Comparing clinical protocols for the treatment of human rabies: the Milwaukee protocol and the Brazilian protocol (Recife)

Abstract INTRODUCTION: Rabies is a major and seriously neglected public health problem worldwide. A treatment consisting of supportive therapy with the use of drugs that show antiviral activity is called the Milwaukee Protocol. In Brazil, this protocol was adapted to the national reality and called the Recife Protocol. In this study, we compared the Milwaukee Protocol with the Recife Protocol, assessing the differences and how these differences may change the course of clinical management. METHODS We searched electronic databases for the use of anti-rabies treatments. A total of 65 articles were published between 2004 and 2019. RESULTS: The protocols have similarities in care related to rabies patients and are important for the treatment of patients in intensive care units. Both protocols indicate deep sedation, antiviral use, constant concern with electrolyte balance, and vasoconstriction related to the condition. Many differences were observed in this study. For the Milwaukee Protocol, sedation should be gradually removed after the eighth day, and on the twelfth day, the patient should be without sedation. In the Recife Protocol, in order to avoid immunomodulation, it is recommended to remove sedation according to the titers of neutralizing antibodies to the rabies virus in the cerebral spinal fluid. CONCLUSIONS: In addition to the differences and similarities raised, our findings indicate that these protocols require a large center for rabies treatment, but the disease most often occurs in places where resources and hospital infrastructure are scarce.

Bufotenine is able to block rabies virus infection in BHK-21 cells

Background Rabies is a fatal zoonotic neglected disease that occurs in more than 150 countries, and kills more than 55.000 people every year. It is caused by an enveloped single stranded RNA virus that affects the central nervous system, through an infection initiated by the muscular nicotinic acetylcholine receptor, according to many authors. Alkaloids, such as acetylcholine, are widespread molecules in nature. They are present in numerous biological fluids, including the skin secretion of many amphibians, in which they act (together with proteins, peptides and steroids) as protection agents against predators and/or microorganisms. Among those amphibians that are rich in alkaloids, there is the genus Rhinella.Methods Bufotenine was isolated from Rhinela jimi skin secretion after a liquid-liquid partition (H2O:CH2Cl2) and reversed phase high-performance liquid chromatography analyses (RP-HPLC). Bufotenine was also extracted from seeds of Anadenanthera colubrina in acetone solution and purified by RP-HPLC, as well. Structural characterization was performed by mass spectrometry and nuclear magnetic resonance analyses. Cytotoxic tests of bufotenine were performed over baby hamster kidney (BHK-21) cells using MTT test. For the antiviral activity,Rabies virus strain Pasteur vaccine (PV) was used on fluorescence inhibition test and fluorescent foci inhibition test, with both simultaneous and time course treatment of the cells with the virus and bufotenine.Results In the present work we describe the effects of bufotenine, obtained either from toads or plants, that can inhibit the penetration of rabies virus in mammalian cells through an apparent competitive mechanism by the nicotinic acetylcholine receptor. Moreover, this inhibition was dose- and time-dependent, pointing out to a specific mechanism of action...

In vitro and in vivo inhibition of rabies virus replication by RNA interference

Rabies is a zoonotic disease that affects all mammals and leads to more than 55,000 human deaths every year, caused by rabies virus (RABV) (Mononegavirales: Rhabdoviridae: Lyssavirus). Currently, human rabies treatment is based on the Milwaukee Protocol which consists on the induction of coma and massive antiviral therapy. The aim of this study was to assess the decrease in the titer of rabies virus both in vitro and in vivo using short-interfering RNAs. To this end, three siRNAs were used with antisense strands complementary to rabies virus nucleoprotein (N) mRNA. BHK-21 cells monolayers were infected with 1000 to 0.1 TCID50 of PV and after 2 hours the cells were transfected with each of tree RNAs in separate using Lipofectamine-2000. All three siRNAs reduced the titer of PV strain in a least 0.72 logTCID50/mL and no cytotoxic effect was observed in the monolayers treated with Lipofectamine-2000. Swiss albino mice infected with 10.000 to 1 LD of PV strain by the intracerebral route were also transfected after two hours of infection with a pool 3 siRNAs with Lipofectamine-2000 by the intracerebral route, resulting in a survival rate of 30% in mice inoculated with 100 LD50, while the same dose led to 100% mortality in untreated animals. Lipofectamine-2000 showed no toxic effect in control mice. These results suggest that intracerebral administration of siRNAs might be an effective antiviral strategy for rabies.

Rabies in a blind patient: Confusion after corneal transplantation.

Two blind persons received corneal transplants from a single donor who showed no signs of rabies before he died. One of the recipients, a young girl, died 16 days later of rabies and the other recipient survived. We discuss the possible mode of transmission of rabies to the first recipient and the management of the second recipient.

