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Imported Human Rabies

The first case of human rabies in the United States since August 1981 has been reported to CDC. The patient, a 30-year-old American architect from Waltham, Massachusetts, was exposed to rabies from a dog bite in Ososo, Nigeria, West Africa. He died on January 28, 1983, 28 days after onset of symptoms.

On October 8, the patient, who worked in Nigeria, was bitten on the right wrist by his pet Doberman pinscher while attempting to free it from a trap. The dog died later that day and was buried without laboratory examination for rabies. The patient sought medical attention at a nearby clinic and received tetanus immunization, but because the dog had recently been immunized against rabies, it was decided that postexposure prophylaxis was unnecessary.

Eleven weeks later, the patient returned to the United States and remained well until January 1, 1983, 85 days after the bite, when he developed numbness and tingling at the healed bite-site. During the next several days, the patient developed low back pain, a temperature of 38.9 C (102 F), sore throat, anorexia, and malaise. On January 5, he complained of difficulty breathing, mild chest discomfort, excessive salivation, and occasional gagging when attempting to drink. He was examined by a physician, who noted that he had non-specific ST-T changes on an electrocardiogram. He was admitted to the Waltham Hospital, Waltham, Massachusetts, for further evaluation.

On admission, the patient was anxious and was producing a large volume of saliva, which he refused to swallow. He suggested that a milk deficiency caused his illness, and exhibited unusual fear of some medical procedures. His pharynx was slightly erythematous, and his neck or throat structures contracted when touched with the hands or examining instruments. The remainder of the physical examination was unremarkable. Laboratory tests revealed a white blood count of 9,900, with a normal differential, normal serum electrolytes and calcium, and normal chest x-ray. On January 6, the patient exhibited marked hyperactivity and refused to swallow barium for a radiologic examination. On the evening of January 6, he had respiratory arrest and a generalized seizure, and an endotracheal tube was inserted. Following the respiratory arrest, his temperature rose to 41.1 C (106 F), and on 40% inspired O((2)), arterial blood gases were a pO((2)) of 60.7 mm Hg, a pCO((2)) of 36 mm Hg, and a pH of 7.26. A lumbar puncture revealed an opening pressure of 200 mm H((2))O, protein of 20 mg/dL, glucose of 113 mg/dL, four leukocytes (one polymorphonucleocyte, three lymphocytes), and no bacteria. A chest x-ray showed diffuse pulmonary infiltrates. A diagnosis of rabies was considered, and the patient was placed in strict isolation. A skin biopsy, taken from the back of his neck above the hairline, was sent to CDC for direct immunofluorescent antibody (FA) testing for rabies.

On January 7, the biopsy was reported positive. The patient was able to communicate rationally with hospital staff by writing notes. He demonstrated marked pharyngeal and laryngeal spasms when his face or neck was stimulated by either a wet sponge or a draught of cool air. Bacterial cultures of cerebrospinal fluid (CSF), blood, urine, and sputum were negative. Computerized tomography and electroencephalogram were normal. The patient continued to require ventilatory support and a dopamine infusion to maintain adequate blood pressure. On January 8, he was started on systemic interferon treatment. He was given human leukocyte interferon, 10 million units twice daily intramuscularly, and 5 million units once daily intraventricularly into a Rickham reservoir connected by a cannula to a lateral ventricle of his brain.

During the next 10 days, the patient became progressively less responsive and was in deep coma by January 18. He had numerous medical complications during the course of illness, including Pseudomonas sepsis and keratoconjunctivitis, recurrent seizures, hypo- and hyperthermia, anemia, hypotension, abnormal blood clotting, and acute renal failure. Marked elevation of lactic dehydrogenase (LDH) and serum transaminases (SGOT and SGPT) were noted, and serum creatine phosphokinase (CPK) peaked at 86,000 units/ml. Urine myoglobin remained negative. The interferon therapy was discontinued on January 25, 17 days after the first dose was administered. The patient developed adult respiratory distress syndrome refractory to ventilation and died of cardiovascular collapse on January 28.

