Lyle R. Petersen

Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses

Mosquito-borne flaviviruses provide some of the most important examples of emerging and resurging diseases of global significance. Here, we describe three of them: the resurgence of dengue in tropical and subtropical areas of the world, and the spread and establishment of Japanese encephalitis and West Nile viruses in new habitats and environments. These three examples also illustrate the complexity of the various factors that contribute to their emergence, resurgence and spread. Whereas some of these factors are natural, such as bird migration, most are due to human activities, such as changes in land use, water impoundments and transportation, which result in changed epidemiological patterns. The three examples also show the ease with which mosquito-borne viruses can spread to and colonize new areas, and the need for continued international surveillance and improved public health infrastructure to meet future emerging disease threats.

Zika Virus and Birth Defects — Reviewing the Evidence for Causality

Summary The Zika virus has spread rapidly in the Americas since its first identification in Brazil in early 2015. Prenatal Zika virus infection has been linked to adverse pregnancy and birth outcomes, most notably microcephaly and other serious brain anomalies. To determine whether Zika virus infection during pregnancy causes these adverse outcomes, we evaluated available data using criteria that have been proposed for the assessment of potential teratogens. On the basis of this review, we conclude that a causal relationship exists between prenatal Zika virus infection and microcephaly and other serious brain anomalies. Evidence that was used to support this causal relationship included Zika virus infection at times during prenatal development that were consistent with the defects observed; a specific, rare phenotype involving microcephaly and associated brain anomalies in fetuses or infants with presumed or confirmed congenital Zika virus infection; and data that strongly support biologic plausibility, including the identification of Zika virus in the brain tissue of affected fetuses and infants. Given the recognition of this causal relationship, we need to intensify our efforts toward the prevention of adverse outcomes caused by congenital Zika virus infection. However, many questions that are critical to our prevention efforts remain, including the spectrum of defects caused by prenatal Zika virus infection, the degree of relative and absolute risks of adverse outcomes among fetuses whose mothers were infected at different times during pregnancy, and factors that might affect a woman’s risk of adverse pregnancy or birth outcomes. Addressing these questions will improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy.

