CHAPTER 68

Emerging Infectious Diseases

Christian B. Ramers, MD, MPH, AAHIVS, and Thomas R. Hawn, MD, PhD

Emerging and reemerging infectious diseases are defined as those for which the incidence in human populations has increased in the past 2 decades or threatens to do so in the near future. They may represent the resurgence of an ancient human scourge, a novel zoo-nosis that has broadened its host range, a common pathogen that has acquired a new antimicrobial resistance profile, or more rarely a previously unidentified or unknown microorganism. A startling diversity of organisms has met these criteria, including viral, bacterial, fungal, and parasitic pathogens. Likewise, a variety of factors affect the emergence or reemergence of these pathogens, including range and susceptibility of human hosts, evolution and antigenic shift of the pathogen, and ecological and environmental changes, such as vector amplification or breakdown of public health measures. Although a select few of these emerging pathogens represent malicious propagation or bioterrorism, most appear spontaneously at ambulatory or emergency health facilities and thus are relevant to the practicing primary care physician. It has only been through astute clinical observation, targeted outbreak investigation, and a coordinated public health response that many emerging infectious diseases have been identified.

In this chapter we review the factors involved in the emergence and reemergence of infectious diseases of public health significance, discuss several specific examples that are likely to be most relevant to pediatric practice, summarize regional and global outbreaks of emerging infectious diseases, and provide practical steps for the primary care physician to access local diagnostic and public health support.

Contributing Factors

The spectrum of infectious diseases has always changed and evolved along with societal and environmental changes. Literature supports the supposition that throughout human history, several general driving forces influence the emergence or reemergence of certain infectious diseases. The most important factors are human migration, environmental and ecological changes, changing patterns of human host susceptibility and immunity and, more recently, the use and overuse of antimicrobial agents. Table 68.1 shows some of the mechanisms identified in recent emerging infectious diseases and provides illustrative examples from the United States and abroad. In reality, many simultaneous contributing factors often are at play, and diseases may emerge or retreat within human populations without clear drivers. Common themes that result in recognizable emergence events typically couple a vulnerable host population with a pathogen to which that population lacks immunity or prior exposure.

Pediatric populations are particularly susceptible to emerging and reemerging diseases in several of these categories. The recent Zika virus epidemic has also shed light on the particular risks to the fetus in the setting of a newly emerging or reemerging infection. After immunity from acquired maternal antibody wanes, children develop adaptive immunity on their own and may experience up to 12 upper respiratory and/or diarrheal diseases per year. In some cases an unexplained increase in pediatric mortality from a typical clinical syndrome, such as upper respiratory or flu-like illness, may be the harbinger of an emerging pathogen. Large institutional settings, such as child care centers and schools, place children at high risk for exposure to infectious agents via close contact, and respiratory and droplet spread. Similarly, differing hygiene practices, such as hand-washing, cough etiquette, sharing of fomites, and fecal/urinary incontinence, place infants and children at particular risk of exposure.

Derived from Morens DM, Folkers GK, Fauci AS. The challenge of emerging and re-emerging infectious diseases. Nature. 2004;430(6996):242–249.

Antimicrobial agents are commonly prescribed in the primary care setting for otitis media, pharyngitis, and respiratory infection, and overuse of antibiotics in this setting has been associated with an increased risk of colonization and infection with drug-resistant organisms. In many cases, what was once a first-line therapy for a particular clinical syndrome must be reconsidered because of the emergence of altered antibiotic susceptibility patterns. Advances in medical care has resulted in growth in the number of vulnerable hosts through increased survival of preterm infants, cancer chemotherapy, organ transplantation, and the use of immunosuppressive or immunomodulatory agents. Additionally, because of parental belief systems, personal choice, and lack of access, immunization rates in certain regions remain suboptimal, placing children at risk of acquiring vaccine-preventable disease.

Special Situations

Increasingly, primary care physicians are required to carefully consider the risks of emerging or reemerging infectious diseases. Some of the unique clinical settings in which less common or emerging infectious diseases warrant consideration include expanded international travel, immigration and international adoption, immune suppression and immunomodulation, and the unvaccinated or undervaccinated child.

