Abstract
Background:
The demonstration that severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) enters the cell via the angiotensin-converting enzyme 2 receptor has raised concerns that, in hereditary angioedema (HAE), a disease characterized by bradykinin-mediated angioedema attacks, coronavirus disease 2019 (COVID-19) may trigger angioedema attacks, increase the frequency and/or severity of attacks, or cause more severe symptoms of COVID-19.
Objective:
The objective was to evaluate the severity of COVID-19 in patients with HAE, the course of HAE attacks, angioedema activity, and the quality-of-life scores during COVID-19 pandemic.
Methods:
Patients diagnosed with HAE for at least 6 months were included in the study. The 7-day Angioedema Activity Score and the Angioedema Quality of Life (AE-QoL) Questionnaire were first completed at the onset of the pandemic between March 12 and June 1, 2020, then during SARS-CoV-2 infection, and in the third month after recovering from COVID-19.
Results:
Ten of 67 patients with HAE (14.9%) were diagnosed with COVID-19. The median (interquartile range) age of the 10 patients diagnosed with COVID-19 was 35.5 years (28.0–55.0 years). Six of the 10 patients (60%) were women. During COVID-19, five of the 10 patients (50%) had no angioedema attack. Two patients with severe HAE experienced a significant increase in angioedema activity during COVID-19 compared with their basal activity scores. The remaining three patients had a similar or lower attack frequency than their basal level. Four (40%) of the 10 patients had a relative increase in their attacks during the convalescence period. There was no statistically significant difference among pre-COVID-19, during COVID-19 and post-COVID-19 periods in function, mood, fear and/or shame, nutrition, and total scores of the AE-QoL Questionnaire although the fear dimension was relatively more affected (p = 0.06).
Conclusion:
Although the sample size was small, analysis of our data supported that the symptoms of COVID-19 were not more severe in HAE. Also, there was no significant difference in the AE-QoL Questionnaire scores, the frequency, and severity of angioedema attacks during the course of COVID-19 in the patients with HAE.
Keywords: AAS, AE-QoL, attack, HAE, COVID-19, hereditary angioedema, pandemic
During the pandemic, it has been a matter of curiosity as to how patients with hereditary angioedema (HAE) would progress in terms of both the course of coronavirus disease 2019 (COVID-19) and angioedema attacks. The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which is the cause of COVID-19, has been shown to enter the cell through angiotensin-converting enzyme 2 (ACE2) receptors.1 It has been demonstrated that ACE2 expression and function, which is important in bradykinin metabolism, can be reduced by the binding of the virus to the receptor and endocytosis of ACE2.2,3 This has raised concerns that COVID-19 might trigger attacks of HAE, a disease characterized by bradykinin-mediated angioedema attacks, might increase the frequency and/or severity of attacks, or might cause more severe symptoms of COVID-19.
HAE is a life-threatening autosomal dominant disease characterized by C1 esterase inhibitor (C1-INH) deficiency.4 The most common types are HAE with deficient C1 INH (type I) (85%) and HAE with dysfunctional C1-INH (type II) (15%). In addition, HAE with normal CI-INH is rare and shows normal complement measurements.5 In addition to investigating the frequency and severity of the attacks, the determination of disease burden by quality-of-life (QoL) assessments are key points to evaluate treatment outcomes and identify improvement targets in patients with HAE.6,7 The Angioedema Activity Score (AAS) is a validated test to measure disease activity in diseases with recurrent angioedema.8,9 The Angioedema Quality of Life (AE-QoL) Questionnaire has been approved as a specific patient-reported outcome tool to assess QoL impairment in patients with recurrent angioedema.10
In the literature, there are few studies that indicate that acute attacks may occur in the convalescence phase of COVID-19, more commonly in patients with more-frequent attacks, and suggest that COVID-19 does not pose a risk in patients with mild HAE.11 In a study that examined patients with HAE and with COVID-19, it was presented that, contrary to expectations, patients with HAE did not show a more-severe disease course than non-HAE population.12 In addition, from the results of the studies conducted in populations other than those with HAE in the literature, it was observed that patients showed an improvement in their symptoms and radiologic abnormalities in the 3-month follow-up after recovering from COVID-19, so we re-investigated the HAE population at the third month after COVID-19.13 In line with these data, we aimed to evaluate the severity of COVID-19 in patients with HAE who were followed up in our clinic, and the course of HAE attacks, activity scores, and QoL during the COVID-19 pandemic.
