Smoothing age/time structure of HIV prevalence, for optimal use in synthetic cohort based incidence estimation

Population-based surveys which ascertain HIV status are conducted in heavily affected countries, with the estimation of incidence being a primary goal. Numerous methods exist under the umbrella of ‘synthetic cohort analysis’, by which we mean estimating incidence from the age/time structure of prevalence (given knowledge on mortality). However, not enough attention has been given to how serostatus data is ‘smoothed’ into a time/age-dependent prevalence, so as to optimise the estimation of incidence.To support this and other related investigations, we developed a comprehensive simulation environment in which we simulate age/time structured SI type epidemics and surveys. Scenarios are flexibly defined by demographic rates (fertility, incidence and mortality – dependent, as appropriate, on age, time, and time-since-infection) without any reference to underlying causative processes/parameters. Primarily using 1) a simulated epidemiological scenario inspired by what is seen in the hyper-endemic HIV affected regions, and 2) pairs of cross-sectional surveys, we explored A) options for extracting the age/time structure of prevalence so as to optimise the use of the formal incidence estimation framework of Mahiane et al, and B) aspects of survey design such as the interaction of epidemic details, sample-size/sampling-density and inter-survey interval.Much as in our companion piece which crucially investigated the use of ‘recent infection’ (whereas the present analysis hinges fundamentally on the estimation of the prevalence gradient) we propose a ‘one size fits most’ process for conducting ‘synthetic cohort’ analyses of large population survey data sets, for HIV incidence estimation: fitting a generalised linear model for prevalence, separately for each age/time point where an incidence estimate is desired, using a ‘moving window’ data inclusion rule. Overall, even in very high incidence settings, sampling density requirements are onerous.The general default approach we propose for fitting HIV prevalence to data as a function of age and time appears to be broadly stable over various epidemiological stages. Particular scenarios of interest, and the applicable options for survey design and analysis, can readily be more closely investigated using our approach. We note that it is often unrealistic to expect even large household based surveys to provide meaningful incidence estimates outside of priority groups like young women, where incidence is often particularly high.

Smoothing age/time structure of HIV prevalence, for optimal use in synthetic cohort based incidence estimation

BackgroundPopulation-based surveys which ascertain HIV status are conducted in heavily affected countries, with the estimation of incidence being a primary goal. Numerous methods exist under the umbrella of ‘synthetic cohort analysis’, by which we mean estimating incidence from the age/time structure of prevalence (given knowledge on mortality). However, not enough attention has been given to how serostatus data is ‘smoothed’ into a time/age-dependent prevalence, so as to optimise the estimation of incidence.MethodsTo support this and other related investigations, we developed a comprehensive simulation environment in which we simulate age/time structured SI type epidemics and surveys. Scenarios are flexibly defined by demographic rates (fertility, incidence and mortality – dependent, as appropriate, on age, time, and time-since-infection) without any reference to underlying causative processes/parameters. Primarily using 1) a simulated epidemiological scenario inspired by what is seen in the hyper-endemic HIV affected regions, and 2) pairs of cross-sectional surveys, we explored A) options for extracting the age/time structure of prevalence so as to optimise the use of the formal incidence estimation framework of Mahiane et al, and B) aspects of survey design such as the interaction of epidemic details, sample-size/sampling-density and inter-survey interval.ResultsMuch as in our companion piece which crucially investigated the use of ‘recent infection’ (whereas the present analysis hinges fundamentally on the estimation of the prevalence gradient) we propose a ‘one size fits most’ process for conducting ‘synthetic cohort’ analyses of large population survey data sets, for HIV incidence estimation: fitting a generalised linear model for prevalence, separately for each age/time point where an incidence estimate is desired, using a ‘moving window’ data inclusion rule. Overall, even in very high incidence settings, sampling density requirements are onerous.ConclusionThe general default approach we propose for fitting HIV prevalence to data as a function of age and time appears to be broadly stable over various epidemiological stages. Particular scenarios of interest, and the applicable options for survey design and analysis, can readily be more closely investigated using our approach. We note that it is often unrealistic to expect even large household based surveys to provide meaningful incidence estimates outside of priority groups like young women, where incidence is often particularly high.

