Why do some Children Get Sick with Recurrent Respiratory Infections?

Respiratory tract infections (RTI) represent a frequent condition, particularly among preschool children, with an important burden on the affected children and their families. It has been estimated that recurrent RTIs affect up to 25% of children during the first 4 years of life. These infections are mainly caused by viruses and are generally self-limiting. Social and environmental factors have been studied in determining the incidence of recurrent RTIs and the mostly recognized are precocious day care attendance, tobacco exposure and pollution. Primary immune defects, local anatomical factors, and genetic disorders such as primary ciliary dyskinesia or cystic fibrosis, may be also involved in recurrent RTIs of a subgroup of children, typically characterized by more severe and chronic symptoms. However, there is increasing awareness that RTIs have a complex pathophysiology and that some underrecognized factors, including genetic susceptibility to infections, low levels of some micronutrients, and respiratory microbiota might shape the probability for the child to develop RTIs. The sum (i.e. the number) of these factors may help in explaining why some children get sick for RTIs whilst other not. In some children iatrogenic factors, including improper use of antibiotics and NSAIDS or glucocorticoids might also aggravate this condition, further weakening the host's immune response and the possibly of establishing a "vicious circle". The present review aims to focus on several possible factors involved in influencing RTIs and to propose a unifying hypothesis on pathophysiological mechanisms of unexplained recurrent RTIs in children.

Activated phosphoinositide 3-dinase delta syndrome (APDS): An update.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte-restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3-kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients' quality of life and prognosis.

Tailored therapies for primary immunodeficiencies.

Primary immunodeficiency disorders (PIDs) are rare inherited monogenic disorders of the immune system, characterized by an increased risk of infection, immune dysregulation and malignancies. To date, more than 420 PIDs have been identified. The recent introduction of high throughput sequencing technologies has led to identifying the molecular basis of the underlying aberrant immune pathway, and candidate targets to develop precision treatment, aimed at modifying the clinical course of the disease. In PID, targeted therapies are especially effective to manage immune dysregulation and autoimmunity, also reducing the incidence of side effects compared to conventional treatments, sparing the use of steroids and immunosuppressive drugs. Moreover, in the last years, the approach of conventional treatments such as immunoglobulin replacement therapies has evolved and the indication has expanded to new diseases, leading to individualized strategies to both improve infection control and quality of life.  Similarly, the new advent of gene therapy in selected PIDs has introduced the benefit to correct the immunological defect, reducing at the same time the complications related to the hematopoietic stem cell transplantation. Here, we illustrate the most recent findings on tailored treatments for PIDs.

Use of remdesivir in children with COVID-19 infection: a quick narrative review.

SARS-CoV-2 infection has a severe course in a small percentage of children. Remdesivir has shown promising results in reducing hospitalisation time in adults, but data on mortality rate are conflicting and few studies are available on its use use in antivirals in children. We performed a quick narrative review of the available literature data regarding the usage of remdesivir in children and neonates. In children, remdesivir showed good safety profile, however bradicardia events have been reported in children. Remdesivir is currently recommended by several guidelines in some subgroups of children with severe COVID-19, and should also be considered in critically ill patients, always in the context of the overall clinical picture and drug availability.

Prevention of recurrent respiratory infections : Inter-society Consensus.

Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.

Inter-society consensus for the use of inhaled corticosteroids in infants, children and adolescents with airway diseases.

