A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome.

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rare LYST variant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C.

Clinical evaluation of a fully electronic microfluidic white blood cell analyzer.

The White Blood Cell (WBC) count is one of the key parameters signaling the health of the immune system. Abnormal WBC counts often signal a systemic insult to the body such as an underlying infection or an adverse side effect to medication. Typically, the blood collected is sent to a central lab for testing, and results come back within hours, which is often inconvenient and may delay time-sensitive diagnosis or treatment. Here, we present the CytoTracker, a fully electronic, microfluidic based instant WBC analyzer with the potential to be used at point-of-care. The CytoTracker is a lightweight, portable, affordable platform capable of quantifying WBCs within minutes using only 50 µl of blood (approximately one drop of blood). In this study, we clinically evaluated the accuracy and performance of CytoTracker in measuring WBC and granulocyte counts. A total of 210 adult patients were recruited in the study. We validated the CytoTracker against a standard benchtop analyzer (Horiba Point of Care Hematology Analyzer, ABX Micros 60). Linear dynamic ranges of 2.5 k/µl- 35 k/µl and 0.6 k/µl- 26 k/µl were achieved for total WBC count and granulocyte count with correlation coefficients of 0.97 and 0.98. In addition, we verified CytoTracker's capability of identifying abnormal blood counts with above 90% sensitivity and specificity. The promising results of this clinical validation study demonstrate the potential for the use of the CytoTracker as a reliable and accurate point-of-care WBC analyzer.

The third pandemic: The respiratory syncytial virus landscape and specific considerations for the allergist/immunologist.

Background: Since its initial identification in 1956, respiratory syncytial virus (RSV) has been the second most common cause of mortality in infants <6 months of age and a major cause of morbidity and mortality associated with lower respiratory tract infection (LRTI) in older adults (ages >60 years) worldwide. Of particular interest to the allergist/immunologist is a growing body of evidence that suggests an association between LRTI caused by RSV in infants with later-life development of asthma, wheezing, or impaired lung function in adults. Efforts to develop a RSV vaccine have been thwarted for >70 years by the occurrence of enhanced respiratory disease (ERD), an adverse RSV vaccine reaction, in the 1960s, in which more-severe illness occurred on natural infection after vaccination of infants who were RSV naive and with a formalin-inactivated RSV vaccine. Recent advances in knowledge of the structural biology of the RSV surface fusion glycoprotein, however, have revolutionized RSV vaccine development for preventive interventions and have offered, at last, the hope of an effective and safe vaccine for the prevention of RSV disease. Objective: The purpose of this report was to examine the current evidence that supports the epidemiology, disease manifestations, molecular biology, treatments, and new vaccine development of RSV vaccines. Results: The host-immune response to RSV infection is carried out by two distinct but overlapping universes of mucosal and systemic immune systems in which a balanced set of B- and T-cell responses are involved in protective immunity that includes the mucosal immune system in which immunoglobulin A (IgA) prevails and the systemic immune system in which IgG neutralizing antibody predominates. The key to developing an effective vaccine is now thought to be linked to the availability of a stabilized prefusion F protein in the immunizing vaccine, which can perform a dual function of a balanced mucosal and/or systemic immune response as well as an effective antibody specifically directed to critical epitopes on the requisite prefusion F protein. Conclusion: The unfortunate manifestation of RSV ERD that occurred in the 1960s has led to a better understanding of the structural biology of the RSV surface fusion glycoprotein and has provided a basis for the development of more effective and safer RSV vaccines and monoclonal antibody preparations for immunoprophylaxis of the dread effects of RSV disease. There are now a large number of clinical trials in progress that are evaluating these products, which include recombinant vector, subunit, particle-based, live-attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. This article gives an overview of the many aspects of RSV disease and development of virus (RSV) vaccines of particular interest to the allergist/immunologist.

Challenges and Barriers to Providing Primary Care to Children of South Asian Origin: Pediatricians' Perspectives.

