Background: Vernal keratoconjunctivitis (VKC) is a rare chronic conjunctivitis characterized by a predominantly eosinophil-mediated inflammatory disorder that could develop critical complications such as blindness. Oxidative stress plays a pivotal role in the pathogenesis of several allergic diseases. The role of oxidative stress has been hypothesized in VKC, but no study explored this issue.Furthermore, cyclosporine A (CsA) exerts an anti-inflammatory and antioxidant action on the conjunctiva. This study aims to assess oxidative stress in VKC patients and controls and to study the effect ofCsA on oxidative stress in these subjects. Methods:Thirty-six consecutive children, including 12 VKC(9 males, 75%; mean age 10,17; SD ± 2.48) patients without treatment,12 VKC treated with CsA(9 males, 75%; mean age 9,08; SD± 2.75) and 12 controls (CT) (7males,58%; mean age8,58; SD ±1,78) were recruited. A cross-sectional study was performed to compare H2O2 in the serum and the tears ofthese children. Results: Compared with CT and VKC children treated with CsA, VKCuntreated children had significantly higher values ofHydrogen peroxide (H2O2) in theserum and the tears.No significant differences were observed between CT and VKC treated with CsA. A significant correlation was found at the linear regression analysis between serum and tear H2O2 levels. Conclusion: This study provides the first report attesting that patients with VKC have high oxidative stress; furthermore, it suggests that CsA could have an anti-inflammatory and antioxidant action that could be useful to prevent the poor VKC outcome.
Interleukin (IL)-5 is a potent mediator of the inflammatory cascade in the allergic response.Its predominant role in atopic reactions makes this cytokine an ideal target for blocking the eosinophilic inflammatory hyper-responsiveness to allergens. The management of allergic diseases in childhood – such as severe asthma, atopic dermatitis, and eosinophilic esophagitis - is a challenge. In particular, there are concerns regarding the use of high-dose corticosteroids. Over the last few years, biologics targeting IL-5 or IL-5 receptor - that are mepolizumab, reslizumab, and benralizumab - represent a new, promising, and more personalized therapeutic option.
Gastrointestinal symptoms are common findings in children with SARS-CoV-2 infection.Diarrhea and vomiting have been reported in about 8-9% of cases, reaching more than 20% in some studies. Children with gastrointestinal involvement appear to be younger than those without, but the severity of the disease seems to be similar between the two groups of subjects.Fecal shedding in children has been reported in 20-30% of children and has been observed both in those with and those without overt gastrointestinal involvement. Moreover, prolonged fecal elimination, lasting several days after negativization of real-time polymerase chain reaction assay on respiratory swabs, have been reported with variable frequency in children with SARS-CoV-2 infection. These observations raise the question regarding the possibility of oral-fecal transmission and the possible role of children in spreading the infection, particularly when they appear asymptomatic or with gastrointestinal symptoms but with no respiratory involvement, as well as during their convalescent phase.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is a new strain of coronavirus that has not been previously identified in humans. SARS-CoV-2 is recognized as a highly contagious respiratory virus with severe morbidity and mortality, especially in vulnerable populations. Being a novel disease, everyone is susceptible, there are no vaccine and no treatment. To contain the spread of the disease, health authorities throughout the world have restricted the social interactions of individuals in various degrees. Allergists like other physicians are faced with the challenge of providing care for their patients, while protecting themselves and patients from getting infected, with strategies that are in continuous evolution as States work through the different stages of social distance. Allergist provides care for patients with the most common noncommunicable disease in the world: asthma, allergic rhinitis, food allergy, venom allergy, drug allergy atopic dermatitis, and urticarial. Some of these diseases are not only considered risk factors for severe reactions but also have symptoms like cough and sneezing that are in differential diagnosis with COVID-19, and as we move forward may prevent allergy patient from working, go to school or access medical services that increasingly are allowing only asymptomatic patients. In this review, we will outline how to take care safety of different allergic patients during the pandemic.
Coronavirus disease 2019 (COVID-19)diagnosis is based on molecular detection of SARS-CoV-2 in respiratory samples such as nasal swab (NS). However, the evidence that NS in patients with pneumonia were sometimes negative raise the attention to collect other clinical specimens. SARS-CoV-2 was shown in 10.3%rectal swabs (RS), 7.7% plasma,1% urine, 0% feces from 143NS positive patients. Potential infection by fluids different from respiratory secretion is possible but unlikely.
Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by Aspergillus induced hypersensitivity that occurs in immunocompetent but susceptible patients with asthma and/or cystic fibrosis (CF). In children, ABPA remains mostly undiagnosed, resulting in one of the most common causes of poorly controlled asthma and highly significant morbidity in children with CF. Currently, no specific diagnostic criteria of ABPA for children are available. Corticosteroids and itraconazole are the mainstays of therapy, althoughthere is a lack of randomized clinical trials regarding their usefulness for ABPA in children. Several monoclonal antibodies, such asomalizumab and mepolizumab, may be potential therapies for refractory ABPA in pediatric patients; however, further data are required to clarify the optimal dose and duration of therapy as a routine treatment approach.
To the Editor, For the EU funded project PERMEABLE (PERsonalized MEdicine Approach for Asthma and Allergy Biologicals SeLEction), which addresses the availability of and access to advanced therapy of asthma in children across Europe, we performed a survey including 37 major pediatric asthma and allergy centers between September 2019 and July 2020. In total, the centers contributing to the survey treated approximately 1.000 young patients with severe asthma in 25 major European countries and Turkey with biologicals. In the light of the Corona Pandemic, we extended our survey asking the responsible clinicians if they experienced a SARS-CoV-2 infection in any of the children they are caring for. The questions pertaining to Corona infections were asked between March and July 2020.Given the prevalence of SARS-CoV-2 infections in the general population and in children, one would expect that at least 1% of the patients would be affected (1). In fact, none of the centers was aware of any symptomatic COVID-19 case in their patient populations or any positive SARS-CoV-2 tests.This leads to the conclusion, that either SARS-CoV-2 infections have a mild or even asymptomatic course also in children with severe asthma or that children with severe asthma (and their parents) were extremely successful in avoiding SARS-CoV-2 infections. Thus, we investigated by structured interview, how centers in those 26 countries had instructed their patients to avoid COVID-19. Interestingly, only 4 European countries (UK, Ireland, Portugal and Malta) had a strict, so called shielding policy in place which followed a principle of maximal segregation of severe asthmatics from the rest of the population: not leaving the house at all, not attending school even when they reopened, wearing face masks also at home, and social distancing even with family members. All other countries followed the principle of continuing or even enforcing asthma treatment in patients and advising to follow the same Corona rules as the general population.Both strategies led to the same result: An absence of COVID-19 cases in children with severe asthma. We conclude from this observation, that shielding is not necessary in children with severe asthma as they and their families are perfectly able to avoid Corona infections. The harm done to children by enforcing seclusion, separation and stigmatization needs to be acknowledged. Deprivation of school, social contact and friends weights heavy on children and the absence of any COVID-19 cases in major European centers for severe asthma in children does not justify a policy of compulsory shielding of children with severe asthma, neither in the first nor in any further Corona wave.Michael Kabesch, M.D.University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany.Member of the Research and Development Campus Regensburg (WECARE) at the Hospital St. Hedwig of the Order of St. John, Regensburg, Germany.ReferencesStringhini S, Wisniak A, Piumatti G, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study [published online ahead of print, 2020 Jun 11]. Lancet . 2020;S0140-6736(20)31304-0.
The prevalence, heterogeneity and severity of type 2 inflammatory diseases, including asthma and atopic dermatitis, continue to rise, especially in children and adolescents. Type 2 inflammation is mediated by both the innate and adaptive immune cells and sustained by a specific subset of cytokines, such as interleukin(IL)‐4, IL‐5,IL‐13, and IgE. IL-4 and IL-13 are considered signature type 2 cytokines, as they both have a pivotal role in many of the pathobiological changes featured in asthma and atopic dermatitis. Several biologics targeting IL-4, IL-5, and IL-13, as well as IgE, have been proposed to treat severe allergic disease in the pediatric population with promising results. A better definition of type 2 inflammatory pathways is essential to implement targeted therapeutic strategies.
