Primary cutaneous mucormycosis in a lung transplant recipient: case report and concise review of the literature

Abstract: Mucormycosis (zygomycosis) is an invasive, opportunistic fungal infection caused by organisms of the class Zygomycetes. Immunocompromised individuals, including both solid organ and hematopoietic stem cell transplant recipients, are preferentially affected. Among solid organ transplant (SOT) recipients, the sinuses, with or without involvement of the orbits and cerebrum, are the most common sites of disease, although the pulmonary allograft appears to be targeted following lung transplantation. Here, we describe the unique case of a lung transplant recipient who developed multifocal cutaneous mucormycosis without involvement of the pulmonary allograft, and review the published literature regarding incidence, treatment, and prognosis of primary cutaneous mucormycosis following SOT.     

Cutaneous mucormycosis

Mucormycosis is an aggressive invasive fungal infection that occurs rarely in immunocompetent but frequently in immunocompromised patients. We present a case of a 68‐year‐old patient with cutaneous mucormycosis due to Rhizopus pusillus. He was initially hospitalized for invasive pulmonary aspergillosis and diabetes mellitus secondary to acute graft‐versus‐host treatment with glucocorticoids after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. Treatment with liposomal amphotericin B and posaconazole was initiated but the patient developed septic shock with multiple organ failure and died 5 days later. The risk factors, clinical presentation, treatment, and prognosis of cutaneous mucormycosis in hematopoietic stem cell and solid organ transplant patients are discussed.     

T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors

Bronchiolitis obliterans (BO) and bronchiolitis obliterans organizing pneumonia (BOOP) are late-onset non-infectious pulmonary complications (LONIPCs) following allogeneic hematopoietic stem cell transplantation (HSCT). In the present study 10 of 197 conventionally prepared stem cell recipients developed BOOP after 365 days and 6 patients developed BO 333 days post-transplant. No BOOP or BO was diagnosed following T-cell depletion (p<0.05). Chronic GVHD was ascertained in all BOOP patients and appeared significantly (p<0,001) more frequent in the conventional transplant group. The data confirm a strong association between T-cell activity, chronic GVHD, BO and BOOP and point out the impact of T lymphocytes in the pathomechanism of BOOP.     

Chronic GVHD with polymyositis after non-myeloablative stem cell transplantation

A 57-year-old man underwent an autologous hematopoietic stem cell transplant for mantle cell lymphoma in August 1999. Anemia and thrombocytopenia appeared in November 2001. He was diagnosed with further hematological examination as having acute myeloid leukemia with multilineage dysplasia following secondary myelodysplastic syndrome. He received the allogeneic hematopoietic stem cell transplant from his HLA DRB1 locus mismatched brother in May 2002. The nonmyeloablative preparative regimen consisted of fludarabine 30mg/m2 for 6 days and busulfan 4mg/kg for 2 days. Eosinophilia, decrease of lacrimal fluid and liver dysfunction appeared on Day 104. We diagnosed this as chronic GVHD and treated the patient with prednisolone 10 mg/day. Thereafter, his chronic GVHD gradually improved. He had fever and myalgia in the extremities and lumbar region with elevated serum CPK and aldolase in January 2003. Histological examination led to a diagnosis of polymyositis simultaneously with chronic GVHD. Prednisolone 50 mg/day as an initial dose was started for the polymyositis following which the prednisolone dose was gradually tapered off. The polymyositis improved promptly after the administration of prednisolone and remains in remission with a current maintenance program of prednisolone 5 mg/day.     

Diagnosis and clinical management of chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) occurs in approximately 60% of patients who survive for more than 100 days after receiving an allogeneic marrow or peripheral blood stem cell transplant without T-cell depletion of the graft. Chronic GVHD represents a major cause of morbidity and mortality among hematopoietic stem cell transplant recipients. Risk factors for the development of chronic GVHD and for mortality among patients who develop this complication have been defined, but the pathogenesis of chronic GVHD is not well understood. This review discusses the clinical manifestations that lead to a diagnosis of chronic GVHD and outlines an approach for therapy with glucocorticoids and extended administration of a calcineurin inhibitor. The judicious use of glucocorticoids at the lowest effective dose and alternate-day administration can minimize steroid-related side effects. Antibiotic prophylaxis to prevent infection and supportive care to minimize morbidity and prevent disability are critically important components in the management of patients with chronic GVHD. Approximately 50% of patients with chronic GVHD are able to discontinue immunosuppressive treatment within 5 years after the diagnosis, and 10% require continued treatment beyond 5 years. The remaining 40% die or develop recurrent malignancy before the chronic GVHD resolves. An improved understanding of the pathogenesis of the disease is needed to develop more effective therapy.     

