TREX-1-Related Disease Associated with the Presence of Cryofibrinogenemia.

PURPOSE: Cryofibrinogenemia is a rare cryopathy presenting as acrocyanosis following exposure to cold. Familial presentation has been described but the underlying molecular cause remained undetermined. METHODS: Forty (40) members from a large family with an initial diagnosis of familial cryofibrinogenemia were interviewed and examined to determine affected status and collect DNA. Exome sequencing was performed on three affected individuals from distinct branches of the pedigree. RESULTS: Seventeen (17) family members reported a history of acrocyanosis with cold exposure. None reported symptoms were suggestive of lupus. Exome sequencing of three subjects identified the heterozygous mutation D18N in the TREX1 gene which was then confirmed by Sanger sequencing in all affected as well as 2 unaffected family members. The mutation is already being associated with familial chilblain lupus erythematosus (CHLE), and a systematic review of literature was undertaken to compare reports of familial CHLE and cryofibrinogenemia. Both entities were found to share highly similar clinical presentations suggesting they are part of a same syndrome in which cryofibrinogenemia and lupus manifestations have variable penetrance. CONCLUSIONS: Familial cryofibrinogenemia without lupus should be added to the spectrum of TREX1-related disease.

Introduction of peanuts in younger siblings of children with peanut allergy: a prospective, double-blinded assessment of risk, of diagnostic tests, and an analysis of patient preferences.

BACKGROUND: The prevalence of peanut allergy in younger siblings of children with peanut allergy has been reported between 7% and 8.5%, but the anaphylactic risk at the time of introduction is currently unknown, which limits our ability to best counsel parents on this issue. OBJECTIVE: To determine the risk of anaphylaxis and working parameters of allergy testing in this context. METHODS: One hundred and fifty-four peanut-naïve younger siblings of peanut-allergic children underwent double-blinded skin testing, followed by parent-led peanut introduction. Questionnaires were dispensed to parents to investigate preferences with regard to peanut introduction in this subgroup. RESULTS: Eight participants (5.2%) presented unequivocal IgE-mediated reactions to peanut upon introduction, including five anaphylaxes. These participants were significantly older compared to the rest of the cohort (median 4.0 vs 1.9 years, P = 0.04). The negative predictive value of skin prick test with peanut extract and peanut butter and of specific IgE was 99%, 100%, and 100%, respectively. Six peanut-tolerant participants had positive peanut allergy tests. The option of introducing at home without prior skin testing was associated with high levels of anxiety (median 8.4 on 10-point Likert scale) when compared to supervised introduction (median 3.8, P < 0.0001) or home introduction after negative skin test (median 4.3, P < 0.0001). CONCLUSIONS: There is an increased risk of anaphylaxis upon peanut introduction in siblings of children with peanut allergy, and parents are reluctant to introduce at home without testing. Allergy testing prior to introduction is negative in over 90% of cases and carries a high negative predictive value.

Basophils are recruited to inflamed lungs and exacerbate memory Th2 responses in mice and humans.

BACKGROUND: Although the contribution of basophils as inducers or amplifiers of Th2 responses is still debated, prolonged basophil/CD4 T cell interactions were observed in lungs but not lymph nodes (LNs) of parasite-infected mice. However, the impact of basophils on the function of tissue CD4 effector T cells remains unknown. METHODS: Basophils were purified from the lungs of ovalbumin (OVA)-sensitized and OVA-challenged (OVA-immunized) mice or human peripheral blood for in vivo and in vitro functional studies. Pulmonary basophils were adoptively transferred to OVA-sensitized hosts to assess airway inflammation in bronchoalveolar lavage fluid (BALF) and Th2 responses in lung explants and draining LNs. Basophils were co-cultured with effector T cells or Ag-specific naïve T cells alone or in combination with dendritic cells (DCs); IL-4 production was determined by flow cytometry and ELISA. RESULTS: Basophils accumulated in lungs of OVA-immunized mice. Adoptive transfer of basophils to OVA-sensitized hosts enhanced lung IL-4 and IL-13 release while co-administration of OVA further aggravated airway inflammation and Th2 responses in LNs. Mechanistic in vitro studies revealed that pulmonary basophils interacted with lung CD4 effectors, in the absence of DCs, to increase T cell survival and Th2 cytokine expression at the single cell level but amplified OVA-loaded DC-driven Th2 differentiation. Finally, human basophils augmented in vitro IL-4 expression in effector memory CD4 T cells that include CRTH2(+) cells through IL-4 and TCR-independent pathways. CONCLUSIONS: Basophils may worsen Th2 inflammatory disorders through direct interactions with pathogenic CD4 T cells as well as by enhancing DC-induced Th2 cell development.