Anaphylaxis in children is a potential acute life-threatening systemic hypersensitivity reaction. Anaphylaxis fatality rate is estimated to be 0.65% to 2%. Food is the main anaphylaxis trigger in children, notably cow’s milk, peanuts and tree nuts. Mucocutaneous manifestations are observed in more than 90% of cases, but it is not essential for diagnosis. Deaths are rather secondary to the laryngeal edema, observed in 40-50% of cases. Personal history of asthma, allergy to particular foods such as peanuts and tree nuts, and adolescence are known risk factors for anaphylaxis and more severe reactions. Epinephrine (adrenaline) is the medication of choice for the first-aid treatment of anaphylaxis. However, adrenaline auto-injectors (AAIs) are commercially available in only 32% of world countries. There are still considerable unmet needs in the field of anaphylaxis in children. Therefore, the Montpellier WHO Collaborating Centre aims to start the global actions plan applied to anaphylaxis.
Multisystem inflammatory syndrome in children (MIS-C) during the COVID-19 pandemic raised a global alert from the Centers for Disease Control and Prevention’s Health Alert Network. The main manifestations of MIS-C in the setting of a severe inflammatory state include fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes, and in some cases it progressed to multi-organ failure. The low percentage of children with asymptomatic cases compared with mild illness and moderate illness could be correlated with the rare cases of MIS-C. One potential explanation for the progression to severe MIS-C disease despite the presence of readily detectable anti-SARS-CoV-2 antibodies could be due to potential role of antibody-dependent enhancement (ADE). We reason that the incidence of the ADE phenomenon whereby the pathogen-specific antibodies can promote pathology should be considered in vaccine development against SARS-COV-2.
The current pandemic of the novel coronavirus SARS-CoV-2 infection has affected over 6 million humans around the planet. The clinical manifestations of Coronavirus disease 2019 (COVID-19) are diverse, ranging from asymptomatic or mild flu-like symptoms to atypical pneumonia, severe respiratory distress syndrome, systemic inflammation, immune dysregulation and dyscoagulation.Inborn errors of immunity (IEI) are a heterogenous group of more than 430 rare congenital disorders with increased susceptibility to infection, autoimmunity, atopy, hyperinflammation and cancer. Autosomal recessive ARPC1B deficiency is an actinopathy, as are DOCK8 deficiency and the Wiskott-Aldrich Syndrome. Defective actin polymerization affects hematopoietic cells, impairing their migration and immunological synapse1, which results in a combined immune deficiency characterized by leukocytosis, eosinophilia, platelet abnormalities and hypergammaglobulinemia; and clinically, by eczema and food allergy, infections caused by bacteria, fungi and viruses, vasculitis, and bleeding diathesis2.Here, we describe a male infant patient with known ARPC1B deficiency who was hospitalized for COVID-19 pneumonia and improved without requiring intensive care or mechanical ventilation.An 8-month-old infant was brought to the emergency department with high-grade fever. His family history is remarkable for one brother who died as a newborn from intracranial bleeding, and an 11-year-old sister with the same genetic defect who underwent hematopoietic stem-cell transplantation twice without success, and is currently on antimycobacterial treatment, antimicrobial prophylaxis and regular subcutaneous immunoglobulin. The patient was first seen at age 1-month old for eczema and rectal bleeding attributed to cow milk protein allergy. At age 4 months, he developed bronchiolitis caused by respiratory syncytial virus (RSV) and oral candidiasis. Laboratory workup revealed leukocytosis (17,500-33,600/mm3), eosinophilia (5,600-20,100/mm3) and a marginally high (467,000) platelet count; as well as high serum IgG (737 mg/dL) and IgA (165 mg/dL) with normal IgM (37.7 mg/dL). CD8+ T lymphocytes were low at 3% (257 cells) and B cells were elevated at 48% (4,116 cells). Whole exome sequencing identified a homozygous 46 base-pair deletion in exon 8 of ARPC1B(chr7:99,392,784 hg38; p.Glu300fs).Upon his arrival to the emergency department he was febrile with tachycardia and signs of septic shock requiring rapid fluid resuscitation. He showed no respiratory or gastrointestinal signs. He also had a post-traumatic ulcerated lesion under the tongue with dark discoloration, which raised a concern for fungal infection. Intravenous antibiotics (ciprofloxacin) with antifungal coverage were started within the first hour, and a dose of intravenous immunoglobulin (IVIG) at 