Combined immunodeficiency (CVID and CD4 lymphopenia) is associated with a high risk of malignancy among adults with primary immune deficiency

Primary immunodeficiency disorders (PID) are a group of heterogeneous disorders characterized by recurrent infections, autoimmunity, increased lymphoproliferative disorders and other malignancies. PID is classified into cellular or humoral disorders or a combination of both. We evaluated the clinical differences among adult patients with three variants of PID: common variable immunodeficiency (CVID), idiopathic CD4 lymphopenia (ICL) and combined immunodeficiency (CID). We retrospectively compared demographics, immunological characteristics, clinical presentations and outcomes of CVID, CID and ICL patients followed from 2012 to 2018. In our cohort, we identified 44 adult patients diagnosed with CVID (22), CID (11) and ICL (11). Malignancy was associated with CID, as seven of 11 patients in this group were diagnosed with malignancy compared to CVID (three of 22) or ICL (two of 11) (P = 0·002 and 0·03, respectively). Malignancies were also linked to male gender [odds ratio (OR) = 5, 95% confidence interval (CI) = 1·12-22·18) P = 0·0342] and a low ratio of CD4/CD8 < 0·8 (OR = 5·1, 95% CI = 1·22-21·28, P = 0·025). Among CID and ICL, two of 11 patients died in each group, while no death was documented among CVID group (P = 0·04). Autoimmune manifestations did not differ between groups. Similarly, the rate of infections was similar between groups, although infectious agents vary. CID is associated with a high risk of malignancy compare to CVID or ICL. Among adults with PID, male gender, low CD4 and a CD4/CD8 ratio of < 0·8 may serve as risk factors of concomitant malignancy. Surveillance of lymphocyte subpopulations should be considered for all adults.

Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group.

When questioned, about 10% of the parents report suspected hypersensitivity to at least one drug in their children. However, only a few of these reactions can be confirmed as allergic after a diagnostic workup. There is still a lack of knowledge on drug hypersensitivity (DH) epidemiology, clinical spectrum, and appropriate diagnostic methods particularly in children. Meanwhile, the tools used for DH management in adults are applied also for children. Whereas this appears generally acceptable, some aspects of DH and management differ with age. Most reactions in children are still attributed to betalactams. Some manifestations, such as nonsteroidal anti-inflammatory drug-associated angioedema and serum sickness-like reactions, are more frequent among young patients as compared to adults. Risk factors such as viral infections are particularly frequent in children, making the diagnosis challenging. The practicability and validity of skin test and other diagnostic procedures need further assessment in children. This study presents an up-to-date review on epidemiology, clinical spectrum, diagnostic tools, and current management of DH in children. A new general algorithm for the study of these reactions in children is proposed. Data are presented focusing on reported differences between pediatric and adult patients, also identifying unmet needs to be addressed in further research.

Hypersensitivity to Nonsteroidal Anti-inflammatory Drugs in Children and Adolescents: Cross-Intolerance Reactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide and are responsible for several types of drug hypersensitivity reactions (DHRs) in all age groups. The 2 major groups of DHRs to NSAIDs are those induced by immunological mechanisms (selective reactions) and those where inflammatory mediators are released through activation of the prostaglandin-leukotriene pathway without specific immunological recognition (cross-intolerance). In the present review, we focus on cross-intolerance reactions, which are the most frequent DHRs and are becoming a topic of major interest in children and adolescents. Paracetamol and ibuprofen are the drugs that most frequently cause DHRs in children; other NSAIDs are responsible for reactions in adolescents. In vivo and in vitro tests are of limited diagnostic value, with some exceptions for the less common selective reactions. In cross-intolerance, the clinical history and controlled administration are in many instances the only way to establish a diagnosis and look for alternatives. The clinical history is diagnostic when consistent symptoms occur repeatedly after exposure to NSAIDs with different chemical structures. Cutaneous and respiratory symptoms often co-occur in young children. The natural history of these reactions in children is unknown, and some patients can develop tolerance over time. Atopy remains a major risk factor for cross-intolerant reactions. The increasing interest in hypersensitivity to NSAIDs with improvements in patient phenotyping and the information provided by pharmacogenetics will improve our understanding and management of these reactions in the near future.

