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The Origins and Emergence of Zika Virus, the Newest TORCH Infection: What's Old Is New Again.

When the Zika virus emerged onto the global public health stage from Brazil in 2015, the West African Ebola epidemic, centered in Guinea, Sierra Leone, and Liberia, was still an active threat. Unlike Ebola virus disease, which had more than 15 minor and major outbreaks before its devastating occurrence for the first time in West Africa, the Zika virus was a previously little-known flavivirus, which was unfamiliar to the public at large and to most health care workers. A Zika virus outbreak had previously occurred on Yap Island in the Federated States of Micronesia in 2007, where it produced a relatively mild illness characterized by rash, arthralgia, and conjunctivitis, but it received scant notice. (1) Six years later, the virus resurfaced, this time in French Polynesia, and subsequently spread through the Pacific to involve the Cook Islands, Vanuatu, Solomon Islands, New Caledonia, and eventually Easter Island between September 2013 and March 2014. [2,3,4] This was to be the largest epidemic of Zika virus that had occurred since the initial discovery of the virus in the Zika Forest of Uganda in 1947. (5) As the Zika virus spread rapidly through the French Polynesian islands, it infected an estimated 28 000 persons, representing approximately 11.5% of the Polynesian population. (6,7) However, the Oceanic epidemic of the Zika virus infection did not receive much global attention, especially because the West African Ebola epidemic was increasing in severity at the same time that the Zika virus epidemic was in decline.

In early 2015, a widespread illness characterized by skin rash and fever was reported to be occurring in several states of northeastern Brazil. The disease was initially thought to be the result of dengue virus infection because its symptoms resembled those of dengue fever, but testing excluded that virus as well as others. On April 29, 2015, the Bahia State Laboratory reported that patient samples tested positive for Zika virus, which was soon confirmed by polymerase chain reaction in Brazil's National Reference laboratory on May 7, 2015. On July 17, 2015, Brazil reported the occurrence of neurologic disorders associated with a history of infection, primarily from the northeastern state of Bahia. Among these reports, there were 49 cases of confirmed Guillain-Barre syndrome. In October and November of 2015, Brazil reported the occurrence of a large increase in the incidence of fetuses and infants with congenital microcephaly and other malformations, which led the Pan American Health Organization (PAHO) and the World Health Organization (WHO) to issue an epidemiologic alert to report cases of neurologic disorders including microcephaly. On December 1, 2015, PAHO and WHO issued an alert regarding the association of Zika virus infection with neurologic syndromes and congenital malformations in the Americas. As the number of fetuses and newborns with congenital microcephaly who were being reported from Brazil increased, on February 1, 2016, WHO declared that the recent association of Zika infection with clusters of microcephaly and other neurologic disorders constituted a Public Health Emergency of International Concern. After many months of intensive collaborative research, during which pathology studies had a prominent role, on April 13, 2016, the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, issued a statement that Zika virus was a cause of microcephaly and other severe fetal brain defects. (8,9)

The most recent reports have confirmed that Zika virus is highly neurotropic, infects the placenta, is hematogenously transmitted to the developing fetus via a transplacental mechanism, and is potentially teratogenic, producing fetal malformations collectively termed the congenital Zika syndrome (CZS). (10)

THE ORIGINS OF ZIKA VIRUS--A BRIEF HISTORY

Where did the Zika virus come from? In the early decades of the 20th century, it was yellow fever, another mosquito-borne flavivirus disease, that was one of the most-feared epidemic infections in many regions of the New and Old Worlds. Yellow fever, called yellow-jack or the black vomit, had been known for several centuries, causing devastating epidemics in Europe, Africa, and South America. The yellow fever outbreak that occurred in 1793 in Philadelphia, Pennsylvania, the capital of the newly created United States, was so devastating that it caused members of the newly formed federal government (including President George Washington, Secretary of State Thomas Jefferson, and Treasury Secretary Alexander Hamilton) to flee the city, and resulted in the deaths of 9% of the city's inhabitants. Yellow fever continued to be a global scourge through the 1800s until the beginning of the 20th century. During that time, a connection between arthropods and human disease remained largely unknown, and yellow fever was believed to be spread by direct human contact.

