1. Introduction {#sec1}
===============

Endogenous endophthalmitis is an ophthalmic emergency that can have severe sight-threatening complications and generally accounts for 2%--18.5% of all reported endophthalmitis cases \[[@B1]--[@B6]\]. Endogenous fungal endophthalmitis is a serious condition with potentially devastating visual outcomes. This condition is usually associated with one or more predisposing systemic conditions, such as diabetes mellitus, liver disease, renal failure, cancer, indwelling catheters, systemic surgery, organ transplantation, acquired immune deficiency syndrome (AIDS), intravenous drug use, and immunosuppressive therapy \[[@B7]--[@B10]\]. Occasionally, endogenous fungal endophthalmitis may occur in healthy, immunocompetent patients without any risk factors \[[@B11]--[@B13]\].

Fungal infections of endogenous origin can be acquired after systemic infections caused by pathogenic fungi or opportunistic fungi \[[@B14]\]. Many fungi that can cause endogenous fungal endophthalmitis have been reported. Most commonly, endogenous fungal endophthalmitis is associated with *Candida* or *Aspergillus* species in the western countries \[[@B7]--[@B9]\] and northern China \[[@B10]\]. However, our previous study reported that the mold was predominant in southern China \[[@B6]\]. The treatments for endogenous fungal endophthalmitis usually include intravitreal antifungal injections, systemic antifungals, and vitrectomy.

The current study aims to report a consecutive series of patients with culture-proven endogenous fungal endophthalmitis treated at a single medical center with specific fungal isolates, treatment strategies, and visual acuity (VA) outcomes.

2. Materials and Methods {#sec2}
========================

Microbiological and clinical records were reviewed for all patients undergoing treatment at the Zhongshan Ophthalmic Center, Guangzhou, China, from January 1, 2006, to March 31, 2016, for intraocular culture-proven endogenous fungal endophthalmitis (*n* = 29). This study was performed in compliance with the principles of the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Zhongshan Ophthalmic Center, Sun Yat-sen University.

Intraocular fluid samples were taken from all patients with suspected or diagnosed endogenous fungal endophthalmitis. Fluids from the anterior chamber were aspirated through the limbus using a needle with a 1 mL syringe. Vitreous specimens were obtained through the pars plana prior to intraocular antibiotic injection or vitrectomy. The collected samples were then inoculated onto sheep blood agar and potato glucose agar to be cultured up to 1 week. All the samples were examined daily for detection of fungal growth. Fungi isolates were identified by trained technicians according to the macroscopic characteristics (color and texture) of the colonies. After the list of possible causative organisms had been obtained, the corresponding medical records of patients with positive culture results for fungi were reviewed, and the clinical presentation, treatment strategy, and outcomes were followed and recorded. Treatment and management decisions were made by the ophthalmologist in charge without a predefined study protocol.

The patients were divided into two groups according to whether the final VA reached a favorable visual outcome (at least enough VA to permit finger counting) or not. An independent sample *t*-test, and a chi-square test were used to analyze the difference between the two groups. Fisher\'s exact test was used if any frequency in the fourfold table was less than five. The level of significance was defined as a *P* value of less than 0.05. All the statistical analyses were performed with SPSS software version 16.0.

3. Results {#sec3}
==========

A total of 32 eyes from 29 patients with culture-proven endogenous fungal endophthalmitis were identified in a 10-year period. The average baseline age of these patients was 33.9 ± 16.2 years (range from 1 to 60 years). Thirteen patients (44.8%) were male and 16 (55.2%) were female. The average length of the follow-up period was 3.8 ± 5.2 months (range from 1 week to 2 years). A summary of the clinical characteristics of these patients is provided in [Table 1](#tab1){ref-type="table"}. Bilateral involvement was found in 3 cases (10.3%), and unilateral involvement was found in 26 cases (89.7%).

Eleven patients (37.9%) had a history of surgery in the past 12 months, among which 5 patients (17.2%) received percutaneous nephrolithotomy (PNL) and 6 patients (20.7%) underwent cesarean section, ankle fracture surgery, hernioplasty, childbirth, induced abortion, and hysterectomy. In addition, ten patients (34.5%) had no identifiable infection focus responsible for endogenous endophthalmitis.

All 3 cases with bilateral disease were identified to have positive intraocular culture results in at least one eye. The presence of mold (15 patients, 51.7%) was slightly higher than that of yeasts (14 patients, 48.3%). The 15 mold cultures included *Aspergillus* (*n* = 7), *Fusarium* (*n* = 2), *Mucor* (*n* = 2), *Helminthosporium* (*n* = 1), and *Penicillium* (*n* = 1); 2 molds could not be identified. Among the 14 yeast cultures, only 3 were identified as *Candida albicans.*

Among all 29 patients (32 eyes), 26 patients (28 eyes) underwent pars plana vitrectomy (PPV), and 19 patients (21 eyes) were tamponaded with silicone oil subsequently. Three patients could not receive PPV due to severe opacity and edema of the cornea. One patient with bilateral endophthalmitis did not receive surgery in the better eye because the VA had improved after treatment with antifungal medicine.

