Differential immune imprinting by influenza virus vaccination and infection in nonhuman primates

Immune memory of a first infection with influenza virus establishes a lasting imprint. Recall of that memory dominates the response to later infections or vaccinations by antigenically drifted strains. Early childhood immunization before infection may leave an imprint with different characteristics. We report here a comparison of imprinting by vaccination and infection in a small cohort of nonhuman primates (NHPs). We assayed serum antibody responses for binding with hemaglutinnins (HAs) both from the infecting or immunizing strain (H3 A/Aichi 02/1968) and from strains representing later H3 antigenic clusters (“forward breadth”) and examined the effects of defined HA mutations on serum titers. Initial exposure by infection elicited strong HA-binding and neutralizing serum antibody responses but with little forward breadth; initial vaccination with HA from the same strain elicited a weaker response with little neutralizing activity but considerable breadth of binding, not only for later H3 HAs but also for HA of the 2009 H1 new pandemic virus. Memory imprinted by infection, reflected in the response to two immunizing boosts, was largely restricted (as in humans) to the outward-facing HA surface, the principal region of historical variation. Memory imprinted by immunization showed exposure to more widely distributed epitopes, including sites that have not varied during evolution of the H3 HA but that yield nonneutralizing responses. The mode of initial exposure thus affects both the strength of the response and the breadth of the imprint; design of next-generation vaccines will need to take the differences into account.

Antigenic exposures determine the acquisition and development of adaptive immunity. The humoral response in a naive individual yields both antibody-secreting plasma cells that recognize the new antigen and memory B cells that can respond to future encounters with related antigens. The combination of these two components can confer long-lasting protection against antigenically stable pathogens. For antigenically diverse pathogens and those that evolve to evade immune pressure (e.g., influenza virus and HIV), serum responses often confer incomplete immunity to future variants (1, 2).The hemagglutinin (HA) and neuraminidase (NA) define the serotype of an influenza virus isolate (3). Antigenic shifts occur when novel animal influenza viruses can transmit to humans, spread rapidly, and initiate pandemics, owing to absence of any preexisting immunity (4, 5). Historically, the descendants of pandemic viruses have become endemic seasonal variants that undergo antigenic drift as they evolve over time to evade dominant human herd immunity (6, 7). For most adults, both processes have shaped human immunity to influenza.Immune memory causes a primary infection to impart an enduring imprint (8–11). Despite a lifetime of repeated exposures to divergent influenza viruses, the relative strength of an individual’s immune response to vaccination or infection correlates with the antigenic similarity of the vaccine or infecting strain to that person’s initial exposure. Until recently, the first encounter was invariably an infection. Because of recent changes in vaccine policy in the United States and Europe, infants and toddlers are now encouraged to receive influenza vaccines before they experience an influenza infection (12, 13). We have little information, however, about the immunological memory to influenza virus established when the primary exposure is vaccination rather than infection.Using nonhuman primates (rhesus macaques) as a model, we have examined how the mode of influenza exposure affects both primary and secondary antibody responses. We found that an initial exposure by infection elicited strong, strain-specific, HA-binding, and neutralizing serum antibody responses. Initial exposure by immunization with the HA protein from the strain used in the infection arm of the study elicited relatively weaker HA-binding responses that lacked neutralization potency but had greater interseasonal forward breadth. Subsequent exposures, by immunization, generated antibodies with increased interseasonal breadth in infected animals and neutralizing activity in the initially immunized monkeys. Initially infected macaques maintained responses that were strongly imprinted by the infecting strain, while those initially immunized with protein retained a serum repertoire that cross-reacted with heterologous HAs. Moreover, the distribution of epitopes bound by serum IgG was different in the two cases. These data suggest that the mode of HA exposure influences its immune imprint and that next-generation vaccine design will need to take this influence into account.     

Clinical Outcomes of Patients Hospitalized with Coronavirus Disease 2019 (COVID-19) in Boston

BackgroundOutcomes of hospitalized patients with COVID-19 have been described in health systems overwhelmed with a surge of cases. However, studies examining outcomes of patients admitted to hospitals not in crisis are lacking.ObjectiveTo describe clinical characteristic and outcomes of all patients with COVID-19 who are admitted to hospitals not in crisis, and factors associated with mortality in this population.DesignA retrospective analysisParticipantsIn total, 470 consecutive patients with COVID-19 requiring hospitalization in one health system in Boston from January 1, 2020 to April 15, 2020.Main MeasuresWe collected clinical outcomes during hospitalization including intensive care unit (ICU) admission, receipt of mechanical ventilation, and vasopressors. We utilized multivariable logistic regression models to examine factors associated with mortality.Key ResultsA total of 470 patients (median age 66 [range 23–98], 54.0% male) were included. The most common comorbidities were diabetes (38.5%, 181/470) and obesity (41.3%, 194/470). On admission, 41.9% (197/470) of patients were febrile and 60.6% (285/470) required supplemental oxygen. During hospitalization, 37.9% (178/470) were admitted to the ICU, 33.6% (158/470) received mechanical ventilation, 29.4% (138/470) received vasopressors, 16.4% (77/470) reported limitations on their desire for life-sustaining therapies such as intubation and cardiopulmonary resuscitation, and 25.1% (118/470) died. Among those admitted to the ICU (N=178), the median number of days on the ventilator was 10 days (IQR 1–29), and 58.4% (104/178) were discharged alive. Older age (OR=1.04, P<0.001), male sex (OR=2.14, P=0.007), higher comorbidities (OR=1.20, P=0.001), higher lactate dehydrogenase on admission (2nd tertile: OR=4.07, P<0.001; 3rd tertile: OR=8.04, P<0.001), and the need for supplemental oxygen on admission (OR=2.17, P=0.014) were all associated with higher mortality.ConclusionsThe majority of hospitalized patients with COVID-19 and those who received mechanical ventilation survived. These data highlight the need to examine public health and system factors that contribute to improved outcomes for this population.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-021-06622-x.     