After many years of research, in 1881, Carlos J. Finlay, MD, a Cuban physician, epidemiologist, and microbiologist, first proposed that yellow fever was transmitted by a mosquito and, 1 year later, specifically by a mosquito belonging to the genus Aedes (Figure 1). His hypothesis was later proven by Walter Reed, MD, Jesse Lazear, MD, and other members of the US Army Yellow Fever Commission working in Cuba, making yellow fever the first recognized arbovirus. Following this important discovery, the recently established Rockefeller foundation (New York, New York) made the control and eradication of yellow fever an international priority. The Foundation initially undertook a comprehensive yellow fever eradication project in Mexico, which proved highly successful. Its International Health Division then established laboratories and field sites in other endemic regions of South America and, later, Africa. After World War II, the Rockefeller Foundation investigators, looking for a new location to study yellow fever transmission, came across the Zika Forest, an isolated area of dense vegetation and swampland in Eastern Uganda (ziika means overgrown in the Luganda language; the second i was dropped by Europeans). Located in the Buganda Kingdom, the 62-acre forest was situated adjacent to an inlet of Lake Victoria, approximately 15 miles (24.1 km) from the capital city of Kampala, and was a little-known area even to the people of Uganda. The Rockefeller scientific team was composed of a Scottish virologist, George W. A. Dick, MBChB, MPH, of the National Institute for Medical Research in London; Alexander J. Haddow, MBChB, DSc, a physician and entomologist from the University of Glasgow; and Stuart F. Kitchen, MD, of the Rockefeller Institute's Yellow Fever Laboratory. After their decision to establish a field site (Figure 2), they imported supplies, built cages, and constructed 120-foot (36.6-m) tall steel towers (referred to as Haddow towers after Dr Haddow who designed them) (Figure 3), where mosquitoes, birds, bats, and a variety of animals could be captured and studied. They also used captive monkeys, which were placed into 6 cages and suspended among the jackfruit and mango trees of the forest where mosquitoes bred (Figure 4). Because the feeding preferences of mosquitoes vary by the height above ground (in addition to the species and time of day), animals and collection cages could be suspended at differing heights from the steel towers (Figure 5). Termed sentinel monkeys, their blood was periodically tested for the presence of yellow fever and other arboviruses. On April 18, 1947, one of the rhesus macaques, named Rhesus 766, developed a fever of 39.7[degrees]C, about 2[degrees]C higher than reference range. The monkey was sent to the laboratory at Entebbe, Uganda, where a blood sample was taken and injected via the intracerebral and intraperitoneal routes into Swiss albino mice and, subcutaneously, into an uninfected ("clean") rhesus macaque named Rhesus 771. The mice inoculated intraperitoneally and Rhesus 771 failed to develop symptoms; however, mice injected via the intracerebral route developed illness beginning 10 days after inoculation. A small virus (then termed a filterable agent) was recovered from brain tissue of the inoculated mice. Although Rhesus 766 never developed any symptoms, except fever, the same filterable agent was isolated from its serum. On January 11 and 12, 1948, the scientists were again trapping mosquitoes in the Haddow towers in an attempt to isolate the yellow fever virus. They homogenized 86 captured Aedes africanus mosquitoes (Figure 6), combined the ground mosquitoes with a blood-saline solution, and injected the mixture into the brains of 6 mice and, subcutaneously, into another rhesus macaque, named Rhesus 758. After 7 days, the mice "appeared inactive," and testing revealed the same "filterable agent" that had been isolated from Rhesus 766. (5) Although Rhesus 758 never developed signs of illness, its serum produced illness and death when injected intracerebrally into uninfected mice. The Rockefeller team named their "hitherto unrecorded virus" the Zika virus. (5,11-15) In view of the recent autopsy pathology findings from microcephalic fetuses and infants infected with Zika virus, (16) an interesting and unusually prophetic conclusion from Dr Dick is his statement that "Zika virus is highly neurotropic in mice and no virus has been recovered from tissues other than the brains of infected mice." (17)