Hypersensitivity Reactions to Nonsteroidal Anti-inflammatory Drugs in Children and Adolescents: Selective Reactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used throughout the world to treat pain and inflammation; however, they can trigger several types of drug hypersensitivity reactions (DHRs) in all age groups. Although most such reactions occur through activation of the leukotriene pathway without specific immunological recognition (cross-intolerance), a significant number of DHRs to NSAIDs are due to immunological mechanisms (selective reactions [SRs]). SRs are thought to be induced by specific IgE antibodies or by T cells. In this manuscript, we focus on SRs, which are of great concern in children and adolescents and comprise a heterogeneous set of clinical pictures ranging from mild entities such as urticaria/angioedema to potentially life-threatening conditions such as Stevens-Johnson syndrome/toxic epidermal necrolysis. Paracetamol and ibuprofen are the most frequent elicitors of IgE-mediated SRs, although pyrazolones have also been implicated. T cell-mediated reactions are infrequent in children but have been associated with ibuprofen, naproxen, and dipyrone. In this review, we analyze the available literature on SRs in children and adolescents, with emphasis on epidemiological data, mechanisms, and drugs involved, as well as on diagnostic procedures.

Hypersensitivity to nonsteroidal anti-inflammatory drugs in children and adolescents: cross-intolerance reactions

Los antiinflamatorios no esteroideos (AINEs) son ampliamente utilizados en todo el mundo y en todos los tramos de edad. Son responsables de un número importante de reacciones de hipersensibilidad a fármacos (RHFs), que no sólo afectan a adultos sino también a niños y adolescentes. Existen dos grandes grupos: reacciones selectivas, inducidas por mecanismos inmunológicos específicos, y de intolerancia cruzada (IC), donde se liberan mediadores inflamatorios en ausencia de reconocimiento inmunológico específico. En esta revisión nos ocuparemos de la IC, que es la causa más frecuente de RHFs y resulta de gran interés en niños y adolescentes. El paracetamol y el ibuprofeno son los medicamentos más frecuentemente implicados en las RHFs en niños. El uso diagnóstico de los tests in vivo e in vitro es muy limitado, con algunas excepciones en las reacciones selectivas. En las de IC, la historia clínica y la administración controlada son en ocasiones la única vía para confirmar el diagnóstico y determinar las alternativas terapéuticas más adecuadas. La historia clínica tiene valor diagnóstico cuando se reproducen síntomas consistentes repetidamente tras la exposición a AINEs no relacionados estructuralmente. En niños de corta edad es especialmente frecuente la combinación de síntomas cutáneos y respiratorios. Aunque se desconoce la historia natural de la IC en niños, es probable que se desarrolle tolerancia a lo largo de la vida. El fenotipado detallado junto con la información proporcionada por la fármaco-genética no sólo proporcionarán un conocimiento más preciso de la IC sino que también facilitará el manejo clínico de estos pacientes (AU)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide and are responsible for several types of drug hypersensitivity reactions (DHRs) in all age groups. The 2 major groups of DHRs to NSAIDs are those induced by immunological mechanisms (selective reactions) and those where inflammatory mediators are released through activation of the prostaglandin-leukotriene pathway without specific immunological recognition (cross-intolerance). In the present review, we focus on cross-intolerance reactions, which are the most frequent DHRs and are becoming a topic of major interest in children and adolescents. Paracetamol and ibuprofen are the drugs that most frequently cause DHRs in children; other NSAIDs are responsible for reactions in adolescents. In vivo and in vitro tests are of limited diagnostic value, with some exceptions for the less common selective reactions. In cross-intolerance, the clinical history and controlled administration are in many instances the only way to establish a diagnosis and look for alternatives. The clinical history is diagnostic when consistent symptoms occur repeatedly after exposure to NSAIDs with different chemical structures. Cutaneous and respiratory symptoms often co-occur in young children. The natural history of these reactions in children is unknown, and some patients can develop tolerance over time. Atopy remains a major risk factor for cross-intolerant reactions. The increasing interest in hypersensitivity to NSAIDs with improvements in patient phenotyping and the information provided by pharmacogenetics will improve our understanding and management of these reactions in the near future (AU)

Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs in children and adolescents: selective reactions

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used throughout the world to treat pain and inflammation; however, they can trigger several types of drug hypersensitivity reactions (DHRs) in all age groups. Although most such reactions occur through activation of the leukotriene pathway without specific immunological recognition (cross-intolerance), a significant number of DHRs to NSAIDs are due to immunological mechanisms (selective reactions [SRs]). SRs are thought to be induced by specific IgE antibodies or by T cells. In this manuscript, we focus on SRs, which are of great concern in children and adolescents and comprise a heterogeneous set of clinical pictures ranging from mild entities such as urticaria/angioedema to potentially life-threatening conditions such as Stevens-Johnson syndrome/toxic epidermal necrolysis. Paracetamol and ibuprofen are the most frequent elicitors of IgE-mediated SRs, although pyrazolones have also been implicated. T cell–mediated reactions are infrequent in children but have been associated with ibuprofen, naproxen, and dipyrone. In this review, we analyze the available literature on SRs in children and adolescents, with emphasis on epidemiological data, mechanisms, and drugs involved, as well as on diagnostic procedures (AU)

