Improved Diagnostics Help to Identify Clinical Features and Biomarkers That Predict Mycoplasma pneumoniae Community-acquired Pneumonia in Children.

BACKGROUND: There are no reliable signs or symptoms that differentiate Mycoplasma pneumoniae (Mp) infection in community-acquired pneumonia (CAP) from other etiologies. Additionally, current diagnostic tests do not reliably distinguish between Mp infection and carriage. We previously determined that the measurement of Mp-specific immunoglobulin M antibody-secreting cells (ASCs) by enzyme-linked immunospot assay allowed for differentiation between infection and carriage. Using this new diagnostic test, we aimed to identify clinical and laboratory features associated with Mp infection. METHODS: This is a prospective cohort study of children, 3-18 years of age, with CAP from 2016 to 2017. Clinical features and biomarkers were compared between Mp-positive and -negative groups by Mann-Whitney U test or Fisher exact test, as appropriate. Area under the receiver operating characteristic curve (AUC) differences and optimal thresholds were determined by using the DeLong test and Youden J statistic, respectively. RESULTS: Of 63 CAP patients, 29 were Mp-positive (46%). Mp positivity was statistically associated with older age (median, 8.6 vs 4.7 years), no underlying disease, family with respiratory symptoms, prior antibiotic treatment, prolonged prodromal respiratory symptoms and fever, and extrapulmonary (skin) manifestations. Lower levels of C-reactive protein, white blood cell count, absolute neutrophil count, and procalcitonin (PCT), specifically PCT <0.25 µg/L, were statistically associated with Mp infection. A combination of age >5 years (AUC = 0.77), prodromal fever and respiratory symptoms >6 days (AUC = 0.79), and PCT <0.25 µg/L (AUC = 0.81) improved diagnostic performance (AUC = 0.90) (P = .05). CONCLUSIONS: A combination of clinical features and biomarkers may aid physicians in identifying patients at high risk for Mp CAP.

Classical versus controlled rapid sequence induction and intubation in children with bleeding tonsils (a retrospective audit).

PURPOSE: To determine whether bag-mask ventilation between induction of anaesthesia and tracheal intubation in children with post-tonsillectomy bleeding reduces the incidence of hypoxaemia and difficult direct laryngoscopy without increasing perioperative respiratory complications. METHODS: Medical records, anaesthesia protocols and vital sign data were analysed from February 2005 to March 2017 for patients undergoing anaesthesia for surgical revision of bleeding tonsils. Type of rapid sequence induction and intubation (RSII; classical, ie, apnoeic, vs controlled, ie, with gentle bag-mask ventilation) was noted. Primary outcomes were incidence of moderate and severe hypoxaemia, grade of direct laryngoscopic views as well as occurrence of noted tracheal intubation difficulties. Haemodynamic alterations during RSII and perioperative adverse events such as noted gastric regurgitation, pulmonary aspiration and perioperative pulmonary morbidity were also recorded. RESULTS: A classical RSII was performed for 22 surgical revisions in 22 children and a controlled RSII was used for 88 surgical revisions in 81 children. Patients undergoing controlled RSII had less incidence of severe hypoxaemia (1 vs 3; P = .025), better direct laryngoscopic views (P = .048) and less hypertension (5 vs 9; P < .001) than those patients managed by classical RSII. No tracheal intubation difficulties occurred. There was no significant perioperative pulmonary morbidity reported in either group. CONCLUSIONS: Controlled RSII had advantages over classical RSII in children with post-tonsillectomy bleeding and may become a strategic option in these patients to avoid hypoxaemia, difficult laryngoscopy and hypertension during induction of anaesthesia and tracheal intubation. Bag-mask ventilation in patients with bleeding tonsils did not lead to pulmonary morbidity.

Two case reports of unexpected tracheal agenesis in the neonate: 3 C's beyond algorithms for difficult airway management.

