Adenovirus 14 - CDC: New Respiratory Bug Has Killed 10

hawkeye · Nov 15, 2007

CDC: New Respiratory Bug Has Killed 10
ATLANTA (AP) - A mutated version of a common cold virus has caused 10 deaths in the last 18 months, U.S. health officials said Thursday.

Adenoviruses usually cause respiratory infections that aren't considered lethal. But a new variant has caused at least 140 illnesses in New York, Oregon, Washington and Texas, according to a report issued Thursday by the U.S. Centers for Disease Control and Prevention.

The illness made headlines in Texas earlier this year, when a so- called boot camp flu sickened hundreds at Lackland Air Force Base in San Antonio. The most serious cases were blamed on the emerging virus and one 19-year-old trainee died.

"What really got people's attention is these are healthy young adults landing in the hospital and, in some cases, the ICU," said Dr. John Su, an infectious diseases investigator with the CDC.

There are more than 50 distinct types of adenoviruses tied to human illnesses. They are one cause of the common cold, and also trigger pneumonia and bronchitis. Severe illnesses are more likely in people with weaker immune systems.

Some adenoviruses have also been blamed for gastroenteritis, conjunctivitis and cystitis.

There are no good antiviral medications for adenoviruses. Patients usually are treated with aspirin, liquids and bed rest.

In the CDC report, the earliest case of the mutated virus was found in an infant girl in New York City, who died last year. The child seemed healthy right after birth, but then became dehydrated and lost appetite. She died 12 days after she was born.

Tests found that she been infected with a form of adenovirus, called Ad14, but with some little differences, Su said.

It's not clear how the changes made it more lethal, said Linda Gooding, an Emory University researcher who specializes in adenoviruses.

Earlier this year, hundreds of trainees at Lackland became ill with respiratory infections. Tests showed a variety of adenoviruses in the trainees, but at least 106?and probably more?had the mutated form of Ad14, including five who ended up in an intensive care unit

In April, Oregon health officials learned of a cluster of cases at a Portland-area hospital. They ultimately counted 31 cases, including seven who died with severe pneumonia. The next month, Washington state officials reported four hospitalized patients had the same mutated virus. One, who also had AIDS, died.

The Ad14 form of adenovirus was first identified in 1955. In 1969, it was blamed for a rash of illnesses in military recruits stationed in Europe, but it's been detected rarely since then. But it seems to growing more common. The strain accounted for 6 percent of adenovirus samples collected in 22 medical facilities in 2006, while none was seen the previous two years, according to a study published this month in the medical journal Clinical Infectious Diseases.

HenryN · Nov 15, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5645a1.htm

Acute Respiratory Disease Associated with Adenovirus Serotype 14 --- Four States, 2006--2007

Adenovirus serotype 14 (Ad14) is a rarely reported but emerging serotype of adenovirus that can cause severe and sometimes fatal respiratory illness in patients of all ages, including healthy young adults. In May 2006, an infant in New York aged 12 days died from respiratory illness caused by Ad14. During March--June 2007, a total of 140 additional cases of confirmed Ad14 respiratory illness were identified in clusters of patients in Oregon, Washington, and Texas. Fifty-three (38%) of these patients were hospitalized, including 24 (17%) who were admitted to intensive care units (ICUs); nine (5%) patients died. Ad14 isolates from all four states were identical by sequence data from the full hexon and fiber genes. However, the isolates were distinct from the Ad14 reference strain from 1955, suggesting the emergence and spread of a new Ad14 variant in the United States. No epidemiologic evidence of direct transmission linking the New York case or any of the clusters was identified. This report summarizes the investigation of these Ad14 cases by state and city health authorities, the U.S. Air Force, and CDC. State and local public health departments should be alert to the possibility of outbreaks caused by Ad14. New York

In May 2006, a fatal case of Ad14 illness occurred in New York City in an infant girl aged 12 days. The infant was born after a full-term pregnancy and uncomplicated delivery. She was found dead in bed, where she had been sleeping. The infant had been examined 3 days after birth and noted to have lost weight but was otherwise healthy. The next week she had decreased tears with crying, suggesting early dehydration. Physical activity and feeding progressively decreased during the week before her death.
Postmortem tracheal and gastric swabs from the infant were sent to the Wadsworth Center laboratory of the New York State Department of Health, where adenovirus was detected by polymerase chain reaction (PCR). Adenovirus also was isolated by culture, confirmed by immunofluorescence assay (IFA), and typed as Ad14 by antibody neutralization assay. Analysis at CDC identified the same unique genetic sequences in this isolate as were later identified in the Ad14 isolates from the three 2007 clusters.

Autopsy and histologic findings at the Office of the Chief Medical Examiner in New York City included presence in the lung of chronic inflammatory cells with intranuclear inclusions, consistent with adenoviral bronchiolitis and acute respiratory distress syndrome. Investigation by the New York City Department of Health and Mental Hygiene has not identified any other local cases of Ad14 illness. Oregon

In early April 2007, a clinician alerted the Oregon Public Health Division (OPHD) regarding multiple patients at a single hospital who had been admitted with a diagnosis of severe pneumonia during March 3--April 6. A total of 17 specimens were obtained from patients; 15 (88%) yielded isolates that were identified by CDC as Ad14. Through retrospective examination of laboratory reports from the three clinical laboratories in the state that have virology capacity and the Oregon State Public Health Laboratory (OSPHL), OPHD identified 68 persons who tested positive (by culture, PCR, or IFA) for adenovirus during November 1, 2006--April 30, 2007. Isolates from 50 (74%) of these patients were available for further adenovirus typing at either CDC or OSPHL. Of the 50 patient isolates, 31 (62%) were identified as Ad14, and 15 (30%) were identified as another adenovirus type (Figure); four (8%) did not test positive for adenovirus.
Among 30 Ad14 patients (i.e., all but one) whose medical charts were reviewed, 22 (73%) were male; median age was 53.4 years (range: 2 weeks--82 years). Five cases (17%) occurred in patients aged <5 years, and the remaining 20 (83%) occurred in patients aged >18 years. Twenty-two patients (73%) required hospitalization, sixteen (53%) required intensive care, and seven (23%) died, all from severe pneumonia. Median age of the patients who died was 63.6 years; five (71%) were male. One death occurred in an infant aged 1 month. Of the 30 Ad14 cases with patient residence information available, 28 (93%) occurred in residents of seven Oregon counties, and two cases occurred in residents of two Washington counties. No link was identified in hospitals or the community to explain transmission of Ad14 from one patient to another.

In comparison with the Ad14 patients, among the 12 adenovirus non-type 14 patients (i.e., all but three) whose medical charts were reviewed, nine (75%) were male. Median age was 1.1 years, and 11 (92%) patients were aged <5 years. Two (17%) adenovirus non-type14 patients required hospitalization; no ICU admissions or deaths were reported in this group. Washington

On May 16, 2007, the Tacoma-Pierce County Health Department notified the Washington State Department of Health (WADOH) of four residents housed in one unit of a residential-care facility who had been hospitalized recently for pneumonia of unknown etiology. The patients were aged 40--62 years; three of the four were female. One patient had acquired immunodeficiency syndrome (AIDS); the three others had chronic obstructive pulmonary disease. All four were smokers.

The patients had initial symptoms of cough, fever, or shortness of breath during April 22--May 8, 2007. Three patients required intensive care and mechanical ventilation for severe pneumonia. After 8 days of hospitalization, the patient with AIDS died; the other patients recovered. Respiratory specimens from all four patients tested positive for adenovirus by PCR at the WADOH laboratory; isolates were available from three patients, and all three isolates were identified as Ad14 by CDC. Ad14 had last been identified in an isolate from a patient from Washington in May 2006, marking the first identification of Ad14 in the state since 2004. Active surveillance among facility residents and staff did not identify any other cases of Ad14 illness. Texas

