key: cord-1022371-m6tkmnhv
authors: Mason, Kelly; Hasan, Sana; Darukhanavala, Amy; Kutney, Katherine
title: COVID-19: Pathophysiology and Implications for Cystic Fibrosis, Diabetes and Cystic Fibrosis-Related Diabetes
date: 2021-10-25
journal: J Clin Transl Endocrinol
DOI: 10.1016/j.jcte.2021.100268
sha: 325d094bf1d17f89051e1786b3428e578ab89b1c
doc_id: 1022371
cord_uid: m6tkmnhv

The novel SARS-CoV-2 coronavirus (COVID-19) has become a global health crisis since its initial outbreak in Wuhan, China in December 2019. On January 30, 2020, the WHO recognized the COVID-19 outbreak as a Public Health Emergency, and on March 11, 2020, it was declared a pandemic. Although all age groups have been affected, patients with cystic fibrosis (CF) and patients with diabetes have been categorized as highly vulnerable to SARS-CoV-2 infection. Thus far, studies have found that the incidence of SARS-CoV-2 in the CF population is lower than the general population. We review the underlying protective mechanisms which may reduce inflammation and lung damage in CF patients, thus decreasing their risk of severe COVID-19. While the effect of SARS-CoV-2 in those with diabetes related to CF is unknown, other forms of diabetes have been associated with more severe disease. To further understand the potential impact of SARS-CoV-2 in cystic fibrosis-related diabetes, we provide a comprehensive overview of the potential factors contributing to COVID-19 severity in other forms of diabetes, including direct viral effect on the pancreas and indirect effects related to hyperglycemia and immune dysregulation.

The novel SARS-CoV-2 coronavirus (COVID-19) has become a global health crisis since its 50 initial outbreak in Wuhan, China in December 2019. On January 30, 2020, the WHO recognized 51 the COVID-19 outbreak as a Public Health Emergency, and on March 11, 2020, it was declared 52 a pandemic. Although all age groups have been affected, patients with cystic fibrosis (CF) and 53 patients with diabetes have been categorized as highly vulnerable to SARS-CoV-2 infection. 54 Thus far, studies have found that the incidence of SARS-CoV-2 in the CF population is lower 55 than the general population. We review the underlying protective mechanisms which may reduce 56 inflammation and lung damage in CF patients, thus decreasing their risk of severe COVID-19. 57 While the effect of SARS-CoV-2 in those with diabetes related to CF is unknown, other forms of 58 diabetes have been associated with more severe disease. To further understand the potential 59 impact of SARS-CoV-2 in cystic fibrosis-related diabetes, we provide a comprehensive overview 60 of the potential factors contributing to COVID-19 severity in other forms of diabetes, including Introduction 68 In 2019, the beginnings of a global pandemic emerged in Wuhan, China and was identified as 69 novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This highly infectious 70 virus triggers a cytokine storm and hyper-inflammation resulting in pneumonia and acute 71 respiratory distress, although it is now evident that the virus affects more than the pulmonary 72 system alone [1, 2] . Among those most severely affected by the virus, there is a high prevalence 73 of concomitant conditions including underlying respiratory disease and diabetes. It is therefore 74 reasonable to hypothesize that individuals with cystic fibrosis-related diabetes (CFRD), who 75 have both an underlying respiratory disorder and related insulin dependent diabetes, would be at 76 high risk for morbidity and mortality with SARS-CoV-2 infection.

Approximately 40%-50% of people with cystic fibrosis (CF) will eventually develop CFRD [3] . 79 CF is the most common life-threatening genetic disease in Caucasians and is caused by an 80 autosomal recessive mutation in the CF transmembrane conductance regulator (CFTR) gene [4] . 81 This leads to viscous secretions in multiple organs, including the pancreas, presenting as The aim of this manuscript is to characterize the effects of SARS-CoV-2 on individuals with 90 CFRD. Due to limited data regarding the effects of the virus on this specific population, we 91 examine the effects of the virus on those with CF and on those with type 1 and type 2 diabetes. 92 We extrapolate our findings to suggest the likely impact of SARS-CoV-2 on those with CFRD. 

