Bullous Cutaneous Eruption due to Extravasation of Acyclovir in an Adolescent with Acute Lymphoblastic Leukemia

A 14-year-old-girl undergoing treatment with the BFMTRALL 2000 protocol (MRG ) because of early pre-B-cellacute lymphoblastic leukemia (ALL ) developed chickenpox on the 33rd d of remission induction. As such, chemotherapywas withdrawn and the patient was quarantined.Acyclovir (1500 mg·m–2·d–1 in three divided doses)was then administered in 100 mL of 0.9% sodium chloride,as 1-h intravenous infusions. On the 9th d of acyclovirtherapy 10 min after infusion of the 27th dose startedthe patient complained of the sensation of minor pain andburning in the region of Intracath catheter insertion, anddeveloped slight erythema with irregular boundaries inthe same region. 
 
The infusion line was checked for patency by gentlywithdrawing blood before, which showed that the linewas patent, and then infusion was continued, but at aslower rate. The line’s patency was checked frequently andremained patent. The patient no longer experienced thesensation of pain and burning, and the erythema improvedslightly; however, at the end of the infusion (the 65th min)a solitary, bullous painless eruption 1 x 1 cm in diameterwas observed on the tract of the vein, 10 cm distal of theIntracath insertion (Figures ​(Figures11,​,22,3,4). Without any medicalintervention the lesion subsided in 8 h and disappearedcompletely in 24 h, leaving behind a residual scar lesion. 
 
 
 
Figure 1 
 
Cutaneous vesicular eruption on the forearm ofthe patient which developed after acyclovir injection. 
 
 
 
 
 
Figure 2 
 
Cutaneous vesicular eruption on the forearm ofthe patient which developed after acyclovir injection. 
 
 
 
 
 
Figure 3 
 
Cutaneous vesicular eruption on the forearm ofthe patient which developed after acyclovir injection. 
 
 
 
The known adverse dermatological effects of acyclovir,including erythema, inflammation, and phlebitis at the siteof intravenous infusion, occur in ≤16% of patients, presumablydue to the alkaline nature of the solution (reconstitutedacyclovir has a pH of 10-11) [1]. It is a knownirritant to venous and soft tissue if extravasated [2].Wethink that both the erythema and bullous eruption inthe presented case were signs of subcutaneous acyclovirextravasation, despite the fact that we frequently checkedthe line and were confident of its patency. 
 
Frequent venipuncture of the same veins and use ofchemotherapeutic agents in oncology patients may rendertheir veins fragile and susceptible to the irritant effects ofdrugs. As such, sensation of pain and burning in oncologypatients should be considered a reliable sign of extravasationeven when good blood return is observed. Nonetheless,cutaneous vesicular eruption following intravenousacyclovir administration is rare [1]. It was reported thatcutaneous vesicular eruptions developed not only at thesite of injection, but far from it [3] and proximal to it [1].Moreover, bullous eruptions were also reported followingtopical and oral acyclovir administration [1]; therefore,rather than extravasation of acyclovir solution, an immunoallergicpattern in the presence of histological leukocytoclasticvasculitis is an etiological consideration [3]. 
 
The presented case shows that the irritant effects ofacyclovir should always be a consideration, especially inoncology patients, and that the development of new vesiculareruptions during acyclovir therapy should not alwaysbe considered progression of herpes infection. 
 
Conflict of Interest Statement 
 
The authors of this paper have no conflicts of interest,including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materialsincluded. 
 
Acknowledgement 
 
I thank Lale Olcay, MD for kindly revising the manuscript.

A 14-year-old-girl undergoing treatment with the BFm TrAll 2000 protocol (mrg) because of early pre-B-cell acute lymphoblastic leukemia (All) developed chicken pox on the 33 rd d of remission induction. As such, chemotherapy was withdrawn and the patient was quarantined. Acyclovir (1500 mg·m -2 ·d -1 in three divided doses) was then administered in 100 ml of 0.9% sodium chloride, as 1-h intravenous infusions. On the 9 th d of acyclovir therapy 10 min after infusion of the 27 th dose started the patient complained of the sensation of minor pain and burning in the region of Intracath catheter insertion, and developed slight erythema with irregular boundaries in the same region.
The infusion line was checked for patency by gently withdrawing blood before, which showed that the line was patent, and then infusion was continued, but at a slower rate. The line's patency was checked frequently and remained patent. The patient no longer experienced the sensation of pain and burning, and the erythema improved slightly; however, at the end of the infusion (the 65 th min) a solitary, bullous painless eruption 1 x 1 cm in diameter was observed on the tract of the vein, 10 cm distal of the Intracath insertion (Figures 1 and 2). Without any medical intervention the lesion subsided in 8 h and disappeared completely in 24 h, leaving behind a residual scar lesion.
The known adverse dermatological effects of acyclovir, including erythema, inflammation, and phlebitis at the site of intravenous infusion, occur in ≤16% of patients, presumably due to the alkaline nature of the solution (reconstituted acyclovir has a pH of 10-11) [1]. It is a known irritant to venous and soft tissue if extravasated [2].We think that both the erythema and bullous eruption in the presented case were signs of subcutaneous acyclovir extravasation, despite the fact that we frequently checked the line and were confident of its patency.
Frequent venipuncture of the same veins and use of chemotherapeutic agents in oncology patients may render their veins fragile and susceptible to the irritant effects of drugs. As such, sensation of pain and burning in oncology patients should be considered a reliable sign of extravasation even when good blood return is observed. nonetheless, cutaneous vesicular eruption following intravenous acyclovir administration is rare [1]. It was reported that cutaneous vesicular eruptions developed not only at the site of injection, but far from it [3] and proximal to it [1]. moreover, bullous eruptions were also reported following topical and oral acyclovir administration [1]; therefore, rather than extravasation of acyclovir solution, an immunoallergic pattern in the presence of histological leukocytoclastic vasculitis is an etiological consideration [3].
The presented case shows that the irritant effects of acyclovir should always be a consideration, especially in oncology patients, and that the development of new vesicular eruptions during acyclovir therapy should not always be considered progression of herpes infection.

Conflict of Interest Statement
The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included.