No 14 - 2016

Update on the Zika virus situation

2015 recorded the largest Zika virus outbreak to date in South and Central America. The outbreak was previously described in EPI-NEWS 49/15, and a thematic issue on Zika virus is available at the website of Statens Serum Institut (SSI) . In the following, we provide an update on the Zika virus epidemic.

Prevalence

The Zika virus outbreak was acknowledged in Brazil in May 2015 following a cluster of cases with rash and fever in the Bahia state in March of 2015. As per 1 April 2016, active spread of Zika virus infection has been detected in 33 countries/areas in South and Central America, six in Oceania and in the Cap Verde islands in West Africa. The countries are presented on the Zika virus theme page at the website of Statens Serum Institut. Additionally, the past nine months have brought cases in another 15 countries/areas.

In Asia, including Thailand and Vietnam, sporadic Zika virus cases are seen. This has, nevertheless, been the case for decades, and there are no signs of an increase in Zika virus infections in connection with the current outbreak in South and Central America. Since 1 January 2007, Zika virus has been observed in a total of 62 countries/areas.

During the current epidemic, the majority of cases have been detected in Brazil where the health authorities estimate that between 0.4 and 1.3 million people were infected in 2015. Columbia is the second-most affected area with a total of approx. 51,000 possible cases as per 3 March 2016. How many people have actually been infected remains unclear because Zika virus only causes symptoms in about 20% of the cases, because the symptoms are not specific to Zika virus and because far from all cases undergo laboratory testing. In Columbia, there are indications that the number of new cases is decreasing.

A range of countries have seen imported cases, including 323 cases in 17 EU countries (as per 31 March 2016). Twenty of these cases occurred in pregnant women.

A recent study - based on an analysis of Zika virus gene sequences - has demonstrated that the Zika virus outbreak in Brazil is due to a single introduction that probably stems from French Polynesia and was introduced between May and December 2013. In this period, the number of airline passengers from Zika endemic areas to Brazil increased by more than 50%.

The situation in Denmark

In the period from 30 December 2015 to 22 March 2016, a total of 297 persons were tested with blood samples at the SSI, 242 women and 55 men with a median age of 32 years (0-76 years). In total, 448 samples were drawn: 119 PCR tests and 329 antibody tests. Four of the persons tested had test results indicating anacute Zika virus infection (one man and three non-pregnant women). All were travellers who had returned from Zika virus affected areas.

Transmission

The main route of transmission for Zika virus is via mosquito bites from two aedes mosquito species, A. aegypti and A. albopictus. However, other aedes species, including A. hensilli and A. polynesiensis, may also have served as vectors during previous outbreaks on the island of Yap in 2007 and in French Polynesia in 2013-14.

Since September of 2015, when an excess incidence of microencephaly was observed in Brazil, evidence has been building to support that Zika virus can be transmitted from mother to child during pregnancy and also through semen. Blood-borne transmission from one human to another is, in theory, possible, but has not yet been observed. Furthermore, virus RNA has been detected in saliva, urine and human milk.

How large the risk of sexual transmission is remains unknown, but virus RNA has been found in semen up to 62 days after symptom onset. In five cases in which men had infected their female sexual partners, and for which detailed epidemiological information is available, all men had symptoms and the interval from symptom onset in the man and in the woman was from 4 to 19 days.

Zika virus, foetal malformations and Guillain-Barré syndrome

Since September 2015, an excess incidence of microencephaly and other foetal malformations has been observed in areas with active Zika virus transmission. Within the past months, a number of studies have considerably strengthened evidence in support of Zika virus as the cause of these malformations. Firstly, Zika virus was detected in amniotic fluid and cerebral tissue from foetuses/children with the mentioned malformations; secondly, it was demonstrated that Zika virus has a special affinity for neuronal stem cells. There is evidence that microencephaly may occur following infection of the mother in any trimester of pregnancy, but the risk seems to be higher following infection in her first semester, in which case the risk of microencephaly is estimated to be approx. 1%.

In a preliminary Brazilian study including pregnant women with a rash that was compatible with Zika virus infection, ultrasound changes were seen in 29% at a scan of the foetus. Nevertheless, all of the women had symptoms of Zika virus infection. It remains unknown if and to which extent asymptomatic infection causes malformation in the foetus.

