
==== Front
Stem Cell Res Ther
Stem Cell Res Ther
Stem Cell Research & Therapy
1757-6512
BioMed Central London

39285456
3924
10.1186/s13287-024-03924-9
Short Report
Mesenchymal stem cell therapy in eosinophilic granulomatosis with polyangiitis-related lower limb gangrene: a case report
Wang Hui 12
Zhang Qian 23
Wu Sensen 1
Pan Dikang 1
Ning Yachan 1
Wang Cong 1
Guo Jianming guojianming@aliyun.com

1
http://orcid.org/0000-0002-2869-9736
Gu Yongquan gu15901598209@aliyun.com

1
1 https://ror.org/013xs5b60 grid.24696.3f 0000 0004 0369 153X Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, No. 45, Changchun Street, Beijing, 100053 China
2 ShangRao Jingkai Health-Biotech United Hospital, ShangRao, 334000 Jiangxi China
3 https://ror.org/024qkwh22 grid.464416.5 0000 0004 1759 7691 Shangrao Normal University, ShangRao, 334000 Jiangxi China
16 9 2024
16 9 2024
2024
15 30730 1 2024
4 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Eosinophilic granulomatosis with polyangiitis (EGPA), a rare but life-threatening systemic vasculitis, is distinguished by marked eosinophilia and presents with diverse symptoms, including asthma, cutaneous purpura, ecchymosis, skin necrosis, cardiac lesions, peripheral neuropathy, and necrotizing vasculitis. The etiology of EGPA involves a complex interaction among humoral, adaptive, innate, and allergic immune responses. Standard treatment employs prolonged high-dose glucocorticoid therapy, which is critical for survival; however, some patients’ symptoms cannot be relieved.

Case report

This case report details the medical management of an 11-year-old patient with EGPA, who was at risk of bilateral lower limb amputation due to differential arterial occlusion and severe, necrotizing vasculitis-induced gangrene in both feet. Treatment modalities administered included systemic infusion of Umbilical Cord Mesenchymal Stem Cells (UC-MSCs), targeted gastrocnemius muscle injections, and application of a Placenta-Derived Mesenchymal Stem Cells (PD-MSCs) hydrogel.

Results

After receiving a four-month regimen of allogeneic mesenchymal stem cell therapy via intravenous and local administration, the patient showed normalized eosinophil counts, reestablished blood flow in the dorsal arteries, and marked improvement in foot ulcerations.

Conclusion

Mesenchymal stem cell therapy is a promising option for severe EGPA cases refractory to glucocorticoids.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-024-03924-9.

Keywords

Mesenchymal stem cell
Eosinophilic granulomatosis with polyangiitis
Churg-Strauss syndrome
Case report
http://dx.doi.org/10.13039/501100012166 National Key Research and Development Program of China No.2021YFC2500500 Gu Yongquan issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Eosinophilic granulomatosis with polyangiitis (EGPA) is a disseminated necrotizing vasculitis accompanied by extravascular granulomas, occurring in patients with asthma and tissue eosinophilia [1, 2]. The incidence of EGPA is 0.5 to 4.2 cases per million per year, with a global prevalence of 10 to 14 cases per million residents [3, 4]. Epidemiological studies indicate that EGPA is less common in Asia, although Japan and South Korea have recently reported some large case series [5, 6]. The disease has a comparable incidence in both males and females, with the average age at diagnosis around 50 years [7], and cases in children are highlysporadic [8].

