Unanswered questions on the use of biologics in pediatric asthma.

The emergence of biologic therapies for the management of asthma has been a revolutionary change in our capacity to manage this disease. Since the launch of omalizumab, several other biologics have been marketed or are close to being marketed, suggesting that a plethora of monoclonal antibodies can be expected in the coming years. This will facilitate the transition to the paradigm of personalized medicine, but on the other hand will decisively further complicate the choice of the most appropriate treatment, in the absence of reliable enough biological markers. For these reasons, along with the relatively short time of use with these treatments, there are recurrently arising questions for which there are not even moderately documented answers, and for which the only solution must be based, with all reservations, on the combination of indirect evidence and expertise. In this paper, we attempt to address such questions, providing relevant commentaries and considering the whole width of the evidence base.

Utility of biomarkers in the diagnosis and monitoring of asthmatic children.

Asthma imposes a heavy morbidity burden during childhood; it affects over 10% of children in Europe and North America and it is estimated to exceed 400 million people worldwide by the year 2025. In clinical practice, diagnosis of asthma in children is mostly based on clinical criteria; nevertheless, assessment of both physiological and pathological processes through biomarkers, support asthma diagnosis, aid monitoring, and further lead to better treatment outcomes and reduced morbidity. Recently, identification and validation of biomarkers in pediatric asthma has emerged as a top priority across leading experts, researchers, and clinicians. Moreover, the implementation of non-invasive biomarkers for the assessment and monitoring of paediatric patients with asthma, has been prioritized; however, only a proportion of them are currently included in the clinical practise. Although, the use of non-invasive biomarkers is highly supported in recent asthma guidelines for documenting diagnosis and supporting monitoring of asthmatic patients, data on the Pediatric population are limited. In the present report, the Pediatric Asthma Committee of the World Allergy Organization (WAO), aims to summarize and discuss available data for the implementation of non-invasive biomarkers in the diagnosis and monitoring in children with asthma. Information on the most studied biomarkers, including spirometry, oscillometry, markers of allergic sensitization, fractional exhaled nitric oxide, and the most recent exhaled breath markers and "omic" approaches, will be reviewed. Practical limitations and considerations based on both experts' opinion and critical review of the literature, on the utility of all "well-known" and newly introduced non-invasive biomarkers will be presented. A critical commentary on biomarkers' use in diagnosing and monitoring asthma during the COVID-19 pandemic, cost and availability of biomarkers in different settings and in developing countries, the differences on the biomarkers use between Primary Practitioners, Pediatricians, and Specialists and their role on the longitudinal aspect of asthma is provided.

Allergic manifestations of inborn errors of immunity and their impact on the diagnosis: A worldwide study.

Background: Allergies have long been observed in Inborn Errors of Immunity (IEI) and might even be the first presentation resulting in delayed diagnosis or misdiagnosis in some cases. However, data on the prevalence of allergic diseases among IEI patients are limited and contradictory. Objective: To provide a worldwide view of allergic diseases, across a broad spectrum of IEI, and their impact on the timely diagnosis of IEI. Methods: This is a worldwide study, conceived by the World Allergy Organization (WAO) Inborn Errors of Immunity Committee. A questionnaire was developed and pilot-tested and was sent via email to collect data from 61 immunology centers known to treat pediatric and/or adult IEI patients in 41 countries. In addition, a query was submitted to The United States Immunodeficiency Network (USIDNET) at its website. Results: Thirty centers in 23 countries caring for a total 8450 IEI patients responded. The USIDNET dataset included 2332 patients. Data from responders showed that a median (IQR) of 16.3% (10-28.8%) of patients experienced allergic diseases during the course of their IEI as follows: 3.6% (1.3-11.3%) had bronchial asthma, 3.6% (1.9-9.1%) atopic dermatitis, 3.0% (1.0-7.8%) allergic rhinitis, and 1.3% (0.5-3.3%) food allergy. As per the USIDNET data, the frequency of allergy among IEI patients was 68.8% (bronchial asthma in 46.9%). The percentage of IEI patients who presented initially with allergic disorders was 8% (5-25%) and diagnosis delay was reported in 7.5% (0.9-20.6%). Predominantly antibody deficiencies had the highest frequency of allergic disease followed by combined immunodeficiency with a frequency of 40.3% (19.2-62.5%) and 20.0% (10-32%) respectively. As per the data of centers, anaphylaxis occurred in 25/8450 patients (0.3%) whereas per USIDNET dataset, it occurred in 249/2332 (10.6%); drugs and food allergy were the main causes in both datasets. Conclusions: This multinational study brings to focus the relation between allergic diseases and IEI. Major allergies do occur in IEI patients but were less frequent than the general population. Initial presentation with allergy could adversely affect the timely diagnosis of IEI. There is a need for policies to raise awareness and educate primary care and other referring specialties on the association of allergic diseases with IEI. This study provides a network among centers for future prospective studies in the field.

