COVID-19 Vaccine Side Effects and Long-Term Neutralizing Antibody Response : A Prospective Cohort Study.

BACKGROUND: Concern about side effects is a common reason for SARS-CoV-2 vaccine hesitancy. OBJECTIVE: To determine whether short-term side effects of SARS-CoV-2 messenger RNA (mRNA) vaccination are associated with subsequent neutralizing antibody (nAB) response. DESIGN: Prospective cohort study. SETTING: San Francisco Bay Area. PARTICIPANTS: Adults who had not been vaccinated against or exposed to SARS-CoV-2, who then received 2 doses of either BNT162b2 or mRNA-1273. MEASUREMENTS: Serum nAB titer at 1 month and 6 months after the second vaccine dose. Daily symptom surveys and objective biometric measurements at each dose. RESULTS: 363 participants were included in symptom-related analyses (65.6% female; mean age, 52.4 years [SD, 11.9]), and 147 were included in biometric-related analyses (66.0% female; mean age, 58.8 years [SD, 5.3]). Chills, tiredness, feeling unwell, and headache after the second dose were each associated with 1.4 to 1.6 fold higher nAB at 1 and 6 months after vaccination. Symptom count and vaccination-induced change in skin temperature and heart rate were all positively associated with nAB across both follow-up time points. Each 1 °C increase in skin temperature after dose 2 was associated with 1.8 fold higher nAB 1 month later and 3.1 fold higher nAB 6 months later. LIMITATIONS: The study was conducted in 2021 in people receiving the primary vaccine series, making generalizability to people with prior SARS-CoV-2 vaccination or exposure unclear. Whether the observed associations would also apply for neutralizing activity against non-ancestral SARS-CoV-2 strains is also unknown. CONCLUSION: Convergent self-report and objective biometric findings indicate that short-term systemic side effects of SARS-CoV-2 mRNA vaccination are associated with greater long-lasting nAB responses. This may be relevant in addressing negative attitudes toward vaccine side effects, which are a barrier to vaccine uptake. PRIMARY FUNDING SOURCE: National Institute on Aging.

Utility of shaking chills as a diagnostic sign for bacteremia in adults: a systematic review and meta-analysis.

BACKGROUND: Accurate prediction of bacteremia is essential for guiding blood culture collection and optimal antibiotic treatment. Shaking chills, defined as a subjective chill sensation with objective body shivering, have been suggested as a potential predictor of bacteremia; however, conflicting findings exist. To address the evidence gap, we conducted a systematic review and meta-analysis of studies to assess the diagnostic accuracy of shaking chills for predicting bacteremia among adult patients. METHODS: We included studies reporting the diagnostic accuracy of shaking chills or chills for bacteremia. Adult patients with suspected bacteremia who underwent at least one set of blood cultures were included. Our main analysis focused on studies that assessed shaking chills. We searched these studies through CENTRAL, MEDLINE, Embase, the World Health Organization ICTRP Search Portal, and ClinicalTrials.gov. Study selection, data extraction, evaluation for risk of bias, and applicability using the QUADAS-2 tool were conducted by two independent investigators. We estimated a summary receiver operating characteristic curve and a summary point of sensitivity and specificity of the index tests, using a hierarchical model and the bivariate model, respectively. RESULTS: We identified 19 studies with a total of 14,641 patients in which the accuracy of shaking chills was evaluated. The pooled sensitivity and specificity of shaking chills were 0.37 (95% confidence interval [CI], 0.29 to 0.45) and 0.87 (95% CI, 0.83 to 0.90), respectively. Most studies had a low risk of bias in the index test domain and a high risk of bias and a high applicability concern in the patient-selection domain. CONCLUSIONS: Shaking chills are a highly specific but less sensitive predictor of bacteremia. Blood cultures and early initiation of antibiotics should be considered for patients with an episode of shaking chills; however, the absence of shaking chills must not lead to exclusion of bacteremia and early antibiotic treatment.

