key: cord-319580-awtp0mpg
authors: McCartney, Stephen A.; Kachikis, Alisa; Huebner, Emily M.; Walker, Christie L.; Chandrasekaran, Suchi; Adams Waldorf, Kristina M.
title: Obesity as a contributor to immunopathology in pregnant and non‐pregnant adults with COVID‐19
date: 2020-08-11
journal: Am J Reprod Immunol
DOI: 10.1111/aji.13320
sha: 
doc_id: 319580
cord_uid: awtp0mpg

The ongoing coronavirus disease 2019 (COVID‐19) pandemic has led to a global public health emergency with the need to identify vulnerable populations who may benefit from increased screening and healthcare resources. Initial data suggests that overall, pregnancy is not a significant risk factor for severe coronavirus disease 2019 (COVID‐19). However, case series have suggested that maternal obesity is one of the most important co‐morbidities associated with more severe disease. In obese individuals, suppressors of cytokine signaling are upregulated and type I and III interferon responses are delayed and blunted leading to ineffective viral clearance. Obesity is also associated with changes in systemic immunity involving a wide range of immune cells and mechanisms that lead to low‐grade chronic inflammation, which can compromise antiviral immunity. Macrophage activation in adipose tissue can produce low levels of pro‐inflammatory cytokines (TNF‐α, IL‐1β, IL‐6). Further, adipocyte secretion of leptin is pro‐inflammatory and high circulating levels of leptin have been associated with mortality in patients with acute respiratory distress syndrome. The synergistic effects of obesity‐associated delays in immune control of COVID‐19 with mechanical stress of increased adipose tissue may contribute to a greater risk of pulmonary compromise in obese pregnant women. In this review, we bring together data regarding obesity as a key co‐morbidity for COVID‐19 in pregnancy with known changes in the antiviral immune response associated with obesity. We also describe how the global burden of obesity among reproductive age women has serious public health implications for COVID‐19.

The emerging coronavirus disease 2019 (COVID-19) pandemic caused by infection with the novel betacoronavirus SARS-CoV-2 continues to challenge public health systems globally. Although the majority of patients with COVID-19 have self-limited disease consisting predominantly of mild respiratory symptoms, approximately 20-30% develop acute respiratory distress syndrome (ARDS) [1] [2] [3] [4] . The Centers for Disease Control have recently refined their risk categories for COVID-19 to state that obesity was a major risk factor 5 . In pregnant women, severe COVID-19 disease is also associated with obesity 6, 7 . Over the last decade, non-communicable metabolic diseases such as hypertension, diabetes and obesity have increased in prevalence globally 8 . In the United States, more than one-third of reproductive age women are considered to be obese [body mass index (BMI)

≥ 30 kg/m 2 ) 9 . At the same time, the immunology and pathophysiology associated with COVID-19 in pregnancy and especially in the setting of other comorbidities such as obesity is poorly understood.

This review is directed towards summarizing how obesity affects the severity of COVID-19 clinical disease and negatively impacts the antiviral immune response.

In non-pregnant populations, obesity has been associated with severe COVID-19 disease. A retrospective review of 770 patients with COVID-19 from the two medical centers in New York found that obese patients were more likely to present with symptoms; obese patients also had a significantly increased risk of ICU admission or death (RR 1.58) even after adjusting for race, age and troponin levels 10 . Another retrospective study from a third medical center in New York including 200 patients with COVID-19 found that a BMI ≥ 35 kg/m 2 was independently associated with higher in hospital mortality compared to a BMI of 25-34 kg/m 2 (adjusted odds ratio 3.78; 95% CI: 1.45-9.83). Similarly, BMI ≥ 35 kg/m 2 was a significant predictor for increasing oxygenation requirements and intubation 11 . An Italian retrospective study demonstrated similar findings with overweight or obese patients more often requiring ventilation and a higher level of care despite younger age than older patients with normal BMI 12 .

