Lisa V. Adams, Elizabeth A. Talbot
Emerging and Reemerging Infectious Diseases
Terms such as “emerging” and “reemerging” diseases increasingly appear in the clinical and even public parlance. Our patients are regularly bombarded by media stories about and images of these diseases and consequently often have questions (or even fears) that they might present to us. Because primary care providers are frequently on the front lines of the global battle to control these pathogens, this chapter intends to provide an overview of this category of diseases to improve our understanding and thereby our preparedness.
Definitions
Emerging infectious diseases result from newly discovered and previously unknown infections that threaten public health. Increased international travel and trade, deforestation and changing ecosystems, and rapid adaptation of microorganisms have contributed to this problem (Box 229-1).1 For example, the 2009-2010 influenza A pandemic that was caused by a novel influenza A H1N1 virus spread within months from Mexico and other countries in the Southern Hemisphere to become the predominant influenza virus circulating in most countries.2
Reemerging infectious diseases are those that had formerly caused so few infections that they were no longer considered a public health threat but have recently reactivated.1 Dengue fever (DF) is an example of a reemerging infectious disease; its vector, the Aedes aegypti mosquito, has distributed it from Africa throughout the Americas via expanding world commerce. In addition, the gradual discontinuation of yellow fever mosquito control programs has allowed the A. aegypti mosquito to expand its geographic distribution in South America, the Caribbean, and now the southern United States, where cases of DF are more prevalent and more severe than in the past.
Risk Factors Favoring Emergence of Pathogens
Our recent history has witnessed a rapid succession of newly identified pathogens—reemergent and now resistant bacteria, reemergent diarrheal illnesses (see Chapter 232) in developing nations, new respiratory pathogens, and vector-borne illnesses. Reasons for the emergence of infectious diseases are outlined in Box-229-1.
Central to the epidemiology of emerging and reemerging pathogens is the concept of globalization. Never before in human history have we been as vulnerable to diseases that were previously geographically contained. With the ease of global transport of people, animals, insect vectors, food, and goods, there is real and imminent risk of the introduction of new diseases that might be seen in primary care. Our interconnected world allows well-known pathogens rapid access to new, immunologically naive populations and facilitates the spread of novel pathogens and antimicrobial resistance. The following are some recent examples:
• Human immunodeficiency virus (HIV) (see Chapter 230) emerged when the simian immunodeficiency virus jumped species from African green monkeys to human populations, and then rapidly spread throughout the world.
In addition to globalization, changes in our societies and lifestyles have also been permissive for emergence and reemergence of certain infectious diseases. For example:
• Tuberculosis (TB) (see Chapter 235) has been an historic plague of humans, but trends toward urbanization and overcrowding have been linked to outbreaks of multidrug-resistant tuberculosis (MDR-TB).
• Epidemics of injection drug abuse have contributed to the HIV and hepatitis C epidemics.
Natural disasters and infrastructure deterioration have also contributed to emergence and reemergence of certain pathogens:
Pathogens
For this discussion, major emerging pathogens are categorized by their syndromes (e.g., respiratory, gastrointestinal), their mechanism of transmission (e.g., vector, zoonotic), and their threat through emerging antibiotic resistance. This discussion is intended to prepare the primary care clinician for expanding differential diagnoses and appropriate referral.
Acute Respiratory Diseases
Coronaviruses.
