Abstract
We report the first case of human rabies in a child from Amazonas after 10 years without an outbreak. An 8-year-old girl was admitted to the local hospital because of headache, myalgia, diarrhea, fever, and vomiting during the previous 4 days. Meningoencephalitis was suspected, and empiric therapy with ceftriaxone and vancomycin was started. However, in the following 3 days, she also presented progressive lower extremities weakness, behavioral changes, photophobia, irritability, sialorrhea, and hallucinations. Thus, she was transferred to our hospital. Phenytoin, dexamethasone, mannitol, and acyclovir were started, and ceftriaxone was continued. Five days later, the mother recalled that the patient was bitten by a feral cat. Thus, human rabies immunoglobulin serum was administered immediately. However, 2 days later, the patient died. Post-mortem brain direct immunofluorescence study confirmed human rabies. Awareness campaigns can be lifesaving since more than 99% of deaths can be prevented if timely treatment is provided.
Introduction
Human rabies is caused by lyssaviruses of the family Rhabdoviridae, which are RNA viruses that infect humans most often through rabid animal bites and not human-to-human transmission.1,2 This disease leads to acute progressive encephalitis and, in most cases, death.1,2
Rabies infects humans through a bite by an infected mammal, predominantly carnivores and bats. 1
In Peru, we have a nationwide surveillance system that reports, among other diseases, cases of urban human rabies and human rabies transmitted by wild animals.
Due to a high rabies incidence rate in the Amazonas region of Peru, a pre-exposure vaccination campaign was performed in 2011. 3 Since then, rabies cases have progressively disappeared. There were no reports of rabies in the Amazonas region from 2013 to 2023. 4
After a decade without an outbreak, healthcare providers can easily decrease their index of suspicion for human rabies, especially in pediatric patients. This lack of awareness of the disease may lead to a diagnosis delay, thus increasing the risk of disease transmission in the community. In 2024, López et al 3 published a letter to the editor which briefly reported an outbreak in the Amazonas region. That report focused on the genetic testing of the rabies virus causing the outbreak. 3
We aim to describe the clinical course of the first case of human rabies in the Amazonas region after 10 years without an outbreak, which was a child who on admission apparently had no history of an animal bite. We also discuss the delays in the diagnosis and the importance of maintaining a high degree of suspicion of this disease in patients with an unexplained altered level of consciousness and progressive neurological deterioration, even when there is no apparent history of an animal bite.
Case Report
An 8-year-old girl from Bagua Grande district, Amazonas region, without previous relevant diseases was admitted to the Bagua Grande Hospital with complaints of headache, myalgia, diarrhea, fever and vomiting during the previous 4 days. She also had backache during the 10 days before admission. On admission, the patient presented an altered level of consciousness (Glasgow Coma Scale of 10) and no motor deficits. The only family member who accompanied the girl to the hospital was her father, who denied that the child had been bitten by an animal or exposed to organophosphates or heavy metals. The initial laboratory tests showed leukocytosis, neutrophilia and negative brucella, typhoid and paratyphoid serology. Meningoencephalitis was suspected and empiric therapy with ceftriaxone and vancomycin was started the day of admission. However, during the following 3 days, the patient presented progressive lower extremity weakness, behavioral changes, photophobia, irritability, sialorrhea and hallucinations. Because of the neurological deterioration the patient was transferred to our hospital.
The patient’s Glasgow Coma Scale (GCS) decreased to 8 during air transport to our hospital. Thus, she was intubated to secure the airway and received mechanical ventilation during the flight. On admission to our hospital the patient was dehydrated, had pinpoint pupils with normal pupillary light response, nuchal rigidity and no apparent signs of focal neurological deficits.
The patient was transferred to the Pediatric Intensive Care Unit (PICU) soon after admission to our hospital. Intravenous therapy with phenytoin, dexamethasone, mannitol and acyclovir was started and treatment with ceftriaxone was continued. A brain CT without contrast was also obtained on admission, which showed bilateral parietotemporal edema with no midline shift. Magnetic resonance imaging was not available in our hospital at that moment. A cerebrospinal fluid biochemical and microbiological study was performed, and results are shown in Table 1. Based on these results, viral or autoimmune encephalitis was suspected. However, we did not have access to autoimmune encephalitis antibody testing. Laboratory blood tests during PICU are detailed in Table 2.
