Zika: A report from the front lines

Dr Lockwood, editor in chief, is Senior Vice President, USF Health, and Dean, Morsani College of Medicine, University of South Florida, Tampa. He can be reached at DrLockwood@ubm.com.

The moment we all dreaded has come: confirmation of local Zika virus transmission by mosquitoes in the continental United States. The first cases were found in the Wynwood section of Miami, an area at particular risk because many of its inhabitants are frequent travelers to areas in the Caribbean and Latin America with active mosquito-borne Zika transmission. Additional cases were then identified in areas of Miami Beach and Tampa Bay.

The state of Florida had been preparing for this moment for some time. Interviewing and testing of potentially infected patients has been ongoing, as has testing of mosquitoes. The state’s response has been efficient, effective, and thus far reasonably successful in containing this incipient outbreak. It has also been very expensive.

Information was up to date at time of publication.  For the latest Zika news visit ContemporaryOBGYN.net/Zika-updates

Lessons from dengue fever

The hope and expectation of tropical disease experts in Florida is that Zika will follow the pattern of another flavivirus infection, dengue, which is endemic in the same tropical regions as Zika. Fortunately, mosquito-borne dengue outbreaks in Florida have been isolated and transient. One occurrence in Key West in 2010 and another in Martin County in 2013 were both quickly contained by aggressive mosquito abatement programs.¹ 

However, effective local control has not been the case for the Zika epidemic in Puerto Rico. There the virus spread quickly across the island and it is expected that 1 in 4 people will have been infected by year end. Indeed, as of this writing, about 8000 locally acquired cases have been documented in Puerto Rico, including nearly 700 in pregnant women.²

Various factors have been cited for the unprecedented rapid spread of the virus in Puerto Rico. Chief among them is an inadequate mosquito control response exacerbated by the island’s current and deepening financial crisis. Other factors cited include more “mosquito-permissive” building designs, especially in rural settings, and a failure to communicate the magnitude of the threat to pregnant women.

The thinking by Florida Department of Health experts is that air-conditioned and tightly screened dwellings, coupled with aggressive epidemiological surveillance and intense mosquito-abatement processes, will prevent the rapid spread of Zika in Florida and that Zika will mimic the dengue pattern of infrequent, transient, easily localized outbreaks. While the sexual transmissibility of Zika adds a wrinkle not present in dengue outbreaks, I believe the virus will follow the dengue pattern of easily contained outbreaks in the continental United States.

What obstetricians need to know today about Zika

In nonpregnant patients, Zika is most often asymptomatic, although it can be associated with fatalities in elderly patients with comorbidities and has been linked to an increased occurrence of postviral Guillain-Barré syndrome.

In pregnancy there is the potential for transplacental transmission with catastrophic neurodevelopmental consequences, including microcephaly. Best epidemiologic estimates of the risk of severe congenital Zika central nervous system (CNS) pathology range from 0.95% to 13.2% of affected pregnancies.³ Other associated CNS abnormalities include ventriculomegaly, hydranencephaly, intracranial calcifications, and hypogyria.^4,5 Ocular findings have been reported as have hydrops, fetal growth restriction, and fetal loss.^4-7

Prevention

The best way to prevent Zika infections is to avoid mosquito bites. The Centers for Disease Control (CDC) recommends that pregnant women not travel to areas with active Zika virus transmission and that those who must or who reside in such areas “strictly follow steps to prevent mosquito bites.”⁸ These include using a mosquito repellent containing DEET or picaridin and wearing permethrin-treated clothing with long sleeves and pants, socks and shoes to keep as much skin covered as possible. As the relevant mosquitoes (Aedes aegypti and Aedes albopictus) are daytime biters, minimizing outdoor activity from dawn to dusk would also be beneficial as would staying indoors in air-conditioned facilities. Also, at-risk women should ensure that screened enclosures have no openings or defects and that standing water near the house is eliminated to reduce mosquito breeding locations.

Pregnant women whose male partners have traveled to or live in an area with active Zika virus transmission should minimize risk of infection by having their partner use condoms throughout the duration of the pregnancy.

Couples considering pregnancy in the near future or who are actively trying to conceive should be discouraged from travelling to areas with ongoing transmission. Moreover, if they must travel to such areas, it is recommended that upon returning, they delay pregnancy attempts for 8 weeks if neither member of the couple is symptomatic with Zika, at least 8 weeks if only the woman is symptomatic, and 6 months if the man is symptomatic because Zika virus has been found in semen for up to 6 months. Women living in areas of active transmission or who frequently travel to such areas and who are not planning pregnancy should use long-acting reversible contraception (LARC).

