A 30 year-old female patient was diagnosed with acute myeloid leukemia (AML) in November 2013. Multiple cures of chemotherapy (idarubicine, cytarabine, fludarabine and amsacrine) led to a remission. In March 2014 (T0) (Fig. 1), because of a high risk of relapse, she received an allogenic hematopoietic stem cell transplantation (HSCT). At T0 + 6 months, she developed ocular, oral, digestive and hepatic graft-versus-host disease (GVHd). Immunosuppressive therapy by tacrolimus, ruxolitinib and oral corticosteroids induced a transient stabilization of GVHd.
Between T0 + 6 and T0 + 12 months, she developed a progressive dyspnea, a dry cough and severe asthenia. Pulmonary function tests (PFT) showed a mixed ventilatory pattern with a very severe obstructive syndrome and severe CO diffusion impairment. Extensive blood analyses and non-invasive microbiological samples did not reveal any sign of infection. High-resolution computed tomography (HRCT) showed a bilateral perihilar mosaicism with zones of ground glass attenuation in a "crazy paving" pattern (Fig. 2, panel A). HRCT was completed by Single Photon Emission Computed Tomography with a ventilation/perfusion phase, which showed that the zones of ground glass attenuation where hypoperfused and hypoventilated when compared to adjacent hypodense lung areas. A bronchoscopy with broncho-alveolar lavage (BAL) and transbronchial biopsies (TBB) was performed. Differential cell count of BAL was normal. All microbiological samples remained culture negative. Histo-pathological analysis of lung parenchyma samples was unremarkable. Because of the severity of the respiratory insufficiency, a surgical lung biopsy was not performed.
At this stage, our patient presented simultaneously a severe obstructive airway disease, potentially attributable to obliterative bronchiolitis (OB), and a parenchymal disorder, with a "crazy paving" mosaic pattern of ground glass attenuation, for which an infection had been reasonably excluded.
To control the probable OB, immunosuppressive treatment was intensified with high-dose oral corticosteroids, and inhaled corticosteroids. Macrolides (as immunomodulators) were added and extracorporeal photopheresis was implemented. This failed to impact on the progression of the airway obstruction and the patient developed a progressive respiratory failure requiring continuous oxygen therapy and subsequently nocturnal non-invasive ventilation. Furthermore, because of her immunosuppression, she underwent recurrent hospitalizations for IV treatment of lower respiratory tract infections.
At T0 + 34 months, indication for a bilateral lung transplant (BLT) was confirmed by the local transplant center. At T0 + 45 months, because of worsening of PFT, appearance of a cavitary subpleural lesion on HRCT (Fig. 2, panel A (red circle)), and high levels of serum galactomannan, posaconazole was introduced for suspicion of a locally invasive pulmonary aspergillosis.
In spite of several adaptations of anti-fungal therapy, the size of the cavitary lesion increased (20 x 24mm with a 4 mm wall). At HSCT +47 months, her respiratory condition required continuous high pressure non-invasive ventilatory support, and high flow of oxygen. After three weeks in the Intensive Care Unit, BLT was performed.
Macroscopically, the explanted lungs were firm and showed a yellow cut surface and a cavity with necrosis (Fig. 2, panel B).
Microscopic analysis of the explanted lungs (Fig. 2, panel C) revealed the presence of 1/obliterative bronchiolitis predominating in the upper lobes; 2/diffuse alveolar lipoproteinosis with xanthomatous pneumonia and 3/a subpleural cavity with aspergillus fragments (confirmed by PCR) without signs of vascular or extrapleural invasion, confirming the co-existence of three disorders: OB, PAP and invasive cavitary pulmonary aspergillosis.
More than two years after BLT, the patient is in good clinical condition, and has normalized her PFT and her lung parenchyma appears normal on HRCT.
Lung CT-scan: "Crazy Paving" pattern with excavated subpleural lesion (circled).