Expanded International Travel

With the increasing accessibility of long-distance international travel, children are more frequently being included in tourist trips or, in the case of immigrant families, visits to friends or relatives in their home country. Children are less likely to seek pretravel advice and consequently are less likely to adhere to recommended travel guidelines. A report from GeoSentinel, a large group of worldwide travel clinics, found that only 32% of children visiting friends and relatives in developing countries received recommended travel vaccines or prophylactic medications even though they were more likely to present with illness and require hospital admission after travel. Primary care physicians evaluating returning travelers must consider detailed travel history, prophylaxis or protective measures taken (if any), risk profile of the region visited, and incubation period of the suspected pathogen. Although by far the most common travel-related illnesses are self-limited diarrheal disease, emerging infections, such as Ebola, Zika, dengue, chikungunya, and H5N1, H7N9, or H1N1 influenza, must be considered along with other infectious diseases, such as malaria and tuberculosis.

Immigration and International Adoption

Increasing rates of international adoption or recent immigration may result in evaluation by primary care physicians of children with unknown or unavailable birth, early childhood, or immunization histories (see Chapter 37 and Chapter 39). Vaccine schedules vary by country of origin, including some vaccines that are no longer given in the United States (eg, bacille Calmette-Guérin, live oral polio virus vaccine). Considerable variation exists in reliability of medical reporting in these situations, with some countries achieving or exceeding developed world standards but most providing reports of dubious quality. Many physicians who specialize in “adoption clinics” or work in settings with large immigrant populations obtain serologic evidence of prior immunization (eg, measles, mumps, varicella, polio, diphtheria, tetanus). Physicians must also be aware of infections with clinically silent latent phases (eg, viral hepatitis, latent tuberculosis, intestinal helminth infections, HIV). Several emerging or reemerging infectious diseases in the United States may be endemic in the countries of origin of adopted or recently arrived immigrant children.

Immune Suppression and Immunomodulation

Therapeutic advances in pediatric oncology, organ transplantation, rheumatology, and care of chronic congenital conditions have resulted in an increasing population of children with immunosuppression. Although typically under the care of specialists, these children may have a medical home in a primary care facility and thus can present with an opportunistic or emerging infectious disease to their primary care physician. The spectrum of risk for infectious diseases varies considerably depending on the type of immunosuppression. For example, tumor necrosis factor-α inhibitors, which are commonly used in the management of juvenile idiopathic arthritis, convey a particularly high risk of fungal and mycobacterial infection. Neutropenia from cytotoxic chemotherapy is associated with an increased risk of bloodstream bacterial infection among others. Similarly, lymphopenia related to solid organ transplantation portends a particular vulnerability to viral infections, ranging from widespread community respiratory viruses to reactivation of common agents, such as varicella-zoster virus. Emerging infectious diseases, such as new coronaviruses (Middle East respiratory syndrome coronavirus [MERS-CoV], severe acute respiratory syndrome [SARS]), human metapneumovirus, or H1N1 influenza, may have particularly severe clinical manifestations in children with immunosuppression compared with the general population.

Unvaccinated or Undervaccinated Child

Despite the ongoing efforts of public health authorities, some regions have noted a worrisome downward trend in immunization rates. Although the most widely cited study linking autism to measles, mumps, rubella (MMR) vaccination was retracted by the Lancet in February 2010, several recent parental surveys indicate persistent beliefs about a suspected vaccine–autism link. In 2004, the Institute of Medicine Immunization Safety Review Committee published a comprehensive report that found no convincing evidence of a causal link between the MMR vaccine or any thimerosol-containing vaccine and autism. In a survey of 1,552 parents conducted in 2009, however, 25% agreed with the statement, “Some vaccines cause autism in healthy children.” Decreasing vaccination rates have resulted in increased risk for outbreaks of reemerging infectious diseases. Measles was officially declared “eliminated” (defined as the absence of endemic measles transmission for >12 months) in the United States in the year 2000. During the first 8 months of 2019, however, more than 1,200 cases of measles were reported in more than 30 states; 75% of the cases occurred in New York State, where individuals had not been vaccinated. This is the greatest number of cases reported since 1992. This compares with a median 60 cases reported annually every year from 2001 through 2011. Similar to resurgent measles outbreaks, a 2010 to 2011 pertussis epidemic in California became the largest since 1955, affecting more than 9,000 individuals and causing 10 infant deaths. Thus, it is crucial for physicians to include vaccination status and exposure history when evaluating children with an infectious syndrome. Increasingly, the differential diagnosis and diagnostic workup must include emerging and reemerging diseases, some of which may be unfamiliar to physicians from their training or clinical experience.