BACKGROUND: Handling neonates with postnatal respiratory failure due to congenital airway malformations implies knowledge about emergency management of unexpected difficult airway. In these stressful situations both technical and communication skills of the caretakers are essential. CASE PRESENTATION: Two cases with prenatally unknown tracheal agenesis are reported. CONCLUSION: In the presented cases, airway malformation and subsequent difficulties upon endotracheal intubation were not adequately communicated between caretakers. We discuss the aspects of culture, communication, and capnography.

Role for early-differentiated natural killer cells in infectious mononucleosis.

A growing body of evidence suggests that the human natural killer (NK)-cell compartment is phenotypically and functionally heterogeneous and is composed of several differentiation stages. Moreover, NK-cell subsets have been shown to exhibit adaptive immune features during herpes virus infection in experimental mice and to expand preferentially during viral infections in humans. However, both phenotype and role of NK cells during acute symptomatic Epstein-Barr virus (EBV) infection, termed infectious mononucleosis (IM), remain unclear. Here, we longitudinally assessed the kinetics, the differentiation, and the proliferation of subsets of NK cells in pediatric IM patients. Our results indicate that acute IM is characterized by the preferential proliferation of early-differentiated CD56(dim) NKG2A(+) immunoglobulin-like receptor(-) NK cells. Moreover, this NK-cell subset exhibits features of terminal differentiation and persists at higher frequency during at least the first 6 months after acute IM. Finally, we demonstrate that this NK-cell subset preferentially degranulates and proliferates on exposure to EBV-infected B cells expressing lytic antigens. Thus, early-differentiated NK cells might play a key role in the immune control of primary infection with this persistent tumor-associated virus.

Oropharyngeal group A streptococcal colonization disrupts latent Epstein-Barr virus infection.

Epstein-Barr virus (EBV) infects >90% of the human population within the first 2 decades of life and establishes reversible latent infection in B cells. The stimuli that lead to switching from latent to lytic EBV infection in vivo are still elusive. Group A streptococci (GAS) are a common cause of bacterial pharyngotonsillitis in children and adolescents and colonize the tonsils and pharynx of up to 20% of healthy children. Thus, concomitant presence of EBV and GAS in the same individual is frequent. Here, we show that EBV carriers who are colonized with GAS shed EBV particles in higher numbers in their saliva, compared with EBV carriers not colonized with GAS. Messenger RNA levels of the master lytic regulatory EBV gene BZLF1 were more frequently detected in tonsils from EBV carriers colonized with GAS than from EBV carriers not colonized. Heat-killed GAS, potentially mimicking GAS colonization, elicited lytic EBV in latently infected lymphoblastoid cell lines (LCLs) partially via Toll-like receptor 2 triggering, as did purified GAS peptidoglycan. Thus, colonization by GAS might benefit EBV by increasing the EBV load in saliva and thereby enhancing the likelihood of EBV spread to other hosts.

Endoscopic airway findings in children with or without prior endotracheal intubation.

BACKGROUND: Airway alterations found after endotracheal intubation are usually associated with mechanical trauma from the tube. However, no studies are available concerning alterations in airways that have never been intubated before. It was the aim of the study to compare endoscopic findings in the larynx and trachea of children who had undergone prior endotracheal intubation with findings in children who had not been intubated before. METHODS: In 1021 children aged from 0 to 6 years, rigid endoscopies were performed before planned elective endotracheal intubation. The anonymized endoscopy videos were reviewed and graded by five international airway experts. Data was compared between the two groups using the chi-square test (P ≤ 0.05). RESULTS: Endoscopic records of 971 children (473 with prior intubation; 498 without prior airway intubation) were included in the final calculations. Most patients (93.7%) with prior intubation had been intubated with a cuffed tube. The number of intubations ranged from 1 to 27. The median interval between intubation and endoscopy was 0.53 years (0.003-5.57 years). Abnormal findings were observed in 31.7% and 26.8% of patients with and without prior intubation, respectively (P = 0.063). Glottic granulomas were significantly more common after intubation (3.6% vs 1.4%; P = 0.028). The incidence of other abnormal findings was similar in both groups. CONCLUSION: Endoscopic airway alterations can be observed in about one-quarter of children presenting for routine surgery without prior intubation. Except for glottic granulomas, the abnormalities are found with similar frequency in patients with and without prior intubation. No relevant airway damage from short-term endotracheal intubation was found.

