Archives of Clinical Case Reports (ACCR)
ISSN: 2688-1071 | Vol. 9, Issue 1, 2026, pp. 8-15

Recurrent Angioedema Misdiagnosed as Anaphylaxis in Hereditary C1 Inhibitor Deficiency: A Review of Published Cases

Sundberg O1, Ortega C2, Conti L3

1Department of Allergy and Clinical Immunology, Karolinska Institute, Stockholm, Sweden
2Department of Emergency Medicine, University of Valencia, Valencia, Spain
3Department of Clinical Genetics, University of Padua, Padua, Italy
DOI: 10.5281/zenodo.22279527 | Published: 2026-07-03 | Article page and PDF

Abstract

Background: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare, bradykinin-mediated disorder

producing recurrent, non-pruritic, non-urticarial swelling frequently mistaken for allergic or anaphylactic angioedema, delaying

life-saving treatment. Objective: To review published case reports, cohorts and guidelines documenting misdiagnosis of HAE-C1INH as anaphylaxis or allergy. Methods: Narrative review of case reports, cohort/registry studies, systematic reviews and society guidelines identified through verified bibliographic search. Findings: Diagnostic delay across published cohorts ranges from 3.9 to 26 years, and roughly 44% of patients carry a prior misdiagnosis, most often allergic angioedema or appendicitis, nearly octupling delay (13.3 versus 1.7 years). Published cases document adrenaline, antihistamines and corticosteroids failing outright, with resolution only after bradykinin-targeted therapy. Serum C4 alone is an insufficient screen (sensitivity 81%). Conclusions: Recognising the absence of urticaria and pruritus, slow evolution of swelling, and failure of standard anaphylaxis treatment, paired with C4 and C1-INH testing, can substantially shorten diagnostic delay and reduce fatal laryngeal attacks.

Keywords: Hereditary angioedema; C1 inhibitor deficiency; Anaphylaxis; Misdiagnosis; Bradykinin

L (2026) Recurrent Angioedema Misdiagnosed as

Abstract

Background: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare, bradykinin-mediated disorder producing recurrent, non-pruritic, non-urticarial swelling frequently mistaken for allergic or anaphylactic angioedema, delaying life-saving treatment. Objective: To review published case reports, cohorts and guidelines documenting misdiagnosis of HAE-C1INH as anaphylaxis or allergy. Methods: Narrative review of case reports, cohort/registry studies, systematic reviews and society guidelines identified through verified bibliographic search. Findings: Diagnostic delay across published cohorts ranges from 3.9 to 26 years, and roughly 44% of patients carry a prior misdiagnosis, most often allergic angioedema or appendicitis, nearly octupling delay (13.3 versus 1.7 years). Published cases document adrenaline, antihistamines and corticosteroids failing outright, with resolution only after bradykinin-targeted therapy. Serum C4 alone is an insufficient screen (sensitivity 81%). Conclusions: Recognising the absence of urticaria and pruritus, slow evolution of swelling, and failure of standard anaphylaxis treatment, paired with C4 and C1-INH testing, can substantially shorten diagnostic delay and reduce fatal laryngeal attacks.

Keywords: hereditary angioedema; C1 inhibitor deficiency; anaphylaxis; misdiagnosis; bradykinin

Introduction

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare autosomal-dominant disorder in which insufficient functional C1 inhibitor permits unregulated bradykinin generation, producing recurrent episodes of subcutaneous and submucosal swelling [1,2]. Because angioedema is also the hallmark of IgE-mediated allergic reactions and anaphylaxis, and because HAE attacks can involve the face, lips, tongue and larynx exactly as anaphylaxis does, HAE-C1INH is repeatedly mistaken for allergy or anaphylaxis in clinical practice — a confusion that matters because epinephrine, antihistamines and corticosteroids, the mainstay of anaphylaxis treatment, do not address the underlying bradykinin pathway and characteristically fail [3,4]. This review is a narrative synthesis, not a report of the authors' own patients, surveying published case reports and cohort data on misdiagnosis of HAE-C1INH as anaphylaxis or allergy, together with the epidemiology, pathophysiology, diagnosis and management literature needed to interpret those cases.