Effect of graft-versus-host disease on hematopoiesis after bone marrow transplantation in mice.

We have examined the effect of graft-versus-host disease (GVHD) on the reconstitution of donor hematopoiesis in a murine bone marrow transplant (BMT) model of GVHD to minor histocompatibility antigens. GVHD had no effect on peripheral blood counts, which normalized by 1 month after BMT, and did not affect numbers of hematopoietic progenitors in the BM, which remained decreased in all transplant recipients. Donor stem cells (colony-forming unit-spleen day 8) and stem cell self-renewal remained low in all mice for 5 months after transplant, but GVHD further damaged the stem cell compartment. Peripheral counts 1 month after transplant were supported by increased numbers of stem cells in cycle and increased splenic hematopoiesis. However, GVHD altered the pattern of extramedullary hematopoiesis, causing dramatically decreased activity in the spleen and increased activity in the liver. We conclude that GVHD further decreases hematopoietic reserve and causes damage to the donor stem cell compartment during hematopoietic reconstitution after transplant, despite unaffected progenitor frequencies and peripheral blood counts.     

Successful T-cell-replete peripheral blood stem cell transplantation from HLA-haploidentical microchimeric mother to daughter with refractory acute lymphoblastic leukemia using reduced-intensity conditioning

A 16-year-old girl with refractory acute lymphoblastic leukemia underwent reduced-intensity hematopoietic stem cell transplantation from her two-locus-mismatched haploidentical mother, who was microchimeric for the patient's hematopoietic cells. The conditioning regimen comprised melphalan, fludarabine, and low-dose total body irradiation. Non-T-cell-depleted peripheral blood stem cells were infused with graft-versus-host disease (GVHD) prophylaxis consisting of tacrolimus, prednisolone, and short-course methotrexate. Complete donor-type engraftment without evidence of residual leukemia was confirmed on day 22. Severe GVHD was not observed despite rapid cessation of immunosuppression. The patient remains well in continuous remission 15 months after transplant. This successful experience suggests that maternal hematopoietic stem cell transplants for children, in the presence of microchimerism, may be associated with hyporesponsiveness to the inherited paternal HLA antigens (IPA); preventing severe GVHD.     

Large pericardial effusion as a complication in adults undergoing SCT

Large pericardial effusion (LPE) leading to cardiac tamponade is a rare complication described in patients undergoing SCT. This complication is considered to be a manifestation of chronic GVHD; however its pathophysiology is poorly understood. Currently, there are no published data systematically describing the incidence, clinical characteristics and outcomes of LPEs in adult stem cell transplant recipients. We retrospectively evaluated 858 adult patients (512 autologous, 148 related and 198 unrelated donor) who underwent hematopoietic stem cell and BM transplants at our institution from 2005 to 2008 for the development of post transplant LPE. Seven patients (0.8%) were found to have LPEs and all these patients had undergone unrelated allografts. The median day of diagnosis post transplant was 229 (range 42-525). None of these patients had active manifestations of GVHD other than serositis at the time of LPE detection. Pericardial window (PW) was successfully placed in all patients who developed cardiac tamponade and most patients with LPE were effectively treated by increasing immunosuppression. We conclude that LPE is a rare late complication after allogeneic transplant in adults and in our study developed only after unrelated transplant. PW can be safely performed in these patients and LPEs can be successfully treated with intensification of systemic immunosupression.     

Independent contribution of bronchoalveolar lavage and serum galactomannan in the diagnosis of invasive pulmonary aspergillosis

The optimal combination of galactomannan index (GMI) testing for the diagnosis of invasive pulmonary aspergillosis (IPA) remains unclear. For diagnostic approaches that are triggered by clinical signs and symptoms in high‐risk patients, institutional variation remains, with some centers routinely relying on only serum GMI or bronchoalveolar lavage (BAL) GMI testing. In addition, use of mold‐active agents before diagnosis of IPA is becoming increasingly common, and understanding the effect of these drugs on test yield is important when making time‐critical treatment decisions. In a single‐center cohort of 210 allogeneic hematopoietic cell transplant recipients, we found that serum and BAL GMI testing contributed independently to IPA diagnosis, supporting the practice of sending both tests simultaneously to ensure a timely diagnosis of IPA. BAL GMI sensitivity was not affected by receipt of mold‐active therapy in our cohort.     

Pulmonary Nocardia and Aspergillus co-infection in a patient with chronic graft-versus-host disease.