South Asian (SA) Americans have a high risk of metabolic and cardiovascular disease. Prevention efforts should start in childhood and should be culturally appropriate. We sought to understand the challenges and barriers that pediatricians face in providing care for SA children to inform professional education on culturally effective care. Qualitative interviews were conducted with a diverse sample (N = 17) of pediatricians. Challenges reported included feeding problems, inadequate physical activity, and mental health concerns. Communication barriers included parents' anxiety around feeding, influence of grandparents, stigma around mental health, and cultural communication gaps. Effective strategies included clear communication, a gradual approach, ensuring buy-in from grandparents, greater attention to family history, and improved cultural knowledge in pediatrician. Addressing feeding problems was the most mentioned challenge, which is especially concerning given the high chronic disease risk in SAs. Education on culturally appropriate strategies can equip pediatricians to effectively counsel SA families to address these risks.

The NJ Alliance for Clinical and Translational Science (NJ ACTS) experience: Responding at "warp speed" to COVID-19.

Introduction: The COVID-19 pandemic's need for life-saving treatments and a "warp speed" vaccine challenged the National Institutes of Health's Clinical and Translational Science Award (CTSA) recipients to improve their methods and processes in conducting clinical research. While CTSA recipient, New Jersey Alliance for Clinical and Translational Science (NJ ACTS), responded to this call to action with significant clinical research milestones, a comprehensive understanding of regulatory metrics during the COVID-19 pandemic is uncertain. The objective of this research is to identify, compare, and contrast metrics that illustrate the effectiveness of NJ ACTS's research mobilization efforts during COVID-19. Methods: Data were collected from the Institutional Review Board (IRB), the Clinical Research Units (CRUs), and the Office of Research and Sponsored Programs (ORSP). IRB data detailed the volume and types of protocols approved and turnaround time (TAT) for approval in 2020 vs. 2019. CRU data examined study metrics of adult and pediatric clinical trials across 2018-2020. ORSP data documented awards received in 2019 and 2020. Results: Analysis revealed a 95% increase in IRB-approved studies in 2020, with a significant decrease in TAT for COVID-19 studies. All CRUs observed a median 5.2-fold increase in the enrollment of adult and pediatric participants for COVID-19-related research. Study income was 106% and 196% greater than 2019 and 2018, respectively, with more than half funded through federal sponsors and 89% for COVID-19 trials. ORSP data revealed that 9% of awards and 26% of 2020 funding were COVID-19 studies. Conclusion: This study demonstrates that NJACTS effectively responded to challenges posed by the pandemic.

Dichotomy between the humoral and cellular responses elicited by mRNA and adenoviral vector vaccines against SARS-CoV-2.

BACKGROUND: Protection from severe disease and hospitalization by SARS-CoV-2 vaccination has been amply demonstrated by real-world data. However, the rapidly evolving pandemic raises new concerns. One pertains efficacy of adenoviral vector-based vaccines, particularly the single-dose Ad26.COV2.S, relative to mRNA vaccines. MAIN BODY: We investigated the immunogenicity of Ad26.COV2.S and mRNA vaccines in 33 subjects vaccinated with either vaccine class 5 months earlier on average. After controlling for the time since vaccination, Spike-binding antibody and neutralizing antibody levels were higher in the mRNA-vaccinated subjects, while no significant differences in antigen-specific B cell and T cell responses were observed between the two groups. CONCLUSIONS: A dichotomy exists between the humoral and cellular responses elicited by the two vaccine classes. Testing only for humoral responses to compare the durability of SARS-CoV-2 vaccine-induced responses, as typically performed for public health and research purposes, is insufficient.

E-cigarette or vaping product use associated lung injury (EVALI) in the time of COVID-19: A clinical dilemma.