THE BIRTH OF TORCH

How did the term TORCH originate? In the 1960s, diagnosis based upon the clinical evaluation of neonates with suspected congenital infections was challenging. Because many of the infectious agents that are transmitted from mothers to their infants produce little or no maternal morbidity and fetal and neonatal infections were clinically indistinguishable from one another, it could be difficult to make a reliable diagnosis of a specific infectious etiology. At that time, prenatal diagnostic methods, such as amniocentesis, were risky and not highly effective; laboratory testing was largely based on serologic methods, microbiologic cultures, and pathology studies, including direct visualization of the agent by light and electron microscopy; and some antibody-based methods (no molecular- or gene-based testing was yet available). Charles Alford, MD, a renowned pioneer in pediatric infectious diseases and congenital infections, stated in 1967, "neonatal diagnoses of infections acquired in utero, natally and postnatally, are inherently difficult." (18) Arguably, the most severe epidemic of a congenital infection occurring during that period was that of the rubella virus outbreak that travelled from Europe and swept through the United States in 1964 and 1965. Occurring as it did before the advent of the rubella vaccine, there were 12.5 million new cases reported. Among these, approximately 50 000 pregnant women were exposed to the virus; it affected 1% of all pregnancies in the United States. Rubella infections occurring in pregnancy resulted in 20 000 children born with congenital rubella syndrome (CRS), of whom, 11 000 were deaf, 3500 were blind, and 1800 had intellectual disabilities. In addition, there were 2100 neonatal deaths and 11 000 abortions. (19-22) In addition to rubella, congenital infections caused by cytomegalovirus, toxoplasmosis, and herpes simplex virus were recognized as public health problems among pregnant mothers and their infants, but it was difficult to differentiate one virus from another clinically.

Recognizing this situation, in 1971, a group of investigators in Atlanta, Georgia, led by Andre Nahmias, MD, developed an acronym to identify 4 of the most-frequent causes of vertically transmitted infections that were recognized at that time. The acronym that they devised--TORCH--represented TOxoplasma, Rubella virus, Cytomegalovirus, and the 2 Herpes simplex viruses (type 1 and type 2). (23) After the introduction of this acronym into the medical literature, it was later modified to reflect the occurrence of additional congenital infections that had potentially serious consequences to the fetus and neonate. Thus, the O of TOxoplasma was changed to represent Other infections.

As the term TORCH became accepted generally in the medical and, in particular, pediatrics and infectious disease medical communities, several proposals for modifying the term arose. In 1975, Harold T. Fuerst, MD, found it "particularly distressing" that an important infectious agent had been omitted from the acronym originally developed by Dr Nahmias and colleagues 4 years previously. Dr Fuerst was the first to suggest revising the term; he suggested the term STORCH to include syphilis, an important cause of congenital infections and perinatal morbidity and mortality. STORCH was German for stork, which Fuerst believed to be "highly suitable." (24) The following year, Roger Brumback, MD, proposed another modification; he suggested that the term TORCHES (TOxoplasmosis, Rubella, Cytomegalovirus, HErpes, Syphilis) be used because pediatricians were already becoming familiar with the concept of TORCH infections. (25) Through the succeeding decades, increasing progress in the recognition and diagnosis of congenitally acquired infections has resulted in the O representing a number of Other infections. Since 1971, the spectrum of pathogens considered to be TORCH agents has greatly expanded.26 Before the current Zika epidemic, a listing of TORCH agents would include such pathogens as syphilis, parvovirus, coxsackievirus, listeriosis, and, in some cases, hepatitis, varicella-zoster virus, Trypanosoma cruzi, enteroviruses, and HIV.

