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ORIGINAL ARTICLE
Year : 2007  |  Volume : 55  |  Issue : 1  |  Page : 27-31

A pilot study on the infiltrating cells and cytokine levels in the tear of fungal keratitis patients


1 Aravind Medical Research Foundation, Aravind Eye Care System, Madurai, India
2 Cornea Clinic,Aravind Eye Care System, Madurai, India
3 Department of Microbiology, Aravind Eye Care System, Madurai, India
4 Department of Biostatistics, Lion's Aravind Institute of Community Ophthalmology, Madurai, India

Date of Submission26-Apr-2005
Date of Acceptance14-Jun-2006

Correspondence Address:
Veerappan Muthukkaruppan
Aravind Medical Research Foundation, No. 1, Anna Nagar, Madurai - 625 020
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0301-4738.29491

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  Abstract 

Aim: To determine the cellular profile and cytokine levels in the tear fluid of fungal keratitis patients.
Materials and Methods: Tear samples were collected from six fungal keratitis patients (Group I) from active stages of the disease up to resolution. Tears collected from the following served as controls: uninfected fellow eye (Group II A) of Group I, patients undergoing cataract surgery (Group II B) and acute conjunctivitis (Group II C). The cellular profile was evaluated. Interleukines (IL-6, IL-8 and IL-1β) were estimated using sandwich enzyme immunoassay. Statistical analysis was carried out using nonparametric two-sample median test.
Results: Polymorphonuclear leukocytes (PMN) were the predominant infiltrating cells in Group I. During the initial stages of fungal infection, levels of IL-6 and IL-8 in the tear samples were found to be significantly increased when compared with Group II A ( P = 0.019 for IL-6, P < 0.001 for IL-8). This was also true for IL -8 ( P = 0.008) levels in Group I and Group II B). While IL-6 levels decreased significantly towards healing, IL-8 remained slightly elevated even after healing. These cytokines were at the base level in Group II A. Lymphocytes and PMN were present in equal proportions in Group II C, which showed elevated levels of cytokines but not to the extent of Group I.
Conclusion: This horizontal study indicates that understanding the nature of the inflammatory response in the tears of fungal keratitis patients is of considerable interest and warrants further investigations.

Keywords: Cytokines, fungal keratitis, infiltrating cells, tear.


How to cite this article:
Vasanthi M, Prajna NV, Lalitha P, Mahadevan K, Muthukkaruppan V. A pilot study on the infiltrating cells and cytokine levels in the tear of fungal keratitis patients. Indian J Ophthalmol 2007;55:27-31

How to cite this URL:
Vasanthi M, Prajna NV, Lalitha P, Mahadevan K, Muthukkaruppan V. A pilot study on the infiltrating cells and cytokine levels in the tear of fungal keratitis patients. Indian J Ophthalmol [serial online] 2007 [cited 2022 May 18];55:27-31. Available from: https://www.ijo.in/text.asp?2007/55/1/27/29491

Percentage of total infiltrating cells in tear of infected eye of fungal keratitis and conjunctivitis patients

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Percentage of total infiltrating cells in tear of infected eye of fungal keratitis and conjunctivitis patients

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Clinical and microbiological profile of fungal keratitis patients

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Clinical and microbiological profile of fungal keratitis patients

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Corneal infection is a major public health problem worldwide. It is further compounded due to increased incidence and severity of presentation in the developing countries and has been recognized as a silent epidemic.[1] Although the epidemiology, diagnostic methods, risk factors and treatment[2] of fungal keratitis have been described, information on the nature of inflammatory response associated with fungal keratitis is very limited.[3]

The inflammatory cytokines associated with bacterial and viral keratitis have been described.[4] Studies on the herpes simplex keratitis using animal models have shown that the predominant cytokines produced in the cornea are Interleukines (IL) -1, IL-6, IL-8, IL-10, IL-12 and interferon-g (INF).[5],[6] IL-1β has been shown to be the principal inflammatory mediator regulating the expression of IL-6 and IL-8 during bacterial infection of the corneal epithelial cell.[7] IL-1β and IL-6 levels were found to be high in corneas with distinct inflammatory signs in conditions of ulceration and keratitis.[8] These evidences suggest that cytokines are strongly involved in corneal inflammation. However, the exact role of cytokines in fungal keratitis remains largely unexplored. Although animal models have been developed to study the pathogenic mechanisms of fungal keratitis,[9],[10] no study is available on humans that describes the cytokine response in the tears of fungal keratitis patients.

