Emerging Infections 4

The global pandemic of human immunodeficiency virus (HIV) infection represents a prime example of an emerging infection. The HIV pandemic has wreaked the majority of its havoc in the developing world, whereas drug-resistant HIV has been a problem among the more privileged economies. It was learned that the use of protease inhibitors as monotherapy or when added to an ongoing regimen was substandard practice, and patients failed with resistant virus. This was followed by another discovery that analogous to tuberculous chemotherapy, prescribing an optimal regimen without the education and support system to encourage patient adherence is no accomplishment and may lead to multiple-drug resistance. One significant difference between tuberculosis and HIV is that the former can be cured. The levels are highest in primary infection, which may be the most infectious period. The genetic barrier to viral escape will have to be raised in using combinations that require multiple mutations and incompatable mutations. The pharmacologic aspects of chemotherapy needs improvement, as many of the protease inhibitors that have relatively short half-lives give trough levels that are really borderline or suboptimal. Drug levels in the various tissue compartments that may represent pharmacologic sanctuaries will have to be attained. It has been learned from multiply resistant tuberculosis that the natural history resembled untreated tuberculosis, especially in the immunosuppressed.

The human enteric caliciviruses, previously known as the Norwalk family of viruses, the "classic human caliciviruses," or the small round-structured viruses, are a group of enteric pathogens that are a common cause of gastroenteritis in children and adults alike. When the gene encoding the capsid was expressed in baculovirus, the resulting protein self-assembled into virus-like particles that looked like natural virus by electron microscopy (EM) and provided replenishable reagents for serologic testing, structural studies, and antigen to develop immunoassays for antigen detection. These molecular discoveries and diagnostic advances have permitted researchers to reassess the clinical and epidemiologic features of illness caused by the caliciviruses and to reconsider public health approaches to their prevention and control. This chapter provides a review to highlight some of the advances in our understanding of calicivirus-associated gastroenteritis following the introduction of new molecular diagnostics, with illustrations drawn from several recent epidemic investigations. Tracing some epidemics back to their source has extended the use of diagnostics to the detection of viruses in contaminated food and water. Despite the major advances in the knowledge of the caliciviruses based upon the understanding of their sequence and molecular organization, the search for simple diagnostic assays has been difficult. Nonetheless, in the process of sequencing many strains, the human enteric caliciviruses fell into two distinct genera. The ability to sequence polymerase chain reaction (PCR) products made it possible to trace the molecular epidemiology of caliciviruses in outbreaks of disease.

This chapter focuses on the use of newer sequence-based methods for discovering novel microbial pathogens and some of the questions raised concerning interpretation of experimental findings. A remarkable degree of microbial diversity has recently emerged from surveys of natural environments that rely on direct acquisition and analysis of microbial gene sequences. Specialization and adaptation to an animal host are believed to involve acquisition of blocks of genes that encode virulence-associated attributes. The use of host markers to measure and predict host inflammation is not new. Two strategies are invoked by those who seek to identify novel or unrecognized microbial pathogens. The first is based on the straightforward notion that these pathogens will be found where there is unexplained disease, and in particular, disease that bears traditional features of infection. The second strategy is based on the observation that pathogens are often found within environmental niches that provide access to more privileged anatomic sites within a host. In addition to the distribution of microbial sequences and other signatures within the human body, the issue of kinetics must be confronted. With increasing experience comes appreciation of subtlety. This holds especially true for the use of microbial sequence-based detection methods. Broad-range ribosomal DNA (rDNA) polymerase chain reaction (PCR) frequently reveals bacterial sequences that are similar to but do not perfectly match any sequence in the available databases.

