Invasive Fusariosis in Pediatric Hematology/Oncology and Stem Cell Transplant Patients: A Report from the Israeli Society of Pediatric Hematology-Oncology.

Invasive Fusarium species infections in immunocompromised patients occur predominantly in those with hematological malignancies. Survival rates of 20−40% were reported in adults, but data in children are limited. Our retrospective, nationwide multicenter study of invasive fusariosis in pediatric hematology/oncology and stem cell transplant (SCT) patients identified twenty-two cases. Underlying conditions included hematological malignancies (n = 16; 73%), solid tumors (n = 2), and non-malignant hematological conditions (n = 4). Nineteen patients (86%) were neutropenic, nine (41%) were SCT recipients, and seven (32%) received corticosteroids. Sixteen patients (73%) had disseminated fusariosis, five had local infection, and one had isolated fungemia. Fifteen patients (68%) had skin involvement and eight (36%) had a bloodstream infection. Four patients (18%) presented with osteoarticular involvement and four with pulmonary involvement. Nineteen patients (86%) received combination antifungal therapy upfront and three (14%) received single-agent treatment. Ninety-day probability of survival was 77%: four of the five deaths were attributed to fusariosis, all in patients with relapsed/refractory acute leukemias. Ninety-day probability of survival for patients with relapsed/refractory underlying malignancy was 33% vs. 94% in others (p < 0.001). Survival rates in this largest pediatric population-based study were strikingly higher than those reported in adults, demonstrating that invasive fusariosis is a life-threatening but salvageable condition in immunosuppressed children.

Changing Trends in the Survival of Immunosuppressed Children with Invasive Fungal Rhinosinusitis.

BACKGROUND: Acute invasive fungal rhinosinusitis has been associated with high mortality rates. OBJECTIVE: We aimed to explore the contribution of novel detection and treatment methods on the outcome of immunosuppressed children with acute invasive fungal rhinosinusitis. METHODS: The records of all children with a hematologic or oncologic disease who developed acute invasive fungal rhinosinusitis between 2005-2020 were reviewed. RESULTS: Thirty-four patients were included. Aspergillosis and mucormycosis were diagnosed in 20 patients (59%) and 12 patients (35%), respectively. Panfungal polymerase chain reaction (PCR) was associated with a change of treatment in 36% of patients. A more aggressive surgical approach as well as treatment with liposomal amphotericin B and novel antifungals were adopted in recent years. Overall, 26% of patients died of disease, however no disease-specific death occurred since 2012. Diagnosis using panfungal PCR (p = .04) and treatment with novel antifungal medications (p = .017) were significantly associated with disease-specific survival. CONCLUSION: Enhanced fungal detection using panfungal PCR and treatment with novel antifungal agents, combined with rapid diagnosis and treatment, aggressive surgical approach and better control over the underlying oncological disease, may significantly improve the outcome of immunosuppressed children with acute invasive fungal rhinosinusitis.

Disseminated Mucormycosis in Immunocompromised Children: Are New Antifungal Agents Making a Difference? A Multicenter Retrospective Study.

BACKGROUND: Mucormycosis is a life-threatening infection with a tendency for angioinvasion that may lead to progressive dissemination. Disseminated mucormycosis, defined as the involvement of two or more non-contiguous sites, is rare in children, and data concerning its management and outcome are scarce. The aim of this study was to assess the contemporary management strategies and outcomes of disseminated mucormycosis in the pediatric population. METHODS: We conducted a retrospective search in six large tertiary medical centers for all cases of disseminated mucormycosis that occurred between 2009-2020 in patients aged 1-20 years. RESULTS: Twelve cases were identified. Underlying conditions included hematological malignancies (n = 10), solid tumor (post-autologous hematopoietic stem cell transplantations; n = 1), and solid organ (liver) transplantation (n = 1). In all cases, amphotericin B formulations were administered as first-line therapy; in eight cases, they were also administered in combination with an echinocandin or triazole. Seven patients underwent surgical debridement procedures. The six-week mortality was 58%. Among the patients diagnosed between 2009-2015, one of the six survived, and of those diagnosed between 2016-2020, four of the six were salvaged. CONCLUSIONS: Disseminated mucormycosis is a life-threatening and often fatal disease, and improved diagnostic and therapeutic strategies are needed. Nevertheless, in this population-based study, five patients (42%) were salvaged through combined liposomal amphotericin/triazole treatment and extensive surgical interventions.

