Recipient Comorbidities for Prediction of Primary Graft Dysfunction, Chronic Allograft Dysfunction and Survival After Lung Transplantation

Since candidates with comorbidities are increasingly referred for lung transplantation, knowledge about comorbidities and their cumulative effect on outcomes is scarce. We retrospectively collected pretransplant comorbidities of all 513 adult recipients transplanted at our center between 1992–2019. Multiple logistic- and Cox regression models, adjusted for donor-, pre- and peri-operative variables, were used to detect independent risk factors for primary graft dysfunction grade-3 at 72 h (PGD3-T72), onset of chronic allograft dysfunction grade-3 (CLAD-3) and survival. An increasing comorbidity burden measured by Charleston-Deyo-Index was a multivariable risk for survival and PGD3-T72, but not for CLAD-3. Among comorbidities, congestive right heart failure or a mean pulmonary artery pressure >25 mmHg were independent risk factors for PGD3-T72 and survival, and a borderline risk for CLAD-3. Left heart failure, chronic atrial fibrillation, arterial hypertension, moderate liver disease, peptic ulcer disease, gastroesophageal reflux, diabetes with end organ damage, moderate to severe renal disease, osteoporosis, and diverticulosis were also independent risk factors for survival. For PGD3-T72, a BMI>30 kg/m2 was an additional independent risk. Epilepsy and a smoking history of the recipient of >20packyears are additional independent risk factors for CLAD-3. The comorbidity profile should therefore be closely considered for further clinical decision making in candidate selection

The potential effect of improved provision of rabies post-exposure prophylaxis in Gavi-eligible countries: a modelling study

Background: Tens of thousands of people die from dog-mediated rabies annually. Deaths can be prevented through post-exposure prophylaxis for people who have been bitten, and the disease eliminated through dog vaccination. Current post-exposure prophylaxis use saves many lives, but availability remains poor in many rabies-endemic countries due to high costs, poor access, and supply. Methods: We developed epidemiological and economic models to investigate the effect of an investment in post-exposure prophylaxis by Gavi, the Vaccine Alliance. We modelled post-exposure prophylaxis use according to the status quo, with improved access using WHO-recommended intradermal vaccination, with and without rabies immunoglobulin, and with and without dog vaccination. We took the health provider perspective, including only direct costs. Findings: We predict more than 1 million deaths will occur in the 67 rabies-endemic countries considered from 2020 to 2035, under the status quo. Current post-exposure prophylaxis use prevents approximately 56 000 deaths annually. Expanded access to, and free provision of, post-exposure prophylaxis would prevent an additional 489 000 deaths between 2020 and 2035. Under this switch to efficient intradermal post-exposure prophylaxis regimens, total projected vaccine needs remain similar (about 73 million vials) yet 17·4 million more people are vaccinated, making this an extremely cost-effective method, with costs of US$635 per death averted and$33 per disability-adjusted life-years averted. Scaling up dog vaccination programmes could eliminate dog-mediated rabies over this time period; improved post-exposure prophylaxis access remains cost-effective under this scenario, especially in combination with patient risk assessments to reduce unnecessary post-exposure prophylaxis use. Interpretation: Investing in post-exposure vaccines would be an extremely cost-effective intervention that could substantially reduce disease burden and catalyse dog vaccination efforts to eliminate dog-mediated rabies. Funding: World Health Organization

Probabilistic transmission models incorporating sequencing data for healthcare-associated Clostridioides difficile outperform heuristic rules and identify strain-specific differences in transmission

Fitting stochastic transmission models to electronic patient data can offer detailed insights into the transmission of healthcare-associated infections and improve infection control. Pathogen whole-genome sequencing may improve the precision of model inferences, but computational constraints have limited modelling applications predominantly to small datasets and specific outbreaks, whereas large-scale sequencing studies have mostly relied on simple rules for identifying/excluding plausible transmission. We present a novel approach for integrating detailed epidemiological data on patient contact networks in hospitals with large-scale pathogen sequencing data. We apply our approach to study Clostridioides difficile transmission using a dataset of 1223 infections in Oxfordshire, UK, 2007–2011. 262 (21% [95% credibility interval 20–22%]) infections were estimated to have been acquired from another known case. There was heterogeneity by sequence type (ST) in the proportion of cases acquired from another case with the highest rates in ST1 (ribotype-027), ST42 (ribotype-106) and ST3 (ribotype-001). These same STs also had higher rates of transmission mediated via environmental contamination/spores persisting after patient discharge/recovery; for ST1 these persisted longer than for most other STs except ST3 and ST42. We also identified variation in transmission between hospitals, medical specialties and over time; by 2011 nearly all transmission from known cases had ceased in our hospitals. Our findings support previous work suggesting only a minority of C. difficile infections are acquired from known cases but highlight a greater role for environmental contamination than previously thought. Our approach is applicable to other healthcare-associated infections. Our findings have important implications for effective control of C. difficile

A metapopulation model of dog rabies transmission in N'Djamena, Chad.

