Results and effects of patients who have recovered from COVID-19: identifying the relationship with risk factors and comorbidities

Resultados e efeitos dos pacientes que se recuperaram da COVID-19: identificação da relação com fatores de risco e comorbilidades

Abstract

The number of deaths from COVID-19 is closely associated with multimorbidities. This study aimed to review the clinical and functional conditions of patients who recovered from COVID-19. Additionally, identify the relationship with risk factors and comorbidities. Systemic arterial hypertension (SAH) was more frequently observed in patients with severe COVID-19. Diabetes mellitus (DM) is one of the comorbidities that has contributed the most to the increase in the number of hospitalizations due to complications and the number of deaths due to infection by COVID-19. Obesity has been shown to be a risk factor for hospitalization in patients with COVID-19 under 60 years of age. Most survivors of COVID-19 suffer primarily from muscle fatigue or weakness. In addition, patients who were more seriously ill during their hospital stay have greater impairment of functional capacity, pulmonary diffusion and fatigue symptoms, and are the main target population for long-term recovery interventions. To optimize the post-hospitalization rehabilitation of patients after discharge from COVID-19, the need for multidisciplinary work in rehabilitation, the reinforcement of public policies to ensure equity in access to the public health system and training should be considered of the health team in view of the new demands and realities generated by COVID-19.

Key words:
COVID-19; Diabetes mellitus; Hypertension; Functionality

Resumo

O número de mortes por COVID-19 está intimamente associado a multimorbidades. O presente estudo teve como objetivo revisar as condições clínicas e funcionais de pacientes que se recuperaram da COVID-19. Adicionalmente, identificar a relação com fatores de risco e comorbidades. A hipertensão arterial sistêmica (HAS) foi observada com mais frequência em pacientes com COVID-19 grave. O diabetes mellitus (DM) é uma das comorbidades que mais tem contribuído para o aumento do número de internações por complicações e do número de óbitos por infecção por COVID-19. A obesidade demonstrou ser um fator de risco para hospitalização em pacientes com COVID-19 com menos de 60 anos. A maioria dos sobreviventes da COVID-19 sofre principalmente de fadiga ou fraqueza muscular. Além disso, os pacientes que estiveram mais gravemente enfermos durante sua internação hospitalar apresentam maior prejuízo da capacidade funcional, pior difusão pulmonar e sintomas de fadiga, sendo assim a população-alvo para intervenções de recuperação a longo prazo.. Para otimizar a reabilitação pós-hospitalização de pacientes após alta por COVID-19, deve-se considerar a necessidade de trabalho multiprofissional na reabilitação, o reforço das políticas públicas para garantir a equidade no acesso ao sistema público de saúde e o treinamento da equipe de saúde frente às novas demandas e realidades geradas pelo COVID-19.

Palavras-chave:
COVID-19; Diabetes mellitus; Hipertensão; Funcionalidade

Background

The COVID-19 pandemic, which began in China in November 2019, had its first confirmed case in Brazil in March 2020, and by April 2021 it had already killed more than 500,000 nodes in Brazil¹. The disease is transmitted in the air through respiratory secretions. The symptoms include fever, malaise, dry cough, dyspnea, myalgia, nausea, diarrhea, hyposmia, dysgeusia, lethargy, and muscle weakness², with findings of ground-glass opacities in chest tomography³. Severe conditions with hypoxemia refractory to oxygen therapy mean some patients face a long period of hospitalization.

In view of the large number of infected individuals, there is also a large number of recovered individuals. After the acute phase, the exact time that the damage caused by the disease continues to affect the individual, especially lung function, functionality, and muscle strength, is still unknown. Individuals who struggle with the chronic effects of COVID-19 will persist. The literature has shown that one of the main consequences seen after the acute phase of COVID-19 infection is peripheral muscle weakness and elevated serum creatine kinase (CK) levels, which occurred in more than 30% of individuals diagnosed with a respiratory syndrome acute caused by COVID-19⁴ and cardiovascular damage by different mechanisms, ultimately leading to cardiomyopathies. Likewise, the reduced functional capacity and ability to perform activities of daily living in patients who had been hospitalized with COVID-19 is striking⁵.

There is an even worse situation when these patients already had underlying cardiovascular comorbidities, such as systemic arterial hypertension (SAH) and coronary artery disease: They are more likely to suffer from a serious infection by COVID-19, requiring intensive care⁶. Hypertensive individuals as well as those with diabetes mellitus (DM) are the main targets of the deleterious effects and have more severe and sometimes fatal complications of COVID-19^7,8. In this context, there is still much to be explored about the potential clinical and functional impairments that can persist after COVID-19 due to these aforementioned comorbidities, which can directly affect the functional capacity and quality of life of these individuals. Hence, rehabilitation plays a prominent role in this recovery scenario.

Risk factors and comorbidities

Risk factors for COVID-19 as well as its aggravation should be considered: age ≥ 65 years, smoking, a sedentary lifestyle, pre-existing cardiomyopathies, decompensated respiratory and pulmonary diseases, immunodeficiency, chronic kidney diseases, chromosomal diseases with a state of immunological weakness, malignant neoplasm, some hematological diseases, and pregnancy^3,9,10. However, of the comorbidities, those that seem to generate the greatest repercussions are SAH, DM, and obesity⁹.

