Seasonal occurrence of nonepisodic angioedema with eosinophilia: A case series of 12 patients

Abstract

Angioedema with eosinophilia is a rare condition characterized by marked eosinophilia and nonpitting edema. Nonepisodic angioedema with eosinophilia (NEAE) is more common in Japan than in other countries. This study analyzed 12 NEAE cases from Akita Prefecture and 70 cases from the literature to examine clinical features and seasonal patterns. In the Akita cases, patients were predominantly women (91.6%) and in their 20s to 30s. Edema mainly affected the lower legs and dorsum of the hands, with common symptoms, such as arthralgia (50%) and skin issues (50%). The mean eosinophil count was 4,678/µL, and most cases occurred from late summer to autumn. The literature review showed similar demographics to those of the Akita cases, and 87.1% of the patients were women in their 20s to 30s. Common symptoms included weight gain (37.1%) and arthralgia (37.1%), with a mean eosinophil count of 8,914/µL. Over half of the patients had onset between September and December. NEAE cases appeared more frequently during peak Mycoplasma pneumoniae infection outbreaks in Akita Prefecture, and both conditions tended to occur predominantly in autumn and winter, suggesting a possible association. These findings highlight a potential association between NEAE and M. pneumoniae infections, possibly through mechanisms such as molecular mimicry. Further large-scale studies are required to clarify NEAE’s pathogenesis.

1. Introduction

Angioedema with eosinophilia (AE) is a rare disease of unknown etiology and is characterized by marked eosinophilia and nonpitting edema. AE is classified into 2 types. One type involves recurrent episodes (episodic angioedema with eosinophilia [EAE]) and the other involves a single episode (nonepisodic angioedema with eosinophilia [NEAE]). Most cases in Japan are NEAE, which tends to be less severe and shows immunoglobulin M (IgM) negativity compared with EAE. A previous study reported that outbreaks of NEAE were concentrated between September and November [1]. However, this is the only report on NEAE seasonality, and its findings have not been further investigated. In this study, we reviewed the characteristics and onset timing of 12 NEAE cases from Akita Prefecture in Japan and 70 cases identified through a literature search.

2. Case report

A 20-year-old woman (case G, Table 1) presented with itching and swelling on the dorsum of both hands and feet extending to the ankles at our hospital. Her medical history included pulmonary valve stenosis, sinusitis, allergic rhinitis, secondary amenorrhea, and anxiety disorder. On examination, nonpitting edema was observed on the dorsum of both hands and feet (Figure 1). Laboratory tests showed an elevated peripheral white blood cell count of 15,000/µL and an elevated eosinophil count of 8,400/µL (56.0%). IgM (474 mg/dL) and IgE (610 IU/mL) levels were above the normal range. Liver, kidney, cardiac, and thyroid function were normal. A chest X-ray and electrocardiogram showed no abnormalities. The patient was diagnosed with NEAE on the basis of peripheral nonpitting edema and eosinophilia after ruling out other conditions, such as heart failure and renal failure. She was managed with observation without specific treatment. After 14 days, her eosinophil count had decreased to 3,470/µL, and the swelling had nearly resolved. After 91 days, her eosinophil count had normalized to 320/µL and she was symptom-free.

Table 1.

Summary of 12 cases in Akita Prefecture in Japan

Case	Age (y)	Sex	Onset month	Edema site	Other symptoms	Peak eosinophil count (/μL)	Elevation of IgM	Steroid treatment
A	32	F	Dec	Legs, arms	Arthralgia	1624	−	+
B	31	F	Aug	Lower legs, hands	Arthralgia, erythema	7884	−	−
C	34	F	Sep	Lower legs	None	8645	−	+
D	31	F	Aug	Lower legs, wrists	Arthralgia	2440	NA	−
E	26	F	Mar	Lower legs, hands	Urticaria	4200	NA	+
F	33	F	Apr	Hands, feet	Erythema	2210	−	+
G	20	F	Oct	Hands, feet	Pruritus, arthralgia	8400	+	−
H	35	F	Jan	Lower legs, wrists	Arthralgia	2830	−	+
I	35	M	Feb	Lower legs	None	7100	−	−
J	30	F	Oct	Lower legs	Pruritus	3285	NA	+
K	25	F	Aug	Lower legs, hands,	Erythema, pruritus, weight gain	3034	−	+
L	31	F	Sep	Lower legs, arms,	Arthralgia	4485	−	+

F, female; M, male; NA, not available.

Figure 1.

Non-pitting edema in both limbs at the initial examination.

In a review of the medical records at 2 regional core hospitals in Akita Prefecture from 1996 to 2021, 12 cases of NEAE, including the case described above, were identified (Table 1). The study parameters included age, sex, onset month, edema site, symptoms other than edema, maximum eosinophil count, IgM elevation, and steroid treatment.

