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Varicella Recurrence Complicated by Pneumonia After Liver Transplantation for APECED

Batra, Akshay*; Davison, Suzanne*; Rajwal, Sanjay*; Hale, Antony; Stringer, Mark D*; McClean, Patricia*

Journal of Pediatric Gastroenterology and Nutrition: May 2007 - Volume 44 - Issue 5 - p 637–639
doi: 10.1097/01.mpg.0000243432.09216.aa
Case Reports

*Children's Liver & GI Unit, St James's University Hospital

Virology Department, Leeds Teaching Hospitals Trust, Leeds, UK

Received 30 December, 2005

Accepted 24 August, 2006

Address correspondence and reprint requests to Patricia McClean, Children's Liver & GI Unit, St James University Hospital, Beckett Street, Leeds LS9 7TF, UK (e-mail:

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Severe infection with varicella zoster virus (VZV) after transplantation typically occurs in patients who are nonimmune before transplantation (1,2). Reactivation of the VZV usually causes shingles. Reinfection with VZV in immunocompetent individuals is extremely rare, but there are several reports of reinfection in immunocompromised patients. Reinfection occurs more often in those who have not had a previous symptomatic infection and typically has a mild course (3). Whether this is truly reinfection or disseminated atypical reactivation is often not clear from the reports in the literature. We choose to describe such infections as recurrent because there are no means to distinguish reinfection from reactivation. We describe VZV recurrence complicated by pneumonia after liver transplantation in a 16-year-old boy with a clear history of chicken pox.

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The patient was a 16-year-old white boy who had received a diagnosis of autoimmune polyendocrinopathy candidiasis and ectodermal dysplasia at the age of 8 years. He was heterozygous for the AIRE 1 mutation 13bp (964 del 113). He had Candida infection of his gastrointestinal tract and nails, photophobia, and hair loss, which had progressed to alopecia totalis by 5 years of age. Other problems included severe constipation and gut dysmotility, exocrine pancreatic insufficiency, ectodermal dysplasia of his nails and teeth, and adrenal insufficiency; all of these features were present by 12 years of age. At 8 years of age he received a diagnosis of autoimmune hepatitis. Autoantibodies were not detected in his serum, but a liver biopsy showed interface hepatitis and septal fibrosis. His liver function test results improved with oral prednisolone.

In March 2005, when the patient was 16½ years old, his serum transaminase levels increased again, and his dose of prednisolone was increased. However, 3 weeks later his condition deteriorated rapidly, and he was transferred to our unit with jaundice, grade III encephalopathy, and severe coagulopathy. A liver transplant was performed with a whole graft from a deceased donor. His posttransplant course was complicated by insulin-dependent diabetes, left-sided weakness, and a biliary stricture, which responded to temporary endoscopic stenting.

By 3 to 4 weeks after transplantation, the patient's immunosuppressive therapy consisted of replacement hydrocortisone and tacrolimus (trough level 8–12 ng/mL). He was still taking cotrimoxazole and fluconazole as prophylaxis for Pneumocystis carinii and Candida infection. At this time, skin lesions developed, which were red and raised with a golden surface but no central blistering (Fig. 1), mainly present on his neck and back and not typical of any specific exanthem. Swabs of the lesions showed a herpesvirus on electron microscopy, and polymerase chain reaction confirmed the presence of VZV DNA. The patient had had chicken pox at about age 4 years, and his pretransplant serum VZV immunoglobulin G (IgG) was 44 enzyme-linked immunosorbent assay units (EU)/mL in the absence of receiving blood or blood products in the previous month. One week after the transplant it was 60 EU/mL (≥20 EU/mL reactive/positive for anti-VZV IgG; Diamedix VZV IgG, Diamedix Corporation, Miami, FL). There was no recognized recent VZV contact. He was given intravenous acyclovir, and the lesions started crusting. Three days after the onset of the rash, he became pyrexial and experienced increasing respiratory distress. A chest radiograph showed extensive consolidation in the left perihilar region extending into the upper and lower zones (Fig. 2A). Intravenous ceftazidime and flucloxacillin were added for the bacterial infection, but during the next 12 hours he experienced increasing respiratory distress and needed supplemental oxygen. A second chest radiograph showed a dramatic improvement in the left lung, but there was new nodular consolidation in the right perihilar region extending to the upper zone (Fig. 2B). His respiratory distress and rash gradually improved during the next 3 days, when a further chest radiograph showed a marked improvement (Fig. 2C). Sputum and blood cultures failed to grow any bacteria, and the result of serology for other atypical organisms was subsequently negative. Throughout his illness his liver function remained normal. The C-reactive protein rose to 122 mg/L, but he had no proven bacterial infection. A convalescent serum sample was positive for VZV IgM and showed a concomitant rise in VZV IgG to 266 EU/mL. Serum immunoglobulin concentrations and lymphocyte subsets were normal. He had no further complications and was discharged home 2 weeks later.

