Inborn Errors of Immunity in Children With Invasive Pneumococcal Disease: A Multicenter Prospective Study.

BACKGROUND: In settings with universal conjugate pneumococcal vaccination, invasive pneumococcal disease (IPD) can be a marker of an underlying inborn error of immunity. The aim of this study was to determine the prevalence and characterize the types of immunodeficiencies in children presenting with IPD. METHODS: Multicenter prospective audit following the introduction of routinely recommended immunological screening in children presenting with IPD. The minimum immunological evaluation comprised a full blood examination and film, serum immunoglobulins (IgG, IgA and IgM), complement levels and function. Included participants were children in whom Streptococcus pneumoniae was isolated from a normally sterile site (cerebrospinal fluid, pleura, peritoneum and synovium). If isolated from blood, features of sepsis needed to be present. Children with predisposing factors for IPD (nephrotic syndrome, anatomical defect or malignancy) were excluded. RESULTS: Overall, there were 379 episodes of IPD of which 313 (83%) were eligible for inclusion and 143/313 (46%) had an immunologic evaluation. Of these, 17/143 (12%) were diagnosed with a clinically significant abnormality: hypogammaglobulinemia (n = 4), IgA deficiency (n = 3), common variable immunodeficiency (n = 2), asplenia (n = 2), specific antibody deficiency (n = 2), incontinentia pigmenti with immunologic dysfunction (n = 1), alternative complement deficiency (n = 1), complement factor H deficiency (n = 1) and congenital disorder of glycosylation (n = 1). The number needed to investigate to identify 1 child presenting with IPD with an immunologic abnormality was 7 for children under 2 years and 9 for those 2 years old and over. CONCLUSIONS: This study supports the routine immune evaluation of children presenting with IPD of any age, with consideration of referral to a pediatric immunologist.

The utility of chest x-ray and lung ultrasound in the management of infants and children presenting with severe pneumonia in low-and middle-income countries: A pragmatic scoping review.

Background: Chest x-ray (CXR) is commonly used (when available) to support clinical management decisions for child pneumonia and provide a reference standard for diagnosis in research studies. However, its diagnostic and technical limitations for both purposes are well recognised. Recent evidence suggests that lung ultrasound (LUS) may have diagnostic utility in pneumonia. This systematic scoping review of research on the utility of CXR and LUS in the management of severe childhood pneumonia aims to inform pragmatic guidelines for low- and middle-income countries (LMICs) and identify gaps in knowledge. Methods: We included peer-reviewed studies published between 2000 and 2020 in infants and children aged from one month to nine years, presenting with severe pneumonia. CXR studies were limited to those from LMICs, while LUS studies included any geographic region. LUS and CXR articles were mapped into the following themes: indications, role in diagnosis, role in management, impact on outcomes, and practical considerations for LMIC settings. Results: 85 articles met all eligibility criteria, including 27 CXR studies and 58 LUS studies. CXR studies were primarily observational and examined associations between radiographic abnormalities and pneumonia aetiology or outcomes. The most consistent finding was an association between CXR consolidation and risk of mortality. Difficulty obtaining quality CXR images and inter-reader variability in interpretation were commonly reported challenges. Research evaluating indications for CXR, role in management, and impact on patient outcomes was very limited. LUS studies primarily focused on diagnostic accuracy. LUS had higher sensitivity for identification of consolidation than CXR. There are gaps in knowledge regarding diagnostic criteria, as well as the practical utility of LUS in the diagnosis and management of pneumonia. Most LUS studies were conducted in HIC settings with experienced operators; however, small feasibility studies indicate that good inter-operator reliability may be achieved by training of novice clinicians in LMIC settings. Conclusions: The available evidence does not support the routine use of CXR or LUS as essential tools in the diagnosis and initial management of severe pneumonia. Further evaluation is required to determine the clinical utility and feasibility of both imaging modalities in low-resource settings.

Cohort study of congenital complete heart block among preterm neonates: a single-center experience over a 15-year period.

