Zika virus: An emerging infectious disease with serious perinatal and neurologic complications.

Zika virus (ZIKV) is a flavivirus that is primarily transmitted by Aedes aegypti, the mosquito vector also important in transmission of the flaviviruses responsible for dengue fever, yellow fever, and chikungunya. Because of occurrence in the same geographic regions, serologic cross-reactivity, and similar but often less severe clinical manifestations, such as dengue and chikungunya infections, ZIKV infection likely has gone undetected, misdiagnosed, or both for many years. ZIKV is somewhat unique among flaviviruses in its ability to also be transmitted through sexual contact, nonsexual body fluids, and perinatally. The relatively recent detection of the link between ZIKV infection and Guillain-Barré syndrome and fetal neurological defects, including microcephaly, has prompted intense efforts aimed at the development of new and specific diagnostic tests. Infection with ZIKV has been postulated to lead to a more severe clinical course from other structurally related viruses, especially dengue, and vice versa because of a phenomenon termed antibody-dependent enhancement. Inactivated whole virus, DNA, RNA, and vectored vaccine approaches to prevent ZIKV infection are in development, as are treatments for active disease that are safe in pregnant women. Here we summarize the important epidemiologic and clinical features of ZIKV infection, as well as the progress and challenges in developing rapid point-of-care diagnostic tests and vaccines to prevent disease. We used electronic databases to identify relevant published data regarding ZIKV MeSH searches.

Ethics, health policy, and Zika: From emergency to global epidemic?

Zika virus was recognised in 2016 as an important vector-borne cause of congenital malformations and Guillain-Barré syndrome, during a major epidemic in Latin America, centred in Northeastern Brazil. The WHO and Pan American Health Organisation (PAHO), with partner agencies, initiated a coordinated global response including public health intervention and urgent scientific research, as well as ethical analysis as a vital element of policy design. In this paper, we summarise the major ethical issues raised during the Zika epidemic, highlighting the PAHO ethics guidance and the role of ethics in emergency responses, before turning to ethical issues that are yet to be resolved. Zika raises traditional bioethical issues related to reproduction, prenatal diagnosis of serious malformations and unjust disparities in health outcomes. But the epidemic has also highlighted important issues of growing interest in public health ethics, such as the international spread of infectious disease; the central importance of reproductive healthcare in preventing maternal and neonatal morbidity and mortality; diagnostic and reporting biases; vector control and the links between vectors, climate change, and disparities in the global burden of disease. Finally, there are controversies regarding Zika vaccine research and eventual deployment. Zika virus was a neglected disease for over 50 years before the outbreak in Brazil. As it continues to spread, public health agencies should promote gender equity and disease control efforts in Latin America, while preparing for the possibility of a global epidemic.

Sex Matters in Neuroinfectious Diseases.

Although sex and gender have a major impact on the susceptibility and immunologic response to infectious diseases, these factors are often neglected. Identifying the mechanisms underlying sex-based differences in infectious diseases will facilitate the rational design and implementation of preventive and therapeutic strategies that reduce risk and improve outcomes for women and men. In this article, we discuss two examples in neuroinfectious diseases of how sex matters: (1) the heightened risk of cerebrovascular disease in women living with HIV infection and (2) the implications of Zika virus infection on sexual and reproductive health and vaccine development for women.

Epidemiology of Zika.

PURPOSE OF REVIEW: Zika virus (ZIKV) is the latest 'emerging virus' that has affected the Americas. First identified in the mid-20th century in Uganda, it was described as a vector arthropod-borne virus (arbovirus) and subsequently found capable of producing illness in humans. The illness was not different from other flavivirus infections and caused a relatively mild disease characterized by low-grade fever, nonspecific exanthem, nonpurulent conjunctivitis, and mild to moderate arthralgia. It was capable of producing infections described as sporadic isolated cases; in 2007, it was confirmed as the pathogen causing the first known ZIKV epidemic subsequently associated with congenital neonatal microcephaly in many countries in the Americas. RECENT FINDINGS: It rapidly spread to other countries in the Americas and, as of September 2016, it has been detected in 46 countries and territories. Different from other flavivirus infections, ZIKV has proven to be related to more serious complications. These include Guillain-Barré syndrome and neonatal congenital malformations, which includes microcephaly and neurologic damage to the developing fetus, particularly if the maternal infection occurs early in pregnancy. These two complications are a cause of great concern. SUMMARY: It is pivotal to conduct epidemiological laboratory-based surveillance and studies on the virus' inherent characteristics to understand the pathophysiology of this infection and develop adequate strategies to mitigate this new threat.

