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. Author manuscript; available in PMC: 2007 Nov 6.
Published in final edited form as: Clin Infect Dis. 2007 Sep 27;45(9):1120–1131. doi: 10.1086/522188

Genotype Prevalence and Risk Factors for Severe Clinical Adenovirus Infection, United States 2004-2006

Gregory C Gray 1, Troy McCarthy 1, Mark G Lebeck 1, David P Schnurr 3, Kevin L Russell 4, Adriana E Kajon 5, Marie L Landry 6, Diane S Leland 7, Gregory A Storch 8, Christine C Ginocchio 10, Christine C Robinson 12, Gail J Demmler 13, Michael A Saubolle 14, Sue C Kehl 15, Rangaraj Selvarangan 9, Melissa B Miller 16, James D Chappell 17, Danielle M Zerr 18, Deanna L Kiska 11, Diane C Halstead 19, Ana W Capuano 1, Sharon F Setterquist 1, Margaret L Chorazy 1, Jeffrey D Dawson 2, Dean D Erdman 20
PMCID: PMC2064001  NIHMSID: NIHMS31747  PMID: 17918073

Abstract

Background

Recently, epidemiological and clinical data have revealed important changes with regard to clinical adenovirus infection, including alterations in antigenic presentation, geographical distribution, and virulence of the virus.

Methods

In an effort to better understand the epidemiology of clinical adenovirus infection in the United States, we adopted a new molecular adenovirus typing technique to study clinical adenovirus isolates collected from 22 medical facilities over a 25-month period during 2004-2006. A hexon gene sequence typing method was used to characterize 2237 clinical adenovirus-positive specimens, comparing their sequences with those of the 51 currently recognized prototype human adenovirus strains. In a blinded comparison, this method performed well and was much faster than the classic serologic typing method.

Results

Among civilians, the most prevalent adenovirus types were types 3 (prevalence, 34.6%), 2 (24.3%), 1 (17.7%), and 5 (5.3%). Among military trainees, the most prevalent types were types 4 (prevalence, 92.8%), 3 (2.6%), and 21 (2.4%).

Conclusions

For both populations, we observed a statistically significant increasing trend of adenovirus type 21 detection over time. Among adenovirus isolates recovered from specimens from civilians, 50% were associated with hospitalization, 19.6% with a chronic disease condition, 11% with a bone marrow or solid organ transplantation, 7.4% with intensive care unit stay, and 4.2% with a cancer diagnosis. Multivariable risk factor modeling for adenovirus disease severity found that age <7 years (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4-7.4), chronic disease (OR, 3.6; 95% CI, 2.6-5.1), recent transplantation (OR, 2.7; 95% CI, 1.3-5.2), and adenovirus type 5 (OR, 2.7; 95% CI, 1.5-4.7) or type 21 infection (OR, 7.6; 95% CI, 2.6-22.3) increased the risk of severe disease.

More than 35 years ago, population-based studies of viral respiratory illnesses among US families were conducted in Ohio [1], Kansas [2], Louisiana [3], New York [4], and Washington [5]. As a result of these investigations, scientists concluded that adenovirus infection was quite common among children. Approximately 50% of infections were asymptomatic, and symptomatic infections were typically mild and resolved without sequelae. In contrast, military populations experienced severe epidemics of acute respiratory disease, including pneumonia and encephalitis, especially involving adenovirus types 4, 7, and 21. For example, in 1958, adenoviral infection was reported to have caused hospitalization of an estimated 10% of military recruits [6] and to be the etiology of most respiratory disease during winter months. Subsequently, vaccines for adenovirus types 4 and 7 were developed and effectively used among US military trainees from the 1970s until the late 1990s [7, 8]. Thus, until recently, adenovirus infection was considered to have little consequence, except for causing morbidity among military trainees.

However, much has changed since these early epidemiological studies were conducted. In contrast to the modest number of adenovirus types recognized 35 years ago, 51 unique serotypes are now recognized. Different serotypes have been found to have different tissue tropisms that correlate with different clinical manifestations of infection. Limited epidemiological investigations have revealed that, among some specific serotypes, multiple genetic variants exist that often have quite different geographical distributions and associated virulence [9-11]. In addition, largely because of molecular diagnostics, adenovirus infection has been associated with a number of acute and chronic diseases, including chronic airway obstruction [12] and pulmonary dysplasia [13], myocarditis and dilated cardiomyopathy [14], mononucleosis-like syndromes [15], intussusception [16], sudden infant perinatal death [17], and obesity [18, 19]. Among some population groups, adenoviral infection is common and, often, severe. For example, the incidence of adenoviral disease among bone marrow transplant recipients varies from 3% to 20% [20], and mortality can exceed 50% [21]. Similarly, multiple recent outbreaks of adenoviral infection in the United States have frequently occurred among institutionalized children and in medical settings, resulting in significant morbidity and mortality among patients and medical staff [22]. In vitro studies suggest that specific adenovirus types are more likely to respond to certain antiviral therapies [23]. Finally, since the military lost its manufacturer of adenovirus types 4 and 7 vaccines in the late 1990s, numerous outbreaks of adenovirus infection have occurred among military trainees, resulting in great morbidity [24, 25]. Subsequently, the US Department of Defense identified a new vaccine manufacturer, and restoration of adenovirus types 4 and 7 vaccines is projected for 2008 [25]. It seems prudent to investigate whether previously very effective and safe vaccines may also benefit some nonmilitary populations. Therefore, an updated look at the epidemiology of human adenovirus infection is warranted. In this report, we present 25 months of viral and patient epidemiological data on clinical adenovirus infection detected through a nationwide network of 22 US military and civilian medical facilities. We used a recently described molecular adenovirus typing technique to characterize the strains of adenovirus [26].

MATERIALS AND METHODS

Population

From July 2004 through September 2006, specimens that were positive for adenovirus by rapid diagnostic test, PCR, or culture were collected from 22 US medical facilities. Of these facilities, 8 were military sites located in California, Georgia, Illinois, Missouri, New Jersey, South Carolina (2 sites), and Texas, and 14 were civilian laboratories located in Arizona, Colorado, Connecticut, Indiana, Florida, North Carolina, New York (2 sites), Missouri (2 sites), Tennessee, Texas, Washington, and Wisconsin. Samples were collected as part of routine testing, labeled with unique study identifiers, and sent to the University of Iowa Center for Emerging Infectious Diseases (Iowa City) for genetic typing. This study was approved by the multiple institutional review boards representing the participating laboratories.

As part of routine viral respiratory pathogen surveillance [25], the military laboratories first submitted specimens to the Navy Respiratory Disease Laboratory in San Diego, California. Each month, after viral identification work, the Navy laboratory shared a sample set of ∼30 specimens with the Center for Emerging Infectious Diseases. This sample set represented specimens that were positive for adenovirus from each of the 8 sites, distributed over time. For adenovirus-positive specimens, the Navy laboratory provided the specimen collection date and the age, sex, and training site of the patient from whom the specimen was obtained.

Civilian laboratories were asked to submit all adenovirus-positive specimens. Limited demographic and clinical data were obtained from each civilian specimen, including the laboratory collection site (city and state), collection date, specimen source (e.g., nasal, pharyngeal or blood), and specimen type (e.g., culture, direct fluorescent antibody, or PCR), as well as patient birth date and sex, whether the patient was hospitalized when the specimen was collected, and whether the patient had undergone transplantation during the 6 months prior to specimen collection. Because of their risk for severe disease, additional information (race and ethnicity, clinical presentation, hospitalization care, disposition, cancer status, and chronic disease status) was obtained from patients with adenovirus infection who were aged <7 years or who had undergone transplantation within 6 months before the positive adenovirus result. The cutoff value of <7 years of age was based on a recent investigation of an outbreak of adenovirus type 7d2 infection (among 93 patients, with a 33% attack rate and 8 deaths), in which children aged <7 years were found to be at increased risk for illness [22].