The role of environmental allergen control in the management of asthma.

Allergen exposure may exacerbate asthma symptoms in sensitized patients. Allergen reduction or avoidance measures have been widely utilized; however, there is ongoing controversy on the effectiveness of specific allergen control measures in the management of children with asthma. Often, allergen avoidance strategies are not recommended by guidelines because they can be complex or burdensome, although individual patients may benefit. Here we explore the potential for intervention against exposure to the major allergens implicated in asthma (ie, house dust mites, indoor molds, rodents, cockroaches, furry pets, and outdoor molds and pollens), and subsequent effects on asthma symptoms. We critically assess the available evidence regarding the clinical benefits of specific environmental control measures for each allergen. Finally, we underscore the need for standardized and multifaceted approaches in research and real-life settings, which would result in the identification of more personalized and beneficial prevention strategies.

Screening of hemophagocytic lymphohistiocytosis in children with severe sepsis in pediatric intensive care.

BACKGROUND: We sought to screen for clinical and laboratory features of hemophagocytic lymphohistiocytosis among pediatric patients with severe sepsis. METHODS: We conducted a retrospective study that analyzed the clinical and laboratory data of 70 pediatric patients who died of severe sepsis. Medical records were revised for the presence of fever, splenomegaly, pancytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia. Soluble CD25 was measured in stored samples. RESULTS: Patients' ages ranged between 0.5 and 11 years with median (interquartile range) 2 (1-5). All patients had fever (≥38.5 °C) and pancytopenia, 58 (82.9%) hepatosplenomegaly, 36 (51.4%) lymphadenopathy, 37 (52.9%) had ferritin >500 ng/ml, 20 (28.6%) had fibrinogen <1.5 mg/ml, 14 (20%) had fasting triglycerides >264 mg/dl while 5 (7.1%) had soluble CD25 >2400 U/ml. Twenty-five (35.7%) patients fulfilled at least 5/6 of the hemophagocytic lymphohistiocytosis-2004 diagnostic criteria. Multivariate backward binary logistic regression analysis revealed lymphadenopathy as an independent predictor for hemophagocytic lymphohistiocytosis criteria fulfilment with odds ratio of 23.9. Fibrinogen had the best performance in discriminating hemophagocytic lymphohistiocytosis fulfilling from non-fulfilling groups (cut-off value: <1.8 mg/ml), followed by ferritin/erythrocyte sedimentation rate ratio (cut-off value: >17). CONCLUSION: There is a significant clinical and laboratory overlap between hemophagocytic lymphohistiocytosis and severe sepsis, making the syndromes difficult to distinguish. The use of current hemophagocytic lymphohistiocytosis-2004 diagnostic criteria should be applied cautiously in those patients.

Update on Immunodeficiency-Associated Vaccine-Derived Polioviruses - Worldwide, July 2018-December 2019.

Since establishment of the Global Polio Eradication Initiative* in 1988, polio cases have declined >99.9% worldwide; extensive use of live, attenuated oral poliovirus vaccine (OPV) in routine childhood immunization programs and mass campaigns has led to eradication of two of the three wild poliovirus (WPV) serotypes (types 2 and 3) (1). Despite its safety record, OPV can lead to rare emergence of vaccine-derived polioviruses (VDPVs) when there is prolonged circulation or replication of the vaccine virus. In areas with inadequate OPV coverage, circulating VDPVs (cVDPVs) that have reverted to neurovirulence can cause outbreaks of paralytic polio (2). Immunodeficiency-associated VDPVs (iVDPVs) are isolated from persons with primary immunodeficiency (PID). Infection with iVDPV can progress to paralysis or death of patients with PID, and excretion risks seeding cVDPV outbreaks; both risks might be reduced through antiviral treatment, which is currently under development. This report updates previous reports and includes details of iVDPV cases detected during July 2018-December 2019 (3). During this time, 16 new iVDPV cases were reported from five countries (Argentina, Egypt, Iran, Philippines, and Tunisia). Alongside acute flaccid paralysis (AFP) surveillance (4), surveillance for poliovirus infections among patients with PID has identified an increased number of persons excreting iVDPVs (5). Expansion of PID surveillance will facilitate early detection and follow-up of iVDPV excretion among patients with PID to mitigate the risk for iVDPV spread. This will be critical to help identify all poliovirus excretors and thus achieve and maintain eradication of all polioviruses.

