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19ВЗАИМОСВЯЗЬ МЕЖДУ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНЬЮ
ЛЕГКИХ И COVID-19
Хакимова Руза Абдурахимовна Махсумова Динора Камоловна Нугманов Озодбек Журабой угли
Андижанский государственный медицинский институт
Хроническая обструктивная болезнь легких (ХОБЛ) — это хроническое заболевание легких, которое затрудняет дыхание. Хроническая обструктивная болезнь легких (ХОБЛ) — это хроническое воспалительное заболевание легких, которое вызывает затруднение потока воздуха из легких. Симптомы включают затрудненное дыхание, кашель, выделение слизи (мокроты) и свистящее дыхание. Обычно это вызвано длительным воздействием раздражающих газов или твердых частиц, чаще всего от сигаретного дыма. Люди с ХОБЛ подвержены повышенному риску развития сердечнососудистых заболеваний, рака легких и ряда других заболеваний. Учитывая разрушительное воздействие, которое COVID-19 может оказать на легкие, естественно опасаться пациентов с ХОБЛ. Оценка их избыточного риска заражения COVID-19 и, в частности, его более тяжелыми респираторными проявлениями была сложной задачей во время этой пандемии по разным причинам. Таким образом, в этой статье мы обсудим взаимосвязь между хронической обструктивной болезнью легких и COVID-19.
Ключевые слова: хроническая обструктивная болезнь легких, хронический воспалительный процесс, кашель, мокрота, свистящее дыхание, рак легкого, COVID-19.
SURUNKALI OBSTRUKTIV O'PKA KASALLIGI VA COVID-19 O'RTASIDAGI O'ZARO
BOG'LIQLIK
Surunkali obstruktiv o'pka kasalligi (COPD) o'pkaning uzoq muddatli kasalligi bo'lib, nafas olishni qiyinlashtiradi. Surunkali obstruktiv o'pka kasalligi (COPD) surunkali yallig'lanishli o'pka kasalligi bo'lib, o'pkada havo oqimiga to'sqinlik qiladi. Simptomlarga nafas olish qiyinlishuvi, yo'tal, shilliq (balg'am) hosil bo'lishi va xirillash kiradi. Odatda tirnash xususiyati ega gazlar yoki zarrachalar, ko'pincha sigaret tutuni bilan uzoq muddatli ta'sir qilish natijasida yuzaga keladi. COPD bilan og'rigan odamlarda yurak xastaligi, o'pka saratoni va boshqa turli kasalliklarni rivojlanish xavfi yuqori bo'ladi. COVID-19 o'pkaga halokatli ta'sirini hisobga olsak, COPD bilan og'rigan bemorlarda qo'rquv yuzaga kelishi tabiiy. Ularning COVID-19 bilan kasallanish xavfini va xususan, nafas olish tizimining yanada og'irroq namoyon bo'lishini baholash uchun pandemiya davri juda qiyin mashq vazifasini bajardi. Shunday qilib, ushbu maqolada biz surunkali obstruktiv o'pka kasalligi va COVID-19 o'rtasidagi o'zaro bog'liqliklarni muhokama qilamiz.
Kalit so'zlar: Surunkali obstruktiv o'pka kasalligi, surunkali yallig'lanish, yo'tal, shilimshiq, xirillash, o'pka saratoni, COVID-19.
INTERRELATIONSHIP BETWEEN CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND
COVID-19
Chronic obstructive pulmonary disease (COPD) is a long-term lung condition that makes it hard to breathe. Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. Symptoms include breathing difficulty, cough, mucus (sputum) production and wheezing. It's typically caused by long-term exposure to irritating gases or particulate matter, most often from cigarette smoke. People with COPD are at increased risk of developing heart disease, lung cancer and a variety of other conditions. Given the devastating impact that COVID-19 can have on the lung, it is natural to fear for patients with underlying COPD. Estimating their excess risk for contracting COVID-19 and, in particular, its more severe respiratory manifestations has been a challenging exercise in this pandemic for various reasons. Thus, in this article we will discuss interrelationship between chronic obstructive pulmonary disease and COVID-19.
Keywords: Chronic obstructive pulmonary disease, chronic inflammatory, cough, mucus, wheezing, lung cancer, COVID-19.
Introduction. Chronic obstructive pulmonary disease (COPD) occurs in older individuals due to persistent inhalation of noxious particles, commonly from cigarette smoking [1]. The pulmonary disease includes airway inflammation and remodelling, with variable alveolar destruction (emphysema) [2]. COPD patients suffer with dyspnoea, cough and sputum production, and may experience sudden worsenings (exacerbations) that are often caused by respiratory tract infections. In addition, COPD is associated with a high prevalence of comorbidities such as cardiovascular disease and diabetes, which is not surprising in an older population with a significant smoking history. COPD and COVID-19 therefore have many potentially negative interrelationships, which may lead to worse outcomes from COVID-19, including impaired pulmonary function, older age and the presence of comorbidities in COPD patients. Furthermore, COPD patients may also be more susceptible to acquiring viral infections including SARS-CoV-2 [3].