Since February 2007, an outbreak of cases of febrile respiratory infection* associated with adenovirus infection has been reported among basic military trainees at Lackland Air Force Base (LAFB). During an initial investigation, conducted from February 3 to June 23, out of 423 respiratory specimens collected and tested, 268 (63%) tested positive for adenovirus; 118 (44%) of the 268 were serotyped, and 106 (90%) of those serotyped were Ad14. Before this outbreak, the only identification of an Ad14 isolate at LAFB occurred in May 2006 (1).
During February 3--June 23, 2007, a total of 27 patients were hospitalized with pneumonia (median hospitalization: 3 days), including five who required admission to the ICU. One ICU patient required extracorporeal membrane oxygenation for approximately 3 weeks and ultimately died. All 16 hospitalized patients from whom throat swabs were collected, including the five patients admitted to the ICU, tested positive for Ad14. Fifteen of these hospitalized patients tested negative for other respiratory pathogens, and one patient had a sputum culture that was positive for Haemophilus influenzae.
All health-care workers from hospital units where trainees had been admitted were offered testing for Ad14, regardless of history of respiratory illness. Of 218 health-care workers tested by PCR, six (3%) were positive for Ad14; five of the six reported direct contact with hospitalized Ad14 patients.
Prevention measures implemented during the outbreak included increasing the number of hand-sanitizing stations, widespread sanitizing of surfaces and equipment with appropriate disinfectants, increasing awareness of Ad14 among trainees and staff members, and taking contact and droplet precautions for hospitalized patients with Ad14. Beginning on May 26, trainees with febrile respiratory illness were confined to one dormitory and both patients and staff members were required to wear surgical masks.
Cases reported postinvestigation. Since the investigation, new cases of febrile respiratory illness have continued to occur at LAFB, but the weekly incidence has declined from a peak of 74 cases with onset during the week of May 27--June 2, to 55 cases with onset during the week of September 23--29 (the most recent period for which data were available). In addition, during March--September 2007, three other military bases in Texas that received trainees from LAFB reported a total of 220 cases of Ad14 illness (Air Force Institute for Operational Health, personal communication, 2007). However, whether Ad14 spread from LAFB to these three bases has not been determined. Ad14 also was detected in April in an eye culture from an outpatient in the surrounding community who had respiratory symptoms and conjunctivitis. No link between this case and the LAFB cases was identified.

Reported by: Oregon Dept of Human Svcs. Washington State Dept of Health Communicable Diseases. 37th Training Wing, 59th Hospital Wing, Air Force Institute for Operational Health, Epidemic and Outbreak Surveillance, US Air Force. Naval Health Research Center, US Navy. Texas Dept of State Health Svcs. New York City Dept of Health and Mental Hygiene. Div of Viral Diseases, National Center for Immunization and Respiratory Diseases; Div of Healthcare Quality Promotion, National Center for Preparedness, Detection, and Control of Infectious Diseases; Career Development Div, Office of Workforce and Career Development, CDC. Editorial Note:

Adenoviruses were first described in the 1950s and are associated with a broad spectrum of clinical illness, including conjunctivitis, febrile upper respiratory illness, pneumonia, and gastrointestinal disease. Severe illness can occur in newborn or elderly patients or in patients with underlying medical conditions but is generally not life-threatening in otherwise healthy adults. Adenoviruses are known to cause outbreaks of disease, including keratoconjunctivitis, and tracheobronchitis and other respiratory diseases among military recruits (2,3). Although adenovirus outbreaks in military recruits are well-recognized (3), infection usually does not require hospitalization and rarely requires admission to an ICU. Beyond the neonatal period, deaths associated with community-acquired adenovirus infection in persons who are not immunodeficient are uncommon and usually sporadic.
Fifty-one adenovirus serotypes have been identified (4). The cases described in this report are unusual because they suggest the emergence of a new and virulent Ad14 variant that has spread within the United States. Ad14 infection was described initially in 1955 (5) and was associated with epidemic acute respiratory disease in military recruits in Europe in 1969 (6) but has since been detected infrequently. For example, during 2001--2002, Ad14 was associated with approximately 8% of respiratory adenoviral infections in the pediatric ward of a Taiwan hospital, with approximately 40% of Ad14 cases in children aged 4--8 years manifesting as lower airway disease (7).
The National Surveillance for Emerging Adenovirus Infections system includes military and civilian laboratories at 15 sites. During 2004--2007, this surveillance system detected 17 isolates of Ad14 from seven sites (8). Ten of the 17 isolates (60%) were collected from three military bases (8). Despite this surveillance, adenovirus infections often go undetected, because few laboratories routinely test for adenovirus and even fewer do serotyping. Wider circulation of Ad14 might have occurred in recent years and might still be occurring.
Further work is needed to understand the natural history of Ad14, risk factors for severe Ad14 disease, and how Ad14 transmission can be prevented effectively. Vaccines against adenovirus serotypes four and seven (i.e., Ad4 and Ad7) were used among military recruits during 1971--1999, before vaccines were no longer available. Adenoviral disease among U.S. military recruits subsequently increased (9). Ad4 and Ad7 oral vaccines have been redeveloped and are being evaluated in clinical trials. Work is ongoing to determine whether the new Ad4 and Ad7 vaccines will protect against Ad14 infection. Management of adenoviral infections is largely supportive. A number of antiviral drugs, including ribavirin, vidarabine, and cidofovir, have been used to treat adenoviral infections such as Ad14, but none have shown definitive efficacy against adenoviruses (2).
Control of adenovirus outbreaks can be challenging because these viruses can be shed in both respiratory secretions and feces and can persist for weeks on environmental surfaces. Guidelines for the care of patients with pneumonia (10) should be followed in cases of suspected adenoviral pneumonia.

Clinicians with questions related to testing of patients for adenovirus or Ad14 infection should contact their state health departments, which can provide assistance. State health departments and military facilities should contact CDC to report unusual clusters of severe adenoviral disease or cases of Ad14 or to obtain additional information regarding laboratory testing. References

Metzgar D, Osuna M, Kajon AE. Abrupt emergence of diverse species B1 and B2 adenoviruses in US military recruit training centers. J Infect Dis. In press.
Adenovirus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious disease. 6th edition. Philadelphia, PA: Churchill Livingstone; 2004.
Dingle JH, Langmuir AD. Epidemiology of acute, respiratory disease in military recruits. Am Rev Respir Dis 1968;97(Suppl):1--65.
Kajon AE, Moseley JM, Metzgar D, et al. Molecular epidemiology of adenovirus type 4 infections in US military recruits in the postvaccination era (1997--2003). J Infect Dis 2007;196:67--75.
Van der Veen J, Kok G. Isolation and typing of adenoviruses recovered from military recruits with acute respiratory disease in The Netherlands. Am J Hyg 1957;65:119--29.
Hierholzer JC, Pumarola A. Antigenic characterization of intermediate adenovirus 14-11 strains associated with upper respiratory illness in a military camp. Infect Immun 1976;13:354--9.
Chen H, Chiou S, Hsiao H, et al. Respiratory adenoviral infections in children: a study of hospitalized cases in southern Taiwan in 2001--2002. J Trop Pediatr 2002;50:279--84.
National Surveillance for Emerging Adenovirus Infections. Available at http://www.public-health.uiowa.edu/adv.
Russell KL, Hawksworth AW, Ryan MA, et al. Vaccine-preventable adenoviral respiratory illness in US military recruits, 1999--2004. Vaccine 2006;24:2835--42.
CDC. Guidelines for preventing health-care--associated pneumonia, 2003. Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR 2004;53(No. RR-3).

* Defined as 1) fever >100.5?F (>38.1?C) plus at least one other sign or symptom of respiratory illness or 2) diagnosis of pneumonia.

Figure

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Sally Furniss · Nov 15, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

Lethal Cold Germ Becomes More Common, U.S. Health Experts Say

http://www.bloomberg.com/apps/news?pid=20601202&sid=ahWfH__NHsic&refer=healthcare

By Elizabeth Lopatto
  Nov. 15 (Bloomberg) -- A cold germ turned deadly for 10 patients and sent dozens of others to the hospital, according to a U.S. health report that says infections with the severe virus strain are becoming more common.
The adenovirus, which usually causes mild cold symptoms, can cause severe lung disease in patients. The strain, called Ad14, sent fifty-three people to the hospital, including a 12- day-old infant, the Centers for Disease Control and Prevention said in its Morbidity and Mortality Weekly Report.
Controlling adenovirus outbreaks can be difficult because the germs are easily spread and can live for weeks on objects and surfaces, the agency said. These viruses aren't life- threatening to otherwise healthy adults, although newborn, elderly and patients with weakened immune systems can become seriously ill.
``Wider circulation of Ad14 might have occurred in recent years and might still be occurring,'' according to an editorial note accompanying the report.
Patients in New York, Oregon, Texas and Washington were identified as having the Ad14 strain, according to the report. The one case in New York resulted in the death of the 12-day-old infant in May 2006. In Oregon, 31 patients were identified with the virus; of these, six adults and one infant died from pneumonia. Those cases occurred between March and May this year.
Four cases were reported in a residential-care facility in Washington state. One patient, who already had AIDS, died. In Texas, 106 people at the Lackland Air Force Base were identified as carrying the virus, including 27 who were hospitalized. Five patients went to the intensive care unit, and one died.
No evidence exists that the outbreaks were related, the CDC said.
The Ad14 strain was first described in 1955, and caused respiratory disease in European military recruits. A number of antiviral drugs, including ribavirin, cidofovir and vidarabine, have been used to treat the illness. No drug has ``shown definitive efficacy against adenoviruses,'' the authors wrote.
To contact the reporter on this story: Elizabeth Lopatto in New York at elopatto@bloomberg.net .