Anaphylaxis to clindamycin following cutaneous exposure.

BACKGROUND: The role and importance of skin barrier as an immunologic organ and as a potent way of sensitization is well known. However, antibiotics anaphylaxis following skin sensitization has not been reported. CASE PRESENTATION: We describe the first case of intravenous clindamycin anaphylaxis, with likely sensitization due to previous topical exposure to clindamycin gel for acne in a 14-year-old boy with history of atopy and mild atopic dermatitis. CONCLUSION: This case highlights the potential sensitization to drug allergens, including antibiotics, via the skin.

CSACI guidelines for the ethical, evidence-based and patient-oriented clinical practice of oral immunotherapy in IgE-mediated food allergy.

BACKGROUND: Oral immunotherapy (OIT) is an emerging approach to the treatment of patients with IgE-mediated food allergy and is in the process of transitioning to clinical practice. OBJECTIVE: To develop patient-oriented clinical practice guidelines on oral immunotherapy based on evidence and ethical imperatives for the provision of safe and efficient food allergy management. MATERIALS AND METHODS: Recommendations were developed using a reflective patient-centered multicriteria approach including 22 criteria organized in five dimensions (clinical, populational, economic, organizational and sociopolitical). Data was obtained from: (1) a review of scientific and ethic literature; (2) consultations of allergists, other healthcare professionals (pediatricians, family physicians, nurses, registered dieticians, psychologists, peer supporters), patients and caregivers; and patient associations through structured consultative panels, interviews and on-line questionnaire; and (3) organizational and economic data from the milieu of care. All data was synthesized by criteria in a multicriteria deliberative guide that served as a platform for structured discussion and development of recommendations for each dimension, based on evidence, ethical imperatives and other considerations. RESULTS: The deliberative grid included 162 articles from the literature and media reviews and data from consultations involving 85 individuals. Thirty-eight (38) recommendations were made for the practice of oral immunotherapy for the treatment of IgE mediated food allergy, based on evidence and a diversity of ethical imperatives. All recommendations were aimed at fostering a context conducive to achieving objectives identified by patients and caregivers with food allergy. Notably, specific recommendations were developed to promote a culture of shared responsibility between patients and healthcare system, equity in access, patient empowerment, shared decision making and personalization of OIT protocols to reflect patients' needs. It also provides recommendations to optimize organization of care to generate capacity to meet demand according to patient choice, e.g. OIT or avoidance. These recommendations were made acknowledging the necessity of ensuring sustainability of the clinical offer in light of various economic considerations. CONCLUSIONS: This innovative CPG methodology was guided by patients' perspectives, clinical evidence as well as ethical and other rationales. This allowed for the creation of a broad set of recommendations that chart optimal clinical practice and define the conditions required to bring about changes to food allergy care that will be sustainable, equitable and conducive to the well-being of all patients in need.

A polysomnographic study of daytime sleepiness in myotonic dystrophy type 1.

