Consensus on COVID-19 Vaccination in Pediatric Oncohematological Patients, on Behalf of Infectious Working Group of Italian Association of Pediatric Hematology Oncology.

Vaccines represent the best tool to prevent the severity course and fatal consequences of the pandemic by the new Coronavirus 2019 infection (SARS-CoV-2). Considering the limited data on vaccination of pediatric oncohematological patients, we developed a Consensus document to support the Italian pediatric hematological oncological (AIEOP) centers in a scientifically correct communication with families and patients and to promote vaccination. The topics of the Consensus were: SARS-CoV-2 infection and disease (COVID-19) in the pediatric subjects; COVID-19 vaccines (type, schedule); who and when to vaccinate; contraindications and risk of serious adverse events; rare adverse events; third dose and vaccination after COVID-19; and other general prevention measures. Using the Delphi methodology for Consensus, 21 statements and their corresponding rationale were elaborated and discussed with the representatives of 31 centers, followed by voting. A high grade of Consensus was obtained on topics such as the potential risk of severe COVID-19 outcome in pediatric oncohematological patients, the need for vaccination as a preventative measure, the type, schedule and booster dose of vaccine, the eligibility of the patients for vaccination, and the timing, definition, and management of contraindications and serious adverse events, and other general prevention measures. All 21 of the statements were approved. This consensus document highlights that children and adolescents affected by hematological and oncological diseases are a fragile category. Vaccination plays an important role to prevent COVID-19, to permit the regular administration of chemotherapy or other treatments, to perform control visits and hospital admissions, and to prevent treatment delays.

Ecthyma Gangrenosum in Children With Cancer: Diagnosis at a Glance: A Retrospective Study From the Infection Working Group of Italian Pediatric Hematology Oncology Association.

BACKGROUND: To depict ecthyma gangrenosum (EG) clinical presentation and evolution in a large multicenter pediatric retrospective collection of children with malignancies or bone marrow failure syndromes, to facilitate early diagnosis. METHODS: EG episodes diagnosed in the period 2009-2019 were identified by a retrospective review of clinical charts at centers belonging to the Italian Pediatric Hematology Oncology Association. RESULTS: Thirty-eight cases of EG occurring in children (male/female 16/22; median age 5.2 years) with hematologic malignancy (29), allogeneic stem cell transplantation (2) or relapsed/refractory solid tumor (3) were collected. The involved sites were: perineal region (19), limbs (10), trunk (6), head and the iliac crest (3). Bacteremia was present in 22 patients. Overall, the germs isolated were Pseudomonas aeruginosa (30), Stenotrophomonas maltophilia (3) and Escherichia coli (1); 31% of them were multidrug-resistant. All patients received antibacterial treatment, while surgery was performed in 24 patients (63.1%). Predisposing underlying conditions for EG were severe neutropenia (97.3%), corticosteroid treatment (71%) and iatrogenic diabetes (23.7%). All patients recovered, but EG recurred in 5 patients. Nine patients (24%) showed sequelae (deep scars, with muscle atrophy in 2). Four patients (10.5%) died, 1 due to relapse of EG with Carbapenem-resistant Enterobacteriaceae co-infection and 3 due to the progression of the underlying disease. CONCLUSIONS: EG requires early recognition and a proper and timely treatment to obtain the recovery and to avoid larger necrotic lesions, eventually evolving in scarring sequelae.

Thermal inactivation of SARS COVID-2 virus: Are steam inhalations a potential treatment?

BACKGROUND: The emergence of SARS-CoV-2 pandemic has upset health systems around the world and caused immeasurable losses and costs. Until a vaccine will become available, the recommended prevention measures remain physical distancing and enhanced hygiene. METHODS AND FINDINGS: The proteic structure external to the virus is the main target that may eventually lead to reduce or block its replication in the upper airways. We developed a protocol based of repeated steam inhalation cycles aimed at reducing the risk of progression to full blown infection if performed soon after contagion. The protocol has been used in a single-center open label trial on ten infected asymptomatic or pauci-symptomatic health care professionals. CONCLUSIONS: The promising results we obtained with this easily accessible, non-invasive and inexpensive procedure should prompt controlled trials.

ß3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment.

Although there is an increasing evidence that cancer stem cell (CSC) niches in the tumor microenvironment (TME) plays a crucial role in sustaining solid tumors progression, several molecular players involved in this regulation still remain unknown. The role of ß-adrenergic signaling in enhancing tumor growth through ß2-adrenoreceptors (ß2-ARs) has been confirmed in different cancer models, but the role played by the ß3-adrenergic receptor (ß3-AR) has recently emerged. Previous studies showed that ß3-AR promotes cancer growth through the activation of different stromal cells in the TME, and leads to melanoma malignancy progression through inflammation, angiogenesis, and immunotolerance. Here we show that in B16 melanoma-bearing mice, the pharmacological ß3-AR blockade is able to reduce the expression of CSC markers, and to induce a differentiated phenotype of hematopoietic subpopulations in TME. In particular, cytofluorimetric analysis (FACS) of the tumor mass shows that ß3-AR antagonist SR59230A promotes hematopoietic differentiation as indicated by increased ratios of lymphoid/hematopoietic stem cells (HSCs) and of myeloid progenitor cells/HSCs, and increases the number of Ter119 and natural killer (NK) precursor cells, and of granulocyte precursors, indicating active hematopoiesis within the tumor tissue. Moreover, pharmacological antagonism of ß3-AR induces mesenchymal stem cell (MSC) differentiation into adipocytes subtracting a potential renewal of the stem compartment by these cells. Here we demonstrate that ß3-AR blockade in the TME by inducing the differentiation of different stromal cells at the expense of stemness traits could possibly have a favorable effect on the control of melanoma progression.