Zika Virus and Patient Blood Management.

Sporadic Zika virus infections had only occurred in Africa and Asia until an outbreak in Micronesia (Oceania) in 2007. In 2013 to 2014, several outer Pacific Islands reported local outbreaks. Soon thereafter, the virus was likely introduced in Brazil from competing athletes from French Polynesia and other countries that participated in a competition there. Transmission is thought to have occurred through mosquito bites and spread to the immunologically naive population. Being also a flavivirus, the Zika virus is transmitted by the Aedes mosquito that is endemic in South and Central America that is also the vector of West Nile virus, dengue, and chikungunya. In less than a year, physicians in Brazil reported a many-fold increase in the number of babies born with microcephaly. Despite initial skepticism regarding the causal association of the Zika virus epidemic and birth defects, extensive basic and clinical research evidence has now confirmed this relationship. In the United States, more than 4000 travel-associated infections have been reported by the middle of 2016 to the Centers for Disease Control and Prevention. Furthermore, many local mosquito-borne infections have occurred in Puerto Rico and Florida. Considering that the virus causes a viremia in which 80% of infected individuals have no symptoms, the potential for transfusion transmission from an asymptomatic blood donor is high if utilizing donor screening alone without testing. Platelet units have been shown to infect 2 patients via transfusion in Brazil. Although there was an investigational nucleic acid test available for testing donors, not all blood centers were initially required to participate. Subsequently, the US Food and Drug Administration issued a guidance in August 2016 that recommended universal nucleic acid testing for the Zika virus on blood donors.In this report, we review the potentially devastating effects of Zika virus infection during pregnancy and its implication in cases of Guillain-Barre syndrome in adults. Furthermore, we urge hospital-based clinicians and transfusion medicine specialists to implement perisurgical patient blood management strategies to avoid blood component transfusions with their potential risks of emerging pathogens, illustrated here by the Zika virus. Ultimately, this current global threat, as described by the World Health Organization, will inevitably be followed by future outbreaks of other bloodborne pathogens; the principles and practices of perioperative patient blood management will reduce the risks from not only known, but also unknown risks of blood transfusion for our patients.

Cumulative risk of Guillain-Barré syndrome among vaccinated and unvaccinated populations during the 2009 H1N1 influenza pandemic.

OBJECTIVES: We sought to assess risk of Guillain-Barré syndrome (GBS) among influenza A (H1N1) 2009 monovalent (pH1N1) vaccinated and unvaccinated populations at the end of the 2009 pandemic. METHODS: We applied GBS surveillance data from a US population catchment area of 45 million from October 15, 2009, through May 31, 2010. GBS cases meeting Brighton Collaboration criteria were included. We calculated the incidence density ratio (IDR) among pH1N1 vaccinated and unvaccinated populations. We also estimated cumulative GBS risk using life table analysis. Additionally, we used vaccine coverage data and census population estimates to calculate denominators. RESULTS: There were 392 GBS cases; 64 (16%) occurred after pH1N1vaccination. The vaccinated population had lower average risk (IDR = 0.83, 95% confidence interval = 0.63, 1.08) and lower cumulative risk (6.6 vs 9.2 cases per million persons, P = .012) of GBS. CONCLUSIONS: Our findings suggest that at the end of the influenza season cumulative GBS risk was less among the pH1N1vaccinated than the unvaccinated population, suggesting the benefit of vaccination as it relates to GBS. The observed potential protective effect on GBS attributed to vaccination warrants further study.

The background occurrence of selected clinical conditions prior to the start of an extensive national vaccination program in Japan.