DNA extraction, PCR, and sequencing

After an initial study, we found that most adenovirus-positive specimens yielded PCR amplification products without requiring additional culture enrichment. Viral DNA was extracted from 200 μL of the original adenovirus-positive specimen in a final elution volume of ∼200 μL using the QIAamp DNA Blood Mini Kit (Qiagen). An initial volume of 5 μL of eluted sample was amplified using a PCR procedure that targeted hypervariable regions 1-6 of the hexon gene [26]. M13 universal priming tails (forward, 5′-TGT AAA ACG ACG GCC AGT-3′; and reverse, 5′-CAG GAA ACA GCT ATG ACC-3′) were added to the previously described primers to facilitate sequencing. Expected amplicons from this reaction ranged from 764 to 896 bp in length. These amplicons were then sequenced on a 3730 xl DNA Analyser (Applied BioSystems). The forward and reverse sequences were combined using BioEdit (Ibis Therapeutics) and were compared with the similar sequences of 51 well-characterized prototype viruses and other well-characterized genotypes from our collections and from GenBank. Specimens that yielded identity scores ≥90%, compared with both our internal sequence database and that of GenBank, were considered to be good genotype matches.

Culture

When PCR amplification failed, the original specimen was inoculated into A549 cells (ATCC) and incubated at 37°C for 4-7 days or until a cytopathic effect was observed. If, after 7 days, no cytopathic effect was detected, cells were cultured again. After cytopathic effect was confirmed, the positive cell culture specimen was characterized by PCR and sequencing.

Validation

A systematic sample of 101 adenovirus-positive specimens containing numerous genotypes was shared with the Viral and Rickettsial Disease Laboratory of the California Department of Health Services (Richmond) for blinded validation using classic serotyping techniques. This laboratory shared 3 of these specimens with the Navy Respiratory Disease Laboratory for further study using a PCR adenovirus typing algorithm [27].

Statistical analyses

Questionnaire and laboratory data were linked by the unique specimen number. In instances in which several adenovirus-positive specimens were obtained from the same patient and clinical event, the linkage of these specimens was indicated by the civilian laboratories using study forms. During studies of clinical outcomes, only the first adenovirus-positive specimen was considered in studies of clinical events. The χ2 test and Fisher’s exact test were used to examine potential risk factor associations. The exact Cochran-Armitage test for trend was used to examine adenovirus genotype prevalence across years. Logistic regression modeling was used to examine potential risk factors for outcomes, such as pneumonia. The proportional odds model was used to examine risk factors for severe adenovirus infection, considering the outcomes of hospitalization, intensive care unit stay, and death in a mutually exclusive, ordinal severity scale based on data on the first adenovirus-positive specimen for the clinical event. These 3 final multivariable models were derived using a saturated model and manual backwards elimination. Analyses were performed using SAS, version 9.1 (SAS Institute).

RESULTS

Validation

In the blinded validation study, 98 (97%) of the 101 adenovirus-positive specimens were typeable using type-specific neutralization. Serotyping agreed with genotyping for all 98 specimens. The remaining 3 specimens of unknown types were studied using a novel and quite different PCR typing algorithm [27], and the blinded results of this algorithm were in agreement with University of Iowa genotyping methods.

Genotyping by PCR and sequencing

During the study period, 2237 adenovirus-positive specimens were received (1653 specimens from civilians and 584 from military trainees). All of the specimens from military trainees resulted from culture. Specimen type information was available for 1170 specimens from civilians; 84.9% of specimens were isolated by culture, 7.9% by direct fluorescent antibody, and 7.2% by PCR assays. Ninety-eight percent of the 2237 adenovirus-positive specimens were successfully typed by PCR and sequencing. Of the 47 initially nontypeable specimens, 27 (57.4%) were eventually typed after statistical analysis had been concluded, 4 (8.5%) were not confirmed to be positive for adenovirus by PCR, and 16 (34.0%) were confirmed to be positive for adenovirus by PCR, but the sequence data were inconclusive. The samples that were not confirmed to be positive for adenovirus by PCR may represent false-positive specimens or specimens with low viral titer that did not yield adenovirus by culture. The samples confirmed to be positive for adenovirus by PCR that had inconclusive sequence data may represent dual adenovirus infections or infection with novel viruses. We are further analyzing these specimens.

The 582 successfully typed specimens from military trainees were comprised primarily of adenovirus hexon sequence genotypes (HSgenotypes) 4 (92.8% of specimens), 3 (2.6%), and 21 (2.4%) (table 1). The age and sex distribution of patients with adenovirus infection were consistent with the demographic characteristics of military training populations. During the study period, there was a statistically significant increasing trend in the prevalence of adenovirus type 21 isolates and a decreasing trend in the prevalence of type 4 isolates. These data represent only a small subset and limited time distribution of adenovirus isolates found in specimens from military trainees. Detailed analyses of a more comprehensive sample set are the subject of a separate report (K.L.R., unpublished data).

Table 1.

Distribution of adenovirus hexon sequence genotypes among specimens from patients in military training facilities.

Total no. of specimens Adenovirus type, no. (%) of specimens
Variable 1 (n = 1) 2 (n = 1) 3 (n = 15) 4 (n = 540) 5 (n = 1) 7 (n = 5) 14 (n = 5) 21 (n = 14)
Collection year
 2004 261 ... 1 (0.4) 6 (2.3) 251 (96.2) ... ... ... 3 (1.1)
 2005 234 1 (0.4) ... 5 (2.1) 223 (95.3) ... ... ... 5 (2.1)
 2006 86 ... ... 4 (4.7) 65 (75.6) 1 (1.2) 5 (5.8) 5 (5.8) 6 (7)
Patient age group
 17-19 years 304 ... ... 8 (2.6) 287 (94.4) ... 1 (0.3) 2 (0.7) 6 (2)
 20-37 years 277 1 (0.4) 1 (0.4) 7 (2.5) 252 (91) 1 (0.4) 4 (1.4) 3 (1.1) 8 (2.9)
Patient sex
 Male 510 1 (0.2) ... 12 (2.4) 474 (92.9) ... 4 (0.8) 5 (1) 14 (2.7)
 Female 61 ... 1 (1.6) 3 (4.9) 55 (90.2) 1 (1.6) 1 (1.6) ... ...
Collection site
 Great Lakes, IL 141 ... ... ... 137 (97.2) 1 (0.7) ... 2 (1.4) 1 (0.7)
 San Diego, CA 91 ... ... ... 90 (98.9) ... ... 1 (1.1) ...
 Ft. Jackson, SC 86 ... 1 (1.2) 6 (7) 78 (90.7) ... 1 (1.2) ... ...
 Ft. Leonard Wood, MO 81 ... ... 3 (3.7) 72 (88.9) ... 4 (4.9) ... 2 (2.5)
 Ft. Benning, GA 65 ... ... 6 (9.2) 55 (84.6) ... ... 2 (3.1) 2 (3.1)
 Parris Island, SC 64 ... ... ... 57 (89.1) ... ... ... 7 (10.9)
 Cape May, NJ 33 ... ... ... 33 (100) ... ... ... ...
 San Antonio, TX 21 1 (4.8) ... ... 18 (85.7) ... ... ... 2 (9.5)
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NOTE. Because of missing data, total counts are not always identical.

Specimens from civilians yielded a more diverse distribution of adenovirus HSgenotypes, with 23 different types detected (table 2). Among the 1608 adenovirus-positive specimens successfully typed, 76.8% were from children aged <7 years, 59% were from male patients, 71.0% were from upper respiratory tract sites, and 49.6% were associated with hospitalization. The most prevalent adenovirus HSgenotypes were types 3 (34.6% of specimens), 2 (24.3%), 1 (17.7%), and 5 (5.3%). The distribution of HSgenotypes differed by age group (with types 1 and 2 being more prevalent among patients aged <7 years) and by specimen source (with types 1, 3, and 2 being most prevalent among blood, upper respiratory tract, and gastrointestinal tract specimens, respectively).

Table 2.

Distribution of the most prevalent adenovirus hexon sequence genotypes among specimens from the studied civilians.

