Pseudo-Allergies in the Emergency Department: A Common Misdiagnosis of Hypersensitivity Type 1 Allergic Reaction.

Type-1 hypersensitivity reaction represents an acute IgE-mediated reaction that can cause life-threatening conditions, such as anaphylactic shock, angioedema, and airway obstruction. Other reactions that can mimic type-1 hypersensitivity reactions include IgE-independent mast cell degranulation, bradykinin-mediated reactions, leukotrienes-mediated reactions, and pseudo-allergies. We use the term pseudo-allergy in this article for histamine-mediated reactions that are mast cell-independent. We did not discuss pseudo-allergic reactions that are not acute or life-threatening, such as celiac disease, Heiner's syndrome, eosinophilic esophagitis, and food protein-induced enterocolitis in our article because the emergency department is not the primary location to diagnose or treat these reactions. Herein, we present some allergic-like reactions that can be life-threatening, such as scombroid food poisoning (SFP), bradykinin-induced angioedema, IgE-independent angioedema, opioid-induced angioedema, and non-steroidal anti-inflammatory drug (NSAID)-induced hypersensitivity and angioedema. These reactions may have different treatments based on their mechanism of reaction. Histamine-mediated reactions, such as SFP, histamine-mediated angioedema, and mast cell degranulation induced by NSAIDs, and opioids can be treated with antihistamines, epinephrine, and corticosteroids. Bradykinin-induced angioedema, including hereditary angioedema and acquired angioedema, can be treated with fresh frozen plasma. Hereditary angioedema can be treated with many FDA-approved targeted medications, such as plasma-derived C1-INH, plasma kallikrein inhibitor (Ecallantide), and selective bradykinin-2 receptor antagonist (Icatibant). However, these targeted agents are not well-studied enough to be used for acquired angioedema. It is crucial for emergency medicine physicians to be familiar with and predict these reactions to prevent misdiagnosis, be prepared to treat these life-threatening conditions appropriately without delay and eliminate patients' exposure to any unnecessary investigations or treatments.

Rethinking Immunological Risk: A Retrospective Cohort Study of Severe SARS-Cov-2 Infections in Individuals With Congenital Immunodeficiencies.

BACKGROUND: Debates on the allocation of medical resources during the coronavirus disease 2019 (COVID-19) pandemic revealed the need for a better understanding of immunological risk. Studies highlighted variable clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. OBJECTIVE: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. METHODS: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged 2 months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020, through March 31, 2022. Risks of hospitalization were assessed using a multivariable logistic regression analysis. RESULTS: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 4.50; 95% confidence interval [95% CI] 1.57-13.4), a diagnosis of any genetically defined immunodeficiency (OR 3.32; 95% CI 1.24-9.43), obesity (OR 4.24; 95% CI 1.38-13.3), and neurological disease (OR 4.47; 95% CI 1.44-14.3). The COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; 95% CI 0.31-0.81). Defects in T cell and innate immune function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. CONCLUSIONS: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunological risk factors for individuals with inborn errors of immunity.

PROMIS Physical Function and Pain Interference Scores Correlate with the Lower Extremity Toronto Extremity Salvage Score.

The Toronto Extremity Salvage Score (TESS) and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) are both utilized to measure patient-reported outcomes in adults with musculoskeletal oncologic conditions. However, the relationship between them has not been studied. We sought to describe a link between Lower Extremity (LE) TESS and PROMIS Physical Function (PF) scores, as well as between LE TESS and Pain Interference (PI) scores, to develop a method for converting scores between TESS and PROMIS and to examine whether TESS and PROMIS captured differences in pain and function between clinically relevant subgroups in our population. Methods: Our study population consisted of 125 adult patients who underwent surgical treatment of a lower-extremity musculoskeletal tumor at a single sarcoma center between December 2015 and October 2018. The LE TESS questionnaire was administered to patients via paper and the PROMIS PF and PI were administered via iPad at a preoperative appointment. The relationship between LE TESS and PROMIS measures was analyzed with use of generalized linear modeling. Subgroup analyses were performed with a 2-tailed t test or 1-way analysis of variance. Results: PROMIS PF had a very strong positive correlation with LE TESS (r = 0.83) and was related through the following equation: PROMIS PF = 0.00294 × (LE TESS)2 + 22.6. PROMIS PI had a strong negative correlation with LE TESS (r = -0.77) and was related through the following equation: PROMIS PI = -0.00259 × (LE TESS)2 + 73.8. PROMIS PF and PI performed similarly to LE TESS across multiple patient subgroups and captured the expected differences between subgroups. Conclusions: LE TESS and PROMIS PF appeared to measure similar information in patients with an orthopaedic oncologic condition. Moreover, PROMIS PI scores were strongly correlated with functional disability as measured with the LE TESS. Understanding the relationship between TESS and PROMIS will allow the comparison and combination of data for both clinical and research purposes. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Rethinking immunologic risk: a retrospective cohort study of severe SARS-CoV-2 infections in individuals with congenital immunodeficiencies.