INTRODUCTION: The COVID-19 pandemic caused by SARS-CoV-2 has now affected tens of millions of people globally. It is the hope that vaccines against SARS-CoV-2 will deliver a comprehensive solution to this global pandemic; however, this will require extensive national vaccination programs. Ultimately, clinical conditions and even sudden unexplained death will occur around the time of vaccination, thus a distinction needs to be made between events that are causally related to the vaccine or temporally related to vaccination. This study aimed to estimate the background occurrence of 43 clinical conditions in the Japanese population. METHODS: A retrospective cohort study was conducted from 2013 to 2019 using data from two large healthcare claims databases (MDV and JMDC) in Japan. The estimated number of new cases and incidence were calculated based on the actual number of new cases identified in the databases. The PubMed and Ichushi-web databases, as well as grey literature such as guidelines and government statistics, were also searched to identify any publications related to incidence of these conditions in Japan. RESULTS AND CONCLUSION: The estimates of the number of total cases and incidence were similar for the MDV and JMDC databases for some diseases. In addition, some estimates were similar to those in the scientific literature. For example, from the MDV and JMDC databases, estimates of incidence of confirmed Bell's palsy in 2019 were 41.7 and 47.9 cases per 100,000 population per year, respectively. These estimates were of the same order from the scientific publication. Determining whether clinical conditions occurring around the time of vaccination are causally or only temporally related to vaccination will be critical for public health decision makers as well as for the general public. Comparison of background occurrence at the population level may provide some additional objective evidence for the evaluation of temporality or causality.

Seasonal influenza vaccine and Guillain-Barré syndrome: A self-controlled case series study.

OBJECTIVE: To evaluate the risk of Guillain-Barré syndrome (GBS) following seasonal influenza vaccination based on French nationwide data. METHODS: All cases of GBS occurring in metropolitan France between September 1 and March 31 from 2010 to 2014 were identified from the French national health data system. Data were analyzed according to the self-controlled case series method. The risk period started 1 day after the patient received vaccine (D1) until 42 days after vaccination (D42). The incidence of GBS during this risk period was compared to that of the control period (D43-March 31). The incidence rate ratio (IRR) was estimated after adjusting for seasonality and presence or not of acute infections. RESULTS: Between September and March, of the 2010/2011 to 2013/2014 influenza vaccination seasons, 3,523 cases of GBS occurred in metropolitan France and were included in the study. Among them, 15% (527 patients) had received influenza vaccination. A total of 140 patients developed GBS during the 42 days following influenza vaccination. The crude risk of developing GBS was not significantly increased during the 42 days following influenza vaccination (IRR, 1.02; 95% confidence interval [CI], 0.83-1.25; p = 0.85). This result remained nonsignificant after adjustment for calendar months and the incidence of acute gastrointestinal and respiratory tract infections (IRR, 1.10; 95% CI, 0.89-1.37; p = 0.38). In contrast, the risk of GBS was fourfold higher after acute respiratory tract infection (IRR, 3.89; 95% CI, 3.52-4.30; p < 0.0001) or gastrointestinal infection (IRR, 3.64; 95% CI, 3.01-4.40; p < 0.0001). CONCLUSIONS: No association between seasonal influenza vaccination and GBS was shown during the 42 days following vaccination.

Vaccine-preventable diseases, vaccines and Guillain-Barre' syndrome.

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy. Infections and vaccines have been hypothesized to play a role in triggering GBS development. These beliefs can play a role in reducing vaccination coverage. In this report, data concerning this hypothesis are discussed. It is shown that an association between vaccine administration and GBS has never been proven for most of debated vaccines, although it cannot be definitively excluded. The only exception is the influenza vaccine, at least for the preparation used in 1976. For some vaccines, such as measles/mumps/rubella, human papillomavirus, tetravalent conjugated meningococcal vaccine, and influenza, the debate between supporters and opponents of vaccination remains robust and perception of vaccines' low safety remains a barrier to achieving adequate vaccination coverage. Less than 1 case of GBS per million immunized persons might occur for these vaccines. However, in some casesimmunization actually reduces the risk of GBS development. In addition, the benefits of vaccination are clearly demonstrated by the eradication or enormous decline in the incidence of many vaccine-preventable diseases. These data highlight that the hypothesized risks of adverse events, such as GBS, cannot be considered a valid reason to avoid the administration of currently recommended vaccines.

