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Journal of Clinical Virology 57 (2013) 363– 369

Contents lists available at SciVerse ScienceDirect

Journal of Clinical Virology

j ourna l h om epage: www.elsev ier .com/ locate / j cv

ase report

atal encephalitis due to BK virus in a patient with common variablemmunodeficiency: A case report

aris G. Bakria,∗, Yacoub G. Bahoub, Firas A. Al-Sammarrai c, Azmy Hadidyd,lmutez Gharaibehe, Ghida K. Zaid f, Azmi Mahafzahg, Osama A. Samarad,idaa A. Ababnehg, Imad Zakh

Department of Medicine – Division of Infectious Diseases, The University of Jordan, PO Box 13046, Amman 11942, JordanDepartment of Medicine, Division of Neurology, The University of Jordan, JordanDepartment of Medicine, Jordan University Hospital, JordanDepartment of Radiology, The University of Jordan, JordanDivision of Ophthalmology, The University of Jordan, JordanFaculty of Medicine, The University of Jordan, JordanDepartment of Microbiology, The University of Jordan, JordanWayne State University – Detroit Medical Center, Detroit, MI, USA

a r t i c l e i n f o

rticle history:eceived 17 February 2013eceived in revised form 18 April 2013

a b s t r a c t

Encephalitis due to BK virus is a rare condition. Here, we describe a young male patient with commonvariable immunodeficiency who developed fatal encephalitis due to BK virus. The patient presentedinitially with ocular symptoms that were followed by behavioral changes and spastic quadriparesis.

ccepted 21 April 2013

eywords:ncephalitisK virus

Diagnosis was made by the compatible clinical findings and detection of viral DNA by polymerase chainreaction in the cerebrospinal fluid. To the best of our knowledge, this is the first report of BK virusencephalitis in a patient with common variable immunodeficiency. We suggest that BK virus should besuspected in cases of encephalitis; particularly in patients with immunodeficiency.

olyoma virusommon variable immunodeficiency

. Why this case is important?

BK virus (BKV) is a member of the Polyomaviridae family, whichlso contains JC virus (JCV) and simian virus 40 (SV40). Infec-ion with BKV is widespread and occurs in 60–90% of the generalopulation. Most primary infections occur during childhood viahe respiratory tract and are usually asymptomatic or minimallyymptomatic with fever and upper respiratory symptoms. After pri-ary infection, the virus remains latent, mainly in the kidneys and

ossibly in other tissues including the brain.1,2 Subsequent viraleactivation, particularly in immunocompromised patients, mayresent as hemorrhagic cystitis, ureteric stenosis, tubulointerstitialephritis, retinitis, encephalitis, and pneumonia.3–5

Encephalitis due to BKV is a rare and emerging condition withost cases being reported in patients with acquired immunode-

ciency syndrome (AIDS) or after transplantion.6,7 To the best of

ur knowledge, this is the first report of encephalitis due to BKVccurring in a patient with common variable immunodeficiencyCVID).

∗ Corresponding author. Tel.: +962 6 5353666x2474; fax: +962 6 5353388.E-mail addresses: fbakri@yahoo.com, fbakri@ju.edu.jo (F.G. Bakri).

386-6532/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.jcv.2013.04.016

© 2013 Elsevier B.V. All rights reserved.

2. Case report

2.1. Case description

A 23 year-old male patient was diagnosed with CVID at the ageof 16 years after suffering several episodes of respiratory and uri-nary tracts infections since age 8 years. At the time of diagnosis, hisIgG 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). Thelymphocytes subsets were: CD3 70%, CD4 31%, CD8 36%, andCD19 17%. Subsequently, he had been maintained on intravenousimmunoglobulin (IVIG) therapy at a dose of 20 g every 3–4 weeksand has been doing very well. In addition, the patient underwentfemoral hernia repair at age 1 year and tonsillectomy at 3 years.His parents were unrelated and there were no similar cases in hisfamily.

