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Association between COVID-19 and Male Fertility: Systematic Review and Meta-Analysis of Observational Studies.
Wang, S, Zhang, A, Pan, Y, Liu, L, Niu, S, Zhang, F, Liu, X
The world journal of men's health. 2023;41(2):311-329
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Several studies have been published documenting possible relationships between Covid-19 and male infertility, but it remains unclear whether Covid-19 affects sperm quality and sex hormones. This meta-analysis and systematic review of observational studies aimed to determine any relationship between Covid-19 infection and male fertility. The results showed that Covid-19 decreased sperm count, sperm concentration, motility, but had no effect on semen volume, immotility, normal morphology or nonprogressive sperm motility. Infection also affected some hormone levels and that effects on hormones were dependent on age of infection onset. Covid-19 infection with or without fever also differentially affected outcomes with those with fever having reduced sperm concentration and progressive sperm motility, which was not seen in those who did not experience fever. Disease severity also affected outcomes with those with moderate Covid-19 having reduced sperm motility, which was not seen in individuals who had mild disease. It was concluded that Covid-19 infection reduced sperm quality and disrupted sex hormones. This study could be used by healthcare professionals to understand that Covid-19 infection may affect the fertility of men.
Abstract
PURPOSE Whether COVID-19 reduces male fertility remains requires further investigation. This meta-analysis and systematic review evaluated the impact of COVID-19 on male fertility. MATERIALS AND METHODS The literature in PubMed, Embase, MEDLINE, Web of Science, and Cochrane Library up to January 01, 2022 was systematically searched, and a meta-analysis was conducted to investigate the effect of COVID-19 on male fertility. Totally 17 studies with a total of 1,627 patients and 1,535 control subjects were included in our meta-analysis. RESULTS Regarding sperm quality, COVID-19 decreased the total sperm count (p=0.012), sperm concentration (p=0.001), total motility (p=0.001), progressive sperm motility (p=0.048), and viability (p=0.031). Subgroup analyses showed that different control group populations did not change the results. It was found that during the illness stage of COVID-19, semen volume decreased, and during the recovery stage of COVID-19, sperm concentration and total motility decreased <90 days. We found that sperm concentration and total motility decreased during recovery for ≥90 days. Fever because of COVID-19 significantly reduced sperm concentration and progressive sperm motility, and COVID-19 without fever ≥90 days, the sperm total motility and progressive sperm motility decreased. Regarding disease severity, the moderate type of COVID-19 significantly reduced sperm total motility, but not the mild type. Regarding sex hormones, COVID-19 increased prolactin and estradiol. Subgroup analyses showed that during the illness stage, COVID-19 decreased testosterone (T) levels and increased luteinizing hormone levels. A potential publication bias may have existed in our meta-analysis. CONCLUSIONS COVID-19 in men significantly reduced sperm quality and caused sex hormone disruption. COVID-19 had long-term effects on sperm quality, especially on sperm concentration and total motility. It is critical to conduct larger multicenter studies to determine the consequences of COVID-19 on male fertility.
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Age-Dependent Relationships Between Disease Risk and Testosterone Levels: Relevance to COVID-19 Disease.
Muehlenbein, M, Gassen, J, Nowak, T, Henderson, A, Morris, B, Weaver, S, Baker, E
American journal of men's health. 2023;17(2):15579883221130195
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A growing body of research finds that in men, testosterone levels may be prognostic of clinical outcomes related to coronavirus disease 2019 (COVID-19 disease). The presence of pre-existing chronic conditions in many patients with COVID-19 disease further complicates the relationship among testosterone and severe outcomes. The aim of this study was to examine whether pre-existing conditions for severe COVID-19 disease were related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This study obtained data from men (n = 142) who participated in the longitudinal study Waco COVID Survey. All data included in the study was collected as part of the initial intake survey and first laboratory appointment. Results show that serum-free testosterone levels decreased as a function of age. In fact, greater burden of pre-existing conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. Furthermore, in men older than 40 years of age the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Authors conclude that their findings add important insights into the complex role of androgens in chronic and infectious diseases and contribute to the growing body of literature on the relationship between chronic disease and men’s testosterone levels.