As shown in [Table 2](#tab2){ref-type="table"}, 30 eyes (27 patients) with initial and final VAs were available for the analysis of possible prognostic factors for the final visual outcome. Two subjects were excluded because they were too young to conduct a VA test. Patients with different levels of initial VA and species of fungi showed significant differences between poor (worse than FC) and relatively good prognosis (FC and better) (*P* = 0.002 and *P* = 0.020, resp.). Whether the patient underwent surgical treatment and whether the tamponading agent (silicone oil) was used did not affect the final visual outcome (*P* = 0.563 and *P* = 0.225, resp.).

4. Discussion {#sec4}
=============

Endogenous fungal endophthalmitis is a rare intraocular infection resulting from the systemic hematogenous spread of the organism to the eye. In the present study, the medical records and visual outcome of 29 subjects with endogenous endophthalmitis were reviewed. We revealed that a majority of patients had a positive history of surgery, and nearly 1/3 of the cases of endogenous endophthalmitis occurred in otherwise apparently healthy immunocompetent individuals without any infection focus elsewhere in the body. The presence of mold was slightly higher than that of yeasts. The risk factors affecting the visual outcome of endogenous fungal endophthalmitis included initial VA worse than FC and type of fungus (mold).

In previous studies, systemic diseases including diabetes mellitus and renal disease were the main risk factors of endogenous endophthalmitis \[[@B8], [@B15], [@B16]\]; however, in our case series, the major predisposing risk factor was recent history of surgery. There were several reasons that may account for this phenomenon. First, the study site is an ophthalmology-specialized hospital; most patients with severe systemic diseases were more likely to visit general hospitals looking for care from both ophthalmologists and other physicians. Second, the abuse of antibiotics in China \[[@B17]\], especially for postoperative patients, may increase the risk of endogenous fungal infection.

Though in most of the cases of endogenous endophthalmitis one or more risk factors are identified, a few cases among otherwise healthy and immunocompetent individuals have also been reported \[[@B11]--[@B13]\]. The etiology and pathogenesis are not fully identified. The visual outcome of such patients is usually poor \[[@B13]\]. The findings in the 10 cases of this study were in agreement with the previous reports. The major organism accounting for these cases was *Aspergillus*. The mononuclear phagocyte defenses are usually the first line of defense against *Aspergillus* infections, followed by the neutrophils \[[@B18], [@B19]\]. Some deficiency may exist in the mononuclear phagocytes and neutrophils defenses of these patients. However, we did not have records of immunity tests in these patients. A detailed examination of immune function should be conducted for such cases to explore the underlying causes in future work.

Most commonly, yeast was the main cause of endogenous fungal endophthalmitis in western countries \[[@B7]--[@B9], [@B20], [@B21]\], and most of them were due to *Candida*. A study in northern China had similar results \[[@B10]\]. However, in our study, the prevalence of mold was more than that of yeast species. Additionally, a lower percentage of *Candida* was found in our endogenous fungal endophthalmitis cases. Environmental and geographic factors may have contributed to this discrepancy because the spectrum and virulence of causative organisms vary depending on the region and the environment. On the other hand, the patients already had severe endophthalmitis, which is more likely to be associated with mold infection, before they were referred to our institution.

PPV was an important management strategy for patients with endophthalmitis and a surgical method to obtain vitreous samples for diagnosis. An early diagnosis can be made, and interventions including vitrectomy can be carried out to improve the visual outcome \[[@B22]\]. Vitrectomy can reduce the burden of microorganisms and inflammatory mediators present in the vitreous cavity. Lee et al. reported that early vitrectomy in patients with initially good visual presentation was significantly related to a successful visual outcome \[[@B23]\]. In this case series study, 70.8% (17/24) patients who had improved VA outcome underwent simple or combined PPV. This again emphasizes the role of vitrectomy in treating endophthalmitis, even for cases caused by endogenous fungal growth. However, not all patients who underwent PPV showed improved VA after surgery, and chi-square analysis indicated that PPV did not influence the visual outcome significantly. A possible reason may be the late presentation of these patients, implying that early interventions were not made. The small sample size can also produce misleading results. Though PPV may not improve VA in an obvious manner, it is necessary for cases with mass vitreous opacity and rapid progression \[[@B24]\].

Previous studies had found that good initial visual acuity greater than FC was related to a good visual outcome \[[@B23], [@B25]\]. This is consistent with our analysis, which suggests that good initial VA is an important predictor for visual outcome. Mold endophthalmitis, however, showed worse visual prognosis than yeast cases. This finding agrees with other studies \[[@B10], [@B20]\], and the possible mechanism may be the invasive patterns of *Aspergillus* infection in the retina and choroid \[[@B26]\]. These findings indicate that earlier and more aggressive interventions should be made for those with mold-induced endophthalmitis to maintain visual acuity as much as possible.

The limitations of the study should be mentioned. This study was retrospectively designed and lacked universal criteria for diagnosis and treatments. The youngest subjects in our series were 1 and 2 years old, limiting the full assessment of visual outcome. Detailed categories of the fungus species were also absent in some cases. Finally, the small sample size may produce bias in the analysis and conclusion.

