Avian paramyxovirus type 1 (APMV-1) is a diverse group of viruses affecting birds worldwide, with outcomes ranging from asymptomatic infections to severe respiratory and neurologic diseases. The virulence of these viruses is contingent upon the specific strain and the avian species infected.
While humans are rarely affected, mild conjunctivitis has been the typical manifestation. In this article, we present a unique and tragic case of a fatal neurologic infection in a 2-year-old immunocompromised child in Australia caused by the pigeon variant of APMV-1 (PPMV-1).
Newcastle disease, caused by virulent strains of APMV-1, is a highly contagious zoonotic infection affecting both wild and domestic birds globally. APMV-1 is a negative-sense, single-stranded RNA virus belonging to the Orthoavulavirus genus within the Paramyxoviridae family. Strains of APMV-1 are classified into two classes (I and II) based on their fusion protein sequence. Notably, class II genotype VI strains, such as pigeon avian paramyxovirus type 1 (PPMV-1), are associated with high pathogenicity, and pigeons and doves serve as natural reservoirs.
Clinical Manifestations in Birds:
Newcastle disease in avian species can manifest with fatal central nervous system (CNS), respiratory, and digestive diseases, depending on the tropism of the specific strain. The wide variation in virulence among APMV-1 strains complicates the understanding and management of outbreaks.
While APMV-1 primarily affects birds, it has the potential to infect non-avian hosts, including primates such as humans and monkeys, as well as rabbits and pigs. In human cases, reported infections have historically presented as mild conjunctivitis, but severe cases leading to fatality have been documented.
The case we present involves a 2-year-old immunocompromised child in Australia who succumbed to a fatal neurologic infection caused by PPMV-1. This tragic incident underscores the significance of considering APMV-1, specifically the pigeon variant, as a potential etiological agent in neurologic conditions of undefined origin, especially in immunocompromised individuals.
Metagenomic sequencing and histopathological analyses played pivotal roles in identifying the causative agent in this case. The use of agnostic metagenomic sequencing methods is highlighted as a valuable tool in diagnosing infections with unclear etiologies. Such techniques facilitate the direct and timely targeting of diagnostic and therapeutic efforts.
Discussion: Unraveling the Complexities of APMV-1 in Human Infections
The documented history of human infections with avian paramyxovirus type 1 (APMV-1) traces back to 1942 in Australia, with subsequent cases reported globally, predominantly in the United Kingdom. While most cases have been mild and self-limiting, presenting as conjunctivitis, the emergence of fatal cases, particularly those caused by the pigeon variant of APMV-1 (PPMV-1), raises concerns about the virulence and potential severity of certain strains.
Human Cases and Fatality:
The rare occurrence of human deaths attributed to APMV-1, specifically PPMV-1, has been reported in the Netherlands, United States, China, and France. Notably, all fatalities resulted from the PPMV-1 strain, with cases displaying respiratory symptoms and succumbing to respiratory failure. In some instances, individuals had underlying immunosuppression, emphasizing the heightened risk in vulnerable populations. The parallels with the case presented in this study, involving a young girl with progressive seizures post-hematopoietic stem cell transplantation, underscore the potential for severe disease associated with PPMV-1 in contrast to other APMV-1 genotypes.
While a small number of human pegivirus (HPgV) reads were detected, the absence of clear evidence linking HPgV to neurotropism or human disease suggests that the child’s death was primarily attributed to encephalitis caused by overwhelming PPMV-1 central nervous system (CNS) infection. The significance of HPgV in this context remains uncertain, possibly representing passive transport into cerebrospinal fluid (CSF) due to its reported seroprevalence in the human population.
In birds, APMV-1 affects various tissues, causing diverse signs dependent on the viral strain. In the described human case, it is hypothesized that PPMV-1 infection initiated in the upper respiratory tract, subsequently progressing to the CNS. The transmission likely occurred through inadvertent contact with pigeon feces or infected fluids, given the stability of the virus in pigeon feces and its potential dispersal through windborne dust. The absence of seroprevalence data in humans underscores the need for further investigation into the relationship between exposure and disease development.
FIRES and Neurologic Impact:
The term Febrile Infection-Related Epileptic Syndrome (FIRES), characterizing an epileptic encephalopathy with intractable seizures following a febrile illness, was notably identified in this case. FIRES, typically affecting healthy children and young adults, has a high rate of sequelae, including cognitive impairment and refractory seizures. The association between avian viruses, particularly APMV-1, and FIRES has not been documented as of October 2023, highlighting the rarity and uniqueness of this case.
APMV-1 as Oncolytic Therapy:
In a surprising turn, APMV-1 strains have been explored in preclinical and clinical trials as oncolytic agents, demonstrating antitumor responses in various cancers. However, the study emphasizes the importance of considering the underlying virulence of APMV-1 genotypes, particularly the potential for devastating off-target effects such as CNS infections if PPMV-1 strains are employed. This revelation introduces a critical aspect for future research in oncolytic therapy involving APMV-1.
Metagenomics and Diagnostics:
This case highlights the pivotal role of metagenomics in diagnosing complex clinical cases. While early diagnosis may not have altered the clinical trajectory in this instance, integrating metagenomics into routine diagnostics can significantly impact patient outcomes. Metagenomic sequencing offers the ability to detect uncommon and novel pathogens, crucial in immunocompromised patients where a broad range of opportunistic pathogens must be considered. The broad scope of metagenomic methods, testing all known pathogens in a single sample, simplifies diagnostics and conserves sample volume, particularly essential for difficult-to-obtain sample types such as cerebral tissue.
Barriers and Challenges:
Despite its potential, incorporating metagenomic sequencing into routine diagnostics presents challenges. The cost and requirement for highly skilled staff, including bioinformaticians, are significant barriers. However, cloud-based metagenomic sequence classification software tools may alleviate these limitations. The potential for low-cost, robust testing could extend the use of metagenomics to lower-income and middle-income countries, enhancing diagnostic capabilities in various clinical settings. Careful sample handling to avoid contamination and nucleic acid degradation is imperative.
Incorporating pathogen-agnostic metagenomic testing into routine laboratory workflows holds promise for improved diagnostics and better responses to emerging disease threats, including zoonoses. This approach has the potential to uncover novel and emergent pathogens, expanding the breadth of infectious-disease diagnosis. Such advancements may pave the way for future targeted treatments and improved outcomes for patients with neurologic infections, presenting a transformative prospect in the realm of infectious disease diagnostics.
reference link : https://wwwnc.cdc.gov/eid/article/29/12/23-0250_article