In March 2020, when SARS-CoV-2 was declared a pandemic by the World Health Organization, 96 it was suspected that the virus would have a significant impact on those with pre-existing 97 conditions. It was a concern of the CF community that those with CF were especially vulnerable, 98 and that individuals with CFRD were at even higher risk. Contrary to initial suspicions, multiple studies have found that the incidence of SARS-CoV-2 in 106 the CF population is lower than the general population [11, 12] . In a retrospective, descriptive, As of the writing of this manuscript, SARS-CoV-2 has resulted in 1,636 confirmed infections 135 and 14 deaths in the CF population. The incidence and mortality rates continue to remain lower 136 than the general population, which may be attributable to established pre-pandemic protective 137 behaviors of the CF population, as well as the generally younger population of CF patients. Previously, studies have shown that viral infections lead to approximately 60% of acute 151 pulmonary exacerbations in CF. One factor that contributes to morbidity in CF is reduced 152 antiviral immunity by airway epithelial cells, resulting in increased viral replication. 153 Interestingly, in preliminary reports, SARS-CoV-2 did not lead to poor outcomes in CF patients.

As noted above, this is likely attributed to the extraordinary precautions taken by the CF 

SARS-CoV-2 enters the host cells by using a spike protein (S protein) to bind to the ACE2 cell 161 membrane protein ( Figure 1 ). Cellular entry is facilitated by Furin and Transmembrane protease 162 serine 2 (TMPRSS2), as they cleave the S protein. ACE2 has a site that is potentially activated 163 by Furin, which regulates epithelial sodium channel (ENaC) to facilitate sodium reabsorption. 164 Therefore, both of these mechanisms play a critical role in infection. As we know, activation of 

Early in the pandemic, there was concern that individuals with diabetes may be more susceptible 223 to infection with SARS-CoV-2 given defects in both innate and cell-mediated immunity [21, 22] . 224 Interestingly, several studies have reported a diabetes prevalence in those with SARS-CoV-2 that 225 approximates the local prevalence, challenging the notion that diabetes increases the risk of 226 infection [23] . In-hospital glycemic control also seems to impact COVID-19 severity. Zhu and colleagues 282 compared 282 patients with well controlled diabetes (glucose 70-180 mg/dL) to 528 patients 283 with poorly controlled diabetes (one or more glucose >180 mg/dL). Relative to those whose 284 diabetes was well controlled throughout hospitalization, those with poorly-controlled diabetes 285 required more intervention, including the use of oxygen supplementation and ventilation [10].

After adjusting for age, gender, COVID-19 severity, and comorbidities, mortality remained 287 higher in those whose diabetes was poorly controlled during their hospital course [10]. Poor 288 glycemic control during hospitalization is also associated with higher mortality in those without 289 a previous diagnosis of diabetes [33] , strengthening the notion that hyperglycemia during 290 hospitalization impacts disease progression. 

Severe COVID-19 disease is characterized by a dysregulated immune response leading to lung 309 inflammation and respiratory failure. Over-activation of innate immunity, apoptosis of T cells, 

Thrombotic dysregulation is also a feature of severe COVID-19 and may contribute to worse 333 It is clear that advanced age is associated with more severe disease. Given the increased 334 prevalence of diabetes in older individuals, age likely contributes to disease severity in this 335 population as well. Indeed COVID-19 mortality increases with increasing age in type 1 and type 336 2 diabetes [22] . However, it should be noted that, in many studies, the increase in mortality 337 remains significant after adjusting for age [10, 27] , suggesting that additional factors play a role.