Immunosuppression and chronic graft-versus-host disease (GVHD) are major risk factors for the development of invasive pulmonary aspergillosis in bone marrow transplant patients. Although nocardial infections are well described in hematopoietic stem cell transplantation (HSCT) recipients, little information is available about the incidence of nocardiosis in patients with chronic GVHD after HSCT. Coexistence of invasive pulmonary aspergillosis and nocardiosis following non-myeloablative HSCT has not been reported previously. With the increasing use of pentostatin in the treatment of chronic GVHD in future and other nucleoside analogues as preparative regimens in patients undergoing reduced-intensity conditioning transplantation, the possibility of co-infection with rare organisms should be kept in mind while assessing at-risk patients.     

Graft-versus-tumor effect in a patient with advanced neuroblastoma who received HLA haplo-identical bone marrow transplantation

A 5-year-old boy received CD34-positive HLA haplo-identical bone marrow transplantation from his father as treatment for refractory advanced neuroblastoma. He had residual disease in the para-aortic lymph nodes and multiple bones after the transplant. However, all of his residual disease had disappeared completely 3 years later. He developed grade I acute graft-versus-host disease (GVHD) but had no symptoms of chronic GVHD or any other complications. This case demonstrates the possibility of a graft-versus-tumor effect against neuroblastoma by HLA-mismatched allogeneic hematopoietic stem cell transplantation.     

Giardiasis in a hematopoietic stem cell transplant patient

Giardiasis can mimic diarrhea secondary to mucosal injury from the conditioning therapy prior to hematopoietic stem cell transplant (HSCT), as well as from graft‐versus‐host disease (GVHD). Herein, we describe the endoscopic diagnosis of giardiasis in a patient 2 months after HSCT for myelodysplastic syndrome. The patient was referred to gastroenterology service for suspected GVHD, but duodenal biopsy results showed Giardia lamblia. He was successfully treated with metronidazole with prompt resolution of all of his gastrointestinal symptoms. This case highlights the need to consider giardiasis in the differential diagnosis of diarrhea in the peri‐transplant period.     

Radiologically guided fine needle lung biopsies in the evaluation of focal pulmonary lesions in allogeneic stem cell transplant recipients

Lung problems are common in allogeneic stem cell transplant (SCT) recipients. To evaluate the feasibility and diagnostic yield of radiologically guided fine needle lung biopsy (FNLB) in allogeneic SCT recipients with focal pulmonary lesions, a retrospective analysis was carried out. Between 1989 and 1998, radiologists performed a total of 30 FNLBs in 21 allogeneic SCT recipients, guided either by ultrasound (n = 17) or computed tomography (n = 13). The median time from SCT to the first FNLB was 131 days (20-343 days). Prophylactic platelet transfusions were given in 19 procedures (66%). The complications of FNLB included clinically insignificant pneumothorax in four procedures (13%) and self-limiting haemoptysis in one case (3%). The first FNLB was suggestive of invasive pulmonary aspergillosis (IPA) in five patients (24%). Additional clinically useful findings of FNLB included Pseudomonas (two patients) and Nocardia (one patient). The final diagnosis of pulmonary lesions was IPA in 14 patients, immunological lung problems in four patients and other in three patients. Radiologically guided FNLB is feasible in allogeneic SCT recipients and has a low complication rate. The diagnostic yield is high especially for IPA.     

Successful T-cell-replete peripheral blood stem cell transplantation from an HLA 2 loci mismatched mother to her son with refractory anemia in myelodysplastic syndrome

A 15-year-old male with refractory anemia in myelodysplastic syndrome underwent peripheral blood stem cell transplantation from his two-loci-mismatched haploidentical mother. The conditioning regimen was comprised of cyclophosphamide, busulfan, and fludarabine. Non-T-cell-depleted peripheral blood stem cells were infused with graft-versus-host disease (GVHD) prophylaxis consisting of tacrolimus and short-course methotrexate. Engraftment was confirmed on day 18, and complete chimera on day 29. Although the patient developed grade II acute GVHD following the transplantation, it responded rapidly to steroid administration. The subsequent course was uneventful, and he remains well in complete remission in 26 months after transplant. This successful experience suggests that maternal hematopoietic stem cell transplant for children, in specific immune tolerance based on the presence of microchimerism and compatibility of minor histocompatibility antigens between mother and child, may have given rise to the favorable preventing effect against severe GVHD.     

