Case Report: Ocular Sporotrichosis—A Seven-Case Series

ABSTRACT.

Ocular infections associated with sporotrichosis can present four clinical manifestations: granulomatous conjunctivitis, dacryocystitis, Parinaud oculoglandular syndrome, and bulbar conjunctivitis. The incidence of ocular sporotrichosis related to zoonotic transmission has significantly increased in endemic regions and is a frequently misdiagnosed cause of granulomatous conjuntivitis. Therefore, we present a series of seven cases of eye injury by Sporothrix strains, including clinical forms, therapeutic approaches, and laboratory procedures to alert health professionals who provide care to these patients.

INTRODUCTION

Sporotrichosis is a subacute to chronic mycosis of humans and animals, emerging in several states of Brazil, and its transmission to humans is mainly associated with contaminated cats through scratching or biting.¹ The zoonotic potential of sporotrichosis has been a major public health issue, with several outbreaks occurring in Brazil. Sporothrix brasiliensis is the most prevalent agent isolated from humans and cats.^2–4

Clinical features of sporotrichosis can be divided into cutaneous and extracutaneous disease. Cutaneous presentation is more common and has three variants: fixed, superficial form, and cutaneous lymphangitic. Extracutaneous forms are uncommon and occur in the majority of cases involving bones and joints, causing periostitis, osteolysis, and tenosynovitis as an extension of the disease. Pulmonary involvement could be acute or chronic.⁵ Cases of ocular sporotrichosis are rare, but reports have been related to hyperendemic areas of this fungal infection. Nevertheless, its classification depends on anatomic criteria. It is noteworthy that the cutaneous form is the most frequent, but ocular presentation has been increasingly diagnosed in epidemic areas.^6,7

The first choice for the treatment of cutaneous sporotrichosis is itraconazole, and terbinafine is a safe and effective alternative when itraconazole is contraindicated. Saturated solution of potassium iodide (SSKI) was the first treatment of sporotrichosis through its immunological action, acting on the breakdown of granulomas, neutrophil chemotaxis, in addition to Sporothrix phagocytosis and inhibition.⁸

Hitherto, we have lacked knowledge about the epidemiology, clinical findings, and outcomes of ocular sporotrichosis in northeastern Brazil, the newest epidemic area. Herein, we present a series of seven cases of ocular sporotrichosis with the involvement of the ocular adnexa without trauma with successful antifungal treatment, followed at a Public Universitary Hospital of Paraíba, Northeast Brazil.

MATERIALS AND METHODS

Location and design of study.

This was a prospective cohort study based on medical appointments and their follow-up in 148 patients referred to the infectious disease outpatient clinic at the tertiary public hospital from January to December 2018 (12 months). The study was conducted in João Pessoa, the capital of the state of Paraíba, in Northeast Brazil. This study received ethics approval from the Ethical Review Board of the Center for Medical Sciences, Federal University of Paraiba, Brazil, under code CAAE 74157817.0.0000.8069.

Study population.

Of the 182 patients, sporotrichosis was confirmed by clinical and microbiological examination in 148. Of these, seven had unilateral granulomatous conjunctivitis associated with purulent secretion, and in three of these patients, lymphadenopathy adjacente (preauricular and/or submandibular) consistent with Parinaud’s oculoglandular syndrome was seen. Moreover, all patients had contact with sick cats. Data were collected regarding the age of presentation, sex, clinical form of sporotrichosis, distribution of lesions, treatment instituted, and laboratory findings.

Mycological laboratory diagnosis.

Biological samples were taken from affected regions by swabbing secretions. We performed direct microscopy using 20% potassium hydroxide and panoptic staining of the secretions. Eye secretions were seeded on Sabouraud dextrose agar plates and incubated for up to 15 days at 25–28°C to obtain the clinical isolate on culture. Slide cultures were stained with lactophenol cotton blue and observed under a light microscope.⁹

Complementary laboratory analysis.

Antifungal susceptibility testing was carried out by broth microdilution according to CLSI M38-A2,¹⁰ and genomic identification was reached by DNA extraction from the mycelial phase, as previously described. Partial sequencing of the calmodulin gene was performed, and BLAST (www.ncbi.nlm.nih.gov/BLAST) analysis was carried out by searching for similar sequences deposited in GenBank.¹¹

RESULTS

Patient 1 is a 15-year-old female student from the city of João Pessoa, capital of Paraíba state (PB), who presented to the ophthalmological emergency department on July 24, 2018, with a history of nodulation in the lower eyelid and bulbar conjunctiva of the right eye over 25 days without history of trauma but with direct contact with a domestic cat. Biomicroscopy showed external and internal hordeolum, with secretion and inflammatory collection in bulbar conjunctiva. Cephalexin and ciprofloxacin eye drops were prescribed. The patient returned on July 26, 2018, with the lesion presenting a granulomatous appearance. A fragment of the bulbar conjunctiva was collected and sent for culture with isolation of Sporothrix spp. Itraconazole (ITZ) at 200 mg/day was started at the ophthalmology outpatient clinic on August 10, 2018, and the patient was referred to the infectious disease outpatient clinic for follow-up. The eye lesion improved after 3 months of treatment, and the patient was discharged without intercurrences and with complete resolution of the lesion.

