cytokine responses in a severe case of glandular fever treated successfully with foscarnet combined...

Journal of Medical Virology 81:99–105 (2009)

Cytokine Responses in a Severe Case ofGlandular Fever Treated Successfully withFoscarnet Combined with Prednisolone andIntravenous Immunoglobulin

Christine Ma,1 Chun K. Wong,2 Bonnie C.K. Wong,1 K.C. Allen Chan,2 Samantha W.M. Lun,2

Nelson Lee,1 Justin Wu,1 Clive S. Cockram,1 Paul K.S. Chan,3 and Julian W. Tang3*1Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin,New Territories, Hong Kong SAR, China2Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin,New Territories, Hong Kong SAR, China3Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin,New Territories, Hong Kong SAR, China

Viral loads and cytokine responses Epstein–Barrvirus (EBV) were measured in an 18-year-old boywith severe glandular fever complicated by amild anaemia, severe thrombocytopaenia andneutropaenia. Hepatosplenomegaly was detectedby abdominal ultrasound in the presence ofsignificant hepatitis. Cytokine testing demon-strated elevated cell-mediated Th1 (IFN-g, IL-12,sTNFR1, CXCL10, CXCL9 and CCL3) and humoralTh2 (IL-4) immune responses. Serum antibodiesto EBV virus capsid antigen (VCA) IgM and IgGantibodies were detected, together with a raisedEBV DNA level (up to about 70,000 DNA copies/mL) in the acute phase of the illness. This EBV DNAload decreased rapidly in response to treatmentwith a combination of foscarnet, intravenousimmunoglobulin and prednisolone, and the boy’ssymptoms settled eventually after approximately50 days of illness, following this combined anti-viral and immune-modulating therapy. Detailedimmunological, virological, haematological andbiochemical laboratory parameters are presentedto document this patient’s severe EBV disease andeventual recovery. J. Med. Virol. 81:99–105,2009. � 2008 Wiley-Liss, Inc.

KEY WORDS: Epstein–Barr virus; infectiousmononucleosis; immune-medi-ated response; chemokine;hepatitis; thrombocytopaenia

INTRODUCTION

Acute, primary Epstein–Barr virus (EBV) infection isoften an asymptomatic or mild illness in young children,but can be more severe in teenagers and young adults as

infectious mononucleosis or glandular fever [Strauset al., 1993; Macsween and Crawford, 2003]. This is dueto clinical disease caused by acute EBV infection beingmainly immune-mediated, with older children andteenagers having a more exaggerated response toprimary EBV infection than younger children [Williamset al., 2004; Hislop et al., 2007]. Severe (life-threatening)complications usually only arise if they have someprimary immunodeficiency, the most serious of whichis X-linked lymphoproliferative disease [Williams et al.,2004; Milone et al., 2005], or if they have acquiredsome form of immunosuppression later in life, e.g.human immunodeficiency virus (HIV) infection orrequire chemotherapy or organ transplantation, whentheir EBV may reactivate, in the absence of effective Tcell immunosurveillance, to cause various forms of B celllymphoproliferative disease [Macsween and Crawford,2003].

In the UK and USA, infectious mononucleosis is notuncommon where perhaps 20–30% of young adults aresusceptible to primary EBV infection [Kangro et al.,1994; Martro et al., 2004], but this is rare in HongKong, where virtually all children have been infectedwith EBV by the age of 10 years [Kangro et al., 1994].Interestingly, one previous study of acute EBV infectionin young Hong Kong children (<2–15 years old) havedemonstrated that their clinical manifestations aredifferent from similar Western paediatric populations,

*Correspondence to: Julian W. Tang, Department of Microbiol-ogy, The Chinese University of Hong Kong, Prince of WalesHospital, Shatin, New Territories, Hong Kong SAR, China.E-mail: [email protected]

Accepted 23 September 2008

DOI 10.1002/jmv.21383

Published online in Wiley InterScience(www.interscience.wiley.com)

� 2008 WILEY-LISS, INC.

in that more Chinese children tend to become sympto-matic with typical features of infectious mononucleosis[Chan et al., 2003]. However, another study suggestedthat primary EBV infection in younger Hong Konginfants may be mild or asymptomatic due to thepresence of anti-EBV maternal antibodies, at least, upto the age of 8 months [Chan et al., 2001].

