Adverse Events Following SARS-CoV-2 mRNA Vaccination in Adolescents: A Norwegian Nationwide Register-Based Study (preprint)

BackgroundVaccination of older adolescents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in the spring of 2021 and continued with younger adolescents throughout the summer and fall. We assessed risks of adverse events following immunization (AEFI) in adolescents aged 12-19 years following SARS-CoV-2 vaccination with a messenger RNA (mRNA) vaccine in Norway. Materials and MethodsThe study sample included 496,432 adolescents born in 2002-2009, residing in Norway, and unvaccinated against SARS-CoV-2 at the beginning of the age-specific waves of vaccination in 2021. The exposures under study were first- and second-dose SARS-CoV-2 mRNA vaccinations vs. no dose. We applied Poisson regression and self-controlled case series (SCCS) analysis to estimate incidence rate ratios (IRRs) of 17 preselected outcomes, with associated 95% confidence intervals (CIs), between vaccinated and unvaccinated subjects using predefined post-vaccination risk windows. ResultsMost outcome-specific numbers of cases were low. There were no statistically significant associations between first-dose vaccination and any of the outcomes. In the main Poisson regression, second-dose vaccination was associated with increased risks of anaphylactic reaction (adjusted IRR [aIRR]: 10.05; 95% CI: 1.22-82.74), lymphadenopathy (aIRR: 2.33; 95% CI: 1.46-3.72), and myocarditis and pericarditis (aIRR: 5.27; 95% CI: 1.98-14.05). We also observed increased incidence of acute appendicitis outside the 14-day risk window. When expanding the risk window to 42 days in a post-hoc analysis, there was increased incidence of acute appendicitis following both first-dose vaccination (aIRR: 1.39; 95% CI: 1.09-1.78) and second-dose vaccination (aIRR: 1.43; 95% CI: 1.07-1.91). Results of the SCCS analysis were similar to the Poisson regression. ConclusionsIn general, potential AEFI were rare among adolescents. We found increased risks of anaphylactic reaction, lymphadenopathy, and myocarditis and pericarditis following second-dose vaccination. There were also indications of increased acute appendicitis risk when applying longer risk windows.

No evidence that analgesic use after COVID-19 vaccination negatively impacts antibody responses (preprint)

Vaccines against SARS-CoV-2, the virus that causes COVID-19, showed high efficacy against symptomatic illness caused by the ancestral strain. Yet recent variants such as Omicron and its sublineages substantially escape vaccine-induced neutralizing antibodies. In response, bivalent mRNA booster vaccines updated to better match the BA.4-5 lineages have been made available. Yet the reactogenicity of these vaccines might negatively impact willingness to receive the booster immunization. While serious side effects following vaccination are rare, mRNA vaccines frequently lead to mild adverse events such as injection site pain, lymphadenopathy, myalgia, and fever. Over-the-counter analgesics might mitigate some of these mild adverse events, but animal models of SARS-CoV-2 infection have shown that non-steroidal anti-inflammatory drugs (NSAIDs) substantially reduce antiviral antibody responses, which are the best correlates of protection against COVID-19. It remains unknown whether these same inhibitory effects are seen in humans after mRNA vaccination. We surveyed 6,010 individuals who received COVID-19 vaccines regarding analgesic use and correlated these results with Spike-specific antibody levels. We found no negative impact of analgesic use on antibody levels, and in fact observed slightly elevated concentrations of anti-Spike antibodies in individuals who used painkillers. Logistic regression analyses demonstrated a higher proportion of those experiencing fatigue and muscle aches between NSAID users and those not taking pain medication, suggesting that the elevated antibody levels were likely associated with inflammation and mild adverse events rather than analgesic use per se. Together, our results suggest no detriment to painkiller use to alleviate symptoms after vaccination against COVID-19.