Challenges and choices in the pharmacological treatment of non-severe pediatric asthma: A commentary for the practicing physician.

In recent years, asthma research has focused intensely on the severe part of the disease spectrum, leading to new treatments, mostly therapeutic monoclonal antibodies. However, severe asthma accounts for not more than 2% of asthma in the pediatric population. Therefore, non-severe asthma remains a major health problem in children, not only for patients and parents but also for healthcare professionals such as general practitioners, pediatricians and allergists who take care of these patients. It is thus essential to identify and put in context novel concepts, applicable to the treatment of these patients. Recent evidence suggests benefits from using anti-inflammatory treatment even for the mildest cases, for whom until now only symptomatic bronchodilation was recommended. Likewise, "reliever" medication may be better combined with an inhaled corticosteroid (ICS). Among "new" treatments (for children), ICS formulation in ultrafine particles has showed promise and tiotropium is gaining access to the pediatric population. Maintenance and reliever therapy (MART) is an option for moderate disease. Most importantly, personalized response to medications appears to be considerable, therefore, it may need to be taken into account. Overall, these new options provide opportunities for multiple new management strategies. The deployment of such strategies in different populations remains to be evaluated.

X-linked agammaglobulinemia (XLA):Phenotype, diagnosis, and therapeutic challenges around the world.

BACKGROUND: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. METHODS: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. RESULTS: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. CONCLUSIONS: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.

Newborn Screening for Primary Immunodeficiencies: The Gaps, Challenges, and Outlook for Developing Countries.

Primary immunodeficiency diseases (PIDs) are genetically inherited diseases characterized by an increased susceptibility to infections, autoimmunity, lymphoproliferation, and malignancies. PIDs are under-diagnosed and the registered cases and reported prevalence are far below the estimated numbers especially in countries with large population and high consanguinity rates. Delays in diagnosis yield major morbidities and mortalities with resultant increased economic burden. Newborn screening using TRECs and KRECs, currently being implemented in some countries, is aimed through early diagnosis, to overcome the delays in the diagnosis and hence the poor outcome of some of the severe PIDs. However, the limited resources in developing countries challenges the implementation of newborn PID screening programs. There are considerable gaps in our knowledge that must be bridged. Setting the norms of TRECs and KRECs for each country is needed. Furthermore, some PIDs that might present in the neonatal period could not be detected by the current screening programs, and their diagnosis requires clinical expertise. Not to mention, local guidelines for the management of patients diagnosed by NBS should be set forth. Also, in the absence of NBS, clinicians should be aware of the early manifestations of PID. All these mandate conducting studies genuine to each country, developing programs for raising public awareness and clinical training of physicians to attain the required immunological skills.

Alpha beta double negative T cells in children with systemic lupus erythematosus: The relation to disease activity and characteristics.

OBJECTIVES: We aimed to investigate alpha beta double negative (αß DN) T-cell percentages in juvenile systemic lupus erythematosus (JSLE) and their relation to disease activity and organ involvement. METHODS: This prospective study was carried out over a period of 12 months and included 21 JSLE patients and 20 healthy matched controls. SLE disease activity index 2000 (SLEDAI-2K) scores were recorded in addition to αß DN T-cell percentages measurement at enrollment and after remission. RESULTS: Enrolled patients (n = 21) were females with age range 10-17 years. Patients were followed up for a duration ranging 5-9 months. αß DN T-cell percentages were higher in cases during activity [median (IQR): 3.7 (3.0-5.7)] versus remission [median (IQR): 1.4 (1.2-1.8)] and during activity and remission versus healthy controls [median (IQR): 1.0 (0.5-1.4)]. αß DN T-cell percentages correlated positively with SLEDAI-2K score (p < .001). The mean αß DN T-cell percentages varied significantly with different degrees of activity per SLEDAI-2K score (p = .002) and with the presence of neurological (p = .028) and hematological (p = .032) manifestations. CONCLUSION: αß DNT cells percentages are elevated in patients with JSLE and their percentages correlate with disease activity. Further studies are needed in conjunction with the proinflammatory cytokine profile, apoptotic assays and histological findings.