Rabies transmission was interrupted for several months in N'Djamena, the capital city of Chad, after two mass vaccination campaigns of dogs. However, there was a resurgence in cases, which was not predicted by previous models of rabies transmission. We developed a deterministic metapopulation model with importation of latent dogs, calibrated to four years of weekly incidence data from passive surveillance, to investigate possible causes for the early resurgence. Our results indicate that importation of latently infective dogs better explains the data than heterogeneity or underreporting. Stochastic implementations of the model suggest that the two vaccination campaigns averted approximately 67 cases of dog rabies (out of an estimated 74 cases without vaccination) and 124 human exposures (out of an estimated 148 human exposures without vaccination) over two years. Dog rabies vaccination is therefore an effective way of preventing rabies in the dog population and to subsequently reduce human exposure. However, vaccination campaigns have to be repeated to maintain the effect or reintroduction through importation has to be prevented

The importance of dog population contact network structures in rabies transmission.

Canine rabies transmission was interrupted in N'Djaména, Chad, following two mass vaccination campaigns. However, after nine months cases resurged with re-establishment of endemic rabies transmission to pre-intervention levels. Previous analyses investigated district level spatial heterogeneity of vaccination coverage, and dog density; and importation, identifying the latter as the primary factor for rabies resurgence. Here we assess the impact of individual level heterogeneity on outbreak probability, effectiveness of vaccination campaigns and likely time to resurgence after a campaign. Geo-located contact sensors recorded the location and contacts of 237 domestic dogs in N'Djaména over a period of 3.5 days. The contact network data showed that urban dogs are socially related to larger communities and constrained by the urban architecture. We developed a network generation algorithm that extrapolates this empirical contact network to networks of large dog populations and applied it to simulate rabies transmission in N'Djaména. The model predictions aligned well with the rabies incidence data. Using the model we demonstrated, that major outbreaks are prevented when at least 70% of dogs are vaccinated. The probability of a minor outbreak also decreased with increasing vaccination coverage, but reached zero only when coverage was near total. Our results suggest that endemic rabies in N'Djaména may be explained by a series of importations with subsequent minor outbreaks. We show that highly connected dogs hold a critical role in transmission and that targeted vaccination of such dogs would lead to more efficient vaccination campaigns

Transmission dynamics and elimination potential of zoonotic tuberculosis in Morocco

Bovine tuberculosis (BTB) is an endemic zoonosis in Morocco caused by Mycobacterium bovis, which infects many domestic animals and is transmitted to humans through consumption of raw milk or from contact with infected animals. The prevalence of BTB in Moroccan cattle is estimated at 18%, and 33% at the individual and the herd level respectively, but the human M. bovis burden needs further clarification. The current control strategy based on test and slaughter should be improved through local context adaptation taking into account a suitable compensation in order to reduce BTB prevalence in Morocco and decrease the disease burden in humans and animals. We established a simple compartmental deterministic mathematical model for BTB transmission in cattle and humans to provide a general understanding of BTB, in particular regarding transmission to humans. Differential equations were used to model the different pathways between the compartments for cattle and humans. Scenarios of test and slaughter were simulated to determine the effects of varying the proportion of tested animals (p) on the time to elimination of BTB (individual animal prevalence of less than one in a thousand) in cattle and humans. The time to freedom from disease ranged from 75 years for p = 20% to 12 years for p = 100%. For p > 60% the time to elimination was less than 20 years. The cumulated cost was largely stable: for p values higher than 40%, cost ranged from 1.47 to 1.60 billion euros with a time frame of 12 to 32 years to reach freedom from disease. The model simulations also suggest that using a 2mm cut off instead of a 4mm cut off in the Single Intradermal Comparative Cervical Tuberculin skin test (SICCT) would result in cheaper and quicker elimination programs. This analysis informs Moroccan bovine tuberculosis control policy regarding time frame, range of cost and levels of intervention. However, further research is needed to clarify the national human-bovine tuberculosis ratio in Morocco

Transmission dynamics and elimination potential of zoonotic tuberculosis in Morocco

Bovine tuberculosis (BTB) is an endemic zoonosis in Morocco caused by Mycobacterium bovis, which infects many domestic animals and is transmitted to humans through consumption of raw milk or from contact with infected animals. The prevalence of BTB in Moroccan cattle is estimated at 18%, and 33% at the individual and the herd level respectively, but the human M. bovis burden needs further clarification. The current control strategy based on test and slaughter should be improved through local context adaptation taking into account a suitable compensation in order to reduce BTB prevalence in Morocco and decrease the disease burden in humans and animals. We established a simple compartmental deterministic mathematical model for BTB transmission in cattle and humans to provide a general understanding of BTB, in particular regarding transmission to humans. Differential equations were used to model the different pathways between the compartments for cattle and humans. Scenarios of test and slaughter were simulated to determine the effects of varying the proportion of tested animals (p) on the time to elimination of BTB (individual animal prevalence of less than one in a thousand) in cattle and humans. The time to freedom from disease ranged from 75 years for p = 20% to 12 years for p = 100%. For p > 60% the time to elimination was less than 20 years. The cumulated cost was largely stable: for p values higher than 40%, cost ranged from 1.47 to 1.60 billion euros with a time frame of 12 to 32 years to reach freedom from disease. The model simulations also suggest that using a 2mm cut off instead of a 4mm cut off in the Single Intradermal Comparative Cervical Tuberculin skin test (SICCT) would result in cheaper and quicker elimination programs. This analysis informs Moroccan bovine tuberculosis control policy regarding time frame, range of cost and levels of intervention. However, further research is needed to clarify the national human-bovine tuberculosis ratio in Morocco