Total no. of specimens Adenovirus type, no. (%) of specimens
Variable 1 (n = 284) 2 (n = 390) 3 (n = 556) 4 (n = 78) 5 (n = 86) 7 (n = 48) 21 (n = 32) 41 (n = 29) Other (n = 105)
Collection year
 2004 307 40 (13) 69 (22.5) 132 (43) 20 (6.5) 20 (6.5) 0 (0) 3 (1) 3 (1) 20 (6.5)
 2005 846 153 (18.1) 212 (25.1) 293 (34.6) 34 (4) 45 (5.3) 23 (2.7) 18 (2.1) 18 (2.1) 50 (5.9)
 2006 455 91 (20) 109 (24) 131 (28.8) 24 (5.3) 21 (4.6) 25 (5.5) 11 (2.4) 8 (1.8) 35 (7.7)
Collection month
 January 197 32 (16.2) 48 (24.4) 71 (36) 6 (3) 8 (4.1) 8 (4.1) 2 (1) 6 (3) 16 (8.1)
 February 163 39 (23.9) 34 (20.9) 56 (34.4) 5 (3.1) 11 (6.7) 4 (2.5) 3 (1.8) 4 (2.5) 7 (4.3)
 March 168 33 (19.6) 44 (26.2) 50 (29.8) 7 (4.2) 7 (4.2) 6 (3.6) 3 (1.8) 3 (1.8) 15 (8.9)
 April 141 31 (22) 38 (27) 39 (27.7) 6 (4.3) 10 (7.1) 6 (4.3) 3 (2.1) 0 (0) 8 (5.7)
 May 95 14 (14.7) 24 (25.3) 28 (29.5) 7 (7.4) 3 (3.2) 6 (6.3) 11 (11.6) 2 (2.1) 0 (0)
 June 105 18 (17.1) 24 (22.9) 37 (35.2) 6 (5.7) 8 (7.6) 1 (1) 3 (2.9) 1 (1) 7 (6.7)
 July 102 11 (10.8) 28 (27.5) 40 (39.2) 5 (4.9) 3 (2.9) 2 (2) 2 (2) 4 (3.9) 7 (6.9)
 August 106 8 (7.5) 18 (17) 42 (39.6) 15 (14.2) 7 (6.6) 4 (3.8) 1 (0.9) 1 (0.9) 10 (9.4)
 September 77 17 (22.1) 10 (13) 32 (41.6) 7 (9.1) 3 (3.9) 2 (2.6) 0 (0) 0 (0) 6 (7.8)
 October 84 17 (20.2) 14 (16.7) 30 (35.7) 5 (6) 6 (7.1) 2 (2.4) 0 (0) 3 (3.6) 7 (8.3)
 November 189 35 (18.5) 48 (25.4) 68 (36) 4 (2.1) 13 (6.9) 3 (1.6) 3 (1.6) 1 (0.5) 14 (7.4)
 December 181 29 (16) 60 (33.1) 63 (34.8) 5 (2.8) 7 (3.9) 4 (2.2) 1 (0.6) 4 (2.2) 8 (4.4)
Patient age group
 <7 years 1235 253 (20.5) 334 (27) 419 (33.9) 38 (3.1) 64 (5.2) 34 (2.8) 13 (1.1) 25 (2) 55 (4.5)
 ≥7 years 373 31 (8.3) 56 (15) 137 (36.7) 40 (10.7) 22 (5.9) 14 (3.8) 19 (5.1) 4 (1.1) 50 (13.4)
Patient sex
 Male 948 182 (19.2) 228 (24.1) 305 (32.2) 53 (5.6) 49 (5.2) 27 (2.8) 21 (2.2) 12 (1.3) 71 (7.5)
 Female 653 102 (15.6) 156 (23.9) 251 (38.4) 25 (3.8) 37 (5.7) 21 (3.2) 11 (1.7) 16 (2.5) 34 (5.2)
Collection site
 New Haven, CT 201 44 (21.9) 33 (16.4) 70 (34.8) 19 (9.5) 15 (7.5) 4 (2) 9 (4.5) 0 (0) 7 (3.5)
 Indianapolis, IN 178 27 (15.2) 30 (16.9) 57 (32) 3 (1.7) 18 (10.1) 9 (5.1) 0 (0) 9 (5.1) 25 (14)
 St. Louis, MO 178 42 (23.6) 47 (26.4) 60 (33.7) 7 (3.9) 12 (6.7) 1 (0.6) 6 (3.4) 0 (0) 3 (1.7)
 Denver, CO 162 40 (24.7) 44 (27.2) 36 (22.2) 6 (3.7) 4 (2.5) 6 (3.7) 2 (1.2) 5 (3.1) 19 (11.7)
 Houston, TX 138 16 (11.6) 50 (36.2) 44 (31.9) 9 (6.5) 6 (4.3) 3 (2.2) 0 (0) 3 (2.2) 7 (5.1)
 Manhasset, NY 120 16 (13.3) 33 (27.5) 50 (41.7) 14 (11.7) 3 (2.5) 1 (0.8) 1 (0.8) 0 (0) 2 (1.7)
 Tempe, AZ 119 19 (16) 24 (20.2) 60 (50.4) 2 (1.7) 3 (2.5) 6 (5) 1 (0.8) 1 (0.8) 3 (2.5)
 Kansas City, MO 107 8 (7.5) 12 (11.2) 68 (63.6) 3 (2.8) 2 (1.9) 6 (5.6) 0 (0) 3 (2.8) 5 (4.7)
 Milwaukee, WI 103 11 (10.7) 43 (41.7) 19 (18.4) 0 (0) 6 (5.8) 1 (1) 0 (0) 5 (4.9) 18 (17.5)
 Nashville, TN 78 7 (9) 16 (20.5) 27 (34.6) 3 (3.8) 3 (3.8) 1 (1.3) 11 (14.1) 1 (1.3) 9 (11.5)
 Seattle, WA 73 10 (13.7) 18 (24.7) 30 (41.1) 3 (4.1) 6 (8.2) 0 (0) 0 (0) 1 (1.4) 5 (6.8)
 Chapel Hill, NC 69 24 (34.8) 17 (24.6) 10 (14.5) 5 (7.2) 4 (5.8) 7 (10.1) 0 (0) 0 (0) 2 (2.9)
 Syracuse, NY 54 18 (33.3) 16 (29.6) 10 (18.5) 4 (7.4) 3 (5.6) 1 (1.9) 1 (1.9) 1 (1.9) 0 (0)
 Jacksonville, FL 28 2 (7.1) 7 (25) 15 (53.6) 0 (0) 1 (3.6) 2 (7.1) 1 (3.6) 0 (0) 0 (0)
Specimen source
 Upper respiratory tract 1142 215 (18.8) 282 (24.7) 461 (40.4) 57 (5) 55 (4.8) 26 (2.3) 21 (1.8) 2 (0.2) 23 (2)
 Lower respiratory tract 58 6 (10.3) 12 (20.7) 16 (27.6) 5 (8.6) 5 (8.6) 1 (1.7) 6 (10.3) 1 (1.7) 6 (0.1)
 Gastrointestinal tract 234 34 (14.5) 65 (27.8) 36 (15.4) 10 (4.3) 20 (8.6) 6 (2.6) 3 (1.3) 26 (11.1) 34 (0.1)
 Urine 44 2 (4.6) 6 (13.6) 3 (6.8) 1 (2.3) 2 (4.6) 4 (9.1) 0 (0) 0 (0) 26 (0.6)
 Blood 37 18 (48.7) 7 (18.9) 2 (5.4) 0 (0) 2 (5.4) 6 (16.2) 0 (0) 0 (0) 2 (0.1)
 Ocular 36 0 (0) 1 (2.8) 22 (61.1) 3 (8.3) 0 (0) 1 (2.8) 1 (2.8) 0 (0) 8 (0.2)
 Othera 57 9 (15.8) 17 (29.8) 16 (28.1) 2 (3.5) 2 (3.5) 4 (7) 1 (1.8) 0 (0) 6 (0.1)
Patient hospitalized when culture obtained
 Yes 798 115 (14.4) 198 (24.8) 247 (31) 40 (5) 49 (6.1) 28 (3.5) 26 (3.3) 20 (2.5) 75 (9.4)
 No 718 155 (21.6) 171 (23.8) 269 (37.5) 35 (4.9) 32 (4.5) 15 (2.1) 6 (0.8) 9 (1.3) 26 (3.6)
 Uncertain 92 14 (15.2) 21 (22.8) 40 (43.5) 3 (3.3) 5 (5.4) 5 (5.4) 0 (0) 0 (0) 4 (4.3)
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NOTE. Counts occasionally include multiple isolates from a single clinical event. Because of missing data, total counts are not always identical.

a

Includes CSF, lymph nodes, combined sources, and no source indicated.