Epidemiology

HAE-C1INH is rare, with prevalence estimates ranging from 0.13 to 1.6 per 100,000 across national registries, higher in Sweden, Denmark and Austria (1.4-1.6 per 100,000) and lower in South Korea (0.13 per 100,000) [5]. Diagnostic delay is the epidemiological signature of the misdiagnosis problem. In a European cohort of 171 patients from eight countries, median delay from first symptom to diagnosis was 8.5 years, with type II disease (21.0 years) delayed far longer than type I (8.0 years) [6]. A systematic review pooling 65 articles and 10,310 patients found mean or median delay ranging from 3.9 to 26 years, with more than 10 years reported in 25 of 34 studies [5]. Delay has narrowed with successive birth cohorts — from a median of 7.0 years in patients born 1950-1960 to 1.4 years in those born 1980-1990 in the Icatibant Outcome Survey — and is shorter when a family history is known (2.0 versus 5.6 years) [7]. Misdiagnosis itself is common and costly: among 418 surveyed patients, 44.3% had received a prior misdiagnosis, most often labelled allergic angioedema or appendicitis, and those misdiagnosed waited a median of 13.3 years for correct diagnosis versus 1.7 years in those who were not [8].

Pathophysiology

HAE-C1INH results from heterozygous mutations in SERPING1, the gene encoding C1 inhibitor. Type I disease (roughly 85% of cases) reflects quantitatively low C1-INH antigen and function; type II (roughly 15%) produces a dysfunctional protein at normal or elevated antigenic levels [9]. C1 inhibitor is the principal regulator of the contact (kallikrein-kinin) system; its deficiency permits unchecked plasma kallikrein activity, cleaving high-molecular-weight kininogen to generate bradykinin, which increases vascular permeability through the bradykinin B2 receptor [1,2]. This mechanism is fundamentally distinct from mast-cell/IgE-mediated angioedema, which depends on histamine, leukotrienes and other mast-cell mediators — the distinction that explains why anaphylaxis-directed treatment fails in HAE-C1INH and why bradykinin-targeted agents (icatibant, C1-INH replacement) succeed where

Figure 1: Diagnostic delay from first symptom to confirmed diagnosis of hereditary angioedema due to C1 inhibitor deficiency, by cohort and misdiagnosis status. Drug-allergy-labelled patients (23.8 years) and misdiagnosed patients in the Icatibant Outcome Survey (13.3
Figure 1: Diagnostic delay from first symptom to confirmed diagnosis of hereditary angioedema due to C1 inhibitor deficiency, by cohort and misdiagnosis status. Drug-allergy-labelled patients (23.8 years) and misdiagnosed patients in the Icatibant Outcome Survey (13.3

years) show markedly longer delay than unlabelled/not-misdiagnosed counterparts (10.2 and 1.7 years) [17,8]; delay has also fallen across birth cohorts, from 7.0 years (born 1950-1960) to 1.4 years (born

1980-1990) [7].

Clinical Presentation

The published case literature illustrates how closely an HAE attack can mimic anaphylaxis at the bedside, and how completely it can fail to respond to anaphylaxis treatment. A woman in her thirties presented with progressive facial, lip, tongue and uvular swelling over 36 hours; intramuscular adrenaline, repeated nebulised adrenaline, intravenous dexamethasone and oral loratadine were all given and all failed, and only after complement testing and icatibant did the attack resolve within three hours — her third such presentation to be treated as an allergic reaction [4]. In a patient with an already-confirmed diagnosis, minor facial trauma triggered bronchospasm and airway compromise unresponsive to steroids, adrenaline and antihistamines, ultimately requiring intubation and resolving only with fresh frozen plasma [10].

Table 1: Published cases of hereditary angioedema due to C1 inhibitor deficiency initially misdiagnosed or mismanaged as anaphylaxis/allergy or acute surgical abdomen [4,13,14,15,10]; N = 5 cases.
Table 1: Published cases of hereditary angioedema due to C1 inhibitor deficiency initially misdiagnosed or mismanaged as anaphylaxis/allergy or acute surgical abdomen [4,13,14,15,10]; N = 5 cases.
Figure 2: Organ involvement among 209 patients with hereditary angioedema followed over 131,110 recorded oedema episodes. Skin and abdominal swelling affect the large majority of patients and account for the large majority of episodes, while laryngeal, soft
Figure 2: Organ involvement among 209 patients with hereditary angioedema followed over 131,110 recorded oedema episodes. Skin and abdominal swelling affect the large majority of patients and account for the large majority of episodes, while laryngeal, soft

palate/uvula and tongue attacks, though comparatively rare as a share of episodes, each affect a substantial minority to about half of all patients over a lifetime [11].