Calcitonin-related peptides in patients with acute leukemia: association of human calcitonin with poor prognosis

Elevated serum levels of peptides hormones in patients with acute leukemia and production of these agents by the leukemic blasts have been described. In 77 patients with acute leukemia the influence of common risk factors and elevations of serum levels of calcitonin-related peptides on clinical outcome was evaluated. By multivariate analysis, only age and elevated serum level of h-CT were found to be significantly correlated to survival. CGRP and s-CT showed no influence on outcome. Closer inspection of the clinical course of these patients showed that patients with elevated h-CT are not likely to survive the first 4 weeks after diagnosis. The possibility that this hormone may influence the biological behavior of the leukemic cells is discussed.     

Observational Study Mortality in Treated Primary Aldosteronism: The German Conn's Registry

In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03-1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04-12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07-6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/L [95% CI, 0.17-0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P<0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls.     

Estimation of the relationship between body mass index and EQ-5D health utilities in individuals with type 2 diabetes: Evidence from the population-based KORA studies

ObjectivesObesity is known to be an important risk factor for type 2 diabetes and its related comorbid conditions; however, its specific impact on generic health-related quality of life (HRQL) is less clear. The objective of this study was to estimate the association between body mass index (BMI) and HRQL in individuals with type 2 diabetes.MethodsThe EQ-5D quality of life questionnaire was administered in a follow-up of 10,385 participants aged 33–94 of the population-based German MONICA/KORA surveys. 1033 participants with type 2 diabetes were identified by self-report combined with validated physician diagnoses. Semiparametric additive regression models were used to estimate the effect of BMI on EQ-5D health utilities adjusted for age, sex, education and comorbidities.ResultsBMI was significantly associated with EQ-5D health utilities even after adjustment for macro- and microvascular complications. The functional relationship between BMI and utilities was nonlinear, reflecting optimal health around 26 kg/m² and significantly decreasing health utilities with increasing levels of overweight and obesity (? 0.09 points between BMI values 26 and 40). Among the diabetic complications, the history of a stroke (? 0.13) and neuropathy (? 0.10) were the strongest predictors of reduced health utility scores.ConclusionsBMI is strongly associated with health utilities in persons with type 2 diabetes. This suggests that lifestyle measures to reduce obesity can markedly improve patients' health-related quality of life and that the negative effect of potential weight gain should be taken into account when determining patient preferences for different type 2 diabetes treatment options.     

Sonographical diagnosis of pneumoretroperitoneum as a result of retroperitoneal perforation

A retroperitoneal perforation is a rare incident. It can occur as a complication of ERCP with papillotomy (0.2-0.5%). Leakage of contrast agent during endoscopy raises the suspicion that this complication has occurred but doesn't always give sufficient information about the leakage extent. In the case of extreme gas emission, a plain abdominal X-ray shows classic pneumoretroperitoneum. The abdominal CT scan can display small amounts of free air which is why it is used for diagnosis in such cases. Ultrasonography also provides a reliable diagnosis and is a good method for monitoring the progression of the condition. Alternative causes of pneumoretroperitoneum can be: trauma, inflammation, infection, tumor as well as ERCP and other interventional procedures, especially endoscopies. Presacral retroperitoneal pneumoradiography was used for the diagnosis of retroperitoneal tumors in the 70 s but is no longer used today. Perforations into the retroperitoneal space come from several locations in the gastrointestinal tract. In the different types of lesions the gas can penetrate the compartments and reach as far as the mediastinum, the intraabdominal cavity, subcutaneum (cervical) or the scrotal compartment (compartment shift). Based on 11 cases (7 perforations during ERCP, 2 perforation during colonoscopy, 2 cases with damage of the distal esophagus), we show the most extensive presentation of the sonographical picture of pneumoretroperitoneum. Typical signs on abdominal ultrasound are an increased echogenicity around the right kidney ("overcasted" or "covered" kidney), air dorsal to the gallbladder, around the duodenum and the head of the pancreas and especially ventral to the great abdominal vessel which can lead to the picture of "vanishing" vessels. The extent of free air is easy to assess. Even very small amounts are detectable ventral to the right kidney. In most cases, a conservative approach with no oral intake, antibiotic coverage, and analgesia in close gastroenterological-surgical cooperation is indicated. Especially after ERCP abscess formation is repeatedly described, sometimes even with a lethal outcome. Sonography is a suitable method for detecting free air in the retro-peritoneum. Pneumoretroperitoneum following bowel-perforation can be effectively shown by ultrasound, it is possible to assess the extent of free air, and sonographic monitoring of the treatment is possible and successful.