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AbstractSchistosomiasis remains a leading cause of chronic morbidity in endemic regions despite decades of widespread mass chemotherapy with praziquantel. Using our whole proteome differential screening approach, and plasma and epidemiologic data from a longitudinal cohort of individuals living in a Schistosoma japonicum–endemic region of the Philippines, we interrogated the parasite proteome to identify novel vaccine candidates for Schistosoma japonicum. We identified 16 parasite genes which encoded proteins that were recognized by immunoglobulin G or immunoglobulin E antibodies in the plasma of individuals who had developed resistance to reinfection, but were not recognized by antibodies in the plasma of individuals who remained susceptible to reinfection. Antibody levels to Sj6-8 and Sj4-1 measured in the entire cohort (N = 505) 1 month after praziquantel treatment were associated with significantly decreased risk of reinfection and lower intensity of reinfection over 18 months of follow-up.

(See the Major Article by Grabowski et al, on pages 1150–60.)…

AbstractBackgroundThere are limited data on individual human immunodeficiency virus (HIV) viral load (VL) trajectories at the population-level after the introduction of universal test and treat (UTT) in sub-Saharan Africa.MethodsHuman immunodeficiency virus VLs were assessed among HIV-positive participants through 3 population-based surveys in 4 Ugandan fishing communities surveyed between November 2011 and August 2017. The unit of analysis was a visit-pair (2 consecutive person-visits), which were categorized as exhibiting durable VL suppression, new/renewed VL suppression, viral rebound, or persistent viremia. Adjusted relative risks (adjRRs) and 95% confidence intervals (CIs) of persistent viremia were estimated using multivariate Poisson regression.ResultsThere were 1346 HIV-positive participants (n = 1883 visit-pairs). The population-level prevalence of durable VL suppression increased from 29.7% to 67.9% during UTT rollout, viral rebound declined from 4.4% to 2.7%, and persistent viremia declined from 20.8% to 13.3%. Younger age (15–29 vs 40–49 years; adjRR = 1.80; 95% CI = 1.19–2.71), male sex (adjRR = 2.09, 95% CI = 1.47–2.95), never being married (vs currently married; adjRR = 1.88, 95% CI = 1.34–2.62), and recent migration to the community (vs long-term resident; adjRR = 1.91, 95% CI = 1.34–2.73) were factors associated with persistent viremia.ConclusionsDespite increases in durable VL suppression during roll out of UTT in hyperendemic communities, a substantial fraction of the population, whose risk profile tended to be younger, male, and mobile, remained persistently viremic.

To the Editor— Professor Abboud highlighted very important issues for research on coronavirus disease 2019 (COVID-19) encephalitis and encephalopathies. The author argued for a possible overestimation of this clinical entity during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as the main limitation of the encephalopathies and encephalitis in COVID-19 (ENCOVID) study.

To the Editor—In their article “Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2–Related Encephalitis,” Pilotto and colleagues reported on the incidence of encephalitis in a multicenter cohort of coronavirus disease 2019 (COVID-19) patients [1]. The reported incidence of 50 per 100 000 may be overestimated. Their definition of encephalitis corresponds to the designation of “possible encephalitis” as proposed by Venkatesan et al in their 2013 consensus article [2]. The diagnosis of probable encephalitis requires presentation with altered mental status (AMS) and at least 3 minor criteria relating to cerebrospinal fluid (CSF) pleocytosis, magnetic resonance imaging (MRI) changes, electroencephalogram changes, new-onset seizures, or focal neurologic deficits [2]. The diagnosis of confirmed encephalitis further requires pathological confirmation or laboratory evidence of a causative organism or highly clinically relevant neuronal autoantibody. The definition used by Pilotto et al (AMS and 2 minor criteria) allows for overestimation of encephalitis. In fact, 8 of their 25 patients (32%) had unremarkable brain MRI and CSF. The diagnosis of encephalitis in those 8 patients was based solely on the clinical picture, which makes the diagnosis questionable at best. Generalized seizures and AMS can occur in the setting of viral sepsis or metabolic derangements associated with COVID-19 infection [3]. They should not be utilized as evidence of encephalitis in this setting. In addition, aphasia and dysarthria are difficult to ascertain in the setting of AMS and should not be considered as focal deficits in altered patients. The fact that nearly half the patients were not tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) in the CSF or for neuronal autoantibodies adds to the limitations of this study by allowing significant misclassification of infectious versus parainfectious versus autoimmune etiologies. The authors concluded that most cases of COVID-19–related encephalitis were parainfectious in nature, secondary to the associated cytokine storm. This claim cannot be made if half the patients were not tested for SARS-CoV-2 PCR in the CSF nor for neuronal autoantibodies in both the serum and CSF. Moreover, the authors did not report on cancer screening in their cohort, possibly missing patients with an incidental paraneoplastic etiology, a major cause of encephalitis [4]. With modern epidemiological data suggesting that autoimmune encephalitis may be as common as viral encephalitis [5], scientific reports addressing encephalitis related to COVID-19 (or any cause) should adhere to certain reporting standards to avoid etiological misclassification. At a minimum, all patients should be tested for common microbiological pathogens of encephalitis as well as clinically relevant neuronal autoantibodies [6]. Patients without evidence of direct CNS infection should undergo cancer screening to rule out paraneoplastic etiologies. Administering unnecessary immunomodulating therapies to encephalopathic patients with COVID-19 can have negative effects, especially in cases complicated by secondary bacterial infections. In addition, overestimating the incidence of COVID-19–related encephalitis may result in missing important alternative causes of encephalitis (eg, cancer or antibody mediated) if full encephalitis workup is not pursued in each case.

