A little-known Old World virus in southern African capable of causing serious illness in horses appears to be the cause of neurological disease in some people, researchers report.
Isabel Fourie and her fellow researchers, writing in the journal PLOS Neglected Tropical Diseases, acknowledge that the Middelburg virus is not well known.
New World alphaviruses are associated with severe neurological disease in humans and horses in the Americas, with a high mortality rate. Middelburg virus is an Old World alphavirus previously associated with neurological disease and fatalities in horses and wildlife in southern Africa, but not yet linked to disease in humans.
The first indication that Middelburg virus could cause severe disease in animals was following its isolation from the spleen of a horse in Zimbabwe that died in 1993 after presenting with clinical signs resembling African Horse Sickness. Signs included a fever, high heart rate, lung problems and swelling, particularly in the head and neck.
Different studies from South Africa between 2008 and 2013 further linked Middelburg virus and Sindbis virus infections with fevers and neurological disease in horses and wildlife. These cases have included fatalities, with Middelburg virus being detected in brain specimens from several horses.
The researchers say findings from southern Africa on Middelburg virus suggest a wide host range, and historic reports of seropositivity in humans point to its potential to infect people.
Fourie and her fellow researchers set out to investigate Middelburg virus and other alphaviruses’ possible association with acute neurological cases in humans in the Gauteng province of South Africa, where numerous horse cases were previously detected.
They carried out a laboratory-based study, using stored cerebrospinal fluid submitted to the National Health Laboratory Service for viral investigation from public sector hospitals in Gauteng. The samples had been taken from people affected by fever and neurological problems. They also tested two blood samples from veterinary students who had been similarly affected.
Molecular-based methods were employed to test all the samples.
Evidence of Middelburg virus was detected in 3 of the 187 cerebrospinal fluid specimens, as well as in one of the two tested blood samples from the vet students.
Full genome sequences were obtained from two cases: One from the whole blood sample from the vet student affected by the virus, and another from one of the cerebrospinal fluid samples which came from a two-year-old child. The boy had been admitted to hospital with seizures, fever, diarrhoea, and vomiting.
The 24-year-old female veterinary student had been affected by a cough, fever, neck stiffness, muscle pain, nausea, and severe headaches. She was diagnosed and treated for tick bite fever although this was not confirmed with laboratory tests. A blood sample taken two weeks after onset of her initial symptoms tested positive for Middelburg virus and negative for 31 other pathogens associated with fever and neurological signs.
The researchers said their detection of Middelburg virus in the cerebrospinal fluid of patients with neurological problems suggests that the virus should be investigated as a human pathogen with the potential of causing or contributing to neurological signs in children and adults.
In all, evidence of Middelburg virus infection was confirmed in 2% of the cases investigated.
Discussing their findings, the researchers said the traditional view of Old World alphaviruses being associated with less severe symptoms than the New World alphaviruses has been challenged by cases of Chikungunya virus infection resulting in severe neurological illness.
The Old World Middelburg and Sindbis alphaviruses have also been shown to be associated with severe neurological problems and even fatalities in horses and other animals from southern Africa.
The authors said their findings suggest that Middelburg virus is able to cross the blood-brain barrier, which may contribute to the severity of observed neurological problems in these patients.
One of the four positives for the virus was an HIV-positive male, they noted. “Given the high burden of HIV in a South African setting, a large proportion of the population is immunocompromised and thus may be more vulnerable to severe disease following viral infections and potentially change the pathogenic potential for previously neglected endemic arboviruses,” they wrote.
They said future investigations aim to identify cases in those with a mild fever as part of a prospective active surveillance study enrolling patients with fevers of unknown origin, with or without neurological signs.
“Middelburg virus should also be investigated elsewhere in Africa and in cases of fever of unknown cause to define the disease spectrum,” they said.
The study team comprised Fourie, June Williams and Marietjie Venter, with the University of Pretoria; Arshad Ismail, with the National Institute of Communicable Diseases in South Africa; Petrus Jansen van Vuren, with the Australian science agency CSIRO; and Anton Stoltz, with Steve Biko Hospital in Pretoria.
Fourie I, Williams J, Ismail A, Jansen van Vuren P, Stoltz A, Venter M (2022) Detection and genome characterization of Middelburg virus strains isolated from CSF and whole blood samples of humans with neurological manifestations in South Africa. PLoS Negl Trop Dis 16(1): e0010020. https://doi.org/10.1371/journal.pntd.0010020