Small-vessel vasculitis: a potential rare adverse event following hysterosalpingo-foam sonography (HyFoSy)

Introduction

Diagnostic imaging plays a pivotal role in both diagnosis and treatment of infertility in an assisted reproduction setting. In the fertility workup of a couple, the evaluation of the fallopian tubes stands as one of the cornerstones in the preliminary investigative process. Indeed, tubal pathology accounts for reproductive dysfunction in approximately 20% of couples. The most common causes of tubal dysfunction are pelvic inflammatory disease, endometriosis and adhesions from previous surgery (1).

Traditionally, the gold standard technique for tubal evaluation has been laparoscopy with chromopertubation (LC), but due to its invasive and costly nature, it was replaced for decades by hysterosalpingography (HSG), as a less invasive first-line alternative (2,3). Nevertheless, HSG involves irradiation of the female pelvis and exposure to iodinated contrast media, linked to potentially severe adverse reactions. Furthermore, it can be associated to discomfort and pain and requires appropriate equipment and facilities (2).

Given this context, hysterosalpingo-contrast sonography (HyCosy) emerged as an alternative, avoiding the aforementioned risks and allowing for the use of either contrast media or saline solution. The accuracy of HyCoSy is comparable to that of HSG and LC, recognized as reference standards for tubal patency testing (4). However, several HyCoSy contrast media are no longer available and saline/air mixture only allows for a brief ultrasound visualisation (5).

Consequently, in 2010, hysterosalpingo-foam sonography (HyFoSy) emerged as a promising alternative to supersede HyCoSy. The HyFoSy technique utilizes a non-embryotoxic gel containing hydroethyl cellulose and glycerol (ExEm^®-gel) mixed with purified water (purified ExEm^®-water) (IQ Medical Ventures BV, Rotterdam, The Netherlands). The ExEm^®-Foam is suitable to pass the fallopian tubes with the sufficient stability to allow ultrasound visualisation for at least five minutes (5).

About HyFoSy

The feasibility, tolerability and safety of HyFoSy in tubal patency assessment, as part of the fertility workup of infertile women, have been widely demonstrated (6-13). A recently published randomized non-inferiority trial has determined that HyFoSy and HSG produced comparable findings in the majority of examined patients withsimilar pregnancy outcomes (14). Furthermore, HyFoSy was reported as significantly less painful than HSG, as previously stated (10). As the gel fills the uterine cavity slowly, the filling pressure is kept low, which is the optimal strategy to mitigate discomfort. Additionally, HyFoSy may also improve the chances of establishing a spontaneous pregnancy, suggesting a potential therapeutic effect (9,15,16). Notwithstanding the previous, further evaluation may be recommended with a complementary method (e.g., HSG or LC) whenever diagnosis or best treatment strategy is uncertain (3).

HyFoSy side effects

Recognized side-effects of HyFoSy include discomfort, vasovagal reaction, fluid loss and spotting, but these do not differ from other tubal patency diagnostic techniques (9,10,17). Overall, HyFoSy is considered a generally safe and well-tolerated procedure. Thanks to the increasing popularity of ultrasound-based tubal patency tests, HyFoSy has emerged as a secure and less painful alternative in many infertility and outpatient settings.

In 2019, Ludwin et al. reported a case of cutaneous small-vessel vasculitis following tubal patency assessment through HyFoSy in a 32-year-old woman, a previously unreported side effect of this technique (18). She had previously experienced an allergic reaction to penicillin, but there were no other identified triggers for hypersensitivity in her medical history. The patient reported mild pain during and after the procedure, with no complications before leaving the clinic. However, the following day, she presented with a red-violet skin rash widely extended and moderate leg pain. Non-thrombocytopenic palpable purpura was observed during the physical examination on the whole body, particularly noticeable on the lower extremities and in the popliteal region. Initially considered as an allergic reaction, fexofenadine was prescribed, leading to the eventual resolution of the skin lesions in one week. No further laboratory tests or skin biopsies were conducted (18).

