key: cord-0962227-poriivyk
authors: Monterrubio-Flores, Eric; Ramírez-Villalobos, María D; Espinosa-Montero, Juan; Hernandez, Bernardo; Barquera, Simón; Villalobos-Daniel, Victor E; Campos-Nonato, Ismael
title: Characterizing a two-pronged epidemic in Mexico of non-communicable diseases and SARS-Cov-2: factors associated with increased case-fatality rates
date: 2021-02-15
journal: Int J Epidemiol
DOI: 10.1093/ije/dyab008
sha: bcf2cfa495a2b573abc09adef996ff2462f770b4
doc_id: 962227
cord_uid: poriivyk

BACKGROUND: People with a previous diagnosis of non-communicable diseases (NCDs) are more likely to develop serious forms of COVID-19 or die. Mexico is the country with the fourth highest fatality rate from SARS-Cov-2, with high mortality in younger adults. OBJECTIVES: To describe and characterize the association of NCDs with the case-fatality rate (CFR) adjusted by age and sex in Mexican adults with a positive diagnosis for SARS-Cov-2. METHODS: We studied Mexican adults aged ≥20 years who tested positive for SARS-Cov-2 during the period from 28 February to 31 July 2020. The CFR was calculated and associations with history of NCDs (number of diseases and combinations), severity indicators and type of institution that treated the patient were explored. The relative risk (RR) of death was estimated using Poisson models and CFR was adjusted using logistic models. RESULTS: We analysed 406 966 SARS-Cov-2-positive adults. The CFR was 11.2% (13.7% in men and 8.4% in women). The CFR was positively associated with age and number of NCDs (p trend <0.001). The number of NCDs increased the risk of death in younger adults when they presented three or more NCDs compared with those who did not have any NCDs [RR, 46.6; 95% confidence interval (CI), 28.2, 76.9 for women; RR, 16.5; 95% CI, 9.9, 27.3 for men]. Lastly, there was great heterogeneity in the CFR by institution, from 4.6% in private institutions to 18.9% in public institutions. CONCLUSION: In younger adults, higher CFRs were associated with the total number of NCDs and some combinations of type 2 diabetes, chronic kidney disease, chronic obstructive pulmonary disease and cardiovascular disease.

The severe acute respiratory syndrome coronavirus 2 disease (COVID-19) 1 can produce mild respiratory symptoms that remit naturally. 2 However, in some cases, it can also evolve into acute respiratory distress syndrome, causing multiple-organ failure and death. 3 As of 8 November 2020, >50.3 million people have been infected with SARS-Cov-2 worldwide and >1.254 million have died from this cause. When comparing the mortality rate per 100 000 inhabitants during this period, Mexico had the sixth highest mortality rate and had officially tested 2.568 million people, reaching 961 938 positive cases. 4 People with a previous diagnosis of non-communicable diseases (NCDs) such as high blood pressure (HBP), type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD), 5, 6 as well as those who are older or male, are more likely to develop serious conditions of COVID-19 or die from this cause. 7 In China, the fatality rate (number of deaths per 100 infected) for COVID-19 was 2.3%. However, it was 6.0% for people with hypertension, 7.3% for adults with diabetes and 10.5% for people with cardiovascular disease. 8 On the one hand, differences were observed in the hazard ratio (HR) of people who developed severe symptoms or died, being higher in men (HR 1.6) than in women (HR 1.0) and in people !65 years old (HR 1.9) as opposed to those <65 years old (HR 1.0). 9 Epidemiological studies have shown that the risk of mortality from SARS-Cov-2 increases 2.5 times when the patient has HBP, 1.9 times when they have diabetes 10 and 7.9 times when they have CVD. 11 In Mexico, the association between obesity and diabetes with a higher risk of SARS-Cov-2 infection, 12 severity and need for hospitalization has been documented. 13 A recent study has also documented a higher risk of complications at the beginning of hospitalization among patients with SARS-Cov-2 who also had co-morbidities like obesity, hypertension and diabetes. 14 In a country like Mexico, where 49% of adults have hypertension, 15 14% have diabetes 16 and 24% develop CVD, 17 it is important to quantify the risk of death among the population with NCDs and COVID-19. It is also important to consider the role of the health system in providing care to patients with SARS-Cov-2 in cases with and without other NCDs. Understanding the magnitude of this association and its related characteristics can improve targeted strategies that aim to identify adults who are most likely to be infected and die of SARS-Cov-2. Our objective is to describe and characterize the association between NCDs and case-fatality rates (CFRs), adjusting by factors that increase the risk of death, such as age and sex, in Mexican adults with a positive diagnosis of SARS- open to the public and is continuously updated. We analysed data from the beginning of the epidemic (28 February 2020) to 31 July 2020. The database contains information on all outpatients and those hospitalized, as well as on deaths from SARS-Cov-2 in Mexico. 18 