Select Emerging Pathogens

Major emerging and reemerging infectious diseases of the past 20 years are shown in Figure 68.1 and Table 68.2. The table is not meant to be an exhaustive list, but rather a sampling of emerging pathogens most likely to present to a primary care physician.

Viruses

Zika

Zika is a flavivirus that was initially isolated from a monkey in the Zika forest in Uganda in 1947. The geographic distribution was previously thought to be limited to Africa with mild clinical manifestations. From 2007 to 2014, however, Zika caused outbreaks in several of the Pacific Islands, after which a major epidemic emerged in Brazil in 2015 with rapid spread throughout the Americas, with outbreaks in the United States in 2016. Currently, Zika is present in more than 80 countries in Africa, Asia, and the Americas. Aedes aegypti as well as other aedes species are the primary vectors with a predilection for urban environments, similar to dengue, chikungunya, and yellow fever. Non-vector routes of transmission include blood transfusions and sexual contact.

Major features of the reemergence of Zika include both the expanded geographic distribution and discovery of its cause of severe fetal neurologic infections. Zika is neurotropic and targets neural progenitor cells in the developing brain. The resurgence of Zika in the Americas has included clinically devastating congenital central nervous system (CNS) malformations, including microcephaly, ventriculomegaly, cerebral calcifications, and ocular abnormalities. In adults, approximately 50% of infected individuals have no symptoms, with the remaining developing a rash, fever, conjunctivitis, and arthralgias. Uncommon manifestations include Guillain-Barré syndrome. The cause of the apparent shift to more prominent CNS clinical manifestations of the recent epidemics is not known. Genetic data indicate that Zika acquired a single amino acid mutation in a surface protein that causes increased neurovirulence, viral replication, and rates of microcephaly in cellular and animal models. This mutation appeared in approximately 2013 and has been stably transmitted during the epidemic. Although this genetic change may explain the new clinical manifestations, it remains possible that neurologic involvement was not previously apparent because of a lower disease incidence.

Figure 68.1. Global examples of recently emerging and reemerging infectious diseases.

Abbreviations: C. difficile, Clostridium difficile ; CRE, carbapenem-resistant Enterobacteriaceae; E. coli, Escherichia coli ; MDR, multi-drug resistant; MERS-CoV, Middle East respiratory syndrome coronavirus; N. gonorrhoeae, Neisseria gonorrhoeae; SARS, severe acute respiratory syndrome; SFTSV, severe fever with thrombocytopenia syndrome virus; vCJD, variant Creutzfeldt-Jakob disease; XDR, extensively drug-resistant.

Reprinted from National Institute of Allergy & Infectious Diseases. Global Examples of Emerging and Re-Emerging Infectious Diseases. Bethesda, MD: National Institute of Allergy & Infectious Diseases; 2017. https://www.niaid.nih.gov/news-events/three-decades-responding-infectious-disease-outbreaks

Several issues are important for clinical management of Zika, including transmission prevention, evaluation and treatment of pregnant women, and treatment of infected neonates. Prevention of vector-borne transmission includes mosquito precautions as well as avoiding or postponing travel during pregnancy. Travel-related precautions pertaining to sexual transmission extend to the post-travel time period because Zika can persist in bodily fluids (eg, RNA is detected for approximately 2 weeks in plasma, 6 weeks in urine, and up to 6 months in semen). Currently, the CDC recommends that men wait at least 3 months before engaging in unprotected sex if they are planning to conceive with their partner and may have had a Zika virus exposure. Previously, the waiting period was 6 months, but the recommendation was updated based on data indicating that the longest period from symptom onset to potential sexual transmission was 32 to 41 days. Evaluation of pregnant women for possible Zika infection includes exposure risk assessment, symptom assessment, and diagnostic testing options that are tiered based on time from exposure and stage of pregnancy. Potential diagnostic tests include nucleic acid tests in serum and urine, immunoglobulin (Ig) M serology, and a plaque reduction neutralization test. For pregnant women diagnosed with acute Zika virus infection, further diagnostic testing in the form of ultrasonography and amniocentesis can be performed to assess for fetal infection and complications. Currently, no specific treatment or vaccine is available for Zika virus.

Abbreviations: 5-FC, 5-fluorocytosine; CSF, cerebrospinal fluid; CNS, central nervous system; Ig, immunoglobulin; MERS-CoV, Middle East respiratory syndrome coronavirus; MRSA, methicillin-resistant Staphylococcus aureus; NSAIDs, nonsteroidal anti-inflammatory drugs; PCR, polymerase chain reaction; SARS, severe acute respiratory syndrome; UTI, urinary tract infection; WNV, West Nile virus.