Since the beginning of 2019, our fertility unit has performed over three hundred HyFoSy procedures for tubal patency testing. Vasovagal reactions had been the main side effect detected, until November 2022. At that time, a 33-year-old woman, with no history of hypersensitivity, allergies or other medical conditions, underwent the HyFoSy procedure for tubal patency assessment. Vaginal disinfection was carried out before the technique, which was performed without previous analgesic, anaesthesia or antibiotics. Both fallopian tubes were found to be patent (Figure 1) and the woman experienced no complications before leaving the clinic. However, twenty-four hours post-HyFoSy, the patient was admitted to the hospital with fever and purpuric lesions on the legs, including minimally raised purpuric lesions on the lower limbs that did not disappear with diascopy (the application of pressure to a skin lesion with a glass slide, which is a helpful technique for identifying non-blanchable lesions, suggestive of purpuric lesions). These acute-onset lesions were associated with diarrhoea and arthritis of the ankles in our patient. The non-thrombocytopenic palpable purpura (Figure 2A), resolved spontaneously ten days after onset. We conducted laboratory tests (serology, a protein electrophoresis, and autoimmunity tests) and blood cultures, all of which were normal. A skin biopsy (Figure 2B) and a direct immunofluorescence study diagnosed leukocytoclastic vasculitis, with negative results for all antisera (IgA, IgG, IgM, C3 and fibrinogen). All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Transvaginal ultrasound two-dimensional images of HyFoSy of the patient. Hyperechogenic foam (ExEm^®-Foam) fills the endometrial cavity and passes through the fallopian tubes (arrows). HyFoSy, hysterosalpingo-foam sonography.

Figure 2 Leukocytoclastic vasculitis following HyFoSy. (A) A 33-year-old woman with non-thrombocytopenic palpable purpura on the lower limbs 24 h after HyFoSy using ExEm^®-Foam gel. (B) Histopathological study of leukocytoclastic vasculitis from a skin biopsy in the patient. Hematoxylin-eosin staining at 60× (B1) and 40× (B2). HyFoSy, hysterosalpingo-foam sonography.

Leukocytoclastic vasculitis, commonly referred to as small-vessel vasculitis, manifests principally as palpable purpura in the lower extremities (19). As can be inferred from the previous, it primarily affects the skin; extracutaneous manifestations are infrequent, occurring in less than 30% of cases (20). This entity can either be idiopathic (about 50% of the cases) or be associated with drugs, infections, autoimmune disorders or malignancies, requiring in the latter case a thorough work-up to determine if it is skin-limited or a manifestation of systemic vasculitis or any other disease. Diagnosis of leukocytoclastic vasculitis relies on histopathological examination. The treatment- once systemic involvement has been excluded-focuses on symptom management through rest, low-dose corticosteroids and, if indicated, colchicine (19). In cases where small-vessel vasculitis is secondary to a drug, the prognosis is favourable, being the discontinuation of the drug usually sufficient to resolve the condition. Notably, the primary distinction between drug-induced and idiopathic vasculitis relies on the fact that in the former, there is a link between disease onset and drug intake, being the discontinuation of the likely causative drug typically sufficient for correcting the autoimmune state in most cases (21). Despite the generally favourable prognosis for small vessel vasculitis of the skin, although infrequent, severe internal organ dysfunction may also occur (19). Furthermore, about 9% of patients may develop chronic or recurrent vasculitis (19).

In the only previously reported case of small vessel vasculitis with the HyFoSy technique, disease onset was caused by the ExEm^®-Foam gel intravasation into the myometrial vessels during the procedure (18). In our patient, intravasation of the gel was not detected during the procedure performed; however, it is highly probable that this event was responsible for the onset of the disease. Additionally, in these two cases now described in the literature regarding this side effect following HyFoSy, discontinuation of the presumed causative agent improved and resolved the patients’ disease within 7 to 10 days. It is important to note that in Ludwin’s report (18) an antihistamine was prescribed on suspicion of an allergic reaction, which was later ruled out by the diagnosis of drug-induced small vessel vasculitis. In our case, the disease remitted without any treatment. Finally, no serious systemic complications were detected in any of the two affected patients.

Unlike HyFoSy, a recognized complication of HSG is the intravasation of the contrast agent used into the veins, occurring in approximately 7% of cases and potentially leading to serious consequences such as pulmonary embolism and other systemic side effects (22). Regarding ultrasound-based techniques for tubal patency assessment (i.e. HyCoSy and HyFoSy), intravasation incidents have been infrequently reported after HyCoSy with air/saline solution and after HyFoSy (18,23). Notwithstanding the previous, regarding HyCoSy, intravasation of SonoVue^® contrast agent has been reported in up to 28% of patients undergoing the procedure (24). In relation to HyFoSy, it is crucial to collect more data on the foam extravasation during the technique to elucidate the causality between HyFoSy and leukocytoclastic vasculitis.

