Oral GVHD post-cardiac xenograft valve replacement: a case report

Abstract

Background

Graft versus host disease (GVHD) is an autoimmune disease that affects the oral cavity as well as other parts of the body. Oral GVHD occurs in 45–83% of cases, and chronic GVHD observed in 30–50% of cases usually manifests as an oral presentation.

Case presentation

In this case report, a 13 years-old girl was referred to the periodontics clinic from the pediatric dentistry clinics for proper diagnosis and management of the oral presentations observed after receiving a prosthetic valve replacement 2 years ago. In this study, the xenograft type used was mainly investigated, as similar soft tissue grafts are used in the oral cavity with no GVHD oral manifestations being observed. This brings about an interesting discussion of the use of xenografts in different areas of the human body, but with different presentations.

Conclusions

Thus, future investigations on early diagnostic tools, including saliva or blood examinations, are needed to create preventive methods or create sensitive testing for early diagnosis in such patients.

Background

Graft versus host disease (GVHD) is an autoimmune disease that affects the oral cavity [1] as well as other body parts, such as the skin, gastrointestinal tract, and liver. Chronic graft versus host disease (cGVHD) or acute (aGVHD) occurs depending on whether the lesions occur after a given history of the patient, which could include undergoing allogeneic hematopoietic stem cell transplantation. The chronic form is observed in 30–50% of allogeneic hematopoietic stem cell transplantation cases, and typically have an oral presentation. Moreover, in 50–70% of cases, acute forms occur in allogeneic transplant patients [2].

Oral cGVHD occurs in 45–83% of cases [3]. In this form of the disease, the oral cavity is possibly the only affected area [4].

The increasing use of hematopoietic cells over bone marrow transplants, use of donors that are not fully human leukocyte antigen (HLA)-compatible[4] regardless of their blood ties to the recipient, and high number of transplants performed per year in all age groups, there is an increase in the number of elderly people suffering from GVHD [5].

According to a previous study [6], the updated list of risk factors for cGVHD includes HLA incompatibility, sex incompatibility (e.g., a male recipient and a female donor), absence of blood ties between the donor and recipient, older donors and recipients, mobilized peripheral blood transplantation, and childbirth in female donors [7].

Immunopathogenesis of the disease is not completely clear, although it is known that donor T cell reactivity against recipient cells is the main triggering factor of GVHD in the form of exacerbated inflammatory responses, direct or indirect [8].

There are general diagnostic criteria for the diagnosis of cGVHD [9] considering the appearance of clinical lichenoid lesions, hyperkeratotic plaques, and limited oral apertures secondary to sclerosis. Distinctive clinical features of cGVHD entail xerostomia, appearance of mucoceles, mucosal atrophy, pseudomembranes, and ulcerations. However, such manifestations alone may not be enough for the diagnosis. Oral manifestations may also appear in the acute and chronic presentations of the disease such as mucositis, gingivitis, erythema, and pain [10].

This autoimmune reaction can be mild, moderate, or severe, depending on the organs involved, oral presentation, symptoms, and the patient’s ability to perform daily activities or limited to such lifestyle. The establishment of specific biomarkers would facilitate early diagnostic measures for such patients [11].

Case presentation

A 13-year-old girl was referred to the periodontics unit from the pediatric dentistry unit for proper diagnosis and treatment because of the oral lesions' presentations. The oral manifestations were noticed two years ago and noticed after cardiac valve replacement, when she complained of halitosis and the lesions persisted (Fig. 1) without pain.

Fig. 1

a Labial mucosa displays reticular cGVHD-like lesions, b Buccal mucosa: reticular type, c Erosion over the tip on tongue, d Palatal attached mucosa, gingival margins, e Upper labial mucosa along marginal gingiva

Her current medications are presented in Table 1; she had no known allergies. She was asymptomatic until the age of 8 years, and her medical history revealed the following: moderate-to-severe congenital mitral regurgitation (MR), moderate TR, and large LA. Her blood pressure during the initial visit was 112/73 mmHg. Her weight and height measurements are presented in Table 2. Her cardiac history started with a fluttering sensation of moderate intensity in the chest, and had constantly experienced shortness of breath. These symptoms were exacerbated by stress and relieved by rest. The course progressed as expected by the cardiology clinic at King Faisal Specialist Hospital and Research Center-Jeddah (KFSHRC,J), Saudi Arabia. Before that, the patient had undergone MR valve repair in 2020 at an outside hospital (KSA) followed by an assessment and diagnosis with atrial septal defect (ASD) and MR. This assessment revealed a murmur, for which the patient had undergone cardiac surgery for ASD closure, mitral valve (MV) replacement, and tricuspid valve (TV) repair (July 2021) at KFSHRC,J.

