|Year : 2022 | Volume
| Issue : 1 | Page : 11-17
A review of the management of pythium keratitis
Ramya Seetam Raju, C V Gopal Raju
Department of Cornea and Anterior Segment, Visakha Eye Hospital, Visakhapatnam, Andhra Pradesh, India
|Date of Submission||28-Mar-2022|
|Date of Decision||16-May-2022|
|Date of Acceptance||17-May-2022|
|Date of Web Publication||05-Oct-2022|
Dr. Ramya Seetam Raju
Visakha Eye Hospital, Visakhapatnam, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Pythium keratitis is one of the chief etiologies of atypical microbial keratitis. It has an extremely grave prognosis. A low index of suspicion, its resemblance to fungal keratitis, and inappropriate diagnosis and management all contribute to the poor outcomes. The absence of adequate literature recommending a standard regimen further worsens the picture. Although Pythium resembles a fungus, it lacks ergosterol. Hence, antifungals are ineffective. While its successful management using antibiotics has been described, some conclude that surgery is the mainstay and recommend techniques to minimize recurrences. This review article aims to bring together the various modalities of diagnosis and therapy of Pythium keratitis. It focuses on the clues to clinical suspicion which would facilitate a prompt diagnosis. It also highlights the importance of high index of suspicion in presumed fungal keratitis with a poor response to antifungals. A search was carried out using PubMed and Google Scholar for articles in English language using the keywords: Pythium insidiosum, Pythium keratitis, management of Pythium keratitis, investigations in Pythium keratitis, Polymerase Chain Reaction in Pythium keratitis, diagnosis of Pythium keratitis, and treatment of Pythium keratitis. Articles were included if they were of high significance for this article. Case reports also were taken into consideration if they conveyed data of importance.
Keywords: Management of Pythium keratitis, oomycete, Pythium insidiosum, Pythium keratitis
|How to cite this article:|
Raju RS, Raju C V. A review of the management of pythium keratitis. J Ophthalmol Clin Res 2022;2:11-7
| Introduction|| |
The organism Pythium is an oomycete causing human, plant, and animal disease. It belongs to the kingdom Stramenophila, family Pythiaceae, and order Pythiales. It is known to occur in tropics, subtropics, and temperate regions. Although it resembles a fungus in morphology, it lacks ergosterol in its cytoplasmic membrane. It has cellulose in its cell walls unlike fungi which possess chitin. Pythium insidiosum is the organism known to cause human infection. Vascular, cutaneous, intestinal, systemic, and ocular forms of human pythiosis have been described.,,,, While the systemic forms occur in patient with preexisting conditions such as thalassemia, aplastic anemia, paroxysmal nocturnal hemoglobinuria, and chronic arterial insufficiency syndrome, the ocular forms occur predominantly in healthy individuals.,>
Pythium keratitis is one of the etiologies of sight-threatening atypical microbial keratitis.,, The prevalence of Pythium keratitis has been estimated to be 5.9% among all the cases that were positive on smear for fungus. It has gained importance over the past decade owing to its particularly poor prognosis and its close resemblance to fungal keratitis which often leads to a misdiagnosis. Researchers have suggested that it is not rare but rather underdiagnosed. It is imperative that we spread more awareness regarding this entity so that it would help a prompt diagnosis and an appropriate intervention. This review aims at bringing together the various diagnostic and treatment methods that are available for this emerging entity at this point in time, so that clinicians would become well versed with it. It also aims to describe the clinical clues to suspecting a diagnosis of Pythium keratitis. To the best of our knowledge, there is no such article that gives such a comprehensive review on how to diagnose and treat Pythium keratitis.
| Methods of Literature Search|| |
An extensive search for articles was carried out using PubMed and Google Scholar, in English language using the keywords: Pythium insidiosum, Pythium keratitis, management of Pythium keratitis, investigations in Pythium keratitis, Polymerase Chain Reaction in Pythium keratitis, diagnosis of Pythium keratitis, and treatment of Pythium keratitis. Articles were included if they were of high significance for this article. Case reports also were taken into consideration if they conveyed data of importance.