Background: Debates on the allocation of medical resources during the COVID-19 pandemic revealed the need for a better understanding of immunologic risk. Studies highlighted variable clinical outcomes of SARS-CoV-2 infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. Objective: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. Methods: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged two months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020 through March 31, 2022. Risks of hospitalization was assessed using a multivariable logistic regression analysis. Results: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 5.29; confidence interval [CI], 1.76-17.0), a diagnosis of any genetically-defined immunodeficiency (OR 4.62; CI, 1.60-14.8), use of B cell depleting therapy within one year of infection (OR 6.1; CI, 1.05-38.5), obesity (OR 3.74; CI, 1.17-12.5), and neurologic disease (OR 5.38; CI, 1.61-17.8). COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; CI, 0.31-0.81). Defective T cell function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. Conclusions: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunologic risk factors for individuals with inborn errors of immunity. Highlights: What is already known about this topic? Outcomes of SARS-CoV-2 infections in individuals with inborn errors of immunity (IEI) are highly variable. Prior studies of patients with IEI have not controlled for race or social vulnerability. What does this article add to our knowledge ? For individuals with IEI, hospitalizations for SARS-CoV-2 were associated with race, ethnicity, obesity, and neurologic disease. Specific types of immunodeficiency, organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization. How does this study impact current management guidelines? Current guidelines for the management of IEIs focus on risk conferred by genetic and cellular mechanisms. This study highlights the importance of considering variables linked with social determinants of health and common comorbidities as immunologic risk factors.

Preoperative and Postoperative Patient-Reported Outcome Measurement Information System Scores in Patients Treated for Benign Versus Malignant Soft Tissue Tumors.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) assesses multiple aspects of patient well-being but has not been thoroughly studied amongst orthopedic oncology patients. QUESTIONS/PURPOSES: How do preoperative/early postoperative PROMIS scores compare in patients with benign versus malignant soft tissue tumors (STTs) for (1) physical function, (2) pain interference, and (3) depression? Are the differences clinically relevant? What other patient/tumor factors impact PROMIS? METHODS: This retrospective cohort study included 314 STT patients who underwent resection of a benign (n = 187) or malignant (n = 127) STT over a period of 4.25 years at a single institution. PROMIS physical function, pain interference, and depression scores were collected preoperatively and at two and six weeks postoperatively. Scores for each time point were compared between groups and to preoperative baselines. Backward-stepwise linear mixed-effects models were produced to identify independent predictors of change in each PROMIS domain. The minimal clinically important difference (MCID) was 4 points. RESULTS: The malignant cohort, but not the benign cohort, demonstrated clinically relevant worsening of physical function postoperatively. Malignant diagnosis (△ = -4.4, p < 0.001) and lower extremity tumors (△ = -4.5, p < 0.001) were identified as clinically relevant, independent predictors of worse physical function at all time points. No predictors of clinically relevant changes in pain interference or depression scores, including malignancy, were identified. CONCLUSIONS: In STT patients, malignancy and lower extremity STT location are associated with clinically relevant worsening in physical function but do not significantly impact pain interference or depression in the early postoperative period. These findings may help establish the utility of PROMIS in an orthopedic oncology population.

Patients With Metastatic Disease Are at Highest Risk for Anxiety and Depression in an Orthopedic Oncology Patient Population.