Diabetes duration has also been examined as a potential risk factor for severe COVID-19 339 infection. A prospective study of 26 adults with type 1 diabetes found no association between 340 diabetes duration and COVID-19 severity [47] . In general, SARS-CoV-2 infection is associated with increased morbidity and mortality in those 360 with underlying diabetes, likely related to hyperglycemia, obesity and related co-morbidities 361 with potential effects from immune dysregulation, thrombotic predisposition, increased age, and 362 direct viral effect on the pancreas. As a result, in March 2020, when the WHO declared a 363 pandemic, the medical community hypothesized that individuals with CFRD would be at 364 increased risk for severe disease. Furthermore, ACE2 variants [20] could alter host susceptibility to SARS-CoV-2 infection by 371 decreased binding to the S protein, though this has not yet been studied in the CF population. Another protective mechanism may include higher levels of ACE2 mRNA [19] , which may 378 reduce inflammation and lung damage by increasing conversion of proinflammatory angiotensin 379 II to anti-inflammatory angiotensin 1-7. Finally, CFTR modulators also play a role by down 380 regulating the NLRP3 inflammasome, thus reducing pro-inflammatory cytokine levels. It should 381 be noted, however, that the effect of CFTR modulators on COVID-19 severity has not been 382 thoroughly investigated. Other factors, including the lower prevalence of obesity and airway 383 clearance techniques, may also contribute to reduced disease severity in the CF population. 

The pathogenesis and treatment of the `Cytokine Storm' in COVID-418 19

The Role of Cytokines including 420

Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like 421

Cystic fibrosis-related 423 diabetes: current trends in prevalence, incidence, and mortality

Insulin-secretion abnormalities 426 and clinical deterioration related to impaired glucose tolerance in cystic fibrosis

HbA1c as a 429 screening tool for cystic fibrosis related diabetes

Early glucose 432 abnormalities in cystic fibrosis are preceded by poor weight gain

Influence of the development of diabetes 435 mellitus on clinical status in patients with cystic fibrosis

Predictors for future cystic fibrosis-438 related diabetes by oral glucose tolerance test

Association of diabetes mellitus with 441 disease severity and prognosis in COVID-19: A retrospective cohort study

Association of blood glucose control and outcomes in 445 patients with COVID-19 and pre-existing type 2 diabetes

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The global 451 impact of SARS-CoV-2 in 181 people with cystic fibrosis

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SARS-CoV-2 458 seroprevalence in a Belgian cohort of patients with cystic fibrosis

No detection of 461 SARS-CoV-2 in cystic fibrosis patients at the Regional (Lazio) Reference Center for CF in Italy

Sars-CoV-2 infection in patients with 464 cystic fibrosis. An overview

COVID-19 meets Cystic Fibrosis: for better or 468 worse? Genes and Immunity

The Pathophysiology of COVID-19 and SARS-CoV-2

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Practical recommendations for the management of 482 diabetes in patients with COVID-19

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Prevalence and impact of diabetes among 491 people infected with SARS-CoV-2

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A comparative study of clinical presentation and risk 499 factors for adverse outcome in patients hospitalized with acute respiratory disease due to MERS 500 coronavirus or other causes

Clinical features and short-term outcomes of 144 patients with SARS in the 504 greater Toronto area

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Diabetes patients with COVID-19 infection are 512 at higher risk of ICU admission and poor short-term outcome

Coronavirus disease 2019 516 and the pancreas

Diabetes, infection risk and COVID-19

Factors 521 associated with COVID-19-related death using OpenSAFELY

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Glycemic characteristics and clinical outcomes of 527

COVID-19 patients hospitalized in the United States

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Admission hyperglycemia 534 and radiological findings of SARS-CoV2 in patients with and without diabetes

Newly diagnosed diabetes is associated 537 with a higher risk of mortality than known diabetes in hospitalized patients with COVID-19

High 541 glucose and hyperglycemic sera from type 2 diabetic patients impair DC differentiation by 542 inducing ROS and activating Wnt/β-catenin and p38 MAPK

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New Onset Diabetes in COVID-19

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COVID-19 severity is tripled in the diabetes community: A prospective analysis of the 577 pandemic's impact in type 1 and type 2 diabetes

The authors would like to thank the Cystic Fibrosis Foundation and the mentors from the