Over the last decade, thermal ablation has become the first-line treatment modality for incompetent saphenous veins [1,2]. Non-thermal, non-tumescent therapy (NTNT) for treatment of saphenous reflux has been introduced to overcome heat-related discomfort or complications of thermal ablations such as radiofrequency ablation (RFA) and endovenous laser ablation. One major NTNT technique involves the use of cyanoacrylate glue (CAG) to induce occlusion and fibrosis of the saphenous trunk. The first CAG developed for this purpose was VenaSeal (Medtronic), which has been most commonly used in clinical trials originating in the United States [3], Western Europe [4], and Korea [5].

The first-in-human trial showed occlusion of the great saphenous vein (GSV) in 92% of the patient cohort at 1 year, along with significant improvement in the Venous Clinical Severity Score [6]. Thereafter, a single-arm multicenter cohort study, the European Sapheon^TM Closure System Observational Prospective study, revealed an occlusion rate of 92.1% at 12 months [4]. Subsequently, the randomized controlled VeClose trial was published, in which the VenaSeal adhesive was compared with RFA [3]. One-year complete occlusion rates were nearly identical in both groups (97.2% and 97.0% in the cyanoacrylate closure [CAC] and RFA groups, respectively). Additionally, symptoms and quality of life were equally improved in both groups. Most adverse events (AEs) were mild to moderate and were unrelated to the device or procedure. The 24-month complete closure rates were 95.3% and 94.0% in the CAC and RFA groups, respectively, demonstrating the continued non-inferiority of CAC to RFA (P=0.0034) [7]. The same study group reported 5-year extension outcomes [8]. At 60 months, the Kaplan-Meier estimates for freedom from recanalization in the randomized CAC and RFA groups were 91.4% and 85.2%, respectively, demonstrating the non-inferiority of CAC to RFA. No serious long-term device- or procedure-related AEs occurred in either group at the 36- and 60-month follow-ups. However, Ko et al. [9] reported a higher recanalization rate in the CAC group than in the RFA group. The recanalization-free rates were 94.7% at <1 month and 77.2% at 6 months in the CAC group. None of the patients in the RFA group underwent recanalization. In this study, recanalization was defined as a stump length of >5 cm.

The trial investigating CAC vs. surgical stripping (CASS) trial for incompetent saphenous veins was the first prospective randomized controlled study to compare the clinical outcomes of nonthermal ablation with those of CAG and surgical stripping [5]. This trial demonstrated that both CAC and surgical stripping achieved complete occlusion of the target vein (TV) at 3 months. Postoperative pain and ecchymosis grades were significantly lower in the CAC group than in the conventional surgical stripping group [10].

Despite good clinical outcomes after CAC, diffuse inflammation in the thigh is a worrisome complication that is commonly observed after CAC for saphenous vein insufficiency. This study aimed to address this complication and ensure its proper management.

First-in-human trials have not reported any inflammatory reactions after CAC [11]. A subsequent trial comparing RFA demonstrated that one of the 108 patients had chronic phlebitis in the treated leg during the 1-year follow-up period [3]. Gibson et al. [7] reported 24-month follow-up results of the VeClose trial, showing no cases of this complication. The same study group reported 5-year outcomes of these trials. No delayed inflammatory reactions were identified in patients in the CAC group aged between 36 and 60 months [8]. Our initial experience showed that this inflammatory reaction occurred in 1 of 21 patients (4.7%) who underwent CAC for bilateral GSV reflux [12]. The CASS trial comparing the clinical outcomes between the CAC and surgical stripping groups showed that 3 of 63 patients (4.8%) experienced this complication after the CAC procedure [10]. A lower incidence of phlebitis (3.2%) than that in our findings was reported by Tekin et al. [13]. However, this may be because of the shorter follow-up period. Koramaz et al. [14] reported that 2.1% of patients experienced this complication. However, Park et al. [15] reported a higher incidence of 25% among patients treated with CAC. Overall, the incidence of this complication has been reported to range from 0%-25%. The varied incidences of this complication may be related to the absence of a clear definition. Therefore, a more reasonable definition or terminology is required to explain the phenomenon.

