Maternal finger-prick allogenic blood for persistent corneal epithelial defects

Abstract

This is a case of a 17-year-old patient with aniridia-related keratopathy and persistent epithelial defect (PED) treated successfully using maternal finger-prick blood (FPB). Maternal allogenic FPB treatment was initiated to the patient who was non-compliant with the use of autologous FPB. The PED was successfully managed with maternal FPB treatment with rapid and complete closure of the epithelial defect. Additionally, there was immediate and sustained symptomatic improvement to pain and recovery of vision in the only seeing eye. There was no immunological reaction to allogenic blood. Maternal finger-prick allogenic blood could serve as a potential alternative to serum eye drops or autologous FPB in the management of refractory PED, particularly in reference to the paediatric or the vulnerable age group. Further studies are required to confirm the role of allogenic blood in the treatment of PED.

Background

The use of autologous finger-prick blood (FPB) has an established role in the treatment of persistent epithelial defects (PEDs) in selected cases.^{1 2} Blood-derived products including autologous serum, allogenic serum and umbilical cord blood serum have been successfully used for ocular surface disorders such as severe dry eye disease (DED), PED, ocular graft versus host disease and limbal stem cell deficiency (LSCD).³

Autologous serum eye drops (auto-SEDs) and allogenic serum eye drops (allo-SEDs) facilitate epithelial healing and both have been shown to have comparable efficacy in cases of PED.^4–6 Maternal serum has been used for the preparation of allo-SED in the treatment of paediatric PED cases, where there are limitations to use the patient’s own blood either in the form of FPB or auto-SED.⁷ However, both the cost of treatment and the likely delay in obtaining allo-SED from maternal blood, which can lead to further progression of the corneal disease, can be a hurdle to treatment. In such cases, the use of maternal FPB could provide a solution for easy and immediate access to an effective treatment strategy.

We report a case of a 17-year-old patient with aniridia-related LSCD and consequent PED treated successfully using maternal FPB. To the best of our knowledge, this is the first case of PED being reported that is treated using allogenic or maternal FPB.

Case presentation

A 17-year-old male patient with aniridia and LSCD presented to the corneal clinic with severe pain and photosensitivity in the right eye during the initial COVID-19 lockdown period. His past best-corrected visual acuity was 6/36 Snellen’s acuity in the right eye and counting fingers in the left eye. The left eye had an established corneal leukoma resulting in longstanding visual loss since the age of five. There was no relevant family history. The right eye had had treatment with carmellose 1% four to six times a day for aniridic keratopathy on his initial presentation to the emergency department. During this visit, he was referred to corneal service. At his first cornea clinic appointment 1 week later, on examination there was an acutely inflamed right eye with a corneal epithelial defect measuring 4 mm×1 mm and visual acuity was reduced to 6/60. There was 360° pannus extending from the limbus 1.5 mm into the cornea. There was no corneal vascularisation or conjunctivalisation. There was no corneal infiltrate and anterior chamber was quiet. He was started on levofloxacin six times a day and intensive lubricant therapy. There was no improvement to treatment after 2 weeks of initial therapy and a bandage contact lens (BCL) was considered which was not tolerated. Two weeks later, the epithelial defect was found to have increased to 4×4.5 mm with no infiltrate or stromal thinning (figure 1). Microbial corneal swabs returned negative results and intensive lubricant treatment was continued with topical antibiotics. A further 4 weeks later, there was still very little epithelial healing and he was in significant distress with further loss of functional vision in the only seeing right eye. Options were explored to protect the ocular surface and promote healing. Botulinum toxin to induce ptosis was ruled out as the patient was heavily dependent on the right eye for any navigation. Similarly, alternative treatments such as lateral tarsorrhaphy or amniotic membrane transplant (AMT), although considered, were not favoured by the patients’ family due to the fact that these options would temporarily limit vision in the only seeing eye. SEDs were discussed but at the height of the COVID-19 lockdown, this posed a significant procurement limitation and delay. Therefore, a trial of autologous FPB treatment was suggested to the patient and family. The patient, however, was not able to source his own FBP due to his aversion to needles. As an alternative to autologous FBP, we decided to use maternally derived allogenic blood using finger-prick method with direct application onto the patient’s ocular surface in the right eye. The mother of the patient was screened for HIV, hepatitis B and C viruses, and syphilis, the results of which were all negative. Her blood group was confirmed as A positive. However, this could not be matched to the patient’s blood group which was unknown and was not investigated due to his extreme aversion to needles. The mother was then instructed and shown the technique of safely drawing a drop of capillary blood from her fingertip using a spring-loaded lancing device and applying a single drop of her blood to the lower fornix of the patient’s right eye. The patient’s mother was asked to apply the FPB three times a day and follow-up in 2 weeks’ time. At 2 weeks, the FPB was found to be well tolerated and the epithelial defect had reduced in size to 1×1.5 mm with improvement to his vision and pain symptoms. There was no corneal conjunctivalisation or vascularisation evident at the site of the epithelial defect. The peripheral pannus was also found to be stable with no evidence of progression. However, there was diffuse stromal haze in the area of PED not accompanied by corneal thinning or stromal melt. At 4-week follow-up, the epithelial defect had completely healed (figure 2) and visual acuity had improved to 6/36 (which was the baseline visual acuity for this patient). The maternally derived FPB treatment was discontinued 2 weeks following closure of epithelial defect and the patient was maintained on preservative-free hyaluronate artificial tear lubricants with a stable ocular surface at 3-month follow-up following the cessation of maternal allogenic FPB.

Figure 1.

Persistent epithelial defect measuring 4×4.5 mm before the start of maternal finger-prick blood treatment.