Genetic and environmental factors influence the etiology of EGPA. The precise mechanisms by which these factors determine susceptibility and clinical manifestations of EGPA are not fully understood [9, 10]. EGPA is predominantly mediated by Th2 lymphocytes, leading to elevated levels of interleukins (IL)-4, IL-13, and IL-5, which facilitate the mobilization of eosinophils from the bone marrow into the bloodstream and result in their infiltration into various organs [11, 12]. The release of eosinophil cationic protein and eosinophil-derived neurotoxin contributes significantly to tissue damage [13]. EGPA is characterized by a triphasic progression: a prodromal phase marked by asthma and allergic rhinitis, an eosinophilic phase with tissue eosinophilia, and a vasculitic phase with multiorgan involvement. Clinical presentations are diverse, including but not limited to respiratory, gastrointestinal, musculoskeletal, renal, cutaneous, and neurological symptoms [14–16]. While these phases may overlap, certain patients can experience severe complications such as thrombosis [17]. The standard treatment for severe prognosis involves a combination of glucocorticoids and immunosuppressants, whereas milder cases might be managed with glucocorticoids alone [18, 19].

Recent literature has increasingly documented the efficacy of mesenchymal stem cells (MSCs) in repairing ischemic ulcerations, predominantly those associated with thromboangiitis obliterans and diabetic foot ulcers [20–22]. Arango-Rodríguez et al. [23] demonstrated that treating patients with chronic limb-threatening ischemia using allogenic Wharton jelly-derived MSCs significantly improved limb salvage rates compared to autologous bone marrow mononuclear cells. Mesenchymal stem cells can be derived from various sources including bone marrow, umbilical cords, placenta, adipose tissue, peripheral blood, and umbilical cord blood [24]. MSCs sourced from umbilical cords are primarily extracted from Wharton’s Jelly, a gelatinous substance found within the umbilical cord rich in mesenchymal stem cells. UC-MSCs show robust proliferative capabilities and multipotent differentiation potential. They possess low immunogenicity, reducing the risk of immune rejection post-transplantation. UC-MSCs have strong anti-inflammatory properties, demonstrating potential in treating various inflammatory diseases, and are primarily used in tissue engineering, immune modulation, and anti-inflammatory treatments [25, 26]. PD-MSCs are mainly extracted from the chorionic and amniotic membranes of the placenta. Like UC-MSCs, PD-MSCs exhibit high proliferative capabilities and differentiation potential, with similarly low immunogenicity. Moreover, PD-MSCs produce an array of secretory factors, such as growth factors and cytokines, which are conducive to tissue repair and regeneration. Their specific cellular characteristics and secretory factors slightly differ from UC-MSCs, potentially offering varied performance in specific applications [27, 28].

Reports of MSCs therapy for severe limb ischemic gangrene secondary to EGPA are scarce, offering limited guidance for managing such wound ulcers. Faced with profound limb ischemia and imminent amputation risk in this patient, and with conventional treatments exhausted, we administered MSCs therapy. To the best of our knowledge, this constitutes the inaugural account of MSCs application in an EGPA-induced ischemic gangrene case.

Case description

Patents

An 11-year-old male presented with bilateral lower limb pain persisting for one year and subsequent bilateral foot gangrene over the past three months. Initially, the pain was localized to the left calf and, within two months, extended to the left foot and right calf without therapeutic intervention. Progressively, the patient developed cyanosis and pain in both hands, with associated blackening and hypothermia of the dorsum of feet and toes, impairing ambulation. Additionally, he exhibited a skin rash characterized by erythematous wheals and intermittent febrile episodes. Despite corticosteroid therapy administered in another hospital, symptomatology remained unaltered. The patient’s specific treatment measures at another hospital are shown in Table 1.

