Fatal encephalitis due to BK virus in a patient with common variable
immunodeficiency: a case report
Faris G Bakri*, Yacoub G Bahou, Firas A Al-Sammarrai, Azmi Al-Hadidy, Almutez Gharaibeh,
Ghida K Zaid, Azmi Mahafzah, Nidaa A Ababneh, Imad Zak
*Faris G. Bakri, MD (Corresponding author)
Department of Medicine - Division of Infectious Diseases
Jordan University Hospital
PO Box 13046
Amman 11942
JORDAN
Tel: (9626) 5353666 ext. 2474
Fax: (9626) 5353388
Email: fbakri@ju.edu.jo
Yacoub G Bahou, MD
Department of Medicine, Division of Neurology, Jordan University Hospital
Firas Al-Samarrai, MD
Department of Medicine, Jordan University Hospital
Azmi Al-Hadidy, MD
Department of Radiology, Jordan University Hospital
Almutez Gharaibeh, MD
Division of Ophthalmology, Jordan University Hospital
Ghida K Zaid
Faculty of Medicine, University of Jordan
Azmi Mahafzah, MD, PhD; Nidaa A Ababneh
Department of Microbiology, Jordan University Hospital
Imad Zak, MD
Wayne State University - Detroit Medical Center, Detroit, MI, USA
Keywords: Encephalitis; BK virus; polyoma virus, common variable immunodeficiency
Abstract:
Encephalitis due to BK virus is a very rare condition. Here, we describe a young male patient
with common variable immunodeficiency who developed fatal encephalitis due to BK virus.
Diagnosis was made by the detection of viral DNA by polymerase chain reaction in the
cerebrospinal fluid and by the compatible clinical findings. The patient presented initially
with eye involvement that was followed later on by spastic quadriparesis and behavioral
changes. To our knowledge, this is the first report of BK virus encephalitis in a patient with
common variable immunodeficiency. We suggest that BK virus should be suspected in cases
of encephalitis particularly in patients with immunodeficiency.
1. Background
BK virus (BKV) is a member of the polyomaviridae family which also includes JC virus (JCV).
Infection with BKV is widespread and occurs in about 60–90% of the general population.
Most primary infections occur during childhood via the respiratory tract and are usually
asymptomatic or minimally symptomatic with fever and upper respiratory symptoms. After
primary infection, the virus remains latent mainly in the kidneys and possibly in other tissues
including the brain (1,2). However, some immunocompromised individuals may experience
viral reactivation with the following conditions: hemorrhagic cystitis, ureteric stenosis,
tubulointerstitial nephritis, retinitis, encephalitis, and pneumonia (3-5).
Encephalitis due to BKV is an emerging condition. It is a very rare disease and has mostly
been described in immunocompromised patients (6). To our knowledge, we present here
the first report of encephalitis due to BKV in a patient with common variable
immunodeficiency (CVID).
2. Case report
2.1 Presentation
A 23 year-old male patient was diagnosed with CVID at the age of 16 years after suffering
several episodes of urinary and respiratory tracts infections since age 8 years. At the time of
diagnosis, his IgG was < 0.5 g/L (normal 7-19 g/L), IgG subclasses undetectable, IgA < 0.16
g/L (0.45-3.5 g/L), and IgM 3 g/L (normal 2-4.5 g/L). CD3 was 70%, CD4 31%, CD8 36%, and
CD19 17%. Since then, he had been maintained on intravenous immunoglobulin (IVIG)
therapy at a dose of 20 grams every 3-4 weeks and had been doing very well. The patient
had history of tonsillectomy at age of 3 years and a femoral hernia repair at age of 1 year.
His parents were unrelated and there were no similar cases in his family.
In August 2008 and while doing Umrah (a pilgrimage to Mecca), the patient complained of
sudden onset of blurred and tunneled vision of the left eye. Few weeks later, an ophthalmic
exam showed decreased visual acuity, mild optic disc atrophy, and left relative afferent
pupillary defect. A subsequent orbit CT with contrast showed no orbital masses. Just before
this trip, however, the patient received a dose of IVIG and his IgG trough level before that
dose was 5 g/L.
