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Managing rabies in a remote setting

Managing Rabies in a Remote Setting

Introduction

Rabies presents as an acute progressive encephalitis that is fatal. Whereas clinical rabies is an infrequently encountered disease in the developed world, substantial reservoirs of the disease are present in the United States. Although rabies in domestic animals has been drastically decreased, numerous wild animal vectors exist and present an exposure risk in the wilderness setting.

Case report

The Wilderness Medicine Institute of National Outdoor Leadership School (NOLS) in partnership with the Harvard Affiliated Emergency Medicine Residency and the Massachusetts General Hospital Director of Wilderness Medicine leads a 28-day course, “Medicine in the Wild,” for third- and fourth-year medical students. “Medicine in the Wild” consists of a 48-hour, classroom-based clinical section (Wilderness Upgrade for Medical Professionals), followed by a 20-day field portion in the Gila Wilderness Area, New Mexico.

On the first night of the field section, a healthy 25-year-old student sleeping outside of a kiva shelter was awakened at 0430hours by foot pain to find a fox biting through his sleeping bag. Despite immediate yelling and movement, the fox only released its bite and ran off after the student was able to slide an arm out of his mummy bag, strike the fox with a trekking pole twice, and then stand up still in his sleeping bag.

After waking other students and instructors, it was discovered that earlier in the evening students in another tent group (located approximately 500m away) had been awakened by a fox walking on their sleeping bags inside their kiva shelter. In addition, the fox had dragged away boots and other items before it was scared away. No bites or direct contact with the fox were noted to have occurred at this time.

On examination of the bitten student, a 1cm superficial transdermal skin avulsion located on the medial aspect of the fourth digit of the right foot was documented. In addition, an obvious tear and puncture holes were present at the foot of the sleeping bag. No other bites were apparent. The wound was immediately irrigated with 2L of water previously treated with chlorine dioxide, and the wound was disinfected with direct application of 2% aqueous chlorine dioxide by an additional course participant, a Harvard Affiliated Emergency Medicine Residency senior resident physician.

After the attack, the fox was intermittently spotted lurking in the dark outside of camp. The course instructors brought all the students to a central area, and a fire was started. The fox repeatedly tried to re-enter the camp area. In an attempt to drive off the oddly-behaving fox on one incursion, an instructor was successful in striking it with 2 stones. Subsequent attempts to locate the fox were unsuccessful. Once daylight arrived, NOLS's Southwest Branch emergency coordinator was contacted via satellite phone to discuss the incident. An evacuation and transportation plan was devised, and oral cephalexin was initiated. An evacuation team consisting of the (fully ambulatory) bitten student, an instructor, a resident physician, and an additional student departed at 0900hours on a 3-mile evacuation hike to the trailhead. From the trailhead the patient was transported by a previously positioned NOLS vehicle and arrived at a regional medical center at approximately 1300hours that same day.

At the medical facility, additional wound cleansing was done with povidone-iodine solution while the local treating emergency physician sought consultation with the New Mexico State Department of Health epidemiologist. After consultation, the emergency physician initiated rabies postexposure prophylaxis (PEP). The bite site was infiltrated with 2mL of human rabies immunoglobulin (HRIG), and an additional 10mL of HRIG was injected intramuscularly into bilateral gluteal muscles. Rabies vaccination was initiated in New Mexico and completed in the student's home state using 1.0mL human diploid cell-purified vaccine (HDCV) administered intramuscularly in the deltoid region using the Essen Protocol of vaccine on days 0, 3, 7, 14, and 28.

A tetanus booster was given at the initial emergency room visit, and cephalexin was discontinued.