AIM: To report on the clinical, laboratory, and radiological findings of adolescents who presented during the SARS-CoV-2 surge with symptoms of Coronavirus disease 2019 (COVID-19), did not test positive for the infection, and were diagnosed with E-cigarette and vaping product use associated lung injury (EVALI). METHODS: A retrospective review of 12 cases of EVALI admitted to the Bristol Meyers Squibb Children's Hospital between February 2020 and June 2020 was conducted. RESULTS: The ages of the patients ranged from 14 to 19 years. There were six males and six females. Three patients had a past history of anxiety, depression, or other psychiatric/mental health disorder, 9 had prolonged coagulation profile (prothrombin time, partial thromboplastin time, and/or International Normalized Ratio), and 11 had elevated inflammatory markers. Eight needed respiratory support. All 12 were negative for SARS-CoV-2 PCR. Four were tested for IgG antibodies and were negative. As these cases were admitted to rule out COVID infection, initial treatment included hydroxychloroquine. Steroids were started only after SARS-CoV-2 PCR was shown to be negative. Urine tetrahydrocannabinol was positive in all cases. Chest X-ray and computed tomography findings showed ground glass opacities. CONCLUSIONS: Clinical and radiological features are similar in both EVALI and SARS-CoV-2 infection. Inflammatory markers are elevated in both conditions. A detailed social and substance use history in patients presenting with "typical" COVID pneumonia like illness is important. EVALI should be ruled in early to start the appropriate treatment. Given the ongoing pandemic, pediatricians and other health-care providers need to be aware of other conditions that can masquerade as SARS-CoV-2.

Dichotomy between the humoral and cellular responses elicited by mRNA and adenoviral vector vaccines against SARS-CoV-2.

Protection from severe disease and hospitalization by SARS-CoV-2 vaccination has been amply demonstrated by real-world data. However, the rapidly evolving pandemic raises new concerns. One pertains efficacy of adenoviral vector-based vaccines, particularly the single-dose Ad26.COV2.S, relative to mRNA vaccines. We investigated the immunogenicity of Ad26.COV2.S and mRNA vaccines in 33 subjects vaccinated with either vaccine class five months earlier on average. After controlling for time since vaccination, Spike-binding antibody and neutralizing antibody levels were higher in the mRNA-vaccinated subjects, while no significant differences in antigen-specific B cell and T cell responses were observed between the two groups. Thus, a dichotomy exists between humoral and cellular responses elicited by the two vaccine classes. Our results have implications for the need of booster doses in vaccinated subjects and might explain the dichotomy reported between the waning protection from symptomatic infection by SARS-CoV-2 vaccination and its persisting efficacy in preventing hospitalization and death.

Determinants and Dynamics of SARS-CoV-2 Infection in a Diverse Population: 6-Month Evaluation of a Prospective Cohort Study.

BACKGROUND: We studied risk factors, antibodies, and symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a diverse, ambulatory population. METHODS: A prospective cohort (n = 831) previously undiagnosed with SARS-CoV-2 infection underwent serial testing (SARS-CoV-2 polymerase chain reaction, immunoglobulin G [IgG]) for 6 months. RESULTS: Ninety-three participants (11.2%) tested SARS-CoV-2-positive: 14 (15.1%) asymptomatic, 24 (25.8%) severely symptomatic. Healthcare workers (n = 548) were more likely to become infected (14.2% vs 5.3%; adjusted odds ratio, 2.1; 95% confidence interval, 1.4-3.3) and severely symptomatic (29.5% vs 6.7%). IgG antibodies were detected after 79% of asymptomatic infections, 89% with mild-moderate symptoms, and 96% with severe symptoms. IgG trajectories after asymptomatic infections (slow increases) differed from symptomatic infections (early peaks within 2 months). Most participants (92%) had persistent IgG responses (median 171 days). In multivariable models, IgG titers were positively associated with symptom severity, certain comorbidities, and hospital work. Dyspnea and neurologic changes (including altered smell/taste) lasted ≥ 120 days in ≥ 10% of affected participants. Prolonged symptoms (frequently more severe) corresponded to higher antibody levels. CONCLUSIONS: In a prospective, ethnically diverse cohort, symptom severity correlated with the magnitude and trajectory of IgG production. Symptoms frequently persisted for many months after infection.Clinical Trials Registration. NCT04336215.

