Histoplasmosis of the nervous system
Histoplasmosis is an infection caused by the fungus Histoplasma capsulatum. Infection is endemic to certain areas of the United States, including the
Jun. 09, 2021
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First discovered in 1947, Zika virus is a single-stranded RNA, mosquito-borne flavivirus that closely resembles dengue, West Nile, and yellow fever viruses. Initially, few documented cases of human Zika infection occurred, and the virus was contained within Africa and Asia. Infection was thought to be largely asymptomatic or cause no more than a mild febrile illness. Common clinical manifestations of Zika infection include maculopapular rash, conjunctivitis, arthralgia, frontal headache, malaise, and fever. Within the past decade, Zika has expanded globally to the Western Pacific and the Americas, with the first documented case in Brazil in 2015 and the first case in the United States in 2016. Since then, researchers have noticed a rise in the incidence of neurologic complications ranging from Guillain-Barre syndrome, encephalomyelitis, sensory neuropathy, seizures, and stroke to congenital Zika syndrome in infants born to mothers infected during pregnancy. The association between Zika virus infection and these severe neurologic sequelae contradicts what was once believed to be a relatively benign virus and is the focus of this article.
• Zika virus is a mosquito-borne flavivirus that is asymptomatic in 80% of those infected and, when symptomatic, generally results in a mild febrile illness.
• Studies have shown that the virus is highly neurotropic in both mice and in vitro cell studies with human embryonic cortical neural progenitor cells.
• Major neurologic complications of Zika virus infection include Guillain-Barre syndrome and congenital Zika syndrome.
• Additional neurologic complications have been suggested as occurring secondary to Zika virus infection, including meningoencephalitis, transverse myelitis, seizure, and stroke.
In 1947, researchers studying yellow fever in Uganda isolated a new virus from the blood of a caged rhesus macaque. They named this virus Zika, after the forest in which it was discovered (32). Before the first major outbreak in 2007 in Yap State, Micronesia, only 14 cases of human infection had been documented in the literature (59; 35; 47). The virus then spread to French Polynesia in 2013 to 2014 (113). One study demonstrated a 1:1 ratio of symptomatic to asymptomatic infection in the general population and a 2:1 ratio amongst school age children (08). The virus arrived in Brazil in March 2015 and has since spread to over 30 additional countries (114; 90). Local transmission in the United States was first reported in Miami Beach in 2016, and in that year, there were 5168 cases of symptomatic Zika virus infection documented in the United States, mostly in travelers (25). So far in 2018, only 34 cases of symptomatic infection have been reported in the U.S. (26). Association of Zika virus infection with Guillain-Barre syndrome first occurred during the 2013 to 2014 outbreak in French Polynesia, whereas the first association of the virus with microcephaly occurred during the 2015 outbreak in Brazil (16).
The symptoms associated with Zika virus infection are variable. Generally, only 20% to 25% of those infected with the virus will demonstrate symptoms, whereas the rest are asymptomatic (69; 21). When symptoms do develop, they are typically mild, nonspecific, of short duration, and can be easily misdiagnosed as dengue fever due to the similar clinical presentation (81).
In 1964, a researcher was infected with Zika virus and documented his own clinical course (101). On day 1 of infection, he developed a frontal headache. On day 2, he described a maculopapular rash that involved all 4 limbs as well as the palms and soles of his hands and feet. He also developed malaise, body aches, and a low-grade fever on day 2 as the rash spread. The malaise and fever resolved by the end of day 2, and he felt well on day 3. The rash faded completely by day 5. This presentation and duration of illness is similar to other reports in the literature, with the illness generally lasting 2 to 7 days. Rash usually begins on the face and spreads downward and is often pruritic (21). Other common manifestations include nonpurulent conjunctivitis, myalgias, and arthralgias, specifically of the smaller joints in the hands and feet (35; 21).
Less common are case reports of hematospermia, swelling of the hands and feet, and possible thrombocytopenia (41; 79; 112; 55). Generally, acute infection has a good prognosis with full recovery. There are low rates of hospitalization from acute infection, and morbidity is usually related to neurologic complications (06).