To understand the immunopathogenesis of fungal keratitis, it is necessary to follow the sequence of events from the initial stages of infection. However, at this stage of the disorder, it may be too invasive to obtain intraocular specimens like aqueous humor. Therefore, we have proposed to make use of the tear fluid from fungal keratitis patients for monitoring inflammatory response, since tear collection is not an invasive procedure,[11] causing minimal discomfort to the patients and the tear film is an important component of the lacrimal functional unit.[12] The aim of the study was to demonstrate the usefulness of tear samples in the understanding the cytokine response in the early stages of fungal keratitis.


  Materials and Methods Top


The patients for this study were recruited from the cornea service of Aravind Eye Hospital, Madurai, India with the approval of Institutional Review Board. Each patient with keratitis had a clinical examination using a slit-lamp biomicroscope to measure size and depth of ulceration following a detailed clinical and demographic history. The scraping of the corneal ulcer was then performed using a Kimura spatula. The initial scrapings were subjected to 10% potassium hydroxide mount to identify fungus and to Gram stain evaluation to identify bacteria. Patients with smear-positive fungal ulcers of 2-35 mm 2sub area and of less than 10 days duration were selected.

After obtaining the informed consent, the tear samples were collected from the infected eye of six fungal keratitis patients (Group I) and from their uninfected fellow eye (Group II A). The patients were then instructed to use 5% natamycin eye drops on an hourly basis between 7 am and 9 pm and 1% atropine sulphate ointment was applied at night. They were examined for the size and depth of the infiltrate at weekly intervals till the healing of the ulcer which was defined as completely healed epithelial defect with no stain on flourescein application and resolution of the stromal infiltration. The patients were scheduled to be seen at weekly intervals for four weeks. The tear samples were also collected during the follow-up visits as well as from five patients undergoing cataract surgery (Group II B) and five acute conjunctivitis patients (Group II C) after obtaining informed consent. Routine cultures from conjunctivitis samples were not performed and hence the etiology of the conjunctivitis could not be determined. The samples were collected in the acute phase (within two to three days), prior to the usage of antibiotics. Serial samples were not collected from conjunctivitis patients because of the rapid resolution of the disease.

The tear fluid (15-25-L) was collected from the lateral canthus using a capillary tube,[13] in two-three minutes interval. Precautions were taken to prevent blinking of the eye by manually holding the eyelid. Each sample was transferred into 0.5 mL sterile microfuge tube and centrifuged for 10 min at 2,000 revolutions per minute (rpm) to separate the cells from the tear fluid. Supernatants were stored at -70 C until assaying for cytokine and protein levels. Cell pellet was resuspended in 200 L of phosphate buffered saline and deposited on to glass slides (10,000 to 20,000 cells per slide) using Shandon cytospin 3 by centrifuging at 400 rpm for 4 min (Thermo Shandon III).[14] After air-drying, cells were stained with Giemsa. The polymorphonuclear leukocytes (PMN), eosinophils, basophils, lymphocytes and monocytes were counted. Total protein concentration was determined in all tear samples by the method of Bradford,[15] using bovine serum albumin as standard.