Abstract
Testosterone levels in men appear to be prognostic of a number of disease outcomes, including severe COVID-19 disease. Testosterone levels naturally decline with age and are lower in individuals with a number of comorbidities and chronic conditions. Low testosterone may therefore be both a cause and a consequence of illness, including COVID-19 disease. The present project examines whether preexisting conditions for severe COVID-19 disease were themselves related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. A clinical risk score for severe COVID-19 disease was computed based on the results of previously published meta-analyses and cohort studies, and relationships between this score and testosterone levels were tested in 142 men ages 19 to 82 years. Greater burden of preexisting conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. In older men, the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Given that older age itself is a predictor of COVID-19 disease severity, these results together suggest that the presence of preexisting conditions may confound the relationship between testosterone levels and COVID-19 disease outcomes in men. Future research examining relationships among testosterone and outcomes related to infectious and chronic diseases should consider potential confounds, such as the role of preexisting conditions.
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Effects of mild/asymptomatic COVID-19 on semen parameters and sex-related hormone levels in men: a systematic review and meta-analysis.
Che, BW, Chen, P, Yu, Y, Li, W, Huang, T, Zhang, WJ, Xu, SH, He, J, Liu, M, Tang, KF
Asian journal of andrology. 2023;25(3):382-388
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Various studies have shown that coronavirus disease 2019 (COVID-19) can cause more harm and a higher mortality rate to men. However, the literature does not clearly show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause serious and lasting damage to male reproductive function. The aims of this study were to explore the effects of mild/asymptomatic COVID-19 on semen parameters and sex-related hormone levels and to analyse the relationship between semen parameter values and semen collection time after infection, fever, and severity of COVID-19. This study is a systematic review and meta-analysis of thirteen studies of which only five were included in the meta-analysis. Results show that COVID-19 has a certain effect on male reproductive function in the short term especially within about 70 days after infection. Additionally, fever after infection only had a significant effect on sperm concentration. Authors conclude by recommending the avoidance of pregnancy for a short period of time when the male partner has been infected with COVID-19.
Abstract
Coronavirus disease 2019 (COVID-19) has yet to be proven to alter male reproductive function, particularly in the majority of mild/asymptomatic patients. The purpose of this study was to explore whether mild/asymptomatic COVID-19 affects semen quality and sex-related hormone levels. To find suitable comparative studies, a systematic review and meta-analysis was done up to January 22, 2022, by using multiple databases (Web of Science, PubMed, and Embase). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to identify and choose the studies. Meta-analysis was used to examine the semen parameters and sex-related hormones of mild/asymptomatic COVID-19 patients before and after infection. The effects of semen collection time, fever, and intensity of verification on semen following infection were also investigated. A total of 13 studies (n = 770) were included in the analysis, including three case-control studies, six pre-post studies, and four single-arm studies. A meta-analysis of five pre-post studies showed that after infection with COVID-19, sperm concentration (I2 = 0; P = 0.003), total sperm count (I2 = 46.3%; P = 0.043), progressive motility (I2 = 50.0%; P < 0.001), total sperm motility (I2 = 76.1%; P = 0.047), and normal sperm morphology (I2 = 0; P = 0.001) decreased. Simultaneously, a systematic review of 13 studies found a significant relationship between semen collection time after infection, inflammation severity, and semen parameter values, with fever having only bearing on semen concentration. Furthermore, there was no significant difference in sex-related hormone levels before and after infection in mild/asymptomatic patients. Mild/asymptomatic COVID-19 infection had a significant effect on semen quality in the short term. It is recommended to avoid initiating a pregnancy during this period of time.
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SARS-CoV-2 effects on sperm parameters: a meta-analysis study.
