What is the treatment approach for pediatric patients, particularly those who are immunocompromised, with severe adenovirus infections using Cidofovir?

Cidofovir Treatment for Adenovirus in Pediatric Patients

Cidofovir should be considered for treatment of severe adenovirus infections in immunocompromised children, particularly those with disseminated disease, pneumonitis, or positive blood PCR, using a dose of 5 mg/kg IV once weekly for 2 consecutive weeks, then every 2 weeks until viral clearance, with mandatory probenecid and saline hydration to mitigate nephrotoxicity. 1, 2

Clinical Indications for Cidofovir Use

Immunocompromised pediatric patients are the primary candidates for cidofovir therapy when adenovirus infection is documented:

• Hematopoietic stem cell transplant (HSCT) recipients with adenovirus detected by PCR, culture, or tissue histopathology should receive cidofovir treatment 2
• Solid organ transplant recipients with disseminated adenoviral disease and respiratory failure warrant cidofovir therapy 3
• Patients with positive blood adenovirus PCR (viral load >560,000 copies/mL) and clinical deterioration despite supportive care should be treated 4
• Common presentations requiring treatment include: diarrhea (53%), fever (21%), hemorrhagic cystitis (12%), pneumonitis (11%), and disseminated disease (14%) 2

The German Society of Hematology and Oncology guidelines specifically recommend cidofovir for severely ill patients with adenovirus-associated disease in immunocompromised hosts 1

Dosing Regimen and Administration Protocol

Standard pediatric dosing:

• 5 mg/kg IV once weekly for 2 consecutive weeks as induction therapy 1, 2
• Then 5 mg/kg IV every 2 weeks for maintenance until 3 consecutive adenovirus-negative samples from all previously involved sites 2
• Infuse over 60 minutes at a constant rate 5

Alternative lower-dose regimen reported in outbreak settings:

• 1 mg/kg IV three times per week with hydration and probenecid 1, 3

Critical caveat: The FDA label states there is insufficient data for appropriate pediatric dosing, and dosages must be determined in consultation with specialists 5, 6. However, the 5 mg/kg weekly regimen has the strongest evidence base in pediatric HSCT populations 2

Mandatory Nephroprotective Measures

Probenecid administration is non-negotiable to reduce cidofovir nephrotoxicity 6:

• 2 grams orally 3 hours before cidofovir infusion 5
• 1 gram orally at 2 hours after infusion completion 5
• 1 gram orally at 8 hours after infusion completion 5
• Total dose: 4 grams per cidofovir administration 5

Aggressive saline hydration is essential 6:

• Minimum 1 liter 0.9% normal saline IV over 1-2 hours immediately before cidofovir 5
• Second liter (if tolerated) at start of or immediately after cidofovir infusion, over 1-3 hours 5

Monitoring Requirements

Renal function monitoring must occur within 48 hours prior to each dose 6:

• Serum creatinine measurement 6
• Urine protein assessment 6
• Dose modification, interruption, or discontinuation required for changes in renal function 6

Additional monitoring parameters:

• Neutrophil counts during therapy (neutropenia is a known adverse effect) 6
• Weekly adenovirus PCR from blood and other involved sites 2
• Clinical assessment for uveitis/iritis (treat with topical corticosteroids if occurs) 6

Efficacy Data in Pediatric Populations

HSCT recipients show favorable outcomes:

• In 57 pediatric HSCT patients (median age 8 years), cidofovir resulted in complete resolution of clinical symptoms in 98% (56/57 patients) with virus becoming undetectable 2
• Only 1 patient (2%) died due to adenovirus pneumonitis despite treatment 2
• Viral clearance accompanied clinical response in 63% of blood-positive cases 7

Immunocompetent children may also benefit in severe cases:

• A previously healthy child with fulminant adenovirus infection (>560,000 copies/mL), lymphopenia, and multi-organ failure requiring ECMO showed viral load decline after first cidofovir dose, becoming undetectable after 3 doses 4
• This case demonstrates potential utility even in immunocompetent hosts with severe disease, though this remains off-label 4

Nephrotoxicity Risk and Management

Dose-dependent nephrotoxicity is the major dose-limiting toxicity 5, 6:

• Acute renal failure requiring dialysis can occur after as few as 1-2 doses 5, 6
• In one pediatric series, 9 of 29 cidofovir courses (31%) were complicated by acute kidney injury, with high mortality in these patients 8
• Neonates are at particularly high risk: they had higher viral loads and shorter times to renal insufficiency compared to older children 8
• Higher weekly doses were associated with greater increases in creatinine levels 8

However, reversible renal dysfunction is more common than irreversible failure:

• In the Boston Children's Hospital series, reversible renal dysfunction was observed but no dose-limiting nephrotoxicity occurred 7
• In the 57-patient HSCT cohort, no cases of dose-limiting nephrotoxicity were observed with the 5 mg/kg weekly regimen 2
• In liver transplant recipients receiving 1 mg/kg three times weekly, adverse effects were mild and transient, not requiring dose modification 3

Key safety principle: Proteinuria may be an early indicator of nephrotoxicity, and continued administration can lead to Fanconi syndrome 5

Contraindications and Special Warnings

Absolute contraindications:

• Concurrent use of other nephrotoxic agents 6
• Pre-existing significant renal impairment (serum creatinine >1.5 mg/dL, calculated creatinine clearance ≤55 mL/min, or urine protein ≥100 mg/dL) 6

FDA black box warnings applicable to pediatric use 6:

• Renal impairment is the major toxicity
• Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred
• Neutropenia has been observed
• Cidofovir was carcinogenic, teratogenic, and caused hypospermia in animal studies

Special pediatric consideration: The use of cidofovir in children with AIDS warrants extreme caution due to risk of long-term carcinogenicity and reproductive toxicity, and should only be undertaken after careful evaluation when potential benefits outweigh risks 6

Clinical Decision Algorithm

Step 1: Confirm adenovirus infection

• Positive blood PCR (quantitative preferred) and/or
• Positive culture/DFA from involved sites and/or
• Tissue histopathology demonstrating adenovirus 2

Step 2: Assess disease severity and immune status

• Immunocompromised (HSCT, solid organ transplant, HIV): Strong indication for cidofovir 1, 2, 3
• Disseminated disease or pneumonitis: Strong indication regardless of immune status 4, 2
• Isolated mild disease in immunocompetent host: Supportive care preferred 4

Step 3: Verify no contraindications

• Check baseline renal function (creatinine, urine protein) 6
• Confirm no concurrent nephrotoxic agents 6
• Assess neutrophil count 6

Step 4: Initiate therapy with nephroprotection

• Begin 5 mg/kg IV weekly × 2 weeks, then every 2 weeks 2
• Mandatory probenecid (4 grams total per dose) 5
• Mandatory saline hydration (minimum 1-2 liters) 5

Step 5: Monitor and adjust

• Check renal function within 48 hours before each dose 6
• Monitor weekly adenovirus PCR 2
• Continue until 3 consecutive negative samples from all sites 2
• Discontinue if significant nephrotoxicity develops 6

Important Clinical Pitfalls to Avoid

• Do not use cidofovir without probenecid and saline hydration – this dramatically increases nephrotoxicity risk 6
• Do not exceed recommended doses – higher weekly doses are associated with greater renal toxicity 8
• Do not continue therapy without monitoring renal function – proteinuria is an early warning sign 5
• Do not use in neonates without extreme caution – they have higher risk of rapid renal deterioration 8
• Do not administer by intraocular injection – cidofovir is formulated for IV infusion only 6
• Do not use as first-line in immunocompetent children with mild disease – reserve for severe/life-threatening infections 4