Recent studies point to risk factors and comorbidities as predictors of more severe complications in individuals with COVID-19^11,12.

Apparently, SARS-CoV-2 infection is associated with the pathophysiology of comorbidities in line with these predisposing factors, aggravating the symptoms and resulting in a worse prognosis. Hence, these individuals have an increased probability of hospitalization and the need for intensive care and, consequently, a greater risk of in-hospital death¹³.

The elderly population is more susceptible to infection by COVID-19 and has a higher percentage of death due to the ease of developing more severe complications¹⁴. The higher mortality rate in older individuals may be related to decreased immunity and increased frailty due to aging^15,16. Interferon type 1 (IFN1) is one factor responsible for activating adaptive immunity. Although SARS-CoV-2 is sensitive to IFN1, the virus is capable of affecting the production of this protein, thus delaying and weakening the body’s defenses to the virus^17-19. There is an even greater chance of symptom worsening in cases of infections in this group when associated with risk factors such as chronic diseases^9,11.

Furthermore, DM is one of the comorbidities that has contributed to the increase in the number of hospitalizations for complications and the number of deaths due to COVID-19 infection²⁰. The probability of contagion between individuals with DM and without DM does not differ; however, the first group is at greater risk of experiencing more severe complications, especially when concomitant with other comorbidities such as pneumonia²¹.

Hussain et al.²² pointed out possible mechanisms that may be associated with negative manifestations in individuals with DM affected by COVID-19. According to these authors, exacerbated inflammatory responses, changes in immune and platelet responses, and a possible relationship between SARS-CoV-2 and glycemic regulation and interference in insulin production have been observed. The lack of glycemic control in individuals with DM favors the creation of an inflammatory environment, making them prone to serious injuries in cases of infection²¹. Finally, it is noteworthy that individuals with DM who develop pneumonia tend to have a poor prognosis and more complications than those without DM²³.

COVID-19 and systemic arterial hypertension

SAH has been more frequently observed in patients with severe COVID-19 compared with non-severe patients^24,25 reported that the prevalence of hypertension was significantly higher among patients with COVID-19 who required care in the intensive care unit (ICU) than among those not admitted to the ICU. Patients with COVID-19 with co-existing SAH, high mean systolic blood pressure, and high systolic/diastolic blood pressure variability during hospitalization were independently associated with hospital mortality and ICU admission, suggesting that lower and stable blood pressure values are predictive of a better prognosis.

Early epidemiological studies suggested that cardiovascular diseases (CVD), including SAH, are associated with mortality or severity in patients affected by COVID-19²⁶ This possibility is worrisome, given that SAH is very common: It affects about 1.39 billion individuals worldwide and the prevalence increases with age, affecting approximately 70% of older adults²⁷.

COVID-19 and obesity

The situation in Brazil regarding obesity and overweight rates and the pandemic requires special attention. The prevalence of obesity and overweight is high in the country and has increased significantly over the years²⁴. Obese patients with COVID-19 and/or with metabolic-associated fatty liver disease had a higher risk of a severe outcome after adjustment for age, sex, smoking, diabetes, hypertension, and dyslipidemia²⁸.

Obesity has been shown to be a risk factor for hospitalization in patients with COVID-19 who are < 60 years old. However, younger patients with a body mass index (BMI) ≥ 40 kg/m² are at a fivefold greater risk of mortality from COVID-19. Severe obesity has also been associated with intubation and mechanical ventilation, impaired chest wall elastance, and reduced respiratory system compliance leading to impaired lung function²⁹. It is noteworthy that obese individuals have a more pronounced pro-inflammatory state, with higher levels of cytokines such as interleukin (IL)-6. A higher risk of thrombosis, once conjugated, contributed to the increased risk of severe COVID-19 in obese patients³⁰.

COVID-19 and respiratory system

Respiratory viruses can adapt quickly and cross the species barrier. Some of these pathogens, such as SARS-CoV-2, occasionally cause epidemics or pandemics and are associated with more serious clinical illness and even mortality. In addition to all these respiratory problems, accumulated evidence from the clinical/medical world strongly suggests that, being opportunistic pathogens, these viruses are able to escape the immune response and cause more severe respiratory complication or even spread to extra-respiratory organs, including the central nervous system⁸, where they could infect resident cells and potentially induce other types of pathology. In this scenario, the need of patients with pulmonary complications for ICU admission has been prevalent since the beginning of the COVID-19 pandemic. Individuals with pre-existing respiratory diseases or comorbidities that reduce the full functionality of the lungs tend to progress to a severe condition.

