key: cord-0746790-ehvilr6x
authors: Xu, Yingyang; Liu, Shuang; Zhang, Yan; Zhi, Yuxiang
title: Does hereditary angioedema make COVID-19 worse?
date: 2020-08-10
journal: World Allergy Organ J
DOI: 10.1016/j.waojou.2020.100454
sha: ca75b1387db9f55365eaba120c606382511f0cde
doc_id: 746790
cord_uid: ehvilr6x

Abstract The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg(9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed.

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly across most of the world. According to the World Health Organization report of June 24, 2020, more than 9 million cases were confirmed, of which more than 480 000 died from this pandemic disease. The numbers of infection and death from COVID-19, globally, are still rising rapidly.

Tremendous efforts have been made to unravel the pathophysiology and prognostic factors of COVID- 19 . It has been established that SARS-CoV-2 enters host cells in the respiratory tract via the transmembrane protein angiotensin-converting enzyme (ACE) 2 and uses the transmembrane serine protease TMPRSS2 for spike (S) protein priming [1] . After entering the host cell, SARS-CoV-2 elicits a series of innate and adaptive immune responses, which are responsible for virial clearance as well as inflammation [2] . In addition, interactions between SARS-CoV and the contact system, the coagulation systems, and the complement pathway are held to be of relevance for the course and outcome of COVID-19 [3] [4] [5] [6] [7] .

Hereditary angioedema (HAE) is a rare genetic disease with an estimated prevalence of 1.1 to 1.6 per 100,000 worldwide [8] , presenting with recurrent attacks of subcutaneous and submucosal edema. The pathophysiology of HAE involves the contact, complement and fibrinolytic systems, among which the contact system is the key pathway [9] . Certain cytokines such as interleukin-1(IL-1) and transforming growth factor-β (TGF-β), may also play a role in the pathophysiology of HAE [10] .

Therefore, it is reasonable to hypothesize that there might be an interaction between J o u r n a l P r e -p r o o f COVID-19 and HAE. As of now, there are no reports of HAE patients infected with SARS-CoV-2, and there is, therefore, no information on the course of COVID-19 in patients with HAE. Given the low prevalence and large spectrum of HAE, it is unlikely that guidance on the management of COVID-19 in patients with HAE will come from clinical observations or studies on HAE patients with COVID-19. It is, therefore, important to explore and analyze the potential association between the two clinical conditions in terms of their known underlying pathophysiologic mechanisms, which is what this review does.

As depicted in Figure 1 , mutations of the SERPING1 gene that result in a deficient or dysfunctional C1 inhibitor (C1-INH) are the cause of type 1 and 2 HAE. In patients with HAE type 1 or 2, the lack of functional C1-INH leads to overactivation of the contact system and its bradykinin (BK) forming cascade. The resulting overproduction of BK causes the attacks of angioedema. des-Arg(9)-bradykinin (DABK) is generated in the process, without claiming a role in the development of angioedema. As a multi-functional serine protease inhibitor, C1-INH has a wide range of substrates including prekallikrein, kallikrein, factor Ⅻ, factor Ⅻa, factor Ⅻf, plasminogen, plasmin, C1r, C1s, and mannose-binding lectin (MBL)-associated serine protease (MASP)-1 and MASP-2 [11] . Thus, in addition to its central function in the contact system, C1-INH also regulates the complement system and the fibrinolytic and coagulation system ( Figure 1 ). Without the inhibition of C1-INH, factor Ⅻ J o u r n a l P r e -p r o o f autoactivates to form factor Ⅻa by contact with the initiating surface, and then further generates a 28.5-kDa fragment called factor Ⅻf [12, 13] . In peripheral blood, prekallikrein and high-molecular-weight kininogen (HMWK) form a biomolecular complex at a ratio of 1:1 [14] . Both factor Ⅻa and factor Ⅻf convert prekallikrein-HMWK complex to kallikrein-HMWK complex, while the generation of kallikrein results in feedback activation of factor Ⅻ [15] . Kallikrein then digests HMWK to BK, which is the essential mediator of swelling attacks. In type 1 and 2 HAE, excessive generation of BK is caused by overactivation of the plasma contact system [16] . Carboxypeptidase N/M removes the C-terminal peptide from bradykinin to generates DABK [9, 17] . BK binds to bradykinin receptor B2 (B2R), while DABK binds mainly to the bradykinin receptor B1 (B1R) but also to B2R on the surface of endothelial cells, which leads to vasodilation and increased vascular permeability [18, 19] , and the production of vasodilators including nitric oxide and prostaglandin E2. In patients with HAE, especially during edema attacks, the level of BK can significantly increase, not only at the local site of involvement but also the circulation [16] . B1R can be induced by cytokines including IL-1 and tumor necrosis factor γ (TNF-γ). Lys-des-Arg(9)-BK, another BK metabolite, stimulates the production of IL-1β, both of which can upregulate the expression of B1R [20, 21] . In addition, BK can be degraded into inactive fragments by ACE, as well as aminopeptidase P and neutral endopeptidase [17, 22] . To summarize, in type 1 and 2 HAE, the deficiency of C1-INH leads to overactivation of the BK-formation cascade and the overproduction of BK and DABK, which cause the attacks of angioedema J o u r n a l P r e -p r o o f ( Figure 1 ). For HAE patients with normal levels of C1-INH, the underlying mechanism is thought to be related to mutations affecting the BK-formation cascade, which includes genes that encode factor XII, angiopoietin-1, plasminogen and kininogen [23] [24] [25] [26] .