Early investigations were made by the evacuation team as to the feasibility of acquiring necessary doses of rabies vaccine (to be released to the accompanying licensed physician), which might enable the student to complete his vaccination schedule in the field. Although potentially technically feasible, given the potentially fatal downside of inadequate PEP, the decision was made by NOLS that the student should not return to the field. The remainder of the evacuation team then returned to the field and completed the full 20-day field section without incident. The student returned home and completed the PEP for rabies following the recommended schedule by the Advisory Committee on Immunization Practices (ACIP).1

Discussion

Awareness of rabies needs to remain high as important reservoirs still exist in populated domestic regions, the wilderness, and abroad. After an exposure, if PEP is not initiated empirically and effectively and clinical rabies develops, it is fatal. Although rare cases of survival of clinical rabies have been reported using various treatment protocols, none has proven effective.2 Only 2 cases with mild to no neurologic sequelae have been documented, most notability a case involving the Milwaukee Protocol; however it has been unsuccessful in subsequent cases.3., 4., 5., 6., 7. Prevention remains the only reasonable option. Worldwide, exposure to rabies from wild and domestic animals results in an estimated 55 000 deaths per year, which occur almost entirely in the developing world.8

In the United States and most developed countries, implementation of rabies control programs (most notably extensive vaccination programs of domestic animals in the 1940s) dramatically decreased the incidence of rabies in domestic animals by the 1960s.9 Since that time the prevalence of rabies in wild animal reservoirs has become more apparent and now represents the dominant exposure risk in the developed world. Wild animals accounted for 93% of rabid animals in the United States during 2007 based on Center for Disease Control and Prevention (CDC) surveillance.10 Despite advances in the eradication of domestic reservoirs, 1 to 2 deaths per year from rabies occur and an average of 16 000 to 39 000 people undergo PEP annually in the United States.11

Rabies prophylaxis is very effective, with no failures documented for correctly completed vaccination series in the United States since cell-purified vaccines have been utilized.12 Proper recognition of exposure risk is pivotal in the prevention of rabies in humans, so that pre-exposure prophylaxis and PEP can be instituted. Of note, in one study in the United States it has been reported that in as many as 40% of cases in which PEP was given, it was not necessary. Perhaps of more concern, this study reported that an even higher rate existed where PEP was indicated and was not given.13 Physician education of the guidelines for rabies prophylaxis and the low threshold for utilization of local public health agencies in questionable cases has been suggested and shown to improve PEP utilization. In New Mexico, where the exposure occurred, such a system has been in place since the 1980s and has improved utilization of rabies PEP.14 The correct utilization of vaccine is of increased importance because a limited supply of vaccine is currently available, only for use in PEP, from both major suppliers of vaccine (Sanofi Pasteur and Novartis). Because of this limited supply, vaccine for pre-exposure prophylaxis is temporarily unavailable to ensure availability for PEP. Supply limitations have resulted from regulatory issues, increased demand, and limited production (Sanofi Pasteur's facility is nonoperational until mid- to late-2009 because of renovations). Currently, RabAvert (Novartis) is available for PEP without restrictions, whereas the availability of Imovax (Sanofi Pasteur) first requires consultation with a rabies state health official for risk assessment.15 It should be anticipated that the vaccine supply will remain limited for the foreseeable future. Expert consultation with public health officials can improve utilization.

Rabies is caused by an RNA virus from the lyssavirus genus, of the Rhabdoviridae family. The virus is bullet-shaped and adapted to replicate in the mammalian central nervous system.16 The importance of each terrestrial endemic rabies reservoir varies with geographic area. In the United States, terrestrial rabies reservoir species include raccoons (Procyon lotor); striped and spotted skunks (Mephitis mephitis, Spilogale putorius and S gracilis); red (Vulpes vulpes), gray (Urocyon cinereoargenteus), and arctic foxes (Alopex lagopus); coyotes (Canis latrans); and mongooses (Herpestes javanicus) in Puerto Rico.9,16 Any bat represents an exposure risk to rabies; however, species of specific note are the silver-haired bat (Lasionycteris noctivagans) and the eastern pipistrelle (Pipistrellus subflavus).17 The incidence of rabies and defined geographic areas in enzootic reservoirs varies with time. Rodents and lagomorphs are not true reservoirs of rabies. Intermittent transmission of rabies from enzootics species to other mammals results in cases of “spillover,” with these atypical mammals then testing positive.10