PURPOSE: Patients with cancer are at risk for anxiety and depression; however, the patterns and predictors of symptoms in an orthopedic oncology population have not been studied. METHODS: We retrospectively reviewed Patient-Reported Outcomes Measurement Information System scores of all adult patients who underwent palliative surgery for metastatic cancer, resection of a sarcoma, or nononcologic total joint arthroplasty at a single institution from 2015 to 2020. Backward stepwise linear regression was used to determine risk factors for perioperative anxiety and depression. RESULTS: Postoperative anxiety and depression were more prevalent in patients with metastatic disease than localized cancer or nononcologic conditions (P < .001 and P < .001, respectively). Worse preoperative pain and function were associated with higher preoperative anxiety (ß = .321, P = .001; ß = -.236, P = .012, respectively) and depression (ß = .245, P = .009; ß = -.279, P = .003, respectively). Worse preoperative anxiety, preoperative depression, and postoperative pain were associated with higher postoperative anxiety (ß = .204, P = .012; ß = .260, P = .001; ß = .447, P < .001, respectively). Worse preoperative depression and postoperative pain also predicted higher postoperative depression (ß = .542, P < .001; ß = .325, P < .001, respectively). CONCLUSION: Anxiety and depression were most prevalent in patients with metastatic disease. Compared with total joint arthroplasty patients, patients with cancer less frequently experienced postoperative improvements in anxiety and depression. Worse preoperative pain and function were independently associated with greater preoperative anxiety and depression. Providers should maintain awareness of the relationship between mental and physical health to optimize outcomes.

Inborn Errors of the Immune System Associated With Atopy.

Atopic disorders, including atopic dermatitis, food and environmental allergies, and asthma, are increasingly prevalent diseases. Atopic disorders are often associated with eosinophilia, driven by T helper type 2 (Th2) immune responses, and triggered by disrupted barrier function leading to abnormal immune priming in a susceptible host. Immune deficiencies, in contrast, occur with a significantly lower incidence, but are associated with greater morbidity and mortality. A subset of atopic disorders with eosinophilia and elevated IgE are associated with monogenic inborn errors of immunity (IEI). In this review, we discuss current knowledge of IEI that are associated with atopy and the lessons these immunologic disorders provide regarding the fundamental mechanisms that regulate type 2 immunity in humans. We also discuss further mechanistic insights provided by animal models.

Depression Is Transiently Increased in Patients Undergoing Two-Stage Revision Arthroplasty.

BACKGROUND: The implications of two-stage revision on mental health are poorly understood. The purpose of this study is to determine (1) whether patients undergoing two-stage revision total hip and knee arthroplasty for prosthetic joint infection were more likely to get Patient-Reported Outcomes Measurement Information System (PROMIS) Depression scores consistent with major depressive disorder (MDD) than those undergoing aseptic revision and (2) whether these symptoms resolved after the procedure. METHODS: Records of all 366 patients that underwent revision total hip or knee arthroplasty from January 1, 2015, - June 20, 2019, were reviewed. Forty-two patients were excluded for missing PROMIS Depression scores or incomplete treatment. Preoperative (<3 months), early postoperative (2-8 weeks), and final postoperative (6-18 months) Depression scores were collected. Patients crossing the PROMIS Depression threshold equivalent to a Patient Health Questionnaire-9 score ≥10, indicative of MDD, were evaluated. RESULTS: More two-stage revision patients developed Depression scores indicative of MDD perioperatively than the aseptic cohort (20.0% vs 6.5%, P = .01). Two-stage revision patients had higher (worse) median Depression scores preoperatively (54.8 vs 51.3, P = .04) and at early follow-up (54.3 vs 49.9, P = .01), but not at final follow-up (50.4 vs 49.1, P = .39). Across all patients, Depression scores improved by 2.4 points at early follow-up (95% confidence interval:1.1-3.7; P < .001) and 3 points at final follow-up (95% confidence interval:1.5-4.5; P < .001; minimal clinically important difference 3.0). CONCLUSIONS: Twenty percent of two-stage revision arthroplasty patients, compared to <7% of aseptic revision patients, developed PROMIS Depression scores consistent with MDD during treatment. At final follow-up, a clinically significant improvement in Depression scores from baseline was evident in both cohorts.