In COVID-19, the S protein on the surface of SARS-CoV-2 has been shown to bind to ACE2 in the lung, which is similar to the mechanism of SARS-CoV-1 [27] . To prepare the host endothelial cells for viral entry, SARS-CoV-1 interacts with ACE2 on the cell surface, inducing membrane fusion and then endocytosis [28] . The translocation of ACE2 from the cell surface to the intracellular space is the part of the process called internalization. It has been reported that the interaction between SARS-CoV-2 and ACE2 increases the activity of ADAM metallopeptidase domain 17 (ADAM17), which can induce the cleavage of ACE2 and the shedding of the ACE2 extracellular domain. Therefore, SARS-CoV infection and S protein on the virion surface reduce the cell-surface expression of ACE2 by both internalization and shedding of ACE2 [29] . ACE2 is a homologue of ACE and participates in the degradation of DABK by cleaving it into inactive products [30] . Partly owing to DABK/B1R axis mediated chemokines release including C-X-C motif chemokine 5, macrophage inflammatory protein-2 (MIP2), C-X-C motif chemokine 1, and TNF-α, ACE2 plays an essential role in the development of pulmonary inflammation [30] .

Thus, the depletion of ACE2 by SARS-CoV-2 infection results in impaired DABK inactivation. Binding of DABK to B1R can prompt neutrophil infiltration, increased J o u r n a l P r e -p r o o f capillary leakage [10] which comprise the key features of acute respiratory distress syndrome (ARDS), and lead to more sever lung injury and inflammation [30, 31] . The accumulation of DABK might result in negative feedback of BK degradation and leave BK binding to B2R on the surface of endothelial cells. Binding of BK to B2R also result in increased vascular permeability and angioedema in lung tissue [9] .

Moreover, BK, histamine and serotonin are known as the essential mediators of acute lung inflammation [32] .

It is possible that the pathophysiologic changes in HAE patients, including a overproduction of BK and subsequently of DABK, followed by upregulated expression of B1R, could facilitate SARS-CoV-2 induced tissue damage in patients with COVID-19 by enhancing vasopermeability and local pulmonary edema via the kinin-kallikrein system, possibly worsening its outcome. Therefore, some researchers have proposed that therapeutic approaches targeting the kinin-kallikrein system, such as the antagonist of B2R (icatibant), C1-INH and selective inhibitors of plasma kallikrein (ecallantide, lanadelumab), may be helpful for the prevention of ARDS in COVID-19 patients [3, 5] . Similarly, in the Chinese recommendation for management of hypertension, experts suggest that icatibant should be considered as a treatment option for COVID-19 patients with respiratory distress or angioedema [33] . As a selective B2R antagonist, icatibant can dysregulate the downstream activity of BK and has been approved for use in the management of acute attacks in patients with HAE in the US and Europe [34] . Additionally, icatibant has been demonstrated to be J o u r n a l P r e -p r o o f effective in the treatment of ACE inhibitor-induced angioedema of the upper aerodigestive tract, which is mediated by the inhibition of the breakdown of BK and subsequent accumulation of BK [35] . C1-INH is a replacement therapy for HAE and has been approved to be used as on-demand and prophylactic treatment. The multi-inhibitory function of C1-INH in not only contact system but also the complements system and the fibrinolytic and coagulation system which are discussed below, might play a beneficial role in the management of patients with COVID-19.