An inflammatory reaction in some patients after endovenous CAC is an erythematous effect that is generally observed near the venous treatment, with symptoms ranging from mild pruritus and/or erythema to recurrent severe inflammation, frank abscess formation, and systemic urticaria. Almeida et al. [6] described this complication as a simple clinical symptoms or signs, such as varicophlebitis, cellulitis, phlebitis, and/or pruritus. In a European multicenter cohort study, a phlebitis reaction was used to describe and treat this complication [4]. Morrison et al. [16] described phlebitis or chronic phlebitis as a unique complication in the VeClose trial 12-month outcomes. Park et al. [15] defined this complication as a phlebitis-like abnormal reaction characterized by unusual, suddenly appearing skin conditions such as erythema, itching, swelling, and pain/tenderness over the treated vein area. Jones et al. [17] described this complication as a type IV hypersensitivity reaction based on pathological findings. They reported a case of repeated recurrence with an unusual presentation. The patient underwent endoscopic venous excision on postoperative day (POD) 200. Histopathological evaluation of the removed tissue showed intraluminal foreign material and evidence of mononuclear cell inflammation, predominantly of the T4 subset compatible with type IV hypersensitivity reaction.

For a rational and definite understanding of this complication, we reviewed all published papers and thoroughly discussed the clinical presentation of the cases. In summary, this complication demonstrated a clear hypersensitivity reaction owing to its typical clinical presentation and pathological findings. However, most signs and symptoms are self-limiting. A few patients experienced repeated recurrences due to the relatively long presence of glue within the vein. This complication occurred mostly in one leg when both the legs were treated with CAG. Therefore, the complex hypersensitivity and irritation reaction (CHAIR) phenomenon is a rational definition to describe this complication [18]. The CASS trial reported a 4.8% incidence of CHAIR phenomenon [10]. Table 1 presents the incidence and suggested terminology for this complication.

Table 1 . Terminology of the complication.

Author	Year	Incidence (%)	Terminology
Almeida et al. [6]	2013	15.8	Varicophlebitis, cellulitis, phlebitis, pruritus
Proebstle et al. [4]	2015	11.4	Phlebitis reaction
Gibson and Ferris [19]	2017	20.0	Phlebitis, allergic reaction
Morrison et al. [16]	2017	0.3	Phlebitis, chronic phlebitis
Park et al. [15]	2019	25.4	Phlebitis-like abnormal reaction
Jones et al. [17]	2019	Case	Type IV hypersensitivity reaction
Gibson et al. [20]	2020	6.3	Hypersensitivity reaction
Lee et al. [18]	2021	5.0	CHAIR phenomenon
Joh et al. [10]	2022	4.8	CHAIR phenomenon

CHAIR, complex hypersensitivity and irritation reaction..

Patients with CHAIR experience various types of pain, heating sensations, itching, induration, erythema, and/or generalized hives. Fig. 1 illustrates typical findings of the CHAIR phenomenon. Fig. 1A shows the diffuse involvement of the redness. The patient experienced mild pain, tenderness, and itching in the treated GSV area. Fig. 1B demonstrates a more defined boundary for the erythematous changes. The patient experienced severe itching, pain, tenderness, and erythema in the treatment area. Erythematous changes were observed beyond the treated GSV. Some patients had generalized hives. Table 2 presents the detailed clinical presentations of each report.

Figure 1. Typical presentation of the complex hypersensitivity and irritation reaction phenomenon. (A) On postoperative day 10, the patient experienced pain, tenderness, and itching over the treated great saphenous vein (arrows). (B) The patient experienced severe itching, pain, tenderness, and erythema over the treatment area. Erythematous changes were observed beyond the treated great saphenous vein.

Table 2 . Clinical presentation and treatment of the complex hypersensitivity and irritation reaction phenomenon.

