Prevalence, Risk Factors, and Approach to Control of Comorbidities Among Hospitalized Patients: Evidence From A 4-Year Longitudinal Study in China

Background: The disease burden of comorbidity is growing steadily in many developing countries, affecting residents' physical and mental health. General Practitioners are considered as the suitable service providers for the prevention and control of comorbidity. However, the current knowledge on the clinical and epidemiological characteristics of comorbidity among inpatients in the general practice departments of hospital is limited, which hinders the precise promotion of the service capacity and quality of GPs. Objective: The current study aimed to analyze the clinical prevalence of comorbidities in central China and to provide evidence-based policy recommendations for quality improvement in general medical services. Methods: The study was conducted at the general practice departments of all 27 tertiary grade-A hospitals of Henan Province, China. 3 registered GPs of each hospital were selected by random, and all direct admissions of the 81 GPs from December 2016 to November 2020 were followed up. The clinical epidemiological characteristics and inuencing factors of comorbidity were evaluated using descriptive statistical analysis and logistic regression models. Results: Comorbidity was present in 93.1 percent of the 2385 direct admitted patients, with a male-to-female ratio of 1: 1. Comorbidity was signicantly more prevalent in patients aged 45-59 years (OR=3.018, 95% CI=1.945-4.683), 60-74 years (OR=4.349, 95% CI=2.574-7.349), ≥ 75 years (OR=7.804, 95% CI=3.665-16.616), and those with body mass index (BMI) ≥ 28 kg/m 2 (OR=3.770, 95% CI =1.453-9.785). The circulatory system is the most commonly involved human body system in comorbidity, accounting for 79% of all cases. The endocrine, nutritional, and metabolic systems, as well as the digestive and respiratory systems, were all signicantly affected, with prevalence rates of 62 percent, 48 percent, and 37 percent, respectively. Conclusion: healthy lifestyle interventions should be strengthened, as should the implementation of the patient-centered prevention and control model. Meanwhile, quality improvement priorities should be given to improving GPs' clinical diagnosis and treatment of the circulatory system, endocrine system, metabolic system, digestive system, and respiratory system.


Introduction
Comorbidity (multimorbidity) refers to patients suffering from two or more chronic diseases at the same time (1,2).
As the course of comorbidities progresses, the interaction between chronic diseases causes greater health damage (3), necessitating more comprehensive and continuous clinical treatments (4)(5)(6). Since the 2009 healthcare reform, China placed high expectations on general medical services in terms of lowering medical costs and improving health status of the population with comorbidity. China now has more than 365,000 GPs, comprising 210,000 registered GPs and 155 quali ed GPs (7). However, there is still a huge gap between the service capacity and quality of these new GPs and that of developed countries (8-10). In order to build an effective and e cient health service system based on GPs, the government began to require all tertiary hospitals to set up general practice departments and designates them as engines for increasing general medical service capacity and quality from 2014. This means that promoting the service capacity and quality of GPs in tertiary hospitals based on the clinical evidence from inpatients with comorbidity will contribute to the improvement of general practice service system in China as a whole.
Usually, the conditions of the inpatients admitted to the general practice department of tertiary hospitals are more complex, which provide a unique perspective for understanding inpatient comorbidity, and a clear path of promoting general practice service training and providing system. But the prevalence and risk factors of comorbidities among this population still remain to be explored. Therefore, the purposes of this article are: 1) to analyze the clinical epidemiological characteristics and related factors of general inpatients in a provincial tertiary hospital in Henan Province, and 2) to provide evidence-based policy recommendations for accurately promoting the prevention and control effectiveness of comorbidities, as well as GPs' diagnosis and treatment capabilities.

Study time and settings
The whole study was started in December 2016 and accomplished in November 2020. The general practice departments of 27 tertiary grade-A hospitals of Henan Province were selected to conduct the 4-year follow-up investigation (shown in Fig.1). All the general practice departments were designated as standardized general practice residents training centers.