| Epidemiology and Risk Factors|| |
Pythium keratitis is predominantly a disease of the tropics and subtropics.,,, Of late, it is being reported in other areas as well. It is common in healthy individuals. Contact lens use is a documented risk factor.,, Exposure to wet environments such as waste water, pool water, and rain water has been reported previously.,, In a retrospective analysis of 46 patients by Agarwal et al., a small number of six patients had injury with vegetative matter. The rest were either white-collared professionals or housewives and had no history of exposure to vegetative matter. A similar observation was made by Hasika et al., in their set of patients where 53.5% of them did not have any exposure to vegetative matter and had nonagricultural occupations. Overall, the risk factors noted were exposure to dust (29%), vegetative matter (12%), dirty water (5%), and insects (5%). In a study by Gurnani et al. from South India, the chief risk factors were prior injury in 24 patients (80%) and exposure to pond water due to bathing in 7 patients (23.3%). The point to be noted here is that unlike in fungal keratitis which is preceded by a trauma with vegetative matter, usually in the agricultural scenario, Pythium keratitis may occur in urban localities without a similar history.
| Clinical Features|| |
Clinically, Pythium keratitis resembles fungal keratitis and is often inappropriately managed as the same.,, Because of the absence of ergosterol in the cell wall, there is a poor response to antifungals. Certain characteristic features of the stromal infiltrates in a case of microbial keratitis could indicate potential Pythium infection. They have been described commonly in literature and should arouse the suspicion of Pythium keratitis. In one of the studies which described 71 cases from a hospital in South India, “tentacle-like infiltrates” were found to be the most common sign in over 50% of the cases. This was followed by “dot-like infiltrates” (21%) and “peripheral furrowing” (12%). Agarwal et al. analyzed 46 patients diagnosed by polymerase chain reaction (PCR) retrospectively and found the “reticular pattern” to be the most common feature among them. However, peripheral guttering as described by other authors was not found. Similarly, in a series of 5 eyes of 4 cases from Thailand, a “reticular pattern” was noted in all the infiltrates. Gurnani et al., in a 30-patient cohort, found subepithelial “dot-like infiltrates” in 7 (23.3%) patients, margins which appeared feathery in 5 (36.6%), furrowing of the peripheral cornea in 11 (16.6%), and tentacle-like projection in 4 (13.3%). Bagga et al. in their retrospective study of 98 cases described “dot-like lesions” (16.3%), “tentacles” (6.1%), “hyphate edges” (5.1%), and “reticular pattern” (1%). Some of these patterns such as a reticular-like pattern with edges seeming feathery, satellite infiltrates, and dot-like lesions were described in various other reports as well.,,,, Radial keratoneuritis also has been reported as a feature in some cases. In end-stage disease, these classical diagnostic signs may not be clearly evident because of the presence of heavy and deep infiltration.,> Sood and Sood found tentacular pattern to be the most common followed by dot-like infiltrates and peripheral furrowing in their analysis of 84 cases. Vishwakarma et al. found dot-like infiltrates and tentacular infiltrates in 44.4% of cases in their retrospective photographic analysis of 18 cases of Pythium keratitis. Based on these studies, the authors suggest that the presence of a reticular pattern, dot-like infiltrates, tentacle-like extensions, or peripheral guttering in cases of microbial keratitis should alert the clinician to the possibility of Pythium infection and adequate steps ought to be taken [Figure 1]. On the contrary, features such as feathery or hyphate margins and endothelial plaques as described in various studies are equivocal as these can suggest fungal keratitis as well. All these were retrospective analyses, and the clinical features were assessed by multiple clinicians. These could have led to certain inconsistencies in the reporting of findings. Studies have yet to prove the sensitivity and specificity of each of the pathognomonic features of this disease.
