Adenovirus infection is common in childhood and is generally associated with self-limited disease. Cidofovir, a viral DNA polymerase inhibitor, is used to treat adenovirus infection in select populations but is not often recommended for immunocompetent patients because of limited antiviral activity and nephrotoxicity. Here, we report a case of fulminant adenovirus infection associated with lymphopenia and multiple organ failure requiring extracorporeal membrane oxygenation support in a previously healthy child. After 1 week of supportive therapy, the patient had persistent organ failure and continued to have adenoviremia of >560 000 copies per mL. Weekly doses of cidofovir with concurrent probenecid for renal protection was initiated. Adenovirus blood load declined after the first cidofovir dose, becoming undetectable after 3 doses. The patient was successfully decannulated from extracorporeal membrane oxygenation, extubated, and eventually discharged at his functional baseline without need for ongoing respiratory support. Lymphopenia improved after viremia resolved, and a subsequent immunologic workup revealed no evidence of primary immunodeficiency. The viral isolate was genotyped as adenovirus type 7. This case reveals the successful use of cidofovir for management of severe adenovirus infection in a previously healthy child. To date, there are no universally accepted recommendations for the use of cidofovir in this population. Further study is warranted to determine the potential role of cidofovir in treating severe adenovirus infections in immunocompetent children.

Adenoviruses are a common cause of acute childhood viral infections.1  Adenovirus infection is typically self-limited but can cause severe and fatal disease in some populations. Immunocompromised status after a transplant, age <7 years, and adenovirus serotypes 5, 7, and 21 are associated with increased severity.2,3  Outbreaks of severe adenovirus infection have been reported recently in select populations, including residents of a long-term care facility.4  Cidofovir, a viral DNA polymerase inhibitor, may be effective in decreasing viral load5  and clinical symptoms of adenovirus infection.6  Cidofovir’s nephrotoxicity necessitates careful consideration of patients warranting treatment of adenovirus infection.7  To date, no widely accepted guidelines exist for cidofovir use in immunocompetent patients. We report the case of an immunocompetent patient with severe adenovirus infection requiring extracorporeal membrane oxygenation (ECMO) support for multiple organ failure (MOF) that recovered after treatment with cidofovir.

A 3-year-old previously healthy white male patient presented to his primary care physician with fever, rhinorrhea, and conjunctivitis. He was prescribed azithromycin for atypical pneumonia and otitis media. Over the subsequent 4 days, he had persistent fever and developed altered mental status. On evaluation in the emergency department, he was somnolent, with respiratory insufficiency and shock. A chest radiograph confirmed bilateral pneumonia. The result of a brain MRI with gadolinium contrast was normal. Lumbar puncture opening pressure was not elevated, and the cerebrospinal fluid was acellular, with normal glucose and protein levels. An EEG was consistent with encephalopathy. Respiratory viral polymerase chain reaction (PCR) panel testing of nasal secretions was positive for adenovirus. After fluid resuscitation and empirical antibiotics, he was admitted to the PICU for further management.

On hospital day 2, the patient developed acute respiratory distress syndrome (ARDS) and circulatory shock requiring mechanical ventilation and vasoactive infusions. Because of refractory hypoxemia and hypotension, he was cannulated onto veno-arterial ECMO. Serum quantitative PCR at the time of decompensation revealed an adenovirus load of >560 000 copies per mL (upper limit of detection), confirming adenoviremia. Blood specimens were genotyped by PCR amplification and sequencing of a ∼400-nt segment of the hexon gene.8  The isolate was genotyped as adenovirus type 7. No additional pathogens were identified on blood, cerebrospinal fluid, or tracheal aspirate cultures. A laboratory evaluation revealed additional evidence of MOF with acute kidney injury (AKI), hepatic dysfunction, pancreatitis, pancytopenia, and coagulopathy. He fulfilled criteria for viral-associated secondary hemophagocytic lymphohistiocytosis9  and was treated with plasma exchange, the interleukin-1 receptor antagonist anakinra, 2 mg/kg per day of methylprednisolone, and intravenous immunoglobulin.

One week into his ECMO course, there were no signs of organ recovery, and serum PCR measurements revealed persistent adenoviremia above the upper limit of detection (Fig 1A). The decision was made, in consultation with the infectious disease service, to administer cidofovir. Because of AKI and fluid overload requiring renal replacement therapy (RRT), he received 1 mg/kg of cidofovir with normal saline hydration and probenecid. Positive fluid balance was maintained for 8 hours after the infusion for renal protection. Three days after the first cidofovir dose, adenoviremia decreased to 285 000 copies per mL. A total of 3 cidofovir doses were administered weekly until adenovirus levels became undetectable. After his AKI and fluid overload resolved (Fig 1B), the cidofovir dose was increased to 5 mg/kg. Severe lymphopenia, with an absolute lymphocyte count (ALC) of ≤500 cells per μL, was present on admission, and the ALC did not exceed 1000 cells per μL until after the third and final dose of cidofovir.