According to the manufacturer’s data (www.exemfoam.com), ExEm^®-Foam has been utilized in over half a million tubal patency testing procedures since its European launch in 2011. Back in 2019, U.S. Food and Drug Administration (FDA) approval was granted, being the only FDA-approved contrast for ultrasound tubal patency assessment. Despite what has been previously described in our paper, no serious complications, teratogenic effects, or allergic reactions have been reported in the literature or by the manufacturer (25). Exalto et al. reported that the individual components of the foam (glycerol, hydroxyethyl cellulose and purified water) are deemed safe for intrauterine application and tubal patency assessment, even in the occasional occurrence of gel intravasation (17). Although, there are lack of data on the safety of combining these components in the gel, though the extensive usage and minimal adverse effects reported can offer reassurance.

Conclusions

The limited data on side effects and the absence of reported serious or fatal complications associated with the technique provide reassurance about the use of HyFoSy in clinical practice. Nonetheless, the potential intravasation during the procedure, coupled with the scarcity of data on its actual incidence and its potential association with diseases—like small-vessel vasculitis—that could lead to more severe systemic complications, requires further exploration.

Overall, this commentary aims to raise awareness among practitioners utilizing this ultrasound-based tubal patency assessment technique, urging the recording and reporting of any detected adverse events. Furthermore, based on the two case reports, it is advisable to include small-vessel vasculitis and its rare complications in the informed consent for the technique, alongside with common side effects such as pelvic and abdominal pain, vasovagal reactions, together with symptoms like nausea, syncope and post-procedure spotting.

Acknowledgments

The authors thank the patient for her authorization to publish this case. The authors also thank all the staff at the Valme University Hospital for their contribution to this work.