Despite the ever-increasing spectrum of congenital infectious diseases, 45 years after its initial publication, the acronym originally proposed--TORCH--continues to be the preferred term to represent all these vertically transmitted infections.

TORCH INFECTIONS

Exactly what is a TORCH infection? Although there is no universal definition of what constitutes a TORCH infection, it is clear that the various descriptions used for this term have many factors in common. The agents of TORCH infections all can infect women during pregnancy; typically, but not always, they are present in the maternal bloodstream as a viremia, bacteremia, or parasitemia, and often do not produce significant disease or even symptoms in the mother. They are also characterized by vertical transmission to the fetus, most often hematogenously, through the placenta before delivery or, less often, via the birth canal around the time of labor and delivery. Following fetal infection, TORCH agents can cause a variety of potentially severe complications, which can include microcephaly, multiorgan disease, congenital malformations, and intrauterine growth restriction. The TORCH agents can also cause miscarriages, stillbirths, and neonatal deaths. Several TORCH infections have a predilection for the central nervous system, causing severe pathologic changes in the brain that can result in neurologic, sensorial, and developmental abnormalities. (27,28)

PLACENTAL PATHOLOGY OF TORCH INFECTIONS

When transmitted from the maternal bloodstream to the fetus through the placenta, most TORCH agents result in recognizable placental abnormalities. These include the presence of acute, granulomatous or chronic villitis, intervillositis, intervillous microabscesses, viral inclusions, villous endothelial cell abnormalities, villous necrosis, avascular villi, or necrotizing inflammation involving the villi, placental membranes, or umbilical vessels. (29-31) Examination of placentas from second- and third-trimester infants having congenital Zika virus infection have shown a different pathologic spectrum. (32) Villitis, which is the histologic hallmark of a maternal hematogenously transmitted infection, has not been a microscopic feature in placentas of fetuses with congenital Zika virus infection. (32) Inflammatory lesions of the umbilical cord (funisitis) and placental membranes (chorioamnionitis), characteristically the result of an ascending infection arising from the maternal cervicovaginal canal, are (as expected) similarly not a feature of congenital Zika virus infection. Thus, there is no evidence of a maternal inflammatory response or a fetal inflammatory response in second- and third-trimester placentas from fetuses with microcephaly that have been examined thus far. There is also an absence of necrosis directly attributable to Zika virus infection in any placental structure. (32)

Similar to placentas from infants with some congenital TORCH infections, placentas from second- and thirdtrimester infants with Zika virus infection demonstrate increased numbers of Hofbauer cells within the stroma of chorionic villi. (32,33) Some Hofbauer cells have been demonstrated to still be in the proliferation phase of the cell cycle, (32) indicating the terminal phase of a hyperplastic response to transplacental Zika virus infection by these fetal-derived macrophages. The Zika virus has been shown to be present in the chorionic villi in placentas from infected fetuses, where the virus has been localized within Hofbauer cells using both nucleic acid (32) and antigenic (33) techniques. These findings from naturally infected human placentas are consistent with a recent report in which Hofbauer cells have been shown experimentally to be permissive to Zika virus replication in isolated cultures in vivo and infected with Zika virus ex vivo in chorionic villous explants. (34)

ZIKA VIRUS IS THE NEWEST TORCH INFECTION

Is the Zika virus a TORCH agent? The clinical and pathologic spectra of the effects of Zika virus infection on the developing fetus continue to expand. Zika virus infection occurring in pregnant women and their fetuses satisfies all of the characteristics of a TORCH agent--it is transmitted vertically during pregnancy from mothers who have mild or absent symptoms, it infects the placenta, (32,33,35) and after intrauterine fetal infection can produce poor obstetric outcomes, including microcephaly and other fetal malformations. (10,16)