Two L of tear sample was diluted with enzyme linked immunosorbent assay (ELISA) buffer (supplied by the manufacturer, BD Biosciences, Pharmingen, Sandiego CA) to a final volume of 200 L.[16] One hundred L aliquots were transferred to wells of a microtiter plate and ELISA performed according to the instructions of the manufacturer. The samples were analyzed in duplicates. Absorbance was read at 450 nm within 30 min of stopping the reaction with a reference background at 570 nm. A standard curve was constructed using different concentrations of recombinant human cytokines, which also served as positive controls in each assay. The sensitivity of the assays was determined to be 15 pg/ mL for IL-6, 4.5 pg/mL for IL-8 and 7.8 pg/mL for IL-1β .

Data were reported as medians with minimum and maximum levels obtained for a group. The experimental groups were compared using the nonparametric two-sample median test. Values during successive visits were compared using repeated measures analysis. Differences were accepted as significant at P values 0.05.


  Results Top


The mean age of the six fungal keratitis patients who participated in the study was 46 years (SD 3.0) and all of them were males. Detailed clinical profiles of these patients are given in [Table - 1].

A predominant infiltration of PMN along with low percentage of lymphocytes and monocytes was observed in the tear samples collected from the infected eye of fungal keratitis patients (Group I) [Figure - 1]A during the initial stages of the disease. The percentage of these infiltrating cells has been depicted in [Table - 2]. No significant difference was observed in the levels of these cells during the course of the disease. However at the fourth follow-up, inflammatory cells were not observed in the tear samples [Table - 2]. They were absent in tears collected from the uninfected eye of fungal keratitis patients during all their visits (Group II A) and cataract controls (Group II B). In patients with conjunctivitis (Group II C), PMN and lymphocyte were present in equal proportions [Figure - 1]B and [Table - 2]. This difference in the pattern of infiltrating cells between fungal keratitis and conjunctivitis patients were found to be statistically significant ( P = 0.008 for PMN, P < 0.001 for lymphocytes and P = 0.04 for monocytes).

No difference was observed in the total protein concentration of tear samples among all the groups studied and during the successive visits [Figure - 2]. However, the cytokine profile was found to be different between the infected and uninfected eye of fungal keratitis patients [Figure - 3][Figure - 4]. IL-8 levels were significantly higher in Group I than in Group II A ( P < 0.001) and Group II B ( P = 0.008). The initial higher levels of IL-8 observed in Group I declined during subsequent visits. However, the IL-8 levels in Group I remained higher than that of the fellow eye (Group II A) even after clinical healing [Figure - 3][Figure - 5]. The increase in the levels of IL-6 in the tear samples of Group I was significant during the early stages of infection but normalized during subsequent visits [Figure - 4][Figure - 5] ( P = 0.019). IL-6 and IL-8 levels in Group II C were marginally lower than in Group I [Figure - 5].

One patient (P3, [Figure - 5]) in Group I (who was also culture-positive for unidentified dematiaceous fungi) [Table - 1], showed a very high level of IL-1b (1009 pg/mL) during the initial visit. Interestingly, the same patient showed a higher level of IL-6 and IL-8. All the other patients in Group I had base levels of IL-1β [Figure - 5].


  Discussion Top


Fungal infection as a cause of suppurative keratitis has reached significant proportions in developing countries.[1] Even though fungi and bacteria have been reported to cause suppurative keratitis almost in equal proportions, anecdotal reports estimate that fungal keratitis is replacing bacterial keratitis as an important cause of ocular morbidity. The severity of fungal keratitis can be gauged by the fact that 25% of patients with fungal keratitis had to be eviscerated as reported in a recent study.[17]

Elevated levels of cytokines were detected in the tear fluid collected during viral keratitis,[18] after photorefractive keratectomy[19] and ocular rosacea.[16] Similarly, we have made use of tear samples from fungal keratitis patients to follow the nature of the inflammatory response from the active stages of disease up to resolution. The inflammatory mediators IL-6 and IL-8 were found to be elevated in the acute phase of the disease. Similar results have been reported from viral keratitis patients.[18] There are several evidences to suggest that the lacrimal gland, conjunctiva, cornea and the interconnecting innervations act as the lacrimal functional unit.[12]

Studies on bacterial,[20] viral[21] and fungal[9] keratitis using animal models indicated that PMN were the predominant infiltrating cells in the cornea. The present study extends the above findings to human subjects with fungal keratitis. It is possible that such infiltrating cells may be involved in the clearance of the infecting organisms.[21] However, the prolonged persistence of these cells might lead to ulceration, possibly through other mediators like matrix metalloproteinases.[22] Further, it is required to establish the source and mechanism of selective infiltration of PMN into the tear fluid of fungal keratitis patients.