Participant recruitment
A two-stage sampling method was used to obtain GPs and their hospitalized patients. At the rst stage, a random sampling method was used to select 3 observation GPs of each hospitals. All the enrolled GPs were (1) quali ed and registered as GP; (2) doctors-in-charge or above; and (3) willing to participate and sign the informed consent form. The rst stage sampling enrolled 81 GPs in total. At the second stage, a cluster sampling was used to obtain all inpatients of each GP, but transferred patients from other department, patients with repeated hospitalization, referred patients from other hospitals and those refused to participate were excluded. A total of 2385 hospitalized patients were investigated in the longitudinal study.

Data collection
We rstly urged the GPs to collect electronic medical record information through the hospital information system. For ambiguous and missing data, we con rmed with the GPs and patients by telephone to obtain accurate information. This study collected information of the 2385 participants on gender, age, marital status, education level, medical insurance payment method, BMI, smoking history, drinking history, occupation, admission diagnosis, past history, discharge diagnosis according to the International Classi cation of Diseases (ICD-10) standards, disease counts, and other clinical and epidemiological characteristics as well as in uencing factors for comorbid condition.

Statistical analysis
The rate and composition ratio were used for descriptive analysis of the clinical and epidemiological characteristics of comorbidities while the Chi-squared test was used for single factor analysis. The in uencing factors of comorbidities were analyzed using the logistic regression model. P<0.05 was considered as the difference was statistically signi cant. SPSS 26.0 software was used for data analysis.

Results
3.1 Risk factors related to comorbidities among inpatients of the general hospital 2385 hospitalized patients were included in the analysis. The age range of study participants were 5 to 98 years, with an average age of 60 years. 165 cases (6.9%) had one chronic disease, and 2220 (93.08%) had two or more chronic diseases. Comorbidity in patients over 75 years was 97.5 percent. The prevalence of comorbidities among participants with normal body mass index (BMI) (18.5 ≤BMI<23.9, 89.4%) was signi cantly lower than those with abnormal BMI (BMI<18.5, 90.1%; 24<BMI BMI≤27.9, 94.4%; BMI ≤28, 97.2%; P<0.01). The prevalence of comorbidities in the fully out-of-pocket group is lower than in basic health insurance and other groups (Fully out-of-

Clinical characteristics of comorbidities involved in the body system
Among the 2385 hospitalized patients, the circulatory system was the most common linked body system to comorbidities, with a prevalence rate of 79%, which was much higher compared to other systems. The other systems associated in comorbidities were Endocrine, nutritional and metabolic systems (62%), Digestive system (48%), Respiratory system (37%), Nervous system (23%), Genitourinary system (23%), Mental and Behavioral disorders (18%), Musculoskeletal system and connective tissue (18%) and Tumors (11%). (see Figure 2)

Discussion And Policy Recommendations
The number of patients with comorbidities will continue to rise in developing countries as the population ages, life expectancy increases, and lifestyles change (11,12). Compared with a single chronic disease, comorbid patients have complex causes, high medical expenses, and poor quality of life, resulting in a heavy burden of disease to the country, society and family (13)(14)(15)(16). In view of this, in December 2016, NICE released the United Kingdom "Comorbidity: Clinical Evaluation and Management", stating that the clinical guidelines for a single disease are not applicable to patients with comorbidities. Medical staff should formulate effective management plans for comorbid patients as part of their overall strategy (17). At present, China and many developing countries have not issued special clinical treatment guidelines for comorbidity. The diagnosis and treatment of comorbidities is still based on specialist diagnosis. The advantages of general medicine in the eld of comorbidity prevention and treatment have not been systematically studied. This article comprehensively analyzes the clinical epidemiological characteristics and in uencing factors of comorbidities in general medicine inpatients in a provincial tertiary hospital in Henan Province, and provides representative evidence for effective prevention and control of comorbidities.
4.1 Establishing a GP-PCIC comorbidity prevention and control model "The Mortality, Morbidity, and Risk Factors in China and Its Provinces from 1990 to 2017" published by The Lancet showed that the prevalence of hypertension and diabetes was 25.2% and 9.7% respectively. The overall prevalence of chronic diseases is gradually increasing, indicating that the current situation of chronic disease management is still severe (18). Due to the combined effects of multiple chronic diseases, patients with comorbidities face reduced quality of life, heavy psychological burden, prolonged hospital stay, increased number of readmissions, increased emergency visit rate, high incidence of multiple medications and adverse drug events and waste of medical resources (19)(20)(21). This study shows that the prevalence of comorbidities among inpatients in the general medicine department of provincial-level tertiary hospitals is extremely high, reaching 93.1%, which is close to the results reported by Feng Mei et al. (22), but higher than that of foreign Ge L et al. (23), Gupta S et al. (24) and Carolina IC et al. (25). This may be due to the fact that the study participants were enrolled from provincial medical center where the overall complexity and likelihood of the cases admitted is relatively high. It can be seen that the prevention and control of comorbid condition should be the key content of the prevention and control of chronic diseases.
Based on the experience of developed countries, the establishment of a patient-centered integrated service system (Patient Centered Integrated Care, PCIC) provides comprehensive, continuous, and proactive services for patients with comorbidities, and raises their awareness on disease risk factors. A healthy lifestyle can prolong the life of patients, improve the quality of life, reduce the economic burden of patients, and reduce medical expenses. General hospitals in China are of large-scale, with many departments, high-quality medical teams, high-tech equipment, and strong rst aid capabilities. However, the cost of diagnosis and treatment is relatively high, characterized with longer waiting times. In addition, primary medical institutions have better access to services and lower cost advantages. Therefore, there should be a link between general medicine department in general hospitals and general practitioners in primary medical institutions to build a general practitioner-based patient centered integrated service system (General Practitioner Based Patient Centered Integrated Care, GP-PCIC). It is hence expected to play an important role in the clinical diagnosis and treatment and comprehensive prevention and control of comorbid diseases.