HenryN · Nov 15, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

The level of recombination in these isolates is remarkable.

AlaskaDenise · Nov 15, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

niman said:
The level of recombination in these isolates is remarkable.

Are you saying there are a lot of changes, or that so much of those changes is due to recombination?

.

HenryN · Nov 15, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

AlaskaDenise said:
Are you saying there are a lot of changes, or that so much of those changes is due to recombination?

.

Adenovirus has OBVIOUS homologous recombination.

HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

AlaskaDenise said:
Are you saying there are a lot of changes, or that so much of those changes is due to recombination?

.

PCR analysis of egyptian respiratory adenovirus isolates, including identification of species, serotypes, and coinfections.

Metzgar D, Osuna M, Yingst S, Rakha M, Earhart K, Elyan D, Esmat H, Saad MD, Kajon A, Wu J, Gray GC, Ryan MA, Russell KL.
Naval Health Research Center, P.O. Box 85122, San Diego, CA 92186-5122, USA. metzgar@nhrc.navy.mil
Eighty-eight adenovirus (Ad) isolates and associated clinical data were collected from walk-in patients with influenza-like illness in Egypt during routine influenza surveillance from 1999 through 2002. Respiratory Ad distributions are geographically variable, and serotype prevalence has not been previously characterized in this region. Serotype identity is clinically relevant because it predicts vaccine efficacy and correlates strongly with both clinical presentation and epidemiological pattern. Species and serotype identities were determined using several well-validated multiplex PCR protocols culled from the literature and supplemented with a few novel primer sets designed to identify rare types. The isolates included common species B1 serotypes (Ad3 and Ad7), common species C serotypes (Ad1, Ad2, and Ad5), the less common species B2 serotype Ad11, and three isolates of the rare species B1 serotype Ad16. Two isolates that appear to be variant Ad16 were also identified. Fifteen coinfections of multiple adenoviral types, primarily AdB/AdC and Ad3/Ad7 dual infections, were detected. The majority of these were verified using redundant PCR tests targeted at multiple genes. PCR is able to resolve coinfections, in contrast to traditional serum neutralization tests. PCR is also comparatively rapid and requires very little equipment. Application of the method allowed an inclusive determination of the serotypes found in the Egyptian respiratory sample set and demonstrated that coinfections are common and may play a previously unrecognized role in adenovirus pathogenesis, evolution, and epidemiology. In particular, coinfections may influence adenoviral evolution, as interserotypic recombination has been identified as a source of emerging strains.

http://www.ncbi.nlm.nih.gov/sites/e...ez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

AlaskaDenise · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

Interesting that out of 88 cases, 15 had coinfections!

and...

.....coinfections are common and may play a previously unrecognized role in adenovirus pathogenesis, evolution, and epidemiology. In particular, coinfections may influence adenoviral evolution.....

.

HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

AlaskaDenise said:
Interesting that out of 88 cases, 15 had coinfections!

and...

.

Yes, recombination requires co-infections, which are common for adenovirus and influenza.

Recombination is the name of the game.

HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

[SIZE=-1]The Journal of Infectious Diseases 2007;196:1465-1473
This article is in the public domain, and no copyright is claimed.
0022-1899/2007/19610-0008[/SIZE]
<HR><TABLE cellPadding=5><TBODY><TR><TD align=middle bgColor=#990000>[FONT=helvetica, arial]MAJOR ARTICLE[/FONT]</TD></TR></TBODY></TABLE>

[SIZE=+2]Abrupt Emergence of Diverse Species B Adenoviruses at US Military Recruit Training Centers [/SIZE]

[FONT=helvetica, arial][SIZE=-1]David Metzgar,1 Miguel Osuna,1 Adriana E. Kajon,2 Anthony W. Hawksworth,1 Marina Irvine,1 and Kevin L. Russell1 [/SIZE][/FONT][FONT=helvetica, arial][SIZE=-1]1Respiratory Disease Laboratory, Department of Defense Center for Deployment Health Research, Naval Health Research Center, San Diego, California; 2Infectious Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico [/SIZE][/FONT]


<CENTER><TABLE cellSpacing=0 cellPadding=0 width="80%" border=0><TBODY><TR><TD>
Background. Adenoviruses (Ads) cause continuous outbreaks of acute respiratory disease (ARD) in US military training facilities. In 1996, the loss of vaccines targeting the dominant recruit-associated serotypes precipitated the reemergence of Ads in these populations. Between 1999 and 2002, serotype 4 accounted for >95% of Ads isolated from recruits and for >50% of ARD cases in training facilities (15,000 cases/year).
Methods. Ads (n = 1867) collected between 2002 and 2006 from recruits with ARD at 8 military training facilities in the United States were serotyped by serum neutralization and polymerase chain reaction. 
Results. The dominance of Ad4 continued through 2005, followed by a simultaneous emergence of diverse species B serotypes at the majority of sites. This included the subspecies B1 serotypes 3, 7, and 21 and the subspecies B2 serotype 14. Ad14 was the most prevalent species B serotype, appearing in high numbers at 3 sites and becoming dominant at 1. 
Conclusions. Subspecies B2 Ads have rarely been associated with ARD, and only in Eurasia. This survey represents the first report of AdB2-associated ARD in the Western Hemisphere. The simultaneous emergence of several species B Ads suggests a common external source (the civilian population) and a decrease in preexisting immunity to species B Ads. 

</TD></TR></TBODY></TABLE></CENTER><HR>
[SIZE=-1] Received 17 April 2007; accepted 11 May 2007; electronically published 31 October 2007.[/SIZE] 
[SIZE=-1] Potential conflicts of interest: none reported. 
Financial support: Department of Defense Global Emerging Infections Surveillance and Response System under research work unit 60701 (Naval Health Research Center report 07-12). 
The views expressed in this work are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of the Army, the Department of Defense, or the US government. [/SIZE]
[SIZE=-1] (See the editorial commentary by Binn et al., on pages 1436?7.) [/SIZE]
[SIZE=-1] Reprints or correspondence: Dr. David Metzgar, Naval Health Research Center, PO Box 85122, San Diego, CA 92186 (david.metzgar@med.navy.mil).[/SIZE]

<HR> Adenoviruses (Ads) were discovered in 1953 [1]. The diverse human pathogens in this family are categorized by hemagglutination into species A?F. They are further characterized by serum neutralization, and there are 51 currently recognized serotypes (Ad1?51) [2 http://www.journals.uchicago.edu/JID/journal/issues/v196n10/38728/38728.text.html#rf3?4]. Higher resolution is offered by whole-genome restriction enzyme analysis (genome typing) [5]. Ad genomes are stable and recombinations are rare, allowing inference of species and serotype from single-locus polymerase chain reaction (PCR) or sequence data [6 http://www.journals.uchicago.edu/JID/journal/issues/v196n10/38728/38728.text.html#rf7 http://www.journals.uchicago.edu/JID/journal/issues/v196n10/38728/38728.text.html#rf8?9]. 
Human Ads of species B (specifically, subspecies B1), C, and E are globally distributed pathogens responsible for outbreaks of respiratory disease and conjunctivitis [10, 11]. Species C Ads are ubiquitous and endemic and are primarily responsible for childhood illness. Healthy adults are more likely to suffer from respiratory disease caused by AdE and AdB1 [10], against which a larger proportion of adults lack protective antibodies [11, 12]. Subspecies B1 Ads, most commonly serotypes 3 and 7, cause recurring epidemics of febrile acute respiratory disease (ARD) in civilian populations, with symptoms ranging from influenza-like fever and discomfort to pneumonia and death [6, 10, 11]. These serotypes, along with the AdB1 serotype 21 and the AdE serotype 4, are also responsible for essentially continuous epidemics of ARD at military recruit training facilities worldwide [12 http://www.journals.uchicago.edu/JID/journal/issues/v196n10/38728/38728.text.html#rf13 http://www.journals.uchicago.edu/JID/journal/issues/v196n10/38728/38728.text.html#rf14?15]. Prevaccination data from US military training facilities showed that 20% of all trainees had to be removed from training for a week or more for recovery from Ad-associated illness, 40% became ill, and 80% were infected [16]. Current data, collected since the loss of the Ad4 and Ad7 vaccines previously used by the US military, reflect similar trends (6.4% removed from training, 25% ill, 98% of those initially seronegative seroconverted) [17]. US recruits suffer 22,000 cases of reported febrile ARD per year, 15,000 of which are associated with Ads [18]. Many more Ad infections go unreported in this population. Studies have shown that less than half of recruits with ARD seek medical care [17, 18]. 
Between 1971 and 1996, the United States used Ad4 and Ad7 vaccines to successfully control adenoviral illness in recruit populations, decreasing ARD by 50%?60% and decreasing Ad-associated ARD by >95% [11, 13, 18]. Other subspecies B1 Ads, including Ad3 and Ad21, appeared in vaccinated recruit populations, although they did not cause a return to prevaccination levels of ARD [14, 19, 20]. 
Subspecies B2 Ads are generally associated with sporadic diseases of the kidney and urinary tract [3]. The literature has, however, recorded occasional respiratory disease outbreaks associated with 2 AdB2 serotypes, Ad11 and Ad14 [21, 22]. 
The US military has conducted population-based ARD surveillance at 8 US training facilities since the loss of vaccine production in 1996, through the subsequent gradual reduction in vaccination between 1997 and 1999, and through the following period of no vaccination [13, 18, 20]. We present here data describing the serotype distributions at those facilities during the years 2002?2006. As part of ongoing population-based surveillance at these sites, 14,548 samples were collected and tested for Ad. The resulting numbers, paired with data on population size, were used to generate estimates of Ad-associated ARD rates. From the resulting set of cultured isolates, 1867 samples were randomly chosen and typed by either serotype-specific antibody neutralization (through March 2004) or serotype-specific PCR (beginning in April 2004; a PCR flow chart is shown in figure 1). The resulting serotype identifications were verified in a subset of cases by sequencing the primary antigenic determinant [8] and by genome typing [5]. 
<TABLE cellSpacing=10><TBODY><TR><TD vAlign=top align=middle>