Coronaviruses are pathogens in animals and humans, well known as a cause of the common cold. SARS is a coronavirus that emerged in 2002 from Guangdong Province, China.3 It caused a severe and often fatal pneumonia, with prominent systemic symptoms. An incubation period of 4 to 7 days was followed by fever, an influenza-like illness, and, a few days later, symptoms of pneumonia, diarrhea, leukopenia, thrombocytopenia, and characteristically lymphopenia. Laboratory diagnosis was best made by detection of antibody, which appears about 10 days into the illness, or reverse transcriptase polymerase chain reaction (RT-PCR) on bronchial secretions.4 About 25% of patients developed severe pneumonia complicated by acute respiratory distress syndrome (ARDS). Mortality was as high as 50% in older patients and hosts with underlying disease,3 and survivors had significantly reduced exercise capacity and health status compared with the general population.5
The intrigue of SARS lies in its abrupt emergence as a new human pathogen. A coronavirus from a palm civet and/or a ferret badger in the live animal markets jumped species into humans and spread rapidly from person-to-person locally and then internationally via air travel. SARS also had high morbidity and mortality rates associated with spread in naive populations, with more than 8000 cases and 780 deaths reported from 29 countries before the outbreak ended in June 2003. We have not seen another case to date, but concern lingers because SARS coronavirus has been isolated from open-market animals and could still be circulating in animals only to reemerge as a human pathogen.6
Middle East Respiratory Syndrome.
MERS is an emerging illness cause by a previously unknown coronavirus called Middle East respiratory syndrome coronavirus. The first case, reported in a 60-year-old man who lived in Saudi Arabia, had a fatal outcome.7 At the time of this writing, all cases have been linked directly or indirectly to countries in the Arabian Peninsula, most notably Saudi Arabia, Qatar, Jordan, and the United Arab Emirates.8 Transmission to health care workers caring for MERS patients has been documented, providing an important reminder to primary care clinicians to screen patients with consistent symptoms for any relevant travel history in order to institute appropriate infection control practices.9
After a 2- to 14-day incubation period, MERS patients typically develop fever, cough, and shortness of breath. Some will have gastrointestinal symptoms including diarrhea and/or nausea and vomiting. As with SARS, most patients progress to ARDS with multiorgan system failure. The mortality rate is approximately 55%.8,10
Those advising patients traveling to the affected region should check the website of the Centers for Disease Control and Prevention (CDC) for any updates on travel advisories. The current recommendations to travelers include fastidious adherence to routine measures to prevent respiratory illnesses, including washing hands, avoiding personal contact such as kissing and sharing eating utensils with ill individuals, and disinfecting frequently used surfaces such as doorknobs.11
Human Metapneumovirus.
Human metapneumovirus (hMPV) is an example of a pathogen that has probably been causing respiratory tract illness for many years but is considered emerging because it has only recently been recognized. Discovered in 2001 by researchers applying molecular polymerase chain reaction (PCR) techniques to children with previously unexplained pneumonia, hMPV is now recognized to cause at least 5% to 10% of pediatric hospitalizations for lower respiratory tract illness in the United States.12 Given how many children are hospitalized each year with lower respiratory tract illness, hMPV represents an important cause of morbidity and mortality. Serologic studies demonstrate antibodies to hMPV in virtually all children by the age of 5 years.12 Although primarily recognized as a pediatric disease, hMPV has also recently been recognized in adults, most clearly as a major cause of severe lower respiratory tract illness in immunocompromised adults and elders.
HMPV causes a spectrum of illness ranging from upper to lower respiratory tract illness and is clinically indistinguishable from the more familiar respiratory syncytial virus (RSV) infection. hMPV is often milder and affects a slightly older group of children (6 to 12 months of age) in contrast to RSV, which often affects infants before 2 months of age.12,13 Like RSV and influenza, hMPV circulates predominately in winter months, which is when it should be especially considered in the differential diagnosis. Because influenza, RSV, and hMPV share common seasonality and hosts, vigilance toward diagnosing coinfections should be maintained.
Diagnosis is best made with real-time PCR on bronchial secretions. The virus is difficult to grow, and serologic tests are yet to be standardized. No vaccine or antiviral therapy is available, but studies show that ribavirin and intravenous immune globulin inhibit hMPV in vitro. Repeated episodes of asymptomatic infection or with common cold symptoms maintain immunity in adults.13
Influenza A.
