Severe Coinfection with Seasonal Influenza A (H3N2) Virus and Staphylococcus aureus — Maryland, February–March 2012

On March 5, 2012, the Maryland Department of Health and Mental Hygiene (DHMH) and the Calvert County Health Department were notified of three deaths following respiratory illness among members of a Maryland family. One family member (patient A) experienced upper-respiratory symptoms and died unexpectedly at home. Two others (patients B and C) sought medical care for fever, shortness of breath, and cough productive of bloody sputum and died during their hospitalizations. All three family members had confirmed infection with seasonal influenza A (H3N2) virus. Patients B and C had confirmed coinfection with methicillin-resistant Staphylococcus aureus (MRSA), which manifested in both patients as MRSA pneumonia and bacteremia. DHMH and the Calvert County Health Department, in collaboration with the District of Columbia Department of Health, local hospitals, and CDC, conducted an investigation to determine the cause of the illnesses and identify additional related cases. Three additional family members with influenza were identified, two of whom were confirmed to have influenza A (H3N2) and required hospitalization, but neither was coinfected with MRSA, and both recovered. Influenza vaccination remains the best method for preventing complications from influenza; when influenza infection is suspected, treatment with influenza antiviral agents is recommended in certain cases. In addition, when high clinical suspicion for serious S. aureus coinfection exists, empiric coverage with antibiotics, including those with activity against methicillin-resistant strains, should be instituted.

Case Reports

Patient A experienced upper-respiratory illness at the end of February and died 4 days later at home. Patient A had not gone to the hospital or seen a clinician but did receive a prescription for levofloxacin 1 day before death. Patients B and C, both family members of patient A, went to a hospital 3 days after patient A's death, with fever, cough productive of bloody sputum, and pleuritic chest pain. Chest radiographs of both patients were notable for extensive bilateral infiltrates with focal areas of consolidation. Patient B was treated with ceftriaxone and azithromycin, and patient C was treated with ceftriaxone, ciprofloxacin, levofloxacin, and vancomycin. Their conditions quickly worsened, and they required intubation; both died the day after admission.

All three patients were aged >50 years, including one aged >65 years; one patient had a history of smoking, and one was a current smoker. Two had known multiple comorbidities, including one requiring chronic low-dose corticosteroids. Two of the three had been vaccinated against seasonal influenza.

Laboratory and Epidemiologic Investigations

Rapid influenza diagnostic testing (RIDT) was performed on a nasopharyngeal specimen from patient B only and was negative, but testing by reverse transcription–polymerase chain reaction (RT-PCR) from upper- and lower-respiratory tract specimens was positive in all three patients for influenza A (H3N2) virus. Testing of original samples at DHMH and CDC indicated that the virus was a typical human seasonal influenza A (H3N2) virus (not an H3N2 variant virus), similar to other influenza A (H3N2) viruses circulating in Maryland and nationally this season. Blood and sputum cultures from patients B and C yielded MRSA. Further testing demonstrated that the MRSA isolates were indistinguishable by pulsed-field gel electrophoresis and were identified as part of the USA300 pulsed-field type. None of the patients had a known history of skin or soft-tissue infections. Extensive testing of upper- and lower-respiratory specimens did not reveal any other infectious agents.

The family members all lived in a small town with a population of <2,000 persons. Patients A, B, and C had extensive and frequent contact with each other and with other members of their extended family, some of whom had experienced upper-respiratory illnesses during the weeks preceding the deaths. DHMH, the Calvert County Health Department, and the District of Columbia Department of Health investigated all reports of severe illnesses among persons known to be associated with the family. In early March, three additional family members (patients D, E, and F) were identified with influenza virus infection. Patient D had a positive RIDT result from an upper-respiratory tract specimen. Patients E and F had negative RIDT results; however, RT-PCR testing was positive for influenza A (H3N2) virus. Although patients E and F were hospitalized, neither they nor other family contacts had pneumonia or MRSA infection. One of the three had been vaccinated against seasonal influenza. Other family members who reported upper-respiratory illness either were not tested or had negative RIDT results, with some confirmed negative by RT-PCR.