For the 1059 unique clinical events experienced by patients with adenovirus infection who were aged <7 years or who had undergone transplantation within 6 months prior to specimen collection, more clinical information was obtained. Of these patients, 95.3% were aged <7 years, 58.9% were male, 11.0% reported to have recently received a transplant, and 4.2% had received a diagnosis of cancer (table 3). Sixty-seven (57.8%) of the 116 transplant recipients had received a bone marrow transplant (data not shown). Thirty-four (58.8%) of the 45 patients with cancer had cancer of lymphatic and hematopoietic origin (data not shown). Four hundred fifty (42.5%) of the 1059 patients with adenovirus infection presented with upper respiratory tract infection. Two hundred fifty-five patients (24.1%) were hospitalized for ≥4 days (median duration of hospitalization, 3 days). Two hundred eight patients (19.6%) had a chronic disease, and 78 (7.4%) had stayed in an intensive care unit. Because certain populations were thought to be at risk of severe adenovirus infection, the characteristics of patients aged <7 years were stratified by immune status and compared with the characteristics of immunocompromised patients aged ≥7 years (table 4). In general, nonimmunocompromised children aged <7 years experienced more adenovirus type 3 infections and more upper respiratory tract infections than did immunocompromised children aged <7 years; however, the nonimmunocompromised children had less severe disease and were less likely to have numerous adenovirus isolates per clinical event.

Table 3.

Medical record information based on a unique clinical event associated with a adenovirus-positive specimen for patients aged <7 years or patients who had received a transplant within 6 months prior to specimen collection (no duplicate isolates).

Total no. of unique clinical events Adenovirus hexon sequence genotype, no. (%) of unique clinical events
Variable 1 (n = 226) 2 (n = 282) 3 (n = 351) 4 (n = 31) 5 (n = 59) 7 (n = 30) 21 (n = 14) 41 (n = 16) Other (n = 50)
Patient age group
 <7 years 1009 215 (21.3) 275 (27.3) 346 (34.3) 29 (2.9) 53 (5.3) 29 (2.9) 12 (1.2) 15 (1.5) 35 (3.5)
 ≥7 years 50 11 (22) 7 (14) 5 (10) 2 (4) 6 (12) 1 (2) 2 (4) 1 (2) 15 (30)
Patient sex
 Male 624 138 (22.1) 170 (27.2) 195 (31.3) 21 (3.4) 34 (5.4) 16 (2.6) 8 (1.3) 7 (1.1) 35 (5.6)
 Female 435 88 (20.2) 112 (25.7) 156 (35.9) 10 (2.3) 25 (5.7) 14 (3.2) 6 (1.4) 9 (2.1) 15 (3.4)
Immunocompromization
 Cancer 7 0 (0) 4 (57.1) 1 (14.3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (14.3) 1 (14.3)
 Cancer and transplantation 38 5 (13.2) 10 (26.3) 5 (13.2) 1 (2.6) 1 (2.6) 3 (7.9) 1 (2.6) 1 (2.6) 11 (28.9)
 Nothing reported 936 203 (21.7) 252 (26.9) 332 (35.5) 28 (3) 48 (5.1) 25 (2.7) 12 (1.3) 11 (1.2) 25 (2.7)
 Transplantation 78 18 (23.1) 16 (20.5) 13 (16.7) 2 (2.6) 10 (12.8) 2 (2.6) 1 (1.3) 3 (3.8) 13 (16.7)
Upper respiratory tract infection
 Yes 450 109 (24.2) 128 (28.4) 154 (34.2) 11 (2.4) 27 (6) 8 (1.8) 4 (0.9) 1 (0.2) 8 (1.8)
 Not reported 609 117 (19.2) 154 (25.3) 197 (32.3) 20 (3.3) 32 (5.3) 22 (3.6) 10 (1.6) 15 (2.5) 42 (6.9)
Pneumonia
 Yes 98 16 (16.3) 27 (27.6) 35 (35.7) 4 (4.1) 5 (5.1) 3 (3.1) 2 (2) 1 (1) 5 (5.1)
 Not reported 961 210 (21.9) 255 (26.5) 316 (32.9) 27 (2.8) 54 (5.6) 27 (2.8) 12 (1.2) 15 (1.6) 45 (4.7)
Conjunctivitis
 Yes 70 7 (10) 9 (12.9) 41 (58.6) 7 (10) 3 (4.3) 1 (1.4) 0 (0) 0 (0) 2 (2.9)
 Not reported 989 219 (22.1) 273 (27.6) 310 (31.3) 24 (2.4) 56 (5.7) 29 (2.9) 14 (1.4) 16 (1.6) 48 (4.9)
Encephalitis
 Yes 4 1 (25) 0 (0) 2 (50) 0 (0) 0 (0) 1 (25) 0 (0) 0 (0) 0 (0)
 Not reported 1055 225 (21.3) 282 (26.7) 349 (33.1) 31 (2.9) 59 (5.6) 29 (2.7) 14 (1.3) 16 (1.5) 50 (4.7)
Duration of hospital stay
 Not recorded 32 4 (12.5) 6 (18.8) 18 (56.3) 0 (0) 3 (9.4) 1 (3.1) 0 (0) 0 (0) 0 (0)
 No stay or unknowna 460 111 (24.1) 123 (26.7) 164 (35.7) 13 (2.8) 17 (3.7) 12 (2.6) 2 (0.4) 6 (1.3) 12 (2.6)
 up to 3 days 300 74 (24.7) 82 (27.3) 103 (34.3) 9 (3) 13 (4.3) 7 (2.3) 3 (1) 1 (0.3) 8 (2.7)
 4-407 days 255 35 (13.7) 68 (26.7) 63 (24.7) 8 (3.1) 26 (10.2) 9 (3.5) 9 (3.5) 9 (3.5) 28 (11)
 Unknown no. of days 12 2 (16.7) 3 (25) 3 (25) 1 (8.3) 0 (0) 1 (8.3) 0 (0) 0 (0) 2 (16.7)
Duration of intensive care unit stay
 Not recorded 3 1 (33.3) 1 (33.3) 1 (33.3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
 No stay or unknowna 973 209 (21.5) 261 (26.8) 331 (34) 29 (3) 48 (4.9) 26 (2.7) 8 (0.8) 15 (1.5) 46 (4.7)
 1-8 days 39 9 (23.1) 9 (23.1) 9 (23.1) 1 (2.6) 6 (15.4) 1 (2.6) 2 (5.1) 1 (2.6) 1 (2.6)
 9-326 days 39 7 (17.9) 9 (23.1) 7 (17.9) 1 (2.6) 5 (12.8) 3 (7.7) 4 (10.3) 0 (0) 3 (7.7)
 Unknown no. of days 5 0 (0) 2 (40) 3 (60) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Cause of death
 Not recorded 1 0 (0) 0 (0) 1 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
 None or unknowna 1046 225 (21.5) 276 (26.4) 350 (33.5) 31 (3) 58 (5.5) 29 (2.8) 12 (1.1) 16 (1.5) 49 (4.7)
 Other unknown cause 6 0 (0) 3 (50) 0 (0) 0 (0) 0 (0) 1 (16.7) 1 (16.7) 0 (0) 1 (16.7)
 Primarily adenovirus infection 6 1 (16.7) 3 (50) 0 (0) 0 (0) 1 (16.7) 0 (0) 1 (16.7) 0 (0) 0 (0)
Chronic disease
 Not recorded 31 6 (19.4) 7 (22.6) 14 (45.2) 1 (3.2) 1 (3.2) 1 (3.2) 0 (0) 0 (0) 1 (3.2)
 No 732 152 (20.8) 201 (27.5) 249 (34) 22 (3) 41 (5.6) 21 (2.9) 8 (1.1) 8 (1.1) 30 (4.1)
 Yes 208 49 (23.6) 56 (26.9) 49 (23.6) 7 (3.4) 11 (5.3) 5 (2.4) 6 (2.9) 6 (2.9) 19 (9.1)
 Unknown 88 19 (21.6) 18 (20.5) 39 (44.3) 1 (1.1) 6 (6.8) 3 (3.4) 0 (0) 2 (2.3) 0 (0)
No. of adenovirus-positive specimens per clinical eventb
 1 980 219 (22.3) 263 (26.8) 328 (33.5) 26 (2.7) 55 (5.6) 23 (2.3) 12 (1.2) 13 (1.3) 41 (4.2)
 2 44 4 (9.1) 10 (22.7) 16 (36.4) 2 (4.5) 3 (6.8) 2 (4.5) 2 (4.5) 2 (4.5) 3 (6.8)
 3 22 1 (4.5) 5 (22.7) 6 (27.3) 3 (13.6) 0 (0) 2 (9.1) 0 (0) 0 (0) 5 (22.7)
 4 1 0 (0) 1 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
 5 4 0 (0) 0 (0) 1 (25) 0 (0) 1 (25) 1 (25) 0 (0) 0 (0) 1 (25)
 6 3 1 (33.3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (33.3) 0 (0) 1 (33.3) 0 (0)
 7 2 1 (50) 1 (50) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
 9 2 0 (0) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
 20 1 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (100) 0 (0) 0 (0) 0 (0)
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a

“Unknown” was a given response on the data forms.

b

No. of adenovirus-positive specimens per clinical event refers to the number of specimens submitted that were associated with a single clinical event for a unique patient on the basis of medical record review at the submitting laboratory.