Case Report: Signal Transducer and Activator of Transcription 3 Gain-of-Function and Spectrin Deficiency: A Life-Threatening Case of Severe Hemolytic Anemia.

STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.

Invasive mucormycosis in children with cancer: A retrospective study from the Infection Working Group of Italian Pediatric Hematology Oncology Association.

BACKGROUND: Invasive mucormycosis is a rare but frequently fatal fungal disease. The acute and rapidly progressive evolution causes unfavourable outcome in 22%-59% of patients and its treatment represents a clinical challenge, especially in immunocompromised patients. Current data in paediatric oncological patients are limited. OBJECTIVES: The infection Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) analysed the episodes of invasive mucormycosis occurred between 2009 and 2016. PATIENTS: Fifteen cases of proven mucormycosis (male/female 8/7; median age 14.1 years, range 7.7-18.6) were reported after chemotherapy for acute leukaemia and lymphoma (12) and allogeneic stem cell transplantation (3). The aetiology was Rhizopus oryzae 4, Lichtheimia corymbifera 3 and Mucor spp. 8. RESULTS: Paranasal sinus was the primary site of infection in 14/15 patients combined with orbital involvement (9), central nervous system (8), lung (4), thyroid gland and kidney (1). All patients received liposomal Amphotericin B (L-AmB) (3-10 mg/kg), with surgical debridement in 14/15 cases. Eleven patients received maintenance treatment with posaconazole (9) or isavuconazole (2). Eight out of fifteen patients (53.3%) died, after 3-6 months. CONCLUSIONS: Mucormycosis involved mainly the sinu-orbital site and affected children >10 years. Despite aggressive treatment with high-dose L-AmB and timely surgical debridement, the mortality rate remains still high.

Guidelines on vaccinations in paediatric haematology and oncology patients.

OBJECTIVE: Vaccinations are the most important tool to prevent infectious diseases. Chemotherapy-induced immune depression may impact the efficacy of vaccinations in children. PATIENTS AND METHODS: A panel of experts of the supportive care working group of the Italian Association Paediatric Haematology Oncology (AIEOP) addressed this issue by guidelines on vaccinations in paediatric cancer patients. The literature published between 1980 and 2013 was reviewed. RESULTS AND CONCLUSION: During intensive chemotherapy, vaccination turned out to be effective for hepatitis A and B, whilst vaccinations with toxoid, protein subunits, or bacterial antigens should be postponed to the less intensive phases, to achieve an adequate immune response. Apart from varicella, the administration of live-attenuated-virus vaccines is not recommended during this phase. Family members should remain on recommended vaccination schedules, including toxoid, inactivated vaccine (also poliomyelitis), and live-attenuated vaccines (varicella, measles, mumps, and rubella). By the time of completion of chemotherapy, insufficient serum antibody levels for vaccine-preventable diseases have been reported, while immunological memory appears to be preserved. Once immunological recovery is completed, usually after 6 months, response to booster or vaccination is generally good and allows patients to be protected and also to contribute to herd immunity.

A Phase II study on the safety and efficacy of a single dose of pegfilgrastim for mobilization and transplantation of autologous hematopoietic stem cells in pediatric oncohematology patients.

BACKGROUND: Limited data are available on the use of pegfilgrastim in pediatric patients as a mobilizing agent in association with chemotherapy. STUDY DESIGN AND METHODS: This was a prospective, multicenter, Phase II study to evaluate the safety and efficacy of a single dose of 100 µg/kg pegfilgrastim in mobilizing peripheral blood stem cells (PBSCs) in pediatric patients. The primary endpoint of the study was the percentage of good mobilizers with pegfilgrastim (blood peak of CD34+ cells ≥ 20 × 10(6) /L). The results were compared with a historical control group. RESULTS: Thirty of 36 recruited patients were classified as good mobilizers (83%). The median value of circulating CD34+ at leukapheresis was 143 × 10(6) /L (range, 20 × 10(6) -1988 × 10(6) /L). No significant adverse effects were associated with the use of pegfilgrastim and no patient was withdrawn from using the drug. A blood peak of 20 × 10(6) /L or more CD34+ was observed in 33 of 36 control patients (92%) and the median CD34+ count at leukapheresis was 158 × 10(6) /kg (range, 28 × 10(6) -4529 × 10(6) /kg; p = 0.7). No significant differences were found between the two groups in terms of toxicity or other variables of mobilization. As at October 2008, 23 patients of the pegfilgrastim group and 32 patients of the filgrastim group underwent autologous transplant. No significant differences were found in terms of early toxicity, myeloid recovery, and Day 100 survival. CONCLUSION: A single dose of 100 µg/kg pegfilgrastim was safe and effective for PBSC collection in pediatric patients. We suggest that these results support the use of pegfilgrastim for pediatric patients.