Table 1 Laboratory tests before and after treatment for the patient

Variable	Before Treatment	During Treatment	After Treatment	
Weight (kg)	23	23	23.4	
Blood Pressure (mmHg)	107/63	120/78	118/80	
Respiratory Rate (breaths/min)	22	20	22	
Pulse (beats/min)	114	110	108	
Red Blood Cells (/L)	4.28*1012	5.15*1012	5.38*1012	
White Blood Cells (/L)	20.12*109	14.06*109	9.8*109	
Platelets (/L)	97*109	256*109	239*109	
Eosinophils (/L)	9.8*109	4.5*109	1.08*109	
Basophils (/L)	0.13*109	0.14*109	0.09*109	
Neutrophils (/L)	7.64*109	4.64*109	4.14*109	
Lymphocytes (/L)	4.50*109	4.10*109	3.68*109	
CRP (mg/L)	29	20	1.9	
Albumin	38.1	40.1	36.8	
Creatinine (μmol/L)	38.3	55.6	40.8	
Uric Acid (μmol/L)	150.12	180.69	214.36	
ALT(U/L)	13.4	32.5	18.7	
AST(U/L)	21.1	14.5	23.9	
CRP: C-Reactive Protein, ALT: Alanine Transaminase, AST: Aspartate Transaminase

Past medical history

The patient has been generally healthy. Three months prior to the onset of the current condition, the patient experienced a left ankle sprain. The patient denies any history of surgeries, blood transfusions, and denies close contact with infectious diseases such as hepatitis and tuberculosis. The patient also denies any history of allergies to food or medications.

Physical examination

Bilaterally enlarged lymph nodes are palpable in the submandibular and cervical regions, the largest measuring approximately 1.5 × 1 cm. Additionally, multiple enlarged lymph nodes are present in the inguinal regions bilaterally, with the largest being roughly 2.5 × 0.5 cm. The necrotic area on the dorsum of the left foot measures approximately 8 × 5.5 cm², while on the dorsum of the right foot, it measures roughly 6 × 5 cm² (Fig. 1. A). No significant pulsation was detectable in the dorsal pedal arteries, and coolness was noted on the dorsum of both feet, with discoloration and coolness also present at the distal toe ends.

Fig. 1 Changes in the patient’s bilateral foot wounds. a: Wound before stem cell therapy; b: Wound 3 months after stem cell therapy; c: Wound at the time of discharge

Laboratory examination

The peripheral blood displayed the following properties: White blood cell count is 20.12 × 10⁹/L, monocyte percentage is 1.06 × 10⁹/L, lymphocytes count is 2.8 × 10⁹/L; eosinophil absolute value is 9.8 × 10⁹/L, accounting for 56.7%, neutrophils 62.7%, C-reactive protein level of 29 mg/L. Additional related laboratory data can be found in Table 1.

Imaging examination

The patient’s cranial magnetic resonance imaging (MRI) reveals inflammation in the right maxillary and ethmoid sinuses. Figure 2 illustrates the results from a computed tomography (CT) angiography of the bilateral lower extremities. The vascular ultrasound of the right lower extremity indicates severe stenosis and occlusion in the right posterior tibial and peroneal arteries, significant stenosis of the distal anterior tibial artery, and intermittent occlusion of the left anterior and posterior tibial arteries, coupled with stenosis in the distal peroneal artery’s lumen. The chest CT scan depicts fine linear and strip-like opacities along the right posterolateral basal pleura, accompanied by dispersed interstitial alterations.

Fig. 2 Patient’s lower extremities CT angiography reconstruction. The left arrow indicates occlusion of the main trunk of the anterior and posterior tibial arteries on the left side; on the right side, (a) severe narrowing of the distal anterior tibial artery can be seen, (b) occlusion of the posterior tibial artery

Organ biopsy and genetic testing

A biopsy of the grey-yellow plaque-like nodule on the patient’s neck, which included five lymph nodes, indicated reactive hyperplasia. This was characterized predominantly by sinus histiocytes and notable eosinophil infiltration in the cervical lymph nodes. Moreover, bone marrow biopsies from the sternum and ilium exhibited active myeloid proliferation with a heightened presence of eosinophils. However, genetic sequencing analysis did not identify any pathogenic variants that could be conclusively associated with the disease phenotype.

Differential diagnosis

(1). Henoch-Schönlein purpura (HSP): HSP is a common vasculitis in children characterized by purpura, joint pain, abdominal pain, and renal involvement. Compared to EGPA, patients with HSP usually do not have significant eosinophilia.

