Avian Flu Diary: OFID: Central Nervous System Involvement by Novel Clade 2.3.2.1e H5N1 Avian Influenza Virus in a Paediatric Patient

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While seasonal flu can occasionally cause neurological symptoms (see 2018's Neuroinfluenza: A Review Of Recently Published Studies) it is relatively rare, and usually only results in mild, and transient symptoms.

Similarly, avian influenza typically presents as a pulmonary infection, but over the past 2 decades we've seen growing evidence of neurological involvement as well.

A few early reports include:

A 2009 PNAS study (Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration ) found that the H5N1 virus was highly neurotropic in lab mice, and in the words of the authors `could initiate CNS disorders of protein aggregation including Parkinson's and Alzheimer's diseases’.

Six years later - following the 2014 death of the first imported H5N1 case in Canada - we saw a study (see CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada), where the authors wrote: `These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals'.

In a 2015 Scientific Reports study on the genetics of the H5N1 clade 2.3.2.1c virus - Highly Pathogenic Avian Influenza A(H5N1) Virus Struck Migratory Birds in China in 2015 – the authors described its neurotropic effects, and warned that it could pose a ` . . . significant threat to humans if these viruses develop the ability to bind human-type receptors more effectively.'

HPAI H5Nx's threat largely receded between 2016-2020, but since 2021 has been on the ascendent again, primarily due to highly successful clades like 2.3.4.4b and 2.3.2.1c/e. Along with this renewed vigor we've also seen a rise in reports of neurological manifestations:

CDC EID Journal: Encephalitis and Death in Wild Mammals at An Animal Rehab Center From HPAI H5N8 - UK

Ontario: CWHC Reports HPAI H5 Infection With Severe Neurological Signs In Wild Foxes (Vulpes vulpes)

In 2022, in Clinical Features of the First Critical Case of Acute Encephalitis Caused by Avian Influenza A (H5N6) Virus, we saw the first known case of neuroinfluenza in an H5N6 patient; a 6-year-old girl who was admitted to a hospital with mild pneumonia - but severe encephalitis - in January of that year.

The following year, in Cell: The Neuropathogenesis of HPAI H5Nx Viruses in Mammalian Species Including Humans, we looked at an excellent review of recent surge in neurological infections reported in mammals and humans.

Highlights
Highly pathogenic avian influenza (HPAI) H5Nx viruses can cause neurological complications in many mammalian species, including humans.

Neurological disease induced by HPAI H5Nx viruses in mammals can manifest without clinical respiratory disease.

HPAI H5Nx viruses are more neuropathogenic than other influenza A viruses in mammals.

Severe neurological disease in mammals is related to the neuroinvasive and neurotropic potential of HPAI H5Nx viruses.

Cranial nerves, especially the olfactory nerve, are important routes of neuroinvasion for HPAI H5Nx viruses.

HPAI H5Nx viruses have a broad neurotropic potential and can efficiently infect and replicate in various CNS cell types.

Vaccination and/or antiviral therapy might in part prevent neuroinvasion and neurological disease following HPAI H5Nx virus infection, although comprehensive studies in this area are lacking.

Even the relatively mild `bovine' H5N1 strain (B3.13) has been shown to have neurotropic qualities (see Preprint: Recent Bovine HPAI H5N1 Isolate is Highly Virulent for Mice, Rapidly Causing Acute Pulmonary and Neurologic Disease), at least in mice.

Thirteen months ago (April 2025) we saw a preliminary report on a neuroinvasive infection in an 8-y.o. girl (see Vietnam: Ho Chi Minh DOH Reports A Rare H5N1 Encephalitis Case In a Child), which reported:

As noted by infectious experts, this is a rare case in which the A/H5N1 avian influenza virus damages the central nervous system and does not attack the respiratory tract.

While much of the following report will be primarily of interest to clinicians, we have a detailed follow up on the Vietnamese case. Follow the link to read it in its entirety.

Central Nervous System Involvement by Novel Clade 2.3.2.1e H5N1 Avian Influenza Virus in a Paediatric Patient

Phung Nguyen The Nguyen , Nguyen Thanh Hung , Ngo Ngoc Quang Minh , Nguyen Thi Thu Hong , Nguyen Thi Thanh Huong , Cao Minh Hiep , Le Nguyen Thanh Nhan , Tran Van Dinh , Du Tuan Quy , Tran Thanh Thuc
Open Forum Infectious Diseases, ofag283, https://doi.org/10.1093/ofid/ofag283

Published: 07 May 2026

Novel clade 2.3.2.1e A(H5N1) virus was detected in cerebrospinal fluid but not in respiratory,rectal-swab and blood samples of an eight-year-old boy presenting with meningoencephalitis without respiratory symptoms. Cerebrospinal fluid A(H5N1)-hemagglutinin-specific antibody levels were higher than that of sera. Clinicians should be aware of emerging clade 2.3.2.1eA(H5N1) associated meningoencephalitis.

(SNIP)

A(H5N1)-associated CNS infection in humans has rarely been reported but typically present as a complication, following respiratory symptoms [3-5]. Notably, our patient presented with meningoencephalitis in the absence of respiratory symptoms. Additionally, unlike the previously reported patients, who had viral RNA detected in both CSF and non-CSF samples [3-5], our patient only had viral RNA detected in serial CSF samples in the absence of viral RNA detected in urine, blood, rectal swab and respiratory samples.

Low respiratory-tract viral loads, transient viral replication in the respiratory tract, and/or delayed sample collection (illness day 6 onward) might explain the negative PCR findings in non-CSF samples, including the endotracheal aspirate sample.

Notably, HPAI A(H5N1) viruses can infect human respiratory tissues by binding to receptors bearing sialic acids linked to galactose by α2,3-linkages, which are found in the lungs and lower respiratory tract, supported by the chest radiograph findings suggestive of lower left lung pneumonia.

(SNIP)

In summary, we report on a HPAI A(H5N1) infection in a child presenting with meningoencephalitis in the absence of respiratory symptoms. Viral RNA was detected in cerebrospinal fluid but not in respiratory, rectal-swab and blood samples.
Testing for IAV and A(H5N1) virus should be considered in patients presenting with CNS infection with a history of exposure (e.g. dead poultry). Clinicians should be aware of meningoencephalitis associated with A(H5N1) infection in the absence of respiratory symptoms.

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Not only can these neurological complications prove quite serious, atypical presentations can significantly delay proper diagnosis, isolation, and treatment.