For decades, Zika virus was believed to cause little more than a mild febrile illness. Now, it is known that Zika infection during pregnancy can lead to the development of congenital Zika syndrome, which includes microcephaly, cerebral calcifications, and ventriculomegaly (14; 94).
In addition, Zika virus infection has been associated with Guillain-Barre syndrome, acute myelitis, meningoencephalitis, acute demyelinating encephalomyelitis, peripheral neuropathy, seizure, and stroke (06; 20; 71; 02; 21). The reports of these severe neurologic complications have resulted in increased efforts by physicians and researchers alike to gain a better understanding of the link between Zika infection and neurologic disorders.
The World Health Organization defines microcephaly as an occipital frontal circumference that is 2 standard deviations smaller than the mean for the same age and sex, whereas severe microcephaly is classified as an occipital frontal cortex that is 3 standard deviations below the mean (17; 87). There were no reports of congenital abnormalities during the time of the Yap Island and French Polynesia outbreaks. Yet, a retrospective analysis of data from the French Polynesia outbreak in 2013 to 2014 demonstrated temporal clustering of 7 cases of microcephaly. These researchers estimated a 1% risk of microcephaly when a woman is infected in the first trimester (12; 22). In Brazil, a study of 42 pregnant women positive for Zika virus detected 16 of the 42 to have fetal abnormalities on fetal ultrasound, whereas ultrasound of 16 pregnant women negative for Zika virus showed no abnormalities (14). The incidence of microcephaly in Brazil was 20 times higher in 2015 than in years past, and Brazil reported over 4000 suspected cases within a 6-month time period in 2016 (17; Miranda-Filho De et al 2016). A prospective cohort study of pregnant women with PCR-confirmed Zika infection was done between March and November of 2016, and this study demonstrated birth defects possibly associated with Zika virus in 7% of fetuses and infants (61). Additionally, this study showed that frequency of defects was higher when the mother was infected earlier in pregnancy, specifically in the first trimester. A separate study found the risk of microcephaly after maternal Zika infection in the first trimester to be 1% to 13% (52). Researchers have shown that it is possible for fetuses to have complications from Zika infection later in pregnancy as well; however, it has been suggested that manifestations from later infections may not become apparent until after birth (61).
The growing reports of congenital malformations due to Zika infection have led researchers to compile a description of “congenital Zika syndrome.” Infants born to mothers infected with Zika during pregnancy share many of the same features as infants born to mothers with other TORCH infections, which is toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus, and herpes. These features include microcephaly, intracranial calcifications, ocular disease, and hearing loss. However, 2 characteristic findings are seen with Zika that are not classically seen with other TORCH infections: severe microcephaly with a partially collapsed skull and cupped appearance of sutures and coarse calcifications at the gray-white matter junction (61). In addition, researchers have noted facial disproportionality, cutis gyrata, hypertonic spasticity, and irritability after birth; abnormal brain imaging with ventriculomegaly; and lissencephaly in children with Zika congenital syndrome (74). Ocular abnormalities are seen in up to 70% of infants with congenital Zika syndrome and include iris coloboma, lens subluxation, cataracts, congenital glaucoma, posterior segment, and retinal abnormalities (de Oliveira et al 2018). The authors go on to hypothesize that retinal pathology in congenital Zika syndrome mimics changes within the central nervous system and likely results from loss of specific neuronal progenitor cells in utero.
The prognosis for children born with microcephaly is typically poor, and these children often have severe developmental disabilities. One study followed 19 children with severe microcephaly and lab evidence of Zika infection at birth and found that after 19 to 24 months, most children had severe motor impairment, seizure disorders, hearing and vision loss, and sleep difficulties (99).
In addition to congenital Zika syndrome, there have also been reports of an increase in the prevalence of Guillain-Barre syndrome in infected adults throughout Brazil and other Zika-endemic areas. Guillain-Barre is a syndrome that causes progressive weakness of the limbs and loss of deep tendon reflexes, and, in its most severe form, it can compromise respiratory function. Loss of respiratory function occurs in about 25% of cases (111; 108). The syndrome is most often associated with antecedent infection with the bacteria C. jejuni, but Epstein-Barr virus, cytomegalovirus, and HIV infections are also prevalent precursors (111; 108). The syndrome has a death rate of about 5%, and up to 14% of patients can be left with severe motor weakness 1 year after onset of the illness (92; 107).