Obese pregnant women are at increased risk for complications of viral infection from influenza, cytomegalovirus, and SARS-CoV-1 and related complications such as ARDS 13-17 . The increased risk of severe respiratory viral disease due to obesity and pregnancy was most strikingly noticed with the Accepted Article H1N1 Pandemic in 2009 17 . In a study of hospitalized patients with a confirmed H1N1 influenza A viral infection in the United States, class III obesity was associated with hospitalization regardless of whether the patient had chronic medical conditions 18 . Immune changes in obesity have also been associated with increased susceptibility of viral infection including increased peak viral loads and delayed clearance in influenza 19 .

Several case series and cohort studies have reported an increased severity of COVID-19 in pregnancies complicated by elevated BMI and obesity (Table 1 ). An early report of two pregnant women with severe COVID-19 necessitating ICU admission in the postpartum period was notable for a BMI of 38 and 47 kg/m 2 in these cases 20 . In a cohort study of 46 pregnant women with COVID-19

in Washington State, obesity emerged as a key co-morbidity in women with severe COVID-19 6 ; of five pregnant women with severe disease in which information to calculate the body mass index was available, four were overweight or obese prior to pregnancy 6 . In a study of pregnant women in Italy, it was reported that of 14 women with severe disease, the median BMI was 30 kg/m 2 , which was significantly elevated compared to women with mild disease (p=0.02) 21 . Another cohort study from 12 medical centers in the United States included 64 pregnant women hospitalized due to COVID-19; of 64 women with severe or critical COVID-19 disease, the average BMI was 33.5 kg/m 2 22 . This study also demonstrated that critically ill pregnant women with COVID-19 had a lower BMI than severely ill women, suggesting that while obesity may be a risk factor for severe disease, obese women may have lower mortality than lean women. Interestingly, the idea that obese women may have a greater disease severity, but lower mortality than lean women mirrors other studies from the critical care literature, which have coined this finding as the "obesity paradox" 23 . Maternal deaths have been linked with obesity, however. A case series from Iran including nine pregnant women with severe COVID-19 disease of which seven died, three women had a BMI > 30 kg/m 2 24 . A case series of 124 maternal deaths from Brazil found that obesity (undefined) was significantly associated with mortality 25 . Further, several case reports or series from the United States and the United Kingdom have reported maternal deaths or severe maternal morbidity in women with obesity 26-32 . Finally, the largest series of pregnant women with COVID-19 to date including 427 cases in the United Kingdom demonstrated that 34% of cases were obese compared to 23% of controls 7 .

This article is protected by copyright. All rights reserved Understanding the immunopathology of infection with this novel virus is rapidly evolving. SARS-CoV-2 shares 80% RNA sequence homology with SARS-CoV-1, allowing extrapolation of likely shared pathophysiology and immune response [33] [34] [35] . Both viruses enter the cell via angiotensinconverting enzyme-related carboxypeptidase 2 (ACE2) receptor, though the SARS-CoV-2 spike protein binds ACE2 with significantly higher affinity than SARS-CoV-1 36 . Healthy individuals have higher concentrations of ACE2 in lung tissues, specifically bronchial smooth muscle cells, alveolar epithelium, type II pneumocytes and alveolar macrophages 37,38 . Extrapulmonary expression of ACE2 occurs in myocardial cells 38 , enterocytes in the ileum and jejunum 39 , proximal tubular cells in the kidney 38 , oral mucosa 40 , and arterial and venous endothelium 41 . In contrast, the strongest evidence suggests negligible placental expression of ACE2 and TMPRSS2, a serine protease that acts as a canonical mediator of cell entry for SARS-CoV-2 in conjunction with ACE2 42 . Multiple cells, predominantly within the lung, but also within other target organs (e.g. heart, kidney) express the canonical receptor for SARS-CoV-2 entry.