Isavuconazole As Successful Salvage Therapy for Mucormycosis in Pediatric Patients.

BACKGROUND: Mucormycosis is a rare but emerging life-threatening fungal disease with limited treatment options. Isavuconazole is a new triazole that has shown efficacy in adults for primary and salvage treatment of mucormycosis. However, data in children are scarce. METHODS: The demographic and clinical data of pediatric patients with proven mucormycosis who were treated with isavuconazole in 2015 to 2019 at 2 centers were collected. RESULTS: Four children of median age 10.5 years (range 7-14) met the study criteria. Three had underlying hematologic malignancies, and 1 had sustained major trauma. Isavuconazole was used as salvage therapy in all: in 3 patients for refractory disease, and in 1 after intolerance to another antifungal drug. Isavuconazole was administered alone or combined with other antifungal agents. Following treatment and surgical intervention, complete clinical, radiologic and mycologic responses were documented in all patients. A literature review identified 8 children with mucormycosis who were successfully treated with isavuconazole, as salvage therapy in the majority. CONCLUSION: Our limited experience supports the use of isavuconazole as salvage therapy in pediatric mucormycosis.

Mucormycosis in children with haematological malignancies is a salvageable disease: a report from the Israeli Study Group of Childhood Leukemia.

Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but contemporary data in children are lacking. We conducted a nationwide multicentre study to investigate the characteristics of mucormycosis in children with haematological malignancies. The cohort included 39 children with mucormycosis: 25 of 1136 children (incidence 2·2%) with acute leukaemias prospectively enrolled in a centralized clinical registry in 2004-2017, and an additional 14 children with haematological malignancies identified by retrospective search of the databases of seven paediatric haematology centres. Ninety-two percent of mucormycosis cases occurred in patients with acute leukaemias. Mucormycosis was significantly associated with high-risk acute lymphoblastic leukaemia (OR 3·75; 95% CI 1·51-9·37; P = 0·004) and with increasing age (OR 3·58; 95% CI 1·24-9·77; P = 0·01). Fifteen patients (38%) died of mucormycosis. Rhinocerebral pattern was independently associated with improved 12-week survival (OR 9·43; 95% CI 1·47-60·66; P = 0·02) and relapsed underlying malignancy was associated with increased 12-week mortality (OR 6·42; 95% CI, 1·01-40·94; P = 0·05). In patients receiving frontline therapy for their malignancy (n = 24), one-year cumulative mucormycosis-related mortality was 21 ± 8% and five-year overall survival was 70 ± 8%. This largest paediatric population-based study of mucormycosis demonstrates that children receiving frontline therapy for their haematological malignancy are often salvageable.

Response of Symptomatic Persistent Chronic Disseminated Candidiasis to Corticosteroid Therapy in Immunosuppressed Pediatric Patients: Case Study and Review of the Literature.