Motivos de abandono do tratamento antirrábico humano pós-exposição em Porto Alegre (RS, Brasil) / Abandon reasons of post-exposure human anti-rabies treatment in Porto Alegre (RS, Brazil)

A raiva é uma doença endêmica no Brasil, com letalidade de 100 por cento. O número de casos tem diminuído, porém o de tratamento pós-exposição continua elevado, assim como o de abandono. O objetivo do estudo foi investigar as causas do abandono do tratamento antirrábico humano pós-exposição em Porto Alegre (RS), no segundo semestre de 2006. Foi utilizado o delineamento de série de casos, sendo selecionados 280 casos por amostragem aleatória sistemática entre os 962 registrados no Sinan como abandono de tratamento. Os dados foram coletados em entrevistas domiciliares, utilizando-se questionário específico. Segundo os entrevistados, 66,4 por cento concluíram o número de vacinas prescritas, não estando esses dados registrados no Sinan. Entre aqueles que foram confirmados como abandono (94/280), 24,5 por cento referiram não ter considerado necessário completá-lo, e 13,8 por cento não se sentiram orientados sobre como proceder. Somente em 19,1 por cento dos casos houve a busca ativa dos faltosos pelos serviços de saúde. O registro no Sinan apresenta falhas. Estas ocorrem devido ao fato de o paciente iniciar o tratamento em um serviço de saúde e dar continuidade em outro, não havendo retroalimentação do sistema com dados sobre a sua conclusão.

In Brazil, rabies is an endemic disease with a fatality rate of 100 percent. The number of cases has decreased, but the number of cases for treatment after exposure and treatment dropout is still high. This study investigated the causes of anti-rabies treatment abandon, after exposure, in Porto Alegre (RS, Brazil), from July to December 2006. A case series was designed. Two hundred and eighty abandon cases were selected through randomized systematic sampling, out of 962 registered in Sinan. Data was collected in people's homes through interviews, by means of a questionnaire. According to the interviewees, 66.4 percent concluded the prescribed number of vaccines. This information was not registered in Sinan. Among the subjects confirmed of abandoning the treatment (94/280), 24.5 percent reported that they thought it was not necessary to complete the treatment, while 13.8 percent felt that they did not receive clear guidelines about what to do. Health services attempted to contact absents in only 19.2 percent of the cases. Data entered in Sinan present failures. These occurred because patients started treatment at one health service and continued in a different one. As a consequence, information about the conclusion of the treatment was not entered into the system.

Administraçäo de tratamento preventivo anti-rábico por soro-vacinaçäo, em diferentes momentos, a camundongos infectados experimentalmente com vírus rábico / Adminstration of preventive anti-rabies treatment with serum-vaccination, on different opportunities, in mice experimentally infected with rabies virus

Tratamentos preventivos anti-rábicos, segundo esquemas de soro e/ou vacinaçäo, em camundongos experimentalmente infectados com vírus, por via intra-plantar iniciados em diferentes momentos relativos à infecçäo, permitiram observar menores índices de mortalidade, estatisticamente significantes, nos animais tratados com soro e vacina, 24 horas antes e 120 horas depois, independentemente dos títulos de anticorpos neutralizantes apresentados pelos animais dos diferentes grupos estudados. Quando da administraçäo de droga imunossupressora, verificou-se a presença de vírus rábico viável em animais tratados preventivamente contra a raiva, após o período de 120 dias da inoculaçäo.

Rabies and post-exposure prophylaxis in Thai children.

Thailand is an endemic area for rabies, with approximately 300 human deaths reported annually. More than half of the rabies patients are children under 14 years of age. This paper reports clinical data of paediatric rabies cases occurring from 1980 to 1986, and the protective efficacies of human diploid cell rabies vaccine (HDCV) and purified Vero cell rabies vaccine (PVRV) in children exposed to rabid animals. The analysis of 120 medical records revealed that rabies in children had incubation periods which ranged from less than fifteen days to more than three months, but generally between one to three months. The most frequent symptoms observed in the patients were hydrophobia, restlessness, fever, vomiting and aerophobia. Most of the rabid children admitted to hospital died within 24 hours. HDCV was administered to 50 children exposed to rabies with the cumulative dosages of 327 ml. All patients survived without serious adverse effects during a-two year follow-up. Mild reactions were seen in 1.5 percent (5/327 doses). Unfortunately, levels of rabies antibody in these vaccinees were not determined. Among another series of children exposed to rabid animals, comprising 27 individuals who received a total of 168 doses of PVRV, only mild local reactions were seen in 6 subjects. No rabies deaths were reported in 2 years of follow-up. The children who received PVRV either with or without human rabies immune globulin developed similar levels of rabies neutralizing (NT) antibody, which reached the high titers on day 30. At one year after the first dose of vaccination, all vaccinees still had NT antibody at titers higher than 0.5 IU/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Estudio hemodinamico del edema agudo pulmonar de altura

Se estudio la dinamica cardiocirculatoria durante la fase aguda del edema agudo pulmonar de altura (EAPA) en 5 residentes nativos de la altura que habian permanecido en el llano por mas de 4 semanas, en 3 pacientes se practico cateterismo cardiaco derecho de control 7 dias despues. Los hallazgos sugirieron que un estudio a largo plazo era necesario, el mismo que demostro una elevacion de las presiones arteriales pulmonares de los pacientes estudiados