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:
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:
References
1. Reploeg MD, Storch GA, Clifford DB. Bk virus: a clinical review. Clin Infect Dis 2001;33(2):191-202.
2. Elsner C, Dorries K. Evidence of human polyomavirus BK and JC infection in normal brain tissue. Virology 1992;191(1):72-80.
3. Akazawa Y, Terada Y, Yamane T, Tanaka S, Aimoto M, Koh H, Nakane T, Koh KR, Nakamae H, Ohsawa M, Wakasa K, Hino M. Fatal BK virus pneumonia following stem cell transplantation. Transpl Infect Dis 2012;14(6):E142-146.
4. Hirsch HH, Randhawa P. BK virus in solid organ transplant recipients. Am J Transplant 2009;9 Suppl 4:S136-146.
5. Ramos E, Drachenberg CB, Wali R, Hirsch HH. The decade of polyomavirus BK-associated nephropathy: state of affairs. Transplantation 2009;87(5):621-630.
6. Lopes da Silva R. Polyoma BK virus: an emerging opportunistic infectious agent of the human central nervous system. Braz J Infect Dis 2011;15(3):276-284.
7. Bogdanovic G, Brytting M, Cinque P, Grandien M, Fridell E, Ljungman P, Lonnqvist B, Hammarin AL. Nested PCR for detection of BK virus and JC virus DNA. Clin Diagn Virol 1994;2(3):211-220.
8. Jorgensen GE, Hammarin AL, Bratt G, Grandien M, Flaegstad T, Johnsen JI. Identification of a unique BK virus variant in the CNS of a patient with AIDS. J Med Virol 2003;70(1):14-19.
9. Bratt G, Hammarin AL, Grandien M, Hedquist BG, Nennesmo I, Sundelin B, Seregard S. BK virus as the cause of meningoencephalitis, retinitis and nephritis in a patient with AIDS. Aids 1999;13(9):1071-1075.
10. Hedquist BG, Bratt G, Hammarin AL, Grandien M, Nennesmo I, Sundelin B, Seregard S. Identification of BK virus in a patient with acquired immune deficiency syndrome and bilateral atypical retinitis. Ophthalmology 1999;106(1):129-132.
11. Stoner GL, Alappan R, Jobes DV, Ryschkewitsch CF, Landry ML. BK virus regulatory region rearrangements in brain and cerebrospinal fluid from a leukemia patient with tubulointerstitial nephritis and meningoencephalitis. Am J Kidney Dis 2002;39(5):1102-1112.
12. Behzad-Behbahani A, Klapper PE, Vallely PJ, Cleator GM, Bonington A. BKV-DNA and JCV-DNA in CSF of patients with suspected meningitis or encephalitis. Infection 2003;31(6):374-378.
13. Green J, Saigal G, Rojas CP, Post MJ. Rare presentation of BK encephalitis in a child: imaging and pathological findings. Pediatr Radiol 2012;42(9):1145-1148.
14. Pereira T, Rojas CP, Garcia-Buitrago MT, Chandar J, Abitbol C, Seeherunvong W, Rusconi P, Bruce JH, Zilleruelo G. A child with BK virus infection: inadequacy of current therapeutic strategies. Pediatr Transplant 2012;16(7):E269-274.
15. van Aalderen MC, Heutinck KM, Huisman C, ten Berge IJ. BK virus infection in transplant recipients: clinical manifestations, treatment options and the immune response. Neth J Med;70(4):172-183.