Ebola

First described near the Ebola river in Zaire (now the Democratic Republic of Congo [DRC]) in 1976, Ebola virus is a member of the genus Filoviridae of hemorrhagic fever viruses. Although until recently only seen in sporadic and remote outbreaks in sub-Saharan African villages, Ebola’s reputation has far outpaced its reach because of a case fatality rate of 88% in early descriptions of the first outbreaks. Four species are known to cause disease in humans, with variable geographic footprints and virulence. Sudan ebolavirus has a case fatality rate of approximately 50% and has caused several moderate-sized outbreaks in the border region of Sudan, Uganda, and the DRC. Zaire ebolavirus, the most lethal species, has caused most of the sporadic outbreaks throughout sub-Saharan Africa, including the largest outbreak ever recorded in 2014 to 2016 that engulfed several West African countries, with approximately 28,600 cases and more than 11,000 deaths. Bundibugyo ebolavirus is a third species discovered in 2007 that has caused 2 well-documented outbreaks in the DRC and along the border of the DRC and Uganda. Finally, Taï Forest ebolavirus has been identified in a single case in Côte d’Ivoire in West Africa. At the time of publication, an ongoing outbreak of the Zaire ebolavirus is occurring in the North Kivu and Ituri provinces of DRC, with at least 129 confirmed or probable cases and 89 deaths.

Although the reservoir of Ebola is unknown, scientists suspect a fruit bat or non-human primate may serve as the natural host, with uncommon “spillover events” occurring after direct human-to-animal contact. Human-to-human transmission can occur after 1 of these events via direct contact (through broken skin or mucus membranes) with infected blood or body fluids, including urine, saliva, sweat, feces, vomit, human milk, and semen. Importantly, human-to-human transmission does not occur in the absence of symptoms. No evidence exists indicating that mosquitos or other insects can transmit Ebola, and secondary foodborne transmission is not thought to occur except from direct consumption of the meat of an infected primate.

After an incubation period of approximately 8 to 10 days (range, 2–21 days), Ebola causes an array of nonspecific systemic symptoms, such as fever, nausea, vomiting, diarrhea, weakness, severe headaches, myalgias, and abdominal pain. The diagnosis should be suspected in cases with both a combination of suspected symptoms and a possible exposure to Ebola virus within the previous 21 days. Isolation of “patients under investigation” and strict contact precautions are necessary to contain outbreaks and prevent spread to health care personnel. Specialized molecular testing for viremia is available in public health laboratories and is typically positive within 3 days of the onset of symptoms.

The pathophysiology of Ebola virus disease (formerly Ebola hemorrhagic fever) involves massive fluid, electrolyte, and protein wasting as well as capillary leak and hemorrhage with resultant blood loss, dehydration, oliguria, circulatory collapse, and respiratory failure. In a well-studied case series of 27 patients evacuated from the West Africa outbreak to the United States or Europe, peak plasma viral RNA levels occurred at a median of 7 days and was cleared a median of 17.5 days after onset of symptoms. With maximal supportive care as well as experimental therapies in 85% of patients, the case fatality rate in this cohort was 18.5%, which was lower than previously reported.

Postmortem human-to-human transmission of Ebola has occurred as well, particularly related to burial rituals such as cremation, cleansing of bodies, and postmortem autopsy evaluations. The CDC has developed guidelines for safe handling of human remains focusing on the use of personal protective equipment as well as proper disposal of medical equipment and safe interment of the body. In survivors who recover from the infection, ocular complications and lingering arthralgias have been described. Persistence of virus has also been observed in immune-privileged sites, such as aqueous humor, cerebrospinal fluid (CSF), and semen; however, the transmission dynamics of convalescing patients are poorly understood.

The foundation of managing Ebola virus disease is supportive care, principally intravenous hydration and electrolyte replacement, oxygen and mechanical ventilation as necessary, renal replacement therapy, blood pressure and blood product support, and antibiotic treatment for any suspected secondary infections. After intensive ethical discussions, experimental treatments were mobilized during the 2014 to 2016 West Africa outbreak, including transfusions using convalescent serum of survivors, monoclonal antibody combinations (ie, ZMapp, ZMab, MIL77), antiviral drugs thought to have inhibitory activity against Ebola (ie, TKM-Ebola, favipiravir, brin-cidofovir, amiodarone), and agents purported to counteract capillary leak (ie, FX06, melanocortin). No agents have been approved by the US Food and Drug Administration for use in individuals with Ebola virus disease, and each of these cases underwent considerable ethical scrutiny and evaluation.