AbstractMost patients with coronavirus disease 2019 (COVID-19) experience asymptomatic disease or mild symptoms, but some have critical symptoms requiring intensive care. It is important to determine how patients with asymptomatic or mild COVID-19 react to severe acute respiratory syndrome coronavirus 2 infection and suppress virus spread. Innate immunity is important for evasion from the first virus attack, and it may play an important role in the pathogenesis in these patients. We measured serum cytokine levels in 95 patients with COVID-19 during the infection’s acute phase and report that significantly higher interleukin 12 and 2 levels were induced in patients with asymptomatic or mild disease than in those with moderate or severe disease, indicating the key roles of these cytokines in the pathogenesis of asymptomatic or mild COVID-19.

AbstractWe evaluated the performance of the Abbott BinaxNOW rapid antigen test for coronavirus disease 2019 (Binax-CoV2) to detect virus among persons, regardless of symptoms, at a public plaza site of ongoing community transmission. Titration with cultured severe acute respiratory syndrome coronavirus 2 yielded a human observable threshold between 1.6 × 104-4.3 × 104 viral RNA copies (cycle threshold [Ct], 30.3–28.8). Among 878 subjects tested, 3% (26 of 878) were positive by reverse-transcription polymerase chain reaction, of whom 15 of 26 had a Ct <30, indicating high viral load; of these, 40% (6 of 15) were asymptomatic. Using this Ct threshold (<30) for Binax-CoV2 evaluation, the sensitivity of Binax-CoV2 was 93.3% (95% confidence interval, 68.1%–99.8%) (14 of 15) and the specificity was 99.9% (99.4%–99.9%) (855 of 856).

AbstractBackgroundThere is limited information on the association between upper respiratory tract (URT) viral loads, host factors, and disease severity in SARS-CoV-2–infected patients.MethodsWe studied 1122 patients (mean age, 46 years) diagnosed by polymerase chain reaction (PCR). URT viral load, measured by PCR cycle threshold, was categorized as high, moderate, or low.ResultsThere were 336 (29.9%) patients with comorbidities; 309 patients (27.5%) had high, 316 (28.2%) moderate, and 497 (44.3%) low viral load. In univariate analyses, compared to patients with moderate or low viral load, patients with high viral load were older, more often had comorbidities, developed Symptomatic disease (COVID-19), were intubated, and died. Patients with high viral load had longer stay in intensive care unit and longer intubation compared to patients with low viral load (P values < .05 for all comparisons). Patients with chronic cardiovascular disease, hypertension, chronic pulmonary disease, immunosuppression, obesity, and chronic neurological disease more often had high viral load (P value < .05 for all comparisons). In multivariate analysis high viral load was associated with COVID-19. Level of viral load was not associated with any other outcome.ConclusionsURT viral load could be used to identify patients at higher risk for morbidity or severe outcome.

AbstractBackgroundTo determine how serologic antibody testing outcome links with virus neutralization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we evaluated individuals for SARS-CoV-2 antibody level and viral neutralization.MethodsWe compared serum Ig levels across platforms of viral antigens and antibodies with 15 positive and 30 negative SARS-CoV-2 controls followed by viral neutralization assessment. We then applied these platforms to a clinically relevant cohort of 114 individuals with unknown histories of SARS-CoV-2 infection.ResultsIn controls, the best-performing virus-specific antibody detection platforms were SARS-CoV-2 receptor binding domain (RBD) IgG (sensitivity 87%, specificity 100%, positive predictive value [PPV] 100%, negative predictive value [NPV] 94%), spike IgG3 (sensitivity 93%, specificity 97%, PPV 93%, NPV 97%), and nucleocapsid protein (NP) IgG (sensitivity 93%, specificity 97%, PPV 93%, NPV 97%). Neutralization of positive and negative control sera showed 100% agreement. Twenty individuals with unknown history had detectable SARS-CoV-2 antibodies with 16 demonstrating virus neutralization. Spike IgG3 provided the highest accuracy for predicting serologically positive individuals with virus neutralization activity (misidentified 1/20 unknowns compared to 2/20 for RBD and NP IgG).ConclusionsThe coupling of virus neutralization analysis to a spike IgG3 antibody test is optimal to categorize patients for correlates of SARS-CoV-2 immune protection status.

To the Editor—We read with interest the review article by Burke et al [1] on the evidence of a link between rotavirus and type 1 diabetes (T1D) and wish to report our experience in Israel showing a correlation between the introduction of free, universal childhood rotavirus vaccination and a reduction in the rate of annual increase in the incidence of T1D in children aged 0–4 years.

AbstractBackgroundVaricella zoster virus (VZV) vasculopathy is characterized by persistent arterial inflammation leading to stroke. Studies show that VZV induces amyloid formation that may aggravate vasculitis. Thus, we determined if VZV central nervous system infection produces amyloid.MethodsAβ peptides, amylin, and amyloid were measured in cerebrospinal fluid (CSF) from 16 VZV vasculopathy subjects and 36 stroke controls. To determine if infection induced amyloid deposition, mock- and VZV-infected quiescent primary human perineurial cells (qHPNCs), present in vasculature, were analyzed for intracellular amyloidogenic transcripts/proteins and amyloid. Supernatants were assayed for amyloidogenic peptides and ability to induce amyloid formation. To determine amylin’s function during infection, amylin was knocked down with small interfering RNA and viral complementary DNA (cDNA) was quantitated.ResultsCompared to controls, VZV vasculopathy CSF had increased amyloid that positively correlated with amylin and anti-VZV antibody levels; Aβ40 was reduced and Aβ42 unchanged. Intracellular amylin, Aβ42, and amyloid were seen only in VZV-infected qHPNCs. VZV-infected supernatant formed amyloid fibrils following addition of amyloidogenic peptides. Amylin knockdown decreased viral cDNA.ConclusionsVZV infection increased levels of amyloidogenic peptides and amyloid in CSF and qHPNCs, indicating that VZV-induced amyloid deposition may contribute to persistent arterial inflammation in VZV vasculopathy. In addition, we identified a novel proviral function of amylin.

