Unlike other studies that have described and analyzed characteristics that influence autopsies overall (19,20), ours describes demographic characteristics and clinicopathologic syndromes associated with autopsy of persons who died of unexplained infectious causes in the United States. The overall percentage of autopsies performed on such decedents during 2003–2006 (39.8%) was higher than estimates of the proportion of overall autopsies in the United States (≈8.5%) (21). The higher percentage of autopsies for persons whose deaths were unexplained might reflect the frequent inclusion of complete autopsies in investigations of natural disease deaths by medical examiners and coroners (22).

Our finding that most characteristics in the multivariate regression analysis were highly significant when complete data for 2003–2006 were included in the analysis probably resulted from the large number of persons in the study whose deaths were unexplained. Unexplained deaths among persons with a history of fever have been reportable in Arizona since 2004, and medical examiners and health care providers are required to report unexplained infectious deaths to their local health departments (18). The Arizona Unexplained Deaths Investigation Protocol identifies appropriate specimens and clinical data needed for investigation, and the Arizona data might elucidate true demographic characteristics and syndromic trends of unexplained deaths in the United States. The analysis of data for Arizona decedents suggests that race, age, and clinicopathologic syndrome are potentially major factors for whether persons who died of unexplained infectious causes undergo autopsy.

Data on religious preferences are not collected on death certificates, but race might have been a proxy for cultural and religious preferences. Religious objections and lack of understanding about cultural or religious influences have been reported as reasons a family might not consent to an autopsy (23,24). For example, many American Indian tribes have traditions contrary to autopsy in which organ specimens are retained by medical examiners and pathologists (25). The observed lower odds for autopsy of decedents of other races possibly resulted from the larger American Indian population in Arizona (5%) than in the United States (1%) (26).

Results from the analysis of the Arizona subset suggest that children and young adults whose deaths resulted from unexplained possibly infectious causes are more likely than older adults to have undergone autopsies. Although some studies have suggested that children are more likely to undergo autopsies (19,20), the literature regarding the association between age and autopsy is limited, and findings have been inconclusive (27,28). Particularly when children die suddenly or unexpectedly, which is often from infectious causes (29), autopsies can contribute to families’ understanding of the circumstances of death or expand medical knowledge (19,30).

Persons whose unexplained deaths were coded as from cardiovascular, sepsis/shock, or multisyndrome causes were less likely than those whose deaths were coded as unknown/other to undergo autopsies. These results could reflect differences in the availability and resources of investigators of unexplained deaths from possibly infectious causes. Sepsis, in particular, remains perplexing and costly, and despite efforts to understand the systemic inflammation and multisystem organ failure characteristics of severe sepsis, the reason many of these patients die remains unknown (31,32). Furthermore, investigators of unexplained deaths or family members of decedents might have believed that additional studies, including autopsy, would not yield substantial findings. According to an opinion survey of pathology and medicine resident physicians, reasons families refuse autopsies included beliefs that the patient has suffered enough and that the autopsy would not be useful (33). Routine microscopic examination has been argued to not provide additional information in forensic pathology cases for which the cause and manner of death are apparent at the time of autopsy (34). However, the reduced likelihood of autopsy or further evaluation of these challenging unexplained deaths could also result in the failure to recognize infectious diseases. For example, Chong et al. illustrated the difficulty of differentiating an emerging disease (SARS) from other causes of sudden cardiovascular death at autopsy (35). Of the14 autopsies performed on persons with suspected or probable SARS, 8 confirmed SARS only on the basis of clinical history, histopathologic evaluation, and testing of autopsy specimens. Therefore, an autopsy should be pursued especially for those whose unexplained deaths were possibly of infectious causes.

Reasons for differences in likelihood of autopsy with respect to race, age, and clinicopathologic syndrome could be multifactorial, and results from our study are subject to limitations. The availability, training, and resources of investigators of unexplained natural deaths differ among institutions and jurisdictions and might account for differences in autopsy performance, testing capabilities, and reporting of autopsy data (12,36). Unfortunately, multiple cause-of-death data do not capture whether autopsies are performed by medical examiners or by hospital-based pathologists, and differences in autopsy rates between medicolegal death investigation systems and hospital-based pathologists in unexplained death remains unknown. Inaccuracy in death certification and reliance solely on ICD-10 classification for unexplained death also has limitations. Codes might be assigned by persons not directly familiar with decedents and who therefore might not be aware of known diagnoses. Death certificates might not have been amended when organism-specific etiologies (i.e., Streptococcus pneumoniae) were determined after broad ICD-10 codes (i.e., bacterial meningitis) were assigned. Results from our study also are limited by the restriction of analyses to unexplained deaths for which autopsy status is known and the large variation of autopsy data reported by states to NCHS. Of deaths that met the unexplained death definition, the percentage of missing autopsy status data by state ranged from 0 to 99% during 2003–2006. Additional data on autopsy status reported to NCHS could have more accurately described unexplained death.

Additional studies are needed to assess the similarities in demographic characteristics and clinicopathologic syndromes of persons who died of unexplained possibly infectious causes and characteristics found in autopsies overall. The statistically significant findings of such characteristics as age and race in this study could reflect general trends of autopsies performed and might not be unique to persons whose infectious deaths are unexplained. Furthermore, results from the analysis of Arizona data might not necessarily reflect unexplained deaths in other states or nationally.

Additional insight into persons who died of unexplained infectious causes and underwent autopsies might help pinpoint areas in which diagnostic capabilities or resources are needed (15) and provide opportunities for additional studies. Retrospective studies using postmortem specimens and improved diagnostic tools could benefit the broader community. Improved understanding by health departments and medical examiners of a specific type of unexplained death for which an autopsy is conducted could increase overall awareness of unexplained deaths from infectious causes; improve approaches in the collection of medical history and laboratory results in the forensic setting (37); and strengthen collaboration between health departments, clinicians, and medical examiners. Awareness of the types of unexplained death for which autopsies are less likely to be conducted is also imperative. Clinicians and pathologists challenged by cultural or religious restrictions can consider alternative methods for diagnosis such as taking biopsy samples (38), collecting appropriate antemortem specimens, or performing virtual autopsies (39,40). Retrospective studies evaluating perceptions by families, physicians, and medical examiners on autopsies of persons who died of unexplained infectious causes also might be helpful. Improving education about unexplained death and autopsy, identifying areas where diagnostic resources are needed, and maintaining cooperation between investigators should be considered. Autopsy findings, in conjunction with clinical history and diagnostic tools, can assist surveillance and investigations of infectious diseases of public health concern.