Allergy and immunology in Africa: Challenges and unmet needs.

The tremendous increase in allergy in the African continent cannot simply be explained by the change in public hygiene. There are many "prehygiene" communities with sewage-contaminated water supplies, helminth infestations, bare footedness, and poor housing, and still there is a high prevalence of allergic disease. Africans can be exposed to many risk factors facilitating severe asthma and wheezing, including airborne viruses, smoke, indoor dampness, cockroaches, and poor access to health care. Although the reporting on food allergy is inadequate to perform systematic reviews or meta-analyses, the available data suggest that food allergy is underdiagnosed. The rate of new HIV infections in high-prevalence settings in Africa remains unacceptably high. Although the annual number of new HIV infections in Sub-Saharan Africa has decreased lately, new HIV infections in the Middle East and North Africa region have increased; however, the current prevalence of 0.1% is still among the lowest globally. Africa is densely populated, and consanguineous mating is high in some areas of North and Sub-Saharan Africa. This allows for emergence of many autosomal recessive primary immunodeficiency diseases. There is urgent need for the establishment of primary immunodeficiency disease registries, stem cell transplantation facilities, and neonatal screening programs. To address these expanding problems and perform local cutting-edge research, Africans need to be empowered by motivated governments, dedicated funds, and compassionate scientific partnership.

Latex hypersensitivity among allergic Egyptian children: relation to parental/self reports.

BACKGROUND: Latex allergy is one of the major health concerns and allergic reactions to latex may be serious and fatal. PURPOSE: In this study, we sought to determine the frequency of latex hypersensitivity in a group of allergic Egyptian infants and children and its relation to the history provided by the patients or caregivers. METHODS: We consecutively enrolled 400 patients with physician diagnosed allergic diseases. The study measurements included clinical evaluation for the site and duration of allergy, history suggestive of latex allergy, family history of allergy, and skin prick testing (SPT) using a commercial latex extract. RESULTS: The study revealed that 16/400 (4%) patients had positive SPT; 11 of them only had positive history of sensitivity to latex. Positive latex SPT was reported in 3.4% (11/326) of patients with bronchial asthma, 5.9% (7/118) of patients with skin allergy, and 4.5% (2/44) of patients with allergic rhinitis. SPT was positive in 7.4% (4/54) of patients with concomitant respiratory and skin allergy. Latex SPT was more specific than sensitive (97.69% and 77.77%, resp.) with a negative predictive value of 99.47%. CONCLUSION: Although underrecognized, latex is an important allergen in the pediatric age group with a sensitization frequency of 4% among allergic children. It was observed to be especially associated with multiple allergic diseases coexisting in the same patient. Pediatric allergologists should educate their patients on latex allergy and encourage the use of latex-free products.

Giant cell arteritis in a 12-year-old girl presenting with nephrotic syndrome.

Giant cell arteritis (GCA) is rare in children. The kidneys are generally spared. We present a case of GCA in a 12-year-old girl with severe headache and tender scalp especially over the right temporal area. The right superficial temporal artery was cord like and nodular and the pulsations were barely felt. Several small tender nodular swellings were felt in the occipital area. She had been previously diagnosed as a case of nephrotic syndrome due to underlying membranoproliferative glomerulonephritis. This report is aimed at drawing attention to this rare form of vasculitis in children aiming at decreasing its morbidities.

Evaluation of banana hypersensitivity among a group of atopic egyptian children: relation to parental/self reports.

PURPOSE: To evaluate the frequency of banana sensitization and allergy among a group of atopic Egyptian children in relation to parental/self reports. METHODS: This is a case-control study included 2 groups of allergic children with and without history of banana allergy, each included 40 patients. They were subjected to skin prick test (SPT) using commercial banana allergen extract and prick-prick test (PPT) using raw banana, in addition to measuring the serum banana-specific IgE. Oral banana challenge was performed in suspected cases. RESULTS: Banana allergy was diagnosed in 3 (7.5%) patients based on positive history of allergy on exposure to banana, positive SPT/PPT and elevated banana-specific IgE. The 3 patients had bronchial asthma with exacerbation upon banana exposure. The PPT results conform with those of SPT both in diagnosis of banana allergy and in the skin reactivity to banana. Serum banana-specific IgE was detectable in the whole studied sample with higher serum level among those without history of banana allergy (P=0.005). Oral banana challenge was negative for 20 patients with history of banana allergy and positive serum banana-specific IgE but negative SPT and PPT. CONCLUSIONS: Self/parental reports of banana allergy is high while the actual banana allergy is uncommon. The PPT seems as reliable as SPT in diagnosis of banana allergy unlike specific IgE which reflects sensitization rather than allergy. Oral food challenge remains the most helpful tool for diagnosis of food allergy in suspected cases.