AbstractInvasive group A Streptococcus (GAS) in immunocompetent individuals is largely linked to hypervirulent strains. Congenital immunodeficiencies and those acquired from chronic disease or immunosuppressant drugs also increase risk of severe illness. We recovered GAS from the blood of a patient receiving a biologic inhibitor of interleukin 6 (IL-6). Growth of this serotype M4 isolate in human blood or a murine bacteremia model was promoted by interleukin 1 or IL-6 inhibition. Hyperinvasive M1T1 GAS was unaffected by IL-6 in both models. These findings based on a natural experiment introduce IL-6 signaling deficiencies as a risk factor for invasive GAS.

AbstractBackgroundFractional dose (one-fifth of full intramuscular dose) of inactivated poliovirus vaccine (fIPV) administered intradermally is used as IPV dose-sparing strategy. We compared the rate of decline of poliovirus antibodies (PVA) in recipients of 2 doses of fIPV or IPV.MethodsA community-based randomized controlled trial was conducted in Karachi, Pakistan. Children aged 14 weeks were randomized into fIPV or full IPV (study arms A, B) and received 1 vaccine dose at age 14 weeks and 1 at age 9 months. PVAs were measured at age 14, 18 weeks and 10, 21 months.ResultsSeroprevalence of poliovirus type 2 antibodies in 170/250 (68%) children after 2 IPV or fIPV doses at age 10 months in A and B reached 100% vs 99% (P = .339), and at 21 months, 86% vs 67% (P = .004). Between age 10 and 21 months antibody log2 titers dropped from ≥ 10.5 to 6.8 in A and from 9.2 to 3.7 in B.ConclusionsThere was a significant decline in antibody titers 12 months following the second IPV dose. The slope of decline was similar for full IPV and fIPV recipients. The results provide further evidence that fIPV is a viable option for IPV dose-sparing.Clinical Trials RegistrationNCT03286803.

AbstractBackgroundInvasive candidiasis (IC) is a growing concern among US healthcare facilities. A large-scale study evaluating incidence and trends of IC in the United States by species and body site is needed to understand the distribution of infection.MethodsAn electronic medical record database was used to calculate incidence and trends of IC in the United States by species and infection site from 2009 through 2017. Hospital incidence was calculated using total unique inpatient hospitalizations in hospitals reporting at least 1 Candida case as the denominator. IC incidence trends were assessed using generalized estimating equations with exchangeable correlation structure to fit Poisson regression models, controlling for changes in hospital characteristics and case mix over time.ResultsCandida albicans remains the leading cause of IC in the United States, followed by Candida glabrata. The overall incidence of IC was 90/100 000 patients, which did not change significantly over time. There were no changes in incidence among C. albicans, C. glabrata, C. parapsilosis, or C. tropicalis; the incidence of other Candida spp. as a whole increased 7.2% annually. While there was no change in candidemia 2009–2017, abdominal and nonabdominal sterile site IC increased significantly.ConclusionsNonbloodstream IC is increasing in the United States. Understanding the epidemiology of IC should facilitate improved management of infected patients.

AbstractAfter 7-valent pneumococcal conjugate vaccine introduction in the United States in 2000, invasive pneumococcal disease (IPD) due to serotype 4 greatly decreased in children and adults. Starting in 2013, serotype 4 IPD incidence increased among adults within 3 of 10 Active Bacterial Core surveillance sites. Of 325 serotype 4 cases among adults in 2010–2018, 36% were persons experiencing homelessness (PEH); incidence of serotype 4 IPD among PEH was 100–300 times higher than in the general population within these 3 areas. Genome sequencing for isolates recovered 2015–2018 (n = 246), revealed that increases in serotype 4 IPD were driven by lineages ST10172, ST244, and ST695. Within each lineage, clusters of near-identical isolates indicated close temporal relatedness. Increases in serotype 4 IPD were limited to Colorado, California, and New Mexico, with highest increases among PEH, who were at increased risk for exposure to and infections caused by these strains.

AbstractBackgroundIt is not known whether reductions in socioeconomic and racial disparities in incidence of invasive pneumococcal disease (defined as the isolation of Streptococcus pneumoniae from a normally sterile body site) noted after pneumococcal conjugate vaccine (PCV) introduction have been sustained.MethodsIndividual-level data collected from 20 Tennessee counties participating in Active Bacterial Core surveillance over 19 years were linked to neighborhood-level socioeconomic factors. Incidence rates were analyzed across 3 periods—pre–7-valent PCV (pre-PCV7; 1998–1999), pre–13-valent PCV (pre-PCV13; 2001–2009), and post-PCV13 (2011–2016)—by socioeconomic factors.ResultsA total of 8491 cases of invasive pneumococcal disease were identified. Incidence for invasive pneumococcal disease decreased from 22.9 (1998–1999) to 17.9 (2001–2009) to 12.7 (2011–2016) cases per 100 000 person-years. Post-PCV13 incidence (95% confidence interval [CI]) of PCV13-serotype disease in high- and low-poverty neighborhoods was 3.1 (2.7–3.5) and 1.4 (1.0–1.8), respectively, compared with pre-PCV7 incidence of 17.8 (15.7–19.9) and 6.4 (4.9–7.9). Before PCV introduction, incidence (95% CI) of PCV13-serotype disease was higher in blacks than whites (17.3 [15.1–19.5] vs 11.8 [10.6–13.0], respectively); after introduction, PCV13-type disease incidence was greatly reduced in both groups (white: 2.7 [2.4–3.0]; black: 2.2 [1.8–2.6]).ConclusionsIntroduction of PCV13 was associated with substantial reductions in overall incidence and socioeconomic and racial disparities in PCV13-serotype incidence.