OBJECTIVES: To assess contributors to excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 (DM1), to characterise subjects with sleep-onset REM periods (SOREMPs), and to verify whether self-reported instruments and respiratory function tests can predict multiple sleep latency test (MSLT) and sleep-disordered breathing. METHODS: A sample of 43 DM1 patients without selection bias underwent polysomnography (PSG) for two consecutive nights and MSLT, completed a sleep diary and Epworth Sleepiness Scale (ESS), and were assessed for respiratory function and narcolepsy symptoms. RESULTS: ESS scores (ES) > or =11 and MSLT mean sleep latency (MSL) < or =8 min were found in 21 (50.0%) and 19 (44.2%) subjects, and either in 30 (69.8%) subjects. ES did not relate to MSL. Subjects with subjective sleepiness (ES> or =11) reported more cataplexy-like and sleep paralysis symptoms, longer habitual sleep times, and higher sleep efficiency and REM sleep per cent than those without. Subjects with objective sleepiness (MSL< or =8 min) had a higher stage 4 sleep per cent. Subjects with > or =2 SOREMPs (25.6%) showed higher muscular impairment, lower MSL, higher ES, and more cataplexy-like symptoms than those with < or =1 SOREMP. Apnoea-hypopnoea index (AHI) > or =5, predominantly obstructive, was found in 37 (86.0%) subjects, and AHI >30 in 12 (27.9%). Neither subjective nor objective sleepiness could be explained by AHI, nor satisfactorily predicted by daytime respiratory abnormalities. CONCLUSIONS: DM1 entails frequent EDS but with different phenotypes and distinct mechanisms involved. The high prevalence of daytime sleepiness and severe sleep apnoeas found in this study supports the routine use of clinical sleep interviews, PSG and MSLT in DM1, and emphasises the need for more randomised trials of psychostimulants.

Consultation with registered dietitian to prevent accidental reactions to food: insight from an egg allergy influenza vaccination cohort.

Egg is an ubiquitous allergen found in many food products. Current food allergy guidelines recognize the importance of consultation with a registered dietitian to ensure nutritional adequacy. However, there is a lack of evidence on its impact on the implementation of allergen avoidance strategies. Taking advantage of a well-characterized cohort of influenza vaccination in egg-allergic children (n=397), we tested the hypothesis that real-life professional dietary advice was associated with a decrease in accidental reactions to egg in allergic children with retrospective questionnaires. Lack of consultation with a dietitian was associated with a 1.89-fold increase in the risk of accidental reactions to egg (confidence interval: 1.47-2.42). The only other independent variable that predicted reactions was having had a history of acute reaction to egg prior diagnosis (relative risk=2.02; confidence interval: 1.64-3.00). These findings support the usefulness of referral to a food allergy-specialized dietitian at time of diagnosis in order to prevent future accidental reactions to egg.

A 10-year study of mortality in a cohort of patients with myotonic dystrophy.

OBJECTIVE: To determine the age and causes of death as well as the predictors of survival in patients with myotonic dystrophy (DM). METHODS: In a longitudinal study, a cohort of 367 patients with definite DM was followed for 10 years. RESULTS: During the 10-year period, 75 of the 367 DM patients (20%) died. The mean age at death (53.2 years, range 24 to 81) was similar for men and women. Among these 75 patients, 32 (43%) died of a respiratory problem, 15 (20%) of cardiovascular disease, 8 (11%) of a neoplasia, and 8 (11%) died suddenly. The ratio of observed to expected deaths was significantly increased to 56.6 (95% confidence interval [CI] 38.7 to 78.0) for respiratory diseases, 4.9 (95% CI 2.7 to 7.7) for cardiovascular diseases, and 2.5 (95% CI 1.1 to 4.6) for neoplasms. The mean age at death was 44.7 years for the childhood phenotype of DM, 47.8 years for the early-adult, 55.4 years for the adult, and 63.5 years for the mild phenotype (F = 4.8, p = 0.005). The age-adjusted risk of dying was 3.9 (95% CI 1.3 to 11.0) times greater for a patient with a distal weakness and 5.6 (95% CI 2.2 to 14.4) times greater for a patient with proximal weakness as compared with a person without limb weakness. CONCLUSIONS: Life expectancy is greatly reduced in DM patients, particularly in those with early onset of the disease and proximal muscular involvement. The high mortality reflects an increase in death rates from respiratory diseases, cardiovascular diseases, neoplasms, and sudden deaths presumably from cardiac arrhythmias.