Author	Symptoms and signs	Onset time (d)	Duration	Treatment
Almeida et al. [6]	Mild pain, erythema, cellulitis	3-14	5.7±4.2 d	NSAID, antihistamine, antibiotics for cellulitis
Proebstle et al. [4]	Pain, redness	3-11	2-12 d	Self-limited, NSAID (in two patients)
Gibson et al. [7]	Phlebitis, generalized hives (1)	1-29	≤1 mo	Self-limited, antihistamine & steroid (general hives)
Morrison et al. [8]	Phlebitis	NA	NA	No treatment
Park et al. [15]	Erythema, itching, swelling, pain, tenderness, and/or hives	3-25	NA	NSAID, antihistamine, steroid
Jones et al. [17]	Pain, tenderness, chill, erythema, swelling	13	2 y	Antihistamine, NSAID cream, antibiotics, steroid, surgical excision of treated vein
Gibson et al. [20]	Pain, tenderness, swelling, itching	1-23	2-28 d	Mild (no or over-the-counter medications), Moderate (steroid) Severe (removal of glue)

Values are presented as mean±standard deviation..

NSAID, nonsteroidal anti-inflammatory drug; NA, not available..

The study of first human use of cyanoacrylate adhesive reported that phlebitis of tributaries adjacent to the treated GSV manifested mild pain and erythema and persisted for an average of 5.7±4.2 days (range, 3-14 days) [6]. In a European multicenter cohort study, postprocedural phlebitic reactions along the treated vein or its tributaries included reddening of the overlying skin and pain upon palpation. The median onset of symptoms was 6 days (range, 3-11 days) after the procedure, with a median duration of 6.5 days (range, 2-12 days) [4].

The WAVES study by Gibson and Ferris [19] first classified the CHAIR phenomenon based on severity into 3-tier grade. The authors developed a classification scheme for phlebitis. In this schema, P1 was defined as phlebitis involving the TV, P2 as phlebitis involving the tributaries/side branches of the TV, and P3 as a non-specific erythematous reaction.

The first randomized controlled trial comparing CAC and RFA reported that all phlebitis cases were mild [16]. Park et al. [15] reported that patients with CHAIR experience erythema, itching, swelling, pain, tenderness, and hives. The mean time of occurrence was 13.6±4.6 days (range, 3-25 days) after the procedure. Jones et al. [17] reported a case of severe CHAIR phenomenon. On POD 13, the patient presented with leg pain and redness. On POD 17, the patient experienced progressive leg pain, chills, and erythema over the medial thigh, suggesting an infection. On POD 124, the patient experienced persistent leg pain, erythema, and swelling. These symptoms persisted until POD 200.

Based on an excellent discussion in a combined retrospective/prospective review of 286 patients by Gibson et al. [20], the CHAIR phenomena were subdivided into mild presentations requiring either no or over-the-counter medications, moderate presentations requiring steroids, and severe presentations if the reaction lasted over 30 days or required glue removal. This study included 379 limbs from 286 patients. Among these, 18 cases of hypersensitivity reactions occurred (6% of the patients and 5.8% of the treated limbs). Twenty patients (7% and 6.4% of limbs) experienced pain, tenderness, and swelling without erythema or itching, consistent with treated venous phlebitis. Of the hypersensitivity reactions, 13 were mild (4.3%), 4 were moderate (1.3%), and 1 was severe (0.3%).

The exact cause of CHAIR has not yet been identified. Several reports have indicated that this complication occurs more frequently after treatment with the GSV than with the small saphenous vein [15,17]. Anatomically, the GSV crosses the knee joint and is involved in knee joint movement. Therefore, we conducted an animal study to evaluate the effects of active movement on the development of CHAIR after CAC procedure [21]. After aseptic preparation, the CAG was injected into the leg vein through a delivery catheter or into the ear vein through a 22G needle (Fig. 2). The pigs were divided into two groups based on joint involvement with the injected glue. Ten days after the glue injection, the veins were harvested for pathological analysis. Pathological findings in the group without joint involvement showed that inflammatory cells (mainly lymphocytes) had infiltrated the venous wall. In the group with joint involvement, the same inflammatory cells infiltrated both the vein wall and surrounding tissue (Fig. 3). In conclusion, glue injection into the actively moving portions may be a risk factor for CHAIR.

