Influenza and bacterial pneumonia - constant companions

Sequential or concomitant influenza and bacterial pneumonia are two common syndromes seen in community-acquired pneumonia. Inadequacies of diagnostic testing make separating simple pneumonia with either bacteria or influenza from concomitant or sequential influenza with both microorganisms difficult, although the novel 2009 H1N1 epidemic may improve the availability of molecular testing for viruses. Given the frequency of viral pneumonia and diagnostic limitations, empirical antivirals may be underutilized in community-acquired pneumonia. Thankfully, increasingly effective vaccines appear to disrupt this synergistic relationship.

In the previous issue of Critical Care, van der Sluijs and colleagues [1] reviewed the pathogenesis of infl uenza and bacterial pneumonia, particularly pneumococcal. Th ey pointed out critical diff erences in pathogenesis between various combinations of infl uenza and bacterial pneumonia. Four potential syndromes are possible. Th e classic syndrome is bacterial pneumonia following an antecedent infl uenza infection [2]. Bacterial pneumonia without any antecedent viral infection has been associated with a slightly better prognosis. Increasingly, concomitant bacterial and infl uenza pneumonia have been described and, while less common, appear to have a worse prognosis than sequential infection. Important pathophysiologic diff erences between these syndromes are illustrated in this review. Unexplored in their review is viral pneumonia without complication by bacterial pneu monia. Primary infl uenza pneumonia without complication by bacterial pneumonia appears to be common in the 2009 H1N1 infl uenza epidemic.
Th e diffi culty with separating these syndromes is the inaccuracy of etiologic diagnosis for community-acquired pneumonia (CAP). Th e CDC (Centers for Disease Control and Prevention) has recognized this diffi culty and conceded to report combined infl uenza and pneumonia deaths since prior to 1900 [3]. Th e cause of the majority of CAP cases remains undefi ned with the usual culture-based approach (mainly blood cultures and occasional sputum or more invasive respiratory cultures). One of the lasting eff ects of the 2009 novel H1N1 infl uenza epidemic may be the increasing sophistication and availability of molecular diagnostic tests for infl uenza (and other respiratory viruses). During the peak of the epidemic, reverse transcriptase-polymerase chain reaction (RT-PCR) for infl uenza was available in many large institutions within 8 to 12 hours of sampling. RT-PCR clearly is faster than culture and much more sensitive than the rapid infl uenza tests previously available. Th e trophism for the lower respiratory tract characteristic of the 2009 H1N1 infl uenza virus had diagnostic implications in addition to the pathophysiologic signifi cance of higher incidence and severity of primary viral pneumonia with acute lung injury/acute respiratory distress syndrome [4]. Th e diag nostic issue was that patients occasionally had negative nasopharyngeal RT-PCR tests while lower respiratory tract samples were positive [5]. Th e frequency with which this occurs with other strains of infl uenza or other respiratory viruses is unknown.
One caveat of the data regarding concomitant CAP is that viral or atypical pathogen co-infection in these studies was often diagnosed only by serologic conversion. Sequential versus concomitant infl uenza and bacterial pneumonia cannot be distinguished in this way. Th erefore, the diff erential eff ect on mortality and morbidity of concomitant versus sequential infl uenza and bacterial pneumonia remains somewhat unclear.
Unfortunately, molecular diagnosis of bacterial infection lags behind that of viral. Th e best routinely available diagnostic aids are the BinaxNOW urinary antigens (Inverness Medical International, Cranfi eld, UK) for both pneumo coccus and Legionella pneumophila. Th e pneumococcal urinary antigen can increase the diagnosis of Abstract Sequential or concomitant infl uenza and bacterial pneumonia are two common syndromes seen in community-acquired pneumonia. Inadequacies of diagnostic testing make separating simple pneumonia with either bacteria or infl uenza from concomitant or sequential infl uenza with both microorganisms diffi cult, although the novel 2009 H1N1 epidemic may improve the availability of molecular testing for viruses. Given the frequency of viral pneumonia and diagnostic limitations, empirical antivirals may be underutilized in community-acquired pneumonia. Thankfully, increasingly eff ective vaccines appear to disrupt this synergistic relationship. pneumo coccal pneumonia by 10% to 30% in prospective studies. False-positives, often after a previous upper respiratory infection such as otitis media, limit its accuracy in children and HIV-positive patients. Th e Legionella urinary antigen is limited to one serogroup of L. pneumo phila which is neither the most common strain nor serotype in certain areas of the world. In addition, the assay picked up only 50% of cases and had almost mutually exclusive results compared with a Legionella PCR assay on sputum.
Whole-blood PCR for bacterial pathogens is generating increasing interest. Recent studies of the pneumococcal lytA gene have increased the number of patients diagnosed with pneumococcal disease, and quantitation appears to have additional prognostic signifi cance [6]. Similar prognostic signifi cance of quantitative PCR has been demonstrated for a meningococcal gene.
Th e result of diagnostic limitations is that most treatment for CAP remains empirical. Empirical antibiotics are the standard, but concern about delayed antivirals in the recent pandemic signifi cantly increased the use of empirical antivirals as well. Clearly, this strategy makes the most sense for concomitant bacterial and infl uenza pneumonia. Given the limitations of etiologic diagnosis, the benefi t of empirical antibiotics for occult bacterial pneumonia in patients with documented infl uenza is unclear. Conversely, empirical antivirals for culture-and urinary antigen-negative CAP patients may be rational since viruses may be the etiology in up to 15% of cases [7], with infl uenza being the most common viral pathogen. Th e incidence of primary infl uenza or concomitant infl uenza CAP is clearly as high as that of community-acquired methicillin-resistant S. aureus (CA-MRSA) [8] or Pseudomonas, for which empirical anti biotics in the appropriate settings have been recommended by guidelines [9].
Th e good news is that prevention of one appears to prevent death from the other. Th e decrease in positive infl uenza cultures and infl uenza-related deaths, particularly among children, starting 6 to 8 weeks after the fi rst dose of the novel 2009 H1N1 vaccine became available is impressive [10]. Conversely, the pediatric conjugate pneumo coccal vaccine decreased invasive pneumococcal disease in infants as well as their adult caregivers [11], even during peak years of epidemic infl uenza. Hopefully, higher valent and adult conjugate vaccines will soon become available to disrupt this lethal relationship even further.

Competing interests
RGW is on the data safety monitoring committee for an adult conjugate pneumococcal vaccine (originally Wyeth [Madison, NJ, USA], now Pfi zer Inc [New York, NY, USA]). In last 2 years, he has received a reimbursement of less than $5,000 for time reviewing data and for meetings.