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Abstract: Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

To pool resources and reduce inequalities in access to transition preparation for patients, transition clinics were created in France. They are places in hospitals, independent of the usual care departments, offering multiple resources and services for adolescents and their parents. Of the 24 physicians from care departments who were surveyed, half of them do not use transition clinics. The implementation of transition clinics in hospitals did not lead to their adoption by the care departments that needed the most support for transition preparation of their patients. A strategy improving adoption is needed to allow transition clinics to reduce inequalities., Competing Interests: Declaration of Competing Interest None of the authors declared conflict of interest, real or perceived., (Copyright © 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged ≥ 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de Référence Déficits Immunitaires Héréditaires registry was identified blindly for case-control analysis, with ≤3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality., (© 2023 by The American Society of Hematology.)

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT., (© 2022 by The American Society of Hematology.)

Newborn screening for severe combined immunodeficiency (SCID) is now routinely performed in many countries across Europe and around the world. The number of T-cell receptor excision circles (TRECs) reflects T cell levels. TREC quantification is possible using dried blood spot (DBS) samples already collected from newborns to screen for other conditions. This method is very sensitive and highly specific. Data in the literature show that the survival rate for children with SCID is much higher when the disease is detected through early screening, as opposed to a later diagnosis. Newborns diagnosed with SCID may receive the appropriate care quickly, before the onset of serious infectious complications, which raises survival rates, improves quality of life, and limits side effects and treatment costs. At the request of the French Ministry of Health, France's National Authority for Health (Haute Autorité de Santé) is expected to issue recommendations on this topic soon. The nationwide DEPISTREC study, involving 48 maternity units across France, showed that routine SCID screening is feasible and effective. Such screening offers the additional benefit of also diagnosing non-SCID lymphopenia within the infant population., (Copyright © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To assess the outcome of HIV-infected individuals attending one of the largest French pediatric HIV centers in 2016-2017 and to compare the rates of antiretroviral coverage and virological suppression with the UNAIDS targets., Patients and Methods: The clinical and immuno-virological status of 163 HIV-1-infected children and adolescents attending Necker Hospital in Paris, France, were investigated. Virological suppression was defined as an HIV-1 viral load<50 copies/mL for at least six months. All genotypic resistance tests performed since birth were analyzed., Results: Most patients were born in Sub-Saharan African countries (41.7%) or in France (38.0%). Their median age was 14 years [IQR 7.3-17.0]. Although 33.7% of individuals had a history of AIDS-defining clinical event(s), 86.5% of children/adolescents were free from HIV-related symptoms at their most recent evaluation. Antiretroviral coverage was high (98.2%; mainly including one integrase inhibitor [42.3%] or one protease inhibitor [23.9%]). At the last visit, most patients (82.8%) had normal CD4T lymphocytes counts (≥25%). Although 61.7% of antiretroviral-experienced children had resistance to≥1 drug class and 9.2% had triple-class resistance, 80.3% of patients receiving antiretrovirals for≥6 months (126/157) were virologically suppressed. International adoptees were more frequently virologically suppressed than other patients (96.0% versus 74.6%, P=0.02)., Conclusions: Antiretroviral coverage exceeded the second UNAIDS 90 target aimed at ending the AIDS epidemic. The rate of virological suppression, one of the highest reported in children in high-income countries, is approaching the third UNAIDS 90 target and the rate observed in French HIV-infected adults on antiretrovirals., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Early onset ataxia telangiectasia (A-T) is a neurodegenerative DNA-instability disorder, which presents early in childhood. Hallmarks of A-T are progressive ataxia and a dramatic increased risk of developing malignancies (25%), especially of hematological origin. In children these malignancies mainly concern aggressive Non-Hodgkin lymphoma, acute leukemias and Hodgkin lymphoma. Of the acute leukemias, T-cell lymphoblastic leukemia (T-ALL) is by far the most common. Since patients with A-T experience increased toxicity to radio- and chemotherapeutic treatment, the optimal treatment strategy of acute leukemia remains subject of debate. Review of literature of treatment of T-ALL in patients with A-T (n = 18) showed that many patients are not diagnosed with A-T at time of presentation of T-ALL. This implicates that physicians must be aware of symptoms of A-T in young patients presenting with T-ALL. Complete remission rates are high following upfront modified as well as unmodified treatment strategies. Treatment of ALL in children with A-T is feasible and should be performed. Definitive treatment strategy must be determined by shared decision making with patient, caretakers and medical team. Future prospective studies are needed to elucidate optimal treatment strategy., (Copyright © 2016. Published by Elsevier Masson SAS.)