West Nile Virus: A Primer for the Clinician

Four centuries of travel and commerce have led to the North American importation of several important vector-borne human pathogens, including dengue, yellow fever, malaria, and plague. The 1999 appearance of the West Nile virus in New York City may prove to be the best-documented introduction of a new, vector-borne human pathogen into the United States in the past century (1). It remains unknown how the West Nile virus came to North America. However, because it first appeared in a major international gateway, travel and commerce may have played a role. The viruss rapid geographic expansion and subsequent persistence in newly established enzootic areas in North America indicate that West Nile virus has become a permanent fixture of the U.S. medical landscape. Key features of the West Nile virus in North America are indicated in Table 1. Table 1. Key Clinical Facts about West Nile Virus in North America Epidemiology West Nile virus was first isolated and identified in 1937 from an infected person in the West Nile district of Uganda (2). Until 1999, the virus was found only in the Eastern Hemisphere, with wide distribution in Africa, Asia, the Middle East, and Europe (3). Since 1937, infrequent human outbreaks, mainly associated with mild febrile illnesses, were reported mostly in groups of soldiers, children, and healthy adults in Israel and Africa (4-7). However, one notable outbreak in Israeli nursing homes in 1957 was associated with severe neurologic disease and death (8). Since the mid-1990s, the frequency and apparent clinical severity of West Nile virus outbreaks have increased (4). Outbreaks in Romania (1996) (9), Russia (1999) (10), and Israel (2000) (11) involved hundreds of persons with severe neurologic disease. It is unclear if this apparent change in disease severity and frequency is due to differences in the circulating viruss virulence or to changes in the age structure, background immunity, or prevalence of other predisposing chronic conditions in the affected populations (12). A large outbreak of West Nile virus infection has yet to occur in the United States. However, national surveillance has documented persons with illness caused by West Nile virus, mostly encephalitis and meningitis, each year since 1999 (62 persons in 1999, 21 in 2000, and 66 in 2001) (13). These persons have been identified over an expanding geographic area (1 state in 1999, 3 in 2000, and 10 in 2001) (Figure 1). From 1999 to 2001, illness onset ranged from 13 July to 7 December, with peak incidence in late August and early September (Figure 2). Figure 1. States reporting epizootic activity and human infections of the West Nile virus, 19992001. Figure 2. Week of symptom onset for persons reported to have West Nile virus infection, 19992001. Ecology In the Eastern Hemisphere, West Nile virus is maintained in an enzootic cycle involving culicine mosquitoes and birds (3, 14). Evidence to date suggests a similar cycle in North America (Figure 3) (4). After passing through three aquatic stages (egg, larva, pupa), adult mosquitoes begin to emerge in the spring in temperate regions. Viral amplification occurs in the birdmosquitobird cycle until early fall, when female mosquitoes begin diapause and infrequently bite. Many environmental factors affect this viral amplification cycle (for example, weather or climate, host and vector predators and parasites, and host immune status). When environmental conditions promote significant amplification, sufficient numbers of bridge vector mosquitoesmosquitoes that bite both humans and birdsbecome infected in late summer and then pose an infection threat to humans. Year-round transmission is possible in more tropical climates. Through spring 2002, West Nile virus had been detected in 29 North American mosquito species; this number will undoubtedly increase as the virus spreads into new ecologic habitats. Although Culex pipiens, Culex restuans, and Culex quinquefasciatus are probably the most important maintenance vectors in the eastern United States, it is unknown which species are most responsible for transmission to humans (15). Figure 3. Transmission cycle of West Nile virus. While arboviral maintenance cycles are normally not apparent, dramatic avian mortality rates have accompanied outbreaks in humans in Israel and the United States (4, 16). Particularly high mortality rates have been noted among American crows (Corvus brachyrhynchos) and other North American corvids (ravens, jays, and other crows). In the northeastern United States, deaths in crows have increased markedly shortly before human cases have developed (17). Surveillance systems involving testing dead birds, sentinel chickens, and ill horses for West Nile virus have demonstrated rapid geographic spread in the United States (4 states in 1999, 12 states and the District of Columbia in 2000, 27 states and the District of Columbia in 2001) and into Canada (southern Ontario in 2001) (Figure 1). Up-to-date maps showing the U.S. distribution of West Nile virus are available at www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm and at cindi.usgs.gov/hazard/event/west_nile/west_nile.html. Virology West Nile virus is a single-stranded RNA virus of the family Flaviviridae, genus Flavivirus. The E-glycoprotein is the viral hemagglutinin and mediates virushost cell binding. As the most immunologically important structural protein, the E-glycoprotein elicits most virus-neutralizing antibodies. West Nile virus is a member of the Japanese encephalitis virus serocomplex, which contains several medically important viruses associated with human encephalitis: Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, and Kunjin virus (an Australian subtype of West Nile virus). The close antigenic relationship of the flaviviruses, particularly those belonging to the Japanese encephalitis complex, accounts for the serologic cross-reactions observed in the diagnostic laboratory (18). West Nile virus can be divided genetically into two lineages. Only viruses of lineage 1 have been definitely associated with human disease. The West Nile virus responsible for the 1999 outbreak in New York City was a lineage 1 virus that circulated in Israel from 1997 to 2000, suggesting viral importation into North America from the Middle East (19, 20). Of interest, both birds and humans have died of West Nile virus infection only in the United States and Israel to date; the reason for this is not known. Since 1999, very few genetic changes have occurred in the variant of West Nile virus circulating in the United States. Clinical Features The incubation period of West Nile virus, although not precisely known, probably ranges from 3 to 14 days. Most human infections are not clinically apparent. A serosurvey conducted during the 1999 New York City epidemic indicated that approximately 20% of persons infected with West Nile virus had developed West Nile fever and only half of these had visited a physician for this illness (21). The frequencies of various symptoms and signs associated with West Nile fever during recent outbreaks are poorly defined because surveillance has focused on patients with neurologic disease. In earlier outbreaks, the disease was described as a febrile illness of sudden onset, often accompanied by malaise, anorexia, nausea, vomiting, eye pain, headache, myalgia, rash, and lymphadenopathy; these symptoms generally lasted 3 to 6 days. Among the 6 symptomatic persons positive for IgM antibody who were identified in the 1999 New York City serosurvey, all reported myalgia, 5 reported fatigue, 5 had headache, and 4 had arthralgia (21). Although recent outbreaks of West Nile virus seem to be associated with increased morbidity and mortality, severe neurologic disease remains uncommon. Two serosurveys conducted in New York City in 1999 and 2000 showed that approximately 1 in 150 infections resulted in meningitis or encephalitis, a result consistent with a 1996 Romanian serosurvey indicating that 1 in 140 to 320 infections led to these diseases (9, 21, 22). Advanced age is by far the most significant risk factor for severe neurologic disease after infection; risk increases markedly among persons 50 years of age and older. An analysis of attack rates per million persons during the 1999 New York City outbreak showed that compared with persons 0 to 19 years of age, the incidence of severe neurologic disease was 10 times higher in persons 50 to 59 years of age and 43 times higher in those at least 80 years of age (1). In addition, the household-based serosurvey in New York City showed that incidence of West Nile virus infection was fairly uniform according to age (21). These results indicated that the higher incidences of severe neurologic disease among older persons were not attributable simply to differences in mosquito exposure. A similar finding was noted during the 1996 Romanian outbreak (9). Among hospitalized persons with West Nile virus infection in the United States (1999), Romania (1996), and Israel (2000), encephalitismeningoencephalitis was more frequently reported than meningitis (62%, 60%, and 58% compared with 32%, 40%, and 16%, respectively) (1, 9, 11). More than 90% of patients hospitalized during these outbreaks had fever; weakness, gastrointestinal symptoms, headache, and changes in mental status were common reported symptoms (Table 2). A skin rash, present in a minority of patients, was described as an erythematous macular, papular, or morbilliform eruption involving the neck, trunk, arms, or legs (1, 23). Table 2. Symptoms of West Nile Virus Reported among Hospitalized Patients during Outbreaks in New York State (1999), Romania (1996), and Israel (2000) Approximately half of the hospitalized U.S. patients had severe muscle weakness. This symptom may provide a clinical clue to the presence of West Nile virus, particularly in the setting of encephalopathy (1, 23). Approximately 10% of patients in the New York outbreak had

