Endogenous Aspergillus Endophthalmitis

Introduction Invasive aspergillosis typically involves the lung, but subsequent hematogenous dissemination to other organs is common in immunosuppressed patients (8,42,49,67). Rarely, disseminated disease can also be acquired following intravenous inoculation. Lesions are typically found in the brain, myocardium, kidneys, and skin with disseminated aspergillosis. An uncommon complication of disseminated aspergillosis is endogenous endophthalmitis, and even more uncommon is isolated endogenous endophthalmitis without other organ involvement. We report 3 cases of endogenous Aspergillus endophthalmitis and present a detailed review of the literature to illustrate the difficulties of diagnosis and treatment associated with this entity. Because endophthalmitis caused by Aspergillus tends to present abruptly with nonspecific symptoms and progresses quickly to irreversible retinal damage, rapid recognition is important. Among the 86 total cases reviewed, certain diagnostic methods and treatment modalities emerged as being more useful than others. Early diagnosis and appropriate treatment may increase the likelihood of a favorable outcome. Methods We searched the English-language literature for cases of Aspergillus endogenous endophthalmitis, through an electronic search (MEDLINE, National Library of Medicine, Bethesda, MD) using key words “Aspergillus,” “endogenous,” and “endophthalmitis” and cross-referencing articles to include older articles, going back to 1949. Cases were included if Aspergillus was confirmed to be present within the eye by growth of the organism from samples of intraocular fluid or by identification of fungal elements typical of Aspergillus species on histopathologic examination of methenamine silver-stained ocular tissue. Cases of exogenous posttraumatic or postoperative endophthalmitis and those with contiguous spread from sinuses were excluded. All cases were assessed for demographic information, risk factors, diagnostic methods, treatment strategies, and outcomes. Data were analyzed using the Student t test for continuous variables and the Fisher exact test for dichotomous variables. Case Reports Case 1 A 56-year-old man presented with a 4-day history of left eye pain, swelling, and decreased visual acuity. These symptoms occurred 15 days after admission to hospital for cough, fever, and dyspnea for which he required endotracheal intubation and mechanical ventilation. He was treated for pneumonia with broad-spectrum antibiotics and received high doses of corticosteroids for management of chronic obstructive pulmonary disease. Past medical history included end-stage renal disease requiring chronic hemodialysis following failure of a renal transplant, chronic obstructive pulmonary disease, hypertension, coronary artery disease, and congestive heart failure. At the time of admission for the ocular symptoms, the patient’s medications included prednisone 15 mg daily and amoxicillin/clavulanic acid 875 mg twice daily. His temperature was 97.1 °F (36.1 °C), respiratory rate 16/min, blood pressure 176/86 mmHg. The left eye had extensive scleral injection, subconjunctival edema inferiorly, and a 1-mm hypopyon in the anterior chamber (Figure 1). Visual acuity was 20/200. Extraocular motions and pupillary reflexes were intact. Funduscopic examination revealed a cloudy vitreous; the retina could not be visualized. The right eye was normal. Chest examination revealed decreased breath sounds; no heart murmur was heard. There were no peripheral stigmata of infective endocarditis, and no neurologic deficits were noted. Laboratory evaluation revealed a white blood cell count of 17,500/L with 88% segmented neutrophils. A right upper lobe infiltrate was noted on chest radiograph.Fig. 1: Case 1, left eye. Subconjunctival edema and scleral injection obscure the 1-mm hypopyon.A vitreous aspirate was obtained; intravitreal vancomycin and ceftazidime were given; and ciprofloxacin, atropine, and prednisolone were administered topically to the left eye. Over the next 2 days, the patient’s cough worsened, he became short of breath and developed hemoptysis, and the pulmonary infiltrate worsened. Computed tomography (CT) of the chest showed bilateral airspace disease without nodules or cavitation. Repeated cultures from blood were negative. Broad-spectrum antibiotics were given for nosocomial pneumonia. Transthoracic echocardiography revealed no evidence of valvular vegetations. All vitreous cultures remained sterile. Cultures taken from the right upper lobe at bronchoscopy yielded yeast, Aspergillus fumigatus, and oral flora; his physicians felt that the Aspergillus was a contaminant. The patient was discharged with topical ciprofloxacin and prednisolone ophthalmic solution for presumed bacterial endophthalmitis and oral levofloxacin for presumed