Bilateral infection-triggered ligneous conjunctivitis in a 6-month-old patient treated successfully with heparin and allogenic serum eye drops

Abstract

Purpose

To report a case of successful management of ligneous conjunctivitis (LC) in a pediatric patient.

Methods

We report the case of a 6-month-old girl presenting with persistent thick membranes on the palpebral conjunctiva after an initial episode of infectious conjunctivitis.

Results

Complete resolution of symptoms was achieved after 4 months of treatment with commercially available heparin-containing artificial tears and allogenic serum drops obtained from maternal blood. Genetic testing later revealed a homozygous pathologic variant of the plasminogen gene (PLG) confirming diagnosis of plasminogen deficiency with associated LC. Clinical remission was sustained 10 months after allogenic serum cessation.

Conclusions

LC with ocular membrane formation is the most common clinical presentation in patients with type I plasminogen deficiency. The fibrin-rich membranes can lead to sight-threatening complications and reduced quality of life. This is a report of full resolution of ocular membranes in LC after a corticosteroid-sparing treatment combining heparin-containing artificial tears and allogenic serum eye drops in a pediatric patient.

1. Introduction

Ligneous conjunctivitis (LC) is a rare form of chronic conjunctivitis characterized by the formation of thick and recurrent membranes on the tarsal conjunctiva.¹ It is associated with plasminogen deficiency (PLGD), an ultra-rare genetic disease with an incidence of 1.6 per million caused by a homozygous or compound heterozygous mutation in the plasminogen gene (PLG) located on chromosome 6q26.^1,2 Plasminogen is the precursor to plasmin, the enzyme responsible for fibrinolysis, an important step in wound healing.² Individuals with PLGD have impaired fibrinolysis and clinically present with the build-up of fibrin-rich membranes on the mucosa of various organ systems after tissue damage from injury or infection.² The most common clinical form of PLGD is an ocular presentation of LC with a prevalence of 81%.^1,3 LC typically presents within the first year of life.^1,3 Treatment approaches to systemic disease include administration of fresh frozen plasma (FFP) or intravenous (IV) plasminogen; however, both carry non-negligible risks for adverse events such as nasopharyngitis, oropharyngeal pain and headaches.⁴ For patients with clinically isolated LC, reported topical treatment options include topical plasminogen drops, cyclosporin A, corticosteroids or surgical excision; however, these treatment options show inconsistent success and currently there are no established guidelines for the treatment of LC nor PLGD.² Due to the ultra-rare nature of the disease, large prospective clinical trials and cohort studies are difficult to implement.¹ Therefore, reporting and sharing clinical experience through case reports has remained a crucial source of knowledge for clinicians and researchers. We report the case of a 6-month-old girl with genetically confirmed PLGD and clinical LC, treated with a combination of commercially available heparin-containing artificial tears and maternal allogenic serum eye drops, with complete resolution of membrane formation after 4 months of this topical treatment.