Table 1 Medications and dosages

Table 2 Patient’s height, weight and body mass index

Her cardiac surgical history included valvuloplasty, MV with cardiopulmonary bypass, ASD repair, secundum with cardiopulmonary bypass, with or without a patch. She visited our pediatric dentists in July 2021 for dental restorations and hygiene improvement, with documentation of tooth exfoliation, gingivitis, gingival recession, and calculus deposits. She was treated under conscious sedation for her proposed dental treatment for cardiac clearance before her second surgery. She periodically visited the cardiology unit and underwent several investigations, including radiography, EKG, and thyroid testing due to being observed as underweight for her age. Her lab results revealed high TSH and FT4 levels, which were later followed-up in six months.

In October 2023, the patient was referred to the periodontics unit for the diagnosis and management of such oral lesions. Upon oral examination (Fig. 1), the manifestations of GVHD-like lesions (reticular forms) were observed all around the gingival and alveolar mucosa (attached photos; Feteih, 2023): (a), lower lip (labial) mucosa (b), cheek mucosa (c), tongue tip (d), and palatal marginal gingiva and (e) upper labial mucosa.

Considering the patient’s history of cardiac surgery with a soft tissue for valve replacement, along with the chronicity of stay and occurrence of oral lesions observed sometime after the surgery, GVHD as an oral manifestation was suspected. The child and her father denied involvement of any other body part in the manifestation of symptoms.

The patient underwent a thorough oral exam, along with careful history recording and the photos and radiographs that were taken were with informed consent.

Upon cardiology consultation, the soft tissue valve replacement was of xenograft; bovine origin, instead of mechanical valves to prevent the lifelong use of anticoagulants (e.g., Coumadin), improving her lifestyle along with the results obtained with soft tissue valve grafts. The discussion was regarding whether GVHD was encountered before with xenografts and was confirmed with a cardiologist who had observed a rare case as such before, yet with much severity, and that the plan for this patient would be continued with regular follow- ups as the results shown in (Tables 3 and 4) at her visit with cardiology in October 2023. Otherwise, for the oral lesions, a mouthwash containing corticosteroids was permissible and would not affect her cardiac situation, and the tissue valve that was placed would remain as the patient’s cardiac condition was stable. From a cardiovascular perspective, the patient was fit for dental procedures with prophylaxis practiced (2 gm of amoxicillin 1 h before any dental procedure), while the patient continued on her medications until her next follow-up visit (6 months).

Table 3 Patient’s vital signs

Table 4 Physical examination and result reviews

Chronic problems previously documented

Congenital MR.

Generalized gingival recessions, inflammation, and halitosis.

Assessment summary

Moderate-to-severe MR, moderate TR, and large LA.

S/P MV repair in Makkah a year earlier (2020).

S/P MV replacement (TissueValve) and TV repair on July 12, 2021.

Current cardiac complaints

No cardiac complaints occurred and the patient is doing well up to date.

Echocardiography

The bioprosthesis was observed in the mitral position with good opening and mobility, with a peak and mean PG of 12 mmHg and 7 mmHg, respectively. Trace MR.

MR. No TS. Mild + TR with a PSPG of 16 mmHg.

No AS. No AI. No PS. Trace PI with an end-diastolic velocity of 149 cm/s.

Dilated LA. Moderately depressed LV systolic dysfunction with an EF of 50% by M‐mode and 51% by Simpson’s method. A mildly depressed RV function and no pericardial effusion.

Dental treatment plan

The patient was managed by detailed history recording, including questions about familial and/or immunity related diseases which were uneventful, reaching a preliminary diagnosis along the clinical presentations observed intra-orally. Upon examination; the oral lesions were non-scrapable, not painful, and with no history of remission and/or exacerbations and the absence of other areas involved, before the cardiac surgery. So, differential diagnoses as infectious, lichen planus or lupus erythematosus were excluded [12]. A cardiology consultation was made, for the possibility of GVHD to occur from xenografts and the response was positive but rare, with the oral mucosa merely involved.

