Preprint: Pathology of Influenza A (H5N1) Infection in Pinnipeds Reveals Novel Tissue Tropism and Vertical Transmission.

 

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Note: CNN is reporting an (as yet) unconfirmed presumed positive human H5 case in Nevada (see Hogvet51's post).  Meanwhile . . . 

#18,609

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

The exact mechanisms behind these neurological manifestations are a matter of some debate, as seasonal flu viruses are generally regarded as being non-neurotropic.

Some researchers have posited that neurological symptoms may be due to neuroinflammation induced by the host's immune response. Regardless of the mechanism, we've seen seen evidence that some influenza viruses - particularly novel flu types - can be more neuroaffective than others.

Initially, H5N1 was considered primarily a respiratory disease, but in 2009 a PNAS study (see 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’.

Although there had been rumors of atypical presentations of H5N1 out of Indonesia & Vietnam, 5 years (2014) later we saw Canada's first imported case; a 28 y.o. nurse who died shortly after returning from Beijing. The following year we saw a study which described her infection as `neurotropic'.

The patient presented with `. . . pleuritic chest and abdominal pain . . . , this was followed by headache, confusion and, ultimately, respiratory failure, coma and death.' After reviewing MRI imaging and histological analyses, the authors wrote: `These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals'.

Also in 2015 a 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 warned of its neurotropic effects, and that it could pose a ` . . . significant threat to humans if these viruses develop the ability to bind human-type receptors more effectively.'

H5N1 went relatively `quiet' from 2016 to 2021, but a new subclade (2.3.4.4b) appeared in 2020 and began its world tour, reaching North America in 2021.  Since then we've seen numerous reports of enhanced neurotropism in mammals, including:

• In early 2023, a report on increased HPAI H5Nx spillover into mammalian species, with many displaying severe neurological symptoms prior to death (see Emerging Microbes & Inf.: Neurotropic HPAI H5N1 Viruses with Mammalian Adaptive Mutations in Free-living Mesocarnivores in Canada).

• Last August, in Preprint: Recent Bovine HPAI H5N1 Isolate is Highly Virulent for Mice, Rapidly Causing Acute Pulmonary and Neurologic Disease, a report on the B3.13 genotype. 
• And last December, a report out of South Dakota (see Emerg. Microbes & Inf.: Marked Neurotropism and Potential Adaptation of H5N1 Clade 2.3.4.4.b Virus in Naturally Infected Domestic Cats) describing profound neurological impacts on H5 infected cats. 

While we've been focused primarily on the H5 spillover into nearly 1,000 dairy herds across the nation, and 70+ human infections over the past 12 months, around the world a half billion birds, and (conservatively) tens of thousands of mammals, have died from the virus (see Nature Reviews: The Threat of Avian Influenza H5N1 Looms Over Global Biodiversity).

Many have exhibited profound neurological manifestations. 

We've previously looked at the  particularly hard-hit colonies of pinnipeds (seals, sea lions,  walruses) in South America (see Preprint: Massive outbreak of Influenza A H5N1 in elephant seals at Peninsula Valdes, Argentina: increased evidence for mammal-to-mammal transmission).

Today we've preprint, which highlights the neurotropism, systemic spread -, and apparent vertical transmission - of the H5N1 virus in pinnipeds in Argentina.  This is a lengthy, and at times technical, (37-page) report, so I've just included the abstract. 

Follow the link to read it in its entirety.  I'll return with  a postscript after the break. 

Pathology of Influenza A (H5N1) infection in pinnipeds reveals novel tissue tropism and vertical transmission.

Carla Daniela Fiorito, Ana Colom, Antonio Fernandez,Paula Alonso Almorox, Marisa Andrada, Daniel Lombardo, Eva Sierra

doi: https://doi.org/10.1101/2025.02.07.636856

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Abstract

In 2023, an unprecedented outbreak of highly pathogenic avian influenza (HPAI) H5N1 resulted in the death of thousands of pinnipeds along the Argentinean coast, raising concerns about its ecological and epidemiological impact. Here, we present clinical, pathological, and molecular findings associated with HPAI H5N1 infection in pinnipeds from Chubut, Argentina.

Necropsies were conducted on three South American Sea Lions (SASLs) (Otaria flavescens) and one Southern Elephant Seal (SES) (Mirounga leonina), followed by histopathological, immunohistochemical and RT-sqPCR analyses. Neurological clinical signs were observed in two SASLs, with one also exhibiting respiratory distress. Neuropathological findings included lymphoneutrophilic meningoencephalomyelitis and choroiditis, neuronal necrosis, gliosis, hemorrhages, and perivascular cuffing. Viral antigen was localized in neurons, glial cells, choroid plexus epithelial cells, ependymal cells, and the neuropil.

Systemic manifestations included HPAI-related necrotizing myocarditis in the elephant seal and placental necrosis in a sea lion, with fetal tissues testing positive for HPAIV. Pulmonary lesions were minimal, limited to bronchial glands in one individual. RT-sqPCR confirmed HPAI H5 in all tested animals.

Our findings highlight the neurotropism of HPAI H5N1 in pinnipeds, and expand the known systemic effects of the virus, revealing new tissue tropism and vertical transmission.

          (Continue  . . . ) 

While there are still more questions than answers, over the years we've looked at numerous studies (see here, here, and here)  linking severe and/or repeated viral infections (including flu) to a variety of neurological diagnoses later in life.

In 2023 we looked at a study (see Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks), which found statistical linkage between viral illnesses and developing neurodegenerative diseases in the future.

Whenever we talk about long-term sequelae from influenza, the mysterious decade-long epidemic of Encephalitis Lethargica (EL) that followed the 1918 pandemic always comes to mind (see The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?).

It is estimated that between 1 and 5 million people were affected with severe Parkinson's-like symptoms. While some scientists have suggested they may have been linked to the pandemic virus, others have pointed to a post-streptococcal immune response, or believe it was an aberrant autoimmune response, and dismiss the link with the 1918 pandemic.

The cause remains a mystery.

But throughout history, there have been reports of similar outbreaks, including febris comatosa which sparked a severe epidemic in London between 1673 and 1675, and in the wake of the 1889–1890 influenza pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared.

Much more recently, we've seen evidence that even a mild SARS-CoV-2 infection can sometimes produce persistent neurological manifestations (see NIH COVID-19 and the Nervous System).

So far, most of the human H5 infections in the United States over the past year have been uncharacteristically mild. 

But in a 2023 a study (see Cell: The Neuropathogenesis of HPAI H5Nx Viruses in Mammalian Species Including Humans) the authors warned that ` . . . highly pathogenic avian influenza (HPAI) H5Nx viruses can cause neurological complications in many mammalian species, including humans'.

Meaning that - until we know more - even a mild H5N1 infection is worth avoiding if at all possible.