Abdominal attacks are the other major source of misdiagnosis. In the largest longitudinal cohort (209 patients, 131,110 recorded episodes), 93.3% of patients experienced abdominal attacks, and skin plus abdominal swelling together accounted for 97.4% of all episodes, while laryngeal attacks — though only 0.9% of episodes — occurred in roughly half of all patients over a lifetime [11]. In a separate treated cohort, 65% of patients presented with attacks involving abdominal symptoms and abdominal pain alone accounted for nearly half of all recorded attacks, a pattern that predisposes to surgical rather than allergic misdiagnosis and to an average delay described in that cohort as roughly a decade [12]. Published cases document decades of abdominal attacks labelled acute gastroenteritis, functional bowel disease or surgical acute abdomen: a man diagnosed 40 years after symptom onset who underwent an appendectomy and three further laparotomies before diagnosis [13]; a woman with roughly two decades of attacks attributed to a functional bowel or neuropsychiatric disorder [14]; and a man whose three episodes of abdominal pain and bowel-wall oedema were each treated as gastroenteritis before HAE was confirmed [15]. In a related population with normal C1 inhibitor levels, 81.2% of patients whose abdominal attack was labelled an acute abdomen underwent unnecessary surgery [16], and drug-allergy mislabelling — often to beta-lactam antibiotics given during misdiagnosed attacks — independently prolongs diagnostic delay (23.8 versus 10.2 years) [17]. Untreated laryngeal attacks carry the greatest immediate danger, evolving over hours and historically implicated in fatal asphyxiation [18,19].

Beyond the illustrative cases above, the recurring clinical picture across the published record is a patient with years of intermittent, self-limited, non-pruritic swelling — sometimes facial or laryngeal and treated as anaphylaxis, sometimes abdominal and treated as a surgical emergency or gastroenteritis — who improves with supportive care alone before symptoms recur, a course that itself should raise suspicion for a bradykinin-mediated process rather than a true allergic or infectious event [1,2].

Diagnostic Approach

The clinical distinction from allergic angioedema rests on the absence of urticaria and pruritus, slower onset over hours rather than minutes, longer untreated duration (typically 2-5 days rather than under 24 hours), and non-response to epinephrine, antihistamines and corticosteroids — all demonstrated directly in the cases above [4,10,3]. Laboratory confirmation combines complement C4, C1-INH antigenic level and C1-INH functional activity. Serum C4 alone has sensitivity of only 81% and specificity 85%, and can be normal in up to 10% of tested episodes, so a normal C4 does not exclude HAE-C1INH, particularly between attacks [20,9]. Combining low C4 with low C1-INH function raises specificity toward 98% [9]. In the illustrative ICU case, rapid C4 testing returned within an hour and guided immediate icatibant therapy, underscoring that expedited complement testing changes acute management [4]. Family history, present in only about 72% of one large cohort, should prompt suspicion but its absence, as in one abdominal-pain case series, does not rule out HAE-C1INH [7,15]. Because complement assays are not universally available at the point of care, guidelines emphasise that a compatible history — recurrent, self-limited, non-urticarial swelling with a poor or absent response to anti-allergic treatment — should itself trigger referral for confirmatory testing rather than waiting for results before considering the diagnosis [21,3]. Where an ELISA-based functional assay is used rather than a chromogenic one, negative predictive value is reported as low as 62%, so a single normal complex-ELISA result in a patient with a convincing history should not be treated as fully reassuring, and repeat testing with an alternative method or specialist referral is warranted [9].

Table 2: Distinguishing bradykinin-mediated (HAE-C1INH) from histamine/mast-cell-mediated angioedema [3,4,10,20,9,11].
Table 2: Distinguishing bradykinin-mediated (HAE-C1INH) from histamine/mast-cell-mediated angioedema [3,4,10,20,9,11].

First-line acute therapy targets the bradykinin pathway directly: the bradykinin B2-receptor antagonist icatibant, plasma-derived or recombinant C1 inhibitor concentrate, and the plasma kallikrein inhibitor ecallantide are each supported by randomised trial evidence and international guidelines [22,3,21]. Fresh frozen plasma, which supplies C1 inhibitor without purification, has been used successfully where targeted agents were unavailable, though it can theoretically worsen attacks by also supplying kininogen substrate [10]. Epinephrine, antihistamines and systemic corticosteroids have no established role and repeatedly failed in the published cases reviewed here [4,10].