HIV-ASSOCIATED TUBERCULOSIS Type of Publication: Case Report (preprint)

A 22 year old adult male shifted from Congo 2 months ago presented to the Emergency Department with complaints of having a fever for the last three weeks. The fever was associated with chills and sweating, and occasional dizziness. Two weeks later, the man developed a cough, which was productive and caused him to develop shortness of breath with its onset. The patient’s overall condition rendered him appetite less, with a poor-quality oral intake of food and fluids. His COVID19 PCR came out negative, and he had no contact with a positive patient.Further history revealed that the patient had developed Malaria a long time ago and was prophylactically treated for it. He is a non-smoker yet occasionally drinks alcohol. His chest x-ray revealed patchy consolidations in the middle and lower zones of the left lung, whereas the chest CT revealed mediastinal lymphadenopathy and air bronchograms. His sputum for AFB and Rapid

Patients Recently Treated for B-lymphoid Malignancies Show Increased Risk of Severe COVID-19.

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non-B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non-recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19. SIGNIFICANCE: Our study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies. This article is highlighted in the In This Issue feature, p. 171.

Association of Lung Fibrotic Changes and Cardiological Dysfunction with Hypertension in Long COVID-19 cohort (preprint)

Background. Long COVID-19 symptoms appeared in many COVID-19 survivors. However, the prevalence and symptoms associated with long COVID and its comorbidities have not been established. Methods. Between May and September 2020 we included 312 patients with post-COVID-19 from 21 primary care centers if they had any persistent symptoms for at least three months from the first onset of the disease. On the 6 months follow up, their lung function was assessed by CT and spirometry, whereas cardiac function was assessed by electrocardiogram (ECG), Holter ECG, Echocardiography, and 24-hour blood pressure monitoring. A six-minute test (6MWT) was conducted on 308 participants during the follow-up visit. All participants were given a questionnaire with items on demographic information, current complaints, comorbidities, and medications, and Chalder Fatigue Scale (CFS) questionnaire. Statistical analysis was done using R vs. 4.1.2. Two-group comparison of continuous variables was performed using a T-test for normally distributed data, and the Mann-Whitney Wilcoxon test, ANOVA, and Kruskal-Wallis tests were applied for multiple comparisons following with Tukey and Dunn tests as post-hoc methods. Hochberg p-value adjustment was used to reduce the false discovery rate during multiple comparisons. Categorical variables were analyzed with Fishers Exact test. Results. Of 312 persons investigated, there was no significant gender difference between post-COVID-19 clinical manifestations except for memory dysfunction and anxiety, more prevalent among female participants. Chalder Fatigue Score was predominant in female participants (243, 78%). 39 (12.5%) participants reported having type 2 diabetes mellitus, and 158 (50.64%) had hypertension. Among the tested parameters, those positively correlated with comorbid conditions include age, BMI, D-dimers, NT-proBNP, C-reactive protein, neutrophils, fasting glucose, and HbA1c; hypertension also shows three associations that were not found in patients when examining the role of diabetes: increased hemoglobin, fibrinogen, and ferritin. 24-hour blood pressure monitoring revealed significantly higher systolic and diastolic blood pressure, left ventricular hypertrophy, and elevated NT-proBNP in participants with hypertension and subjects with type 2 diabetes. Left ventricular diastolic dysfunction is more frequently present in patients with hypertension. Chest CT was conducted on 227 (72.8%) participants 5.8+/-0.9 months after the onset of COVID-19. The most common registered CT abnormality was chronic bronchitis (198, 87.2%), followed by fibrotic changes in (83, 36.6%) and mediastinal lymphadenopathy (23, 10.1%). Immunological test results showed that SARS-CoV19 IgG antibodies were present in 241 subjects (77.2%), and SARS-CoV19 IgM antibodies were present in 9 subjects (2.88%). Conclusions. Our study provides valuable clues for long-term post-sequelae in a cohort of the Long COVID-19 subjects. We demonstrated a strong association of signs of cardiac dysfunction, lung fibrotic changes, increased hemoglobin, fibrinogen, and ferritin with hypertension but not with other comorbidities. Our results are of importance for understanding the Long Covid-19 syndrome.

