A Historical Perspective on RSV Prevention: A Journey Spanning Over Half a Century from the Setback of an Inactive Vaccine Candidate to the Success of Passive Immunization Strategy.

The efforts to prevent RSV infection in infants span over half a century. RSV vaccine development began in the 1960s, and it confronted a significant disappointment after testing a formalin inactivated RSV (FI RSV) vaccine candidate. This inactivated RSV vaccine was not protective. A large number of the vaccinated RSV naïve children, when subsequently exposed to natural RSV infection from wild type virus in the community, developed severe lung inflammation termed enhanced respiratory disease. This resulted in a halt in RSV vaccine development. In the 1990s, attention turned to the potential for passive protection against severe RSV disease with immunoglobulin administration. This led to studies on using standard intravenous immunoglobulins in high-risk infants, followed by high-titer RSV immunoglobulin preparation and, subsequently, the development of RSV monoclonal antibodies. Over the past 25 years, palivizumab has been recognized as a safe and effective monoclonal antibody as a prevention strategy for RSV in high-risk children. Its high cost and need for monthly administration, however, has hindered its use to ~2% of the birth cohort, neglecting the vast majority of newborns, including healthy full-term infants who comprise the largest portion of RSV hospitalizations and the greatest part of the burden of RSV disease. Still these efforts, helped pave the way for the present advances in RSV prevention that hold promise for mitigating severe RSV disease for all infants.

Molecular Imaging of Diffuse Cardiac Fibrosis with a Radiotracer That Targets Proteolyzed Collagen IV.

Purpose To develop an approach for in vivo detection of interstitial cardiac fibrosis using PET with a peptide tracer targeting proteolyzed collagen IV (T-peptide). Materials and Methods T-peptide was conjugated to the copper chelator MeCOSar (chemical name, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid) and radiolabeled with copper 64 (64Cu). PET/CT scans were acquired following intravenous delivery of 64Cu-T-peptide-MeCOSar (0.25 mg/kg; 18 MBq ± 2.7 [SD]) to male transgenic mice overexpressing ß2-adrenergic receptors with intermediate (7 months of age; n = 4 per group) to severe (10 months of age; n = 11 per group) cardiac fibrosis and their wild-type controls. PET scans were also performed following coadministration of the radiolabeled probe with nonlabeled T-peptide in excess to confirm binding specificity. PET data were analyzed by t tests for static scans and analysis of variance tests (one- or two-way) for dynamic scans. Results PET/CT scans revealed significantly elevated (2.24-4.26-fold; P < .05) 64Cu-T-peptide-MeCOSar binding in the fibrotic hearts of aged transgenic ß2-adrenergic receptor mice across the entire 45-minute acquisition period compared with healthy controls. The cardiac tracer accumulation and presence of diffuse cardiac fibrosis in older animals were confirmed by gamma counting (P < .05) and histologic evaluation, respectively. Coadministration of a nonradiolabeled probe in excess abolished the elevated radiotracer binding in the aged transgenic hearts. Importantly, PET tracer accumulation was also detected in younger (7 months of age) transgenic mice with intermediate cardiac fibrosis, although this was only apparent from 20 minutes following injection (1.6-2.2-fold binding increase; P < .05). Conclusion The T-peptide PET tracer targeting proteolyzed collagen IV provided a sensitive and specific approach of detecting diffuse cardiac fibrosis at varying degrees of severity in a transgenic mouse model. Keywords: Diffuse Cardiac Fibrosis, Molecular Peptide Probe, Molecular Imaging, PET/CT © RSNA, 2024.

Respiratory Syncytial Virus Infection and Apnea Risk As Criteria for Hospitalization in Full Term Healthy Infants.