Safety and tolerance of vaccines against SARS-CoV-2 infection in systemic lupus erythematosus: results from the COVAD study.

OBJECTIVE: To determine COVID-19 vaccine-related adverse events (AEs) in the seven-day post-vaccination period in patients with SLE vs autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HC). METHODS: Data were captured through the COVID-19 Vaccination in Autoimmune Diseases (COVAD) questionnaire (March-December 2021). Multivariable regression models accounted for age, gender, ethnicity, vaccine type and background treatment. RESULTS: Among 9462 complete respondents, 583 (6.2%) were SLE patients (mean age: 40.1 years; 94.5% females; 40.5% Asian; 42.9% Pfizer-recipients). Minor AEs were reported by 83.0% of SLE patients, major by 2.6%, hospitalization by 0.2%. AE and hospitalization frequencies were similar between patients with active and inactive SLE. Rashes were more frequent in SLE patients vs HC (OR; 95% CI: 1.2; 1.0, 1.5), chills less frequent in SLE vs AIRDs (0.6; 0.4, 0.8) and nrAIDs (0.5; 0.3, 0.8), and fatigue less frequent in SLE vs nrAIDs (0.6; 0.4, 0.9). Pfizer-recipients reported higher overall AE (2.2; 1.1, 4.2) and injection site pain (2.9; 1.6, 5.0) frequencies than recipients of other vaccines, Oxford/AstraZeneca-recipients more body ache, fever, chills (OR: 2.5, 3.0), Moderna-recipients more body ache, fever, chills, rashes (OR: 2.6, 4.3). Hospitalization frequencies were similar across vaccine types. AE frequencies were similar across treatment groups, although chills were less frequent in antimalarial users vs non-users (0.5; 0.3, 0.9). CONCLUSION: While COVID-19 vaccination-related AEs were reported by four-fifths of SLE patients, those were mostly minor and comparable to AEs reported by healthy individuals, providing reassurance regarding COVID-19 vaccination safety in SLE.

Effects of CAR-T Cell Therapy on Immune Cells and Related Toxic Side Effect Analysis in Patients with Refractory Acute Lymphoblastic Leukemia.

Objective: To observe the effects of chimeric antigen receptor T (CAR-T) cell immunotherapy on immune cells and related toxic side effects in patients with refractory acute lymphoblastic leukemia (ALL). Methods: A retrospective study was conducted in 35 patients with refractory ALL. The patients were treated with CAR-T cell therapy in our hospital from January 2020 to January 2021. The efficacy was evaluated at one and three months post treatments. The venous blood of the patients was collected before treatment, 1 month after treatment, and 3 months after treatment. The percentage of regulatory T cells (Treg cells), natural killer (NK) cells, and T lymphocyte subsets (CD3+, CD4+, and CD8+ T cells) was detected by flow cytometry. The ratio of CD4+/CD8+ was calculated. Patient's toxic side effects such as fever, chills, gastrointestinal bleeding, nervous system symptoms, digestive system symptoms, abnormal liver function, and blood coagulation dysfunction were monitored and recorded. The incidence of toxic and side effects was calculated, and the incidence of infection was recorded. Results: After one month of CAR-T cell therapy in 35 patients with ALL, the efficacy evaluation showed that complete response (CR) patients accounted for 68.57%, CR with incomplete hematological recovery (CRi) patients accounted for 22.86%, and partial disease (PD) patients accounted for 8.57%, and the total effective rate was 91.43%. In addition, compared with that before treatment, the Treg cell level in CR+CRi patients treated for 1 month and 3 months decreased prominently, and the NK cell level increased dramatically (P < 0.05). Compared with that before treatment, the levels of CD3+, CD4+, and CD4+/CD8+ in patients with CR+CRi in the 1-month and 3-month groups were markedly higher, and the levels of CD4+/CD8+ in the 3-month group were memorably higher than those in the 1-month group (P < 0.05). During CAR-T cell therapy in 35 patients with ALL, fever accounted for 62.86%, chills for 20.00%, gastrointestinal bleeding for 8.57%, nervous system symptoms for 14.29%, digestive system symptoms for 28.57%, abnormal liver function for 11.43%, and coagulation dysfunction for 8.57%. These side effects were all relieved after symptomatic treatment. During the course of CAR-T therapy in 35 patients with ALL, 2 patients had biliary tract infection and 13 patients had lung infection. No correlations were found between the infection and age, gender, CRS grade, usage of glucocorticoids or tocilizumab, and laboratory indicators such as WBC, ANC, PLT, and Hb (P > 0.05). Conclusion: CAR-T cell therapy had a good effect on patients with refractory ALL by regulating the immune function of the body via mediating the content of immune cells. CAR-T cell therapy may have therapeutic effect on refractory ALL patients with mild side effects and high safety.

