Utility of the 3Di short version in the identification and diagnosis of autism in children at the Kenyan coast.

Introduction: The precise epidemiological burden of autism is unknown because of the limited capacity to identify and diagnose the disorder in resource-constrained settings, related in part to a lack of appropriate standardised assessment tools and health care experts. We assessed the reliability, validity, and diagnostic accuracy of the Developmental Diagnostic Dimensional Interview (3Di) in a rural setting on the Kenyan coast. Methods: Using a large community survey of neurodevelopmental disorders (NDDs), we administered the 3Di to 2,110 children aged between 6 years and 9 years who screened positive or negative for any NDD and selected 242 who had specific symptoms suggestive of autism based on parental report and the screening tools for review by a child and adolescent psychiatrist. On the basis of recorded video, a multi-disciplinary team applied the Autism Diagnostic Observation Schedule to establish an autism diagnosis. Internal consistency was used to examine the reliability of the Swahili version of the 3Di, tetrachoric correlations to determine criterion validity, structural equation modelling to evaluate factorial structure and receiver operating characteristic analysis to calculate diagnostic accuracy against Diagnostic Statistical Manual of Mental Disorders (DSM) diagnosis. Results: The reliability coefficients for 3Di were excellent for the entire scale {McDonald's omega (ω) = 0.83 [95% confidence interval (CI) 0.79-0.91]}. A higher-order three-factor DSM-IV-TR model showed an adequate fit with the model, improving greatly after retaining high-loading items and correlated items. A higher-order two-factor DSM-5 model also showed an adequate fit. There were weak to satisfactory criterion validity scores [tetrachoric rho = 0.38 (p = 0.049) and 0.59 (p = 0.014)] and good diagnostic accuracy metrics [area under the curve = 0.75 (95% CI: 0.54-0.96) and 0.61 (95% CI: 0.49-0.73] for 3Di against the DSM criteria. The 3Di had a moderate sensitivity [66.7% (95% CI: 0.22-0.96)] and a good specificity [82.5% (95% CI: 0.74-0.89)], when compared with the DSM-5. However, we observed poor sensitivity [38.9% (95% CI: 0.17-0.64)] and good specificity [83.5% (95% CI: 0.74-0.91)] against DSM-IV-TR. Conclusion: The Swahili version of the 3Di provides information on autism traits, which may be helpful for descriptive research of endophenotypes, for instance. However, for accuracy in newly diagnosed autism, it should be complemented by other tools, e.g., observational clinical judgment using the DSM criteria or assessments such as the Autism Diagnostic Observation Schedule. The construct validity of the Swahili 3Di for some domains, e.g., communication, should be explored in future studies.

Validation of the developmental, dimensional and diagnostic interview -short version (3Di-sv) for diagnosis of autism spectrum disorder in Chinese children.

The purpose of this study was to evaluate the psychometric features of the Chinese version of the developmental dimensional diagnostic interview-short version (3Di-sv). A total sample of 138 children including 79 children with autism spectrum disorder (ASD) and 59 typically developing children completed the 3Di-sv interview. The Chinese version of the 3Di-sv has a good internal consistency (0.94). Test-retest analysis confirmed the instrument's time stability (0.89). The instrument's concurrent validity with the Autism Behavior Checklist (ABC), the Childhood Autism Rating Scale (CARS) and clinical diagnosis was verified; the correlation between total scores was 0.72, 0.82 and 0.90, respectively. The 3Di-sv significantly distinguished between autistic children and non-autistic children in every area of autism symptoms. Optimal cutoffs were derived using receiver operating characteristics curves. Using clinical diagnosis as criterion, overall sensitivity was 98 % and specificity was 90 %. The study determined that the Chinese version of 3Di-sv can well distinguish autistic children from typically developing children.

Delivery of subcutaneous immunoglobulin by rapid "push" infusion for primary immunodeficiency patients in Manitoba: a retrospective review.