Indications of pediatric tonsillectomy.

Possible indications for tonsillectomy include sleep apnea and other obstructive sleep-related breathing disorders, recurrent tonsillitis, peritonsillar abscess, periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA), and other miscellaneous rare conditions. Over the last century indications have changed, with a decrease in infectious causes and an increase in sleep apnea disorders. Sleep apnea in children is difficult to diagnose short of polysomnography (PSG) which is expensive and disturbing, especially in young children. In sleep apnea confirmed by PSG, tonsillectomy relieves the trouble in close to 80% of patients. What remains unclear is how to diagnose sleep-related breathing disorders without PSG and the efficacy of tonsillectomy in this population. Recurrent tonsillitis is generally poorly documented and randomized studies assessing the efficacy of tonsillectomy are sparse. When frequent infections are present for several years (>7 episodes/1 year, >5/2, >3/3) some benefit from tonsillectomy could be found. If fewer infectious episodes are present, the benefit of tonsillectomy is low. Peritonsillar abscess tends to be treated with quinsy tonsillectomy. Some PFAPA and psoriasis children might benefit from tonsillectomy. Tonsillectomy for other conditions is not warranted.

Hemorrhage after tonsillectomy: does the surgical technique really matter?

A thorough review of the publications on surgical techniques used for tonsillectomy is provided, emphasizing randomized studies and meta-analysis. In the assessment of the data it is important to clearly define and categorize the types of posttonsillectomy bleeding (PTB), as well as the various factors that have been associated with increased PTB. In recent audits of a large number of tonsillectomies, the PTB rates seem to concur: 1% early and 2.5% delayed PTB; 10% anamnestic, 2% objective, and 2% re-operation PTB. Objective PTB rates beyond 10% should require an audit. The bipolar technique seems associated with the least early PTB, while the cold technique is associated with the least delayed PTB. Because of the lack of large well-conducted randomized trials, it is difficult to conclude which technique is the best. With electrocautery techniques, the current power should be adjusted to the minimal level providing hemostasis. Surgical techniques for tonsillectomy that should probably be abandoned include monopolar electrocautery, Coblation, various lasers, and the harmonic scalpel. Vessel-sealing systems might hold promise and deserve further evaluation. Tonsillotomy might be associated with less postoperative pain, but the hemorrhagic advantage in randomized studies is not obvious. Tonsil regrowth rates and efficacy to treat obstruction need also further evaluation.

Case report and review of the literature: rare fetus-in-fetu presenting as oropharyngeal epignathus.

An epignathus is caused by a continuous spectrum of masses of the oral cavity or oropharynx ranging in its entity from mature teratoma to the exceedingly rare fetus-in-fetu. Due to its location, regardless of the entity, the occurrence of an epignathus is frequently associated with life threatening airway obstruction. Here we demonstrate a case of a fetus-in-fetu presenting as an epignatus. We describe its successful management and review the available literature. Early diagnosis and knowledge of the preoperative workup are essential to enable a multidisciplinary management. Once the airway is secured, surgical excision is the treatment of choice often resulting in a good clinical outcome and prognosis.

Transsphenoidal extension of heterotopic glioneuronal tissue: pathoanatomic considerations in symptomatic neonates.

