ABSTRACT
PURPOSE: Sinonasal mucoceles (SM) are benign, expansive neoformations which require surgical marsupialization to prevent severe complications. The present study reports the larger case history ever published: a 28-years expertise in the surgical management of SM. METHODS: A retrospective study was conducted on patients surgically treated for SM at the Departments of Otorhinolaryngology of Varese and Pavia, between 1994 and 2022. RESULTS: 398 patients were reported. An endoscopic endonasal marsupialization of SM was performed in 92,5% of cases. 7% of patients underwent a combined approach while 0,5% required an exclusive open surgery. The average follow-up after surgery was 10-60 months. SM overall recurrence was observed in 11,4% of cases. CONCLUSION: Endonasal endoscopic SM marsupialization is a feasible technique which allows the preservation of the anatomy and physiology avoiding the surgical invasiveness of the external approaches. The well-established surgical expertise in the endonasal endoscopy together with technological improvements widened the indication range of the exclusive endoscopic technique over the traditional open surgery.
ABSTRACT
OBJECTIVES: To test the usefulness of an extended panel of lymphocyte subsets in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a paediatric rheumatology centre. METHODS: Patients referred from 2015 to 2018 to our rheumatology unit for an autoimmune or autoinflammatory condition were retrospectively analysed. Oliveira's required criteria [chronic lymphoproliferation and elevated double-negative T (DNT)] were applied as first screening. Flow cytometry study included double-negative CD4-CD8-TCRαß+ T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+ T cells, B220+ T cells and CD27+ B cells. Data were analysed with a univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated. RESULTS: A total of 264 patients were included in the study and classified as: (i) autoimmune diseases (n = 26); (ii) juvenile idiopathic arthritis (JIA) (35); (iii) monogenic systemic autoinflammatory disease (27); (iv) periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (100); (v) systemic undefined recurrent fever (45); (vi) undetermined-systemic autoinflammatory disease (14); or (vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαß+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed five clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαß+B220+ lymphocytes. CONCLUSIONS: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαß+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to the paediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.
Subject(s)
Autoimmune Diseases/diagnosis , Autoimmune Lymphoproliferative Syndrome/diagnosis , Hereditary Autoinflammatory Diseases/diagnosis , Age of Onset , Autoimmune Diseases/blood , Autoimmune Lymphoproliferative Syndrome/blood , CD4-CD8 Ratio , Child , Child, Preschool , Early Diagnosis , Female , Flow Cytometry , Hereditary Autoinflammatory Diseases/blood , Humans , Infant , Male , Receptors, Antigen, T-Cell, alpha-beta/blood , Retrospective StudiesABSTRACT
In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In addition, immune-dysregulation, secondary to marrow failure, has been reported as being, in some cases, the most evident and early sign of the disease and making the diagnosis of both groups of disorders challenging. Dyskeratosis congenita is a disorder characterized by premature telomere erosion, typically showing marrow failure, nail dystrophy and leukoplakia, although incomplete genetic penetrance and phenotypes with immune-dysregulation features have been described. We report on a previously healthy 17-year-old girl, with a cousin successfully treated for acute lymphoblastic leukemia, who presented with leukopenia and neutropenia. The diagnostic work-up showed positive anti-neutrophil antibodies, leading to the diagnosis of autoimmune neutropenia, a slightly low NK count and high TCR-αß+-double-negative T-cells. A next-generation sequencing (NGS) analysis showed the 734C>A variant on exon 6 of the TINF2 gene, leading to the p.Ser245Tyr. The telomere length was short on the lymphocytes and granulocytes, suggesting the diagnosis of an atypical telomeropathy showing with immune-dysregulation. This case underlines the importance of an accurate diagnostic work-up of patients with immune-dysregulation, who should undergo NGS or whole exome sequencing to identify specific disorders that deserve targeted follow-up and treatment.
