DR BHARAT GURNANI

Dr.Josephine Christy, Dr.SHIVANANDA NARAYANA, DR. KIRANDEEP KAUR

Semi Finals

Abstract

Aim-To study demographics, risk factors, clinical challenges and treatment outcome in managing Pediatric Pythium Keratitis.

Methods-Retrospective analysis of 7 culture proven Pediatric Pythium subjects was performed from October 2017 to December 2019.Demographic details, risk factors, clinical course, treatment and visual outcome were analysed.

Results-Mean age was 11.42 years.Presenting VA ranged from 20/30 to PL+.Risk factors were mud injury, stick injury and bath in pond water.Based on diagnostic algorithm and culture results patients were treated with antifungals and 0.2% Linezolid and 1 % Azithromycin. 2 patients healed with medical management. 3 underwent TPK,1 had Re‐TPK. 3 underwent Optical PK and 2 were awaiting optical PK.2 had reinfection.2 improved to 20/30 and 5 patients has final VA ranging from 20/200-20/1200.Globe salvage was 100%.

Conclusion-Prompt diagnosis, clinical awareness and specific treatment options are needed for managing this devastating corneal entity

Full Text

Aim-To study demographics, risk factors, clinical challenges, and treatment outcomes in managing Pediatric Pythium Keratitis.

Methods-Retrospective analysis of culture-proven Pediatric Pythium subjects was performed from October 2017 to December 2019. Demographic details, risk factors, microbiological details, clinical course, treatment, and visual outcome were analysed in detail.

Results-A total of 7 patients were analyzed. The mean age was 11.42 ± 1.2  years. Presenting visual acuity ranged from 20/20 to perception of light (PL+). The most common predisposing risk factors were mud injury in 3 (42.85%) patients, stick injury in 2 (28.57%) patients, and 1 (14.28%) bath in pond water.  The most common clinical presentation was subepithelial infiltrate, tentacular projections, and peripheral furrowing in 4 (57.14%) patients each, and 3 (42.85%) patients showed stromal infiltrate. The microbiological diagnosis was based on growth on blood agar culture, and confirmation was based on vesicles with zoospore formation by the leaf incarnation method. Based on diagnostic algorithm and culture results, patients were treated with antifungals 5% Natamycin or 1 % Itraconazole/ Voriconazole and 0.2% Linezolid and 1 % Azithromycin. 2 patients healed with medical management. Three underwent Therapeutic keratoplasty (TPK),1 had Repeat‐TPK. Three underwent Optical Penetrating Keratoplasty (OPK), and two were awaiting optical PK. 2 had reinfection. Two improved to 20/30, and 5 patients had final VA ranging from 20/200-20/1200. Globe salvage was 100%.

Conclusion-Pediatric Pythium Keratitis is a rare entity. Non-resolving fungal keratitis should be kept as a differential diagnosis. Prompt diagnosis, clinical awareness, and specific treatment options are needed for managing this devastating corneal entity.

Keywords– Pediatric Pythium Keratitis, Pythium insidiosum, Tentacles, Leaf Incarnation

Introduction

Infectious keratitis is a significant cause of ocular comorbidity in the pediatric age group. If not treated aggressively, it can lead to irreversible visual sequelae like corneal opacity, amblyopia, and phthisis bulbi.^[1] The variety of microbial keratitis in pediatric cases includes fungal, bacterial, and viral keratitis.^[2]  Although microbial keratitis is not very common in the pediatric age group, a detailed analysis from southern California reported an 11 % prevalence of pediatric keratitis among all microbial keratitis cases.^[3] Recently pediatric keratitis has seen an emergence of a new world species in the form of Pythium insidiosum keratitis, which is rarely reported. Pythium keratitis closely mimics fungal keratitis clinically and is difficult to manage devastating ocular pathology. Pythium Insidiosum is Oomycete and belongs to Phylum Straminipila, Class Oomycetes, Order Pythiales, and Family Pythiaceae.^[4] Previously, it was considered fungus until histopathological analysis revealed that the cytoplasmic membrane does not contain ergosterol, and the organism multiplies through asexual reproduction by forming sporangia containing zoospores as well.^[5] The first report of this rare entity dates back to Thailand, where it was initially considered endemic; since then it numerous reports have emerged from Australia^[6], China^[7], Israel^[8], and India^[9]. The various forms of Pythium reported are ocular, vascular, cutaneous/subcutaneous, and disseminated. On slit-lamp examination, Pythium closely resembles fungal keratitis. Still, few important differentiating features which can clinch the diagnosis are stromal infiltrate with hyphated edges, tentacular projections, peripheral furrowing, and thick cotton wool-like infiltrate. The treatment options available are antifungal drugs (5% Natamycin, 1% Itraconazole, and 1 % Voriconazole)  antibiotics, cyanoacrylate glue for melt, and therapeutic keratoplasty.^[10]

