Unexplained sudden illnesses and deaths can be sentinels for the recognition of newly emerging infections and for the early detection of outbreaks of naturally occurring or intentionally released infectious agents. If laboratory tests are negative or inconclusive and a patient dies, thorough pathologic investigation aides in identifying the etiologic agent. Over the past several decades, the Centers for Disease Control and Prevention (CDC) has effectively used infectious disease pathology to diagnose the causes of sudden illness and death and to assist in identifying sources of multiple high-profile outbreaks, many of which were caused by new and reemerging etiologic agents.

When hantavirus pulmonary syndrome was first identified in 1993 in the Four Corners area of the southwestern United States, pathologic examination was critical for characterizing the illness and contributed to discovery of the etiologic agent (22). Autopsy and examination of biopsied tissues played a major role in the investigation of the bioterrorism-related anthrax cases in 2001 in the United States. During the early phase of the epidemic of severe acute respiratory syndrome (SARS) in 2003, investigations focused on characterizing the etiologic agent of what appeared to be a severe respiratory illness spreading among household contacts and to health care workers. Attempts to identify an infectious agent by standard laboratory testing failed to produce consistent results. As the number of SARS-related deaths increased, specimens examined by virus isolation techniques, electron microscopy, and pathologic examination led to identification of the causative agent of SARS as a novel coronavirus (23). More recently, infectious disease pathology has been instrumental in the investigation of a multistate outbreak of fungal meningitis associated with epidural injection of steroid preparations and in the identification of several organ transplant–associated infections, such as lymphocytic choriomeningitis virus, Balamuthia disease, and rabies.

We briefly described only selected examples of low-incidence, high-consequence pathogens. Many other similar infectious diseases with relatively low incidence but high-rates of death occur in many parts of the world. Besides those mentioned above, other low-incidence, high-consequence pathogens described in this issue of Emerging Infectious Diseases include Crimean-Congo hemorrhagic fever and Rift Valley fever. Ongoing surveillance and public health research of high-consequence pathogens are critical for identifying their natural reservoirs, developing diagnostic tests, and devising appropriate control and prevention measures. Studying the molecular characteristics of these pathogens is critical to understanding their pathogenesis and ultimately to developing vaccines and antimicrobial drugs. Despite low incidence of these diseases, maintaining a preparedness posture to tackle the challenges posed by the emergence or reemergence of some of these pathogens should remain a priority. Public health resources are wisely spent by adequately preparing for the inevitable emergence or reemergence of infectious diseases that might currently be of low incidence but have the potential to spread to immunologically naive populations. The application of the age-old tools of pathology bolstered with a wide array of bioassays, developed by using modern advances in molecular diagnostics, has helped CDC tackle old infectious disease challenges and newly emerging and reemerging diseases. Advanced molecular detection approaches in concert with infectious disease pathology can play a prominent role in emergency preparedness and in addressing the public health challenges of the future.