Zika Virus Infection:

What Anesthesiologists Should Know

Elizabeth A.M. Frost, MD

Clinical Professor of Anesthesia
Icahn Medical Center at Mount Sinai
New York, New York
Editorial Advisory Board Member Anesthesiology News

Zika virus was first isolated in Uganda in the 1940s. Until recently, it was thought to be relatively innocuous. But that was then .…

According to a recent poll (spring 2016) conducted by the Associated Press-NORC Center for Public Affairs Research at the University of Chicago, a significant number of Americans claim to have heard only a little or nothing about Zika virus. Those who are aware of the virus expressed little concern.¹That Congress disbanded for a 7-week recess in late July without appropriating funds to fight the virus would appear to be further proof that the risk for a developing epidemic is minimal.

But is this virus so innocuous? Should we be concerned for ourselves and for the implications it might have for our patients?

Present Status

The World Health Organization (WHO) estimates that 2 billion people are at risk for infection with Zika virus. In Latin America, 1.65 million women risk infection during pregnancy. Infection has reached epidemic proportions throughout Puerto Rico. According to The New York Times (August 4, 2016), there were 1,658 cases of Zika virus in the United States reported to the Centers for Diseases Control and Prevention (CDC) as of July 26, 2016. At least 41 people in the military contracted Zika virus abroad. Female-to-male transmission during sexual activity has been described, as has transmission to a relative from an elderly man who died of the disease in Utah.

While most cases in the United States have resulted after foreign travel to infected areas, several new cases from bites from “local” mosquitoes have been reported in the Miami, Florida, area as of August 2016. Scientists are uncertain whether this outbreak represents mutation to a new strain of mosquito that can transmit the virus or whether it is evidence of further worldwide spread. After all, mosquitoes have been found from pole to pole.

In early August both the CDC and the New York State Department of Health issued a Health Advisory with travel and testing guidance. Travel to a specific neighborhood within Miami was not recommended, and testing was advised for all pregnant women who had been to that area after mid-June. Persistent viremia has been identified in several patients beyond 6 weeks and as long as 53 days.

The Virus and the Mosquito

Zika virus belongs to the family Flaviviridae and the genus Flavivirus (Figures 1 and 2). It is spread mainly by daytime activity of the Aedes mosquitoes, including Aedes aegypti and Aedes albopictus.² Only the female mosquito carries the virus, which was first isolated in the Zika Forest of Uganda in 1947.³ The virus appears to have spread slowly until around 2013 and 2014. It proliferated in Brazil last year for unclear reasons. It may be due to genetic mutations, or it may be that it was noticed because it hit a large population who lacked immunity.

 

Zika virus is related to other viruses that are responsible for chikungunya, dengue, yellow fever, Japanese encephalitis, and West Nile virus. The first documented outbreak among humans occurred in 2007 in the Federated States of Micronesia.⁴ By early 2016, the disease was occurring in 20 regions of the Americas as well as in Africa, Asia, and the Pacific. After an outbreak in Brazil in 2015, WHO declared it a “Public Health Emergency of International Concern” in February 2016 because of clusters of fetal microcephaly and other neurologic disorders.

As Zika virus infection has spread with no indication of slowing down, the United States has issued travel alert warnings. Sporting events were relocated from Puerto Rico to the US mainland in May 2016. Although controversy arose regarding conducting the Summer Olympic Games in Brazil in August 2016, the decision was made to continue as planned.

Transmission

Vertebrate hosts of Zika virus were initially monkeys in an enzootic mosquito–monkey–mosquito cycle. Transmission to humans was rare, seldom causing infection before the start of the current pandemic in 2007. However, other arboviruses had already been identified as causes and transmitters of human disease and spread in a mosquito–human–mosquito cycle, such as yellow fever and dengue (both flaviviruses) as well as chikungunya (a togavirus).

Transmission also has been confirmed via blood transfusion from infected humans.⁵ The FDA recommended screening blood donors and deferring high-risk donors for 4 weeks. In one study in French Polynesia, 2.8% of donors from November 2013 to February 2014 tested positive for Zika RNA but were all asymptomatic at the time of blood donation. Eleven of the positive donors reported symptoms of Zika virus after donation.⁶

Zika virus can be transmitted sexually.⁷ In fact, the virus has been shown to exist in semen for at least 2 weeks, and possibly up to 10 weeks, after the onset of symptoms of Zika virus. Transmission, while initially thought to be only from men to women, also has been shown to occur from women to men.