Subject(s)
Dyskeratosis Congenita , Neutropenia , Humans , Dyskeratosis Congenita/genetics , Telomere , Exons , Neutropenia/genetics , Bone Marrow , Telomere-Binding Proteins/geneticsABSTRACT
The differential diagnosis of marrow failure (MF) is crucial in the diagnostic work-up, since genetic forms require specific care. We retrospectively studied all patients with single/multi-lineage MF evaluated in a single-center to identify the type and incidence of underlying molecular defects. The diepoxybutane test was used to screen Fanconi Anemia. Other congenital MFs have been searched using Sanger and/or Next Generation Sequencing analysis, depending on the available tools over the years. Between 2009-2019, 97 patients (aged 0-32 years-median 5) with single-lineage (29%) or multilineage (68%) MF were evaluated. Fifty-three (54%) and 28 (29%) were diagnosed with acquired and congenital MF, respectively. The remaining 16 (17%), with trilinear (n=9) and monolinear (n=7) MF, were found to have an underlying primary immunodeficiency (PID) and showed clinical and biochemical signs of immune-dysregulation in 10/16 (62%) and in 14/16 (87%) of cases, respectively. Clinical signs were also found in 22/53 (41%) and 8/28 (28%) patients with idiopathic and classical cMF, respectively. Eight out of 16 PIDs patients were successfully transplanted, four received immunosuppression, two did not require treatment, and the remaining two died. We show that patients with single/multi-lineage MF may have underlying PIDs in a considerable number of cases and that MF may represent a relevant clinical sign in patients with PIDs, thus widening their clinical phenotype. An accurate immunological work-up should be performed in all patients with MF, and PID-related genes should be considered when screening MF in order to identify disorders that may receive targeted treatments and/or appropriate conditioning regimens before transplant.
Subject(s)
Bone Marrow Failure Disorders/genetics , Bone Marrow/pathology , Primary Immunodeficiency Diseases/genetics , Adolescent , Adult , Bone Marrow/metabolism , Bone Marrow Failure Disorders/pathology , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Genetic Testing , High-Throughput Nucleotide Sequencing , Humans , Infant , Male , Primary Immunodeficiency Diseases/pathology , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Functional variants of the cytotoxic T-lymphocyte antigen-4 (CTLA4) could contribute to the pathogenesis of disorders characterized by abnormal T-cell responses. CASE PRESENTATION: We report a case of a 13-year-old girl who first presented with polyarticular juvenile idiopathic arthritis poorly responsive to treatment. During the following years the patient developed cytopenias, chronic lymphoproliferation, high values of T-cell receptor αß+ CD4- CD8- double-negative T cells and defective Fas-mediated T cells apoptosis. Autoimmune lymphoproliferative syndrome was diagnosed and therapy with mycophenolate mofetil was started, with good hematological control. Due to the persistence of active polyarthritis, mycophenolate mofetil was replaced with sirolimus. In the following months the patient developed hypogammaglobulinemia and started having severe diarrhea. Histologically, duodenitis and chronic gastritis were present. Using the next generation sequencing-based gene panel screening, a CTLA4 mutation was detected (p.Cys58Serfs*13). At the age of 21 the patient developed acute autoimmune hemolytic anemia; steroid treatment in combination with abatacept were started with clinical remission of all symptoms, even arthritis. CONCLUSIONS: Targeted immunologic screening and appropriate genetic tests could help in the diagnosis of a specific genetically mediated immune dysregulation syndrome, allowing to select those patients who can take advantage of target therapy, as in the case of abatacept in CTLA4 deficiency.
Subject(s)
Abatacept/therapeutic use , Arthritis, Juvenile/drug therapy , Autoimmune Lymphoproliferative Syndrome/drug therapy , CTLA-4 Antigen/deficiency , Immune Checkpoint Inhibitors/therapeutic use , Mutation , Adolescent , Arthritis, Juvenile/complications , Arthritis, Juvenile/pathology , Autoimmune Lymphoproliferative Syndrome/complications , Autoimmune Lymphoproliferative Syndrome/pathology , CTLA-4 Antigen/genetics , Female , Humans , PrognosisABSTRACT
In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.
Subject(s)
Abatacept/therapeutic use , Adaptor Proteins, Signal Transducing/deficiency , CTLA-4 Antigen/agonists , Immunologic Deficiency Syndromes/drug therapy , Protein Deficiency/drug therapy , Protein-Losing Enteropathies/drug therapy , Age of Onset , CTLA-4 Antigen/deficiency , Child, Preschool , Humans , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/metabolism , Immunologic Deficiency Syndromes/pathology , Immunosuppressive Agents/therapeutic use , Male , Prognosis , Protein Deficiency/complications , Protein Deficiency/metabolism , Protein Deficiency/pathology , Protein-Losing Enteropathies/complications , Protein-Losing Enteropathies/metabolism , Protein-Losing Enteropathies/pathologyABSTRACT
Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.