Prevention of Ebola virus disease has relied mainly on early diagnosis as well as strict isolation and infection control procedures. An experimental vaccine was developed and preliminarily tested in 2015 in Guinea during the large outbreak in that country. In a small trial, the vaccine appeared to be highly protective against Ebola virus disease. The National Institutes of Health is conducting an ongoing open label, pre-exposure clinical trial in adults at potential occupational risk.

Measles

Measles, which is caused by a virus from the Paramyxoviridae family, began to decline as a major threat in the United States after a safe and effective vaccine was developed in 1963. A significant resurgence occurred between 1989 and 1991, however, largely because of a pool of vulnerable, unvaccinated preschool-age children. Nearly 55,000 cases and 130 deaths occurred in the United States, prompting a renewed effort at prevention through vaccination. A second dose of vaccine for school-age children was also recommended after this outbreak. Another resurgence of new cases occurred after 2004, but with new epidemiologic features; 90% of the cases were either directly imported from travelers or immigrants, or were associated with importation from outside the United States. Large outbreaks in the United States have been reported in 2008, 2011, 2013, 2014, and 2019.

Measles is a highly contagious pathogen passed via respiratory droplets. Secondary transmission is thought to be greater than 90% among susceptible household contacts. Approximately 10 days after exposure, clinical illness is characterized by a distinctive febrile prodrome (ie, conjunctivitis, coryza, cough), followed by Koplik spots (blue-gray enanthem on buccal mucosa) and, ultimately, the classic maculopapular erythematous eruption. Diagnosis is usually ascertained based on clinical evidence alone given the distinct clinical presentation; however, for confirmatory testing, the immunoglobulin (Ig) M serology is nearly 100% sensitive if performed after the onset of rash. Respiratory droplet isolation should occur until 4 days following appearance of the rash in immunocompetent patients and until the clinical illness resolves in those who are immunocompromised. Treatment is largely supportive; however, respiratory and neurologic complications can occur in 6% and 0.1% of patients, respectively. Further control of this reemerging infectious disease will likely depend on renewed attention to domestic vaccination efforts and the roll-out of vaccination worldwide.

Mumps

Although the clinical syndrome of the mumps virus is distinct from that of measles, the 2 members of the Paramyxoviridae family share a similar history of initial control and recent reemergence. A live, attenuated mumps vaccine was licensed in 1967 and incorporated into the Advisory Committee on Immunization Practices recommended schedule by 1977. Due to high vaccination rates, mumps had declined by more than 99% by 2005. However, there have been 2 major resurgences in the United States. In 2005 to 2006 a total of 6,584 cases were reported in a multistate outbreak in the Midwestern United States. Although numerically most of these cases occurred among college students who had been previously vaccinated, attack rates were considerably higher in unvaccinated individuals. Equally large outbreaks involving more than 6,000 cases were reported in 2016 and 2017. During the first 8 months of 2019, there were more than 2,360 reported cases in 47 states.

The clinical presentation of mumps typically involves fever, malaise, and parotitis. Complications are rare, but in some studies up to 10% of patients had aseptic meningitis, of which hearing loss is an important sequela. Up to 37% of adolescent and adult males can present with orchitis, which may result in sterility. Diagnosis is typically made based on a compatible clinical syndrome with confirmation by isolation or polymerase chain reaction (PCR)-based detection of the virus from saliva, CSF, urine, or semen. Immunoglobulin M serology is also a useful confirmatory method.

Management is generally supportive, with analgesics used for the pain of parotitis and/or orchitis. For severe cases, intravenous Ig has been used to mitigate immune-mediated postinfectious complications, and interferon-α-2b has been used to alleviate orchitis.

The previously discussed outbreaks have been the focus of considerable scrutiny as indicators of vaccine effectiveness and community vaccination rates. Based on extensive analyses, MMR vaccine is still considered to be 80% to 90% effective after 2 doses. However, a significant portion of the population remains vulnerable to occasional outbreaks. No change was made to immunization schedules or interim recommendations after these outbreaks.