See Chapter 231. Pandemic influenza A by definition is an emerging pathogen, which can cause staggering human morbidity and mortality, and an accompanying massive resource expenditure. Pandemic flu classically arises through an antigenic shift, which is a rearrangement of animal influenza genes into a human influenza virus. But we now also know that lesser changes (“antigenic drift”) can sometimes cause pandemics, as was shown by sequencing the 1918 pandemic influenza virus, which killed as many as 30 million people worldwide.14
Influenza A impels us toward improved understanding of zoonotic viruses, continued surveillance in human and animal populations through international networks, and development of an influenza vaccine that offers broad protection against different viral variants. One vivid example of a recently emerged influenza virus is the 2009-2010 influenza pandemic. International air travel rapidly disseminated a new influenza A virus globally: within 6 months after the virus’s emergence was recognized in Mexico, the World Health Organization (WHO) declared that the criteria for a pandemic had been met.2,15,16 Global initiatives enabled public health jurisdictions to implement diagnostic and clinical management algorithms and international networks for surveillance and research, to track the virus and its evolution, and to optimize clinical outcomes.
We now know that the causative H1N1 influenza A virus is antigenically distinct from the preexisting seasonal human influenza virus and resulted from the reassortment between two influenza A (H1N1) swine viruses that themselves were the products of several independent avian to mammalian cross-species transmissions and prior reassortments among avian, human, and swine viruses.17 Like the viruses responsible for the influenza pandemics of 1957 and 1968, the 2009 H1N1 virus is a descendant of the 1918 pandemic virus.18 Unlike with seasonal influenza, children and young adults rather than elders experienced the highest attack rates from influenza A (H1N1) because most adults older than 60 years had protection from cross-protective antibodies they had developed from prior exposure to antigenically related influenza viruses.19
Clinical features, diagnostic approaches, treatment, and prevention of influenza A (H1N1) are discussed in Chapter 231.
Avian Influenza A (H5N1).
Avian influenzas are always circulating among birds but do not usually “jump species” to infect mammalian cells. In 1997, a small outbreak of avian influenza A (H5N1) occurred within the live poultry markets of Hong Kong. This outbreak was unique in that the virus jumped from birds to humans and caused severe illness in 18 previously healthy adults, six of whom died. There was no human-to-human transmission, and an unprecedented culling of the entire poultry population of Hong Kong contained the outbreak. But in 2003, the same virus reemerged as the cause of a massive poultry outbreak across Asia. Human cases of H5N1 have followed in parallel to the geographic spread of the poultry pandemic. Most human cases had direct exposure to diseased birds. Although there have been family clusters, human-to-human transmission remains limited and unsustained.20
Primary care clinicians have a paramount role in providing their patients with seasonal influenza vaccination. The seasonal influenza vaccine will not protect us from avian influenza (H5N1), but 30,000 to 50,000 die each year in the United States from current endemic influenza strains, and immunization will prevent other influenza illnesses from being confused with avian influenza should human-to-human transmission become more facile. In 2013, the Food and Drug Administration approved the first adjuvanted vaccine to prevent avian influenza.21 This vaccine could prove very useful if the H5N1 virus develops the capability for efficient human-to-human spread, which could lead to the next human pandemic.
Acute Diarrheal Illnesses
Vibrio cholerae.