BACKGROUND: Both intravenous and subcutaneous human immune globin G (IgG) replacement (IVIG and SCIG, respectively) reduce severe infection and increase serum IgG levels in primary immune deficiency disorder (PIDD) patients who require replacement. SCIG can be administered either with the aid of an infusion pump, or by patients or caregivers themselves, using butterfly needles and a syringe ("SCIG push"). SCIG offers advantages over IVIG, including higher steady state IgG levels, improved patient quality of life indicators, and decreased cost to the healthcare system, and for these reasons, SCIG has been increasingly used in Manitoba starting in 2007. We sought to determine the effectiveness of SCIG push in our local adult PIDD population. METHODS: We conducted a retrospective chart review of all adult patients enrolled in the SCIG push program in Manitoba, Canada from its inception in November 2007 through September 2018. We included patients who were naïve to IgG replacement prior to SCIG, and those who had received IVIG immediately prior. We collected data regarding serum IgG levels, antibiotic prescriptions, hospital admissions, and adverse events during a pre-defined period prior to and following SCIG initiation. Statistical significance was determined via two-tailed t-test. RESULTS: 62 patients met inclusion criteria, of whom 35 were on IVIG prior and 27 were IgG replacement naïve. SCIG push resulted in an increase in serum IgG levels in those naïve to IgG replacement, as well as in those who received IVIG prior. SCIG push also resulted in a statistically significant reduction in number of antibiotic prescriptions filled in the naïve subgroup, and no significant change in antibiotics filled in the IVIG prior group. 8/62 PIDD patients (12.9%) left the SCIG program during our review period for varying reasons, including side-effects. CONCLUSIONS: In a real-life setting, in the Manitoba adult PIDD population, SCIG push is an effective method of preventing severe infections, with most patients preferring to continue this therapy once initiated.

Review of the Manitoba cohort of patients with hereditary angioedema with normal C1 inhibitor.

BACKGROUND: Hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) is a rare, underappreciated condition characterized by recurrent subcutaneous angioedema. The underlying pathophysiology and diagnostic criteria continues to evolve. There is a significant overlap between HAE-nC1 INH and idiopathic nonhistaminergic angioedema, ultimately this may be found to be the same condition. Characterization of cohorts suspected to have either of these conditions is warranted to help refine diagnosis, pathophysiology, and treatment response. METHODS: A retrospective chart review of 418 patients diagnosed with angioedema was conducted. The following inclusion criteria was used: lack of response to antihistamines, steroids, and epinephrine; normal C4, C1 inhibitor (C1 INH) level and function; lack of urticaria or pruritus; occurrence without offending drugs; and positive family history. Enzyme immunoassays for C1 INH function were performed at the Mayo Clinic. Charts meeting these criteria were reviewed for frequency and type of episodes as well as use and response to therapies. RESULTS: 6 patients met the above criteria. 3 of these completed genetic testing, none were found to have factor XII abnormalities. None had angiopoietin 1 or plasminogen gene sequencing. 5 of 6 patients were successfully treated with C1 INH or tranexamic acid for acute treatment of attacks (4 with C1 INH and 1 with tranexamic acid). 4 patients have used Icatibant with good response (typically under 40 min for near full recovery); of these, 3 required Icatibant as acute treatment after other therapies (C1 inhibitor and tranexamic acid) were ineffective. There were 9 patients who otherwise met criteria, but due to a lack of family history were classified as having idiopathic non-histaminergic angioedema. CONCLUSIONS: This retrospective chart review found 6 HAE-nC1 INH patients in Manitoba. 1 responded to tranexamic acid and not C1 INH, 4 typically responded to C1 INH, and 1 responded exclusively to Icatibant. All patients-4 total-who used Icatibant responded; of these 4 patients, 3 required Icatibant after other therapies had failed.

Sustained suppression of IL-18 by employing a vaccine ameliorates intestinal inflammation in TNBS-induced murine colitis.