Dengue

Dengue fever virus is a member of the Flaviviridae family and is known to occur in 4 serotypes. It is transmitted via a vector, usually A aegypti, and is present in more than 100 countries throughout the Americas, Asia, and Africa. Although historically dengue fever virus was confined to tropical and subtropical regions roughly overlapping with malarial zones, its range is expanding. In the United States, no cases of locally acquired dengue were reported between 1946 and 1980. Since 1980, sporadic cases have been reported along the United States–Mexico border, but in 2009 to 2010 a small outbreak of locally acquired dengue occurred in Key West, Florida. During the first 8 months of 2019, 408 cases were reported in the United States, with 6 additional cases in US territories. The worldwide incidence of dengue has increased at least 4-fold in the past 3 decades for unclear reasons.

Clinical manifestations occur over a wide spectrum, from asymptomatic seroconversion to severe, even fatal disease. Headache and petechial rash are common. Classically the disease is thought to occur in 3 forms: undifferentiated febrile illness, dengue fever, and dengue hemorrhagic fever. In reality, however, clinical manifestations are diverse and may include hepatitis, myocarditis, pericarditis, and encephalopathy. Leukopenia and thrombocytopenia are common laboratory findings, and in severe cases, a coagulopathy and bleeding manifestations seem to be the most dangerous sequelae. Diagnosis can be made with a compatible clinical history and confirmed on serologic testing. No direct-acting antivirals exist, nor is a vaccine available. Care is generally supportive.

Influenza Viruses

In 2009, a novel strain of influenza A known as H1N1 caused the first global influenza pandemic since 1968, with an estimated 59 million illnesses and 12,000 deaths in the United States alone. Although early in the year it seemed as though “bird flu” or H5N1 influenza would be the greatest concern to public health, it was a different strain of swine origin that resulted in a global pandemic. In April 2013, a different strain of bird flu known as H7N9 emerged in China with a disturbing 28% case fatality rate. Like the related H5N1 strain, however, human-to-human transmission was not observed, and outbreaks have been limited to clusters of individuals with very high levels of exposure to poultry.

Influenza viruses have a segmented genome and thus are able to adapt and evolve quite rapidly to evade slower adaptive immune responses. Through antigenic drift, small changes occur in cell surface genes through time, resulting in subtle structural changes to the cell surface proteins neuraminidase and hemagglutinin and decreased recognition by the immune system. In antigenic shift, genome segments from diverse strains recombine in a single new virus particle, resulting in abrupt and substantial changes in antigenic variation. Typically, shifts are more likely to cause pandemics because of the increased number of nonimmune hosts in the population.

Although the clinical manifestations of H1N1 influenza seemed to be similar to those of prior influenza outbreaks, this strain resulted in more severe cases and higher mortality in previously healthy young people than in typical influenza epidemics. Testing for H1N1 most commonly involves antigen-based PCR methods with variable sensitivities and specificities. Management of severe cases consists either of oral oseltamivir phosphate or inhaled zanamivir. Although oseltamivir phosphate resistance outside the United States has been reported, it remains the drug of choice.

The more recently recognized H7N9 strain seems to be more virulent than H1N1, with a high proportion of patients presenting with severe pulmonary manifestations. In the preliminary reports of the first 111 patients in China, 77% were admitted to an intensive care unit and 28% died. Because of the ability of influenza virus to change rapidly with genetic drift and shift, health officials are on alert for any increase in H7N9 activity in the fall influenza season. The 2018 to 2019 influenza season was moderately severe, and the 21-week season was longer than seasons from the prior 10 years. The 2 major strains were H1N1 and H3N2.

Chikungunya

A vector-borne disease transmitted primary by Aedes species mosquitoes, chikungunya was first described in Tanzania in 1953. It often occurs in epidemic outbreaks rather than steady endemic patterns and is most commonly seen in tropical Africa and Asia. More recently, outbreak ranges have expanded slightly, occurring in Italy and Madagascar. Chikungunya virus disease became a nationally notifiable condition in 2015. A total of 156 chikungunya virus disease cases with illness onset in 2017 have been reported from 28 US states. All reported cases occurred in travelers returning from affected areas. No locally transmitted cases have been reported in the United States. The clinical hallmark of chikungunya fever is the presence of intense arthralgias and occasionally frank arthritis after a febrile illness with rash and conjunctivitis. Whereas the clinical illness of malaise and fever may last days to weeks, the joint symptoms may last months to years. Other than the possibility of persistent and nagging arthralgias, severity is typically mild, and fatality is rare. Management of chikungunya is generally supportive, because no specific antiviral agents are available.

