A Grand Rounds Review
Daniel S. Chertow, MD, MPH; Matthew J. Memoli, MD, MS
ABSTRACT
Bacterial coinfection complicated nearly all influenza deaths in the 1918 influenza pandemic and up to 34% of 2009 pandemic influenza A(H1N1) infections managed in intensive care units worldwide. More than 65 000 deaths attributable to influenza and pneumonia occur annually in the United States. Data from 683 critically ill patients with 2009 pandemic influenza A(H1N1) infection admitted to 35 intensive care units in the United States reveal that bacterial coinfection commonly occurs within the first 6 days of influenza infection, presents similarly to influenza infection occurring alone, and is associated with an increased risk of death. Pathogens that colonize the nasopharynx, including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, are most commonly isolated. Complex viral, bacterial, and host factors contribute to the pathogenesis of coinfection. Reductions in morbidity and mortality are dependent on prevention with available vaccines as well as early diagnosis and treatment.
PATIENT PRESENTATION
The patient, a 58-year-old man, presented to a community hospital with fever, cough, myalgias, and shortness of breath that worsened over 5 days. The history was significant for past tobacco use. Temperature on presentation was 36.5°C, and physical examination revealed wheezing and rhonchi in bilateral lungs. A nasopharyngeal wash for viral testing and sputum for bacterial Gram stain and culture were obtained. Treatment for suspected community-associated pneumonia was initiated with moxifloxacin. Emergency department evaluation showed severe hypoxia, and the patient was transferred to a tertiary care center for further assessment.
On arrival at the receiving center, the patient's arterial blood gas analysis showed a pH of 7.42, PCO2 of 31 mm Hg, and PaO2 of 59 mm Hg (fraction of inspired oxygen, 100%). Laboratory testing revealed findings consistent with severe sepsis: leukopenia (white blood cell count, 1.3 cells × 109/L), thrombocytopenia (platelet count, 106 × 103 cells/?L), acute kidney injury (creatinine level, 2.04 mg/dL [180.34 ?mol/L]), liver injury (aspartate aminotransferase level, 308 U/L [5.14 ?kat/L]; alanine aminotransferase level, 197 U/L [3.29 ?kat/L]), coagulopathy (prothrombin time, 16.3 seconds; partial thromboplastin time, 41.1 seconds; international normalized ratio, 1.3), and tissue hypoperfusion (lactate level, 3.7 mmol/L). Chest radiography showed diffuse bilateral infiltrates.
The patient was intubated and admitted to the intensive care unit for hypoxic respiratory failure and subsequent vasopressor-dependent septic shock. Refractory respiratory failure was managed with high-frequency oscillatory ventilation, and shock was managed with high-dose norepinephrine. Initial sputum Gram stain showed gram-positive cocci in clusters, and intravenous vancomycin was started. Oseltamivir (75 mg by nasogastric tube) was also started.
Respiratory failure complicated by hemoptysis and progressive shock led to cardiac arrest. Cardiopulmonary resuscitation was initiated, with temporary return of spontaneous circulation. A family decision for no further resuscitative efforts was made, and the patient died within 24 hours of admission. Polymerase chain reaction testing of an initial nasopharyngeal wash specimen was positive for 2009 pandemic influenza A(H1N1), and sputum and blood cultures were positive for methicillin-resistant Staphylococcus aureus (MRSA) .
COMMENT
The 1918 influenza pandemic resulted in an estimated 50 million deaths worldwide.1 A review of 8398 autopsies performed during that time confirmed bacterial coinfection in nearly all deaths.2 The 2009 pandemic influenza A(H1N1) virus resulted in an estimated 284 400 deaths worldwide. Many deaths occurred in countries with limited medical services.3 Even in countries with advanced medical services, including in the United States, Canada, Spain, Argentina, Australia, and New Zealand, bacterial coinfection complicated between 18% and 34% of 2009 pandemic influenza A(H1N1) cases managed in intensive care units (ICUs)4- 9 and up to 55% of fatal cases, based on published autopsy series.10- 12
This article describes the epidemiology of influenza and pneumonia in the United States over the past 30 years, emphasizing the continued central role of bacterial coinfection in severe and fatal cases. The clinical course, pathogenesis, and rational clinical management of severe coinfection are discussed.
