Background. Adenovirus (ADV) infections were difficult to diagnose in the past, and many infections were unrecognized. Direct fluorescent assay (DFA) for the rapid diagnosis of ADV infection, as part of a viral respiratory panel, became available at Primary Children’s Medical Center (Salt Lake City, UT) in December 2000.
Objective. To describe children with ADV infection diagnosed by DFA and viral culture and document the impact of rapid ADV testing on patient care.
Methods. DFA testing for respiratory viruses including ADV was performed on nasal wash specimens with parallel viral culture. Chart review was performed for all ADV-positive patients identified from microbiology records between December 2000 and May 2002.
Results. Of 1901 patients positive for respiratory viruses, 143 (7.5%) were ADV-positive by DFA or culture. The mean age of ADV-positive children was 23 months; 90% were ≤60 months old. Eighty percent were previously healthy, and 56% required admission with a mean length of stay of 3.4 days. The most common diagnoses included fever (31%), bronchiolitis (24%), and pneumonia (14%). Other conditions included suspected Kawasaki disease (KD) and hepatitis. Forty-six percent of ADV-positive children were given antibiotics at presentation, but only 2 (1.4%) had documented bacterial infection (one had Escherichia coli urinary tract infection and one had Moraxella catarrhalis bacteremia). Thirty-six percent of children had a change in management based on positive ADV DFA. In children with suspected KD (n = 5), 100% had positive ADV DFA, and immune globulin was withheld in 4. One immunocompetent patient with fulminant liver failure received cidofovir treatment after a positive ADV DFA and recovered before liver transplant.
Conclusions. ADV is a common infection in young children and often results in admission and unnecessary antibiotic therapy. Identifying ADV as the cause of illness can favorably impact care and in some instances may be life-saving. DFA testing for ADV should be considered for infants and children requiring admission for fever, respiratory illness, suspected KD, and hepatitis.
Adenovirus (ADV) is a well-known cause of respiratory illness in children.1–4 It may produce upper or lower respiratory infection including bronchiolitis and pneumonia.5 In addition, ADV infection is frequently associated with entities such as pharyngoconjunctival fever and epidemic conjunctivitis that are often diagnosed based on clinical examination alone.6 Although most infections are self-limited, ADV can be associated with severe or lethal infection in both immunocompromised and healthy individuals.7–10
In clinical practice, ADV may be underdiagnosed. Isolation of ADV from cell culture is quite sensitive, but results take several days, limiting clinical utility.6 At Primary Children’s Medical Center (PCMC), in Salt Lake City, UT, rapid testing for ADV became available in December 2000 as part of a 7-valent viral respiratory direct fluorescent assay (DFA) panel (SimulFluor Respiratory Screen, Light Diagnostics, Temecula, CA). This test provides results in several hours. The purpose of our study was to describe the spectrum of illness in children with ADV infection and investigate the impact of rapid ADV testing on patient care. We hypothesized that ADV infections would be relatively common and that a positive DFA result would impact patient care.
Approval to conduct this research was obtained from the University of Utah Institutional Review Board.
The study was conducted at PCMC, a 232-bed children’s hospital that serves as a community hospital for Salt Lake County, UT, and as a tertiary referral center for the intermountain west. The emergency department (ED) evaluates 33 000 children per year, and there are ∼10 000 admissions to the hospital each year. PCMC cares for the majority of chronically ill children in the state; this population may be overrepresented in the data but is likely similar to the populations cared for in other children’s hospitals.
No protocols were in place during the study period that would dictate which children had DFA testing. Testing for respiratory viruses was performed at the discretion of the attending physician. In general, DFA testing was routinely requested for infants <90 days old with fever and for infants and children with acute respiratory illness who presented to the PCMC ED. The patient charge for DFA testing was $32.