Public Health Actions

In accordance with CDC guidelines, antiviral chemoprophylaxis was recommended for contacts at greater risk for serious influenza complications. No special recommendations for antiviral chemoprophylaxis or MRSA decolonization were made. Through press releases and other media statements disseminated in Maryland and the District of Columbia, residents were urged to practice hand hygiene and respiratory hygiene with cough etiquette, get vaccinated for seasonal influenza if they had not yet done so, and seek medical care in accordance with CDC guidance if ill with symptoms of influenza or pneumonia.* In addition, guidance on testing, treatment, and chemoprophylaxis was disseminated to health-care providers locally and throughout Maryland. No additional cases of severe influenza and S. aureus coinfection have been reported.

Reported by

Linda O'Brien, Calvert Memorial Hospital; Nancy Donegan, MPH, Washington Hospital Center; Ann Flaniken, David Rogers, MD, Calvert County Health Dept; Robert Myers, PhD, Jafar Razeq, PhD, Ruth Thompson, Maryland Dept of Health and Mental Hygiene. Seema Jain, MD, Stephen Lindstrom, PhD, Influenza Div, National Center for Immunizations and Respiratory Diseases; Alexander Kallen, MD, Div of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Diseases; Maria A. Said, MD, Adena Greenbaum, MD, Tiana Garrett, PhD, EIS officers, CDC. Corresponding contributor: Maria A. Said, [email protected], 410-767-7395.

Editorial Note

Bacterial coinfection with S. aureus is a known complication of influenza that has been described since the 1918 influenza pandemic (1). These infections can be caused by methicillin-susceptible and methicillin-resistant strains. Although these reported cases occurred in three older persons, two of whom had comorbidities, coinfection with S. aureus can occur among otherwise healthy children and adults and has been associated with high mortality rates (2,3). This familial cluster of invasive MRSA with influenza highlights the potentially serious consequences of these coinfections.

Patients described in this report had severe, rapidly progressive, respiratory disease with bloody sputum. The rapid worsening of symptoms soon after illness onset and the subsequent severe outcomes are consistent with simultaneous coinfection with influenza and MRSA rather than a biphasic infection course (i.e., influenza infection followed by S. aureus infection); simultaneous coinfection has been reported previously (4). Health-care providers should consider the possibility of influenza and S. aureus coinfection, particularly among patients with severe or rapidly worsening disease or with imaging indicative of cavitary or necrotizing pneumonia; this recommendation applies especially when influenza is known to be circulating in the community† (5). Empiric treatment for both organisms should be considered for patients with these features (5).

Data from 2001–2004 indicated that approximately 25%–35% of children and adults are colonized with S. aureus, but only 1.5% are colonized with MRSA (6). MRSA can cause disease in the community among patients with and without health-care exposures, although community-associated MRSA accounts for only 18% of invasive MRSA infections (7). Community-associated MRSA most commonly produces skin and soft-tissue infections, which often are caused by USA300 (8). These strains present a treatment challenge because they are resistant to beta-lactam antibiotics, which are commonly used to treat outpatient infections. Among families in which someone is known to be infected with MRSA, the infected person should keep wounds clean and covered, and other household members who have direct contact with that person should employ frequent hand hygiene and not share personal items (e.g., towels or razors). Whereas decolonization of colonized persons is sometimes considered in specific circumstances (e.g., cases of recurrent MRSA-related skin infections), its role in preventing S. aureus pneumonia is unknown (5). Additional information regarding MRSA prevention and treatment is available§ (5).

For optimal patient management, health-care providers should test persons hospitalized with respiratory illness for influenza, including those with suspected community-acquired pneumonia, especially when influenza is known to be circulating. Testing by PCR is preferred when available because it is more sensitive than rapid antigen tests that can yield false-negative results (9). Specimens that can be tested for influenza virus include nasopharyngeal or throat swabs, nasal or endotracheal aspirates, nasopharyngeal or bronchial washes, or sputum specimens. When influenza is suspected, droplet precautions should be practiced (10).