Dedifferentiated chondrosarcoma with minimal or small dedifferentiated component.

Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone sarcoma characterized by low-intermediate grade cartilage component with abrupt transition to a high-grade non-chondrosarcomatous component. Generally, the dedifferentiated (DD) component is large. However, rare cases have minimal (<1 cm) or small (1-2 cm) areas of DD. We describe the clinicopathologic features of such tumors and evaluate the prognostic significance of this finding compared to cases with large DD (>2 cm). Available slides were re-reviewed for assessment of histologic features. The medical record was reviewed for imaging studies and clinical characteristics. Thirty-five cases were included. Six patients had minimal DD, four had small DD and 25 had large DD. None of the minimal DD showed definitive imaging evidence of DD. Two minimal DD (33%) locally recurred and 2 (33%) developed distant metastases. None of the small DD cases showed definitive imaging evidence of DD. None of the small DD locally recurred and at least 1 (25%) developed distant metastases. There was no significant difference in age, gender, pelvic site, tumor size >8 cm, tumor necrosis or undifferentiated pleomorphic sarcoma-like morphology between minimal or small DD compared to large DD, though osteosarcomatous differentiation was significantly more common in large DD. There was no significant difference in overall survival between minimal or small DD compared to large DD (p = 0.81 and p = 0.17, respectively), or in progression-free survival (p = 0.47 and 0.29, respectively), or metastasis-free survival (p = 0.06 and 0.62, respectively). DDCS with minimal or small DD show similar demographic distribution, anatomic localization and histologic features to large DD. DD in these cases is unlikely to be detected on imaging. Furthermore, at least a subset of these tumors is extremely aggressive despite the limited extent of DD. This highlights the need for thorough gross and histologic examination and sampling.

Patterns of Extrapulmonary Metastases in Sarcoma Surveillance.

Soft tissue sarcomas (STS) most commonly metastasize to the lungs. Current surveillance guidelines variably recommend abdominal and pelvic imaging, but there is little evidence to support this. We sought to determine the proportion of initial pulmonary versus extrapulmonary metastases, the time to development of each, and factors to identify patients that would benefit from abdominopelvic surveillance. We retrospectively reviewed 382 patients who underwent surgical treatment for STS at a single institution. Of the 33% (126/382) of patients who developed metastases, 72% (90/126) were pulmonary, 22% (28/126) were extrapulmonary, and 6% (8/126) developed both simultaneously. Initial extrapulmonary metastases occurred later (log rank p = 0.049), with median 11 months (IQR, 5 to 19) until pulmonary disease and 22 months (IQR, 6 to 45) until extrapulmonary disease. Pulmonary metastases were more common in patients with high grade tumors (p = 0.0201) and larger tumors (p < 0.0001). Our multivariate analysis did not identify any factors associated with initial extrapulmonary metastases. A substantial minority of initial metastases were extrapulmonary; these occurred later and over a broader time range than initial pulmonary metastases. Moreover, extrapulmonary metastases are more difficult to predict than pulmonary metastases, adding to the challenge of creating targeted surveillance protocols.

Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1.

BACKGROUND: We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection. OBJECTIVES: We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias. METHODS: Whole-exome sequencing was performed on both patients, and the impact of the identified variants was validated by functional assays using the patients' PBMCs. RESULTS: Each patient was found to have a unique heterozygous truncation variant in suppressor of cytokine signaling 1 (SOCS1). SOCS1 is an essential negative regulator of type I and type II IFN signaling. The patients' PBMCs showed increased levels of signal transducer and activator of transcription 1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II IFN-stimulated genes and proapoptotic genes. The enhanced IFN signature exhibited by the patients' unstimulated PBMCs parallels the hyperinflammatory state associated with multisystem inflammatory syndrome in children, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of multisystem inflammatory syndrome in children. CONCLUSIONS: Heterozygous loss-of-function SOCS1 mutations are associated with enhanced IFN signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias.

High-risk and Long-term Opioid Prescribing to Military Spouses in the Millennium Cohort Family Study.