bacterial pneumonia. Oral corticosteroids were tapered over the following 2 weeks. He continued to have dense vitritis, visual loss, and pain. Three weeks later, he underwent pars plana vitrectomy for persistent vitritis. Retinal vascular occlusions and necrotic retinal tissue were found. Eight weeks after the onset of symptoms he underwent enucleation of the left eye for refractory pain. Pathologic examination of the removed globe revealed acute suppurative and chronic granulomatous endophthalmitis with extensive necrosis of the retina, reactive retinal gliosis, severe panuveitis, intraocular hemorrhage, and episcleral inflammation and scarring. The methenamine silver stain revealed branching septate hyphae consistent with Aspergillus species (Figure 2), which prompted the initiation of a 6-week course of treatment with liposomal amphotericin B, 5 mg/kg per day, followed by oral itraconazole solution 200 mg twice daily. During treatment, the patient developed low back pain. Magnetic resonance imaging (MRI) showed inflammation of the L1-L2 disc space with increased signal on T2-weighted images. A CT-guided biopsy of the intervertebral disc showed only chronic inflammation; the material yielded no growth on culture. Two months later he presented with respiratory distress and died shortly thereafter. No autopsy was performed.Fig. 2: Case 1, enucleation specimen of the left eye. Fragments of branching septate hyphae are seen within the vitreous. (Gomori methenamine silver stain; original magnification × 630.)Case 2 A 57-year-old woman presented with a 7-day history of right eye pain and redness. She had a 10-year history of bronchiolitis obliterans organizing pneumonia (BOOP) which had required intermittent prolonged courses of oral corticosteroids. Three months before admission she was treated with ceftazidime and tobramycin and then ofloxacin and trimethoprim/sulfamethoxazole for cough and shortness of breath. When her symptoms persisted after 6 weeks, a course of prednisone was initiated. Ten days later, she developed right eye pain with movement, redness, photophobia, and decreased visual acuity. An aspiration of the aqueous humor and vitreous body yielded rare Staphylococcus epidermidis after 48 hours. With the development of an anterior chamber hypopyon and increasing vitritis, an intravitreal injection of vancomycin and ceftazidime was performed. Visual acuity was 20/300 in the right eye. Because of persistent symptoms, a second intravitreal injection of vancomycin was given 6 days later. On admission, she had a temperature of 99.0 °F (37.2 °C) and a heart rate of 110 beats/min. There was severe right conjunctival injection, and a hypopyon was present in the anterior chamber (Figure 3). Bilateral rhonchi were present, and a previously described II/VI systolic murmur at the apex was heard. On the right lateral thigh there were a few firm, nontender erythematous nodules. Laboratory evaluation revealed a white blood cell count of 25,000/L with 87% segmented neutrophils. The chest radiograph showed changes consistent with BOOP as well as a right upper lobe nodular opacity that was new compared with a radiograph performed the preceding month.Fig. 3: Case 2, right eye. Photograph taken under slit lamp examination demonstrates a small hypopyon and conjunctival injection with a lateral subconjunctival hemorrhage.Initial management included an increase in prednisone dosage to 60 mg daily and treatment with intravenous vancomycin and levofloxacin. A CT of the sinuses and orbits disclosed no source of infection contiguous with the eye. Pars plana vitrectomy with vitreous biopsy was performed, and vancomycin, gentamicin, and amphotericin B were injected into the eye. A. fumigatus was obtained on culture of the vitreous sample. The patient subsequently developed pain in the other eye, and further evaluation revealed changes consistent with endophthalmitis. Transthoracic echocardiography revealed an 8 × 13 mm mobile vegetation on the mitral valve and severe mitral regurgitation. Blood cultures yielded no organisms. Therapy with amphotericin B was initiated. A. fumigatus was isolated from sputum, urine, and a skin biopsy specimen. She developed progressive visual loss, expressive aphasia, and right-sided hemiplegia, and died on the 12th hospital day. Case 3 A 73-year-old man was admitted with loss of vision in the left eye. Studies performed during a 34-day hospital admission in the preceding 2 months had suggested BOOP, for which he was treated with corticosteroids. On admission, a chest radiograph showed new changes consistent with a fungus ball and airspace disease in the right lower and left upper lobes. Pars plana vitrectomy was performed because of concern for possible fungal endophthalmitis. At the time of the procedure, 10 μg of intravitreous amphotericin B and 400 μg of dexamethasone