Increase in Clostridium difficile–related Mortality Rates, United States, 1999–2004

Reported mortality rates from Clostridium difficile disease in the United States increased from 5.7 per million population in 1999 to 23.7 per million in 2004. Increased rates may be due to emergence of a highly virulent strain of C. difficile. Rates were higher for whites than for other racial/ethnic groups.


The Study
CDAD-related deaths were identifi ed by using multiple cause-of-death data from national mortality records for 1999-2004. CDAD-related deaths were defi ned as all deaths for which the underlying cause of death or any of the contributing causes of death included the International Classifi cation of Diseases, 10th revision (ICD-10) code A04.7 (enterocolitis due to C. diffi cile). Information about the size and demographic breakdown of the US population for each year during 1999-2004 was obtained from censal and intercensal year estimates with bridged race data (9,10). Age-adjusted mortality rates were calculated by using the age distribution of the 2000 US population as a standard (11). The US population was divided into 5 racial/ethnic categories: white, Hispanic, Asian/Pacifi c Islander, black, and American Indian/Alaska Native.
During 1999-2004, CDAD was reported as a cause of death for 20,642 persons. CDAD was reported as the underlying cause for 12,264 (59%) of these deaths. A total of 3,256 deaths were reported related to all other intestinal infectious diseases combined (ICD-10 codes A00 to A09, excluding A047) over the same period. The median age of death for CDAD patients was 82 years. Age-adjusted mortality rates from CDAD were slightly higher for men than for women (Table) and were higher for whites than for any other racial/ethnic group. Most CDAD-related deaths occurred in hospitals (n = 16,557, 80%); 1,634 (8%) occurred in long-term care facilities, and 2,027 (10%) occurred at home.
The overall rate of C. diffi cile-related deaths during the study period was 12.2 deaths per million population. Mortality rates related to CDAD increased during the study period ( Figure), rising from 5.7 deaths per million population in 1999 to 23.7 deaths per million population in 2004. Poisson regression estimates showed mortality rates increased by 35% per year (coeffi cient = 0.30, standard error = 0.004, 95% confi dence interval = 0.29-0.31) during the study period.

Conclusions
Due to the inclusion of CDAD-related deaths when CDAD was not reported as the underlying cause of death, reported death rates in this study were higher than those published in an earlier analysis of CDAD-related deaths in the United States (7). C. diffi cile is a cause of a substantial and increasing proportion of deaths in the United States and may be underrecognized as a cause of death. Little attention has been paid to C. diffi cile prevention; media and public health awareness efforts have focused largely on the prevention of disease from other intestinal pathogens such as Escherichia coli or Salmonella spp. However, the incidence of deaths from C. diffi cile is greater than the extent of deaths from all other intestinal infectious diseases combined. C. diffi cile-related mortality rates were higher for whites than for other racial/ethnic groups. Racial/ethnic differences in insurance status and access to care (12) may render elderly whites more likely to receive treatment with antimicrobial drugs that put them at risk for C. diffi cile infection. However, genetic or other factors may also be involved, and further research is needed to determine the causes of racial/ethnic differences in C. diffi cile-related deaths.
Previous research showed increases in CDAD-related mortality rates in the United States until 2002 (7,8). This analysis estimates the rate of increase at 35% per year, and shows that mortality rates continued to increase at least until 2004. Increases in incidence and deaths from CDAD may be associated with the emergence of a new and more virulent strain of C. diffi cile (5). The emergence of virulent strains of C. diffi cile makes continued assessment of mortality statistics important.
Infection with C. diffi cile is associated with recent use of antimicrobial medications and with residence in hospitals. Most CDAD cases are acquired in healthcare settings (1), and as many as 90% of cases may be associated with antimicrobial drug use (2,3). High C. diffi cile death rates call attention to the importance of proper infection control practices in hospitals and long-term care facilities and the judicious use of antimicrobial medications. Further research is needed to explore current questions concerning which antimicrobial medications, if any, will lead to CDAD (13,14).
Infections such as septicemia, pneumonia, and urinary tract infections were commonly reported in conjunction with C. diffi cile-related deaths. For some of these patients, the administration of antimicrobial medications to treat infections from other pathogens may have paved the way for infection with C. diffi cile. However, other risk factors are known, so that in many cases the careful use of antimicrobial agents may not be enough to prevent C. diffi cile infection. HIV infection was only reported in a small fraction of CDAD-related deaths. However, immunosuppression and the use of prophylactic antimicrobial drugs in persons with AIDS may increase the risk for CDAD (15), and the effects of HIV should not be overlooked. In persons 25-54 years  of age, in whom HIV infection is most common, HIV infection was reported in approximately one tenth of CDADrelated deaths. Thus, HIV can considerably increase C. diffi cile death rates for demographic groups in which HIV prevalence is high. Death certifi cate data may underrepresent the extent of CDAD-related deaths. This analysis was limited to deaths in which ICD-10 code A047 (enterocolitis due to C. difficile) was mentioned and may have failed to capture CDADrelated deaths in which colitis was not present. In addition, death certifi cate data may be affected by reporting error. Supplemental information such as decedents' medical histories was unavailable. No data were available regarding which strains of C. diffi cile were responsible for reported CDAD-related deaths.
C. diffi cile is an underrecognized cause of severe illness and death. This analysis underscores the importance of CDAD as a public health problem and the increasing incidence of CDAD-related deaths in the United States.
Mr Redelings is an epidemiology analyst with the Los Angeles County Department of Public Health. He previously served as a humanitarian worker in Sudan. His current research interests include the epidemiology of gastrointestinal infections and the prevention of disease in refugee situations.