CLINICAL

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LABORATORY OBSERVATIONS

Concomitant Use of Acyclovir and Intravenous Immunoglobulin Rescues an Immunocompromised Child With Disseminated Varicella Caused Multiple Organ Failure
Ying-Chun Lu, MD, Hueng-Chuen Fan, MD, PhD, Chih-Chien Wang, MD, PhD, and Shin-Nan Cheng, MD, PhD

Summary: Varicella is a common and mild disease in healthy children. However, when patients are in immunocompromised conditions, such as receiving chemotherapy for cancer treatment, they are highly vulnerable and it can even prove lethal. Herein, we report a 14-year-old boy with acute lymphoblastic leukemia who was receiving chemotherapy for induction with vincristine, idarubicin, L-asparaginase, and prednisolone, presented with typical varicella skin lesions and varicella-zoster virus was detected in his serum by real-time polymerase chain reaction (PCR). His condition was advanced to multiple organs failure, including fulminant hepatitis, disseminated intravascular coagulation, and myocarditis despite acyclovir administration. After a combined therapy with intravenous acyclovir and high-dose intravenous immunoglobulin, his condition was dramatically improved. We suggest that IVIG may be used immediately with acyclovir when immunocompromised patients with varicella advanced to dissemination are identied. Key Words: varicella, ALL, acyclovir, IVIG

CASE REPORT
A formerly healthy 14-year-old boy, who had not received the varicella vaccine, was diagnosed with B-cell precursor ALL. Thereafter, he underwent 4 weeks of induction chemotherapy according to the Taiwan Pediatric Oncology Group (TPOG)-ALL2002 protocol with vincristine, idarubicin, L-asparaginase, and prednisolone.3 After induction chemotherapy, his vital signs were stable, and his blood cell counts, liver, and heart function studies were all in normal ranges. On the 30th day of induction chemotherapy, the boy felt fatigue and generalized weakness and he visited our pediatric physician for further evaluation. On physical examination, there were pruritic maculopapular rashes over his scalp, face, neck, and shoulders and less than 10 vesicles with umbilication developed. With concern for his immunocompromised condition and advanced varicella dissemination, he was admitted to the pediatric ward of our hospital. On admission, blood cell counts, liver function tests, blood urea nitrogen, creatinine, serum sodium, and serum potassium levels were all normal. Reports of chest radiography and electrocardiogram were normal. Because varicella was suspected of being the pathogen, his serum was tested by VZV DNA by PCR, and the result was positive. Consequently, 1500 mg/m2of acyclovir divided into 3 doses per day was administered intravenously. The patients condition deteriorated within the rst 48 h. His cutaneous lesions with more than 500 vesicles erupted. His skin also showed generalized ecchymosis. Laboratory tests showed Ddimer 3655 ng/mL, brin degradation product was more than 40 mg/mL, brinogen 634 mg/dL, thrombocytopenia, and prolonged thrombin time. All these ndings supported that he was in DIC status. In addition, his liver function test showed aspartate aminotransferase and alanine aminotransferase were 1579 U/L and 2497 U/L, respectively, and abdominal sonography showed no focal lesions of the liver. Moreover, his heart rate was 125 beats per minute, and respiratory rate was 28 per minute. Electrocardiogram showed diused low voltage of QRS-wave and T-wave inversion. Cardiac enzymes were elevated. Echocardiography showed 30 percentage of ejection fraction. All these data suggested that he was in a multiple organ failure situation. Therefore, this patient was transferred to the intensive care unit for close monitoring of his downward vital signs. On the basis of clinical observation, we highly suspected the varicella in this boy was in a rapid proliferation phase. Hence, PCR for VZV DNA was done again, and the result supported our impression. To synergize the antiviral eect of acyclovir, IVIG 400 mg/kg/d was concomitantly administrated. After a 5-day course of IVIG treatment, his poor myocardial function with unstable hemodynamic systems recovered. His abnormal blood cell counts, abnormal coagulation factors, and abnormal liver enzymes returned to normal range, and no new skin vesicles were visible. On the 14th day, he was discharged without any sequelae or complications from our hospital.

