Chediak-Higashi syndrome: Lessons from a single-centre case series.

BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare and potentially fatal autosomal recessive disease characterized by frequent bacterial infections, bleeding tendency, oculocutaneous albinism, photosensitivity and progressive neurologic dysfunction. Owing to the rarity of this condition, the objective of this study was to describe patients with CHS. METHODS: Retrospective evaluation of patients followed in a paediatric tertiary centre of Allergy and Immunology of São Paulo, Brazil, between 1986 and 2018 with a confirmed diagnosis of CHS. Data were obtained from medical records. Demographic aspects, family history, clinical findings, laboratory data, diagnosis, treatment and outcome were described. RESULTS: A total of 14 patients (five male) were included. Clinical manifestations were first recognized at a median age of two months (at birth-20 months). Median age at diagnosis was 1.7 years (0-5 years). All patients had recurrent infections. Albinism was present in 13 patients and silvery or light hair was present in 14. Seven patients developed hemophagocytic lymphohistiocytosis (HLH); the median age at the diagnosis of HLH was 5.7 years (2.6-6.7 years) and the median interval between the diagnosis of CHS and HLH was 3.3 years (0-5 years). Four of the most recently diagnosed patients underwent bone marrow transplantation (BMT). Nine patients are deceased, and one was lost to follow-up. The median age of death was 6.7 years (3.8-22 years). Five patients died of HLH, one of lymphoma, and three of infection. All the patients who had HLH before the year of 2000 died of HLH. The two most recently diagnosed patients with HLH were able to cure the HLH, although they died of other causes. Four patients are alive, three of them after successful BMT. CONCLUSION: Thirty years of follow up showed an improvement in the prognosis in patients with CHS. The better understanding of the underlying biological mechanisms of HLH allowed the standardization of management protocols, resulting in survival improvement. BMT is the only treatment that can change CHS prognosis, which emphasizes the need for early identification of the disease.

Baked milk tolerant patient: Is there any special feature?

BACKGROUND: Determining whether patients with cow's milk allergy (CMA) can tolerate foods produced with baked milk could provide a better quality of life, a better prognosis, and an option for desensitization. OBJECTIVES: The aim of this study was to identify which patients over four years of age with persistent CMA could tolerate baked milk, to compare the clinical and laboratory characteristics of reactive and non-reactive groups and to describe their clinical evolution. MATERIALS AND METHODS: A cross-sectional study was conducted (January/13 to November/14) that included all the patients followed at a food allergy center who met the inclusion criteria. The patients underwent an oral food challenge (OFC) with a muffin (2.8g of cow's milk protein). To exclude cow's milk (CM) tolerance, the patients were subsequently challenged with unheated CM. RESULTS: Thirty patients met all the inclusion criteria. Fourteen patients (46.7%) were considered non-reactive to baked milk and reactive to unheated CM. When the groups that were reactive and non-reactive to baked milk were compared, no statistically significant differences in clinical features were found. The prick test for α-lactalbumin (p=0.01) and casein (p=0.004) and the serum specific IgE for casein (p=0.05) presented statistical differences. After one year, none of the patients who were reactive to baked milk were ingesting CM, while 28% of the tolerant patients were consuming fresh CM (p=0.037). CONCLUSIONS: Baked milk can be tolerated by patients with CMA, especially those with lower levels of casein and α-lactalbumin. This option can improve quality of life and accelerate tolerance.

Establishing a cut-off for the serum levels of specific IgE to milk and its components for cow's milk allergy: results from a specific population.