In August 2008, the patient made an Umrah trip (a type of pil-grimage to Mecca). Just before the trip, however, he received a doseof IVIG and his IgG trough level before that dose was 5 g/L. A fewdays after arrival to Mecca, the patient complained of sudden onset

of blurred vision in the left eye. Three months later, an ophthalmicexamination showed decreased visual acuity, mild optic disk atro-phy, and left relative afferent pupillary defect. Subsequent orbitalcomputed tomography with contrast showed no orbital masses

364 F.G. Bakri et al. / Journal of Clinical Virology 57 (2013) 363– 369

F ricula( ite arrp ).

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ig. 1. Axial FLAIR images show coalescent high signal abnormality in the periventa) and (b)). Focal signal abnormality is seen in the periphery of the cerebellum (whrogression of signal abnormality in the bilateral cerebral peduncles (white arrows

In January 2009, the patient developed an unsteady gait, leftody weakness, and slurred speech. A brain magnetic resonance

maging (MRI), performed at 3 weeks after the onset of these com-laints revealed hyperintense lesions affecting the periventricular,eep white matter, and cerebellar areas (Fig. 1a–c).

In April 2009, the patient was admitted to our hospital forurther investigation. He denied having fever, neck pain, nausea,

omiting, or photophobia. On physical examination the patient wasonscious and oriented. He was afebrile and had no neck stiffness.e had memory impairment, behavioral changes manifesting as

rritability, spastic dysarthria, decreased visual acuity in the left eye,

r and deep cerebral white matter without significant mass effect (white arrows inow in (c)). Coronal FLAIR images from April 2009 (d) and August 2009 (e) showing

and spastic quadriparesis. An ophthalmologic examination showedpositive left relative afferent pupillary defect with optic disk atro-phy.

Laboratory findings showed 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. Erythrocyte sedi-mentation rate 12 mm in the first hour, and C-reactive protein

15 mg/L (normal <5 mg/L). Liver, kidney, total protein, vitamin B12, thyroid function, and cosyntropin tests were all normal. Test-ing for human immunodeficiency virus (HIV), rapid plasma reagin(RPR), anti-nuclear antibody, and cytomegalovirus (CMV) serum

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F.G. Bakri et al. / Journal of Cl

olymerase chain reaction (PCR) were all negative. Serum andrine protein electrophoresis were normal. Chest X-ray was nor-al. Brain MRI revealed persistent periventricular abnormalitiesith involvement of mid brain (Fig. 1d). Brain magnetic resonance

ngiogram (MRA) and magnetic resonance venography (MRV) wereoth normal. Cervical spine MRI was normal. Electroencephalogra-hy (EEG) showed a mild degree of generalized neurophysiologicalisturbances with no epileptiform discharges. Cerebrospinal fluidCSF) showed glucose of 46 mg/dL, protein 81 mg/dL, WBC nil, redlood cell count 120 cells/mL, absent oligoclonal bands, and neg-tive bacterial culture. CSF testing for polyomavirus by PCR wasositive for BKV.

In August 2009, because of clinical deterioration and worsen-ng brain MRI (Fig. 1e), intravenous ganciclovir was administeredor 2 weeks. However, the patient had no improvement and wasubsequently discharged home for palliative care. He continued toeceive IVIG during his entire illness every 4 weeks until 2 monthsrior to his death in September 2010.

.2. Virological investigation

DNA extraction: DNA was extracted from the CSF using QIAampNA mini kit (Qiagen, Hilden, Germany).

Nested PCR for the detection of polyomavirus: the DNA sampleas frozen at (–20 ◦C) before analysis. A nested PCR specific for the

arly regions of JCV and BKV was used as previously described.8 Aolume of 5 �L of DNA was used in the first round of nested PCRith the outer primer set to produce 631 bp for JCV and 372 bp

or BKV. The second round performed with the inner primer setesulted in a fragment of 173 bp for JCV and 176 bp for BKV. SinceCV has 75% genome homology with BKV, the JCV (173-bp) and BKV176-bp) amplification products were distinguished by BamHI andinf1 restriction enzymes.

Digestion of nested PCR products with restriction enzyme: BamHIleaves the JCV amplimer in two fragments of 120 and 53 bp, whilehe SV40 and BKV fragment remain uncleaved. HinfI cleaves theV40 into three fragments (110, 54, and 4 bp), the JCV in two frag-ents (141 and 32 bp), and the BKV into three fragments (90, 54,

nd 32 bp).