First, the reporting on cases has concentrated on hospitalised and intensive care unit (ICU) patients, rather than on mild, outpatient cases. This is in part also due to the variability in testing strategies across the world, where some nations with stricter testing requirements and scarce testing resources have focused on testing only those requiring hospitalisation. We have also not yet quantified how many COPD patients might have chosen never to present to a hospital in this pandemic, only to subsequently appear in the statistics for excess mortality during this time [4, 5]. Second, the underestimation of COPD in the general population is a problem that predates the COVID-19 era [6-8] and one that is likely to be exacerbated in overburdened hospitals where the precise ascertainment of comorbidities may be overlooked and spirometry cannot be performed. Moreover, how the diagnosis of COPD has been adjudicated in these studies has not been clearly delineated, possibly giving rise to variability in prevalence across the world.
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Figure 1. Schematic representation of a) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding to the angiotensin-converting enzyme 2 (ACE-2) receptor following activation of the spike protein (s) by transmembrane serine protease 2 (TMPRSS2), which leads to endocytosis and infection. b) Human organs that have been reported by ZOU et al. [105] to show ACE2 expression, with the respiratory system highlighted in red. c) The renin-angiotensin system (RAS) and the proposed SARS-CoV-2 action. The
generation of angiotensin II from angiotensin I by angiotensin-converting enzyme (ACE) induces vasoconstriction of blood vessels and pro-inflammatory effects through the binding of angiotensin II receptor type 1 (AT1R), while the receptor type 2 (AT2R) may negatively regulate this pathway. ACE inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) are very successful anti-hypertensives by promoting vasodilation of blood vessels. ACE-2 inhibits the activity of angiotensin II by converting angiotensin I to angiotensin 1-9 and angiotensin II to angiotensin 1-7, which binds to the MAS1 proto-oncogene (Mas) receptor with anti-inflammatory effects. Upon SARS-CoV-2 binding to ACE-2, there is a shift in the ACE/ACE-2 balance towards a predominance of ACE, resulting in increased pro-inflammatory effects and tissue damage.
Some group scientists [9] say that these research questions can best be answered by developing standards for transparent data reporting across the globe and harnessing the power of international networks that can quickly collate the data of COVID-19 COPD patients. Similarly, the efforts of translational research scientists at the laboratory bench who are working to characterise the pathophysiology of COVID-19 infections in the airway are critical to developing new therapies for a world in which there are currently very few. According to them that why COPD patients appear to suffer worse outcomes upon contracting COVID-19 (even if their risk of contracting to begin with may not be high) is worth some speculation. First, recent evidence that COPD patients and smokers may display the machinery required for SARS-CoV-2 cellular entry differently has come to light. Similar to SARS-CoV (which was responsible for the 2002-2003 SARS pandemic) [10], SARS-CoV-2 bears an envelope spike protein that is primed by the cellular serine protease TMPRSS2 to facilitate fusion of the virus with the cell's angiotensin-converting enzyme 2 (ACE-2) receptor and subsequent cell entry (Figure 1) [11-14]. Our group has recently demonstrated that in three separate cohorts with available gene expression profiles from bronchial epithelial cells, ACE-2 expression was significantly elevated in COPD patients compared to control subjects [15]. Current smoking was also associated with higher ACE-2 expression compared with former and never smokers, an observation which has subsequently been validated by other groups in separate cohorts of lung tissue and airway epithelial samples [16-18] and supported by additional evidence linking ACE-2 expression with nicotine exposure [19, 20]. It is important to note, though, that ACE-2 expression alone has not been shown yet to confer increased susceptibility or increased severity of disease. Moreover, the relatively low expression of ACE-2 in the bronchial epithelium in comparison to the nasal epithelium [21] has unclear implications for disease susceptibility in patients with predominantly small airways pathology.
Another group of scientists [22] is of the opinion that the main conclusion highlights evidence from epidemiological analyses that COPD patients have worse outcomes from COVID-19. There are biological mechanisms that cause COPD patients to be more susceptible to acquiring viral infections, and to the pathophysiological consequences of COVID-19, including micro-thrombosis, the effects of intrapulmonary shunting and secondary bacterial infection. Interestingly, evidence suggests that ICS may protect against COVID-19, although this has not been directly confirmed in COPD patients. These interrelationships between COPD and COVID-19 are summarized in Table 1. A consequence of COVID-19 has been increased anxiety and isolation in COPD patients, with potentially harmful long-term consequences.
