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Vaping use has rapidly increased. In this final report from the Wisconsin and Illinois departments of public health, a severe respiratory illness in otherwise healthy young people is described. Of the 98 case patients identified in this investigation, 95% were hospitalized, 26% were intubated, and 2 persons died.

Test-negative designs (TNDs) are used to assess vaccine effectiveness (VE). Protection from infection-induced immunity may confound the association between case and vaccination status, but collecting reliable infection history can be challenging. If vaccinated individuals have less infection-induced protection than unvaccinated individuals, failure to account for infection history could underestimate VE, though the bias is not well understood. We simulated individual-level SARS-CoV-2 infection and COVID-19 vaccination histories and a TND. VE against symptomatic infection and VE against severe disease estimates unadjusted for infection history underestimated VE compared to estimates adjusted for infection history, and unadjusted estimates were more likely to be below 0%, which could lead to an incorrect interpretation that COVID-19 vaccines are harmful. TNDs assessing VE immediately following vaccine rollout introduced the largest bias and potential for negative VE against symptomatic infection. Despite the potential for bias, VE estimates from TNDs without prior infection information are useful because underestimation is rarely more than 8 percentage points. The test-negative study design has been widely used to evaluate COVID-19 vaccine effectiveness, but the accuracy of estimates is likely to be impacted by prior infection and vaccination history. Here, the authors perform a simulation study to quantify how these impacts may bias vaccine effectiveness estimates.

Few studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk. We assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected four controls from among contacts who did not develop TB disease, matching on gender and year of age. We also conducted a one-stage individual-participant data (IPD) meta-analysis searching PubMed and Embase to identify prospective studies of vitamin D and TB disease until June 8, 2019. We included studies that assessed vitamin D before TB diagnosis. In the primary analysis, we defined vitamin D deficiency as 25-(OH)D < 50 nmol/L, insufficiency as 50-75 nmol/L, and sufficiency as >75nmol/L. We estimated the association between baseline vitamin D status and incident TB using conditional logistic regression in the Lima cohort and generalized linear mixed models in the meta-analysis. We further defined severe vitamin D deficiency as 25-(OH)D < 25 nmol/L and performed stratified analyses by HIV status in the IPD meta-analysis. In the Lima cohort, we analyzed 180 cases and 709 matched controls. The adjusted odds ratio (aOR) for TB risk among participants with baseline vitamin D deficiency compared to sufficient vitamin D was 1.63 (95% CI 0.75-3.52; p = 0.22). We included seven published studies in the meta-analysis and analyzed 3,544 participants. In the pooled analysis, the aOR was 1.48 (95% CI 1.04-2.10; p = 0.03). The aOR for severe vitamin D deficiency was 2.05 (95% CI 0.87-4.87; p trend for decreasing 25-(OH)D levels from sufficient vitamin D to severe deficiency = 0.02). Among 1,576 HIV-positive patients, vitamin D deficiency conferred a 2-fold (aOR 2.18, 95% CI 1.22-3.90; p = 0.01) increased risk of TB, and the aOR for severe vitamin D deficiency compared to sufficient vitamin D was 4.28 (95% CI 0.85-21.45; p = 0.08). Our Lima cohort study is limited by the short duration of follow-up, and the IPD meta-analysis is limited by the number of possible confounding covariates available across all studies. Our findings suggest vitamin D predicts TB disease risk in a dose-dependent manner and that the risk of TB disease is highest among HIV-positive individuals with severe vitamin D deficiency. Randomized control trials are needed to evaluate the possible role of vitamin D supplementation on reducing TB disease risk.

In an Essay, Mark Tenforde and colleagues advocate continued provision of baseline CD4 cell count testing in HIV care in low- and middle-income countries.In an Essay, Mark Tenforde and colleagues advocate continued provision of baseline CD4 cell count testing in HIV care in low- and middle-income countries.