BACKGROUND: In 2019, a multidisciplinary panel of experts from eight Italian scientific paediatric societies developed a consensus document for the use of inhaled corticosteroids in the management and prevention of the most common paediatric airways disorders. The aim is to provide healthcare providers with a multidisciplinary document including indications useful in the clinical practice. The consensus document was intended to be addressed to paediatricians who work in the Paediatric Divisions, the Primary Care Services and the Emergency Departments, as well as to Residents or PhD students, paediatric nurses and specialists or consultants in paediatric pulmonology, allergy, infectious diseases, and ear, nose, and throat medicine. METHODS: Clinical questions identifying Population, Intervention(s), Comparison and Outcome(s) were addressed by methodologists and a general agreement on the topics and the strength of the recommendations (according to the GRADE system) was obtained following the Delphi method. The literature selection included secondary sources such as evidence-based guidelines and systematic reviews and was integrated with primary studies subsequently published. RESULTS: The expert panel provided a number of recommendations on the use of inhaled corticosteroids in preschool wheezing, bronchial asthma, allergic and non-allergic rhinitis, acute and chronic rhinosinusitis, adenoid hypertrophy, laryngitis and laryngospasm. CONCLUSIONS: We provided a multidisciplinary update on the current recommendations for the management and prevention of the most common paediatric airways disorders requiring inhaled corticosteroids, in order to share useful indications, identify gaps in knowledge and drive future research.

Inborn errors of immunity with atopic phenotypes: A practical guide for allergists.

Inborn errors of immunity (IEI) are a heterogeneous group of disorders, mainly resulting from mutations in genes associated with immunoregulation and immune host defense. These disorders are characterized by different combinations of recurrent infections, autoimmunity, inflammatory manifestations, lymphoproliferation, and malignancy. Interestingly, it has been increasingly observed that common allergic symptoms also can represent the expression of an underlying immunodeficiency and/or immune dysregulation. Very high IgE levels, peripheral or organ-specific hypereosinophilia, usually combined with a variety of atopic symptoms, may sometimes be the epiphenomenon of a monogenic disease. Therefore, allergists should be aware that severe and/or therapy-resistant atopic disorders might be the main clinical phenotype of some IEI. This could pave the way to target therapies, leading to better quality of life and improved survival in affected patients.

Tuberculosis and TNF-α inhibitors in children: how to manage a fine balance.

Since the introduction of biologic response modifiers (BRMs) in the management of children affected by the immune-mediated inflammatory disease, these patients substantially improved their quality of life. BRMs are generally well tolerated and effective in most children and adolescents refractory to conventional immunosuppressive therapy. On the other hand, patients receiving BRMs, especially TNF-α inhibitors, display an increased risk of primary infections or reactivations, i.e. due to Mycobacterium tuberculosis. M. tuberculosis can cause severe disease with consequent short- and long-term morbidity in children on anti-TNF-α treatment. The present paper analyses the increased risk of reactivation of latent tuberculosis infection (LTBI) or de novo TB infection in children treated with TNF-α inhibitors, with the purpose to provide recommendations for screening strategies and safety monitoring of paediatric patients. Special attention is also given to the currently available TB screening tools (IGRAs and TST) and their utility in the diagnosis of LTBI before starting the biologic therapy and during the treatment. Finally, the paper analyses the suggested TB-preventing therapies to adopt in these children and the correct timing to overlap anti-TB and anti-TNF-a treatment.

Update in Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are inherited disorders classically characterized by increased susceptibility to infections. Nevertheless, in the last two decades, genomic analysis (such as NGS) coupled with biochemical and cellular studies led to a more accurate definition for a growing number of novel genetic disorders associated with PIDs. This revealed new aspects of the immune system and its function and regulation within these diseases. In particular, it has been clarified that the clinical features of PIDs are much broader that originally thought and extend beyond an increased susceptibility to infections. More specifi- cally, immune dysregulation is very often described in novel characterized PIDs and can lead to multiple autoimmune diseases, lymphoproliferation and malignancies. If not promptly diagnosed, these could negatively impact patient's prognosis. The aim of this review is to increase the awareness of recently discovered PIDs, characterized predominantly by immune dysregulation phenotypes. Findings highlighted in this review  suggest screening for immunodeficiency in patients with lymphoproliferation or early onset/multiple autoimmune diseases. Prompt diagnosis would potentially allow most successful treatment and clinical outcome for patients with PIDs.

Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients.

Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients' clinical management and their quality of life.

Prevalence of Immunological Defects in a Cohort of 97 Rubinstein-Taybi Syndrome Patients.