PURPOSE: In this clinical investigation, we aimed (1) to re-evaluate the nature of glioneuronal tissue with transsphenoidal extension and how it fits into the nomenclature of midline malformations and mass lesions; (2) to find out if our imaging findings support current pathoanatomic concepts of clefts and canals in the sphenoid body of newborns. METHODS: In two neonates with respiratory distress due to nasopharyngeal masses, 3T MRI was performed, and CT in one of them. Imaging features were analyzed in consensus by two pediatric neuroradiologists with histological reports being available. An interdisciplinary panel compared the findings to those of case publications and differential entities from our institutional case collection. RESULTS: Referring to our rare case of transsphenoidal cerebral heterotopia and unique case of hypothalamic hamartoma with transsphenoidal herniation, glioneuronal heterotopia may definitely extend through the sphenoid bone. Consequently, there is reason for brain heterotopias to be labeled as such also in case of an intracranial component. Connection between heterotopic glioneuronal tissue in the nasopharynx and a hypothalamic hamartoma may go along with indistinct margins to normal brain. Neither extension through a transsphenoidal cleft nor association with a cleft palate are specific for cerebral heterotopia. Our findings support the hypothesis that transsphenoidal cerebral heterotopias do not or at least not invariably follow the route of Rathke's pouch, known as the craniopharyngeal canal. CONCLUSION: Transsphenoidal glioneuronal heterotopia should be the top differential diagnosis in MR imaging if a non-enhancing nasopharyngeal mass of an infant extends through a craniopharyngeal cleft within the intersphenoid synchondrosis.

Pediatric epstein-barr virus carriers with or without tonsillar enlargement may substantially contribute to spreading of the virus.

BACKGROUND: Human-to-human transmission of the persistent infection establishing Epstein-Barr virus (EBV) occurs via saliva. Tonsils act as important portal of entry and exit of EBV. The contagiousness of pediatric EBV carriers and the role played by tonsillar enlargement (TE) are not known. METHODS: We compared EBV shedding in mouthwash samples from pediatric EBV carriers with or without TE to that in mouthwash samples from pediatric patients with infectious mononucleosis (IM), the symptomatic form of primary infection if delayed after the age of 5 years. EBV DNA was quantified by polymerase chain reaction, and contagiousness was assessed using the cord lymphocyte transformation assay. RESULTS: EBV carriers with TE shed EBV DNA at an almost similar frequency (although in lower amounts) as pediatric patients with acute IM but more frequently (P <.001) and in higher amounts (P = .038) than EBV carriers without TE. EBV DNA levels in mouthwash samples from EBV carriers with TE mirrored levels in tonsils and gradually declined after tonsillectomy. Almost half of the mouthwash samples from pediatric EBV carriers contained infectious EBV. CONCLUSIONS: Pediatric EBV carriers--in particular, those with TE-may considerably contribute to the spreading of EBV in industrialized countries.

Bone marrow T helper cells with a Th1 phenotype induce activation and proliferation of leukemic cells in precursor B acute lymphoblastic leukemia patients.

Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.

[Evaluation of the pediatric airway]. / Evaluation des voies aériennes chez l'enfant.

Obstruction is the most common manifestation of airway pathology by children. The practitioner may be confronted to this relatively frequent problem. The pathology spectrum is very wide, and includes congenital malformations, infections, traumas, and tumours. The most frequent etiology of congenital upper airway obstruction is laryngomalacia. Adenotonsillar hypertrophy is by far the most common cause of obstruction by children aged 2 - 7 years. The medical history and the clinical examination allow to determine the degree of emergency, to orientate the diagnosis, and to decide when to refer the patient to a specialist. Endoscopy is the gold standard examination for diagnosis. In some cases, others investigations, such as radiological examinations, may be necessary.

Tonsillar CD56brightNKG2A+ NK cells restrict primary Epstein-Barr virus infection in B cells via IFN-γ.