1g/kg. Blood counts revealed leukocytosis, neutrophilia, and mild eosinophilia without lymphopenia, while platelets were initially found within normal limits. A day later, blood culture had grownPseudomonas aeruginosa .During his second day of hospitalization, the patient persisted febrile, tachycardic and tachypneic, with oxygen desaturation into the low 80s. Chest X-ray showed nonspecific bilateral interstitial opacities in the perihilar regions (Figure 1 ). Real-time Polymerase chain reaction (RT-PCR) for SARS-Cov2 came back positive, and he was then transferred to a COVID-19 isolation area. The potassium hydroxide (KOH) test for oral thrush was negative for yeast cells, after which amphotericin was switched to fluconazole. Supplemental oxygen was discontinued on day 6 of hospitalization, when mild thrombocytopenia and a prolonged thromboplastin time (aPTT) (but normal fibrinogen and ferritin serum levels) were reported. After completing 14 days of antimicrobial treatment, the patient was discharged without ever requiring intensive care unit admission or mechanical ventilation.The behavior of COVID-19 in patients with IEI might help dissect the immune response to SARS-Cov2. A few cases of adults with COVID-19 and predominantly antibody deficiencies have been reported3,4; some of them developed acute respiratory distress syndrome (ARDS), while some had a milder course of illness. Based on what we know, innate immune defects in genes involved in type 1 interferon response (such as IRF7, IRF9, TLR3) are the most likely candidates to result in severe disease and death in patients with flu-like virus infection5. In a few cases of fatal influenza A (H1N1), variants in genes associated with familial hemophagocytic lymphohistiocytosis (FHL) and a decreased cytolytic function of NK cells, were also reported6.Our patient was on monthly supplemental IVIG treatment, and he received an additional dose during his hospital stay. This, and his young age, might have ameliorated the clinical course7. He had a favorable evolution, despite the known susceptibility to viral infection and immune dysregulation in ARPC1B deficient patients1. There were no signs of severe infection, ARDS, hyperinflammation or of “cytokine storm” unleashed by SARS-CoV-2. Despite his having a combined immune deficiency, our patient fully recovered without the need of additional supportive measures other than IVIG, supplemental oxygen and antibiotic treatment directed against the documented bacteremia.Although pediatric cases of COVID-19 are fewer compared to adults, some severe presentations and deaths among children have been reported. The presence of a restricted repertoire of IgG (since infants have no previous exposure to coronaviruses) might play a role in the better outcome seen in pediatric patients. Antibody-dependent enhancement has been implicated in the development of severe COVID-19 in the elderly8. Additionally, lung cells from children and women show a lower expression of membrane-bound ACE-2, which may also be protective against severe pneumonia.Conceivably, some immune defects could protect patients with certain IEIs from mounting a full uncontrolled inflammatory response against SARS-Cov2. The cytoskeleton is a regulator of gene transcription, coupling cell mechanics with the activity of NF-κB. Coronaviruses are thought to alter the cytoskeleton architecture to facilitate viral replication and output9. Thus, ARPC1B deficiency and other actinopathies might limit SARS-CoV-2 replication. Furthermore, Th2 cytokines modulate ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 expression in airway epithelial cells10, and children with allergies (asthma and/or allergic rhinitis) have a lower expression of ACE211. Patients with ARPC1B deficiency often have allergic diseases; their Th2-biased response could help explain the milder presentation seen in our patient. Insights from protective mechanisms in children, with and without certain immune defects, could facilitate the identification of therapeutic targets.Lina Maria Castano-Jaramillo1, MDMarco Antonio Yamazaki-Nakashimada1, MDSelma Cecilia Scheffler Mendoza1, MD, MSJuan Carlos Bustamante-Ogando2, MD, MSSara Elva Espinosa-Padilla2, MD, PhDSaul O. Lugo Reyes2, MD, MS.From the (1) Clinical Immunology Service, and the (2) Immunodeficiencies Research Unit, at the National Institute of Pediatrics, Mexico City, Mexico.Conflict of interests: NoneEthical statement: The patient and his family gave written informed consent for the diagnostic procedures and for publication of the case report.KEY WORDS: Primary immune deficiency, inborn errors of immunity, combined immune deficiency, ARPC1B deficiency, actinopathy, children, COVID-19, SARS-Cov-2, allergy, pneumonia, sepsis.