Long-Term Prophylaxis

Long-term prophylactic options now include the plasma kallikrein inhibitor monoclonal antibody lanadelumab, shown in a randomised trial to reduce attack frequency compared with placebo [23], and the oral plasma kallikrein inhibitor berotralstat, which reduced attacks by 44% at the 150 mg dose in a placebo-controlled trial, with further reduction to 79% during long-term extension [24,25]. International (WAO/EAACI) and US (HAEA Medical Advisory Board) guidelines converge on individualised prophylaxis based on attack frequency, severity and impact on quality of life, alongside patient self-management education and access to on-demand acute therapy [3,21]. Both guidelines also stress that every patient, once diagnosed, should carry a personalised action plan specifying which agent to self-administer or bring to an emergency department, precisely because the cases reviewed here show that a diagnosed patient re-presenting during an attack can still be treated as anaphylaxis by clinicians unfamiliar with the diagnosis unless the plan and supporting documentation are immediately available [21,3].

Outcomes and Prognosis

Correct diagnosis and access to targeted therapy transform prognosis: after diagnosis and access to icatibant, one patient with a 40-year delay went from roughly 19 hospitalisations per year to zero over the following 10 months [13], and cases diagnosed through rapid complement testing resolved within hours rather than the days typical of untreated attacks [4]. Left undiagnosed, the risk is substantial: pooled data across nine studies estimate an 8.6% risk of death from asphyxiation, historically concentrated in patients whose disease was unrecognised or inappropriately treated as allergic reactions [5,26]. The reverse error — labelling non-hereditary, mast-cell-mediated recurrent angioedema as HAE — also occurs and exposes patients to years of ineffective, costly bradykinin-targeted therapy before recognition and response to omalizumab, underscoring that the misdiagnosis problem runs in both directions [27].

Beyond mortality, the burden of prolonged misdiagnosis in the published record includes repeated emergency department attendance, avoidable intubation and intensive care admission, unnecessary abdominal surgery, and years of ineffective symptomatic treatment with its own costs and side effects. Reversing this pattern depends less on new diagnostic technology than on clinicians in emergency medicine, gastroenterology, surgery and primary care recognising the clinical pattern described above and pursuing confirmatory complement testing early, since every case in this review that reached diagnosis subsequently did well on targeted therapy [4,13,10].

Conclusion

The published literature consistently shows that hereditary angioedema due to C1 inhibitor deficiency is misdiagnosed as anaphylaxis or allergy in a substantial minority of patients, at a cost measured in years of delay, unnecessary surgery, repeated ineffective epinephrine and corticosteroid administration, and a real risk of fatal laryngeal obstruction. Recognising the absence of urticaria, the characteristic non-response to standard anaphylaxis treatment, and the limits of serum C4 as a rule-out test — supported by prompt C1-INH functional testing — offers a practical path to earlier diagnosis, access to bradykinin-targeted acute and prophylactic therapy, and substantially better outcomes for a rare but treatable disease.