Introduction Apnea is recognized as a serious and potentially life-threatening complication associated with Respiratory Syncope Virus (RSV). The literature reports a wide range of apnea rates for infants with comorbid factors. Prematurity and young chronological age have been historically associated with the risk of apnea in hospitalized infants. Few studies have specifically examined the risk of apnea in healthy infants presenting to the emergency department. Methods This is a retrospective review of infants diagnosed with RSV using a PCR assay. Patients were divided into "mild" and "severe" cohorts based on symptoms at presentation. This study occurred in the NYU Langone Long Island (NYULI) pediatric emergency department (ED), a midsize academic hospital in the Northeast United States. The study included infants <6 months of age, born full term without comorbid conditions such as chronic lung or cardiac conditions, seen in NYULI ED over three consecutive RSV seasons (2017-2020). The primary outcome was the risk of apneic events. Secondary outcomes included hospital admission, ICU admission, length of stay, and supplemental oxygen support. Results The risk of apnea was <2%, regardless of disease severity. There were no significant differences in demographics between mild and severe disease. Cohorts differed significantly in the number of hospitalizations (41 milds vs. 132 severe), ICU admissions (2 milds vs. 27 severe), need for oxygen support (17 milds vs. 92 severe), hospital readmissions (2 milds vs. 42 severe), and length of stay (2 days milds vs. 3 days severe). Conclusions Apnea does not pose a significant risk for healthy full-term infants with RSV disease of any severity. The decision to admit this population to the hospital should be based on clinical presentation and not solely on the perceived risk of apnea.

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides.

Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or ß+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, ß-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain ß+-emitting gallium-68 and ß-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.

Clinical Outcomes of Children With Extended-spectrum ß -Lactamase Urinary Tract Infection Receiving Discordant Empiric Antibiotic: A Comparative Study of Fever Duration, Length of Stay, and Readmissions.

There has been a recent increase in the incidence of urinary tract infections (UTIs) caused by extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, which are resistant to third-generation cephalosporins. Our goal was to compare the clinical responses of patients with ESBL UTI and non-ESBL UTI who received empiric third-generation cephalosporins. A retrospective analysis was performed on data collected between June 1, 2013, and June 30, 2017, from children aged 0 days to 19 years old who presented to NYU Langone Long Island Hospital's pediatric ED and/or were admitted with a UTI caused by Enterobacteriaceae. There was no significant difference in median length of fever duration. However, ESBL patients had significantly longer hospital stays, higher 30-day readmission rate, and higher 7-day revisit rate. It is reasonable to maintain an empiric UTI antibiotic choice rather than selecting a broad-spectrum antibiotic, such as carbapenem for children at high risk of ESBL UTI.

Children Lagging with COVID-19 Vaccination.

Children account for a growing share of coronavirus disease 2019 (COVID-19) infections in the United States. Since the widespread availability of COVID-19 vaccine in adults, there has been an upward trend of cases in children, accounting for approximately 20% of the weekly new cases. The majority (38.3%) reported in high school students age 14 to 17 years. Children are also at risk of a postinflammatory condition, known as multisystem inflammatory syndrome in children, after COVID-19. In addition, infected children could transmit the virus to vulnerable adults, contributing to ongoing pandemic. We believe that children need to be vaccinated against COVID-19 and review the available evidence. [Pediatr Ann. 2022;51(5):e180-e185.].

Assessment of the epi-pericardial fibrotic substrate by collagen-targeted probes.

The identification of the fibrotic arrhythmogenic substrate as a means of improving the diagnosis and prediction of atrial fibrillation has been a focus of research for many years. The relationship between the degree of atrial fibrosis as a major component of atrial cardiomyopathy and the recurrence of arrhythmia after AF ablation can correlate. While the focus in identification and characterisation of this substrate has been centred on the atrial wall and the evaluation of atrial scar and extracellular matrix (ECM) expansion by late gadolinium-enhancement (LGE) on cardiac magnetic resonance imaging (CMRI), LGE cannot visualise diffuse fibrosis and diffuse extravasation of gadolinium. The atrial pericardium is a fine avascular fibrous membranous sac that encloses the atrial wall, which can undergo remodelling leading to atrial disease and AF. Nevertheless, little attention has been given to the detection of its fibrocalcification, impact on arrhythmogenesis and, most importantly, on the potential prothrombotic role of epi-pericardial remodelling in generation of emboli. We have recently reported that tracers against collagen I and IV can provide a direct assessment of the ECM, and thus can estimate fibrotic burden with high sensitivity. Here, we show the ability of these optical tracers to identify epi-pericardial fibrosis, as well as to demonstrate subtle interstitial fibrosis of the atrial wall in a mouse model of beta-2-adrenergic receptor (ß2-AR) cardiac overexpression.