The inclusion of the group B streptococcus (GBS) in a book on emerging infections published in 2000 may puzzle some readers, since GBS was recognized as a new clinical problem three decades ago. By 1938, however, Fry reported three fatal postpartum maternal infections caused by GBS which presented as pneumonia with multiple liver abscesses and two cases of puerperal sepsis complicated by endocarditis. The responsibility for decisionmaking regarding GBS disease was diffused—therapy for neonatal infections was the province of pediatricians, but interventions to prevent this disease had to be administered by obstetric care givers before delivery. In the screening-based approach, women are screened at 35 to 37 week's gestation, and those who are GBS carriers are offered intrapartum antibiotics. The recommendations appear in the book Guidelines for Perinatal Care, published jointly by American College of Obstetricians and Gynecologists (ACOG) and American Academy of Pediatrics (AAP). While reported practice may be suggestive of increased prevention, the most important benchmark is whether actual disease patterns are altered. Antibiotic prophylaxis was intended to reduce maternal to infant transmission of GBS. Various unintended consequences are potential concerns, and monitoring systems or evaluation projects have been developed to assess some of them. Antibiotic resistance among GBS and other organisms was a major concern. To date, several investigators have evaluated GBS strains from recent patients for susceptibility testing. Clinicians can reduce the chances of serious anaphylaxis by taking very careful histories of penicillin allergy from patients.

Noncholera vibrio infections have emerged as an important public health concern in the United States, Canada, Japan, Taiwan, and many other countries. The majority of noncholera vibrio infections are food-borne, and the major food vehicle is raw molluscan shellfish. Most noncholera vibrios are halophilic (or salt-requiring), and their growth is enhanced by specific ranges of salinity, water temperatures, and pH. The number of noncholera vibrio infections has increased over the past few years, after years of remaining relatively stable. Over the past 10 years, Vibrio parahaemolyticus and V. vulnificus have been the most commonly isolated noncholera Vibrio species. Among the 553 culture-confirmed v. vulnificus infections reported to CDC between 1988 and 1998 through the Vibrio Surveillance System, 44% were classified as primary septicemia, 43% as wound infections, and 7% as gastroenteritis, while 6% were from other or unknown sites of infection. Noncholera Vibrio strains that cause gastroenteritis are usually susceptible to antimicrobial agents used for enteric infections, although most cases of gastroenteritis are mild and self-limited, and they can effectively be treated with oral rehydration. On the other hand, wound and primary septicemia infections require antimicrobial treatment to improve the course of illness and prevent complications. The author recommends that consumers avoid eating raw or undercooked oysters, especially during the warmer months because illness is associated with consuming oysters harvested from warm water. Due to the recent increase in noncholera vibrio infections, all states should consider making infection with any Vibrio species reportable.

In the late 1970s, the first clues that an epidemic due to human immunodeficiency virus type 1 (HIV-1) was beginning to unfold were the opportunistic infections that clinicians recognized in previously healthy individuals who, by the laboratory parameters available and in use at the time, appeared to have no underlying disease. Opportunistic infections continue to occur in HIV-infected individuals in the United States in 2000. Epidemiologic data concerning the frequency of opportunistic infections in the era of highly active antiretroviral therapy, as well as specific studies of clinical outcome for patients enrolled in clinical trials, clearly demonstrate that highly active antiretroviral therapy (HAART) reduces susceptibility to opportunistic infection. Viral load is an independent predictor of the likelihood of developing opportunistic infections, but the risk of developing such complications is still effectively predicted by the current CD4+ T-lymphocyte count. The revised United States Public Health Service-Infectious Disease Society of America guidelines on prophylaxis of opportunistic infections, which were published in August 1999, continue to stress the importance of initiating primary prophylaxis for pneumocystosis, Mycobacterium avium complex disease, toxoplasmosis, and tuberculosis for patients who meet the well-established criteria.

There is considerable controversy as to which biological agents should concern us, either for defense against military use or, for defense against terrorism. The mosquito-transmitted yellow fever virus is classified as biosafety level 3 (BSL 3), but it is aerosolinfectious and has a high case fatality, which are ameliorated by the existence of a very effective vaccine. The viral hemorrhagic fever (VHF) has appropriate properties for aerosol weapons, and this chapter concentrates on three viruses: Machupo virus, Rift Valley fever (RVF) virus, and Marburg virus. The RVF virus is the most stable of the VHF when stored in the liquid or frozen state. Intravenous ribavirin would be expected to be fairly effective against Machupo virus and perhaps helpful in RVF, but stocks are limited and not readily accessible. VHF seems to be very likely agents for lethal state-sponsored actions against large numbers of people. The severe dramatic disease they produce, with its attendant need for intensive supportive care, would increase their impact. Education of clinicians is extremely important as well and is occurring in the context of both travel medicine and bioterrorism defense.