Acute respiratory distress syndrome and COVID-19 in a child with systemic lupus erythematosus.

We report a case of COVID-19 in a pediatric patient with systemic lupus erythematosus (SLE), who presented with respiratory distress marked by increased work of breathing and low oxygen saturation. Lab tests confirmed COVID-19, and showed lymphocytopenia and elevated markers of inflammation and coagulopathy. Chest X-ray showed bilateral mid-lung opacities, and the patient required intubation early in his disease course. Imaging and clinical findings were consistent with acute respiratory distress syndrome (ARDS) with inflammation. The patient was treated with different combinations of antivirals (hydroxychloroquine and remdesivir), cytokine inhibitors (anakinra and tocilizumab), glucocorticoids (hydrocortisone and methylprednisolone), and an anticoagulant (enoxaparin). Inflammatory markers decreased before clinical improvement in lung aeration. This case highlights the potential for pediatric patients with SLE to present with COVID-19 similar to the clinical presentation described in adults.

Culturally-adapted behavioral intervention to improve colorectal cancer screening uptake among foreign-born South Asians in New Jersey: the Desi Sehat trial.

Objectives: Colorectal cancer (CRC) is the third most common cancer among Americans of South Asian (SA) descent and is a significant public health concern in SA communities. Rates of screening compliance among foreign-born SAs are very low. The goal of this study was to report on the development, acceptability, and preliminary impact of a culturally-targeted 1:1 intervention delivered in English, Hindi, and Urdu, called Desi-Sehat.Design: Ninety-three foreign-born SAs between the ages of 50 and 75 were recruited using community-based organization methods. Participants completed a baseline survey, participated in a 1:1 session with a community health educator, and a follow-up survey was administered four months after the baseline.Results: The acceptance rate was moderate (52.8%). Attendance at the intervention session was high. More than half of the population did not complete the follow-up survey (58.7%). Participant evaluations of the intervention were high. Intent-to-treat analyses indicate a 30% four month follow-up CRC screening uptake. There were significant increases in knowledge and significant reductions in perceived barriers to screening, worry about CRC screening tests, and worry about CRC. Effect sizes for significant changes were in the medium to large range.Conclusions: Desi Sehat was a well-evaluated and participation in the session was high, participant knowledge significantly increased, and screening barriers, worry about CRC, and worry about CRC screening tests declined significantly. Future studies should focus on enhancing recruitment and retention and include a randomized control design.

Effectiveness of a Cultural Stroke Prevention Program in the United States-South Asian Health Awareness About Stroke (SAHAS).

There are few stroke education programs focused on the South Asian population in the United States. The South Asian Health Awareness about Stroke (SAHAS) program was developed to provide culturally appropriate stroke education to South Asians from 2014 to 2017. Participants recruited for the SAHAS program were educated through a uniquely developed, culturally-specific, educational presentation. Each participant was asked to complete identical educational questionnaires both before (pre-) and after (post-) the intervention, which were then scored and evaluated. Overall, the 357 participants who completed the SAHAS program had a significant, modest 9% improvement in questionnaire score (p < 0.0001). After adjusting for confounders, those ≤ 60 years had a 2.9-point greater increase in score than those > 60 (p < 0.0001). Having programs targeted and developed for specific minority groups with an emphasis on familial commitment and active participation may aid in raising awareness and reducing the elevated adverse stroke outcomes in South Asians.

Pediatric COVID-19 and Appendicitis: A Gut Reaction to SARS-CoV-2?