SARS-CoV-2 Cumulative Incidence and Period Seroprevalence: Results from a Statewide Population-Based Serosurvey in California

Background California has reported the largest number of COVID-19 cases of any U.S. state, with more than 3.5 million confirmed as of March 2021. However, the full breadth of SARS-CoV-2 transmission in California is unknown since reported cases only represent a fraction of all infections. Methods We conducted a population-based serosurvey, utilizing mailed, home-based SARS-CoV-2 antibody testing along with a demographic and behavioral survey. We weighted data from a random sample to represent the adult California population and estimated period seroprevalence overall and by participant characteristics. Seroprevalence estimates were adjusted for waning antibodies to produce statewide estimates of cumulative incidence, the infection fatality ratio (IFR), and the reported fraction. Results California’s SARS-CoV-2 weighted seroprevalence during August–December 2020 was 4.6% (95% CI: 2.8–7.4%). Estimated cumulative incidence as of November 2, 2020 was 8.7% (95% CrI: 6.4%–11.5%), indicating 2,660,441 adults (95% CrI: 1,959,218–3,532,380) had been infected. The estimated IFR was 0.8% (95% CrI: 0.6%–1.0%), and the estimated percentage of infections reported to the California Department of Public Health was 31%. Disparately high risk for infection was observed among persons of Hispanic/Latinx ethnicity and people with no health insurance and who reported working outside the home. Conclusions We present the first statewide SARS-CoV-2 cumulative incidence estimate among adults in California. As of November 2020, approximately one in three SARS-CoV-2 infections in California adults had been identified by public health surveillance. When accounting for unreported SARS-CoV-2 infections, disparities by race/ethnicity seen in case-based surveillance persist.

Two-Source Capture-Recapture Method to Estimate the Incidence of Acute Flaccid Paralysis in the Marches Region (Italy)

A combination of high infant immunization coverage and surveillance of acute flaccid paralysis (AFP) cases, plays a critical role in polio eradication. This study aimed to estimate the incidence of AFP, to evaluate the completeness of AFP ascertainment during the years, age groups and gender, and to define the main associated diagnosis among children aged under 15 in the Marches region of Italy. Analysis was performed on data from the active AFP surveillance system and the hospital discharge records in the 2006–2014 period. The two-source capture-recapture method was applied. After cross-validation, 30 AFP compatible conditions as defined by the WHO were identified, with an incidence estimate of 1.91 cases of AFP per 100,000 children under 15 years (95% CI = 1.4–2.6/100,000). Guillain–Barrè syndrome was the most common diagnosis. A significant difference (p < 0.05) has been registered in the estimated probability of case ascertainment in females. The reasons for the lower reporting of cases in females are unknown. Specific research and the implementation of a more sensitive surveillance system are essential in verifying potential inequalities and to succeed in the polio eradication initiative.

The Refeeding Syndrome: a neglected but potentially serious condition for inpatients. A narrative review

The Refeeding Syndrome (RFS) is a potentially serious, but still overlooked condition, occurring in individuals who are rapidly fed after a period of severe undernourishment. RFS derives from an abnormal electrolyte and fluid shifts leading to many organ dysfunctions. Symptoms generally appear within 2–5 days of re-feeding and may be absent/mild or severe and life threating, depending on the pre-existing degree of malnutrition and comorbidities. The lack of a standard definition and the nonspecificity of the symptoms make both incidence estimate and diagnosis difficult. In 2020, the American Society for Parenteral and Enteral Nutrition (ASPEN) proposed a unifying definition for the RFS and its severity classification. The awareness of the condition is crucial for identifying patients at risk, preventing its occurrence, and improving the management. The objectives of this narrative review were to summarize the current knowledge and recommendations about the RFS and to provide useful tips to help physicians to recognize and prevent the syndrome.