The clinical microbiology technicians at PCMC performed testing for respiratory viruses in a 2-step process. Each nasal wash sample collected between December 12, 2000 and September 10, 2001 was prepared by cytospin and tested by using the SimulFluor Respiratory Screen (Chemicon International, Temecula, CA) followed by SimulFluor FluA/FluB and SimulFluor Para 1,2,3/Adeno stains if the screen was positive. The DFA panel identifies respiratory syncytial virus (RSV), influenza viruses A and B, parainfluenza viruses 1, 2, and 3, and ADV. The test was performed 3 to 5 times daily depending on the season. After DFA testing, viral respiratory culture using 4 shell vials with 72-hour and 10-day exit stains was performed on all specimens. Beginning September 11, 2001, viral culture was offered only for DFA-negative specimens and for those positive for parainfluenza virus to document serotype. Using viral culture positivity as the gold standard, we analyzed the sensitivity, specificity, and negative and positive predictive values for the DFA test based on 1188 specimens obtained in the first period of the study.
Review of Medical Records
To review the characteristics of ADV infection in children, we queried the microbiology records for patients who tested positive by DFA or culture for ADV between December 12, 2000 and May 23, 2002. The records were reviewed, and data abstracted included demographic and clinical information for children with ADV infection and the impact of rapid viral testing on patient care.
During the 17-month study period, viral testing was performed on 4568 nasal wash specimens; 1901 (42%) were positive for respiratory viruses. Test performance results for rapid DFA testing are shown in Table 1. Of the 1901 patients with positive specimens, 143 (7.5%) were identified with ADV. The DFA test was positive for >1 virus in 5/143 children (3%); all had coinfections with ADV and RSV. In all cases we counted them as ADV-infected; 3 children had bronchiolitis, 1 had fever, and 1 had dehydration.
Of the ADV-positive patients, 89 (62%) were identified by DFA, and viral culture identified the remainder. In a subset of 17 patients with severe or life-threatening disease, the DFA was positive in 88% (P = .03 compared with 62% of all patients with ADV infection). The mean time to DFA results was 4 hours, and the mean time to positive viral culture was 9 days (range: 4–16 days)
Epidemiology and Patient Characteristics
ADV infections were identified during nearly all study months (Fig. 1). The frequency peaked between January and March 2002. Demographic characteristics of ADV-infected patients are shown in Table 2. The mean age of the ADV-positive patients was 23 months, and 90% were ≤60 months old. Twenty percent of patients had chronic illnesses including history of prematurity; cerebral palsy; congenital heart disease; genetic conditions including cystic fibrosis, CHARGE, and DiGeorge syndromes; and malignancy. Of patients with ADV infection, 56% required hospitalization with a mean length of stay of 3.4 days. Children with chronic conditions required admission more frequently than those without underlying illness (83% vs 50%; P = .028).
Clinical Features of ADV Infection (Table 2)
Fever and Respiratory Illness
Fever was present in 80% of the 143 patients and was the admitting diagnosis in 31%. Seventy-seven patients had fever documented in the hospital with a mean temperature of 39.6°C. Fever duration at the time of discharge from the hospital ranged from 0 to 21 days with a mean duration of 2.7 days. Other clinical signs, such as conjunctivitis and rash, commonly associated with ADV infection were infrequent in our patient population. Conjunctivitis was present in 25 patients (17%), and rash was noted in 10 patients (7%).
The majority of patients presented with respiratory conditions. The most common diagnoses were bronchiolitis (24%) and pneumonia (14%). A chest radiograph was performed for 82 patients (57%). Abnormalities were diagnosed in 51 patients (62%), including perihilar infiltrates or atelectasis in 30 (36%) and a focal infiltrate consistent with pneumonia in 21 (26%). More than one-quarter (27%) of children had a new oxygen requirement. The duration of oxygen requirement among patients without a previous need ranged from 1 to 11 days with a mean of 4 days. Of patients with a new oxygen requirement, 14 (36%) were discharged with home oxygen. Four patients (2.8%) required endotracheal intubation and mechanical ventilation for respiratory failure associated with ADV infection. One of the 4 had an underlying condition of prematurity; the remainder had been previously healthy. The duration of mechanical ventilation ranged from 1 to 7 days.
Suspected Kawasaki Disease
Five patients with documented ADV infection presented to the hospital with suspicion of Kawasaki disease (KD) (Table 3). Their mean age was 51 months. Two fulfilled all clinical criteria for the diagnosis of KD. All had elevated inflammatory markers; 3 had an erythrocyte sedimentation rate (ESR) of >60 mm/hour and a C-reactive protein (CRP) of >4 mg/dL. However, platelet counts were normal in 4 children and only modestly elevated in 1 child. All 5 children had positive DFA results, and intravenous immune globulin (IVIG) was withheld in 4. The child who received IVIG did not have the DFA test until after the infusion of IVIG was initiated. This same patient had a normal echocardiogram and was discharged from the hospital immediately after the positive ADV result was obtained.