The first link between Guillain-Barre syndrome and Zika infection was documented during the French Polynesia outbreak in 2013 (81). Within French Polynesia, the major outbreak of Zika infection occurred 3 weeks before a subsequent increase in Guillain-Barre syndrome was observed (16). Forty-two patients were diagnosed with Guillain-Barre between November 2013 and February 2014. In the preceding 4 years, no more than 10 cases of Guillain-Barre had been documented. Researchers discovered that 41 out of the 42 patients with Guillain-Barre had Zika virus IgM, and 100% had neutralizing antibodies versus only 54% of the control group. Common presenting symptoms in these patients were generalized muscle weakness, inability to walk, facial nerve palsy, and cytoalbuminologic dissociation in the CSF; 29% of the patients ultimately required respiratory assistance (18). The most common subtype of Guillain-Barre documented within this study was acute motor axonal neuropathy (AMAN). The researchers were not able to obtain the viral genotype from the CSF of patients with Guillain-Barre during the French Polynesia study. Instead, they made the diagnosis using IgM antibodies. This lead the way to speculation that the increase in Guillain-Barre syndrome could be due to dengue virus infection, which has high crossreactivity with Zika antibodies and is also known to cause the syndrome (44; 93). However, researchers in Brazil were able to obtain the full Zika genotype from a patient with Guillain-Barre syndrome in 2014 (15). This lends further evidence to the hypothesis that Zika virus infection can be complicated by Guillain-Barre syndrome. Since then, many additional case reports and case series of Guillain-Barre syndrome related to Zika virus infection have been documented (40; 04; 05; 29). The most common subtype amongst these studies remained acute motor axonal neuropathy, but acute inflammatory demyelinating polyneuropathy (AIDP), sensory demyelinating polyneuropathy, and Miller-Fisher subtypes have also been documented (04; 05; 29). In a case control study by Anaya and colleagues, dysautonomia was seen in up to 76% of patients with Zika associated Guillain-Barre syndrome (04), which was noted to be higher than in patients with Guillain-Barre syndrome of other etiologies (45). Carod-Artal proposed that autonomic symptoms secondary to a viral infection may be due to both invasion of the central nervous system and also toxin-mediated and immune-mediated effects on peripheral and autonomic nerves (19).
Several hypotheses have emerged in an attempt to explain how Zika virus infection leads to Guillain-Barre syndrome. Lucchese and Kanduc suggested that cross-reaction between Zika polyprotein peptides and human proteins may contribute to an autoimmune response leading to Guillain-Barre syndrome (65). Another study supported this molecular mimicry theory, showing that the median onset of Guillain-Barre syndrome after onset of Zika virus infection was 7 days, which is consistent with direct viral or antibody mediated pathophysiology (29). Additionally, some authors have suggested that antibody-dependent enhancement (ADE) of Zika virus could contribute to the severity of neurologic complications (109; 02), and multiple investigators have observed this phenomenon in laboratory settings (31; 88). Interestingly, one study found prior infection with M. pneumoniae to be associated with development of Guillain-Barre syndrome (04).
The prognosis for those with Guillain-Barre syndrome in the French Polynesia study was favorable (18). At 3 months after discharge from the hospital, approximately 57% of the patients could walk. There were no deaths. One case control study of 29 patients with Zika virus associated Guillain-Barre syndrome found that dysautonomia was the main risk factor for poor progression (04). There is no cure for the disease, but many patients make a full recovery. Intravenous immunoglobulin and plasmapheresis can increase the rate of recovery, and, if needed, patients can be intubated to assist with respiration if they lose function of their diaphragms. Recovery time is variable and can range from weeks to years before full function is restored (111; 108).
