gms | German Medical Science

Several studies have evaluated the galactomannan (GM) assay in pediatric patients, and there is convincing evidence for its usefulness as screening tool in patients with leukemia or post allogeneic hematopoietic stem cell transplantation (HSCT). Much less is known about the utility of the assay in monitoring patients with established invasive aspergillosis. Here we report the long-term kinetics of serum galactomannan in two severely immunocompromised adolescents with invasive pulmonary aspergillosis (IPA) that were cured after complicated clinical courses and prolonged antifungal treatment.

Patient 1 was a 15 year old girl with refractory acute myeloid leukemia (AML) and limited response to experimental treatments, including clofarabine, gemtuzumab, and sorafenib. When first radiological signs of invasive pulmonary mould infection occurred on high-resolution computer tomography (HR-CT), she had a 3 month history of granulocytopenia and presented with persistent fever despite broad-spectrum antibiotics. Antifungal prophylaxis with voriconazole 300 mg IV BID was augmented by liposomal amphotericin B 3 mg/kgBW QD and caspofungin 50 mg QD. Repeat CT-scans revealed growth of the two existing lesions with a rising halo sign; imaging of the central nervous system around that time and throughout was within normal limits. Repeat galactomannan (GM) serum levels were between 8.4 and 11.9 pg/mL; bronchoscopy with bronchoalveolar lavage was not performed as the diagnosis of probable IPA was established and the patient was in unstable condition. Due to persistent granulocytopenia, the patient received G-CSF stimulated granulocyte transfusion on two occasions with concomitant increase in pulmonary opacification but no change in GM serum levels.

Six weeks after diagnosis of IPA, matched related allogeneic HSCT was performed in aplasia following conditioning with treosulfan and melphalane. Nine days post stem cell infusion, stable hematopoietic engraftment (ANC >500/µl) was documented, followed by a rapid decrease of GM serum levels to 1.0 pg/mL at day +19. CT imaging around that time showed a morphological change with occurrence of an air-crescent sign. Along with a steady clinical stabilization, antifungal therapy was stepwise reduced to voriconazole 300 mg PO BID.

Five weeks post transplantation, a transient flare of GM serum levels of up to 9.0 pg/mL was observed in the wake of acute graft- vs. host-disease (GVHD), corticosteroid treatment and Cytomegalovirus (CMV) reactivation. Clinically, the patient presented with new fever and transient respiratory distress, modest pleural effusion, but no new inflammatory infiltrates. Granulocyte counts were stable. Three months after transplantation, the patient developed gastrointestinal GVHD with a prolonged course, requiring augmented immunosuppression with corticosteroids in changing doses for a period of three month. No impact on GM-serum levels was noted, and signs and symptoms of IPA resolved under continuous treatment with voriconazole with disappearance of active lesions and negative GM levels in serum five months post-transplant.

Patient 2 was a 13 year old girl with myelodysplastic syndrome/refractory cytopenia (MDS) and matched unrelated allogeneic HSCT following conditioning with fludarabine, thiotepa and ATG. Probable IPA was diagnosed during aplasia at day +25 post-transplant by HR-CT, detection of GM in serum (range, 2.6–4.3 pg/mL) and broncho-alveolar lavage (BAL) fluid (7.1 pg/mL) and molecular detection of A.fumigatus in BAL fluid by polymerase chain reaction (PCR); imaging of the CNS was normal. Empirical therapy with liposomal amphotericin B 3 mg/kgBW QD was augmented by voriconazole 200 mg IV BID and caspofungin 50 mg QD. After three separate granulocyte transfusions, hematopoietic engraftment was documented at day +43. Antifungal therapy was reduced to voriconazole; repeat CT-scans showed decreasing volume of all existing lesions and sequestrations, and the GM-serum levels fell below 1,0 pg/ml. The patient's further course was complicated by acute GVHD and systemic Cytomegalo- and Adenovirus reactivation, requiring prolonged augmented immunosupression with corticosteroids and use of antiviral agents, respectively. During that time, new pulmonary infiltrates occurred on HR-CTs and antifungal therapy was escalated by the addition of caspofungin. Due to secondary graft failure, the patient received a stem cell boost without conditioning, resulting in persisting hematopoietic engraftment within 10 days. Around that time, GM-serum levels showed a transient increase.

In the following, GVHD and virus reactivations required augmented immuno-supressive treatment with glucocorticosteroids and myelosuppressive antiviral therapy for several months. Permanent stabilization of granulocyte counts was seen at three month after the stem cell boost, and normal CD3/CD4+ T-lymphocyte counts after eight month. During that period GM-serum levels showed a high variability without clear correlation to pulmonary CT findings. Nine month after the stem cell boost, GM serum-levels dropped permanently to under 1.0 pg/ml; HR- CTs showed successive reduction of infiltrative and cavitary pulmonary lesions.

Taken together, the two case reports suggest a limited utility of serum galactomannan monitoring for long-term assessment of treatment responses of established IPA relative to clinical and radiographic findings. This limited utility may be related to a reduced sensitivity of the assay during mould-active antifungal therapy and various clinical confounders in severely immunocompromized patients with multiple co-morbidities. Monitoring of serum galactomannan in these patients may only be useful for response assessment in conjunction with clinical and imaging parameters.