As per the detailed literature review, this is the first case series on pediatric Pythium keratitis. This retrospective analysis aimed to highlight the clinico‑microbiological profile of a case series of pediatric patients of Pythium keratitis presenting between October 2017 to  December 2019 at our tertiary eye care referral center in South India. This paper also details the risk factors, demographic profile, clinical features, microbiological profile, management, and treatment outcomes. We have also aimed to propose a diagnostic and treatment flowchart for Pythium cases, which will help all the ophthalmologists while dealing with this virulent infection.

Methodology

This was a retrospective observational study done for 27 months from October 2017 to December 2019 at our tertiary eye care hospital in South India. The study complied with the tenets of the Declaration of Helsinki. The study approval was obtained from the Institutional Review Board (IRB) of the Institutional Ethical Committee (IEC). The data of all individual cases and microbiology records of all culture-positive Pediatric Pythium insidiosum patients were obtained from Electronic Medical Records (EMR) data system [Fig. 1 Diagnostic Flowchart]. The data were evaluated for demographic details, a time lag of presentation, risk factors, clinical features, microbiological profile, medical and surgical treatment response, and visual outcome. The study’s inclusion criteria were(1) All culture-positive Pediatric Pythium cases upto 18 years of age and (2) Post keratoplasty button culture-positive cases. The criteria for exclusions were: (1) Incomplete medical records and (2) Absence of laboratory investigations despite clinical suspicion. The demographic, risk factors, uncorrected and best-corrected visual acuity by Snellen chart, detailed anterior and posterior segments findings along with microbiological results were retrieved from the medical case records. At our center, we routinely perform corneal scrapings under topical anesthesia using 0.5% proparacaine. These specimens include scrapings for smear examination (Grams stain and 10% potassium hydroxide wet mount) along with subsequent sequential scraping for culture on blood agar and potato dextrose agar. Additionally, zoospore formation of Pythium insidiosum was also confirmed by the incubated carnation leaf method. The treatment was initiated when clinical and microbiological results were available. Pythium hyphae closely mimic fungal hyphae on smear examination, so before the culture results were available, the eyes with positive smears having hyphae were treated with hourly topical antifungals in the form of 5% Natamycin suspension, 1% Itraconazole, or 1% Voriconazole. If the ulcer size was less than 4 mm x 4 mm, the eyes were treated with single antifungal in the form of 5% Natamycin hourly suspension, and if the ulcer size was more than 4 x 4 mm, they were treated with a dual drug therapy of either 5% natamycin and 1% Itraconazole hourly or 5% Natamycin and 1% Voriconazole hourly during waking hours. After five days, when the culture results were available, the flat, feathery colorless colony growth of the Pythium species on the blood agar prompted the possibility of Pythium, which was further confirmed by zoospore formation on an incubated carnation leaf. If the culture result was positive for Pythium insidiosum, the patients were treated with topical Linezolid 0.2% hourly if the ulcer size was less than 4 x 4 mm and topical Linezolid 0.2% and Azithromycin 1% combination if the ulcer was more than 4 x 4 mm during waking hours. Patients who had poor response despite adequate and appropriate antimicrobial therapy, corneal perforation, and non-resolving ulcers involving limbus were subjected to Therapeutic keratoplasty (TPK). The excised corneal button was also cultured on blood agar and potato dextrose agar and was processed for species identification. Postoperatively, all eyes were treated with topical Linezolid 0.2% alone or topical Linezolid 0.2% and Azithromycin 1% combination on an hourly basis for a minimum period of 3 weeks based on clinical picture preoperatively. Moreover, if the culture was positive, but button culture was negative post keratoplasty, patients were started on steroids and antibiotic combination in the form of 0.1% Dexamethasone or 1% Prednisolone with 0.5% Moxifloxacin after a minimum of 2 weeks of anti-Pythium therapy. However, if the culture was positive and button culture was also positive post keratoplasty, patients were started on steroids and antibiotic combination in the form of 0.1% Dexamethasone or 1% Prednisolone with 0.5% Moxifloxacin after a minimum of 3 weeks of anti-Pythium therapy. On follow-up, the steroids were started in tapering doses under close observation only if there was no recurrence of infection postoperatively. Patients continued to be on a maintenance dose of anti-Pythium therapy for at least four weeks after initiation of topical steroids. They were closely monitored for the development of re-infection. Those patients with an active infection in the form of graft infiltrate or melt are taken for repeat TPK. Graft infections after the second TPK were conservatively treated with lateral tarsorrhaphy