BACKGROUND: Cow's milk allergy diagnosis many times requires double-blind placebo-controlled food challenge (DBPCFC), which presents high accuracy but involves risks, specifically in infants and anaphylactic patients. The identification of the cut-off values for specific IgE to milk or its components would contribute to cow's milk allergy (CMA) diagnosis. The aim of this study was to compare discriminating concentration of a cow's milk specific IgE and its fractions (α-lactoalbumin, ß-lactoglobulin, casein) in children for the CMA diagnosis. METHODS: this study included 123 patients (M:F=1.3:1) median age at diagnosis=1.91 years, (3.5m to 13.21y) with CMA diagnosis via DBPCFC (n=26), proven anaphylaxis due to cow's milk (n=46) or a suggestive clinical history associated with a positive skin prick test (n=51) and open oral food challenge. The control group included 61 patients (1 male:1.1 female) ages ranging from 0.66 to 16.7 years (median=6.83 years). Receiver operator characteristics (ROC) curves were constructed to determine the best cut-offs that guarantees high specificity (>95%) for cow's milk and its components. RESULTS: considering 98% specificity, cut-off points were: 3.06 kU/L for cow's milk, 2.06 kU/L for α-lactalbumin, 1.85 kU/L for ß-lactoglobulin and 1.47kU/L for casein. The best ROC curve (area under the curve=0.929) was obtained evaluating cow's milk. CONCLUSION: this study showed that the cut-off point detected for whole cow's milk revealed a better discriminatory capacity for CMA diagnosis without the necessity of the milk components testing.

Double-blind, placebo-controlled food challenges in Brazilian children: adaptation to clinical practice.

BACKGROUND: A double-blind, placebo-controlled food challenge (DBPCFC) is considered the gold standard for diagnosing food allergy, but because of methodological difficulties it is rarely conducted in clinical practice, especially in paediatric patients. The purpose of the study was to propose a DBPCFC protocol that is adapted to our conditions for the diagnosis of an IgE-mediated cow's milk allergy (CMA) in a Brazilian reference centre for paediatric allergies. METHODS: This study includes the experimental phase (choice of materials, adjustments made to protocols described in the literature) and the test execution phase. DBPCFCs were performed in 58 patients aged 1-15 years who were separated into two groups: Group 1 (n=39), sex 1.6 M:F, 5.3 years median age, suggestive history of IgE-mediated CMA; and Group 2 (n=19), sex 1.4 M:F, 8.3 years median age with symptoms not associated with milk ingestion and laboratory data not compatible with IgE-mediated CMA. RESULTS: The materials were standardised for testing: containers and disposable products, low-lactose cow's milk (CM) and vehicles, such as natural fruit juice, vegetable soup and soybean-based beverages. Each DBPCFC was performed in a single day with two blind, randomised phases with a 2-h interval between them. The milk doses were gradually increased and offered in regular intervals of 15-30 min. Following negative or inconclusive results, patients underwent an open oral challenge test with 200 mL of low-lactose CM. CONCLUSIONS: The proposed adaptation for the DBPCFC allowed to implement this important test for the diagnosis of IgE-mediated CMA in a reference centre for paediatric allergies. It was considered feasible and safe if performed in an appropriate setting with physician supervision.

Common variable immunodeficiency associated with hepatosplenic T-cell lymphoma mimicking juvenile systemic lupus erythematosus.

Common variable immunodeficiency (CVID) is a heterogeneous disorder with susceptibility to infections, autoimmune manifestations, and cancer. To our knowledge, CIVD with T-cell lymphoma mimicking juvenile systemic lupus erythematosus (JSLE) was not described in the literature, and one case was reported herein. An 8-year-old female was admitted in our Pediatric Immunology Unit with a clinical history of hypogammaglobulinemia, recurrent upper respiratory infections, and pneumonias. She had a marked decrease of three serum immunoglobulin isotypes, and the diagnosis of CVID was established. At the age of 17 years, she presented with oral ulceration, nonerosive arthritis, nephritis, serositis, cytopenia, positive antiphospholipid antibodies, and positive antinuclear antibody fulfilling the American College of Rheumatology (ACR) criteria for SLE. She was treated with intravenous methylprednisolone for three consecutive days, and intravenous immunoglobulin, and maintenance therapy of chloroquine, azathioprine and prednisone 40 mg/day. Two months later, she died of septic shock secondary to acute pneumonia. The necropsy showed hepatosplenic T-cell lymphoma with diffuse involvement of bone marrow, spleen, liver, and lungs. The lymphoma cells were positive for CD3 immunostaining and negative for CD20 and lysozyme. In conclusion, the association of CVID and hepatosplenic T-cell lymphoma may simulate JSLE diagnosis.

Molecular characterization of patients with X-linked Hyper-IgM syndrome: description of two novel CD40L mutations.