were injected into the vitreous. The vitrectomy specimen grew A. fumigatus. Sputum samples also yielded Aspergillus. The prednisone was tapered, intravenous amphotericin B was begun, and a second intravitreal injection of amphotericin B, 10 μg, and dexamethasone, 400 μg, was performed. A transesophageal echocardiogram demonstrated no evidence of endocarditis. He was prescribed itraconazole 200 mg twice daily on discharge after having received 1 g of amphotericin B. The following month he developed low back pain. An MRI demonstrated post-Gadolinium enhancing thoracic spine lesions with increased signal on T2-weighted images at T7, T9, and T10. Discitis was also seen at the L2-L3 disc space. A CT-guided biopsy of the L2 intervertebral lesion was performed, but cultures yielded no growth. Four months later, visual acuity in the right eye remained only finger counting at 1–6 feet. There were posterior synechiae for 360° extending to the lens with a fibrovascular retrolenticular membrane. On ocular ultrasound there was no retinal or choroid detachment, and only mild diffuse mobile vitreous opacities were found. Itraconazole therapy was stopped after a total of 3 years of treatment. Results Demographics Case reports of 86 patients (109 eyes) with endogenous Aspergillus endophthalmitis, including the 3 patients in the present report, were reviewed (1,4,6,7,9,11–16,20,21,26,29,30,33,35–37,39–41,43–46,48,50,51,53–55,57–60,63,65,68,75,78,81–87,89). Cases were reported from 1949 to 2001. The mean age (± SD) was 42.3 ± 19.8 years (range, 10 d to 91 yr); 46 (55%) patients were male and 37 (45%) were female (no sex listed for 3 patients). Underlying diseases and risk factors The majority of the 84 patients for whom data were available had serious underlying illnesses, and many were immunosuppressed (Table 1). The most common underlying conditions were intravenous drug use, which was present in 23 (27%) patients (4,16,20,21,33,35,39,40,48,57,68,78,85,87); receipt of a solid organ transplant (23%) (1,6,11,30,37,45,59,65,86); and lung disease, including chronic obstructive pulmonary disease, asthma, and BOOP (17%) (29,44,50,51,65,85). Exposure to corticosteroids proved to be a strong risk factor. A total of 36 (43%) patients had received corticosteroid therapy; 36% of these had received corticosteroids for only a brief time (<3 mo). The reporting authors could identify no risk factor for development of Aspergillus endophthalmitis in 5 patients (12,54,58,75,81).TABLE 1: Underlying conditions in 84 patients with endogenous Aspergillus endophthalmitis*Clinical characteristics Of the 86 patients, 63 (73%) had unilateral involvement. Of those, the left eye was involved in 30 (48%), the right in 25 (40%), and in 8 (12%) only “unilateral involvement” was reported. In 23 (27%) of cases, both eyes became the onset of symptoms and were available for 13 of these 23 cases with bilateral involvement. In 6 there was bilateral at the onset of disease, and in the eye from 2 to days later. The mean time that before medical was ± days after the onset of symptoms for patients for whom data were Of these 46 presented within days of the onset of symptoms, and presented after 10 or more days (range, the patients for whom symptoms were 46 presented with of vision or were found to have visual acuity. pain and also were common symptoms, as eye swelling, photophobia, and were reported (Table 2: symptoms in patients with endogenous Aspergillus examination showed in of cases retinal lesions or in and an in the vitreous in Of the patients with a vitreous 8 were described as having a or included conjunctival injection and as well as anterior chamber and hypopyon (Table 3). In (23%) cases, retinal could not be because of dense vitritis. patients presented with visual acuity of or Two patients had only anterior chamber 3: in patients with endogenous Aspergillus patients had isolated endophthalmitis, and had of organs other than the eye (Table Of the 30 patients with isolated eye (73%) admitted to intravenous drug 1 of the 23 patients with intravenous drug as a risk factor had Aspergillus infection anterior The respiratory was the presumed of for patients not intravenous patients had evidence of pulmonary and had disseminated aspergillosis organs Aspergillus was present in 8 had valve endocarditis, and 6 had valve in 86 patients with endogenous Aspergillus The diagnosis of Aspergillus endophthalmitis proved to be The diagnosis was only after enucleation or at autopsy in those patients in whom the diagnosis was the was obtained by culture of vitrectomy The diagnosis was by culture or fungal stain in of vitrectomy compared with 6 of vitreous aspirate 1 of anterior chamber yielded Aspergillus species 1 patient had Aspergillus isolated from a culture taken from blood A. fumigatus was isolated in 36 and A. in of the patients for