FIGURE 1

A, Adenoviral load and ALC through acute illness. Circles represent adenoviral load (copies per milliliter; left y-axis). Squares represent ALC (cells per microliter; right y-axis). B, Creatinine levels through acute illness. Triangles represent creatinine levels (milligrams per deciliter). The shaded area represents the duration of RRT. Arrows indicate timing of cidofovir doses. Time is displayed as days since admission.

FIGURE 1

A, Adenoviral load and ALC through acute illness. Circles represent adenoviral load (copies per milliliter; left y-axis). Squares represent ALC (cells per microliter; right y-axis). B, Creatinine levels through acute illness. Triangles represent creatinine levels (milligrams per deciliter). The shaded area represents the duration of RRT. Arrows indicate timing of cidofovir doses. Time is displayed as days since admission.

Close modal

The patient was successfully decannulated from ECMO 3 days after the second dose of cidofovir and was extubated 2 days after the third dose. Total ECMO duration was 18 days. On hospital day 40, he was transferred to a pediatric inpatient rehabilitation facility and later discharged from the hospital breathing on room air, walking independently, and eating by mouth. Further immunologic evaluation 1 month after discharge revealed recovering, albeit abnormal, T, B, and natural killer cells but normal T- and B-cell mitogen responses to pokeweed and normal T-cell responses to phytohemagglutinin. A 207-gene primary immunodeficiency panel revealed a variant of uncertain significance in RTEL1 c3664G.A (p.Glu1222Lys) predicted to be tolerated.

Severe adenovirus infection progressing to ARDS requiring ECMO or complicated by secondary hemophagocytic lymphohistiocytosis has been described previously.1012  Cidofovir use for adenoviremia has been described in patients who are immunocompromised.1315  This case challenges the current clinical paradigm by demonstrating successful use of cidofovir in an immunocompetent child requiring ECMO for MOF and highlights the need for additional research into the risks and benefits of cidofovir therapy in immunocompetent patients with severe adenovirus infections. The following discussion will focus on the current state of knowledge of adenovirus infections as well as treatment in patients who are immunocompromised and patients who are immunocompetent.

Patients who are immunocompromised are at high risk for severe adenovirus infection, with high mortality in those affected. In recipients of pediatric hematopoietic stem cell transplants, an ALC <200 cells per μL has been shown to be a risk factor for adenovirus infection.16  Greater than 75% mortality is reported with disseminated infection,17  and higher cumulative adenovirus load is associated with risk of death.18  These observations have generated interest in identifying effective antiviral agents for the treatment of adenovirus in this population, although no agents have received approval from the US Food and Drug Administration or an equivalent agency outside of the United States. Supportive care combined with reduction of immunosuppression, when possible, is the first line of treatment in the patient with adenovirus disease who is immunocompromised.13,19  Historically, despite in vitro data suggesting activity against some but not all tested strains (mainly adenovirus species C), anecdotal reports describing the use of intravenous ribavirin failed to provide convincing evidence of the efficacy of this agent in this patient population. Interest was then focused on the use of cidofovir for adenovirus disease in immunocompromised hosts, which appears to be supported by in vitro data.20,21  Whereas, in the literature, some patients clearly appeared to respond to cidofovir (or its analogue brincidofovir), others failed to demonstrate either a clinical or a virological response.14,22,23  The reasons for these clinical failures have not been well studied and remain unknown but may be related to inadequate or delayed dosing.23  Notably, some patients have improved with reduction in immunosuppressive medication and without antiviral drugs.22  Taken together, these reports suggest that further study is needed determine the optimal approach to antiviral treatment, incorporating individual variability in host-pathogen interactions. Nonetheless, in the absence of definitive evidence to the contrary, use of these antiviral agents has become standard for the immunocompromised host,24,25  and guidelines have been developed for both preemptive and therapeutic treatment of adenovirus in those who are immunocompromised by using cidofovir.15,26 

Less is known about the prevalence, severity, and optimal management of adenovirus infection in the general pediatric population, but limited reports suggest that adenovirus infections are a significant source of morbidity and mortality. Adenovirus accounts for a significant proportion of viral infections in children who are hospitalized.1,27  In a recent retrospective study of 415 immunocompetent children hospitalized with adenovirus infection, a mortality rate of 15% was observed.28  Cases and outbreaks of severe adenovirus pneumonia have been linked to types 3, 4, 7, 11, and 55.2932  Multiple recent outbreaks of severe and fatal adenovirus 7–related illness have been reported in the United States.3335 