AIM: To develop IL-18 peptide-based virus-like particle vaccines that elicit autoantibodies against IL-18 and to evaluate the in vivo effects of the vaccines in murine colitis. METHODS: Recombinant IL-18 vaccines were constructed, and the effects of the vaccines were evaluated in trinitrobenzene sulfonic acid-induced acute and chronic colitis in mice. RESULTS: Two murine IL-18 peptide-based vaccines (A and D) were developed, which induced relative long-lasting specific antibodies against IL-18. Vaccine-immunized mouse antisera could partially block IL-18-induced IFN-γ production in vitro. Mice receiving vaccine D, not vaccine A, had a significant decrease in intestinal inflammation, collagen deposition and pro-inflammatory cytokine levels in colon tissue. CONCLUSION: IL-18 vaccine may provide a potential therapeutic approach in the treatment of Crohn's disease.

Drug allergy.

Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions with varying mechanisms and clinical presentations. This type of adverse drug reaction not only affects patient quality of life, but may also lead to delayed treatment, unnecessary investigations, and even mortality. Given the myriad of symptoms associated with the condition, diagnosis is often challenging. Therefore, referral to an allergist experienced in the identification, diagnosis and management of drug allergy is recommended if a drug-induced allergic reaction is suspected. Diagnosis relies on a careful history and physical examination and, in some instances, skin testing and graded challenges. Induction of drug tolerance procedures may also be required. The most effective strategy for the management of drug allergy is avoidance or discontinuation of the offending drug. When available, alternative medications with unrelated chemical structures should be substituted. Cross-reactivity among drugs should be taken into consideration when choosing alternative agents. Additional therapy for drug hypersensitivity reactions is largely supportive and may include topical corticosteroids, oral antihistamines and, in severe cases, systemic corticosteroids. In the event of anaphylaxis, the treatment of choice is injectable epinephrine. If a particular drug to which the patient is allergic is indicated and there is no suitable alternative, induction of drug tolerance procedures may be considered to induce temporary tolerance to the drug. This article provides a background on drug allergy and strategies for the diagnosis and management of some of the most common drug-induced allergic reactions, such as penicillin, sulfonamides, cephalosporins, radiocontrast media, local anesthetics, general anesthetics, acetylsalicylic acid and non-steroidal anti-inflammatory drugs, and therapeutic monoclonal antibodies.

Primary immunodeficiency.

Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. PIDs are broadly classified as disorders of adaptive immunity (i.e., T cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). Although the clinical manifestations of PIDs are highly variable, many disorders involve an increased susceptibility to infection. Early consultation with a clinical immunologist is essential, as timely diagnosis and treatment are imperative for preventing significant disease-associated morbidity. PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID. Patients with multiple autoimmune diseases should also be evaluated. Diagnostic testing often involves lymphocyte proliferation assays, flow cytometry, measurement of serum immunoglobulin (Ig) levels, assessment of serum specific antibody titers in response to vaccine antigens, neutrophil function assays, stimulation assays for cytokine responses, and complement studies. The treatment of PIDs is complex and generally requires both supportive and definitive strategies. Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. The disorders affecting the activity of the T-cell arm of the adaptive system, such as severe combined immunodeficiency, require immune reconstitution as soon as possible. The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation. This article provides an overview of the major categories of PIDs and strategies for the appropriate diagnosis and management of these rare disorders.

An introduction to immunology and immunopathology.

Beyond structural and chemical barriers to pathogens, the immune system has two fundamental lines of defense: innate immunity and adaptive immunity. Innate immunity is the first immunological mechanism for fighting against an intruding pathogen. It is a rapid immune response, initiated within minutes or hours after aggression, that has no immunologic memory. Adaptive immunity, on the other hand, is antigen-dependent and antigen-specific; it has the capacity for memory, which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen. There is a great deal of synergy between the adaptive immune system and its innate counterpart, and defects in either system can provoke illness or disease, such as inappropriate inflammation, autoimmune diseases, immunodeficiency disorders and hypersensitivity reactions. This article provides a practical overview of innate and adaptive immunity, and describes how these host defense mechanisms are involved in both heath and illness.