whom culture data were Of the patients in whom A. was were intravenous drug with no other risk The of the intravenous drug injection and A. was The species were A. A. A. A. and A. In cases, Aspergillus was but not In cases, the diagnosis was on in ocular tissue patients, of whom had the diagnosis or received no no data on therapy were reported. Of the patients were noted to have received treatment, were treated with intravenous amphotericin B for of of these received intravitreal amphotericin B, with or without in to intravenous amphotericin B. Of the patients received only intravenous amphotericin B, were before autopsy or 5 of these patients had and had of an anterior chamber patients received intravitreal of amphotericin doses from 5 μg to μg (Table Repeated were typically The patients received the 5 μg on were administered 2 ± (range, Four patients received intravitreal therapy with amphotericin B without the of an Aspergillus. Oral was given with amphotericin B in patients, and patients received itraconazole following treatment with amphotericin B. injection of dexamethasone was administered with amphotericin B to Subconjunctival of amphotericin B and corticosteroids occurred in 5 and 3 patients, and topical and corticosteroids were also in treatment for endogenous Aspergillus endophthalmitis in of 86 patients useful Two of those patients had only anterior chamber only patients with posterior chamber vision in the eye. All of these patients had received intravenous amphotericin B, and 6 of the also had received intravitreal amphotericin B and had patients required and patients were left with a visual acuity of or in the eye. had presented after the onset of symptoms ± than patients had ± this to patients were reported to have had or Four in the eye, in the eye, 2 developed and 1 patient had progressive lesions the skin and a heart The of days to or diagnosis of infection was ± days (range, is a rare of aspergillosis that reported in those patients to be at risk for aspergillosis. In 1 from the only 1 patient patients with pulmonary aspergillosis developed endophthalmitis in other patients with and this complication was not reported emerged as a risk factor for the development of Aspergillus endophthalmitis. We found that of patients had treated with corticosteroids before the development of Aspergillus endophthalmitis. is that corticosteroid was not over of those treated with corticosteroids received therapy for than 3 a risk factor for and and and The of cases (27%) that occurred intravenous drug is A of have to the of of Aspergillus in drug Aspergillus species not the of the injection described as the source of an of endophthalmitis in is more that the drug or the material to the drug is with Aspergillus. In 1 from the of Aspergillus species were isolated from of samples and only of of injection of Aspergillus species was second only to that of species the Aspergillus were not to species A. was isolated in of the cases in which intravenous drug was the risk factor for of disease, and of A. were from intravenous drug In this of endophthalmitis were A. compared with of as A. in a hospital that reported on of aspergillosis Aspergillus species have to in the A. is as the of on and found in of samples species of Aspergillus also have found to A. isolated from to A. and A. and A. have reported to that at of the patients in this were reported to have drug through and that 3 injected which also is through could be a source of A. in intravenous drug The diagnosis of Aspergillus endophthalmitis is only at and to severe visual is the in the majority of of the diagnostic difficulties because there are few that Aspergillus endophthalmitis from other of endophthalmitis. visual pain, and are common to endophthalmitis caused by a of organisms. There are a few that to Aspergillus as a possible of endogenous endophthalmitis. drug to be an risk factor. is also a risk factor for endophthalmitis but is noted as a risk factor for bacterial endophthalmitis for also the of that Aspergillus species are the of endophthalmitis endophthalmitis that in an immunosuppressed patient blood cultures is more to Aspergillus than The development of of pulmonary as a or on a CT also the of Aspergillus species as the of endogenous endophthalmitis. to be a strong risk factor for bacterial endophthalmitis is not noted as a risk factor for fungal endophthalmitis ocular may and Aspergillus endophthalmitis. A or to be for Aspergillus endophthalmitis. was in only 8 of reported this is present, but to be an uncommon Retinal lesions are seen in both and Aspergillus endophthalmitis. the lesions associated with infection to be more may be because endophthalmitis is blood cultures infection to disease is noted before to the vitreous developed In the of vitreous is present at the time of the A compared histopathologic changes