Voriconazole-refractory invasive aspergillosis

Abstract

Invasive aspergillosis (IA) is one of the most common life-threatening complications in immunocompromised patients. Voriconazole is currently the drug of choice for IA treatment. However, some patients with IA suffer clinical deterioration despite voriconazole therapy. Management of voriconazole-refractory IA remains challenging; no useful recommendations have yet been made. Voriconazole-refractory IA can be further categorized as disease attributable to misdiagnosis or co-infection with another mold; inadequate blood voriconazole blood; inadequate tissue drug concentrations attributable to angioinvasion; immune reconstitution inflammatory syndrome; or infection with voriconazole-resistant Aspergillus. Hence, when encountering a case of voriconazole-refractory IA, it is necessary to schedule sequential tests to decide whether medical treatment or surgical intervention is appropriate; to adjust the voriconazole dose via drug monitoring; to seek CYP2C19 polymorphisms; to monitor serum galactomannan levels; and to examine the drug susceptibility of the causative Aspergillus species.

Keywords: Aspergillosis; Aspergillus; Immunocompromised host; Therapy; Voriconazole.

Figure 1.

Images obtained from a 60-year-old female with tuberculosis mimicking invasive aspergillosis. She had received a kidney transplant 4 months prior. (A, B) conventional computed tomography (CT) lung images (5-mm-thick) obtained at the level of the right middle lobe (RML). (A) Image reveals macronodular consolidation along the bronchovascular bundle of the RML, and bronchial wall thickening. The bronchoalveolar lavage fluid was strongly positive for galactomannan and the initial diagnosis was of probable invasive pulmonary aspergillosis. (B) After 4 months of voriconazole treatment, follow-up chest CT showed that the irregularly shaped mass had increased in size and exhibited a tree-inbud appearance. Percutaneous core lung and supraclavicular lymph node biopsies revealed chronic granulomatous inf lammation with caseous necrosis. A member of the Mycobacterium tuberculosis complex was cultured from sputum and aspirated lung tissue. The patient received empirical anti-tuberculous therapy. Follow-up chest radiographs showed that the RML lung nodules had decreased in size (C: before anti-tuberculous therapy; D: after 8 weeks of anti-tuberculous therapy).

Figure 2.

A 62-year-old female underwent total colectomy because of sigmoid colon perforation and panperitonitis developing on day 10 after kidney transplantation. (A) The resected large intestine, a segment of the terminal ileum, the small intestine, and pericolic adipose tissue. Multiple ulcerative lesions (in a 6.2 × 5.4 × 0.2 cm region) are evident in the mucosal area. (B) The fungal morphology, as revealed by H&E (×400), was suggestive of mucormycosis. Mucormycetes invade tissues and cause vascular embolization. After surgery, despite the prescription of amphoterecin B, the infection was not controlled and a second-look operation involving total gastrectomy, splenectomy, graftectomy, and ileal repair was performed. Fungal balls were evident in the stomach and ileal walls. (C) Fungal hyphae associated with mycotic thromboemboli were evident in the stomach, liver, spleen, and peripancreatic tissue. The fungal hyphae were thin, evenly distributed, septated, and branched at an acute angle, suggestive of aspergillosis rather than mucormycosis (periodic acid-Schiff staining, ×400). (D) Mucormycosis immunohistochemistry (IHC) staining (×400) was positive and aspergillosis IHC was negative.

Figure 3.

Computed tomography (CT) images obtained from a 50-year-old female with angio-invasive pulmonary aspergillosis under induction chemotherapy. (A, B) High-resolution CT lung images (1-mm-thick) obtained at the level of the right middle lobe. Ill-defined macronodules with halo signs are evident in both lungs. One week after discharge, the patient presented to the emergency department with massive hemoptysis. (C, D) Conventional CT images (5-mm-thick) revealed that the number and size of nodules had increased in both lungs (especially the right lung), and cavitary changes were evident. The patient underwent bilobectomy of the right middle and right lower lobes. The pathology of the resected lung revealed aspergillosis featuring pulmonary artery invasion (insets in B and D).

Figure 4.

A proposed sequential approach to investigating cases of voriconazole-refractory aspergillosis.