Epidemiology of Influenza and Pneumonia and the Role of Bacterial Coinfection
The overall precise mortality rate associated with influenza and bacterial coinfection is unknown. The National Vital Statistics System collects and presents the leading causes of death in the United States. Cause of death, as typically determined by the treating physician at the time of death, is derived from International Classification of Diseases codes on death certificates, and aggregate data are presented annually. Deaths attributable to influenza and bacterial coinfection are not directly measured and so must be extrapolated from available data. Based on these extrapolated data, on average from 1976 to 2009, 66 324 (range, 45 030-91 871) deaths were attributed annually to the combined categories of influenza and pneumonia.13 Modeling estimates predict that on average 23 607 (range, 3349-48 614) deaths with underlying respiratory and circulatory causes from 1976 to 2007 in the United States were associated with influenza.14
Based on National Vital Statistics System data, mortality rates from the combined categories of influenza and pneumonia are highest in individuals 65 years or older and have declined from 1976 to 2009 predominantly in the oldest and youngest age groups (Figure 2). Although influenza infection typically results in lower mortality rates in younger individuals, H3N2 influenza viruses that were prevalent in 1997 and 2003 (ie, A/Sydney[H3N2] and A/Fujian[H3N2])15 and the emergence of the 2009 pandemic influenza A(H1N1) virus resulted in excess mortality in younger age groups.
Bacterial coinfection complicates approximately 0.5% of all influenza cases in healthy young individuals and at least 2.5% of cases in older individuals and those with predisposing conditions.16 Individuals at high risk of developing influenza-related complications including coinfection include adults 65 years or older, children younger than 5 years, pregnant women, people who are morbidly obese (body mass index ?40, calculated as weight in kilograms divided by height in meters squared), and people with preexisting medical conditions including chronic pulmonary, cardiovascular, renal, hepatic, neurologic, metabolic, or immune-suppressing conditions.17
Colonization of the nasopharynx with pathogenic bacteria may predispose to coinfection. Specifically, colonization with Streptococcus pneumoniae has been associated with increased risk of ICU admission or death in the setting of influenza infection,18 and coinfection with S aureus, which colonizes the nares of 30% of the adult population,19 has been associated with increased risk of death in adults and children infected with influenza.8,20 MRSA coinfection in particular has repeatedly been associated with severe disease and death in adults and children.20- 24
Clinical Course and Microbiology of Severe Influenza and Bacterial Coinfection
The typical time course of influenza illness in healthy adults experimentally challenged with influenza virus is as follows: symptom onset occurs within 24 hours of influenza infection; peak viral shedding correlates with peak symptom severity occurring 2 to 3 days postinfection; and symptoms and viral shedding abate by day 8 postinfection.25
In a series of 683 adults admitted to 35 ICUs in the United States with severe 2009 pandemic influenza A(H1N1) infection, 207 had clinical evidence of bacterial coinfection, as defined by presumed bacterial pneumonia documented in the medical record or a positive blood culture within 72 hours of ICU admission. The mean time from symptom onset to hospitalization in the coinfected group was 5.2 (SD, 4.9) days.8 Allowing for a 24-hour asymptomatic period, on average these individuals developed coinfection within the first 6.2 (range, 1.3-11.1) days of influenza infection. This time course of illness suggests that coinfection predominantly occurs during periods of high influenza viral shedding but may occur concurrently with or shortly after influenza infection.