Cerebrospinal Fluid Findings.
Abbreviation: RT-PCR, real-time polymerase chain reaction.
Laboratory Blood Tests During PICU Hospitalization.
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase, Ca, calcium (total); Cr, creatinine; CRP, C-reactive protein; GGT, gamma-glutamyl transpeptidase; Hb, hemoglobin; INR, International Normalized Ratio; K, potassium; Na, sodium; PT, prothrombin time; PTT, partial thromboplastin time; PLT, platelet count; WBC, white blood cell count.
On the 3rd day, sedation was weaned off to evaluate the neurological state of the patient. Twelve hours later she presented a generalized tonic-clonic seizure (GTCS) that ceases with benzodiazepines. A methylprednisolone pulse was administered due to the possibility of autoimmune etiology.
On the 4th day, another GTCS occurred, and phenobarbital was added. Later the same day, in a phone interview with the patient’s mother, she recalled having travelled to a faraway town with the girl 12 days before the start of symptoms. During the trip, the patient was bitten by a feral cat in her right hand and the child’s 10-year-old cousin was also bitten in the knee. The patient’s father did not know the children were bitten by an animal. None of the children had ever been vaccinated against rabies. After asking for the clinical condition of the patient’s cousin, we found out that she also presented with headaches and fever 2 days after the first symptoms of our patient. The diagnosis of probable human rabies was considered, and human rabies immunoglobulin serum was administered immediately.
On the 5th day, the patient had hypotension, bradycardia, mydriatic pupils, diabetes insipidus and electrolyte disbalances. Thus, inotropes and electrolyte management were started. A saliva sample was obtained for rabies virus RT-PCR testing, which yielded a negative result.
On the 6th day, hypotension, oliguria and prolonged capillary refill were evident despite hemodynamic management. The next day, the patient died. Post-mortem brain direct immunofluorescence study confirmed the diagnosis of human rabies. The detail about the genetic testing of the rabies virus identified can be found in a previous publication by López et al. 3
The patient’s cousin died 10 hours after our patient’s death in a healthcare facility of the Amazonas region. Rabies virus antibodies were found in the cerebrospinal fluid of the patient’s cousin. 3 Thus, rabies was also considered her cause of death.
Discussion
Around the world, thousands die each year because of rabies. 5 However, many people die at home undetected by epidemiological surveillance systems. 5 Thus, the real burden of this disease is unknown. 5
The disease spreads from animals to animals and from animals to people. 6 Specifically, rabies infects humans through a bite by an infected mammal, predominantly carnivores and bats. 1 In South America, rabies-transmitting animals are mainly vampire bats and dogs. 6 Desmodus rotundus occurs throughout South America, from northern Mexico to northern Argentina and Chile. 7 This bat is the main reservoir of the virus in Peru 8 and feeds on several types of animals, mainly cattle. 7 Other species attacked by this bat include horses, chickens, goats and pigs. 7
Pathogen isolation studies from cat bites show that the most frequent microorganism is Pasteurella multocida. 9 However, depending on the geographical area, rabies transmission might be an important risk. 9 Stray and feral cats usually lack anti-rabies vaccinations, and they may be exposed to bat-borne rabies due to the overlap of habitats and cats’ hunting habits. 10 Cats are considered dead-end hosts. 10 Thus, human rabies transmitted by cats is very unusual. 10
After being bitten by an animal with rabies, symptoms frequently start between 30 and 90 days later. 6 Rabies manifests mostly as an encephalitis or as a paralysis. 11 Some authors suggest the disease has three clinical stages in humans: prodromal, excitation and paralysis. 6 Rabies encephalitis is characterized by hallucinations, disorientation, bizarre behavior, hyperexcitability, autonomic dysfunction and hypersalivation. 11 Paralysis is preceded by weakness in the bitten extremity. 11 Hydrophobia occurs in 50% of patients. 11 Brain death occurs before cardiac arrest and failure of vegetative functions. 5 Death is caused by cardiac dysfunction, respiratory failure or autonomic dysfunction. 11 Our patient exhibited symptoms that were compatible with those described in the literature.
