Introduction Autoimmune cytopenias (AICs) are a group of disorders characterized by immune-mediated destruction of blood cells. In children, they are often secondary to immune dysregulation that may ...require long-lasting immunosuppression. Mycophenolate mofetil and sirolimus represent two well-tolerated options to treat these disorders, often as a steroid-sparing option. However, no data are available on the infection risk for patients undergoing long-lasting treatments. Patients and methods The rate of severe infective events was calculated in episodes per 100 persons/months at risk (p/m/r) documented by the analysis of hospitalization charts between January 2015 and July 2023 of patients treated with mycophenolate mofetil or sirolimus given for isolated AIC or AICs associated with autoimmune lymphoproliferative syndrome (ALPS)/ALPS-like syndromes in two large Italian pediatric hematology units. Results From January 2015 to July 2023, 13 out of 96 patients treated with mycophenolate mofetil or sirolimus developed 16 severe infectious events requiring hospitalization. No patients died. Overall infection rate was 0.24 person/*100 months/risk (95% CI 0.09–0.3). Serious infectious events incidence was higher in patients with ALPS-like compared to others (0.42 versus 0.09; p = 0.006) and lower in patients who underwent mycophenolate treatment alone compared to those who started sirolimus after mycophenolate failure (0.04 versus 0.29, p = 0.03). Considering only patients who started treatment at the beginning of study period, overall cumulative hazard was 18.6% at 60 months (95% CI 3.4–31.4) with higher risk of infectious events after 5 years in ALPS-like patients (26.1%; 95% CI 3.2–43.5) compared to other AICs (4%; 95% CI 0–11.4; p = 0.041). Discussion To the best of our knowledge, this is the first study to describe the infectious risk related to mycophenolate and sirolimus chronic treatment in patients with AICs and immune dysregulation. Our data highlight that infection rate is very low and mainly related to the underlying hematological condition. Conclusions Mycophenolate and sirolimus represent a safe immunosuppressive therapy in AICs and immune dysregulation syndromes.
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.
IgG4-related disease (IgG4-RD) is a recently discovered immune-mediated fibroinflammatory condition, uncommon in the pediatric population, that could involve multiple organs and induce cancer-like ...lesions and organ damage. Its main features are multiple injuries in different sites, a dense lymphoplasmacytic infiltrate rich in IgG4 plasma cells, storiform fibrosis, and often high serological concentrations of IgG4. Autoimmune pancreatitis is the most common manifestation, mainly in adults. Two cases of IgG4-RD in children with lymph node localization of disease are reported. Localized or systemic lymph node involvement is common, but lymph node enlargement as the first and only manifestation of IgG4-RD is unusual, and therefore, hard to differentiate from other diseases. IgG4-related lymphadenopathy (IgG4-LAD) is most likely a distinct disease, described as isolated lymphadenopathy, related to the presence of elevated numbers of IgG4-positive plasma cells. Both disorders are likely to be misdiagnosed in children because they are characterized by rare and polymorphic features. IgG4-RD and IgG4-LAD should be considered in the differential diagnosis of disorders characterized by lymphadenopathy of uncertain etiology.
A nationwide questionnaire-based survey was designed to evaluate the management and prophylaxis of febrile neutropenia in pediatric patients admitted to hematology-oncology and hematopoietic stem ...cell transplant units. Of the 34 participating centers, 40 and 63%, respectively, continue to prescribe antibacterial and antimycotic prophylaxis in low-risk subjects and 78 and 94% in transplant patients. Approximately half of the centers prescribe a combination antibiotic regimen as first-line therapy in low-risk patients and up to 81% in high-risk patients. When initial empirical therapy fails after seven days, 63% of the centers add empirical antimycotic therapy in low-and 81% in high-risk patients. Overall management varies significantly across centers. Preventive nursing procedures are in accordance with international guidelines. This survey is the first to focus on prescribing practices in children with cancer and could help to implement practice guidelines.
This retrospective study investigated the effects of rituximab in 19 pediatric patients (15 girls and 4 boys) with chronic refractory symptomatic immune thrombocytopenic purpura (ITP). Patients ...received from 2 to 5 weekly infusions of rituximab (375 mg/m(2)); 15 patients were younger than 12 years when treated. The median follow-up time was 30 months (range, 9-43 months). The overall response rate was 68% (13/19 patients). Six responders relapsed at a median of 4.5 months (range, 3-8 months). Seven patients still displayed a platelet count >150,000/microL at a median of 33 months (range, 14-43 months) after rituximab treatment. Six of 15 patients treated with 4 or 5 weekly infusions and 1 of 4 patients treated with 2 or 3 infusions are still in remission. No difference was detected between splenectomized and nonsplenectomized patients. The duration of ITP disease at the time of treatment did not influence the response rate. Patients still in remission showed significantly lower levels of CD19+ cells after 4 and 6 months than nonresponding or relapsed patients (P < .05). No major infections were reported during follow-up. Our data show the efficacy and tolerability of rituximab in young children with refractory symptomatic ITP. Nonrelapsed patients showed a more prolonged B-cell depletion.
ALPS is a congenital disorder secondary to defects of FASmediated apoptosis, usually showing during the first years of life with variable phenotype, mainly characterized by lymphoproliferation and ...autoimmunity. Most patients carry mutation on FAS gene, more rarely defects on FASL/CASP10 are involved. Very few cases of ALPS-CASP10 have been reported, therefore clinical and immunological characteristics of such patients need to be better defined. Some mutations with a role in the pathogenesis of the disease have been reported over the years (Leu285Phe, Ile406Leu). Although others with conflicting interpretation have been afterwards classified as polymorphisms (Val410Ile, Tyr446Cys), nonetheless they have been associated with a defective apoptosis function.