Life Cycle of the Mosquito

Standing water is essential for the life cycle of the mosquito. It can live in salt water or freshwater, in brackish water, and especially in the stagnant water found in tires or in holes in trees. Mosquitoes have 4 life cycles:

• The female mosquito lays several hundred eggs on the surface of water or in an area that is about to be flooded. Unhatched eggs are extremely resistant to adverse conditions and can adhere densely to the sides of any contained area.
• The eggs of most species hatch in 2 to 3 days, and the larvae feed on organic matter in the water for about a week before changing into pupae.
• The pupae continue to live in the water for another 2 to 3 days and then metamorphose into adult mosquitoes.
• Male mosquitoes feed on flower nectar and do not bite. However, the females require blood to produce eggs.

Feeding is approximately every 3 days; a female mosquito typically will consume its own weight in blood. The virus divides in the midgut epithelial cells of the mosquito and then spreads to its salivary gland cells. After 5 to 10 days, viruses are found in the mosquito’s saliva from which they are transmitted to human skin. Inoculation of mosquito saliva into human skin results in infection of epidermal keratinocytes, skin fibroblasts, and the Langerhans cells. Spread continues to lymph nodes and hence into vascular spaces.⁸

Zika Virus

Flaviviruses are human neuropathogens that can cause a wide range of clinical syndromes ranging from fever, meningitis, encephalitis, and a flaccid paralysis characteristic of Guillain-Barré syndrome.⁹ Chikungunya is more likely to cause high fever, lymphopenia, severe arthralgia, arthritis, and rash; dengue is more likely to cause neutropenia, shock, thrombocytopenia, hemorrhage, and death.

Since aspirin and nonsteroidal anti-inflammatory drugs can increase the risk for bleeding in people with dengue, and because the clinical presentations of these illnesses are similar, acetaminophen should be used to manage pain in people suspected of having either chikungunya or dengue. Note also that coinfection with these viruses is possible.

Most cases of Zika virus have no symptoms, but when present, they are usually mild and can resemble those of dengue. Symptoms may include fever, red eyes, joint pain, headache, and a maculopapular rash. Symptoms generally last less than a week. Death is very rare during the initial infection, although complications can develop later. Infection during pregnancy, however, may result in microcephaly and other neurologic abnormalities in the fetus.⁹

Complications of microcephaly include mental retardation, seizures, and vision and hearing problems, among other morbidities. While microcephaly generally occurs in 2:100,000 live births, several thousand cases have been reported in Brazil, the country most affected by Zika virus. In addition, a spike has been seen in Guillain-Barré cases, with over 400 cases associated with Zika virus infection, according to WHO.

Zika virus targets several vital areas of the brain, including the corpus callosum, the structure that facilitates communication between both hemispheres; the basal ganglia, which affects thinking and emotion; and the cerebellum, which is responsible for movement and speech. Imaging has revealed that damage can continue even after birth, and may be present even in babies whose appearance is normal. Early scans can give more accurate information than ultrasound studies, thus allowing for more reasoned decision making as to continuance of the pregnancy.

Diagnosis

Zika virus can be identified by reverse transcriptase-polymerase chain reaction. The period of viremia is variable, but WHO recommends testing be done on serum collected within 1 to 3 days of symptom onset or on saliva or urine samples collected during the following 3 to 5 days.¹⁰ When evaluating paired samples, Zika virus was detected more frequently in saliva than serum. The virus also may be detected in urine.¹¹

Prevention

As treatment is not specific, measures should be taken to avoid contracting the infection. Several guidelines have been developed, including:

• covering legs, arms, and brows;
• using insect repellents;
• staying indoors at dusk and dawn;
• removing standing water;
• drilling holes in garbage containers;
• chlorinating swimming pools; and
• ensuring the integrity of window and door screens.

Several factors increase the attraction of mosquitoes to a host. Mosquitoes use visual, thermal, and olfactory stimuli, of which the olfactory system is probably the most important. Daytime feeding insects appear to be oriented to the host by dark-colored clothing. Visual stimuli help flight orientation, especially at far distances.

Up close, smell seems to be the primary stimulus. Of the 3 to 400 compounds that are released from the body as byproducts of human metabolism, some 100 volatile substances can be detected in breath. Mosquitoes are most attracted to carbon dioxide and lactic acid. Carbon dioxide is a long-range airborne attractant and can be detected by mosquitoes at up to 100 ft. Chemoreceptors on the antennae of insects are stimulated by lactic acid. These same chemoreceptors may be inhibited byN,N-diethyl-meta-toluamide (DEET)-based insect repellents.¹²

Skin temperature and moisture attract. The propensity to bite around the head or feet may be due to local temperature and eccrine sweat gland output. Mosquitoes are generally not attracted to anhidrotic individuals. Other chemoattractants include volatile compounds derived from the sebum, eccrine, and apocrine sweat glands, as well as the cutaneous microfloral actions on these secretions. Floral fragrances, perfumes, soaps, lotions, and shampoos also can increase the likelihood of being bitten.