The mean time from symptom onset to hospital admission in this series did not differ significantly between the coinfected group and the influenza-alone group (5.0 [SD, 4.5] days). Similarly, the prevalence of presenting symptoms of fever, cough, dyspnea, and myalgias did not differ between groups. One hundred fifty-four of the 207 patients (74%) with suspected coinfection had positive bacterial cultures. The pathogens most commonly isolated from respiratory cultures were S aureus (45%), S pneumoniae (16%), and Streptococcus pyogenes (4%). Sixty-two percent of the S aureus isolates were methicillin resistant.
In a series of 838 critically ill children with 2009 pandemic influenza A(H1N1) infection, 274 (33%) had clinical evidence of bacterial coinfection, defined as a diagnosis of bacterial pneumonia or other evidence of bacterial infection within 72 hours of pediatric ICU admission.20 One hundred eighty-three of the 274 patients (67%) with suspected coinfection had positive bacterial cultures. The pathogens most commonly isolated from respiratory cultures were S aureus (39%), Pseudomonas species (16%), S pneumoniae (8%), Haemophilus influenzae (7%), and S pyogenes (4%). Forty-eight percent of S aureus isolates were methicillin resistant. Eighty-seven percent of patients with Pseudomonas infection had chronic lung disease; many had tracheostomies in place.
Coinfection may also occur in the hospital setting following admission for influenza infection alone. Bacterial pathogens frequently isolated in hospital-associated coinfection include MRSA, P aeruginosa, Acinetobacter species, and other resistant enterobacteriaceae.4,26 In summary, coinfection typically occurs within a few days of influenza infection at times of high viral shedding, presents similarly to severe influenza infection alone, and prominent coinfecting bacterial pathogens include S aureus, S pneumoniae, and S pyogenes, which commonly colonize the nasopharynx.
Pathogenesis of Coinfection
Synergistic lethality of influenza and bacterial coinfection has been observed in animal models since shortly after influenza viruses were first isolated in early 1930s.27- 28 Influenza viral infection contributes to respiratory epithelial cell dysfunction and death through disruption of protein synthesis and induction of apoptosis.29- 31 Viral neuraminidase cleaves respiratory epithelial cell sialic acids, contributing to increased bacterial adhesion and dissemination. This effect is reversed by neuraminidase inhibitors.32- 34 PB1-F2, a proapoptotic influenza protein expressed by many strains—although not by 2009 pandemic influenza A(H1N1)—increases susceptibility to bacterial coinfection through unknown mechanisms.35 Proteases secreted by certain strains of S aureus cleave influenza hemagglutinin,36- 37 a step required for multicycle viral replication. Propagation of virus along the respiratory tree impairs mucociliary clearance of bacteria from the lower respiratory tract,38- 39 and epithelial cell death exposes the basal cell layer and basement membrane, allowing for increased bacterial adherence and invasion.
Clinical Management
Clinical management of severe coinfection relies on measures to prevent, diagnose, and treat both influenza and bacterial infection. The following paragraphs and the Box describe a logical approach to prevention, diagnosis, and treatment of severe coinfection.
Box. Key Points Regarding Bacterial Coinfection in Influenza
Epidemiology
Between 1979-2009 there were an average of 66 000 deaths per year attributable to coinfection with influenza and pneumonia
Bacterial coinfection is more common in the elderly, the very young, pregnant women, patients with preexisting conditions, and morbidly obese patients
Prevention
Influenza vaccination in all persons older than 6 mo is recommended
23-Valent pneumococcal vaccine is recommended for adults older than 65 y; 13-valent pneumococcal polysaccharide conjugate vaccine is recommended for children aged 2-59 mo
Diagnosis
Diagnosis of coinfection can be difficult but should be suspected in patients who present with influenza-like illness and dyspnea, tachypnea, hypoxia, or signs and symptoms of sepsis
Treatment
Early empirical antiviral treatment and antibiotic treatment with a respiratory fluoroquinolone or a combination ?-lactam plus a macrolide should be initiated in all individuals with suspected coinfection
Antibiotic coverage for methicillin-resistant Staphylococcus aureus should be initiated when patients have signs of necrotizing pneumonia, including rapid onset of acute respiratory distress or hemoptysis