Assessment of a disease-specific muscular impairment rating scale in myotonic dystrophy.

OBJECTIVE: To document the intra/interrater reliability and the construct validity of the Muscular Impairment Rating Scale (MIRS) in assessing patients with myotonic dystrophy type 1 (DM1). The MIRS is a ordinal five-point rating scale, established in accordance with the clinically recognized distal to proximal progression of the muscular involvement in DM1, based partly on a manual muscle testing (MMT) of 11 muscle groups. METHODS: To assess the reliability of the MIRS, 55 patients with DM1 were examined by three different observers, one of them evaluating each patient twice. Intra- and interobserver reliability of the MIRS was measured using Cohen's weighted kappa. To assess the construct validity of the MIRS, correlations were made with the Functional Status Index (FSI) and eight timed functional tasks. RESULTS: The intraobserver reliability of the MIRS was excellent (weighted kappa = 0.84), and the interobserver reliability was interpreted as a substantial agreement (weighted kappa = 0.77 to 0.79). The correlation coefficients between MMT scores and MIRS grades were all highly significant (r(s) = -0.81 to -0.88, p < 0.001). The FSI showed a significant progressive increase of the total median dependence score in activities of daily living from 0 in MIRS grade 1 to 39 in MIRS grade 5 (p < 0.001). The time needed to perform the eight functional tasks was also found to significantly increase in relation with the progression of the MIRS grades. CONCLUSION: The MIRS is a quick, simple, and reliable measurement of muscular impairment in DM1. The FSI questionnaire and the timed motor activities supported its construct validity. The MIRS is useful to monitor major stages of DM1 progression, to study the natural history of the disease, and to identify homogeneous groups of patients for clinical trials.

Anesthetic and surgical complications in 219 cases of myotonic dystrophy.

The objective of this study was to assess the frequency, type, and severity of perioperative complications after a first surgery under general anesthesia in patients with myotonic dystrophy (DM) and to measure the association with suspected risk factors. Numerous cases of perioperative complications in DM patients have been reported. Hazards have been associated with the use of thiopentone, suxamethonium, neostigmine, and halothane. A retrospective study of perioperative complications was conducted for 219 DM patients who had their first surgery under general anesthesia at the Chicoutimi Hospital. The overall frequency of complications was 8.2% (18 of 219). Most complications (16 of 18) were pulmonary, including five patients with acute ventilatory failure necessitating ventilatory support, four patients with atelectasis, and three patients with pneumonia. Using multivariate analysis, we found that the risk of perioperative pulmonary complications (PPC) was significantly higher after an upper abdominal surgery (odds ratio (OR), 24.4; 95% CI, 4.0 to 149.3) and for patients with a severe muscular disability, as assessed by the presence of proximal limb weakness (OR, 14.1; 95% CI, 1.5 to 134.4). The likelihood of PPC was not related to any specific anesthetic drug. Because of the increased risk of PPC, careful monitoring during the early postoperative period, protection of upper airways, chest physiotherapy, and incentive spirometry are mandatory in all symptomatic DM patients, particularly those with a severe muscular disability or those who have undergone an upper abdominal surgery.

Bronchodilatation with a metered-dose inhaler plus an extension, using tidal breathing vs jet nebulization.

The bronchodilating response to two doses of 100 micrograms of salbutamol introduced into an extension device (Aero-chamber [AC]), each followed by four tidal breaths, was compared with the nebulization of 2.5 mg of salbutamol in a saline solution during tidal breathing in a crossover study of ten patients with reversible airway obstruction. The forced expiratory volume in one second (FEV1) and the forced vital capacity 30 min after the drug administration improved significantly with both methods (p less than .001). The improvement of FEV1 with the AC (52.1 percent) compared with the nebulization (55.7 percent) was similar (p greater than .05).