(J Pediatr Hematol Oncol 2011;33:e350e351)

rimary varicella-zoster virus (VZV) infection is a common and usually mild childhood disease.1 Progressive varicella may occur in adults or immunocompromised children and is associated with signicant morbidity and mortality.2 Children with hematological malignancies are vulnerable to disseminated varicella while receiving chemotherapy or systemic corticosteroids administration, especially when they are in an immunocompromised status. We report a case of a boy with acute lymphocytic leukemia (ALL), who presented with fulminant varicella. His lesions did not recover after acyclovir administration. On the contrary, his condition was advancing and he was presented with acute hepatitis, disseminated intravascular coagulation (DIC), and myocarditis. We show that a combination with acyclovir and intravenous immunoglobulin (IVIG) may provide an eective treatment for immunocompromised children with disseminated varicella.

Received for publication March 23, 2010; accepted June 8, 2010. From the Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC. The authors declare no conict of interest. Reprints: Shin-Nan Cheng, MD, PhD, Department of Pediatrics, TriService General Hospital, National Defense Medical Center; No. 325, Cheng-Kung Rd., Sec. 2, Neihu, Taipei 114, Taiwan (e-mail: loveisid@yahoo.com.tw). Copyright r 2011 by Lippincott Williams & Wilkins

DISCUSSION
Evidence shows that varicella in immunocompromised patients tends to disseminate.4 Moreover, the mortality rate of disseminated varicella is extremely high in children with


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J Pediatr Hematol Oncol

Volume 33, Number 8, December 2011

J Pediatr Hematol Oncol

Volume 33, Number 8, December 2011

Combined Therapy With IV Acyclovir and Human IV Immunoglobulin Rescues an Immunocompromised Child With Disseminated Varicella

ALL, not only because its clinical course is fulminant and its presentations are untypical, but also because it is irrelevant to whether these patients have received varicella vaccine or were administered intravenous acyclovir.5,6 PCR for VZV DNA is a very powerful diagnostic tool because it is very sensitive and only needs a tiny amount of tissue or serum to detect VZV DNA.79 If VZV was identied in immunocompromised patients, antiviral drugs, such as acyclovir, should be used emergently.10 One of the mechanisms of acyclovir against varicella is to cease varicella progression and shorten the duration of viral replication. However, from the Veit et al6 report showing that 3 deaths occurred in children, with ALL who developed disseminated varicella despite early administration of acyclovir, we think that acyclovir may not be able to fully suppress viremia, which is caused by varicella, in patients with an immunocompromised condition. Interestingly, Parnham et al11 reported their experiences of concomitant administration of varicella-zoster immunoglobulin and acyclovir to rescue those renal transplant patients with severe disseminated varicella zoster. Similarly, our patient was also in an immunocompromised situation. To rescue him from such a life-threatening situation, it might be worthy of a trial to concomitantly use IVIG with acyclovir, and his condition indeed improved after the IVIG 5-day course was completed. Therefore, we propose that IVIG should not be withheld in patients with such an emergent condition. Alternatively, it may be early concomitantly to use IVIG with acyclovir as long as varicella is clinically suspected in immunocompromised patients. Basically, the mechanisms of antiviral eects of IVIG are not so simple. First, IVIG may provide antibodies to neutralize invading varicella.4 Second, evidence shows that IVIG may enhance and proliferate NK cells, which is believed to play a very important role in eradicating virus, especially in immunocompromised patients.12 Last, but not the least, is that IVIG may synergize the antiviral eects of acyclovir, and our case is a typical one. Although varicellazoster immunoglobulin G (IgG) has better antivaricella eects, a report showed that varicella-specic IgG preparations and IVIG preparations have equivalent antibody response.13 On the basis of this, we suggest that clinicians should concomitantly use IVIG with acyclovir to treat patients at high risk, such as immunocompromised patients exposed to or those infected with VZV when the antiviral eects of acyclovir cannot be activated.

In conclusion, varicella is a common and usually mild childhood disease. However, disseminated varicella may cause signicant morbidity and mortality in patients with immunocompromised conditions. PCR can provide a rapid and sensitive diagnosis. A combination of acyclovir and IVIG may rescue a patients life, as it did in this case.

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