Adults were suspected of having COVID-19 if they reported at least two of the following symptoms within the past 7 days: fever, headache and cough, accompanied by at least one of the following signs: arthralgia, conjunctivitis, pain in the chest, dyspnea, myalgia, odynophagia or rhinorrhea. For all suspected cases, two protocols were followed: testing for SARS-Cov-2 and epidemiological surveillance. 18 As authorized by the National Committee for Epidemiological Surveillance (CONAVE, Spanish acronym), 18 cases were confirmed using the polymerase chain reaction test based on the Berlin protocol. 19 

An adult was considered to have an NCD when the patient reported having been previously diagnosed with: HBP, T2D, obesity (OB), CVD, chronic kidney disease (CKD) or COPD. We selected these NCDs because they are those with the highest prevalence in Mexico and because of their association with greater severity of COVID-19. [15] [16] [17] The instrument used to collect the information was an official standardized questionnaire used by the federal government's Epidemiological Surveillance System. 18 It collects: socio-demographic information (age and sex), personal pathological history (presence of NCDs, date on which the symptoms associated with the infection began and exposure to tobacco), treatment characteristics and indicators of severity such as the presence of pneumonia, need for hospitalization, assistance in the Intensive Care Unit and the use of assisted mechanical intubation (IMA). We classified information on NCDs by number, as follows: no NCDs, one NCD, two NCDs and three or more NCDs.

We included the institution in which patients received care in the analysis. We categorized the healthcare institutions as Private, Ministry of Navy (SEMAR), Federal Ministry of Health (SS), (Red CrossþDIFþMunicipalþUniversity), Ministry of National Defense (SEDENA), not specified, State Secretaries of Health, Petroleos Mexicanos (PEMEX), Institute of Security and Social Services for State Workers (ISSSTE) and Mexican Institute of Social Security (IMSS).

Fatality due to SARS-Cov-2 was calculated through the CFR and expressed in percentages (number of deaths from COVID/total patients identified with COVID in the period described  100) with their 95% confidence intervals (95% CIs).

The CFR was disaggregated by sex, age and NCDs. To assess trends between age groups and the number of NCDs, tests were performed using robust estimates by Bootstrap. The relative risk (RR) was estimated using Poisson models and the probability of death (CFR adjusted) using logistic regression, which in both cases were adjusted in the models for age, sex, the presence of preexisting diseases (asthma, immunosuppression, other comorbidities non-specified) and dummy variables for health institutions. Robust estimates were used in all models. Data analysis was performed using the statistical software STATA 20 and the statistical software R. 21 

The database used in this study included information on 842 025 adults aged !20 years who were tested for COVID-19. Of these, 3600 (0.4%) observations were eliminated for not having information related to NCD diagnosis. We analysed only information on confirmed SARS-Cov-2 cases (n ¼ 406 966). Of these, 53.2% were men (mean age, 47.0 years: 95% CI, 46.9, 47.1) and 46.5% women (mean age, 45.6 years; 95% CI, 45.6, 45.7).

Participants' characteristics by sex are described in Table 1 Table 2 shows the CFR for SARS-Cov-2 by sex and NCDs. In the total population, the average CFR was 12.1% (95% CI, 12.0, 12.2) and was higher among men (CFR 14.6%; 95% CI, 14.5, 14.8) than women (CFR 9.1%; 95% CI, 9.0, 9.3) . Trend analyses showed that the In the group of patients without NCDs and stratified by sex, the CFR was lower in women (3.4%; 95% CI, 3.3, 3.5) than in men (8.0%; 95% CI, 7.8, 8.1). When stratifying by type of institution, the CFR was higher in the IMSS (CFR , 10.7%; 95% CI, 10.5, 10.9), followed by the ISSSTE (CFR, 9.5%; 95% CI, 8.9, 10.1). In patients with at least three NCDs, the CFR was higher in women (CFR, 29.9%; 95% CI, 29.0, 30.0) than in men (CFR, 35.8%; 95% CI, 34.8, 36.7), whereas, when stratifying by type of institution, the CFR was higher in the IMSS (CFR, 44.0%; 95% CI, 42.9, 45.1), followed by the ISSSTE (CFR, 37.5%; 95% CI, 35.0, 40.1). The trend test by number of NCDs was p < 0.001 (Table 3 ). Figure 1 shows that the CFR increases with the number of NCDs in a triple interaction (p < 0.01) with sex and age. Adults aged 20-29 years with at least three NCDs have a greater risk compared with those without NCDs, in women (RR, 46.6; 95% CI, 28.2, 76.9) and men (RR, 16.5; 95% CI, 9.9, 27.3). Moreover, the risk among adults aged !80 years with at least three NCDs compared with those without NCDs is 1.2 in women (95% CI, 1.0, 1.3) and 1.0 in men (95% CI, 0.9, 1.1). The model is shown in Supplementary Appendix 1, available as Supplementary data at IJE online, and Table 1 .