AbstractBackgroundThis is a prospective, multicenter, observational study in cytomegalovirus (CMV)-seropositive kidney transplant recipients with pretransplant CMV-specific cell-mediated immunity (CMV-CMI) receiving antithymocyte globulin (ATG). We aimed to investigate posttransplant CMV-CMI over time and the impact of the dose-dependent ATG.MethodsCMV-CMI was assessed at days +30, +45, +60, and +90 after transplantation with the QuantiFERON-CMV assay. A reactive result (interferon-γ [IFN-γ] ≥ 0.2 IU/mL) indicated a positive CMV-CMI.ResultsA total of 78 positive CMV-CMI patients were enrolled in the study, of which 59.5% had a positive CMV-CMI at day +30 and 82.7% at day +90. Multivariate logistic regression analysis showed that ATG dose was not associated with positive CMV-CMI at any point. However, pretransplant IFN-γ level (>12 IU/mL vs ≤12 IU/mL) was associated with positive CMV-CMI at day +30 (odds ratio, 12.9; 95% confidence interval, 3.1–53.3; P < .001). In addition, all the patients who did not recover CMV-CMI at day +90 had a pretransplant IFN-γ level ≤12 IU/mL.ConclusionsMore than half of CMV-seropositive kidney transplant recipients receiving ATG recover (or maintain) CMV-CMI by the first month after transplantation. The pretransplant IFN-γ level, but not the ATG dose, shows a strong association with the kinetics of this recovery.

AbstractBackgroundGlobally, decreased susceptibility to ceftriaxone in Neisseria gonorrhoeae is rising. We aimed to compile a global collection of N. gonorrhoeae strains and assess the genetic characteristics associated with decreased susceptibility to ceftriaxone.MethodsWe performed a literature review of all published reports of N. gonorrhoeae strains with decreased susceptibility to ceftriaxone (>0.064 mg/L minimum inhibitory concentration) through October 2019. Genetic mutations in N. gonorrhoeae genes (penA, penB, mtrR, and ponA), including determination of penA mosaicism, were compiled and evaluated for predicting decreased susceptibility to ceftriaxone.ResultsThere were 3821 N. gonorrhoeae strains identified from 23 countries and 684 (18%) had decreased susceptibility to ceftriaxone. High sensitivities or specificities (>95%) were found for specific genetic mutations in penA, penB, mtrR, and ponA, both with and without determination of penA mosaicism. Four algorithms to predict ceftriaxone susceptibility were proposed based on penA mosaicism determination and penA or non-penA genetic mutations, with sensitivity and specificity combinations up to 95% and 62%, respectively.ConclusionMolecular algorithms based on genetic mutations were proposed to predict decreased susceptibility to ceftriaxone in N. gonorrhoeae. Those algorithms can serve as a foundation for the development of future assays predicting ceftriaxone decreased susceptibility within N. gonorrhoeae globally.

AbstractBackground We investigated whether higher-intensity exercise provided greater decrease in markers of inflammation, and whether responses differed by HIV serostatus.MethodsPeople with HIV (PWH; n = 32) and controls (n = 37) aged 50–75 years completed 12 weeks moderate-intensity exercise, then were randomized to moderate- or high-intensity exercise for 12 additional weeks (n = 27 and 29, respectively). Inflammation biomarkers were measured at 0, 12, 24 weeks. Mixed and multiple regression models were adjusted for baseline inflammation, age, and body mass index.ResultsBaseline tumor necrosis factor-α (TNF-α), soluble TNF receptor 2 (sTNFR2), and soluble CD14 (sCD14) were significantly higher among PWH than controls (P < .04). From week 0–12, changes in interleukin-6 (IL-6), TNF-α, and sTNFR1 were not significantly different by HIV serostatus. We found no significant interaction between HIV serostatus/exercise intensity on week 12–24 changes in IL-6, TNF-α, and sTNFR1. Among high-intensity exercisers, PWH and controls had significant increases in sCD14 (P ≤ .003), controls significant increases in IL-10 (P = .01), and PWH nonsignificant decrease in highly sensitive C-reactive protein (P = .07). Other markers were not significantly different by serostatus or intensity.ConclusionsModerate and high-intensity exercise elicited similar effects on inflammation among PWH and controls, with additional beneficial effects seen among high-intensity exercisers. Increase in sCD14 and attenuated IL-10 increase (PWH only) merit further study.Clinical Trials RegistrationNCT02404792.

AbstractBackgroundInfluenza vaccination has been suggested to protect against death and recurrent events among patients with cardiovascular disease or chronic obstructive respiratory disease, but there is limited evidence in older adults, who have higher risks of influenza-associated hospitalization and mortality.MethodsPatients aged ≥60 years hospitalized for cardiovascular or respiratory diseases from the Beijing Urban Employee Basic Medical Insurance database during 3 influenza seasons (2013–2014 through 2015–2016) were pooled to estimate the effects of influenza vaccination on hospitalization outcomes. Vaccination status was ascertained through cross-referencing the Beijing Elderly Influenza Vaccination database. The summer months (June–August) were used as a reference period to adjust for unmeasured confounders during influenza seasons.ResultsAfter adjustment for both measured and unmeasured confounders, influenza vaccination was associated with lower risks of in-hospital deaths among patients hospitalized for cardiovascular (odds ratio [95% confidence interval], 0.85 [.68–1.06]) or respiratory diseases (0.66 [.54–.82]). Influenza vaccination was associated with a lower risk of readmission among patients with cardiovascular (odds ratio [95% confidence interval], 0.81 [.69–.95]) but not respiratory diseases (1.12 [.92–1.35]). Influenza vaccination was also associated with lower direct medical costs, but not with length of stay.ConclusionsInfluenza vaccination protected against hospitalization outcomes among older adults with cardiovascular or respiratory diseases.

AbstractDirect acting antiviral therapies rapidly clear chronic hepatitis C virus (HCV) infection and restore natural killer (NK) cell function. We investigated NK-cell memory formation following HCV clearance by examining NK-cell phenotype and responses from control and chronic HCV patients before and after therapy following sustained virologic response at 12 weeks post therapy (SVR12). NK-cell phenotype at SVR12 differed significantly from paired pretreatment samples, with an increase in maturation markers CD16, CD57, and KLRG1. HCV patients possessed stronger cytotoxic responses against HCV-infected cells as compared to healthy controls; a response that further increased following SVR12. The antigen-specific response was mediated by KLRG1+ NK cells, as demonstrated by increased degranulation and proliferation in response to HCV antigen only. Our data suggest that KLRG1+ HCV-specific memory NK cells develop following viral infection, providing insight into their role in HCV clearance and relevance with regard to vaccine design.