Investigation of bioterrorism-related anthrax, United States, 2001: epidemiologic findings.

In October 2001, the first inhalational anthrax case in the United States since 1976 was identified in a media company worker in Florida. A national investigation was initiated to identify additional cases and determine possible exposures to Bacillus anthracis. Surveillance was enhanced through health-care facilities, laboratories, and other means to identify cases, which were defined as clinically compatible illness with laboratory-confirmed B. anthracis infection. From October 4 to November 20, 2001, 22 cases of anthrax (11 inhalational, 11 cutaneous) were identified; 5 of the inhalational cases were fatal. Twenty (91%) case-patients were either mail handlers or were exposed to worksites where contaminated mail was processed or received. B. anthracis isolates from four powder-containing envelopes, 17 specimens from patients, and 106 environmental samples were indistinguishable by molecular subtyping. Illness and death occurred not only at targeted worksites, but also along the path of mail and in other settings. Continued vigilance for cases is needed among health-care providers and members of the public health and law enforcement communities.

West Nile Virus: Review of the Literature

IMPORTANCE Since its introduction in North America in 1999, West Nile virus has produced the 3 largest arboviral neuroinvasive disease outbreaks ever recorded in the United States. OBJECTIVE To review the ecology, virology, epidemiology, clinical characteristics, diagnosis, prevention, and control of West Nile virus, with an emphasis on North America. EVIDENCE REVIEW PubMed electronic database was searched through February 5, 2013. United States national surveillance data were gathered from the Centers for Disease Control and Prevention. FINDINGS West Nile virus is now endemic throughout the contiguous United States, with 16,196 human neuroinvasive disease cases and 1549 deaths reported since 1999. More than 780,000 illnesses have likely occurred. To date, incidence is highest in the Midwest from mid-July to early September. West Nile fever develops in approximately 25% of those infected, varies greatly in clinical severity, and symptoms may be prolonged. Neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis) develops in less than 1% but carries a fatality rate of approximately 10%. Encephalitis has a highly variable clinical course but often is associated with considerable long-term morbidity. Approximately two-thirds of those with paralysis remain with significant weakness in affected limbs. Diagnosis usually rests on detection of IgM antibody in serum or cerebrospinal fluid. Treatment is supportive; no licensed human vaccine exists. Prevention uses an integrated pest management approach, which focuses on surveillance, elimination of mosquito breeding sites, and larval and adult mosquito management using pesticides to keep mosquito populations low. During outbreaks or impending outbreaks, emphasis shifts to aggressive adult mosquito control to reduce the abundance of infected, biting mosquitoes. Pesticide exposure and adverse human health events following adult mosquito control operations for West Nile virus appear negligible. CONCLUSIONS AND RELEVANCE In North America, West Nile virus has and will remain a formidable clinical and public health problem for years to come.

Estimated risk of West Nile virus transmission through blood transfusion during an epidemic in Queens, New York City

BACKGROUND : Human West Nile virus (WNV) infection has been documented in the eastern United States since its discovery there in 1999. Epidemics of WNV encephalitis and meningitis raise concern that transmission of WNV may occur through voluntary blood donations.