Type 1, X-linked Hyper-IgM syndrome (HIGM1) is caused by mutations in the gene encoding the CD154 protein, also known as CD40 ligand (CD40LG). CD40L is expressed in activated T cells and interacts with CD40 receptor expressed on B lymphocytes and dendritic cells. Affected patients present cellular and humoral immune defects, with infections by intracellular, opportunistic and extracellular pathogens. In the present study we investigated the molecular defects underlying disease in four patients with HIGM1. We identified four distinct CD40L mutations, two of them which have not been previously described. P1 harboured the novel p.G227X mutation which abolished CD40L expression. P2 had a previously described frame shift deletion in exon 2 (p.I53fsX65) which also prevented protein expression. P3 demonstrated the previously known p.V126D change in exon 4, affecting the TNF homology (TNFH) domain. Finally, P4 evidenced the novel p.F229L mutation also located in the TNFH domain. In silico analysis of F229L predicted the change to be pathological, affecting the many hydrophobic interactions of this residue. Precise molecular diagnosis in HIGM syndrome allows reliable detection of carriers, making genetic counselling and prenatal diagnosis possible.

Prevalence of symptoms of asthma, rhinitis, and atopic eczema in Brazilian adolescents related to exposure to gaseous air pollutants and socioeconomic status.

OBJECTIVES: To evaluate the relationship between exposure to gaseous air pollutants (ozone [O3], carbon monoxide [CO], nitrogen dioxide [NO2], and sulfur dioxide [SO2]) socioeconomic status and the prevalence of symptoms of asthma, rhinitis and atopic eczema in adolescents. SUBJECTS AND METHODS: A sample of 16 209 adolescents from São Paulo West (SPW), São Paulo South (SPS), Santo André (SA), Curitiba (CR), and Porto Alegre (PoA) were enrolled. Data on air pollutants and socioeconomic status were compared to prevalence of symptoms with the Spearman correlation coefficient. RESULTS: Socioeconomic status was quite similar in all cities. The levels of O3 in SPW, SPS, and SA, and of CO in SA were higher than the acceptable ones. In relation to O3 and CO exposures, adolescents from SPW and SA had a significant risk of current wheezing, whereas living in SPW was associated with a high risk of rhinoconjunctivitis, eczema, and flexural eczema and living in CR to rhinitis. Exposure to NO2 was associated with a high risk of current wheezing in SPW and SA, and of severe asthma in SPW and PoA. Exposure to SO2 was associated with a high risk of current wheezing in SPW and SA, severe asthma in SPW and PoA, and nighttime cough, eczema, flexural eczema and severe eczema in SPW. Living in SPW, CR, or PoA was associated with a high risk of rhinitis, rhinoconjunctivitis, and severe rhinitis. CONCLUSIONS: Although we did not detect a characteristic pattern for all symptoms evaluated or a specific air pollutant, our data suggest a relationship between higher exposure to photochemical pollutants and high prevalence or risk of symptoms of asthma, rhinitis, and atopic eczema.

Prevalence of asthma, rhinitis and eczema in 6 - 7 years old students from the western districts of São Paulo City, using the standardized questionnaire of the "International Study of Asthma and Allergies in Childhood" (ISAAC)-phase IIIB.

UNLABELLED: The aims of the present work were the evaluation of allergic disease prevalence among 6 and 7 year-old students from the western districts of São Paulo city and the comparison of these data with those obtained in the International Study of Asthma and Allergies in Childhood (ISAAC) phase I, performed in the central-southern districts of São Paulo, using the ISAAC standardized written questionnaire. METHODS: 5,040 questionnaires were distributed and 3,312 were returned. Proportional differences were estimated by Chi square or Fisher exact tests. Odds Ratio and 95% confidence intervals between genders and allergic diseases were calculated. Values of p<0.05 were considered statistically significant. RESULTS: The corrected prevalences found were: asthma 24.4%, medical diagnosis of asthma 5.7%, rhinitis 25.7%, rhinoconjunctivitis 11.3%, medical diagnosis of rhinitis 20.0%, atopic eczema 9.2%. Significant associations between asthma and rhinitis (OR=3.3), asthma and eczema (OR=2.2), and rhinitis and eczema (OR=2.8) occurred. The male gender was prevalent regarding asthma and rhinitis. Compared to data from ISAAC phase I, higher asthma prevalence and severity, and lower values for rhinitis and eczema were observed in this study. CONCLUSIONS: The present study evidenced high prevalences for asthma and rhinitis compared to the children's medical diagnosis. The male gender predominated in all positive responses regarding asthma and rhinitis. The most frequent associations observed were between asthma and rhinitis and asthma and eczema. In the western districts of São Paulo, a higher prevalence of asthma symptoms and severity and lower prevalences for rhinitis and eczema occurred compared to the central-southern districts of the city.