Table 4.

Medical and genotyping information for adenovirus-infected patients per unique clinical event for patients aged <7 years or patients who had received a transplant within 6 months before specimen collection (no duplicate isolates), by age group and immunocompromization status.

No. (%) of unique clinical events
Patients aged <7 years
 Immunocompromised patients aged ≥7 years (n = 50)
Variable Immunocompromised (n = 73) Nonimmunocompromised (n = 936)
Serotype
 1 12 (16.4) 203 (21.7) 11 (22)
 2 23 (31.5) 252 (26.9) 7 (14)
 3 14 (19.2) 332 (35.5) 5 (10)
 4 1 (1.4) 28 (3) 2 (4)
 5 5 (6.9) 48 (5.1) 6 (12)
 6 2 (2.7) 7 (0.8) 0 (0)
 7 4 (5.5) 25 (2.7) 1 (2)
 11 1 (1.4) 0 (0) 6 (12)
 12 3 (4.1) 1 (0.1) 0 (0)
 14 0 (0) 3 (0.3) 0 (0)
 15 1 (1.4) 0 (0) 0 (0)
 19 0 (0) 7 (0.8) 1 (2)
 21 0 (0) 12 (1.3) 2 (4)
 22 0 (0) 1 (0.1) 0 (0)
 25 0 (0) 1 (0.1) 0 (0)
 31 3 (4.1) 4 (0.4) 2 (4)
 34 0 (0) 0 (0) 4 (8)
 35 0 (0) 1 (0.1) 2 (4)
 41 4 (5.5) 11 (1.2) 1 (2)
Sex
 Male 42 (57.5) 550 (58.8) 32 (64)
 Female 31 (42.5) 386 (41.2) 18 (36)
Upper respiratory tract infection
 Not reported 60 (82.2) 503 (53.7) 46 (92)
 Yes 13 (17.8) 433 (46.3) 4 (8)
Pneumonia
 Not reported 71 (97.3) 845 (90.3) 45 (90)
 Yes 2 (2.7) 91 (9.7) 5 (10)
Conjunctivitis
 Not reported 73 (100) 866 (92.5) 50 (100)
 Yes 0 (0) 70 (7.5) 0 (0)
Encephalitis
 Not reported 72 (98.6) 933 (99.7) 50 (100)
 Yes 1 (1.4) 3 (0.3) 0 (0)
Duration of hospital stay
 Not recorded 26 (35.6) 6 (0.6) 0 (0)
 No stay or unknowna 11 (15.1) 432 (46.2) 17 (34)
 Up to 3 days 5 (6.9) 293 (31.3) 2 (4)
 4-407 days 30 (41.1) 194 (20.7) 31 (62)
 Unknown no. of days 1 (1.4) 11 (1.2) 0 (0)
Duration of intensive care unit stay
 Not recorded 0 (0) 3 (0.3) 0 (0)
 No stay or unknowna 64 (87.7) 867 (92.6) 42 (84)
 1-8 days 1 (1.4) 34 (3.6) 4 (8)
 9-326 days 8 (11) 28 (3) 3 (6)
 Unknown no. of days 0 (0) 4 (0.4) 1 (2)
Cause of death
 Not recorded 0 (0) 1 (0.1) 0 (0)
 None or unknowna 69 (94.5) 931 (99.5) 46 (92)
 Other or unknown cause 1 (1.4) 3 (0.3) 2 (4)
 Primarily adenovirus infection 3 (4.1) 1 (0.1) 2 (4)
Chronic disease
 Not recorded 2 (2.7) 29 (3.1) 0 (0)
 No 14 (19.2) 706 (75.4) 12 (24)
 Yes 24 (32.9) 149 (15.9) 35 (70)
 Unknown 33 (45.2) 52 (5.6) 3 (6)
Number of adenovirus-positive specimens per clinical event
 1 51 (69.9) 893 (95.4) 36 (72)
 2 5 (6.9) 34 (3.6) 5 (10)
 3 10 (13.7) 9 (1) 3 (6)
 ≥4b 7 (9.6) 0 (0) 6 (12)
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a

“Unknown” was a given response on the data forms.

b

Participants had up to 20 unique adenovirus types detected.

A number of laboratories submitted multiple adenovirus-positive specimens for a single clinical event. Most of these specimens were of the same genotype; however, 20 unique clinical events were found to be associated with laboratory evidence of infection with ≥2 adenovirus HSgenotypes (table 5). Most of these infections involving multiple adenovirus HSgenotypes occurred in immunocompromised patients who were aged <7 years.

Table 5.

Data on patients whose collected specimen yielded ≥2 adenovirus hexon sequence genotypes for a single clinical event.

Patient information
 Isolate information
Clinical event Age Transplant Cancer Collection month/year Adenovirus type No. of isolates
1 2 Pancreas and small bowel None 1/2005 2 2
1/2005 5 1
2 4 Bone marrow None 1/2005 41 1
2/2005 41 4
3/2005 2 1
3 9 Bone marrow Lymphatic and hematopoietic tissue 11/2004 2 3
10/2004 3 1
12/2004 2 1
4 4 Bone marrow Lymphatic and hematopoietic tissue 11/2005 18 1
11/2005 7 1
11/2005 6 2
11/2005 15 1
5 5 Bone marrow None 1/2006 2 1
1/2006 3 1
6 43 None None 6/2005 1 2
6/2005 2 1
7 27 Bone marrow None 1/2006 2 3
1/2006 7 1
2/2006 1 1
2/2006 2 1
8 52 Kidney None 10/2005 2 1
10/2005 6 1
11/2005 NT 1
9 3 Bone marrow Lymphatic and hematopoietic tissue 11/2005 1 4
10/2005 1 8
10/2005 NT 1
9/2005 1 5
9/2005 NT 1
9/2005 7 1
10 3 Bone marrow Lymphatic and hematopoietic tissue 12/2005 1 1
1/2006 3 1
11 3 Bone marrow Lymphatic and hematopoietic tissue 7/2005 2 2
8/2005 NT 1
8/2005 2 2
8/2005 NT 1
8/2005 1 1
8/2005 NT 1
8/2005 NT 1
12 0 None None 4/2006 19 1
3/2006 19 1
3/2006 7 1
13 4 Bone marrow None 5/2006 3 1
5/2006 1 2
14 2 Bone marrow Medulloblastoma 3/2006 3 1
2/2006 4 2
15 2 Bone marrow Lymphatic and hematopoietic tissue 12/2005 3 1
12/2005 2 1
3/2006 1 1
1/2006 2 1
3/2006 41 1
4/2006 2 1
16 5 Bone marrow Lymphatic and hematopoietic tissue 12/2005 6 2
12/2005 3 1
12/2005 6 1
12/2005 7 1
17 4 None Lymphatic and hematopoietic tissue 9/2005 2 1
9/2005 6 1
10/2005 6 1
18 17 None Bone, connective tissue, skin, or 5/2006 7 2
breast 6/2006 35 1
19 9 None Lymphatic and hematopoietic tissue 8/2004 3 1
8/2004 4 1
20 6 Bone marrow None 1/2005 7 1
7/2005 15 1
8/2005 7 1
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NOTE. NT, nontyped adenovirus.