|Figure 1: (a and b) Corneal infiltrate with tentacle-like extensions (arrows), (c) Dense corneal infiltrate with dot-like lesions superiorly (arrow), (d) Peripheral guttering with central dense infiltrate (arrows) in Pythium Keratitis|
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| Diagnosis|| |
Staining and microscopy
Corneal scraping with direct microscopy and culture is the standard investigation to be performed as in any microbial keratitis. This organism resembles fungi on not only clinically but also microscopically. However, careful observation of the filaments would reveal certain differentiating features. The filaments of Pythium are seen as long, broad, with branches, with few or no septae, and with numerous vesicles inside the filaments.,,,,, Microbiology results with potassium hydroxide (KOH) mount and Gram stain detected hyphae in 77.5% of the patients in a study by Hasika et al. In the above cohort of patients, most cases were erroneously medicated with antifungals as they were mistaken for fungal keratitis. In an analysis of 13 cases of Pythium keratitis by Mittal et al., all of them were diagnosed on examination as fungal keratitis and were reported to have sparsely septate hyphae on KOH mount. Similarly, in a retrospective analysis, KOH mounts revealed hyaline ﬁlaments with few septations. KOH/calcofluor stain and lactophenol cotton blue stain diagnosed poorly septate hyphae which had branches at right angles in P. insidiosum. In yet another study conducted by Sane et al., the above-described typical microscopic features were noted in 95.23% of cases on KOH/calcofluor white staining, whereas Gram staining revealed the same in about 85.71% of them. These show that Pythium can be easily mistaken as fungal keratitis, especially by the novice, because of its filamentous structure, unless there is an eye for it.
A variety of staining procedures have been described, though not used commonly. Mittal et al. described the various histopathological staining methods in their study. They found that Pythium filaments appeared to be ghost-like structures of pale pink color on hematoxylin and eosin (H and E) stain. Their hue was like the stain of the corneal stroma. Krajaejun et al. studied 102 human pythiosis cases in a retrospective manner and found infiltration of eosinophils and giant cells in tissues. Pythium ﬁlaments were particularly clearly visualized on GMS stain. In all samples sent for histopathological examination, P. insidiosum filaments showed extensive positive staining with Gomori methenamine silver and had very meager number of septations, in a study done by Puangsricharern et al. Vishwakarma et al. described 93.8% positivity for GMS stain and 100% positivity for iodine-potassium iodide-sulfuric acid stain. However, PAS stain did not yield good staining. This poor staining on PAS stain was also reported by Badenoch et al. in their case report. Mittal et al. also described a novel, effective, sensitive, and speciﬁc stain using potassium iodide and sulfuric acid (IKI-H2SO4) for its diagnosis which could be used on both scrapings and tissue specimens. The principle underlying it was when cellulose present in Pythium reacts with acids, it forms an intermediary compound which forms a blue compound with potassium iodide. Thus, Pythium filaments would stain blue whereas fungi would stain yellow brown, on the contrary. Although this stain showed great results, further studies would be required to prove it on a large scale. They also concluded that P. insidiosum may not always appear broad and aseptate. It could appear narrow or show septae. P. insidiosum had few branches and sparsely appearing septae with short hyphae and with changing length and diameter. Another staining method using trypan blue was described by Sharma et al., in their recent study which showed aseptate ribbon-like filaments consistent with Pythium keratitis in one case. All these staining methods would further add to the diagnosis whenever there is a suspicion of Pythium. Thus, the authors suggest that the presence of longer, broader ribbon shaped filaments with sparse septae or absent septae or the presence of vesicles should point toward a diagnosis of Pythium as opposed to fungal keratitis in a routine smear examination using Gram stain or KOH mount [Figure 2]. However, this need not be the case in all Pythium infections. On histopathology, the appearance and description of ﬁlaments, occurrence in the posterior part of the corneal stroma, inadequate staining with PAS, and conﬁrmation using a potassium iodide staining can help the pathologist in arriving at the diagnosis.
|Figure 2: (a) Broad, ribbon-shaped hyphae of Pythium on Gram's staining, ×40 magnification (arrow), (b) Vesicles inside the hyphae (Arrows) on Gram's staining, ×100 magnification|
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In a series of PCR-proven Pythium keratitis from 21 eyes, culture on Sabouraud dextrose agar revealed finely radiated colorless to white colonies. On blood agar, colonies appeared to be relatively flat, having edges that were feather like, and looked incompletely submerged and glabrous [Figure 3]. They were either colorless or light brown colonies. The above description was given by Sharma et al. and Kulanthai et al.,> Similarly, colonies showed classical signs like appearing flat topped or like a carpet, having feathery edges, and seeming colorless. These also could not be scraped with ease, and the average time to appear was 4.72 ± 2.19 days in a case series of 18 cases by Vishwakarma et al. Another identical elucidation of colorless appearing growth on blood agar with a flat surface and margins that were filiform was given by Hasika et al. They also concluded that these colonies took, on an average, 3–5 days to appear on the agar plates in the laboratory. Thus, such morphology of a colony should certainly elicit the suspicion of Pythium keratitis.
