Edward T. Ryan

The Practice of Travel Medicine: Guidelines by the Infectious Diseases Society of America

David R. Hill, Charles D. Ericsson, Richard D. Pearson, Jay S. Keystone, David O. Freedman, Phyllis E. Kozarsky, Herbert L. DuPont, Frank J. Bia, Philip R. Fischer, and Edward T. Ryan National Travel Health Network and Centre and Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, England; Department of Medicine, University of Toronto, and Center for Travel and Tropical Medicine, Toronto General Hospital, Toronto, Ontario, Canada; Department of Internal Medicine, Clinical Infectious Diseases, University of Texas Medical School at Houston, Department of Internal Medicine, St. Luke’s Hospital, and Center for Infectious Diseases, University of Texas at Houston School of Public Health, and Department of Medicine, Baylor College of Medicine, Houston, Texas; Departments of Medicine and Pathology, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia; Departments of Medicine and Epidemiology, Division of Geographic Medicine, University of Alabama at Birmingham, Birmingham; Department of Medicine, Infectious Diseases, Emory University School of Medicine, and 16 Division of Global Migration and Quarantine, Centers for Disease Control and Prevention, Atlanta, Georgia; Department of Medicine and Laboratory Medicine, Yale Medical School, New Haven, Connecticut; Department of Pediatrics, Division of General Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, and Mayo Eugenio Litta Children’s Hospital, Mayo Clinic, Rochester, Minnesota; and Department of Medicine, Division of Infectious Diseases, Harvard Medical School, Harvard School of Public Health, and Tropical and Geographic Medicine Center, Massachusetts General Hospital, Boston, Massachusetts

Susceptibility to Vibrio cholerae Infection in a Cohort of Household Contacts of Patients with Cholera in Bangladesh

Background Despite recent progress in understanding the molecular basis of Vibrio cholerae pathogenesis, there is relatively little knowledge of the factors that determine the variability in human susceptibility to V. cholerae infection. Methods and Findings We performed an observational study of a cohort of household contacts of cholera patients in Bangladesh, and compared the baseline characteristics of household members who went on to develop culture-positive V. cholerae infection with individuals who did not develop infection. Although the vibriocidal antibody is the only previously described immunologic marker associated with protection from V. cholerae infection, we found that levels of serum IgA specific to three V. cholerae antigens—the B subunit of cholera toxin, lipopolysaccharide, and TcpA, the major component of the toxin–co-regulated pilus—also predicted protection in household contacts of patients infected with V. cholerae O1, the current predominant cause of cholera. Circulating IgA antibodies to TcpA were also associated with protection from V. cholerae O139 infection. In contrast, there was no association between serum IgG antibodies specific to these three antigens and protection from infection with either serogroup. We also found evidence that host genetic characteristics and serum retinol levels modify susceptibility to V. cholerae infection. Conclusions Our observation that levels of serum IgA (but not serum IgG) directed at certain V. cholerae antigens are associated with protection from infection underscores the need to better understand anti–V. cholerae immunity at the mucosal surface. Furthermore, our data suggest that susceptibility to V. cholerae infection is determined by a combination of immunologic, nutritional, and genetic characteristics; additional factors that influence susceptibility to cholera remain unidentified.

Blood Group, Immunity, and Risk of Infection with Vibrio cholerae in an Area of Endemicity

ABSTRACT Individuals with blood group O are more susceptible than other individuals to severe cholera, although the mechanism underlying this association is unknown. To assess the respective roles of both intrinsic host factors and adaptive immune responses that might influence susceptibility to infection with Vibrio cholerae, we prospectively followed a cohort of household contacts of patients with cholera in Bangladesh. In this study, we made the novel observation that persons with blood group O were less likely than those with other blood groups to become infected with V. cholerae O1 (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.53 to 0.85; P = 0.008). Consistent with prior studies, however, household contacts with blood group O were more likely to develop severe illness if infected with V. cholerae O1 (OR, 2.3; 95% CI, 0.98 to 5.59; P = 0.05). While blood group O protected significantly against infection with V. cholerae O1, there was no evidence of protection against V. cholerae O139. A multivariate analysis demonstrated that the association between blood group O and protection from infection with V. cholerae O1 was independent of age, gender, and baseline anti-cholera toxin and vibriocidal antibody titers. Based on this epidemiologic evidence, we propose a hypothesis for understanding the association between blood group O and the risk of infection with V. cholerae O1 and O139 as well as the risk of developing severe symptoms once infected.

Infectious diseases of severe weather-related and flood-related natural disasters.

Purpose of reviewThe present review will focus on some of the possible infectious disease consequences of disastrous natural phenomena and severe weather, with a particular emphasis on infections associated with floods and the destruction of infrastructure. Recent findingsThe risk of infectious diseases after weather or flood-related natural disasters is often specific to the event itself and is dependent on a number of factors, including the endemicity of specific pathogens in the affected region before the disaster, the type of disaster itself, the impact of the disaster on water and sanitation systems, the availability of shelter, the congregating of displaced persons, the functionality of the surviving public health infrastructure, the availability of healthcare services, and the rapidity, extent, and sustainability of the response after the disaster. Weather events and floods may also impact disease vectors and animal hosts in a complex system. SummaryWeather or flood-related natural disasters may be associated with an increased risk of soft tissue, respiratory, diarrheal, and vector-borne infectious diseases among survivors and responders.