The multivariable risk factor modeling (table 6) for adenovirus disease severity (death or intensive care unit stay vs. hospitalization vs. other disease) revealed some interesting findings. As expected, patients aged <7 years (OR, 3.2; 95% CI, 1.4-7.4), patients with chronic disease (OR, 3.6; 95% CI, 2.6-5.1), and patients who had recently undergone transplantation (OR, 2.7; 95% CI, 1.3-5.2) had an increased risk of severe disease. However, unexpectedly, patients infected with adenovirus type 5 (OR, 2.7; 95% CI, 1.5-4.7) or 21 (OR, 7.6; 95% CI, 2.6-22.3) also had a higher risk of developing severe adenovirus disease. Similar multivariable modeling was performed for the outcome of pneumonia, but no specific adenovirus types were associated with this condition (data not shown).

Table 6.

Risk factors for adenovirus clinical severity on the basis of the proportional odds model.

Severity level
Sample distribution
 OR (95% CI)
Variables Death or ICU stay Hospitalization Other Unadjusted Adjusteda
Age group
 <7 years 76 456 449 0.5 (0.3-0.8) 3.2 (1.4-7.4)
 ≥7 years 9 24 17 Reference Reference
Adenovirus hexon sequence genotype
 1 16 94 111 1.1 (0.8-1.5) 0.9 (0.7-1.3)
 2 22 130 123 1.3 (1-1.8) 1.1 (0.8-1.6)
 3 19 150 170 Reference Reference
 4 2 16 13 1.4 (0.7-2.9) 1.1 (0.6-2.3)
 5 11 28 17 2.5 (1.5-4.3) 2.7 (1.5-4.7)
 7 4 13 12 1.6 (0.8-3.3) 1.4 (0.7-3)
 21 6 6 2 10.3 (3.6-29.2) 7.6 (2.6-22.3)
 41 1 9 6 1.7 (0.6-4.4) 1 (0.4-2.7)
 Other 4 34 12 2.6 (1.5-4.7) 1.8 (0.9-3.3)
Chronic disease
 Yes 40 123 45 4.1 (3-5.5) 3.6 (2.6-5.1)
 No or unknown 45 357 421 Reference Reference
Transplantation during the 6 months previous to specimen collection
 Yes 19 44 24 2.8 (1.8-4.2) 2.7 (1.3-5.2)
 No or unknown 66 436 442 Reference Reference
Open in a new tab

NOTE. The model included only the first adenovirus isolate per unique medial event. Only isolates that were genotyped were considered. Adenovirus severity was classified as an ordinal outcome (death or ICU stay or hopitalization vs. other illness). ICU, intensive care unit.

a

Statistically significant covariates, after manual backward elimination from a saturated model. The adjusted model included only the variables shown.

DISCUSSION

Sequencing of hypervariable regions 1-6 of the adenovirus hexon gene [26] appears to correlate well with serological and other molecular methods for typing human adenovirus and, unlike serological methods that can take weeks to perform, can generally be completed within 2 days. It is likely that PCR and sequencing will replace older, classic adenovirus serotyping methods, because PCR and sequencing have the potential to provide rapid results to clinicians and public health officials evaluating and treating specific patients and responding to outbreaks of adenovirus infection. Conversion from classic serotyping to genotyping of adenovirus is not unlike similar recent shifts for the study of group A streptococci [28] and enterovirus [29].

Typing results yielded some interesting observations. The high prevalence of infection with adenovirus type 4 HSgenotypes among patients in the military is consistent with a recent report [25]. However, the increased prevalence of adenovirus type 21 infection among both military and civilian patients was unexpected (tables 1 and 2). Because prevalence figures for adenovirus infection have been known to fluctuate over time, these changes were not significantly alarming. However, adenovirus type 21 infection has caused sporadic outbreaks among military [30-32] and civilian populations [33, 34], and changes in prevalence must be evaluated as possible indicators of the emergence of a novel strain. Because of such outbreaks, adenovirus type 21 vaccine development efforts were attempted [30, 35, 36] but never finalized, because morbidity associated with adenovirus 21 infection has remained low [7]. The high prevalence of hospitalization among the patients with adenovirus infection (table 2) was surprising. This may reflect the desire of clinicians to more frequently determine the etiology of an infection in patients sick enough to merit hospitalization. However, this high prevalence of hospitalization, the significant number of patients with adenovirus infection who require hospitalization in an intensive care unit, and the relatively long duration of hospitalization that is experienced for patients with adenovirus infection reflect the impact on morbidity that adenovirus infection has in US medical care facilities today.

Before this surveillance effort was initiated, adenovirus type 7 infection was predicted to have a strong association with severe morbidity. Worldwide, various adenovirus type 7 genotypes have emerged to cause epidemics and severe disease [9, 37-47]. However, thus far in this surveillance, adenovirus type 7 infection has not been implicated to have a strong association with severe morbidity. This could be because of a stabilization of circulating adenovirus type 7 genotypes in the United States—as was recently apparent in Iowa for the strain adenovirus type 7d2 [10]—with subsequent increases in herd immunity and reductions in adenovirus type 7 infections. Previous reports have noted that outbreaks of adenovirus type 7 infection seem to be sporadic [40, 48] and may be the result of the emergence of new type 7 subtypes [9, 40, 48].

The association of adenovirus types 5 and 21 with severe disease (table 6) was unexpected. Although adenovirus types 5 and 21 are associated with novel strains [49], epidemics [33, 34, 50, 51], severe disease [52], and death [53], these observations have been relatively rare. Our data revealed that, of the 13 patients with adenovirus infection who died, 1 had been infected with adenovirus type 5 (1.7% of the patients infected with type 5), and 2 had been infected with type 21 (14.3% of the patients infected with type 21). Although the data supporting these findings are rather sparse, the observations merit continued study.

Additionally interesting was the relatively high number of patients detected as having infections with multiple adenovirus isolates over time, with multiple adenovirus types being identified during a single clinical event (tables 3, 4 and 5). Recent reports regarding repeat adenovirus detections in immunocompromised patients [54] and multiple strains causing concomitant infection in US military trainees [55] seem to reinforce our observation, illustrating the complexities of evaluating adenovirus infection. Molecular typing strategies are thus useful in evaluating adenovirus infection epidemics and individual patients. For instance, a transplant clinician might use molecular typing to discern whether a patient is experiencing a reactivation of a latent adenovirus infection, a nosocomial infection, a community-acquired infection, or a donor-associated adenovirus infection.

This research has a number of limitations. Although a large number of adenovirus-positive specimens were tested in this study, the specimens were collected for diagnostic purposes and, thus, were likely to have been obtained from the most severely affected patients. In addition, although 98% of the specimens were genotyped with good identity score agreements, relying solely on the hypervariable regions of the hexon gene to distinguish strains may cause to be missed other important genetic differences in strains that may correlate better with host immunologic response and strain virulence. For instance, the fiber protein possesses cell receptor binding sites, and alteration of these sites can alter the tissue tropism of an adenovirus [56]. Similarly, genes coding for certain adenovirus early proteins may influence adenovirus cell-to-cell transmission [57]. Thus, the hexon gene sequencing approach will merit further study augmented with other molecular typing methods to reduce the risk of missing important recombinations of adenovirus.

In conclusion, the hexon gene sequence typing strategy used in this study seems to be very useful. Additional studies of such typing in concert with other molecular typing methods are warranted. Molecular methods have the potential to assist clinicians in evaluating and treating specific patients and in aiding public health officials in investigating adenovirus infection epidemics. The suggestion that adenovirus types 3, 5, and 21 may be associated with more frequent or more severe disease, as well as the unexpected lack of such associations with adenovirus type 7, merit further molecular investigation to determine whether there are viral predictors of disease severity. Finally, our findings that clinical adenovirus infection was often associated with hospitalization and that, more often than expected, multiple adenovirus types could be detected add to our new appreciation of the morbidity associated with adenovirus infection.

Acknowledgments

We thank the numerous University of Iowa graduate students and laboratory interns who have contributed to the molecular study of the viral specimens; Dr. Jennifer Goodrich (University of North Carolina Hospitals) and Dr. David Metzgar (Navy Respiratory Disease Laboratory), for their assistance in providing laboratory specimens; Dr. Kevin L. Knudtson (University of Iowa DNA Facility), for his much appreciated assistance in sequencing work; and Dr. Leta Crawford Miksza (California Department of Health Services) and Dr. Gary Doern (University of Iowa College of Medicine), for their assistance with study design.