Results

A total of 2039 ulcers presented to us during the study period, out of which 1003 were culture negative, 847 were positive for fungus, 161 were bacterial, and 30 were positive for Pythium. Out of 30, 7 pediatric Pythium Keratitis subjects were analyzed during the study period. The mean age of the subjects was 11.42 ± 1.2  years, with a range of 7-18 years. The male: female ratio was 4:3. The right eye was involved in 5 (71.42%) patients, and the left eye was involved in 2 (28.57%) patients. All subjects were students. The most common risk factors were Mud injury in 3 patients, stick injury in 2 patients, and no trauma history in 2 patients. The average time taken from the onset of symptoms to the presentation was nine days. There was a presentation lag of <5 days in 2 (28.57 %) patients, 6-14 days in 4 (57.14 %) patients and >14 days in 1 (14.28 %) patients. Visual acuity at presentation ranged from 20/20 to PL+ [Table 1a]. Two subjects had visual acuity in the range of 20/20-20/200, 4 had 20/240-20/1200, and 1 had HM⁺  to PL+. Based on severity grading of ulcers, a total of 2 (28.57%) were mild ulcers, 3 (43.85%) were moderate, and 2 (28.57 %) fell into the severe category. The mean size of the ulcer was 32.04 ± 1.2 mm2 with a range of 4‑81 mm2. The clinical features were patchy subepithelial dot‑like infiltrates in 4 (57.14%) patients, tentacular projection in 4 (57.14 %), stromal infiltrate with feathery margins in 3 (42.85 %), subtotal infiltrate with peripheral furrowing in 4 (57.14%), thick endothelial plaque in 3 (26.6%), and total corneal melt in 2 (28.57 %) patients. Hypopyon and anterior chamber exudates were present in 3 (42.85%) patients [Table 1b] [Fig. 2a-d]. Healing margins were present in 3 (23.3%) out of 7 patients. The smear examination revealed slender hyaline hyphae of all patients on 10% KOH wet mount [Fig. 3a]. The hyphae are studded with numerous vesicles. The culture results after five days showed a flat, feathery, colorless colony of P. insidiosum grow at 37°C on 5% sheep blood agar [Fig. 3b, c]. All seven patients were positive for Pythium in their first corneal scraping, 3 (42.85%) patients tested positive on repeat scraping, and 4 (17.8%) patients again tested positive when the corneal button removed for keratoplasty turned positive for Pythium. Additionally, Pythium identification was also confirmed by Zoospore formation on incubated carnation leaf [Fig. 3d]. Before culture results were available, 5 (71.42 %) patients were treated with topical 5% Natamycin suspension hourly alone, 2 (50%) were treated with topical 5% Natamycin and 1% Voriconazole hourly eye drops. After culture results, all seven patients were treated with topical 0.2% Linezolid and in 5  (71.42 %) patients were treated with topical 0.2% Linezolid and 1% Azithromycin eye drops combination [Table 2a, 2b].

A total of 3 (42.85 %) patients healed with medical treatment, 4 (57.14%) underwent TPK. The graft reinfection was seen in 2 (28.57%), and both patients underwent repeat TPK [Fig. 4a-d]. The mean time from presentation to TPK was seven days. The time for recurrence after TPK varied from 0 to 23 days with a means of 14.3 days. Adjunctive measures like cyanoacrylate glue for perforation in 2 patients eventually improved with medical management. The average time of occurrence of perforation was ten days after the initial presentation. The most common complication was choroidal detachment in 2 (28.57%) patients followed by graft reinfection in 1(14.28%) patients, and none of the patients had endophthalmitis or underwent evisceration—[AQ1 Table 3].

Among the medically healed and TPK group, the average time taken for the presentation was 3.4 days in the former and 12.16 days in the latter. The final visual acuity was 20/20‑ 20/200 in 3 (42.85%) patients, 20/240‑20/1200 in 3 (42.85 %) patients, and hand movement to a positive perception of light in 1 patient a.