In January 2009, the patient started to have unsteady gait, left body weakness, and slurred
speech. A brain MRI, performed after three weeks from the onset of these complaints,
revealed periventricular hyperintense lesions with minimal cerebellar involvement
suggestive of encephalitis (Figure 1). Subsequently, the patient was admitted to our hospital
in April 2009 for further investigation. He denied having fever, neck pain, nausea, vomiting,
or photophobia. On physical exam the patient was conscious and oriented. He was afebrile
and had no neck stiffness. He had memory impairment, behavioral changes manifesting as
irritability, spastic dysarthria, decreased visual acuity in left eye, and spastic quadriparesis.
An ophthalmologic exam showed positive left relative afferent pupillary defect with optic
disc atrophy.
Laboratory findings showed a serum hemoglobin of 16.3 g/dL, white blood cell count (WBC)
7.45 × 109 /L (57% neutrophils, 27% Lymphocytes), and platelet count 144 × 109 /L. ESR 12
mm/1st hour (normal 0-15 mm/1st hour) and C-reactive protein 15 mg/L (normal < 5 mg/L).
Liver, kidney, vitamin B 12, and thyroid function tests were all normal. Total protein was 7.8
g/dL (normal, 6.2-8.7 g/dL). The chest X-ray was normal. A brain MRI revealed the same
earlier findings with involvement of the internal capsules (Figure 2). Brain MRA and MRV
were both normal and without evidence of vasculitis. Cervical spine MRI was normal. The
CSF showed glucose of 46 mg/dL, protein 81 mg/dL, WBC nil, red blood cells count 120
cells/ml, and absent oligoclonal bands. The CSF bacterial culture was negative. Urine protein
electrophoresis was normal. Testing for human immunodeficiency virus (HIV), rapid plasma
reagin (RPR), anti-nuclear antibody (ANA), and cytomegalovirus serum PCR were all
negative. The cosyntropin test was normal. EEG showed mild degree of generalized
neurophysiological disturbances with no epileptiform discharges.
Because the brain MRI findings suggested the presence of progressive multifocal
leukoencephalopathy (PML), testing the CSF for polyomavirus by polymerase chain reaction
(PCR) was performed and was positive for BKV.
2. 2 Virological investigation
DNA extraction: DNA was extracted from the CSF sample using QIAamp DNA mini kit
(Qiagen, Hilden, Germany) according to the manufacturer’s instructions.
Nested PCR for the detection of polyomavirus: the DNA sample was frozen at (-20C0) before
analysis. A nested PCR specific for the early regions of both JCV and BKV was used here as
previously described by Bogdanovic et al. (7). A volume of 5 microl of DNA was used in the
first round of nested PCR with the outer primer set to produce 631 bp for JCV and 372 bp for
BKV. The second round performed with the inner primer set resulted in a fragment of 173 bp
for JCV and 176 bp for BKV (Figure 4). Since JCV has 75% genome homology with BKV, the
JCV (173-bp) and BKV (176-bp) amplification products were distinguished by BamHI and
Hinf1 restriction enzymes.
Digestion of nested PCR products with restriction enzyme: BamHI cleaves the JCV amplimer
in two fragments of 120 and 53 bp respectively, while the SV40 and BKV fragment remain
uncleaved. HinfI cleaves the SV40 into three fragments (110, 54, and 4 bp, respectively), the
JCV in two fragments (141 and 32 bp, respectively), and the BKV in three fragments (90, 54,
and 32 bp, respectively) (Figure 3).
2.3 Follow up
In Sept 2009, the patient received ganciclovir intravenously for two weeks. However, he had
no improvement. His ophthalmologic exam showed deterioration of best corrected visual
acuity to hand motion in left eye and established left optic atrophy with no affection of best
corrected visual acuity in the right eye. His kidney function remained normal. A follow up
brain MRI (Figure 4) showed worsening of earlier findings. The patient was discharged home
for palliative care and eventually died in Sept. 2010. He continued to receive IVIG during his
entire illness course every four weeks until 2 months prior to his death.