Mycobacterium bovis dissemination (BCG strain) among immunodeficient Brazilian infants.

This study reports Mycobacterium bovis (BCG strain) dissemination in four primary immunodeficient (PID) patients. Their diagnoses were: chemotaxis defect, cellular immunodeficiency, combined immunodeficiency and chronic granulomatous disease (CGD). Patients were vaccinated with BCG (Moreau strain) between 17 days and 4 months of age. Identification of the BCG strain was performed in many sites, such as bone marrow, ganglionic mass, cerebrospinal fluid and in the site of vaccination. The first therapeutic schedule included rifampicin, isoniazid and ethambutol; no uniform treatment could be used for these patients. Therapy was adjusted as required on the basis of BCG sensitivity results. This study shows that PID patients are susceptible to BCG dissemination and demonstrates the importance of an early diagnosis for their prognosis.

Clinical and laboratorial features of visceral toxocariasis in infancy.

Forty children with a diagnosis of Visceral Toxocariasis were evaluated prospectively from February 1982 to June 1989. Diagnosis was established by clinical, laboratory and serological (ELISA - ES Toxocara canis antigen) evaluations. A great clinical polymorphism was found in our patients, ranging from unspecific or absent manifestations to an exuberant symptomatology. The laboratory findings were: leukocytosis, eosinophilia and elevation of serum gammaglobulin and isohemagglutinin levels. No significant relationship between clinical findings and laboratory parameters was found. Serology (ELISA) was a method of great diagnostic support but did not show a correlation with clinical and laboratory findings in this study. There was a significant relationship between pulmonary manifestations and the presence of signs and/or symptoms, when the patients were sent to us. Our findings, especially the high incidence of pulmonary manifestations, suggest that Visceral Toxocariasis has to be included in the differential diagnostic of children with pulmonary manifestations, characteristic epidemiological data and associated eosinophilia.

Chédiak-Higashi syndrome: presentation of seven cases.

CONTEXT: Chédiak-Higashi Syndrome (CHS) is a rare autosomal recessive disease characterized by recurrent infections, giant cytoplasmic granules, and oculocutaneous albinism. OBJECTIVE: To describe clinical and laboratory findings from CHS patients. DESIGN: Case report. SETTING: The patients were admitted into the Allergy and Immunology Unit of the Instituto da Criança, a tertiary public care institution. CASES REPORT: Seven patients had oculocutaneous albinism, recurrent infections and giant cytoplasmic granules in the leukocytes. One patient had low IgG levels and three showed impaired bactericidal activity of neutrophils. Six patients died of infectious complications during the accelerated phase. Therapy included ascorbic acid and antibiotics. Chemotherapy was used for the accelerated phase in two patients. Bone marrow transplantation (BMT) was proposed for one patient. DISCUSSION: The authors emphasize the need for early diagnosis and therapy of CHS. BMT should be indicated before the accelerated phase of the disease has developed.

[Methotrexate for steroid-dependent asthmatic children and adolescents]. / Metotrexate em crianças e adolescentes com asma corticodependente.

INTRODUCTION: The administration of methotrexate as an antiinflammatory drug in asthma has been discussed and most of the studies were developed in adults. Its indication is restricted to steroid-dependent or steroid-resistant asthmatic patients. OBJECTIVE: This study evaluates the clinical and espirometric parameters of steroid-dependent asthmatic children, receiving methotrexate therapy. METHODS: Perennial steroid-dependent asthmatic patients (prednisone 30 or 40 mg/dia), without associated disease, were evaluated by means of clinical and spirometric parameters. A maintenance dose of 10 to 17.5 mg/ week of methotrexate was administered. RESULTS: Six patients (3M;3F), aged 7 to 13 years old were included. There was improvement of clinical symptoms during the administration of methotrexate, in all patients, without significant change in the pulmonary function. During the use of methotrexate therapy three patients presented adverse reactions: leukopenia (1/3), vomiting (1/3) or Herpes zoster (1/3). The dose of prednisone was reduced in all patients, with total exclusion of prednisone in 3. Afterwards, there was a worsening of asthmatic symptoms in all patients, with reintroduction of corticosteroids. CONCLUSION: Methotrexate represents an alternative therapy for steroid-dependent asthmatics, and it may help to control symptoms of asthma and steroids use. Nevertheless, double-blind studies should be developed in children. Adverse effects must be considered before its indication, restricting its use to specialized centers.

