Voriconazole-Induced acute interstitial pulmonary edema with angioedema: A case report

Abstract

Background

Voriconazole is a first-line antifungal agent for invasive fungal infections. Reports of voriconazole-induced interstitial pulmonary edema are exceedingly rare.

Case presentation

We describe a 74-year-old woman with pneumonia who developed facial edema, dyspnea, and pink frothy sputum after four days of voriconazole therapy. Chest computed tomography (CT) revealed bilateral pleural effusions and interlobular septal thickening. She was initially misdiagnosed with acute heart failure, but failed to respond to diuretics. Both B-type natriuretic peptide (BNP) levels and echocardiography were unremarkable. The diagnosis of voriconazole-induced acute interstitial pulmonary edema was established. Voriconazole withdrawal and corticosteroid therapy resulted in rapid clinical resolution.

Conclusion

Voriconazole hypersensitivity may manifest as acute interstitial pulmonary edema with concomitant angioedema, a presentation that can mimic cardiogenic pulmonary edema. Early recognition and timely corticosteroid intervention are crucial for favorable outcomes.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12890-026-04141-1.

Case presentation

A 74-year-old woman was admitted with a 4-day history of cough and sputum production, accompanied by chest tightness and dyspnea but without chest pain or fever. Her past medical history included hypertension for over 10 years (maximum blood pressure 180/100 mmHg), type 2 diabetes mellitus for more than 10 years, and bronchial asthma diagnosed 1 year previously. She was receiving nifedipine controlled-release tablets, irbesartan, and atorvastatin for hypertension, and metformin plus miglitol for diabetes. Asthma was managed with budesonide–formoterol inhalation, with serum total IgE of 455.2 IU/ml. Four years earlier, she underwent surgical resection of a gastrointestinal stromal tumor. Additional comorbidities included bilateral thyroid nodules (consistent with multinodular goiter) and a left adrenal adenoma identified one year earlier. She denied any history of coronary artery disease, infectious diseases (hepatitis, typhoid, or tuberculosis), or food and drug allergies.

On admission: T 36.4 °C, P 90/min, R 19/min, BP 130/80 mmHg. Chest auscultation revealed coarse breath sounds bilaterally with moist rales in the left lung. Chest CT showed bilateral patchy infiltrates. Laboratory tests: WBC 13.3 × 10⁹/L (neutrophils 76.2%), CRP 34.9 mg/L, ESR 64 mm/h, glucose 8.98 mmol/L. Other laboratory tests, including BNP, troponin, liver and renal function, and sputum for tuberculosis, were unremarkable. The initial diagnosis was community-acquired pneumonia with acute asthma exacerbation. She was treated with piperacillin–tazobactam, levofloxacin, carbocisteine, ambroxol, methoxyphenamine, montelukast, budesonide–formoterol inhalation, and continued antihypertensive and hypoglycemic therapy.

After 7 days of therapy, her respiratory symptoms improved, but repeat CT showed resolution of right-sided infiltrates with progression to consolidation in the left lung, raising suspicion for fungal pneumonia. Bronchoscopy with bronchoalveolar lavage (70 ml saline, 40 ml turbid return) was performed. Metagenomic tNGS detected no pathogens. After an additional week, although cough improved, the patient continued to expectorate thick, white mucoid sputum, and fungal infection could not be excluded. Cefepime was discontinued and voriconazole (0.2 g IV q12h) was initiated. Cough subsequently improved and sputum became easier to expectorate. However, within 4 days of voriconazole therapy, she developed progressive facial edema, bilateral lower extremity swelling, dyspnea, and nausea. On the 5th day of voriconazole therapy, symptoms worsened with orthopnea, wheezing, and expectoration of pink frothy sputum. Chest CT showed bilateral pleural effusions and interlobular septal thickening that was predominant in the bilateral upper and lower lobes with symmetrical distribution. Ground-glass opacities were present, without subpleural sparing. The interlobular septal thickening was non-smooth, and there was no definite peribronchovascular cuffing (Fig. 1). These findings were consistent with interstitial pulmonary edema.

Fig. 1.

Chest computed tomography (CT) on day 5 of voriconazole treatment demonstrates interlobular septal thickening in both lungs, accompanied by bilateral pleural effusion

Congestive heart failure was initially suspected. However, repeated intravenous furosemide (20 mg) was ineffective. Cardiac biomarkers, troponin, BNP, ECG, and echocardiography were all normal. Specifically, echocardiography revealed a left ventricular ejection fraction of 60%, no evidence of diastolic dysfunction, no valvular abnormalities, normal inferior vena cava caliber without dilation or stenosis, and color Doppler flow imaging showed homogeneous filling without regurgitation or filling defects. These findings excluded cardiogenic pulmonary edema.

