The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged in Wuhan (Hubei Province, China), in December 2019, and COVID-19 pandemic has spread rapidly worldwide. Only a small percentage of patients develop the potentially lethal complications of acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and multiorgan failure (MOF)19,20. After entering the host, SARS-CoV-2 elicits a series of innate and adaptive immune responses, which are responsible for viral clearance as well as inflammation. Emerging evidences suggest that complement is chronically activated in severe COVID-19 and plays a key role in critically ill patients, due to a dysregulated inflammation characteristic of severe COVID-1921. Therefore, we decided to evaluate HAE patients infected with SARS-CoV-2 in order to describe its influence on their prognosis. Of interest, we compared with patients diagnosed with HAE-nC1-INH, considering that C1-INH is normal in this HAE type.
As a collaborative study, we were able to collect data from 66 patients and no differences were evidenced comparing patients with or without C1 inhibitor deficiency. This result was not expected since C1-INH is a major regulator of all three pathways of complement activation22. Through covalent bond formation with the complement components C1s, C1r, MASP1 and MASP2 and reversible binding to C3a, C1-INH attenuates the consequences of complement activation, including the generation of proinflammatory anaphylatoxins, especially C5a, and the formation of the membrane attack complex (MAC) that leads to cell lysis22,23. Coagulation and fibrinolytic pathways are also regulated by C1-INH and it is presumed that the lower C1-INH activity could predispose to more severe SARS-CoV-2 infection24. Moreover, C1-INH has been demonstrated to interact with components of the extracellular matrix, leading to the hypothesis that these components concentrate C1-INH at the local site of inflammation in order to regulate complement and contact systems25.
The similar course of disease in our patients compared to the general population, can be explained by some findings. Females were the predominant sex in our group as it is described in most HAE casuistries26-30. Men have been described with higher severity of COVID-19 in comparison with women31,32. The median age observed by us was in the 30s and it may have influenced the prognosis. Seven HAE patients were older than 60 years of age and this is a risk factor for severe COVID-19. Unfortunately, one 71-year-old patient died from pulmonary complications and multiorgan disfunction related to COVID-19, 28 days after the beginning of symptoms. No additional comorbidity was reported in this patient and she was under HAE prophylaxis with danazol. This death accounted for 1.5% of total cases, less than the mortality reported for general population in Latin American countries33. Furthermore, approximately 70% of our HAE patients had no comorbidities; however, 12% of them were obese. Additionally, low C4 serum levels found in HAE patients might prevent further complement activation and deleterious clinical effects derived from increased complement activity. All these factors could contribute to the better prognosis observed in our population. Different trials inhibiting complement activation, targeting either C3 or C5, have been proposed for critically ill patients34.
Long term prophylaxis was reported in 52% (34/66) of HAE patients, and attacks occurred in 45.5% of patients with HAE during SARS-CoV-2 infection. Four patients reported feeling an upper airway obstruction and laryngeal edema, not well characterized; facial edema was associated in two of them. The continued depletion of ACE2 by SARS-CoV-2 infection increases the extracellular levels of des-Arg9-Bradykinin and bradykinin23. This effect could contribute to attacks in patients with both HAE-C1-INH and HAE-nC1-INH. In addition, the loss of inhibitory activities of C1-INH would be expected to enhance complement activation together with microvascular injury, leading to worse evolution of SARS-CoV-2 infection25.
Androgens, which are able to induce C1-INH liver production, have been the most accessible therapy in Latin American countries; therefore, it is possible that prophylaxis improved the evolution or severity of COVID-19 in HAE patients. On the other hand, a role of a co-receptor for SARS-CoV-2 infection, transmembrane protease serine 2 (TMPRSS2), was described to be upregulated by androgens in a lung-derived cell line model, but not confirmed in physiologic settings35. Although this might be a concern in male patients treated with androgens because of the possibility to influence the outcome of COVID-19, none of our 13 male patients had severe clinical manifestations of SARS-CoV-2 infection.
Eight patients were treated with tranexamic acid and no thromboembolism was reported. One patient with HAE-nC1-INH and no variant identified was hospitalized due to high D-dimer values; however, this finding is described in HAE patients during attacks36 and in COVID-19. This patient was not experimenting angioedema symptoms and evolved with no complications except for involvement of 25% of the lungs during the symptomatic phase.
Long term prophylaxis treatment, to reduce the severity and frequency of HAE episodes, includes infusion of C1-INH, which not only reduces kinin-kallikrein activation and BK production, but also might protect against lung injury by inhibiting the cytotoxic activity of extracellular histones37. This treatment may improve the outcome of HAE patients with SARS- Cov-2 infection, however, access in Latin America is still limited.
Treatment of acute episodes of HAE includes icatibant, a bradykinin receptor 2 antagonist, or ecallantide, a kallikrein antagonist both of which reduce BK production having a modulatory effect on the “bradykinin storm” described in the pathophysiology of COVID-1938. Some of our patients were treated with icatibant for acute episodes and the clinical response was adequate.
We evaluated a more representative number of patients with HAE C1-INH and HAE-nC1-INH infected with SARS-CoV-2. The expression of the COVID-19 was not different from the population without HAE, possibly due to the predominance of female and young patients as well as HAE therapy. Our findings suggest that SARS-CoV-2 infection is a trigger for angioedema attacks, however, the prognosis was not influenced, as previously observed by us and others in a much smaller casuistry18,39. Fortunately, none of our children had MIS-C; and it is believed that pediatric COVID-19 has a more favorable prognosis40. This study exposes the paradox of COVID-19 in HAE patients in real life.