Xie, Y, Mirzaei, M, Kahrizi, MS, Shabestari, AM, Riahi, SM, Farsimadan, M, Roviello, G
Journal of assisted reproduction and genetics. 2022;39(7):1555-1563
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Infertility is a reproductive system disorder. Viruses as a major cause of fertility problems can potentially interfere with reproductive function in men. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found to be the causing viral pathogen of COVID-19 and capable of affecting human health. The aim of this study was to evaluate the effects of SARS-CoV-2 on different semen parameters including sperm count, sperm concentration, volume, motility, and progressive motility. This study is a meta-analysis of twelve studies of which seven were case control studies and five were retrospective cohort studies. Results show that SARS-CoV-2 infection could lead to significant impairments of male reproductive function through exerting negative influences on different semen parameters namely semen volume, sperm concentration, sperm count, and sperm motility. Authors conclude that their findings revealed the vulnerability of semen quality to SARS-CoV-2 infection.
Abstract
AIM: The rapid outbreak of the coronavirus disease 2019 (COVID-19) pandemic posed challenges across different medical fields, especially reproductive health, and gave rise to concerns regarding the effects of SARS-CoV-2 on male infertility, owing to the fact that the male reproductive system indicated to be extremely vulnerable to SARS-CoV-2 infection. Only a small number of studies have investigated the effects of SARS-CoV-2 on male reproduction, but the results are not consistent. So, we performed this meta-analysis to draw a clearer picture and evaluate the impacts of COVID-19 on male reproductive system. METHOD We searched Embase, Web of Science, PubMed, and Google Scholar databases to identify the potentially relevant studies. Standardized mean difference (SMD) with 95% confidence interval (CI) was applied to assess the relationship. Heterogeneity testing, sensitivity analysis, and publication bias testing were also performed. RESULTS A total of twelve studies including 7 case control investigations and 5 retrospective cohort studies were found relevant and chosen for our research. Our result showed that different sperm parameters including semen volume [SMD = - 0.27 (- 0.46, - 1.48) (p = 0.00)], sperm concentration [SMD = - 0.41 (- 0.67, - 0.15) (p = 0.002)], sperm count [SMD = - 0.30 (- 0.44, - 0.17) (p = 0.00)], sperm motility [SMD = - 0.66 (- 0.98, - 0.33) (p = 0.00)], and progressive motility [SMD = - 0.35 (- 0.61, - 0.08) (p = 0.01)] were negatively influenced by SARS-CoV-2 infection. However, sperm concentration (p = 0.07) and progressive motility (p = 0.61) were not found to be significantly associated with SARS-CoV-2 infection in case control studies. No publication bias was detected. CONCLUSION The present study revealed the vulnerability of semen quality to SARS-CoV-2 infection. Our data showed a strong association of different sperm parameters with SARS-CoV-2 infection. The results suggested that SARS-CoV-2 infection in patients may negatively influence their fertility potential in a short-term period, but more studies are needed to decide about the long-term effects.
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Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths.
Grant, WB, Lahore, H, McDonnell, SL, Baggerly, CA, French, CB, Aliano, JL, Bhattoa, HP
Nutrients. 2020;12(4)
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This narrative review article looks at the role of Vitamin D in reducing the risk of respiratory tract infections, in relation to the incidence and prevalence of influenza and COVID-19. It also discusses how Vitamin D testing and optimisation with supplementation might be a simple measure to reduce risk. The authors site evidence supporting the possible role of Vitamin D: the fact that the outbreak occurred in winter when Vitamin D concentrations are lowest; vitamin D deficiency has been shown to contribute to acute respiratory distress; and case fatality rates increasing with age and incidence of underlying conditions, both of which are associated with lower Vitamin D concentrations. The authors goal is to raise Vitamin D concentrations to 100-150 nmol/l. Nutrition Practitioners wanting to support overall health and resilience to seasonal viral infections may want to consider testing and supplementing Vitamin D.
Abstract
The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40-60 ng/mL (100-150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
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Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes.