The CFR for SARS-Cov-2 in men and women by number and all possible combinations of NCDs is shown in Supplementary Appendix 2, available as Supplementary data at IJE online, and Table 1 . For two NCDs, the combination with the greatest CFR was T2DþCKD (CFR, 44.0; 95% CI, 39.2, 48.8); for three NCDs, it was T2DþCOPDþCVD (CFR, 57.5; 95% CI, 38.4, 75.8).

When categorizing by number of NCDs (from none to at least three), and disaggregating by age group, a greater risk of mortality for older age was found in all categories, except for T2DþCOPD and CVDþCKD combinations. The combinations with the highest CFR (from 50.0% to 75.0%) were: CVDþHBPþCKDþT2DþOB, CVDþCKD þCOPD, CVDþT2DþCOPD, CVDþHBPþCKDþOBþ COPD, HBPþCKDþT2DþOBþCOPD, CVDþCKDþ T2DþCOPD; and 31 combinations with CFR between 30.0% and 49.0% were observed. The lowest CFRs were with OB or no NCDs ( Figure 2 ). We did not see a specific pattern by sex (Supplementary Appendix 3, available as Supplementary data at IJE online, and Figures 1 and 2) . Figure 3a and b shows that younger adults had a higher RR of death when they had T2D combined with one or more NCDs (women: RR, 12.5; 95% CI, 7.1, 22.2; men: RR, 5.8, CI 95% 3.1, 10.9). A similar pattern was observed in all diseases and combinations in the age group of !60 years. The model is shown in Supplementary Appendix 1, available as Supplementary data at IJE online, and Table 2 .

In our analysis, the CFR was associated with sex, age and number of NCDs (HBP, obesity, CVD, CKD or COPD). We observed greater CFR heterogeneity among institutions.

There is evidence that a country's average age can explain up to 66% of the variation in CFR for COVID-19. 22 Much of the variation between countries is due to the age of people evaluated and diagnosed with the virus. In our analysis, the average age of the population infected with SARS-Cov-2 was 45 years, similarly to that in China (49 years) but younger than that in Italy (62 years). 2 This could be due to the fact that the median age is similar in Mexico (30 years) 3 and China (35 years), 4 but higher in Italy (46 years). 4 Adults with underlying NCDs are more likely to experience more severe symptoms or die from a SARS-Cov-2 infection. 23 In our analysis, 40.5% of adults with SARS-Cov-2 had at least one NCD. This is lower than the prevalence found in the general Mexican adult population, in which 49.2% have at least one NCD. 24 On the other hand, men have fewer antibodies that decrease the expression of IL-6, which is linked to deregulation of the immune system and lung damage. Likewise, men have higher concentrations of angiotensin-converting enzyme 2 (ACE2) in the alveolar membrane of the lungs through which SARS-CoV-2 enters and infects its host. 25 Consistently with this infection mechanism and men's diminished immunesystem response, the CFR in our study was higher in men (CFR, 14.6) than in women (CFR, 9.1).