INTRODUCTION: The use and misuse of opioids by active service members has been examined in several studies, but little is known about their spouses' opioid use. This study estimates the number of military spouses who received high-risk or long-term opioid prescriptions between 2010 and 2014, and addresses how the Military Health System can help prevent risky prescribing in order to improve military force readiness. MATERIALS AND METHODS: This study used data from the Millennium Cohort Family Study, a nationwide survey of 9,872 spouses of service members with 2 to 5 years of military service, augmented with information from the military's Pharmacy Data Transaction Service about prescriptions for controlled drugs dispensed to these service members' spouses. Our objectives were to estimate the prevalence of opioid prescribing indicative of long-term use (≥60 day supply or at least one extended-release opioid prescription in any 3-month period) and, separately, high-risk use (daily dosage of ≥90 morphine mg equivalent or total dosage of ≥8,190 morphine mg equivalent, or prescriptions from more than three pharmacies, or concurrent prescriptions). For each of these dependent variables, we conducted bivariate analyses and multiple logistic regression models using information about spouses' physical health, sociodemographic characteristics, substance use behaviors, perceived social support, and stresses associated with military stress, among others. Informed consent, including consent to link survey responses to medical and personnel records, was obtained from all participants. The Naval Health Research Center's Institutional Review Board and the Office of Management and Budget approved the study. RESULTS: Spouses were predominantly female (86%), had not served in the military themselves (79%), and were spouses of enlisted (91%) active duty (86%) service members. Almost half (47.6%) of spouses obtained at least one opioid prescription during the 2-year observation window, and 8.5% had received opioid prescriptions that posed risk to their health. About 7% met the criteria for receipt of high-risk opioid prescriptions, 3% obtained opioids from three or more pharmacies during a 3-month period, and 4% of spouses who received any opioids received both long-term and high-risk prescriptions. Adverse childhood experiences, physical pain, and lack of social support were associated with increased odds of obtaining high-risk opioid prescriptions. CONCLUSIONS: Approximately 48% of military spouses had used Military Health System insurance to fill at least one opioid prescription during the 2-year observation period. The Department of Defense has taken measures to minimize high-risk opioid prescribing, including passing prescribing guidelines in 2017, establishing the controlled drug management analysis reporting tool, establishing a pain management education and training program, and more. These efforts should continue to expand as reducing the numbers of service members and spouses at risk for adverse events may be effective in reducing opioid misuse and improve the overall health and safety of military spouses and thus, the readiness of the U.S. Armed Forces.

Does Advanced Imaging Have a Role in Detecting Local Recurrence of Soft-tissue Sarcoma?