Zhu, L, She, ZG, Cheng, X, Qin, JJ, Zhang, XJ, Cai, J, Lei, F, Wang, H, Xie, J, Wang, W, et al
Cell metabolism. 2020;31(6):1068-1077.e3
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The novel coronavirus disease 2019 (COVID-19) is caused by infection from the newly emerged, highly contagious coronavirus SARS-CoV-2. The aim of this study was to analyse the association between plasma glucose levels and clinic outcomes in COVID-19 patients with type 2 diabetes (T2D). The study is a retrospective longitudinal, multi-centre study from a cohort of 7,337 COVID-19 cases enrolled among 19 hospitals. Results show that patients with pre-existing T2D received significantly more intensive integrated treatments to manage their symptoms of COVID-19 than the non-diabetic subjects. Furthermore, findings indicate that well-controlled blood glucose was associated with a markedly improved outcome of patients with COVID-19 and pre-existing T2D. Authors conclude that T2D is an important risk factor for COVID-19 progression and adverse endpoints, and well-controlled blood glucose is associated with a significant reduction in the composite adverse outcomes and death.
Abstract
Type 2 diabetes (T2D) is a major comorbidity of COVID-19. However, the impact of blood glucose (BG) control on the degree of required medical interventions and on mortality in patients with COVID-19 and T2D remains uncertain. Thus, we performed a retrospective, multi-centered study of 7,337 cases of COVID-19 in Hubei Province, China, among which 952 had pre-existing T2D. We found that subjects with T2D required more medical interventions and had a significantly higher mortality (7.8% versus 2.7%; adjusted hazard ratio [HR], 1.49) and multiple organ injury than the non-diabetic individuals. Further, we found that well-controlled BG (glycemic variability within 3.9 to 10.0 mmol/L) was associated with markedly lower mortality compared to individuals with poorly controlled BG (upper limit of glycemic variability exceeding 10.0 mmol/L) (adjusted HR, 0.14) during hospitalization. These findings provide clinical evidence correlating improved glycemic control with better outcomes in patients with COVID-19 and pre-existing T2D.
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Targeting the Adipose Tissue in COVID-19.
Malavazos, AE, Corsi Romanelli, MM, Bandera, F, Iacobellis, G
Obesity (Silver Spring, Md.). 2020;28(7):1178-1179
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A UK study showed that 72% of COVID-19 patients in critical care units had either overweight or obesity, whilst studies in Italy have shown that 99% of deaths occurred in patients who had at least one underlying chronic condition, including obesity, diabetes and hypertension. As obesity is tightly connected with diabetes and other inflammatory conditions, it is difficult to separate the effects of the obesity per se, from other chronic conditions that are commonly associated with the obesity. The authors discuss possible molecular mechanisms by which the fat tissue itself may increase the risk of more severe COVID-19 disease, such as angiotensin converting enzyme 2 (ACE2) receptors and dipeptidyl peptidase 4 (two receptors which occur in fat tissue and may be entry points of the virus into the cell) and an imbalance between the secretion of anti‐ and proinflammatory compounds from visceral fat cells. The authors conclude that the role of the adipose (fat) tissue during infectious diseases, such as COVID‐19, could be important and note that this is a modifiable risk factor.
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Melatonin: Roles in influenza, Covid-19, and other viral infections.
Anderson, G, Reiter, RJ
Reviews in medical virology. 2020;30(3):e2109
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Viruses like influenza and coronaviruses change quickly, making it challenging to develop effective treatments and vaccines in a short time frame. Consequently, the use of generic substances that limit viral effects are of high interest. In this paper, the authors summarize a range of mechanisms in which melatonin can alter the impact of virus infections and infection-associated inflammatory overdrive aka cytokine storm. Melatonin, the sleep hormone, is well known for its potent antioxidant and anti-inflammatory action. It seems highly likely that melatonin can modulate the cellular function of all cells, mostly via mitochondrial function. This is particularly relevant in immune cells. For example, the daytime variance in immune function seems to be closely linked with mitochondrial activity and energy production. Other relevant mechanisms described are the antiviral role of melatonin-induced sirtuins - proteins that regulate cellular health-, the impact of viruses on cell coordinating microRNA, the role of the gut microbiome and gut permeability, as well as sympathetic nervous system activation and the protective effects of parasympathetic activation. Also considered are pre-existing health conditions and conditions that are linked with a decline in melatonin along with ageing, all being groups in which severity of viral infections is felt. This paper may be of interest to those who like to explore in more depth the mechanisms behind melatonin and its ability to influence viral disease progression.