Use of in vivo-induced antigen technology (IVIAT) to identify genes uniquely expressed during human infection with Vibrio cholerae

In vivo-induced antigen technology is a method to identify proteins expressed by pathogenic bacteria during human infection. Sera from 10 patients convalescing from cholera infection in Bangladesh were pooled, adsorbed against in vitro-grown El Tor Vibrio cholerae O1, and used to probe a genomic expression library in Escherichia coli constructed from El Tor V. cholerae O1 strain N16961. We identified 38 positive clones in the screen, encoding pili (PilA and TcpA), cell membrane proteins (PilQ, MshO, MshP, and CapK), methyl-accepting chemotaxis proteins, chemotaxis and motility proteins (CheA and CheR), a quorum-sensing protein (LuxP), and four hypothetical proteins. Analysis of immune responses to purified PilA and TcpA in individual patients demonstrated that the majority seroconverted to these proteins, confirming results with pooled sera. These results suggest that PilA and its outer membrane secretin, PilQ, are expressed during human infection and may be involved in colonization of the gastrointestinal tract. These results also demonstrate substantial immune responses to TcpA in patients infected with El Tor V. cholerae O1. In vivo-induced antigen technology provides a simple method for identifying microbial proteins expressed during human infection, but not during in vitro growth.

Environmental Enteric Dysfunction: Pathogenesis, Diagnosis, and Clinical Consequences

Stunting is common in young children in developing countries, and is associated with increased morbidity, developmental delays, and mortality. Its complex pathogenesis likely involves poor intrauterine and postnatal nutrition, exposure to microbes, and the metabolic consequences of repeated infections. Acquired enteropathy affecting both gut structure and function likely plays a significant role in this outcome, especially in the first few months of life, and serve as a precursor to later interactions of infection and malnutrition. However, the lack of validated clinical diagnostic criteria has limited the ability to study its role, identify causative factors, and determine cost-effective interventions. This review addresses these issues through a historical approach, and provides recommendations to define and validate a working clinical diagnosis and to guide critical research in this area to effectively proceed. Prevention of early gut functional changes and inflammation may preclude or mitigate the later adverse vicious cycle of malnutrition and infection.

Meeting cholera's challenge to Haiti and the world: a joint statement on cholera prevention and care.

Cholera in Haiti: Acute-on-Chronic Long before the devastating earthquake on January 12, 2010, Haiti struggled beneath the burdens of intractable poverty and ill health. The poorest country in the Western Hemisphere, Haiti also faces some of the highest rates of maternal and infant mortality—widely used indicators of the robustness of a health system—in the world ([S1] in Text S1; [2], [3]). The October 2010 cholera outbreak is the most recent of a long series of affronts to the health of Haitis population; it is yet another acute symptom of the chronic weakness of Haitis health, water, and sanitation systems. Water and sanitation conditions highlight these systemic weaknesses. In 2002, Haiti ranked last out of 147 countries for water security [4], [5]. Before the earthquake struck, only half of the population in the capital, Port-au-Prince, had access to latrines or other forms of modern sanitation, and roughly one-third had no access to tap water [6]. Across the country, access to sanitation and clean water is even more limited: only 17% of Haitians had access to adequate sanitation in 2008, and 12% received treated water [7]. Not surprisingly, diarrheal diseases have long been a significant cause of death and disability, especially among children under 5 years of age [6]. The cholera outbreak began less than a year after a 7.0-magnitude earthquake took the lives of more than 300,000 people and left nearly 1.5 million homeless [6]. Almost 1 million Haitians still live in spontaneous settlements known as internally displaced persons (IDP) camps [8]. While post-earthquake conditions in Haiti were ripe for outbreaks of acute diarrheal illness, cholera was deemed “very unlikely to occur” by the United States Centers for Disease Control and Prevention (CDC) and other public health authorities [9]. Cholera had never before been reported in Haiti [S2] [10], [11]; health providers were unprepared for an influx of patients presenting with acute watery diarrhea. The cholera epidemic has been most severe in rural areas and large urban slums. Rural communities were charged with hosting hundreds of thousands of displaced people after the earthquake, placing greater demands on their already-scarce resources, including water. Surface water drawn directly from the source or piped from rivers and streams constitutes the principal supply of drinking water in rural Haiti. The lack of adequate piping, filtration, and water treatment systems (including chlorination) made these rural regions vulnerable to the rapid spread of waterborne disease. While most IDP camps have been supplied with potable water, large urban slums have had to rely on existing water sources—some of them containing Vibrio cholerae—and have therefore been vulnerable to rapid disease spread. Most slums also have poor sanitation infrastructure. Since the first cases were reported in Saint-Marc and Mirebalais, cholera has spread to every department in Haiti, and to other countries, too [S3] [12]–[14]. Public suspicion (ultimately validated by genomic sequence analyses [15]) of the strains link to South Asia, home to a group of United Nations peacekeepers stationed in central Haiti, triggered blame and violence that interfered with response efforts. As we have learned from the global AIDS pandemic and other infectious disease epidemics, cycles of accusation can continue for years, diverting attention and resources from the delivery of care and prevention services [16]. Systemic problems that brought cholera to epidemic levels in Haiti will (unless addressed) continue to facilitate its spread. As a disease of poverty, cholera preys upon the bottom of the social gradient; international trade, migration, and travel—from South Asia or elsewhere—open direct channels for pathogens that follow social fault lines.