METHODS
Patients diagnosed with HAE for at least 6 months according to the latest World Allergy Organization/European Academy of Allergy and Clinical Immunology (WAO/EAACI) guideline4 and > 18 years of age who were followed up at Hacettepe University Department of Adult Allergy and Clinical Immunology were included in the study. The diagnosis of HAE with normal C1-INH was made based on clinical criteria in previously published expert consensus.14 To confirm the diagnosis and classify the subtypes factor XII, plasminogen, and angiopoietin 1 gene mutations were screened.15 The disease severity criteria of the patients were defined in accordance with the literature.16 The 7 consecutive days AAS (AAS-7) and AE-QoL Questionnaire scores were completed at the beginning of the pandemic between March 12 and June 1 were used as baseline values. The AAS-7 and the AE-QoL Questionnaire were filled by telephone contact with patients diagnosed with COVID-19 in the process. The follow-up visits had been planned for the patients in the third month after COVID-19 and the same scales were re-performed.
The AE-QoL Questionnaire is used for patients with recurrent angioedema, such as HAE, and consists of 17 items and is used to analyze four dimensions: functioning, fatigue/mood, fear/shame, nutrition.10 The total AE-QoL Questionnaire score and each dimension are scored between 0 (best) and 100 (worst). The AE-QoL Questionnaire dimension scores were calculated by using the following formula: ([Σ items – minimum Σ items]/[maximum Σ items – minimum Σ items]) × 100.10 AAS is a patient-based scale that measures angioedema activity.8 For AAS-7, the patients were asked to state whether they had experienced an attack of HAE, the length of the attack, the extent of their physical impairments, difficulties performing daily activities, impairments of appearance, and an overall assessment of the attack. Each AAS item was scored between 0 and 3 points, that is, the minimum and maximum daily AAS were 0 and 15 points, respectively. The daily AAS were summed up to AAS-7 and ranged from 0 to 105.
The Turkish validations of the AAS and the AE-QoL Questionnaire were studied and presented but have not yet been published.9 Therefore, the Turkish translation of the AAS-7 and the AE-QoL Questionnaire was performed in several different steps. In the first step, the investigator (O.C.B.) and one other allergist (G.T.) independently translated the questionnaire into the Turkish language. They then prepared, with consensus, a common translation text. The text was translated into German by another physician who was not aware of the original questionnaire; then the reverse translation was compared with the original German version. A pilot assessment of the final version of the Turkish questionnaire was performed on 10 people who were not included in the study.
In the diagnosis of COVID-19, the real-time reverse transcription polymerase chain reaction (RT-PCR) method is the most commonly used test in our country due to its features, such as high sensitivity, specificity, and fast results. Although the criterion standard for diagnosis is the RT-PCR test, a computed tomography (CT) of the thorax is an important guide, especially in patients with clinical symptoms and negative test results. RT-PCR tests had been performed primarily for the COVID-19 diagnosis of the patients in the study and confirmation was made with a CT of the thorax in case of a negative test result but with compatible clinical findings and a contact history of COVID-19.
The statistical analyses were performed with IBM SPSS Statistics, version 25.0 (IBM Corp., Armonk, NY). Continuous variables were checked for normal distribution by the Shapiro-Wilk test and presented as mean ± SD if normally distributed, median (interquartile range [IQR]) if not normally distributed, whereas categorical variables were expressed as numbers or percentages. The QoL scores of the patients were analyzed by using the repeated-measures analysis of variance test to compare AE-QoL Questionnaire parameters according to COVID-19 periods.
The study was approved by the ethics committee of Hacettepe University (approval 2021/09-07) and the Ministry of Health of the Republic of Turkey. Written consent was obtained from all the participants before the study procedures. The study complied with the recommendations of the World Medical Association Declaration of Helsinki. A.F. Kalyoncu conceived of the presented idea, O.C. Bostan, G. Tuncay contributed to sample preparation. O.C. Bostan took the lead in writing the manuscript. A.F. Kalyoncu, E. Damadoglu, and G. Karakaya contributed to the design and implementation of the research, to the analysis of the results, and to the writing of the manuscript.
RESULTS
Seventy-six patients with HAE who have been followed up in the Hacettepe University Adult Allergy and Clinical Immunology Clinic were evaluated in the study. Six of these patients were excluded because they had not had have any follow-up in the previous year, and three patients were excluded due to incomplete questionnaire data. Sixty-seven patients were included in the analysis. Of these, 49 (73.1%) had type I, 13 (19.4%) had type II, and 5 (7.5%) had HAE with normal C1-INH (Table 1). The factor XII mutation was detected in one of the five patients with HAE and normal C1-INH. The median (IQR) age was 38 years (21.0–66.0 years) and 40 were women (59.7%). The median (IQR) time to HAE diagnosis was 13 years (2–32 years). A total of 19 patients were being followed up under long-term prophylaxis, one patient was on regular C1-INH, 13 patients were on danazol, and five patients were on tranexamic acid.
Table 1.