associated with and Aspergillus endogenous endophthalmitis from autopsy or enucleation Of the 13 cases of Aspergillus endophthalmitis, demonstrated of the and 8 were found to have of posterior hyphae were seen in the space and through the of blood to was more with of cases in the vitreous with to retinal A diagnosis of Aspergillus endophthalmitis growth of the The of Aspergillus from of the aqueous and vitreous was The was found with vitrectomy Blood cultures are these yielded Aspergillus in only 1 Because endophthalmitis to Aspergillus is a to disseminated biopsy of lung, or other organs may a diagnosis by or culture may be to given the in of Aspergillus species to those of other as diagnostic methods that on ocular samples or blood may in the have for the treatment of endogenous Aspergillus endophthalmitis. amphotericin B, the of for most patients with aspergillosis intraocular other methods of as topical subconjunctival injection, and intravitreal injection, have The topical of amphotericin B is and to an and in the Subconjunctival not drug within the vitreous of amphotericin B into the to be and The of intravitreal amphotericin B in not on μg to be and to intraocular The patients had doses of intravitreal amphotericin B administered not have associated with the injection doses of μg have to including retinal necrosis and in demonstrated with doses as low as μg the drug was in to retinal tissue this can be by injection into the of the vitreous In an to with liposomal of amphotericin B have in and The and of intravitreal amphotericin B on vitrectomy performed. vitrectomy the is days and there to be of the drug in the and retina In eyes that have the is to 2 days without evidence of in ocular and itraconazole are not useful in the treatment of Aspergillus endophthalmitis. is not Aspergillus and itraconazole into the eye The patients were treated with itraconazole in this received the drug for treatment of other of aspergillosis after therapy with amphotericin B. new may useful for Aspergillus endophthalmitis. a new is for Aspergillus and in the vitreous At this there is no reported using for endophthalmitis. an also to be for but is intraocular are The of endogenous Aspergillus endophthalmitis is Of the 84 patients with retinal disease, only visual acuity with endogenous endophthalmitis, for which of vision in of patients All patients with Aspergillus endophthalmitis received intravenous amphotericin B, and 6 also received intravitreal amphotericin B and had a vitrectomy performed. In to diagnostic vitrectomy may also be of as infective fungal to in had to endogenous endophthalmitis of the patients vision presented with visual acuity or and had retinal with in presented than those with the of recognition and treatment. The of seen in this of patients with endogenous Aspergillus endophthalmitis is than the reported for aspergillosis The lower in this is to the high of intravenous drug had no underlying and had infection to the eye. A to the diagnosis and treatment of endogenous Aspergillus endophthalmitis be as present with symptoms of endogenous endophthalmitis with a history of intravenous drug use, corticosteroid use, or with blood cultures be at examination of posterior disease with with or without dense aspergillosis. the risk factors and pars plana vitrectomy for both and diagnostic culture is The of μg of amphotericin B intravitreal injection at the time of vitrectomy is to the possible therapy of cultures and for fungal as well as other A evaluation for other of infection be tissue taken to a diagnosis of and intravenous amphotericin B therapy if there is of aspergillosis. an Aspergillus species is confirmed as the intravitreal of amphotericin B is given the short of amphotericin B in the posterior after with or without intravitreal amphotericin B, may also be on the subsequent of the posterior The total of intravenous amphotericin B be not only by the ocular but also by the of aspergillosis. Repeated by an are in the course of treatment, to in the involved eye or the development of disease in the eye. We reviewed 86 cases of endogenous Aspergillus endophthalmitis reported 1949. medical conditions were present in drug was noted in solid organ in underlying lung disease in and had received corticosteroids. The organism endophthalmitis was A. fumigatus of of patients had A. species was to the of intravenous Of the patients with endophthalmitis to A. were intravenous drug The diagnosis of endogenous Aspergillus endophthalmitis is and only at Pars plana vitrectomy to be the for the of vitrectomy yielded Aspergillus compared with of vitreous were only of the 84 patients with posterior chamber useful with intravenous amphotericin B with intravitreal injection of amphotericin B and vitrectomy to be the most of the patients reported to have useful vision had received treatment.