The plasma kallikrein inhibitor, ecallantide, and the monoclonal antibody against kallikrein, lanadelumab, which function via inhibition of kallikrein activity and activation of the BK forming cascade, might be also promising treatment strategies in COVID-19 patients with respiratory distress or angioedema. All three of these drugs are already approved for the treatment of HAE, have well-established safety and side-effect profiles, and are available in clinics. Pharmacologic inhibition of FXIIa or FXI also shows promising protective effects against systemic inflammatory response syndrome in animal models, while exerting little impact on hemostasis and host immunity, indicating that the contact activation system may serve as a potential therapeutic target for the treatment of patients with COVID-19 [36] .

The contact system has close interactions with the coagulation and fibrinolytic systems ( Figure 1 ). In HAE patients, increased coagulation and fibrinolytic activity have been demonstrated during both attacks and remission periods [37, 38] . As J o u r n a l P r e -p r o o f illustrated in Figure 1 , C1-INH inhibits the activation of factor Ⅻ, HMWK-factor Ⅻ and plasminogen, the formation of thrombin, and the activity of plasmin [9] . When functional C1-INH is deficient, the levels of prothrombin fragment 1 + 2, thrombin, and fibrin D-dimer have been observed to be higher in HAE patients than in healthy controls; these parameters were elevated even further during attacks compared with remission [37] [38] [39] . For HAE patients with normal C1-INH levels, mutations in the factor XII gene that cause a reduced activation threshold of the contact system is a common mechanism [9] . However, the risk for bleeding or thrombosis does not increase. 39 The coagulable state in HAE patients has not been fully explained.

Concerns about hematologic abnormalities associated with COVID-19 are increasing.

Based on well-known information, the initial hematologic abnormality is an elevation of D-dimer and other fibrin degradation products, but without overt bleeding, which is likely to be a result of the inflammatory response [40] [41] [42] . The immunologic and inflammatory responses can lead to further progression of hematologic changes, culminating in symptoms of ischemia and thrombotic events in critically ill patients [7] . A D-dimer level greater than 1 μg/mL on admission is a potential risk factor for poor outcomes in COVID-19 [43] . An elevated D-dimer level is the result of not only the activation of coagulation, but also the COVID-19 related inflammatory response [40] . Severe infection can lead to disseminated intravascular coagulopathy in critically ill patients via coagulation activation and inflammatory response [44] .

It is reasonable to investigate whether the known increased coagulation and J o u r n a l P r e -p r o o f fibrinolytic activity in HAE patients predisposes them to develop a more severe condition after infection with SARS-CoV-2, and also whether strategies targeting the hematologic response will benefit HAE patients with COVID-19.

As a serpin, C1-INH regulates the complement system by inactivating C1r, C1s and MASP-2. In HAE patients, without the inhibition of C1-INH, C1r and C1s transform to their respective activated types C1 ̅ and C1 ̅ then form the complex C1

, which digests C4 and C2, and may initiate or facilitate the activation of the complement cascade ( Figure 1 ). Concerning the involvement of MASP-2 in the lectin pathway of complement activation, it is presumed that MASP activity and the lectin pathway would be enhanced during C1-INH deficiency. However, compared with healthy controls, the activity of the MBL pathway and MASP-2 were found to be similar or even lower in HAE patients [45, 46] . It was explained that the lower MASP-2 levels were due to the consumption, and that the lectin pathway was still activated but depressed in HAE [46] . In one study, the concentrations of MASP-2 and ficolin-3/MASP-2 complex were increased during angioedema attacks compared with remission periods in the same HAE patient [47] , indicating that the lectin pathway inflammation in order to regulate the local complement and contact system [11] . In vitro, C1-INH can interact with C3b in a reversible manner, operating as a down regulator for the alternative pathway of complement activation [48] . As shown in Figure 1 , C3b is an essential component of the C5 convertase, C4b2b3b, initiating the common pathway of complement activation. In a study of C1-INH-HAE patients, the level of C3 was lower than in healthy controls and C3 was overactivated [46, 49] .