2. Case report

A 6-month-old girl was referred to the ophthalmology department by the pediatric emergency room for evaluation of the left eye that showed conjunctival hyperemia, palpebral swelling and abundant clear discharge for the past four days. The patient was reported to have had an upper respiratory tract infection 14 days prior treated with salbutamol puff. At the time of presentation, the patient was afebrile, and bloodwork showed no elevation of C-reactive protein and normal complete blood count. On initial portable slit lamp examination, the patient showed left-sided unilateral conjunctival hyperemia, follicular reaction and large membranes on the tarsal conjunctiva (Fig. 1). Physical exam by the pediatrician showed no signs of other organ system involvement. The initial assumed diagnosis was viral membranous conjunctivitis; thus, the membranes were removed with forceps under topical anesthesia and light sedation with inhaled nitrous oxide followed by treatment with tobramycin-dexamethasone combination eye drops three times daily and hourly saline flushing. Follow-up examinations were performed every 48 hours thereafter for further membrane peeling. At each follow-up visit, thick, woody and adherent membranes would rapidly reform on the tarsal conjunctiva extending to the conjunctival fornices, limiting the complete palpebral opening of the left eye. After 4 weeks of treatment with limited clinical improvement, the diagnostic hypothesis of LC was made. To confirm the diagnosis, the patient's membranes were sent for a histological examination, which showed fibrin-rich material with necrosis and polynuclear neutrophil infiltration. The patient's serum plasminogen activity levels were low at 46% (reference values: 75%–150%) supporting the diagnostic hypothesis of LC. Therefore, a genetic panel with trio sampling of the patient and the parents for the PLG gene was ordered. In correspondence with the new diagnostic hypothesis, the treatment was adapted to topical treatment with fluorometholone eye drops three times daily and heparin-containing artificial tears (HYLO PARIN®, URSAPHARMA, Saarbrücken, Germany) four times daily due to their affordability and ease of use. Membrane removal was continued on a weekly basis under topical treatment to avoid mechanical damage to the cornea from membranes and stimulus deprivation amblyopia because the membrane hindered normal palpebral opening. After two weeks of this treatment, fluorometholone was discontinued as the parents missed follow-up visits and treatment with topical corticosteroids was therefore deemed unsafe. Instead, 20% allogenic serum eye drops from maternal blood eight times per day were added to the treatment with heparin-containing artificial tears. After three weeks of this treatment, the membranes were still reforming, however they were less adherent, sometimes shedding by themselves, and the palpebral aperture was improving. Five weeks after initiating allogenic serum drops, the patient presented with purulent discharge in the left eye and microbiological examination of conjunctival swabs showed superinfection with Streptococcus mitis/oralis, Haemophilus influenzae andMoraxella catarrhalis. Tobramycin drops four times daily were added to the treatment with heparin-containing artificial tears and allogenic serum. Upon superinfection the patient was also examined by a pediatrician and no signs of other organ system involvement were found. At the next follow-up visit the infection had spread to the right eye and both eyes now showed conjunctival hyperemia and thick conjunctival membranes. The reinforced treatment with tobramycin, allogenic serum eye drops, and heparin-containing artificial tears was thus extended to the right eye. The superinfection resolved in both eyes after a few days and tobramycin drops were stopped while heparin-containing artificial tears and allogenic serum drops were continued for the persistent LC membranes in both eyes. At the follow-up visit four months from presentation, membranes were no longer seen in either eye and the treatment was continued unchanged. On follow-up at five months from presentation, the parents reported that for personal reasons it had not been possible to perform the blood draws for the allogenic serum production and the patient had therefore only been treated with heparin-containing artificial tears four times daily since the last follow-up visit. On examination, both eyes showed no membranes and a quiet anterior segment. Consequently, the decision was taken to continue treatment exclusively with heparin-containing artificial tears. No new membranes formed 10 months following the cessation of allogenic serum drops. Genetic analysis showed that the patient is homozygous for the pathogenic variant c.112A > G, p.Lys38Glu of PLG gene confirming the diagnosis of LC secondary to PLGD. Each parent was a heterozygous carrier of the mutation.

Fig. 1.

Color photograph of the left eye of a 6-month-old patient with ligneous conjunctivitis showing conjunctival hyperemia and membranes on the upper tarsal conjunctiva. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

3. Discussion

Isolated ocular presentation with LC is the most common clinical form of PLGD and entails the potential for sight-threatening complications secondary to mechanical damage to the cornea.

The ultra-rare nature of PLGD causes difficulties in the diagnosis and management of affected patients and limits the development of specialized centers for treatment. Multiple treatment approaches exist based on the variable clinical presentation of patients with PLGD, nonetheless no treatment guidelines have been established.⁵ Past treatment strategies have included systemic treatments with FFP or IV administration of plasminogen, human-tvmh (Ryplazim, Prometic Biotherapeutics Inc., Laval, Canada), a plasma-derived human Glu-PLG.^4,5 These treatments are limited by the risk of systemic complications, as well as the high burden associated with the need for frequent IV administrations.^4,6 Their use is, therefore, commonly restricted to patients requiring systemic therapy for disease with multiorgan involvement.

In PLGD patients with isolated ocular disease, a localized treatment approach with topical drugs and membrane excision with or without amniotic membrane grafting is commonly adopted.7, 8, 9, 10 Options for topical treatment include plasminogen eyedrops, topical FFP drops, heparin drops and topical anti-inflammatories such as steroids and cyclosporin A.6, 7, 8, 9 Replacement therapy with topical plasminogen drops has proven effective in the treatment of LC; however, this treatment is not widely available and very expensive.⁸ Additionally, plasminogen drops must be stored at −20°C and frequently instilled, leading to a high burden of treatment for the patients.⁸ FFP drops are employed for the remaining plasminogen activity in the plasma, yet they yield inconsistent results, and have been reported to be most effective when combined with surgical excision.⁶ Further, FFP drops must also be stored frozen and thawed for use, making dispensing difficult.⁶