[SIZE=-1](49 kB)[/SIZE]</TD><TD vAlign=top align=left>[FONT=arial,helvetica][SIZE=-1]Figure 1. [/SIZE][/FONT][FONT=arial,helvetica][SIZE=-1]Flow chart representing the series of polymerase chain reactions (PCRs) used to identify adenovirus (Ad) strains in this study. The PCR indicated by the asterisks discriminates the highly divergent genome types Ad4a and Ad4p on the basis of an amplicon length polymorphism (see table 1). ARD, acute respiratory disease.[/SIZE][/FONT]
</TD></TR></TBODY></TABLE>
To address the epidemiological consequences of serotype turnover events, rate data are presented for 1 site at which a particularly sharp serotype emergence occurred. Serotyping results are discussed in relation to both general Ad epidemiology and in relation to the current effort to reinstitute the Ad4 and Ad7 vaccines. 
[FONT=helvetica, arial][SIZE=+1]MATERIALS AND METHODS [/SIZE][/FONT]
ARD case definition and sample collection. Collaborators and Naval Health Research Center (NHRC) staff at each site monitor trainee populations for symptoms of febrile respiratory illness. A case of febrile respiratory illness is defined as occurring when a recruit presents for medical care and meets the following 2 criteria: fever with oral temperature

38?C (100.5?F) and a respiratory symptom (cough or sore throat). Clinical specimens are obtained as pharyngeal swabs in viral transport medium (Remel) from a subset of recruits who seek medical care. These samples are then sent on dry ice to the NHRC to be tested for respiratory pathogens. 
Origin of virus strains. Serotyping work was done on a collection of 1867 Ad strains isolated from the pharyngeal swabs of military trainees presenting with symptoms of ARD between 2002 and 2006 at 8 training sites in the Unites States: Fort Jackson, South Carolina; Fort Benning, Georgia; Fort Leonard Wood, Missouri (all Army); Naval Recruit Training Command, Great Lakes, Illinois; Lackland Air Force Base, San Antonio, Texas; Coast Guard Training Center, Cape May, New Jersey; Marine Corps Recruit Depot (MCRD) Parris Island, Parris Island, South Carolina; and MCRD San Diego, San Diego, California. Initial identifications were made in the College of American Pathologists?accredited NHRC diagnostic microbiology laboratory either by culture/immunofluorescence in A549 cell monolayers or by PCR. PCR identifications were followed by culture/immunofluorescence to verify the result and produce high-titer stocks for molecular serotype analysis. 
Serotype determination. The serotype identifications presented in this study were done using a microneutralization assay [23], PCR, or both. PCR primers, as well as the source of the primers and references to previous validations in the hands of the original authors, are shown in table 1. PCR methods have been used as a primary means of serotype identification since April 2004, when type-specific serum became increasingly difficult to obtain [6]. These methods have also been retrospectively applied to thousands of archived samples collected before 2003, which were initially serotyped by traditional neutralization (by both ourselves [6, 20, and unpublished data] and others [7, 9]) to validate the ability of PCR to predict serotype. All such validations have shown an exceptionally high level of correlation between different methods. 
<TABLE cellSpacing=10><TBODY><TR><TD vAlign=top align=middle>

</TD><TD vAlign=top align=left>[FONT=helvetica, arial][SIZE=-1]Table 1. [/SIZE][/FONT] [FONT=arial,helvetica][SIZE=-1]Primers.[/SIZE][/FONT]</TD></TR></TBODY></TABLE>
We performed a validation of PCR relative to serum neutralization by using PCR to reanalyze isolates previously serotyped by neutralization, including all serotypes that had been collected by the laboratory during the previous 5 years of recruit surveillance activity. Initially, PCR identifications of species B and E were made using the B/E portion of the A?F species multiplex [9], as described elsewhere [6]. Later, we developed the BCE multiplex (described below) in order to capture all respiratory species (B, C, and E) while simultaneously differentiating the 2 very distinct genome types of Ad4, 4a and 4p [24]. Both methods were validated using the same set of cultured clinical specimens, and both yielded identical results. Results are shown only for the BCE multiplex. A similar validation was performed for the published Ad3/Ad7/Ad21 serotype-specific multiplex [7] used in this study. The numbers of clinical isolates used in each validation, along with the resulting sensitivity and specificity measures, are shown in table 2. 
<TABLE cellSpacing=10><TBODY><TR><TD vAlign=top align=middle>

</TD><TD vAlign=top align=left>[FONT=helvetica, arial][SIZE=-1]Table 2. [/SIZE][/FONT] [FONT=arial,helvetica][SIZE=-1]Performance of polymerase chain reaction (PCR)?based adenovirus (Ad) identification, species typing, and serotyping with respect to culture/immunofluorescence and serum neutralization.[/SIZE][/FONT]</TD></TR></TBODY></TABLE>
The primers used to test for Ad11 and Ad14 [6] were developed in-house using all available sequence data and tested for sensitivity against appropriate control strains from the American Type Culture Collection. These serotypes had never been seen before in US recruit ARD surveillance; therefore, clinical samples previously identified as Ad11 or Ad14 were unavailable for validation. Positive identifications made using these primers were verified by secondary analysis of a subset of samples, including 1 each from San Diego, Great Lakes, and Fort Benning, by sequencing hypervariable region (HVR) 7 of the hexon gene [8]. BLAST analysis [25] of these sequences by means of GenBank allowed sequence-based assignment of serotype. The analyzed gene includes the primary serotype determinants and, hence, offers the most direct opportunity for molecular inference of serotype [8]. 
All PCRs were subjected to specificity tests against control samples of a wide variety of respiratory pathogens, commensals, and environmentally common bacteria (40 bacteria and 50 viruses), including several serotypes of Ad. No cross-reactions were detected (data not shown). Specificity testing also included a large number of culture-negative patient specimens, as indicated in table 2. 
Secondary verification of the serotype of all Ad3, Ad7, Ad14, and Ad21 isolates and >100 Ad4 isolates was performed at the Lovelace Respiratory Research Institute by traditional whole-genome restriction enzyme analysis with BamHI (genome typing) [24]. 
PCR. PCRs were done as shown in the flow chart (figure 1). Both monoplex and multiplex PCRs were formulated as described elsewhere [6], under essentially standard conditions with the addition of the solvent betaine (Q-Solution; Qiagen). The only exception to the previously described conditions was for the BCE multiplex, which used 0.1

mol/L concentration of each primer instead of 0.2

mol/L. 
Cycling conditions included a 10-min final extension at 72?C and a final hold at 4?C. Regarding other parameters, reactions were cycled as shown in table 3. 
<TABLE cellSpacing=10><TBODY><TR><TD vAlign=top align=middle>