Smoking and chronic obstructive pulmonary disease (COPD) are associated with increased expression of angiotensin II-converting enzyme (ACE-2), increasing the possibility of SARS-CoV-2 entering epithelial cells, taking into account the role of ACE-2 functioning as the main determinant of infection by this virus³¹. Hence, people who smoke and/or have COPD are also more susceptible to more severe forms of COVID-19³¹. Indeed, a document issued by the CDC in 2020 reported that there is an association between smoking and the negative progression of the disease. According to observed results, the chances of progression to severe cases are 1.91-times higher compared with individuals who have never smoked³². It is known that smoking poses risks to the respiratory system, increasing damage to the lungs; thus, it can be hypothesized that COVID-19 causes damage to an already weakened endothelium, and consequently generates more complications.

Chronic lung disease has also appeared as one of the comorbidities with a high rate of hospital admissions of patients with COVID-19³. As mentioned above, the explanation for this phenomenon is related to the high amount of ACE2 receptors found in airways, a phenomenon also observed in smokers. The role of ACE2 in the respiratory system is unknown, however, its high expression may be related precisely to the fact that the pulmonary structures are already compromised by COPD and the current use of tobacco^33,34.

The literature contains many reports showing that respiratory tract diseases are important causes of illnesses and hospitalizations and a potential cause of reduced quality of life. Indeed, these conditions often cause functional incapacities in individuals, and in more critical cases, they can lead to death. Based on the above fact, it is essential to develop prevention and care strategies, considering the current pandemic context. Finally, although the effects of COVID-19 on the respiratory system are known, there is still a lot to understand about the long-term effects.

COVID-19 and the cardiovascular system

Several studies have shown that the cardiovascular system can also be negatively impacted by COVID-19^28,35,36. There is evidence of various impairments in this system, such as findings of myocardial damage, myocarditis, arrhythmias and conduction blocks, vascular dysfunction, and cardiac death³⁵. Additionally, the presence of previous diseases of the cardiovascular system, as well as their risk factors, have been described as potential aggravators of multimorbidity in COVID-19^35,37. The mechanisms of this relationship are being unveiled. The infection caused by SARS-CoV-2 can worsen chronic cardiac pathologies due to decompensation and can lead to cardiac complications that did not exist before infection³⁷.

Guo et al.³⁷ identified a greater susceptibility to cardiac tissue damage, assessed by the elevation of troponin T levels, as well as a higher mortality rate in these patients compared with those without previous cardiovascular impairment. In addition, Wang et al.²⁵ demonstrated greater myocardial damage, denoted by the elevation of biomarkers such as creatine kinase MB (CK-MB) and ultra-sensitive troponin I in patients with severe symptoms compared with those who did not require ICU admission. The damage to the myocardium resulting from COVID-19, as well as in other systems, is also dependent on the interaction of the virus with ACE-2 receptors, which promotes a disruption of the protective functions of these receptors to the heart, allowing greater inflammation and consequent damage to the myocardium³⁸. Based on this same rationale, the expression of ACE-2 receptors is increased in diseases such as SAH and DM. Individuals with SAH³⁹, type II DM⁴⁰ or chronic heart failure are more likely to evolve severe conditions due to COVID-19 infection and thus require intensive care⁶. They also have higher morbidity and mortality after COVID-19 infection⁴¹.

It is noteworthy that in these patients there is a basal inflammation arising from the pre-existing disease itself, which adds to the inflammatory process caused by SARS-CoV-2, with an imbalance between the increased metabolic demand induced by the infection and the reduction in cardiac reserve. Additionally, both disease courses lead to an imbalance in the performance of the autonomic nervous system (ANS), with pronounced activation of the sympathetic nervous system^41,42 and reduction of the parasympathetic nervous system⁴¹. Faced with SARS-CoV-2 infection and a pronounced systemic inflammatory response, ANS dysfunction becomes evident and is mainly related to cytokine release and sympathetic activation^43,44. Another hypothesis is that the ANS is a direct target of the virus, which can also trigger autonomic dysfunction⁴⁵. As a consequence, after the acute phase of infection by SARS-Cov2, these patients who already had autonomic dysfunction will go through a process of more pronounced ANS imbalance⁴⁶.

The vascular endothelium has also been highlighted in discussions about the pathophysiology of COVID-19. This organ has primary functions for the maintenance of hemostasis and defense of the body and does so through several important actions such as vasomotor control, anti-inflammation, antioxidation, vascular permeability, and acting as a protective barrier⁴⁶. However, infection with SARS-CoV-2 causes notable endothelial dysfunction with a direct relation to worse outcomes by inciting pro-thrombotic and pro-inflammatory processes⁴⁶.

The elevation of pro-inflammatory cytokines (IL1β, IL-6, and tumor necrosis factor alpha [TNFα]) in patients with COVID-19 induces the loss of antithrombotic and anti-inflammatory function of endothelial cells, leading to dysregulation of coagulation, platelet activation, and recruitment of leukocytes in the microvasculature. Histopathological evidence of direct viral infection of endothelial cells, diffuse endothelitis, and micro- and macrovascular thrombosis in the circulation have been found in patients with COVID-19⁴⁷.