Furthermore, there are many reports of other concerning neurologic complications. A 15-year-old girl presented with symptoms of Zika virus and was subsequently diagnosed with acute myelitis (71). Zika virus was identified in her CSF, serum, and urine. Other case reports have also emerged suggesting Zika virus infection as a cause of parainfectious transverse myelitis (85; 04; 02). Proposed mechanisms include molecular mimicry, as in Zika associated Guillain-Barre syndrome (02), and damage due to direct microbial infection or indirect infection producing a systemic inflammatory response that damages neurons (11). A review by Acosta-Ampudia and colleagues details multiple reports of encephalopathy, meningitis, meningoencephalitis, transverse myelitis, and peripheral palsies related to Zika virus infection (02). Additionally, Martinez and colleagues and Medina and associates both document case reports of purely sensory neuropathy associated with Zika virus infection (72; 67). Both patients presented with asymmetric, distal hypoalgesia with associated changes in vibratory and proprioceptive senses. Seizures have been documented both in adult patients with complicating encephalopathy and infants with congenital Zika syndrome (07; 83). Interestingly, 1 study analyzed sleep EEG in infants with congenital Zika syndrome and found that EEGs were consistently abnormal even in infants who had not yet developed seizures (Carvalho et al 2017). Finally, several other case reports have suggested ischemic stroke secondary to infectious vasculitis as a complication of Zika virus infection (60; 53; 78; 95). The full extent of the neurologic complications of Zika infection is not yet known; however, studies are ongoing in order to develop a better understanding.
The following is a fictitious clinical vignette based on accounts of Zika infection that have occurred in travelers to South American and Caribbean countries over the past year.
A 28-year-old female who was 3 months pregnant (G1P0) returned from vacation with her husband in Puerto Rico. During the first week of her trip she developed malaise, a slight fever, and a frontal headache followed by a generalized maculopapular rash. The illness quickly resolved within 2 to 3 days, and she was able to enjoy the rest of her vacation. On returning to the U.S., she resumed normal prenatal care. Her doctor was concerned that the illness during her trip resembled Zika infection and ordered a real-time polymerase chain reaction of her urine. The test returned positive for infection with Zika virus. An ultrasound obtained at 20 weeks showed no signs of fetal anomalies. However, at week 29 of gestation, the woman noticed decreased fetal movements, and a repeat ultrasound at 30 weeks’ gestation demonstrated intrauterine growth restriction, a head circumference well below the second percentile, ventriculomegaly, and numerous placental and cerebral calcifications. At birth, the infant had severe microcephaly and eye abnormalities.
The virus is spread mainly via the Aedes aegypti and Aedes albopictus species of mosquitoes, which also transmit other common viral illnesses, including dengue and chikungunya. Aedes aegypti is the main vector in the Americas. Zika has also been isolated from Aedes furcifer, vittatus, taylori, and hirsutus species (50). Concern for further spread exists as at least half of the world population lives in Aedes species-infested areas (42). As the reach of the virus expands, researchers have become more concerned about other modes of transmission as well.
In the past few years, there have been many documented cases of sexual transmission of Zika virus infection, and its presence has been detected in genital fluids (77; 21). This feature is unique amongst arboviruses. Cases have been both asymptomatic and symptomatic and appear to be mostly male-to-female transmission, although female-to-male and male-to-male transmissions have also been recorded. Although it is still unknown exactly how long Zika remains infectious while in genital fluids, the virus has been documented in semen as long as 188 days after symptom onset (77). Another preliminary study showed viral RNA clearance from semen in 34 to 125 days (89). Additionally, it has been suggested that Zika virus may be more effectively transmitted sexually than through solitary mosquito bites (21).
More worrisome, however, is perinatal transmission of Zika virus due to risk of congenital Zika syndrome. One study reviewed the United States ZIKV Pregnancy Registry from January 2016 to September 2016 and found that among 442 completed pregnancies with laboratory evidence of infection, 6% of fetuses or infants demonstrated Zika-associated birth defects (49). Birth defects were noted most frequently when infection occurred during the first trimester versus second or third trimester. It remains unclear how Zika virus crosses the placenta. One study suggests that the virus must evade type-III interferon produced by placental syncytiotrophoblasts in order to gain access across the placenta (10). More studies are needed to fully elucidate the mechanism by which Zika crosses the placenta. Interestingly, although Zika nucleic acid has been found in breast milk, there are to date no documented cases of transmission via breast milk (34; 38).