|Figure 3: Brown, flat, filiform, glabrous colonies on blood agar of Pythium insidiosum|
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Oomycetes reproduce by asexual reproduction with zoospore formation. This has been recommended as a tool for identiﬁcation of Pythium.,> Sharma et al. recommended the routine adoption of this technique for every classical colony on blood or chocolate agar with negligible colonies on Sabouraud dextrose agar. Here, the cultures are incubated in an induction medium with a carnation leaf for 24 h. A typical sporangiophore with rapidly motile zoospores is seen. Although zoospore formation is a regularly occurring feature of P. insidiosum, it can occur in other oomycetes, namely Phytophthora and Lagenidium. Hence, Pythium keratitis can be suspected on the basis of culture, staining procedures, and induction of zoospores but can be confirmed only by DNA sequencing.
Serology has not been of significance since the anti-P. insidiosum antibody in the blood of people with Pythium keratitis usually cannot be detected. Permpalung et al. compared the levels of serum anti-Pythium antibody in globe salvage versus nonglobe salvage (enucleation/evisceration) group in a series of 30 patients. They did not find any difference between the two and concluded that these would not be useful in the monitoring of the disease. According to Krajaejun et al., these assays can be of help in systemic infection but not in Pythium keratitis.
Polymerase chain reaction
Vanittanakom et al. used PCR in the identification of 4 cases using the PCR technique. Nested PCR which targeted the 18S ribosomal RNA had 91.7% sensitivity, 81.8% specificity, and 83% accuracy (95% confidence interval, 74.5–89.1) against both culture and immunoperoxidase staining for Pythium keratitis. These were compared by Kosirukvongs et al. in tissues from 100 patients. Sharma et al. evaluated 264 cases of unidentified fungal infection. 13/264 cases (4.9%) were confirmed to be P. insidiosum using PCR-based DNA sequencing. Hasika et al. reported a study of 71 cases where Pythium was proven by culture and DNA sequencing of ITS region. This targeting of ITS (internal transcribed spacer) region was done for identification in most earlier studies. This takes 3–4 days.
Novel polymerase chain reaction
Kulandai et al. described a novel duplex PCR which targeted both the ITS region and 18S rRNA (ribosomal RNA of P. insidiosum) and concluded that it had 100% specificity from culture and corneal specimens but had 100% sensitivity from culture specimens and only 92.8% sensitivity from corneal specimens. Thus, PCR may be used as an adjunctive tool wherever the facility is available.
Pythium filaments have been described to manifest as hyperreflective branching structures, structures with branches and few septations simulating fungal hyphae, and irregular hyphae with patterns that appear like “X” and “Y” shapes on In vivo confocal microscopy.,, Anutarapongpan et al. analyzed the clinical data of 20 patients (21 eyes) with proven Pythium infection and showed that the confocal features were nonspecific and resembled those of fungal keratitis. IVCM can give a fast picture of visualization of P. insidiosum hyphae but cannot distinguish from fungal keratitis. Thus, confocal microscopy can detect hyphae but cannot confirm the diagnosis. The disadvantages of this modality are that it has limited availability, is highly user dependent, and has a steep learning curve for its interpretation. Furthermore, clinical presentations, like thinned or perforated ulcers, can limit its usage.