Congenital complete heart block (CCHB) is a very rare condition, with high risk of mortality. Prematurity is associated with immaturity of the cardiovascular system. Morbidity related to CCHB and prematurity has never been described. We describe a tertiary perinatal center experience over a 15-year period on CCHB management and complications in preterm infants. This is a single-center observational cohort study. All neonates admitted to neonatal intensive care unit with a diagnosis of isolated CCHB between January 2006 and January 2021 were identified. All preterm neonates (< 37 weeks) were compared with a control cohort of term neonates (≥ 37 weeks). Antenatal data, complications of prematurity, medical, and surgical management of CCHB were recorded. Twenty-four neonates with isolated CCHB (16 preterm and 8 term) were born during the study period, including 5 very preterm (< 32 weeks) and 11 preterm (32 to 37 weeks). All very preterm were born via emergency caesarian section without antenatal steroid administration. They had multiple severe morbidities including chronic lung disease, necrotizing enterocolitis, grades 3-4 intraventricular hemorrhage, cystic periventricular leukomalacia, and longer periods of mechanical and non-invasive ventilatory support than preterm. Thirteen out of sixteen preterm infants had permanent pacemakers inserted, compared to 1/8 for term newborns. All babies born before 35-week gestation were either paced or died.Conclusion: Premature neonates with CCHB have high risk of mortality and morbidity especially if undiagnosed and born by unnecessary emergency caesarian section without antenatal steroids. Prematurity below 35 weeks may be associated with death or pacemaker insertion. This supports better antenatal screening to avoid induced prematurity. What is Known: • Congenital complete heart block is a very rare condition associated with high morbidity and mortality. • Antenatal risk factors for poor outcome include fetal hydrops, low ventricular rate (HR <55 beats per minute), and congenital heart defect. What is New: • Infants born <32 weeks with CCHB had no antenatal steroid administration, and sustained high burden of morbidity (chronic lung disease, intraventricular hemorrhage, and cystic periventricular leukomalacia). • Birth <35 weeks is strongly associated with requiring pacing prior to discharge or death.

Tale of two viruses: parvovirus B19 and HIV.

We present a HIV-infected patient who developed severe anaemia due to chronic parvovirus B19 infection and subsequently had an unplanned pregnancy. This is in the context of poor adherence to antiretroviral therapy and significant immunosuppression; there was a delay in diagnosis of chronic parvovirus infection due to attribution of anaemia to HIV. She received immunoglobulin therapy and effective antiretroviral therapy, with reduction in parvovirus load and improvement in anaemia. She was counselled regarding the need for monitoring in pregnancy due to risk of intrauterine infection. We review the literature of management of chronic parvovirus infection in the immunosuppressed and the consequences of intrauterine infection.

Stop, think SCORTCH: rethinking the traditional 'TORCH' screen in an era of re-emerging syphilis.

BACKGROUND: The epidemiology of congenital infections is ever changing, with a recent resurgence in syphilis infection rates seen in the UK. Identification of congenital infection is often delayed; early recognition and management of congenital infections is important. Testing modalities and investigations are often limited, leading to missed diagnostic opportunities. METHODS: The SCORTCH (syphilis, cytomegalovirus (CMV), 'other', rubella, toxoplasmosis, chickenpox, herpes simplex virus (HSV) and blood-borne viruses) acronym increases the awareness of clinicians to the increased risk of congenital syphilis, while considering other infectious aetiologies including: zika, malaria, chagas disease, parvovirus, enterovirus, HIV, hepatitis B and C, and human T-lymphotropic virus 1, in addition to the classic congenital infections recognised in the 'TORCH screen' (toxoplasmosis, 'other', rubella, CMV, HSV). The SCORTCH diagnostic approach describes common signs present in infants with congenital infection, details serological testing for mother and infant and important direct diagnostics of the infant. Direct diagnostic investigations include: radiology, ophthalmology, audiology, microbiological and PCR testing for both the infant and placental tissue, the latter also warrants histopathology. CONCLUSION: The traditional 'TORCH screen' focuses on serology-specific investigations, often omits important direct diagnostic testing of the infant, and fails to consider emerging and re-emerging congenital infections. In recognition of syphilis as a re-emerging pathogen and the overlapping clinical presentations of various infectious aetiologies, we advocate for a broader outlook using the SCORTCH diagnostic approach.

Changing Epidemiology and Predisposing Factors for Invasive Pneumococcal Disease at Two Australian Tertiary Hospitals.