</TD><TD vAlign=top align=left>[FONT=helvetica, arial][SIZE=-1]Table 3. [/SIZE][/FONT] [FONT=arial,helvetica][SIZE=-1]Polymerase chain reaction (PCR) conditions.[/SIZE][/FONT]</TD></TR></TBODY></TABLE>
All products were analyzed by standard agarose gel electrophoresis and ethidium bromide/UV visualization, as described elsewhere [6]. 
Development of a new PCR test for respiratory Ads. The novel BCE PCR test used in the present work was developed to target the relevant species (B, C, and E) by use of a gene (E1A) that is very well conserved within species but that is highly divergent between species while simultaneously discriminating between the 2 primary genome types of species E, Ad4a and Ad4p. Discrimination of Ad4a and Ad4p is based on a 30-bp insertion/deletion mutation in the E1A gene. This PCR was briefly described in an earlier work [24], in which it was used to confirm the results of another test. 
Sequence analysis of hexon genes. Fragments of 599 bp spanning HVR7 of the hexon gene of Ad14 were amplified and sequenced using the primers HVR7f (5

-GTCTTATGTACTATAACAGTACTGG-3

) and HVR7r (5

-GTGGTTGAATGGGTTGAC-3

). Amplification reactions contained 1.5 mmol/L MgCl2, 1 U of iProof Taq polymerase (Bio-Rad Laboratories), 200

mol/L dNTP, 1? iProof high-fidelity buffer, and 1

mol/L each primer in a total volume of 50

L. Cycling conditions consisted of denaturation for 30 s at 94?C followed by 50 cycles of 30 s at 94?C, 45 s at 51?C, and 45 s at 72?C. A final extension for 5 min at 72?C was added. Amplicons were purified with Montage PCR columns and Micropure-EZ columns (Millipore). Sequencing reactions used the same primers and standard conditions. Sequencing services were contracted from the DNA Research Services of the University of New Mexico Health Sciences Center. 
Sequence data analysis was done using SeqMan software for contig assembly and MegAlign software for sequence alignments (Lasergene 7.0.0; DNAStar). Ad14 hexon sequences were deposited in GenBank under accession numbers EF503568, EF503569, and EF503570. 
Ethics. This research has been conducted in compliance with all applicable federal and international regulations governing the protection of human subjects in research (Department of Defense protocol NHRC.2005.0017). 
[FONT=helvetica, arial][SIZE=+1]RESULTS [/SIZE][/FONT]
Serotype data are shown in figure 2. Ad4 (species E) was identified in >95% of recruit ARD samples collected from 2002 through 2005, following the trend seen in the preceding surveillance period [20]. Ad3, Ad7, and Ad21 (all subspecies B1) were occasionally seen during this time period, as were 3 scattered cases of species C Ads. Ad3 cases were concentrated at San Diego and Fort Benning in 2004. Ad7 cases were clustered at Great Lakes in 2004, and Ad21 was primarily identified at Parris Island in 2005. 
<TABLE cellSpacing=10><TBODY><TR><TD vAlign=top align=middle>

[SIZE=-1](120 kB)[/SIZE]</TD><TD vAlign=top align=left>[FONT=arial,helvetica][SIZE=-1]Figure 2. [/SIZE][/FONT][FONT=arial,helvetica][SIZE=-1]Serotype identification of 1867 adenovirus (Ad) isolates from military recruits at 8 US training centers, 2002?2006. Each block represents 1 sample from a recruit with febrile acute respiratory disease. Split blocks represent coinfections with 2 serotypes. The sample to the right of the asterisk was a triple infection with Ad4, Ad7, and Ad14. The decrease in sampling density at Lackland after 2004 resulted from a decrease in trainee density that essentially ended Ad outbreaks at that site. Otherwise, changes in sample volume are not representative of changes in disease rate but rather of changes in sampling effort. The relative proportions of different serotypes are representative of the relative frequency of isolation: Ad-positive samples were chosen randomly for serotyping. Results before April 2004 are from traditional serum neutralization; later results are from type-specific polymerase chain reaction.[/SIZE][/FONT]
</TD></TR></TBODY></TABLE>
In March and April of 2006, Ad14 (subspecies B2) simultaneously emerged at 5 training centers, including San Diego, Lackland, Fort Leonard Wood, Great Lakes, and Fort Benning, thereby affecting all services except the Coast Guard (Cape May). At 3 of these centers, Ad14 first appeared in coinfections with AdB1 serotypes and in 1 case as part of a triple infection with Ad4 and Ad7. Ad14 maintained a consistent presence at Fort Benning, San Diego, and Great Lakes during summer 2006. At the same time, a variety of AdB1 serotypes emerged at all sites except Cape May. Ad3 cases were clustered at Fort Jackson, Ad7 at Fort Leonard Wood and Parris Island, and Ad21 at Parris Island and Fort Benning. All 6 identified serotypes were seen at Fort Benning during one 2-month period. Many coinfections were identified, the majority of which were coinfections with Ad4 and one of the species B serotypes. 
All whole-genome BamHI restriction patterns (genome types) were concordant with PCR-inferred serotypes (or subspecies type, in the case of many of the AdB serotypes?BamHI patterns can readily distinguish B1 from B2 subspecies, but many serotype determinations require analysis with additional enzymes). Likewise, all identifications based on hexon sequencing were concordant with the original PCR-inferred identifications. ARD rates at MCRD San Diego, the site with the most complete turnover between Ad4 and Ad14 (i.e., between species E and subspecies B2), did not shift noticeably during the most distinct period of Ad14 dominance (figure 3). Note that the general increase in the isolation rate over time is not a function of increased disease burden but rather of increased sampling effort. 
<TABLE cellSpacing=10><TBODY><TR><TD vAlign=top align=middle>

[SIZE=-1](51 kB)[/SIZE]</TD><TD vAlign=top align=left>[FONT=arial,helvetica][SIZE=-1]Figure 3. [/SIZE][/FONT][FONT=arial,helvetica][SIZE=-1]Acute respiratory disease (ARD) rate at the Marine Corps Recruit Depot (MCRD) San Diego, 2002?2006. The red line indicates the approximate time at which adenovirus (Ad) 14 emerged as a significant contributor to the Ad burden at this site. The figure suggests that the emergence of Ad14 did not cause a greatly increased level of ARD but rather that Ad14 partially replaced Ad4 as a causative agent, with little impact on the overall rate of ARD.[/SIZE][/FONT]
</TD></TR></TBODY></TABLE>
[FONT=helvetica, arial][SIZE=+1]DISCUSSION [/SIZE][/FONT]
All AdB1 serotypes previously seen in recruit training centers in the United States (Ad3, Ad7, and Ad21) have simultaneously reemerged against the background of Ad4 (figure 2). For the first time, an AdB2 serotype (Ad14) has emerged as a significant contributor to ARD in the Western Hemisphere. The simultaneous emergence of many serotypes has been broadly spread across many geographically isolated facilities, although Ad4 remains common at all sites. Population-based ARD rate data do not suggest that the emergence and subsequent dominance of Ad14 at San Diego in early 2006 had any effect on the overall rate of ARD (figure 3). 
Soon after the original identification of Ads as agents of adult ARD in the 1950s [16], 4 scattered ARD outbreaks associated with the AdB2 serotype 14 were reported in military and civilian adult populations. Ad14 was initially discovered in an outbreak of ARD in Dutch recruits in 1955 [21]. Civilian outbreaks were reported in Great Britain in 1955 [26], in Uzbekistan in 1962 [27], and in Czechoslovakia in 1963 (the only sustained outbreak of Ad14 ever previously recorded) [28]. An apparent Ad11/Ad14 intermediate strain (denominated Ad14?11) was isolated after a large outbreak during a military training exercise in Spain in 1969 [29]. In general, AdB2 serotypes are more commonly associated with sporadic illness, most often kidney and urinary tract infections [3, 6]. 
Although both military and civilian surveys of Ad-associated ARD have commonly included assays capable of detecting and identifying Ad14 [30, 31], this serotype was not reported in large outbreaks of ARD between the 1960s and the turn of the century. Such surveys reported, for example, no Ad14 at all (0 of 1792 Ad isolates from children with respiratory illness in the United States) [30] or very little (<1% of AdB serotypes other than Ad3 or Ad7 among 3313 Ad isolates from children and adults with respiratory illness in the United Kingdom) [31]. 
A few recent studies yielded greater numbers of AdB2 identifications. A survey of adults and children with ARD in Egypt yielded a surprising proportion of Ad11 (4% of isolated Ads) [6], and recent studies in Taiwan yielded similar proportions of Ad14 (2%?11% of isolates) [32, 33]. Ad11 was recently identified in 2 German military troops returning from an exercise in Turkey [22]. The affected troops had severe ARD symptoms and were strictly quarantined while the agent was identified. The exercise itself was subject to a widespread outbreak of ARD, which may well have been associated with the identified strain of Ad11. 
These data point to a recent emergence of AdB2 serotypes as agents of ARD in healthy adults and children in Eurasia. This is similar to the current emergence of AdB2 in US military recruits, as described here. However, given that the serotypes involved are diverse, it seems unlikely that the simultaneous emergence of AdB2 serotypes as respiratory pathogens in multiple continents is resulting from the spread of recently evolved and adaptively superior strains. 
The temporal distribution of Ads causing ARD in recruits can be highly varied. Sometimes single serotypes will dominate in a specific region, being very sharply replaced by other serotypes at intervals of a few years (see van der Veen et al. [34], for example). Sometimes 2 or 3 types will share dominance in specific outbreaks; this is commonly seen with Ad3 and Ad7 (see Ryan et al. [15], for example). Before the institution of vaccination protocols, subspecies B1 (Ad3 and/or Ad7) and species E (Ad4) were often seen in significant numbers in the same year at the same site in US recruit facilities [35], and many vaccinated recruits with Ad-associated ARD were found to harbor species E and B serotypes simultaneously [36]. However, since the gradual withdrawal of vaccination measures in the United States between 1996 and 1999, Ad4 has dominated recruit training facilities. Ad4 has been associated with >98% of Ad-associated ARD cases from 1999 through 2005 ([20] and figure 2), and AdE/AdB coinfections have been rare ([36] and figure 2). The data presented here, which show many AdE/AdB coinfections associated with the general AdB reemergence in 2006, suggest that coinfections are the result of cocirculation and that neither coinfection nor cocirculation is directly related to vaccination status. 
Coinfections are shown as split boxes in figure 2. Coinfections are important because they provide the opportunity for Ad strains to recombine and form new variants [6, 36]. Strains responsible for recent outbreak waves, including Ad7h and the genome type of Ad4 that has dominated most of the recruit training facilities for the last 10 years (Ad4a) [24], appear to be interserotypic recombinants [37, 38]. Coinfections with multiple Ads have only recently been recognized, owing to the advent of PCR typing [36]. Immunological methods such as neutralization are often done with low challenge doses (