In this report, an unusually severe case of primaryEBV infection in an 18-year old Hong Kong Chinese boyis presented. Functional hepatic and haematologicalabnormalities were present as well as a significant EBVviral load. Combination treatment with intravenousimmunoglobulin (IVIG), steroids and antiviral therapysuccessfully controlled the patient’s disease allowinga full recovery. His cytokine profile was monitoredthroughout his acute illness and these results guided inpart the clinical management of his disease.

MATERIALS AND METHODS

Case Report

An 18-year-old previously fit and healthy boy, with nopast evidence of immunodeficiency and no recent travelhistory, was admitted with 10-day history of fever(39.58C on admission), myalgia, sore throat and malaise.On examination, he had a congested throat, bilateralcervical lymphadenopathy, a fine, generalized macularrash, and mild hepatosplenomegaly. His blood pressurewas 105/75 mmHg with a pulse of 80 bpm. On admission,his routine blood test results showed a mild thrombocy-topaenia with severe hepatitis, with a total white cellcount of 6.9�109 L�1 (neutrophils 31%, lymphocytes60–3% atypical lymphocytes), platelets 118�109 L�1,hemoglobin (Hb) 13.2 g/dL, alanine aminotransferase(ALT) 1600 IU/L, alkaline phosphatase (ALP) 302 IU/L,bilirubin 26 mmol/L, lactic dehydrogenase 1415 IU/L,prothombin time 14.5 sec and activated partialthromboplastin time 47.5 sec. A rapid monospot andconfirmatory Epstein–Barr virus (EBV) virus capsidantigen (VCA) IgM tests were positive, consistent with adiagnosis of infectious mononucleosis due to primary,acute EBV infection. Serological and polymerase chainreaction (PCR) tests were performed to rule out otherpossible viral causes of severe hepatitis and an abdomi-nal ultrasound scan was also performed, several daysafter admission.

His condition continued to deteriorate and by thethird week of his illness he had developed severejaundice, progressive leuco- and thrombocytopaenia, apurpuric skin rash and a persistent, swinging fever. Lowhaptoglobin levels (<0.2 g/L) and a positive Coomb’stest, with a raised total bilirubin (up to 285 mmol/Lon day 28 post-illness onset), suggested a hemolyticanaemia. This deterioration was thought to be due toan EBV-induced immunopathological response, so theantiviral drug foscarnet (intravenous, 4.5 g every 12 hr)was started on day 21 of illness. Drug response wasmonitored using an in-house quantitative real-timeEBV DNA PCR assay.

Despite effective viral suppression and regressionof his lymphadenopathy and splenomegaly, his feverpersisted and he developed bilateral pleural effusionswith ECG abnormalities (T-wave inversion over lateralleads). By day 26 his thrombocytopaenia reached anadir of 26�109 L�1 with an Hb of 9.4 g/dL. A bonemarrow examination showed normocellular marrowwith reactive hemophagocytosis.

Intravenous immunoglobulin (IVIG, Intragam P, CSLLtd., Australia, 400 mg/kg/day for 5 days) and oralprednisolone (1 mg/kg/day for 7 days) were startedon days 27 and 29 of illness, respectively. By day 31 ofillness, his fever began subsiding with recovery of his Hband platelet counts. Foscarnet was stopped after 17 daysonce EBV suppression was achieved, due concerns abouta potential neutropenic adverse drug reaction. Despitethis, 5 days later, the patient developed a severeneutropaenia (other cell lines preserved), with theabsolute neutrophil count dropping to �0�109 L�1.He was treated with G-CSF (30 MU/day, subcutane-ously) for 3 days, with a good response and subsequentnormalization of the cell counts. He was finally dis-charged well after 48 days of illness, then followed up inthe infectious diseases clinic 2 weeks later, where hereported having remained well and asymptomatic.