| Treatment|| |
Recently, multiple reports of successful management of Pythium keratitis using medical management have been emerging. Ramappa et al. treated one patient successfully with topical linezolid 0.2% and topical preparation containing 1% azithromycin and systemic administration of azithromycin 500 mg/day, orally, thrice a week. Bagga et al. compared antibiotics versus antifungals in a subset of patients their prospective study of 114 patients. They studied the use of topically administered linezolid and both topical and oral administration of azithromycin and concluded that this regimen had a favorable outcome. However, they could not prove statistical significance. Surgical interventions were less in the antibiotic group as against the antifungal group. They also studied the efficacy of tigecycline, mupirocin, and minocycline, in vitro, against P. insidiosum. In yet another recent retrospective series, Bagga et al. elucidated that 55.1% of the cases resolved using medical therapy. They also mentioned poor prognostic factors among those cases that underwent a therapeutic keratoplasty. They were a longer time to presentation, larger size of infiltrate, poorer visual acuity, more posterior involvement, and lesser amount of pinhead-like lesions surrounding the infiltrate. They recommended that for mild-to-moderate cases, antibiotics can be continued for a period of 2 weeks and a decision on surgical management can be taken based on the clinical response. Hasika et al. reported that only three patients responded to medical management with itraconazole 1% eye drops when treated for a prolonged duration. Similarly, in a recent retrospective analysis, Sane et al. proved that over 80% of their cohort of 17 cases which received medical therapy using three-medicine combination of topical linezolid, and azithromycin, and oral linezolid resolved with prolonged therapy. Contrarily, in 26 eyes, only 2 had resolved with topical medication in an analysis by Puangsricharern et al. However, these two cases were treated with multiple drugs including antibiotics, natamycin, and amphotericin B. Maeno et al. described the treatment and healing of a case of Pythium keratitis treated with topical minocycline ointment four times a day, topical chloramphenicol, and oral linezolid 1200 mg/day based on susceptibility testing. Likewise, various other studies have mentioned success of medical management. Gurnani et al. reported that 23.3% of their cases responded to topical linezolid and azithromycin. Prior research showed in vitro susceptibility of P. insidiosum to antibiotics such as tigecycline, macrolides, tetracyclines, and linezolid, used alone or in combination with an antifungal drug.,> Chaterjee et al. described a case wherein the infection in a 7-year-old case was treated with topical and oral azithromycin (1% hourly and 250 mg once a day thrice a week, respectively). This management was undertaken for a period of 4 weeks and the ulcer healed.
Hence, for all mild-to-moderate and superficial ulcers, the authors recommend the triple-drug regimen using topical linezolid and azithromycin and oral azithromycin as advocated by Bagga et al.
Although medical management is being popularized of late, surgery remains the prime treatment modality of Pythium keratitis. There have been multiple case reports and series that have shown that surgery is the only effective therapeutic strategy against this entity.,,,, However, one needs to note that most of this research was undertaken before the suggestion of topical linezolid and azithromycin as the drugs of choice by Bagga et al in 2018. Tanhehco et al. described a case Pythium keratitis associated with contact lens wear that recurred despite two keratoplasties and required enucleation. Krajaejun et al. in their analysis across various tertiary hospitals in Thailand reported that more than 79% of the ocular pythiosis cases required enucleation/evisceration. Thanathanee et al. reported that all 5 eyes in their case series underwent therapeutic keratoplasty in spite of topical antifungal medication and vaccination. Hasika et al. stated that 67.6% underwent keratoplasty in their large retrospective study. However, in their cohort, the cases were treated initially with antifungal agents, and this could have led to failed medical management. Similarly, Gurnani et al. stated that over 60% of their cases had to undergo surgery. In their cohort, 83.35% of the cases were moderate to severe. This could have been the reason for higher rates of surgery. Bagga et al. compared topical antifungal to antibiotic regimen in a subset of patients in their study. They found that the rate of TPK was higher in the group treated with antifungals (TPK – 11/13, 84.6%) when compared to the group on antibacterials (TPK – 11/17, 64.7%), but this difference was not statistically significant (P = 0.22). In another retrospective analysis in which they reviewed the outcomes of 69 eyes of 69 cases, 55.1% healed with medical management with topical linezolid 0.2%, topical 1% azithromycin, and oral azithromycin and 44.9% underwent a therapeutic keratoplasty. This was much lesser when compared to their previous report as stated above. They also stated that there was no recurrence of infection in these cases. P. insidiosum keratitis resolved in 38 of 69 eyes (55.1%) with medical therapy. 