(2). Granulomatosis with polyangiitis (formerly known as Wegener’s Granulomatosis, GPA): GPA is also a type of small vessel vasculitis that often affects the respiratory tract and kidneys. Unlike EGPA, patients with GPA typically have symptoms of upper respiratory tract involvement such as sinusitis, nasal septum perforation, and nosebleeds, with less frequent eosinophilia.

(3). Microscopic polyangiitis (MPA): MPA is another type of small vessel vasculitis that primarily affects the kidneys and lungs. Compared to EGPA, patients with MPA usually have normal or only slightly elevated eosinophil counts and no history of asthma.

Diagnosis

The American College of Rheumatology’s 1990 criteria outlines six diagnostic criteria for EGPA: asthma, eosinophilia exceeding 10%, neuropathic symptoms, variable pulmonary infiltrates, anomalies in paranasal sinuses, and evidence of eosinophils outside blood vessels upon biopsy. Diagnosis requires at least four indicators, achieving an 85% sensitivity and 99.7% specificity [29]. This patient meets the necessary criteria for an EGPA diagnosis.

Ethics approval and consent to participate

This clinical study was approved by the ethical committee board of ShangRao Jingkai Health-Biotech United Hospital; the title of the approved project is Clinical Study on Perinatal Tissue Mesenchymal Stem Cells in the Treatment of Severe Lower Limb Ischemia (Approval number: 2021001; Date of approval: June 25, 2021). The patient provided written informed consent before participating in this study.

MSCs production and characterization testing

We used allogeneic clinical-grade human prenatal MSCs derived from either umbilical cord (UCMSC) or placenta (PL-MSC) tissue, which were obtained from allogeneic donors. MSCs, derived through enzymatic digestion from placental and umbilical cord tissues, are sieved using a 200-mesh cell strainer before collection and subsequent culture expansion. The quality and purity of MSCs are assessed via flow cytometry, as well as their multipotent differentiation potential. The expression levels of MSCs molecular markers CD73, CD90, and CD105 are 98.95%, 98.98%, and 99.16% respectively, as indicated in Fig. 3. Moreover, these cells exhibit the capacity to differentiate into osteoblasts and adipocytes. PD-MSCs gel is composed of placental mesenchymal stem cells mixed with alginate. Cell viability is tested through PI staining conducted on samples. Short-term storage can be maintained at 4 °C, while long-term preservation requires conditions of -20 °C or -80 °C. The stem cells and related drugs used in this study all come from the Hans Union Group. This group’s production of injectable UC-MSCs and PD-MSCs hydrogel for clinical trials has obtained implied permission from the National Medical Products Administration’s Center for Drug Evaluation (CDE) (CXSL2000335) and has passed the national clinical drug trial permit (CTR20201158).

Fig. 3 Detection of mesenchymal stem cell surface molecular markers by flow cytometry. MSC mesenchymal stem cell surface marker expression: CD73+, CD90+, CD105 + > 95%, CD19-, CD34-, CD11b-, CD45-, HLA-DR- < 2%.

Treatment and results

Upon hospitalization, the patients underwent debridement and dressing changes and received anti-infective therapy. A multimodal stem cell treatment regimen was employed, consisting of: (1)Biweekly intravenous infusion of UCMSCs at a dosage of 1 × 106 cells per kilogram of body weight, administered seven times in total; (2)Application of Placenta- PDMSCs hydrogel, dosed at 2 ml for each 10cm2 of the wound surface, applied biweekly; (3)Localized injections of UCMSCs into the gastrocnemius muscles of both lower limbs, with each infusion containing 2 × 107 cells, a total of 10 injection sites were used, with approximately 0.5 ml injected at each site, at a depth of about 1 cm. repeated eight times; (4)Seven times application of a mesenchymal stem cell nutritive fluid topically. We attempt to reduce the systemic eosinophil count and overall inflammation in patients through intravenous injection of stem cells. Each time the hydrogel is applied locally, it is necessary to first debride the wound and remove necrotic tissue. The injection of umbilical cord mesenchymal stem cells into the patient’s lower limbs aims to effectively establish blood circulation and collateral circulation in the limbs. Considering the severe ulceration of the patient’s lower limbs, we provide treatment every two weeks after excluding various immune and adverse reactions following the initial treatment.