Radiological Imaging of Viral Pneumonia Cases Identified Before the COVID-19 Pandemic Period and COVID-19 Pneumonia Cases Comparison of Characteristics (preprint)

Background: Thoracic CT imaging is widely used as a diagnostic method in the diagnosis of COVID-19 pneumonia. Radiological differential diagnosis and isolation of other viral agents causing pneumonia in patients gained importance, especially during the pandemic period. Aims: We aimed to investigate whether there is a difference between the CT imaging findings characteristically defined in COVID-19 pneumonia and the findings detected in pneumonia due to other viral agents, and which finding may be more effective in the diagnosis. Study Design: The study included 249 adult patients with pneumonia found in thorax CT examination and positive COVID-19 RT-PCR test and 94 patients diagnosed with non-COVID pneumonia (viral PCR positive, no bacterial/fungal agents were detected in other cultures) from the last 5 years before the pandemic. It was retrospectively analyzed using the PACS System. CT findings were evaluated by two radiologists with 5 and 20 years of experience who did not know to which group the patient belonged, and it was decided by consensus. Methods: Demographic data (age, gender, known chronic disease) and CT imaging findings (percentage of involvement, number of lesions, distribution preference, dominant pattern, ground-glass opacity distribution pattern, nodule, tree in bud sign, interstitial changes, crazy paving sign, reversed halo sign, vacuolar sign, halo sign, vascular enlargement, linear opacities, traction bronchiectasis, peribronchial wall thickness, air trapping, pleural retraction, pleural effusion, pericardial effusion, cavitation, mediastinal/hilar lymphadenopathy, dominant lesion size, consolidation, subpleural curvilinear opacities, air bronchogram, pleural thickening) of the patients were evaluated. CT findings were also evaluated with the RSNA consensus guideline and the CORADS scoring system. Data were divided into two main groups as non-COVID-19 and COVID-19 pneumonia and compared statistically with chi-square tests and multiple regression analysis of independent variables. Results: Two main groups; RSNA and CORADS classification, percentage of involvement, number of lesions, distribution preference, dominant pattern, nodule, tree in bud, interstitial changes, crazy paving, reverse halo vascular enlargement, peribronchial wall thickness, air trapping, pleural retraction, pleural/pericardial effusion, cavitation and mediastinal/hilar lymphadenopathy were compared, significant differences were found between the groups (p < 0.01). Multiple linear regression analysis of independent variables found a significant effect of reverse halo sign ({beta} = 0.097, p <0.05) and pleural effusion ({beta} = 10.631, p <0.05) on COVID-19 pneumonia. Conclusion: Presence of reverse halo and absence of pleural effusion was found to be efficient in the diagnosis of COVID-19 pneumonia.

Presence of Mediastinal Lymphadenopathy in Hospitalized Covid-19 Patients in a Tertiary Care Hospital in Pakistan - A cross-sectional study (preprint)

BackgroundThe aim of this study was to investigate the presence of mediastinal lymphadenopathy in hospitalized Covid-19 patients in a tertiary care hospital in the metropolitan city of Lahore, Pakistan from September 2020 till July 2021. MethodsWe retrospectively collected data of Covid-19 patients hospitalized from September 2020 till July 2021. Only those patients who tested PCR positive through a nasopharyngeal swab, were enrolled in the study. Patients whose data were missing were excluded from this study. Our exclusion criteria included patients who tested negative on Covid-19 PCR, patients with comorbidities that may cause enlarged mediastinal lymphadenopathies such as haemophagocytic lymphohistiocytosis, neoplasia, tuberculosis, sarcoidosis or a systemic disease. The extent of lung involvement in Covid-19 patients was quantified by using a 25-point visual quantitative assessment called the Chest Computed Tomography Score. This score was then correlated with the presence of mediastinal lymphadenopathy. FindingsOf the 210 hospitalized patients included in the study, 131 (62.4%) had mediastinal lymphadenopathy. The mean and median Severity Score of Covid-19 patients with mediastinal lymphadenopathy (mean: 17.1, SD:5.7; median: 17, IQR: 13-23) were higher as compared to those without mediastinal lymphadenopathy (mean: 12.3, SD:5.4; median: 12, IQR:9-16) InterpretationOur study documents a high prevalence of mediastinal lymphadenopathy in hospitalized patients with Covid-19 with the severity score being higher in its presence representing a more severe course of disease.