Invasive rhinosinusitis due to Penicillium chrysogenum in an adolescent man with new-onset leukaemia: a diagnostic dilemma.

An adolescent boy with newly diagnosed T-cell acute lymphoblastic leukaemia developed right eye and facial pain, and a 1 cm × 2 cm area of black eschar over his hard palate. Initial differential diagnosis included rhinocerebral mucormycosis and aspergillosis, and he was started on liposomal amphotericin B. Later, he underwent nine surgical debridements of his sinus cavities, resection of a third of his palate and right orbital exenteration. While histological specimens exhibited features of both Aspergillus and Mucor, a PCR assay detected Penicillium chrysogenum He was successfully treated with amphotericin B and Posaconazole. P. chrysogenum has been reported in a rare case of endocarditis, a case of post-traumatic endophthalmitis, disseminated infection in a child with Henoch-Schonlein syndrome, and one fatal adult case of invasive rhinosinusitis. While infection from Penicillium species is rare, it should be considered as a cause of invasive rhinosinusitis in cases of unclear histopathology.

Collagen-Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis.

Background Cardiac fibrosis is the excessive deposition of extracellular matrix in the heart, triggered by a cardiac insult, aging, genetics, or environmental factors. Molecular imaging of the cardiac extracellular matrix with targeted probes could improve diagnosis and treatment of heart disease. However, although this technology has been used to demonstrate focal scarring arising from myocardial infarction, its capacity to demonstrate extracellular matrix expansion and diffuse cardiac fibrosis has not been assessed. Methods and Results Here, we report the use of collagen-targeted peptides labeled with near-infrared fluorophores for the detection of diffuse cardiac fibrosis in the ß2-AR (ß-2-adrenergic receptor) overexpressing mouse model and in ischemic human hearts. Two approaches were evaluated, the first based on a T peptide that binds matrix metalloproteinase-2-proteolyzed collagen IV, and the second on the cyclic peptide EP-3533, which targets collagen I. The systemic and cardiac uptakes of both peptides (intravenously administered) were quantified ex vivo by near-infrared imaging of whole organs, tissue sections, and heart lysates. The peptide accumulation profiles corresponded to an immunohistochemically-validated increase in collagen types I and IV in hearts of transgenic mice versus littermate controls. The T peptide could encouragingly demonstrate both the intermediate (7 months old) and severe (11 months old) cardiomyopathic phenotypes. Co-immunostainings of fluorescent peptides and collagens, as well as reduced collagen binding of a control peptide, confirmed the collagen specificity of the tracers. Qualitative analysis of heart samples from patients with ischemic cardiomyopathy compared with nondiseased donors supported the collagen-enhancement capabilities of these peptides also in the clinical settings. Conclusions Together, these observations demonstrate the feasibility and translation potential of molecular imaging with collagen-binding peptides for noninvasive imaging of diffuse cardiac fibrosis.

SARS-CoV-2 Among Infants <90 Days of Age Admitted for Serious Bacterial Infection Evaluation.

OBJECTIVES: To determine the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants hospitalized for a serious bacterial infection (SBI) evaluation and clinically characterize young infants with SARS-CoV-2 infection. METHODS: A retrospective chart review was conducted on infants <90 days of age hospitalized for an SBI evaluation. The study was conducted at 4 inpatient facilities in New York City from March 15, 2020, to December 15, 2020. RESULTS: We identified 148 SBI evaluation infants who met inclusion criteria. A total of 22 infants (15%) tested positive for SARS-CoV-2 by nasopharyngeal reverse transcription polymerase chain reaction; 31% of infants admitted during periods of high community SARS-CoV-2 circulation tested positive for SARS-CoV-2, compared with 3% when community SARS-CoV-2 circulation was low (P < .001). The mean age of infants with SARS-CoV-2 was higher than that of SARS-CoV-2-negative infants (33 [SD: 17] days vs 23 [SD: 23] days, respectively; P = .03), although no age difference was observed when analysis was limited only to febrile infants. An isolated fever was the most common presentation of SARS-CoV-2 (n = 13; 59%). Admitted infants with SARS-CoV-2 were less likely to have positive urine culture results (n = 1 [5%] versus n = 25 [20%], respectively; P = .002), positive cerebrospinal culture results (n = 0 [0%] versus n = 5 [4%], respectively; P = .02), or be admitted to intensive care (n = 2 [9%] versus n = 47 [37%]; P < .001), compared with infants without SARS-CoV-2. CONCLUSIONS: SARS-CoV-2 was common among young infants hospitalized for an SBI evaluation during periods of high but not low community SARS-CoV-2 circulation in New York City, although most infants did not require intensive care admission.