Exposure to rabies virus from animals can be broken into categories of bite and nonbite exposures.1 Transmission of rabies to humans typically occurs when virus, excreted in the saliva of the animal, is introduced by the bite of an overtly infected animal. Nonbite exposures can occur from a scratch by a paw contaminated with the saliva of a rabid animal, contact of infected saliva or neural material with mucosal surfaces, or inhalation of large amounts of aerosolized rabies virus.1 Rabies cannot be transmitted through intact skin.16,18 While the presence of the virus in the saliva of infected animals typically occurs concomitantly with clinical signs, the presence of rabies in the saliva of a rabid animal can occur several days before the development of signs. Based on the pathogenesis of rabies, virus must be present in the central nervous system for there to be excretion into saliva; although the animal may appear healthy, testing of the animal's central nervous system will be positive.12,19

Wild mammals can be divided into 3 important categories in terms of exposure to rabies and need for PEP: terrestrial mammalian carnivores, bats, and other wild mammals (Table). Exposure to terrestrial mammalian carnivores tends to be obvious and memorable, in the form of an attack, resulting in noticeable bite and scratch injuries.1 Terrestrial mammalian carnivores are regarded as rabid unless proven negative for rabies by diagnostic testing. Immediate initiation of PEP is recommended.1

The extent of contact with a bat may be difficult to determine, and bite or scratch injuries can be difficult to detect.12 The ACIP guidelines for initiation of PEP for bat exposures reflect this difficulty. To emphasize this point, the majority of cases of clinical human rabies acquired in the United States in recent years are found to be caused by bat variants and often without patient recall of exposure.20 Therefore, a simplified recommendation is that any direct contact with a bat should be considered an exposure risk and evaluated for initiation of PEP. Postexposure prophylaxis is likely indicated unless the bat is available and tests negative for rabies.1 A Department of Health consultation is strongly advised.

A third wild animal category includes other mammals. Small rodents and lagomorphs are almost never found to be rabid and not known to transmit rabies to humans. Incidents of rabid large rodents including woodchucks and beavers (Marmota monax and Castor canadensis) in the Mid-Atlantic States occur in areas where rabies is enzootic in raccoons.9 Many other mammals not typically associated with rabies have sporadically tested positive for rabies.10 We would again stress the recommendation by the ACIP that any patient who is bitten by a wild animal should seek medical care and guidance from local and state health agencies.1,21

The gray fox reservoir of rabies has been endemic to areas of Texas and Arizona for decades.10 During 2007, 8 cases of rabid gray foxes were newly reported in southwestern New Mexico in Catron County, an area not previously noted to harbor this rabies potential. By October 2008, an additional 16 infected gray foxes were documented in an increasingly broad geographic area. In New Mexico, the gray fox now represents the majority of 25 animals that have tested positive for rabies during 2008.22,23 Previously cases of rabid wild animals in New Mexico were predominantly recorded in skunks and bats; however, neighboring states Arizona and Texas reported 22 and 31 cases, respectively, in gray foxes during 2007, both increases from previous years.10 The additional extension of gray fox variant rabies has been observed along the Pecos River in Texas, suggested to have been driven by recent years of drought in the region.10 Specifically in the area of the Gila Wilderness Area where the attack reported here occurred (the Catwalk), 3 attacks by gray foxes on hikers have been reported: 1 in 2007 resulting in trail closure and an additional attack occurring earlier in the same month as this report.22 Gradual expansion of endemic rabies in a species’ geographical area is common and sometimes occurs precipitously and in this case is likely spillover from Arizona into a susceptible animal population.10

Although the signs of rabid wild animals cannot be reliably interpreted, the fox in this case was very suspicious for being rabid (an unprovoked attack of a sleeping victim by an oddly-behaving animal that had lost fear of humans). Regardless, any bite by the gray fox, a terrestrial carnivore known to be a reservoir of rabies, is independently at high risk of exposure to rabies.1,18 Exposure in this case occurred via a transdermal bite, for which the ACIP recommends immediate PEP.1