The extent to which microencephaly and other harm caused to the foetus occurs in each country is very uncertain, among others because different definitions of microencephaly are used, i.e. different head circumference measures. As per 31 March 2016, the WHO has reported microencephaly and other harm caused to the foetus in six countries: Brazil (944 cases), Columbia (32 cases), French Polynesia (eight cases) The Cap Verde islands (two cases), Martinique and Panama (one case each). Brazil has previously reported more than 4,000 cases, but these were suspected cases, and not all were confirmed.

A total of 13 countries with Zika virus outbreaks have reported an increased number of cases of Guillain Barré syndrome (GBS) and/or findings of Zika virus in GBS patients. In French Polynesia, a total of 42 cases of GBS were diagnosed during the Zika virus epidemic in 2013-14, which is 20 times the expected for the period. It was estimated that the GBS risk was 1/4,000. Other neurological complications to Zika virus in the form of meningoencephalitis and acute myelitis have also been reported.

Diagnostics

In the laboratory, Zika virus can be diagnosed through detection of blood (IgM/IgG) and/or through direct detection of Zika virus RNA by PCR testing of blood and urine. These analyses can be performed at the SSI.

When diagnosing acute Zika virus infection, it is important to determine if the patient has both Zika virus RNA (PCR) and antibodies against Zika virus as the presence of Zika virus RNA and/or IgM/IgG will depend on when the patient was infected relative to the time of sampling. For reference diagnostics, it is recommended to test also for dengue and chikungunya fever when Zika virus testing is performed as the three mosquito-transmitted conditions are similar and are transmitted by the same mosquito species. Double infections have also been seen. Therefore, all three results of such analysis may be of importance to the result and the interpretation.

PCR analysis in blood or urine is expected only to yield a positive result during the acute infection, when only approx. 20% present with clinical symptoms. Nevertheless, PCR may remain positive for longer in urine and may be detected in semen for weeks to months after infection. Zika virus IgM antibodies typically rise at the end of the acute infection, and high titres can be detected for weeks to months. Zika virus IgG antibodies increase considerably few days after the IgM increase and remain increased for months to years.

Early titre increase can be detected in two consecutive blood samples taken a few weeks apart. Low, unchanged IgG titres may be due to cross reaction with previous flavivirus infections (e.g. Dengue fever), which are a common finding in South Americans, or recent vaccination in travellers (e.g. yellow fever vaccination). Cross-reacting antibodies show no titre increase in contrast to the specific antibodies.

The interpretation depends on travel anamnesis, clinical examination and the specific PCR and serology results; and for pregnant women these should be followed up by diagnostic foetal scans at a specialist department, as any harm caused to the foetus takes longer to develop, in line with the guidelines from The Danish Health Authority, updated 14 March 2016.

When considering work-up for Zika virus infection, it is important to keep in mind that this is generally an influenza-like, self-limiting condition that is not associated with chronic sequelae. Symptoms may include a slight fever, rash, red injected eyes and arthralgia.

Current advice for Danish travellers

The Danish Health Authority and the SSI have prepared recommendations for travellers going to or returning from areas with Zika virus outbreaks. These are published at The Danish Health Authority website and the website of Statens Serum Institut (SSI).

Commentary/perspectives

The Zika virus outbreak was declared a Public Health Emergency of International Concern (PHEIC) by the WHO. This is primarily because of the presumed association between Zika virus infection and malformations. Therefore, the WHO recommends that the countries affected by the outbreak allocate the resources needed to curb the outbreak, including through enhanced monitoring and reporting and through extermination of the mosquitoes that spread the condition. This does not necessarily mean that the WHO considers the Zika virus situation to be as dangerous as, e.g., Ebola which was also characterised as a PHEIC. It simply indicates that the WHO wants to strengthen national and international efforts at monitoring, combating and conducting research into Zika virus.

Effective mosquito control is particularly difficult and a risk exists of spreading to more countries native to the aedes mosquito. In Southern Europe, the Aedes albopictus mosquito is found. Therefore, a theoretical risk exists of outbreaks in this area following introduction of virus, e.g., via travellers, but continued spreading of the infection is not very probable. The aedes mosquito is not found in Denmark, and there is no fear that the disease will spread here.

