Parapneumonic Empyema Deaths during Past Century, Utah

Vaccine strategies and antimicrobial drug stockpiling to control empyema will increase preparedness as we prepare for the next influenza pandemic.

Bacterial pneumonia with empyema is a serious complication of infl uenza and commonly resulted in death during the 1918 infl uenza pandemic. We hypothesize that deaths caused by parapneumonic empyema are increasing in Utah once again despite advances in critical care and the availability of antimicrobial drugs and new vaccines. In this study, we analyzed the historical relationship between deaths caused by empyema and infl uenza pandemics by using 100 years of data from Utah. Deaths caused by empyema have indeed increased from 2000-2004 when compared with the historic low death rates of . Vaccine strategies and antimicrobial drug stockpiling to control empyema will be important as we prepare for the next infl uenza pandemic.
A n infl uenza pandemic is thought to be the most likely and most severe biological emergency facing the United States (1)(2)(3). Bacterial pneumonia is a serious complication of infl uenza infection and was likely a major cause of the excess deaths seen during the 1918 infl uenza pandemic (4)(5)(6)(7)(8). Even today, though the overall disease mortality rate due to infectious diseases is declining in the United States, death from pneumonia and infl uenza remains one of the top 10 causes of death overall (9,10).
Parapneumonic empyema, a serious complication of bacterial pneumonia frequently caused by Streptococcus pneumonia and Staphylococcus aureus, is increasing in North and South America, Europe, and Asia (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). As we prepare for an infl uenza pandemic, changes in the microbiology of pneumonia and the increasing rates of empyema must be considered. In this study, we analyzed the historical relationship between deaths due to empyema and infl uenza pandemics using 100 years of data from Utah.

Utah Population Database
The Utah Population Database (UPDB) is a computerized genealogical database linking multiple data sources. The resource includes genealogical records of the original Utah pioneers (members of the Church of Jesus Christ of Latter Day Saints) who settled in Utah in 1847 and their descendants. These records have been linked to disease data for Utah, including death certifi cate records dating back to 1904. We used a version of the database without individual identifi ers that spans 100 years .

Identifi cation of Patients
The institutional review boards for both the University of Utah and the UPDB reviewed and approved this study. Each death record in the UPDB contains a primary cause of death that was coded with the International Classifi cation of Diseases (ICD) nomenclature. All death certifi cates between 1956 and 2004 were encoded by using ICD revisions 6 through 10. For death certifi cates from 1904 through 1955, a nosologist with a University of Utah research project used the literal information and coded cause of death to ICD revision 10 using the 2000 Medical Data System and supplemented this system with hand coding. During 1985-1995, the Bureau of Vital Statistics added selected secondary causes of death, including pneumonia, empyema, and infl uenza. Beginning in 1996, death certificate records contained multiple secondary causes of death and classifi ed persons with each. We searched the UPDB for deaths associated with empyema on the basis of ICD codes: ICD-10 J869, ICD-9 510.9, ICD-8 510, ICD-7 518, and ICD-6 518. For infl uenza deaths, we used the following ICD codes: ICD-10 J10, J11, ICD-9 487, ICD-8 470-474, ICD-7 480-483, and ICD-6 480-483.

Statistical Analysis
We analyzed empyema-related deaths by decade and population to examine trends in death related to empyema. We analyzed empyema deaths in 2 age groups: children (0-18 years of age) and adults (>18 years of age). Utah population was determined based on national census data. Utah's population data have been available every 10 years from 1900 through 2000 and for 2005. Using available data, we fi tted a cubic curve of log-transformed population for 1 year to estimate Utah's population for other years. We defi ned 3 notable periods in Utah history. Period 1, 1917Period 1, -1920, represents the Spanish infl uenza pandemic. Period 2, 1950Period 2, -1975, represents the post-antimicrobial drug era and encompasses smaller infl uenza pandemic periods of 1957-58 and 1968-69. Period 3, 2000Period 3, -2004, includes the period of increasing incidence of empyema in children (15,22) and recent increases in empyema deaths. A Poisson model was used to estimate risk for death in different years and compare estimates among the 3 identifi ed periods.

Results
Empyema and infl uenza death rates in Utah over a 100-year period are shown in the Figure. A high rate of deaths caused by empyema occurred during 1900-1909. Deaths caused by empyema peaked at 18/10,000 personyears during the decade 1910-1919, which included the 1918-19 Spanish infl uenza pandemic (period 1). Empyema deaths steadily decreased in the decades after the Spanish infl uenza pandemic. This decline is most apparent in the 1930s, coincident with the widespread introduction of sulfonamide antibiotics. With the introduction of penicillin during World War II, deaths caused by empyema leveled off substantially in the 1940s-1950s. During the period from 1950 through 1975 (period 2), empyema deaths remained at a nadir of 0.4-0.8/10,000 person-years. The rate of deaths increased signifi cantly during the fi nal 5-year period from 2000-2004 (period 3). Compared with period 2, the death rate for persons with empyema in Utah during period 3 was 3.2/10,000 person years, >6-fold higher (rate ratio 6.6; 95% confi dence interval 3.2-13.4: p<0.005).
During the pre-antimicrobial drug era and during the 1918-19 infl uenza pandemic, children 0-18 years of age accounted for 31%-37% of all empyema deaths. Between 1940 and 1999, deaths among children decreased more dramatically than among adults and accounted for <4% of all empyema deaths. Almost all (97%) of the empyema deaths seen recently in period 3 are in adults >18 years of age, most among persons >65 years of age.
Death rates attributed to infl uenza peaked dramatically during the decade 1910-1919, associated with the peak in empyema deaths. After 1970, the number of infl uenza deaths declined steadily and has remained very low.