The aim of this study is to describe the phenotype of a cohort of patients carrying CASP10 variants. The clinical and immunological parameters included in the ALPS diagnostic criteria were evaluated as CD3+TCRaβ+CD4-CD8- (DNTs), the biomarkers (IL10,IL-18,sFAS, Vitamin B12), the ALPS panel signature (high DNT, high DNTsB220+, and low CD27+, low CD3+CD25+/CD3+HLADR+ ratio), and the apoptosis test.
Thirty-two patients aged 0–53 years (median 10.9) were studied. Six carried the known Ile406Leu mutation, 11 presented some unreported variants as Cys401Leufs* (3), Pro501Leu (4), Ser239Cys (1), Arg104*(2), c684+4G>A (1). The remaining 16 carried polymorphic variants. Overall, only 18 patients (56%) showed lymphoproliferation and/or splenomegaly. Twenty-seven patients (84%) showed autoimmune features including autoimmune cytopenia (65%) in 19 cases. DNTs were raised in 64% of cases and apoptosis test was positive in 74% of patients including all cases with novel mutations. Five (15%) patients showed hypogammaglobulinemia. Twelve (37%) and 10/32 (31%) patients showed an ALPS and ALPS-like phenotype, respectively. The remaining 10 (31%) presented a different immune-dysregulation pattern. Two patient (6%) developed a lymphoma. Table 1 shows details of clinical and immunological characteristics. Median follow-up was 5.9 years (0.5–24).
This is the largest reported cohort of patients carrying CASP10 variants showing that most of them have a clinical phenotype other than ALPS, mainly presenting with milder immune dysregulation showing at older age. Due to this different clinical pattern, ALPS diagnostic criteria should be reviewed and patients with CASP10 variants should be considered as having a different disorder.Table 1Clinical and immunological characteristics of patients carrying CASP10 variants.Total (З2)Casp10 polymorphic variants (16)Casp10 pathogenic variants (16)pALPS phenotype12 (37%)6 (37%)6 (37%)nsALPS-like phenotype10 (31%)6 (37%)4 (25%)nsOther immunedysregulation10 (31%)4 (25%)6 (37%)nsIL-1S >(500 pg/mL)10 (31%)7 (44%)3 (19%)<0.05B12(>663 pg/mL)11 (34%)5 (31%)6 (37%)nsIL-10 (>20 pg/mL)1 (3%)1 (6%)0 (0%)nssFAS ligand (>200 pg/mL)0 (0%)0 (0%)0 (0%)nsDNT cells (%CD3) (>1,5%)21 (65%)10 (62%)11 (69%)nsCD3CD25+/CD3HLADR+ ratio (<1%)21 (65%)10 (62%)11 (69%)nsTCR αβ+ B220+ (>60%)10 (31%)5 (31%)4 (25%)nsLinfoB CD27+ (CD19tot) (<15%)20 (62%)11 (69%)9 (56%)nsALPS Panel positive 4/45 (15%)3 (19%)2 (12%)ns
X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce.
Our aim was to ...describe the natural history of XLA.
A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients’ laboratory, clinical, and imaging data were recorded on an annual base.
Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease.
This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients’ clinical management and increase awareness among physicians.
Recently, an association between Helicobacter pylori (HP) and iron deficiency anemia (IDA) was proposed. We describe 9 pediatric patients with a history of long-standing IDA and HP infection. After ...HP test results were confirmed to be positive, anti-HP therapy consisting of omeprazole, clarithromycin, and amoxicillin was administered for 2 weeks. The hematologic profile and iron status were assessed before and periodically after the end of the eradication regimen. The eradication of HP was associated with stable normalization of iron stores. HP infection may be involved in cases of IDA of unknown origin, and the eradication of HP is associated with the resolution of anemia.
Gut involvement is frequent in immunologic disorders, especially with inflammatory manifestations but also with cancer. In the last years, advances in functional and genetic testing have improved the ...diagnostic and therapeutic approach to immune dysregulation syndromes. CTLA-4 deficiency is a rare disease with variable phenotype, ranging from absence of symptoms to severe multisystem manifestations and complications. We describe a rare case of CTLA-4 deficiency in a boy with gastric cancer, very early onset inflammatory bowel disease and polyautoimmunity, the second-ever reported in the literature with the same characteristics. A 17-year-old boy was referred to Bambino Gesù Children's Hospital of Rome, a tertiary care center, for a gastric mass and a long-term history of very early onset inflammatory bowel disease, diabetes mellitus type 1, polyarthritis and psoriasis. Histology of gastric biopsies revealed the presence of neoplastic signet ring cells. Imaging staging showed localized cancer; therefore, the patient underwent subtotal gastrectomy with termino-lateral gastro-jejunal anastomosis. Immunological work up and genetic testing by next-generation sequencing panels for primary immunodeficiencies led to the diagnosis of CTLA-4 deficiency. Good disease control was obtained with the administration of Abatacept. The patient experienced an asymptomatic SARS-CoV-2 infection without any concern. Eighteen months after treatment initiation, the patient is alive and well. Immunologic and genetic testing, such as next-generation sequencing, should always be part of the diagnostic approach to patients with complex immune dysregulation syndrome, severe clinical course, poor response to treatments or cancer. The early recognition of the monogenic disease is the key for disease management and targeted therapy.
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