3. Discussion
Our case documents the diagnosis of fatal encephalitis due to BKV in a patient with CVID.
The initial complaint manifested as a unilateral visual difficulties during the Umrah trip. The
subsequently diagnosed unilateral optic atrophy was most probably a sequel of a previous
attack of optic neuritis. Retinitis in association with BKV encephalitis is rare and has been
reported in one previous case (8-10). We also highly suspect, because of the travel history,
that the patient's disease represented an acquired primary infection rather than a
reactivation process. Primary infection with BKV resulting in encephalitis has been described
in two previous cases; in the first, the development of primary infection was confirmed by
serological testing (11). While in the second, a primary infection was proposed because of
the very young age (5 years) of the patient (12).
So far, there have been 26 reported cases of encephalitis due to BKV in the Pubmed. In
these reports, the underlying immune status or risk factor was reported as
immunocompetent (9 cases), acquired immunodeficiency syndrome (AIDS) (5 cases),
hemato-oncological diseases under chemotherapy or bone marrow transplant (7 cases),
AIDS and chemotherapy for non Hodgkin's lymphoma (1 case), cardiac transplant (2 cases),
renal transplant (1 case), and long term steroid use (1 case) (6,13,14). Death occurred in ten
patients and all those who died had an underlying immunodeficiency. Hence, the prognosis
appears to be largely dependent on the patient's immune condition (6). Treatment for BK
virus encephalitis is not yet established. However, using antiretroviral agents in AIDS
patients and decreasing immunosuppression in transplant patients have been employed
with moderate success (6). In refractory cases of BKV-associated disease, antiviral agents
such as cidofovir, leflunomide, IVIG, and quinolones may be applied. However, the
effectiveness of these agents is doubtful and some of them can cause severe side effects
(15).
CVID represents a large heterogeneous group of antibody deficiency syndromes. It is a rare
condition with prevalence rate between 5-100 per million and is the most common cause for
primary immunodeficiency following selective IgA deficiency (16,17). Patients with CVID are
at risk for recurrent infections mostly in the upper and lower respiratory and gastrointestinal
tracts. Encephalitis, on the other hand, is generally an infrequent infection in CVID and the
reported etiologies include enteroviruses (18), West Nile virus (19), herpes simplex virus
(20), cytomegalovirus (21), measles (22), toxoplasma (23), and JCV (18,24-29).
Here, the development of encephalitis despite having both a satisfactory IgG trough level
and a recent administration of IVIG along with the tendency of the BKV to affect patients
with cell medicated immune deficiency suggest a deficiency in the cell mediated immune
arm. This is not surprising as patients with CVID might also have decreased cellular immune
function consisting of numerical and/or functional defects involving T-cells, natural killer
cells, dendritic cells, macrophages, and monocytes (30-33).
The main limitation in this report is the lack of documentation of brain involvement with the
BKV either by immunohistochemistry or by in-situ hybridization. However, the presence of
viral DNA in the CSF, immunodeficiency, compatible radiological findings with involvement
of the periventricular areas, and absence of other alternative diagnosis strongly favor the
diagnosis of BKV encephalitis (6).
In conclusion, Encephalitis due to BK virus is an emerging and devastating condition.
Physicians should be aware of this condition and test the CSF for BKV especially in the
immunocompromised patients. In addition, further research is needed to establish better
treatment options for this condition.
Conflict of interest
None declared.
Figure 1: Axial T2WI (FLAIR) showing bilateral periventricular hyperintense lesions (arrows).
Figure 2: Axial diffusion MRI showing bilateral periventricular diffusion restriction.
Figure 3: Differentiation between JCV and BKV viruses by restriction enzyme analysis of the
amplified PCR product. Lane 1 negative control; lane 2 undigested PCR product; lane 3
digested BKV product with BamHI; lane 4 DNA marker (100-bp ladder); lane 5 digseted BKV
product with HinfI.
Figure 4:
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