Whether in an urban or wilderness setting, prophylaxis of a suspected rabies exposure should begin with good wound management, focusing on immediate cleansing of the wound with soap and water as thoroughly as possible and with application of a virucial antiseptic such as povidone iodine or alcohol. Thorough wound care has been shown to drastically decrease rabies infection rates.18 In this case, neither iodine nor alcohol was immediately available (searching through first aid kits in the dark), however, aqueous chlorine dioxide used by the course participants for disinfecting drinking water was substituted. Although not preferred because of its caustic nature, chlorine dioxide is known to be virucial and was readily available.24 Wound care is likely the extent of care advisable in the wilderness setting. Additional wound treatment, including antibiotics and tetanus vaccination, should be guided as clinically indicated by conventional wound care of an animal bite. Primary closure with suture should be avoided.1 In this case the wound was very superficial and not a true puncture wound, therefore antibiotics were discontinued.

Suspected rabies exposure in general is a medical urgency, but not emergency, and requires definitive medical care (the initiation of PEP) preferably within 24 to 48hours. Although early initiation is prudent, PEP should certainly be pursued even if lengthy delay has occurred.1 Any significant delay in PEP would place the patient at unnecessary risk, as cases of reported failures of PEP have been attributed to a delay in initiation.25 In this case, evacuation was atypically brisk, a short evacuation hike of 3 miles to reach a course van. Waiting until morning light to assess options and coordinate an orderly evacuation, so as not to pose additional risk to the team, was prudent. An evacuation team of 4 was organized using NOLS protocol for an ambulatory evacuee. The goal with an evacuation group size of 4 is redundancy. A team of 4 has enough resources to be self-contained, to split up if another injury/illness occurs, to have good decision-making processes, and to maintain optimal safety. Although not always possible, NOLS policy is to send an evacuation group of 4 as often as can be managed.

In addition to appropriate wound care, PEP involves both passive and active immunization of the patient to the rabies virus. Rabies immunoglobulin (RIG) is administered to provide immediately-effective, virus-neutralizing antibodies. Administration of a course of approved rabies vaccine provides a lasting immune response. In the United States, only RIG of human origin (HRIG) is used in PEP, whereas outside of the United States other biologics (equine origin) are available.1 Internationally, the World Health Organization recommendations prefer the use of HRIG over the other passive biologics available but use is constrained by limited availability.18 Human rabies immunoglobulin is given at a dose of 20IU/kg, with as much of the dose administered at the exposure site as anatomically possible, taking care to thoroughly infiltrate all wounds. Any remaining HRIG is administered distant to the vaccination site intramuscularly.1,21 In this case, given the distal digital nature of the wound, the volume of HRIG locally administered at the exposure site was limited to 2mL of the total 12mL dose. The remainder of the HRIG dose was administered intramuscularly to bilateral gluteal muscles. Concern of causing compartment syndrome from injection of HRIG into a digit has been raised, as a large number of bites occur on digits; however, no evidence of circulation compromise has been noted when injection is carried out by experienced providers.26

In the United States, 2 purified cell vaccines are available for rabies vaccination: HDCV (Imovax) and purified chick embryo cell vaccine (RabAvert). In this case, vaccination was carried out in accordance with ACIP guidelines with HDCV: 1.0mL administered IM in the deltoid region following the Essen Protocol of vaccination on days 0, 3, 7, 14, and 28. In patients that have received pre-exposure rabies prophylaxis, HRIG is not necessary as the patient already has developed antibodies to bind rabies virus. In these previously vaccinated patients, a shortened immunization schedule with 1.0mL of vaccine administered on days 0 and 3 is used.1 All vaccinations should be given intramuscularly to the deltoid in adults and may be given in the anterolateral thigh in children. In contrast to HRIG, rabies vaccines should never be administered in the gluteal area as it has been associated with decreased efficacy and PEP failure.21,25 Rabies vaccine should never be administered at the same site as HRIG or using the same needle/syringe.21