Challenging Axillary Lymph-Nodes on F-18-FDG, F-18-Choline and Ga-68-DOTATOC PET/CT in Cancer Patients throughout Covid-19 Vaccination Era (preprint)

Objectives: unexpected detection of axillary lymphadenopathy (AxL) in cancer patients (Pts) represents a real concern during COVID-19 vaccination era. Benign reactions may take place after vaccine inoculation, confounding image interpretation in patients undergoing F-18-FDG, F-18-Choline and Ga-68-DOTATOC PET/CT. It may simulate loco-regional metastases/disease. To assess PET/CT findings after COVID-19 vaccination in cancer patients and the consequent impact on their management. Methods: we evaluated 333 patients undergoing PET/CT (257 F-18-FDG, 54 F-18-Choline and 23 Ga-68 DOTATOC) scans after first vaccination with mRNA vaccine (Pfizer-BioNTech). Uptake index (SUVmax) of suspected AxL was defined significant when the ratio >1.5 as compared to the contralateral inoculation site. Besides, co-registered CT (Co-CT) features of target lymph-nodes were evaluated. Nodes with aggregate positivity were further investigated. Results: overall, the prevalence of apparently positive lymph-nodes on PET scans was 17.1% during vaccination era. 107 Pts had undergone PET/CT before COVID-19 pandemic and only 3 shown reactive lymph-nodes with a prevalence of 2.8% (p<0.001 as compared to vaccination era). 84.2% exhibited benign characteristics on Co-CT images and only 9 Pts needed additional appraisal. Conclusions: the correct interpretation of images is crucial to avoid unnecessary management changes and to rule out invasive procedures in cancer Pts undergoing diagnostics. An accurate anamnestic interview and the precise assessment of nodes’ Co-CT characteristics when performing PET/CT may help to address the diagnostic hypothesis.

Comparative Study of HRCT Imaging Characteristics of Psittaci Pneumonia and COVID-19 Pneumonia (preprint)

Backgroud : Both Chlamydia psittaci and COVID-19 virus can cause lung inflammation, which manifests extremely similarly in clinical symptoms and imaging. Especially during the epidemic of COVID-19, psittacosis pneumonia is easily misdiagnosed as COVID-19 pneumonia. The identification of the chest imaging between the two diseases is of special significance when the epidemiological contact history is unclear, and the etiology and nucleic acid test results are not available. This study conducts to compare the imaging characteristics on chest high-resolution CTs (HRCT) between patients with psittaci pneumonia and COVID-19 pneumonia. Methods: : A retrospective analysis of the imaging characteristics on chest HRCTs of 10 psittaci pneumonia patients and 13 COVID-19 pneumonia patients. The similarities and differences in HRCT images of patients with psittaci pneumonia and COVID-19 pneumonia were analyzed. Results: : HRCT showed that among the 10 psittaci pneumonia patients, 8 cases (80.00%) had single lobe involvement, and 2 cases (20.00%) had multiple lobe involvement. Among the 13 COVID-19 pneumonia patients, 2 cases had single lobe involvement (15.38%), and 11 cases had multiple lobe involvement (84.62%). The types of lesions in 10 psittaci pneumonia patients included simple consolidation in 5 cases (50.00%), and ground-glass opacity (GGO) with consolidation in 5 cases (50.00%). The types of lesions in 13 COVID-19 pneumonia patients included simple GGO in 6 cases (46.15%), GGO with consolidation in 4 cases (30.77%), GGO with paving stone sign in 2 cases (15.38%), and simple consolidation in 1 case (7.69%). Lymphadenopathy was observed in 1 psittaci pneumonia patient (10.00%) and 1 COVID-19 pneumonia patient (7.69%). Among the 10 psittaci pneumonia patients, 8 cases (80.00%) had bronchial inflation, and 6 patients (60.00%) had pleural effusion. Among the 13 COVID-19 pneumonia patients, 5 patients (38.46%) showed signs of bronchial inflation, while no pleural effusion was observed in 13 patients. Conclusion: : Chest HRCTs can distinguish COVID-19 pneumonia from psittaci pneumonia, and can provide early diagnoses of these two diseases.

