Objective:

To evaluate whether detection of both influenza A(H1N1) and A(H3N2) during the same admission identified a clinically distinct, high-risk phenotype among adults hospitalized with influenza-associated community-acquired pneumonia (CAP).

Approach:

• Study Design and Population: This retrospective single-center study included 97 adults hospitalized with influenza-associated CAP at Guangyuan Central Hospital in China from September 2024 through March 2025.
• Data Linkage and Testing: Clinical workbooks were linked with bronchoalveolar lavage fluid (BALF) pathogen-spectrum records. Influenza A was detected using RT-PCR, and BALF pathogens were assessed using targeted next-generation sequencing.
• Comparison Groups: Investigators compared 51 patients who were H1N1 mono-positive with 46 who were positive for both H1N1 and H3N2 during the same admission. No H3N2 mono-positive comparator was available.
• Outcomes and Analysis: The primary outcome was composite adverse hospital disposition, defined as in-hospital death or discharge against medical advice. Baseline severity, oxygenation, inflammatory markers, pathogen co-detection, invasive mechanical ventilation, and short-term outcomes were compared. Associations were evaluated using binomial generalized linear models and Firth sensitivity analyses.

Key Findings:

• Dual-positive patients had lower median PaO2/FiO2 than H1N1 mono-positive patients (244.17 vs 293.94; *P* = .018), as well as higher C-reactive protein and interleukin-6 levels.
• Invasive mechanical ventilation was more frequent with dual positivity (23.9% vs 7.8%; *P* = .047).
• Fungal co-detection was more common among dual-positive patients (47.8% vs 25.5%; OR, 2.68; *P* = .034), driven primarily by *Pneumocystis jirovecii* detection.
• Composite adverse hospital disposition occurred in 26.1% of dual-positive patients and 3.9% of H1N1 mono-positive patients (OR, 8.65; 95% CI, 1.82–41.13).
• The association remained significant after adjustment for age and sex (OR, 8.24; 95% CI, 1.65–41.09) but attenuated after additional adjustment for PaO2/FiO2 (OR, 4.38; 95% CI, 0.59–32.30).
• In-hospital mortality was numerically higher among dual-positive patients (15.2% vs 3.9%), but the difference was not statistically significant (*P* = .081).

Interpretation:

Detection of both H1N1 and H3N2 during the same hospitalization identified patients with worse hypoxemia, greater inflammatory activation, more fungal co-detection, increased use of invasive ventilation, and more adverse hospital dispositions. Attenuation of the outcome association after adjustment for PaO2/FiO2 identified oxygenation as a major clinical correlate of excess risk, although this analysis did not establish mediation or causation. Dual positivity represented virologic co-detection and did not confirm simultaneous coinfection.

Limitations:

• The retrospective, single-center design and small number of outcome events limited generalizability and multivariable precision.
• Only patients with available BALF targeted-sequencing data were represented, creating potential severity-related selection bias.
• No H3N2 mono-positive group was available, so effects associated specifically with dual positivity could not be separated from H3N2-associated severity.
• Viral-load measurements and genomic confirmation were unavailable; true simultaneous coinfection could not be distinguished from sequential infection, overlapping viral shedding, or residual nucleic acid.
• Exact BALF collection and invasive-ventilation timestamps were unavailable, and later intensive care exposure may have influenced pathogen co-detection.
• Fungal detections were not adjudicated as invasive disease, postdischarge vital status was unavailable, and multiple exploratory comparisons were not adjusted for multiplicity.

Conclusion:

H1N1/H3N2 dual positivity was an exploratory marker of more severe influenza-associated CAP, characterized by worse hypoxemia, greater inflammatory burden, more invasive ventilation, increased fungal co-detection, and a higher burden of adverse hospital disposition. The findings support cautious, oxygenation-centered and microbiologically vigilant assessment, but larger multicenter studies with serial virologic testing, standardized fungal evaluation, precise treatment and sampling timelines, and postdischarge follow-up are needed.