Urticaria and angioedema.

Urticaria (hives) is a common disorder that often presents with angioedema (swelling that occurs beneath the skin). It is generally classified as acute or chronic. Second-generation, non-sedating, non-impairing histamine type 1 (H1)-receptor antihistamines represent the mainstay of therapy for both acute and chronic urticaria. Angioedema can occur in the absence of urticaria and can be broadly divided into histamine-mediated and non-histamine-mediated angioedema. Histamine-mediated angioedema can be allergic, pseudoallergic or idiopathic. Non-histamine mediated angioedema is largely driven by bradykinin and can be hereditary, acquired or drug-induced, such as with angiotensin-converting enzyme inhibitors. Although bradykinin-mediated angioedema is often self-limited, laryngeal involvement can lead to fatal asphyxiation. The mainstay of management for angioedema is to avoid specific triggers, if possible. For hereditary angioedema, there are specifically licensed treatments that can be used for the management of acute attacks, or for prophylaxis in order to prevent attacks. In this article, the authors will review the causes, diagnosis and management of urticaria (with or without angioedema) and isolated angioedema. The diagnostic and therapeutic approaches to these two conditions are considerably different, and this review is designed to highlight these differences to the reader.

Prevalence of beta-lactam allergy: a retrospective chart review of drug allergy assessment in a predominantly pediatric population.

BACKGROUND: Research suggests that 90% of patients labeled beta-lactam allergic are able to tolerate penicillins following further assessment. This study aims to define and describe the frequency of true beta-lactam allergy following allergy patient evaluation in a predominantly pediatric population. METHODS: 306 primary care patients referred between January 2010 and June 2015 were assessed for a suspected beta-lactam allergy. Patient demographics, history and test results were extracted from electronic medical records. Testing performed was based on specialist recommendation following review of patient history. RESULTS: 34% of the study participants had intradermal testing. Oral challenge was given to 96.7% of the sample. 96% of patients with a prior history of beta-lactam allergy were advised that they could re-introduce beta-lactam antibiotics following evaluation. CONCLUSIONS: Among patients with a documented beta-lactam allergy or a recent history of a reaction there is a low rate of 'true' beta-lactam allergy. Consistent evaluation of beta-lactam antibiotic allergies can reduce rates of broad spectrum antibiotic prescribing, among other harmful consequences.

Clinical Experience with Octagam® 10 %, a solvent detergent virus inactivated intravenous immunoglobulin: a Canadian retrospective review of utilization.

In Canada, intravenous immune globulin (IVIg) products are licensed for six disease indications, however it has been demonstrated that patients with a number of other conditions also benefit from IVIg. Here we report the routine clinical use of Octagam(®) 10 % across three Canadian institutions. A total of 135 patients were treated with Octagam(®), for conditions represented by five distinct indication groups. The results of this review indicate that Octagam(®) has been well adopted and is prescribed to Canadian patients similar to other IVIg products. In alignment with current practices, 85 % of Octagam's utilization was classified as appropriate based on Canadian IVIg guidelines.

A retrospective comparison of false negative skin test rates in penicillin allergy, using pencilloyl-poly-lysine and minor determinants or Penicillin G, followed by open challenge.