Although recurrent infections in Rubinstein-Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment. Graphical Abstract.

Endoscopic removal of tracheobronchial foreign bodies: results on a series of 51 pediatric patients.

PURPOSE: Rigid bronchoscopy (RB) is still considered the gold standard approach for the removal of airway foreign bodies (FBs) in children; however, flexible bronchoscopy (FOB) has recently been proposed both as diagnostic and therapeutic means. Our purpose was to evaluate the outcomes of FOB, associated with the Dormia basket, for the removal of FBs. METHODS: Retrospective data about 124 children who underwent bronchoscopy for the suspicion of a FB aspiration between January 2008 and January 2019 in our department were collected. RESULTS: In a total of 51 cases, FBs were removed through FOB or RB associated with forceps or Dormia basket. Male to female ratio was 1.8:1, mean age 30 ± 26.1 months. Thirty-four (67%) FBs were directly removed through FOB, in most of the cases using Dormia basket and twelve (23%) patients underwent RB. The overall left-versus-right distribution was 57% vs. 43%. The mean retrieval procedural time was 36.29 ± 24.99 min for FOB and 52.5 ± 29.74 min for RB; the success rate of the procedures was 97% vs. 67%. CONCLUSION: FOB can be used not only as a diagnostic procedure, but also as the first method for the removal of airway FBs. The Dormia basket is a useful tool, especially to remove peripherally located FBs.

Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

BACKGROUND: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce. OBJECTIVE: Our aim was to describe the natural history of XLA. METHODS: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base. RESULTS: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease. CONCLUSIONS: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.

Updated Guidelines for the Management of Acute Otitis Media in Children by the Italian Society of Pediatrics: Prevention.

BACKGROUND: In recent years, new information has been acquired regarding the diagnosis, treatment and prevention of acute otitis media (AOM). The Italian Pediatric Society, therefore, decided to issue an update to the Italian Pediatric Society guidelines published in 2010. METHODS: The search was conducted on Pubmed, and only those studies regarding the pediatric age alone, in English or Italian, published between January 1, 2010 and December 31, 2018, were included. Each study included in the review was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology. The quality of the systematic reviews was evaluated using the A MeaSurement Tool to Assess systematic Reviews (AMSTAR) 2 appraisal tool. The guidelines were formulated using the GRADE methodology by a multidisciplinary panel of experts. RESULTS: The importance of eliminating risk factors (passive smoking, environmental pollution, use of pacifier, obesity, limitation of day-care center attendance) and the promotion of breastfeeding and hygiene practices (nasal lavages) was confirmed. The importance of pneumococcal vaccination in the prevention of AOM was reiterated with regard to the prevention of both the first episode of AOM and recurrences. Grommets can be inserted in selected cases of recurrent AOM that did not respond to all other prevention strategies. Antibiotic prophylaxis is not recommended for the prevention of recurrent AOM, except in certain carefully selected cases. The use of complementary therapies, probiotics, xylitol and vitamin D is not recommended. CONCLUSIONS: The prevention of episodes of AOM requires the elimination of risk factors and pneumococcal and influenza vaccination. The use of other products such as probiotics and vitamin D is not supported by adequate evidence.

First Case of Patient With Two Homozygous Mutations in MYD88 and CARD9 Genes Presenting With Pyogenic Bacterial Infections, Elevated IgE, and Persistent EBV Viremia.

We described for the first time a female patient with the simultaneous presence of two homozygous mutations in MYD88 and CARD9 genes presenting with pyogenic bacterial infections, elevated IgE, and persistent EBV viremia. In addition to defective TLR/IL1R-signaling, we described novel functional alterations into the myeloid compartment. In particular, we demonstrated a defective production of reactive oxygen species exclusively in monocytes upon E. coli stimulation, the inability of immature mono-derived DCs (iDCs) to differentiate into mature DCs (mDCs) and the incapacity of mono-derived macrophages (MDMs) to resolve BCG infection in vitro. Our data do not provide any evidence for digenic inheritance in our patient, but rather for the association of two monogenic disorders. This case illustrates the importance of using next generation sequencing (NGS) to determine the most accurate and early diagnosis in atypical clinical and immunological phenotypes, and with particular concern in consanguineous families. Indeed, besides the increased susceptibility to recurrent invasive pyogenic bacterial infections due to MYD88 deficiency, the identification of CARD9 mutations underline the risk of developing invasive fungal infections emphasizing the careful monitoring for the occurrence of fungal infection and the opportunity of long-term antifungal prophylaxis.