Early detection

Much remains to be discovered about the optimal strategies for early detection and management of Zika infections in pregnant women and we are currently dependent on expert opinion leavened with early case series and epidemiologic data. Here are my recommendations:

1. For ob/gyns who practice in areas without documented local mosquito-borne Zika transmission, the CDC recommends that patients be queried at each prenatal visit for possible exposure related to travel to areas with known Zika outbreaks or a history of unprotected sex with someone residing in or traveling to such areas or who was diagnosed with an infection.⁸

It is also possible that contact with other bodily secretions of an infected person may cause transmission, as was apparently the case for a family caregiver of an elderly patient with a very high Zika viral load.⁹ If this exposure history is positive, inquire about possible Zika-related signs and symptoms (ie, nonpurulent conjunctivitis, maculopapular rash, arthralgia of small joints in the hands and feet, and fever).

A. Symptomatic Patients:

Estimate time from clinical presentation and: 

i. If < 2 weeks, order serum and urine real-time reverse transcription-polymerase chain reaction (rRT-PCR) testing for Zika RNA. A positive result confirms an infection. A negative result should prompt an immediate order for IgM antibody tests for both Zika and dengue. Given a positive or equivocal Zika or dengue virus IgM result, next assess a plaque reduction neutralization test (PRNT). A negative (< 10) Zika virus PRNT indicates no Zika virus infection. A positive (≥10) PRNT titer for Zika virus together with a negative (<10) PRNT titer for dengue virus should be treated as confirmation of Zika infection.

However, preliminary data indicate that PRNT might not consistently discriminate between Zika and other flaviviruses in patients with prior infections by, or vaccinations for, other flaviviruses (ie, dengue, West Nile, Japanese encephalitis, and yellow fever viruses) since a new infection enhances previously established flavivirus immune responses.¹⁰ Thus, if both the Zika and dengue virus PRNT values are ≥10, there is evidence of a nonspecific flavivirus infection. In this case, I would presume a possible Zika infection and begin ultrasound surveillance. These tests should be available from your state department of health, the CDC, and increasingly, commercial labs, although commercial labs’ fees may not be reimbursable.

ii. If 2 to 12 weeks, order IgM for Zika and dengue. Negative IgM results for both viruses indicate no recent infection has occurred. If the Zika IgM is positive or equivocal, order reflex rRT-PCR on the same serum sample. I also recommend sending a urine sample for rRT-PCR to maximize sensitivity. Again the presence of viral RNA confirms the diagnosis. However, if the Zika IgM is negative but the dengue IgM is positive or equivocal, or if the Zika IgM was positive but the rRT-PCR was negative, order PRNT. A positive (≥10) PRNT titer for Zika and negative (<10) PRNT for dengue should also be considered diagnostic of infection as noted above.

iii. If >12 weeks, obtain a Zika IgM and begin serial fetal ultrasounds. If the IgM is positive or equivocal, or there are characteristic fetal abnormalities present on ultrasound, order rRT-PCR on serum and urine (also consider amniocentesis for amniotic fluid rRT-PCR testing if the ultrasound is abnormal). Note, false-negative IgM and rRT-PCR results are possible >12 weeks after exposure or symptom onset since IgM and viral RNA levels decline over time. Given the limitations of testing beyond 12 weeks after symptom onset or latest possible exposure history, serial fetal ultrasounds should be considered in such cases.

B. Exposed Asymptomatic Patients:

Our approach at the University of South Florida is to estimate time from last exposure and: 

i.  If <2 weeks, order serum and urine rRT-PCR testing for Zika RNA. A positive result confirms infection. A negative result should prompt ordering IgM for Zika at 2 to 12 weeks with PRNT studies if positive or equivocal.

ii.  If 2 to 12 weeks, order IgM for Zika. If positive or equivocal, order reflex rRT-PCR testing of the same serum sample, and I would add urine testing as well. Again the presence of viral RNA confirms the diagnosis. If the rRT-PCR is negative, PRNT should be performed and again a positive Zika and negative dengue PRNT should also be considered diagnostic of infection as noted above.

iii.  If >12 weeks obtain Zika IgM and serial fetal ultrasound as described above.

2. For ob/gyns practicing in areas with documented local mosquito-borne Zika transmission or when patients frequently travel to such areas:

A.  Query patients about possible Zika-related signs and symptoms and if positive immediately initiate testing as outlined under the guidance for symptomatic patients listed above.