[IgA deficiency: clinical and laboratory evaluation of 60 patients from the "Instituto da Criança"]. / Deficiência de IgA: avaliação clínico-laboratorial de 60 pacientes do Instituto da Criança.

OBJECTIVES: To evaluate the main clinical findings that suggest DIgA and describe the complications observed. PATIENTS AND METHOD: Sixty IgA deficient patients (IgA < 5mg/dl) were included, retrospectively. They were submitted to clinical evaluation and specific laboratorial tests. Their evolution was followed up to 15 years. RESULTS: The main complaints were: recurrent infections (50%), allergies (34%) or autoimmune diseases (10%). The respiratory system was the most affected by infections, and asthma and rhinitis were the most frequent allergic symptoms. No immunological impairment was detected, except for IgA deficiency. IgG and IgM levels were elevated in 50% of the patients. There was improvement of clinical symptoms and some of the patients became asymptomatic during the follow-up. CONCLUSION: IgA deficiency has a large clinical spectrum and early diagnosis would indicate prophylaxis for infections and allergy.

Sensitisation to aeroallergens in Brazilian adolescents living at the periphery of large subtropical urban centres.

OBJECTIVES: To evaluate the sensitization to aeroallergens determined by skin prick test (SPT) in Brazilian adolescents, and to correlate its positivity with the diagnosis of asthma and/or rhinitis based on the written questionnaire (WQ) of ISAAC phase III study. PATIENTS AND METHODS: A total of 996 adolescents (387 boys) were selected by systematic samples. A standard allergen extracts panel (positive/negative control, D pteronyssinus [Dpt], P americana [Pa], B germanica [Bg], dog, cat, fungal and grass mix) was used and its positivity compared with positive responses to asthma, rhinitis or both. RESULTS: Positive SPT to at least one allergen was observed in 466 adolescents (46.8 %), with sensitisation to Dpt in 79.1 %. Positivity to more than one allergen occurred in 232 students (49.8 %). The frequency of positive SPTs was significantly higher among adolescents with asthma (OR = 2.16), rhinitis (OR = 1.69), and asthma and rhinitis (OR = 2.03). Positive SPT to four or more allergens were higher among asthmatics (OR = 2.6) and among adolescents with asthma and rhinitis (OR = 3). CONCLUSIONS: A high sensitisation rate to aeroallergens was observed, significantly higher among those with asthma, rhinitis or a combination of both, especially in multiple sensitisations.

[Drug hypersensitivity in AIDS patients: report of a case]. / Hipersensibilidade a drogas em paciente com SIDA: relato de caso.

Drug allergy is a common symptom in HIV infected patients, with higher prevalence that in general population. We describe a child with AIDS and adverse reactions to several drugs indicated for Pneumocystis carinii prophylaxis and antibiotics. Reaction to intravenous pentamidine was present in this case and it is not an usual findings in HIV infected children. Alternative therapy and desensitization to TMP-SMX are also discussed.

[Asthma - Clinical and epidemiological aspects of 237 outpatients in a specialized pediatric unit] / Asma - aspectos clínico-epidemiológicos de 237 pacientes de um ambulatório pediátrico especializado.