BACKGROUND: A history of penicillin allergy in patients is common, but only 10-15 % are truly allergic. While the gold standard for diagnosing penicillin allergy is challenge, it is not recommended that this be done without first carrying out diagnostic skin testing. This is carried out with the major determinant benzylpenicilloyl (PPL) and the minor determinant mixture (MDM), consisting of penilloate, penicilloate and Penicillin G. However, since availability of the MDM is limited, Penicillin G alone has been used. METHODS: A retrospective chart review was carried out on patients tested for penicillin allergy in the Clinical Immunology and Allergy Clinic at the Health Sciences Centre, Winnipeg, Canada between 2005 and 2013. A total of 521 patients charts were reviewed, of whom 240 had skin testing, ImmunoCap(®) for IgE to Penicillin G and V and had oral challenges with penicillin, amoxicillin or cloxacillin. RESULTS: 17/240 (7.5 %) were skin test positive, 8 to PPL, 4 to MDM and 5 to Penicillin G. One was also positive on ImmunoCap(®) testing. Three patients had negative skin tests but weakly positive ImmunoCap(®). 222 patients with negative skin tests and serological tests were challenged. Of these, 12 patients reacted to challenge. Three of the challenges were equivocal. Of the nine patients with definite positive challenges, three were tested with Penicillin G and six with MDM. Therefore the false negative rates for testing were 2.3 % with PPL and Penicillin G and 6.97 % for PPL and MDM. The difference was not significant (p = 0.0856). CONCLUSIONS: In this group of patients with a history of penicillin allergy tested with the major determinant of benzyl penicillin and either MDM or Penicillin G, there was no difference in the rate of false negative testing, based on oral penicillin challenges. Therefore, Penicillin G can be safely used as an alternative to MDM in diagnosing penicillin allergy.

The potential protective role of caveolin-1 in intestinal inflammation in TNBS-induced murine colitis.

BACKGROUND: Caveolin-1 (Cav-1) is a multifunctional scaffolding protein serving as a platform for the cell's signal-transduction and playing an important role in inflammation. However, its role in inflammatory bowel disease is not clear. A recent study showed that Cav-1 is increased and mediates angiogenesis in dextran sodium sulphate-induced colitis, which are contradictory to our pilot findings in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. In the present study, we further clarified the role of Cav-1 in TNBS-induced colitis. METHODS: In BALB/c mice, acute colitis was induced by intra-rectal administration of one dose TNBS, while chronic colitis was induced by administration of TNBS once a week for 7 weeks. To assess the effects of complete loss of Cav-1, Cav-1 knockout (Cav-1-/-) and control wild-type C57 mice received one TNBS administration. Body weight and clinical scores were monitored. Colon Cav-1 and pro-inflammatory cytokine levels were quantified through ELISAs. Inflammation was evaluated through histological analysis. RESULTS: Colon Cav-1 levels were significantly decreased in TNBS-induced colitis mice when compared to normal mice and also inversely correlated with colon inflammation scores and proinflammatory cytokine levels (IL-17, IFN-γ and TNF) significantly. Furthermore, after administration of TNBS, Cav-1-/- mice showed significantly increased clinical and colon inflammatory scores and body weight loss when compared with control mice. CONCLUSIONS AND SIGNIFICANCE: Cav-1 may play a protective role in the development of TNBS-induced colitis. Our findings raise an important issue in the evaluation of specific molecules in animal models that different models may exhibit opposite results because of the different mechanisms involved.

Validation of the Developmental, Dimensional and Diagnostic Interview (3Di) Among Chinese Children in a Child Psychiatry Clinic in Hong Kong.

Autism spectrum disorder (ASD) is a disorder with high levels of co-morbidities. The Developmental, Dimensional and Diagnostic Interview (3 Di) is a relatively new instrument designed to provide dimensional as well as categorical assessment of autistic behaviours among children with normal intelligence. Its sound psychometric properties and relatively short administration time make it a versatile instrument. The 3 Di was translated into Chinese (Cantonese) and its applicability among 194 clinic children was examined. Results found excellent reliability and validity, and achieved a sensitivity of 95% and specificity of 77%. It was able to capture the diagnosis of ASD among children presenting with attention deficit hyperactivity disorder. However, although the disorder of ASD is considered universal, the use of a western instrument in a Chinese context should also take note of cultural influences that may impact on the manifestation of its symptoms.