References

  1. Zuraw, B.L. (2008) Hereditary angioedema. New England Journal of Medicine, 359(10): 1027-1036.
  2. Longhurst, H., Cicardi, M. (2012) Hereditary angio-oedema. The Lancet, 379(9814): 474-481.
  3. Maurer, M., Magerl, M., Betschel, S., Aberer, W., Ansotegui, I.J., Aygören-Pürsün, E., et al. (2022) The international WAO/EAACI guideline for the management of hereditary angioedema—The 2021 revision and update. Allergy, 77(7): 1961-1990.
  4. Dungan, L.S., Khalib, K., Curley, D., Keogan, M. (2025) Urgent diagnosis of hereditary angioedema in the ICU and ED: the critical role of rapid complement testing – a case report. International Journal of Emergency Medicine, 18(1): 254.
  5. Guan, X., Sheng, Y., Liu, S., He, M., Chen, T., Zhi, Y. (2024) Epidemiology, economic, and humanistic burden of hereditary angioedema: a systematic review. Orphanet Journal of Rare Diseases, 19(1): 256.
  6. Zanichelli, A., Magerl, M., Longhurst, H., Fabien, V., Maurer, M. (2013) Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe. Allergy, Asthma & Clinical Immunology, 9(1): 29.
  7. Zanichelli, A., Magerl, M., Longhurst, H.J., Aberer, W., Caballero, T., Bouillet, L., et al. (2018) Improvement in diagnostic delays over time in patients with hereditary angioedema: findings from the Icatibant Outcome Survey. Clinical and Translational Allergy, 8(1): 42.
  8. Zanichelli, A., Longhurst, H.J., Maurer, M., Bouillet, L., Aberer, W., Fabien, V., et al. (2016) Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting. Annals of Allergy, Asthma & Immunology, 117(4): 394-398.
  9. Henao, M.P., Kraschnewski, J.L., Kelbel, T., Craig, T.J. (2016) Diagnosis and screening of patients with hereditary angioedema in primary care. Therapeutics and Clinical Risk Management, 12: 701-711.
  10. Ahmed, A.S., Fayyaz, S. (2020) Novel use of fresh frozen plasma in treating hereditary angioedema: a success story from Pakistan. Cureus, 12(8): e9669.
  11. Bork, K., Meng, G., Staubach, P., Hardt, J. (2006) Hereditary angioedema: new findings concerning symptoms, affected organs, and course. The American Journal of Medicine, 119(3): 267-274.
  12. Rubinstein, E., Stolz, L.E., Sheffer, A.L., Stevens, C., Bousvaros, A. (2014) Abdominal attacks and treatment in hereditary angioedema with C1-inhibitor deficiency. BMC Gastroenterology, 14(1): 71.
  13. Honda, D., Ohsawa, I., Iwanami, K., Rinno, H., Tomino, Y., Suzuki, Y. (2021) A case of hereditary angioedema due to C1-inhibitor deficiency with recurrent abdominal pain diagnosed 40 years after the occurrence of the initial symptom. Clinical Journal of Gastroenterology, 14(4): 1175-1179.
  14. Shrestha, S., Yadav, A.K., Khadka, D., Shrestha, R., Paudel, M.S. (2025) A two-decade-delayed diagnosis of hereditary angioedema: a case report. Cureus, 17(5): e85019.
  15. Zhang, B., Zhao, H. (2026) Recurrent self-limiting abdominal pain with bowel wall edema misdiagnosed as gastroenteritis: a case report of C1-inhibitor-deficient hereditary angioedema. Frontiers in Medicine, 13: 1818323.
  16. Gutierrez, M., Veronez, C.L., Rodrigues Valle, S.O., Gonçalves, R.F., Ferriani, M.P.L., Moreno, A.S., et al. (2021) Unnecessary abdominal surgeries in attacks of hereditary angioedema with normal C1 inhibitor. Clinical Reviews in Allergy & Immunology, 61(1): 60-65.
  17. Wong, J.C.Y., Cheong, N., Lau, C.S., Li, P.H. (2022) Prevalence and impact of misdiagnosed drug allergy labels among patients with hereditary angioedema. Frontiers in Allergy, 3: 953117.
  18. Bork, K., Siedlecki, K., Bosch, S., Schopf, R.E., Kreuz, W. (2000) Asphyxiation by laryngeal edema in patients with hereditary angioedema. Mayo Clinic Proceedings, 75(4): 349-354.
  19. Bork, K., Hardt, J., Witzke, G. (2012) Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. Journal of Allergy and Clinical Immunology, 130(3): 692-697.
  20. Tarzi, M.D., Hickey, A., Förster, T., Mohammadi, M., Longhurst, H.J. (2007) An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clinical and Experimental Immunology, 149(3): 513-516.
  21. Busse, P.J., Christiansen, S.C., Riedl, M.A., Banerji, A., Bernstein, J.A., Castaldo, A.J., et al. (2021) US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema. The Journal of Allergy and Clinical Immunology: In Practice, 9(1): 132-150.e3.
  22. Cicardi, M., Banerji, A., Bracho, F., Malbrán, A., Rosenkranz, B., Riedl, M., et al. (2010) Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. New England Journal of Medicine, 363(6): 532-541.
  23. Banerji, A., Riedl, M.A., Bernstein, J.A., Cicardi, M., Longhurst, H.J., Zuraw, B.L., et al. (2018) Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks. JAMA, 320(20): 2108.
  24. Zuraw, B., Lumry, W.R., Johnston, D.T., Aygören-Pürsün, E., Banerji, A., Bernstein, J.A., et al. (2021) Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial. Journal of Allergy and Clinical Immunology, 148(1): 164-172.e9.
  25. Adatia, A., Magerl, M. (2024) Berotralstat for hereditary angioedema with C1 inhibitor deficiency: a practical guide for clinicians. Frontiers in Immunology, 15: 1442671.
  26. Farkas, H. (2010) Management of upper airway edema caused by hereditary angioedema. Allergy, Asthma & Clinical Immunology, 6(1): 19.
  27. Buttgereit, T., Fijen, L.M., Vera, C., Bergmann, K.-C., Maurer, M., Magerl, M. (2022) Case report: recurrent angioedema: diagnosing the rare and the frequent. Frontiers in Medicine, 9: 1048480.