Management of the child with allergy to non-antibiotic drugs.

Non-steroidal anti-inflammatory drugs, perioperative drugs, radio contrast media and chemotherapeutics drugs are, after the non-antibiotic drugs, the drugs most commonly responsible for allergic reactions in children. Management is different depending on the drug involved.

Drug desensitization in allergic children.

Drug allergy is an increasing problem worldwide, affecting all populations and races, children and adults, and for which diagnosis and treatment are not well standardized yet. Besides classical treatments, new drugs have been developed, especially for patients suffering from malignancies and chronic inflammatory diseases, that specifically target the cause of the disease. For those patients requiring such molecules, it is sometimes difficult to find an alternative drug when hypersensitivity reactions occur. Desensitization is therefore the best option whenever no alternative therapy is available but also when alternative treatments are considered therapeutically inferior and or more toxic. Despite its clinical success, little is known about the mechanisms and molecular targets of drug desensitization. Desensitization protocols use a gradual dose escalation to allow the safe administration of a treatment to which a patient previously presented a hypersensitivity reaction. The procedure requires special training and coordination of an allergy team, including physicians, nurses, and pharmacists, working together to safely and successfully implement desensitization protocols when appropriate. There is no difference in desensitization protocol between adults and children, except for the final cumulative dose of the administered drug.

Pediatric drug hypersensitivity: which diagnostic tests?

Along with the anamnesis and clinical evaluation, diagnostic tests are one of the mainstream key points in the evaluation and management of drug hypersensitivity reactions (DHR). A wide knowledge gap, both in diagnosis and management of pediatric DHR, must be filled.  Only a few published studies evaluated sensitivity and specificity of skin and in vitro tests in children. However, selected case series show that diagnostic work-up for adults could be useful, with some limitations, in pediatric age. Indeed, despite improvement in in vivo and in vitro diagnosis, drug provocation test remains the gold standard in pediatric age, too. Unmet needs in children include multi-centric studies on incidence of DHR, utility and feasibility of in vivo and in vitro diagnostic tests and specifically dedicated guidelines for the diagnosis and management of DHR in children.

B-cell hyperfunction in children with immune thrombocytopenic purpura persists after splenectomy.

BACKGROUND: Immune thrombocytopenic purpura (ITP) is characterized by reduced platelet count secondary to immune-mediated destruction, this results in an increased bleeding risk. Autoantibodies binding to platelets tag them for premature destruction in the spleen. For this reason, splenectomy is often performed as treatment of chronic forms of disease that are resistant to pharmacological therapy. METHODS: We studied 30 patients with ITP and compared them with age-matched controls. RESULTS: We show that B cells of patients with chronic ITP are intrinsically hyperreactive, producing more than normal IgG in vivo and plasma cells in vitro. In normal individuals after splenectomy, a significant depletion of memory B cells is observed, associated with loss of reactivity to CpG oligodeoxynucleotide and consequent inability to form antibody-producing cells. In Enzyme-Linked ImmunoSpot Methods, we compared three splenectomized ITP patients relapsing after surgery, 30 healthy controls, and 37 individuals splenectomized for trauma, spherocytosis, thalassemia, nonhematological tumor, and other diseases. CONCLUSIONS: We confirmed that B cells of ITP patients remain hyperreactive in vitro and form high numbers of antibody-producing cells after splenectomy. Thus, chronic ITP may be associated with intrinsic B-cell hyperfunction, leading to the production of antibodies with multiple specificities including that against platelets.