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Journal of Clinical Virology 45 (2009) 262–264

Contents lists available at ScienceDirect

Journal of Clinical Virology

journa l homepage: www.e lsev ier .com/ locate / j cv

ase report

Viral” myocarditis in a patient following allogenic stem cell transplant:iagnostic dilemma and management considerations

anjay Bhattacharyaa, Shankara Paneeshab, Sridhar Chagantib, Richard Lovellb,areth Slocombec, Donald Milliganb, Husam Osmana,∗

HPA West Midlands Public Health Laboratory, UKDepartment of Haematology, Heart of England Foundation Trust, Birmingham, UKDepartment of Haematology, Shrewsbury and Telford Hospital, UK

r t i c l e i n f o

rticle history:

eceived 14 April 2009eceived in revised form 30 April 2009ccepted 1 May 2009

eywords:yocarditis

iralon-infective

. Case report

Establishing aetiology of myocarditis is important in order toirect management strategies appropriately. In presence of mul-iple risk factors and co-morbidities definitive diagnosis is oftenifficult if not impossible. We report an unusual post-transplantomplication in a 54-year-old female who received single antigenismatch, reduced intensity, unrelated donor stem cell transplant

or acute myeloid leukaemia. Alemtuzumab was incorporated intohe conditioning regimen. On day +12 post-transplant she devel-ped profuse diarrhoea and vomiting with isolation of adenovirusrom blood and faeces samples as well as nose and throat swabs.iral DNA load in blood peaked at 8.2 million copies/mL. Thereas good response to treatment with cidofovir (5 mg/kg/week forweeks) with resolution of the viraemia.

Four months post-transplant she was admitted with short his-ory of severe shortness of breath and worsening orthopnea withistory of coryzal symptoms and sore throat 2 weeks back. Shead tachycardia, tachypnea and hypoxia. CT scan of chest revealed

ilateral pleural effusions, ECG showed sinus tachycardia with non-pecific ST-T changes and an echocardiogram confirmed markedlyilated, hypokinetic ventricles with poor LV ejection fraction of 17%.diagnosis of myocarditis/dilated cardiomyopathy with conges-

∗ Corresponding author at: HPA West Midlands Laboratory, Birmingham Heart-ands Hospital, Bordesley Green East, Birmingham, B9 5SS, UK.el.: +44 0121 424 2513; fax: +44 0121 772 6229.

E-mail address: husam.osman@heartofengland.nhs.uk (H. Osman).

386-6532/$ – see front matter © 2009 Elsevier B.V. All rights reserved.oi:10.1016/j.jcv.2009.05.005

tive cardiac failure (NYHA class IV) was made. Therapeutic pleuralfluid drainage followed by aggressive treatment of heart failure withdiuretics, nitrates and ACE-inhibitors resulted in dramatic clinicalresponse. The haemoglobin was low (3.4 g/L) without accompany-ing reticulocytosis, modest reductions in white cell and plateletcounts, mild transaminitis and high serum ferritin (7570 ng/mL).Parvovirus PCR showed high level viraemia (peak viral DNA load of500 million IU/mL; genotype 1) (Fig. 1). Serology was positive forparvovirus IgM but not IgG antibodies. Bone marrow biopsy showedeythroid hypoplasia with bizarre erythroblasts, features consistentwith Parvovirus infection. There was concomitant EBV reactivationwith peak viral load of 64,000 copies/mL. The patient was treatedwith gradual withdrawal of immunosuppression (cyclosporine)and human normal intravenous immunoglobulin (400 mg/kg/dayintravenous infusion for 5 days, repeated after 4 weeks). Six monthslater her ejection fraction continues to be low (19%), with leftventricular dilation, dysfunction and thinned myocardium but thepatient remains asymptomatic. Parvovirus and EBV DNA loads havereduced to 28,400 IU/mL and 6000 copies/mL, respectively. In orderto rule out the possibility of donor derived Parvovirus infection, aplasma sample collected from donor at the time of donation wasretrospectively tested for parvovirus DNA with negative result.

2. Discussion

The aetiology of myocarditis is multifactorial (infections,immunological, toxins, drugs, and physical agents such as radia-tion). Viral infections are considered one of the important factors

S. Bhattacharya et al. / Journal of Clinical Virology 45 (2009) 262–264 263

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ig. 1. Clinical, virological and haematological parameters in the SCT recipient withherapy; HNIG, human normal immunoglobulin therapy; green bar represents lowend have been superimposed on the same X axis to reflect chronological sequenceyocarditis. (For interpretation of the references to color in this figure legend, the r

n pathogenesis of myocarditis. In this patient we had multiple fac-ors both viral and drug related (chemotherapeutic agents suchs fludarabine, idarubicin, cytosine arabinoside) that could haveontributed to myocarditis.1–3 In addition female gender and his-ory of hypokalaemia or hypomagnesaemia had been identified asisk factors in development of chemotherapy related myocarditis.4

ur patient with no previous cardiac problems had one episode ofypokalaemia (3.1 mmol/L) and few episodes of hypomagnesaemianadir magnesium level 0.36 mmol/L) in the post-transplant period.ime of onset of myocarditis as a side effect of chemotherapy variesrom few days to years.4

