Fatal dual-viral infection emerged after return from Mecca
A previously healthy 26-year-old man returned to France from Mecca and died 36 hours after hospital admission with hemorrhagic fever, fulminant hepatitis, shock, and disseminated intravascular coagulation. Postmortem testing found low-level evidence of dengue virus infection, but the dominant signal came from an unexpected diagnosis: disseminated avian orthoavulavirus 1 at extremely high levels in blood, liver, urine, sputum, and cerebrospinal fluid. The clinical picture was severe enough to mimic other high-consequence tropical and viral hemorrhagic illnesses, yet routine testing for malaria, Ebola virus, Zika virus, chikungunya virus, influenza, SARS-CoV-2, and hepatitis viruses was negative.
The case matters because the illness did not unfold like ordinary traveler’s fever. It moved quickly from febrile syndrome to multiorgan failure, and the laboratory profile tracked that collapse with unusual intensity. Fever reached 40°C, respiratory rate climbed to 45 breaths per minute, and perfusion deteriorated despite early fluid resuscitation and empirical antimicrobials. Conjunctival hemorrhage and hematuria appeared early, followed by anuria, creatinine of 600 μmol/L, lactate of 4.4 mmol/L, and massive hepatic injury with alanine aminotransferase and aspartate aminotransferase more than 100 times the upper limit of normal. Factor V fell to 51%, prothrombin time to 52%, and platelets to 29 × 10^9/L.
The bedside syndrome pointed to catastrophic systemic vascular and inflammatory injury. Purpuric livedo, refractory shock, and disseminated intravascular coagulation signaled a body-wide failure of endothelial and coagulation control, the kind of pattern seen when viral injury is not limited to a single organ compartment. C-reactive protein reached 320 mg/L and procalcitonin reached 136 µg/L, reinforcing the impression of explosive inflammation rather than an isolated hepatic process. Computed tomography did not reveal a structural explanation, leaving infection as the only coherent driver of the collapse.
Low-level dengue evidence contrasted with massive avian paramyxovirus burden
Initial blood testing for dengue was negative by PCR and by IgM and IgG serology, and metagenomic analysis of liver tissue did not detect dengue at the time of death. Postmortem reassessment changed the picture only partially: urine later tested positive by quantitative reverse transcription PCR for dengue at very low levels, with cycle thresholds of 39 on a pan-dengue assay and 40 on a dengue-1–specific assay, both with a robust fluorescence curve. Serum also tested positive for dengue NS1 antigen with a positivity ratio of 2.5. Those findings support dengue infection, but they do not explain the violence of the syndrome on their own.
The much stronger signal came from metagenomic shotgun next-generation sequencing, which detected avian orthoavulavirus 1 at 191,718 reads per million in liver tissue and 244,781 reads per million in plasma. Complete coverage of the viral coding sequence was obtained, and phylogenetic analysis placed the strain in clade II, genotype VI, subgenotype VI.2.1.2. The fusion protein cleavage site carried the multibasic motif RRRKRF, a signature of velogenic avian orthoavulavirus 1. In avian disease, that cleavage pattern is what permits systemic spread; in human tissue, it offers a biologically plausible route to multiorgan dissemination rather than localized respiratory or ocular disease.
Disseminated infection tracked across multiple body fluids and tissues
Real-time PCR confirmed avian orthoavulavirus 1 in postmortem liver biopsy with a Ct of 17.23, plasma with a Ct of 15.74, premortem urine with a Ct of 18.23, cerebrospinal fluid with a Ct of 35.9, and sputum with a Ct of 18.5. Those values are consistent with widespread dissemination, not incidental contamination or a localized upper-airway infection. The liver biopsy showed normal architecture with extensive parenchymal necrosis and no viral inclusions, a pattern compatible with fulminant injury in the absence of a classic inclusion-body signature.
The liver may have been the organ where the systemic process became clinically impossible to reverse. Severe hepatocellular necrosis, coagulopathy, and shock developed in parallel, suggesting that hepatic failure was not merely a downstream complication of hypotension. Instead, the laboratory and tissue findings fit with direct viral injury plus an overwhelming host response. The absence of an alternate infectious diagnosis narrows the list sharply.
Cytokine storm and interferon excess likely amplified organ failure
Plasma immune profiling showed extremely high levels of IFN-α and IFN-β, both above 10^4 pg/mL, along with very high IFN-γ, CXCL10, CXCL11, interleukin 6, and tumor necrosis factor-α. This pattern is not a routine inflammatory blip. It reflects a cytokine storm dominated by type I and type III interferon signaling and downstream chemokine recruitment, the kind of immune surge that can drive endothelial dysfunction, capillary leak, microvascular thrombosis, and collateral tissue injury. In practical terms, the host response itself likely became a major injury pathway.
Human avian orthoavulavirus 1 infection is usually described as localized and self-limited in immunocompetent hosts, most often conjunctivitis with or without mild systemic symptoms. Severe disease has been reported mainly in immunosuppressed patients, including pneumonia and encephalitis, and fatal cases are rare enough that each one expands the known clinical spectrum. Hepatitis had not been described as a human presentation before this case, yet a velogenic strain with broad tissue tropism makes that possibility biologically credible.
Travel exposure and the limits of standard first-pass testing
The travel history adds an epidemiologic clue without proving a transmission route. The patient stayed for 2 weeks near the Grand Mosque in Mecca, where pigeons are numerous, and genotype VI.2 avian orthoavulavirus 1 has circulated in backyard pigeons in eastern Saudi Arabia. He reported no animal contact, contaminated food or water exposure, insect bites, or similar illness among family members traveling with him. Even so, the ecological overlap between a pigeon-adapted virus and dense human congregation around a major pilgrimage site makes the setting epidemiologically plausible.
The case also exposes a diagnostic blind spot. Standard testing initially failed to identify dengue, and broad routine pathogen testing did not reveal the driver of the illness. Only postmortem urine dengue PCR, NS1 antigen testing, and metagenomic sequencing uncovered the dual infection. In unexplained severe febrile illness after travel, especially when shock, hepatitis, and cytopenia evolve rapidly, metagenomic sequencing can reveal pathogens that conventional panels miss entirely.
Why this case changes the differential for fulminant traveler’s fever
Severe dengue occurs in about 5% of cases, and primary dengue can still progress to life-threatening disease even without prior immunity. Yet the magnitude of avian orthoavulavirus 1 burden, the multiorgan distribution, and the striking interferon excess make it difficult to attribute the fatal course to dengue alone. The more defensible reading is multifactorial injury, with disseminated velogenic avian orthoavulavirus 1 as the strongest documented contributor and dengue as a possible cofactor.
This is now one of the clearest human examples of a fatal disseminated avian orthoavulavirus 1 infection outside the previously recognized respiratory and neurologic syndromes. It also leaves a practical warning for clinicians: severe traveler’s fever with hepatic failure, shock, and hemorrhagic features should not stop at conventional tropical testing when the initial workup is unrevealing. The unresolved question is not whether avian orthoavulavirus 1 can disseminate in humans; this case shows that it can. The open question is how often that diagnosis is being missed before death, and whether earlier metagenomic testing could change the outcome.