100 TCID50) using single antisera and, as such, are unlikely to identify mixtures of multiple serotypes. 
Ad4 is ubiquitous in the recruits' physical environment, and transmission appears to be independent of regular import from outside sources to training centers [17]. During the past 10 years of high Ad4 prevalence, different genome types have predominated at different sites, with a pattern of circulation that suggests that Ad4 population dynamics are driven by internal, possibly environmental, reservoirs [24]. The data presented here suggest different dynamics for AdB serotypes. The emergence of Ad14, Ad21, and Ad7 at multiple sites, all in the course of 1 year and following a decade during which these types had little or no impact at all, suggests that these emergences are driven by importation from shared outside reservoirs. This reservoir is most likely the US civilian population, from which the affected trainees are recruited. 
Dozens of publications from around the world during the last 40 years have documented the consistent circulation and clinical importance of Ad3, Ad7, and Ad21 in civilian populations. US recruit camps process tens of thousands of recruits from all parts of the United States every year. It would seem reasonable to assume that the influx of so many people from so many places would generate a constant influx of these common strains to the camps. It is therefore a mystery why all of the AdB1 serotypes that have ever been implicated in major ARD outbreaks in US recruits suddenly reemerged during the same year along with a previously rare AdB2 serotype. 
We hypothesize that the main factor determining the variable presence of AdB serotypes among recruits is preexisting immunity in the recruit source population. In 1993, seropositivity for Ad7 among incoming recruits was estimated at 27% [39]. A study from the postvaccination era, when Ad4 was dominant, estimated incoming recruit seropositivity for Ad7 at 61% [17]. The same 2 studies reported a relatively constant level of incoming seropositivity for Ad4 (29% and 34%, respectively). Unfortunately, comparable data from 2006 or from prevaccination periods of greater Ad diversity are not available. We hope that future work can address seropositivity on a more regular basis, because changes in source-population susceptibility may well predict the relative activity of different Ad serotypes in recruit facilities. 
The previously deployed Ad4 and Ad7 vaccines, essentially identical to those currently in testing for future redeployment, do not directly target some of the currently circulating Ad serotypes. During previous periods of vaccination, Ad3 and Ad21 did continue to circulate among recruits, yet they never caused a return to prevaccination levels of disease. In fact, the vaccines appeared to prevent >95% of Ad-associated ARD and >50% of total recruit ARD despite the presence of these heterotypic Ads [18]. In studies using serum obtained from military recruits vaccinated with the Ad4 and Ad7 vaccines, Ad7 immunization was shown to generate a significant increase in levels of neutralizing antibodies against Ad3 and Ad14 [40]. The cross-protective interaction between Ad7 and Ad14 may be reflected in the data presented here (figure 2): Ad7 and Ad14 are almost exclusively clustered at different sites. It will be important to track the response of different serotypes if and when the vaccines are redeployed. It would certainly be possible to develop vaccines against other ARD-associated Ads in the advent that currently circulating strains of Ad3, Ad14, or Ad21 are found to cause high rates of disease after reinstitution of the Ad4 and Ad7 vaccines, although previous evidence suggested that the addition of Ad21 to the Ad4/Ad7 combination decreased the effectiveness of all 3 [41]. 
[FONT=helvetica, arial]Acknowledgments [/FONT]
We thank Dr. Leonard Binn for suggesting critical historical references. We acknowledge the administrative support of the Henry M. Jackson Foundation for Military Medicine and the efforts of the entire Naval Health Research Center team, especially the technicians and collection personnel whose efforts are represented in this work. We also acknowledge the clinic commanders and medical staff at Fort Benning, GA; Fort Jackson, SC; Fort Leonard Wood, MO (US Army); Lackland Air Force Base, San Antonio, TX (US Air Force); Naval Training Center, Great Lakes, IL (US Navy); Marine Corps Recruit Depot, San Diego, CA; Marine Corps Recruit Depot, Parris Island, SC (US Marine Corps); and Coast Guard Training Center, Cape May, NJ (US Coast Guard) for the permissions, access, and assistance necessary to conduct these studies. 
<TABLE cellSpacing=0 cellPadding=0>[FONT=helvetica, arial]References [/FONT]
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HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

[SIZE=-1]The Journal of Infectious Diseases 2007;196:1436-1437
This article is in the public domain, and no copyright is claimed.
0022-1899/2007/19610-0003$15.00[/SIZE]
<HR><TABLE cellPadding=5><TBODY><TR><TD align=middle bgColor=#990000>[FONT=helvetica, arial]EDITORIAL COMMENTARY[/FONT]</TD></TR></TBODY></TABLE>

[SIZE=+2]Emergence of Adenovirus Type 14 in US Military Recruits?A New Challenge [/SIZE]

[FONT=helvetica, arial][SIZE=-1]Leonard N. Binn,1 Jose L. Sanchez,2 and Joel C. Gaydos2 [/SIZE][/FONT][FONT=helvetica, arial][SIZE=-1]1Division of Viral Diseases, Walter Reed Army Institute of Research, and 2Department of Defense Global Emerging Infections Surveillance and Response System, Silver Spring, Maryland [/SIZE][/FONT]



[SIZE=-1] Received 4 June 2007; accepted 4 June 2007; electronically published 31 October 2007.[/SIZE] 
[SIZE=-1] Potential conflicts of interest: none reported. 
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the true views of the Department of the Army or the Department of Defense. [/SIZE]
[SIZE=-1] (See the article by Metzgar et al., on pages 1465?73.) [/SIZE]
[SIZE=-1] Reprints or correspondence: Dr. Leonard N. Binn, Div. of Viral Diseases, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910 (leonard.binn@na.amedd.army.mil).[/SIZE]

