SEARCH

SEARCH BY CITATION

Keywords:

  • Encephalitis;
  • heart transplantation, herpesvirus

Abstract

  1. Top of page
  2. Abstract
  3. Case History
  4. Discussion
  5. References

Human herpesvirus-6 (HHV-6), a beta herpesvirus closely related to cytomegalovirus (CMV), infects the majority of the population in childhood. Human herpesvirus-6 can be reactivated in the immunosuppressed patient. After bone marrow and orthotopic liver transplant, it has been linked to various clinical syndromes, including undifferentiated febrile illness, encephalitis, pneumonitis and bone marrow suppression. To date its infectious role after orthotopic heart transplant has not been well documented. We present the case of a 32-year-old cardiac transplant recipient who initially presented 8 weeks after his transplant with high fever and headache. He developed increasing confusion, pulmonary infiltrates and neutropenia. Cytomegalovirus viral loads were negative. Polymerase chain reaction (PCR) of blood and cerebrospinal fluid detected HHV-6 DNA, consistent with HHV-6-related encephalitis, pneumonitis and bone marrow suppression. He was treated with foscarnet with gradual improvement in clinical status. We review the literature on the significance of this virus post cardiac transplant.


Case History

  1. Top of page
  2. Abstract
  3. Case History
  4. Discussion
  5. References

A 32-year-old man was admitted with fever, rigors, anorexia and mild frontal headache. He denied any history of a rash, diarrhea, or focal neurologic symptoms. He had received an orthotopic heart transplant (CMV-donor positive, -recipient negative) for a nonischemic dilated cardiomyopathy 8 weeks earlier (early Spring). He received rabbit antithymocyte globulin as induction therapy at the time of transplant and required a steroid bolus for the treatment of ISHLT grade 3B rejection on initial biopsy. His subsequent early post-transplant recovery course was unremarkable. His immunosuppressive regimen on admission consisted of tacrolimus 3 mg b.i.d., mycophenolate mofetil 1250 mg b.i.d. and prednisone 20 mg q.d. He had been treated with valganciclovir 900 mg q.d. for 4 weeks and remained on acyclovir prophylaxis (800 mg t.i.d.). He was also on sulfamethoxazole/trimethoprim (SMZ/TMP) prophylaxis. On initial examination, he was febrile (38.6 °C), with no evidence of meningismus or focal neurological signs. Examination was otherwise unremarkable. Chest X-ray on admission showed clear lung fields. Echocardiogram demonstrated normal left and right ventricular function, with a small posterior pericardial effusion. In view of his CMV status, he was empirically treated with intravenous ganciclovir 5 mg/kg b.i.d. and CMV immunoglobulin (150 mg/kg). Brain MRI showed a few nonspecific subcortical white-matter areas of abnormal intensity, most prominent in the right parietal region. High fever, nausea and headache persisted and following admission, he became increasingly drowsy and confused. On day 2 post admission a lumbar puncture was performed, which demonstrated moderate lymphocytic leucocytosis (white-cell count = 90/μL, 88% lymphocytes, 12% monocytes, no neutrophils), elevated protein and normal glucose in the cerebrospinal fluid (CSF): a pattern suggestive of viral meningo-encephalitis. A hybrid capture CMV DNA assay on peripheral blood was reported as negative on day three. He developed progressive leucopenia and mycophenolate mofetil and ganciclovir were discontinued on day three because of concerns about potential drug-related myelosuppression and the negative tests for CMV.

His condition deteriorated over the subsequent days, with persistent high fever, confusion, decreasing responsiveness, new onset diplopia, and progressive hypoxemia, requiring mechanical ventilatory support on day eight. Laboratory tests revealed progressive neutropenia (WBC = 900/μL), which was treated with recombinant granulocyte colony-stimulating factor and withdrawal of remaining immunosuppressants (tacrolimus). An electroencephalogram showed continuous slow waves consistent with a diffuse encephalopathic process. Repeat lumbar puncture demonstrated increasing lymphocytic leucocytosis (white cell count = 218/μL, 91% lymphocytes). Repeat chest X-ray demonstrated bilateral diffuse infiltrates. Blood and CSF bacterial cultures were negative. Cerebrospinal fluid (CSF) PCR was negative for herpes simplex virus (HSV) types 1 and 2, and Varicella-Zoster virus (VZV), and peripheral blood PCR was negative for Epstein-Barr virus (EBV). Viral cultures of CSF and stool for enterovirus were negative. Cryptococcal antigen and serologies for histoplasmosis, blastomycosis, coccidioidomycosis and West Nile Virus were negative. Serology for toxoplasmosis was consistent with prior infection. Bone marrow examination demonstrated maturation arrest at the promyelocyte stage consistent with early recovery from agranulocytosis. Subsequent PCRs of plasma and CSF were positive for HHV-6 (Specialty Laboratories, Inc, Santa Monica, CA), consistent with active infection. Foscarnet therapy was commenced (60 mg/kg intravenously t.i.d. for 3 weeks) in view of the lack of apparent response to ganciclovir and concerns about its myelosuppressive potential.