In a pattern similar to other systems, it has been suggested that this endothelial dysfunction is directly related to ACE-2 receptors expressed in endothelial cells due to a reduction in their expression or an indirect relationship to potentiate immunothrombosis and to impair the antiviral response⁴⁸. In this scenario, the presence of previous comorbidities such as hypertension, DM, and obesity - in which there is evidence of pre-existing endothelial dysfunction⁴⁸ associated with dysfunction induced by SARS-CoV-2 - will contribute to the worsened clinical presentation of the disease with deleterious pulmonary and extrapulmonary complications.

A striking feature in the progression of severe COVID-19 is marked hypoxemia. The combination of pre-existing ANS and endothelial diseases and alterations with hypoxemia and inflammation makes the individual more prone to have fatal cardiac arrhythmias and dysfunctions⁴¹. Electrolyte imbalances and adverse drug effects can also be potential stressors to previously impaired systems, as well as immune dysregulation, recognized as an important factor in the pathogenesis of vascular disease.

Finally, it has been noted that there is a clear increase in morbidity and mortality due to COVID-19 in individuals with a previous diagnosis of CVD or its risk factors. Some plausible mechanisms of this association translate into a possible worse ability of this already impaired system to respond to the increased demand of a severe viral disease alongside reduced systemic oxygenation^49-51.

Impact of COVID-19 on exercise/functional capacity

Most COVID-19 survivors are mainly troubled by fatigue or muscle weakness, sleep difficulties, and anxiety or depression after discharge from the hospital. In addition, patients who were more severely ill during their hospital stay present more severely impaired functional capacity, lung diffusion, and fatigue symptoms, and they are the main target population for long-term recovery interventions⁵². An elegant study published by Huang et al.⁵³ demonstrated the COVID-19 consequences 6 months after discharge from the hospital: The proportion of median 6-min walking distances less than the lower limit of the normal range was 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5-6.

Interestingly, a previous study of Ong et al.⁵⁴ investigating the combination of pulmonary function and exercise capacity in a group of SARS survivors showed that although residual mild pulmonary function defects were detected in over half of recovered SARS patients three months after hospital discharge, 41% presented impaired exercise capacity that could not be explained by pulmonary limitation. In fact, the high use of corticosteroids during hospitalization, nutritional status, bioenergetic changes, as well as myopathy due to disuse due to prolonged hospitalization⁵⁵ were factors to explain the important peripheral muscle weakness of these patients.

Many derangements of the musculoskeletal have been described in critically ill patients with COVID-19 that presented prolonged hospitalization^56,57. Prolonged immobilization associated with malnutrition could explain the marked reduction in muscle strength in intensive care unit-acquired weakness (ICU-AW)⁵⁶ In addition, muscle shortening, contractures, deformities, and decubitus ulcers⁵⁸ compromise and in most of cases delay early rehabilitation. Most importantly, the excessive, long-term use of steroids and neuromuscular blocking agents during hospitalization leads to polyneuropathy and myopathy⁵⁹.

In the hospitalization phase, the patient’s functional performance for active or active-assisted mobilization in bed, as well as the patient’s ability to understand the task, must be evaluated early in the ICU. As soon as the patient is able to cooperate, evaluations should begin. Peripheral muscle strength, respiratory muscle strength, cooperation for changes in decubitus, and functional independence measure (FIM) scores should be evaluated⁶⁰. The ability to cooperate, especially in postural changes, may be noted and passed on from shift to shift for physiotherapy professionals. The Medical Research Council Sum Score (MRCSS) and functional outcomes - including the Physical Function in Intensive Care Test (PFIT) score, the De Morton Mobility Index (DEMMI), and the Modified Barthel Index (MBI) - may be measured on the first day the patient received the physical therapy intervention and at discharge⁶¹. In addition, it is of fundamental importance that the therapist assesses the trunk balance and tolerance time in the sitting posture and from the first time the patient stands with support. The first ambulation should be recorded, especially the patient’s limit tolerance time (TTlim), desaturation, and symptoms, using a subjective effort scale. These parameters will be used to guide patients to hospital discharge. If possible, ladder tests will allow clinicians to assess whether the patient is able to move up one flight of stairs when they are discharged from the hospital. Mobility status using the Activity Measure for Post-Acute Care 6-Clicks basic mobility (6-Clicks mobility) and the Johns Hopkins Highest Level of Mobility scales can be considered⁶². The Perme Score can be considered to evaluate the barriers to mobilization⁶³. Moreover, a walking test can be applied to some patients before they are discharged.

After discharge, patients may be assessed for functional performance of Activities of Daily Living (ADLs), as well as for tolerance to submaximal exercise and respiratory and peripheral muscle strength. The standing balance, 4-meter gait speed, 5-repetition sit-to-stand motion⁶⁴, Glittre ADL⁶⁵, and timed up-and-go tests can represent objectives and global forms of evaluation of COVID-19 patients, because they are based on the International Classification model of Functionality, Disability and Health. Furthermore, the 6-minute walking⁶⁰, shuttle walking, and step tests⁶⁶ may identify exercise intolerance, signals, and symptoms when monitored by a oximeter and dyspnea and muscle fatigue scores. On the other hand, a symptom-limited cardiopulmonary exercise test (CPET) with breath-by-breath gas-exchange monitoring, electrocardiogram registration, and blood pressure and saturation monitoring constitutes a gold standard method to analyze the primary limitation to physical exercise (whether cardiovascular, ventilatory or peripheral muscle)⁶⁷. However, this functional assessment and can only be applied to a subgroup of patients, due to its high cost and the need for a specialized team.

