Carolina Aranda

Pulmonary complications in patients with antibody deficiency

OBJECTIVE The aim of this study was to evaluate pulmonary complications in patients with primary antibody deficiency (X-linked agammaglobulinaemia [XLA] and common variable immunodeficiency [CVID]). METHODS Thirty patients over six years of age regularly followed in a reference out-patient clinic on primary immunodeficiency were studied. All of them have been treated with intravenous immunoglobulin (IVIG) replacement therapy. Pulmonary complications were evaluated analysing clinical data (medical records review), lung function test (spirometry) and pulmonary imaging (chest computed tomography [CCT]). RESULTS Patients with normal CCT (N = 14) and those with abnormal CCT (N = 16) have shown no differences regarding the age at onset of symptoms, age of diagnosis, and duration of IVIG treatment. The mean number of pneumonia episodes before IVIG replacement was significantly higher among patients with abnormal CCT (4 vs 7 episodes, p = 0.008). CCT abnormalities observed in 16 patients were: bronchiectasis (12/16); peribronchial thickening (3/16); air trapping (5/16); lung volume reduction (4/16); atelectasis (2/16), follicular bronchiolitis and ground-glass abnormality (2/16) and parenchyma nodule (1/16). Lung function tests showed ventilatory disturbance in 18/30: obstructive pattern in 38.8%, restrictive pattern in 44.4%, and mix pattern in 16.7%. There were no significant differences in lung function between those with and without CCT abnormalities. Negative significant correlations were observed between lung function and number of episodes of pneumonia. Chronic persistent cough was associated with a reduction in lung function. CONCLUSIONS Pulmonary complications are not rare in patients with antibody deficiencies and they must be monitored.

Laronidase hypersensitivity and desensitization in type I mucopolysaccharidosis: a case report

To the Editor, Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disorder, resulting from the deficiency of lysosomal alpha-Liduronidase enzyme. It is a rare disorder, with an estimated prevalence ranging from 0.69 to 3.8 per 100,000 live births (1). The disorder affects independently the central nervous, skeletal, digestive, cardiac, upper and lower respiratory systems at different grades of severity (1). Untreated patients with MPS-I have a lower life expectancy and higher morbidity. The enzyme replacement therapy (ERT) with laronidase has been approved for MPS-I treatment since 2003 in the United States and 2005 in Brazil (2). We describe the first case of a MPS-I patient with hypersensitivity to laronidase, who was successfully treated with a three bags, 12 steps rapid desensitization protocol. An 11-yr-old female subject was referred to our allergy outpatient clinic for evaluation of hypersensitivity reactions during ERT with laronidase. The patient had a history of multiple surgeries and was diagnosed with MPS-I when she was 9 yr old. In January 2012, she started ERT with laronidase (20.3 mg/wk). She received four uneventful infusions and, during the fifth infusion, 90 min after starting the procedure (infusion rate 80 ml/h), she experienced hives in ears, neck, and back, lip swelling, increase in corporal body temperature (37.3°C) without respiratory, digestive, or cardiovascular symptoms. The infusion was stopped, and the patient was treated with hydroxyzine 0.5 mg/kg and methylprednisolone 2 mg/kg. The symptoms improved, and the infusion was restarted 1 h later (20 ml/h). After 3 min, she experienced a new episode of widespread hives, and the infusion was discontinued. Three weeks after the reaction, laronidase-specific IgG antibodies were detected (enzyme immunoassay/radioimmunoprecipitation test; Genzyme, Cambridge, MA, USA). On the other hand, in vitro specific IgE to laronidase (enzyme-linked immunosorbent assay – ELISA; Genzyme) was not found. A skin prick test with undiluted laronidase (0.58 mg/ml) was positive with a 3 mm-diameter wheal and flare as compared with the negative control. The test was negative in 10 disease-free controls and in one patient with MPS-I on ERT. Because laronidase was considered first line therapy, a three bags, 12-step laronidase desensitization protocol was elaborated based on previous chemotherapy protocols (3) (Tables 1 and 2), and informed consent was obtained. The patient was pre-medicated with ranitidine 35 mg, loratadine 10 mg, and montelukast 10 mg, 20 min before the procedure, and loratadine 10 mg and montelukast 10 mg before the 3rd bag. The desensitization was done in the intensive care unit, and no reaction occurred while the target dose of 20.3 mg was reached successfully. The patient was treated for 8 months weekly without any reactions. During 28th desensitization, after a dose adjustment for her weight, she experienced widespread urticaria at step 12. The protocol was amended by adding cetirizine 10 mg before step 9. The patient has been tolerating weekly infusions of laronidase adjusted to her weight for the last 2 months using the amended protocol without any reactions. Treatment with laronidase is the single best therapeutic option for patients over 18 months of age with MPS-I, and hypersensitivity reactions may prevent their continued treatment. Although the most frequent adverse events associated with ERT are mild and infusion-related (flushing, arthralgia, and headache), severe anaphylactic hypersensitivity reactions, requiring discontinuation of therapy, were described in 1/45 patients in a phase III clinical trial to evaluate the efficacy and safety of laronidase in the treatment of MPS-I (4). Our patient showed a mild (urticaria and angioedema) immediate hypersensitivity reaction during laronidase infusion. Due to the lack of any other factor or concomitant drugs that could account for the reaction observed, and the recurrence of symptoms when restarting the infusion, laronidase was considered the primary suspect drug. Immediate hypersensitivity reactions to drugs are those occurring up to 1 h after exposure, and, in most cases, are caused by IgE-mediated mechanism, that is,, mainly urticaria, angioedema, bronchoconstriction, rhinitis, and anaphylatic shock. As the symptoms were suggestive of IgE-mediated reaction, prick testing with undiluted laronidase was done with positive results. Because the predictive value and the potential for non-specific irritation were unknown, 10 controls and one patient on laronidase treatment were tested with negative results (5). In vitro IgG antibodies were found but not IgE. IgG levels in non-reactors vary and are present in 93%. The clinical