Severe combined immunodeficiencies (SCID) are a group of inherited diseases of the immune system characterized by profound abnormalities of T-cell development. Infants with SCID require prompt clinical intervention to prevent life-threatening infection and studies show significantly improved survival in babies diagnosed at birth based on previous family history. SCID follows the criteria for population-based newborn screening because it is asymptomatic at birth and fatal within the 1st year of life if there is no intervention, the confirmation of the disease is easy, there is a curative treatment, and it is known that early hematopoietic stem cell transplantation significantly improves survival, the quality of immune reconstitution, and quality of life. Quantification of T-cell receptor excision circles (TRECs) in DNA extracted from Guthrie samples is a sensitive and specific screening test for SCID. We conducted a nationwide prospective study of neonatal screening of SCID in a population of 200,000 French newborns over a period of 2 years. The objective was to study the clinical utility and the cost-effectiveness ratio, and to demonstrate that universal SCID screening could result in a substantial benefit to detect individuals, making screening relatively cost-effective in spite of the low incidence of the disease., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Granulomas may develop as a response to a local antigenic trigger, leading to the activation of macrophages and T-lymphocytes. Primary immunodeficiency (PID) is associated with the development of extensive cutaneous granulomas, whose aetiology remains unknown. We performed high-throughput sequencing of the transcriptome of cutaneous granuloma lesions on two consecutive index cases, and RT-PCR in a third consecutive patient. The RA27/3 vaccine strain of rubella virus-the core component of a universally used paediatric vaccine-was present in the cutaneous granuloma of these three consecutive PID patients. Controls included the healthy skin of two patients, non-granulomatous cutaneous lesions of patients with immunodeficiency, and skin biopsy samples of healthy individuals, and were negative. Expression of viral antigens was confirmed by immunofluorescence. Persistence of the rubella vaccine virus was also demonstrated in granuloma lesions sampled 4-5 years earlier. The persistence of the rubella virus vaccine strain in all three consecutive cutaneous granuloma patients with PID strongly suggests a causal relationship between rubella virus and granuloma in this setting., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

On the basis of a nationwide database of 160 patients with Wiskott-Aldrich syndrome (WAS), we identified a subset of infants who were significantly more likely to be attributed with an Ochs score of 5 before the age of 2 (n = 26 of 47 [55%], P = 2.8 × 10(−7)). A retrospective analysis revealed that these patients often had severe refractory thrombocytopenia (n = 13), autoimmune hemolytic anemia (n = 15), and vasculitis (n = 6). One patient had developed 2 distinct cancers. Hemizygous mutations predictive of the absence of WAS protein were identified in 19 of the 24 tested patients, and the absence of WAS protein was confirmed in all 10 investigated cases. Allogeneic hematopoietic stem cell transplantation (HSCT) was found to be a curative treatment with a relatively good prognosis because it was successful in 17 of 22 patients. Nevertheless, 3 patients experienced significant disease sequelae and 4 patients died before HSCT. Therefore, the present study identifies a distinct subgroup of WAS patients with early-onset, life-threatening manifestations. We suggest that HSCT is a curative strategy in this subgroup of patients and should be performed as early in life as possible, even when a fully matched donor is lacking.

Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.

The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily characterized by a progressive loss of naive T cells. The in vivo consequences include recurrent bacterial and viral infections and autoimmune manifestations. MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2. Conversely, FAS expression and the FAS-mediating apoptotic pathway were up-regulated. These abnormalities suggest that increased cell death of naive and proliferating T cells is the main mechanism underlying this novel immunodeficiency. Our results characterize a new mechanism in primary T-cell immunodeficiencies and highlight a role of the MST1/FOXO1 pathway in controlling the death of human naive T cells.

In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications.

Different types of hereditary immune deficiencies are at risk of severe fungal infections. Such infections can reveal the deficit. The type of micro-organisms involved, the clinical presentation, the immune reaction observed around the germ can then guide the etiological diagnosis. As often in the field of immunodeficiencies, advances in the pathophysiology provide crucial informations on the natural defense mechanisms against these organisms. Therapeutic advances have dramatically improved the prognosis of these potentially serious and disabling infections., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Optimal staging and evaluation of residual lesions of invasive fungal infections (IFIs) are major challenges in the immunocompromised host. Preliminary data have suggested that [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) uptake may be observed in the course of active invasive fungal infections. The aim of this study was to assess the role of positron emission tomography with [¹⁸F]FDG ([¹⁸F]FDG-PET) in the diagnosis and staging of IFI. A prospective monocentric study evaluating [¹⁸F]FDG-PET in 30 consecutive adults and children with European Organization for Research and Treatment of Cancer/Mycoses Study Group probable or proven IFI was performed. Twenty males and ten females (median age, 45 years (range 6-7 years)) were enrolled. Twenty-six were immunocompromised, as follows: haematological malignancy (18) with allogeneic stem cell transplantation (16/18), solid tumour (three), solid organ transplantation (two), diabetes mellitus (two) and cystic fibrosis (one). IFIs were acute invasive aspergillosis (ten), chronic disseminated candidiasis (ten), zygomycosis (two), black grains eumycetoma (two), pulmonary Histoplasma capsulatum var. capsulatum histoplasmosis (two), and Phomopsis sp. osteoarthritis, Scedosporium apiospermum and Candida krusei spondylodiscitis, and acute pulmonary coccidioidomycosis in one case each. An increased uptake of [¹⁸F]FDG was observed in all areas previously identified by computed tomography and/or magnetic resonance imaging to be involved by IFI. In 4/10 chronic disseminated candidiasis cases, [¹⁸F]FDG-PET revealed small splenic abscesses that were unapparent on the corresponding computed tomography scan. [¹⁸F]FDG uptake disappeared after 6 months of antifungal therapy in three patients with chronic disseminated candidiasis for whom the [¹⁸F]FDG-PET was performed to assess the evolution of the disease. [¹⁸F]FDG-PET could potentially be useful for the initial diagnosis and staging of IFI. Whether or not [¹⁸F]FDG-PET might be useful for assessing the optimal duration of IFI therapy should now be assessed in a specific prospective study., (© 2010 The Authors. Clinical Microbiology and Infection © 2010 European Society of Clinical Microbiology and Infectious Diseases.)

X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.

FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm(3) and 1232/mm(3) CD3(+) cells, 647/mm(3) and 868/mm(3) CD4(+) T cells, 213/mm(3) and 425/mm(3) naive CD4(+) T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3(+) cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discontinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for severe combined immunodeficiency (SCID). Detailed assessment of the long-term outcome of HSCT, ie, the occurrence of clinical events and the quality and stability of immune reconstitution, is now required. We performed a single-center retrospective analysis of the long-term outcome of HSCT in 90-patient cohort followed for between 2 and 34 years (median, 14 years). Clinical events and immune reconstitution data were collected. Almost half the patients have experienced one or more significant clinical events, including persistent chronic graft-versus-host disease (GVHD), autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, chronic human papilloma virus (HPV) infections, and a requirement for nutritional support. With the notable exception of severe HPV infection, these complications tend to become less common 15 years later after HSCT. A multivariate analysis showed that the occurrence of these events correlated with non-genoidentical donors, diagnosis of Artemis SCID, and quality of immune reconstitution. In most cases, HSCT enables long-term survival with infrequent sequelae. However, the occurrence of relatively late-onset complications is a concern that requires specific means of prevention and justifies careful patient follow-up.

Cytotoxic T lymphocytes (CTLs) and natural killer cells help control infections and tumors via a killing activity that is mediated by the release of cytotoxic granules. Granule secretion at the synapse formed between the CTL and the target cell leads to apoptosis of the latter. This process involves polarization of the CTL's secretory machinery and cytotoxic granules. The small GTPase Rab27a and the hMunc13-4 protein have been shown to be required for both granule maturation and granule docking and priming at the immunologic synapse. Using a tandem affinity purification technique, we identified a previously unknown hematopoietic form of Slp2a (Slp2a-hem) and determined that it is a specific effector of the active form of Rab27a. This interaction occurs in vivo in primary CTLs. We have shown that (1) Rab27a recruits Slp2a-hem on vesicular structures in peripheral CTLs and (2) following CTL-target cell conjugate formation, the Slp2a-hem/Rab27a complex colocalizes with perforin-containing granules at the immunologic synapse, where it binds to the plasma membrane through its C2 domains. The overexpression of a dominant-negative form of Slp2a-hem markedly impaired exocytosis of cytotoxic granules-indicating that Slp2a is required for cytotoxic granule docking at the immunologic synapse.

Recurrent respiratory tract infections are a common motif of paediatric consultations. Most of the time, children are healthy and their immune system has a delayed but normal maturation. Sometimes, paediatricians have to rule out an underlying pathology, especially a primary immunodeficiency when a child presents a higher susceptibility to infections. Oriented by the medical history and the physical examination, some laboratory tests will have to be performed. However, their interpretation can be uneasy because it depends on the age, the vaccine status and the infectious medical history. A precise diagnosis should be made in order to rule out a severe primary immunodeficiency. These children may also need a specialized medical environment.

Fever is a common symptom in children and may sometimes be prolonged or recurrent. There are many differential diagnoses, which may lead to significant diagnostic delay. Diagnosis is based on the clinical presentation as well as a widespread panel of investigations that are necessary in order to exclude the many potential causes of fever before reaching a definite diagnosis. In particular, the physician will look for infections and malignancies before considering the disease as inflammatory. This chapter reviews the differential diagnosis of prolonged or recurrent fever, and discusses most of the inflammatory syndromes presenting with fever.