Muscle strength tests with handheld dynamometers can be useful for measuring muscle strength⁶⁸. The one repetition maximum (1RM) tests can also accurately assess peripheral muscle strength in these patients during formal rehabilitation programmes⁶⁹. In addition, inspiratory muscle strength can be measured by maximal inspiratory pressure and endurance tests. All strength tests can be compared with predicted values and are also important parameters for the progression of exercise intensity, as well as for assessing the effects of numerous rehabilitation interventions⁷⁰.

In this context, Figure 1 illustrates a functional flowchart for physiotherapists with targets during the hospitalization phase, at discharge, and for the beginning of the rehabilitation program. The proposal aims to guide professionals regarding the importance of functional assessment, considering simple, viable, and inexpensive outcomes, which can be applied in the physiotherapist’s daily routine.

Figure 1
Functional flowchart for physiotherapists with targets during the hospitalization phase.

Challenges for patient rehabilitation due to the functional repercussions generated by COVID-19

In general, the rehabilitation of patients who have recovered from COVID-19 involves a multidisciplinary health care team, composed of physicians, physiotherapists, speech therapists, psychologists, nutritionists, and physical education professionals. The primary objective is to improve the health and functionality of the affected individuals, whether through the restoration of capacities, minimization of incapacities, or adaptations to carry out daily and professional activities.

Due to recent demands for post-hospitalization rehabilitation of patients who have recovered from COVID-19, many treatment programs lack clinical trials investigating the effectiveness of the interventions used. Furthermore, and similarly, the reliability and validity of various assessment methods are unknown to date in this population. Another challenge for post-hospitalization rehabilitation is related to the large number of professionals working within the hospital environment due to the high demand of those infected with COVID-19. Thus, there is a need to reorganize the health system in order to direct the flow of professionals, equalizing possible discrepancies in care.

The inequality in the health system in developing countries, such as Brazil, is a crucial point that challenges the full assistance of rehabilitation professionals to these patients. To exemplify this condition, we can consider telerehabilitation, an important strategy in times of social isolation for access to health care without the need for personal contact with the professional who assists you. However, for the full implementation of telerehabilitation, it is necessary for several aspects to work, especially infrastructure and socioeconomic determinants. In other words, how will a patient have access to telerehabilitation if the place where they live does not have access to the Internet or if they do not have a connection device (cell phone or computer)?

The example of telerehabilitation is particular due to the need for social isolation, but the distortion in access to health systems in Brazil is chronic. In terms of reflection, how many public health services have teams with all the professionals listed here? Despite the legal and normative support for the creation and maintenance of rehabilitation services in the public health system, they still face difficulties with integrality and equity, with numerous challenges regarding articulation with the whole of health care and with the implementation of expected results of rehabilitation. Based on this complex scenario, some points should be considered to optimize the post-hospitalization rehabilitation of patients who had COVID-19: (i) the need for multidisciplinary work in rehabilitation; ii) the reinforcement of public policies to guarantee equity in access to the public health system; and (iii) the training of the health team in view of the new demands and realities generated by COVID-19 regarding the functionality of patients.