Assay of Serum Concentrations ofCytokines and Chemokines

Serum was prepared from clotted blood by centrifu-gation (2000g for 10 min). Concentrations of cytokinesand chemokines IL-12p70, IFN-g, TNF-a, IL-1b, IL-10,IL-4, IL-6, CXCL8, CCL3, CCL5, CXCL9 and CXCL10were measured using cytometric bead array (CBA) withflex set reagents (BD PharMingen, San Diego, CA, USA)on a 4-color FACSCalibur flow cytometer (BectonDickinson, San Jose, CA, USA) located in a biosafetylevel-2 laboratory [Wong et al., 2004; Wong et al., 2007].These were chosen to measure both the Th1 and Th2immune responses to acute EBV infection. In CBA,different bead populations with distinct fluorescenceintensities had been coated with capturing antibodiesspecific for different cytokines or chemokines. Afterincubating with 50 mL of serum, the cytokine/chemokinecaptured beads were mixed with phycoerythrin-conjugated detection antibodies to form sandwich com-plexes. Fluorescence flow cytometry of the beads providesimultaneous quantification of a panel of cytokines andchemokines. Serum concentrations of soluble tumornecrosis factor receptor1 (sTNFR1) were assayed usinga human TNF R1 quantitative colorimetric sandwichELISA kit (R&D systems Corp., MN, USA). Thecoefficients of variation for all cytokines and chemokinesassays were less than 10%. Their respective normalranges have been derived from measurement of �100healthy subjects [Wong et al., 2004, 2007].

Assay of Plasma EBV DNA Levels

Plasma was prepared from EDTA blood after centri-fugation (2000g for 10 min). DNA was extracted from

J. Med. Virol. DOI 10.1002/jmv

100 Ma et al.

800 mL of plasma using the QIAamp Blood Mini Kit(Qiagen, Valencia, CA, USA) according to the ‘‘bloodand body fluid protocol’’ as recommended by themanufacturer and eluted with 50 mL of water. Theplasma EBV DNA levels were measured using a real-time quantitative PCR system targeting the BamHI-Wfragment region of the EBV genome using the primersW-44F (50-CCCAACACTCCACCACACC-30) and W-119R (50-TCTTAGGAGCTGTCCGAGGG-30) and thedual-labeled fluorescent probe W-67T [50-(FAM)CACA-CACTACACACACCCACCCGTCTC(TAMRA)-30] [Loet al., 1999]. Fluorogenic PCR reactions were set up ina reaction volume of 50 ml using components (exceptfor the fluorescent probes and amplification primers)supplied in a TaqMan PCR Core Reagent Kit (AppliedBiosystems, Foster City, CA, USA). Each reactioncontained 5 mL of 103 buffer A; 300 nM of each of theamplification primers; 25 nM of the fluorescent probe;4 mM MgCl2; 200 mM each of dATP, dCTP, and dGTP;400 mM dUTP; 1.25 units of AmpliTaq Gold; 0.5 unit ofAmpErase uracil N-glycosylase, and 5 mL of plasmaDNA amplifications were carried out in a 96-wellreaction plate format in an Applied Biosystems7300 Sequence Detector. Each sample was analyzed induplicate and the mean of the two results was taken.

RESULTS

Serological tests for acute hepatitis A, B, C and E wereall negative. Polymerase chain reaction (PCR) testing inan acute serum sample was negative for humancytomegalovirus, parvovirus B19 and human herpesvi-ruses 6 and 7. Furthermore, no virus was isolated from athroat and oral swab, urine, nasopharyngeal aspirate orbone marrow sample. These confirmed that primaryEBV infection was the most likely cause of the patient’ssevere thrombocytopaenia and hepatitis. The abdomi-nal ultrasound showed hepatosplenomegaly (liver span14.5 cm, spleen 15 cm), mild ascites and bilateral bulkykidneys.

Table I shows that the patient’s main haematologicalabnormalities were a mild anaemia (Hb 8.8–11.9 g/dL),a severe thrombocytopaenia ((33–127)�109 L�1), amoderate to severe neutropaenia (1–40%) and mild tomoderate lymphocytosis (48–83%) despite a relativelynormal total white cell count (WCC). Derangement ofhis liver function tests including a mild clotting impair-ment (international normalized ratio, INR, up to 1.36;activated thromboplastin time, APTT, up to 60.5 sec), alow albumin (as low as 23 g/L), a raised total bilirubin (ashigh as 218 mmol/L), a raised alkaline phosphatase (ALPup to 635 IU/L) and grossly raised alanine transaminase(ALT, up to 1600 IU/L). It can be seen that there is a briefand rapid improvement in the patient’s haematologicalparameters during the period when he was on the IVIG,prednisolone or the foscarnet during days 27–39 post-illness onset.