During the initial stage of most viral infections, the type I and type III interferon (IFN) response is the primary mechanism leading to viral clearance. Immune cells detect viral nucleic acids through pattern 

This article is protected by copyright. All rights reserved inflammatory response by producing pro-inflammatory cytokines (TNF-, IL-1, IL-6), which, in turn, lead to additional lung injury and immune cell recruitment 51,52 . Cytokines and chemokines result in activation of adaptive immune T and B cells as well as recruitment of neutrophils and monocytes. Viral-specific CD8 T cells are cytotoxic primarily to infected cells and serve to limit the release of additional viral particles, while neutrophils non-specifically release reactive oxygen species and leukotrienes, which are directly toxic to pneumocytes and endothelial cells. Additionally, high levels of IFN and pro-inflammatory cytokines also lead to cell death directly with and without viral infection through induction of apoptosis. Patients with severe COVID-19 typically have high levels of systemic pro-inflammatory cytokines, lymphopenia, and inflammatory lung infiltrates, which is consistent with a maladaptive patterns of cytokine production and inflammatory misfiring 53-56 . Elevated cytokines are also associated with multiple pathologic effects in the lung including endothelial apoptosis and vascular leaking, an ineffective antiviral response, diffuse alveolar damage, inflammatory cellular infiltrates and intravascular thrombosis [57] [58] [59] .

Adipose tissue is an active endocrine and immune organ consisting primarily of adipocytes, but also multiple immune cell types, which represent the second most frequent type of cells in this tissue 60, 61 .

Macrophages are the most common immune cell type in adipose tissue and, in lean individuals, produce type 2 cytokines (IL-4, IL-10) and anti-inflammatory molecules 62, 63 . However, in obese individuals, activated macrophages in adipose tissue produce pro-inflammatory cytokines TNF-, IL-1 and IL-6, which results in recruitment and activation of additional monocytes, as well as NKT cells and mast cells. Adaptive immune cells also play a role in obesity-associated inflammation. Adipose tissue from lean individuals is composed primarily of CD4+ Th2 cells and regulatory T cells (Treg), which promote an anti-inflammatory environment, while obese adipose tissue is enriched for CD4+ Th1 and Th17 cells as well as cytotoxic CD8+ T cells [64] [65] [66] . Changes in T cell polarization may be due to altered metabolite availability in obesity, which contributes to T cell differentiation and response to pulmonary infection 67, 68 . In addition to changes in T-helper cell phenotype, obesity is also associated with T cell dysfunction. Obesity results in increased production of memory T cells, and in a mouse model of viral infection, the memory T cell response to viral infection in obese animals resulted in increased pathogenesis rather than a protective response 69 

This article is protected by copyright. All rights reserved also been associated with T cell exhaustion, which may be responsive to treatment with biologic therapies 70, 71 .

Adipose tissue and cytokine-like hormone released from adipocytes, called adipokines, may directly and indirectly impair the pulmonary immune response. The adipocyte overflow hypothesis suggests that when an adipocyte can no longer hypertrophy to accommodate storage of new lipids, an "overflow" of fatty acids occurs into the body 72, 73 ; lipids may then be recognized by innate immune pathogen recognition receptors at ectopic sites to stimulate a low-grade inflammatory response 74 .

Adipose tissues also release adipokines that can act as powerful regulators of the immune response.

Leptin is a key adipokine and can regulate both innate and adaptive immunity to mediate a proinflammatory immune response 75 . An inflammatory microenvironment can also downregulate production of adiponectin by adipocytes, which impairs the anti-inflammatory response. Interestingly, high-levels of leptin that are typical in obese individuals increase the risk of the severity of respiratory infections in both humans and mouse models 76 . High circulating leptin levels were associated with mortality in non-pregnant adults hospitalized for acute respiratory distress syndrome due to pneumonia, even after adjusting for BMI 76 . The placental trophoblast and amnion also secrete leptin, which may further impair the pulmonary immune response in pregnant women 77 . Finally, adipose tissue is present in subcutaneous, visceral, and omental locations; the cellular and metabolic properties of each type of tissue are unique. Alterations in visceral adiposity have been associated more closely with adverse metabolic and health outcomes and immunologic dysfunction 78, 79 .

In addition to inducing immunologic dysfunction, excess adipose tissue also changes the mechanics and physiology of respiration. The increased metabolic requirements in obesity results in higher oxygen consumption and increased work of breathing 80 . Obesity also results in greater production of carbon dioxide, which leads to decreased respiratory drive. Mechanically, increased fat deposits within the abdominal cavity reduce the compliance of the respiratory system 81 . Increased abdominal adipose tissue mass leads to elevated abdominal pressure and lower lung volume by reducing expiratory reserve and functional residual capacity 82 . Obesity is also associated with airway narrowing which can lead to gas trapping 83 . The combination of decreased lung volumes, increased abdominal pressure and narrowing of the airway leads to increased work of breathing with early fatigue of respiratory muscles.