Subject(s)
Apoptosis/genetics , Autoimmune Lymphoproliferative Syndrome/genetics , Caspase 10/genetics , Polymorphism, Genetic , Adult , Autoimmune Lymphoproliferative Syndrome/pathology , Caspase 8/genetics , Fas Ligand Protein/physiology , Female , Heterozygote , Homozygote , Humans , Male , Mutation , Phenotype , fas Receptor/physiologyABSTRACT
It is recognized that chimerism following hematopoietic stem cell transplantation (HSCT) is a dynamic process. The aims of this study were to describe the evolution of chimerism in children with nonmalignant diseases who underwent allogeneic HSCT, and to analyze the risk factors influencing chimerism status. A total of 101 HSCTs were performed in 85 patients with nonmalignant diseases. The donor was unrelated in 62.4% of HSCTs. Reduced-intensity conditioning (RIC) regimen was administered in 48.5% of patients. Acute graft-versus-host disease (aGVHD) occurred in 51.7% and chronic GVHD (cGVHD) in 39.7% of patients. Analysis of chimerism was performed through amplification of 9 specific short tandem repeats by polymerase chain reaction at engraftment and 1, 6, and 12 months after HSCT. Upon first evaluation, complete chimerism (CC) was detected in 34.7% and mixed chimerism (MC) in 55.4%, whereas graft failure occurred in 9.9% of patients. Severe aGVHD was associated with CC (P = .031). The last chimerism evaluation showed CC in 72.1%, stable MC in 12.8%, and progressive MC in 3.5%. CC was associated with a higher incidence of aGVHD (P = .016) and cGVHD (P = .022), whereas the RIC regimen was associated with graft failure (P = .026). One- and 3-year overall survival (OS) was 87.4% and 80.5%, respectively, with a lower OS at 3 years in patients with CC compared with those with MC (P = .008). aGVHD and cGVHD represent factors favoring CC, thus close, careful follow-up of chimerism is recommended in patients affected by nonmalignant disease.
Subject(s)
Chimerism/statistics & numerical data , Hematopoietic Stem Cell Transplantation/methods , Adolescent , Child , Child, Preschool , Female , Graft Rejection , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Male , Polymerase Chain Reaction , Risk Factors , Survival Analysis , Time Factors , Tissue Donors , Transplantation Conditioning/methods , Transplantation, HomologousSubject(s)
Autoimmunity , Neutropenia , B-Cell Activating Factor , B-Lymphocytes , Humans , Neutropenia/geneticsABSTRACT
The management of refractory autoimmune cytopenias in childhood is challenging due to the lack of established evidence on escalating treatments. The long-term efficacy of immunosuppressive drugs was evaluated in children with refractory autoimmune cytopenias referred to the Haematology Unit of the Gaslini Children's Hospital between 2001 and 2014. Patients were grouped into three categories: autoimmune lymphoproliferative syndrome (ALPS), ALPS-related syndrome (at least one absolute/primary additional criterion for ALPS) and primary autoimmune cytopenia (PAC, cytopenia with no other immunological symptoms/signs). Fifty-eight children (aged 1-16 years) entered the study: 12 were categorized with ALPS, 24 were ALPS-related and 22 had PAC. Five didn't receive treatment. Fifty-three were initially treated with steroids/intravenous immunoglobulin. Fourteen responded, whereas 39 did not. Of these 39 patients, 34 (87%) received mycophenolate mofetil (MMF) as second/further-line treatment and 22 (65%) responded. Within these 34 subjects, ALPS patients responded better (11/11, 100%) than the two other groups pooled together (11/23, 48%; P = 0·002). Sirolimus was given as second/further-line treatment to 16 children, and 12 (75%) responded, including 8 who previously failed MMF therapy. Median follow-up was 3·46 years. MMF and Sirolimus were well-tolerated and enabled partial/complete and sustained remission in most children. These drugs may be successfully and safely used in children with refractory autoimmune cytopenias with or without ALPS/ALPS-related disorders and may represent a valid second/further line option.