The Clinical and Economic Burden of Norovirus Gastroenteritis in the United States

Background Although norovirus outbreaks periodically make headlines, it is unclear how much attention norovirus may receive otherwise. A better understanding of the burden could help determine how to prioritize norovirus prevention and control. Methods We developed a computational simulation model to quantify the clinical and economic burden of norovirus in the United States. Results A symptomatic case generated $48 in direct medical costs, $416 in productivity losses ($464 total). The median yearly cost of outbreaks was $7.6 million (range across years, $7.5–$8.2 million) in direct medical costs, and $165.3 million ($161.1–$176.4 million) in productivity losses ($173.5 million total). Sporadic illnesses in the community (incidence, 10–150/1000 population) resulted in 14 118–211 705 hospitalizations, 8.2–122.9 million missed school/work days, $0.2–$2.3 billion in direct medical costs, and $1.4–$20.7 billion in productivity losses ($1.5–$23.1 billion total). The total cost was $10.6 billion based on the current incidence estimate (68.9/1000). Conclusion Our study quantified norovirus’ burden. Of the total burden, sporadic cases constituted &gt;90% (thus, annual burden may vary depending on incidence) and productivity losses represented 89%. More than half the economic burden is in adults ≥45, more than half occurs in winter months, and &gt;90% of outbreak costs are due to person-to-person transmission, offering insights into where and when prevention/control efforts may yield returns.

Epidemiology of Clostridioides difficile infections, France, 2010 to 2017

Background Clostridioides difficile is a leading cause of healthcare-associated diarrhoea in middle and high-income countries. Up to 2018, there has been no systematic, annual surveillance for C. difficile infections (CDI) in France. Aims To provide an updated overview of the epidemiology of CDI in France between 2010 and 2017 based on five different data sources. Methods This is a descriptive study of retrospective surveillance and alerts data. Incidence of CDI cases was estimated through the CDI incidence survey (2016) and data from the French National Uniform Hospital Discharge Database (PMSI; 2010–16). Testing frequency for CDI was estimated through the CDI incidence survey and point prevalence studies on healthcare-associated infections (HAI; 2012 and 2017). The national early warning response system for HAI (HAI-EWRS, 2012–17) and National Reference Laboratory data (2012–17) were used to follow the number of severe CDI cases and/or outbreaks. Results In 2016, CDI incidence in acute care was 3.6 cases per 10,000 patient days (PD). There was a statistically significant increase in CDI incidence between 2010 and 2016 (+ 14% annually) and testing frequency was 47.4 per 10,000 PD. The number of CDI HAI-EWRS notifications decreased between 2015 and 2017 with only a few large outbreaks reported. Conclusion The CDI incidence estimate increased from 2010, but remained below the European average of 7 per 10,000 PD in 2014; there were fewer severe cases or clusters reported in France. The consistency between PMSI and laboratory-based estimated CDI incidence could allow for more routine monitoring of CDI incidence.

Influence of Age on Risk for Acute and Chronic Graft Versus Host Disease in Children Receiving HLA Identical Sibling Bone Marrow Transplantation