. Other similar and contrasting cases in the literature

BKV has been isolated from normal brain tissue,2 brain tumors,9

SF of patients without neurological symptoms–although rare,10

he brain or CSF of patients with heterogenic neurological man-festations notably progressive multifocal leukoencephalopathyPML),11–13 and patients with evidence of encephalitis. This lat-er finding is rare and has been reported so far in only 24atients.6,7,10,14–28 Those patients and the present case are shown

n Table 1.In patients with encephalitis due to BKV, the underlying

mmune status or risk factor was reported as: immunocompetent9 cases); AIDS (5 cases), hemato-oncological diseases undergo-ng chemotherapy or bone marrow transplant (5 cases); AIDS andhemotherapy for non Hodgkin’s lymphoma (1 case); cardiac trans-lant (2 cases); renal transplant (1 case); and long-term steroid use1 case) (Table 1).

The outcome in patients with encephalitis was mentioned in 16f the 24 reported cases; nine (56%) of them died, 6 (38%) survived,nd one was in compromised state. Mortality occurred in a rangeetween few days to 10 months of onset of neurologic disease with

median of 1 month. Follow up for those who survived rangedetween 2 months to 3 years with a median of 8 months. Thoseho died were all immunocompromised. In contrast, those who

urvived included: one patient who was immunocompetent15; one

Virology 57 (2013) 363– 369 365

who was on steroids that were discontinued during the illness25;one was a renal transplant patient whose immunosuppressive ther-apy was decreased23; and two AIDS patients who were eitherstarted on anti-HIV therapy28 or the anti-HIV therapy was changedto more potent agents.6 Hence, the prognosis appears to be depend-ent on the immune condition.

4. Discussion

Our case documents the diagnosis of fatal encephalitis due toBKV in a patient with CVID. The initial complaint manifested asa unilateral visual difficulty during the Umrah trip. The detectedunilateral optic atrophy was most probably a sequel of a previ-ous attack of optic neuritis. Ocular findings in association withBKV encephalitis are rare and have so far included retinitis withonly one reported case.16–18 We also highly suspect, because ofthe travel history, that the disease resulted from an acquired pri-mary infection rather than from reactivation. Primary infectionwith BKV resulting in encephalitis has been described in two cases;in the first, the development of primary infection was confirmedby serological testing,21 whereas in the second, primary infectionwas proposed because of the young age (5 years) of the patient.22

Testing for polyomavirus was performed here because the ini-tial reading of imaging suggested PML. However, this suggestionwas later excluded in favor of encephalitis because the imaginghere showed progressive and extensive coalescent T2 signal abnor-mality in the periventricular and deep cerebral white matter, witha relatively symmetric involvement that eventually included thebrain stem. On the other hand, MRI findings in PML involve subcor-tical U-fibers, deep cerebral white matter, and basal ganglia withrelative sparing of the periventricular white matter. Lesions tendto be patchy, and asymmetric with relatively large T2 signal abnor-mality without mass effect or enhancement.31 It is also interestingto note that in several cases, testing for BKV was performed becausethe patients were initially suspected to have PML.23,25,28

Other causes of encephalitis, notably West Nile virus (WNV) andherpes simplex virus (HSV), were felt to be unlikely. WNV causessevere headache, high fever, neck stiffness, stupor, deteriora-tion, coma, tremors, convulsions, muscle weakness, and abnormalmovement. MRI is usually normal in most patients. However, it mayshow patchy foci of abnormal T2 signal lesions in the cerebral hemi-spheric white matter, brainstem, basal ganglia, and thalami.32,33

HSV encephalitis usually has an abrupt onset with rapid progres-sion over a few days. It also causes an invariably abnormal EEG ofeither early non-specific slowing or later PLEDS (periodic lateraliz-ing epileptiform discharges). The typical MRI findings show areas offocal edema in the temporal lobes and orbital surface of the frontallobes, as well as the insular cortex and angular gyrus.34

CVID is a rare condition with prevalence rate between 5and 100 per million and is the most common cause for pri-mary immunodeficiency following selective IgA deficiency.35,36