Financial support. National Institute of Allergy and Infectious Diseases (NIAID), National Surveillance for Emerging Adenovirus Infections, National Institutes of Health (NIH; NIH/NIAID R01 AI053034 to G.C.G.).

Potential conflicts of interest. G.C.G. serves on the data monitoring board for adenovirus vaccine trials sponsored by Duramed. All other authors: no conflicts.

Footnotes

Publisher's Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, the US Centers for Disease Control and Prevention, or the US Government.

References

  • 1.Jordan WJ. The frequency of infection with adenoviruses in a family study population. Ann NY Acad Sci. 1957;67:273–8. doi: 10.1111/j.1749-6632.1957.tb46050.x. [DOI] [PubMed] [Google Scholar]
  • 2.Wenner H, Bera G, Weston J, Chin T. The epidemiology of acute respiratory illness. I. Observations of adenovirus infections prevailing in a group of families. J Infect Dis. 1957;101:275–86. doi: 10.1093/infdis/101.3.275. [DOI] [PubMed] [Google Scholar]
  • 3.Hall CE, Brandt CD, Frothingham TE, Spigland I, Cooney MK, Fox JP. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. IX. A comparison of infections with several respiratory pathogens in New York and New Orleans families. Am J Epidemiol. 1971;94:367–85. doi: 10.1093/oxfordjournals.aje.a121332. [DOI] [PubMed] [Google Scholar]
  • 4.Fox JP, Brandt CD, Wassermann FE, et al. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. VI. Observations of adenovirus infections: virus excretion patterns, antibody response, efficiency of surveillance, patterns of infections, and relation to illness. Am J Epidemiol. 1969;89:25–50. doi: 10.1093/oxfordjournals.aje.a120913. [DOI] [PubMed] [Google Scholar]
  • 5.Fox JP, Hall CE, Cooney MK. The Seattle virus watch. VII. Observations of adenovirus infections. Am J Epidemiol. 1977;105:362–86. doi: 10.1093/oxfordjournals.aje.a112394. [DOI] [PubMed] [Google Scholar]
  • 6.Hilleman M. Efficacy of and indications for use of adenovirus vaccine. Am J Public Health Nations Health. 1958;48:153–8. doi: 10.2105/ajph.48.2.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Gaydos CA, Gaydos JC. Adenovirus vaccines in the U.S. military. Mil Med. 1995;160:300–4. [PubMed] [Google Scholar]
  • 8.Gaydos CA, Gray GC.Plotkin SA, Orenstein WA, Offit PA.Adenovirus vaccines Vaccines Elsevier; (in press) Edinburgh: 5th ed. [Google Scholar]
  • 9.Erdman DD, Xu W, Gerber SI, et al. Molecular epidemiology of adenovirus type 7 in the United States, 1966-2000. Emerg Infect Dis. 2002;8:269–77. doi: 10.3201/eid0803.010190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Gray GC, Setterquist SF, Jirsa SJ, DesJardin LE, Erdman DD. Emergent strain of human adenovirus endemic in Iowa. Emerg Infect Dis. 2005;11:127–8. doi: 10.3201/eid1101.040490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Kajon AE, Murtagh P, Garcia Franco S, Freire MC, Weissenbacher MC, Zorzopulos J. A new genome type of adenovirus 3 associated with severe lower acute respiratory infection in children. J Med Virol. 1990;30:73–6. doi: 10.1002/jmv.1890300116. [DOI] [PubMed] [Google Scholar]
  • 12.Russkanen O, Meurman O, Kusjavi A. Adenoviruses. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical virology. Churchill Livingstone; New York: 1997. pp. 525–47. [Google Scholar]
  • 13.Couroucli XI, Welty SE, Ramsay PL, et al. Detection of microorganisms in the tracheal aspirates of preterm infants by polymerase chain reaction: association of adenovirus infection with bronchopulmonary dysplasia. Pediatr Res. 2000;47:225–32. doi: 10.1203/00006450-200002000-00013. [DOI] [PubMed] [Google Scholar]
  • 14.Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol. 2003;42:466–72. doi: 10.1016/s0735-1097(03)00648-x. [DOI] [PubMed] [Google Scholar]
  • 15.Melon S, Mendez S, Iglesias B, et al. Involvement of adenovirus in clinical mononucleosis-like syndromes in young children. Eur J Clin Microbiol Infect Dis. 2005;24:314–8. doi: 10.1007/s10096-005-1333-7. [DOI] [PubMed] [Google Scholar]
  • 16.Guarner J, de Leon-Bojorge B, Lopez-Corella E, et al. Intestinal intussusception associated with adenovirus infection in Mexican children. Am J Clin Pathol. 2003;120:845–50. doi: 10.1309/LBRN-GF9M-JW2M-HT97. [DOI] [PubMed] [Google Scholar]
  • 17.Bajanowski T, Wiegand P, Cecchi R, et al. Detection and significance of adenoviruses in cases of sudden infant death. Virchows Arch. 1996;428:113–8. doi: 10.1007/BF00193939. [DOI] [PubMed] [Google Scholar]
  • 18.Dhurandhar NV. Contribution of pathogens in human obesity. Drug News Perspect. 2004;17:307–13. doi: 10.1358/dnp.2004.17.5.829034. [DOI] [PubMed] [Google Scholar]
  • 19.Atkinson RL, Dhurandhar NV, Allison DB, et al. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes (Lond) 2005;29:281–6. doi: 10.1038/sj.ijo.0802830. [DOI] [PubMed] [Google Scholar]
  • 20.Wang WH, Wang HL. Fulminant adenovirus hepatitis following bone marrow transplantation: a case report and brief review of the literature. Arch Pathol Lab Med. 2003;127:e246–8. doi: 10.5858/2003-127-e246-FAHFBM. [DOI] [PubMed] [Google Scholar]
  • 21.Hierholzer JC. Adenoviruses in the immunocompromised host. Clin Microbiol Rev. 1992;5:262–74. doi: 10.1128/cmr.5.3.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Gerber SI, Erdman DD, Pur SL, et al. Outbreak of adenovirus genome type 7d2 infection in a pediatric chronic-care facility and tertiary-care hospital. Clin Infect Dis. 2001;32:694–700. doi: 10.1086/319210. [DOI] [PubMed] [Google Scholar]
  • 23.Morfin F, Dupuis-Girod S, Mundweiler S, et al. In vitro susceptibility of adenovirus to antiviral drugs is species-dependent. Antivir Ther. 2005;10:225–9. [PubMed] [Google Scholar]
  • 24.Gray GC, Goswami PR, Malasig MD, et al. Adult adenovirus infections: loss of orphaned vaccines precipitates military respiratory disease epidemics. For the Adenovirus Surveillance Group. Clin Infect Dis. 2000;31:663–70. doi: 10.1086/313999. [DOI] [PubMed] [Google Scholar]
  • 25.Russell KL, Hawksworth AW, Ryan MA, et al. Vaccine-preventable adenoviral respiratory illness in US military recruits, 1999-2004. Vaccine. 2006;24:2835–42. doi: 10.1016/j.vaccine.2005.12.062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Lu X, Erdman DD. Molecular typing of human adenoviruses by PCR and sequencing of a partial region of the hexon gene. Arch Virol. 2006;151:1587–602. doi: 10.1007/s00705-005-0722-7. [DOI] [PubMed] [Google Scholar]
  • 27.Metzgar D, Osuna M, Yingst S, et al. PCR analysis of egyptian respiratory adenovirus isolates, including identification of species, serotypes, and coinfections. J Clin Microbiol. 2005;43:5743–52. doi: 10.1128/JCM.43.11.5743-5752.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Facklam R, Beall B, Efstratiou A, et al. emm Typing and validation of provisional M types for group A streptococci. Emerg Infect Dis. 1999;5:247–53. doi: 10.3201/eid0502.990209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Thoelen I, Lemey P, Van Der Donck I, Beuselinck K, Lindberg AM, Van Ranst M. Molecular typing and epidemiology of enteroviruses identified from an outbreak of aseptic meningitis in Belgium during the summer of 2000. J Med Virol. 2003;70:420–9. doi: 10.1002/jmv.10412. [DOI] [PubMed] [Google Scholar]