References

• ¹
  Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223):507-513.
• ²
  Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, Yuen KY. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020; 9(1):221-236.
• ³
  Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020; 382(18):1708-1720.
• ⁴
  Stainsby B, Howitt S, Porr J. Neuromusculoskeletal disorders following SARS: a case series. J Can Chiropr Assoc 2011; 55(1):32-39.
• ⁵
  Belli S, Balbi B, Prince I, Cattaneo D, Masocco F, Zaccaria S, Bertalli L, Cattini F, Lomazzo A, Dal Negro F, Giardini M, Franssen FME, Janssen DJA, Spruit MA. Low physical functioning and impaired performance of activities of daily life in COVID-19 patients who survived hospitalisation. Eur Respir J 2020; 56(4):2002096.
• ⁶
  Tan W, Aboulhosn J. The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease. Int J Cardiol 2020; 309:70-77.
• ⁷
  Cuschieri S, Grech S. COVID-19 and diabetes: the why, the what and the how. J Diabetes Complications 2020; 34(9):107637.
• ⁸
  Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, Bikdeli B, Ahluwalia N, Ausiello JC, Wan EY, Freedberg DE, Kirtane AJ, Parikh SA, Maurer MS, Nordvig AS, Accili D, Bathon JM, Mohan S, Bauer KA, Leon MB, Krumholz HM, Uriel N, Mehra MR, Elkind MSV, Stone GW, Schwartz A, Ho DD, Bilezikian JP, Landry DW. Extrapulmonary manifestations of COVID-19. Nat Med 2020; 26(7):1017-1032.
• ⁹
  Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229):1054-1062.
• ¹⁰
  Prevention CFDCA. CDC updates, expands list of people at risk of severe COVID-19 illness [Internet]. 2021. [cited 2021 out 5]. Available from: https://www.cdc.gov/media/releases/2020/p0625-update-expands-covid-19.html
  » https://www.cdc.gov/media/releases/2020/p0625-update-expands-covid-19.html
• ¹¹
  Rong-Hui Du, Li-Rong Liang, Cheng-Qing Yang, Wen Wang, Tan-Ze Cao, Ming Li, Guang-Yun Guo, Juan Du, Chun-Lan Zheng, Qi Zhu, Ming Hu X-YL. "Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study". Eur Respir J 2020; 56(3):2050524.
• ¹²
  Feitoza TMO, Chaves AM, Muniz GTS, Cruz MCC, Cunha Junior IF. Comorbidades e COVID-19. Interfaces 2020; 8(3):711-723.
• ¹³
  Singh AK, Gupta R, Misra A. Comorbidities in COVID-19: outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes Metab Syndr Clin Res Rev 2020; 14(4):283-287.
• ¹⁴
  Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China. JAMA 2020; 323(13):1239.
• ¹⁵
  Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 2018; 14(10):576-590.
• ¹⁶
  Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol 2018; 8:1960.
• ¹⁷
  Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020; 181(5):1036-1045.e9.
• ¹⁸
  Brito SBP, Braga IO, Moraes MM, Cunha CC, Leão SC, Takenami I. Immunopathological mechanisms involved in SARS-CoV-2 infection. J Bras Patol e Med Lab 2020; 56:e3352020.
• ¹⁹
  Vellas C, Delobel P, De Souto Barreto P, Izopet J. COVID-19, virology and geroscience: a perspective. J Nutr Health Aging 2020; 24(7):685-691.
• ²⁰
  Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G, Bonanomi E, Cabrini L, Carlesso E, Castelli G, Cattaneo S, Cereda D, Colombo S, Coluccello A, Crescini G, Forastieri Molinari A, Foti G, Fumagalli R, Iotti GA, Langer T, Latronico N, Lorini FL, Mojoli F, Natalini G, Pessina CM, Ranieri VM, Rech R, Scudeller L, Rosano A, Storti E, Thompson BT, Tirani M, Villani PG, Pesenti A, Cecconi M. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern Med 2020; 180(10):1345-1355.
• ²¹
  Anghebem MI, Rego FGM, Picheth G. COVID-19 e diabetes: a relação entre duas pandemias distintas. Rev Bras Anal Clín 2020; 52(2):154-159.
• ²²
  Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: knowledge in progress. Diabetes Res Clin Pract 2020; 162:108142.
• ²³
  Fernandes V, Ramalho J, Santos MJ, Oliveira N, Lopes Pereira M. Diabetes e hiperglicemia: fatores de prognóstico na pneumonia adquirida na comunidade. Rev Port Endocrinol Diabetes e Metab 2015; 10(2):133-140.
• ²⁴
  Lin D, Liu L, Zhang M, Hu Y, Yang Q, Guo J, Guo Y, Dai Y, Xu Y, Cai Y, Chen X, Zhang Z, Huang K. Co-infections of SARS-CoV-2 with multiple common respiratory pathogens in infected patients. Sci China Life Sci 2020; 63(4):606-609.
• ²⁵
  Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus - infected pneumonia in Wuhan, China. JAMA 2020; 323(11):1061-1069.
• ²⁶
  Leiva Sisnieguez CE, Espeche WG, Salazar MR. Arterial hypertension and the risk of severity and mortality of COVID-19. Eur Respir J 2020; 55(6):2001148.
• ²⁷