As Zika virus spreads very quickly, and infection probably produces prolonged immunity, one possible scenario in the countries where the aedes mosquito occurs is that the virus infection will become endemic in the course of some years. If this happens, women will typically be infected at an early age and will therefore have gained immunity when they later become pregnant.
Intensive work is ongoing to develop a vaccine, but it will probably take years before a vaccine is widely available.
(A. Koch, N. Mellerup, P.H. Andersen, Department of Infectious Disease Epidemiology, A. Fomsgaard, Department of Microbiological Diagnostics and Virology)

Status quo on the Ebola virus outbreak in West Africa

On 29 March, the WHO Emergency Committee announced that the West African Ebola virus outbreak no longer constitutes a Public Health Emergency of International Concern as the risk of international spreading is now small. Therefore, there is no basis for maintaining any travel or trade restrictions. The Committee notes that, as expected, new minor clusters of Ebola infectees are observed in the period in which Ebola virus gradually clears from the reservoir of Ebola survivors. To this date, transmission has been curbed in 11 of the 12 detected clusters after a maximum of two infection generations, which shows that the monitoring is effective.

As the last of the three primarily affected countries in West Africa, Liberia was (for the third time) declared free of Ebola infection on 14 January 2016 (nevertheless, see description of the latest cluster below) . Previously, Sierra Leone and Guinea were declared free of Ebola infection on 7 November and 29 December 2015, respectively, EPI-NEWS 1/16. Even so, a small cluster counting two cases was confirmed in Sierra Leone on 14 January 2016, after which the country could be declared free of Ebola for the second time on 17 March 2016.

On 17 March 2016, a cluster was detected that counted two confirmed and three suspected cases from the Nzérékoré Prefecture in South-eastern Guinea. Until 30 March, an additional three confirmed cases and one suspected case have been reported. The initial three suspected patients died in the period from 27 February to 30 March without having been tested for Ebola, and their burials were not done in accordance with the precautions that are in place to avoid transmission of the virus.

The source of infection for these three cases is being investigated. The subsequent five confirmed cases are all epidemiologically linked to the first three suspected cases. Virus sequencing from one of the confirmed cases shows that this virus is very similar to an Ebola virus that circulated in South-east Guinea in November 2014.

More than 1,000 contacts to the patients of the current cluster have been identified, including 171 high-risk contacts. A total of ten contacts have not been traced. In addition to observation of contacts, these and the contacts of the contacts from 22 March and onwards have also received an experimental vaccine (VSV-EBOV). Furthermore, in four villages a requirement for regular health checks and limitation of free movement outside of the village has been introduced. The WHO assesses that due to the large number of contacts, it is expected that more Ebola cases will occur that are associated with this cluster.

On 31 March 2016, a new cluster was detected in Liberia counting two patients. A woman and her three children had crossed the border from Guinea to Liberia on 21 March after her husband had died from unknown causes some days before. The woman fell ill while staying with her family in Liberia, and on 31 March she died due to Ebola while she was on her way to a hospital in Monrovia after seeking help at local treatment sites. Subsequently, Ebola has also been detected in one of her three children. A total of 84 contacts have been identified; all are kept under observation. It remains unknown if this cluster is connected with the Guinean cluster described above.

It has been shown that Ebola can survive in semen and in the eyeballs of Ebola survivors; and in Liberia more than 350 male Ebola survivors have completed screening tests for Ebola virus in their semen and have received advice related hereto. In Sierra Leone, more than 2,600 Ebola survivors have completed a general health examination including a special eye examination as sight problems are a frequent complaint among Ebola survivors. Furthermore, all three countries run Ebola tests in patients with fever and in connection with deaths as part of enhanced monitoring efforts in the wake of the epidemic.

To date, a total of 28,610 cases of Ebola have been detected in the three countries, including 11,308 fatalities (40%).

Commentary

Despite the fact that the epidemic has concluded, a considerable need for international aid remains; partly to ensure maintenance of a diagnostic capacity and continued monitoring, partly to provide advice, testing and treatment of Ebola survivors, and - last but not least - to ensure sufficient resources for other parts of the healthcare systems in the three countries that have suffered from the Ebola epidemic. As described, new minor clusters of Ebola infection are to be expected in the aftermath of the epidemic. It is therefore decisive to maintain the monitoring capacity.
(P.H. Andersen, A. Koch, Department of Infectious Disease Epidemiology) 

Link to previous issues of EPI-NEWS

6 April 2016