Transmission via blood transfusion has also been suggested by case reports (09). During the French Polynesia outbreak in 2013 to 2014, molecular screening of blood donors demonstrated that 3% of asymptomatic donors were positive for Zika. Similar screening in Puerto Rico showed 0.5% of asymptomatic blood donors to be positive (34). United States FDA currently recommends screening all donations (U.S. Food and Drug Administration 2016), but a study in the New England Journal of Medicine found that testing blood donations for Zika was very costly with low yield (97). Additionally, there have been a few cases of iatrogenic infections transmitted within laboratory settings (34).
Given the rise in neurologic complications following Zika infection, great focus has been placed on elucidating the mechanisms by which Zika virus affects neurons. Several studies have shown that Zika virus infects neural stem cells and neural progenitor cells, alters gene expression, causes cell cycle abnormalities, induces apoptosis and autophagy, and inhibits proliferation (70; 98; 02; 51). One study suggests that these cytopathic effects are related to expression of Zika virus proteins (62). The authors found 5 structural and 2 nonstructural Zika virus proteins that produced cytopathic effects in host cells, including restriction of cell proliferation, induction of hypertrophy, and triggering of cellular oxidative stress, all of which led to cell death. Nonstructural protein 4A (NS4A), membrane-anchored capsid (anaC), membrane protein (M), and envelope protein (E) resulted in G2/M cell cycle accumulation, whereas premembrane protein (prM) produced G1 accumulation (62). Interestingly, Janssens and colleagues found that Zika virus alters DNA methylation of neural progenitor cells, astrocytes, and differentiated neurons at genes implicated in neurologic disorders including schizophrenia, implying that even asymptomatic, exposed individuals may have long-term consequences (51).
Interferon responses are known to be key components of host cell defenses against viral infection and replication (33). Multiple studies have shown that Zika virus avoids host interferon signaling, effectively creating viral resistance to interferon defenses (33; 46; 58). One mechanism through which this is accomplished is NS5 expression by Zika virus, which resulted in proteasomal degradation of the interferon regulated transcriptional activator STAT2 (46). Additionally, another investigation showed that Zika virus can also evade host NK cell cytotoxic response by upregulating MHC I (43). Another study demonstrated that Zika virus evades host interferon defenses inside human brain microvascular endothelial cells (hbMECs) and that these cells both act as a reservoir for persistent viral replication and also allow passage of Zika virus directly across the blood brain barrier (75). Furthermore, a study by Mesci and colleagues demonstrated that microglia, specifically macrophages, interact with Zika virus-infected neural precursor cells to propagate viral spread and increase apoptosis (73). O’Connor and colleagues found monocytes to also be targets for Zika virus infection that could contribute to persistent viral dissemination (80). One study showed that Zika virus can use adhesion factors, specifically Axl, to bind and enter target cells such as microglia, astrocytes, and blood-brain barrier endothelial cells (98).
Many researchers have worked to create murine models of Zika virus infection to study pathogenesis. Oh and colleagues created a humanized model to study Zika infection of the peripheral nervous system and found that peripheral neural stem cells are susceptible to Zika infection similar to central nervous system stem cells (82). Additionally, this study demonstrated Zika within Schwann cells but not skeletal muscle cells, suggesting tissue specific vulnerability. Another investigation by Swartwout and colleagues demonstrated persistent infection of trigeminal and dorsal root ganglia and suggested that this may provide a reservoir for viral shedding into secretions (104). Finally, another study showed that neutrophils protected mice from showing motor deficits following infection with Zika virus (115).