Axillary Adenopathy Secondary to SARS-CoV-2 Vaccination: a Case Report (preprint)

Introduction: SARS-CoV-2 mRNA vaccines are safe and effective for the prevention of COVID-19 infection, though local reactions are commonly reported. Axillary lymphadenopathy has also been reported, which has the potential of causing diagnostic confusion and unnecessary testing and procedures. Case Description: A 58 year-old female with untreated latent tuberculosis was noted to have a pulmonary nodule on chest radiograph. Evaluation for Mycobacterium tuberculosis was undertaken, and a FDG PET/CT was performed to rule out malignancy. While the nodule demonstrated low avidity, highly avid lymph nodes were noted in the left axillary region. Further questioning elicited a recent history of mRNA-1273 (Moderna) COVID-19 vaccination in her left deltoid muscle three weeks prior, and a sensation of axillary fullness. She was managed conservatively with spontaneous resolution of her lymphadenopathy. Conclusions: Axillary lymphadenopathy following mRNA vaccination has been reported, and appears to be more common with mRNA-1273 (Moderna) than BNT162b2 vaccine (Pfizer-BioNTech), in those aged 18 to 64 as compared to age ≥65, and following the second vaccine dose compared to the first dose. Vaccination should be considered in the differential diagnosis of axillary lymphadenopathy, particularly ipsilateral to the vaccination site, to avoid unnecessary testing, treatment, and patient anxiety.

Performances of Clinical Characteristics and Radiological Findings in Identifying COVID- 19 From Suspected Cases (preprint)

Background: To identify effective factors and establish a model to distinguish COVID-19 patients from suspected cases. Methods: : The clinical characteristics, laboratory results and initial chest CT findings of suspected COVID-19 patients in 3 institutions were retrospectively reviewed. Univariate and multivariate logistic regression were performed to identify significant features. A nomogram was constructed, with calibration validated internally and externally. Results: : 239 patients from 2 institutions were enrolled in the primary cohort including 157 COVID-19 and 82 non-COVID-19 patients. 11 features were included for multivariate logistic regression analysis after LASSO selection. We found that the COVID-19 group are more likely to have fever (OR, 4.22), contact history (OR, 284.73), lower WBC count (OR, 0.63), left lower lobe involvement (OR, 9.42), multifocal lesions (OR, 8.98), pleual thickening (OR, 5.59), peripheral distribution (OR, 0.09), and less mediastinal lymphadenopathy (OR, 0.037). The nomogram developed accordingly for clinical practice showed satisfactory internal and external validation. Conclusions: : In conclusion, fever, contact history, decreased WBC count, left lower lobe involvement, pleural thickening, multifocal lesions, peripheral distribution and absence of mediastinal lymphadenopathy are able to distinguish COVID-19 patients from other suspected patients. The corresponding nomogram is a useful tool in clinical practice.

Three doses of COVID-19 mRNA vaccination are safe based on adverse events reported in electronic health records (preprint)

Recent reports on waning of COVID-19 vaccine induced immunity have led to the approval and roll-out of additional dose and booster vaccinations. At risk individuals are receiving additional vaccine dose(s), in addition to the regimen that was tested in clinical trials. The risks and the adverse event profiles associated with these additional vaccine doses are currently not well understood. Here, we performed a retrospective study analyzing vaccine-associated adverse events using electronic health records (EHRs) of individuals that have received three doses of mRNA-based COVID-19 vaccines (n = 47,999). By comparing symptoms reported in 2-week time periods after each vaccine dose and in a 2-week period before the 1st vaccine dose, we assessed the risk associated with 3rd dose vaccination, for both BNT162b2 and mRNA-1273. Reporting of severe adverse events remained low after the 3rd vaccine dose, with rates of pericarditis (0.01%, 0%-0.02% 95% CI), anaphylaxis (0.00%, 0%-0.01% 95% CI), myocarditis (0.00%, 0%-0.01% 95% CI), and cerebral venous sinus thrombosis (no cases), consistent with earlier studies. Significantly more individuals (p-value < 0.05) report low-severity adverse events after their 3rd dose compared with after their 2nd dose, including fatigue (4.92% after 3rd dose vs 3.47% after 2nd dose), lymphadenopathy (2.89% vs 2.07%), nausea (2.62% vs 2.04%), headache (2.47% vs 2.07%), arthralgia (2.12% vs 1.70%), myalgia (1.99% vs 1.63%), diarrhea (1.70% vs 1.24%), fever (1.11% vs 0.81%), vomiting (1.10% vs 0.80%), and chills (0.47% vs 0.36%). Our results show that although 3rd dose vaccination against SARS-CoV-2 infection led to increased reporting of low-severity adverse events, risk of severe adverse events remained comparable to the standard 2-dose regime. This study provides support for the safety of 3rd vaccination doses of individuals that are at high-risk of severe COVID-19 and breakthrough infection.

