Cidofovir in Immunocompetent Pediatric Patients With Severe Adenovirus Infection: Lower Than Expected Nephrotoxicity-an Opportunity for Early and Widespread Use?

To the Editors: Severe adenoviral infection is typically associated with immunocompromised hosts; however, life-threatening disease may also occur in immunocompetent children.1,2 Antiviral treatment options remain limited, and no Food and Drug Administration-approved therapy exists.1 Cidofovir (CDV), a viral DNA polymerase inhibitor, is commonly used in high-risk patients despite concerns regarding nephrotoxicity, while evidence in immunocompetent children is restricted to case reports and small series.1,3–5 We report our single-center experience with CDV treatment in immunocompetent pediatric patients with severe adenoviral infection, focusing on clinical response and renal safety. Between January 2019 and May 2025, 185 children with polymerase chain reaction (PCR)-confirmed adenovirus infection were identified at a tertiary pediatric hospital. Fourteen (7.6%) received intravenous CDV; 7 were immunocompetent and included in this analysis. Patients with primary or secondary immunodeficiency or a history of transplantation were excluded. The individual clinical characteristics, treatment details and laboratory results of the included patients are summarized in Tables 1 and 2. The median age was 36 months (range: 10–180). Five patients required pediatric intensive care unit admission and invasive mechanical ventilation, while 2 were managed on the ward. Severe respiratory involvement was present in all cases; 1 patient had myocarditis and 2 had neurological involvement accompanying pneumonia. CDV was administered at a standard dose of 5 mg/kg weekly with intensive hydration and probenecid when available. The median number of doses was 2 (range: 1–3). In the 2 ward-treated patients, fever resolution and marked respiratory improvement were observed within 24 hours after CDV administration; their radiological findings are shown in Figures 1–5, Supplemental Digital Content 1, https://links.lww.com/INF/G528. Patients treated later in the disease course—particularly those requiring intensive care—had prolonged hospitalizations and higher morbidity, suggesting a potential benefit of earlier antiviral intervention. The timing of CDV initiation in relation to hospital stay, intensive care unit admission and mechanical ventilation is illustrated in Figures 1–5, Supplemental Digital Content 1, https://links.lww.com/INF/G528. CDV was initiated a median of 14 days after symptom onset and 3 days after PCR positivity. TABLE 1. - Demographic, Clinical, Laboratory Characteristics and Treatment Response in Immunocompetent Children Diagnosed With Adenoviral Infection Patient Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Age (months)/gender 24/F 180/M 36/F 83/F 13/F 120/M 10/M Onset time August April June January May May April Underlying condition – Cerebral palsy Bronchopulmonary dysplasia, hypotonia – Malnutrition Obesity Hydrocephalus, epilepsy, malnutrition Clinical presentation Fever, cough, tachypnea on admission; seizures during follow-up Fever, cough, tachypnea Fever, cough, tachypnea Fever, cough, tachypnea Fever, tachypnea, diarrhea, vomiting Fever, cough, tachypnea Fever, vomiting, diarrhea, tachypnea and lethargy Disease presentation Pneumonia and neurological involvement (convulsion) Pneumonia, renal failure Pneumonia Pneumonia Myocarditis + gastroenteritis Pneumonia Pneumonia and neurological involvement (cerebellitis, encephalitis)* Concomitant virus Enterovirus/rhinovirus – – – Parainfluenza virus type 3 – HHV-7 detected by PCR in cerebrospinal fluid Concomitant bacteria Pseudomonas spp. isolated from catheter culture – Pseudomonas aeruginosa and Klebsiella spp. isolated from endotracheal aspirate culture – – – – Required pediatric intensive care unit (PICU) admission Y Y Y N Y N Y Mechanical ventilation time (day) 44 17 32 – 7 – 3 Duration of oxygen therapy (days) 83 24 63 8 18 14 14 Length of PICU time (day) 84 21 43 – 17 – 19 Length of hospital stay (day) 89 26 63 9 24 16 19 Antibiotic treatment Mem, Amk, Flc Mem Mem, Amk, Lev, Tec, Cst Cro, Cli, Azm Tzp, Tec, Amk Amp/Sulb, Cli, Azm Cro, Van, Acv Number of CDV doses 2 2 3 1 2 2 3 Probenecid Y Y Y N Y Y† Y Time to CDV from adenovirus