Cholera epidemics (see Chapter 232) characteristically emerge, decline, and reemerge throughout human history, brought on by natural disasters, civil war, and displaced populations. Six pandemics, caused by the classic biotype Vibrio cholerae O1, occurred before 1926, originated in Asia and India, and traveled in infected patients to Europe and the Americas. The seventh and current pandemic is caused by a new classic biotype, El Tor, first isolated in Egypt. It causes milder disease, which remained sporadic and endemic throughout Africa, Europe, and Asia for many years. Emergence of a new strain, V. cholerae O139, began in India and Bangladesh in 1992. Past exposure to V. cholerae O1 offers no immunity to V. cholerae O139, which has also been noted to be resistant to trimethoprim-sulfamethoxazole.22
V. cholerae is naturally found in water, attached to algae, crustaceans, and plankton. Warmer-than-usual waters (e.g., because of El Niño) facilitate its growth by changes in nutrients and salinity (e.g., from monsoons, tsunamis, and typhoons).23 In this activated state, humans are more likely to become infected and transmit infection through fecally contaminated food or water. Direct person-to-person spread is unlikely because of the large inoculum required for infection. Infants and young children bear the brunt of epidemics in resource-limited nations, where 80% of all diarrheal deaths occur in children younger than 5 years.24
Disasters provide ready availability of contaminated water and food. In a recent tragic example of this reality, the catastrophic January 2010 earthquake in Haiti killed over 200,000 people and displaced over 1 million. Ten months after the earthquake, the Haitian Ministry of Public Health and Population was notified of a sudden increase in patients with watery diarrhea and dehydration. On October 21, 2010, the Haiti National Public Health Laboratory identified the pathogen as V. cholera. The first cholera outbreak in Haiti in at least a century was announced, and, at the time of this writing, over 470,000 cases of cholera have now been reported in Haiti, with 6631 attributable deaths. This marks the worst cholera outbreak in recent history, as well as the best-documented cholera outbreak in modern public health.25
Severe dehydration, electrolyte imbalance, renal failure, and metabolic acidosis can be fatal complications of cholera, and oral or intravenous rehydration is the most important intervention to avert death. Mortality is as high as 10% in epidemic settings without adequate health care support but 3% or less in centers versed in simple hydration techniques. Antibiotics are secondary in importance to hydration. One 300-mg dose of doxycycline, 1 g of ciprofloxacin, or 1 tablet of trimethoprim-sulfamethoxazole twice daily for 3 days is effective treatment if the organism is sensitive. Emerging antibiotic resistance is a problem for developing nations. Fortunately, cholera is a predictably reemergent disease most likely to be encountered after natural disasters, in refugee camps, and in urban slums where it is endemic. Simple measures to dispose of human waste, to avoid contaminated water, and to provide a potable water supply are critical public health priorities in these situations. Travelers intending to work or volunteer in such settings should be appropriately counseled about prevention methods, symptoms, and the need for prompt fluid replacement, and considered for emergency standby treatment.
Escherichia coli O157:H7.
E. coli O157:H7 was first recognized as a food-borne pathogen in the United States in 1982. Outbreaks occurred through distribution of contaminated hamburger meat, and enterohemorrhagic Escherichia coli (EHEC) soon became a common cause of bloody diarrhea. From January 2009 to December 2010, the CDC estimated 29,444 food-borne illnesses annually in the United States, resulting in 1184 hospitalizations and 23 deaths. Shiga toxin–producing E. coli caused 16% of the food-borne illnesses, and 22 of the 23 deaths.26 See also Chapter 232.
Association of E. coli O157:H7 diarrhea with childhood hemolytic-uremic syndrome (HUS) exemplifies how a pathogen can evolve and cause increased, unexpected pathology. HUS was previously an unexplained illness, defined by hemolysis, thrombocytopenia, and acute renal failure, often in children. We now know that EHEC evolved to acquire a symbiotic relationship with a bacteriophage that encodes a Shiga-like toxin (SLT), a toxin also present in Shigella dysenteriae. SLT attaches to a receptor, globotriaosylceramide (GB), on enterocytes in the gut. GB receptors also exist on endothelial cells of glomerular capillaries and other small capillary beds. Damage to these capillary beds by circulating SLT explains the occurrence of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia, which define HUS.27 Further investigation demonstrates that HUS is the most common cause of acute renal failure in children. Elders are also vulnerable to E. coli O157:H7 because neutralizing antibodies to SLT decline as a person ages. E. coli O157:H7 has emerged as a common cause of HUS, a disease not previously recognized as infectious.28
Treatment of EHEC diarrhea is hydration and correction of electrolyte imbalance. Antibiotic treatment induces release of SLT and had been thought to worsen the risk of HUS, although a recent systematic review did not show an increased risk.29 Practically, though, by the time HUS appears, the acute diarrhea has already subsided, so antibiotics are not likely to help. E. coli O157:H7 is also mandatorily reported to health departments.
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