Isolated unilateral axillary lymphadenopathy diagnosed in a teenager by ultrasonography after BNT162b2 COVID-19 vaccination (preprint)

Axillary lymphadenopathy is a local reaction to mRNA COVID-19 vaccination. A 19-year-old healthy woman presented with a mass in the axilla diagnosed by ultrasonography as vaccine-induced hyperreactive lymphadenopathy. After two weeks, ultrasonography revealed that the lymph node had shrunk and that the blood flow signal in the hilum had disappeared.

A Sigh of Relief: Vaccine-Associated Hypermetabolic Iymphadenopathy Following the Third Covid-19 Vaccine Dose is Short in Duration and Uncommonly Interferes with the Interpretation of [18F]FDG PET-CT Studies Performed in Oncologic Patients (preprint)

Purpose: The incidence of Covid-19 vaccine-associated hypermetabolic lymphadenopathy (VAHL) is high following the administration of the first and second BNT162b2 vaccine doses. The impact of this finding on [ 18 F]FDG PET-CT interpretation and its correlation with the induced humoral immunity have been reported. Assuming the amnestic immune response is different following the third vaccine dose, we aimed to explore the incidence of VAHL over time after the third BNT162b2 dose administration, and its relevance to [ 18 F]FDGPET-CT interpretation in oncologic patients. Methods: : A total of 179 consecutive oncologic patients that underwent [ 18 F]FDG PET-CT after a third BNT162b2 vaccine dose were included. The presence of VAHL was assessed. On VAHL-positive scans, the SUVmax, number, location and size of the“hot” nodes were recorded. The median time interval between vaccination and imagingwas 8 (IQR,5-14) days. Results: : The incidences of all-grade VAHL and grade 3-4 VAHL were 47.5% and 8.9%,respectively. VAHL was identified on 82.5% of studies performed within the first 5 days from vaccination. Grade 3-4 VAHL was observed on 28.1% of studies performed within the first 5 days from vaccination, but was not detected on studies performed more than 5 days from vaccination. Separation between VAHL and malignant lymphadenopathy was not possible in only 2 of the 179 study patients. On a multivariable logistic regression, independent predictors of grade 3-4 VAHL were short time interval between vaccination and imaging (Pv<0.01), younger age (Pv<0.01) and lower BMI (Pv=0.03). Conclusion: VAHL is commonly identifiedon [ 18 F]FDG PET-CT performed within the first 5 days from the third BNT162b2 vaccine doseadministration. High-grade VAHL is unlikely to be observed on a scan performed 6 days or longer from vaccination, and is even less likely in older and obese patients.

Supraclavicular Lymphadenitis Following COVID-19 (preprint)

IntroductionCervical lymphadenopathy in children is a common problem in daily clinical practice. Many cases of cervical lymphadenopathy after the COVID-19 vaccine were reported. However, there is no yet reporting a case of supraclavicular cervical lymphadenopathy as a result of COVID-19.Case presentationA 12-years-old girl presented with fever, cough, fatigue, anosmia, and ageusia. COVID-19 was confirmed by real-time PCR. The symptoms were resolved within 10 days. After 7 days, she complained of supraclavicular swelling. Physical examination revealed painless, multiple, and mobile supraclavicular lymph nodes. Ultrasound and fine-needle aspiration cytology were suspicious. Therefore, an excisional biopsy of the largest node was performed. The specimen was sent for histopathology and immunohistochemistry evaluation which confirmed the benign nature of the lymph node.ConclusionTo our best knowledge, this is the first case of supraclavicular lymphadenopathy in a child with COVID-19. It is essential to put COVID-19 in the differential diagnosis of cervical lymphadenopathy.