Patient characteristics
| Variable | Total | COVID-19 Group | Non–COVID-19 Group |
|---|---|---|---|
| Patients with HAE, n (%) | |||
| Total | 67 (100) | 10 (14.9) | 57 (85.1) |
| With type I | 49 (73.1) | 6 (60) | 43 (75.4) |
| With type II | 13 (19.4) | 3 (30) | 10 (17.5) |
| With HAE-normal C1-INH | 5 (7.5) | 1 (10) | 4 (7) |
| Age, median (IQR), y | 38 (21.0–66.0) | 35.5 (28.0–55.0) | 40.0 (21.0–66.0) |
| Women, n (%) | 40 (59.7) | 6 (60) | 34 (59.6) |
| Smoker, n (%) | 23 (34.3) | 4 (40) | 19 (33.3) |
| Time after diagnosis, median (IQR), y | 13 (2–32) | 12.5 (3–30) | 13 (2–32) |
| Long-term prophylaxis, n (%) | 19 (28.3) | 2 (20) | 17 (29.3) |
| C1-INH | 1 (1.5) | 0 (0) | 1 (1.8) |
| Danazol | 13 (19.4) | 1 (10) | 12 (21.1) |
| Tranexamic acid | 5 (7.5) | 1 (10) | 4 (7) |
COVID-19 = Coronavirus disease 2019; HAE = hereditary angioedema; C1-INH = C1-esterase inhibitor; IQR = interquartile range.
Ten of the 67 patients (14.9%) were diagnosed with COVID-19. There was no significant difference between the groups with and without a COVID-19 diagnosis in terms of age, gender, smoking status, and duration of diagnosis. The median (IQR) age of 10 patients diagnosed with COVID-19 was 35.5 years (28.0–55.0 years). Six were women (60%) and four were men (40%). The patients were evaluated according to the annual disease severity score. The symptom levels for the patients were as follows: one patient (10%) was asymptomatic, one patient (10%) had minimal, one patient (10%) had mild, two patients (20%) had moderate, and four patients (40%) had severe symptoms.16 In patients diagnosed with COVID-19, two (20%) (one [10%] used danazol and one [10%] used tranexamic acid) had been receiving long-term prophylaxis according to the disease severity criteria. Although seven of the patients (70%) were diagnosed with COVID-19 by RT-PCR, three patients (30%) (patients nos. 1, 7, and 10) were diagnosed by a CT of the thorax performed due to the evident symptoms despite negative RT-PCR results. Two patients diagnosed with COVID-19 had hypertension, one patient had diabetes mellitus and hypertension, one patient had asthma, and one patient was obese. Only one patient (10%) (patient no. 1) had been hospitalized due to hypoxia, dyspnea, and fever. No patient had an intensive care unit admission.
No angioedema attack was detected during COVID-19 in five of the 10 patients (50%). Two patients with severe HAE (patient nos. 4 and 6) experienced a significant increase in angioedema activity during COVID-19 compared with basal activity scores. The remaining three patients had a similar or lower attack frequency than their previous level. Four patients (40%) had a relative increase in their attacks during the convalescence period (Fig. 1). When the AE-QoL Questionnaire scores of the patients at their last visit before COVID-19 were compared with the AE-QoL Questionnaire scores during and in the third month after recovering from COVID-19, no statistically significant difference was found between these three periods in function, mood, fear/shame, nutrition, and total scores. However, it was observed that the impact on the QoL tended to increase during the COVID-19 period, and the fear dimension was relatively more affected (p = 0.06) (Fig. 2).
Figure 1.
Results of AAS-7 scores. No angioedema attack was detected during COVID-19 in 5 of the 10 patients. Two patients experienced a significant increase in angioedema activity during COVID-19 compared with basal activity scores. Three patients had a similar or lower attack frequency than their previous level. Four patients had a relative increase in their attacks during the post–COVID-19 period. AAS-7 = 7-day Angioedema Activity Score; COVID-19 = coronavirus disease 2019.
Figure 2.
Results of AE-QoL Questionnaire scores. Box and whisker plots demonstrate the distribution of the AE-QoL Questionnaire scores in the study according to COVID-19 periods. (The band around the middle of the box shows the median, and the ends of the whiskers show the minimum and maximum values.) Higher values indicate higher impairment. No statistically significant difference was found among the three periods in function, mood, fear/shame, nutrition, and total scores. AE-QoL = Angioedema Quality of Life; COVID-19 = coronavirus disease 2019.