Blood tests during the hospitalization of our patient showed increased sodium, alanine transaminase, aspartate transaminase, alkaline phosphatase and gamma-glutamyl transpeptidase. Hypernatremia was caused by diabetes insipidus, which has been reported in human rabies patients. 12 The increase in the rest of the mentioned laboratory parameters was attributed to multiple organ failure, which is very common in patients who are aggressively managed in critical care units. 12 CSF findings in our patient included pleocytosis, normal glucose and increased protein levels, all of which has also been reported in human rabies patients. 12
There are two types of vaccination against rabies: pre-exposure and post-exposure. 2 When a person receives both vaccines, the effectiveness is high, with no reported deaths. 2 However, there is a case report of a fatal case of rabies in a patient who had only the pre-exposure vaccine. 2
Pre-exposure prophylaxis consists of the application of vaccines that can be co-administered with others in children or can be applied separately. 2 This prophylaxis involves applying three intramuscular or intradermal doses on days 0, 7, and 28. 2 The purpose is to generate memory in the immune system in case it is exposed to a virus resulting from the bite of a rabid animal. 2
In Peru, the Guidelines for the Surveillance, Prevention, and Control of Rabies from the Ministry of Health state that vaccination against rabies before exposure (pre-exposure prophylaxis) should be done in people who work in areas at risk of the presence of the rabies virus, as well as people who travel to those areas, veterinarians who work with animals susceptible to transmit rabies and all people who live in areas where the presence of the rabies virus is confirmed. 13
According to the World Health Organization and Robert Koch Institute guidelines, suspected rabies exposure is defined as a mammal’s bite, scratch or licking of a wound or mucous membrane. 1 Rabies exposure can be defined as the contact of an individual’s broken skin or intact mucous membrane with the saliva of a rabid animal. 2 When this happens, post-exposure prophylaxis is given to the patient. 2
All wounds need proper irrigation and cleaning with an antiseptic (povidone-iodine, mercurochrome, 70% alcohol, 1% to 4% benzalkonium chloride or 1% centrimonium bromide).6,11 Moreover, as in similar wounds, tetanus vaccination must be updated if necessary. 11
The current standard of post-exposure prophylaxis includes active immunization (rabies vaccine) and passive immunization (human rabies immunoglobulin), which is the same for both adult and pediatric patients.1,2 The vaccine most used is the inactivated or killed rabies virus vaccine. 2 Non-immunized people should receive rabies vaccine according to the Institut Pasteur du Cambodge (intradermal on days 0-0-3-7), Essen (intramuscular on days 0-3-7- and a fourth dose between days 14 and 28) or Zagreb (intramuscular on days 0-0-7-21) regimen.1,14 Rabies immunoglobulin is administered in a dose of 20 UI/kg body weight very closely around the wound as soon as possible, no more than 7 days after exposure, and the rest can be given intramuscularly (ideally in the vastus lateralis muscle).1,6 According to WHO guidelines, the intramuscular injection of the remainder immunoglobulin is not mandatory except for a high likelihood of additional small wounds, exposure to a bat or in case of nonbyte exposures (eg, aerosols). 14 If the injection of the remaining immunoglobulin is indicated, it needs to be given as close as possible to the presumed exposure site. 14 The efficacy of post-exposure prophylaxis increases when administered soon after exposure and decreases once rabies symptoms appear. 2 Unfortunately, 16 days after the exposure passed until a mammal bite was confirmed in our patient, and 8 days passed after the onset of symptoms. Thus, it was too late to administer post-exposure prophylaxis effectively.