BACKGROUND: Chronic disseminated candidiasis (CDC) is a severe invasive fungal infection principally observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Its pathophysiology remains unclear. We describe the management of 6 children with symptomatic CDC who did not respond to antifungal therapy. METHODS: The databases of the hematology-oncology departments of 2 tertiary pediatric medical centers were searched for all patients diagnosed with CDC from 2003 to 2015, who responded to corticosteroids after failing antifungal therapy. Clinical, laboratory and radiologic data were collected. RESULTS: Six patients (3 women, 3 men; 9-18 years of age) met the study criteria. Underlying diseases were acute lymphoblastic leukemia (n = 3) and large B-cell lymphoma, acute myeloid leukemia and severe aplastic anemia (n = 1 each). Presenting symptoms/signs of CDC were fever in all cases, with abdominal or chest pain, and/or mucositis. Candida infection was identified in blood cultures in 4 patients and in bronchoalveolar lavage fluid in one. In the absence of response to antifungal agents (4-50 days from CDC diagnosis), prednisone 2 mg/kg/day or equivalent was administered. CDC-attributable clinical symptoms resolved in 4 patients within 6-19 days; one patient required an additional nonsteroidal anti-inflammatory agent. Abnormalities on imaging decreased or disappeared within 5 months to 2 years in 4 patients. CONCLUSIONS: In children with persistent symptomatic CDC, despite adequate antifungal therapy, administration of corticosteroids may yield rapid resolution of symptoms and decreased inflammatory markers. In patients who do not respond to steroids, the addition of a nonsteroidal anti-inflammatory drug should be considered.

Acute Rhinosinusitis in Immunosuppressed Children: Diagnostic and Therapeutic Management.

BACKGROUND: Immunosuppressive therapy places pediatric patients at risk of developing life-threatening sinonasal infections. Diagnosis and treatment are challenging owing to nonspecific signs and symptoms. The aim of this study was to present our department's experience with the surgical management of acute rhinosinusitis in immunosuppressed children. METHODS: The records of all children with a hematologic or oncologic disease who underwent endoscopic sinus surgery (ESS) for acute rhinosinusitis from January 2005 to May 2014 were reviewed. Data were retrospectively collected on demographics, clinical and imaging characteristics, microbiology, pathology, treatment and outcome. RESULTS: Thirty-four-immunosuppressed children underwent ESS for acute rhinosinusitis. Most patients had a fungal infection. Nineteen patients died at the end of follow-up; 10 deaths were infection-related. Facial swelling was the only symptom that correlated with death of infection. Relapse of the underlying disease, bone marrow transplantation, and long duration of neutropenia correlated with infection-related mortality. Fungal infection, and specifically Aspergillus, correlated with death from infection. CONCLUSIONS: ESS is a safe and efficient procedure for diagnosing and treating immunosuppressed pediatric patients with acute rhinosinusitis. Early detection and aggressive medical and surgical treatment, with control of underlying risk factors, are crucial to improve outcome.

Treatment of T cell lymphoblastic lymphoma in children and adolescents: Israel Society of Pediatric Hematology Oncology retrospective study.

BACKGROUND: Survival in T cell lymphoblastic lymphoma has improved over the past 30 years, largely due to treatment protocols derived from regimens designed for children with acute lymphoblastic leukemia. OBJECTIVES: To assess the outcome of the NHL-BFM-95 protocol in children and adolescents hospitalized during the period 1999-2006. METHODS: We conducted a retrospective multi-institutional, non-randomized study of children and adolescents up to age 21 with T cell lymphoma admitted to pediatric departments in six hospitals in Israel, with regard to prevalence, clinical characteristics, pathological characteristics, prognostic factors, overall survival (OS) and event-free survival (EFS). All patients had a minimal follow-up of one year after diagnosis. The study was based on the NHL-BFM-95 protocol. RESULTS: At a median follow-up of 4 years (range 1-9 years), OS and EFS for all patients was 86.5% and 83.8%, respectively. OS was 86.7% and 83.3% for patients with stage III and stage IV, respectively, and EFS was 83.3% and 83.3%, respectively. EFS was 62.5% for Arab patients and 89.7% for Jewish patients (P = 0.014). Patients who did not express CD45 antigen showed superior survival (P = 0.028). Five patients (13.5%) relapsed, four of whom died of their disease. Death as a consequence of therapy toxicity was documented in one patient while on the re-induction protocol (protocol IIA). CONCLUSIONS: Our study shows that OS and EFS for all patients was 86.5% and 83.8%, respectively.