Discussion

Pythium keratitis is a devastating ocular entity that closely mimics fungal keratitis. P. insidiosum is an oomycete that morphologically exhibits features of branching, sparsely septate or aseptate filaments, and causes severe vision-threatening keratitis. Recently there have been numerous ocular and systemic reports of Pythium from all over the world. In this case series, we have described clinicopathological and microbiological details of pediatric Pythium cases, which as per the detailed literature review, is the first clinical case series of pediatric Pythium cases.

Our first case was a nine-year-old boy who had a presenting visual acuity of 20/40 with a two-third depth 4×3 mm creamy white infiltrate in the right eye. The culture report was negative; hence the patient was managed with antifungals initially. The child underwent TPK 45 days later, post which button culture was positive. He developed a graft infection 15 days later, for which he was planned for repeat TPK.

The second case was a 14-year-old boy who developed Pythium infection after having a bath in pond water in the left eye. Presenting VA was 20/1200, two-third depth 5×5 mm stromal infiltrate with tentacles. Five days culture report was positive for Pythium. The child was managed conservatively with antibacterials and had a final visual acuity of 20/40 after one month.

The third case was an 11-year-old boy who had a presenting visual acuity of HM+, 6X5 mm feathery infiltrate, 2/3 depth in the right eye. There was no history of trauma, and the child was culture positive for Pythium. The child was managed conservatively for one month with antibacterials. He developed a leucomatous scar for which he was planned for PKP.

The fourth case was a 14-year-old girl with mud injury in the left eye, presenting visual acuity was 20/1200, 5×5 mm full-thickness corneal infiltrate with a history of injury since five days. She was culture positive for Pythium, for which she was managed with antibacterials for two months. She had excellent visual recovery with a VA of 20/30 on the last visit.

The fifth case was a nine-year-old boy who had a stick injury in the right eye post which he developed a 5×3 mm anterior stromal infiltrate with hyphated edges. He was culture positive for PK. He underwent TPK 1 month later; after three months, he was under PKP +IOL. On follow up at one year, he had a failed graft with corneal opacity with final visual acuity of HM⁺

The sixth case was a nine-year-old girl who had developed a 5X5 mm peripheral stromal infiltrate with tentacular projection post stick injury in RE. She was culture positive for Pythium, managed conservatively with antibacterials and glue, and BCL for stromal melt. She underwent TPK for descemetocele. She had a leucomatous opacity two months of follow-up and was planned for PKP.

The last case was a 13-year girl who developed a 6×6 mm full-thickness cheesy infiltrate and landed with perforation after six days in the right eye. The presenting visual acuity was 20/600. She was culture positive for Pythium and underwent TPK 1 week later.

Badenoch et al. ^[7] reported a case of Pythium in an Australian child after swimming in a pool. The conservative management with PHMB and Voriconazole was an unsuccessful post in which he underwent TPK. We treated our patient with antibacterials as per the in vitro susceptibility evidence shown by  Bagga et al. Three of our patients healed with medical management, thus proving the efficacy of antibacterials. Moreover, the majority of the previous reports list TPK as the treatment of choice for this devastating entity. Rapidly progressive infiltrate, early, or impending perforation, AC exudates and infiltrate involving limbus should undergo early TPK. Four of our patients also underwent TPK to salvage the eye. But owing to the small sample size, it is difficult to pinpoint treatment with conclusive evidence. The strengths of our study were successful management of 2 patients with good visual acuity, three healed with medical treatment, early and prompt intervention. There was no case of endophthalmitis, evisceration, or Phthisis bulbi. The limitations were small sample size, retrospective analysis, none of the patients underwent PCR, and non-availability of confocal microscopy.  There are limited reports of pediatric Pythium keratitis in the available literature. A prospective study with a larger sample size would help us to arrive at better conclusions. Further large-scale randomized clinical trials are needed to exactly pinpoint more appropriate and definitive medical therapy.

Conclusion

Pediatric Pythium keratitis is an entity less reported to date. It closely mimics fungal keratitis and needs early and prompt intervention in the form of antibacterial 0.2% Linezolid or 1 % Azithromycin to salvage the eye and prevent vision-threatening sequelae in the form of corneal opacity, amblyopia, endophthalmitis, or Phthisis bulbi. TPK remains the mainstay of treatment in aggressive and non-resolving cases. Besides this, cyanoacrylate glue can be a potential treatment modality to salvage vision in cases with early stromal melt.

All ophthalmologists should be aware of this vision-threatening keratitis as a differential in the pediatric age group as treatment is poles apart compared to fungal keratitis.

References

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