Birth Defects Among Fetuses and Infants of US Women With Evidence of Possible Zika Virus Infection During Pregnancy

Importance Understanding the risk of birth defects associated with Zika virus infection during pregnancy may help guide communication, prevention, and planning efforts. In the absence of Zika virus, microcephaly occurs in approximately 7 per 10 000 live births. Objective To estimate the preliminary proportion of fetuses or infants with birth defects after maternal Zika virus infection by trimester of infection and maternal symptoms. Design, Setting, and Participants Completed pregnancies with maternal, fetal, or infant laboratory evidence of possible recent Zika virus infection and outcomes reported in the continental United States and Hawaii from January 15 to September 22, 2016, in the US Zika Pregnancy Registry, a collaboration between the CDC and state and local health departments. Exposures Laboratory evidence of possible recent Zika virus infection in a maternal, placental, fetal, or infant sample. Main Outcomes and Measures Birth defects potentially Zika associated: brain abnormalities with or without microcephaly, neural tube defects and other early brain malformations, eye abnormalities, and other central nervous system consequences. Results Among 442 completed pregnancies in women (median age, 28 years; range, 15-50 years) with laboratory evidence of possible recent Zika virus infection, birth defects potentially related to Zika virus were identified in 26 (6%; 95% CI, 4%-8%) fetuses or infants. There were 21 infants with birth defects among 395 live births and 5 fetuses with birth defects among 47 pregnancy losses. Birth defects were reported for 16 of 271 (6%; 95% CI, 4%-9%) pregnant asymptomatic women and 10 of 167 (6%; 95% CI, 3%-11%) symptomatic pregnant women. Of the 26 affected fetuses or infants, 4 had microcephaly and no reported neuroimaging, 14 had microcephaly and brain abnormalities, and 4 had brain abnormalities without microcephaly; reported brain abnormalities included intracranial calcifications, corpus callosum abnormalities, abnormal cortical formation, cerebral atrophy, ventriculomegaly, hydrocephaly, and cerebellar abnormalities. Infants with microcephaly (18/442) represent 4% of completed pregnancies. Birth defects were reported in 9 of 85 (11%; 95% CI, 6%-19%) completed pregnancies with maternal symptoms or exposure exclusively in the first trimester (or first trimester and periconceptional period), with no reports of birth defects among fetuses or infants with prenatal exposure to Zika virus infection only in the second or third trimesters. Conclusions and Relevance Among pregnant women in the United States with completed pregnancies and laboratory evidence of possible recent Zika infection, 6% of fetuses or infants had evidence of Zika-associated birth defects, primarily brain abnormalities and microcephaly, whereas among women with first-trimester Zika infection, 11% of fetuses or infants had evidence of Zika-associated birth defects. These findings support the importance of screening pregnant women for Zika virus exposure.

Acute Flaccid Paralysis and West Nile Virus Infection

Acute weakness associated with West Nile virus (WNV) infection has previously been attributed to a peripheral demyelinating process (Guillain-Barré syndrome); however, the exact etiology of this acute flaccid paralysis has not been systematically assessed. To thoroughly describe the clinical, laboratory, and electrodiagnostic features of this paralysis syndrome, we evaluated acute flaccid paralysis that developed in seven patients in the setting of acute WNV infection, consecutively identified in four hospitals in St. Tammany Parish and New Orleans, Louisiana, and Jackson, Mississippi. All patients had acute onset of asymmetric weakness and areflexia but no sensory abnormalities. Clinical and electrodiagnostic data suggested the involvement of spinal anterior horn cells, resulting in a poliomyelitis-like syndrome. In areas in which transmission is occurring, WNV infection should be considered in patients with acute flaccid paralysis. Recognition that such weakness may be of spinal origin may prevent inappropriate treatment and diagnostic testing.

Duration of time from onset of human immunodeficiency virus type 1 infectiousness to development of detectable antibody

Background: For persons newly infected with the human immunodeficiency virus type 1 (HIV‐1), the time from the onset of infectivity to the development of detectable HIV‐1 antibody is unknown. Persons who donate blood during this period account for nearly all instances of HIV‐1 transmission from HIV‐1 antibody‐screened blood transfusions.

Interim guidelines for prevention of sexual transmission of Zika virus — United States, 2016

Zika virus is a mosquito-borne flavivirus primarily transmitted by Aedes aegypti mosquitoes (1,2). Infection with Zika virus is asymptomatic in an estimated 80% of cases (2,3), and when Zika virus does cause illness, symptoms are generally mild and self-limited. Recent evidence suggests a possible association between maternal Zika virus infection and adverse fetal outcomes, such as congenital microcephaly (4,5), as well as a possible association with Guillain-Barré syndrome. Currently, no vaccine or medication exists to prevent or treat Zika virus infection. Persons residing in or traveling to areas of active Zika virus transmission should take steps to prevent Zika virus infection through prevention of mosquito bites (http://www.cdc.gov/zika/prevention/).