Discussion
The rates of empyema leading to death in Utah have signifi cantly increased between 2000-2004. This increase occurred in the absence of a major infl uenza pandemic and in spite of advances in medical care. The recent increase in empyema deaths is unexplained and may have broad implications for future infl uenza pandemics.
Empyema caused substantial illness and death in the era before antibiotics. In the 8th edition of his book, published just before the Spanish infl uenza pandemic, Osler described empyema as "a most common complication [of pneumonia] occurring in 2.2 percent of clinical cases" seen over an 8-year period at Johns Hopkins Hospital (22). He described pneumococcus as the most common pathogen leading to empyema. Pneumonia and empyema were, at the time, "the most fatal of all acute diseases" (22). Osler himself died of pneumonia and empyema in 1919.
Infl uenza has historically been linked to pneumonia deaths. According to our study, deaths caused by empyema peaked during the Spanish infl uenza pandemic of 1918-19. The estimated worldwide death toll attributed to Spanish infl uenza has been estimated at 21-50 million (23). Pneumonia, especially due to S. pneumoniae, is thought to be a major contributor to the excess deaths seen during the 1918 infl uenza pandemic (5,6). As seen in the Figure, data from the UPDB demonstrate an increase in deaths caused by empyema during this period, although it is not as dramatic as the increase in deaths attributed to infl uenza. This fi nding suggests that empyema contributed to the deaths from pneumonia associated with the infl uenza pandemic.
The number of deaths due to empyema fell moderately during the decades of the 1920s and 1930s but fell dramatically after 1940 and World War II. This decrease in  1900-1909 1910-1919 1920-1929 1930-1939 1940-1949 1950-1959 1960-1969 1970-1979 1980-1989 1990-1999 2000-2005 Empyema deaths/10,000 person-years empyema deaths corresponds with the beginning of the antimicrobial drug era. During the 1950s and 1960s, when the pandemics of 1957 and 1968 occurred, the rate of deaths caused by empyema remained low. We did not observe a signifi cant increase in the deaths caused by infl uenza over the same period. This lack of an increase may have been due to the relatively mild nature of these pandemics compared with the 1918 pandemic, the availability of antimicrobial drugs, improvements in the management of pneumonia and its complications, and perhaps the insensitivity inherent in examining death rates by decade. We noted a statistically signifi cant increase in the number of empyema deaths in Utah at the turn of the 21st century (2000)(2001)(2002)(2003)(2004) when compared with the mid-20th century . This increase in empyema deaths has taken place without the advent of an infl uenza pandemic and in the setting of continued advances in medical care. The increase in death rates/person years caused by empyema is primarily seen in the adult population and is most apparent in patients >65 years of age. What might account for this increase in empyema deaths? We speculate that increased mortality rates from empyema are caused by changes in the organisms that cause pneumonia and empyema worldwide.
S. pneumoniae is thought to have been the major cause of death from secondary bacteria in prior pandemic infl uenza outbreaks. Comparing all 3 of the infl uenza pandemics of the twentieth century, 1 study estimates that 50% of bacterial pneumonia cases associated with infl uenza were caused by S. pneumoniae (24). Experimental as well as epidemiologic data support the association between serious S. pneumoniae infections and infl uenza. Studies by McCullers and others have shown that infl uenza virus infection preferentially predisposes mice to fatal infections with S. pneumoniae (25)(26)(27). Recent studies have demonstrated a clear temporal association between seasonal infl uenza and invasive pneumococcal disease in children (28).
Changes in circulating serotypes of S. pneumoniae have been reported from many regions worldwide (11,14,16,17,(29)(30)(31)(32). These changes may play a role in the increase in deaths caused by empyema. The annual incidence of invasive disease caused by S. pneumoniae has decreased signifi cantly in all age groups with the introduction of the 7-valent pneumococcal conjugate vaccine (PCV-7) in 2000 (33). Further, disease caused by resistant S. pneumoniae has also decreased signifi cantly with the introduction of the PCV-7 vaccine, which targeted the resistant serotypes (33,34). Thus, antimicrobial drug resistance to S. pneumoniae seems unlikely to be responsible for the increase in empyema deaths since the introduction of PCV-7. In spite of the recent decreases in invasive pneumococcal disease, hospitalizations for empyema are increasing in US children (20). Recent reports further show that the incidence of empyema due to non-PCV-7 serotypes, especially types 1, 3, and 19A, has increased signifi cantly worldwide in the post PCV-7 era (11)(12)(13)(14)(15)(16)(17)21,32). These serotypes are historically associated with severe invasive disease, particularly empyema, and might contribute to the increased rates of deaths caused by empyema among adults (17,35,36).