His clinical status gradually improved, with resolution of the neutropenia and gradual improvement in his neurologic status. Immunosuppressants were re-introduced after 7 days once his neutrophil count had normalized. Repeat lumbar puncture after 3 weeks of foscarnet therapy demonstrated resolution of the CSF leucocytosis, although PCR for HHV-6 remained positive. He required 6 weeks of mechanical ventilatory support before being successfully weaned with intensive respiratory rehabilitation. Eight weeks after admission he was discharged to a rehabilitation center, with no focal neurologic deficits except for persistent difficulties with short-term memory and recall.

Discussion

  1. Top of page
  2. Abstract
  3. Case History
  4. Discussion
  5. References

Fever, headache and progressive deterioration in the mental state of a patient 2 months post cardiac transplantation are very suggestive of infectious meningoencephalitis. The most likely etiologic agents at this stage post transplant are viral, most commonly those of the herpesvirus family (CMV, VZV and HSV), but enteroviruses (Coxsackie) and arboviruses (West Nile Virus) also need to be considered. HSV typically presents earlier after transplantation and more commonly takes the form of mucosal ulcerations. Both HSV and VZV would be less likely in the setting of adherence to acyclovir prophylaxis. In view of the rapid deterioration in his clinical condition and his CMV status (donor positive, recipient negative), empiric treatment of an undefined febrile illness like this, with ganciclovir, should be considered (as well as other appropriate empiric therapy) pending results of confirmatory laboratory tests. However this is not a common presentation for CMV (1). Mid-summer and autumn have become associated with West Nile virus. His serology was repeatedly negative. The combination of encephalitis with a pericardial effusion raises the suspicion of enterovirus (Coxsackie), although the stool and CSF cultures were not supportive. Bacterial meningitis resulting from Streptoccocalpneumoniae, Haemophilus influenza or Neisseria meningitidis would typically have produced a polymorphonuclear CSF pleocytosis, and more signs of meningeal irritation. Other potential agents in immunocompromized patients include Listeria, (less likely as the patient was on SMZ-TMP prophylaxis), Toxoplasmosis gondii (serology consistent with prior exposure) and Cryptococcusneoformans (typically appears later, usually greater than 6 months post transplant). This patient's CSF profile was strongly suggestive of a viral etiology (elevated protein, normal glucose with lymphocytic leucocytosis), and subsequent negative bacterial cultures and negative antigen testing for Cryptococcus helped exclude the more common nonviral pathogens. Previous reports have linked HHV-6 to similar clinical syndromes (encephalitis, pneumonitis and bone marrow suppression) in patients post bone marrow transplantation (BMT) and other solid organ transplants (renal and liver). Confirmation of HHV-6 as the etiologic agent was accomplished by plasma and CSF PCR.

Human herpesvirus-6 was first isolated in 1986, in a series of patients with lymphoproliferative disorders, and was transiently labeled as human B-lymphotropic virus (HBLV) (2). However, it rapidly became clear that it shared many similarities with other members of the herpesvirus family, particularly CMV. Cell tropism for this virus is greatest for T lymphocytes. It was soon identified as the etiologic agent of the childhood exanthema, roseola (exanthem subitum) or ‘sixth disease’ (3), although the majority of childhood infections present as an undifferentiated transient febrile illness. Infection by this virus is almost ubiquitous in childhood and seroprevalence studies suggest that greater than 90% of adults are seropositive for HHV-6 (4). Similar to other herpesviruses, it remains latent in human cells, and may reactivate during states of immunosuppression (5).

