Features of a number of important but poorly explained human clinical syndromes strongly indicate a microbial etiology. In these syndromes, the failure of cultivation-dependent microbial detection methods reveals our ignorance of microbial growth requirements. Sequence-based molecular methods, however, offer alternative approaches for microbial identification directly from host specimens found in the setting of unexplained acute illnesses, chronic inflammatory disease, and from anatomic sites that contain commensal microflora. The rapid expansion of genome sequence databases and advances in biotechnology present opportunities and challenges: identification of consensus sequences from which reliable, specific phylogenetic information can be inferred for all taxonomic groups of pathogens, broad-range pathogen identification on the basis of virulence-associated gene families, and use of host gene expression response profiles as specific signatures of microbial infection.

Since 1986, approximately 170,000 cases of bovine spongiform encephalopathy (BSE) have occurred among approximately one million animals infected by contaminated feed in the United Kingdom. A ruminant feed ban in 1988 resulted in the rapid decline of the epidemic. Transmissible spongiform encephalopathies due to agents indistinguishable from BSE have appeared in small numbers of exotic zoo animals; a small outbreak among domestic cats is declining. Creutzfeldt-Jakob disease (CJD) has been intensively monitored since 1990 because of the risk BSE could pose to public health. In 1995, two adolescents in the United Kingdom died of CJD, and through the early part of 1996, other relatively young people had cases of what became known as new variant CJD, whose transmissible agent (indistinguishable from that of BSE) is responsible for 26 cases in the United Kingdom and one in France. Areas of concern include how many cases will appear in the future and whether or not use of human blood and blood products may cause a second cycle of human infections.

A recent upsurge of malaria in endemic-disease areas with explosive epidemics in many parts of Africa is probably caused by many factors, including rapidly spreading resistance to antimalarial drugs, climatic changes, and population movements. In Africa, malaria is caused by Plasmodium falciparum and is transmitted by Anopheles gambiae complex. Control efforts have been piecemeal and not coordinated. Strategies for control should have a solid research base both for developing antimalarial drugs and vaccines and for better understanding the pathogenesis, vector dynamics, epidemiology, and socioeconomic aspects of the disease. An international collaborative approach is needed to build appropriate research in a national context and to effectively translate research results into practical applications in the field. The Multilateral Initiative for Malaria in Africa can combine all of the above strategies to plan and coordinate partnerships, networking, and innovative approaches between African scientists and their Northern partners.

Historically, staphylococci, pseudomonads, and Escherichia coli have been the nosocomial infection troika; nosocomial pneumonia, surgical wound infections, and vascular accessrelated bacteremia have caused the most illness and death in hospitalized patients; and intensive care units have been the epicenters of antibiotic resistance. Acquired antimicrobial resistance is the major problem, and vancomycin-resistant Staphylococcus aureus is the pathogen of greatest concern. The shift to outpatient care is leaving the most vulnerable patients in hospitals. Aging of our population and increasingly aggressive medical and surgical interventions, including implanted foreign bodies, organ transplantations, and xenotransplantation, create a cohort of particularly susceptible persons. Renovation of aging hospitals increases risk of airborne fungal and other infections. To prevent and control these emerging nosocomial infections, we need to increase national surveillance, "risk adjust" infection rates so that interhospital comparisons are valid, develop more noninvasive infection-resistant devices, and work with health-care workers on better implementation of existing control measures such as hand washing.

In the past few years, emergent disease episodes have increased; nearly all have involved zoonotic or species-jumping infectious agents. Because there is no way to predict when or where the next important new zoonotic pathogen will emerge or what its ultimate importance might be, investigation at the first sign of emergence of a new zoonotic disease is particularly important. Such investigation may be described in terms of a discovery-to-control continuum: from recognition of a new disease in a new setting to complex phases involving the hard science disciplines pertaining to discovery, the epidemiologic sciences pertaining to risk assessment, and activities pertaining to risk management. Today, many activities involving zoonotic disease control are at risk because of a failed investigative infrastructure or financial base. Because zoonotic diseases are distinct, their prevention and control will require unique strategies, based more on fundamental research than on traditional approaches. Such strategies require that we rebuild a cadre of career-committed professionals with a holistic appreciation of several medical and biologic sciences.

Because all known influenza A subtypes exist in the aquatic bird reservoir, influenza is not an eradicable disease; prevention and control are the only realistic goals. If people, pigs, and aquatic birds are the principal variables associated with interspecies transfer of influenza virus and the emergence of new human pandemic strains, influenza surveillance in these species is indicated. Live-bird markets housing a wide variety of avian species together (chickens, ducks, geese, pigeon, turkeys, pheasants, guinea fowl), occasionally with pigs, for sale directly to the public provide outstanding conditions for genetic mixing and spreading of influenza viruses; therefore, these birds should be monitored for influenza viruses. Moreover, if pigs are the mixing vessel for influenza viruses, surveillance in this population may also provide an early warning system for humans.

Vector-borne infectious diseases are emerging or resurging as a result of changes in public health policy, insecticide and drug resistance, shift in emphasis from prevention to emergency response, demographic and societal changes, and genetic changes in pathogens. Effective prevention strategies can reverse this trend. Research on vaccines, environmentally safe insecticides, alternative approaches to vector control, and training programs for health-care workers are needed.

Powerful diagnostic technology, plus the realization that organisms of otherwise unimpressive virulence can produce slowly progressive chronic disease with a wide spectrum of clinical manifestations and disease outcomes, has resulted in the discovery of new infectious agents and new concepts of infectious diseases. The demonstration that final outcome of infection is as much determined by the genetic background of the patient as by the genetic makeup of the infecting agent is indicating that a number of chronic diseases of unknown etiology are caused by one or more infectious agents. One well-known example is the discovery that stomach ulcers are due to Helicobacter pylori. Mycoplasmas may cause chronic lung disease in newborns and chronic asthma in adults, and Chlamydia pneumoniae, a recently identified common cause of acute respiratory infection, has been associated with atherosclerosis. A number of infectious agents that cause or contribute to neoplastic diseases in humans have been documented in the past 6 years. The association and causal role of infectious agents in chronic inflammatory diseases and cancer have major implications for public health, treatment, and prevention.

The threat of bioterrorism, long ignored and denied, has heightened over the past few years. Recent events in Iraq, Japan, and Russia cast an ominous shadow. Two candidate agents are of special concern: smallpox and anthrax. The magnitude of the problems and the gravity of the scenarios associated with release of these organisms have been vividly portrayed by two epidemics of smallpox in Europe during the 1970s and by an accidental release of aerosolized anthrax from a Russian bioweapons facility in 1979. Efforts in the United States to deal with possible incidents involving bioweapons in the civilian sector have only recently begun and have made only limited progress. Only with substantial additional resources at the federal, state, and local levels can a credible and meaningful response be mounted. For longer-term solutions, the medical community must educate both the public and policy makers about bioterrorism and build a global consensus condemning its use.