<HR> In this issue of the Journal, Metzgar et al. [1] report a significant addition to the adenovirus (Ad) types infecting US military recruits with acute respiratory disease (ARD). Their ongoing epidemiological studies, which use rapid molecular diagnostic procedures, enabled the detection and identification of a species B2 Ad, type 14 (Ad14), that had not been previously observed in US military recruits. This virus was originally recovered >50 years ago from Dutch recruits [2], with only 2 subsequent reports of ARD associated with Ad14 [1, 3]. In contrast to the B1 Ads (i.e., types 3, 7, and 21) that often infect the respiratory tract, Ad14 respiratory infections have been very rarely observed in adult military and civilian populations [4]. 
At present, studies are under way at military training centers to field test replacements for the live oral Ad4 and Ad7 vaccines that had been used for >25 years but were lost when production ceased in the 1990s [5 http://www.journals.uchicago.edu/JID/journal/issues/v196n10/38935/38935.text.html#rf6?7]. The recent recovery of Ad14 raises new questions as to whether Ad14 will take hold as a respiratory disease agent in civilian and military populations and whether the candidate Ad4 and Ad7 vaccines will protect against Ad14. The absence of identified Ad14 respiratory infections in the United States suggests that we have highly susceptible civilian and military populations. 
Review of past experience with the live oral Ad vaccines may be of value in assessing the long-term threat of Ad14 to recruits. Previous observation of responses to the Ad4 and Ad7 vaccines indicated that they were highly effective against homologous viruses and Ad3 [6, 7]. Vaccines responses to Ad3 were attributed to some level of Ad3 occurring naturally and to Ad3 being antigenically related to Ad7, both being species B1 viruses. Therefore, after exposure to the Ad7 vaccine virus, heterotypic responses to Ad3 occurred [8]. In contrast to Ad3, naturally occurring background infections with Ad21, also a species B1 virus, have been considered rare. Recent studies of recruits with ARD found only small numbers infected with Ad21 [1]. Only a few additional Ad21 infections were identified via antibody testing, suggesting that the virus currently is not highly communicable [9, 10]. However, in 1975?1976, Ad21 was recovered from large numbers of recruits with ARD who had been vaccinated against Ad4 and Ad7. ARD-associated Ad21 infections continued for months at most training facilities, resulting in the testing of an experimental live oral vaccine [11, 12]. However, long-term observation revealed that Ad21 did not persist as a significant cause of ARD, even though outbreaks occurred in the 1970s and again in 1985 [13]. Thus, there has been no interest in renewing studies of an Ad21 vaccine. 
It is possible that Ad14 and other Ads could cause significant ARD morbidity among military recruits for a limited period and then disappear as an important cause of respiratory disease. It is also possible that some protection against emerging Ads could be provided as a result of heterotypic antibody responses to other viruses, including the Ad7 vaccine virus. Past studies in The Netherlands found that Ad14-associated ARD did not persist in their recruits [2, 14]. Additionally, the development of heterotypic antibody to Ad14 after Ad7 immunization was reported in 1960 [15]. 
Contemporary serologic surveys of new US military recruits will provide important information on their susceptibility. Testing archival serum-bank specimens from recruits vaccinated against Ad4 and Ad7 and from recruits with ARD who had laboratory confirmation of a specific Ad type could provide data on the occurrence of heterotypic antibody responses to Ad14. Additionally, measurement of Ad14-associated ARD during the current Ad4 and Ad7 vaccine trials will be important, as will measurement of immunity to Ad14 associated with immunization. Molecular studies should be conducted to characterize recovered Ad14 isolates and to determine whether changes may have occurred in the genome that could affect communicability and pathogenicity, a situation that was described in Spanish recruits in 1976 [16]. 
The events described by Metzgar et al. provide strong support for ongoing, laboratory-based surveillance in military training populations. Because little is known about the dynamics involved in the emergence of important acute febrile respiratory disease pathogens in military populations, studies describing agent persistence and transmission within military communities and surveillance of associated civilian communities should be continued. Whether Ad14 will persist as a significant cause of ARD in recruits cannot be predicted. Therefore, it is advisable to preserve candidate specimens of Ad14 for passage in suitable cells for vaccine seed virus and molecular studies. 
After the licensure of the Ad4 and Ad7 vaccines currently being tested, complacency regarding the control of acute febrile respiratory diseases in military populations cannot occur. Continued surveillance will be necessary to assess the effectiveness of the new vaccines and to detect the presence of emergent Ads, influenza viruses, and other respiratory agents that cause morbidity and interfere with military training. The application of the modern tools of molecular biology should greatly enhance our understanding of these agents and the dynamics of acute febrile respiratory diseases in the unique environment of military recruits undergoing their initial entry (i.e., basic) military training. 
<TABLE cellSpacing=0 cellPadding=0>[FONT=helvetica, arial]References [/FONT]
<TBODY><TR><TD vAlign=top align=right>1. </TD><TD vAlign=top align=left>Metzgar D, Osuna M, Kajon AE, Hawksworth AW, Irvine M, Russell KL. Abrupt emergence of diverse species B adenoviruses at US military recruit training centers. J Infect Dis 2007; 196:1465?73 (in this issue). First citation in article </TD></TR><TR><TD vAlign=top align=right>2. </TD><TD vAlign=top align=left>van der Veen J, Kok G. Isolation and typing of adenoviruses recovered from military recruits with acute respiratory disease in the Netherlands. Am J Hyg 1957; 65:119?29. First citation in article | PubMed </TD></TR><TR><TD vAlign=top align=right>3. </TD><TD vAlign=top align=left>Lin K-H, Lin Y-C, Chen H-L, et al. A two decade survey of respiratory adenovirus in Taiwan: the reemergence of adenoviruses types 7 and 4. J Med Virol 2004; 73:274?9. First citation in article | PubMed | CrossRef </TD></TR><TR><TD vAlign=top align=right>4. </TD><TD vAlign=top align=left>Hierholzer JC. Adenoviruses. In: Lennette EH, Lennette DA, Lennette ET, eds. Diagnostic procedures for viral, rickettsial, and chamydial infections. 7th ed. Washington, DC: American Public Health Association, 1995:169?88. First citation in article </TD></TR><TR><TD vAlign=top align=right>5. </TD><TD vAlign=top align=left>Lyons A, Longfield J, Kuschner R, et al. A double-blind, placebo controlled study to evaluate the safety and immunogenicity of the new, live, oral type 4 and type 7 adenovirus vaccines. In: Program and abstracts of the VIIIth International Symposium on Respiratory Virus Infections (Kohala Coast, Hawaii). 2006

-13. First citation in article </TD></TR><TR><TD vAlign=top align=right>6. </TD><TD vAlign=top align=left>Hilleman MR. Epidemiology and control by vaccination of adenovirus caused respiratory disease. Proceedings of the Sixth International Congress on Tropical Medicine and Malaria (Lisbon). Vol. 5. Lisbon: Instituto de Medicina Tropical, 1959:489?98. First citation in article </TD></TR><TR><TD vAlign=top align=right>7. </TD><TD vAlign=top align=left>Gaydos CA, Gaydos JC. Adenovirus vaccine. In: Plotkin SA, Orenstein WA, eds. Vaccines. 4th ed. Philadelphia: Saunders, 2004:863?85. First citation in article </TD></TR><TR><TD vAlign=top align=right>8. </TD><TD vAlign=top align=left>Grayston T, Loosli CG, Johnston PB, Smith ME, Woolridge RL. Neutralization and complement fixing antibody response to adenovirus infection. J Infect Dis 1956; 99:199?206. First citation in article | PubMed </TD></TR><TR><TD vAlign=top align=right>9. </TD><TD vAlign=top align=left>Kolavic-Gray SA, Binn LN, Sanchez JL, et al. Large epidemic of adenovirus type 4 infection among military trainees: epidemiological, clinical, and laboratory studies. Clin Infect Dis 2002; 35:808?18. First citation in article | PubMed </TD></TR><TR><TD vAlign=top align=right>10. </TD><TD vAlign=top align=left>Vento TJ, Houng H-S, Gaydos JC, Sun W, Kuschner R, Binn L. Adenovirus type 4 loads on throat and hand specimens from military basic trainees [abstract 343]. In: Program and abstracts of the 41st Annual Meeting of the Infectious Diseases Society of America (San Diego). Arlington, VA: Infectious Diseases Society of America, 2003. First citation in article </TD></TR><TR><TD vAlign=top align=right>11. </TD><TD vAlign=top align=left>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. First citation in article | PubMed </TD></TR><TR><TD vAlign=top align=right>12. </TD><TD vAlign=top align=left>Top FH Jr, Brandt WE, Russell PK. Adenovirus ARD in basic combat trainees. In: Research in biological and medical sciences: annual progress report, 1975/1976. Washington, DC: Walter Reed Army Institute of Research, 1976:462?5. First citation in article </TD></TR><TR><TD vAlign=top align=right>13. </TD><TD vAlign=top align=left>Gaydos CA, Gaydos JC. Adenovirus vaccines in the US military. Mil Med 1995; 160:300?4. First citation in article | PubMed </TD></TR><TR><TD vAlign=top align=right>14. </TD><TD vAlign=top align=left>van der Veen J, Oie KG, Abarbanel MFW. 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. First citation in article | PubMed </TD></TR><TR><TD vAlign=top align=right>15. </TD><TD vAlign=top align=left>van der Veen J, Prins A. Studies on the significance of the recall phenomenon in the antibody response to adenovirus vaccine and infection. J Immunol 1960; 84:562?8. First citation in article | PubMed </TD></TR><TR><TD vAlign=top align=right>16. </TD><TD vAlign=top align=left>Hierholzer JC, Pumarola A. Antigenic characterization of intermediate adenovirus 14-11 strains associated with upper respiratory illness in a military camp. Infect Immun 1976; 13:354?9. First citation in article | PubMed </TD></TR>

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HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

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Reports<SCRIPT language=JavaScript1.2></SCRIPT> </TD><TD vAlign=top align=right>

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gi|153861616|gb|EF503568|[153861616]
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HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

AlaskaDenise said:
Interesting that out of 88 cases, 15 had coinfections!

and...