Reported cases of modern PEP failure, although exceedingly rare, are thought to have resulted from deviation from strict adherence to PEP guidelines.25 Identified errors in prophylaxis include: no injection, insufficient injection, or failure to locally inject RIG at the wound site; insufficient wound care; additional small unidentified and untreated wounds; delay in seeking PEP; and injection of vaccine into gluteal muscles, which is associated with poor vaccine response.21,25,27 Yet there are cases documented where modern PEP appears to have been administered appropriately but failed. Potential risk factors for failure of PEP include virus inoculation into highly innervated areas of the body, including the hands and face; direct inoculation into peripheral nerves, thereby by-passing protection from RIG; large viral inoculum or severe wounds; dog bites; and an unidentified immunocomprised state.25,27 Small unknown or unreported deviations from PEP treatment protocol cannot be excluded. This stresses that PEP be guided by Department of Health consultation in the hands of an experience clinician. Of note, no PEP failures have occurred in the United States since cell culture vaccines have become standard.21

The risk of exposure to rabies from bats is underappreciated by many including those at particular risk—cavers and spelunkers. Rabies is present in bats throughout the United States, excluding Hawaii.10 The majority of human rabies cases acquired in the United States in recent decades have been bat variants.20 Since the 1960s, it has been advised that cavers receive pre-exposure prophylaxis to rabies. However, a study conducted at the National Speleological Society Convention in 2000 found that 15% of respondents thought that a bite from a bat was not a risk for acquiring rabies and only 20% had received rabies prophylaxis.28 Cavers risk exposure to rabies from bats through direct contact resulting in a bite or potentially by scratch or mucous membrane exposure. Aerosol transmission of rabies has been proposed as the cause of a few human cases, but data remain limited. The 2 cases of human rabies attributed to aerosol transmission in caves are based on weak historical evidence and are more likely to have occurred from bites or direct exposure.29

At the backcountry wilderness medical course for senior medical students, a licensed physician was part of the field and evacuation team—a resource not often available. With this physician's input, a plan to return to the field with the necessary supplies to continue the vaccination series in the backcountry was considered. A primary concern included an assessment of the logistics of safely storing the vaccine. Systems to assure temperature-controlled storage of the vaccine were investigated in collaboration with the medical director of the vaccine manufacturer. An additional assurance of vaccine stability was provided by a stability indicator included in standard vaccine preparations. In addition, HDCV has been shown to be stable and effective at the temperatures likely to be encountered at the course for greater than the duration of the vaccination schedule; however, such storage is not recommended by the manufacturer.30 These reassuring factors notwithstanding, numerous obvious reasons remained to not pursue this course. Transporting a system of PEP known to be very effective and safe in a traditional clinical setting into the backcountry, where uncertainty is commonplace and limited resources are the rule, places the patient at an unnecessary risk of potential failure of PEP with a consequence of certain death.

A bite from any animal in the wilderness setting warrants evacuation for further assessment and management. In this case, the risk of rabies exposure is obvious, with an aggressive, small, mammalian carnivore without fear of humans acting almost cartoonishly out of the ordinary. In different cases, the exposure risk may not be as readily apparent, such as after inadvertent contact with bats or a bite from an animal not typically associated with rabies transmission. Ultimately the exposure should be evaluated by a medical provider in consultation with public health authorities outside the backcountry setting.

This case illustrates that even when there is an abundance of sophisticated medical professional care in the field, requirements for prophylaxis make any suspected rabies exposure an indication for immediate evacuation. Also of note from this case is the critical need for up-to-date surveillance by public health officials. This case also highlights the importance of newly expanding territories and potential changes in wild animal vectors. As local and global environmental changes occur, it should be expected that the potential for new patterns of rabies endemic ranges and species will demand continued study and careful public health surveillance.

Acknowledgments

The authors would like to thank the National Outdoor Leadership School and Wilderness Medicine Institute community including Gates Richards, Dave Weber, John Hovey, Julia Fairbank, and Tod Schimelpfenig for their help, professional abilities, and passion for outdoor education. Note: The US Center for Disease Control maintains an expert consultation hotline available 24hours/7 days a week at (877)554–4625.

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