In conclusion, we assessed the clinical features and visual outcome of 29 patients with culture-proven endogenous fungal endophthalmitis. The major predisposing risk factor was recent history of surgery. The main organism in patients without identifiable systemic risk factors was *Aspergillus*. The presence of mold was slightly higher than that of yeasts. The factors affecting visual outcome of endogenous fungal endophthalmitis included initial VA and species of fungus. Whether PPV with silicone oil tamponade was used or not may not influence the visual outcome in severe cases.

This work was supported in part by funds from the National Natural Science Foundation of China (81400381 and 81570839).

Conflicts of Interest
=====================

The authors report no conflicts of interest.

###### 

Clinical summary of patients with endogenous fungal endophthalmitis.

  -------------------------------------------------------------------------------------------------------------------------------------------------
  Patients   Age   Gender   Eye   Fungus                    Predisposing risk factors   Initial vision   Vitrectomy   Silicone oil   Final vision
  ---------- ----- -------- ----- ------------------------- --------------------------- ---------------- ------------ -------------- --------------
  1          57    M        OD    *Aspergillus terreus*     IT, LD                      LP               Yes          Yes            FC

  2          2     F        OS    Mold                      None                        ---              Yes          Yes            ---

  3          43    F        OS    *Mucor*                   PNL                         FC               Yes          No             20/63

  4          41    F        OD    Yeast                     PNL                         FC               Yes          Yes            20/50

  5          60    M        OD    Yeast                     Cholecystitis\              FC               Yes          No             20/800
                                                            Hernioplasty                                                             

  6          35    F        OD    Yeast                     Cervicitis                  FC               Yes          No             20/800

  7          30    F        OS    Yeast                     Hysterectomy                HM               Yes          Yes            HM

  8          28    M        OU    Yeast                     AFS                         20/50\           No\          No\            20/40\
                                                                                        20/400           Yes          No             20/25

  9          10    F        OS    *Helminthosporium*        None                        HM               Yes          Yes            FC

  10         55    M        OS    *Aspergillus nidulans*    TB                          HM               No           No             HM

  11         30    F        OS    *Aspergillus nidulans*    None                        0.1              Yes          No             NLP

  12         43    F        OD    Yeast fungus              None                        HM               Yes          Yes            LP

  13         53    M        OD    *Candida albicans*        PNL                         FC               Yes          Yes            FC

  14         13    M        OD    *Fusarium*                None                        LP               No           No             NLP

  15         6     M        OD    *Aspergillus*             None                        20/200           Yes          Yes            20/400

  16         51    M        OU    *Candida albicans*        PNL                         20/200\          Yes\         Yes\           20/32\
                                                                                        FC               Yes          Yes            20/40

  17         26    M        OS    *Aspergillus ochraceus*   None                        LP               Yes          No             HM

  18         44    M        OD    Yeast                     Pneumonia                   FC               Yes          Yes            20/800

  19         39    M        OD    *Aspergillus flavus*      None                        HM               Yes          Yes            20/400

  20         34    M        OS    *Penicillium*             LD                          LP               Yes          No             NLP

  21         27    F        OD    Yeast                     IA                          FC               Yes          Yes            20/63

  22         50    F        OU    *Candida albicans*        PNL                         FC\              Yes\         Yes\           20/200\
                                                                                        HM               Yes          Yes            20/400

  23         26    F        OD    *Mucor*                   CM                          LP               Yes          Yes            HM

  24         34    F        OS    Yeast                     CS                          FC               Yes          Yes            20/100

  25         1     F        OS    *Fusarium moniliforme*    None                        ---              Yes          Yes            ---

  26         25    F        OS    Yeast                     Pneumonia                   FC               Yes          Yes            20/800

  27         25    F        OS    Yeast                     Childbirth                  FC               Yes          Yes            20/400

  28         56    F        OS    Mold                      None                        HM               Yes          Yes            HM

  29         31    M        OD    *Aspergillus flavus*      IT                          HM               No           No             20/200
  -------------------------------------------------------------------------------------------------------------------------------------------------

*Note*. NLP: no light perception; HM: hand motion; FC: finger counting; OD: right eye; OS: left eye; OU: both eyes; IT: immunosuppressive therapy; LD: liver disease; PNL: percutaneous nephrolithotomy; CS: cesarean section; AFS: ankle fracture surgery; TB: tuberculosis; IA: induced abortion; CM: colpitis mycotica.

###### 

Prognostic factors associated with favorable visual outcome.

  Factors                 Final visual outcome   *P* value   
  ----------------------- ---------------------- ----------- -------
  Initial visual acuity                                      
   FC or better than FC   16                     1           0.002
   Worse than FC          5                      8           
  Vitrectomy                                                 
   No                     2                      2           0.563
   Yes                    19                     7           
  Silicone oil                                               
   No                     6                      5           0.225
   Yes                    15                     4           
  Fungi                                                      
   Yeast                  15                     2           0.020
   Mold                   6                      7           

[^1]: Academic Editor: Stephen Charn Beng Teoh