Patients with CVID are at risk for recurrent infections mostly inthe respiratory and gastrointestinal tracts. Encephalitis, however, isgenerally an infrequent infection in CVID and the reported etiologyincludes enteroviruses,37 WNV,38 HSV,39 CMV,40 measles virus,41

Toxoplasma,42 and JCV.37,43–48

Here, the tendency of the BKV to affect patients with cell medi-ated immunodeficiency, the development of disease despite asatisfactory IgG trough level, and recent administration of IVIG allsuggest associated cellular immunodeficiency. This is not surpris-

ing because patients with CVID might also have decreased cellularimmune function consisting of numerical and/or functional defectsinvolving T-cells, natural killer cells, dendritic cells, macrophages,and monocytes.49–52

366F.G

. Bakri

et al.

/ Journal

of Clinical

Virology

57 (2013) 363– 369Table 1Clinical characteristics of reported patients with BKV encephalitis.

Ref Sex Age (y) Immune status Radiology Diagnosis Negative tests for othercauses

Treatment Outcome

14 M 27 AIDS; hemophiliatype A

Marked internal hydrocephalus withperiventricular lucencies

CSF, brain, kidneys, lungBKV PCR+

Brain, kidney, lung stainingfor HSV, CMV, VZV, and HIV

NM Died after 3 m

15 M 34 Immunocompetent • Initially: normal• At height of clinical illness: diffusehyperintensity in the white matterwithout swelling or enhancement• After clinical recovery: reversal ofhyperintensity

CSF BKV PCR+ BKV IgG andIgM

All other agents that canpotentially causeencephalitis includingHIV-1 and 2

NM Alive at 1 y

16,17,18 M 26 AIDS Increased meningeal enhancement andthickness

CSF, brain, eye, urine, bloodBKV PCR+; brain, kidneystaining+; eye and bloodCMV PCR+

CSF PCR for EBV and CMV;CSF and blood for VDRLand Borrelia flagellaantigen; Brain and eye forJCV and EBV PCR

Ganciclovir;steroids;anti-TB

Died after 10 m

19 M 44 AIDS; NHL underCT

Diffuse areas of hyperintensity of theperiventricular white matter

CSF, blood, bone marrow,urine BKV PCR+; brain,kidney, bladder, stomach,mesenteric lymph nodeBKV PCR+; brain staining+

Brain EBV PCR; staining forHIV and HSV

NM Died after 5 m

20 M 37 AIDS Bilateral supratentorial signalalteration, partially confluent in longTR sequence and hypointense in T1without enhancement, present infronto parietal white matter andextending from medial aspect of bothlateral ventricles to the vertex andextending to the right toward theinsula

CSF BKV PCR+ NM NM Alive at the timeof writing but incompromisedstate

21 M 49 CLL under CT;splenectomy

• First imaging: no bleed, no masseffect, no infarction• Second imaging: mildcommunicating hydrocephalus,abnormal signal supratentorially, andleptomeningeal enhancement• Third imaging: acute and subacuteinfarcts of left cerebellum and rightinternal capsule• Perfusion scan: diffuse perfusionabnormalitieswith patchy activitymore in the left frontal lobe

CSF, brain, kidney, urineBKV PCR+

CSF bacteria, fungi,mycobacteria, cryptococcalantigen, HSV PCR

Ganciclovir + IVIG;Later: acy-clovir + antibacterial

Died after 1 m

22 F 24 Immunocompetent Diffuse white matter lesions, chiefly inthe parietal region

CSF BKV PCR+; serumantibody to BKV+

CSF JCV PCR; serumantibody to JCV; HIV

NM NM

F 30 Immunocompetent NM CSF BKV PCR+ HIV NM NMM 32 Immunocompetent NM CSF BKV PCR+ CSF for bacteria, fungi, AFB,

TB PCR; HIVNM NM

M 29 Immunocompetent NM CSF BKV PCR+CSF AFB+, TB PCR+

HIV NM NM

F 26 Immunocompetent NM CSF BKV PCR+ CSF for bacteria, fungi, AFB,TB PCR; HIV

NM NM

10 a F 5 Immunocompetent NM CSF BKV PCR+ CSF HSV 1/2; VZV, CMV,enterovirus, JCV

NM NM

M 16

F.G.