PCR detection (day) 1 6 9 1 3 5 1 Time to CDV from admission (day) 3 11 12 3 5 9 3 Time to CDV from symptom onset (day) 14 41 14 11 16 15 5 Immune modulatory therapy Dexamethasone (7 days) – IVIG (2 g/kg)+ Dexamethasone (12 days) Dexamethasone (11 days) IVIG (2 g/kg) Dexamethasone (5 days) IVIG (2 g/kg) + Dexamethasone (5 days) ≥1 additional nephrotoxic medication with CDV (furosemide, antibiotic) Y (2) Y (1) Y (3) N Y (2) N Y (3) Outcome Survived to hospital discharge Survived to hospital discharge Survived to hospital discharge Survived to hospital discharge Survived to hospital discharge Survived to hospital discharge Survived to hospital discharge Long-term clinical outcome Subglottic stenosis, critical illness polyneuropathy Postinfectious bronchiolitis obliterans Dilated cardiomyopathy *In case 7, HHV-7 was detected in the cerebrospinal fluid and adenovirus in the respiratory tract sample. The clinical picture was primarily encephalitis, which was associated with HHV-7 infection. However, considering the concurrent adenovirus positivity and pneumonia findings, cidofovir treatment was administered for both infections. Adenovirus was considered as the causative agent of pneumonia and not as the causative agent of neurologic involvement.†Probenecid was administered with the cidofovir treatment, but the patient could not tolerate the drug due to vomiting after taking it orally. Repeated doses could not be administered due to the limitation in the supply of the drug, and probenecid intake was considered suspicious.Acv indicates acyclovir; Amk, amikacin; Amp-sulb, ampicillin–sulbactam; Azm, azithromycin; Cli, clindamycin; Cro, ceftriaxone; Cst, colistin; Flc, fluconazole; Lev, levofloxacin; Mem, meropenem; N, no; Tec, teicoplanin; Tzp, piperacillin–tazobactam; Van, vancomycin; Y, yes. TABLE 2. - Initial Laboratory Parameters in Immunocompetent Children With Adenoviral Infection Patient Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 White blood count (/mm3) 49,490 13,910 11,520 4480 18,880 10,530 17,560 Absolute neutrophil count (/mm3) 15,530 10,190 10,160 1720 12,640 7110 13,430 Hemoglobin (g/dL) 10.3 8.5 11.7 10.9 9.1 12.1 9.6 Platelets (/mm3) 468,000 288,000 350,000 311,000 262,000 338,000 367,000 C-reactive protein (mg/L) 2.2 65 42.6 19.7 33.2 71 11.7 AST (U/L) 35 69 310 99 165 38 63 ALT (U/L) 22 42 241 33 146 22 34 Urea (mg/dL) 24 169 19 17 26 17 26 Creatinine (mg/dL) 0.27 4.44 0.28 0.35 0.38 0.53 0.32 Lactate dehydrogenase (U/L) 299 260 >1800 701 673 430 376 Albumin (g/L) 34.2 22.9 30.9 34.6 40.3 38.7 46.4 ALT indicates alanine aminotransferase; AST, aspartate aminotransferase. Renal safety was a primary concern. One patient presented with acute kidney injury before CDV initiation, which resolved before treatment. No new-onset acute kidney injury or persistent renal dysfunction was observed following CDV administration, including in 1 patient who received 5 mg/kg without probenecid due to limited availability (Figures 1–5, Supplemental Digital Content 1, https://links.lww.com/INF/G528). Long-term follow-up (6 months to 6 years) revealed no evidence of chronic kidney disease. Although no mortality occurred, 3 patients developed significant long-term sequelae, including bronchiolitis obliterans, dilated cardiomyopathy following myocarditis and airway complications related to prolonged intubation. These findings emphasize the potential severity of adenoviral disease even in immunocompetent children. This report is limited by its retrospective design, small sample size, absence of a control group and lack of adenovirus typing or viral load quantification. Concomitant use of antibiotics and immunomodulatory therapies also limits attribution of outcomes solely to CDV. Nevertheless, our observations align with emerging evidence suggesting that CDV may be better tolerated in immunocompetent pediatric patients than previously assumed.1,3,5 In conclusion, our experience suggests that CDV, when administered with appropriate hydration and monitoring, may have an acceptable renal safety profile and potential clinical benefit in selected immunocompetent children with severe adenoviral infection. These findings should be considered hypothesis-generating and support the need for larger, prospective studies to define optimal timing and patient selection.