Figure 2. Procedure details of animal study. (A) After accessing the superficial vein in the hindlimb, cyanoacrylate glue is injected using 5F delivery catheter. (B) To inject glue into the ear vein, direct injection is performed using a 3 mL syringe and 21-gauge angiocath.

Figure 3. Pathological findings. Lymphocyte infiltration was mainly observed within the vein walls in the joint noninvolvement group (A-C). However, in the joint involvement group, lymphocytic infiltration was observed in both the vein wall and surrounding tissue (D-F).

To assess the risk factors for CHAIR, we reported the clinical outcomes of 100 consecutive patients who underwent CAC [18]. The CHAIR phenomenon occurred when the CAG was injected into the below-the-knee GSV. Mechanical irritation due to knee joint movement is a possible mechanism underlying the development of hypersensitivity reactions (Table 3).

Table 3 . Clinical analysis to determine the risk factors of the complex hypersensitivity and irritation reaction phenomemon.

Risk factor	Number	CHAIR (–)	CHAIR (+)	P-value
Age (y)	100	56.3±12.3	39.6±14.0	0.004a
Body weight (kg)	63	65.7±13.9	71.5±16.4	0.428a
Height (cm)	63	162.6±9.8	168.0±10.8	0.292a
Preoperative VCSS	78	4.8±2.2	3.6±3.9	0.422a
Preoperative AVVQ	78	12.9±9.5	12.7±8.3	0.974a
Procedure time (min)	95	76.4±32.8	69.8±28.6	0.658a
Treated truncal vein	190	185	5	0.008b
Great saphenous vein	137	132 (71.4)	5 (100)
Small saphenous vein	53	53 (28.6)	0
Access site of great saphenous vein	137	132	5	<0.001b
Above the knee joint	132	132 (100)	0
Below the knee joint	5	0	5 (100)

Values are presented as mean±standard deviation, number only, or number (%)..

Adapted from the article of Lee et al. (J Surg Ultrasound 2021;8:19-24) [18]..

VCSS, Venous Clinical Severity Score; AVVQ, quality of life score with Aberdeen Varicose Vein Questionnaire..

^aStatistical analysis was performed using the independent t-test. ^bStatistical analysis was performed using the Fisher exact test..

Sermsathanasawadi et al. [22] conducted a retrospective study to evaluate the risk factors for CHAIR. A total of 126 saphenous veins, including 106 GSVs (84.1%), 7 anterior accessory saphenous veins (5.6%), and 13 small saphenous veins (10.3%) in 101 patients were included. CHAIR occurred in 16 of the 101 patients (15.8%). Multivariate analysis revealed that suprafascial saphenous vein with a subcutaneous distance between the anterior vein wall and skin of <1 cm and saphenous vein diameter >8 mm were independent factors associated with the CHAIR phenomenon. O’Banion et al. [23] conducted a retrospective review of patients who underwent CAC at four tertiary United States institutions between 2012 and 2022. Among the 595 patients who underwent 881 CAC procedures, there were 92 (10.4%) cases of CHAIR in 79 patients (13%). Clinical, etiologic, anatomic, and pathophysiologic (CEAP) data classes 3 and 4, younger age, and smoking predicted a higher risk of CHAIR. Table 4 summarizes the possible risk factors for and preventive measures against CHAIR.

Table 4 . Possible risk factors and strategies for preventing the complex hypersensitivity and irritation reaction phenomenon.

Possible risk factors	Prevention
- Active movement over the treated vein. -. Great saphenous vein treatment -. Epifascial saphenous vein with depth <1 cm. -. Saphenous vein diameter ≥8 mm. -. CEAP class 3 and 4. -. Younger age. -. Smoker.	- Avoidance of cyanoacrylate glue in patients with allergies to adhesives such as prosthetic eyelashes and fingernails. -. Careful removal of the delivery catheter to avoid leaving adhesives in the subcutaneous tissue