Experimental studies have shown that vaccination can reduce viral replication to attenuate progression of influenza-associated lower respiratory tract illness (LRTI). However, clinical studies are conflicting, possibly due to use of non-specific outcomes reflecting a mix of large and small airway LRTI lacking specificity for acute lung or organ injury. We developed a global ordinal scale to differentiate large and small airway LRTI in hospitalized adults with influenza using physiologic features and interventions (PFIs): vital signs, laboratory and radiographic findings, and clinical interventions. We reviewed the literature to identify common PFIs across 9 existing scales of pneumonia and sepsis severity. To characterize patients using this scale, we applied the scale to an antiviral clinical trial dataset where these PFIs were measured through routine clinical care in adults hospitalized with influenza-associated LRTI during the 2010-2013 seasons. We evaluated 12 clinical parameters among 1020 adults; 210 (21%) had laboratory-confirmed influenza, with a median severity score of 4.5 (interquartile range, 2-8). Among influenza cases, median age was 63 years, 20% were hospitalized in the prior 90 days, 50% had chronic obstructive pulmonary disease, and 22% had congestive heart failure. Primary influencers of higher score included pulmonary infiltrates on imaging (48.1%), heart rate ≥110 beats/minute (41.4%), oxygen saturation <93% (47.6%) and respiratory rate >24 breaths/minute (21.0%). Key PFIs distinguishing patients with severity < or ≥8 (upper quartile) included infiltrates (27.1% vs 90.0%), temperature ≥ 39.1°C or <36.0°C (7.1% vs 27.1%), respiratory rate >24 breaths/minute (7.9% vs 47.1%), heart rate ≥110 beats/minute (29.3% vs 65.7%), oxygen saturation <90% (14.3% vs 31.4%), white blood cell count >15,000 (5.0% vs 27.2%), and need for invasive or non-invasive mechanical ventilation (2.1% vs 15.7%). We developed a scale in adults hospitalized with influenza-associated LRTI demonstrating a broad distribution of physiologic severity which may be useful for future studies evaluating the disease attenuating effects of influenza vaccination or other therapeutics.

To the Editor: Humoral and cellular immune responses con-tribute to overall protective immunity against SARS-CoV-2, with neutralizing antibody playing a key role in preventing viral infection. [...]a recent study has shown that booster responses to Omicron infection are affected by previous SARS-CoV-2 infec-tions (5). [...]having additional information on the types of neutralizing antibody responses induced after infection with different SARS-CoV-2 variants will be helpful in addressing this important issue. In vaccinated Delta-infected patients, neutralization titers against Delta and WA1 were similar, but again were much low-er against BA.1 (17-fold) and BA.2 (9-fold) (Figure 1B). [...]both unvaccinated and vaccinated Delta-infected patients had significantly lower neutralizing antibody responses to Omi-cron (as determined by Wilcoxons rank sum test).

Mark W. Tenforde, James E. Scriven * E-mail: mark.tenforde@gmail.com Affiliations Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, Washington, United States of America, Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, United States of America James E. Scriven Contributed equally to this work with: Mark W. Tenforde, James E. Scriven Affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom ORCID http://orcid.org/0000-0001-8463-7137 Thomas S. Harrison Affiliations Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa Joseph N. Jarvis Affiliations Botswana-UPenn Partnership, Gaborone, Botswana, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, Department of Clinical Research, Faculty of Infectious Diseases and Tropical Medicine, London School of Hygiene and Tropical Medicine, London, United KingdomCitation: Tenforde MW, Scriven JE, Harrison TS, Jarvis JN (2017) Immune correlates of HIV-associated cryptococcal meningitis. Phagocytosis occurs through antibody- and complement-mediated, opsonin-dependent pathways and non-opsonin-dependent interaction of cryptococcus surface epitopes with receptors including mannose, dectin-1, CD14, and Toll-like receptor 4 [8, 9]. Other risk factors include solid organ transplantation, long-term use of immunosuppressive drugs, diabetes mellitus, rheumatological diseases, advanced liver and renal disease, and hematological malignancies [17]. Phagocytic Fc[gamma] receptor 3A 158 F/V polymorphisms have recently been found to be a risk factor for cryptococcal disease, with Fc[gamma]R3A VV homozygosity conferring higher risk, as have the...