Thus, the activation of complement was increased in these patients [49] .

The activation of the complement system has been observed in COVID-19. The 

Compared with healthy controls, the levels of IL-17, IL-21, transforming growth factor-β (TGF-β), and granulocyte-macrophage colony stimulating factor (GM-CSF) are significantly higher in HAE patients in remission [10] . These cytokines, plus IL-6, platelet derived growth factor, TNF-α, and vascular endothelial growth factor [60] .

A pathologic study of COVID-19 found an increase in Th17 cells [61] , which are differentiated from Th0 cells by the stimulation of IL-6, TGF-β, IL-21 and IL-23 [62] .

IL-6, which is an important member of the cytokine storm in COVID-19 and has been found to be significantly elevated in patients with severe COVID-19 [63] , works as a central participant in the acute phase of inflammation [64] .

Taken together, it can be inferred that a pre-existing state of elevated cytokines and Th17 in HAE might favor the cytokine release storm in COVID-19, although further evidence is needed.

HAE is a genetic disorder caused by mutations mainly found on SERPING1 and several other genes including FXII, ANGPT1, and PLG [9, 23, 25, 26] . However, there is great heterogeneity in clinical manifestations among HAE patients, even when they carry the same mutation. These differences include the age of onset, severity of edema and the frequency of attacks. It has also been observed that not all carriers of SERPING1 mutations present with recurrent edema. Indeed, a minority of HAE patients never develop edema at any point in their lifetime.

It is possible that COVID-19 and HAE form a reciprocal interaction loop in which the pathophysiologic mechanisms of each disease reinforce those of the other. The pathophysiological overlap between COVID-19 and HAE was summarized in Table 1 .

The continued depletion of ACE2 by SARS-CoV-2 infection increases the extracellular levels of DABK and BK via the kinin-kallikrein pathway, as well as the injury and inflammation in lung tissue [19] . Cellular injury and inflammation upregulate the expression of B1R [65, 66] . The excessive generation of BK and DABK, in addition to the upregulation of B1R, contribute to angioedema. the COVID-19 pandemic is cause for concern. Currently, it is not known whether the poorer clinical outcomes and higher rate of death from COVID-19 in men compared with women represent a casual or causal relationship [69] . Two plausible mechanisms have been proposed [70] . The first is based on evidence that the co-receptor for J o u r n a l P r e -p r o o f SARS-CoV-2 infection, TMPRSS2, can be regulated by androgen in a lung-derived cell line model, although the role of androgen in physiologic settings has not been specified [71] . In patients with prostate cancer, androgen-deprivation therapies can decrease the level of TMPRSS2 and partially protect these patients from SARS-CoV-2 infections [72] . The second possible mechanism involves the immune modulation effect of androgens, which might suppress the antiviral immune response to SARS-CoV-2 [70] . Considering the fact that danazol remains the mainstay medication for HAE in the many countries where first-line treatments are not available, the potential aggravating effect of androgen in COVID-19 deserves special attention during the pandemic. We suggest that danazol should only be used with great caution, or even discontinued, in HAE patients who contract COVID-19.

In summary, we hypothesize that HAE might play a detrimental role in COVID-19

progression based on emerging knowledge about the potential participation of the contact activation system, complement system, and coagulation and fibrinolytic systems, as well as certain cytokines and Th17 cells during SARS-CoV-2 infection. Activation of the contact activation system is the core pathophysiological change in HAE. Excessive generation of BK and DABK, and subsequent upregulation of B1R, lead to vasopermeability and angioedema.

The nucleocapsid (N) proteins of SARS-CoV-2 bind to MASP-2, which is key to the lectin pathway of complement activation. 

Coagulopathy is common in critically ill COVID-19 patients, presenting as elevation D-dimer and other fibrin degradation productions, symptoms of ischemia and thrombotic events, and even DIC.

Increased coagulation and fibrinolytic activity have been demonstrated during both attacks and remission periods in HAE.

An elevated proinflammatory cytokine profile is very common in patients with severe COVID-19, indicating a potentially important role of hyperinflammation. An increase in Th17 cells has been found in COVID-19 patients. 

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