A rare association between leukocyte adhesion deficiency type I and psoriasis in humans.

The ß2 integrins are expressed exclusively on leukocytes and participate in many immune and inflammatory processes. This subfamily comprises four heterodimeric glycoproteins with a common ß-subunit, designated ß2 (CD18). Spontaneous mutations of the CD18 gene result in leukocyte adhesion deficiency type I (LAD-I). Low level of CD18 expression has also been implicated in the pathogenesis of psoriasis. We here describe a child with recurrent skin infections without pus formation, persistent gingivitis and periodontitis. His blood counts showed persistent leukocytosis (neutrophilia). CD11b expression was defective on neutrophils, while that of CD18 was normal. So, our patient represents a mild variant of LAD-I with possible dysfunctional CD18. Moreover, he developed psoriasis with reduced CD18 expression on CD4(+) T-cells. Psoriasiform dermatitis has been described before in association with LAD-I, however, clinically and histologically confirmed psoriasis in association with LAD-I has been described only in CD18 hypomorphic mice. Therefore, our patient represents the first clinically and histopathologically documented association between LAD-I and psoriasis in humans. It lends support to the role of ß2 integrins in the etiopathogenesis of psoriasis.

Cardiovascular autonomic function assessed by autonomic function tests and serum autonomic neuropeptides in Egyptian children and adolescents with rheumatic diseases.

OBJECTIVE: Cardiovascular autonomic neuropathy (CAN) in patients with rheumatic diseases may result in sudden death, possibly from arrhythmia and myocardial infarction due to its frequent association with microvascular disease. Autonomic dysfunction may contribute to initiation and perpetuation of rheumatic diseases. Thus, we aimed to assess cardiovascular autonomic function in lupus and juvenile idiopathic arthritis (JIA) patients. METHODS: Assessment of cardiovascular autonomic function was done in 20 lupus and 20 JIA patients, aged 8-16 years, by five non-invasive autonomic function tests (AFTs) and serum levels of neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP), as indicators of sympathetic and parasympathetic functions, respectively, in comparison with 40 matched healthy control subjects. RESULTS: Clinical evidence of CAN was found in 65 and 40% of lupus and JIA patients, respectively, and in none of healthy controls. Lupus and JIA patients had significantly lower serum NPY and VIP than controls (P < 0.001). The five AFTs score had significant negative correlations to NPY and VIP (P < 0.001). Patients with CAN had significantly lower serum NPY and VIP than patients without (P < 0.001). Clinical evidence of CAN was found in 41.7 and 14.3% of asymptomatic lupus and JIA patients, respectively. There was significant positive association between CAN and important disease manifestations, including activity, in these patients. CONCLUSIONS: CAN is common in lupus and JIA patients, even in absence of relevant symptoms. Thus, assessments of cardiac autonomic function, by AFTs and serum autonomic neuropeptides (NPY and VIP), and the therapeutic effects of NPY and VIP are recommended in these patients.

Altered CD19/CD22 balance in Egyptian children and adolescents with systemic lupus erythematosus.

B cells from systemic lupus erythematosus (SLE) patients display signalling defects that may underlie disease pathogenesis activity.CD19 and CD22 play a major role as regulators of B-cell response. The aim of this study was to clarify the relationship between B cell surface markers namely CD19, CD20 and CD22 expression and clinical and laboratory indices of SLE activity. The study included 33 SLE patients and 20 healthy children and adolescents as controls. Flowcytometric assay of dual markers, CD19/CD20, and CD20/CD22 was done. SLE disease activity was assessed by SLEDAI score. CD22% was significantly higher while CD20% was significantly lower in the study compared to the control group. No significant difference was observed in both groups with respect to CD19% or CD19/CD22% ratio. The level of CD22 expression was significantly lower in high and very high active cases than in mild and moderate cases and negatively correlated with SLDEAI score and ESR. Results obtained showed that, B cell surface receptors CD20 and CD22 are significantly affected in patients with SLE, pointing to their possible involvement in the aetiopathogenesis of the disease and in the regulatory mechanisms in response to the immune disturbance.