Introduction: In adult HLA matched sibling donor (MSD) hematopoietic cell transplantation, both recipient and donor age have been shown to be a risk factors for graft versus host disease (GVHD). While it is widely recognized that pediatric patients are at lower risk for GVHD than adults, the importance of age within the pediatric age group in MSD transplantation has not been examined. We, therefore, assessed the impact of age on GVHD risk after MSD bone marrow transplantation (BMT) in 477 pediatric patients with acute leukemia. Methods: This is a Center for International Blood and Marrow Transplantation registry study. Patients younger than 18 years with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in 1st or 2nd complete remission (CR), who received myeloablative conditioining, T cell-replete HLA MSD BMT and calcineurin inhibitor based GVHD prophylaxis between 2000-2013 were included. Patients who received a lymphocyte depleting antibody were excluded. Because donor and recipient ages were highly correlated, their effects could not be independently assessed. We, therefore, assessed only recipient age. Results: The transplants were drawn from 101 centers. The median age of the recipients was 10.1 years. 21% had ALL in 1st CR, 24% ALL in 2nd CR, 47% AML in 1st CR and 8% AML in 2nd CR. 73% received cyclosporine and Methotrexate for GVHD prophylaxis. In a preliminary model, using grade 3-4 acute GVHD as the endpoint, we identified two cut points, 2 years and 13 years using the likelihood ratio test. In all final models, three age groups were used to define recipient age: < 2 years (n=60), 2 to 12.99 (n=255) years and 13-17.99 years (n=162). The cumulative incidence of grade 2-4 acute GVHD at 100 days post-transplant was 19% (95% confidence interval, CI, 16-23%); 24% (95% CI 14-35%), 13% (95% CI 9-18%) and 28% (95% CI 21-35%) for recipients <2 years, 2-12.99 years, and 13-17.99 years of age, respectively (p-value=0.001). For grade 3-4 acute GVHD, the cumulative incidence estimate at 100 days was 8% (95% CI 3-17%), 3% (95% CI 1-6%) and 14% (95% CI 9-20%) (p <0.001) and the cumulative incidence estimate for chronic GVHD at 1 year was 15% (95% CI 7-25%), 10% (95% CI 7-14%) and 27% (95% CI 20-34%) (p <0.001) for recipients <2 years, 2-12.99 years, and 13-17.99 years of age, respectively (Figures 1-3). In the multivariate analyses, using age 13-17.99 as the baseline and .01 as the threshold for significance, age 2-12.99 years (HR 0.43, 95% CI 0.26-0.71, p=0.001), but not age < 2 years (HR 0.59, 95% CI 0.3-1.18, p=0.14), was associated with a lower risk for grade 2-4 acute GVHD (after adjustment for GVHD prophylaxis, performance score and year of transplant). For grade 3-4 acute GVHD, again age 2-12.99 years (HR 0.24, 95% CI 0.1-0.56, p=0.001), but not age < 2 years (HR 0.75, 95% CI 0.29-1.94, p=0.55), was associated with a lower risk, after adjustment for year of transplant. For chronic GVHD (after adjustment for donor-recipient birth order, and GVHD prophylaxis), age 2-12.99 years (HR 0.32, 95% CI 0.19-0.54, p<0.001) was associated with lower risk; the effect was similar in age < 2 years, but did not reach significance (HR 0.36, 95% CI 0.16-0.82, p=0.016). Year of transplant had a strong effect on acute, but not chronic GVHD. Its effect did not appear to be mediated by changes in GVHD prophylaxis. Using 2000-2004 as the baseline, the HR for grade 2-4 acute GVHD was 0.38 (95% CI 0.20-0.64, p=0.0006) and 0.28 (95% CI 0.13-0.59, p=0.0008) for 2005-2008 and 2009-2013, respectively. For grade 3-4 acute GVHD, they were 0.23 (95% CI 0.08-0.65, p=0.0057) and 0.23 (95% CI 0.07-0.78, p=0.0183) for these periods, respectively. There was no difference in overall survival, leukemia-free survival or transplant related mortality between the age groups. Conclusion: Our results indicate that children 2-12.99 years have a lower risk for acute and chronic GVHD than those 13 years and older. Children less than 2 years may also have a reduced risk for chronic GVHD, but this possibility needs to be re-examined in a larger sample. It is plausible that pubertal changes underlie the rise in risk for GVHD during adolescence. An important limitation of our study was that we were unable to examine the impact of donor age because of the strong correlation between donor and recipient age. A study with a larger sample is also needed to further investigate this matter. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.