Use of cidofovir in pediatric patients with adenovirus infection

Abstract

Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity. Methods: We conducted a retrospective 5-year review at Boston Children’s Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction. Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. Conclusions: CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.

Update in the treatment of non-influenza respiratory virus infection in solid organ transplant recipients

“…In a cohort of lung transplant recipients, the reported incidence of AdV infection was 22.5%, with most being asymptomatic and no association with rejection or decline in pulmonary function [31]. However, others have reported pediatric and adult SOTRs with severe necrotizing pneumonia ( Figure 1) and AdV-associated mortality [13,14,[32][33][34]. Patients who receive antilymphocyte antibodies are at an increased risk of developing AdV infection, and an increase in AdV-specific T lymphocytes has been associated with resolution of AdV in blood and lungs [35,36].…”

“…Therefore, the mainstays of therapy for AdV pneumonia are reduction in immunosuppression and supportive care [30]. However, cidofovir, a cytosine analog that interrupts AdV replication in vitro, is often used for treatment of more severe infections [30,33,35]. The intracellular diphosphate form of cidofovir acts as an AdV DNA polymerase substrate that is preferred over other cellular substrates, and cidofovir possesses in vitro activity against all AdV serotypes [30,37,38].…”

“…No prospective controlled trials have been conducted using cidofovir for AdV infection, and its efficacy remains uncertain. Data come from non-randomized series and case reports (mostly in hematopoietic stem cell transplant [HSCT] recipients [HSCTRs] and for various sites of infection including cystitis and enteritis), with varying results including failures [39] as well as clearance of viremia and possible mortality benefit [13,33,[40][41][42][43][44].…”

“…Monitoring AdV PCR viral load may help in assessing recovery [45], although case reports have also reported apparent early clinical and virologic improvement with subsequent respiratory failure and death [16,33]. Some centers, particularly those caring for pediatric HSCTRs, may perform regular AdV blood PCR for preemptive monitoring, with initiation of cidofovir at the onset of viremia to try to prevent disease [39].…”

“…The usual dosing is 5 mg/kg/wk for 2 weeks as induction therapy followed by 5mg/kg every 2 weeks with careful monitoring of renal function [30]. Alternate dosing is 1 mg/kg three times weekly [33,35].…”