Evaluation of phase correction and low gas density to improve thoracic gas volume measurement.

We investigated two methods of decreasing the error on plethysmographic determinations of thoracic gas volume (TGV) related to cheeks movements during panting maneuvers: lowering gas density in the airways with an 80% He-20% O2 mixture and computing TGV from the in-phase component of the plethysmographic signal (TGVr). The methods were tested by measuring how TGV estimates varied when panting frequency was raised from 0.8 to 2.5 Hz during the same occlusion. The measurements were performed in 6 normal subjects and 12 patients with chronic bronchitis with and without cheeks support and when the airway was connected to an external device simulating an increased cheeks compliance. A small negative frequency dependence of TGV (delta TGV/delta f = -1.2 +/- 0.8%/Hz with cheeks support), most probably unrelated to upper airway walls, was found in normal subjects. Delta TGV/delta f was positive and algebraically larger in patients than in normals, reaching 2.2 +/- 3.4%/Hz without cheeks support and 11.8 +/- 8.0%/Hz with the additional cheeks. The latter value was only 20% smaller when computed on the basis of TGVr, demonstrating the limited usefulness of the phase-based correction. In contrast, breathing He-O2 decreased delta TGV/delta f to approximately 50% of its air value (P less than 0.01) and appears as an effective way to diminish the error in obstructive patients.

Transient heart failure in an adult with Kawasaki disease.

Kawasaki disease is a mucocutaneous lymph node syndrome with important cardiovascular complications that usually afflicts young children. We describe a 31-year-old woman who developed transient heart failure during the acute phase of Kawasaki disease. The diagnosis was supported by the presence of all six criteria of the disease: fever, conjunctivitis, strawberry tongue, cervical lymphadenopathies, truncal exanthem, and periungual membranous desquamation. Related clinical and laboratory findings included heart failure, arthralgias, transverse nail grooves, thrombocytosis, and elevated serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and bilirubin. Alternative diagnoses were excluded. During her acute febrile illness, the patient developed tachycardia, hypotension, pulmonary rales, S3 gallop, and hepatojugular reflux. The chest roentgenogram showed new Kerley A and B lines. A first-pass isotopic ventriculography showed diffuse hypokinesia and decreased ventricular ejection fractions; spontaneous recovery occurred after a few days. A coronarography performed two months later showed no aneurysmal dilatation. Kawasaki disease is a cause, albeit rare, of myocardial dysfunction in the adult human, and should be sought for actively in a patient with heart failure during the course of an acute febrile illness, associated with mucocutaneous changes.

Health supervision and anticipatory guidance in adult myotonic dystrophy type 1.

The complexity and variability of disease manifestations in myotonic dystrophy (DM1) pose a challenge for the clinical management of patients. The follow-up of DM1 patients has been described as fragmented, inadequate or even deficient for many patients. Through a systematic review of the medical and social literature and a validation process with a DM1 expert panel, we summarized systemic and social concerns clinically relevant to DM1 and revisited recommendations for treatment. This article summarizes common manifestations of the central nervous system, visual, respiratory, cardiac, gastro-intestinal, genito-urinary, muscular and metabolic impairments. In addition, we emphasized the social features of DM1 such as low education attainment, low employment, poor familial and social environment and poor social participation. While cardiac, respiratory and swallowing problems affect life expectancy, it is often excessive daytime sleepiness, fatigue, gastro-intestinal and cognitive behavioural manifestations that are the most disabling features of the disorder. A more holistic approach in the management of DM1 and a purposeful integrated organization of care involving all members of the patients' environment including family, clinicians, decision-makers and community organizations are needed to move out of the spiral of disease and handicap and move toward optimal citizenship and quality of life.