Bakri et

al. /

Journal of

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irology 57 (2013) 363– 369

367Table 1 (Continued)

F 13

23 M 56 Renal transplant Suggestive of PML CSF, urine BKV PCR+ CSF bacteria, fungi, AFB,cryptococcal antigen, VZV,HSV 1/2, CMV, JCV; Bloodfor CMV

MMF stopped;steroids;leflunomide

Alive at 2 m

24 F 38 BMT Widespread hyperintensity incerebellum, cerebral white matter,thalami, globus pallidum

Brain biopsy BKV PCR+ further medical andlaboratory evaluation didnot yield a diagnosis

Ganciclovir,acyclovir,valacyclovir;reduction ofimmunosup-pressant

Neurologicalstatus improvedbut died after 5m of medicalproblems

25 M 70 Long-term steroidtherapy

Hypointense in T1 and hyperintense inT2 non enhancing abnormalities in thewhite matter in the rightparieto-occipital areas without masseffect

CSF BKV PCR+ CSF JCV PCR, mycobacteria,cryptococcal −; HIV 1/2

Supportive Alive at 4 m

6 M 43 AIDS Lesion in the gray matter of the lefttemporo-parietal lobe and rightoccipital lobe

CSF, brain BKV PCR+ CSF PCR for all humanherpes viruses, JCV,Toxoplasma gondii

Efavirenzchanged toatazanavir-ritonavir;continue AZTand 3TC

Alive at 3 y

26 M NM BMT Encephalopathy with edemaparieto-occipital in the cerebral whitematter and cerebellum

CSF, urine BKV PCR+ CSF adenovirus, EBV, CMV,VZV, HSV, HHV-6, HHV-8,JC, toxoplasma; CSFbacterial and fungal culture

NM Died after fewdays

27 M 46 NHL under CT No lesions CSF BKV PCR+ CSF microbiology; CSF JCV,HSV 1/2, CMV, VZV,HHV-6; HIV

NM Alive at 2 m

28 M 48 AIDS Multifocal and infratentorialabnormalities atypical for PML

urine BKV PCR+; brainstaining SV40+

CSF JCV PCR− Startingemtricitabine-tenofovir,lopinavir-ritonavir

Alive at 3 y

7 F 48 BMT Widespread lesions mainly in pons,around third ventricle, left frontal andparietal lobes, cortical and subcorticalareas

CSF, brain, urine BKV PCR+ CSF mycobacteria,toxoplasma, Treponiumpallidum, Cryptococcus;CSF PCR for EBV, CMV,HHV6, VZV, HSV 1/2, JCV

Foscarnet,steroids,cyclosporinechanged tomycopheno-late, AmB,meropenem

Died after 21days

29 F 6 Cardiac transplant Abnormality in medulla andcervicomedullary junction

CSF BKV PCR+; brain BKVPCR+

CSF enterovirus, HSV, VZV,JCV

IVIG + cidofovir Died after 1 m

30 F 6 Cardiac transplant Abnormality in brain stem, cerebellum,frontal and parietalcortical/subcortical/deep white matter,gangliocapsular and thalamus

CSF BKV PCR+ NM NM Died after about3 weeks

Present case M 24 CVID Periventricular, mid brain, cerebellarhyperintense lesions

CSF BKV PCR+ CSF JCV PCR; CSF culture;blood CMV PCR, RPR, HIV

Ganciclovir Died after 2 y

AFB, acid fast bacilli; ALL, acute lymphoblastic leukemia; AmB, amphotericin B; AZT, zidovudine; BMT, bone marrow transplant; CLL, chronic lymphocytic leukemia; CT, chemotherapy; EBV, Epstein–Barr virus; HHV6, humanherpesvirus-6; m, month; MMF, mycophenolate mofetil; NHL, non-Hodgkin’s lymphoma; NM, not mentioned; TB, tuberculosis; VDRL, venereal disease research laboratory; VZV, varicella zoster virus; y, year; 3TC, lamivudine.

a Two patients (5 year-old girl and 3 year-old boy) from this study had positive CSF BKV PCR but were excluded from this table because they did not have encephalitis.