The case was managed by an oral hygiene visit including oral hygiene instructions (OHI) for the gingival inflammation observed with plaque accumulation. The patient was regularly monitored with Cardiology and periodically with Periodontics for almost a year. Also, an oral corticosteroid mouthwash was prescribed for the oral manifestations (leukoplakia, reticular features similar to lichen planus, marginal gingival inflammations), which did not much affect the lesions observed. A biopsy was planned and performed to confirm the diagnosis. The labial mucosal lining was very thin along ulcers observed, and upon soft tissue manipulation the areas readily bled and were easily torn. Also, periodic periodontal follow-ups were planned for monitoring of the oral lesions, a future biopsy may be required for any soft tissue changes and a referral to gastroenterology (GI) for further investigation.

Discussion

GVHD would most “likely” be or “in favor” to be suspected in this case due to the nature of the lesions presented, signs and symptoms and timing of occurrence, the classical clinical oral presentations as well as the extent of mucosal areas involved [11]. No history of eye dryness nor eye lubricants used [11]. Lungs and joints were unremarkable for daily routines [11]. Lichen planus and lupus were excluded as there was no history of remission and exacerbation or skin, scalp or other mucous areas (e.g. genitalia) with lesions involved, except slight eczema [11]. Skin color was normal for ethnicity. No history of diarrhea, but rather constipation episodes was confirmed. Medications reviewed and did not seem to cause such side effects. Infections, such as fungal was also excluded as non-scrapable lesions and confirmed with negative biopsy results, for both fungal microorganisms and malignancy. Upon the histologic examination (Meliti 2024) from the biopsy obtained (Fig. 2), it showed tangentially oriented fragment of squamous mucosa (2a), with mild to moderate acute and chronic inflammatory reaction, with small neutrophilic microabscesses and mild spongiosis (2b,2c,2d). No apoptotic figures, vacuolar changes or cell necrosis were found and the morphological cell features reported were concluded as non-specific, and clinical correlations were recommended.

Fig. 2

a Hematoxylin and eosin-stained Sect. (40X) demonstrates tangentially oriented mature squamous mucosa. b Hematoxylin and eosin-stained Sect. (100X) demonstrates moderate neutrophilic infiltration (blue arrow) with small micro-abscess formation (red arrow). c Hematoxylin and eosin-stained Sect. (200X) demonstrates evidence of intraepithelial neutrophils (blue circle) and mild spongiosis (black arrow). d Hematoxylin and eosin-stained Sect. (200X) demonstrates evidence of intraepithelial lymphocytes (yellow circle and blue asterisks)

Despite GVHD being known to occur in allograft transplants; this rare case reported that soft tissue valve xenografts may also give similar immune responses. A study showed the effect of human cells when implanted in a xenograft model, resulting in an immune response expressed as GVHD [13]. Some studies reported “the importance of glutaraldehyde in decreasing the immune response” with the use of xenograft prosthetic valves (e.g., bovine, porcine) [14], while others showed that sugars found in xenografts "alpha-galactose" (α-Gal) and N-glycolylneuraminic acid (NeuGc) [15] elicited immune responses that activated certain antibodies against the host cell [16] despite valve treatment with glutaraldehyde. Therefore, it would be of value to further explore cell mediated responses in depth [17], observe the time for host tissue re-vascularization and/or desensitization [18] post immune response activation, epitope modification, gene editing, tissue engineering [19] or imaging of the immune responses [20] that would foresee or prevent possible organ damage. Thus, avoiding lifelong inflammatory diseases and preventing future chronic lesions. This would give rise to substantial discussions in this area, regarding the identification of biomarkers, which would help in the early detection of GVHD-like lesions to reduce the manifestations in its early stages, as an immune system trigger. It is yet unclear how it exerts its effect within the human body, as complex and dynamic as it is, including the timing of a biopsy collected at its appropriate stage [12].

Conclusion

In this case report, the biopsy results did not confirm nor negate GVHD. However, it is possible for a graft material to cause a GVHD-like reaction or elicit an immune response, depending on the host’s immune system susceptibility. There is much to explore e.g. immune therapy as an area to investigate for such rare cases, especially if its benefits outstand a lifetime use of cortisone mostly in children during their periods of growth. As a precautionary measure, the use of cortisone prior to grafting, may be an area to explore, however it is not the standard of practice prior to valve replacement. Any allergies including medications a patient may be prone to, would also be invaluable to examine via blood and/or skin testing specific to certain elements in graft materials.

Xenografts and allografts are much used in dentistry [21, 22] and its use as bone or tissue grafts in a highly vascular region (e.g. oral cavity) are known to yield positive results and better soft tissue healing with some materials [23, 24]; nonetheless, GVHD-like lesions are not usually observed with the use of such materials. Thus, this report remains noteworthy for further discussion and investigation for future encountered cases, from an immunologic perspective along other specialties, to generate lab innovations for future prevention measures.