Although much of the evidence regarding severe adenovirus infection is derived from observational studies of patients who are immunocompromised, there exists a growing body of evidence in the immunocompetent population. The authors of a recent review of 163 immunocompetent children with adenovirus pneumonia requiring ECMO reported a survival rate of 38%, with the need for RRT associated with mortality.10  It is unclear what proportion of these patients, if any, received antiviral therapy. To date, there are no universally accepted recommendations for the use of cidofovir in adenovirus infections for immunocompetent patients. Published cases of cidofovir use for severe adenovirus infections in this population are summarized in Table 1.1,12,3641 

TABLE 1

Reported Cases of Adenovirus Infection in Immunocompetent Patients Treated With Cidofovir

StudyYearCountryNPatient CharacteristicsClinical Presentation and Organ SupportAdenovirus TypeCidofovir AdministrationAdverse Effects of CidofovirImmune Modulatory TherapyOutcome
Huh et al36  2019 South Korea 5a Adults Acute febrile respiratory illness and adenovirus detected in respiratory samples B55 Cidofovir, dose not reported None None All survived to hospital discharge 
Yoon et al37  2018 South Korea 17-y-old male patient Pneumonia and gastroenteritis Unknown Cidofovir, 5 mg/kg per wk None None Survived to hospital discharge 
Lee et al38  2017 South Korea 2b 22-y-old male patient, military recruit ARDS; MV, VV ECMO Unknown Cidofovir, 5 mg/kg every 1–2 wk None None Survived to hospital discharge 
    21-y-old male patient, military recruit ARDS; MV, VV ECMO, CRRT   None None Died 
Ha et al12  2016 South Korea 46-y-old female patient ARDS; MV, VV ECMO, CRRT Unknown Cidofovir, 5 mg/kg per wk None MP 1 mg/kg q 24 h Survived to hospital discharge, normal daily activities at 1 y 
    60-y-old male patient with hypertension and angina ARDS; MV, VV ECMO, CRRT   None MP 2 mg/kg q 24 h Survived to hospital discharge, ambulatory at 1 y 
Kim et al39  2015 South Korea Ages 19–22 y, military hospital Pneumonia with rapid deterioration; all received supplemental oxygen, 2 received MV and vasopressor B55 Cidofovir, 5 mg/kg per wk Skin rash (1 patient) IVIg (6 of 7 patients) All survived to hospital discharge 
Heo et al40  2012 South Korea 1c 22-y-old male patient, military recruit ARDS, pulmonary fibrosis; MV, subsequent lung transplant Unknown Cidofovir, dose not reported None None reported Died 
Rocholl et al1  2004 United States 1d Child Pneumonia, fulminant hepatic failure, pancreatitis, encephalopathy; MV Unknown Cidofovir, dose not reported None None Survived to hospital discharge without need for liver transplant 
Barker et al41  2003 United States 2e Adult female patient ARDS, septic shock, AKI; MV Cidofovir, 3 mg/kg (dose adjusted for AKI); single dose None None Survived to weaning from MV 
    Adult female patient ARDS, septic shock, AKI; MV   None IVIg Died 
StudyYearCountryNPatient CharacteristicsClinical Presentation and Organ SupportAdenovirus TypeCidofovir AdministrationAdverse Effects of CidofovirImmune Modulatory TherapyOutcome
Huh et al36  2019 South Korea 5a Adults Acute febrile respiratory illness and adenovirus detected in respiratory samples B55 Cidofovir, dose not reported None None All survived to hospital discharge 
Yoon et al37  2018 South Korea 17-y-old male patient Pneumonia and gastroenteritis Unknown Cidofovir, 5 mg/kg per wk None None Survived to hospital discharge 
Lee et al38  2017 South Korea 2b 22-y-old male patient, military recruit ARDS; MV, VV ECMO Unknown Cidofovir, 5 mg/kg every 1–2 wk None None Survived to hospital discharge 
    21-y-old male patient, military recruit ARDS; MV, VV ECMO, CRRT   None None Died 
Ha et al12  2016 South Korea 46-y-old female patient ARDS; MV, VV ECMO, CRRT Unknown Cidofovir, 5 mg/kg per wk None MP 1 mg/kg q 24 h Survived to hospital discharge, normal daily activities at 1 y 
    60-y-old male patient with hypertension and angina ARDS; MV, VV ECMO, CRRT   None MP 2 mg/kg q 24 h Survived to hospital discharge, ambulatory at 1 y 
Kim et al39  2015 South Korea Ages 19–22 y, military hospital Pneumonia with rapid deterioration; all received supplemental oxygen, 2 received MV and vasopressor B55 Cidofovir, 5 mg/kg per wk Skin rash (1 patient) IVIg (6 of 7 patients) All survived to hospital discharge 
Heo et al40  2012 South Korea 1c 22-y-old male patient, military recruit ARDS, pulmonary fibrosis; MV, subsequent lung transplant Unknown Cidofovir, dose not reported None None reported Died 
Rocholl et al1  2004 United States 1d Child Pneumonia, fulminant hepatic failure, pancreatitis, encephalopathy; MV Unknown Cidofovir, dose not reported None None Survived to hospital discharge without need for liver transplant 
Barker et al41  2003 United States 2e Adult female patient ARDS, septic shock, AKI; MV Cidofovir, 3 mg/kg (dose adjusted for AKI); single dose None None Survived to weaning from MV 
    Adult female patient ARDS, septic shock, AKI; MV   None IVIg Died 

