Chronic Obstructive Pulmonary Disease (COPD) predisposes patients to invasive pulmonary aspergillosis (IPA) through impaired airway defenses, impaired macrophage function, and iatrogenic immunosuppression. Voriconazole is guideline-recommended first-line therapy for IPA, but treatment failure with azole monotherapy is increasingly reported. Caspofungin, an echinocandin that inhibits β-(1,3)-D-glucan synthesis, may provide complementary antifungal activity. This retrospective analysis examined whether the addition of caspofungin to voriconazole improves clinical outcomes, accelerates symptom relief, lowers fungal and inflammatory biomarkers, and modulates immune markers in COPD patients with IPA.
This single-center retrospective cohort included 152 COPD patients with confirmed IPA treated between April 2022 and April 2024. Inclusion required adult age (≥18 years), COPD diagnosed per GOLD criteria (post-bronchodilator FEV1/FVC <0.70), and IPA confirmed by modified EORTC/MSG criteria (BALF GM index ≥1.0 or serum ≥0.5, positive BALF culture/PCR, or compatible imaging). Patients with major organ dysfunction, malignancy, interstitial pneumonia, or concurrent infections were excluded. The Ethics Committee of Jinhua People’s Hospital approved the study. Baseline characteristics including age, BMI, COPD duration and grade, smoking and drinking history, and comorbidities were comparable between groups (P>0.05).
Both groups received standard supportive care (oxygen, electrolyte correction, acid-base maintenance) and the same voriconazole intravenous-to-oral sequential regimen: 6 mg/kg IV first day, 4 mg/kg IV second day, then oral voriconazole 200 mg every 12 hours for a total of 14 days per protocol described. The observation group received additional intravenous caspofungin: 70 mg on day 1 then 50 mg daily for 7 days. Treatment allocation was by clinician discretion; multivariate approaches were applied to adjust for confounders.
Specimens included fasting venous blood and bronchoalveolar lavage fluid (BALF) obtained before and after treatment. BALF volume was staged at ~1 mL/kg per lavage (total <20 mL). Laboratory assays: G test for 1,3-β-D-glucan (BG), GM assay for galactomannan (I value), ELISA for BALF cytokines (IL-12, IL-15, IL-17, TNF-α), serum CRP and WBC on an automated analyzer, ELISA for PTX3, and qPCR for peripheral blood TLR2 and PTX3 mRNA (relative quantification by 2−ΔΔCt normalized to GAPDH). Arterial blood gases and pulmonary function (FEV1, FVC, FEV1/FVC) were measured with standard equipment. Quality of life and symptom burden were assessed with SGRQ and CAT respectively.
Co-primary endpoints were total treatment efficacy rate (composite of cure, obvious improvement, and effective) and time to clinical response (days to cough relief and fever resolution). Secondary endpoints included BALF biomarkers (BG, I value), time to resolution of pulmonary signs, length of stay, inflammatory cytokines, serum immune markers (PTX3, TLR2 mRNA), arterial blood gases, pulmonary function, SGRQ and CAT scores, and adverse events. Data were analyzed with SPSS 22.0. Normality was evaluated (Shapiro–Wilk); parametric tests were used for normally distributed data. Bonferroni correction adjusted co-primary endpoint testing; secondary outcomes used FDR control. Multivariate logistic regression identified factors associated with lung function improvement and adjusted comparisons.
The observation group (voriconazole + caspofungin) achieved a higher total effective rate: 89.47% (68/76) compared with 65.79% (50/76) in the voriconazole-alone group (χ2 = 8.102, P = 0.004). The reported number needed to treat (NNT) was 5 (95% CI 3–10), and the risk difference favoring combination therapy was 23.68% (95% CI 10.34–36.02).
Post-treatment BALF 1,3-β-D-glucan concentrations and GM I values decreased in both groups, with greater reductions in the combination arm. After treatment BG was 15.64 ± 7.94 pg/mL versus 20.16 ± 5.33 pg/mL in controls (t = 4.120, P < 0.001). Corresponding GM I values post-treatment were 0.75 ± 0.22 versus 0.96 ± 0.34 (t = 4.521, P < 0.001).
Patients receiving combination therapy had faster symptom relief: cough resolved in 5.36 ± 1.25 days versus 7.89 ± 1.34 days, and fever resolved in 7.06 ± 1.47 days versus 9.44 ± 1.62 days (both P < 0.05). Length of hospital stay was shorter in the observation group (12.28 ± 3.11 vs. 15.62 ± 4.08 days, P < 0.05). Time to resolution of pulmonary signs improved correspondingly; detailed values are provided in the source tables.
Bronchoalveolar lavage fluid cytokines—including IL-12, IL-15, IL-17, and TNF-α—declined more after combination therapy (P < 0.05). Serum CRP also showed greater reduction in the observation group. Serum PTX3 and peripheral blood TLR2 mRNA expression were assessed by qPCR/ELISA and demonstrated improved post-treatment levels in the combination group as reported in the tables.
Arterial blood gas parameters and oxygenation indices were measured pre- and post-treatment. Pulmonary function improved more with combination therapy; post-treatment FEV1/FVC was 57.56% in the observation group versus 54.02% in controls (P < 0.05). Quality-of-life (SGRQ) and symptom severity (CAT) scores improved significantly after combination therapy (P < 0.05).
Adverse event rates were similar between groups: 7.89% in the combination group vs. 13.16% in the control group (P > 0.05). Adverse events were classified per CTCAE v5.0, with predefined thresholds for hepatic injury and procedures for ophthalmologic referral for visual symptoms. Drug attribution required exclusion of fungal progression by repeat diagnostics.
Multivariate logistic regression adjusted for age, smoking history (pack-years), baseline PaO2, COPD grade, BMI, comorbidities, and glucocorticoid use. The analysis identified treatment group among covariates associated with lung function improvement (≥5% increase in FEV1/FVC); detailed regression coefficients and model statistics are presented in the source tables.
In this retrospective cohort, adding caspofungin to voriconazole for COPD-associated IPA was associated with higher composite clinical efficacy, faster symptom resolution, greater reductions in BALF fungal biomarkers (BG, GM I value), larger declines in BALF inflammatory cytokines, improved lung function, and better patient-reported outcomes. Safety profiles were comparable between arms. The study applied multiple statistical safeguards including normality testing, prespecified corrections for primary and secondary endpoints, and multivariate adjustment to mitigate confounding from nonrandomized allocation.
Among hospitalized COPD patients with IPA in this cohort, oral-sequential voriconazole combined with short-course intravenous caspofungin was associated with superior clinical efficacy, more rapid symptom resolution, lower fungal and inflammatory biomarkers, and improved pulmonary function and quality of life compared with voriconazole monotherapy, with similar adverse event rates. Detailed numerical results and multivariate analyses are provided in the source tables.