Seasonal variation of respiratory viral infections: a comparative study between children with cancer undergoing chemotherapy and children without cancer.

Respiratory viral infections (RVIs) affect children year-round, with seasonal-specific patterns. Pediatric oncology patients are uniquely vulnerable to infection, but whether this predisposes them to different patterns of RVIs than healthy children is unknown. There is also limited data on the impact of RVIs on cancer patients. We conducted a retrospective study of children ages 1-21 with cancer presenting to the clinic and emergency department (ED) and a randomly selected subset of patients without cancer presenting to the ED who had positive nasopharyngeal viral polymerase chain reactions at our institution from 2014 to 2019. Sixty-seven cancer patients (206 RVI episodes) and 225 pediatric non-cancer patients (237 RVI episodes) were included. Human rhino/enterovirus (HRE) was the most common infection in both groups in the spring, summer, and fall. In the winter, the most common RVI was influenza in cancer patients verses respiratory syncytial virus in non-cancer patients. On age-adjusted analysis, the likelihood of detecting coronavirus in the winter, HRE in the spring and fall, and parainfluenza in the summer was significantly greater in cancer patients (OR = 2.60, 2.52, 5.73, 3.59 respectively). Among cancer RVI episodes, 50% received parenteral antibiotics, 22% were severely neutropenic, 22% had chemotherapy delays for a median of six days, 16% were hospitalized, and 6% received intravenous immunoglobulin. We conclude that there are differences in the seasonal patterns of RVIs between children with and without cancer. RVIs also cause significant morbidity in children with cancer.

Imaging Somatostatin Positive Tumors with Tyr3-Octreotate/Octreotide Conjugated to Desferrioxamine B Squaramide Radiolabeled with either Zirconium-89 or Gallium-68.

Radiolabeled derivatives of Tyr3-octreotide and Tyr3-octreotate, synthetic analogues of the peptide hormone somatostatin, can be used for positron emission tomography (PET) imaging of somatostatin receptor expression in neuroendocrine tumors. In this work, a squaramide ester derivative of desferrioxamine B (H3DFOSq) was used attach either Tyr3-octreotide or Tyr3-octreotate to the metal binding ligand to give H3DFOSq-TIDE and H3DFOSq-TATE. These new peptide-H3DFOSq conjugates form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or zirconium-89 (t1/2 = 3.3 days). The new complexes were evaluated in an AR42J xenograft model that has endogenous expression of SSTR2. All four agents displayed good tumor uptake and produced high-quality PET images. For both radionuclides, the complexes formed with H3DFOSq-TATE performed better, with higher tumor uptake and retention than the complexes formed with H3DFOSq-TIDE. The versatile ligands presented here can be radiolabeled with either gallium-68 or zirconium-89 at room temperature. The long radioactive half-life of zirconium-89 makes distribution of pre-synthesized tracers produced to certified standards feasible and could increase the number of clinical centers that can perform diagnostic PET imaging of neuroendocrine tumors.

An Overview of the Ongoing Clinical Issues of COVID-19.

Childhood cases of coronavirus disease 2019 (COVID-19) are on the rise as the pandemic continues to rage across the globe. Most children acquire infection from an adult household member. Children may stay asymptomatic, have a pre-symptomatic stage, or present with symptoms (fever, cough, and difficulty breathing being the most common). Nearly one-third of the pediatric cases (32%) in the United States occurred in children age 15 to 17 years. Children are also at risk of a postinfectious hyperinflammatory syndrome called multisystem inflammatory syndrome in children (MIS-C). The risk of vertical transmission is low (2%) in newborns of mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nucleic acid amplification testing (NAAT) is the gold standard for (SARS-CoV-2). Serology should be considered in a child with high clinical suspicion for COVID-19 when NAAT is negative and at least 2 weeks have passed since symptom onset and for assessment of MIS-C. Easy fatigability after COVID-19 infection is reported in adults; however, data in children are lacking. Implementation of early and robust containment strategies coupled with universal COVID-19 vaccination are vital to halt the spread. [Pediatr Ann. 2021;50(2):e84-e89.].