Normal human reflex tears have been shown to contain 11.6 pg/mL IL-6, 276 pg/mL IL-8 and undetectable levels of IL-1β .[23] Similar levels of IL-6 and IL-1β were observed in the tear samples of Group II A controls, except for IL-8.

IL-6 is a potential mediator of intraocular inflammation and there are several lines of evidences indicating an important role for this multifunctional cytokine in corneal infection and inflammation.[24] As part of the early warning alarm system, IL-6 was shown to appear rapidly after both viral and bacterial infection of the cornea in studies using animal models.[5],[6],[25] Fenton et al .[24] reported that IL-6 enhanced the production of macrophage inflammatory proteins (MIP)-2 and MIP-1 alpha, chemokines, important in the recruitment of neutrophils into the HSV-1 infected cornea. Thus the increase in IL-6 levels in the tear of fungal keratitis patients during the initial stages of the disease suggests that this cytokine may be involved in the recruitment of PMN and their activation.[26]

IL-8, a potent chemotactic factor for neutrophils has been shown to play a key role in cellular infiltration of the cornea during ocular inflammation.[27],[28] Increased levels of IL-8 observed in the fungal keratitis tear fluid could be responsible for the increased levels of PMN. However, the nonsignificant persistence of IL-8 in the tear fluid of Group I even after healing when no inflammatory cells were present could not be explained.

IL-1β is primarily produced by macrophages and monocytes but also by resident corneal epithelial cells.[7],[29] Rudner and his colleagues[30] demonstrated that prolonged elevation of IL-1 expression contributed to corneal destruction by continued stimulation of PMN influx into the cornea. In our study, minimal levels of IL-1β were observed in the tear samples collected from fungal keratitis patients except in one eye affected by dematiaceous fungus [Table - 1].

During the initial stage of the disease, IL-1β level was much higher in this patient than that observed in tear samples collected from other patients. It is quite possible that in this patient the elevated level of IL-1β may be correlated with the severity of the disease and the longer time taken for healing as evidenced by the studies in murine model.[30]

A certain level of conjunctival congestion was present in all cases of fungal keratitis and this may potentially be a cause for the presence of cytokines. To possibly understand the contribution of cytokines due to conjunctival congestion, tears from acute conjunctivitis patients were studied. The levels of IL-6 and IL-8 observed in fungal keratitis patients were only marginally higher than that of conjunctivitis patients. However, a significantly different profile of infiltrating cells in conjunctivitis tear fluid may indicate that the inflammatory response observed in the fungal keratitis tear may not be due to the involvement of the conjunctiva. Further studies on other cytokines in conjunctivitis would reveal the difference more clearly.

In our study we have also used tear samples from patients with cataracts as one of the controls. Though strictly not comparable they may serve as a control for noninflammatory ocular pathologies. Copious tearing due to ocular surface irritation may dilute the cytokine concentration which can be considered as a limitation of the study.

This horizontal study indicates that understanding the nature of the inflammatory response in tears of fungal keratitis patients is of considerable interest. However, this study involved only a small number of patients, followed over a limited period of time and further large-scale studies, involving a larger armamentarium of cytokines would be required to confirm these findings. It is anticipated that further studies in this direction will allow the development of effective therapeutic strategies for fungal keratitis.


  Acknowledgments Top


This study was supported by an unrestricted educational grant from Allergan Inc. Irvine, USA.

 
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    Figures

  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]
 
 
    Tables

  [Table - 1], [Table - 2]


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