A pesar de su eficacia en el tratamiento del dolor y la inflamación los antiinflamatorios no esteroideos (AINE), los medicamentos de mayor consumo mundial, también son la causa más frecuente de reacciones de hipersensibilidad a fármacos (RHFs) en cualquier tramo de edad. Aunque en muchas de estas reacciones se liberan mediadores inflamatorios en ausencia de reconocimiento inmunológico específico (intolerancia cruzada), un porcentaje considerable de las RHFs a AINE se producen a través de mecanismos inmunológicos (reacciones selectivas, SRs). En éstas participarían anticuerpos IgE específicos o células T. Las SRs son de gran interés en niños y adolescentes e incluyen un conjunto heterogéneo de entidades que comprenden desde manifestaciones clínicas de poca gravedad como la urticaria y el angioedema hasta otras como el síndrome de Stevens-Johnson y la necrolisis epidérmica tóxica, que pueden suponer una amenaza para la vida. En niños el paracetamol y el ibuprofeno son los medicamentos más frecuentemente implicados en las SRs mediadas por IgE aunque también se ha descrito la participación de las pirazolonas. Las reacciones mediadas por linfocitos T son menos frecuentes pero también se han descrito en relación con la administración de ibuprofeno, naproxeno y dipirona. En esta revisión analizaremos la literatura actual sobre las SRs en niños y adolescentes, centrándonos en los datos epidemiológicos, mecanismos y fármacos implicados, así como las pruebas disponibles para su diagnóstico (AU)

Community acquired acute bacterial meningitis in children and adults: an 11-year survey in a community hospital in Israel.

OBJECTIVES: We aimed to investigate the association between the presenting clinical manifestations of bacterial meningitis and the duration of time elapsed before lumbar puncture and start of antibiotic treatment. DESIGN: Retrospective epidemiologic study using the clinical records in Barzilai Medical Center Emergency Department between 1988 and 1999. RESULTS: 97 patients, 72 children and 25 adults with ABM were identified. 30 of 97 (31%) were diagnosed by the primary physicians at primary care units. Acute meningitis was suspected by emergency department (ED) physicians in 51% of the referred patients. Patients with a scarce clinical picture at hospital arrival (those without fever, headache or nuchal rigidity) showed a trend toward a longer median delay until a diagnostic lumbar puncture was performed and antibiotic therapy was started (median of 14.7 h compared with 2.1 h for those with severe clinical picture) (p<0.02). Nevertheless, the clinical outcome for the total cohort did not yield a significant difference when analyzed regarding the duration of time between arrival to emergency department and antibiotic treatment initiation (p>0.3). CONCLUSIONS: The interval before diagnosis of community acquired ABM in both children and adults is longer for those patients who present to the emergency department with an atypical clinical picture, mostly, without fever and without nuchal rigidity. Until bacterial meningitis can be effectively prevented, we can expect this life-threatening infection to continue to cause diagnostic and medical difficulties.

Efficacy of nasal Staphylococcus aureus eradication by topical nasal mupirocin in patients with perennial allergic rhinitis.

BACKGROUND: Staphylococcus aureus (SA) colonization is frequent in patients with perennial allergic rhinitis (PAR). Mupirocin has well-recognized antistaphylococcal activity, and its nasal formulation is approved for the eradication of SA nasal colonization. OBJECTIVE: To investigate the frequency of SA nasal carriage, its possible influence on AR severity, and nasal mupirocin's role on AR clinical severity. METHODS: Sixty patients, aged 5 to 60 years, with AR were included, and 55 healthy individuals served as a control group. Nasal smear specimens were drawn from both nares. A skin prick test to inhalational allergens and a score-graded clinical evaluation of AR were performed. Carriers of SA were treated with topical nasal mupirocin. RESULTS: The SA carrier (SAC) state was found in 23 (38%) of the patients with AR and in 8 (15%) of the healthy controls (P = .004). Comparing SACs with AR SA noncarriers, nasal symptom scores (SSs) tended to be higher in the SAC group (mean [SD], 11.09 [2.16] vs 8.86 [1.43]; P < .005). Treatment with topical nasal mupirocin diminished the SAC state to 10% (P = .009) but did not change AR clinical severity, as assessed by the SS. CONCLUSIONS: In patients with PAR, the SAC state is more prevalent compared with the healthy population. Topical nasal mupirocin reduces the SAC state but fails to clinically improve PAR, as assessed by the SS.