Funding: None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-695/coif). A.O.V. is the recipient of a predoctoral program fellowship (FPU19/03393) awarded by the Ministry of Science, Innovation and Universities, Government of Spain. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dun EC, Nezhat CH. Tubal factor infertility: diagnosis and management in the era of assisted reproductive technology. Obstet Gynecol Clin North Am 2012;39:551-66. [Crossref] [PubMed]
2. Saunders RD, Shwayder JM, Nakajima ST. Current methods of tubal patency assessment. Fertil Steril 2011;95:2171-9. [Crossref] [PubMed]
3. Optimal evaluation of the infertile female. Fertil Steril 2006;86:S264-7. [Crossref] [PubMed]
4. Luciano DE, Exacoustos C, Johns DA, Luciano AA. Can hysterosalpingo-contrast sonography replace hysterosalpingography in confirming tubal blockage after hysteroscopic sterilization and in the evaluation of the uterus and tubes in infertile patients? Am J Obstet Gynecol 2011;204:79.e1-5. [Crossref] [PubMed]
5. Emanuel MH, Exalto N. Hysterosalpingo-foam sonography (HyFoSy): a new technique to visualize tubal patency. Ultrasound Obstet Gynecol 2011;37:498-9. [Crossref] [PubMed]
6. Emanuel MH, van Vliet M, Weber M, Exalto N. First experiences with hysterosalpingo-foam sonography (HyFoSy) for office tubal patency testing. Hum Reprod 2012;27:114-7. [Crossref] [PubMed]
7. Van Schoubroeck D, Van den Bosch T, Meuleman C, Tomassetti C, D’Hooghe T, Timmerman D. The use of a new gel foam for the evaluation of tubal patency. Gynecol Obstet Invest 2013;75:152-6. [Crossref] [PubMed]
8. Piccioni MG, Riganelli L, Filippi V, Fuggetta E, Colagiovanni V, Imperiale L, Caccetta J, Panici PB, Porpora MG. Sonohysterosalpingography: Comparison of foam and saline solution. J Clin Ultrasound 2017;45:67-71. [Crossref] [PubMed]
9. Tanaka K, Chua J, Cincotta R, Ballard EL, Duncombe G. Hysterosalpingo-foam sonography (HyFoSy): Tolerability, safety and the occurrence of pregnancy post-procedure. Aust N Z J Obstet Gynaecol 2018;58:114-8. [Crossref] [PubMed]
10. Ramos J, Caligara C, Santamaría-López E, González-Ravina C, Prados N, Carranza F, Blasco V, Fernández-Sánchez M. Diagnostic Accuracy Study Comparing Hysterosalpingo-Foam Sonography and Hysterosalpingography for Fallopian Tube Patency Assessment. J Clin Med 2021;10:4169. [Crossref] [PubMed]
11. Lim SL, Jung JJ, Yu SL, Rajesh H. A comparison of hysterosalpingo-foam sonography (HyFoSy) and hysterosalpingo-contrast sonography with saline medium (HyCoSy) in the assessment of tubal patency. Eur J Obstet Gynecol Reprod Biol 2015;195:168-72. [Crossref] [PubMed]
12. Melcer Y, Zilberman Sharon N, Nimrodi M, Pekar-Zlotin M, Gat I, Maymon R. Hysterosalpingo-Foam Sonography for the Diagnosis of Tubal Occlusion: A Systematic Review and Meta-analysis. J Ultrasound Med 2021;40:2031-7. [Crossref] [PubMed]
13. Van Schoubroeck D, Van den Bosch T, Ameye L, Boes AS, D’Hooghe T, Timmerman D. Pain during Fallopian-tube patency testing by hysterosalpingo-foam sonography. Ultrasound Obstet Gynecol 2015;45:346-50. [Crossref] [PubMed]
14. van Welie N, van Rijswijk J, Dreyer K, van Hooff MHA, de Bruin JP, Verhoeve HR, et al. Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial. Hum Reprod 2022;37:969-79. [Crossref] [PubMed]
15. Piccioni MG, Tabacco S, Merlino L, Del Negro V, Mazzeo A, Logoteta A, Del Prete F, Riganelli L, Giannini A, Monti M. Does hysterosalpingo-foam sonography have any therapeutic effect? A systematic review. Minerva Ginecol 2020;72:55-8. [Crossref] [PubMed]
16. Engels V, Medina M, Antolín E, Ros C, Bermejo C, Manzour N, Pelayo I, Amaro A, Martinez-Ten P, De-Guirior C, Rodríguez R, Sotillo L, Brotons I, de la Cuesta-Benjumea R, Martinez O, Sancho J, Alcázar JL. Factors Associated with a Post-Procedure Spontaneous Pregnancy after a Hysterosapingo-Foam-Sonography (HyFoSy): Results from a Multicenter Observational Study. Diagnostics (Basel) 2023;13:504. [Crossref] [PubMed]
17. Exalto N, Stassen M, Emanuel MH. Safety aspects and side-effects of ExEm-gel and foam for uterine cavity distension and tubal patency testing. Reprod Biomed Online 2014;29:534-40. [Crossref] [PubMed]
18. Ludwin A, Ludwin I, Szczeklik W, Martins WP. Cutaneous small-vessel vasculitis following hysterosalpingo-foam sonography (HyFoSy). Ultrasound Obstet Gynecol 2019;54:831-4. [Crossref] [PubMed]
19. Micheletti RG, Werth VP. Small vessel vasculitis of the skin. Rheum Dis Clin North Am 2015;41:21-32. vii. [Crossref] [PubMed]
20. Baigrie D, Goyal A, Crane JS. Leukocytoclastic Vasculitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing, 2024.
21. Sunderkötter CH, Zelger B, Chen KR, Requena L, Piette W, Carlson JA, et al. Nomenclature of Cutaneous Vasculitis: Dermatologic Addendum to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheumatol 2018;70:171-84. [Crossref] [PubMed]
22. Dusak A, Soydinc HE, Onder H, Ekinci F, Görük NY, Hamidi C, Bilici A. Venous intravasation as a complication and potential pitfall during hysterosalpingography: re-emerging study with a novel classification. J Clin Imaging Sci 2013;3:67. [Crossref] [PubMed]
23. Ludwin A, Ludwin I, Martins WP. Venous intravasation during evaluation of tubal patency by ultrasound contrast imaging. Ultrasound Obstet Gynecol 2018;51:143-5. [Crossref] [PubMed]
24. He Y, Wu H, Xiong R, Liu H, Shi J, Xu J, Zhang N, Liu Y. Intravasation Affects the Diagnostic Image Quality of Transvaginal 4-Dimensional Hysterosalpingo-Contrast Sonography With SonoVue. J Ultrasound Med 2019;38:2169-80. [Crossref] [PubMed]
25. Exalto N, Emanuel MH. Clinical Aspects of HyFoSy as Tubal Patency Test in Subfertility Workup. Biomed Res Int 2019;2019:4827376. [Crossref] [PubMed]