Primary infection in adulthood is rare and most clinical features associated with HHV-6 appear to result from reactivation (typically occurring within the first 2 months post transplant) (5). In transplant patients, numerous disease associations with HHV-6 reactivation have been reported. However the ubiquitous nature of HHV-6 infection and its wide tissue tropism (HHV-6 DNA can be isolated from many cells types by PCR despite viral latency) make confirmation of a conclusive etiologic association difficult. Infection with HHV-6 has been associated with undifferentiated febrile illness, skin rashes, encephalitis, interstitial pneumonitis and myelosuppression, predominantly in BMT recipients, and to a lesser extent in orthotopic liver and renal transplants (6). High fevers (41.6 °C in one renal transplant recipient) have been reported (7). Viral antigen by immunohistochemical staining has been demonstrated in lung tissue obtained from BMT patients with interstitial pneumonitis, while other cases have demonstrated the coexistence of additional pathogens such as CMV and adenovirus, making conclusive proof of its pulmonary pathogenicity difficult (8). Encephalitis, presenting with fever, headache and confusion, has been reported in a number of case reports. Several fatal cases with subsequent histological confirmation have been reported in BMT recipients (9). Bethge reported two cases of encephalitis (CSF positive for HHV-6 DNA) treated successfully with foscarnet (10). Encephalitis has also been reported in liver transplant recipients (11). In a review of 14 reported cases of HHV-6 encephalitis (13 after BMT, one after a liver transplant), a mortality rate in excess of 50% was documented (6). Typical findings are a lymphocytic CSF pleocytosis, with elevated protein levels. Either normal MRI imaging or symmetrical nonenhancing, nonspecific white or gray matter lesions have been noted. Bone marrow suppression in association with HHV-6 has been reported, most frequently after BMT, but also following liver transplantation (12,13). This effect may be either owing to direct bone marrow infection or a cytokine-mediated immunosuppressive effect (13). Human herpesvirus-6 often coexists with CMV, and in a prospective study of 88 liver transplant recipients, symptomatic CMV disease was more common in patients with HHV-6 infection than in those without, with HHV-6 being an independent risk factor for developing CMV disease (14).

Human herpesvirus-6 IgG or IgM serology is not helpful in confirming active infection. Most people aged older than 2 years have HHV-6 antibodies and approximately 5% of healthy adults are IgM positive at any one time, making this test unreliable for definitive diagnosis. In addition, transplant recipients with HHV-6 reactivation may not mount an IgM response. The diagnostic ‘gold-standard’ test for HHV-6 is culture of the virus from blood or other tissue samples. This is time-consuming and labor intensive. Polymerase chain reaction is now increasingly being used as a rapid and sensitive test in immunocompromized patients. It has been argued that PCR may detect latent HHV-6 DNA in lymphocytes in peripheral blood. Modifications that raise the threshold above that encountered in peripheral blood mononuclear cells during latent infection, or isolating DNA by PCR from acellular plasma samples, may provide better diagnostic accuracy. Viral DNA should not normally be isolated from the CSF, and PCR for HHV-6 DNA in CSF is regarded as the gold standard for the diagnosis of active CNS infection (15).

There are only limited reports documenting infection post heart or heart/lung transplantation (16–18). The largest series (19 heart/lung and 11 lung transplants) followed longitudinally from time of transplant demonstrated that 66% developed infection (PCR for viral DNA or cell culture) within the first 100 days (16). No clinical manifestations could clearly be associated with HHV-6 infection alone. Those with HHV-6 had a higher mortality rate than those without (seven of 20 vs. 0 of 10; p = 0.04). Overall there was no significant difference in rates of infections between both groups. Those with HHV-6 had more viral (three CMV, one HSV and one Epstein-Barr virus infection) and fungal infections than those without HHV-6 (1 CMV infection) (16). Several other reports have associated HHV-6 infection, with increased CMV severity, as well as increasing the risk of fungal infections, suggesting a potential immunomodulatory role for this virus (14). A Medline review revealed only one case report demonstrating a convincing association between HHV-6 infection and clinical disease (gastroduodenitis and pancreatitis) post heart transplant (17). Why infection in BMT appears to result in more clinical sequelae is unclear, but the myelosuppressive potential of this virus may play a role.

To the best of our knowledge this case is the first to document severe meningoencephalitis in association with HHV-6 infection post cardiac transplant. The concurrence of myelosuppression and encephalitis in our patient is intriguing. We did not confirm HHV-6 in the bone marrow, nor are we able to exclude other potential causes of the myelosuppression (ganciclovir, immunosuppressants). Our report of encephalitis is similar to other reports after bone marrow and liver transplant. Of note, our patient was treated with antithymocyte globulin as induction therapy at the time of transplant. The association of similar drugs, OKT3 in a renal transplant (7) and anti-CD3 monoclonal antibody in a BMT (19), with HHV-6 infection raises the possibility that these potent immunosuppressants may impact on the pathogenicity of this virus. The efficacy of ganciclovir could not be assessed in our patient, as it was discontinued after only 3 days because of concerns of myelosuppression. Foscarnet was used successfully in this case and similar responses have been documented in other case reports (10). To date no controlled studies have been performed. In vitro, HHV-6 has similar antiviral susceptibility patterns to CMV (ganciclovir and foscarnet are active against HHV-6, but acyclovir is not) (2). Some have suggested that a subtype of HHV-6 [HHV-6 A, suggested to have more neurotoxicitiy (20)] may be less susceptible to ganciclovir. Drug doses are not well defined but doses similar to those used for treatment of CMV (ganciclovir 5 mg/kg b.i.d. and foscarnet 60 mg/kg t.i.d. for at least 3 weeks) have been used.