There are few opinions about the disease. Cellular tropism of SARS-CoV-2 infection is determined by the expression of receptors for the virus, including angiotensin-converting enzyme 2 (ACE2). Bronchial and alveolar epithelial cells, and pulmonary endothelial cells express ACE2, and are infected with virus in COVID-19 cases. Protein and gene expression studies have reported increased expression of ACE2 in COPD epithelial cells compared to controls, with increased expression in COPD patients with a higher BMI and more frequent exacerbations also observed. There are inconsistent findings regarding changes in accessory protein expression, including transmembrane serine protease 2 (TMPRSS2) and furin. Expression of intracellular adhesion molecule-1 (ICAM-1), the receptor for rhinovirus, is also increased in the lungs of COPD
patients. Overall, these observations suggest increased opportunities for viral entry in COPD lungs. However, this by itself is unlikely to determine the clinical outcome to infection; reduced host antiviral defence and immune system dysfunction in COPD patients may also combine to promote host permissiveness [23,24].
SARS-CoV-2 infection; mechanisms of increased susceptibility in COPD Clinical outcomes in COPD patients with COVID-19 Worse COVID-19 clinical outcomes in COPD patients; mechanistic explanations COPD, COVID-19 and ICS
Increased ACE2 expression in lung epithelium Reduced antiviral defence Dysfunctional immunity Confounding factors need to be controlled for in epidemiological data. Analyses adjusted for confounding variables show increased hospitalization and mortality Increased risk for micro-thrombosis due to endothelial cell dysfunction and coagulopathy. Detrimental effects of increased intra-pulmonary shunting Secondary bacterial infection Corticost eroids reduce SARS-CoV-2 replication. Systemic and inhaled corticosteroids improve COVID-19 related outcomes, although not studied specifically in COPD
Table 1. COPD and COVID-19 interrelationships; key points.
There is evidence that host antiviral responses, notably interferons, are dampened in COPD patients. During experimental rhinovirus infection, the production of interferon (IFN)-a, P and X from bronchoalveolar lavage cells was lower in COPD patients than in controls, albeit only significant for IFN-p. COPD patients experienced more respiratory symptoms and also had a higher viral load and increased markers of inflammation. An immunohistochemistry study showed significantly lower bronchial epithelial and alveolar macrophage expression of IFN-P in COPD patients compared to controls. Furthermore, sputum levels of IFN-P and IFN-X are lower from COPD patients with more exacerbations, suggesting that reduced host defence against viral infection associates with worse clinical outcomes. Reduced IFN production may be caused by reduced signalling by pattern recognition receptors; bronchial epithelial expression of melanoma differentiation-associated gene-5 (MDA-5) and retinoic acid-inducible gene-1 (RIG-1) are reduced in COPD patients compared with controls, suggesting that COPD bronchial epithelial cells are less adept at mounting antiviral responses. Indeed, Veerati et al. reported that IFN-P production and antiviral gene expression by COPD epithelial cells were delayed following rhinovirus infection. Although antiviral responses using COPD lung cells exposed to SARS-CoV-2 have not been studied, evidence using other viral exposure models indicates a downregulation of interferon defence mechanisms [25-27].
Lymphopoenia and T cell dysfunction are associated with worse outcomes in COVID-19. T cells in the lungs of COPD patients display increased expression of programmed cell death protein 1 (a marker of T-cell exhaustion), while T-cell receptor (TCR) expression is decreased compared with controls. These observations indicate that COPD T cells are dysfunctional; this is supported by reports of reduced degranulation by COPD lung T-cells in response to influenza infection, and reduced cytokine production from COPD blood T-cells following TCR activation. T-cell dysfunction in COPD patients may cause suboptimal host defence responses to SARS-CoV-2 infection [28,29].
As far as some group scientists go said [30] that PRSs combining multiple risk alleles are predictive of incident severe COVID-19. Meanwhile, high genetic risk was associated with a higher risk of incident severe COVID-19, regardless of preexisting COPD. These findings could have important implications for understanding the mechanisms underlying severe COVID-19 and provide future opportunities for risk stratification and early intervention. According to the investigations, in this population-based cohort study of more than 430,000 participants, both high genetic risk and COPD were independently associated with an increased risk of incident severe COVID-19. The risk of incident severe COVID-19 at high genetic risk combined with preexisting COPD was 2.05-fold higher than that at low genetic risk and without preexisting COPD.