There is a sex and age preference, as men are bitten more frequently than women, adults (except for the very old) more often than children, and larger people more often than thinner ones (perhaps because of greater relative heat and carbon dioxide production).

Insect Repellents

Although the attraction of mosquitoes for humans can be chemically decreased, there is marked species variation, and a long-acting repellent that could be taken orally without side effects does not exist. Thus, one must resort to topical preparations, which also may have problems, as shown by Florida’s difficulty with its attempts to control mosquitoes. Repellents all become less effective in the rain, as an individual sweats, as the temperature rises (a 10∞C rise in temperature causes a 50% decrease in effectiveness), and as wind speeds increase.

Chemical Repellents

Several chemical repellents are generally effective for up to 8 hours against the mosquitoes that transmit Zika and West Nile virus.¹³ The most effective are DEET, picaridin, oil of lemon eucalyptus, and IR3535. The gold standard is DEET, which effectively “blinds” the insect’s senses so that the biting/feeding instinct is not triggered by humans. It does not appear to affect the insect’s ability to smell carbon dioxide.

DEET is recommended in concentrations less than 10% for children and up to 30% for adults, although it can be used at 100% strength. It is greasy and has a distinct odor, and at high concentrations can dissolve spandex. Picaridin is a newer repellant and has none of the side effects seen with DEET. It is usually sold at up to 20% concentration.

Plant-Derived Repellents

Although thousands of plant-derived compounds have been tested for repellent activity, none have tested as effective as DEET with regard to duration and broad-spectrum activity. Generally, protection lasts less than 2 hours. Citronella oil has been used widely in candles as an insect repellent. However, studies have shown a nearly equal protective effect from plain candles, perhaps due to the action of the latter as a decoy of warmth, moisture, and carbon dioxide. Pyrethrum is a rapidly acting insecticide that is neurotoxic to the insect. It is derived from theChrysanthemum genus and is a synthetic pyrethroid. The agent is effective against several insects, has low toxicity, and is rapidly inactivated by ester hydrolysis. It should be applied directly to clothing or to screens or nets. Potency is maintained for up to 2 weeks.

Electronic Devices

Handheld ultrasonic devices that are advertised to emit sounds that repel mosquitoes are not effective.¹⁴ Similarly, larger devices that are hung to attract and electrocute insects (ie, bug zappers) are ineffective against mosquitoes. Of the insects killed by these instruments, only about 0.1% are female mosquitoes. It has been estimated that 71 billion to 350 billion beneficial insects are killed in this manner annually.¹⁵

Controlling the Mosquito Population

The A. aegypti mosquito transmits several tropical diseases. Oxitec, working at Oxford University in the United Kingdom, has developed a means to genetically modify the male mosquito. These mosquitoes, known as OX513A, have been tested in field trials in Brazil and Panama, and were shown to reduce target mosquito populations by more than 90%.¹⁶ A self-limiting gene prevents the offspring from surviving. Male modified mosquitoes, which do not bite, are released to mate with females. Their offspring inherit the gene and die before reaching adulthood.

The mosquito control effect is nontoxic and species-specific since the OX513A mosquitoes are A. aegypti and only breed with A. aegypti. A proposal is under review, which has been met with some resistance, to release altered mosquitoes in Florida.

Radiation also has been proposed to sterilize male larvae so that when they mate, they will produce no progeny.

Another means to control the mosquito population, which has received enthusiastic support from local governments, is the use of fathead minnows. These little fish eat the mosquito larvae, consuming several times their own weight on a daily basis.

Patients

Death due to Zika virus is extremely rare; so is transmission by casual contact, as in the operating room. What is of concern are the ethical and surgical considerations that arise should a pregnant woman realize that her fetus has microcephaly and/or other life-threatening abnormalities.

There is no known cure for microcephaly. Babies exhibit severe mental retardation, speech difficulties, and seizures; and their life span is shortened. Religious or moral objections might exist on the part of both the patient and the anesthetic care provider to performing an abortion. Moreover, many states have severely restricted access to abortion, especially late-term abortion, making it almost impossible for a woman to get help. A law passed in Utah in May 2016 requires that all women undergoing an abortion after 20 weeks’ gestation be given general anesthesia to prevent pain to the fetus.¹⁷ Ethical committees and intense psychological support become imperative.

Conclusion

Zika virus is found worldwide. While it usually only causes no or mild, short-lived systemic disturbances, it can be devastating to the fetus of a pregnant woman. The best means to control the outbreak is to adopt measures to lessen the mosquito population and to better protect ourselves from mosquito bites.

References

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16. Carvalho DO, McKemey AR, Garziera L, et al. Suppression of a field population ofAedes aegypti in Brazil by sustained release of transgenic male mosquitoes. PLoS Negl Trop Dis. 2015;9(7):e0003864.