Development of a fluorescence-based method for the rapid determination of Zika virus polymerase activity and the screening of antiviral drugs.

Zika virus (ZIKV) is an emerging pathogen that has been associated with large numbers of cases of severe neurologic disease, including Guillain-Barré syndrome and microcephaly. Despite its recent establishment as a serious global public health concern there are no licensed therapeutics to control this virus. Accordingly, there is an urgent need to develop methods for the high-throughput screening of antiviral agents. We describe here a fluorescence-based method to monitor the real-time polymerization activity of Zika virus RNA-dependent RNA polymerase (RdRp). By using homopolymeric RNA template molecules, de novo RNA synthesis can be detected with a fluorescent dye, which permits the specific quantification and kinetics of double-strand RNA formation. ZIKV RdRp activity detected using this fluorescence-based assay positively correlated with traditional assays measuring the incorporation of radiolabeled nucleotides. We also validated this method as a suitable assay for the identification of ZIKV inhibitors targeting the viral polymerase using known broad-spectrum inhibitors. The assay was also successfully adapted to detect RNA polymerization activity by different RdRps, illustrated here using purified RdRps from hepatitis C virus and foot-and-mouth disease virus. The potential of fluorescence-based approaches for the enzymatic characterization of viral polymerases, as well as for high-throughput screening of antiviral drugs, are discussed.

Preventive and curative effects of cyclophosphamide in an animal model of Guillain Barrè syndrome.

The immunosuppressive agent cyclophosphamide (CY) was tested in rat experimental allergic neuritis (EAN), a preclinical model of Guillain Barrè syndrome (GBS). CY prophylaxis (day 0 and 14 post-immunization [p.i.]) effectively prevents clinical and histological signs of EAN and also reduces the cytokine and the NF-kappaB p65 expression in the nervous tissue. When administered therapeutically (day 14th p.i.) to rats with established disease CY only affects the clinical symptoms. Both the prophylactic and therapeutic treatment with CY reduced ex vivo antigen-specific T cell proliferative responses. These results warrant studies with CY in those cases of GBS resistant to conventional therapies.

Zika and Public Health: Understanding the Epidemiology and Information Environment.

Because Zika is a newly emerging infectious disease with little previous information known about it, there are many epidemiologic and clinical questions. The complexity of providing care to those who are at risk for infection or are already infected with Zika in this evidence-scarce environment cannot be understated. In this article, we provide an overview of the Zika virus (ZIKV) in the context of public health and pediatric health care. A broad public health focus is used to provide relevant information for addressing important questions about the epidemic and to facilitate communication with patients, parents, and caregivers within the current information environment. We explore issues regarding the epidemiology of the virus (including why ZIKV outbreaks are occurring), what has changed since the sporadic case reports before the outbreaks, why the true incidence is difficult to estimate, why attack rates vary by population and geography, and why the association between Zika and congenital Zika syndrome and Guillain-Barré syndrome have only come to light recently. Additionally, challenges related to the current information environment, traditional and informal information sources about the ZIKV, and examples of Zika public health communication campaigns are discussed. Importantly, we review the existing findings regarding the US population's Zika-related knowledge, attitudes, beliefs, and behavior by highlighting variations and gaps. We conclude by identifying related research questions that remain critical.

[Surveillance of acute flaccid paralysis in Belarus].

