A 69-year-old man with severe COPD requiring chronic oxygen supplementation (1 L/min) and suspected underlying X-linked granulomatous disease was admitted to the ICU with acute-on-chronic respiratory failure. He had a progressively worsening cough, shortness of breath, increased sputum production and had experienced a 10 kg weight loss with muscle depletion in the preceding three months. The patient had been treated for pulmonary tuberculosis at the age of 23 years, with no subsequent recurrence of infection. Chronic treatment with clomipramine (75 mg/day) was ongoing for a major depressive syndrome which had been diagnosed five years earlier. He was being monitored with monthly seriated electrocardiograms for QT prolongation attributable to clomipramine therapy.
At ICU admission, the patient presented with severe dyspnea. Arterial blood-gas analysis showed mixed respiratory failure (pH 7.22, PaO2 58 mmHg, PaCO2 80 mmHg, HCO3- 35 mMol/L) requiring non-invasive ventilation. Chest examination revealed bilateral crackles, with no signs of chronic heart failure. Blood tests showed the white blood cell count to be in the normal range (8000/mm3), with no neutropenia (neutrophil count 1846/mm3), but mild lymphopenia was present (lymphocytes 810/mm3). The patient was anemic (Hb 10.9 g/dL). Platelet count was high (438,000/muL) and C-reactive protein (CRP) was markedly increased (35 mg/L; normal level <5 mg/L). Renal function was normal (serum creatinine 0.9 mg/dL), as were liver function tests (aspartate transaminase [AST] 11 IU/L, alanine transaminase [ALT] 14 IU/L, gamma-glutamyl transpeptidase [GGT] 30 IU/L, total bilirubin 0.15 mg/dL). Baseline electrocardiogram showed a sinus rhythm with a right bundle branch block and prolonged QT interval (453 ms).
Chest x-ray showed multiple bilateral lung opacities. CT and [18F] fluorodeoxyglucose (FDG)-PET/CT scans revealed bilateral nodular infiltrates.
Due to the patient's critical condition and the multiple potential etiologies for the pulmonary infection, a bronchoscopy was performed, which demonstrated purulent secretions. Broncho-alveolar lavage (BAL) fluid was negative for bacteria, fungi, mycobacteria, Actinomyces spp. and Nocardia, but tested positive for galactomannan (GM; ODI 2.6).
According to the European Organisation for Research and Treatment of Cancer (EORTC) criteria for non-neutropenic patients, the diagnosis of probable IPA was made based on the presence of baseline predisposing comorbidities (severe COPD and suspected X-linked granulomatous disease), the presence of bilateral nodular infiltrates, and GM positivity on BAL.
Voriconazole was considered unsuitable due to the patient's baseline QT prolongation and the risk of a drug-drug interaction with clomipramine, potentially leading to further QT prolongation and severe cardiac arrhythmias. Isavuconazole therapy was selected, and started with a loading dose of 200 mg every 8 h for six doses, following by 200 mg daily.
After starting antifungal treatment with isavuconazole, the patient showed a progressive improvement in his clinical condition. At week 2, the arterial blood-gas analysis showed resolution of the decompensated respiratory acidosis, with normalization of pH (pH 7.40, PaO2 62 mmHg, PaCO2 50 mmHg, HCO3- 30 mMol/L). There was no further need of non-invasive ventilation. On day 17, the patient was moved from the ICU to the infectious diseases ward, and required only low flow oxygen supplementation (1 L/min). He was discharged on day 42. CT scanning and FDG-PET/TC after eight weeks of antifungal treatment confirmed the improvement of pulmonary infiltrates. In total, a three-month course of isavuconazole treatment was completed, and there were no clinical or radiologic signs of infection after six months' follow-up. Isavuconazole was well-tolerated, with no adverse events and no change in liver enzymes. Serial ECG monitoring showed no prolongation of the QT interval.