CLINICAL

AND

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 identified. 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 patient’s condition deteriorated within the first 48 h. His cutaneous lesions with more than 500 vesicles erupted. His skin also showed generalized ecchymosis. Laboratory tests showed Ddimer 3655 ng/mL, fibrin degradation product was more than 40 mg/mL, fibrinogen 634 mg/dL, thrombocytopenia, and prolonged thrombin time. All these findings 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 diffused 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 effect 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:e350–e351)

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 significant 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 effective treatment for immunocompromised children with disseminated varicella.

P

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 conflict 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 

e350 | www.jpho-online.com

J Pediatr Hematol Oncol

Volume 33, Number 8, December 2011

Bone Marrow Transplant. Durandy A. not only because its clinical course is fulminant and its presentations are untypical. 1991. 12. Immunology.com | e351 . 2006. 2. et al. the mechanisms of antiviral effects of IVIG are not so simple. Varicella-zoster virus. In conclusion.158(supp. J Infect Dis. Leukemia. Clin Microbiol Rev. 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. December 2011 Combined Therapy With IV Acyclovir and Human IV Immunoglobulin Rescues an Immunocompromised Child With Disseminated Varicella ALL. Arvin AM. Kuijpers TW. Springer W. Interestingly. 2001. but not the least. 1995. Pediatrics. 13. especially in immunocompromised patients. First. 11. in patients with an immunocompromised condition. Heininger U. 2008.5. and our case is a typical one. 4. such as acyclovir.43:753–770. et al. Lovato J.J Pediatr Hematol Oncol  Volume 33.12 Last. Varicella-specific immunoglobulin G titers in commercial intravenous immunoglobulin preparations. et al. 8. To rescue him from such a life-threatening situation. Ozaki T. Number 8. is that IVIG may synergize the antiviral effects of acyclovir.97:187–192. it might be worthy of a trial to concomitantly use IVIG with acyclovir. Yang CP. 5. Liang DC. Recent steroid therapy increases severity of varicella infections in children with acute lymphoblastic leukemia. et al. Saker BM.24: 397–405. et al. r 2011 Lippincott Williams & Wilkins www. Management of HSV. which is caused by varicella. we think that acyclovir may not be able to fully suppress viremia. Pediatrics. Varicella. et al. Choo PW.10 One of the mechanisms of acyclovir against varicella is to cease varicella progression and shorten the duration of viral replication. 3. Kido S. Varicella-related deaths in children and adolescents–Germany 2003-2004. Veit G. Seward JF. 10. Flexman JP. Kries R. St Louis: Mosby. disseminated varicella may cause significant morbidity and mortality in patients with immunocompromised conditions. Alternatively. The epidemiology of varicella and its complications. IVIG may provide antibodies to neutralize invading varicella. we propose that IVIG should not be withheld in patients with such an emergent condition.9:115–118. et al. VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on infection in leukemia. Lin DT.124:e484–e488. 2009. Ivan R. Lancet. which is believed to play a very important role in eradicating virus. Styczynski J. 1):2–13. Detection of varicella-zoster virus (VZV) DNA in clinical samples from patients with VZV by the polymerase chain reaction. A combination of acyclovir and IVIG may rescue a patient’s life. Gerber S. but also because it is irrelevant to whether these patients have received varicella vaccine or were administered intravenous acyclovir. a report showed that varicella-specific IgG preparations and IVIG preparations have equivalent antibody response. Donahue JG. Primary varicella in adult renal transplant recipients: a report of three cases plus a review of the literature. 6.116:e525–e529. 2005. Manson JE. such as immunocompromised patients exposed to or those infected with VZV when the antiviral effects of acyclovir cannot be activated. Kaveri SV. 2008. 2010. et al. we suggest that clinicians should concomitantly use IVIG with acyclovir to treat patients at high risk.368: 1365–1376.6 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. Brostoff J.29: 76–79. from the Veit et al6 report showing that 3 deaths occurred in children. Although varicellazoster immunoglobulin G (IgG) has better antivaricella effects.7–9 If VZV was identified in immunocompromised patients. 9:361–381. Hill G. antiviral drugs. our patient was also in an immunocompromised situation. Chauvene AR. as it did in this case. Basically. Kempf W. evidence shows that IVIG may enhance and proliferate NK cells. 9. Acta Paediatr.jpho-online. Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia. and his condition indeed improved after the IVIG 5-day course was completed. Clin Transplant.4 Second. Clin Exp Immunol. 7. Swiss Med Wkly. with ALL who developed disseminated varicella despite early administration of acyclovir. 1995. Parnham AP. it may be early concomitantly to use IVIG with acyclovir as long as varicella is clinically suspected in immunocompromised patients. Swiss recommendations for the management of varicella zoster virus infections. Reusser P. 2009. Therefore. et al. 2007. Meylan P.137:239–251. Similarly. However. varicella is a common and usually mild childhood disease.172: 706–712. 1996.13 On the basis of this. REFERENCES 1. Maranich AM. Rajnik M. Einsele H. PCR can provide a rapid and sensitive diagnosis. J Clin Microbiol. However. should be used emergently. Intravenous immunoglobulins–understanding properties and mechanisms. Asada H.