Advisory Committee for Immunization Practices guidelines recommend oseltamivir or zanamivir to treat 1) hospitalized patients with suspected or confirmed influenza, 2) outpatients who are at greater risk for influenza complications, and 3) persons with suspected or confirmed influenza who have evidence of severe illness (e.g., signs or symptoms of lower-respiratory tract infection or clinical deterioration), regardless of vaccination status (9). Empiric influenza antiviral treatment should be provided to such patients even if test results are not available immediately or if patients are not tested. Although benefits of antiviral treatment are likely to be greatest if treatment is initiated as soon as possible, treatment of hospitalized patients is recommended even >48 hours after illness onset. Approximately 99% of circulating seasonal strains of influenza A (H3N2), A (H1N1), and B viruses that were tested by CDC during October 1, 2011–April 7, 2012 were sensitive to oseltamivir and zanamivir. Postexposure chemoprophylaxis for influenza might be considered on the basis of the exposed person's risk for influenza complications, the type and duration of contact, recommendations from public health authorities, and clinical judgment (9). Postexposure chemoprophylaxis should be started ≤48 hours after the most recent exposure (9).

The cases in this report are a reminder that influenza and S. aureus coinfections, although uncommon, can lead to severe outcomes, including death. Although influenza vaccine is not 100% effective, influenza vaccination remains the best method for preventing influenza and its complications and should be encouraged for all persons aged ≥6 months. In addition to treatment with influenza antiviral agents, antibiotics should be considered when clinical suspicion for bacterial coinfection exists in an effort to reduce severe outcomes.

Acknowledgments

Jennifer Cotner, Calvert Memorial Hospital; Babs Buchheister, Christina Halt, Dan Williams, Calvert County Health Dept; Brian Bachaus, MS, Naomi Barker, MS, David Blythe, MD, Alvina Chu, MHS, Zachary Faigen, MSPH, Katherine Feldman, DVM, Damini Jain, MS, Jonathan Johnston, MD, Emily Luckman, MPH, Maya Monroe, MPH, Rene Najera, MPH, Dale Rohn, MPH, John Sweitzer, ScM, Lucy Wilson, MD, Maryland Dept of Health and Mental Hygiene. Infection Control Dept, Washington Hospital Center; John Davies-Cole, PhD, Gabrielle Ray, MPH, District of Columbia Dept of Health. Lyn Finelli, DrPH, Tim Uyeki, MD, Alexander Klimov, PhD, Lashondra Berman, MS, Bo Shu, MD, Influenza Div, National Center for Immunization and Respiratory Diseases; Valerie Albrecht, MPH, Linda McDougal, MS, Div of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Diseases, CDC.

References

1. Chickering HT, Park JH. Staphylococcus aureus pneumonia. JAMA 1919;72:617–26.
2. Hageman JC, Uyeki TM, Frances JS, et al. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003–04 influenza season. Emerg Infect Dis 2006;12:894–9.
3. Kallen AJ, Brunkard J, Moore Z, et al. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Ann Emerg Med 2009;53:358–65.
4. Jones TF, Creech CB, Erwin P, Baird SG, Woron AM, Schaffner W. Family outbreaks of invasive community-associated methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis 2006;42:e76–8.
5. Liu C, Bayer A, Cosgrove S, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18–55.
6. Gorwitz R, Kruszon-Moran D, McAllister S, et al. Changes in the prevalence of nasal colonization with Staphylococcus aureus in the United States, 2001–2004. J Infect Dis 2008;197:1226–34.
7. Kallen A, Mu Y, Bulens S, et al. Health care-associated invasive MRSA infections, 2005–2008. JAMA 2010;304:641–8.
8. Limbago B, Fosheim GE, Schoonover V, et al.; Active Bacterial Core surveillance MRSA investigators. Characterization of methicillin-resistant Staphylococcus aureus isolates collected in 2005 and 2006 from patients with invasive disease: a population-based analysis. J Clin Microbiol 2009;47:1344–51.
9. CDC. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60(No. RR-1).
10. Siegel J, Rhinehart E, Jackson M, Chiarello L; Health Care Infection Control Practices Advisory Committee. 2007 guideline for isolation precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control 2007;35(10 Suppl 2):S65–164.