University of Alabama at Birmingham

Gorgas Case 2016-08

Universidad Peruana Cayetano Heredia
The Gorgas Course in Clinical Tropical Medicine spent its last week with a 4-day field trip to Iquitos, Perú on the banks of the Amazon River. Iquitos, with a population of approximately 450,000, is the largest city in the world that is reachable only by air or by river. The nearest road ends over 400 km away.

The following patient was seen on the inpatient service of the Regional Hospital of Loreto.
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History: 22 year-old female evacuated to the Regional Hospital of Loreto with a 6-day history of muscular weakness, gait difficulty and abdominal pain. She initially presented with right ankle pain (6/10 intensity) that radiated to the calf; two days later, the pain became bilateral and a feeling of pruritus developed. One day later, the pain spread to thighs and hips bilaterally with muscular weakness and difficulty in walking. On the fifth day of illness, sharp then colicky lower abdominal pain spread to the epigastrium on the day of admission. Diffuse headache (7/10) then developed at which point she was evacuated from her hometown. On the second hospital day, dysphagia to both solids and liquids as well as psychomotor agitation developed.

Epidemiology: Born and lives in the remote riverfront Amazonian indigenous community of Yancuntich (population 231), located on the Morona River a few kilometers from the border with Ecuador. Three children from the same community had been evacuated around the same time with similar symptoms and had died. G5 P5, all home deliveries without prenatal care. No recent animal or mammal bites, no recent trauma. No known TB exposure. No high risk sexual activity. History of a bat bite at 7 years old.

Physical Examination: HR 104 RR 20 BP 144/91 mmHg T 36.7°C SO2 98% Patient in obvious distress due to abdominal pain and dyspnea. Chest: diffuse rhonchi bilaterally. CVS: Normal cardiac auscultation. Abdomen: normal bowel sounds, diffusely tender to deep palpation. Neurologic: Alert and oriented x3. No meningismus. Decreased muscle strength and hyporreflexia in both lower limbs, normal muscle strength and reflexes in upper limbs. Sensory examination normal throughout. Hoffman and Babinski signs: negative. Skin: no rash or other abnormalities. Vital signs (during hospitalization) are shown in Image B. The bars represent systolic and diastolic BP, pulse is in red, the upper blue line corresponds to temperature.

Laboratory Examination (on admission): Hb 12.5 g/dL, Hct 37.2 %, WBC 9.5 (76 neutrophils), platelets 210 000. INR 1.37. Arterial blood gases, electrolytes normal. Glucose 129 (N=100). BUN, creatinine, normal. Bilirubin, albumin, total protein normal. AST 52 (N=40), ALT 64, Alkaline phosphatase 165 (N=110). CSF: protein 49 (N <45), glucose 86, Adenosine deaminase normal. 2 WBC, 0-1 RBC. Gram stain: negative, AFB stain: negative, India ink: negative. HIV negative. CT scan (hospital day 5): diffuse cerebral edema (Image A).
Diagnosis: Rabies (genotype 1) infection paralytic form
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Discussion: Total immunoglobulin against rabies virus in both serum and CSF obtained on hospital day 2 and measured by indirect immunofluorescence were positive. The patient had no history of rabies vaccination. PCR for rabies on brain tissue obtained post-mortem was positive at the Peruvian INS (national reference lab). Negri bodies were not seen histologically. In general, in studies on dog rabies in Africa, rabies can be efficiently diagnosed with PCR of saliva on 3 samples; if any are positive rabies is confirmed and will quickly guide the best course of action. A number of abnormalities on brain CT have been described in rabies but none are diagnostic.

Furious rabies is the most common presentation but this case as with almost all cases transmitted by vampire bats represents the less distinctive paralytic form or rabies disease. After prodromal symptoms, which include fever, headache and local paresthesias (perhaps perceived as pruritus in this patient), an ascending flaccid paralysis with pain and fasciculation in the affected muscles and mild sensory disturbance ensues. Symptoms tend to begin around the site of the bite in the affected limb. A careful search for the telltale bite should be undertaken (example from another patient in Image C). Paraplegia and sphincter involvement then develop and the terminal even is usual a fatal paralysis of the swallowing and respiratory muscles. Hydrophobia, common in furious rabies, is rate. Survival from onset of disease may be several weeks if no complications ensue. Other possible diagnoses include HSV encephalitis and VEE, plus many other arboviral encephalomyelitides e.g Oropouche. Guillain Barré (ascending paralysis) and severe tetanus with autonomic instability may present with similar peripheral symptoms.

Rabies is caused by RNA viruses in the genus Lyssavirus. Rabies virus (genotype I) is the most common of the 12 viral species in the genus, and it is responsible for greater than 55,000 human deaths annually. Outside of the Americas most human cases are associated with canine bites and exposures. Rabies virus is transmitted in the saliva after the bite of an infected mammal. In the Americas, bats and carnivores are the major reservoirs and multiple insectivorous bat species transmit the virus to humans in the United States. In Latin America, rabies is transmitted by the vampire bat (Desmodus rotundus) which is unique to this region of the world. Wide circulation of rabies among vampire bats, which are efficient transmitters, throughout their geographic range occurs throughout Latin America has resulted in outbreaks in a number of Latin American countries including Ecuador, Venezuela, Brazil as well as Peru. A variety of bat lyssaviruses in the genus circulate widely in bats in other parts of the world and have been associated with a relatively small numbers of cases of clinical disease similar to rabies.

In Peru rabies in canines has decreased dramatically since 1995 and in 2014 the 14 cases in canines were restricted to Puno, Puerto Maldonado, and in 2015 an emergence of 10 canine cases occurred in Arequipa with 1 human case. A number of significant outbreaks of rabies in humans associated with vampire bat rabies have occurred throughout the jungle regions of the country over the past several decades. No human cases of rabies were reported in Peru in 2015 but 13 cases associated with vampire bat rabies have been reported already in 2016 including the cluster involving this patient.

During epizootics of vampire bat rabies, cows (a preferential food source for vampire bats) become infected first and dying cattle with evidence of vampire bat bites often herald human outbreaks. Bat bites, most of which are un-noticed, as in our present case are common in indigenous regions. Recently, it has been noted that 11% of healthy individuals randomly tested in Loreto had neutralizing antibodies to rabies (Am. J. Trop. Med. Hyg., 87(2), 206-215, 2012) indicating that sub-clinical and/or non-fatal infection with lyssaviruses is possible. Risk factors for bat exposure included age less than or equal to 25 years and owning animals that had been bitten by bats.

On day 2 the treating team elected to sedate the patient with ketamine, midazolam, and fentanyl and mechanically ventilated (so-called Milwaukee protocol). She continued with episodes of dysautonomia including tachycardia/bradycardia and hypertension (Image B). Artificial hypothermia was induced. On day 5 diabetes insipidus ensued with a serum Na 172 mEq/L and polyuria (urinary volume 13 080 ml/24 hours) and vasopressin was started. At this time, the pupils were dilated and non-reactive to light and the CT scan showed severe cerebral edema (Image A). On day 11 sedation was withdrawn and palliative care instituted; the patient expired on Day 12. While one of the variants in the Milwaukee protocol is often implemented due to the usual 100% fatal outcome in rabies, as a desperate measure, no evidence for its utility in any trial has been found (J Neurol Sci 2014: 339: 5–7; Can J Neurol Sci 2016: 43: 44–51). Neither rabies vaccine nor rabies immune globulin (not available in Peru) is of benefit after the onset of clinical rabies.

We would like to thank Professor David Warrell and Dr. Mary Warrell for helpful discussion of this case.