Although mouse models can be helpful for studying pathogenesis of Zika virus infection, nonhuman primate models more closely represent infection in humans. Martinot and colleagues infected pregnant female rhesus macaques and showed that vascular compromise and neuroprogenitor cell dysfunction were central to congenital Zika syndrome pathogenesis (68). Additionally, they found that congenital abnormalities in macaque fetuses could be traced to necrosis and gliosis of highly vascularized deep gray matter tissues and abnormal migration of progenitor cells. Another study demonstrated persistence of Zika virus in multiple tissues following acute illness, including lymphoid tissues, joints, muscle, and male and female reproductive tissues, for 28 to 35 days post infection (48).
Given the similarities between Zika virus and dengue virus, there has been concern that Zika virus may exhibit antibody-dependent enhancement similar to dengue virus. Although this phenomenon has been shown in in vitro experiments, nonhuman primate models have not demonstrated that Zika infection worsens with prior flavivirus infection history (13).
Additionally, Asian strains of Zika virus have been found to be less pathogenic with poorer induction of apoptosis and lower infection rate than African strains (100).
These studies have provided insight into the pathogenesis of Zika virus infection, but further research needs to be done to fully elucidate Zika’s mechanisms of infectivity.
Zika virus was first discovered in Uganda in 1947. There are 2 major lineages of the virus: African and Asian (39; 02). Serological studies have shown a wide distribution of the virus throughout Africa and Asia, including Uganda, Egypt, India, Malaysia, Indonesia, and Pakistan (102; 103; 66; 84). The virus has largely expanded its territorial range in the last 10 years, spreading from Africa and Asia to Yap in 2007, then to French Polynesia in 2013 to 2014, and to the Americas in 2015 (69; 90). Since its arrival in Brazil, the virus has spread to at least 33 different South and Central American countries and infected 440,000 to 1.3 million people (76). Local transmission in the U.S. was first reported in Miami Beach in 2016, and in that year, there were 5168 cases of symptomatic Zika virus infection documented in the U.S., most in travelers (CDC Case Counts 2016). So far in 2018, only 34 cases of symptomatic infection have been reported in the U.S. (CDC Case Counts 2018). The strain currently present in the Americas is most closely related to the Asian strain and shares 99.7% nucleotide homology with the strain identified in the French Polynesia outbreak (37).
Zika virus infection is symptomatic in about 20% to 25% of those infected. During the first major outbreak in Yap, an estimated 73% of residents were infected, and 19% were symptomatic (59; 35; 47). During the French Polynesia outbreak, it was estimated that 11% of the population was symptomatic, whereas 94% of the population was likely infected (54; 57).
Strategies to prevent spread of the disease at this point should include the use of Environmental Protection Agency-registered insect repellent, use of mosquito bed nets at night, and wearing long clothing that covers the arms and legs (27). Men who have returned from endemic areas should avoid sexual intercourse with pregnant partners or use condoms consistently throughout pregnancy. Couples trying to conceive should wait at least 8 weeks after returning from an endemic region and 6 months if the male partner was symptomatic (110).
Although no vaccine was available at the publication of this article, more than 50 Zika virus vaccine candidates are currently in various stages of research and development (64). Ongoing clinical trials are investigating inactivated whole viruses, recombinant measles virus-based vaccines, DNA and mRNA vaccines, and a mosquito salivary peptide vaccine (21; 64; 105). As there is a significant protein overlap between the human genome and Zika virus, one of the challenges in creating a safe and effective vaccine has been identifying and utilizing peptide sequences unique to the virus that will not cause autoimmune cross-reactions (Lucchese et al 2016).
Differential diagnosis includes dengue fever, chikungunya, rubella, and parvovirus, as these viral infections can often result in a clinical presentation that is very similar to Zika infection. Some of the common symptoms include rash, arthralgias, and fever. Dengue fever and chikungunya are transmitted via the same mosquito vector as Zika; however, both usually present with higher fevers, and chikungunya typically presents with more severe arthralgias (25). In addition, dengue has the potential for hemorrhagic transformation. Coinfection with dengue and Zika has been shown to occur, and differentiating serology can be difficult due to cross-reacting anti-flavivirus antibodies (36). This may be responsible for many missed diagnoses of Zika infection. Rubella infection can cause a maculopapular rash or arthritis, and it can result in congenital abnormalities as well. However, almost 100% of women of childbearing age in industrialized countries are vaccinated against this virus as children (96). Parvovirus infection in adults is known to cause acute onset arthralgia, although a rash may or may not be present. In utero transmission can result in hydrops fetalis, as well as stillbirth and fetal death (03). The report of rash, arthralgias, and living within or visiting an area where the presence of the Zika vector is known is often enough to make a clinical diagnosis.