AbstractA successful Staphylococcus aureus vaccine remains elusive, and one controversy in the field is whether humans generate a protective adaptive immune response to infection. We developed a bacterial challenge murine assay that directly assesses the protective capacity of adoptively transferred human serum samples. We first validated the model by showing that postpneumococcal vaccine serum samples from humans induced effective clearance of Streptococcus pneumoniae in mice. We then found that human serum samples adoptively transferred from children with invasive S. aureus infections exhibited protection from disease in a murine model, with some samples conferring near complete protection. These findings demonstrate that human serum samples are capable of conferring a protective adaptive response generated by humans during invasive staphylococcal disease, allowing for the study of protective factors in a murine model. Identification of the protective factors present in the most efficacious serum samples would be of high interest as potential staphylococcal vaccine candidates or passive therapeutics.

AbstractBackgroundImmune reconstitution inflammatory syndrome (IRIS) is a common cause of morbidity among people with human immunodeficiency virus (PWH) who initiate antiretroviral therapy (ART) with severe lymphopenia. Easily accessible tools that reliably predict emergence and elucidate pathogenesis of IRIS are needed to facilitate improved clinical management.MethodsPlasma levels of biomarkers were measured before ART initiation in a large multinational cohort of ART-naive PWH with severe immunosuppression (CD4+ count <100 cells/mm3) in United States, Kenya, and Thailand. We performed a series of multiparametric analyses of inflammatory and clinical biomarkers and developed a composite score merging relevant biomarkers for use in a prediction model.ResultsWe identified a distinct baseline inflammatory profile and changes in inflammatory networks among biomarkers in participants who subsequently developed mycobacterial or viral IRIS. We also developed a composite score incorporating biomarkers associated with IRIS (interleukin-6 [IL-6], IL-10, IL-27, sCD14, interferon-γ, tumor necrosis factor-α, hyaluronic acid, D-dimer, body mass index, and hemoglobin) that accurately predicted mycobacterial IRIS and death in this cohort.ConclusionsSystemic inflammatory profiles in PWH with severe immunosuppression are predictive of IRIS. Composite scores for the prediction of mycobacterial IRIS and death could be useful for risk stratification in PWH and lymphopenia initiating ART.Clinical Trials Registration NCT00286767.

AbstractBackgroundAntibody Fc-mediated functions, such as antibody-dependent cellular cytotoxicity, contribute to vaccine-induced protection against viral infections. Fc-mediated function of anti-Ebola glycoprotein (GP) antibodies suggest that Fc-dependent activation of effector cells, including natural killer (NK) cells, could play a role in vaccination against Ebola virus disease.MethodsWe analyzed the effect on primary human NK cell activation of anti-Ebola GP antibody in the serum of United Kingdom–based volunteers vaccinated with the novel 2-dose heterologous adenovirus type 26.ZEBOV, modified vaccinia Ankara–BN-Filo vaccine regimen.ResultsWe demonstrate primary human NK cell CD107a and interferon γ expression, combined with down-regulation of CD16, in response to recombinant Ebola virus GP and post-vaccine dose 1 and dose 2 serum samples. These responses varied significantly with vaccine regimen, and NK cell activation was found to correlate with anti-GP antibody concentration. We also reveal an impact of NK cell differentiation phenotype on antibody-dependent NK cell activation, with highly differentiated CD56dimCD57+ NK cells being the most responsive.ConclusionsThese findings highlight the dual importance of vaccine-induced antibody concentration and NK cell differentiation status in promoting Fc-mediated activation of NK cells after vaccination, raising a potential role for antibody-mediated NK cell activation in vaccine-induced immune responses.

Z. Yousaf and K. Mushtaq…

AbstractBackgroundPersons living with human immunodeficiency virus (HIV) are at elevated risk of developing the malignant diseases that require allogeneic stem cell transplantation (ASCT). Recent data suggest that these individuals are also at an elevated risk of certain complications post-ASCT. This risk may result from preexisting HIV-related factors affecting dynamics of immune reconstitution post-ASCT. However, to date, there has been little work describing the dynamics of immune reconstitution post-ASCT in persons with HIV and none comparing these data to controls without HIV.MethodsWe assessed T-cell reconstitution in 6 ASCT with HIV recipients (HIV+ASCT) compared to a control population of 21 ASCT without HIV recipients. In a subset of HIV+ASCT recipients we performed additional flow cytometry profiling of CD8+ T-cell subsets and antigen specificity of reconstituting CD4+ and CD8+ T cells.ResultsWe observe no difference in post-ASCT CD4+ T cells between HIV+ASCT and HIV-negative ASCT recipients, despite much lower pre-ASCT CD4+ T-cell counts in the HIV+ASCT group. In contrast, we observed significantly higher CD8+ T-cell numbers in the HIV+ASCT group post-ASCT. The reconstituting CD8+ T-cells were predominantly CD45RO+, whereas homing markers and antigen specificity of these cells varied between participants.ConclusionThis study represents the most extensive characterization of immune-reconstitution post-ASCT in persons with HIV, and the first to our knowledge to compare these data to ASCT controls without HIV. The results indicate that immune reconstitution in this group can be affected by preexisting HIV infection and post-ASCT antigen exposure.

To the Editor—The nucleocapsid protein (NP) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the widely used antigens in serodiagnostics of the novel coronavirus disease 2019 (COVID-19). We appreciate Guo and colleagues for shedding new light on the humoral response profile of COVID-19 [1]. They have generated recombinant whole nucleocapsid protein (rNP) of SARS-CoV-2 using the Escherichia coli expression system and used it to develop an enzyme-linked immunosorbent assay (ELISA) to detect anti–SARS-CoV-2 antibodies in plasma. The rNP ELISA was negative in the plasma of all of the 285 non–COVID-19 individuals tested. The authors have also shown that rNP does not have cross-reactivity with antibodies of other common coronaviruses (NL63, 229E, OC43, and HKU1). However, we have observed controversial findings and suggest the advantage of N-terminally truncated nucleocapsid protein (ΔN-NP).