BACKGROUND: We describe the temporal pattern of COVID-19 admissions to a tertiary care children's hospital in central New Jersey during the SARS-CoV-2 surge, covering the time period from March 29 to July 26, 2020. METHODS: Medical charts were reviewed for the date of admission, past medical history, and demographic variables, presenting signs and symptoms, admitting laboratory values, diagnostic imaging, diagnosis, treatment modalities, and outcomes including length of stay and disease severity. RESULTS: Patients with symptomatic SARS-CoV-2 infection tended to present with pneumonia early during the study period, which coincided with the early surge in New Jersey cases. Approximately 2 weeks after the peak in reported SARS-CoV-2 cases in New Jersey, we began to see fewer pneumonia cases and an increase in admissions for Multi-Inflammatory Syndrome in Children and cases of acute appendicitis in association with a diagnosis of SARS-CoV-2 infection. CONCLUSIONS: We present a novel association of acute appendicitis in children infected with SARS-CoV-2 and postulate that it may represent a postinfectious hyperinflammatory complication of SARS-CoV-2 infection occurring 2 weeks after the early manifestation of acute pneumonia disease in children.

South Asian Health: Inflammation, Infection, Exposure, and the Human Microbiome.

This paper presents the results of the literature review conducted for the working group topic on inflammation, infection, exposure, and the human microbiome. Infection and chronic inflammation can elevate risk for cardiovascular disease and cancer. Environmental exposures common among South Asian (SA) subgroups, such as arsenic exposure among Bangladeshis and particulate matter air pollution among taxi drivers, also pose risks. This review explores the effects of exposure to arsenic and particulate matter, as well as other infections common among SAs, including human papillomavirus (HPV) and hepatitis B/C infection. Emerging research on the human microbiome, and the effect of microbiome changes on obesity and diabetes risk among SAs are also explored.

Latent Tuberculosis Infection Beliefs and Testing and Treatment Health Behaviors Amongst Non-US-Born South Asians in New Jersey: A Cross-Sectional Community Survey.

Latent tuberculosis infection (LTBI) remains a problem in the United States as reactivation leads to active TB disease particularly in persons with risk factors. The objective of this study is to assess the knowledge, attitudes and health behaviors related to testing and treatment of LTBI among non-US-born South Asians (SA) in New Jersey (NJ). A cross-sectional, community-based survey was the primary tool for gathering data. Eligibility criteria included being at least 18 years of age, self-identifying as SA, verbal consent for participation, and birth in a high TB endemic country. A hardcopy survey was distributed at local South Asian health fairs. The survey included questions about demographics, knowledge, beliefs on TB, and health behaviors (testing and treatment). Descriptive statistics were performed for all survey responses. Logistic regression models were constructed to assess the association of characteristics/beliefs and study outcomes. The survey sample size included 387 respondents. A total of 197 (54%) of respondents reported ever been tested for TB. Those who were tested for TB were generally younger, had higher educational levels, higher household incomes, and were more likely to have health insurance than those not ever tested for TB. Significantly more respondents who self-reported ever been tested for TB believed that TB was very or extremely serious (71.1% vs. 56.2%, p = 0.004). Also, significantly more respondents who self-reported ever been tested for TB believed that it was important to get tested (91.2% vs. 63.3%, p < 0.001). The survey analysis concluded that high-risk SA residents in NJ demonstrated a low rate of testing for TB.

Cutaneous Leishmaniasis in an American Adolescent Returning From Israel.

We present here the case of a healthy 16-year-old American girl who returned from an organized trip to Israel with cutaneous leishmaniasis caused by Leishmania major; the infection was treated successfully with paromomycin-gentamicin ointment. She was initially misdiagnosed with staphylococcal and pseudomonal cellulitis. Although cutaneous leishmaniasis is seen only rarely in the United States, it should be considered when diagnosing new skin lesions after travel to affected countries.

Adverse Outcomes Among Asian Indian Singleton Births in New Jersey, 2008-2011.

The study determined the incidence of low birth weight (LBW), small for gestational age (SGA), preterm birth, and perinatal morbidity among Asian Indians (AI) in New Jersey (NJ), as well as identified predictors of SGA. We analyzed birth records for singletons born to mothers identified as AI and non-Hispanic white from 2008 to 2011, obtained from the NJ Department of Health. For AI, rates of LBW and SGA were elevated, rates of preterm birth were similar, and neonatal intensive care unit admission was lower, compared to whites. Factors associated with SGA in AI included nulliparity, anemia, hypertension, placental abruption, and lack of prenatal care. Maternal education, marital status, substance abuse, and timing of prenatal care were associated with SGA in whites, but not in AI. SGA incidence was higher among AI despite preterm rates similar to whites. Anemia was associated with SGA uniquely among AI.

Clinical and cost burden of rotavirus infection before and after introduction of rotavirus vaccines among commercially and Medicaid insured children in the United States.

This study aims to quantify clinical and economic burden of rotavirus (RV) infection pre- and post-vaccine introduction in commercially insured and Medicaid populations. Beneficiaries with continuous enrollment for ≥6 months while <5 years of age were identified separately in commercial (2000-2010) and Medicaid (2002-2009) claims databases. Commercial and Medicaid databases included 3,998,708 and 1,034,440 eligible children, respectively, observed from enrollment start date(s) to end of eligibility or 5-years-old. Rates of RV-coded and diarrhea-coded encounters and first RV episodes, and incremental cost of first RV episodes were calculated. In the post-vaccine period, rates per 10,000 person-years for RV-coded hospitalizations, outpatient visits and ER visits were 5.58 (95% CI, 5.37-5.80), 6.96 (95% CI, 6.75-7.20), and 4.85 (95% CI, 4.66-5.06), respectively (pre-vaccine, 16.67 [95% CI, 16.19-17.15], 13.20 [95% CI, 12.78-13.63], 11.26 [95% CI, 10.87-11.66], respectively), for commercially insured. In Medicaid the corresponding rates were 10.53 (95% CI, 9.60-11.56), 11.72 (95% CI, 10.73-12.80), and 9.11 (95% CI, 8.24-10.07) (pre-vaccine, 19.78 [95% CI, 19.14-20.45], 19.39 [95% CI, 18.75-20.05], 27.61 [95% CI, 26.84-28.40]). Incidence rate per 10,000 person-years for first RV episode pre- vs. post-vaccine were 27.03 (95% CI, 26.42-27.65) vs. 10.14 (95% CI, 9.86-10.44) in the commercially insured population and 37.71 (95% CI, 36.81-38.63) vs. 18.64 (95% CI, 17.37-19.99) in Medicaid. Incremental per-patient per-month cost of first RV episode was $3363 (95% CI, $3308-$3418) among commercially insured and $1831 (95% CI, $1768-$1887) in Medicaid. Since vaccine introduction clinical burden of RV disease decreased among children; costs associated with RV episodes remained significant across insured populations.

Treatment Response in Association with Adherence Patterns to Highly Active Antiretroviral Therapy in Pediatric Patients with Perinatally Acquired HIV Infection.

BACKGROUND: Assessment of longitudinal adherence patterns on virologic and immunologic responses to HAART in perinatally acquired HIV patients has not been studied. METHODS: Perinatally infected pediatric HIV patients with adherence documented at least twice and corresponding viral load and T-cell (%) data measured during 2008-2009 were studied. Multiple adherence measures were utilized to identify patients with persistent adherence, nonadherence, or alteration of adherence. Virologic and immunologic outcomes were assessed. RESULTS: Persistent adherence, nonadherence, and alteration of adherence to HAART were recorded in 41.9%, 8.1%, and 50.0% of 62 studied patients. Persistent adherence was associated with higher likelihood for persistent virologic suppression and lower risk for persistent virologic failure. CONCLUSION: Alteration of adherence to HAART is a significant predictor of persistent virologic failure and high viremia in perinatally infected HIV patients. Implementation of longitudinal adherence assessments may target patients with nonsustained adherence patterns and help decrease the risk for virologic failure and disease progression.