Characteristics of Hospitalized Children With SARS-CoV-2 in the New York City Metropolitan Area.

OBJECTIVES: To describe the characteristics of hospitalized children with severe acute respiratory syndrome coronavirus 2 in New York City metropolitan area. PATIENTS AND METHODS: This was a multicenter, retrospective cohort study at 4 hospitals comprising 82 hospitalized children (0-21 years) who tested positive for severe acute respiratory syndrome coronavirus 2 after symptoms and risk screening between March 1 and May 10, 2020. We subdivided patients on the basis of their admission to acute or critical care units and by age groups. Further subanalyses were performed between patients requiring respiratory support or no respiratory support. RESULTS: Twenty-three (28%) patients required critical care. Twenty-nine (35%) patients requiring respiratory support, with 9% needing mechanical ventilation, and 1 required extracorporeal support. All patients survived to discharge. Children with any comorbidity were more likely to require critical care (70% vs 37%, P = .008), with obesity as the most common risk factor for critical care (63% vs 28%, P = .02). Children with asthma were more likely to receive respiratory support (28% vs 8%, P = .02), with no difference in need for critical care (P = .26). Children admitted to critical care had higher rates of renal dysfunction at presentation (43% vs 10%, P = .002). CONCLUSIONS: Children with comorbidities (obesity and asthma in particular) were at increased risk for critical care admission and/or need for respiratory support. Children with renal dysfunction at presentation were more likely to require critical care.

Mucocutaneous Manifestations of Multisystem Inflammatory Syndrome in Children During the COVID-19 Pandemic.

Importance: To date, no study has characterized the mucocutaneous features seen in hospitalized children with multisystem inflammatory syndrome in children (MIS-C) or the temporal association of these findings with the onset of systemic symptoms. Objective: To describe the mucocutaneous findings seen in children with MIS-C during the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City in 2020. Design, Setting, and Participants: A retrospective case series was conducted of 35 children admitted to 2 hospitals in New York City between April 1 and July 14, 2020, who met Centers for Disease Control and Prevention and/or epidemiologic criteria for MIS-C. Main Outcomes and Measures: Laboratory and clinical characteristics, with emphasis on mucocutaneous findings, of children who met criteria for MIS-C. The characterization of mucocutaneous features was verified by 2 board-certified pediatric dermatologists. Results: Twenty-five children (11 girls [44%]; median age, 3 years [range, 0.7-17 years]) were identified who met definitional criteria for MIS-C; an additional 10 children (5 girls [50%]; median age, 1.7 years [range, 0.2-15 years]) were included as probable MIS-C cases (patients met all criteria with the exception of laboratory test evidence of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection or known exposure). The results of polymerase chain reaction tests for SARS-CoV-2 were positive for 10 patients (29%), and the results of SARS-CoV-2 immunoglobulin G tests were positive for 19 patients (54%). Of the 35 patients, 29 (83%) exhibited mucocutaneous changes, with conjunctival injection (n = 21), palmoplantar erythema (n = 18), lip hyperemia (n = 17), periorbital erythema and edema (n = 7), strawberry tongue (n = 8), and malar erythema (n = 6) being the most common findings. Recognition of mucocutaneous findings occurred a mean of 2.7 days (range, 1-7 days) after the onset of fever. The duration of mucocutaneous findings varied from hours to days (median duration, 5 days [range, 0-11 days]). Neither the presence nor absence of mucocutaneous findings was significantly associated with overall disease severity. Conclusions and Relevance: In this case series of hospitalized children with suspected MIS-C during the COVID-19 pandemic, a wide spectrum of mucocutaneous findings was identified. Despite their protean and transient nature, these mucocutaneous features serve as important clues in the recognition of MIS-C.