FIG. 1

FIG. 1

FIG. 2

FIG. 2

Unfortunately, 3 months later he experienced biopsy-proven late acute rejection with features of ductopenic chronic rejection and was treated with 2 courses of pulsed methyl prednisolone, an increased dose of tacrolimus, and the addition of mycophenolate mofetil. Sadly, 8 months after his transplant he collapsed with pneumococcal pneumonia and septicemia and died of an intracranial hemorrhage.

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The VZV is a member of the herpes group of viruses and is responsible for both chicken pox and herpes zoster. Primary VZV infection occurs almost exclusively in childhood. In healthy children it has a fairly benign course; complications are more likely in immunocompromised newborns and adults. Commonly associated complications include superinfection of the cutaneous lesions, laryngitis, pneumonia, cerebellitis, and encephalitis (4). VZV pneumonia is 3 to 4 times more common in immunocompromised children than in healthy children (5). Both primary VZV infection and vaccination induce enduring antibodies and lasting protection against clinical infection (6). Recurrence is rare in immunocompetent individuals but can occur in immunocompromised individuals (3). Usually there is no history of a previous symptomatic chicken pox illness, and the recurrence results only in a mild atypical exanthematous rash. Patients with recurrence often have low IgG antibody titers at the time of infection (3). Our patient was unusual in that he had had previous symptomatic chicken pox and had good VZV IgG titers before transplantation and before infection. Despite this, the complication of pneumonia developed.

Pneumonia usually presents early in the course of infection, at about 1 to 6 days, with acute dyspnea and hypoxemia (7) and is associated with a high mortality and morbidity (8,9). The radiographic findings of VZV pneumonia include diffusely disseminated, small, poorly defined nodular shadows that may be confluent and fleeting, together with increased bronchovascular markings (7,10). In mild cases these lesions resolve in 3 to 5 days, but they can persist for several weeks and even calcify (10). The diagnosis of VZV pneumonia is usually based on a skin rash with VZV in the vesicles and on the typical chest radiographic appearance. Bacterial superinfection is common, but consolidation is not usually as fleeting as that seen in our patient. The diagnosis can be confirmed by bronchoscopy and bronchoalveolar lavage, but this was not justified in our case because our patient recovered quickly.

Prompt treatment with high-dose intravenous acyclovir has been shown to be effective in VZV pneumonia, although some cases of resistance have been reported in immunocompromised children. Steroids may decrease the mortality and morbidity associated with VZV pneumonia (8,9). It was unusual for our patient to experience pneumonia with VZV recurrence, but it had a relatively mild course, perhaps because of his previous good antibody levels, the prompt use of high-dose intravenous acyclovir, and the concurrent treatment with steroids.

Our patient was significantly immunosuppressed because of his underlying condition, the long-term treatment with steroids before transplantation, and the immunosuppressive therapy after his transplant. There are 3 other reports of liver transplantation in patients with autoimmune polyendocrinopathy candidiasis and ectodermal dysplasia in the literature, with 2 long-term survivors (11). These patients may be at greater risk of primary infection and reactivation than most children needing a liver transplant.

In summary, this case report highlights that disseminated VZV infection with pneumonia can occur after liver transplant regardless of previous symptomatic chicken pox infection and good antibody titers. A high index of suspicion of VZV for any atypical rash in an immunocompromised patient should prompt virological confirmation and early treatment with high-dose acyclovir.

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The authors thank Drs J. Hosker, A. Natarajan, F.M. Shackley, and J.K. Wales, and Prof M. S. Tanner for the ongoing care of the patient whose case is described here.

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