AbstractBackgroundEscherichia coli is the most common cause of bacteremia in high-income countries. To enable the development and implementation of effective prevention strategies, a better understanding of the current epidemiology of invasive E. coli infections is needed.MethodsA systematic review of literature published between 1 January 2007 and 31 March 2018 on the burden and epidemiology of E. coli bacteremia in populations that include adults in high-income countries was conducted. Meta-analysis was performed for descriptive purposes.ResultsDuring the studied time interval, the estimated incidence rate of E. coli bacteremia was 48 per 100 000 person-years, but this increased considerably with age: rates per 100 000 person-years were >100 in 55-to-75-year-olds and >300 in 75-to-85-year-olds. Overall, E. coli accounted for 27% of documented bacteremia episodes: 18% if hospital acquired, 32% if community-onset healthcare associated, and 33% if community acquired. The estimated case fatality rate was 12%. Approximately 44% of episodes were community acquired, 27% community-onset healthcare associated, and 27% hospital acquired. Urinary tract infection (UTI) was the primary source for 53% of episodes.ConclusionsThis systematic review confirms the substantial burden of E. coli bacteremia in older adults and justifies the implementation of community-level programs to prevent E. coli bacteremia and ideally UTI in this age group.

To the Editor—Life is destined to be dramatic.

AbstractBackgroundThe increasing global prevalence of pulmonary nontuberculous mycobacteria (NTM) disease has called attention to challenges in NTM diagnosis and management. This study was conducted to understand management and outcomes of patients with pulmonary NTM disease at diverse centers across the United States.MethodsWe conducted a 10-year (2005–2015) retrospective study at 7 Vaccine and Treatment Evaluation Units to evaluate pulmonary NTM treatment outcomes in human immunodeficiency virus–negative adults. Demographic and clinical information was abstracted through medical record review. Microbiologic and clinical cure were evaluated using previously defined criteria.ResultsOf 297 patients diagnosed with pulmonary NTM, the most frequent NTM species were Mycobacterium avium-intracellulare complex (83.2%), M. kansasii (7.7%), and M. abscessus (3.4%). Two hundred forty-five (82.5%) patients received treatment, while 45 (15.2%) were followed without treatment. Eighty-six patients had available drug susceptibility results; of these, >40% exhibited resistance to rifampin, ethambutol, or amikacin. Of the 138 patients with adequate outcome data, 78 (56.5%) experienced clinical and/or microbiologic cure. Adherence to the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) treatment guidelines was significantly more common in patients who were cured (odds ratio, 4.5, 95% confidence interval, 2.0–10.4; P < .001). Overall mortality was 15.7%.ConclusionsDespite ATS/IDSA Guidelines, management of pulmonary NTM disease was heterogeneous and cure rates were relatively low. Further work is required to understand which patients are suitable for monitoring without treatment and the impact of antimicrobial therapy on pulmonary NTM morbidity and mortality.

nontuberculous mycobacteriaguidelinesdiagnostic criteriaMycobacteriumpulmonary disease…

AbstractBackgroundEchinococcus multilocularis is one of the most severe and lethal parasitic diseases of humans, most often reported in Europe and Asia. Only 1 previous case has been documented in the contiguous United States from Minnesota in 1977. European haplotypes have been identified in carnivores and domestic dogs as well as recently in patients in western and central Canada.MethodsWe used immunohistochemical testing with the monoclonal antibody Em2G11 and a species-specific enzyme-linked immunosorbent assay affinity-purified antigen Em2, as well as COX1 gene sequencing.ResultsUsing pathology, immunohistochemical staining, specific immunodiagnostic testing, and COX1 gene sequencing, we were able to definitively identify E. multilocularis as the causative agent of our patient’s liver and lung lesions, which clustered most closely with the European haplotype.ConclusionsWe have identified the first case of a European haplotype E. multilocularis in the United States and the first case of this parasitic infection east of the Mississippi River. Given the identification of this haplotype in Canada, this appears to be an emerging infectious disease in North America.

alveolar echinococcosisclinical managementincubation periodrisk factors…

AbstractBackgroundData on safety and efficacy of second-line tuberculosis drugs in pregnant women and their infants are severely limited due to exclusion from clinical trials and expanded access programs.MethodsPregnant women starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa, from 1 January 2013 to 31 December 2017, were included. We conducted a record review to describe maternal treatment and pregnancy outcomes, and a clinical assessment to describe infant outcomes.ResultsOf 108 pregnant women treated for MDR/RR-tuberculosis, 88 (81%) were living with human immunodeficiency virus.. Favorable MDR/RR-tuberculosis treatment outcomes were reported in 72 (67%) women. Ninety-nine (91%) of the 109 babies were born alive, but overall, 52 (48%) women had unfavorable pregnancy outcomes. Fifty-eight (54%) women received bedaquiline, and 49 (45%) babies were exposed to bedaquiline in utero. Low birth weight was reported in more babies exposed to bedaquiline compared to babies not exposed (45% vs 26%; P = .034). In multivariate analyses, bedaquiline and levofloxacin, drugs often used in combination, were both independently associated with increased risk of low birth weight. Of the 86 children evaluated at 12 months, 72 (84%) had favorable outcomes; 88% of babies exposed to bedaquiline were thriving and developing normally compared to 82% of the babies not exposed.ConclusionsMDR/RR-tuberculosis treatment outcomes among pregnant women were comparable to nonpregnant women. Although more babies exposed to bedaquiline were of low birth weight, over 80% had gained weight and were developing normally at 1 year.