AbstractObjectivesTo characterize the clinical severity of covid-19 associated with the alpha, delta, and omicron SARS-CoV-2 variants among adults admitted to hospital and to compare the effectiveness of mRNA vaccines to prevent hospital admissions related to each variant.DesignCase-control study.Setting21 hospitals across the United States.Participants11 690 adults (≥18 years) admitted to hospital: 5728 with covid-19 (cases) and 5962 without covid-19 (controls). Patients were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and, if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: alpha (11 March to 3 July 2021), delta (4 July to 25 December 2021), and omicron (26 December 2021 to 14 January 2022).Main outcome measuresVaccine effectiveness calculated using a test negative design for mRNA vaccines to prevent covid-19 related hospital admissions by each variant (alpha, delta, omicron). Among patients admitted to hospital with covid-19, disease severity on the World Health Organization’s clinical progression scale was compared among variants using proportional odds regression.ResultsEffectiveness of the mRNA vaccines to prevent covid-19 associated hospital admissions was 85% (95% confidence interval 82% to 88%) for two vaccine doses against the alpha variant, 85% (83% to 87%) for two doses against the delta variant, 94% (92% to 95%) for three doses against the delta variant, 65% (51% to 75%) for two doses against the omicron variant; and 86% (77% to 91%) for three doses against the omicron variant. In-hospital mortality was 7.6% (81/1060) for alpha, 12.2% (461/3788) for delta, and 7.1% (40/565) for omicron. Among unvaccinated patients with covid-19 admitted to hospital, severity on the WHO clinical progression scale was higher for the delta versus alpha variant (adjusted proportional odds ratio 1.28, 95% confidence interval 1.11 to 1.46), and lower for the omicron versus delta variant (0.61, 0.49 to 0.77). Compared with unvaccinated patients, severity was lower for vaccinated patients for each variant, including alpha (adjusted proportional odds ratio 0.33, 0.23 to 0.49), delta (0.44, 0.37 to 0.51), and omicron (0.61, 0.44 to 0.85).ConclusionsmRNA vaccines were found to be highly effective in preventing covid-19 associated hospital admissions related to the alpha, delta, and omicron variants, but three vaccine doses were required to achieve protection against omicron similar to the protection that two doses provided against the delta and alpha variants. Among adults admitted to hospital with covid-19, the omicron variant was associated with less severe disease than the delta variant but still resulted in substantial morbidity and mortality. Vaccinated patients admitted to hospital with covid-19 had significantly lower disease severity than unvaccinated patients for all the variants.

The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain. Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naïve adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm). We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-γ), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis. Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55-6.81) and IP-10 (aOR 1.89, 95% CI: 1.05-3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13-5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB. Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.

Hepatitis B virus (HBV) infection in pregnancy has been associated with risk of adverse maternal and infant outcomes in highly endemic settings, but this association is not well characterized in the United States. We conducted a retrospective population-based cohort study in Washington State using linked birth certificate and hospital discharge records from 1992-2014. Among pregnant women with hepatitis B (n = 4391) and a hepatitis B-negative group (n = 22 410), we compared the risk of gestational diabetes, pre-eclampsia, eclampsia, placenta previa, preterm delivery, low birthweight, small for gestational age, and large for gestational age using multivariate logistic regression. Hepatitis B-infected pregnant women were more likely to be Asian (61% vs 8%, < .001), foreign-born (76% vs 23%, < .001), and older in age (77% vs 64% ≥26 years, < .001). They were less commonly overweight or obese (33% vs 50%, < .001). There was a lower risk of small for gestational age infants among HBV-infected women (adjusted RR [aRR], 0.79; 95% confidence interval [CI], 0.67-0.93). The risk of other adverse outcomes was not significantly different between hepatitis B-infected and -negative women (gestational diabetes: aRR, 1.11; 95% CI, 0.92-1.34; pre-eclampsia: aRR, 1.06; 95% CI, 0.82-1.35; eclampsia: aRR, 2.31; 95% CI, 0.90-5.91; placenta previa: aRR, 1.16; 95% CI, 0.35-3.84; preterm delivery: aRR, 1.15; 95% CI, 0.98-1.34; low birth weight: aRR, 1.08; 95% CI, 0.90-1.29; large for gestational age: aRR, 1.01; 95% CI, 0.82-1.24). In a low-burden setting in the United States, hepatitis B infection was not associated with adverse pregnancy outcomes.