One immunocompetent patient presented with fulminant hepatic failure, pancreatitis, and encephalopathy. The patient also had a new oxygen requirement, and basilar pneumonia was evident on chest radiograph. Prothrombin time and ammonia were elevated; transaminases peaked at >5000 IU. An evaluation for liver transplantation was initiated. A nasal wash specimen obtained on the first day of hospitalization was DFA-positive for ADV. Diagnostic testing for hepatitis A, B, and C, and Epstein-Barr virus, cytomegalovirus, and herpesviruses was negative. The patient was treated with cidofovir, responded to this treatment, and recovered without transplantation.
Because of the presence of fever, many of the ADV-positive patients were evaluated for infection with bacterial cultures of blood, urine, and cerebral spinal fluid. Seventy-three (51%) patients had at least 1 bacterial culture. Two children (1.4%) had a culture-confirmed bacterial infection. The dual infections included an Escherichia coli urinary tract infection in an 11-month-old and bacteremia with Moraxella catarrhalis in a 22-month-old.
Antibiotics were commonly given to patients with ADV infection. At presentation to the ED, 33% of the patients were receiving oral antibiotics for their illness. After evaluation in the ED, 46% received antibiotics, with intravenous antibiotics used most frequently.
The positive ADV DFA resulted in documented changes in clinical care for 51 patients (36%). The most common changes in management were the discontinuation of antibiotics and/or discharge of the patient from the hospital (n = 39). A positive DFA also changed management in 4 of the 5 children with suspected KD. Finally, in the patient with fulminant hepatitis, the positive ADV result may have been life-saving, because antiviral therapy was initiated based on a positive DFA.
In this study, ADV infection was documented in 7.5% of children with a positive DFA test for respiratory viruses. This is similar to earlier studies that have documented ADV as a cause of ∼7% to 8% of pediatric respiratory infections.4,11 The mean age of patients in our study was 23 months, and 90% of patients were ≤60 months old. This is consistent with previous studies that reported very few cases of school-aged children requiring hospital evaluation for ADV.2 As expected, the seasonal distribution showed a wintertime peak, but illness occurred year-round.4,12,13 Although the majority of ADV infections resulted in respiratory illness, nearly 20% of the children had nonrespiratory diagnoses. Unique findings in this study include documentation of the serious nature of ADV infections in previously healthy children and the impact early diagnosis can have on patient management.
To be useful clinically, viral diagnostic testing must be sensitive, timely, affordable, able to detect a range of pathogens, and influence clinical decision-making. The DFA test used in this study begins to meet these requirements. Although the sensitivity of the DFA for ADV was not optimal (63%) despite using nasal washes, there are still many benefits to recommending this type of testing. In our laboratory, the results were very timely, with positive results available, on average, 4 hours after testing. Moreover, ADV testing is part of a panel that includes other common pediatric pathogens, and the sensitivities for RSV, influenza A and B, and parainfluenza are greater than that of ADV (Table 1).14 The test is inexpensive and reproducible. We have been able to show that ADV testing as well as the complete DFA panel influence the decision to administer antibiotics and improve antibiotic stewardship in the hospital setting.15 Although based on modest numbers, the DFA was positive in 88% of patients with severe or life-threatening disease, suggesting that it is more sensitive among those most likely to benefit by early diagnosis and antiviral therapy. Testing multiple specimens might improve the test sensitivity, but we have not formally evaluated this approach. In the future, the polymerase chain reaction may offer a more sensitive alternative to DFA testing.16,17
Half of the previously healthy children with ADV infection and 83% of those with underlying conditions required hospitalization. The primary reason for admission was respiratory distress or hypoxia. Over a quarter of the children had a new oxygen requirement. This finding, along with the occasional severe illness seen in normal hosts10 as well as life-threatening disease in the immunocompromised18,19 highlights the clinical importance of ADV disease in children.