15/18 cases underwent keratoplasty in another retrospective analysis by Vishwakarma et al. One patient required only medical treatment. Puangsricharern et al. retrospectively analyzed the records of 26 eyes with Pythium keratitis. They had found out that the risk of requiring a removal of the globe was directly related to age, a delay in the beginning of topical medication or severe disease, and fulminant hyphal infiltration. Furthermore, all patients in another series by Agarwal et al. did not get better with or had deteriorated with the triple regimen. All cases eventually required surgery. Recurrence occurred in 28/54 TPKs (51.8%) that were done in 42 eyes. The authors suggested that recommended treatment for Pythium keratitis was surgical by means of a TPK and, in worse cases, evisceration. They found that medical management and adjunctive medical therapy after surgery did not show any benefit for minimizing recurrence. They suggested that in TPK with a clear margin of 1 mm, when clinically clear cornea is left behind in addition, cryotherapy may not be essential. However, when the limbus is involved, the risk of recurrence is greater. Adjunctive procedures such as application of cryotherapy and absolute alcohol during surgery seemed to be beneficial additionally decreasing recurrence and could be included as routine care.,> Rathi et al. described one patient with Pythium keratitis leading to panophthalmitis and eventually death due to fatal cavernous sinus thrombosis. Agarwal et al. studied the role of ethanol in Pythium keratitis. In their report, a patient with recurrent infection after a keratoplasty responded to the locally applied absolute ethanol, and the other case, where scraping showed Pythium appearing in a day, did not grow the organism from the cornea treated with alcohol before excising it during surgery. Based on the above literature, the authors recommend that for small-to-medium sized ulcers that are superficial, it would be ideal to initiate medical therapy with topically applied linezolid 0.2% preparation and topically applied azithromycin 1% drops and orally administered azithromycin. In ulcers unresponsive to medical treatment, large ulcers, deep ulcers, those which threaten to involve the limbus, ulcers with impending perforation, and ulcers with a long duration of symptoms, it would be wise to for an immediate, large therapeutic keratoplasty wherever possible, it would be wise to go for an immediate, large therapeutic keratoplasty wherever possible. In addition, application of absolute alcohol to the margins or cryotherapy to the adjacent sclera would reduce the possibility of recurrences and hence the risk of a re-surgery or an eventual evisceration.
The role of Pythium vaccination has been studied previously and is controversial. Thanathanee et al. suggested that Pythium vaccination may be used along with medical therapy and radical surgery. Permpalung et al. concluded that the role of vaccination was inconclusive for both ocular and systemic pythiosis.
Reinprayoon et al. narrated a case of keratitis mimicking pythiosis, in a 43-year-old woman who was initially diagnosed and treated as fungal keratitis. Direct microscopy showed hyphal filaments with no septae. Biopsy revealed showed longitudinal and transverse filaments with no septae when stained with hematoxylin and eosin and GMS. Rapid growth of translucent submerged colonies was found in Sabouraud agar. Based on these, Pythium was suspected. PCR with DNA sequencing revealed the internal transcribed spacer regions similar to those of Lagenidium species. Thus, this organism can cause an infection similar to that caused by Pythium and can be of the differential diagnosis in such clinical scenarios.
| Conclusion|| |
This review draws the attention of the ophthalmologist readers to the emerging entity Pythium keratitis. It enables us to suspect it and to go about its management. It makes us aware that this is more common in white collar professionals as opposed to the agriculturists as is the case in fungal keratitis. There is a need to be well versed with this entity as it is often erroneously diagnosed as fungal infection because of identical features clinically and is inappropriately managed, often leading to blindness. While there are emerging reports of successful medical management of the disease, the prognosis still seems bleak with most literature recommending the use of therapeutic keratoplasty in Pythium keratitis. A high index of suspicion, its distinction from fungal keratitis, when unresponding to antifungal medication, and an early initiation of appropriate medical therapy or a timely surgical intervention could prevent loss of vision and an eye and the untoward effects on a patient's quality of life. We recommend that for mild-to-moderate cases, the triple regimen using topical linezolid and azithromycin and oral azithromycin be followed, but in more severe cases or where there is failure to respond to medical management, an early therapeutic keratoplasty should be the interventional modality of choice preferably with the use of adjunctive measures such as cryotherapy or absolute alcohol to minimize recurrences. At this juncture, there is no well-designed randomized trial that proves the benefit of one particular regimen. There is a necessity for more research so that we would be at a better position to manage it, 1 day.
The authors would like to acknowledge and thank profusely Dr. Venkatesh Prajna. N., for his constant support and his permission for images for this article. We thank Department of Cornea and Department of Microbiology, Aravind Eye Hospital, Madurai for their help in procurement of images. We also acknowledge Dr Hasika Ravula for her kind assistance in acquiring the images.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]