Breastfeeding mother-child clinical outcomes after COVID-19 vaccination (preprint)

This is a prospective cohort study of 88 lactating women in Singapore who received two doses of BNT162b2 vaccination (Pfizer/BioNTech), whereby outcomes of mother-child dyads within 28 days after the second vaccine dose were determined through a structured questionnaire. Minimal effects related to breastfeeding were reported in this cohort; 3 of 88 (3.4%) women had mastitis with 1 of 88 (1.1%) women experiencing breast engorgement. We report an incidence of lymphadenopathy in our cohort at 5 of 88 (5.7%). Reassuringly, there was no change in reported breastmilk supply after vaccination. The most common side effect was pain/redness/swelling at the injection site, which was experienced by 57 of 88 (64.8%) women. There were no serious adverse events of anaphylaxis and hospital admissions. No adverse symptoms were reported in 67 of 88 (76.1%) breastfed children.

Female-Male Differences in COVID Vaccine Adverse Events Have Precedence in Seasonal Flu Shots: A Potential Link to Sex-Associated Baseline Gene Expression Patterns (preprint)

Nearly 150 million doses of FDA-authorized COVID vaccines have been administered in the United States. Sex-based differences of adverse events remain poorly understood, mandating the need for real-world investigation from Electronic Health Records (EHRs) and broader epidemiological data sets. Based on an augmented curation of EHR clinical notes of 31,064 COVID-vaccinated individuals (19,321 females and 11,743 males) in the Mayo Clinic, we find that nausea and vomiting were documented significantly more frequently in females than males after both vaccine doses (nausea: RRDose 1 = 1.67, pDose 1 <0.001, RRDose 2 = 2.2, pDose 1 < 0.001; vomiting: RRDose 1 = 1.58, pDose 1 < 0.001, RRDose 2 = 1.88, pDose 1 = 3.4x10-2). Conversely, fever, fatigue, and lymphadenopathy were more common in males after the first dose vaccination (fever RR = 0.62; p = 8.65x10-3; fatigue RR = 0.86, p = 2.89x10-2; lymphadenopathy RR = 0.61, p = 3.45x10-3). Analysis of the Vaccine Adverse Events Reporting System (VAERS) database further confirms that nausea comprises a larger fraction of total reports among females than males (RR: 1.58; p<0.001), while fever comprises a larger fraction of total reports among males than females (RR: 0.84; p<0.001). Importantly, increased reporting of nausea and fever among females and males, respectively, is also observed for prior influenza vaccines in the VAERS database, establishing that these differences are not unique to the recently developed COVID-19 vaccines. Investigating the mechanistic basis underlying these clinical findings, an analysis of bulk RNA-sequencing data from 12,158 human blood samples (8626 female, 3532 male) reveals 85 genes that are not only significantly different in their gene expression between females and males at baseline, but also have established literature-based associations to COVID-19 as well as the vaccine-related adverse events of clinical consequence. The NLRP3 inflammasome and the NR3C1 glucocorticoid receptor emerge as particularly promising baseline links to sex-associated vaccine adverse events, warranting targeted investigation of these signaling pathways and associated cell types. From a public health standpoint, our clinical findings shall aid in educating patients on the sex-associated risks they should expect for COVID-19 vaccines, and promote better clinical management of vaccine-associated adverse events.Funding Statement: None to declare. Declaration of Interests: AJV, PK, ES, MS, RS, PL, EG, EL, and VS are employees of nference and have financial interests in the company and in the successful application of this research. JCO receives personal fees from Elsevier and Bates College, and receives small grants from nference, Inc, outside the submitted work. ADB is a consultant for Abbvie, is on scientific advisory boards for nference and Zentalis, and is founder and President of Splissen therapeutics. JCO, GJG, AWW, AV, MDS, and ADB are employees of the Mayo Clinic. The Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. All other authors have nothing to declare. Ethics Approval Statement: This study was reviewed by the Mayo Clinic Institutional Review Board (IRB) and determined to be exempt from the requirement for IRB approval (45 CFR 46.104d, category 4).