tuberculosisdrug resistancepregnancywomenadverse effects…

sepsishematopoietic cell transplantSIRSqSOFANEWS…

AbstractBackgroundWe recently mitigated a clonal outbreak of hospital-acquired Mycobacterium abscessus complex (MABC), which included a large cluster of adult patients who developed invasive infection after exposure to heater-cooler units during cardiac surgery. Recent studies have detailed Mycobacterium chimaera infections acquired during cardiac surgery; however, little is known about the epidemiology and clinical courses of cardiac surgery patients with invasive MABC infection.MethodsWe retrospectively collected clinical data on all patients who underwent cardiac surgery at our hospital and subsequently had positive cultures for MABC from 2013 through 2016. Patients with ventricular assist devices or heart transplants were excluded. We analyzed patient characteristics, antimicrobial therapy, surgical interventions, and clinical outcomes.ResultsTen cardiac surgery patients developed invasive, extrapulmonary infection from M. abscessus subspecies abscessus in an outbreak setting. Median time from presumed inoculation in the operating room to first positive culture was 53 days (interquartile range [IQR], 38–139 days). Disseminated infection was common, and the most frequent culture-positive sites were mediastinum (n = 7) and blood (n = 7). Patients received a median of 24 weeks (IQR, 5–33 weeks) of combination antimicrobial therapy that included multiple intravenous agents. Six patients required antibiotic changes due to adverse events attributed to amikacin, linezolid, or tigecycline. Eight patients underwent surgical management, and 6 patients required multiple sternal debridements. Eight patients died within 2 years of diagnosis, including 4 deaths directly attributable to MABC infection.ConclusionsDespite aggressive medical and surgical management, invasive MABC infection after cardiac surgery caused substantial morbidity and mortality. New treatment strategies are needed, and compliance with infection prevention guidelines remains critical.

pneumococcal conjugate vaccineconjunctivitisviral conjunctivitisbacterial conjunctivitis…

AbstractBackgroundBacterial conjunctivitis is most commonly caused by nontypeable Haemophilus influenzae (NTHi), followed by Streptococcus pneumoniae. No population-based data on the impact of pneumococcal conjugate vaccines (PCVs) on the incidence of bacterial conjunctivitis have been published. We assessed rate dynamics of overall, pneumococcal, and NTHi conjunctivitis in children aged 2–23 months in southern Israel before and after PCV implementation.MethodsThis is a 12-year prospective, population-based surveillance, from July 2004 through June 2017. Our medical center serves a captive population of approximately 30 000 children < 2 years of age, and its clinical microbiology laboratory processes > 80% of all community-derived cultures, enabling incidence calculation. The 7-valent and 13-valent PCVs (PCV7 and PCV13, respectively) were implemented in the national immunization program in July 2009 and November 2010, respectively. Pneumococci, NTHi, Moraxella catarrhalis, and Streptococcus pyogenes were considered pathogens. Continuous annual incidences and incidence rate ratios comparing the PCV13 period (2015–2017) to the pre-PCV period (2004–2008) were calculated.ResultsDisease caused by PCV13 serotypes declined by 93%, without significant replacement with non-PCV13 serotypes. Rates of pneumococcal, NTHi, and overall culture-positive episodes declined by 59%, 41%, and 42%, respectively, while rates of culture-negative and other pathogens episodes did not change significantly. An overall reduction in all submitted culture rates of 35% was observed. This pattern was seen across all ages, including infants aged 2–5 months.ConclusionsPCV7/PCV13 implementation resulted in a marked and significant decline in pneumococcal, NTHi, and overall conjunctivitis rates in children < 2 years of age. The impact on NTHi episodes alludes to the role of pneumococcus–NTHi interaction in conjunctivitis. The impact in infants aged < 6 months suggests herd protection.

AbstractBackgroundSepsis disproportionately affects allogeneic hematopoietic cell transplant (HCT) recipients and is challenging to define. Clinical criteria that predict mortality and intensive care unit end-points in patients with suspected infections (SIs) are used in sepsis definitions, but their predictive value among immunocompromised populations is largely unknown. Here, we evaluate 3 criteria among allogeneic HCT recipients with SIs.MethodsWe evaluated Systemic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) in relation to short-term mortality among recipients transplanted between September 2010 and July 2017. We used cut-points of ≥ 2 for qSOFA/SIRS and ≥ 7 for NEWS and restricted to first SI per hospital encounter during patients’ first 100 days posttransplant.ResultsOf the 880 recipients who experienced ≥ 1 SI, 58 (6.6%) died within 28 days and 22 (2.5%) within 10 days of an SI. In relation to 10-day mortality, SIRS was the most sensitive (91.3% [95% confidence interval {CI}, 72.0%–98.9%]) but least specific (35.0% [95% CI, 32.6%–37.5%]), whereas qSOFA was the most specific (90.5% [95% CI, 88.9%–91.9%]) but least sensitive (47.8% [95% CI, 26.8%–69.4%]). NEWS was moderately sensitive (78.3% [95% CI, 56.3%–92.5%]) and specific (70.2% [95% CI, 67.8%–72.4%]).ConclusionsNEWS outperformed qSOFA and SIRS, but each criterion had low to moderate predictive accuracy, and the magnitude of the known limitations of qSOFA and SIRS was at least as large as in the general population. Our data suggest that population-specific criteria are needed for immunocompromised patients.

