A previously healthy 26-year-old man returned to Paris, France, from Mecca, Saudi Arabia, and sought care in January 2025 after 4 days of fever, myalgia, headache, abdominal pain, and diarrhea. On admission to the intensive care unit he was febrile (40°C) with tachypnea, poor tissue perfusion, oliguria, conjunctival hemorrhage, and hematuria. Cardiopulmonary, abdominal, and neurologic examinations were otherwise unremarkable.
Despite prompt fluid resuscitation and escalation of broad-spectrum antimicrobial therapy, the patient rapidly developed multiple organ dysfunction syndrome. Clinical and laboratory features included hypotension, purpuric livedo, anuria, acute kidney failure (creatinine 600 μmol/L), elevated lactate (4.4 mmol/L), and severe hepatic dysfunction with alanine aminotransferase and aspartate aminotransferase values exceeding 100 times the upper limit of normal and factor V at 51%. Hemostasis abnormalities were consistent with disseminated intravascular coagulation: thrombocytopenia (29 × 10^9/L), decreased prothrombin time (52%), and reduced hematocrit (39%). Inflammatory biomarkers were markedly elevated (C-reactive protein 320 mg/L; procalcitonin 136 µg/L). Body computed tomography was unremarkable.
Routine etiologic testing performed on premortem samples included PCR for malaria, SARS-CoV-2, influenza, cytomegalovirus, Ebola virus, Zika virus, and chikungunya virus and serology for HIV and hepatitis A, B, C, and E; all results were negative. Initial blood PCR and IgM/IgG serology for dengue virus (DENV) were also negative. The patient experienced refractory shock and fulminant hepatitis and died 36 hours after hospital admission.
Postmortem analyses were performed after the patient’s death. Urine tested positive for dengue RNA by quantitative reverse transcription PCR with a pan-dengue cycle threshold (Ct) of 39 and a DENV-1–specific Ct of 40; both assays produced robust fluorescence curves. Serum was positive for dengue NS1 antigen with a reported positivity ratio of 2.5 by the VIDAS Dengue NS1 assay. A postmortem liver biopsy showed normal architecture by Sirius red staining but extensive parenchymal necrosis on hematoxylin and eosin without viral inclusions.
Metagenomic shotgun next-generation sequencing (mNGS) performed on plasma and liver biopsy samples detected extremely high levels of reads matching avian orthoavulavirus 1 (AOAV-1) (191,718 reads per million in liver tissue and 244,781 reads per million in plasma). Complete coverage of all AOAV-1 coding sequences was obtained and deposited (GenBank accession no. PX575854). Specific real-time PCR subsequently confirmed AOAV-1 presence in multiple specimen types: liver biopsy (Ct 17.23), plasma (Ct 15.74), premortem urine (Ct 18.23), sputum (Ct 18.5), and cerebrospinal fluid (Ct 35.9), consistent with a disseminated infection.
Phylogenetic analysis classified the AOAV-1 strain as clade II, genotype VI, subgenotype VI.2.1.2 — a lineage historically associated with pigeons and referred to as pigeon paramyxovirus type 1. The viral fusion protein carried a polybasic, velogenic cleavage site motif (RRRKRF). The authors note that velogenic AOAV-1 variants are defined by a polybasic fusion-protein cleavage site that permits broader protease activation and systemic multiorgan tropism, in contrast to low-virulence strains that remain largely confined to respiratory and enteric tracts.
AOAV-1 viral loads were high across tested compartments (plasma, liver, urine, sputum), as reflected by low Ct values on confirmation PCR, indicating active and disseminated replication at the time of sampling. By contrast, evidence for dengue virus was limited to low-level RNA detection in urine (high Ct values) and circulating NS1 antigen; mNGS on liver biopsy did not detect DENV sequences.
Plasma cytokine profiling demonstrated an extreme systemic interferon and proinflammatory response. Single-molecule array digital-ELISA measurement showed very high type I interferon concentrations with IFN-α and IFN-β reported at greater than 10^4 pg/mL. Multiplexed Luminex assays documented markedly elevated IFN-γ, CXCL10, CXCL11, interleukin 6 (IL-6), and tumor necrosis factor–α (TNF-α). The pattern is consistent with a profound innate immune activation and hyperinflammatory state concurrent with disseminated viral infection.
This report describes a fulminant fatal febrile illness in a young, previously healthy traveler with two notable virologic findings: low-level evidence of dengue virus infection and unexpectedly high-titer, disseminated AOAV-1 infection. The clinical team could not definitively determine the relative contribution of each virus to the patient’s rapid deterioration and death.
However, the magnitude of AOAV-1 detection — extremely high mNGS read counts in liver and plasma, complete genome recovery, and low Ct values across multiple tissues and fluids — provides strong evidence that AOAV-1 played a major pathogenic role. The AOAV-1 genotype identified belongs to a pigeon-adapted, velogenic lineage with a polybasic fusion-protein cleavage site associated with systemic tropism in animal hosts.
The case highlights several important points for clinicians and laboratorians: severe, rapidly progressive febrile illness may reflect unexpected zoonotic or avian viral pathogens; metagenomic sequencing can identify unexpected high-burden pathogens when standard panels are negative; and profound interferon and cytokine responses may accompany disseminated AOAV-1 infection in humans. The authors underscore that causality between coinfecting agents may be difficult to attribute definitively and that this single case documents an uncommon, severe human infection with a velogenic avian orthoavulavirus along with concurrent evidence of dengue infection.