BACKGROUND: Invasive pneumococcal disease (IPD) is associated with significant morbidity and mortality in children. Universal pneumococcal conjugate vaccination has changed the epidemiology of IPD. In vaccinated children, IPD can be a marker of an underlying immunodeficiency. METHODS: This is a retrospective audit of children younger than 18 years with IPD admitted to 2 tertiary pediatric hospitals in Australia between 2011 and 2017. Data on predisposing conditions, immunologic evaluation, pneumococcal serotype, antibiotic susceptibility and treatment were collected. RESULTS: During the 7-year period, there were 131 presentations with IPD in 127 children; 3 children had recurrent IPD. Patients presented with sepsis (41%), empyema (29%), meningitis (18%), mastoiditis (12%), pneumonia (10%) and septic arthritis (4%). In 19 (15%) presentations, risk factors for IPD were present, including malignancy, hematologic disorder, chronic liver disease, chronic kidney disease and cochlear implant. Pneumococcal serotypes were determined in 78/131 (60%) of presentations: the most frequent serotypes were 19A (19%), 3 (13%), 7F (10%) and 19F (8%) and non-vaccine serotypes 22F (8%), 35B (6%), 15A (4%) and 38 (4%). Overall, 11% of isolates were non-susceptible to ceftriaxone. Only 36 patients (32%) had an immunologic evaluation, and 4 patients had proven or probable immunodeficiency. CONCLUSION: Although pneumococcal conjugate vaccine serotypes 19A, 3, 19F and 7F remain frequent causes of IPD, non-vaccine serotypes are emerging. Our data support vancomycin treatment for children with pneumococcal meningitis given 11% of our isolates were not susceptible to ceftriaxone. It is important to consider underlying conditions predisposing to IPD in a population with high rates of pneumococcal vaccination.

Complicated Henoch-Schönlein purpura.

We present a case of Henoch Schonlein pupura in a 6-year-old boy demonstrating some of the diagnostic pitfalls, complications and management challenges of this common paediatric condition.

A combined effect of dextromethorphan and melatonin on neuropathic pain behavior in rats.

Previous study has shown that administration of melatonin into the anterior cingulate cortex contralateral to peripheral nerve injury prevented exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats. In the present study, we examined the effect of the individual versus combined treatment of melatonin and/or dextromethorphan (DM), a clinically available N-methyl-d-aspartate (NMDA) receptor antagonist, on pain behaviors in WKY rats with chronic constriction sciatic nerve injury (CCI). Pain behaviors (thermal hyperalgesia and mechanical allodynia) were established at one week after CCI. WKY rats were then treated intraperitoneally with various doses of melatonin, DM or their combination once daily for the following week. At the end of this one-week treatment, behavioral tests were repeated in these same rats. While DM alone was effective in reducing thermal hyperalgesia at three tested doses (15, 30 or 60 mg/kg), it reduced mechanical allodynia only at high doses (30 or 60 mg/kg). By comparison, administration of melatonin alone was effective in reducing thermal hyperalgesia only at the highest dose (120 mg/kg, but not 30 or 60 mg/kg) tested in this experiment. Melatonin alone failed to reverse allodynia at all three tested doses (30, 60 and 120 mg/kg). However, the combined intraperitoneal administration of melatonin (30 mg/kg) and DM (15 mg/kg) effectively reversed both thermal hyperalgesia and mechanical allodynia although each individual dose alone did not reduce pain behaviors. These results suggest that a combination of melatonin with a clinically available NMDA receptor antagonist might be more effective than either drug alone for the treatment of neuropathic pain.

Spinal translocator protein (TSPO) modulates pain behavior in rats with CFA-induced monoarthritis.

Translocator protein 18 kDa (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), is predominantly located in the mitochondrial outer membrane and plays an important role in steroidogenesis, immunomodulation, cell survival and proliferation. Previous studies have shown an increased expression of TSPO centrally in neuropathology, as well as in injured nerves. TSPO has also been implicated in modulation of nociception. In the present study, we examined the hypothesis that TSPO is involved in the initiation and maintenance of inflammatory pain using a rat model of Complete Freund's Adjuvant (CFA)-induced monoarthritis of the tibio-tarsal joint. Immunohistochemistry was performed using Iba-1 (microglia), NeuN (neurons), anti-Glial Fibrillary Acidic Protein, GFAP (astrocytes) and anti-PBR (TSPO) on Days 1, 7 and 14 after CFA-induced arthritis. Rats with CFA-induced monoarthritis showed mechanical allodynia and thermal hyperalgesia on the ipsilateral hindpaw, which correlated with the increased TSPO expression in ipsilateral laminae I-II on all experimental days. Iba-1 expression in the ipsilateral dorsal horn was also increased on Days 7 and 14. Moreover, TSPO was colocalized with Iba-1, GFAP and NeuN within the spinal cord dorsal horn. The TSPO agonist Ro5-4864, given intrathecally, dose-dependently retarded or prevented the development of mechanical allodynia and thermal hyperalgesia in rats with CFA-induced monoarthritis. These findings provide evidence that spinal TSPO is involved in the development and maintenance of inflammatory pain behaviors in rats. Thus, spinal TSPO may present a central target as a complementary therapy to reduce inflammatory pain.