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68 F.G. Bakri et al. / Journal of Cl

Treatment of BKV is not yet established. In refractory casesf BKV-associated disease, antiviral agents such as cidofovir,eflunomide, IVIG, and quinolones may be applied. However, theffectiveness of these agents is doubtful and some of them can causeevere side effects.53 In the few reported cases of BKV encephalitis,he use of antiretroviral therapy in AIDS patients and decreasinghe immunosuppression in the transplant patients have resulted in

successful outcome.6,23,28,54

The main limitation in the present report is the lack of docu-entation of brain involvement with BKV. However, the presence

f viral DNA in the CSF, immunodeficiency, compatible radiologicalndings, and absence of other alternative diagnosis strongly favorhe diagnosis of BKV encephalitis.54

In conclusion, encephalitis due to BKV is an emerging and dev-stating condition. Physicians should be aware of this disease andest for BKV, especially in the immunocompromised patients.

onflict of interest statement

None declared.

unding

None.

ompeting interest

None declared.

thical approval

Not required.

eferences

1. Reploeg MD, Storch GA, Clifford DB. BK virus: a clinical review. Clin Infect Dis2001;33:191–202.

2. Elsner C, Dorries K. Evidence of human polyomavirus BK and JC infection innormal brain tissue. Virology 1992;191:72–80.

3. Akazawa Y, Terada Y, Yamane T, Tanaka S, Aimoto M, Koh H, et al. FatalBK virus pneumonia following stem cell transplantation. Transpl Infect Dis2012;14:E142–6.

4. Hirsch HH, Randhawa P. BK virus in solid organ transplant recipients. Am JTransplant 2009;9(Suppl. 4):S136–46.

5. Ramos E, Drachenberg CB, Wali R, Hirsch HH. The decade of polyomavirus BK-associated nephropathy: state of affairs. Transplantation 2009;87:621–30.

6. Vidal JE, Fink MC, Cedeno-Laurent F, Delbue S, Ferrante P, Dauar RF, et al. BKvirus associated meningoencephalitis in an AIDS patient treated with HAART.AIDS Res Ther 2007;4:13.

7. Lopes da Silva R, Ferreira I, Teixeira G, Cordeiro D, Mafra M, Costa I, et al. BK virusencephalitis with thrombotic microangiopathy in an allogeneic hematopoieticstem cell transplant recipient. Transpl Infect Dis 2011;13:161–7.

8. Bogdanovic G, Brytting M, Cinque P, Grandien M, Fridell E, Ljungman P, et al.Nested PCR for detection of BK virus and JC virus DNA. Clin Diagn Virol1994;2:211–20.

9. Abend JR, Jiang M, Imperiale MJ. BK virus and human cancer: innocent untilproven guilty. Semin Cancer Biol 2009;19:252–60.

0. Behzad-Behbahani A, Klapper PE, Vallely PJ, Cleator GM. BK virus DNA inCSF of immunocompetent and immunocompromised patients. Arch Dis Child2003;88:174–5.

1. Barcena-Panero A, Van Ghelue M, Khan MT, Echevarria JE, Fedele G, Moens U.BK virus-associated infection in cerebrospinal fluid of neurological patients andmutation analysis of the complete VP1 gene in different patient groups. J CellPhysiol 2012;227:136–45.

2. Moret H, Guichard M, Katlama C, Hauw J, Huraux J, Ingrand D. Presence of BKvirus in brain tissues of four AIDS patients detected by polymerase chain reaction(PCR). In: The ninth international conference on AIDS. 1993.

3. Vago L, Cinque P, Sala E, Nebuloni M, Caldarelli R, Racca S, et al. JCV-DNA and BKV-DNA in the CNS tissue and CSF of AIDS patients and normal subjects. Study of 41

cases and review of the literature. J Acquir Immune Defic Syndr Hum Retrovirol1996;12:139–46.

4. Vallbracht A, Lohler J, Gossmann J, Gluck T, Petersen D, Gerth HJ, et al. Dissemi-nated BK type polyomavirus infection in an AIDS patient associated with centralnervous system disease. Am J Pathol 1993;143:29–39.