Follow-up

After four months, the patient exhibited complete healing of bilateral foot wounds, as evidenced by Fig. 1B and C. Concomitantly, routine hematological parameters normalized, and vascular ultrasound confirmed restored blood flow in both feet. At the one-year follow-up, the patient’s symptoms had not recurred.

Discussion

The pathogenesis of EGPA is intricate, involving diverse mechanisms. The case in question pertains to the subset of ANCA-negative patients, whose condition is predominantly driven by eosinophilic activity, with immune dysregulation as the central pathological feature. The immunomodulatory capacities of MSCs have the potential to alter the disease course in EGPA. This paper will elucidate the immune dysregulation mechanisms within EGPA and examine the therapeutic impact of MSCs.

Th2 cells are considered critical participants in the pathogenesis of EGPA, with the abnormal proliferation of eosinophils being a diagnostic and actual specific manifestation of the disease. The disease is characterized by T lymphocytes polarizing towards a Th2 phenotype, leading to upregulation of eosinophil chemotactic factors and increased secretion of various eosinophilic cytokines (such as IL-3, IL-4, IL-5, and IL-13), etc.). Eosinophils, in turn, can synergize with the action of Th2, leading to abnormal accumulation of eosinophils. Granulomas form as giant cells encapsulate them, apoptotic cell processes are impaired, and tissue toxicity due to eosinophil products is elevated, causing tissue damage [9, 30, 31]. However,, to besides the role of Th2, there is evidence that Th1 and Th17 cells are involved in the late stages of EGPA, secreting large amounts of IL-17 A. Moreover, during the active phase of the disease, the significant reduction in regulatory T-cell numbers also exacerbate the progression of EGPA [32, 33]. The primary treatment modalities for EGPA are glucocorticoids and immunosuppressants, with cyclophosphamide being particularly common, and corticosteroids are regarded as the treatment foundation, according to the EGPA Consensus Task Force [34]. Recent studies have identified azathioprine, rituximab, various immunoglobulins, and plasma exchange as emerging therapeutic alternatives. However, symptom relief is achieved in only 85% of cases, and relapse occurs in over a third of patients [35, 36]. These challenges underscore the need for continued exploration of novel treatments, among which stem cell therapy emerges as a promising avenue.

UCMSCs and PDMSCs, allogeneic in nature, demonstrate a high tolerance and minimal immune rejection due to their immunomodulatory abilities [37, 38]. Their anti-inflammatory properties are essential in treating EGPA, as they can disrupt antigen presentation—a process typically facilitated by dendritic cells presenting to naive T cells. MSCs inhibit the differentiation of monocytes into antigen-presenting cells, reducing their antigen-presenting function and T-cell activation [39, 40]. Additionally, UCMSCs also suppress T cell proliferation and influence the differentiation of activated T cells into various regulatory T (Treg) cell subsets, such as CD4 + CXCR5 + Foxp3+, CD4 + CD25 + Foxp3+, and CD8 + CD25 + Foxp3 + Treg cells. This modulation impedes the development of TH1 and TH17 cells, curbing the release of pro-inflammatory cytokines like INF-γ, IL-6, IL-8, and TNF-α [41, 42]. Finally, Treg cell enhancement dampens Th2 cell activation, leading to lower levels of Th2-related interleukins—IL-4, IL-5, and IL-13—after MSCs treatment [43]. These cytokines reduction signifies a decline in Th2 cell number and activity, supported by the observed decrease in eosinophil counts of resulting in diminished IL-5 chemotaxis [44](Fig. 4).