Coronaviruses: Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome

From 2002 to 2004, an epidemic of severe pneumonia resulting from a previously unrecognized coronavirus (ie, SARS-CoV) caused considerable international concern because of its highly infectious nature and high mortality rate. Epidemiologic studies resulted in identification of palm civets as the main reservoir of transmission to humans from contact in the marketplace. Further studies suggested that horseshoe bats were the likely natural reservoir. The epidemic, which originated in China, eventually spread to 29 countries with an overall mortality rate of 9.6%, which included numerous health workers. Clinical features included a mean incubation period of 4.6 days, with a presentation of severe pneumonia with a high rate of respiratory failure. Additional clinical manifestations included watery diarrhea and hepatitis. Common laboratory features included lymphopenia, neutropenia, and disseminated intravascular coagulation. The cornerstone of management was supportive care. Although many individuals received ribavirin, no proven role for it or any antiviral agent existed during the outbreak. Despite the impressive nature of this epidemic, it subsided rapidly and no evidence exists of ongoing SARS-CoV transmission. This epidemic highlighted an agent with high transmissibility, morbidity, and mortality but with only a transient global impact.

In 2012, a second emerging coronavirus was identified as the cause of a severe acute respiratory infection in a patient in Saudi Arabia. From 2012 to 2013, 130 cases were reported, all of which involved direct or indirect travel or residence in 4 countries: Saudi Arabia, Qatar, Jordan, and the United Arab Emirates. The reservoir has not been conclusively established yet, although a zoonotic origin has been suggested resulting from the identification of related coronaviruses in bats and camels. As of 2017, approximately 2,000 cases have been confirmed in countries in the Arabian peninsula. The clinical features include an incubation period of 5.2 days with symptoms that range from none or mild to severe disease, including death in 45% of reported cases. A large proportion of patients (96%) have underlying comorbidities, and 80% required ventilatory support.

Bacteria: Drug-Resistant

Community-Acquired Methicillin-Resistant Staphylococcus Aureus

Methicillin-resistant S aureus (MRSA) strains were recognized shortly after the introduction of methicillin in the 1960s and have been a substantive problem in health care settings for several decades. Health care-associated MRSA (HA-MRSA) has well-established risk factors, including exposure in the health care setting (eg, hospital, nursing facility) and the presence of comorbid medical conditions (eg, malignancy, chronic liver or lung disease, indwelling catheters). In the 1990s, a new strain of community-acquired MRSA (CA-MRSA) appeared that was not associated with these traditional risk factors, because often it was found in otherwise healthy individuals with no health care– related exposure. Furthermore, CA-MRSA carries the mecA resistance gene on a type IV or V cassette chromosomes in contrast to HA-MRSA, which carries type I through III cassette chromosomes. Community-acquired MRSA is also more likely to contain the Panton-Valentine leukocidin genes, which may encode virulence factors that influence clinical symptoms. These genotypic differences have facilitated epidemiologic studies that suggest that CA-MRSA is a distinct MRSA strain that has increased in frequency throughout the United States and is a bona fide emerging pathogen. In addition to genotypic differences, CA-MRSA is less likely than HA-MRSA to have a multidrug–resistant susceptibility pattern. Treatment of CA-MRSA follows similar principles to HA-MRSA with the exception that more antibiotic choices are generally available. For an uncomplicated cutaneous abscess, incision and drainage without antibiotics is often sufficient. For deeper or more severe infections, empiric treatment with trimethoprim- sulfamethoxazole, clindamycin, a tetracycline (doxycycline or minocycline), or linezolid are empiric options while awaiting antibiotic susceptibilities. Although linezolid is an effective drug, it is far more expensive than the other choices. Tetracyclines should not be used in children younger than 8 years. For impetigo and other minor infections, topical mupirocin can be used.

Resistant Gram-Negative Bacteria and Streptococcus Pneumoniae

Similar to CA-MRSA, other resistant bacteria have established significant niches. For example, S pneumoniae was historically uniformly sensitive to penicillin. Currently, penicillin- and ceftriaxone-resistant strains of S pneumoniae are now common and circulating in the community. Similarly, several gram-negative bacteria, such as Escherichia coli and Klebsiella pneumoniae, are highly resistant because of a variety of plasmid and chromosomally encoded mechanisms, such as β-lactamases, cephalosporinases, carbapenemases, porins, and efflux pumps. These strains are most common in the nosocomial setting, although community circulation of these strains has also occurred. Although the emergence of these strains is not as extensive or as clearly delineated as CA-MRSA, each of these strains has similarly “emerged” to a prevalence level in the population that substantially affects human health.

