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BRIEF COMMUNICATIONS: Clinical Transplantation


Fall, Andrew J.1; Aitchison, J. Douglas2 3; Krause, Anne4; Hasan, Asif2; Hamilton, J. R. Leslie2; Gould, F. Kate4

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Donor-transmitted infection is a well-recognized cause of morbidity and mortality after organ transplantation. Viral infections pose a particular problem in these immunocompromised patients, and infections associated with herpes viruses are the most commonly encountered. Graft-transmitted cytomegalovirus (CMV) with the potential to cause severe disease is well described in solid organ recipients (1). Varicella zoster virus (VZV) causes one of two clinical syndromes in this population: primary varicella in the seronegative recipient after contact with an infected individual; or in the seropositive patient, herpes zoster, a VZV reactivation. We report to our knowledge the first case of organ-transmitted varicella in a cardiac transplant recipient.

A critically ill 15-month-old girl with dilated cardiomyopathy secondary to endocardial fibroelastosis in whom maximal medical therapy had failed was referred for urgent cardiac transplant assessment. She was maintained on intravenous inotropic support while the transplant assessment was undertaken. After 4 days without improvement, a compatible donor heart became available. This was from a 4-year-old who had died from pneumococcal meningitis but who, 10 days previously, had had severe chicken pox. Routine pretransplantation serological work-up of the recipient showed no evidence of previous infection with VZV. Intravenous acyclovir 200 mg t.i.d. was given from the time of transplantation until the sixth postoperative day and thereafter continued orally at the same dose.

Surgery, and the immediate postoperative period, was uneventful. Immunosuppression was achieved using induction with antithymocyte globulin for 7 days, methylprednisolone for 3 days, cyclosporine, and azathioprine. The child was transferred from the intensive care unit on the sixth postoperative day.

On the 12th postoperative day, the child developed a fever of 38.5°C, with no localizing signs. Blood count showed a moderate anemia and leukopenia (hemoglobin 8.0 g/dl, white cells 4.9×109/L). Cultures from blood, nasopharyngeal secretions, urine, central venous line tip, and bronchoalveolar lavage failed to identify pathogenic bacteria, viruses, or fungi. Direct immunofluorescence of nasopharyngeal secretions and of bronchoalveolar lavage fluid revealed no respiratory viruses. CMV early antigen was not detected by fluorescent foci testing. Echocardiography showed excellent myocardial function. An endomyocardial biopsy specimen revealed grade 1a (mild) rejection, which was considered unlikely to be the cause of her fever and not requiring treatment.

On the second day of her fever she developed a nonspecific macular, erythematous rash, pharyngeal injection, and mild generalized lymphadenopathy. Two days later three isolated vesicles appeared on the soft palate; there were no cutaneous or genital lesions. The presence of VZV was demonstrated by direct immunofluorescence of vesicular fluid, but the virus failed to grow in tissue culture. Serum obtained on the 14th postoperative day showed the presence of VZV IgM. All other serology and CMV antigenemia testing were negative.

The dose of acyclovir was increased to 400 mg intravenously five times daily for 7 days and orally for a further 7 days, before reverting to the previous regimen of 200 mg t.i.d. for 2 months. The dose of cyclosporine was reduced by 25% for 2 weeks, achieving cyclosporine levels of 100 ng/ml, instead of our usual target of 300 ng/ml. Renal function was assessed daily. Both fever and rash subsided within 5 days, and the child made a complete and uncomplicated recovery.

VZV IgG became detectable 4 months after transplantation. Eighteen months postoperatively she has shown no further signs or complications of VZV infection and no cardiac problems.

We believe this to be the first report of organ-transmitted varicella in a cardiac transplant patient. A management decision regarding use of the donor organ with the associated VZV infectious risk was required. In view of the clinical state of the patient and the scarcity of pediatric organ donors, it was considered that the risks of further waiting outweighed the inherent risks of transplantation. The recipient received intravenous acyclovir but not varicella zoster immunoglobulin. We felt varicella zoster immunoglobulin prophylaxis might afford incomplete protection with the risk of subsequent atypical, visceral disease (2). The risk of antithymocyte globulin-based immunosuppressive regimens associated with increased incidence of VZV infection is noted (3), although in this case the infection was not severe.

The presence of the enanthem was an important pointer to the diagnosis of fever, especially as the exanthem was so atypical of VZV (4). After identification of VZV by immunofluorescence, the acyclovir dosage was further increased. Subsequent testing demonstrated VZV DNA in donor lymphocytes and rising VZV IgM titers in recipient serum. The recipient’s palatal ulcer fluid was not available for polymerase chain reaction typing.

The increased susceptibility of immunocompromised patients to herpes viruses is well known. Primary VZV infection in transplant patients can be particularly severe with life-threatening complications, including consumptive coagulopathy, encephalitis, viral pneumonia, bacterial superinfection, or hepatitis (1). Reactivation disease is more common in the transplant patient than in the general population (5) but is generally clinically less severe than primary infection (1). The incidence of VZV infection after pediatric cardiac transplant is unknown. In adult cardiac transplant recipients it is 11–22% in the first year after transplantation, with a mortality of 13% (3, 6). In pediatric renal or hepatic transplantation, the incidence ranges from 10% to 16% and mortality from 5% to 25% (2, 4, 7, 8).

In the immunocompromised patient, first-line treatment of VZV infection comprises high-dose intravenous acyclovir for 10–14 days. Resistant VZV mutants have been isolated from patients with acquired immunodeficiency virus, due to Tk gene alteration causing deficient thymidine kinase production (9). Treatment in this case would require the use of foscarnet, a DNA polymerase inhibitor.

In transplant patients who have become infected with VZV, dose reduction of the immunosuppressive agents is of the utmost importance. In one study, patients were significantly more likely to develop severe disease if the immunosuppression was not reduced within 72 hr after clinical onset of varicella (4).

Immunization has been proposed to prevent varicella in transplant patients during the early, most susceptible time period. A live attenuated varicella vaccine has been shown to be safe and effective in children with renal transplants (10). However attractive preoperative immunization sounds, timing might prove to be the limiting factor for potential pediatric cardiac transplant recipients because the medical condition requiring transplantation often progresses rapidly. A child, recently vaccinated with a live vaccine, may not be an appropriate candidate for a transplant.

Balancing the prevention of organ rejection against the risk of infection will always be one of the many challenges of transplantation medicine. There are no easy answers. The decision whether to use a certain organ or to perform transplantation in an individual patient must be decided after careful consideration of all available clinical information.


We thank Mrs. L. Lowery for help with obtaining specimens and the Public Health Laboratory Service (Newcastle) for performing direct immunofluorescence and varicella zoster viral DNA testing.


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