BACKGROUND: Early detection of soft-tissue sarcoma recurrences may decrease the morbidity of reoperation and improve oncologic outcomes. The benefit of imaging compared with clinical surveillance for detecting local recurrences remains controversial, as prior studies have varied in terms of inclusion criteria, factors analyzed, and outcomes reported. QUESTIONS/PURPOSES: (1) What proportion of local recurrences were detected by surveillance imaging compared with clinical signs and symptoms? (2) Were local recurrences detected by imaging smaller than those detected by clinical surveillance? (3) Were relevant tumor, patient, or operative characteristics associated with clinically occult local recurrence? METHODS: Over a 20-year period ending in 2018, we treated 545 patients for soft-tissue sarcoma. During that period, we recommended that patients receive a surgical excision as well as radiation therapy based on current clinical guidelines. Of those we treated, 9% (51 of 545) were excluded for having a low-grade liposarcoma, and 4% (21 of 545) were excluded for being metastatic at the time of presentation. Of the remaining patients, 22% (107 of 473) were lost to follow-up before 2 years but were not known to have died. There were a remaining 366 patients for analysis in this retrospective study of electronic medical records from a single center. Patients routinely underwent advanced imaging and clinical follow-up at intervals based on currently available guidelines for sarcoma surveillance. We recommended that patients with high-grade sarcomas be followed every 3 months until 2 years, then every 6 months until 3 years, then annually thereafter. In contrast, we recommended that patients with low-grade sarcomas be followed every 6 months until 2 years, then annually thereafter. In addition, patients were encouraged to return for evaluation if they noted a new mass or other symptoms. In general, patients with high-grade sarcomas received postoperative radiation therapy unless they underwent amputation, while intermediate- and low-grade sarcomas were radiated according to clinical concern for local recurrence, as determined by the multidisciplinary sarcoma team. Seventeen percent (61 of 366) of patients developed or presented with a local recurrence. Of the local recurrences detected by surveillance imaging, 17 were detected by MRI, three were detected by position emission tomography, and one was detected by CT scan. The proportion of local recurrences first identified by advanced imaging versus clinical detection (physical examination, self-detection, or symptomatic presentation) were compared. Logistic regression with a Wald chi-square test was performed to evaluate if tumor, patient, or operative characteristics are associated with clinical versus imaging detection of local recurrences. RESULTS: A higher proportion of local recurrences were detected by clinical signs and symptoms than by routine imaging (66% (40 of 61) versus 34% (21 of 61), binomial proportion 0.66 [95% CI 0.55 to 0.77]; p = 0.007). With the numbers available, there was no difference in the tumor size detected by clinical signs and symptoms compared with surveillance imaging. The median (interquartile range) largest tumor dimension was 3.9 cm (2.5 to 7.8) for clinical surveillance versus 4.5 cm (2.7 to 6.2) for imaging surveillance (p = 0.98). We were unable to identify any associated factors, alone or in combination, with detection by physical exam, including patient age, tumor size, tumor depth, tumor location, operative closure type, or radiation status. Characteristics such as larger tumors, more superficial tumors, low BMI, the absence of a flap reconstruction or radiation treatment, were not associated with a greater likelihood of detection by physical examination. CONCLUSIONS: We found that although a high proportion of local recurrences were detected by clinical signs and symptoms, approximately one-third were detected by imaging. Although not all patients may benefit equally from routine imaging, we were unable to identify any patient, tumor, or operative characteristics to define a subgroup of patients that are more or less likely benefit from this surveillance technique. These findings support current surveillance guidelines that recommend the use of advanced imaging; however, other factors may also warrant consideration. Futher insight could be gained by studying surveillance imaging in terms of optimal frequency, cost-effectiveness, and psychosocial implications for patients. LEVEL OF EVIDENCE: Level III, diagnostic study.

Immunoglobulins in the treatment of COVID-19 infection: Proceed with caution!

The COVID-19 pandemic is one of the greatest infectious challenges in recent history. Presently, few treatment options exist and the availability of effective vaccines is at least one year away. There is an urgent need to find currently available, effective therapies in the treatment of patients with COVID-19 infection. In this review, we compare and contrast the use of intravenous immunoglobulin and hyperimmune globulin in the treatment of COVID-19 infection.

RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness.

BACKGROUND: Decreased TNF-α production in whole blood after ex vivo LPS stimulation indicates suppression of the Toll-like receptor (TLR)4 pathway. This is associated with increased mortality in pediatric influenza critical illness. Whether antiviral immune signaling pathways are also suppressed in these patients is unclear. OBJECTIVES: We sought to evaluate suppression of the TLR4 and the antiviral retinoic acid-inducible gene-I (RIG-I) pathways with clinical outcomes in children with severe influenza infection. METHODS: In this 24-center, prospective, observational cohort study of children with confirmed influenza infection, blood was collected within 72 hours of intensive care unit admission. Ex vivo whole blood stimulations were performed with matched controls using the viral ligand polyinosinic-polycytidylic acid-low-molecular-weight/LyoVec and LPS to evaluate IFN-α and TNF-α production capacities (RIG-I and TLR4 pathways, respectively). RESULTS: Suppression of either IFN-α or TNF-α production capacity was associated with longer duration of mechanical ventilation and hospitalization, and increased organ dysfunction. Children with suppression of both RIG-I and TLR4 pathways (n = 33 of 103 [32%]) were more likely to have prolonged (≥7 days) multiple-organ dysfunction syndrome (30.3% vs 8.6%; P = .004) or prolonged hypoxemic respiratory failure (39.4% vs 11.4%; P = .001) compared with those with single- or no pathway suppression. CONCLUSIONS: Suppression of both RIG-I and TLR4 signaling pathways, essential for respective antiviral and antibacterial responses, is common in previously immunocompetent children with influenza-related critical illness and is associated with bacterial coinfection and adverse outcomes. Prospective testing of both pathways may aid in risk-stratification and in immune monitoring.