Serum collected daily from the patient and tested at CDC for rabies antibody by the rapid fluorescent focus inhibition test turned positive at 1:12 on the 16th day of illness and remained minimally positive at 1:25 or less until his death. CSF samples tested for rabies antibody were negative through the 19th day of illness and were unavailable for testing after that time. Rabies virus was isolated by mouse inoculation from CSF, sputum, nasal secretions, and saliva, both before and after the start of interferon therapy (Table 1). Rabies monoclonal antibodies obtained from the Wistar Institute, Philadelphia, Pennsylvania, demonstrated that the isolates were in the rabies group and not a rabies-related virus, such as Mokola or Lagos bat virus (1). Further testing with monoclonal antibodies produced at CDC suggested that the isolates were typical street rabies virus. Direct FA testing of skin biospies and a brain biopsy taken early in the illness from the frontal lobe cortex were positive; corneal impressions were negative. At postmortem, many tissues were positive for rabies virus, including specimens from brain and spinal cord, skin and nerve from the bite site, pancreas, liver, bladder, periaortic lymph node, pericardium, adrenal gland, and salivary gland.

A total of 132 persons were evaluated for potential contact with infectious secretions from the patient. Twenty-eight persons received rabies postexposure prophylaxis, including seven physicians, 14 nurses, three respiratory therapists, one microbiologist, two friends or relatives of the patient, and one other hospital contact. In addition, three pathologists received pre-exposure prophylaxis before the patient's death. Reported by D Duhme, MD, D Butman, MD, S Aoki, MD, D Thompson, MD, AM Testamarta, MD, N Rodberg, MD, P Sullivan, MD, MA McMahon, RN, L Hamilton, Waltham Hospital, Waltham, NJ Fiumara, MD, State Epidemiologist, Massachusetts State Dept of Public Health; TC Merigan, MD, Stanford University Medical Center, Stanford, California; Div of Viral Diseases, Center for Infectious Diseases, Div of Field Svcs, Epidemiology Program Office, CDC.

Editorial Note

Editorial Note: Of the 18 cases of human rabies treated in the United States since 1975, seven resulted from a bite acquired in another country from a rabid dog. In addition, another American died in 1981 in Belgium from rabies acquired from a dog bite received in Africa (2). It should be emphasized that any dog or cat bite acquired outside the United States in a country known to have endemic rabies should be suspect; the exposed individual should receive rabies postexposure prophylaxis unless the animal is available either for quarantine or for laboratory examination using only the most sensitive rabies diagnostic procedures. Persons living in or planning an extended stay in countries where rabies is a constant threat should also consider receiving pre-exposure prophylaxis. All of Latin America and Africa, and most of Asia (except Japan and Taiwan) should be considered risk areas for rabies exposure. Australia, New Zealand, and most of Pacific Oceania are rabies-free. The vaccination status of the biting animal should not be used to determine whether human postexposure prophylaxis should be administered; the last two rabies patients seen in the United States were bitten outside the United States by dogs reported to have been adequately immunized against rabies.

This is the second case of human rabies treated with human leukocyte interferon in the United States (3). Both cases had remarkably similar presentations, clinical courses, and durations of illness before death. It is interesting to note that serum antibody titers for rabies remained either absent (previous patient), or minimal (this patient), for the duration of illness. In other human rabies patients treated in recent years without interferon, rabies antibody titers typically rose to levels of 1:10,000-1:60,000, suggesting that interferon may have depressed the development of neutralizing antibody. Whether this is beneficial or harmful is unclear. While high levels of neutralizing antibody present before the onset of clinical disease are associated with protection, there are experimental data to suggest that antibody-mediated immune cytolysis may be associated with rabies pathology and death (4,5). Conversely, a depressed immune response can lead to increased virus replication and resultant nerve destruction (4).

It is probable that human leukocyte interferon given in the dose schedule used in these two patients did not affect the outcome of the disease--the duration of illness in both patients approximated the 26 day average observed in human rabies patients receiving intensive supportive care. Other therapeutic interventions after the onset of clinical illness, such as the administration of passive rabies antibody or immunization with rabies vaccine, have also been ineffective in increasing survival. Only three known survivors of human rabies have been reported despite the best efforts of treatment and support. Rabies remains a disease best controlled through prevention rather than treatment.

References

  1. Wiktor TJ, Flamand A, Koprowski H. Use of monoclonal antibodies in diagnosis of rabies virus infection and differentiation of rabies and rabies-related viruses. J Virol Methods 1980;1:33-46.

  2. CDC. Human rabies--Rwanda. MMWR 1982;31:135.

  3. CDC. Human rabies acquired outside the United States from a dog bite. MMWR 1981;30:537-40.

  4. Murphy FA. Rabies pathogenesis. Arch Virol 1977;54:279-97.

  5. Smith JS, McClelland CL, Reid FL, Baer GM. Dual role of the immune response in street rabiesvirus infection of mice. Infect Immun 1982;35:213-21.

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