The number of chronic co-morbidities influences the risk of being infected with SARS-Cov-2 and dying from it. 26 People with more NCDs and of older age have a higher risk of death. 10 In China, reports indicate that, among people !60 years old, the risk of death was greater among those with two or more NCDs (RR, 2.59) in comparison to those with only one NCD (RR, 1.79). [11] [12] [13] [14] [15] [16] This is consistent with our findings, where risk of death was also greater in adults !60 years old and those with two or more NCDs (RR, 24.1) vs those with one (RR, 14.3). Regardless of age, adults with SARS-Cov-2 and comorbidities are at increased risk of death. Adults with SARS-Cov-2 and COPD have a higher expression of the functional receptor in the lower respiratory tract and this explains the extent of damage and the increased risk of death in patients with COPD and SARS-CoV-2. 27 COPD combined with CVD or CKD significantly increases the risk of death, due to the systemic inflammatory response induced by hypoxia, as well as the homeostatic imbalance caused by CKD. [28] [29] [30] The combination of three NCDs with the highest CFR among Mexicans was CVDþT2DþCOPD. This combination is one of the most common in adults worldwide 28 and can be attributed to the fact that multiorgan failure is associated with elevated plasminogen levels, leading to coronary thrombosis and pulmonary embolism. 31 In general, we found that a greater number of NCDs increases the CFR because it reflects multiple-organ dysfunction, severity and worse prognosis. 32, 33 We observe a triple interaction between the number of NCDs, age and sex. In the group aged 20-29 years, the RR of death when having at least three NCDs compared with not having any NCDs was higher in women (RR, 46.6) than in men (RR, 16.5), unlike that in the age group !80 years old, in which the RR was similar between women (RR, 1.0) and men (RR, 1.2). The greater RR in women aged 20-29 years is explained by the low CFR when they did not have any NCDs (women, 0.37%; men, 0.82%) and the higher CFR observed in women when they presented with at least three NCDs (women, 16.9%; men, 12.9%). In the youngest age group (20-29 years) , women with at least NCDs had a higher CFR than men. This can be explained because the youngest have risk behaviours such as high alcohol and tobacco consumption that contribute to the generation of NCDs at very early ages 34 but, in Mexico, these risk behaviours are more frequent in women than in men. 35, 36 We observed similar associations in other publications that use the same sources. 13-14-15 -37 However, our research was an exhaustive analysis that focused on the effect of six NCDs. This considers that they have a similar physiopathology, based on expression of ACE2 and a deficient immune system in diabetics that delays the phagocytic and antibacterial activity of neutrophils and macrophages together with oxidative stress that also exacerbates the chronic inflammatory processes. 37, 38 Thus, the smoking variable was eliminated because we do not believe it captures the tobacco habit in a robust way, as proposed by international expert recommendations. 39 In Mexico, the difference observed in the CFR by institution providing health services may be due to the type of users treated (with formal employment or without employment, with different levels of poverty and different ages of the beneficiaries). It could also be due to the limited material and personnel infrastructure that local public institutions have (less testing capacity, especially at the beginning of the pandemic). In comparison, federal public institutions and private institutions have more availability of therapeutic supplies and intensive-care equipment. In our study, the CFR was lower in private institutions and federal public institutions. To explain these differences in more detail, a more comprehensive analysis is needed in the future. 40, 41 Limitations We acknowledge that the main limitation of our study lies within its design, considering it is an observational study. This impedes us from making precise inferences or assuming causal relationships. We lacked information on clinical biomarkers at the time of registration to evaluate the baseline health status of the patients with SARS-Cov-2. With this information, we could have estimated, with less error and/or confounders, the effect of NCDs on mortality from SARS-Cov-2.

Another possible limitation is due to the data source, which was compiled through the Ministry of Health Epidemiologic Surveillance System and favours surveillance of high-risk cases or specific risk factors. This increases the probability of registering cases with severe symptoms and under-representing cases with lower risk who have moderate symptoms.

A third limitation of this study is that, to preserve the confidentiality of participants, the database does not include the specific medical unit in which the patients received care. It did not allow us to control for the specific effect of each healthcare unit and the clustering of observations at the healthcare unit, which may affect mainly the variance of our estimates.

A strength of our study is that it is the first to examine the association between CFR and NCDs in SARS-Cov-2 patients by correcting for the institution of care in all data of Mexican adults registered as SARS-Cov-2-positive. Our findings are consistent with those of other publications that state that NCDs increase mortality in SARS-Cov-2 cases. It therefore contributes to a better understanding of the interaction between SARS-Cov-2 and pre-existing NCDs.

We found that, among Mexican adults, mortality from SARS-Cov-2 increases with the number of NCDs. The combination of diseases such as T2D, CKD, COPD and CVD that were diagnosed in young people may mean that Mexicans are exposed early to risk factors like alcohol and tobacco intake, adiposity and poor diet, and in greater magnitude. This accelerates disease onset and may explain the higher mortality in young Mexicans. Our findings are consistent with the scientific literature and contribute to the understanding of these associations. More studies are needed to understand the heterogeneity observed by mortality and type of health institution. The evidence generated by this study can be useful for decision makers in the health sector, at both population and clinical levels.

The study does not require ethical review because it is based on open, anonymized data from the Mexican Ministry of Health.

Supplementary data are available at IJE online. 

We did not receive funding for this investigation.

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None declared.