The ten-years experience of acute flaccid paralysis (AFP) surveillance in Belarus has been summarized. Among 456 AFP cases reported from 1996 to 2005, 11 were classified as vaccine-associated paralytic poliomyelitis (VAPP), 445--as non-polio AFP. The risk of VAPP for the period 1996-2001 was 1 case per 745,000 used doses of oral poliovaccine (OPV). For the recipients of OPV the risk was 1 case per 911,700 doses and for the first-dose recipients--1 case per 96,000 doses. The high incidence of VAPP was a reason for implementation of sequential polio vaccination schedule in 2000. Guillain-Barre syndrome dominated among non-polio AFP (39.3% of cases); more rare were traumatic neuritis (27.9% of cases), transient monoparalysis (12.1%), myelitis (7.6%). Non-polio AFP differed from VAPP by following epidemiological and virological characteristics: predominance of previously repeatedly vaccinated against poliomyelitis; development of paralysis in long-term period after vaccination; isolation of non-polio viruses belonged to three serotypes of Coxsackie B viruses (B1, B4, B6) and six serotypes of Echo viruses (6, 7, 11, 14, 24, 25) in 8.1% of cases; absence of typical for polio residual paralyses in patients who excreted vaccine polioviruses.

[Epidemiology and human rights: Zika virus outlook and reproductive rights in Latin America]. / Epidemiología y derechos humanos: panorama del virus del Zika y los derechos reproductivos en Latinoamérica.

With this article we review the current Zika virus (ZIKV) epidemic. We also look back over the last scientific evidence relating ZIKV to microcephaly and Guillain-Barré syndrome. Finally, we also address the challenges in terms of reproductive rights in Latin America.

En el presente artículo realizamos un recuento de la actual epidemia del virus del Zika (ZIKV). Asimismo, hacemos una revisión de la última evidencia científica que asocia al ZIKV con la microcefalia y el síndrome Guillain-Barré en recién nacidos. Por último, resaltamos los retos de la epidemia en términos de los derechos reproductivos en Latinoamérica.

[Molecular Mimicry and Guillain-Barré Syndrome].

One-thirds of patients develop Guillain-Barré syndrome subsequent to Campylobacter jejuni enteritis. Molecular mimicry exists between C. jejuni lipo-oligosaccharides and human peripheral nerve gangliosides GM1 and GD1a. IgG antibodies against GM1 or GD1a are produced in one out of 5,000 patients with C. jejuni enteritis. The autoantibodies bind to gangliosides at the nodes of Ranvier in the peripheral motor nerves and activate complement in situ. This is followed by the disappearance of the voltage-gated sodium channel clusters at the nodes and disruption of axo-glial junctions at the paranodes. This results in the development of motor nerve conduction failure and muscle weakness in the four limbs.

[Epidemiology of Guillain-Barré Syndrome].

The epidemiologic features of the Guillain-Barré syndrome (GBS) have been reported from North America, England, Iceland, and Norway before 1979. The population incidence rates of GBS fulfilling the NINCDS (National Institute of Neurological and Communicative Disorders and Stroke) criteria in USA, Canada, Italy, Spain, and Sweden ranged from 0.62 cases to 2.66 cases per 100,000 person-years across all age groups, with a relative risk of 1.78 for males. GBS incidence increased by 20% for every 10-year increase in age. In Japan, the incidence of GBS was 1.15 per 100,000 person-years. Males were affected 1.5 times more frequently than females. The average age of patients with GBS was 39.1 ± 20.0 years, which is lesser than that in North America and Europe. The relative ratio of the occurrence of Fisher syndrome among patients with GBS was higher than that in other Asian countries.

Ontologies to capture adverse events following immunisation (AEFI) from real world health data.

Immunisation is an important part of health care and adverse events following immunisation (AEFI) are relatively rare. AEFI can be detected through long term follow up of a cohort or from looking for signals from real world, routine data; from different health systems using a variety of clinical coding systems. Mapping these is a challenging aspect of integrating data across borders. Ontological representations of clinical concepts provide a method to map similar concepts, in this case AEFI across different coding systems. We describe a method using ontologies to be flag definite, probable or possible cases. We use Guillain-Barre syndrome (GBS) as an AEFI to illustrate this method, and the Brighton collaboration's case definition of GBS as the gold standard. Our method can be used to flag definite, probable or possible cases of GBS. Whilst there has been much research into the use of ontologies in immunisation these have focussed on database interrogation; where ours looks to identify varying signal strength.