ABSTRACT
Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. Several studies show alterations of the immunological status of FA patients including defects in peripheral blood lymphocyte subsets, serum immunoglobulin levels, and inflammatory cytokines. However scanty information is available on the response of FA cells to specific infectious antigens. In this work we examined the response of FA cells to different immunological stimuli and found a defective response of IL-1ß, TNF-α and IL-17 to Candida albicans stimulation thus pointing to a potentially impaired response to fungal infections of FA patients.
Subject(s)
Candida albicans/immunology , Fanconi Anemia/immunology , Fanconi Anemia/microbiology , Immunity , Adolescent , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Cells, Cultured , Child , Child, Preschool , Cytokines/biosynthesis , Fanconi Anemia/pathology , Humans , Infant , Young AdultSubject(s)
Autoimmune Lymphoproliferative Syndrome , Immunosuppression Therapy , Adolescent , Adult , Autoimmune Lymphoproliferative Syndrome/blood , Autoimmune Lymphoproliferative Syndrome/pathology , Autoimmune Lymphoproliferative Syndrome/therapy , Child , Child, Preschool , Female , Humans , Infant , MaleABSTRACT
Despite advances in endoscopic approaches, instrumentations and imaging guidance systems, the management of frontal sinus is still challenging. Failure of the endoscopic procedure and restenosis of the newly formed ostium have been demonstrated even with large frontal sinusotomy. We describe a newly designed double nasoseptal flap to cover the bare bone after endoscopic modified Lothrop procedure (EMLP). Five fresh, double-injected cadavers were dissected through an endoscopic endonasal approach. Posteriorly based nasoseptal flap on one side and laterally based nasoseptal flap on the other side were harvested before performing wide EMLP. Feasibility of the procedure, versatility of the flap, coverage area and measurements were calculated. Harvesting the mucoperichondrial/mucoperiosteal flap over the septectomy site was straightforward step. Two different designed flaps (one on each side) are more practical to avoid torsion of the flap. The flap measures 2 × 3 cm on average that was able to cover the bare bone of the anterior and posterior wall of frontal sinus. Osteoneogenesis and progressive osteoplastic activity after EMLP plays a major role in restenosis of frontal sinus. Vascularized nasoseptal flap helps in preventing closure of the newly formed ostium. Applying these flaps over the bare bone enhances the healing process and minimizes the crust formation.
Subject(s)
Endoscopy/methods , Frontal Sinus/pathology , Frontal Sinus/surgery , Surgical Flaps , Cadaver , Chronic Disease , Constriction, Pathologic/prevention & control , Humans , Paranasal Sinus Diseases/pathology , Paranasal Sinus Diseases/prevention & control , Paranasal Sinus Diseases/surgery , Recurrence , Retrospective StudiesSubject(s)
Anemia, Hemolytic, Autoimmune/therapy , Autoimmune Lymphoproliferative Syndrome/therapy , Immunologic Deficiency Syndromes/therapy , Stem Cell Transplantation/methods , Transplantation, Haploidentical/methods , Anemia, Hemolytic, Autoimmune/complications , Anemia, Hemolytic, Autoimmune/genetics , Antigens, CD19 , Autoimmune Lymphoproliferative Syndrome/complications , Autoimmune Lymphoproliferative Syndrome/genetics , Child, Preschool , Cytomegalovirus Infections/complications , Hematopoietic Stem Cell Mobilization/methods , Homeodomain Proteins/genetics , Humans , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/genetics , Male , Receptors, Antigen, T-Cell, alpha-beta , Transplantation Conditioning/methodsSubject(s)
Purpura, Thrombocytopenic, Idiopathic/therapy , Salvage Therapy/methods , Sirolimus/therapeutic use , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Male , Mycophenolic Acid/pharmacology , Mycophenolic Acid/therapeutic use , Retrospective Studies , TOR Serine-Threonine Kinases/antagonists & inhibitors , Treatment Outcome , Young AdultABSTRACT
In this study, the immunological status of 61 patients with Fanconi anemia (FA) with advanced marrow failure before hematopoietic stem cell transplantation was analyzed by assessing the phenotype of peripheral blood lymphocytes, serum immunoglobulin (Ig) levels, and inflammatory cytokines. In patients with FA, total absolute lymphocytes (P < 0.0001), B cells (P < 0.0001), and NK cells (P = 0.003) were reduced when compared with normal controls. T cells (CD3), that is, cytotoxic T cells, naïve T cells, and regulatory T cells, showed a relative increase when compared with controls. Serum levels of IgG (P < 0.0001) and IgM (P = 0.004) were significantly lower, whereas IgA level was higher (P < 0.0001) than in normal controls. TGF-ß (P = 0.007) and interleukin (IL)-6 (P = 0.0007) levels were increased in the serum of patients when compared with controls, whereas sCD40L level decreases (P < 0.0001). No differences were noted in the serum levels of IL-1ß, IL-2, IL-4, IL-10, IL-13, IL-17, and IL-23 between FA subjects and controls. This comprehensive immunological study shows that patients with FA with advanced marrow failure have an altered immune status. This is in accordance with some characteristics of FA such as the proinflammatory and proapoptotic status. In addition, B lymphocyte failure may make tight and early immunological monitoring advisable.