Treatment approaches for CHAIR vary among different reports. In the study of first human use of CAG adhesive, all patients with phlebitis were treated with nonsteroidal anti-inflammatory drugs (NSAIDs). One patient with phlebitis and pruritus was administered antihistamines. One patient developed low-grade cellulitis that resolved after a 14-day course of oral antibiotics [6]. In contrast, Proebstle et al. [4] did not use any medication for CHAIR, owing to a self-limited course. Only two patients with this condition received NSAID for 2 and 15 days, respectively. In the WAVES trial, all CHAIR cases resolved within 1 month [19]. One patient developed total-body hives within the first week after the procedure, which improved after treatment with antihistamines and a short course of oral steroids. Park et al. [15] prescribed NSAIDs, antihistaminics, and intravenous dexamethasone. Jones et al. [17] reported a case of severe CHAIR. They initially administered antihistaminics and NSAID cream for CHAIR. Thereafter, confirmed infection was treated with an antibiotic. Steroids were also prescribed to control persistent leg pain, erythema, and swelling. The patient underwent endoscopic vein excision on POD 200. After excision, the patient experienced symptoms of pain and swelling in the treated limb that persisted for 2 years despite reduction. Gibson et al. [20] classified hypersensitivity reactions as mild, moderate, or severe. All patients with moderate hypersensitivity reactions were treated with a 6-day tapered course of oral steroids (methylprednisolone [24 mg] tapered to 4 mg). The details of the treatments used in each study are presented in Table 2.

CHAIR phenomenon should be managed according to clinical severity. Fig. 4 shows the management algorithm for the CHAIR phenomenon. Mild CHAIR is managed by simple observation or medications, such as NSAID, antibiotics, and/or antihistamines. Moderate CHAIR can be managed with steroids. Severe CHAIR phenomena, including intractable symptoms despite medications and frank abscess formation, should be treated with surgical removal of the glue.

Figure 4. Complex hypersensitivity and irritation reaction (CHAIR) phenomenon management algorithm. NSAID, nonsteroidal anti-inflammatory drug.

To date, prevention of CHAIR has not been reported. Gibson et al. [20] suggested the avoidance of CAG in patients with known allergies to CAG (such as used for application of prosthetic eyelashes and fingernails), multiple contact allergies, and skin conditions such as psoriasis or atopic dermatitis.

Careful removal of the delivery catheter to avoid leaving the adhesive in the subcutaneous tissue may protect against hypersensitivity. This can be achieved simply by withdrawing the delivery catheter into the access sheath before removing the entire apparatus [24]. Clinically relevant granulomas are uncommon and generally related to the extravasation of adhesives upon withdrawal of the delivery catheter [25].

CHAIR can be prevented avoiding CAG in patients with possible risk factors. Other non-thermal modalities can be considered for patients with varicose vein of younger age, CEAP 3/4 class, and smokers. If the treatment segment is involved in joint movement, other modalities should be used, or segmental excision of the vein crossing the joint should be performed to prevent CHAIR. Moreover, the epifascial saphenous vein with a depth of <1 cm can be easily removed without CAG injection. From a technical point of view, to prevent the CHAIR phenomenon, careful removal of the delivery catheter for the capture of glue is recommended according to updated instructions.

The CHAIR phenomenon is a relatively common complication of CAC. The severity of the clinical symptoms varies. Depending on the severity of the symptoms, management should be categorized as no treatment, surgical excision, or treatment with NSAID, antihistaminics, and steroids. The suggested possible risk factors are active movement over the treated vein, GSV treatment, epifascial saphenous vein with a depth <1 cm, and saphenous vein diameter ≥8 mm. Therefore, alternative treatment modalities must be considered. Furthermore, CAC should be avoided in patients with allergies to adhesives such as prosthetic eyelashes and fingernails. Careful removal of the delivery catheter to avoid leaving the adhesive in the subcutaneous tissue is an important technical practice for preventing CHAIR.

The authors have nothing to disclose.

Concept and design: all authors. Analysis and interpretation: all authors. Data collection: all authors. Writing the article: all authors. Critical revision of the article: all authors. Final approval of the article: all authors. Statistical analysis: all authors. Obtained funding: none. Overall responsibility: all authors.