Diagnosis and treatment of chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after hematopoietic stem cell transplant (HSCT). GVHD also is associated with a potent anti-leukemic effect. Chronic GVHD resembles autoimmune diseases and can likely affect any organ or tissue of the body. Skin, oral, liver, and lacrimal gland involvement are most common. The incidence and presentation have been in evolution as new stem cell sources and transplant approaches have been introduced. Although progress in the diagnosis and treatment of chronic GVHD has been limited for many years, there is renewed interest in this disorder. New prognostic scores and animal models of chronic GVHD have been developed. Large, multicenter phase III therapy and biology studies have been undertaken. The challenge for the future will be the discovery of targeted approaches that allow the anti-leukemic effect to be retained and for the reconstitution of normal immunity, thereby reducing infectious complications.     

Herpes simplex thymidine kinase (HStk) transgenic donor lymphocytes

Patients with recurrent leukemia after an allogeneic hematopoietic stem cell transplant may be treated with donor lymphocyte infusions (DLI). The transfusion of lymphocytes from the original hematopoietic stem cell donor induces remission in approximately one third of relapsed AML cases and 80% of relapsed CML. DLI may be complicated by delayed and sometimes lethal graft-versus-host disease (GVHD). In an attempt to avoid this complication, several centers have initiated DLI trials in which the infused lymphocytes carry a suicide gene, herpes simplex thymidine kinase (HStk), which confers sensitivity to ganciclovir (GCV). In the event of severe GVHD, administration of GCV should terminate or ameliorate GVHD.     

Incidence and outcome of idiopathic pneumonia syndrome in pediatric stem cell transplant recipients

Idiopathic pneumonia syndrome (IPS) is a rare complication following stem cell transplant (SCT) and its incidence among pediatric SCT recipients is not known. To assess the incidence of IPS, we retrospectively reviewed the incidence of IPS at our center. IPS is defined as the presence of multilobar infiltrates by chest radiograph or computed tomography scan, need for supplemental oxygenation with declining pulse oximetry and no identifiable pulmonary infection. Between July 1999 and August 2005, 11 of 93 children who received a fully ablative allogeneic SCT (11.8%) developed IPS. All 11 patients had normal pulmonary evaluation before transplant. IPS developed at a median of 17 days (range 8-42 days) after transplant. Recipients of unrelated donor transplant had increased risk of developing IPS. There was a significant association between acute or hyperacute graft-versus-host disease (GVHD) and IPS (P=0.035). All patients had significant hypoxia and five patients required assisted ventilation. IPS was the cause of death in two patients. Although there was complete resolution of respiratory symptoms in the other nine patients, overall transplant-related mortality was significantly higher among patients with IPS (64 vs 17%, P=0.002). IPS is a relatively common complication in pediatric SCT recipients and acute GVHD is an important associated factor.     

Central nervous system (CNS) tuberculosis following allogeneic stem cell transplantation

Tuberculosis is an uncommon infectious complication after stem cell transplantation. We report a patient who presented with a brain mass, 3 months after pulmonary tuberculosis had been diagnosed and while he was receiving triple antituberculous therapy. He had extensive chronic GVHD. The diagnosis was made after biopsy of the lesion. The cerebral mass was excised, antituberculous treatment was maintained and the patient made a complete neurologic recovery. Six months later, he died of gram-negative septic shock. Mycobacterial infections should be considered in allograft recipients with chronic GVHD and solid lesions in the brain. Bone Marrow Transplantation (2000) 25, 567-569.     

Early onset invasive pulmonary zygomycosis following allogeneic peripheral blood stem cell transplantation in a patient with therapy-related myelodysplastic syndrome

A 39-year-old woman received an allogeneic peripheral blood stem cell transplantation from her daughter for secondary myelodysplastic syndrome. On day +12, a cough and fever developed. Chest X-ray and computed tomography demonstrated a consolidation in the left lung. A diagnosis of pulmonary zygomycosis was made on the histology from a transbronchial lung biopsy. Although amphotericin B (AMPH-B) showed efficacy, dose reduction was necessary because of renal toxicity. The patient died of pulmonary zygomycosis, confirmed by an autopsy. We strongly hope for authorization as soon as possible of the use of such a drug as liposomal AMPH-B which appears less toxic.     

Bacterial and mycobacterial pneumonia in transplant recipients

Bacteria and myobacteria are important pulmonary pathogens in transplant recipients and are the focus of this article. Although considerable overlap exists, there are significant differences in the epidemiology and clinical presentation of these organisms in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. The first section of this article focuses on infections in SOT recipients (predominantly heart, liver, lung, and kidney transplant recipients), and the latter addresses these infections in HSCT recipients.