Antibiotic allergy.

Although allergy to ß-lactam and non-ß-lactam antibiotics is commonly claimed, true allergy to these drugs is often absent. Reactions to antibiotics can be classified according to the interval between the last administration of the drug and the onset of symptoms, but except for immediate reactions occurring within an hour of exposure, which are almost always either IgE-mediated or due to direct stimulation of mast cells, reactions occurring later than 1 hour probably have multiple mechanisms, including being IgE-mediated or involving cell-mediated reactions. The latter are likely caused by drug-specific T lymphocytes. The diagnosis of antibiotic allergy can be difficult.

Employing an IL-23 p19 vaccine to block IL-23 ameliorates chronic murine colitis.

BACKGROUND: Overexpression of IL-23 has been implicated in the pathogenesis of Crohn's disease. Using vaccines to block overexpressed endogenous cytokines has emerged as a new therapeutic strategy for the long-term treatment of the disease. AIM: We sought to develop peptide-based vaccines specific to IL-23 and evaluate their effects in colitis mice. MATERIALS & METHODS: The vaccine was developed by inserting a peptide derived from mouse IL-23 p19 into the carrier protein, hepatitis B core antigen, using molecular engineering methods. One vaccine against IL-23 p19 was obtained that induced high-titered and long-lasting antibodies to IL-23 without the use of adjuvants. The inhibitory effect of vaccine-immunized serum was subsequently evaluated in vitro. To evaluate the in vivo effects, mice were subcutaneously injected with the vaccine, carrier or saline three times. Two weeks after the last injection, chronic colitis was induced in mice by seven weekly administrations with 2,4,6-trinitrobenzene sulfonic acid. RESULTS: In vitro studies revealed that serum IL-23 p19-specific IgG significantly suppressed IL-23-induced IL-17 production by splenocytes. In vivo evaluation of the effect of the vaccine in mice with chronic colitis indicated that vaccine-immunized mice exhibited a decrease in colon inflammation, collagen deposition and levels of IL-23 and IL-12 cytokines, compared with control groups. CONCLUSION: IL-23 p19 vaccine is capable of downregulating inflammatory responses in chronic murine colitis, providing a novel therapeutic approach in Crohn's disease.

The role and potential therapeutic application of myeloid-derived suppressor cells in TNBS-induced colitis.

MDSCs, a heterogeneous population of cells that expand during many pathogenic conditions, have remarkable abilities to suppress T cell responses. Their role in murine colitis, induced by TNBS and therapeutic application, remains unclear. Murine colitis was induced through intrarectally administrating TNBS, twice. MDSCs in spleen and colonic LPMCs were identified using flow cytometric analysis. In adoptive transfer, MDSCs were isolated from spleen after TNBS challenges by using microbeads or generated in vitro by coculturing bone marrow cells with HSCs and then transferred into naïve mice. Two hours later, mice were then challenged with TNBS, once/week for 2 weeks. The mice were killed four days after the second TNBS delivery, and intestinal inflammation and cytokine levels and MDSC percentages were evaluated. The percentages of CD11b+Gr-1+MDSCs and subsets (CD11b+Ly6C+ and CD11b+Ly6G+MDSCs) were increased in spleen and/or colonic LPMCs in colitis mice and also correlated with the severity of intestinal inflammation. MDSCs isolated from colitis mice suppressed the proliferation of splenocytes in vitro. Adoptive transfer of MDSCs, isolated from colitis mice or generated in vitro, decreased intestinal inflammation, levels of IFN-γ, IL-17, and TNF, and percentages of spleen MDSCs when compared with controls. MDSCs that have inhibitory function in vitro and in vivo are increased and correlated with intestinal inflammation, suggesting that they may be used as a biomarker of disease activity and a cell-based biotherapy in IBD.