B. Initiate screening in asymptomatic patients:

i. At first visit, order IgM for Zika, and if results are positive or equivocal, order reflex rRT-PCR of serum. I would again suggest testing a urine sample to maximize sensitivity. A positive rRT-PCR result is diagnostic of infection. If the rRT-PCR study is negative, order PRNT analyses and assess as described above. If the initial Zika IgM is negative, repeat at 16 to 24 weeks.

ii.  I would recommend “screening” ultrasounds at 18 and 22 weeks where resources are available. Characteristic Zika-related ultrasound abnormalities should prompt rRT-PCR and serologic testing.

All confirmed Zika infections should be followed by serial ultrasounds. Current CDC recommendations call for scans every 3 to 4 weeks, however, I would recommend obtaining these every 2 weeks starting 6 weeks after the presumed date of infection and ideally by 18 weeks’ gestation. The presence of characteristic CNS abnormalities in a patient with a confirmed infection is diagnostic of congenital Zika infection and patients should be counseled accordingly. For those not opting for pregnancy termination either by choice or because of advanced gestational age, fetal testing may be indicated given the risk of hydrops, fetal growth restriction, and fetal loss. However, such decisions should be made after a full discussion of fetal prognosis with the parents.

Some have questioned the utility of serologic and rRT-PCR testing in exposed patients, suggesting that serial ultrasounds should detect major abnormalities. I disagree. Confirmation of an actual infection should prompt more frequent and more targeted sonographic assessments. Another concern of ob/gyns in areas of active transmission, is the potential for subtle or severe long term neurodevelopmental sequelae in children who did not display overt fetal CNS abnormalities on prenatal ultrasound.² 

While there is no current evidence to support such a thesis, some patients with serologically confirmed infections, particularly those occurring earlier in pregnancy, may opt for termination to mitigate such risks or if diagnosed near mid-gestation may elect termination for fear that fetal CNS abnormalities may present after the legal limit of termination. Clearly such “unknowns” present complex challenges to counseling affected patients.

Information was up to date at time of publication.  For the latest Zika news visit ContemporaryOBGYN.net/Zika-updates

Take-home message

Ob/gyns who practice in areas with active mosquito-borne transmission should initiate routine screening. All other US ob/gyns should query patients at every visit about possible exposure and have a protocol in place to detect early infections. Local surveillance and control of outbreaks require considerable financial resources. The financial burden on local and state health departments that perform serologic and rRT-PCR testing will also be substantial. Thus, it is time for Congress to expeditiously act to adequately fund these initiatives as well as to fund research in optimal vector control and both active and passive vaccine development. And while the federal government should be fully accountable for such expenditures, this is no time for partisan wrangling.

References

1. Florida Health. Dengue Fever. http://www.floridahealth.gov/diseases-and-conditions/dengue/index.html. Accessed August 8, 2016.

2. The New York Times. Zika cases in Puerto Rico are skyrocketing. http://www.nytimes.com/2016/07/31/health/zika-virus-puerto-rico.html?_r=0. Accessed August 8, 2016.

3. Johansson MA, Mier-y-Teran-Romero L, Reefhuis J, Gilboa SM, Hills SL. Zika and the Risk of Microcephaly. N Engl J Med. 2016;375(1):1-4.

4. Sarno M, Sacramento GA, Khouri R, et al. Zika Virus Infection and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal Demise. PLoS Negl Trop Dis. 2016;10(2):e0004517.

5. Hazin AN, Poretti A, Turchi Martelli CM, Huisman TA; Microcephaly Epidemic Research Group, et al. Computed Tomographic Findings in Microcephaly Associated with Zika Virus. N Engl J Med. 2016;374(22):2193-5.

6. Brasil P, Pereira JP Jr, Raja Gabaglia C, et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro - Preliminary Report. N Engl J Med. 2016 Mar 4. [Epub ahead of print]

7. Moshfeghi DM, de Miranda HA 2nd, Costa MC. Zika Virus, Microcephaly, and Ocular Findings. JAMA Ophthalmol. 2016 Jun 2. [Epub ahead of print]

8. Morbidity and Mortality Weekly Report. Update: Interim Guidance for Health Care Providers Caring for Pregnant Women with Possible Zika Virus Exposure - United States, July 2016. http://www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm6529e1.pdf Accessed August 8, 2016.

9. The Los Angeles Times. A mysterious case of Zika raises new fears of person-to-person transmission. http://www.latimes.com/science/sciencenow/la-sci-sn-zika-mystery-utah-20160718-snap-story.html Accessed August 8, 2016.

10. Morbidity and Mortality Weekly Report. Interim Guidance for Interpretation of Zika Virus Antibody Test Results. http://www.cdc.gov/mmwr/volumes/65/wr/mm6521e1.htm Accessed August 8, 2016.