In people with immunosuppression, post-exposure prophylaxis should consist of a 5-dose vaccine regimen (days 0, 3, 7, 14, and 28), considering that despite applying a fifth dose the immune response may still be inadequate. 15
Clinical rabies has nearly universal mortality. 5 Thus, treatment strategies available are not effective. 11 Up to only 20 survivor cases worldwide have been reported. 11 Management strategies in symptomatic patients include supportive/palliative therapy or an aggressive/intensive care treatment. 11 If intensive care is available, these patients should receive it since recovery is possible (albeit very rarely). 16 Palliative care is imperative and the only option when medical, logistical or financial reasons make intensive care not feasible. 16
The Milwaukee Protocol is a treatment strategy that has been used in at least 10 survivor cases, all of whom were 4 to 17 years old. 11 This protocol includes holding back vaccine and immunoglobulin, antivirals, deep sedation, vasoconstriction management and electrolyte disturbances correction. 11 The original protocol involved the use of ketamine, midazolam, phenobarbital, amantadine and ribavirin. 5 Later, this protocol was modified; for example, ribavirin is no longer used. 5 Despite the efforts, the success of the Milwaukee protocol in the case of a girl with rabies in 2004 has not been effectively reproduced. 5 Corticosteroids and immunosuppressives are not recommended since they could inhibit viral clearance, accelerating symptom onset and death. 5 Once a mammal bite was confirmed, our patient already had clinical rabies. Thus, supportive therapy following several Milwaukee Protocol recommendations was given (ie, vaccine withholding, immunoglobulin, anticonvulsant therapy, electrolyte management, sedation). However, the patient died. Amantadine was not available in our hospital.
Inducing coma via intravenous anesthetic agents impairs the neurological examination, leads to vasopressor dependency, and is associated with intensive care unit mortality. 17 The Milwaukee protocol justifies sedation therapy to prevent fatal consequences related to autonomic instability in rabies. 17 However, some authors claim that no scientific evidence supports that statement. 17 Thus, sedation is controversial in patients with rabies. Our patient’s GCS was decreased on admission to our hospital. Therefore, given the risks of over-sedation in our patient, cautious sedation or avoiding sedation at all were both possible choices since there is no consensus yet.
According to some authors, most experts recommend offering only palliative strategies and avoiding expensive and probably futile efforts. 5 Palliative treatment includes calm and quiet conditions; oral care and giving foods with high water content such as fruits instead of water (due to hydrophobia); intravenous fluid hydration; antipyretics; benzodiazepines, haloperidol or chlorpromazine for anxiety, agitation and seizures; anticholinergics for hypersalivation and uncoordinated swallowing; and opioids such as morphine and fentanyl for pain management. 5
Awareness campaigns increase people knowledge about the disease and vaccination schedules, which can be lifesaving. 2 Knowing when and how to manage potential exposures can prevent more than 99% of deaths if treatment is provided early after exposure. 11
Conclusion
Rabies is fatal if appropriate management is not ensured for suspected or confirmed cases of rabies exposure. In addition, public health strategies are essential to prevent new cases. Within these strategies, it is vital to do surveillance not only in areas at risk of rabies but also in areas where the virus was present and now appears to be absent. It is also important to keep awareness among populations that geographically are at greater risk or were at risk of being exposed to rabid animals, so they give great importance to any bite by a domestic or wild animal. Public health strategies can avoid fatal outcomes like the one described in our case report.
Footnotes
Acknowledgements
We thank Dr. Ruth Elizabeth Chávez-Nomberto for her useful comments and suggestions on the manuscript.
Authors’ Note
Author Contributions
KC contributed to the conception, formulation, data collection, and drafting of the article. WP, HV, and MV participated in writing and revising the final manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.
Data Availability Statement
Anonymized data for the purpose of medical research or teaching can be requested from the Department of Pediatrics at Hospital Nacional Dos de Mayo, Lima, Peru.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval and Consent
Patient information was obtained with the written informed consent of the patient’s father. The Institutional Ethics Review Board of the Hospital Nacional Dos de Mayo approved this report (Ethical Approval Code: 085-2024-CEIB-HNDM).