The changing face of food hypersensitivity in an Asian community.

BACKGROUND: Food allergy seems to be increasing in Asia as well as world-wide. Our aim was to characterize food protein sensitization patterns in a population of Asian children with possible food allergy. METHODS: Children presenting to our allergy clinic over 3 years with symptomatic allergic disease and at least one specific food allergen sensitization documented on skin prick testing were included in the analysis. RESULTS: Two hundred and twenty-seven patients fulfilled inclusion criteria. Ninety (40%) of the positive skin tests were positive to egg, 87 (39%) to shellfish, 62 (27.3%) to peanut, 30 (13.2%) to fish, 27 (11.8%) to cow's milk, 21 (9.3%) to sesame, 13 (3.7%) to wheat and eight (3.2%) to soy. Peanut sensitization was the third most common sensitizing allergen, and seen mostly in young atopic children with multiple food hypersensitivities and a family history of atopic dermatitis. The median reported age of first exposure to fish and shellfish was 6 and 12 months, respectively. The mean age at presentation of children with shellfish hypersensitivity was at 6.7 years of age. The likelihood of shellfish sensitization was increased in children with concomitant sensitization to cockroaches. CONCLUSIONS: In contrast to previously reported low peanut allergy rates in Asia, in our review, peanut sensitization is present in 27% (62/227) of food-allergic children, mostly in patients with multiple food protein sensitizations. Temporal patterns of first exposure of infants to fish and shellfish are unique to the Asian diet. Shellfish are a major sensitizing food source in Asian children, especially in allergic rhinitis patients sensitized to cockroaches.

Sensitization to dust mites in children with allergic rhinitis in Singapore: does it matter if you scratch while you sneeze?

BACKGROUND: Previously published data established Blomia tropicalis, as the major source of allergic sensitization in asthmatic children in tropical Singapore. Objective To define the prevalence, clinical characteristics and risk factors of species-specific mite sensitization in paediatric allergic rhinitis (AR) patients in this unique environment. METHODS: We performed a prospective evaluation of newly diagnosed AR patients, from 1 May 2003 to 30 April 2004, from the otolaryngology and allergy outpatient clinics of the Kendang Kerbau Children's Hospital in Singapore. Patients included in the study showed evidence of sensitization to at least one respiratory allergen source and completed a detailed questionnaire. Relative risk of sensitization and associated risk factors were calculated using logistic regression analysis with the forward stepwise model. Multivariate regression analysis was performed to adjust for confounding interactions. Continuous values were compared using anova, SPSS 9.0 for Windows (SPSS Inc., 1999). RESULTS: One hundred and seventy-five patients were included, 119 (68%) males, 142 (81%) Chinese, age mean 7.9 years (range 2-16). Sixty-eight patients (39%) reported a concomitant diagnosis and/or clinical complaints of bronchial asthma and 84 (48%) of atopic dermatitis. Skin prick test results were positive for traditional house dust mites (Dermatophagoides pteronyssinus. and D. farinae mix) in 85% of patients and for B. tropicalis in 62%. Overall mite sensitization was 98%, household pets 10%, moulds 9% and food proteins 12%. By far the single most significant factor associated with Dermatophagoides sensitization in this group was the presence of allergic eczema (odds ratio (OR) 31.8%, 95% confidence interval (CI) 3.6-285, P=0.002). Allergic eczema was negatively associated with B. tropicalis sensitization (OR 0.26%, 95% CI 0.14-0.5). CONCLUSIONS: Children with AR and concomitant atopic dermatitis show a preferential sensitization to the Dermatophagoides mites. In our population, B. tropicalis sensitization is more prominent in children with pure respiratory allergy.

Adverse drug reactions in Singaporean children.

INTRODUCTION: Allergic reactions to drugs are considered rare in the paediatric population. Host genetic and environmental factors influence the reported incidence and characteristics of adverse drug reactions (ADRs), and cause significant variation according to the population described and case definition used. We aimed to define the prevalence and characteristics of reported drug allergies in hospitalised children in Singapore. METHODS: A retrospective case control study was performed through the hospital's inpatient electronic medical record (EMR) for the period of August 2002 to December 2002. The EMR was used to identify children with a previously reported ADR. The control group was randomly selected from patients hospitalised during the same period. RESULTS: Of the 8437 patients hospitalised during the study period, reports of previous ADRs were found in the records of 222 patients. The mean age of the patients was 7.4 years, range 2 months to 17 years (95 percent confidence interval [CI] 6.3 - 8.4). There were 146 males and 160 Chinese. The most commonly-involved medications were betalactam antibiotics (45 percent) and non steroidal anti-inflammatory drug (18.5 percent). Compared to the control group, children with a reported ADR were more likely to be older, with a mean age of 7.4 years versus 4.6 years (p-value less than 0.001), male (odds ratio [OR] 1.7, 95 percent CI 1.2-2.4), of Chinese descent (OR 1.8, 95 percent CI 1.5-5), have an associated chronic illness (OR 3.5, 95 percent CI 2.5-5), and a diagnosis of asthma (OR 2.7, 95 percent CI 1.7-4.5). CONCLUSION: In our paediatric inpatient population, the risk of reported ADRs increases with age, male gender, Chinese descent and the presence of chronic disease. The major drugs involved are betalactam antibiotics and non-steroidal anti inflammatory drugs.