Building the integrated two-way referral model between tertiary hospitals and primary hospitals
As the general medicine department of the provincial tertiary hospitals support hierarchical diagnosis and treatment and maintains close contact with the grass-roots community health service centers, thereby building a bridge linking grass-roots medical institutions and comprehensive clinical specialties is important. There should be an establishment of chronic disease management system so as to realize the effective sharing of electronic medical records between hospitals and community health services. The general medicine department of a tertiary hospital should be transferred to a ward or to a lower-level hospital or community health service center for treatment according to the patient's condition and needs. Through chronic disease management platforms, comprehensive, coordinated and continuous medical services should be provided to patients. Constructing a hierarchical diagnosis and treatment system is an important measure for the allocation of medical resources and the promotion of the equalization of basic medical and health services. This can be achieved through the integration and sharing of medical and health resources in the medical consortium, innovative health management, medical consortium operation management, hierarchical diagnosis and treatment, and medical insurance payment models.

Strengthening comprehensive interventions for comorbidity in elderly and obese patients from both clinical and healthy lifestyle levels
This study found that old age and obesity are risk factors for comorbidity. As age increases, the prevalence of comorbidities increases signi cantly, which is consistent with the ndings of SCHRAM et al (26). The increase in age causes the body's metabolic rate to slow down, the body and organs gradually decline in function, and the possibility of chronic diseases in various body systems increases. Obesity is another major factor that increases the risk of chronic diseases. Obesity will increase the risk of heart disease, hypertension, diabetes and other diseases. The "Report on the Status of Nutrition and Chronic Diseases of Chinese Residents (2020)" issued by the National Health and Family Planning Commission shows that more than 50% of adult residents in China are overweight and obese (27). As a result, treating comorbidities is more complicated than simply diagnosing and treating a single disease. Hence, it is necessary to effectively cope with multiple risk factors at the same time. According to the clinical characteristics of patients with comorbidities, there is a need to explore the connection between clinical treatment and healthy lifestyle. From a practical standpoint, a clinical diagnosis and treatment plan for comorbid patients is established based on general practitioners, with "patient-centered, clinical, and healthy lifestyle integration" to achieve a hospital-community-family trinity health management model (28).
Relevant studies point out that lifestyle medicine plays an irreplaceable role in improving the health outcomes of most chronic diseases and hence signi cantly reduces medical expenses. Main interventions include weight control, reasonable diet, adequate exercise, adequate sleep, smoking cessation and alcohol restriction (29-32) (see Table 4).
In the future general practice diagnosis and treatment, general practitioners should explore healthy lifestyle intervention programs suitable for hospitalized patients with comorbidities as one of the core contents of clinical treatment programs.