Female-male differences in COVID vaccine adverse events have precedence in seasonal flu shots: a potential link to sex-associated baseline gene expression patterns (preprint)

Nearly 150 million doses of FDA-authorized COVID vaccines have been administered in the United States. Sex-based differences of adverse events remain poorly understood, mandating the need for real-world investigation from Electronic Health Records (EHRs) and broader epidemiological data sets. Based on an augmented curation of EHR clinical notes of 31,064 COVID-vaccinated individuals (19,321 females and 11,743 males) in the Mayo Clinic, we find that nausea and vomiting were documented significantly more frequently in females than males after both vaccine doses (nausea: RRDose 1 = 1.67, pDose 1 <0.001, RRDose 2 = 2.2, pDose 1 < 0.001; vomiting: RRDose 1 = 1.58, pDose 1 < 0.001, RRDose 2 = 1.88, pDose 1 = 3.4x10-2). Conversely, fever, fatigue, and lymphadenopathy were more common in males after the first dose vaccination (fever RR = 0.62; p = 8.65x10-3; fatigue RR = 0.86, p = 2.89x10-2; lymphadenopathy RR = 0.61, p = 3.45x10-3). Analysis of the Vaccine Adverse Events Reporting System (VAERS) database further confirms that nausea comprises a larger fraction of total reports among females than males (RR: 1.58; p<0.001), while fever comprises a larger fraction of total reports among males than females (RR: 0.84; p<0.001). Importantly, increased reporting of nausea and fever among females and males, respectively, is also observed for prior influenza vaccines in the VAERS database, establishing that these differences are not unique to the recently developed COVID-19 vaccines. Investigating the mechanistic basis underlying these clinical findings, an analysis of bulk RNA-sequencing data from 12,158 human blood samples (8626 female, 3532 male) reveals 85 genes that are not only significantly different in their gene expression between females and males at baseline, but also have established literature-based associations to COVID-19 as well as the vaccine-related adverse events of clinical consequence. The NLRP3 inflammasome and the NR3C1 glucocorticoid receptor emerge as particularly promising baseline links to sex-associated vaccine adverse events, warranting targeted investigation of these signaling pathways and associated cell types. From a public health standpoint, our clinical findings shall aid in educating patients on the sex-associated risks they should expect for COVID-19 vaccines and also promote better clinical management of vaccine-associated adverse events.

Correlation Between BNT162b2 mRNA Covid-19 Vaccine-associated Hypermetabolic Lymphadenopathy and Humoral Immunity in Patients With Hematologic Malignancy (preprint)

Purpose: Vaccine-associated hypermetabolic lymphadenopathy (VAHL) is frequently observed on [ 18 F]FDG PET-CT following BNT162b2 administration. Recent data suggest a prominent B-cell germinal-center (GC) response elicited by mRNA vaccines in draining lymph nodes. Thus, in this study we aimed to explore the correlation between VAHL and humoral immunity as reflected by post-vaccination serologic testing, and by comparing the incidence of VAHL between lymphoma patients treated recently with B-cell depleting therapy and those that did not. Methods: : A total of 137 patients with hematologic malignancy that had post-vaccination [ 18 F]FDG PET-CT were included (All-PET group), 86 received both vaccine doses before imaging (PET-2 group). Their VAHL status and grade on imaging were recorded. Among 102 lymphoma patients, 34 (33.3%) were treated during the year prior vaccination with anti-CD20 antibody containing therapy. A subgroup of 54 patients also underwent serologic testing 2-3 weeks after the booster dose, and their anti-spike titers were recorded and graded as well. Results: : The overall incidence of VAHL in patients with hematologic malignancy was 31.4%. The 34 lymphoma patients treated during the year prior vaccination with anti-CD20 antibody containing therapy had significantly lower rates of VAHL comparted to all other lymphoma patients (8.8% versus 41.2% in all-PET patients, Pv < 0.01). VAHL rates were 10% in patients with negative serology, 31.3% in patients with low anti-spike titers and 72.2% in patients with high anti-spike titers. The positive predictive values of VAHL were 90% and 93.3% in all-PET and PET-2 patients, respectively. A positive statistically significant correlation was found between VAHL and serology ranks in All-PET patients (r s = 0.530, Pv < 0.001), and stronger correlation was found in PET-2 patients (r s = 0.642, Pv < 0.001). Conclusion: VAHL on [ 18 F]FDG PET-CT of patients with hematologic malignancy may reflect GC B-cell proliferation and an effective humoral response elicited by BNT162b2 vaccine.