OBJECTIVE: The authors describe and evaluate epidemiological and clinical features of asthmatic outpatients attending a specialized pediatric unit. METHODS: Asthmatic patients of the Allergy and Immunology Unit of Department of Pediatrics (University of São Paulo) followed in the period from 1988 up to 1995 were evaluated in a non-randomized and retrospective study. The patients were submitted to a protocol for associated diseases (gastroesophageal reflux, toxocariasis, tuberculosis, immunodeficiencies and other atopic diseases). Asthma severity was classified according to the 1st Brazilian Consensus for Asthma Management. RESULTS: 237 patients (128M:109F) were admitted with mean age of 86 months. The first episode of wheezing occurred during the first year in 56% of them. Parental history of atopy was present in 61.6%. 53% of the patients had severe asthma in the first evaluation and it decreased for 35% at the time of this protocol. Cold weather (78.3%) and house dust (64.7%) were the commonest triggering factors. The following associated diseases were diagnosed: gastroesophageal reflux (n=57), toxocariasis (n=17), tuberculosis (n=7) and immunodeficiencies (n=16). 90.2% had other atopic conditions.CONCLUSION: The authors emphasize that the first asthmatic episode occurred earlier but there is a delay in sending the patients to specialized centers. The evaluation of clinical and epidemiological findings besides familial history are necessary for adequate treatment and early introduction of prophylactic measures.

Secondary hypogammaglobilinemia after use of carbamazepine: case report and review.

Immunologic disorders related to anticonvulsant therapy have been described in the last three decades, including cellular and humoral alterations that result in recurrent infections; however, the physiopathologic mechanisms are not completely understood. This report describes a patient with complex partial epilepsy and hypogammaglobulinemia while in treatment with carbamazepine, with significant improvement in clinical signs and laboratory tests after substitution to sodium valproate. The authors stress the importance of clinical and laboratory evaluation of patients in continuous anticonvulsant therapy, including immunoglobulins levels and peripheral blood evaluations.

[Severe combined immunodeficiency: description of a clinical case]. / Imunodeficiência combinada severa: descrição de caso clínico.

A Severe Combined Immunodeficiency (SCID) is a rare disease, with recessive autosomic or X linked inheritance. The clinical phenotype is related to the defect of specific antigen response. The authors describe a patient presenting recurrent infections, affected by SCID, with multiple hospitalizations. Immunologic evaluation was performed and adenosine deaminase deficiency was excluded. The patient was submitted to herniography and he died seven days after the surgery. The preparation for bone marrow transplantation was provided. The anatomo-pathological findings had showed immunologic system alterations. The early clinical diagnosis and the therapy are discussed.

[X-linked agammaglobulinemia in nine patients: review of the literature]. / Agamaglobulinemia ligada ao cromossomo X em nove pacientes: revisão de literatura.

The X-linked agammaglobulinemia (XLA) is a rare immunodeficiency, characterized by absence or accentuated diminuition of all the isotypes of serum immunoglobulins and greater susceptibility to infections, mainly after the sixth mouth of life. The authors present nine patients bearers of XLA, with recurrent infectious processes (pneumonias 7/9, otitis 7/9, sinusitis 5/9, sepsis 5/9, diarrheas 3/9, infectious arthritis 3/9, meningitis 3/9, pyodermitis 3/9, viral encephalitis 1/9), with the beginning of symptoms on average in a nine months life. The laboratory examination showed absence of antibody response, with normal cellular immunity. The patients received immunoglobulin with control of the infectious processes. Five children received prophylactic antibiotic therapy for sinusitis control. The precocious diagnosis of XLA is of extreme importance, with institution of therapy with intravenous immunoglobulin for reduction in infectious process occurrence and complications, besides improving the patient's life quality.

[Hereditary angioedema: clinical and laboratory aspects of 7 cases]. / Angioedema hereditário: aspectos clínico-laboratoriais de sete casos.

Hereditary angioedema is caused by a defect in C1 inhibitor activity (C1INH). Its occurrence is rare and it is associated with an autosomal dominant mode of inheritance. We describe seven patients (4M:3F), age from 12 to 50 years old, who are affected by hereditary angioedema; four of them belong to the same family. The main clinical manifestations were: angioedema of face, hands and feet (6/7) and abdominal pain (2/7). No triggering factors were associated with symptoms in 4/7 patients and trauma (2/7) and menses (1/7) were reported in the other three ones. One patient was submitted to laparotomy for partial intestinal resection, before diagnosis. Laboratory complement analysis revealed the absence of hemolytic function of complement, reduced C4 (6/7) and low C1INH levels. All patients received Danazol (100 mg/day) with clinical control. Hereditary angioedema has to be considered in the differential diagnosis of angioedema, since an early diagnosis of this immunodeficiency, leading to specific treatment in order to decrease the complications.