[Effect of equal temperature bladder irrigation in patients with transurethral resection of prostate: A meta-analysis].

OBJECTIVE: To evaluate the effect of equal temperature bladder irrigation on bladder spasm, postoperative bleeding, vital signs and discomfort of chills in patients of transurethral resection of prostate using meta-analysis. METHODS: Several electronic databases included Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang, VIP, China Biology Medicine (CBM) were searched systematically for published randomized controlled trial about equal temperature bladder irrigation in patients with transurethral resection of prostate before November 20, 2019. Two reviewers selected independently the literature in the light of the inclusion and exclusion criteria, assessed the risk of bias by quality assessment and extracted data which were consisted of clinical efficacy indexes, such as incidence of bladder spasm, severity of bladder spasm, incidence of tube plugging, amount of bladder flushing fluid, time of bladder flushing, heart rate, systolic pressure, diastolic pressure, and incidence of chills. Data were pooled using fixed-effects model or random-effects model, and the summary effect measure was calculated by risk ratio (RR) or mean difference (MD) and 95% confidence interval (95%CI). Meta-analysis was performed by Review Manager 5.3 Software. RESULTS: In the study, 13 randomized controlled trails met the requirement with a total of 2 033 patients of transurethral resection of prostate were included, of whom 1 015 were carried out with equal temperature bladder irrigation and 1 018 with room temperature bladder irrigation. The results of meta-analysis showed that incidence of bladder spasm [RR=0.51, 95%CI (0.45, 0.57), P < 0.001], severity of bladder spasm [MD=-1.61, 95%CI (-2.00, -1.23), P < 0.001], incidence of urinary blockage [RR=0.29, 95%CI (0.19, 0.44), P < 0.001], dosage of bladder irrigation [MD=-6.75, 95%CI (-7.33, -6.17), P < 0.001], time of bladder rinse [MD=-7.60, 95%CI (-11.91, -3.29), P < 0.001], heart rate [MD=-13.68, 95%CI (-15.19, -12.17), P < 0.001], systolic pressure [MD=-29.26, 95%CI (-31.92, -26.59), P < 0.001], diastolic pressure [MD=-29.36, 95%CI (-31.75, -26.98), P < 0.001], incidence of chills and discomfort [MD=0.37, 95%CI (0.31, 0.44), P < 0.001] in equal temperature group of the patients with transurethral resection of prostate had significantly statistical difference compared with room temperature group. CONCLUSION: Based on current available evidence, equal temperature bladder irrigation reduced the incidence of bladder spasm and urinary blockage, relieved bladder spasm, reduced dosage and time of bladder irrigation, and hardly affected normal vital signs and increased the patient' s comfort.

Predictive symptoms for COVID-19 in the community: REACT-1 study of over 1 million people.

BACKGROUND: Rapid detection, isolation, and contact tracing of community COVID-19 cases are essential measures to limit the community spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to identify a parsimonious set of symptoms that jointly predict COVID-19 and investigated whether predictive symptoms differ between the B.1.1.7 (Alpha) lineage (predominating as of April 2021 in the US, UK, and elsewhere) and wild type. METHODS AND FINDINGS: We obtained throat and nose swabs with valid SARS-CoV-2 PCR test results from 1,147,370 volunteers aged 5 years and above (6,450 positive cases) in the REal-time Assessment of Community Transmission-1 (REACT-1) study. This study involved repeated community-based random surveys of prevalence in England (study rounds 2 to 8, June 2020 to January 2021, response rates 22%-27%). Participants were asked about symptoms occurring in the week prior to testing. Viral genome sequencing was carried out for PCR-positive samples with N-gene cycle threshold value < 34 (N = 1,079) in round 8 (January 2021). In univariate analysis, all 26 surveyed symptoms were associated with PCR positivity compared with non-symptomatic people. Stability selection (1,000 penalized logistic regression models with 50% subsampling) among people reporting at least 1 symptom identified 7 symptoms as jointly and positively predictive of PCR positivity in rounds 2-7 (June to December 2020): loss or change of sense of smell, loss or change of sense of taste, fever, new persistent cough, chills, appetite loss, and muscle aches. The resulting model (rounds 2-7) predicted PCR positivity in round 8 with area under the curve (AUC) of 0.77. The same 7 symptoms were selected as jointly predictive of B.1.1.7 infection in round 8, although when comparing B.1.1.7 with wild type, new persistent cough and sore throat were more predictive of B.1.1.7 infection while loss or change of sense of smell was more predictive of the wild type. The main limitations of our study are (i) potential participation bias despite random sampling of named individuals from the National Health Service register and weighting designed to achieve a representative sample of the population of England and (ii) the necessary reliance on self-reported symptoms, which may be prone to recall bias and may therefore lead to biased estimates of symptom prevalence in England. CONCLUSIONS: Where testing capacity is limited, it is important to use tests in the most efficient way possible. We identified a set of 7 symptoms that, when considered together, maximize detection of COVID-19 in the community, including infection with the B.1.1.7 lineage.

Spring 2020 COVID-19 Surge: Prospective Relations between Demographic Factors, Personality Traits, Social Cognitions and Guideline Adherence, Mask Wearing, and Symptoms in a U.S. Sample.

BACKGROUND: To date, much of the research on individual difference correlates of coronavirus guideline adherence is cross-sectional, leaving prospective associations between these factors unaddressed. Additionally, investigations of prospective predictors of mask-wearing, COVID-19 symptoms, and viral testing remain wanting. PURPOSE: The present study examined prospective relations between demographic factors, personality traits, social cognitions and guideline adherence, mask-wearing, symptoms, and viral testing in a U.S. sample (N = 500) during the initial surge of COVID-19 deaths in the United State between late March and early May 2020. METHODS: Guided by a disposition-belief-motivation framework, correlational analyses, and path models tested associations among baseline personality traits, guideline adherence social cognitions, health beliefs, guideline adherence and follow-up guideline adherence, mask-wearing, symptom counts, and 30-day viral testing. RESULTS: Modeling results showed greater baseline agreeableness, conscientiousness, and extraversion were associated with more frequent baseline guideline adherence. More liberal political beliefs, greater guideline adherence intentions, and more frequent guideline adherence at baseline predicted more frequent mask-wearing at follow-up. Sex (female), lower perceived health, and greater neuroticism at baseline predicted greater symptom counts at follow-up. Reports of viral testing were quite low (1.80%), yet were consistent with concurrent national reporting and limited availability of testing. CONCLUSIONS: Results show how inconsistencies and politicization of health policy communication were concomitant with the effects of individual-level political beliefs on mask-wearing during the initial surge. The results further clarify how personality traits related to social responsibility (i.e., agreeableness, conscientiousness) are associated with following new norms for prescribed behaviors and how symptom reporting can be as much a marker of perceived health as emotional stability.

'Defrosting' music chills with naltrexone: The role of endogenous opioids for the intensity of musical pleasure.

The endogenous opioid system has been implicated during experiences of pleasure (i.e., from food or sex). Music can elicit intense emotional and bodily sensations of pleasure, called 'Chills'. We investigated the effects of an opioid antagonist (50 mg naltrexone) or placebo (40 µg d3-vitamin) while listening to self-selected music or other 'control' music selected by another participant. We used a novel technique of continuous measurement of pleasantness with an eye tracker system, where participants shifted their eyes along a visual analogue scale, in the semblance of a thermometer so that, as the music unfolded, gaze positions indicated the self-reported hedonic experience. Simultaneously, we obtained pupil diameters. Self-reported pleasure remained unchanged by naltrexone, which - however - selectively decreased pupillary diameters during 'Chills'. Hence, the endogenous µ-opioid signaling is not necessary for subjective enjoyment of music but an opioid blockade dampens pupil responses to peak pleasure, consistent with decreased arousal to the music.

Chills, fatigue, chest distress, and an abnormal increase in WBC, neutrophil, CRP, and PCT induced by terconazole: A case report.

The vaginal routes of administration of terconazole, a synthetic triazole derivative, is widely used by patients with uncomplicated vulvovaginal candidiasis (VVC). A 32-year-old woman suffered from chills, fatigue, and chest distress after receiving one 80-mg terconazole vaginal suppository for the treatment of uncomplicated VVC. Then, the symptom persisted for 10 hours until the residue of terconazole was removed, and the vagina was repeatedly washed with iodophor. In addition, white blood cell (WBC), neutrophil, C-reactive protein (CRP), and procalcitonin (PCT) were tested and showed marked increase when the patient visited our hospital again on the next day after the treatment with terconazole. Intriguingly, these parameters gradually decreased after a single dose of intravenous fluids (0.9% sodium chloride injection 500 mL and 10% glucose injection 500 mL) instead of the antibiotic therapy. On the third day, WBC and neutrophils returned to normal levels. Thus, according to the Naranjo adverse drug reaction probability scale, terconazole was the probable cause of the symptoms and the elevated WBC, neutrophil, CRP, and PCT. To date, this is the first report that chest distress, and at the same time, elevation of WBC, neutrophil, CRP, and PCT were caused by terconazole. This would be beneficial to avoid the overuse of antibiotics. Resolving the adverse drug reaction with drug removal and intravenous fluids would be beneficial to avoid the overuse of antibiotics. Resolving the adverse drug reaction with drug removal and intravenous fluids would be beneficial to avoid the overuse of antibiotics.

Emergency Department Utilization by In-hospital Healthcare Workers after COVID-19 Vaccination.

BACKGROUND: This is an observational study to analyze an emergency department (ED) utilization pattern of coronavirus disease 2019 (COVID-19) vaccinated in-hospital healthcare workers (HCWs). METHODS: We included 4,703 HCWs who were administered the first dose of the COVID-19 vaccine between March 4 and April 2, 2021, in a tertiary hospital in Korea where fast-track and post-vaccination cohort zone (PVCZ) were introduced in ED. We analyzed data of participants' age, sex, occupation, date and type of vaccination, and their clinical information using SPSS v25.0. RESULTS: The sample comprised HCWs, who received either the ChAdOx1 (n = 4,458) or the BNT162B2 (n = 245) vaccines; most participants were female (73.5%), and 81.1% were under 50 years old. Further, 153 (3.3%) visited the ED and reported experiencing fever (66.9%) and myalgia (56.1%). Additionally, 91 (59.5%) of them were in their 20s, and 106 (67.5%) were assigned to the PVCZ. Lastly, 107 (68.2%) of the patients received parenteral management. No patient required hospitalization. CONCLUSION: In conclusion, vaccinated HCWs who visited the ED with adverse events had a high incidence of fever and a low likelihood of developing serious illnesses. As the COVID-19 vaccination program for Korean citizens continues to expand, strategies to minimize unnecessary ED overcrowding should be put into effect.

Risk of bacteremia in patients presenting with shaking chills and vomiting - a prospective cohort study.

Chills and vomiting have traditionally been associated with severe bacterial infections and bacteremia. However, few modern studies have in a prospective way evaluated the association of these signs with bacteremia, which is the aim of this prospective, multicenter study. Patients presenting to the emergency department with at least one affected vital sign (increased respiratory rate, increased heart rate, altered mental status, decreased blood pressure or decreased oxygen saturation) were included. A total of 479 patients were prospectively enrolled. Blood cultures were obtained from 197 patients. Of the 32 patients with a positive blood culture 11 patients (34%) had experienced shaking chills compared with 23 (14%) of the 165 patients with a negative blood culture, P = 0.009. A logistic regression was fitted to show the estimated odds ratio (OR) for a positive blood culture according to shaking chills. In a univariate model shaking chills had an OR of 3.23 (95% CI 1.35-7.52) and in a multivariate model the OR was 5.9 (95% CI 2.05-17.17) for those without prior antibiotics adjusted for age, sex, and prior antibiotics. The presence of vomiting was also addressed, but neither a univariate nor a multivariate logistic regression showed any association between vomiting and bacteremia. In conclusion, among patients at the emergency department with at least one affected vital sign, shaking chills but not vomiting were associated with bacteremia.

Clinical characteristics and outcome of COVID-19 pneumonia in kidney transplant recipients in Razi hospital, Rasht, Iran.

BACKGROUND: In late December 2019, a novel coronavirus SARS-CoV-2 started to spread around the world in different populations. Its clinical and laboratory characteristics and outcome in kidney transplant recipients are little known. Therefore, we describe 22 kidney transplant recipients with SARS-CoV-2-induced pneumonia. METHODS: All kidney transplant recipients who referred to the Razi Hospital of Rasht with a diagnosis of SARS-CoV-2 infection from February 20 to 19th of April 2020 have been included in this observational study. RESULTS: We present 22 cases of COVID-19 in kidney transplant recipients (median age 52 years [interquartile range 40.75-62.75 years]) and baseline eGFR 60 (mL/min/1.73 m2 ) (44.75-86.75). Patients complained of cough (72.7%), dyspnea (63.6%), fever (68.2%), and chill (72.7%) with greater prevalence. We decreased the dose of immunosuppression and started stress dose of intravenous hydrocortisone or equivalent oral prednisolone. Each patient received antiviral therapy based on the latest updated version of local protocol at the time of admission. CT scan findings in 90.9% of patients showed bilateral multifocal lesions. Acute kidney injury (AKI) was observed in 12 patients during hospitalization. Six patients died after a median of 12 days from admission (IQR, 1-21). CONCLUSIONS: In this small observational study, we observed high AKI occurrence and mortality rate in kidney transplant recipients with COVID-19.

Immunophenotypical Characterization of a Brazilian POIS (Post-Orgasmic Illness Syndrome) Patient: Adding More Pieces to Puzzle.

Post-orgasmic illness syndrome (POIS) is a rare condition characterized by post-ejaculatory symptoms. Here is reported the first Brazilian POIS patient. Immunological investigation did not confirm the previous hypothesis of a hypersensitivity reaction. Cell immunophenotyping comparing healthy individuals produced evidence of abnormalities not associated to clinical manifestations. The patient was submitted to specific immunotherapy with transient clinical response and was referred to a psychologist but did not demonstrate clinical improvement of symptoms. Therefore, etiology of POIS remains unclear.

Chilliness in Japanese middle-aged women is associated with anxiety and low n-3 fatty acid intake.

Objective: This cross-sectional study investigated chilliness, which is the most prevalent sexual-vasomotor symptom in middle-aged Japanese women.Methods: First-visit records of 475 Japanese women (age 40-65 years) enrolled in the health and nutrition education program at a menopause clinic were analyzed. Chilliness was estimated based on responses to the Menopausal Symptom Scale. Effects of age, menopausal status, body composition, cardiovascular parameters, resting energy expenditure, physical fitness, menopausal symptoms, lifestyle, and estimated daily intake of nutrients were assessed using a multivariate logistic regression analysis.Results: Severe chilliness was found in 28.4% of women. It was not related to age, menopausal status, body mass index, or body fat percentage. The anxiety subscale score of the Hospital Anxiety and Depression Scale was the sole background characteristic independently associated with severe chilliness (adjusted odds ratio, 1.09; 95% confidence interval, 1.04-1.15 per point). Daily intakes of vitamin D and n-3 fatty acids were significantly lower in women with severe chilliness. Daily intake of n-3 fatty acids was negatively associated with severe chilliness after adjustment (odds ratio, 0.54; 95% confidence interval, 0.29-0.95 per g/1000 kcal intake).Conclusions: Chilliness is associated with anxiety and low intake of n-3 fatty acids.

Case report: one case of coronavirus disease 2019 (COVID-19) in a patient co-infected by HIV with a normal CD4+ T cell count.

BACKGROUND: The COVID-19 has been a severe pandemic all around the world. Nowadays the patient with co-infection of HIV and SARS-CoV-2 was rarely reported. Here we reported a special case with HIV and SARS-CoV-2 co-infection, which showed a prolonged viral shedding duration. CASE PRESENTATION: The patient was infected with HIV 8 years ago through sexual transmission and had the normal CD4+T cell count. She was found SARS-CoV-2 positive using real-time Polymerase Chain Reaction (RT-PCR) during the epidemic. Most importantly, the patient had a prolonged viral shedding duration of SARS-CoV-2 about 28 days. CONCLUSION: The viral shedding duration may be prolonged in people living with HIV. The 14 days isolation strategy might not be long enough for them. The isolation or discharge of these patients needs further confirmation for preventing epidemics.

Decision rule to predict pneumonia in children presented with acute febrile respiratory illness.

BACKGROUND: It is a frequent challenge for physicians to identify pneumonia in patients with acute febrile respiratory symptoms, particularly in stable pediatric patients without respiratory distress. A decision rule is required to assist judgement on the need of ordering a chest radiograph. METHOD: This was a multicenter prospective study in 3 emergency departments. Children younger than 6 years old with an acute onset of fever and respiratory symptoms were recruited. Split sample method was adopted for derivation and validation of the Pediatric Acute Febrile Respiratory Illness rule (PAFRI Rule). PAFRI was derived from logistic regression with weighting based on adjusted odds ratios. RESULTS: Out of 967 children evaluated, 530 had taken chest radiograph examination, with 91 demonstrated evidence of pneumonia on radiograph. PAFRI Rule was derived from logistic regression with 5 weighed predictors: duration of fever <3 days (0 points), 3-4 days (2 points), 5-6 days (4 points), ≥7 days (5 points), chills (2 points), nasal symptoms (-2 points), abnormal chest examination (3 points), SpO2 ≤96% or tachypnea (3 points). The Area under ROC curve of the PAFRI Rule, the Bilkis Decision Rule and Bilkis Simpler Rule were 0.733, 0.600 and 0.579 respectively. A PAFRI score of ≥0 gives a sensitivity of 91.7% and negative predictive value of 97.7%. CONCLUSION: PAFRI rule can be used as a reference tool for guiding the need for taking Chest radiograph examination for pediatric patients. While promising, the PAFRI rule requires further validation. WHAT'S KNOWN ON THIS SUBJECT: It is often a challenge for physicians to identify pneumonia in children acutely febrile with respiratory symptoms, particularly in those who are stable without respiratory distress. The decision to order chest radiograph was based on clinical assessment with heterogenous practice. A valid and verified clinical prediction rule for ordering chest radiograph examination for stable febrile children without signs of respiratory distress would therefore assist in management of this group of patients. WHAT THIS STUDY ADDS: The PAFRI rule, based on parameters from clinical bedside assessment, can be used as a reference tool for guiding the need for referral to emergency department or taking use of chest radiograph for pediatric patients, and triaging for higher priority of clinical care.

Unique manifestations and risk factors of Jarisch-Herxheimer reaction during treatment of child congenital syphilis.

OBJECTIVES: The objective of this retrospective study was to summarise the clinical manifestations of, and to analyse the incidence and risk factors of, Jarisch-Herxheimer reaction (JHR) during the treatment of children with symptomatic congenital syphilis. METHODS: Clinical data of 60 children with clinically and laboratory diagnosed congenital syphilis, hospitalised in Beijing Ditan Hospital between January 2010 and November 2015, were collected and analysed. RESULTS: A total of 11 patients with congenital syphilis (11/60, 18.3%) developed JHR. JHR occurred in 1-6 hour after the first dose of penicillin. Common clinical manifestations included fever (11/11, 100%), irritability (11/11, 100%), rapid pulse and breathing (11/11, 100%), exacerbation of existing rash (5/11, 45.6%) and chills (3/11, 27.3%). Of the 11 patients who developed JHR, 9 patients (9/11, 81.8%) had bone syphilis, 10 (10/11, 90.9%) had more than three organs affected by syphilis and 10 (10/11, 90.9%) had a high plasma concentration of rapid plasma reagin (RPR) (≥1:256); these percentages were significantly higher than in patients who had not developed JHR (p<0.05), suggesting that the occurrence of JHR was related to bone syphilis, having more than three organs affected by syphilis and a high plasma concentration of RPR. CONCLUSIONS: Clinicians should be familiar with the risk factors for this reaction and its common clinical manifestations.

Pertuzumab and trastuzumab infusion related cytokine release syndrome in a chemotherapy naive patient with metastatic breast cancer.

Pertuzumab is a monoclonal antibody that targets and down regulates HER-2/neu expression in ductal breast tumors. Other HER-2/neu monoclonal antibodies, particularly trastuzumab, have been implicated to induce infusion related reactions such as cytokine release syndrome (CRS). Here, we report a case of pertuzumab associated CRS prior to infusion of trastuzumab which warranted hospitalization for symptom management.

The Jarisch-Herxheimer reaction in syphilis: could molecular typing help to understand it better?

OBJECTIVES: The Jarisch-Herxheimer reaction (JHR) is a febrile inflammatory reaction that may occur in patients after treatment of syphilis. The overall rate is estimated to be 10-25% with broad variations over time. It appears to be related to factors like stage of the disease or reagin titres. In this study, we aimed to describe the incidence of and risk factors including strain typing for JHR among patients with syphilis. METHODS: From January through October 2015, 224 consecutive patients (82 of them with HIV) who were diagnosed with early syphilis were enrolled in this prospective observational study in a referral STI clinic in Barcelona. An appointment was offered to them after 10-14 days of treatment to inquire about the reaction with the use of a standardized form. Treponema pallidum molecular typing was made to detect a possible strain related to reaction. RESULTS: Overall, 28% of patients developed JHR. This varied from 56% in secondary, 37% in primary to 7% in early latent syphilis. The most frequent types of reaction were fever (57.5%) and worsening of the lesions (31%). The median time to development of JHR was 6 h [IQR 4-10 h] and lasted a median of 9 h [IQR 4-24 h]. The JHR was less probable in early latent compared to primary/secondary syphilis (P = 0.04) and in patients treated with doxycycline compared to those treated with penicillin (P = 0.01). No differences were seen regarding reagin titres or HIV status, and no association with a specific strain was found. CONCLUSIONS: In this study, JHR occurred in a similar frequency as in other contemporary studies. Symptomatic syphilis and treatment with penicillin were associated with an increased risk of JHR, whereas the previous episode of syphilis was associated with a low risk of it. We could not find associations with specific strains of T. pallidum.

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.

BACKGROUND: Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. METHODS: This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0-1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed. FINDINGS: Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3-4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95-99 h (3·9-4·1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. INTERPRETATION: Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. FUNDING: National Cancer Institute and Merck KGaA.