Background: Asthmatic children on corticosteroids can develop hypothalamic-pituitary-adrenal axis suppression (HPAS). Single nucleotide polymorphisms (SNPs) rs242941 and rs1876828 of the corticotrophin-releasing hormone receptor 1 (CRHR1) gene were associated with lower stimulated cortisol (F) levels, whereas rs41423247 of the glucocorticoid receptor (NR3C1) gene was associated with higher basal F levels. The objective of the current study was to confirm whether these three SNPs are associated with HPAS in asthmatic children. Methods: DNA was extracted from saliva obtained from 95 asthmatic children, who had previously undergone basal F and metyrapone testing. Thirty-six children were classified as suppressed. Non-suppressed children were sub-classified according to their post-metyrapone ACTH (PMTP ACTH) level into a middle (106-319 pg/ml) and a high (>319 pg/ml) ACTH response group. TaqMan® polymerase chain reaction assays were utilized. Results: Only rs41423247 was inversely associated with HPAS (OR = 0.27 [95% CI 0.06-0.90]). Its GC genotype was inversely associated with HPAS (log odds = - 1.28, p = 0.021). √PMTP ACTH was associated with CC (effect size = 10.85, p = 0.005) and GC genotypes (effect size = 4.06, p = 0.023). The C allele is inherited as a dominant trait (effect size = -1.31 (95% CI -2.39 – -0.33; p = 0.012). In the high ACTH response group, both genotypes affected the PMTP ACTH (effect sizes 1.41 and 15.46; p-values 0.023 and < 2x10-26 for GC and CC respectively). Conclusions: The C allele of rs41423247 was found to be protective against HPAS. CC genotype is associated with the highest PMTP ACTH response.
This review highlights the novelties in understanding the underlying immunological mechanisms of drug hypersensitivity reactions (DHRs) as well as tiny changes in clinical classification and diagnosis of DHRs with special reference to beta-lactams (BLs) in the pediatric population, in the last couple of years. Viral infections are very often in children and they can provoke skin rashes which is difficult to differentiate from DHRs. Because of that allergy to BLs in children is overdiagnosed. The correct diagnosis of BLs allergy in children is still an important and hot topic. In this review has been outlined the need for correct diagnosis of BLs allergy in children as well as needed to change the paradigm.
Comment on Matricardi PM et al.: The first, holistic immunological model of COVID-19: implications for prevention, diagnosis, and public health measuresTO THE EDITOR:We read with great interest the review article by Matricardi and colleagues  depicting mechanisms of disease for COVID-19 and analyzing both viral and host factors influencing its course. We particularly agree with Authors on the pivotal role of innate immunity in the very early phase of disease, being crucial for the subsequent evolution. Most known weapons of innate immune system are represented by natural antibodies, non-specific antimicrobial proteins, interferons, cytokines and cellular elements (i.e. natural killer cells). However, innate immunity could be influenced by other, still underrecognized, factors.At present, a solid proof of evidence is available on the ability of vitamin D in modulating immune response. Most of data are available from the field of bacterial infections and sepsis, being low vitamin D levels associated with a higher risk of infection and mortality.In addition, vitamin D could play a role against viruses by maintaining physical barriers (i.e. tight junctions, gap junctions, etc.), enhancing natural immunity (i.e. production of cathelicidin, defensins, etc.) and modulating adaptive immune response (i.e. modulation of TH1/TH2 response and inflammation). On this connection, emerging data support the role of vitamin D supplementation in reducing the risk and severity of influenza. Both influenza and COVID-19 show their maximum spread in winter season and the highest severity in elderly people. Reduced vitamin D levels could represent a possible pathophysiological explanation, among others, in both cases.[5,6] With this regard, it has been hypothesized that variations in vitamin D status across countries and latitudes could, at least in part, explain variations of mortality from COVID-19.[6,7]However, at present the exact vitamin D status among COVID-19 patients is unknown. Moreover, the role and mechanisms of vitamin D in the treatment of COVID-19 are still unexplored and several interventional trials are ongoing. Should these hypotheses be confirmed, universal vitamin D supplementation would represent a possible and inexpensive strategy to enhance natural immunity against COVID-19.Antonio Mirijello, MDMaria Maddalena D’Errico, MDAntonella Lamarca, MDPamela Piscitelli, MDSalvatore De Cosmo, MDDepartment of Medical Sciences, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy