Background Most children with primary immunodeficiencies (PIDs) now reach adulthood. However, few studies have evaluated their health status and health-related quality of life (HRQoL). Objective To ...investigate long-term morbidity, the French Reference Center for PIDs initiated a prospective multicenter cohort: the French Childhood Immune Deficiency Long-term Cohort. The data collected were used to assess the physical health condition of patients who reached adulthood and the effect on their quality of life. Methods Patients were asked to complete health status questionnaires. A severity score (grade 1 mild to grade 4 life-threatening) was assigned to each health condition. The HRQoL of patients was compared with age- and sex-matched French normal values by using the 36-item Short-Form Survey (SF-36) HRQoL questionnaire. Results Among 329 participants, the mean age at evaluation was 27.6 years, with a 21-year mean follow-up after diagnosis; 43% reported at least 1 grade 4 health condition, and 86% reported at least 1 grade 3 (severe) or 4 health condition. Twenty-five (7.6%) patients had been treated for cancer. Compared with the French normal values, adults with PIDs scored significantly lower for all HRQoL domains. HRQoL was strongly associated with the burden of health conditions. The association with grade 4 or grade 3-4 health conditions was highly significant for all physical and mental domains. Conclusion Adults with PIDs diagnosed during childhood experienced a heavy burden of health conditions, which affected their HRQoL. Our results emphasize the need to closely monitor this vulnerable population.
Background Chronic granulomatous disease (CGD) is a rare phagocytic disorder that results in not only infections but also potentially severe inflammatory manifestations that can be difficult to ...diagnose and treat. Objective To describe inflammatory manifestations in a single-center cohort of patients with CGD. Methods Medical records of patients treated at Necker-Enfants Malades Hospital (Paris, France) between 1968 and 2009 and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH) were retrospectively reviewed. Results In a study population of 98 patients, a total of 221 inflammatory episodes were recorded in 68 individuals (69.4%). The incidence rate of inflammatory episodes was 0.15 per person-year (0.18 in patients with X-linked XL CGD and 0.08 in patients with autosomal-recessive AR CGD). The most commonly affected organs were the gastrointestinal tract (in 88.2% of the patients), lungs (26.4%), the urogenital tract (17.6%), and eyes (8.8%). Inflammation at other sites (the skin, central nervous system, and tympanum) and autoimmune manifestations (lupus, arthritis, etc) were recorded in 19.1% and 10.3% of the patients, respectively. Granuloma was found in 50% of the 44 histological analyses reviewed. The risk of inflammatory episodes was 2-fold higher in patients with XL-CGD than in patients with AR-CGD (relative risk, 2.22; 95% CI, 1.43-3.46). Conclusions Patients with XL-CGD have a higher risk of developing inflammatory episodes than do patients with AR-CGD. Although the most commonly affected organ is the gastrointestinal tract, other sites can be involved, making the management of patients with CGD a complex, multidisciplinary task.
Background Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in 1 or more organs. Gastrointestinal manifestations of systemic mastocytosis have been previously studied ...in small cohorts of patients, and no specific histologic description is available. Objective We sought to assess the clinical and pathologic features of gastrointestinal manifestations in patients with mastocytosis. Methods Medical history and gastrointestinal symptoms of patients with mastocytosis (n = 83) were compared with those of matched healthy subjects (n = 83) by means of patient questionnaire. Data were analyzed for epidemiologic, clinical, biological, and genetic factors associated with gastrointestinal symptoms for patients with mastocytosis. A comparative analysis of gastrointestinal histology from patients with mastocytosis (n = 23), control subjects with inflammatory bowel disease (n = 17), and healthy subjects (n = 19) was performed. Results The following gastrointestinal symptoms occurred more frequently and were more severe in patients with mastocytosis than in healthy subjects: bloating (33% vs 7.2%, P < .0001), abdominal pain (27.3% vs 4.8%, P < .0001), nausea (23% vs 8.4%, P = .02), and diarrhea (33.85% vs 1.2%, P < .0001). Patients with mastocytosis had a significantly higher incidence of personal history of duodenal ulcer ( P = .02). Wild-type (WT) c-Kit was associated with diarrhea ( P = .03). Specific histologic lesions were present in patients with mastocytosis but were not correlated with clinical symptoms. Conclusion Gastrointestinal manifestations in patients with mastocytosis are highly prevalent and often severe. Clinical symptoms do not correspond to histologic findings, are nonspecific, and can simulate irritable bowel syndrome.
Background Telangiectasia macularis eruptiva perstans (TMEP) has not been fully characterized. Objective We sought to estimate the frequency and clinical characteristics of TMEP in a cohort of adult ...patients with cutaneous mastocytosis, and to assess the presence of systemic involvement. Methods We included all consecutive patients evaluated for cutaneous mastocytosis in 2 centers: the Mastocytosis Competence Center of the Midi-Pyrénées from May 2006 to December 2013, and the French Reference Center for Mastocytosis from January 2008 to September 2013. Skin phenotype, histopathology, presence of KIT mutation in the skin, and assessment of systemic involvement according to World Health Organization (WHO) criteria were prospectively investigated. Results Of 243 patients with cutaneous mastocytosis, 34 (14%) were given a diagnosis of TMEP. The diagnosis of systemic mastocytosis was established in 16 patients (47%) with TMEP. Three patients (9%) had aggressive systemic mastocytosis (C-findings according to WHO). In all, 32 patients (94%) exhibited at least 1 mast cell activation–related symptom. Limitations Patient recruitment was undertaken at 2 referral centers with expertise in the diagnosis and treatment of mastocytosis so that the clinical findings and incidence of systemic involvement may be overestimated in comparison with the overall population of patients with TMEP. Conclusion TMEP accounts for about 14% of patients with cutaneous mastocytosis. The disease manifests as mast cell activation symptoms in almost all patients and can be associated with systemic involvement in about 50% of cases.
Apart from the common alteration in elastic fibers, the other pathological features are not observed in the STAT3-deficient patient. ...interaction between STAT3 and elastin has never been reported. ......this is the first detailed report on a unique and previously uncharacterized vasculopathy associated with STAT3 deficiency.
Immunosuppressive agents (corticosteroids and azathioprine) are associated with significant adverse effects, mostly infections. ...in a series of 5 patients treated with anti-TNF- agents,3 infections ...were more frequent, and 2 deaths occurred despite effectiveness in severe colitis, thus raising concerns regarding their safety in such patients. Because patients 3 and 6 experienced improvement in their pseudomass lesions after 6 and 12 months (see Figs E2 and E3), patients 4 and 5 did not show any improvement in their interstitial pattern, fibrotic pattern, or both (see Fig E4).
Background Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM ...expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. Objective We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. Methods We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. Results Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. Conclusion Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.
Abstract Objectives Mastocytosis is a heterogeneous group of clonal mast cell disorders in which bone manifestations are frequently seen, but poorly understood. In this study, we analyzed correlation ...of clinical findings in mastocytosis patients with bone mineral density and bone turnover markers. Methods Serum levels of bone turnover markers were measured in mastocytosis patients and healthy volunteers. Bone disease was evaluated using radiographic imaging, and measurement of bone mineral density. Results Of 45 adult mastocytosis patients, bone abnormalities were detected in 34 (75%). Bone lesions were documented on radiographic imaging in 16 patients (36%), and bone mineral density in 24 patients (53%), of which 9 patients (20%) had osteoporosis and 15 (33%) had osteopenia. Serum levels of bone turnover markers that evaluate bone resorption (C-telopeptide, deoxypyridinoline), bone formation (bone-specific alkaline phosphatase), and bone remodeling (osteoprotegerin) were significantly higher in the patient population than in the control population (n = 28). Levels of C-telopeptide and osteoprotegerin were higher in patients with advanced systemic mastocytosis than in patients with cutaneous or indolent systemic mastocytosis. Moreover, C-telopeptide and osteoprotegerin levels were significantly correlated with those of serum tryptase, a diagnostic marker of mastocytosis. Conclusion The observed bone turnover markers variations indicate a complex process of bone turnover in mastocytosis-related bone manifestations. The highly significant correlation between serum tryptase and serum bone turnover markers levels, and the positive correlation of levels of bone turnover markers with advanced disease, support the existence of a link between bone remodeling and mast cell burden.
Background Recent identification of STAT3 mutations in autosomal dominant (AD) hyper-IgE syndrome (HIES) has improved the clinical, genetic, and molecular classification of the HIES. Objective We ...sought to characterize the cutaneous signs observed in molecularly diagnosed AD-HIES. Methods We conducted a retrospective study of 21 patients with AD-HIES and confirmed STAT3 mutations, treated at Necker-Enfants Malades Hospital, Paris, France. Results A papulopustular rash on the face and scalp before the age of 2 months was observed in 67% of patients. This “early rash” was distinguished from other neonatal pustular eruptions by crusted papules and pustules, rash intensity, and a continuum with chronic dermatitis. An eczematous dermatitis was almost always present before the age of 18 months (95% of patients) and was mainly confined to the face, scalp, chest, and buttocks. All patients presented with infected dermatitis ( Staphylococcus aureus ) and 59% had chronic candidiasis of the oral mucosa and nails. Cutaneous herpes virus infections were not unusually severe. Coarse facial skin at puberty, and sometimes at a younger age, with prominent follicular ostia resembling atrophoderma vermiculatum was not related to severe acne or facial abscesses. Limitations This was a retrospective study with a small number of patients. Conclusion When associated with serum IgE levels 10 times the age-appropriate level, a neonatal papulopustular rash progressing to a chronic impetiginized eczematous dermatitis that differs from classic atopic dermatitis is highly suggestive of AD-HIES. Early recognition is important for initiation of prophylactic antistaphylococcal and antifungal treatment.
Background Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not ...known whether patients able to secrete IgM (eg, those with hyper-IgM HIgM syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia PHG). Objective This study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome. Methods A cohort of patients with HIgM syndrome (n = 25) and a cohort of patients with PHG (n = 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured. Results When compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti–nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections. Conclusions IgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.
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