4

4

Virology 57 (2013) 363– 369

5. Voltz R, Jager G, Seelos K, Fuhry L, Hohlfeld R. BK virus encephalitis in animmunocompetent patient. Arch Neurol 1996;53:101–3.

6. Bratt G, Hammarin AL, Grandien M, Hedquist BG, Nennesmo I, Sundelin B, et al.BK virus as the cause of meningoencephalitis, retinitis and nephritis in a patientwith AIDS. AIDS 1999;13:1071–5.

7. Jorgensen GE, Hammarin AL, Bratt G, Grandien M, Flaegstad T, Johnsen JI. Iden-tification of a unique BK virus variant in the CNS of a patient with AIDS. J MedVirol 2003;70:14–9.

8. Hedquist BG, Bratt G, Hammarin AL, Grandien M, Nennesmo I, Sundelin B,et al. Identification of BK virus in a patient with acquired immune defi-ciency syndrome and bilateral atypical retinitis. Ophthalmology 1999;106:129–32.

9. Lesprit P, Chaline-Lehmann D, Authier FJ, Ponnelle T, Gray F, Levy Y. BK virusencephalitis in a patient with AIDS and lymphoma. AIDS 2001;15:1196–9.

0. Garavelli PL, Boldorini R. BK virus encephalitis in an HIV-seropositive patient.Preliminary data. Recenti Prog Med 2002;93:247.

1. Stoner GL, Alappan R, Jobes DV, Ryschkewitsch CF, Landry ML. BK virus regu-latory region rearrangements in brain and cerebrospinal fluid from a leukemiapatient with tubulointerstitial nephritis and meningoencephalitis. Am J KidneyDis 2002;39:1102–12.

2. 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;31:374–8.

3. Hix JK, Braun WE, Isada CM. Delirium in a renal transplant recipient associatedwith BK virus in the cerebrospinal fluid. Transplantation 2004;78:1407–8.

4. Friedman DP, Flanders AE. MR imaging of BK virus encephalitis. AJNR Am J Neu-roradiol 2006;27:1016–8.

5. Cabrejo L, Diop M, Blohorn-Sense A, Mihout B. Progressive BK virus associatedmultifocal leukoencephalopathy in an immunocompromised patient treatedwith corticosteroids. Rev Neurol (Paris) 2005;161:326–30.

6. Behre G, Becker M, Christopeit M. BK virus encephalitis in an allogeneichematopoietic stem cell recipient. Bone Marrow Transplant 2008;42:499.

7. Ferrari A, Luppi M, Marasca R, Potenza L, Morselli M, Volzone F, et al. BK virusinfection and neurologic dysfunctions in a patient with lymphoma treated withchemotherapy and rituximab. Eur J Haematol 2008;81:244–5.

8. Kinnaird AN, Anstead GM. Hemorrhagic cystitis and possible neurologic diseasefrom BK virus infection in a patient with AIDS. Infection 2010;38:124–7.

9. Pereira T, Rojas CP, Garcia-Buitrago MT, Chandar J, Abitbol C, SeeherunvongW, et al. A child with BK virus infection: inadequacy of current therapeuticstrategies. Pediatr Transplant 2012;16:E269–74.

0. Green J, Saigal G, Rojas CP, Post MJ. Rare presentation of BK encephalitis in achild: imaging and pathological findings. Pediatr Radiol 2012;42:1145–8.

1. Shah R, Bag AK, Chapman PR, Cure JK. Imaging manifestations of progressivemultifocal leukoencephalopathy. Clin Radiol 2010;65:431–9.

2. Kramer LD, Li J, Shi PY. West Nile virus. Lancet Neurol 2007;6:171–81.3. Zak IT, Altinok D, Merline JR, Chander S, Kish KK. West Nile virus infection. AJR

Am J Roentgenol 2005;184:957–61.4. Kennedy PG. Viral encephalitis: causes, differential diagnosis, and management.

J Neurol Neurosurg Psychiatry 2004;75(Suppl 1):i10–5.5. Salzer U, Unger S, Warnatz K. Common variable immunodeficiency (CVID):

exploring the multiple dimensions of a heterogeneous disease. Ann N Y AcadSci 2012;1250:41–9.