Subject(s)
Fanconi Anemia/immunology , Adolescent , Adult , Child , Child, Preschool , Cytokines/blood , Cytokines/immunology , Fanconi Anemia/blood , Female , Humans , Immunoglobulins/blood , Immunoglobulins/immunology , Immunophenotyping , Lymphocyte Subsets/immunology , Male , Retrospective Studies , Young AdultABSTRACT
Dyskeratosis congenita is a rare congenital telomeropathy characterized by cutaneous and nail dystrophy, oral leukoplakia, and bone marrow failure. Pulmonary fibrosis and cancers are late manifestations. Allogeneic hematopoietic stem cell transplant represents the only cure for those with bone marrow failure with this disease, but outcomes reported are overall poor, with organ toxicities, graft failure, and graft-versus-host disease as main issues. Although reduced intensity conditioning regimens seem to be related to better outcomes, a standard regimen for dyskeratosis congenita has never been defined. Here, we report a successful long-term outcome of an 8-year-old girl with dyskeratosis congenita who received 2 consecutive allogeneic hematopoietic stem cell transplants from different unrelated donors, because of rejection after the first one, both conditioned with fludarabine-based reduced intensity conditioning regimen. The second transplant was complicated by severe hemorrhagic cystitis and acute grade IV graft-versus-host disease in the early phase and mild chronic graft-versus-host disease and ureteral stenosis in the late phase. This experience confirms that dyskeratosis congenita is at high risk for transplant-related morbidity but that a fludarabine-based reduced intensity conditioning regimen is a safe and feasible option as a preparative regimen, as shown here in a second transplant after first graft rejection. To reduce the risk of graft-versus-host disease, more effective prophylaxis schedules should be chosen in cases of unrelated donor, and haploidentical hematopoietic stem cell transplant with in vitro α/ ß + and CD19+ depletion should be considered.
Subject(s)
Dyskeratosis Congenita , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Female , Humans , Child , Graft Rejection/prevention & control , Unrelated Donors , Dyskeratosis Congenita/diagnosis , Dyskeratosis Congenita/surgery , Dyskeratosis Congenita/complications , Transplantation Conditioning/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & controlABSTRACT
Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte homeostasis classically due to mutation of FAS, FASL, and CASP10 genes (ALPS-FAS/CASP10). Despite recent progress, about one-third of ALPS patients does not carry classical mutations and still remains gene orphan (ALPS-U, undetermined genetic defects). The aims of the present study were to compare the clinical and immunological features of ALPS-FAS/CASP10 versus those of ALPS-U affected subjects and to deepen the genetic characteristics of this latter group. Demographical, anamnestic, biochemical data were retrieved from medical record of 46 ALPS subjects. An enlarged panel of genes (next-generation sequencing) was applied to the ALPS-U group. ALPS-U subjects showed a more complex phenotype if compared to ALPS-FAS/CASP10 group, characterized by multiorgan involvement (P = 0.001) and positivity of autoimmune markers (P = 0.02). Multilineage cytopenia was present in both groups without differences with the exception of lymphocytopenia and autoimmune neutropenia that were more frequent in ALPS-U than in the ALPS-FAS/CASP10 group (P = 0.01 and P = 0.04). First- and second-line treatments were able to control the symptoms in 100% of the ALPS-FAS/CASP10 patients, while 63% of ALPS-U needed >2 lines of treatment and remission in some cases was obtained only after target therapy. In the ALPS-U group, we found in 14 of 28 (50%) patients 19 variants; of these, 4 of 19 (21%) were known as pathogenic and 8 of 19 (42%) as likely pathogenic. A characteristic flow cytometry panel including CD3CD4-CD8-+TCRαß+, CD3+CD25+/CD3HLADR+, TCR αß+ B220+, and CD19+CD27+ identified the ALPS-FAS/CASP10 group. ALPS-U seems to represent a distinct entity from ALPS-FAS/CASP10; this is relevant for management and tailored treatments whenever available.