Transcriptional Profiling of Vibrio cholerae Recovered Directly from Patient Specimens during Early and Late Stages of Human Infection

ABSTRACT Understanding gene expression by bacteria during the actual course of human infection may provide important insights into microbial pathogenesis. In this study, we evaluated the transcriptional profile of Vibrio cholerae, the causative agent of cholera, in clinical specimens from cholera patients. We collected samples of human stool and vomitus that were positive by dark-field microscopy for abundant vibrios and used a microarray to compare gene expression in organisms recovered directly from specimens collected during the early and late stages of human infection. Our results reveal that V. cholerae gene expression within the human host environment differs from patterns defined in in vitro models of pathogenesis. tcpA, the major subunit of the essential V. cholerae colonization factor, was significantly more highly expressed in early than in late stages of infection; however, the genes encoding cholera toxin were not highly expressed in either phase of human infection. Furthermore, expression of the virulence regulators toxRS and tcpPH was uncoupled. Interestingly, the pattern of gene expression indicates that the human upper intestine may be a uniquely suitable environment for the transfer of genetic elements that are important in the evolution of pathogenic strains of V. cholerae. These findings provide a more detailed assessment of the transcriptome of V. cholerae in the human host than previous studies of organisms in stool alone and have implications for cholera control and the design of improved vaccines.

Antigen-Specific Memory B-Cell Responses to Vibrio cholerae O1 Infection in Bangladesh

ABSTRACT Cholera, caused by Vibrio cholerae, is a noninvasive dehydrating enteric disease with a high mortality rate if untreated. Infection with V. cholerae elicits long-term protection against subsequent disease in countries where the disease is endemic. Although the mechanism of this protective immunity is unknown, it has been hypothesized that a protective mucosal response to V. cholerae infection may be mediated by anamnestic responses of memory B cells in the gut-associated lymphoid tissue. To characterize memory B-cell responses to cholera, we enrolled a cohort of 39 hospitalized patients with culture-confirmed cholera and evaluated their immunologic responses at frequent intervals over the subsequent 1 year. Memory B cells to cholera antigens, including lipopolysaccharide (LPS), and the protein antigens cholera toxin B subunit (CTB) and toxin-coregulated pilus major subunit A (TcpA) were enumerated using a method of polyclonal stimulation of peripheral blood mononuclear cells followed by a standard enzyme-linked immunospot procedure. All patients demonstrated CTB, TcpA, and LPS-specific immunoglobulin G (IgG)and IgA memory responses by day 90. In addition, these memory B-cell responses persisted up to 1 year, substantially longer than other traditional immunologic markers of infection with V. cholerae. While the magnitude of the LPS-specific IgG memory B-cell response waned at 1 year, CTB- and TcpA-specific IgG memory B cells remained significantly elevated at 1 year after infection, suggesting that T-cell help may result in a more durable memory B-cell response to V. cholerae protein antigens. Such memory B cells could mediate anamnestic responses on reexposure to V. cholerae.

Implications of Acquired Environmental Enteric Dysfunction for Growth and Stunting in Infants and Children Living in Low- and Middle-Income Countries:

Changes in small bowel function early in infancy in developing countries are increasingly being demonstrated, probably accompanied by altered mucosal architecture in most individuals, including reduced enterocyte mass and evidence of immune activation and inflammation in the mucosa. These alterations appear to be the result of factors of uncertain nature in the environment, and may be a cause of growth faltering and stunting in young children. For these reasons, this constellation of findings is being referred to as environmental enteropathy, or as we propose herein, environmental enteric dysfunction. If the causes were known and effective interventions were available, strategies and policies to intervene at—or possibly before—birth could be developed and promoted in order to prevent subsequent malnutrition and recurrent infection, which are known to interact in a cyclical and synergistic manner in a downward clinical course often ending in death. Resources would be mobilized and applied differently, and the emphasis would change from treatment to prevention. In order to move in this highly desired direction, investments in research will be required to establish the criteria to assess environmental enteric dysfunction, determine its predictive value for growth faltering and stunting, identify the causes, and propose and test potential interventions. The concepts and tools are available. What is required is the decision to move forward along this pathway to better health for infants and children in low-income countries.