DISCUSSION
The fact that COVID-19 enters the cell through the ACE2 receptor and causes bradykinin accumulation by reducing the ACE levels has raised concerns that attacks might be triggered during COVID-19 or that COVID-19 symptoms might be more severe in patients with HAE. Although there were individual differences among the patients in our study, no significant increase was found in the attacks during and after the course of COVID-19. However, although the frequency and severity of the attacks were stable and even better during the course of COVID-19, an increase was observed during the convalescence period in most patients in the study. There are few studies in the literature that examined the exacerbation frequency of patients with HAE during COVID-19. In a study that presented the characteristics of 13 patients with COVID-19 and HAE, it was reported that acute attacks were mostly seen in the convalescence period of COVID-19 in the patients with HAE and a history of frequent attacks, similar to the population of our study.11
In the present study, 50% of the patients with HAE had acute angioedema attacks during SARS-CoV-2 infection. This was slightly higher than other studies in the literature. In the study by Grumach et al.,12 this rate was 38%, and it was found to be 31% in the study by Belbézier et al.11 The higher attack rates of the patients in our study might be attributed to their higher disease severity and lower long-term prophylaxis rates. One of the reasons for the lower prophylaxis rate was the absence of oxandrolone and lanadelumab in our country, and the fact that most patients are under on-demand treatment due to the common adverse effects of androgens. The patient who had a significant increase in the AAS during COVID-19 (patient no. 4) had no other distinctive findings other than a high basal activity score and high annual disease severity. In the other patient with a similar baseline activity score (patient no. 2), no activation was observed during COVID-19, although the AAS increased significantly in the post–COVID-19 period (Table 2). This may raise the suspicion that acute attacks may be triggered by SARS-CoV-2 infection in patients with HAE and with high disease activity and severity.
Table 2.
Patients with HAE diagnosed with COVID-19
| Patient No. | Age, y/gender | Comorbidities | HAE Type | Annual Disease Severity* | Long-Term Prophylaxis | AAS-7 Scores | Attacks during COVID-19 | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Before COVID-19 last visit | During COVID-19 | After COVID-19, 3rd month | No. | Location | Treatment | ||||||
| 1 | 36/M | None | 1 | Mild | On demand | 0 | 0 | 5 | None | None | None |
| 2 | 33/F | None | 1 | Moderate | On demand | 16 | 5 | 37 | 2 | Abdomen | Icatibant |
| 3 | 38/F | DM + HT | 1 | Moderate | On demand | 9 | 0 | 0 | None | None | None |
| 4 | 35/F | None | 1 | Severe | On demand | 15 | 59 | 10 | 5 | Larynx/abdomen | C1-INH/icatibant |
| 5 | 55/F | HT | 1 | Minimum | Danazol | 0 | 0 | 0 | None | None | None |
| 6 | 30/M | HT | 1 | Severe | On demand | 3 | 9 | 2 | 2 | Extremities | Icatibant |
| 7 | 44/M | Asthma | 2 | Severe | On demand | 4 | 4 | 17 | 1 | Extremities | C1-INH |
| 8 | 28/F | None | 2 | Severe | On-demand | 8 | 0 | 10 | None | None | None |
| 9 | 33/M | None | 2 | Asymptomatic | On demand | 0 | 0 | 0 | None | None | None |
| 10 | 38/F | Obesity | nC1 | Minimum | Tranexamic acid | 0 | 2 | 2 | 1 | Extremities | None |
HAE = Hereditary angioedema; COVID-19 = coronavirus disease 2019; AAS-7 = 7-day Angioedema Activity Score; DM = diabetes mellitus; HT = hypertension; C1-INH = C1 esterase inhibitor; nC1 = HAE with normal C1-INH.
*From Ref. 16.
The results of the QoL questionnaires of the patients showed that the dimension that was affected more during and after COVID-19 was fear. These data were compatible with the study by Eyice Karabacak et al.,17 which showed that the anxiety, stress, and fear levels of patients with HAE increased, even if they did not have COVID-19 during the pandemic. Perhaps this situation can be considered as one of the reasons for the increase in attacks within 90 days after COVID-19 and may lead us to prompt patients with HAE for early immunization to decrease the fear of COVID-19. In a recent study, there was no evidence that COVID-19 was more severe in patients with HAE.3 In the present study, only one of 10 patients who were diagnosed with COVID-19 had hypoxemia, dyspnea, and cough that required hospitalization, and no patient required intensive care or respiratory support. Although all patients were symptomatic during COVID-19, 9 of 10 patients experienced mild symptoms.
CONCLUSION
Although the sample size was small, analysis of our data supports that the symptoms due to COVID-19 were not more severe in HAE. Also, there was no significant increase in the frequency of angioedema attacks during the course of COVID-19 in patients with HAE. The QoL during and after COVID-19 was more likely to be affected by the fear dimensions. Interestingly, there was a relative increase in acute attacks during the convalescence period of COVID-19 rather than the period of illness. Further studies are needed in this regard.
Footnotes
No external funding sources reported
The authors have no conflicts of interest to declare pertaining to this article
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