When compared with previously recognized TORCH agents, Zika virus appears most similar to the rubella virus, which was the prototypical TORCH virus. When occurring in nongravid persons, both rubella and Zika viruses may by asymptomatic or can produce a mild illness characterized by a rash. The most serious consequences of both viruses occur when pregnant women become infected. Both rubella and Zika viruses are teratogenic and produce a syndrome of fetal malformations--the CRS (36) and the CZS, respectively. (10) Microcephaly and destructive brain lesions are components of the malformation syndromes produced by both viruses. There are also similarities in the timing of maternal infection and risk for development of fetal malformations in these viruses. In the case of rubella, the most important factor affecting the transplacental transmission rate and severity of fetal infection is the gestational age at which a primary maternal infection first occurs. Although fetal infection with rubella can occur at any time during pregnancy, the probability of fetal infection and development of the CRS increases with maternal infection occurring at an earlier gestational age. The CRS occurs in up to 90% of fetuses when maternal infection occurs before 11 weeks of pregnancy, decreasing to 33% between 11 and 12 weeks, 11% at 13 to 14 weeks, 24% at 15 to 16 weeks, and 0% after 16 weeks of gestation. (37,38) This relationship between maternal infection occurring earlier in gestation being associated with a greater risk of fetal infection and malformation is recently being recognized for Zika virus, further strengthening their similarities. (10) In one Brazilian study, (39) the production of fetal microcephaly by the Zika virus was found to correlate best with maternal viral infection occurring at approximately 17 weeks gestation--early in gestation, but somewhat later than malformations caused by rubella. In a study from Bahia, Brazil, Johansson et al (40) found that the risk for the development of microcephaly was greatest when Zika infection occurred in the first trimester of pregnancy. They estimated that the probability of having a fetus with microcephaly varied from approximately 1% to 13% when a woman developed Zika virus infection during the first trimester. There was negligible risk for development of the CZS when maternal infection developed in the second and third trimesters. (40)

Rubella, and especially the congenital malformation syndrome associated with it, was a major public health problem throughout the world before the licensing in 1970-1971 of live attenuated vaccines in the United State and Europe. (20) Systematic vaccination against rubella, most often in combination with measles, has virtually eliminated both the acquired and congenital forms of the disease from some resource-rich nations, including the United States. In April 2015, the WHO Region of the Americas was declared the first in the world to be free of endemic rubella transmission. (41) Similar to rubella, the occurrence of the congenital varicella syndrome is also now a rare event in resource-rich countries because of the widespread use of the varicella vaccine.

Rubella can be viewed as a model for a TORCH virus that has been controlled through the widespread distribution of an efficacious vaccine. It is hoped that, with the development of an effective vaccine for Zika virus, the same success will be reached for mothers and their infants in preventing this newest of the TORCH infections from causing fetal infection, congenital malformations, and further suffering.

I thank Moira Rankin, MA, senior archivist, in the Archives and Special Collections of the Library at the University of Glasgow for her assistance in obtaining the photographs from the Alexander Haddow Collection. I also thank Katie Giesen, BA, managing editor of the Archives of Pathology & Laboratory Medicine, for her patience and expertise in helping to publish this special Zika virus issue of the ARCHIVES.

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Accepted for publication September 1, 2016.

Published as an Early Online Release October 20, 2016.

From the Medical College of Georgia, Augusta University, Augusta.

The author has no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2016-0429-ED

Reprints: David A. Schwartz, MD, MS Hyg, 1950 Grace Arbor Ct, Atlanta, GA 30329 (email: davidalanschwartz@gmail.com).