Abstract
There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid-19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial "cytokine storm", as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian "resetting" of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl-CoA is a necessary cosubstrate for arylalkylamine N-acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus- and cytokine-storm-driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus-and cytokine storm-driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid-19 and other viral infections.
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Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched.
Muller, AE, Tveito, K, Bakken, IJ, Flottorp, SA, Mjaaland, S, Larun, L
Journal of translational medicine. 2020;18(1):484
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Chronic fatigue syndrome /myalgic encephalomyelitis (CFS/ME) is complex and probably triggered by several interconnected factors and the identification of these is essential to develop better treatments and preventative measures. This systematic scoping review of 1161 studies aimed to discuss potential causal factors of CFS/ME. The results showed that there were several main causal factors that were investigated in the literature and no single factor dominated the research; immunological, psychological/psychosocial/socioeconomic, infectious, and neuroendocrinal/hormonal/metabolic. Studies varied in their design and methods. Interestingly research in this area was at its highest before 1995 and from 2015-2019, studies have markedly decreased. It was concluded that large variations in methods and design of studies of causal factor studies, is problematic. More large, well designed studies are required especially as research has declined recently and considering post covid-19 fatigue. This study could be used by healthcare professionals to understand where there are gaps in the research to design more robust studies in the future.
Abstract
BACKGROUND Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is understood as a complex condition, likely triggered and sustained by an interplay of biological, psychological, and social factors. Little oversight exists of the field of causal research. This systematic scoping review explores potential causal factors of CFS/ME as researched by primary studies. METHODS We searched eight databases for primary studies that examined potential causal factors of CFS/ME. Based on title/abstract review, two researchers independently sorted each study's factors into nine main categories and 71 subordinate categories, using a system developed with input given during a 2018 ME conference, specialists and representatives from a ME patient advocacy group, and using BMJ Best Practice's description of CFS/ME etiology. We also extracted data related to study design, size, diagnostic criteria and comparison groups. RESULTS We included 1161 primary studies published between January 1979 and June 2019. Based on title/abstract analysis, no single causal factor dominated in these studies, and studies reported a mean of 2.73 factors. The four most common factors were: immunological (297 studies), psychological (243), infections (198), and neuroendocrinal (198). The most frequent study designs were case-control studies (894 studies) comparing CFS/ME patients with healthy participants. More than half of the studies (that reported study size in the title/abstract) included 100 or fewer participants. CONCLUSION The field of causal hypotheses of CFS/ME is diverse, and we found that the studies examined all the main categories of possible factors that we had defined a priori. Most studies were not designed to adequately explore causality, rather to establish hypotheses. We need larger studies with stronger study designs to gain better knowledge of causal factors of CFS/ME.
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Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study.
Holman, N, Knighton, P, Kar, P, O'Keefe, J, Curley, M, Weaver, A, Barron, E, Bakhai, C, Khunti, K, Wareham, NJ, et al
The lancet. Diabetes & endocrinology. 2020;8(10):823-833
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Diabetes, cardiovascular disease, and hypertension are the most common chronic conditions predisposing people to severe COVID-19 disease. The aim of this population-based cohort study, using data from 98% of general practices in England, was to investigate the associations between various risk factors, including poor blood sugar control, and COVID-19-related deaths in people with type 1 and type 2 diabetes. Between Feb 16 and May 11, 2020, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes, of which almost 30% had COVID-19 listed on the death certificate, either a primary underlying or secondary cause of death. Male gender, age and being of Black or Asian ethnicity were associated with an increased mortality from COVID-19. Poor blood sugar control, as determined by HbA1C, prior to infection was strongly associated with COVID-19-related death, independent of other risk factors. Obesity (BMI of 30 or over) as well as being underweight were also significantly associated with COVID-19 mortality. The authors discuss that people with diabetes are at increased risk of many serious infections and that high blood glucose levels are known to impair immunity and may amplify the hyperimmune response associated with severe COVID-19.