Viral load monitoring for EBV DNA showed a rapid3 log10 decrease in EBV levels from 69831 to 22 copies/mL


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Cytokines in Treated Glandular Fever 101

plasma on intravenous foscarnet during days 21–36post-illness onset (Fig. 1, Table II).

The cytokine analysis showed significantly markedelevation (at least 1 log10 above their reference ranges)in serum levels of Th1 cytokines IFN-g and solubleTNFR1, Th1-related chemokines CXCL10, CXCL9and CCL3 for chemotatic migration of Th1 cells andmacrophages, on days 11–27 post-illness onset. An earlyspike of the Th1 cytokine IL-12 was observed on day 11post-illness onset (Table II).

DISCUSSION

In this severe case of glandular fever in a Chineseteenager, the opportunity was taken to further inves-tigate the immunopathogenesis of this severe EBVinfection with serial cytokine studies. The most signifi-cant findings of the cytokine analysis was markedelevation in levels of IFN-g, CXCL10, CXCL9 andCCL3 on days 11–27 after illness-onset.

Previous cytokine studies on acute EBV infectionhave shown that Th1 responses are prominent inglandular fever, with elevated IL-2, IL-12 and IFN-glevels [Andersson, 1996; Corsi et al., 2004]. In this case,the hyper-Th1 response was observed with the increasein levels of IFN-g, IL-12, sTNFR1, CXCL10, CXCL9 andCCL3. This Th1 (cell-mediated immunity) cytokine andchemokine storm was probably due to an EBV-inducedTh1 immune response, via the IL-12 driven activation ofIFN-g- and CCL3-producing CD8þ cytotoxic T cells

[Attarbaschi et al., 2003]. The unusual concomitantincreased Th2 (humoral immunity) cytokine IL-4could be due to a pronounced increase in IFN-g andIL-4 co-expressing CD4þ T cells [Attarbaschi et al.,2003]. Such a response, in some immunosuppressedindividuals, may potentially lead to the developmentof B cell lymphoproliferative disease caused by theclonal outgrowth of EBV-infected B-cells [Ohga et al.,2002].

A comparison with some of the acute phase (generallywithin 7–10 days of illness onset) cytokine levelsmeasured in this and other reported cases of infectiousmononucleosis can be seen in Table III. The specificcytokines listed in Table III are those that have othervalues for comparison, as reported in the literature forpatients with infectious mononucleosis, so not all theones listed in Table II are shown in Table III. In thisstudy, the earliest sample was taken about 11 days afterillness onset, due to the relatively late presentation ofthis case. Hence, only the day 11 cytokine levels arereported for this study in Table III. It can be seen thatthese cytokine levels vary considerably between thesestudies, which may be due to several differencesbetween each study, including patient ages, days afterillness onset and laboratory cytokine testing kits.Therefore, it is likely that a meaningful comparisoncan only be made between patients within the samestudy protocol. However, despite this, concentrations ofthe Th1 cytokine IFN-g and the inflammatory cytokinesIL-6 and CXCL8 were found to be possibly higher in this


Fig. 1. Epstein–Barr viral load (copies/mL plasma, thick black line, solid diamonds ^), and serumcytokine responses (all in pg/mL) in severe infectious mononucleosis: IL4 (open diamonds }), CXCL8 (solidtriangles ~), CXCL10 (open triangles ~), CCL3 (solid squares &), IL-6 (open squares &), CXCL9 (solidcircles *), IFN-g (open circles *). Solid, dotted and dashed arrows: duration of IVIG (5 days, 27–31),prednisolone (7 days, 29–35) and foscarnet (17 days, 21–37), respectively.

102 Ma et al.

study than in these previously reported studies of EBVinfectious mononucleosis [Biglino et al., 1996; Wright-Browne et al., 1998; Corsi et al., 2004].

Foscarnet rapidly curtailed the EBV replication andgradually suppressed the accompanying Th1 and Th2immune responses in this case. However, persistentelevation of inflammatory cytokine IL-6 and CXCL8could only be suppressed after combined treatment withIVIG and prednisolone. Th1 response and aberrantproduction of IL-6 and CXCL8 could lead to theactivation of macrophages and the subsequent hemo-phagocytic syndrome, resulting in an exaggerated hostimmune response and possible fatal outcome [Wonget al., 2004].

