Is It Influenza or Adenovirus?

Janis C. Kelly

February 02, 2018

Some cases of human adenovirus type 4 (HAdV-4) have been severe or even fatal, and researchers say the number of cases in patients with influenza-like illness (ILI) may be underestimated, according to a report published in the February issue of Emerging Infectious Diseases.

HAdV-4 causes acute respiratory disease (ARD); it occurs most commonly in military settings, but the virus has also been isolated from civilians.

"Surveillance studies conducted in the United States and other countries have demonstrated a leading role for this particular adenovirus type in the etiology of outbreaks of febrile respiratory illness in military recruit training facilities, where crowding and environmental contamination appear to facilitate transmission among nonvaccinated trainees," the authors explain.

The lack of a sentinel system for HAdV infection outside of the military makes assessment of the burden of HAdV-4 infection among civilians more difficult.

The study was conducted by Adriana E. Kajon, PhD, from the Infectious Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, and colleagues from the New York State Department of Health, Albany; the Centers for Disease Control and Prevention, Atlanta, Georgia; Yale University School of Medicine, New Haven, Connecticut; and the University of Rochester Medical Center, New York.

The researchers analyzed HAdV-4 isolates recovered from civilian adults including 27 college students, four residents of long-term care facilities or nursing homes, a patient in a cancer center, and otherwise healthy young adults with acute febrile respiratory disease during 2011 to 2015.

The specimens came from patients with ARD/ILI characterized by fever greater than 37.8°C and cough, sore throat, or other respiratory symptoms. The selected cases had either been identified by the New York State Department of Health as part of the US Sentinel Physician ILI Surveillance Network or had been referred to the Centers for Disease Control and Prevention for investigation as a result of disease severity or occurrence during an outbreak. The virus was isolated from respiratory specimens and typed at the Centers for Disease Control and Prevention or at the New York State Department of Health Virology Laboratory. Isolates identified as HAdV-4 were genotyped by restriction enzyme analysis, followed by next-generation genome sequencing of 12 isolates selected as representative of the set of identified variants. Genomic sequences were aligned with reference strains for phylogenetic analysis.

The variants most common in military settings, HAdV-4 genome types 4a1 and 4a2, were also the variants found in most of the civilian cases. However, two novel a-like variants were recovered from college students. The researchers also recovered a prototype-like variant from one patient, which raised concern about possible virus transmission from the vaccine strain given to US military recruits; however, whole-genome sequencing showed that this variant was different from the strain used in the vaccine.

Some Outcomes Serious or Fatal

The HAdV-4 infections were associated with serious and even fatal outcomes. Of 15 patients with ILI at a long-term care facility for the elderly, four had confirmed HAdV-4 infections, and three of the four died from complications of ARD. A case of severe pneumonia in one patient began with a 3-day illness involving severe headache, photophobia, nausea, vomiting, and chills that was unresponsive to azithromycin. The patient was hospitalized and treated with ceftriaxone and azithromycin but developed severe respiratory distress and required intubation and transfer to intensive care. He recovered with supportive therapy.

A 43-year-old patient with cough was prescribed levofloxacin for presumed pneumonia but required hospital admission 4 days later for worsening cough, shortness of breath, and rigors. She developed severe hypoxic hypercarbic respiratory failure requiring venous-venous extracorporeal mechanical oxygenation after unsuccessful treatment with several broad-spectrum antibiotics. The patient was treated with cidofovir but developed multiple complications including severe kidney injury, acute tubular necrosis, cerebral edema, intracranial hemorrhage, and persistent hypertension. After 40 days of mechanical ventilation, she was weaned from the ventilator and discharged to in-patient rehabilitation on hospital day 53. She continued to have bronchiectasis and dyspnea on exertion 1 year after discharge.

"Our data and reports of cases of severe ARD associated with HAdV-4 infection in Italy and Singapore suggest that the role of this HAdV type in the etiology of adult civilian ARD might have been underestimated in the absence of access to molecular (or other) typing resources," the authors write.

They recommend inclusion of HAdV in differential diagnostic test panels to assess the role of HAdVs in causing severe respiratory illness and to prevent unnecessary treatment of influenza-negative patients with anti-influenza agents.

"In addition, while the failure to detect influenza virus does not guarantee the virus was never present, the detection of HAdV in these cases assists in alleviating concerns regarding influenza vaccine failure," the researchers explain.

Vaccination with a live oral formulation of the nonattenuated p-like strain of HAdV-4 is used to prevent infection in military settings, and the authors suggest regulatory authorities also consider licensing the HAdV-4 vaccine for other susceptible populations living in closed communities, such as college settings, summer camps, and long-term care facilities.

The authors have disclosed no relevant financial relationships.

Emerg Infect Dis. 2018;24:201-209. Full text

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