Association with Disease of Polyomaviruses Infection
C. Association with Disease
Primary polyomavirus infections have not been associated with
any specific clinical syndromes. Most infections seem to be
subclinical although some children developed mild respiratory
symptoms and others had cystitis. It is thought that primary BKV
infections may on occasions be associated with either acute
respiratory disease or cystitis but further work is required.
Progressive multifocal leucoencephalopathy - JC
virus is now firmly associated with PML. It has not been
established whether PML is the result of a primary
infection with JCV in a person with impaired immunity or
whether it follows reactivation of latent virus. The fact
that PML is relatively uncommon in children and young
persons and more often develops in people in the fifth
and sixth decades of life suggests that latent virus is
the more likely cause. The pathogenesis of PML is not
fully understood but it is postulated that in patients
with disorders of immunoregulation, polyomaviruses are no
longer contained in a latent state and replicate within
the oligodendrocytes, causing the destruction of the cell
and the breakdown of the myelin sheath. PML is a unique
demyelinating disease which usually occurs in a person
with abnormal immune responses resulting from serious
disease, treatment with cytotoxic drugs or irradiation,
or long term immunosuppression. The pathology of PML is
distinctive and consists of multiple foci of
demyelination of varying size from pinpoint lesions to
areas of several centimetres. The lesions may occur
anywhere but are usually in the cerebral hemispheres,
less often in the cerebellum and brain stem and rarely in
the spinal cord. The oligodendrocytes in the peripheral
zone surrounding an area of demyelination are grossly
abnormal. The nuclei of abnormal oligodendrocytes are
packed with JC virions. Typically, PML evolves gradually,
with impairment of mental function and disturbance of
speech and vision. Movement may also be affected. The
disease then progresses rapidly and the patient is
severely disabled, eventually becoming demented, blind
and paralyzed and finally coma and death. PML is
frequently associated with lymphoproliferative and other
chronic diseases, such as AIDS, Hodgkin's disease, CLL,
sarcoidosis, TB, SLE and organ transplantation. Only
rarely has PML been reported occurring spontaneously in
an apparently healthy person. Occasionally, PML may
spontaneously arrest. PML has been reported in children
with congenital severe combined immunodeficiency which
suggests that a primary JCV infection is responsible.
Ureteric stenosis in renal transplant recipients -
the only other disease with which ureteric stenosis have
been associated is ureteric stenosis in renal transplant
patients. The polyomavirus infection induces
proliferation of the transitional epithelial cells in the
ureter and this can lead to partial obstruction or actual
stricture formation. The affected cells had inclusion
bodies. 9 cases have been recognized and both JC and BK
have been implicated. The ureteric obstruction occurred
between 50 to 300 days post-transplant.
Other possible associations - BK virus was
associated with cases of acute haemorrhagic cystitis
following bone marrow transplantation. However, it is
possible that two independent but synchronous events may
be taking place - reactivation of BKV and haemorrhagic
cystitis. The genomes of JC and BK virus were detected in
several tumours, but there is no evidence that human
polyomaviruses are associated with the causation of any
tumours.
D. Laboratory Diagnosis
PML - The clinical diagnosis of PML is confirmed
by histological and virological examination of brain
material obtained by brain biopsy or at postmortem.
Before a biopsy is done, both serum and CSF should be
examined for antibodies against JCV. A positive result
will not confirm PML, but a negative result makes the
diagnosis of PML very unlikely. It is rare to detect
antibodies against JC in the CSF. When it is detected, it
is suggestive of active multiplication of JCV within the
CNS. The brain biopsy or autopsy material can be examined
by EM or IEM. The specimen can also be examined directly
for JCV antigen by immunofluorescence or immunoperoxidase
staining. Virus isolation is very difficult for JCV. When
attempted, primary human fetal glial cells are used. The
presence of the virus in culture is confirmed by EM, IF
or haemagglutination. JC is rarely excreted in the urine
of patients suffering form PML.
Renal Tract Infections - the methods generally
employed to detect the presence of polyomavirus in urine
are cytological examination of the urine for
inclusion-bearing cells, EM and virus isolation. The
cytology of urine in human polyomavirus infection is
quite characteristic. The inclusion-bearing cells have a
characteristic appearance and are often present in large
numbers. Electron Microscopy of the urinary sediment
after centrifugation at 20000 may reveal the presence of
polyomavirus particles. It is difficult to isolate JC and
BK viruses: Primary PHFG cells must be used for isolation
of JCV; BKV have a wider host cell range and HEK cells
can be used as well as PHFG cells. More sensitive
techniques are being developed, such as dot- blot and
PCR.
Serological Diagnosis - HAI is the most widely
used serological technique for measuring antibodies
against the polyomaviruses. CFT, neutralization, ELISA
and RIAs have also been used.
E. Management
Because of the invariably fatal outcome of PML, various
antiviral drugs have been tried. The only drug that may have had
an effect is cytarabine. Reports have been published on 8
laboratory confirmed cases of PML treated with cytarabine.
Long-term improvement was seen in 2 patients. In another person,
there was a dramatic response to therapy within 24 hours but this
was not maintained. The rapid progression of the disease was
halted in a fourth patient but the neurological damage was
severe. The remaining 4 individuals did not show any improvement.
One should also consider relaxing any immunosuppression regimes
in such patients.