Does skin prick test correlate with basophil-associated mite-specific IgE in atopic children?

Skin prick test (SPT), as the standard diagnostic tool for immediate hypersensitivity to aeroallergens, is an expression of IgE-dependent mediator release from dermal mast cells. Though probably involved in the late-phase response, peripheral blood basophils (PBB) don't seem to participate in the immediate hypersensitivity response in the skin. We aimed to assess a possible correlation between the SPT to mites and levels of basophil-associated mite-specific IgE. We sequentially enrolled 15 children with allergic rhinitis and documented class > II mite sensitization, mean age 13 years (range 9.5-18), 11 males, 4 females. Symptoms score was determined using a validated questioner. SPT area under the curve (AUC) for 10 common respiratory allergens was measured in all patients. Heparinized blood after basophil enrichment, was lysed with CHAPS. Determination of allergen-specific and total IgE in serum and cell lysate supernatant was performed using standard commercial kits. Basophil-associated, mite-specific IgE could be reliably determined only in 10 patients with a skin reaction greater than 70 mm2, OR 36 (95% CI 1.8-732, p = 0.02). We found a strong linear correlation (R2 = 0.74, p = 0.001) between mite-specific basophil-associated IgE density (IgE molecules per cell) and the SPT AUC. This finding suggests that skin mast cell precursors and basophil both bind specific IgE at a common site prior to the arrival of mast cells to the skin.

[Diagnosis of drug hypersensitivity--state of the art].

Adverse drug reactions are ubiquitous in outpatient as well as inpatient clinical care. An allergic drug reaction is an immunologically mediated adverse drug reaction that exhibits specificity and recurrence on re-exposure to the offending drug. The diagnosis and treatment of drug allergies is limited by a number of factors. In most instances the exact epitope causing the reaction is unknown, the immunological mechanism is unclear, the presence of immunological recognition is not predictive of a clinical reaction and the gold standard for diagnosis, the drug challenge, a complicated and sometimes dangerous endeavor. Nevertheless, during the past few years a serious attempt at standardization and validation of in vitro and in vivo techniques for the diagnosis of drug allergies, has been in progress. New methods, like the basophil surface marker for activation, CD63 are replacing old ones like histamine release for immediate type hypersensitivity reactions. For instance, in the field of beta-lactam hypersensitivity, the specific epitopes are better defined and standardized protocols for both immediate and delayed type reactions are in the process of being introduced. A standardized European Network of Drug Allergies (ENDA) questioner, published in 1999, permits systematic data gathering of events surrounding the acute drug reaction, facilitating later immunological investigation and diagnosis. This review attempts to summarize the present and some of the future options in the diagnosis of this common iatrogenic complication.

A new exon 9 glucose-6-phosphate dehydrogenase mutation (G6PD "Rehovot") in a Jewish Ethiopian family with variable phenotypes.

Hereditary nonspherocytic hemolytic anemia (HNSHA) is a rare manifestation of glucose-6-phosphate dehydrogenase (G6PD) gene mutations, caused mainly by mutations located in exon 10 of the G6PD gene and less commonly by mutations in other parts of the gene. A new, exon 9, single-base mutation representing a T --> C transition at cDNA nucleotide 964 was found in three brothers and their carrier mother of Jewish Ethiopian descent. Biochemical characterization of the resultant protein was not performed. Though clinical manifestations included HNSHA in all cases, the severity of hemolysis and the transfusion requirement differed markedly. Severe congenital neutropenia (Kostmann's syndrome)--a disorder never reported before in conjunction with G6PD deficiency--was observed in one case. Levels of white blood cell G6PD activity of the three patients were 0-5% of normal controls. Neutrophil oxidative and bactericidal activities were inherently impaired in the patient with Kostmann's syndrome, but were well preserved in his two siblings.