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Pregnancy provides both a physiologic and immunologic challenge for the maternal host during which it must balance providing access to nutrition, protection from infection, and tolerance of a genetically foreign fetus. To accommodate these functions, there is dynamic regulation of the maternal immune system, both systemically and at the maternal-fetal interface during pregnancy.

Pregnancy requires both pro-inflammatory and tolerogenic immune responses at specific times during gestation [84] [85] [86] . During the early first trimester, a localized inflammatory response is necessary for embryonic implantation into the uterine decidua 87, 88 . At the time of human parturition, a functional progesterone withdrawal in humans coupled with an inflammatory response direct the cascade of biological events that culminate in birth [89] [90] [91] [92] Accepted Article levels are one of the strongest clinical correlates for severe COVID-19 disease 104, 105 . In addition, a change in CD4+ T cell polarization from Th2 and Treg cytokines (IL-4, IL-10, IL-13) to a proinflammatory Th1 and Th17 response observed in obese individuals is associated with production of pro-inflammatory cytokines, such as TNF-, IL-1, IL-6, and IL-17, which provides a potential mechanism for an earlier initiation of cytokine release and inflammatory misfiring in obese patients.

The expression of ACE2 by adipocytes and immune cells also suggests the possibility that adipose tissue may represent a potential reservoir for viral infection and may lead to increased viral burden or persistence; however, no studies to date have demonstrated that adipocytes can be directly infected with SARS-CoV-2. These obesity-driven alterations in the immune response likely contribute to the severity of COVID-19 in obese pregnant women.

Maternal obesity has emerged as a key risk factor increasing susceptibility of pregnant women to severe COVID-19 disease. This is likely the result of complex immunologic, metabolic, endocrine and physiologic changes associated with obesity, which affect the immune response to viral infection.

The increasing global burden of obesity may lead to more severe pregnancy morbidity and has the potential to regress decades of progress in global health and, by extension, to improvements in reproductive and pregnancy care worldwide. Analyses comparing obesity rates in over the last three decades show that obesity among pregnant women has increased drastically worldwide 106 . In 2017-2018, obesity among women 20 years and over was 41.9% in the United States 9 . Currently the US also has the highest number of COVID-19 infections worldwide 107 . In light of the global COVID-19 pandemic, there has been a call for renewed prioritization of non-communicable diseases such as obesity that increase susceptibility of women with SARS-CoV-2 infection to severe disease or mortality 108 . Carefully designed epidemiologic studies are required to assess the linkage between COVID-19 disease severity, obesity and associated socioeconomic factors. There is also an urgent need to focus research on how risk factors, like obesity, alter the immune response to SARS-CoV-2 and influence disease pathogenesis of COVID-19 (Box 1). Finally, given global trends in the rise of obesity over the last 3 decades, urgent action is needed to address this critical health condition for global health 106 . 

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Box 1. Research Questions 1. What is the mechanism of increased risk for severe COVID-19 disease in obese nonpregnant and pregnant women?

Does the second and third trimester of pregnancy represent a time of increased risk for severe COVID-19? If yes, how does gestational age modify the effect of obesity on COVID-19 disease severity?

Is preterm birth more common in obese pregnant women with COVID-19 due to concern for respiratory compromise?

Are certain therapies more effective for treatment of severe COVID-19 in obese pregnant women compared to lean or non-pregnant women?

Does increased surveillance for COVID-19 in obese pregnant women improve health outcomes?

Can adipose tissue serve as a reservoir for SARS-CoV-2 viral infection through adipocyte ACE2 expression?

Are viral loads higher of SARS-CoV-2 in obese versus lean pregnant women? Are the kinetics of viral clearance different in obese versus lean pregnant women?

Can we design epidemiologic studies to further assess whether the risk of severe COVID-19 infection in obese pregnancy is directly related to obesity itself or to associated socioeconomic factors? Accepted Article