The present case illustrates the autocrine loop of bothTh1 and Th2 in an acute and the subsequent persistentinflammatory immune response in prolonged EBVinfection [Ohga et al., 2002]. This may provide a basisfor understanding the effectiveness of the immune-modulating effects of IVIG and steroid treatment in thisand other previously reported severe cases of infectiousmononucleosis [Brandfonbrener et al., 1986; Dotevalland Westin, 1989; Cyran et al., 1991].

For treatment considerations, it is known thatEpstein–Barr virus viral loads in blood may be higherin more severely symptomatic patients [Williams et al.,2004; Balfour et al., 2005] and that a reduction of EBVviral loads is associated with clinical benefit [Balfouret al., 2007]. Hence, in this case, the severe clinicalpresentation indicated that an attempt should be madeto reduce the patient’s EBV viral load, which was of theorder of 4 log10 (about 70,000 EBV DNA copies/mL) inthe acute phase—a similar level to some previouslyreported studies of infectious mononucleosis [Balfouret al., 2005, 2007].

Several treatments have been tried for severe infec-tious mononucleosis, including steroids either alone orin combination with acyclovir. However, neither of theseregimens have been shown to be consistently effective.Steroids may produce rapid symptom relief, but mayincrease the risk of more severe complications such asencephalitis and myocarditis. Therefore, steroid use,alone, is generally not recommended except for severecases, e.g. those with impending airways obstruction[McGowan et al., 1992; Straus et al., 1993; Macsweenand Crawford, 2003].

The use of steroids in combination with acyclovir hasalso been reported, with mixed results. This class ofantiviral drugs has less effect on EBV-associated diseasebecause their inhibitory effects only act on the linearform of the viral DNA genome whereas both the linearand circular forms are used in EBV replication in acuteinfection [Straus et al., 1993]. Also, acute EBV disease ismainly immunopathological rather than a direct effectof the virus itself [Macsween and Crawford, 2003;Hislop et al., 2007], unlike other herpesvirus infectionssuch as herpes simplex types 1, 2 and varicellazoster, against which acyclovir is more effective.Although acyclovir has been found to suppress oralshedding of EBV, a randomized, multi-center, double-


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blind, placebo-controlled study found no statisticallysignificant differences between the groups on theduration of overall symptoms [Tynell et al., 1996]. Thisconfirms the findings from earlier studies on thistreatment regimen [Brandfonbrener et al., 1986; Ander-sson and Ernberg 1988].

There have been individual case reports of successfultreatment of severe acute EBV infection with otherdrugs, including valacyclovir [Balfour et al., 2007],ganciclovir [Adams et al., 2006], intravenous immuno-globulin [Cyran et al., 1991], pulsed methylprednisolone[Takahashi et al., 2007] and anti-CD20 (rituximab, amonoclonal antibody that specifically eliminates B cells)[Milone et al., 2005], but so far, none describing afoscarnet-based combination (with steroid and IVIG)regimen.

Thus, this case provides additional data to theliterature on the treatment of severe EBV infectiousmononucleosis in an otherwise previously fit andhealthy, immunocompetent young adult.

REFERENCES

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TABLE III. Comparison of Some Cytokine Levels in EBV Infectious Mononucleosis Across Different Studies

Serum cytokine/chemokine(all units pg/mL, unless statedotherwise)

This study n¼ 1,18 years, M

Biglino et al., n¼ 18,23 5.6 years, 4F:14M

Wright-Browne et al.,n¼ 14, 20 2 years

‘college students’, NGCorsi et al., n¼ 23,

NG, NG

IL-12p70 10.2 — — 73.9 3.5 (as ‘IL-12’)TNF-a 1.4 115 59 7.75 (median) —IL-10 29.3 — 35.15 (median) —IL-6 20.4 13 12 4.85 (median) —IL-1b 3.6 21 30 0 —CXCL8 (IL-8) 40.7 — 0 —IL-4 95.6 1725 1833 — —IFN-g 231.3 170 127 — 6.3 2.7

n, number of patient results reported; M, male; F, female; NG, not given; —, not tested/reported.

104 Ma et al.

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Wright-Browne V, Schnee AM, Jenkins MA, Thall PF, Aggarwal BB,Talpaz M, Estrov Z. 1998. Serum cytokine levels in infectiousmononucleosis at diagnosis and convalescence. Leuk Lymphoma30:583–589.



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