Peripheral blood mononuclear cells from severe asthmatic children release lower amounts of IL-12 and IL-4 after LPS stimulation

INTRODUCTION Asthma is an inflammatory disorder of the airways associated with bronchial hyperresponsiveness, airway obstruction, and increased mucus production, with a predominance of type 2 immune response (Th2). According to the hygiene hypothesis, exposure to environmental bacterial lipopolysaccharide (LPS) may induce a type 1 immune response (Th1), modulating the development of asthma. OBJECTIVE In this study we investigated cytokine production by peripheral blood mononuclear cells (PBMC) from children and adolescents with severe asthma, in response to LPS stimulation in vitro. MATERIALS AND METHODS 26 children were selected: 13 severe asthmatics and 13 healthy controls, aged between 5 and 18 years. They were evaluated through routine medical history, physical examination and lung function test to diagnose severe asthma. Allergy status was confirmed by skin prick test and specific IgE assay. We collected blood samples to analyse in vitro LPS-induced cytokines release by PBMC. RESULTS PBMC from severe asthmatic children produced lower levels of IL-12p70 in basal conditions and after 12 and 24h stimulation with LPS compared to healthy controls. PBMC from severe asthmatic children produced lower levels of IL-4 after 24h LPS stimulation compared to healthy controls. PBMC from severe asthmatic children produced more levels IL-17 and IL-10 after stimulus with LPS compared to healthy controls. The release of IFN-γ, IL-5 and TNF-α by PBMC from severe asthmatic children was similar to healthy controls. CONCLUSION Our results demonstrate that LPS directly influence the cytokine profile of PBMC in children with severe asthma. These observations may be potentially helpful in developing new treatment strategies.

Prevalence and factors associated with smoking among adolescents

OBJECTIVE Despite anti-smoking prevention programs, many adolescents start smoking at school age. The main objectives of this study were to determine the prevalence and risk factors associated with smoking in adolescents living in Uruguaiana, RS, Brazil. METHODS A prospective study was conducted in adolescents (12-19 years), enrolled in municipal schools, who answered a self-administered questionnaire on smoking. RESULTS 798 adolescents were enrolled in the study, with equal distribution between genders. The tobacco experimentation frequency (ever tried a cigarette, even one or two puffs) was 29.3%; 14.5% started smoking before 12 years of age and 13.0% reported smoking at least one cigarette/day last month. Having a smoking friend (OR: 5.67, 95% CI: 2.06-7.09), having cigarettes offered by friends (OR: 4.21, 95% CI: 2.46-5.76) and having easy access to cigarettes (OR: 3.82, 95% CI: 1.22-5.41) was identified as factors associated with smoking. Having parental guidance on smoking (OR: 0.67, 95% CI: 0.45-0.77), having no contact with cigarettes at home in the last week (OR: 0.51, 95% CI: 0.11-0.79) and knowing about the dangers of electronic cigarettes (OR: 0.88, 95% CI: 0.21-0.92) were identified as protection factors. CONCLUSION The prevalence of smoking among adolescents in Uruguaiana is high. The implementation of measures to reduce/stop tobacco use and its new forms of consumption, such as electronic cigarettes and hookah, are urgent and imperative in schools.