.

The sample to the right of the asterisk was a triple infection with Ad4, Ad7, and Ad14.

HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

AlaskaDenise said:
Interesting that out of 88 cases, 15 had coinfections!

and...

.

In March and April of 2006, Ad14 (subspecies B2) simultaneously emerged at 5 training centers, including San Diego, Lackland, Fort Leonard Wood, Great Lakes, and Fort Benning, thereby affecting all services except the Coast Guard (Cape May). At 3 of these centers, Ad14 first appeared in coinfections with AdB1 serotypes and in 1 case as part of a triple infection with Ad4 and Ad7. Ad14 maintained a consistent presence at Fort Benning, San Diego, and Great Lakes during summer 2006. At the same time, a variety of AdB1 serotypes emerged at all sites except Cape May. Ad3 cases were clustered at Fort Jackson, Ad7 at Fort Leonard Wood and Parris Island, and Ad21 at Parris Island and Fort Benning. All 6 identified serotypes were seen at Fort Benning during one 2-month period. Many coinfections were identified, the majority of which were coinfections with Ad4 and one of the species B serotypes.

HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

AlaskaDenise said:
Interesting that out of 88 cases, 15 had coinfections!

and...

.

Coinfections are important because they provide the opportunity for Ad strains to recombine and form new variants [6, 36]. Strains responsible for recent outbreak waves, including Ad7h and the genome type of Ad4 that has dominated most of the recruit training facilities for the last 10 years (Ad4a) [24], appear to be interserotypic recombinants [37, 38]. Coinfections with multiple Ads have only recently been recognized, owing to the advent of PCR typing [36].

HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

<TABLE style="MARGIN-BOTTOM: 8px" cellSpacing=0 cellPadding=0 width=450 border=0><TBODY><TR><TD class=listTitleLg>Molecular Epidemiology of Adenovirus Type 4 Infections in US Military Recruits in the Postvaccination Era (1997

2003)</TD></TR></TBODY></TABLE><TABLE cellSpacing=0 cellPadding=0 width=450 border=0><TBODY><TR><TD class=contentAuthor><AUTHOR><FNAME>Adriana E. </FNAME><SURNAME>Kajon</SURNAME></AUTHOR>, <AUTHOR><FNAME>Jennifer M. </FNAME><SURNAME>Moseley</SURNAME></AUTHOR>, <AUTHOR><FNAME>David </FNAME><SURNAME>Metzgar</SURNAME></AUTHOR>, <AUTHOR><FNAME>Huo-Shu </FNAME><SURNAME>Huong</SURNAME></AUTHOR>, <AUTHOR><FNAME>Aya </FNAME><SURNAME>Wadleigh</SURNAME></AUTHOR>, <AUTHOR><FNAME>Margaret A. K. </FNAME><SURNAME>Ryan</SURNAME></AUTHOR>, and <AUTHOR><FNAME>Kevin L. </FNAME><SURNAME>Russell</SURNAME></AUTHOR></TD></TR><TR><TD>
</TD></TR><TR><TD>Volume 196(2007), pages 67 - 75
DOI: 10.1086/518442</TD></TR></TBODY></TABLE>
<TABLE cellSpacing=0 cellPadding=0 border=0><TBODY><TR><TD>Abstract</TD></TR><TR><TD>Background. Military recruits are at a higher risk of respiratory infection than their civilian counterparts. Continuous outbreaks of adenovirus (Ad)

associated acute respiratory disease were documented among US trainees before the implementation of serotype 4 (Ad4) and serotype 7 vaccines in 1971. The discontinuation of Ad vaccination programs in 1999 precipitated the reemergence of Ad in training sites, with Ad4 accounting for 98% of all diagnosed cases.
Methods. A total of 724 Ad4 strains isolated from recruits presenting with febrile respiratory illness at 8 training sites nationwide between 1997 and 2003 were genome typed by restriction enzyme analysis.
Results. Seven genome types were identified, all of which were distinct from the prototype Ad4p and the vaccine type 4p1. Results showed very different, and often stable, genome type distributions at different geographic sites, despite the homogeneity of the recruit source population.
Conclusions. The data support the hypothesis that reservoirs for Ad outbreaks are within recruit training sites or in their immediate environments, not in the incoming recruit population. Molecular characterization beyond serotype is critical to understanding the transmission dynamics of Ad infection in these unique susceptible populations and to the implementation of effective prevention approaches.
</TD></TR></TBODY></TABLE>

JJackson · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

If the virus is not being imported by the new recruits but is latent in the base what is thought to be responsible more the disease in the recruits? Immunosuppression due to the stresses of basic training?

sharon sanders · Nov 16, 2007

Re: Adenovirus 14 Reported At Lackland

Re: Adenovirus 14 Reported At Lackland

All adenoviruses are contagious.

Standard sanitary precautions can help.

Hand Washing

Hand Washing Materials

Why should I wash my hands?

Washing your hands is one of the most important things you and your family can do to prevent illness.

Clean hands can help protect you from infectious and food-borne illnesses. If you get sick, it can keep you from passing your illness to others.

Hand washing protects your health by helping to remove dirt and germs that get on your hands during almost any activity.

If you don't wash your hands, the germs on your hands can get into your mouth, nose, eyes, cuts and scrapes, even your food, and make you sick.

But my hands look clean!

Even though your hands may look clean they can still have dirt and germs on them. Germs are too small to see with the human eye. They can only be seen through a microscope.

When should I wash my hands?

Wash your hands BEFORE:

[*]Eating
[*]Feeding Children, The Ill or Elderly
[*]Touching Foods - Especially Foods That Won't Be Cooked
[*]Cooking Food
[*]Touching or Bandaging a Cut or Scrape
[*]Inserting or Removing Contact Lenses
[*]Taking Care of a Sick Person

Wash your hands AFTER:

[*]Eating
[*]Working
[*]Playing
[*]Touching Animals
[*]Touching Foods - Especially Raw Meat, Poultry, Fish and Eggs
[*]Using The Bathroom or Helping Others in the Bathroom
[*]Changing Diapers
[*]Cleaning Up Animal Feces
[*]Coughing, Sneezing or Blowing Your Nose
[*]Taking Care of a Sick Person
[*]Touching Blood or Other Body Fluids
[*]Touching Cuts, Sores or Rashes
[*]Cleaning The House
[*]Handling Garbage

What is the right way to wash my hands?

Wash your hands with running water and soap for at least 15 seconds.

[*] The water should be running. Moving water helps remove dirt and germs. Standing water allows dirt and germs that were washed off to get back onto your hands.
[*] Your hands should be under the stream of water so the front and back, and as far up to your wrists as possible, get wet.
[*] The water should be comfortable to the touch. If the water is too hot, you can burn yourself. If it is too cold, the dirt and germs may not get washed off.

Get soap all over your hands

[*]
Include the fronts and backs of your hands and as far up your wrists as you can get.
[*]
You can use any kind of soap.

Take your hands out from under the water and rub your hands together to make a lather. Do this for at least 15 seconds.

The lather should cover the front and back of your hands and your wrists.

[*]
Work hard on the areas between the fingers and under the nails where the dirt hides.
[*]
You can use a sponge or cloth to help get the dirt off, but do not use the same cloth or sponge to wash more than one person's hands. Wash sponges or cloths regularly.

Rinse your hands.

[*]
The water should run back into the sink, not down your arms.

Dry your hands completely, using a clean towel.

[*]
Use paper towels or air dryers in places where there are a lot of people.

Also, since the virus can live for approximately 48 hours on surfaces, it is important to wipe down door knobs, toliet knobs, tv remotes, etc. with rubbing alcohol or other sterilizer.

http://lapublichealth.org/acd/HandWash.htm

HenryN · Nov 16, 2007

Re: CDC: New Respiratory Bug Has Killed 10

Re: CDC: New Respiratory Bug Has Killed 10

These data appear to be quite alarming.

For the general population, the case fatality rate is close to 25% for ad14!

For the recruits it is less than 1%, but the number of cases has skyrocketed in 2007, and monitoring of the general population is poor.

sharon sanders · Nov 16, 2007

Re: Adenovirus 14 - CDC: New Respiratory Bug Has Killed 10

Link to earlier thread on Ad 14 -

http://www.flutrackers.com/forum/showthread.php?t=26814

Adenovirus 14 - CDC: New Respiratory Bug Has Killed 10

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