  Kario K, Morisawa Y, Sukonthasarn A, Turana Y, Chia YC, Park S, Wang TD, Chen CH, Tay JC, Li Y, Wang JG. COVID-19 and hypertension - evidence and practical management: guidance from the HOPE Asia Network. J Clin Hypertens 2020; 22(7):1109-1019.
• ²⁸
  Zheng Y-Y, Ma Y-T, Zhang J-Y, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020; 17(5):259-60.
• ²⁹
  Jose RJ, Manuel A. Does coronavirus disease 2019 disprove the obesity paradox in acute respiratory distress syndrome? Obesity (Silver Spring) 2020; 28(6):1007.
• ³⁰
  Sattar N, McInnes IB, McMurray JJV. Obesity is a risk factor for severe COVID-19 infection. Circulation 2020; 142(1):4-6.
• ³¹
  Leung JM, Yang CX, Tam A, Shaipanich T, Hackett TL, Singhera GK, Dorscheid DR, Sin DD. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. Eur Respir J 2020; 55(5):2000688.
• ³²
  Patanavanich R, Glantz SA. Smoking is associated with COVID-19 progression: a meta-analysis. Nicotine Tob Res 2020; 22(9):1653-1656.
• ³³
  Cardoso AP. A DPOC e a COVID-19. Pulmão RJ 2020; 29(1):43-46.
• ³⁴
  Silva ALO, Moreira JC, Martins SR. COVID-19 e tabagismo: uma relação de risco. Cad Saude Publica 2020; 36(5):e00072020.
• ³⁵
  Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020; 17(9):543-558.
• ³⁶
  Peng W, Wu H, Tan Y, Li M, Yang D, Li S. Mechanisms and treatments of myocardial injury in patients with corona virus disease 2019. Life Sci 2020; 262:118496.
• ³⁷
  Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 2020; 5(7):811-818.
• ³⁸
  Oudit GY, Kassiri Z, Patel MP, Chappell M, Butany J, Backx PH, Tsushima RG, Scholey JW, Khokha R, Penninger JM. Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc Res 2007; 75(1):29-39.
• ³⁹
  Scholz JR, Lopes MACQ, Saraiva JFK, Colombo FC. COVID-19, sistema renina-angiotensina, enzima conversora da angiotensina 2 e nicotina: qual a inter-relação? Arq Bras Cardiol 2020; 115(4):708711.
• ⁴⁰
  Nandy K, Salunke A, Pathak SK, Pandey A, Doctor C, Puj K, Sharma M, Jain A, Warikoo V. Coronavirus disease (COVID-19): a systematic review and meta-analysis to evaluate the impact of various comorbidities on serious events. Diabetes Metab Syndr Clin Res Rev 2020; 14(5):1017-1025.
• ⁴¹
  Del Rio R, Marcus NJ, Inestrosa NC. Potential role of autonomic dysfunction in covid-19 morbidity and mortality. Front Physiol 2020; 11:561749.
• ⁴²
  Kumagai H, Oshima N, Matsuura T, Iigaya K, Imai M, Onimaru H, Sakata K, Osaka M, Onami T, Takimoto C, Kamayachi T, Itoh H, Saruta T. Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure. Hypertens Res 2012; 35(2):132-141.
• ⁴³
  Staedtke V, Bai RY, Kim K, Darvas M, Davila ML, Riggins GJ, Rothman PB, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature 2018; 564(7735):273-277.
• ⁴⁴
  Konig MF, Powell M, Staedtke V, Bai RY, Thomas DL, Fischer N, Huq S, Khalafallah AM, Koenecke A, Xiong R, Mensh B, Papadopoulos N, Kinzler KW, Vogelstein B, Vogelstein JT, Athey S, Zhou S, Bettegowda C. Preventing cytokine storm syndrome in COVID-19 using a-1 adrenergic receptor antagonists. J Clin Invest 2020; 130(7):3345-3347.
• ⁴⁵
  Guilmot A, Maldonado Slootjes S, Sellimi A, Bronchain M, Hanseeuw B, Belkhir L, Yombi JC, De Greef J, Pothen L, Yildiz H, Duprez T, Fillée C, Anantharajah A, Capes A, Hantson P, Jacquerye P, Raymackers JM, London F, El Sankari S, Ivanoiu A, Maggi P, van Pesch V. Immune-mediated neurological syndromes in SARS-CoV-2-infected patients. J Neurol 2021; 268(3): 751-757.
• ⁴⁶
  Dani M, Dirksen A, Taraborrelli P, Torocastro M, Panagopoulos D, Sutton R, Lim PB. Autonomic dysfunction in 'long COVID': rationale, physiology and management strategies. Clin Med (Northfield Il) 2021; 21(1):e63-e67.
• ⁴⁷
  Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Crit Care 2020; 24(1): 353.
• ⁴⁸
  Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J 2020; 41(32):3038-3044.
• ⁴⁹
  Adão R, Guzik TJ. Inside the heart of COVID-19. Cardiovasc Res 2020; 116(6):e59-e61.
• ⁵⁰
  Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, Brown TS, Der Nigoghossian C, Zidar DA, Haythe J, Brodie D, Beckman JA, Kirtane AJ, Stone GW, Krumholz HM, Parikh SA. Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic. J Am Coll Cardiol 2020; 75(18):2352-2371.
• ⁵¹
  Xiong T-Y, Redwood S, Prendergast B, Chen M. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J 2020; 41(19): 1798-800.
• ⁵²
  George PM, Barratt SL, Condliffe R, Desai SR, Devaraj A, Forrest I, Gibbons MA, Hart N, Jenkins RG, McAuley DF, Patel BV, Thwaite E, Spencer LG. Respiratory follow-up of patients with COVID-19 pneumonia. Thorax 2020; 75(11):1009-1016.
• ⁵³
  Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, Kang L, Guo L, Liu M, Zhou X, Luo J, Huang Z, Tu S, Zhao Y, Chen L, Xu D, Li Y, Li C, Peng L, Li Y, Xie W, Cui D, Shang L, Fan G, Xu J, Wang G, Wang Y, Zhong J, Wang C, Wang J, Zhang D, Cao B. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2021; 397(10270):220-232.
• ⁵⁴
  Ong K-C. Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome. Eur Respir J 2004; 24(3):436-442.
• ⁵⁵
  Lad H, Saumur TM, Herridge MS, Dos Santos CC, Mathur S, Batt J, Gilbert PM. Intensive care unit-acquired weakness: not just another muscle atrophying condition. Int J Mol Sci 2020; 21(21):7840.
• ⁵⁶
  Cabañes-Martínez L, Villadóniga M, González-Rodríguez L, Araque L, Díaz-Cid A, Ruz-Caracuel I, Pian H, Sánchez-Alonso S, Fanjul S, Del Álamo M, Regidor I. Neuromuscular involvement in COVID-19 critically ill patients. Clin Neurophysiol 2020; 131(12):2809-2816.
• ⁵⁷
  Disser NP, De Micheli AJ, Schonk MM, Konnaris MA, Piacentini AN, Edon DL, Toresdahl BG, Rodeo SA, Casey EK, Mendias CL. Musculoskeletal Consequences of COVID-19. J Bone Jt Surg 2020; 102(14):1197-1204.
• ⁵⁸
  Gasparino RC, Lima MHM, Souza Oliveira-Kumakura AR, Silva VA, Jesus Meszaros M, Antunes IR. Prophylactic dressings in the prevention of pressure ulcer related to the use of personal protective equipment by health professionals facing the COVID-19 pandemic: a randomized clinical trial. Wound Repair Regen 2021; 29(1):183-188.
• ⁵⁹
  Wang P, Li Y, Wang Q. Sarcopenia: an underlying treatment target during the COVID-19 pandemic. Nutrition 2021; 84:111104.
• ⁶⁰
  Liu K, Zhang W, Yang Y, Zhang J, Li Y, Chen Y. Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study. Complement Ther Clin Pract 2020; 39:101166.
• ⁶¹
  Li L, Yu P, Yang M, Xie W, Huang L, He C, Gosselink R, Wei Q, Jones AYM. Physical therapist management of COVID-19 in the intensive care unit: The West China Hospital experience. Phys Ther 2021; 101(1):pzaa198.
• ⁶²
  Johnson JK, Lapin B, Green K, Stilphen M. Frequency of physical therapist intervention is associated with mobility status and disposition at hospital discharge for patients with COVID-19. Phys Ther 2021; 101(1):pzaa181.
• ⁶³
  Timenetsky KT, Serpa Neto A, Lazarin AC, Pardini A, Moreira CRS, Corrêa TD, Caserta Eid RA, Nawa RK. The Perme Mobility Index: a new concept to assess mobility level in patients with coronavirus (COVID-19) infection. PLoS One 2021; 16(4):e0250180.
• ⁶⁴
  Paneroni M, Vogiatzis I, Bertacchini L, Simonelli C, Vitacca M. Predictors of low physical function in patients with COVID-19 with acute respiratory failure admitted to a subacute unit. Arch Phys Med Rehabil 2021; 102(6):1228-1231.
• ⁶⁵
  Deshpande C, Alaparthi GK, Krishnan S, Chakravarthy Bairapareddy K, Ramakrishna A, Acharya V. Comparison of Londrina activities of daily living protocol and Glittre ADL test on cardio-pulmonary response in patients with COPD: a cross-sectional study. Multidiscip Respir Med 2020;15(1):694.
• ⁶⁶
  Houchen-Wolloff L, Daynes E, Watt A, Chaplin E, Gardiner N, Singh S. Which functional outcome measures can we use as a surrogate for exercise capacity during remote cardiopulmonary rehabilitation assessments? A rapid narrative review. ERJ Open Res 2020; 6(4):00526-2020.
• ⁶⁷
  Houchen-Wolloff L, Daynes E, Watt A, Chaplin E, Gardiner N, Singh S. Cardiopulmonary exercise testing might be helpful for interpretation of impaired pulmonary function in recovered COVID-19 patients. Eur Respir J 2021; 57(1):2004265.
• ⁶⁸
  Ho FK, Petermann-Rocha F, Gray SR, Jani BD, Katikireddi SV, Niedzwiedz CL, Foster H, Hastie CE, Mackay DF, Gill JMR, O'Donnell C, Welsh P, Mair F, Sattar N, Celis-Morales CA, Pell JP. Is older age associated with COVID-19 mortality in the absence of other risk factors? General population cohort study of 470,034 participants. PLoS One 2020; 15(11):e0241824.
• ⁶⁹
  Pedersen S, Johansen D, Casolo A, Randers MB, Sagelv EH, Welde B, Winther AK, Pettersen SA. Maximal strength, sprint, and jump performance in high-level female football players are maintained with a customized training program during the COVID-19 lockdown. Front Physiol 2021;12:623885.
• ⁷⁰
  Curci C, Pisano F, Bonacci E, Camozzi DM, Ceravolo C, Bergonzi R, De Franceschi S, Moro P, Guarnieri R, Ferrillo M, Negrini F, de Sire A. Eur J Phys Rehabil Med 2020; 56(5):633-641.

Edited by

Chief editors:

Maria Cecília de Souza Minayo, Romeu Gomes, Antônio Augusto Moura da Silva

Publication Dates

• Publication in this collection
  22 July 2022
• Date of issue
  Aug 2022

History

• Received
  21 July 2021
• Accepted
  06 Nov 2021
• Published
  14 May 2022