Currently, the CDC recommends testing for Zika virus in any symptomatic person with possible Zika virus exposure, symptomatic pregnant women with possible exposure, asymptomatic pregnant women with continuing possible exposure, and pregnant women with possible exposure who have ultrasound findings consistent with Zika virus infection (24).
The gold standard for diagnosing Zika virus infection is detection of viral genomic sequences using nucleic acid amplification tests (NAATs), most of which are reverse transcription-polymerase chain reaction (RT-PCR) tests (21). However, as many of these tests require extensive laboratory equipment that may not be available in all endemic Zika areas, additional simpler NAATs have been developed that can be completed at bedside in 15 minutes (28; 01). Although initially RT-PCR on serum was first line for diagnosis of Zika virus infection, urine is now the recommended specimen for testing, as recent studies have demonstrated that viral RNA can be detected in urine for at least as long as in serum (21).
NAATs are only useful for detecting Zika virus infection while the virus is still circulating, which is usually up to 14 days after infection (21). Beyond that time frame, the CDC recommends testing serum for antibodies to the virus (23). Testing for virus-specific IgM is not as specific, as cross-reactivity exists with other flaviviruses, including dengue and yellow fever viruses. Zika-specific antibodies can be determined using plaque-reduction neutralization tests (PNRTs), but these tests lack specificity, are costly, and have no commercially available kit for testing (50). Research is ongoing to determine more refined methods to detect Zika virus infection and eliminate cross-reactivity with other viruses. One study designed recombinant antigens displaying regions of Zika virus envelope proteins and found that although some cross-reactivity still occurred with Zika and dengue virus, these antigens consistently detected Zika-specific IgG in ZIKV-immune sera but not cross-reactive IgG in dengue-immune sera in the late convalescence period (91).
As Zika virus causes a mild, self-limited febrile illness, treatment is mainly supportive in nature, including intravenous fluids and acetaminophen. NSAIDs and aspirin should be avoided until dengue virus can be ruled out (34).
Although no approved antiviral medications exist for Zika virus infection to date, investigations are underway to search for possible therapeutic targets. One study found that sofosbuvir, a hepatitis C NS5 inhibitor, blocked viral infection in neural progenitor cells (73). Additionally, another study demonstrated that viperin, a host protein produced in response to infection, caused selective degradation of Zika virus non-structural-3 protein (NS3), which is involved in many steps of the viral life cycle (86). Finally, one promising potential drug, now called galidesivir, has shown potent anti-Zika activity in infected nonhuman primate studies (Lim et al 2016). Further studies are warranted to evaluate potential therapeutic candidates.
Risk associated with the development of microcephaly when infected during pregnancy seems to be related to the time period in which the female was infected. In 1 study, 60% to 70% of mothers whose children were born with microcephaly demonstrated maculopapular rash within the first trimester of pregnancy (74). Another study retrospectively analyzed 547 cases of microcephaly in Brazil and identified a link between the outbreak of Zika infection and an increase in the prevalence of microcephaly 9 months later (56). This link provides evidence for perinatal transmission occurring during the first trimester of pregnancy. As previously mentioned, infection in the first trimester has been associated with higher risk of birth defects than in second and third trimesters, but infection later in pregnancy may have consequences that do not manifest until after birth.
Regarding identification of infection in the fetuses of infected or exposed mothers, the Society for Maternal-Fetal Medicine (SMFM) recommends ultrasound evaluation for fetal abnormalities (38). Additionally, if head circumference is found to be more than 2 standard deviations below the mean, evaluation of fetal intracranial anatomy is warranted. If this is normal, SMFM still recommends follow up ultrasound scans in 3 to 4 weeks.
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