Viral myocarditis has been associated with large number ofnfections. In many cases it is not clear if these are associations orctual causations. The presence of virus either in peripheral bloodr in cardiac myocardium could be incidental, because of concomi-ant infection in other organs or from previous virus seeding fromrior infection.5,6 Moreover, pathogenesis of myocarditis could beost-infectious immune mediated response.7 In the present casehree different viral infections had occurred with long episodes ofiraemia. Adenoviruses were commonest viral pathogens identifiedrom endomyocardial biopsy samples in patients with myocardi-is and dilated cardiomyopathy.1 In a recent outbreak of fatalyocarditis among paediatric patients, adenovirus was detected in

5% (6/8) of the cases.8 EBV infection, even as a chronic active vari-nt, has been reported to cause myocarditis and mimic myocardialnfarction.9,10 In immunocompromised patients where polymicro-ial frequent infections are common, attributing aetiology to aondition is not easy and specific management decisions are moreifficult because of lack of specific therapy or toxic side effects ofherapeutic agents. Reducing immunosuppressions as a mean ofontrolling viral infections could also be difficult because of risk of

raft loss in these type of patients.

In this case we noted that onset of myocarditis coincided withhe period of parvovirus viaremia. Although this does not excludehe possibility of other agents (viral or drug related), there wassignificant temporal correlation between the occurrence of her

arditis. Viral load in log 10 copies/mL; RBC count in factors × 1012/L; CDV, cidofoviral limit of RBC count. The scales (Y axis) for viral load and RBC count are different

asterisk represent time point of onset of clinical events-bone marrow hypoplasia,is referred to the web version of the article.)

symptoms and signs and detection of parvovirus viaremia. Par-vovirus B19 infection is common in community and is usuallytransmitted through contact with infected respiratory secretions.The disease is also transmitted through contaminated blood andblood products, and intra-uterine from mother to the foetus. Per-sistent infection in bone marrow has been reported even fromapparently immunocompetent individuals.11–13 Delay in diagnos-ing parvovirus infections occurs mainly because of relative lack ofawareness about epidemiology of this infection. Moreover unlikeCMV where routine surveillance is in place, no such protocol exitsfor Parvovirus infection in SCT recipients. In our case although someevidence of Parvovirus infection was present such as (anaemia,bone marrow hypoplasia in the absence of reticulocyte response)it was use of quantitative real time PCR on plasma samples whichconfirmed the diagnosis and helped in monitoring the response toHNIG therapy.

Parvovirus induced myocarditis is a well recognised entity. Thedisease has variable prevalence (2.5–60% positivity in endomyocar-dial biopsies of viral myocarditis cases).14 Although the presentcase presented with heart failure and dyspnoea, cases may presentwith chest pain, malaise, oedema or elevation of cardiac enzymessuch as creatine kinase or troponin I.15 Clinical course of parvovirusmyocarditis is variable ranging from full recovery to heart fail-ure and death. Failure to eliminate the virus from myocardiumis associated with adverse prognosis. In a series published fromthe Mayo clinic, Parvovirus associated myocarditis was diagnosedmore among SCT recipients (12.5%) than solid organ transplantrecipients (2.9%).16 There are no randomised control trials regard-ing use of HNIG for treatment of parvovirus infection and mostof the evidence for its efficacy is derived from case reports, withsome cases demonstrating dose dependent virological and haema-

tological response to treatment.17 In a systematic review for thetreatment regimen (immunoglobulin therapy with or withoutreduction of immunosuppression) of parvovirus infection in renaltransplant recipients, Liefeldt et al. reported that although clini-cal response was noted in majority of reports, virological response

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64 S. Bhattacharya et al. / Journal o

as either not found or not determined in a large number oftudies.18

The present case illustrates unusual presentations of infec-ions with common pathogens can occur in immunocompromisedatients. List of possibilities in differential diagnosis of myocarditis

s large. Infective agents such as viruses may persist in immuno-ompromised patients for long period of time. There is a needo distinguish between asymptomatic shedding, chance detec-ion, association and causation. Awareness of these possibilitiesith appropriate and timely investigations, specialist referral and

herapy would be helpful in reducing morbidity and improvingutcome.

onflict of interest

The authors have no conflict of interest.

cknowledgement

We thank Dr. Kevin Brown at the Centre of Infections, Healthrotection Agency, London, for parvovirus PCRs results.

eferences

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2. Gähler A, Hitz F, Hess U, Cerny T. Acute pericarditis and pleural effusion com-

plicating cytarabine chemotherapy. Onkologie 2003;26:348–50.

3. Ritchie DS, Seymour JF, Roberts AW, Szer J, Grigg AP. Acute left ventricular fail-ure following melphalan and fludarabine conditioning. Bone Marrow Transplant2001;28:101–3.

4. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treat-ment and prevention. Drug Saf 2000;22:263–302.

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6. Schenk T, Enders M, Pollak S, Hahn R, Huzly D. High prevalence ofhuman parvovirus B19 DNA in myocardial autopsy samples from subjectswithout myocarditis or dilated cardiomyopathy. J Clin Microbiol 2009;47:106–10.

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18. Liefeldt L, Buhl M, Schweickert B, Engelmann E, Sezer O, Laschinski P, et al. Eradi-cation of parvovirus B19 infection after renal transplantation requires reductionof immunosuppression and high-dose immunoglobulin therapy. Nephrol DialTransplant 2002;17:1840–2.