  • 30.Takafuji ET, Gaydos JC, Allen RG, Top FH., Jr. Simultaneous administration of live, enteric-coated adenovirus types 4, 7 and 21 vaccines: safety and immunogenicity. J Infect Dis. 1979;140:48–53. doi: 10.1093/infdis/140.1.48. [DOI] [PubMed] [Google Scholar]
  • 31.van der Veen J, Oei KG, Abarbanel MF. Patterns of infections with adenovirus types 4, 7 and 21 in military recruits during a 9-year survey. J Hyg (Lond) 1969;67:255–68. doi: 10.1017/s0022172400041668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.van der Veen J, Dijkman J. Association of type 21 adenovirus with acute respiratory illness in military recruits. Am J Hyg. 1962;76:149–59. doi: 10.1093/oxfordjournals.aje.a120270. [DOI] [PubMed] [Google Scholar]
  • 33.van der Avoort HG, Adrian T, Wigand R, Wermenbol AG, Zomerdijk TP, de Jong JC. Molecular epidemiology of adenovirus type 21 in The Netherlands and the Federal Republic of Germany from 1960 to 1985. J Clin Microbiol. 1986;24:1084–8. doi: 10.1128/jcm.24.6.1084-1088.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.de Jong JC, van der Avoort HG, Wigand R, Adrian T. Revival of adenovirus 21 in Netherlands and West Germany. Lancet. 1985;2:776. doi: 10.1016/s0140-6736(85)90649-x. [DOI] [PubMed] [Google Scholar]
  • 35.Dudding BA, Bartelloni PJ, Scott RM, Top FH, Jr, Russell PK, Buescher EL. Enteric immunization with live adenovirus type 21 vaccine. I. Tests for safety, infectivity, immunogenicity, and potency in volunteers. Infect Immun. 1972;5:295–9. doi: 10.1128/iai.5.3.295-299.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Scott RM, Dudding BA, Romano SV, Russell PK. Enteric immunization with live adenovirus type 21 vaccine. II. Systemic and local immune responses following immunization. Infect Immun. 1972;5:300–4. doi: 10.1128/iai.5.3.300-304.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Benyesh-Melnick M, Rosenberg HS. The isolation of adenovirus type 7 from a fatal case of pneumonia and disseminated disease. J Pediatr. 1964;64:83–7. doi: 10.1016/s0022-3476(64)80321-8. [DOI] [PubMed] [Google Scholar]
  • 38.Simila S, Ylikorkala O, Wasz-Hockert O. Type 7 adenovirus pneumonia. J Pediatr. 1971;79:605–11. doi: 10.1016/s0022-3476(71)80307-4. [DOI] [PubMed] [Google Scholar]
  • 39.Brown RS, Nogrady MB, Spence L, Wiglesworth FW. An outbreak of adenovirus type 7 infection in children in Montreal. Can Med Assoc J. 1973;108:434–9. [PMC free article] [PubMed] [Google Scholar]
  • 40.Wadell G, Varsanyi TM, Lord A, Sutton RN. Epidemic outbreaks of adenovirus 7 with special reference to the pathogenicity of adenovirus genome type 7b. Am J Epidemiol. 1980;112:619–28. doi: 10.1093/oxfordjournals.aje.a113034. [DOI] [PubMed] [Google Scholar]
  • 41.Centers for Disease Control and Prevention Adenovirus type 7 outbreak in a pediatric chronic-care facility—Pennsylvania, 1982. MMWR Morb Mortal Wkly Rep. 1983;32:258–60. [PubMed] [Google Scholar]
  • 42.Straube RC, Thompson MA, Van Dyke RB, et al. Adenovirus type 7b in a children’s hospital. J Infect Dis. 1983;147:814–9. doi: 10.1093/infdis/147.5.814. [DOI] [PubMed] [Google Scholar]
  • 43.de Silva LM, Colditz P, Wadell G. Adenovirus type 7 infections in children in New South Wales, Australia. J Med Virol. 1989;29:28–32. doi: 10.1002/jmv.1890290106. [DOI] [PubMed] [Google Scholar]
  • 44.Porter JD, Teter M, Traister V, Pizzutti W, Parkin WE, Farrell J. Outbreak of adenoviral infections in a long-term paediatric facility, New Jersey, 1986/87. J Hosp Infect. 1991;18:201–10. doi: 10.1016/0195-6701(91)90144-w. [DOI] [PubMed] [Google Scholar]
  • 45.Azar R, Varsano N, Mileguir F, Mendelson E. Molecular epidemiology of adenovirus type 7 in Israel: identification of two new genome types, Ad7k and Ad7d2. J Med Virol. 1998;54:291–9. doi: 10.1002/(sici)1096-9071(199804)54:4<291::aid-jmv9>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  • 46.Yamadera S, Yamashita K, Akatsuka M, Kato N, Inouye S. Trend of adenovirus type 7 infection, an emerging disease in Japan: a report of the National Epidemiological Surveillance of Infectious Agents in Japan. Jpn J Med Sci Biol. 1998;51:43–51. doi: 10.7883/yoken1952.51.43. [DOI] [PubMed] [Google Scholar]
  • 47.Mitchell LS, Taylor B, Reimels W, Barrett FF, Devincenzo JP. Adenovirus 7a: a community-acquired outbreak in a children’s hospital. Pediatr Infect Dis J. 2000;19:996–1000. doi: 10.1097/00006454-200010000-00011. [DOI] [PubMed] [Google Scholar]
  • 48.Noda M, Yoshida T, Sakaguchi T, Ikeda Y, Yamaoka K, Ogino T. Molecular and epidemiological analyses of human adenovirus type 7 strains isolated from the 1995 nationwide outbreak in Japan. J Clin Microbiol. 2002;40:140–5. doi: 10.1128/JCM.40.1.140-145.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Adrian T, Schlipkoter U, Roggendorf M, Wigand R. Nosocomial and endemic infections with a genome type of adenovirus type 5. Zentralbl Bakteriol. 1989;271:339–44. doi: 10.1016/s0934-8840(89)80032-5. [DOI] [PubMed] [Google Scholar]
  • 50.Shult PA, Polyak F, Dick EC, Warshauer DM, King LA, Mandel AD. Adenovirus 21 infection in an isolated antarctic station: transmission of the virus and susceptibility of the population. Am J Epidemiol. 1991;133:599–607. doi: 10.1093/oxfordjournals.aje.a115932. [DOI] [PubMed] [Google Scholar]
  • 51.Larsen RA, Jacobson JT, Jacobson JA, Strikas RA, Hierholzer JC. Hospital-associated epidemic of pharyngitis and conjunctivitis caused by adenovirus (21/H21 + 35) J Infect Dis. 1986;154:706–9. doi: 10.1093/infdis/154.4.706. [DOI] [PubMed] [Google Scholar]
  • 52.Becroft DM. Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in young children. J Clin Pathol. 1971;24:72–82. doi: 10.1136/jcp.24.1.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Chatterjee NK, Samsonoff WA, Balasubramaniam N, Rush-Wilson K, Spargo W, Church TM. Isolation and characterization of adenovirus 5 from the brain of an infant with fatal cerebral edema. Clin Infect Dis. 2000;31:830–3. doi: 10.1086/314041. [DOI] [PubMed] [Google Scholar]
  • 54.Kroes AC, de Klerk EP, Lankester AC, et al. Sequential emergence of multiple adenovirus serotypes after pediatric stem cell transplantation. J Clin Virol. 2007;38:341–7. doi: 10.1016/j.jcv.2007.01.001. [DOI] [PubMed] [Google Scholar]
  • 55.Vora GJ, Lin B, Gratwick K, et al. Co-infections of adenovirus species in previously vaccinated patients. Emerg Infect Dis. 2006;12:921–30. doi: 10.3201/eid1206.050245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Hesse A, Kosmides D, Kontermann RE, Nettelbeck DM. Tropism modification of adenovirus vectors by peptide ligand insertion into various positions of the adenovirus serotype 41 short-fiber knob domain. J Virol. 2007;81:2688–99. doi: 10.1128/JVI.02722-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Subramanian T, Chinnadurai G. Temperature-sensitive replication-competent adenovirus shRNA vectors to study cellular genes in virus-induced apoptosis. Methods Mol Med. 2007;130:125–34. doi: 10.1385/1-59745-166-5:125. [DOI] [PubMed] [Google Scholar]

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