CRRT, continuous renal replacement therapy; IVIg, intravenous immunoglobulin; MP, methylprednisolone; MV, mechanical ventilation; VV ECMO, veno-venous extracorporeal membrane oxygenation.

a

Case series of 32 adults who were immunocompetent, 5 of whom received cidofovir.

b

Case series of 3 adults (1 omitted from the table because of preexisting immunocompromise).

c

Reported in a case series of 6 patients with severe adenovirus pneumonia.

d

Reported in a retrospective chart review of 1901 pediatric patients with respiratory viruses, 143 of whom with adenovirus.

e

Case report of twin sisters.

Given the dose-dependent risk of renal injury and the absence of definitive data confirming its effectiveness, the use of cidofovir is considered with caution because nephrotoxicity has been associated with mortality.42  This effect is thought to be mediated by the human renal organic anion transporter.43  Probenecid, an organic acid transport inhibitor, has been used to mitigate these effects. In a 5-year retrospective review, renal dysfunction after cidofovir use was transient in most patients, all of whom received probenecid.6  Cidofovir is typically administered in a 5 mg/kg weekly dose. Our patient’s preexisting AKI warranted careful consideration of risks and benefits of antiviral therapy and conservative dosing. A modified dosing regimen of 1 mg/kg 3 times a week has been described with less nephrotoxicity yet similar efficacy.44  Considering our patient’s AKI, 1 mg/kg of cidofovir was given weekly, with close monitoring of renal function and adenovirus load. Given decreased viremia without evidence of worsening nephrotoxicity (Fig 1B), this regimen was continued until he had improvement of his renal function to baseline. This patient’s AKI improved with RRT before initiation of cidofovir and continued to improve despite administration of this medication. This case provides 1 example of safe use of cidofovir for a severe adenovirus infection even with preexisting renal dysfunction.

We describe a case of severe adenovirus infection presenting with ARDS, shock, and MOF requiring ECMO, with successful reduction of viremia in close temporal association with cidofovir treatment. Notably, there was low suspicion of primary immunodeficiency in this patient, which was confirmed on follow-up testing. AKI and fluid overload were present before treatment with cidofovir, and probenecid was given to mitigate potential nephrotoxicity. Despite cidofovir administration, there was no further renal injury appreciated. Mortality is high in patients requiring ECMO for adenovirus infection, and there is a paucity of data to guide cidofovir use in immunocompetent children. Accordingly, further study of the role of cidofovir in the general pediatric population with severe adenovirus infection is warranted.

Drs Alcamo and Wolf drafted the initial manuscript and reviewed and revised the original manuscript; Dr Alessi gathered clinical data pertinent to this report and reviewed and revised the original manuscript; Dr Chong provided results and interpretation of immunologic testing and reviewed and revised the original manuscript; Dr Green contributed to the discussion of current evidence regarding adenovirus infection and treatment and reviewed and revised the original manuscript; Dr Williams performed genotyping of the adenovirus isolate, contributed to the discussion of current evidence regarding adenovirus infection and treatment, and reviewed and revised the original manuscript; Dr Simon reviewed and revised the original manuscript; and all authors participated equally in conceptualizing and organizing this case report, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: Drs Alcamo and Wolf were supported by National Institutes of Health grant T32 HD040686. Funded by the National Institutes of Health (NIH).

     
  • AKI

    acute kidney injury

  •  
  • ALC

    absolute lymphocyte count

  •  
  • ARDS

    acute respiratory distress syndrome

  •  
  • ECMO

    extracorporeal membrane oxygenation

  •  
  • MOF

    multiple organ failure

  •  
  • PCR

    polymerase chain reaction

  •  
  • RRT

    renal replacement therapy

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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