ABSTRACT
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a valuable alternative for children with nonmalignant disease and ex vivo negative selection of TCR-αß+ cells is an emerging graft manipulation option that carries several potential advantages in terms of reduced risk of graft-versus-host disease (GvHD) and improved immune reconstitution. We report all consecutive patients with a diagnosis of nonmalignant disease who received a TCR-αß+ and CD19+depleted haplo-HSCT at "IRCCS Istituto Giannina Gaslini" from 2013 to 2019; the conditioning regimen was myeloablative or non-myeloablative, depending on underlying disease; all patients received antithymocyte globulin and rituximab. No post-transplantation GvHD prophylaxis was given in presence of a TCR-αß+ cell dose in the graft lower than the threshold of 1 × 105/kg of the recipient's weight. Among 20 HSCTs, engraftment occurred in 17 (85%) after a median of 14 and 12 days from graft infusion for neutrophils and platelets, respectively. Primary graft failure was diagnosed in 3 (15%) patients, and 2 (10%) experienced secondary rejection; all of these patients underwent a second HSCT. The cumulative incidence of a-GvHD and c-GvHD was 15% (2 = grade 1, 1 = grade 4) at 90 days and 5% (1 = grade 1) at 7 months, respectively. Cytomegalovirus reactivation requiring pre-emptive treatment was observed in 9 patients (45%). One patient developed a JC virus-related progressive multifocal leukoencephalopathy, successfully managed with donor-derived virus-specific T-cell infusions. A complete immunological recovery was reached in most patients within 6 months. After a median follow-up of 4 years, 18 patients are alive, with a cumulative survival probability of 90%. Haplo-HSCT after ex vivo TCR-αß+/CD19+ negative selection may be considered a good option for children with nonmalignant diseases because it ensures a high engraftment rate with an acceptable risk of graft failure, very low incidence of significant GvHD, and good immune reconstitution with low frequency of severe virus-related disease. However, the control of viral infection/reactivation should be kept high to promptly provide pre-emptive treatments and approaches of antiviral adoptive immunotherapy.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Antigens, CD19 , Child , Graft vs Host Disease/prevention & control , Humans , Receptors, Antigen, T-Cell, alpha-beta , Transplantation ConditioningABSTRACT
Background: Evans syndrome (ES) is a rare disorder classically defined as the simultaneous or sequential presence of autoimmune haemolytic anaemia and immune thrombocytopenia, but it has also been described as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying inborn error of immunity (IEI) that can benefit from specific treatments. Aims: The aim of this study is to investigate the clinical and immunological characteristics and the underlying genetic background of a single-centre cohort of patients with ES. Methods: Data were obtained from a retrospective chart review of patients with a diagnosis of ES followed in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both haematological and immunological disorders, in particular IEI. Results: Between 1985 and 2020, 40 patients (23 men, 17 women) with a median age at onset of 6 years (range 0-16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine of the 40 (8%) patients had a positive family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 27/40 (67%) of cases, respectively. Seventeen out of 40 (42%) children fit the ALPS diagnostic criteria. The remaining 21 (42%) and 2 (5%) were classified as having an ALPS-like and an idiopathic disease, respectively. Eighteen patients (45%) were found to have an underlying genetic defect on genes FAS, CASP10, TNFSF13B, LRBA, CTLA4, STAT3, IKBGK, CARD11, ADA2, and LIG4. No significant differences were noted between patients with or without variant and between subjects with classical ES and the ones with other forms of multilineage cytopenias. Conclusions: This study shows that nearly half of patients with ES have a genetic background being in most cases secondary to IEI, and therefore, a molecular evaluation should be offered to all patients.