There are common variants that were previously identified to be associated with the high risk of severe COVID-19, and their combined impact can be indicated by the PRS. Our results demonstrated that the PRS was associated with the risk of developing severe COVID-19. Although the previous study has evaluated the predictive performance of PRSs based on six DNA polymorphisms in severe COVID-19 among sports players to guide screening, the limited sample size with case-control design in previous studies often led to discouraging results. In the present study, we found that our PRS was significantly associated with the risk of severe COVID-19 in a prospective cohort study. Our study has included a larger sample size and a significantly more comprehensive indicator of the genetic risk to increase the power for risk estimation. We have also adjusted for multiple potential confounding factors (economic and social background, lifestyle factors, comorbidities, etc.). Several genetic variants used in the present study associated with severe COVID-19 may affect the immune response and transmission of SARS-CoV-2. Furthermore, our results demonstrated the lack of interactions between genetic risk and preexisting COPD, which suggests that it provides information regarding severe COVID-19 that is independent of preexisting COPD. These findings in the present study provided additional insights into the genetic basis of severe COVID-19, which would further advance our understanding of severe COVID-19 susceptibility [31,32].
From a clinical perspective, methodologically similar to assessing other diseases by using PRS, our PRS may help to identify individuals at the greatest risk for severe COVID-19. The risk of incident severe COVID-19 at high genetic risk was 1.50-fold higher than that at low genetic risk, suggesting that our PRS potentially was suitable to the risk stratification among those with COVID-19. In addition, the availability of the PRS throughout the life course suggests that PRS might be helpful for predicting severe COVID-19 in scenarios in which up-to-date clinical information is not available (e.g., COPD). From a disease management perspective, the distinct incidence risk for populations within different categories of genetic risk as defined by the PRS provides support to carry out PRS-informed severe COVID-19 screening and individualized prevention, independent of clinical risk factors such as age, sex, and COPD exposure. Furthermore, individuals with higher genetic risk might be warned to be more likely to maintain social distancing and carry out life planning to reduce the risk of developing severe COVID-19. Therefore, one potential application is using the PRS to help predict susceptibility to severe COVID-19 in initially healthy people, so as to focus preventive interventions on those at the highest risk of severe COVID-19 [33].
Several studies have consistently reported an increased risk of developing severe COVID-19 in participants with preexisting COPD. However, these findings are limited by small sample sizes and incomplete data on comorbidities, and the relevance of composite genetic risk and COPD in predicting the risk of severe COVID-19 remains unclear. Based on the population-based cohort study, our results demonstrated that participants with preexisting COPD had increased risks of developing severe COVID-19 as compared with participants without preexisting COPD, regardless of the individuals' genetic risk. Moreover, the real-life setting of our large-scale cohort study has provided further support that COPD is a risk factor for severe COVID-19, even in participants genetically not predisposed to developing severe COVID-19. Although the underlying mechanisms remain to be elucidated, it is suggested that angiotensin-converting enzyme 2 plays an important
role in this association. Studies of cellular mechanisms suggest that angiotensin-converting enzyme 2 expression, which is the main receptor for the cellular entry of SARS-CoV-2, is significantly upregulated in participants with COPD. The findings in the present study indicate that patients with COPD should follow basic infection-control measures to help prevent severe COVID-19, and medical workers should pay more attention to patients with COPD who are infected with COVID-19 [34-36].
There are several limitations that should be taken into account. First, we have limited information about the exposure to SARS-CoV-2 among participants without COVID-19 in the UK Biobank, which might have resulted in the selection bias, as in previous studies. However, this concern is mitigated because these results did not markedly change after restricting analyses to participants with SARS-CoV-2 test and participants with positive SARS-CoV-2 test results. Second, additional variants or genetic patterns associated with severe COVID-19 are likely to be identified in the future, which may prove useful for refining estimates of genetic risk. Third, because the PRS was calculated based on the GWAS of European ancestry, we must cautiously generalize the inferences to other populations. Individuals of Black, Asian, and other minority race or ethnicity groups may be at increased risk for SARS-CoV-2 infection and potentially worse clinical outcomes, including ICU admission and mortality, when compared with White individuals. Race refers to self-identifying groups based on beliefs concerning shared culture, ancestry, and history. And ancestry is determined biographically or genetically. Although race may be a social construct, differences in genetic ancestry that happen to correlate to many of today's racial constructs are real. As such, the findings in our study highlight that future GWASs and large-scale epidemiologic research should consider predicting the risk of incident severe COVID-19 among non-European ancestry groups. Fourth, the measures did not include information about the epidemiology of COVID-19 and medical care practices to treat COVID-19 infections, such as type of virus and use of drug, possibly leading to imprecise measurements. Finally, there are very few severe COVID-19 cases among participants in the UK Biobank, which might reduce the power in these analyses. Thus, further research involving more patients with severe COVID-19 is needed in the future [37,38].
Conclusion. In conclusion, in this article we have discussed interrelationship between chronic obstructive pulmonary disease and COVID-19. We have analyzed the opinions and conclusions of several scientists on this topic. We believe that this article can be an impetus for further in-depth research.
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