Improving general practitioners' ability to diagnose and treat diseases in key systems and their comprehensive prevention and control capabilities.
This study found that the most commonly affected systems of comorbidities are the circulatory system, endocrine, nutrition and metabolism, digestive system, and respiratory system. Therefore, general practitioners in provinciallevel tertiary hospitals should be targeted to improve the clinical treatment of common diseases and frequentlyoccurring diseases in the corresponding system. At the same time, given that patients with comorbidities often have multiple health risk factors, general practitioners also need to have the ability to identify, mitigate and control the main system-speci c health risk factors. Therefore, the ability of general practitioners to effectively prevent and control comorbidities should have the following capabilities: (1) Diagnosis and processing capabilities of diseases and disorders Rapid diagnosis of the circulatory, endocrine, nutrition, and metabolism systems, as well as the digestive, respiratory, and other systems; (2) Ability to respond effectively to patients' family problems (33) and (3) To Detect, control, and propose healthy lifestyle intervention programs suitable for the residents.
Correspondingly, the education and training system of general practitioners in China should be updated so as to better meet the needs of residents for the diagnosis and treatment capabilities of the practitioners. To be speci c, there is a need to scale up the residency training model (5+3) and rapidly increase the number of general practitioners familiar with general medicine concepts, all of which can serve as a foundation for establishing a GP-PCIC comorbidity prevention and control model. Secondly, on the basis of harmonizing national audit standards and training quality monitoring systems for general practitioner transfer training (34,35), speci c capacity improvement training for speci c chronic disease epidemic trends in speci c regions should be provided to address the problem of general practitioners in the circulatory system. Thirdly, there is a need to provide more trainings to the general practitioners, and the focus to establish and improve the mechanism for the comprehensive prevention and control of diseases and comorbidities.

Strengths And Weaknesses
In most health service systems, GPs are classi ed as primary health care providers. However, in the special health care context of China, GPs in tertiary hospitals play a dual role of service provider and primary general practitioner trainer. Exploring prevalence, risk factors, and approach to control of comorbidities among hospitalized patients of these GPs working at tertiary hospitals contributes to the improvement of general practice service system in China as a whole. Therefore, the advantage of this article is that it makes use of four years of continuous inpatient data from GPs working at tertiary grade-A hospitals, as well as a prospective analysis of clinical epidemiology of comorbidities among hospitalized patients at the provincial-level tertiary hospital. The true status of comorbid admissions is expected to serve as a decision-making basis for the development of a general medicine service system and the precise enhancement of general practitioners' diagnostic and treatment capabilities. The defect of this study is that only 81 GPs in tertiary hospitals were investigated, and follow-up surveys involving multiple centers and a large sample size should be enhanced.

Conclusions
Given the escalating severity of aging population and chronic diseases, it is critical to prioritize the effective prevention and control of comorbidities. As far as the ndings of this article are concerned, the prevention and control of comorbidities should focus on the elderly and obese people. Effective countermeasures include establishing a GP-PCIC comorbidity prevention and control model and enhancing the comorbidity of elderly and obese patients at both the clinical and healthy lifestyle levels. We also call upon timely intervention and improvement in the diagnosis and treatment capabilities and comprehensive prevention and control measures of general practitioners on the circulatory, endocrine, digestive, respiratory and other systems.

Declarations
Ethics approval and consent to participate All enrolled patients gave written informed consent before the clinical treatment in the sampled hospitals. The ethics committee of Henan Provincial People's Hospital ruled that no formal ethics approval was required in this particular case.   Health information collection and evaluation of routine comprehensive items: A baseline assessment should be performed for 35-40 years old; an assessment once in 12-18 months for 40-50 years old (according to the level of cardiovascular risk factors and lifestyle/behavioral status); after 50 years of age, to be evaluated once a year. Figure 1 Study setting and distribution of sampled hospitals. Note: * Henan Province, with a population of 100 million, is a most representative province in China in terms of social economy, geographical area, and health resources allocation. ** In China's hospital system, tertiary Grade-A hospitals are medical institutions with the most comprehensive service ability, which undertake three main functions of clinical service, teaching and scienti c research (followed by tertiary Grade-B, tertiary Grade-C, secondary and primary hospitals). Note: The designations employed and the presentation of the material on this map do not imply the expression of any opinion whatsoever on the part of Research Square concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. This map has been provided by the authors.