AbstractBackgroundKnowledge of the epidemiology and clinical characteristics of varicella zoster virus (VZV) encephalitis remains limited.MethodsNationwide prospective cohort study of adults treated for microbiologically confirmed VZV encephalitis at Danish departments of infectious diseases from 2015 to 2019. Modified Poisson regression analysis was used to compute adjusted relative risks (RRs) of unfavorable outcome.ResultsWe identified 92 adults (49% female) with VZV encephalitis, yielding an incidence of 5.3/1 000 000 per year (95% CI, 4.2–6.6). Median age was 75 years (IQR, 67–83) and immunocompromising conditions were frequent (39%). Predominant symptoms were confusion (76%), headache (56%), nausea (45%), gait disturbance (42%), and personality changes (41%). Cranial imaging showed cerebral vasculitis (including infarction and hemorrhage) in 14 (16%) patients and encephalitic abnormalities in 11 (13%) with predilection for the brainstem and deep brain structures. Intravenous acyclovir treatment was initiated a median (IQR) of 13.4 hours (5.2–46.3) since admission, while cranial imaging and lumbar puncture were performed after 6.3 hours (2.5–31.0) and 18.5 hours (4.9–42.0). In-hospital, 1-month, and 3-month mortalities were 4%, 9%, and 11%, respectively. Unfavorable outcome (Glasgow Outcome Score of 1–4) was found in 69% at discharge, with age (adjusted RR [aRR], 1.02; 95% CI, 1.01–1.03), vasculitis (aRR, 1.38; 95% CI, 1.02–1.86), and Glasgow Coma Scale (GCS) <15 (aRR, 1.32; 95% CI, 1.01–1.73) identified as independent risk factors.ConclusionsVZV encephalitis occurs primarily in elderly or immunocompromised patients with a higher incidence than previously estimated. The diagnosis is often delayed; risk factors for unfavorable outcome are age, cerebral vasculitis, and GCS <15.

(See the Major Article by de Wiesenfeld et al on pages 1181–9.)…

AbstractBackgroundAnaerobic organisms are important pathogens in acute pelvic inflammatory disease (PID). The currently recommended PID regimen of a single dose of ceftriaxone and doxycycline for 14 days has limited anaerobic activity. The need for broader anaerobic coverage is unknown and concerns have been raised about metronidazole tolerability.MethodsWe conducted a randomized, double-blind, placebo-controlled trial comparing ceftriaxone 250 mg intramuscular single dose and doxycycline for 14 days, with or without 14 days of metronidazole in women with acute PID. The primary outcome was clinical improvement at 3 days following enrollment. Additional outcomes at 30 days following treatment were the presence of anaerobic organisms in the endometrium, clinical cure (absence of fever and reduction in tenderness), adherence, and tolerability.ResultsWe enrolled 233 women (116 to metronidazole and 117 to placebo). Clinical improvement at 3 days was similar between the 2 groups. At 30 days following treatment, anaerobic organisms were less frequently recovered from the endometrium in women treated with metronidazole than placebo (8% vs 21%, P < .05) and cervical Mycoplasma genitalium was reduced (4% vs 14%, P < .05). Pelvic tenderness was also less common among women receiving metronidazole (9% vs 20%, P < .05). Adverse events and adherence were similar in each treatment group.ConclusionsIn women treated for acute PID, the addition of metronidazole to ceftriaxone and doxycycline was well tolerated and resulted in reduced endometrial anaerobes, decreased M. genitalium, and reduced pelvic tenderness compared to ceftriaxone and doxycycline. Metronidazole should be routinely added to ceftriaxone and doxycycline for the treatment of women with acute PID.Clinical Trials RegistrationNCT01160640.

AbstractBackgroundSince 2013, quadrivalent influenza vaccines containing 2 B viruses gradually replaced trivalent vaccines in the United States. We compared the vaccine effectiveness of quadrivalent to trivalent inactivated vaccines (IIV4 to IIV3, respectively) against illness due to influenza B during the transition, when IIV4 use increased rapidly.MethodsThe US Influenza Vaccine Effectiveness (Flu VE) Network analyzed 25 019 of 42 600 outpatients aged ≥6 months who enrolled within 7 days of illness onset during 6 seasons from 2011–2012. Upper respiratory specimens were tested for the influenza virus type and B lineage. Using logistic regression, we estimated IIV4 or IIV3 effectiveness by comparing the odds of an influenza B infection overall and the odds of B lineage among vaccinated versus unvaccinated participants. Over 4 seasons from 2013–2014, we compared the relative odds of an influenza B infection among IIV4 versus IIV3 recipients.ResultsTrivalent vaccines included the predominantly circulating B lineage in 4 of 6 seasons. During 4 influenza seasons when both IIV4 and IIV3 were widely used, the overall effectiveness against any influenza B was 53% (95% confidence interval [CI], 45–59) for IIV4 versus 45% (95% CI, 34–54) for IIV3. IIV4 was more effective than IIV3 against the B lineage not included in IIV3, but comparative effectiveness against illnesses related to any influenza B favored neither vaccine valency.ConclusionsThe uptake of quadrivalent inactivated influenza vaccines was not associated with increased protection against any influenza B illness, despite the higher effectiveness of quadrivalent vaccines against the added B virus lineage. Public health impact and cost-benefit analyses are needed globally.

(See the Major Article by de Vries et al on pages 1171–8.)…

AbstractBackgroundRickettsial disease (RD) is a prevalent and underestimated cause of febrile illness worldwide, especially in the absence of an inoculation eschar. We attempted to quantify this underestimation at our clinic, by investigating past cases of febrile illness in travelers who had tested negative for leptospirosis, a disease that can initially present similarly to non-eschar RD, and which we routinely consider when other important causes of unspecified febrile illness have tested negative.MethodsWe performed a retrospective analysis in febrile returned travelers from Asia, Africa, or the Americas between 2010 and 2017, who had tested negative for leptospirosis. Serologic immunofluorescence assays were performed for Orientia tsutsugamushi (scrub typhus), typhus group, and spotted fever group RD. We performed a medical records review of all patients who tested positive. In case of a fitting medical history, cases were deemed either confirmed (based on convalescent serology) or suspected (based on single serology).ResultsAmong 97 patients, convalescent serology was available in 16 (16.5%) patients, and a single serology in 81 (83.5%) patients. RD was the likely diagnosis in 8 of 16 (50.0%) patients with convalescent serology, and in 8 of 81 (9.9%) with single serology. Of the 16 confirmed/suspected cases, 11 (69%) had been missed and 7 (44%) had not received adequate empiric antibiotic therapy.ConclusionsThis study shows that non-eschar RD is an important and poorly recognized cause of illness in travelers, even in a specialized travel clinic. A lower threshold to test and treat for RD is warranted in returning travelers with febrile illness.