Natural killer (NK) cells constitute the first line of defense against viruses and cancers cells. Epstein-Barr virus (EBV) was the first human virus to be directly implicated in carcinogenesis, and EBV infection is associated with a broad spectrum of B cell lymphomas. How NK cells restrict EBV-associated oncogenesis is not understood. Here, we investigated the efficacies and mechanisms of distinct NK cell subsets from tonsils, the portal of entry of EBV, in limiting EBV infection in naïve, germinal center-associated and memory B cells. We found that CD56bright and NKG2A expression sufficiently characterizes the potent anti-EBV capacity of tonsillar NK cells. We observed restriction of EBV infection in B cells as early as 18 hours after infection. The restriction was most efficient in naïve B cells and germinal center-associated B cells, the B cell subsets that exhibited highest susceptibility to EBV infection in vitro. IFN-γ release by and partially NKp44 engagement of CD56bright and NKG2A positive NK cells mediated the restriction that eventually inhibited B-cell transformation. Thus, harnessing CD56brightNKG2A+ NK cell function might be promising to improve treatment strategies that target EBV-associated B cell lymphomas.

Bilateral congenital deafness: What investigations should be performed?

BACKGROUND: The introduction of newborn hearing screening has led to earlier identification of children with congenital sensorineural hearing loss (SNHL). Aetiological clarification offers several benefits. There is currently a lack of agreement on which examinations should be recommended. OBJECTIVE: Descriptive review of the literature reporting investigations performed to establish the aetiology of congenital SNHL and comparison of the management policy in Swiss referral centres. METHODS: PubMed Search from 1985 to March 2016 with specific search terms; study selection according to inclusion/exclusion criteria; narrative analysis by use of defined criteria and question-naire. RESULTS: Ninety-two studies were finally included in this review. Forty studies investigated more than a single aetiology. Overall frequencies of aetiological parameters investigated were: genetic (47 studies), radiological (35), ophthalmic (35), serological (32), cardiac (25), renal (14), endocrine (12), neurological (8). Most of the studies were retrospective and various limitations such as poor population description, incomplete data or deficiencies in methodological quality were frequently detected. The variability detected in the investigative approach chosen by Swiss referral centres reflects the heterogeneous data seen in the literature. CONCLUSIONS: The evidence in the literature regarding an appro-priate evaluation is mostly of low quality and difficult to assess owing to high heterogeneity. Nevertheless, imaging, genetic testing, neuropaediatric and ophthalmological evaluations, electrocardiograms and cytomegalovirus analysis have been identified as examinations to be included in the assessment of children with congenital SNHL. There is a need for international consensus on the various issues of such an evaluation, such as choice of investigations and diagnostic criteria.

Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells.

Primary infection of the immunocompromised host with the oncovirus Epstein-Barr virus (EBV) that targets mainly B-cells is associated with an increased risk for EBV-associated tumors. The early events subsequent to primary infection with potential for B-cell transformation are poorly studied. Here, we modeled in vitro the primary infection by using B-cells isolated from tonsils, the portal of entry of EBV, since species specificity of EBV hampers modeling in experimental animals. Increasing evidence indicates that the host DNA damage response (DDR) can influence and be influenced by EBV infection. Thus, we inoculated tonsillar B-cells (TBCs) with EBV-B95.8 and investigated cell proliferation and the DDR during the first 96 hours thereafter. We identified for the first time that EBV infection of TBCs induces a period of hyperproliferation 48-96 hours post infection characterized by the activation of ataxia telangiectasia and Rad3-releated (ATR) and checkpoint kinase-1 (Chk1). Whereas inhibition of Chk1 did not affect B-cell transformation, the specific inhibition of ATR robustly decreased the transformation efficiency of EBV. Our results suggest that activation of ATR is key for EBV-induced B-cell transformation. Thus, targeting the interaction between ATR/Chk1 and EBV could offer new options for the treatment of EBV-associated malignancies.

Management of laryngomalacia in children with congenital syndrome: the role of supraglottoplasty.