Figure 2.

Fluorescein staining showing completely healed epithelium 4 weeks after treatment with maternal finger-prick blood.

Outcome and follow-up

The patient made a full recovery with allogenic FPB. This is the first time to our knowledge that allogenic FPB has been used to treat a PED and we recommend that this should be used as an alternative therapy when SEDs are unavailable and the patient is unable to use his own blood through finger-prick method.

Discussion

Epithelial erosions and PED are commonly reported in cases of aniridia. Aniridia keratopathy is believed to be a result of abnormality in limbal stem cell microenvironment.⁸ PAX6 gene mutations result in abnormalities of corneal epithelial cytoskeleton protein (cytokeratin 12) and cell adhesion molecules (desmoglein and α-catenin and β-catenins) which in turn results in the typically described aniridic chronic keratopathy.⁹ The gene mutation also interferes with epithelial cell proliferation, migration and wound healing.^{8 9} It is, therefore, not uncommon to have non-healing epithelial wounds resulting in PEDs in patients with aniridia.

Treatment options of PED include intensive lubricant therapy, BCLs, botulinum toxin to induce ptosis, lateral tarsorrhaphy or AMT.¹⁰ Many of these options might not be suitable for young and paediatric patients particularly in the context of learning difficulties.

Blood-derived products are a source of epitheliotropic and neural growth factors such as Epithelial Growth Factor (EGF), Fibroblast Growth Factor (FGF), Nerve Growth Factor (NGF), Platelet Derived Growth Factor (PDGF) and Insulin-like Growth Factor (IGF), which facilitate epithelial cell healing and adhesion.³ Auto-SED treatment has been shown to be beneficial in aniridia keratopathy.⁴ It has biochemical properties similar to healthy tear film, in addition to the non-allergenic and antimicrobial properties.⁴ Because the epitheliopathy in aniridia is primarily due to a change in the stem cell niche, SED is believed to help by providing epitheliotropic factors and was shown to be superior to lubricant therapy in mild to moderate cases.⁴

In patients in whom autologous blood is difficult to obtain, allo-SED has been considered an effective alternative to auto-SED, as demonstrated by Chiang et al.⁵ Among the 36 patients in their cohort, almost 64% healed within 4 weeks.⁵ A retrospective, cross-over study from New Zealand compared the use of auto-SED and allo-SED in patients with dry eye, who served as their own controls. The study found a comparable efficacy and tolerability between the two topical treatment options.⁶

Although cornea and conjunctiva bear ABO blood group antigens and Human Leukocyte Antigens (HLA), alloimmunisation is said to be unlikely since serum is essentially cell-free. It is not clear if the proteins in the serum could have any immunogenic effect on the ocular surface.¹¹ Harritshøj et al proposed that since pregnancy is likely to induce HLA antibodies and other leucocyte-specific antibodies in female serum, blood from male donors be used for ABO-specific allogenic SED preparation.¹² However, clinical experiences from using mix-gendered blood donors have not reported any hypersensitivity reactions or safety concerns.¹¹ In fact, maternal blood was successfully used by Kalhorn et al to prepare allo-SED for paediatric patients with PED secondary to cranial nerve palsies.⁷ There was no incidence of adverse reactions and PED in all five eyes resolved within 3 weeks of initiating the treatment. It is therefore likely that maternal serum is safe to use in the preparation of SED where autologous blood is difficult to obtain.

Processing the serum and preparing SEDs can cause a delay in initiating the treatment. Moreover, the cost involved in the production of auto-SED alone is estimated to be $412 per month.¹ In the midst of a pandemic, SED treatment for our patient would have meant delaying therapy and possibility of infection and stromal melt in the only seeing eye.

Finger-prick autologous blood has been shown to be a readily available, effective treatment option in cases of PED.^{1 2} It is believed that the finger-prick causes traumatic injury to capillaries, resulting in platelet activation. The α-granule exocytosis results in the release of growth factors during the finger-prick, blood stasis on fingertip and at the time of applying the blood drop to the ocular surface.¹ Balal et al also highlighted the cost-effectiveness of this method which was estimated to be $26 per month including the disinfectant wipes, single-use lancets and sharps bin for disposal.¹

We gave a trial of finger-prick autologous blood treatment to our patient that failed his compliance. Therefore, we decided to try finger-prick maternal blood treatment for this patient given his mother was keen to volunteer. We observed a complete resolution of the epithelial defect with improvement in vision and symptomatology within 4 weeks that was resistant to conventional topical therapy for 3 months. There were no adverse events observed in using the maternally derived finger-prick allogenic blood.

To the best of our knowledge, this is the first case to be reported where finger-prick allogenic blood was used to treat PED related to aniridia. Allogenic FPB derived from the mother could be an effective, cost neutral and readily available alternative for the treatment of PED in the young and vulnerable patients with PED. It could be considered in patients who need immediate treatment but are unsuitable for use of autologous FPB. There were no hypersensitivity reactions to the use of maternal-derived allogenic blood observed in our patient; however, larger studies might be required to establish the immunogenicity of the cells by using finger-prick allogenic blood, as compared with allogenic serum.

Learning points.

• There is no observed adverse reaction when using finger-prick allogenic blood for the treatment of persistent epithelial defect (PED) in the cornea that may be attributed to immunogenic causes.

• We recommend that allogenic finger-prick blood (FPB) should be used as an alternative therapy when serum eye drops are unavailable, and the patient is unable to use his/her own blood through finger-prick method.

• Further studies must be done to confirm the non-immunogenic nature of FPB in the treatment of PED in the cornea.