S. aureus is increasingly recognized as a signifi cant cause of complicated pneumonia. A recent study from France demonstrated a mortality rate of >50% in patients infected with S. aureus that contained Panton-Valentine leukocidin (PVL), which caused necrotizing pneumonia (37). A study among children from Houston demonstrated a marked increase in complicated pneumonia in patients with PVL-containing S. aureus infection (29). The PVL gene is now considered one of the identifying features of community-associated methicillin-resistant S. aureus (CA-MRSA) and is at least a marker for invasiveness and virulence, although the exact contribution of PVL remains unclear (38).
CA-MRSA has become more widespread over the past decade and has been responsible for increasing amounts of severe complicated pneumonias in the community (19). The Centers for Disease Control and Prevention reported a signifi cant increase in CA-MRSA pneumonia associated with infl uenza infection in the United States during 2006-2007, including deaths among previously healthy children (18).
History reminds us that we must be prepared to deal with severe bacterial pneumonia when planning for future infl uenza threats. Good evidence exists that infl uenza will interact with bacterial pathogens to cause severe pneumonia and increased mortality rates. Thus, the recent increase in deaths caused by empyema has potential implications for pandemic infl uenza preparedness. The rise of pneumococcal serotypes with a propensity to cause complicated pneumonia and increasing rates of community acquired pneumonias due to CA-MRSA should be considered when developing strategies to prevent and treat infl uenza complications. These strategies might include broadening recommendations for existing or enhanced pneumococcal vaccines that cover serotypes associated with empyema, such as 1, 3, and 19A. Determining who should be vaccinated with these pneumococcal vaccines during an infl uenza pandemic would have to be done on the basis of risk and the availability of vaccines. Further, the stockpiling of antimicrobial drugs active against CA-MRSA and other resistant pathogens may also be needed. Currently, the US Department of Health and Human Services Pandemic Infl uenza Plan from 2005 does not specifi cally account for secondary bacterial infections or the need for bacterial vaccines (1,39).
However, the Infectious Diseases Society of America called for improved antibacterial agents and vaccines as a key need in pandemic infl uenza preparedness (40). Our data provide support for this concept. Extending the range of conjugate pneumococcal vaccines to include the serotypes now commonly associated with empyema and encouraging broader use of the polysaccharide vaccine may help lessen the effects of S. pneumoniae infection on a pandemic. If high vaccination rates cannot be routinely achieved, stockpiles of pneumococcal vaccine might be needed. Antimicrobial drug stockpiling, particularly agents with activity against MRSA, should be included in the discussion of antiviral drug stockpiling as well. Further, because the treatment for empyema frequently requires drainage either through chest tubes or surgical procedures, planning for these healthcare resources should also be considered.
This study has some limitations. Cause of death in death certifi cate data is not always accurate, and the accuracy may vary by disease. The clinical manifestations of empyema were well described by 1900 (22). Empyema was common during the pre-antimicrobial drug era and relatively easy to document with clinical examination and chest radiographs. Thus, it seems unlikely that recognition or reporting of empyema changed with time during the period covered in this historical study. There is no reason to suspect that empyema was more readily diagnosed in the fi nal 5 years of the study, that defi nitions changed, or that it was more readily listed as a cause of death. Infl uenza, in contrast, is more diffi cult to diagnose clinically and may have been more readily listed as a cause of death during known pandemics and after virologic testing became available. Our data do not include microbiology results, so the association between empyema deaths and specifi c organisms is speculative.
We observed a signifi cant increase in deaths caused by bacterial empyema during the period of the infl uenza pandemic of 1918-19 and an unexplained increase from 2000 through 2005. As secondary bacterial pneumonia historically has been a signifi cant cause of illness and death in infl uenza pandemics, understanding the recent increase in empyema deaths is critical as we prepare for the next infl uenza pandemic. Changes in prevalent bacteria, including S. pneumoniae serotypes and the virulence of S. aureus, should be further explored. Pneumococcal vaccines targeting the serotypes most associated with empyema and antimicrobial agents against resistant bacteria such as CA-MRSA should be key components in national and international infl uenza pandemic planning. J.M.B. is the recipient of a NIH Rocky Mountain Regional Center for Excellence in Biodefense and Emerging Diseases young investigator award U54 AI065357. C.L.B. receives support through NIH/NICHD K24-HD047249, NIH/NIAID U-01 A1061611-01 and U-01 AI74419-01 for development of viral diagnostics for infl uenza and has received support from Wyeth Pharmaceuticals for molecular epidemiology of empyema. Partial support for all datasets within the UPDB was provided by the University of Utah, Huntsman Cancer Institute.
Dr Bender is a fellow in pediatric infectious diseases at the University of Utah at Primary Children's Medical Center in Salt Lake City. His primary research interest is genetic susceptibility to infl uenza virus infection and the resultant implications for pandemic planning. He has studied the evolving serotypes of S. pneumoniae that lead to empyema in children.