David A. Schwartz, MD, MS Hyg, has an educational background in anthropology, pathology, emerging infections, women's health, and medical epidemiology. His pathology subspecialties include obstetric, placental, and perinatal pathology, as well as infectious disease pathology. Dr Schwartz has professional and research interests in reproductive health, diseases of pregnancy, and maternal and infant morbidity and mortality in both resource-rich and resource-poor countries. An experienced author, editor, and consultant, Dr Schwartz investigates the anthropologic, biomedical, and epidemiologic aspects of pregnancy and its complications as they affect society, in particular in indigenous populations and when they involve emerging infections, and has extensive field experience in these specialties in the resource-poor nations of the world, including Africa, Asia, and Latin America. Dr Schwartz has been a recipient of many grants, was a Pediatric AIDS Foundation scholar, and has organized and directed projects involving maternal health, placental pathology, and perinatal infectious disease transmission for such US agencies as the Centers for Disease Control and Prevention, the National Institutes of Health, and the US Agency for International Development, as well as for the governments of other nations. His most-recent book, Maternal Mortality: Risk Factors, Anthropological Perspectives, Prevalence in Developing Countries and Preventive Strategies for Pregnancy-Related Deaths, was published in October 2015. He is currently completing a book for Springer Nature entitled Maternal Health, Pregnancy-Related Morbidity and Death Among Indigenous Women of Mexico & Central America: An Anthropological, Epidemiological and Biomedical Approach. Dr Schwartz is editing a second new book for Springer Nature dealing with the West African Ebola outbreak, which is entitled Pregnant in the Time of Ebola: Women and Their Children in the 2013-2015 West African Epidemic. Dr Schwartz currently serves on the editorial boards of 3 international journals and is currently a clinical professor of pathology at the Medical College of Georgia in Augusta. Dr Schwartz has extensive experience at understanding and integrating the anthropologic, biomedical, epidemiologic, and public health aspects of pregnancy, childbirth, and infectious diseases as they affect society. Dr Schwartz also serves as an associate editor in anatomic pathology for the Archives of Pathology & Laboratory Medicine.

Please Note: Illustration(s) are not available due to copyright restrictions.

Caption: Figure 1. A page from a handwritten laboratory notebook of Carlos Finlay, MD, describing his studies with yellow fever ("fiebre amarilla"). This page is from the author's collection.

Caption: Figure 2. The present day Zika Forest Research Field Station is located in the Zika Forest of Uganda, where the Zika virus was originally identified in 1947. Note that the second "i" in "Ziika" was later dropped. Photograph used with permission from Andrew D. Haddow, PhD.

Caption: Figure 3. A view looking down from the inside of a 120-foot-tall (37-m-high) Haddow tower. Photograph from the Alexander Haddow archive with permission of the University of Glasgow.

Caption: Figure 4. Local boys were hired to catch the mosquitoes required for Haddow's studies. These catches often took place on platforms in the trees to determine which species were active at different heights. Here, one of the boys climbs an 82-foot-high (25-m-high) platform. Photograph from the Alexander Haddow archive with permission of the University of Glasgow.

Caption: Figure 5. This diagram shows some of the results obtained from the steel tower in the Zika forest. The graphs give the vertical distribution of 4 different mosquito species, including Aedes africanus, the species from which the Zika virus was first isolated. Each number on the left axis represents one of the levels of the tower. Aedes africanus is most active at 60 feet (18 m), just below the canopy. Photograph from the Alexander Haddow archive with permission of the University of Glasgow.

Caption: Figure 6. A page from Dr Haddow's notes showing the standard format he used to record the results for 24-hour catches of mosquitoes. This was a technique he pioneered, where all the biting insects at a specific location would be caught, stored, and grouped by the hour in which they were caught. The mosquitoes would later be identified, and the number of each species caught each hour at each level was recorded. In this particular record, the entry for A. (S) africanus is annotated "Zika Virus" in red ink (left side of page [asterisk] and inset): this was the first batch of mosquitoes from which the Zika virus was isolated. Photograph from the Alexander Haddow archive with permission of the University of Glasgow.
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Title Annotation:Special Issue--The Zika Virus Global Pandemic: The Latest Emerging Infection
Author:Schwartz, David A.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jan 1, 2017
Words:5298
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