Heparin eye drops are employed for their local action on coagulation by blocking the conversion of fibrinogen to fibrin. They have not been used as monotherapy and are typically combined with topical anti-inflammatory drugs. Heparin drops have been employed as maintenance therapy for long-term control of membranes with good results.⁹ We used heparin-containing artificial tears (HYLO PARIN®, URSAPHARMA, Saarbrücken, Germany) with 1300 I.E./ml heparin sodium in our treatment approach because of their affordability and accessibility. Otherwise, compounded heparin eye drops can be produced in hospital pharmacies with heparin concentrations ranging from 1000 to 5000 I.E./ml.¹¹

Topical antibiotics and anti-inflammatory drugs have a limited role in treatment, as LC has been reported to show poor response to these agents.6, 7, 8, 9 Our case supports this as the patient failed to improve clinically while undergoing initial treatment with tobramycin-dexamethasone combination drops. Nonetheless, these drugs have been successfully used in combination with other treatments such as topical FFP and surgery and some authors have hypothesized that they are necessary for long-term control of disease.^6,9

Autologous serum eye drops have been used for the treatment of various ocular surface diseases for over 20 years, leading to widespread availability and accessibility in most hospital pharmacies. They contain vitamin A, epidermal growth factors, fibronectin and plasminogen, making them similar in composition to natural tears and beneficial for the treatment of epithelial defects and inflammation.^11,12 We chose a treatment with serum eyedrops prepared from the patient's mother's serum to deliver supposed functional maternal plasminogen directly to the patient's ocular surface.¹² Our objective was to promote normal fibrinolysis and wound healing in our patient with PLGD. Additionally, the known anti-inflammatory and epitheliotrophic properties of serum eye drops were presumed to be beneficial for the healing of the patient's ocular surface.¹¹ Few previous accounts of LC treatment with allogenic serum have been published in the literature; however, they differ significantly from our treatment approach.^10,13,14 Both Ozkan et al. and Lee et al. combined allogenic serum eye drops with topical anti-inflammatory drugs, either cyclosporin A or steroids.^10,14 Gonçalves dos Santos Martins et al. employed a treatment with 50% heterologous serum eyedrops; however, they required instillation every 3 hours.¹³ Ozkan et al. and Gonçalves dos Santos Martins et al. reported no recurrence of membranes at 12 months of treatment while our patient showed successful treatment response after 4 months of treatment with allogenic serum eye drops combined with heparin-containing artificial tears, and no recurrence after allogenic serum drops discontinuation.^10,13 Continued long-term treatment with heparin-containing artificial tears was chosen since cases in the literature report treatment with local therapy for a year or longer after membrane resolution.^8,12,13 A limiting factor of the case is that no direct measurement of the plasminogen activity in the maternal allogenic serum drops was obtained in spite of the maternal carrier status of the pathologic variant of the PLG gene. Because PLGD is an autosomal recessive disease and carriers usually do not display disease phenotype, we hypothesized that the plasminogen activity in maternal blood would be sufficient for our treatment purposes. The treatment success supports this hypothesis. It remains possible that the plasminogen activity in the maternal serum is below normal; however, other case reports utilizing serum from family members with proven normal plasminogen activity did not report faster resolution of membranes.^10,13 A further limitation of this report is the relatively short follow-up period compared to other cases found in the literature and long-term follow-up of the patient will be necessary to confirm the treatment's success and management of potential future relapses.

4. Conclusion

Treatment of an ultra-rare disease presents a specific challenge given the small number of affected individuals and geographic distribution of cases. This leads to a limited understanding of the disease and high cost in the development of a disease-specific treatment. Our treatment approach addresses these challenges by combining commercially available heparin-containing drops with allogenic serum drops into a low-cost and widely available treatment with promising clinical outcomes.

CRediT authorship contribution statement

Celia-Louise Comberg: Writing – original draft, Data curation. Menes Kamga: Data curation. Maureen Masset: Supervision. Tom Buelens: Writing – review & editing, Supervision. Majda Rachdi: Writing – review & editing, Supervision, Data curation, Conceptualization.

Patient consent

Written informed consent was obtained from the patient's guardian for the purpose of publication.

Authorship

All authors attest that they meet the current ICMJE criteria for authorship.

Funding

No funding or grant support

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

FFP –

fresh frozen plasma

IV –

intravenous

LC –

ligneous conjunctivitis

PLG -

plasminogen

PLGD –

plasminogen deficiency