BACKGROUND/IMPORTANCE: Supraglottoplasty is the surgical procedure of choice for severe laryngomalacia and has shown to be successful in most cases; however, patients with medical comorbidities present a higher rate of failure. To date, the best management of laryngomalacia in children with congenital syndrome remains unclear. PURPOSE: To study the outcome of supraglottoplasty in children with severe laryngomalacia, and to analyze the management and outcome in infants with a congenital syndrome. METHODS: Retrospective medical records review from January 2003 to October 2012 of all patients who underwent laser supraglottoplasty for severe laryngomalacia at the University Children's Hospital Zurich, Switzerland. RESULTS: Thirty-one patients were included; median age at time of surgery was 3.5 months. Three patients (10%) had a genetically proven congenital syndrome with associated neurologic anomalies. Overall success rate was 87%. Failures were observed in four (13%) of 31 cases; including all three patients presenting a congenital syndrome. CONCLUSIONS: Supraglottoplasty is an effective and safe treatment for laryngomalacia in otherwise healthy children. Signs of a possible underlying predominant neurologic origin and discrepancy between the clinical presentation and the endoscopic findings have to be taken into account, as in children with congenital syndrome with neurologic anomalies the risk of failure is higher.

Prevalence and characteristics of tracheal cobblestoning in children.

BACKGROUND: Tracheal follicular pattern or so-called tracheal cobblestoning is a poorly described entity in the literature and is depicted as a nodular or lumpy appearance of the tracheal wall mucosa suggesting tracheal irritation from factors like gastro-esophageal reflux (GERD) or pulmonary infection. The aim of the present study was to investigate the prevalence and characteristics of tracheal cobblestones in a large pediatric population. METHODS: A large database of rigid tracheoscopies recorded in children (0-6 years of age) undergoing general anesthesia with planned tracheal intubation for elective surgical procedures was retrospectively analyzed. Tracheoscopy records were reviewed by five pediatric airway experts (authors 3-7). Data were compared using the Mann-Whitney test, chi-square or Fisher exact test as appropriate (P < 0.05). RESULTS: A total of 971 rigid tracheoscopy records were analyzed. The median age of the patients was 3.3 years (range 0.4-6.0 yrs). Cobblestones were present in 377 out of 971 patients (38.8%) with a male to female prevalence of 254 (40.6%)/123 (35.5%). None of the children under four months of age showed the presence of cobblestones. The prevalence of cobblestones was significantly less in patients under 3 years of age compared to over 3 years (P < 0.01). There was no association between prevalence of cobblestones and GERD, current or recent respiratory infection or concomitant enlarged tonsils. CONCLUSION: The prevalence of tracheal cobblestones in otherwise healthy children is high and is not associated with GERD or respiratory infection. The gender and age related differences are novel interesting findings that require further investigations.

The prevalence of tracheal bronchus in pediatric patients undergoing rigid bronchoscopy.

BACKGROUND: Tracheal bronchus (TB) is defined as an abnormal bronchus that originates directly from the lateral wall of the trachea above the carina and goes towards the upper lobe territory of the lung. We analyzed rigid endoscopies of the trachea in children to determine the incidence and characteristics of TB. METHODS: In total, 1021 rigid endoscopies of the trachea recorded from children aged 0 to 6 years were analyzed. Endoscopic examination was performed from supraglottic region to carina using a 0-degree Hopkins rod-lens telescope. Patients with a TB were identified and the site of origin of the TB and its level above the carina was noted. Data of the identified patients was reviewed for the presence of preoperative airway findings such as stridor, upper lobe pneumonia and wheezing or atelectasis, other congenital anomalies, and intraoperative complications. RESULTS: TB was detected in 11 (1.06%) of 1021 upper airway endoscopic examinations. All originated from the right lateral wall of the trachea. Six children had retained secretions in the TB, and 3 children had perioperative airway problems unrelated to the TB. One child showed right main stem bronchus narrowing as seen at the true carina, in the presence of a TB. All the children with TB exhibited at least 1 additional congenital anomaly at birth besides TB. CONCLUSIONS: TB is a relatively common congenital endoscopic lower airway anomaly in childhood, which is itself rarely symptomatic, but almost always coexists with other congenital anomalies.