Abstract
BACKGROUND Diabetes has been associated with increased COVID-19-related mortality, but the association between modifiable risk factors, including hyperglycaemia and obesity, and COVID-19-related mortality among people with diabetes is unclear. We assessed associations between risk factors and COVID-19-related mortality in people with type 1 and type 2 diabetes. METHODS We did a population-based cohort study of people with diagnosed diabetes who were registered with a general practice in England. National population data on people with type 1 and type 2 diabetes collated by the National Diabetes Audit were linked to mortality records collated by the Office for National Statistics from Jan 2, 2017, to May 11, 2020. We identified the weekly number of deaths in people with type 1 and type 2 diabetes during the first 19 weeks of 2020 and calculated the percentage change from the mean number of deaths for the corresponding weeks in 2017, 2018, and 2019. The associations between risk factors (including sex, age, ethnicity, socioeconomic deprivation, HbA1c, renal impairment [from estimated glomerular filtration rate (eGFR)], BMI, tobacco smoking status, and cardiovascular comorbidities) and COVID-19-related mortality (defined as International Classification of Diseases, version 10, code U07.1 or U07.2 as a primary or secondary cause of death) between Feb 16 and May 11, 2020, were investigated by use of Cox proportional hazards models. FINDINGS Weekly death registrations in the first 19 weeks of 2020 exceeded the corresponding 3-year weekly averages for 2017-19 by 672 (50·9%) in people with type 1 diabetes and 16 071 (64·3%) in people with type 2 diabetes. Between Feb 16 and May 11, 2020, among 264 390 people with type 1 diabetes and 2 874 020 people with type 2 diabetes, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes. Of these total deaths, 464 in people with type 1 diabetes and 10 525 in people with type 2 diabetes were defined as COVID-19 related, of which 289 (62·3%) and 5833 (55·4%), respectively, occurred in people with a history of cardiovascular disease or with renal impairment (eGFR <60 mL/min per 1·73 m2). Male sex, older age, renal impairment, non-white ethnicity, socioeconomic deprivation, and previous stroke and heart failure were associated with increased COVID-19-related mortality in both type 1 and type 2 diabetes. Compared with people with an HbA1c of 48-53 mmol/mol (6·5-7·0%), people with an HbA1c of 86 mmol/mol (10·0%) or higher had increased COVID-19-related mortality (hazard ratio [HR] 2·23 [95% CI 1·50-3·30, p<0·0001] in type 1 diabetes and 1·61 [1·47-1·77, p<0·0001] in type 2 diabetes). In addition, in people with type 2 diabetes, COVID-19-related mortality was significantly higher in those with an HbA1c of 59 mmol/mol (7·6%) or higher than in those with an HbA1c of 48-53 mmol/mol (HR 1·22 [95% CI 1·15-1·30, p<0·0001] for 59-74 mmol/mol [7·6-8·9%] and 1·36 [1·24-1·50, p<0·0001] for 75-85 mmol/mol [9·0-9·9%]). The association between BMI and COVID-19-related mortality was U-shaped: in type 1 diabetes, compared with a BMI of 25·0-29·9 kg/m2, a BMI of less than 20·0 kg/m2 had an HR of 2·45 (95% CI 1·60-3·75, p<0·0001) and a BMI of 40·0 kg/m2 or higher had an HR of 2·33 (1·53-3·56, p<0·0001); the corresponding HRs for type 2 diabetes were 2·33 (2·11-2·56, p<0·0001) and 1·60 (1·47-1·75, p<0·0001). INTERPRETATION Deaths in people with type 1 and type 2 diabetes rose sharply during the initial COVID-19 pandemic in England. Increased COVID-19-related mortality was associated not only with cardiovascular and renal complications of diabetes but, independently, also with glycaemic control and BMI. FUNDING None.