Ehrlichiosis and Anaplasmosis

Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis (HME), and Anaplasma phagocytophilum, the etiologic agent of human granulocytic anaplasmosis (HGA [formerly human granulocytic ehrlichiosis]), are examples of infections that were identified after the development of new diagnostic tests. Both infections were initially recognized as infections of the veterinary world until the application of molecular methods to humans with undiagnosed febrile illnesses. These infections likely have caused human disease for a long time, although the incidence may have increased with the recent resurgence of populations of some animal reservoirs, such as the white-tailed deer. In the early 1990s, E chaffeensis and A phagocytophilum were identified as human pathogens that are transmitted by ticks. Ehrlichia chaffeensis is transmitted by several ticks (ie, Amblyomma americanum, Dermacentor variabilis, Ixodes pacificus) and is found in the Southeastern and South Central United States as well as California. Anaplasma phagocytophilum is transmitted by Ixodes scapularis and is found in the northern United States. Both agents cause a febrile illness with headache, myalgia, and malaise that is often accompanied by thrombocytopenia, leukopenia, and transaminitis. Rash, which occurs in 90% of subjects with Rocky Mountain spotted fever (caused by Rickettsia rickettsii), is less often found with HME (31%) and rarely with HGA. Diagnosis of these infections can be made by PCR testing and less commonly with direct microscopy because the latter methods are insensitive (<10% for HME and 25%–75% for HGA). Because of the potential severity of the illness, however, if clinical suspicion is high empiric treatment should be initiated while awaiting the diagnostic workup. Doxycycline is the drug of choice for management of HGA and HME. Because of a lack of reliable alternative drugs, doxycycline is recommended for children younger than 8 years as well.

Fungi: Cryptococcus Gattii

Cryptococcus gattii (formerly Cryptococcus neoformans var gattii) and C neoformans are yeast that cause pneumonia and CNS infections in immunocompetent and immunocompromised hosts. Although C neoformans is present in most regions of the world, C gattii has a restricted geographic distribution and previously had been identified in tropical and subtropical countries such as Australia, New Zealand, and Papua New Guinea. In the early 2000s, C gattii was identified as a cause of meningoencephalitis for the first time on Vancouver Island in British Columbia. From 1999 to 2007, 218 cases were reported, with a case fatality rate of 8.7%. Subsequent studies identified its presence in the Pacific Northwest, including the states of Washington and Oregon. Similar to many emerging pathogens, the increased number of cases may be the result of improved diagnostics and surveillance as opposed to the actual emergence of a new infection to a region. Some molecular evidence suggests that the strain on Vancouver Island is novel, however. Clonal analysis suggests that it arose from an unusual type of sexual mating that generated a hypervirulent strain. This mechanism of emergence suggests that a species endemic to an original location (eg, tropics) can emerge in a new geographic region (eg, Vancouver Island) in a clonal manner. The clinical presentation of C gattii is similar to C neoformans, although C gattii may be associated with an increased frequency of cryptococcoma in the lungs and CNS. Treatment principles are the same for both species and include initial management with amphotericin B and 5-fluorocytosine for meningitis followed by consolidation therapy with fluconazole. For uncomplicated pulmonary disease, fluconazole is the cornerstone of treatment. Cryptococcus species, including gattii, infect children as well, and treatment principles are similar to those for adults.

Summary

Contrary to myopic claims that public health would conquer infectious diseases in the 20th century, new pathogens have continued to emerge and old ones have reemerged time and time again, making for a challenging future of disease identification and control. Transcontinental air travel has made even the most remote areas of the world reachable within 24 hours, bringing the distant populations much closer and exponentially increasing the potential for disease transmission and outbreak propagation. The tools used by public health include surveillance and response; however, most of the major epidemics identified in the past 20 years began with astute clinical observation at the primary care level. Thus, it is essential for primary care physicians and others caring for children to remain vigilant to the constant and unpredictable nature of emerging infectious diseases. With astute primary care physicians, attentive scrutiny of new outbreaks, and collaboration with regional and national public health laboratories and officials, it is hoped that the medical field will keep pace with emerging and reemerging pathogens.

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