All 12 patients were aged in their 20s–30s, and 11 (91.6%) were women. The edema sites were mostly in the lower legs and dorsum of the hands and were not proximal to the knee and elbow joints. Other than edema, the most common symptoms were arthralgia (n = 6) and skin symptoms (itching and urticaria) (n = 6). Weight gain was observed in 1 (8.3%) patient. Two (16.6%) patients had no symptoms other than edema. The mean maximum eosinophil count was considerably elevated at 4,678/µL, with considerable variability among the cases (standard deviation: 2602/µL). Elevated IgM levels were observed in 1 (8.3%) patient. Eight (66.6%) patients received steroid treatment of mainly prednisolone 10–20 mg/day. The most frequent onset month was August in 3 (25.0%) patients, followed by September and October in 2 (16.6%) patients each. None of the patients showed recurrence within the observable period, so we diagnosed them with NEAE.

3. Discussion

On the basis of a review of NEAE cases from 2006 to 2022 identified in Japanese medical journals and PubMed, we examined 70 cases with available patient details (Supplementary Table 1, http://links.lww.com/PA9/A60). Most (81.4%) patients were aged in their 20s and 30s, and the majority (87.1%) were women. The NEAE cases were predominantly reported in Japan, with only 2 cases each in Canada and Italy outside of Asia. Other than edema, the most common symptoms were weight gain and arthralgia, which were observed in 26 (37.1%) cases each, followed by skin symptoms in 22 (31.4%) cases. Ten (14.3%) patients had no symptoms other than edema. The mean eosinophil count was higher (8914/µL) and the standard deviation was larger (10,556/µL) than those of the Akita Prefecture cases. Only 4 (5.7%) patients had elevated IgM levels. Twenty-six (37.1%) patients received steroid treatment. When we compared the cases from our region with those from the literature, there were no significant differences in their characteristics. Of the 34 cases with available data for the month of onset, 19 (55.9%) had onset between September and December (Figure 2A). Although this percentage is less than that in a previous report [1], these findings combined with the present finding showed that 52.2% of cases occurred from September to December.

Figure 2.

(A) Onset month for 34 reported cases of NEAE. The results of the 34 cases with available data for the month of onset are shown. Although one study [2] reported that 12 patients developed NEAE between September and December, the numbers per month were not specified. Therefore, we assigned these 12 patients evenly as 3 patients per month. The data of these 12 patients are shown in light blue. (B) Mycoplasma pneumoniae infection outbreaks and the incidence of NEAE in Akita Prefecture. Cases A–J represent the patients in this prefecture and are plotted by year of onset. Cases K and L were excluded because they developed NEAE before 2010.

Several cases of NEAE have been reported to develop following infections, such as Mycoplasma pneumoniae infection and coronavirus disease 2019 [3, 4]. All of the cases from Akita Prefecture reviewed in this study occurred before the coronavirus disease 2019 pandemic. Therefore, we investigated their potential association with M. pneumoniae infections in the region. The incidence of M. pneumoniae infections in the prefecture was extracted from the Annual Report of the National Institute of Infectious Diseases [5]. Data for the weekly case numbers reported by sentinel sites have been available since 2010. Figure 2B shows the incidence of M. pneumoniae infections and the occurrence of NEAE at our facilities during 10 years. Peaks in M. pneumoniae infection cases were observed in autumn to winter in 2012, 2017, 2018, and 2019. In 2018 and 2019, the numbers of M. pneumoniae infection cases were particularly high, and 6 of 12 NEAE cases in the present study were observed during this period. Case H had a clinical diagnosis of M. pneumoniae infection, albeit after the appearance of NEAE symptoms. There was no evidence of preceding M. pneumoniae infection in any of the other cases. While a clear relationship between the cases reviewed and M. pneumoniae infection could not be established, several observations suggest an association. NEAE cases appeared more frequently during peak periods of M. pneumoniae infection outbreaks in Akita Prefecture, and both conditions tend to occur predominantly in autumn and winter. These findings suggest that M. pneumoniae infection is associated with the onset of NEAE.

If this hypothesis is correct, molecular mimicry, similar to that observed in rheumatic fever and Guillain–Barré syndrome [6], might play a role in the pathogenesis of NEAE. To further understand the disease mechanism, large-scale epidemiological and immunological studies are necessary.

Conflicts of interest

The authors have no conflicts of interest.

Authors contributions

Shigeharu Ueki conceived the idea of the study. Ryo Hasegawa, Akiko Saga, and Haruka Hikichi contributed to data collection. Kotono Takahashi searched the literature, compiled and analyzed the data, and drafted the manuscript. Yuki Fujioka, Haruka Hikichi, Tomoo Saga, Yuki Moritoki, and Shigeharu Ueki reviewed the manuscript and revised it critically for intellectual content. All authors read and approved the final manuscript.

Acknowledgments

We express our sincere gratitude to the Medical Affairs Department of Akita University Hospital and one of the regional core hospitals in Akita Prefecture for their assistance in identifying the NEAE cases. We would like to thank Ms. Ogawa who works at the Akita Prefectural Information Center for Infectious Diseases, for providing us with information on the outbreak of Mycoplasma pneumoniae infection in Akita Prefecture. We also thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

The study was funded in part by Research Grants on Allergic Disease and Immunology from the Japan Agency for Medical Research and Development (JP22ek0410097), JSPS KAKENHI (24K11593), and MHLW 202213003A.

Supplementary material

Supplementary Table 1 can be found via 10.5415/apallergy.2022.12.e38

Supplementary Table 1

Click here to view