Wheezing and low birthweight.

tests, highlighting the need to standardize IDT by determining the suitable non-irritant injection volumes and the optimal size of injection papules, particularly in the pediatric population. From another point of view, our data showed that children with a positive immediate-reading IDT had a higher rate of positive OPT (delayed reactions) than those with a negative test (p < 0.05). One may consider that performing IDT before would prevent positive response to OPT. However, our previous study showed that 88 children needed to undergo skin testing to identify only four patients with a mild BL hypersensitivity (3). On the basis of our results and data from the literature (2, 4, 8), we conclude that OPT without previous skin or in vitro testing is an easy and safe approach that should be considered in every patients developing a benign rash during a BL treatment. This will allow lowering the number of patients falsely labeled as ‘penicillin allergic’.

Conhecimento médico sobre as imunodeficiências primárias na cidade de São Paulo, Brasil

OBJECTIVE: To evaluate medical knowledge of primary immunodeficiency in the city of Sao Paulo (SP). METHODS: A 14-item questionnaire about primary immunodeficiency was applied to physicians who worked at general hospitals. One of the questions presented 25 clinical situations that could be associated or not with primary immunodeficiency, and the percentage of appropriate answers generated a knowledge indicator. RESULTS: Seven hundred and forty-six participated in the study, among them 215 pediatricians (28.8%), 244 surgeons (32.7%), and 287 clinicians (38.5%). About 70% of the physicians responded that they had learned about primary immunodeficiency in graduate school or in residency training. Treatment of patients that use antibiotics frequently was reported by 75% dos physicians, but only 34.1% had already investigated a patient and 77.8% said they did not know the ten warning signs for primary immunodeficiency. The knowledge indicator obtained showed a mean of 45.72% (±17.87). Only 26.6% if the pediatricians and 6.6% of clinicians and surgeons showed a knowledge indicator of at least 67% (equivalent to an appropriate answer in two thirds of the clinical situations). CONCLUSION: There is a deficit in medical knowledge of primary immunodeficiency in the city of Sao Paulo, even among pediatricians, despite having greater contact with the theme over the last few years. The improvement of information on primary immunodeficiency in the medical community is an important step towards the diagnosis and treatment process of these diseases.ABSTRACT Objective: To evaluate medical knowledge of primary immunodeficiency in the city of Sao Paulo (SP). Methods: A 14-item questionnaire about primary immunodeficiency was applied to physicians who worked at general hospitals. One of the questions presented 25 clinical situations that could be associated or not with primary immunodeficiency, and the percentage of appropriate answers generated a knowledge indicator. Results: Seven hundred and forty-six participated in the study, among them 215 pediatricians (28.8%), 244 surgeons (32.7%), and 287 clinicians (38.5%). About 70% of the physicians responded that they had learned about primary immunodeficiency in graduate school or in residency training. Treatment of patients that use antibiotics frequently was reported by 75% dos physicians, but only 34.1% had already investigated a patient and 77.8% said they did not know the ten warning signs for primary immunodeficiency. The knowledge indicator obtained showed a mean of 45.72% (±17.87). Only 26.6% if the pediatricians and 6.6% of clinicians and surgeons showed a knowledge indicator of at least 67% (equivalent to an appropriate answer in two thirds of the clinical situations). Conclusion: There is a deficit in medical knowledge of primary immunodeficiency in the city of Sao Paulo, even among pediatricians, despite having greater contact with the theme over the last few years. The improvement of information on primary immunodeficiency in the medical community is an important step towards the diagnosis and treatment process of these diseases.

Doctors' awareness concerning primary immunodeficiencies in Brazil

BACKGROUND PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs.

Isoleucine and atopic dermatitis

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Drug-Induced Anaphylaxis: Clinical Scope, Management, and Prevention

Opinion statementDrug-induced anaphylaxis (DIA) is a severe, life-threatening reaction occurring after drug exposure. It is an important cause of anaphylaxis and accounts for up to one third of drug hypersensitivity reactions. As in other anaphylaxis reactions, immunoglobulin E (IgE) has an important role in its mechanism, but other non-immunological reactions may also occur in DIA. Cutaneous and respiratory symptoms are present in a majority of patients, and cardiovascular events are more common in elderly patients. A complete work up is recommended not just to offer safe alternatives, but also to avoid incorrect labeling of patients as allergic to drugs. The investigation includes in vitro tests when available, followed by skin prick and intradermal tests. Although provocation tests are still considered the “gold standard” for the diagnosis of drug allergy, in DIA, the risk versus benefit ratio must be analyzed. Non-steroid anti-inflammatory drugs and antibiotics are the drug classes more frequently involved. Neuromuscular blocking agents, chemotherapeutic drugs, and biologics are commonly related to reactions in a hospital setting. Prevention measures include an individualized education plan, with recommendations to avoid the culprit drug and potential cross-reactive medications. In selected patients, desensitization can induce a temporary state of tolerance. Protocols are available and can be adapted for drugs used in different situations, from cancer treatment to enzyme replacement therapy.

Increased sensitization to several allergens over a 12-year period in Brazilian children

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