Morbidity of pandemic H1N1 influenza in children with cancer.

BACKGROUND: To define the mortality and the current impact of the H1N1 pandemic in pediatric hematology-oncology centers, we performed a specific survey. PROCEDURE: Pharyngeal swabs from patients with fevers of unknown origin, flu-like symptoms or bronchopneumonia were screened for H1N1 using PCR. RESULTS: Sixty-two patients with documented H1N1 infection were reported: 16 had recently stopped therapy, 2 were at the diagnosis stage, and 44 were receiving therapy. The clinical course was severe (requiring ICU admission) in only 1 patient, moderate (requiring hospital admission) in 38, and mild in the remaining 23 (37%), treated as outpatients. While none of the patients died of H1N1-related complications, two patients died of progressive cancer; in all of the remaining cases, symptoms resolved within 11 days. The clinical course was complicated by respiratory distress or bronchopneumonia in 10 cases. Oseltamivir was given to 82% of patients. Chemotherapy was temporarily withdrawn in 54% of cases for a median time of 21 days (range, 4-43 days). CONCLUSION: H1N1 infection in children with cancer was not reported as the cause of death in any case but resulted in reduced intensity of anti-cancer therapy.

Multidrug resistant Pseudomonas aeruginosa infection in children undergoing chemotherapy and hematopoietic stem cell transplantation.

Pseudomonas aeruginosa is one leading gram-negative organism associated with nosocomial infections. Bacteremia is life-threatening in the immunocompromised host. Increasing frequency of multi-drug-resistant (MDRPA) strains is concerning. We started a retrospective survey in the pediatric hematology oncology Italian network. Between 2000 and 2008, 127 patients with Pseudomonas aeruginosa bacteremia were reported from 12 centers; 31.4% of isolates were MDRPA. Death within 30 days of a positive blood culture occurred in 19.6% (25/127) of total patients; in patients with MDRPA infection it occurred in 35.8% (14/39). In the multivariate analysis, only MDRPA had significant association with infection-related death. This is the largest series of Pseudomonas aeruginosa bacteremia cases from pediatric hematology oncology centers. Monitoring local bacterial isolates epidemiology is mandatory and will allow empiric antibiotic therapy to be tailored to reduce fatalities.

The use of B-type natriuretic peptide in paediatric patients: a review of literature.

OBJECTIVE: Plasma levels of brain natriuretic peptide (BNP) and its inactive fragment N-terminal pro-BNP are recognized as reliable markers of ventricular dysfunction in adults. We aimed to verify BNP applications in children. METHODS: A review of the literature on this subject was carried out. RESULTS: When dealing with paediatric patients, age and sex-related normal values must be considered. Higher BNP plasma levels are reported in children with chronic heart failure; they are related with the type of dysfunction and with prognosis. Moreover, increased BNP levels have been reported in asymptomatic children and adolescents pretreated with anthracyclines, who are at risk for ventricular dysfunction. CONCLUSION: BNP and pro-BNP also seem to be effective markers of ventricular dysfunction in paediatric patients. Clinical use may be extended not only for the characterization of heart dysfunction, but also for monitoring asymptomatic patients at specific risk. To this purpose, wider application in clinical trials appears warranted.

An increasing incidence of chickenpox central nervous system complications in children: what's happening in Tuscany?

BACKGROUND: The most frequent noncutaneous site of involvement of chickenpox is the central nervous system (CNS) and complications include cerebellar ataxia, encephalitis, and meningitis. OBJECTIVES: We have recently observed an unusually high number of children with chickenpox CNS complications in our university children's hospital. A study to evaluate the incidence of these complications over time in children living in Tuscany was carried out. STUDY DESIGN: We evaluated all cases of chickenpox and chickenpox complications leading to hospitalization in children aged 1 month-14 years reported to the Tuscany public health centre between 1997 and 2004. The International Classification of Disease Ninth Revision-CM hospital discharge diagnostic codes and medical records were used. RESULTS: The incidence (95% confidence interval) of CNS complications/1000 chickenpox cases was stable between 1997 and 2001 [1997: 0.80 (0.29-1.74); 1998: 0.73 (0.29-1.50); 1999: 0.67 (0.25-1.46); 2000: 0.56 (0.15-1.44); 2001: 0.59 (0.16-1.50)] but increased significantly (chi(2) for trend: 9.401; p=.0021) in 2002 [1.56 (0.83-2.66)], in 2003 [1.73 (0.95-2.90)] and in 2004 [1.51 (0.74-2.27)]. Non-CNS complications remained stable over time. CONCLUSIONS: Possible factors biasing the result were taken into account. Reasons of increased CNS complications remain unknown, but the possible emergence of a particularly neurotropic strain of varicella-zoster virus should be further investigated.