The complete blood count showed an eosinophil count of 0.05 × 10⁹/L, and serum albumin was 40 g/L. During the treatment period, there was no recent large-volume intravenous infusion, nor any recent use of nephrotoxic or cardiovascular-active drugs, and no blood transfusion was administered. Further differential diagnoses are as follows: The extent of lesions on chest CT has not increased, and infection markers have significantly decreased, which does not support infection progression. During episodes, diffuse wet rales were heard throughout both lungs without obvious wheezing, which is not consistent with acute asthma exacerbation. There was no systemic inflammatory response syndrome, no refractory hypoxemia, and diuretics were ineffective while corticosteroids led to rapid improvement, which is not consistent with acute respiratory distress syndrome. Electrocardiogram, serum D-dimer, lower extremity vascular ultrasound, and echocardiography showed no evidence of pulmonary embolism. Renal function was normal, with no oliguria, no fluid overload, and no use of nephrotoxic drugs. Serum albumin and thyroid function were normal, excluding edema related to hypoalbuminemia or hypothyroidism. No blood transfusion was given throughout the course, excluding transfusion-related acute lung injury or transfusion-associated circulatory overload.

Given the temporal relationship to voriconazole and rapid progression of symptoms, drug-induced interstitial pulmonary edema was suspected. Voriconazole was discontinued, and intravenous methylprednisolone (40 mg) was administered. Symptoms and edema rapidly resolved within 6 h. The patient remained stable thereafter and experienced no recurrence during hospitalization or follow-up. A repeat chest CT performed seven days later showed complete resolution of the interstitial pulmonary edema.

Discussion

Voriconazole is widely used in the management of invasive fungal infections [1], and its adverse effects have been well documented, including hepatotoxicity, visual disturbances, and skin reactions [2]. Peripheral edema has been listed as a potential adverse reaction in drug labeling, yet only sporadic cases have been reported in the literature [3]. To our knowledge, this represents one of the very few reported cases of voriconazole induced interstitial pulmonary edema worldwide.

Unlike cardiogenic pulmonary edema, voriconazole-induced edema appears to be hypersensitivity-mediated, as evidenced by normal BNP levels and lack of response to diuretics. Instead, symptoms improved rapidly with corticosteroids, consistent with an allergic or immune-mediated mechanism. The patient’s history of asthma and elevated IgE placed her at increased risk for drug hypersensitivity [4]. Clinicians should maintain a high index of suspicion for voriconazole hypersensitivity in patients who develop unexplained dyspnea and pulmonary infiltrates, particularly those with predisposing allergic conditions. Once suspected, immediate discontinuation of voriconazole is warranted, along with systemic corticosteroids (e.g., methylprednisolone 40–80 mg/day) and antihistamines (H1 antagonists such as diphenhydramine, H2 antagonists such as famotidine) to suppress the inflammatory cascade.

This case highlights a probable and unique clinical–radiological pattern of voriconazole-induced interstitial pulmonary edema, and provides key differentiating features from cardiogenic pulmonary edema (i.e., normal BNP, poor response to diuretics, rapid resolution with steroids). Future studies should explore the genetic susceptibility (e.g., HLA typing), potential biomarkers (e.g., serum tryptase, IL-5), and preventive strategies such as prophylactic antihistamines in high-risk populations. These efforts may advance individualized antifungal therapy and precision prevention of drug-induced hypersensitivity reactions.

Conclusion

Voriconazole-induced interstitial pulmonary edema is an exceptionally rare but potentially serious adverse reaction. Clinicians should suspect this entity in patients developing pulmonary edema during voriconazole therapy, particularly when BNP levels remain normal and diuretic therapy is ineffective. This case expands the spectrum of voriconazole-associated adverse reactions and underscores the need for vigilance when prescribing the drug, especially in patients with asthma or allergic predisposition.

Authors' contributions

Yuzhen Jin: Writing – original draft, Project administration, Conceptualization. Lijie Qin: Conceptualization, Writing – review & editing; Peng Liu: Writing – original draft, Visualization, Data curation. Zhaoxia Song: Writing – review & editing, Investigation. Mengjie Li: Writing – review & editing, Supervision, Conceptualization. All authors contributed to the study and approved the final version of the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

Declarations

Consent for publication

Written consent has been obtained from the patient described in the case report for the reporting of this condition, including the anonymised figures.

Competing interests

The authors declare no competing interests.