This case highlights the potential pathogenicity and morbidity of HHV-6 infection post cardiac transplant and the importance of considering it as a potential pathogen in the setting of post-transplant encephalitis. Clinicians should consider HHV-6 PCR testing in a transplant recipient who presents with a compatible clinical syndrome, or a CMV-like syndrome in which CMV assays are negative. A prospective study to evaluate the incidence and clinical associations of infection with HHV-6 in the early post cardiac transplant period is needed to determine the frequency of HHV-6 infection in this population, elucidate its true role in mediating clinical disease, and provide us with a better perspective on the significance of infection with this virus.

References

  1. Top of page
  2. Abstract
  3. Case History
  4. Discussion
  5. References
  • 1
    Chaudhuri A, Kennedy PG. Diagnosis and treatment of viral encephalitis. Postgrad Med J 2002; 78: 57583.
  • 2
    Dockrell DH. Human herpesvirus 6: molecular biology and clinical features. J Med Microbiol 2003; 52: 518.
  • 3
    Salahuddin SZ, Ablashi DV, Markham PD et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986; 234: 596601.
  • 4
    Levy JA, Ferro F, Greenspan D, Lennette ET. Frequent isolation of HHV-6 from saliva and high seroprevalence of the virus in the population. Lancet 1990; 335: 10471050.
  • 5
    Singh N, Carrigan DR. Human herpesvirus-6 in transplantation: an emerging pathogen. Ann Intern Med 1996; 124: 10651071.
  • 6
    Singh N, Paterson DL. Encephalitis caused by human herpesvirus-6 in transplant recipients: relevance of a novel neurotropic virus. Transplantation 2000; 69: 24742479.
  • 7
    Jacobs U, Ferber J, Klehr HU. Severe allograft dysfunction after OKT3-induced human herpes virus-6 reactivation. Transplant Proc 1994; 26: 3121.
  • 8
    Carrigan DR, Drobyski WR, Russler SK, Tapper MA, Knox KK, Ash RC. Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Lancet 1991; 338: 147149.
  • 9
    Drobyski WR, Knox KK, Majewski D, Carrigan DR. Brief report: fatal encephalitis due to variant B human herpesvirus-6 infection in a bone marrow-transplant recipient. N Engl J Med 1994; 330: 13561360.
  • 10
    Bethge W, Beck R, Jahn G, Mundinger P, Kanz L, Einsele H. Successful treatment of human herpesvirus-6 encephalitis after bone marrow transplantation. Bone Marrow Transplant 1999; 24: 12451248.
  • 11
    Montejo M, Ramon Fernandez J, Testillano M et al. Encephalitis caused by human herpesvirus-6 in a liver transplant recipient. Eur Neurol 2002; 48: 234235.
  • 12
    Singh N, Carrigan DR, Gayowski T, Marino IR. Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity. Transplantation 1997; 64: 674678.
  • 13
    Drobyski WR, Dunne WM, Burd EM et al. Human herpesvirus-6 (HHV-6) infection in allogeneic bone marrow transplant recipients: evidence of a marrow-suppressive role for HHV-6 in vivo. J Infect Dis 1993; 167: 735739.
  • 14
    Humar A, Malkan G, Moussa G, Greig P, Levy G, Mazzulli T. Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver transplant recipients. J Infect Dis 2000; 181: 14501453.
  • 15
    Avery RK, Pappas PG. Infections after heart (and heart/lung) transplantation. In: McGiffin, DC, ed. Heart Transplantation. New York : Churchill Livingstone, 2002: 564566.
  • 16
    Jacobs F, Knoop C, Brancart F et al. Human herpesvirus-6 infection after lung and heart-lung transplantation: a prospective longitudinal study. Transplantation 2003; 75: 19962001.
  • 17
    Randhawa PS, Jenkins FJ, Nalesnik MA et al. Herpesvirus 6 variant A infection after heart transplantation with giant cell transformation in bile ductular and gastroduodenal epithelium. Am J Surg Pathol 1997; 21: 847853.
  • 18
    Moschettini D, De Milito A, Catucci M et al. Detection of human herpesviruses 6 and 7 in heart transplant recipients by a multiplex polymerase chain reaction method. Eur J Clin Microbiol Infect Dis 1998; 17: 117119.
  • 19
    Zerr DM, Gooley TA, Yeung L et al. Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients. Clin Infect Dis 2001; 33: 763771.
  • 20
    Hall CB, Caserta MT, Schnabel KC et al. Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. Clin Infect Dis 1998; 26: 132137.