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

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 ).

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 ).

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. 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. 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.

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.

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