the olfactory nerve
route. In addition, both primary
infection and reactivation of latent DNA in the brain may lead to damage of
neurons in the brain involved
in memory, learning, and behavior, as observed in infected, acyclovir-treated
mice (3). The current
introduction of a live apathogenic varicella-zoster virus (VZV) vaccine to
immunize children against
chickenpox (4) may suggest that the time is ripe for immunization of children
and adults against HSV-1
infections, especially infections by the olfactory nerve route, to prevent
potential brain damage.
3. Clin Infect Dis 1992 Oct;15(4):650-3
Presence of cytomegalovirus and herpes simplex virus in middle ear
fluids from children with acute otitis media.
Chonmaitree T, Owen MJ, Patel JA, Hedgpeth D, Horlick D, Howie VM
Department of Pediatrics, University of Texas Medical Branch, Galveston 77550.
Twenty-seven (10%) of 271 infants and children with acute otitis media (AOM)
were found to be
infected with cytomegalovirus (CMV) or herpes simplex virus type 1 (HSV). CMV or
HSV, alone or in
combination with bacteria or other viruses, was isolated from the middle ear
fluid (MEF) of 10 patients.
In three cases, CMV alone was isolated from the MEF, and in one case, HSV alone
was isolated. One of
the CMV cases involved an acute primary or reactivation of CMV infection, with
CMV-bacterial otitis
and conjunctivitis as major manifestations. One patient with AOM and stomatitis
had purulent otitis
associated with the presence of HSV in MEF, with no other bacterial or viral
pathogens noted in MEF or
nasal wash specimens. While most patients with CMV infection were probably
asymptomatic excreters
at the time of development of AOM, CMV did enter the middle ear. The presence of
CMV in MEF was
prolonged, and the patients continued to have clinical signs of otitis despite
negative bacterial cultures.
Among patients with bacterial otitis, a higher proportion of those who had CMV
found only in nasal wash
specimens had persistent bacteria in MEF, compared with those who were
concurrently infected with
other viruses (57% vs. 19%; P less than .04). This report is the first to
suggest an etiologic role for CMV
and HSV in AOM.
PMID: 1330014, UI: 93042417
4. Gesser RM, et al. Latent herpes simplex virus type 1 gene expression in
ganglia innervating the human
gastrointestinal tract. J Virol. 1997 May;71(5):4103-6.
5. Gesser RM, et al. Oral inoculation with herpes simplex virus type 1
infects enteric neuron and mucosal nerve fibers within the gastrointestinal
tract in mice. J Virol. 1996 Jun;70(6):4097-102.
6. Gesser RM, et al. Oral inoculation of SCID mice with an attenuated herpes
simplex virus-1 strain causes persistent enteric nervous system infection and
gastric ulcers without direct mucosal infection.
Lab Invest. 1995 Dec;73(6):880-9.
7. Antiviral Res 1999 Nov;44(1):75-8
Effect of recombinant human interferon alpha B/D (rHu-IFN-alpha
B/D) in combination with acyclovir in experimental HSV-1 encephalitis.
Wintergerst U, Gangemi JD, Whitley RJ, Chatterjee S, Kern ER
The efficacy of recombinant human interferon alpha B/D in experimental HSV-1
encephalitis was
investigated in the murine system. Recombinant Hu-IFN-alpha B/D significantly
reduced the mortality in
a mouse encephalitis model (about 30%, P = 0.021), whereas natural mouse
interferon was inactive.
Combination of acyclovir with Hu-IFN-alpha B/D had an additive effect.
PMID: 10588335, UI: 20053556
8. Cytokine-induced viral purging -- role in viral pathogenesis.
Guidotti LG, Chisari FV. Curr Opin Microbiol 1999 2.388-91.
The authors mention type I and II interferons as well as TNF-alpha as
cytokines that can induce non-cytolytic viral clearance (in some cell
types).