One significant finding in our study was that 5 children were admitted with suspected KD. All had prolonged fever and conjunctivitis; 4 of 5 had rash and elevated CRP and/or ESR, 3 had mucous membrane changes and 3 had lymphadenopathy, and 2 had swelling of the hands and feet. Thus ADV infection can be a convincing imitator of KD. Others have documented that ADV infection, in contrast to what is seen in other viral illnesses, typically elevates ESR and CRP.20,21 Barone et al20 compared 7 children with ADV infection initially suspected of having KD with 36 children with KD. They found substantial overlap between the 2 groups, but exudative conjunctivitis was more common in ADV infection, and perineal rash or peeling and higher platelet counts helped to identify KD.20
Isolated reports have noted individuals believed to have both KD and ADV,22,23 and some have hypothesized that DNA viruses may be triggers of KD.24 However, at this time ADV is not believed to be the cause of KD, and it is one of the viruses that should be excluded before the diagnosis of KD is made.25
It seems prudent to test all patients suspected of having KD for ADV infection. During the study period 41 children were diagnosed with KD at our institution, but not all had testing for ADV. If we include the patients described in this article, children with ADV disease accounted for at least 10% of those with suspected KD. Positive DFA results for ADV could help to exclude KD, especially in immunocompetent children. This could avoid unnecessary, expensive, and potentially harmful treatment for KD.26–29 In addition, the prospective study of ADV infection in children with suspected KD could help clarify important issues such as how often ADV and KD occur together, whether asymptomatic shedding of ADV occurs in children with KD, and which serotypes of ADV mimic KD.
Fulminant hepatitis is a known complication of ADV infection in preterm infants, children with disseminated disease, and in the immunocompromised7,18,30–32 and has a high mortality rate. One patient in this study had fulminant ADV hepatitis. The availability of a rapid test for ADV allowed for initiation of antiviral therapy with cidofovir on day 1 of hospitalization. Despite advanced liver failure, the patient recovered without liver transplantation, although the role of cidofovir is unclear. The availability of antiviral agents with activity against ADV increases the importance of rapidly establishing the diagnosis of ADV, especially in children with life-threatening disease.19,33,34
We could clearly document a change in management for 50 additional patients (36%) based on the diagnosis of ADV despite the retrospective nature of the study. The most common change in management we observed was the discontinuation of antibiotics as a result of the diagnosis of ADV. Other changes included hospital discharge and, as discussed previously, the withholding of IVIG in patients with suspected KD. Possibly, ADV DFA testing had a greater impact than could be documented by this study. Frequently patients were discharged from the ED shortly after the nasal wash sample was obtained with the expectation that the primary care physician would use the results in the outpatient setting.
This study has several limitations. First, all the ADV testing was performed in a hospital setting and may overestimate the serious nature of ADV infections in children. Second, ADV testing was performed primarily in children with respiratory symptoms. Children with ADV disease, especially gastrointestinal disease, may have been missed. Third, ADV infections may have been missed in the second year of the study if children had positive DFA testing for another respiratory virus and no back-up culture was performed. Fourth, typing of ADV isolates was not performed, so we cannot comment on clinical entities associated with individual ADV types. Fifth, long-term follow-up of children with suspected KD who did not receive IVIG therapy was not performed. Finally, we were limited by our lack of access to outpatient records for patients discharged from the ED before the diagnosis of ADV.
Despite these limitations, our data lead to several conclusions. First, ADV infection remains a common cause of pediatric illness. Although most infections are self-limited, ADV can cause serious infection in previously healthy children and often results in hospitalization. ADV can mimic bacterial infection and KD. DFA testing is a reasonably sensitive and timely way to detect ADV infection. Identifying ADV infection can affect care favorably and in some cases may be life-saving. Consequently, DFA testing for ADV—or other rapid, sensitive tests—should be strongly considered for infants and children requiring admission for fever, respiratory illness, suspected KD, and hepatitis.
Dr Byington was supported by the Robert Wood Johnson Generalist Physician Faculty Scholar Program.
- Received July 14, 2003.
- Accepted September 18, 2003.
- Address correspondence to Carrie L. Byington, MD, Department of Pediatrics, University of Utah, 50 N Medical Dr, Salt Lake City, UT 84132. E-mail:
Portions of these data were presented at the Pediatric Academic Societies Annual Meeting, May 3, 2003, Seattle, WA.
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