6. Deane S, Selmi C, Naguwa SM, Teuber SS, Gershwin ME. Common variableimmunodeficiency: etiological and treatment issues. Int Arch Allergy Immunol2009;150:311–24.

7. Rudge P, Webster AD, Revesz T, Warner T, Espanol T, Cunningham-RundlesC, et al. Encephalomyelitis in primary hypogammaglobulinaemia. Brain1996;119(Pt 1):1–15.

8. Alonto AM, Aronoff DM, Malani PN. West Nile virus meningitis in patient withcommon variable immunodeficiency. Emerg Infect Dis 2003;9:1353–4.

9. Borish L, Ayars AG, Kirkpatrick CH. Common variable immunodeficiencypresenting as herpes simplex virus encephalitis. J Allergy Clin Immunol2011;127:541–3.

0. Witte T, Werwitzke S, Schmidt RE. CMV complications in common variableimmunodeficiency. Immunobiology 2000;202:194–8.

1. Graham DG, Gordon A, Ashworth B, Yap PL. Immunodeficiency measlesencephalitis. J Clin Lab Immunol 1983;10:117–20.

2. Hofmann A, Zaharatos G, Miller M. Case report and review of the literature:Toxoplasma gondii encephalitis in a 40-year-old woman with common variableimmunodeficiency and a new diagnosis of large granular lymphocytic leukemia.Can J Infect Dis Med Microbiol 2008;19:309–10.

3. Bezrodnik L, Samara R, Krasovec S, Garcia Erro M, Sevlever G. Progressive mul-tifocal leukoencephalopathy in a patient with hypogammaglobulinemia. ClinInfect Dis 1998;27:181–4.

4. Narula S, LaRosa DF, Kamoun M, Dalmau J, Levinson AI. Progressive multifo-cal leukoencephalopathy in a patient with common variable immunodeficiencyand abnormal CD8+ T-cell subset distribution. Ann Allergy Asthma Immunol2007;98:483–9.

5. Tasca G, Iorio R, Basile U, Lauriola L, Tartaglione R, Mirabella M, et al. Pro-gressive multifocal leukoencephalopathy in a patient with Franklin disease andhypogammaglobulinemia. J Neurol Sci 2009;284(1–2):203–4.

6. Snyder MD, Storch GA, Clifford DB. Atypical PML leading to a diagnosis of com-mon variable immunodeficiency. Neurology 2005;64:1661.

7. Scotton PG, Vaglia A, Carniato A, Marchiori GC. Progressive multifocal leukoen-cephalopathy in a patient with common variable immunodeficiency. Clin InfectDis 1998;26:215–6.

inical

4

4

5

5

5

F.G. Bakri et al. / Journal of Cl

8. Shintaku M, Matsumoto R, Sawa H, Nagashima K. Infection with JC virus and pos-sible dysplastic ganglion-like transformation of the cerebral cortical neurons ina case of progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol2000;59:921–9.

9. van Assen S, de Haan A, Holvast A, Horst G, Gorter L, Westra J, et al. Cell-mediated immune responses to inactivated trivalent influenza-vaccination are

decreased in patients with common variable immunodeficiency. Clin Immunol2011;141:161–8.

0. Giovannetti A, Pierdominici M, Mazzetta F, Marziali M, Renzi C, Mileo AM, et al.Unravelling the complexity of T cell abnormalities in common variable immu-nodeficiency. J Immunol 2007;178:3932–43.

5

5

Virology 57 (2013) 363– 369 369

1. Bayry J, Hermine O, Webster DA, Levy Y, Kaveri SV. Common variableimmunodeficiency: the immune system in chaos. Trends Mol Med 2005;11:370–6.

2. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clin-ical and immunological features of 248 patients. Clin Immunol 1999;92:34–48.

3. van Aalderen MC, Heutinck KM, Huisman C, ten Berge IJ. BK virus infectionin transplant recipients: clinical manifestations, treatment options and theimmune response. Neth J Med 2013;70:172–83.

4. Lopes da Silva R. Polyoma BK virus: an emerging opportunistic infectious agentof the human central nervous system. Braz J Infect Dis 2011;15:276–84.