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.
Case Description
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.
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.
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.
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.
Discussion
Severe adenovirus infection progressing to ARDS requiring ECMO or complicated by secondary hemophagocytic lymphohistiocytosis has been described previously.10–12 Cidofovir use for adenoviremia has been described in patients who are immunocompromised.13–15 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 55.29–32 Multiple recent outbreaks of severe and fatal adenovirus 7–related illness have been reported in the United States.33–35
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 1.1,12,36–41
Reported Cases of Adenovirus Infection in Immunocompetent Patients Treated With Cidofovir
| Study | Year | Country | N | Patient Characteristics | Clinical Presentation and Organ Support | Adenovirus Type | Cidofovir Administration | Adverse Effects of Cidofovir | Immune Modulatory Therapy | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 1 | 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 | 2 | 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 | 7 | 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 | 3 | 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 |
| Study | Year | Country | N | Patient Characteristics | Clinical Presentation and Organ Support | Adenovirus Type | Cidofovir Administration | Adverse Effects of Cidofovir | Immune Modulatory Therapy | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 1 | 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 | 2 | 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 | 7 | 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 | 3 | 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.
Case series of 32 adults who were immunocompetent, 5 of whom received cidofovir.
Case series of 3 adults (1 omitted from the table because of preexisting immunocompromise).
Reported in a case series of 6 patients with severe adenovirus pneumonia.
Reported in a retrospective chart review of 1901 pediatric patients with respiratory viruses, 143 of whom with adenovirus.
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.
Conclusions
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).
Comments
RE: Succesful Treatment Of Severe Adenoviral Pediatric Acute Respiratory Distress Syndrome (PARDS) with Cidofovir In A Child With Cerebral Palsy
To The Editor,
We have read the case presented by Alcamo et al1 in the last issue of Pediatrics with great interest. They reported that cidofovir was successfully used for the treatment of a severe adenovirus infection in an immunocompetent child requiring ECMO.1 We recently treated a patient with severe pediatric acute respiratory distress syndrome (PARDS) and multiorgan failure (MOF) secondary to adenovirus infection who perfectly recovered after cidofovir treatment, and wanted to share our experience. A 14 year old patient with cerebral palsy and severe malnutrition had been followed on the ward and was transferred to our pediatric intensive care unit (PICU) when he had fever, decompensated shock findings and renal failure. He received fluid and ampicillin sulbactam and renal functions improved on the 3rd day of PICU admission.
On the 5th day of admission, high fever and respiratory distress emerged. Chest X-ray showed bilateral new infiltrates. He was intubated because of respiratory failure and mechanically ventilated. Patient’s oxygen index (OI) was 16.5 suggestive of severe PARDS. We changed antibiotics as vancomycin, meropenem, levofloxacin, colistin and fluconazole. Adenovirus PCR was positive in nasopharyngeal swab and tracheal aspirate samples. Other viruses and bacteria were negative in all cultures. Despite 7 days of mechanical ventilation, he showed no signs of improvement. On the 12th day of admission, cidofovir and probenecid was initiated because of clinical deterioration and he received 2 doses, one week apart. We discontinued all antibiotics except meropenem. After cidofovir treatment on the 19st day of PICU admission, OI decreased to 3.7 and he was extubated. Repeat chest X-ray showed significant improvement with total resolution of the infiltrates on the left and minimal infiltrates on the right. He recovered from severe PARDS and was transferred to the ward on the 21th day of PICU admission.
Adenovirus infections are common in childhood and usually self-limiting.1 But systemic adenovirus infection could be severe and can be associated with multiorgan involvement with high mortality rate up to 50% in immunocompromised patients. Antiviral treatment with cidofovir is often not recommended for immunocompetent patients due to limited viral activity and nephrotoxicity1, but it remains the only treatment option for immunocompromised patients although it is only moderately effective.2,3 Cidofovir is administered intravenously and nephrotoxic effect could be reduced by giving probenecid before and after cidofovir administration.4 Also, we used probenecid to our patient for the same reason. Hoffman et al reported 8 children with immunodeficiency and adenovirus-positive infection who had been treated successfully with cidofovir.3 On the other hand, Amy et al presented 7 patients with adenovirus infection who were treated with cidofovir that only 4 of them recovered.4 Lastly, cidofovir well experienced in adults.5
In conclusion, although not frequent, adenovirus may cause sepsis syndrome, PARDS, MOF and mortality in immunocompromised patients. Cidofovir treatment comprises the main treatment of severe adenovirus infections in patients with or without immunodeficiency. Cidofovir treatment may be life-saving in severe adenovirus infections without serious side effects as in our case and Alcamo et al’s report.
References
1. Alcamo AM, Wolf MS, Alessi LJ, Chong HJ, Green M, Williams JV, et al. Successful Use of Cidofovir in an Immunocompetent Child With Severe Adenoviral Sepsis. Pediatrics. 2019.
2. Alcamo AM, Pinchasik DE, Mo JQ, Grimley MS, O'Brien MM. Successful Treatment of Disseminated Adenovirus Infection in an Infant With Acute Lymphoblastic Leukemia. J Pediatr Hematol Oncol. 2015;37(3):e178-181.
3. Hoffman JA, Shah AJ, Ross LA, Kapoor N. Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001;7(7):388-394.
4. Caruso Brown AE, Cohen MN, Tong S, Braverman RS, Rooney JF, Giller R, et al. Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients. Antimicrob Agents Chemother. 2015;59(7):3718-3725.
5. Kim SJ, Kim K, Park SB, Hong DJ, Jhun BW. Outcomes of early administration of cidofovir in non-immunocompromised patients with severe adenovirus pneumonia. PLoS One. 2015;10(4):e0122642.