K. Paciaroni1, G. De Angelis1, C. Gallucci1, C. Alfieri1, M. Ribersani1, A. Roveda1, A. Isgrò1, M Marziali1, I.P. Aloi2, A. Inserra2, J. Gaziev1, P. Sodani1 and G. Lucarelli1
1 International Centre for
Transplantation in Thalassemia and Sickle Cell Anaemia, Mediterranean
Institute of Haematology, Policlinic of “Tor Vergata” University, Rome,
2 Departments of Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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Sickle Cell Anaemia (SCA) is the most common inherited blood disorder and is associated with severe morbidity and decreased survival. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is the only curative approach. Nevertheless the decision to perform a bone marrow transplant includes the risk of major complications and transplant-related mortality. Infections represent the leading cause of death in SCA patients undergoing HSCT. Invasive Pulmonary Aspergillosis (IPA) is a devastating opportunistic infection and remains a significant cause of morbidity and mortality in HSCT recipients. Data regarding IPA in the setting of SCA are lacking. In the present report, we describe a patient with SCA, who developed IPA after allogeneic bone marrow transplant. The fungal infection was treated by systemic antifungal therapy in addition to surgery, despite mild chronic graft versus host disease (GVHD) and continuing immunosuppressive therapy. This case shows that IPA occurring in bone marrow recipients with SCA can be successfully treated.
Sickle Cell Anaemia (SCA) is a hereditary anaemia and a multisystem
chronic disease that reduces the quality of life and increases
mortality significantly since the third decade of life.
Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is the only
definitive cure for SCA. The decision to perform a bone marrow
transplant (BMT) in SCA patients involves careful weighing of
individual patient’s risk and benefits. The transplant-related
mortality for SCA patients is approximately 7%, similar in all series
of studies, and infections constitute the leading cause of death.[2-3]
Invasive Pulmonary Aspergillosis (IPA) is a possible infective
complication and is a known cause of attributable mortality in HSCT
recipients endangering their successful treatment. Data
regarding the optimal management of IPA in transplanted SCA patients
are lacking. Here we describe the first case of successful treatment of
IPA in a sickle cell anaemia patient, recipient of bone marrow
A 17-year-old Nigerian boy with a diagnosis of SCA disease and
recurrent episodes of vaso-occlusive crisis was referred to our centre
as candidate to related allogeneic BMT. According to our internal
protocol aimed at evaluating the possible lung damage of SCA patients
before the transplant, computed tomography (CT) scan of the lung and
spirometry were performed. The CT scan revealed no signs of infection
and the spirometry test documented a restrictive pattern with a basic
forced volume vital capacity of 79% and a not reached peak expiratory
flow (64%). The condition regimen adopted for the HLA-identical related
allogeneic transplant included: fludarabine (30mg/m2/day
for 5 days), busulfan (16.48 mg/kg for 4 days) and cyclophosphamide
(200mg/kg for 4 days). The graft-versus-host-disease (GVHD) prophylaxis
consisted of intravenous cyclophosphamide, short-course methotrexate,
prednisolone, and cyclosporine. Because of neurological toxicity signs
on day +4 after transplant, cyclosporine was replaced initially by
mycophenolate and then by the combination mycophenolate and tacrolimus
(day +26). The neutropenic period lasted until the day +18 when the
absolute neutrophil count was > 500 cells/mm3.
The hospital stay after transplant was 32 days. Throughout the BMT
pre-engraftment phase and the early post-transplant phase fluconazole
was administered as the primary prophylaxis therapy. Microbiological
cultures of sputum and of oral, nasal and pharyngeal swabs and serum
galactomannan assay were weekly performed as surveillance.
On day +40 after transplant, aII degree skin GVHD was diagnosed and immunosuppressive treatment was intensified by the use of multiple immunosuppressive agents (mycophenolate, tacrolimus and methylprednisolone 2 mg/kg). The acute GVHD was ameliorated and evolved in a mild chronic GVHD controlled with mycophenolate associated with low dose of steroids (0.5mg/kg) from day +122 after transplant. At day +83 after transplant, the first positive galactomannan test was detected (index 0.78, normal <0.5). The general condition of the patient was fair, and a mild productive cough without fever was the only symptom. A lung CT scan was performed and revealed a large pericardial rounded nodule (diameter 3 cm) with cavitation in the right upper lung lobe, suggestive of invasive aspergillosis (see Figure 1, A). In the same time, Aspergillus terreus was isolated from a sputum microbiological culture. The minimum inhibitory concentration (MIC μg/ml) of individual antifungal agents was determined by the methods described by European Committee for Antimicrobial Susceptibility Testing (EUCAST). The MICs of itraconazole and posaconazole against the A. terreus were 0.5μg/ml and 0.125μg/ml respectively, and were reported as susceptible (S). The MIC of Voriconazole was 0.03g/ml and was accompanied by the comment Insufficient Evidence (IE), according to epidemiological cut-offs established by the EUCAST. The amphotericin B was not tested against the Aspergillus terreus as EUCAST indicates for this species. Antifungal treatment with intravenous itraconazole at a dosage of 200 mg/d was promptly administered, according to the available antifungal susceptibility testing. Control lung CT scan performed one month after the initiation of the antifungal treatment showed minimal nodule size reduction (diameter 2.26 cm). However, the Aspergillus galactomannan antigen decreased and became negative 12 days after the initiation of treatment. After 42 days, intravenous itraconazole was switched to oral posaconazole. No hepatic toxicity was documented during itraconazole treatment, but the patient reported severe nausea and loss of appetite. Seven months after transplant (5 months after the antifungal therapy initiation), the immune system was partially recovered as documented by the immunophenotyping test (on day +209 after transplant the T-cells populations measured by flow cytometry were: CD3+ 1807/mm3, CD4+ 420/mm3, CD8+ 1301/mm3 CD19+ 240/mm3, CD16+CD56+ 578/mm3). Nevertheless, the control CT lung scans showed the persistence of the unmodified pulmonary lesion (Figure 1, B). As a consequence, in order to prevent possible pericardial erosion of the paracardiac pulmonary lesion, surgical therapy was considered. At day +226 after transplant, lung surgical segmentectomy was performed. The post-operative course was complicated by pneumothorax with prolonged air leak (14 days) treated with the use of a Bülau chest tube. Hospital stay was 22 days. Histological analysis of the excised tissue revealed an abscess cavity delimitated by fibrosis with a massive inflammatory reaction replacing the normal pulmonary parenchyma and numerous hyphae and fungal spores. Microbiological culture of the tissue also resulted in the growth of Aspergillus terreus. The lung CT scan performed 42 days after surgery documented the presence of a fibrotic replacement of the previous cystic lesion. (Figure 1, C). The patient was discharged and could go back to Nigeria maintaining a single-drug immunosuppression therapy and secondary prophylactic antifungal treatment with voriconazole (the only triazole available in his country). One year after transplant the immunosuppression therapy and antifungal treatment were discontinued. To date, 20 months after transplant, no evidence of recurrent fungal infection has been documented.
|Figure 1. Lung computed tomography CT scan image: (A) large paracardiac rounded cavitary lesion (diameter 3 cm) in the right upper lobe, consistent with invasive pulmonary aspergillosis (IPA). (B): persistence of the cavitary lesion after five months of antifungal therapy (C) Complete disappearance of pulmonary aspergillosis, with a fibrotic lesion in place of the previous cystic lesion.|