Fig. 4 The pathogenesis mechanism of eosinophilic granulomatosis with polyangiitis and the action targets of mesenchymal stem cell. ① MSCs inhibit the differentiation of monocytes into antigen-presenting cells, reducing their antigen-presenting function and T-cell activation. ② MSCs also suppress T-cell proliferation, hinder the development of TH1 and TH17 cells, and inhibit the release of pro-inflammatory cytokines such as IFN-γ, IL-6, IL-8, and TNF-α. ③ Following MSC treatment, there is a decrease in the levels of Th2-related interleukins—IL-4, IL-5, and IL-13

MSCs also address the etiology of diseases and significantly contribute to wound healing and vascular reconstruction, which is crucial for limb preservation. PDMSCs hydrogels attenuate the inflammatory response and enhance IL-10 expression, an anti-inflammatory cytokine vital for moderating early-stage inflammation and accelerating wound closure while facilitating granulation tissue development [45]. UCMSCs, when administered locally, release a suite of growth factors, chemokines, and cytokines, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), primary essential fibroblast growth factor (bFGF), epidermal growth factor (EGF), keratinocyte growth factor (KGF), and transforming growth factor-beta (TGF-β). These mediators orchestrate angiogenesis, dampen inflammation, and modulate immune responses [46]. VEGF, in particular, has a high specificity for endothelial cells and plays a unique role in mediating angiogenesis. Zhang et al. [47] conducted a 3-year Phase I clinical trial that confirmed local and intravenous injections of human umbilical cord-derived mesenchymal stem cells can promote vascular reconstruction in the lower limbs and effectively restore blood supply to the legs. Additionally, the study demonstrated that injecting mesenchymal stem cells directly into damaged muscle significantly enhances the immune response, thereby promoting corresponding tissue repair [48, 49]. Therefore, this patient restored the blood supply to the lower limbs quickly, providing a favorable environment for wound healing.

Limitations

Due to the nature of this study being a case report, while it offers a new perspective on the treatment of EGPA, some limitations are inevitable. First, the study focuses more on describing specific clinical manifestations and treatment processes, lacking extensive data collection and analysis. Second, the findings from a case report are difficult to replicate and verify in other cases or larger study samples. This restricts its application and dissemination in scientific research. Further validation in animal models or in vitro experiments is necessary to pave the way for more in-depth studies.

Conclusion

Thus far, there is an absence of research documenting the use of MSCs in the management of EGPA. Present findings suggest that MSCs therapy is a safe and productive option for EGPA. After MSCs treatment, patient outcomes have demonstrated stabilization. This investigation introduces a potentially novel and hopeful strategy for EGPA treatment. Nonetheless, further investigation through expanded clinical trials is necessary to discern the efficacy of this modality comprehensively.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

Not applicable.

Author contributions

HW, QZ, YCN, and CW contributed to data collection; SW and DKP were major contributors to data collection and the writing of the manuscript; HW, JMG, and YQG participated in data interpretation and contributed to the writing of the manuscript. All authors have read and approved the final manuscript.

Funding

This research was funded by the National Key Research and Development Program of China (2021YFC2500500).

Data availability

All data generated and analyzed during this study are included in the published article.

Declarations

Ethics approval and consent to participate

This clinical study was approved by the ethical committee board of ShangRao Jingkai Health-Biotech United Hospital, the title of the approved project is: Clinical study on perinatal tissue mesenchymal stem cells in the treatment of severe lower limb ischemia (Approval number: 2021001; Date of approval: June 25, 2021). The patient provided written informed consent prior to participation in this study. Placenta and umbilical cord donors have signed informed consent for stem cell extraction, use by others, and publication of articles.

Consent for publication

The parents of the patients included in this study have been informed about the relevant details of the study and the associated clinical outcomes, and they have signed written consent forms supporting the publication of this research.

Competing interests

The authors declare that they have no competing interests.

Hui Wang is the first author.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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