Patient 2 is a 13-year-old male student from João Pessoa-PB, who reported a history of contact with exudate from a cat skin lesion and subsequent appearance of a lesion in the right eye 2 months ago, when he sought care at the ophthalmological emergency department. He performed swab culture of the eye lesion on August 14, 2018, which was positive for Sporothrix spp.; ITZ was started at 100 mg/day. He was referred to the infectious disease outpatient clinic on October 2, 2018, and ITZ at 100 mg/day was maintained after medical consultation until the patient was discharged.

Patient 3 is a 28-year-old housewife from Santa Rita-PB (João Pessoa metropolitan region), who attended the infectious disease outpatient clinic on December 4, 2018, with a history of contact with cat wounds and subsequent appearance of a lesion on the left hand (Figure 1A) accompanied by subcutaneous nodules on the left forearm (Figure 1B) followed by the appearance of a lesion in the tarsal and bulbar conjunctiva of the right eye for about 4 months (Figure 1C and D). The patient was evaluated by the ophthalmological emergency department. Cultured secretions from the lesion in the left hand and right eye were performed, which revealed the growth of Sporothrix spp. in both. She started treatment with ITZ at 200 mg/day, which was maintained until the patient was discharged.

Figure 1.

(A and B) Ulcerated lesions on the left hand accompanied by nodules on the left forearm. (C) Lesion in the tarsal conjunctiva and (D) upper eyelid of the right eye. (E) Painful lymphatic nodules on the left and (F) submandibular lymphadenopathy on the same side. (G) Watery eyes and nodular lesions in the left eye. (H and I) granulomatous lesion in the lower eyelid of the right eye. (J) Micromorphology from the colony grown on potato dextrose agar for 15 days at 25°C showing septate mycelial filaments, delicate conidiophores, and conidia arranged sympodially with floral arrangements. Lactophenol cotton blue staining; magnification ×1,000.

Patient 4 is a 24-year-old male public employee who was admitted to the infectious disease infirmary on April 18, 2018, with an ulcerated lesion on the left forearm, which appeared 1 month ago after he was scratched by a domestic cat. The patient also presented with painful lymphatic nodules (Figure 1E) on the same side associated with submandibular and left cervical lymphadenopathy (Figure 1F), watery eyes, and nodular lesions in the left eye (Figure 1G). He had arthralgia in the elbows, knees, and ankles, in addition to pain in the heel. Biomicroscopy of the left eye showed a nodule in the region of the lacrimal gland, painful on palpation, and inflammation. Culture of ocular secretions from the left eye revealed growth of Sporothrix sp. He was discharged with clinical improvement on April 24, 2018, with ITZ 400 mg/day, which was reduced to 200 mg/day in the first visit at the infectious disease outpatient clinic on May 14, 2018. On July 21, 2018, he was discharged from the outpatient clinic after 3 months of treatment with ITZ and complete resolution of the fungal infection.

Patient 5 is an 8-year-old female student from João Pessoa-PB. The patient presented to the ophthalmological emergency on July 19, 2018, with hyperemia and secretion in the right eye associated with preauricular adenomegaly that appeared about 30 days ago, without association with trauma. However, the child had a history of direct contact with a cat family. Biomicroscopy of the right eye revealed hyperemia and granulomas in the superior and inferior tarsal conjunctiva. A culture of conjunctival secretion from the right eye was collected, which isolated Sporothrix sp. She was evaluated at the infectious disease outpatient clinic on July 8, 2018, when SSKI (1 g/mL) in increasing divided doses of 8/8 hours was started, increasing to reaching 3 g/day. The patient had dyspeptic complaints when trying to maintain the dosage at 3 g/day; the dosage was reduced to 1.5 g/day and then increased to 2.25 g/day with good tolerability. After 3 months of treatment, she was discharged on November 20, 2018, with complete resolution of the lesions.

Patient 6 is a 50-year-old housewife from João Pessoa who presented to the ophthalmological emergency department on November 1, 2018, with a complaint of burning and tearing in the right eye for approximately 90 days. The patient did not report trauma but reported a history of direct contact with a domestic cat. Ophthalmic examination showed hyperemia with tarsal conjunctival secretion and granuloma in the lower eyelid. Scraping culture of the lesion in the palpebral conjunctiva of the right eye from November 5, 2018, was positive for Sporothrix sp., and on November 8, 2018, ITZ 200 mg/day was prescribed. She completed 6 months of treatment on May 8, 2019, with complete resolution of the eye injury and was discharged from the infectious disease outpatient clinic on July 8, 2019.

Patient 7 is a 27-year-old unemployed individual from João Pessoa-PB, with no history of contact with animals or trauma. The patient was evaluated on December 11, 2018, at the infectious disease outpatient clinic with a report of a granulomatous lesion in the right eye associated with conjunctival hyperemia and preauricular and cervical lymphadenomegaly for about 60 days, unrelated to trauma or contact with animals (Figure 1H and I). On examination, a granulomatous lesion in the lower eyelid of the right eye was observed. In this medical appointment, the patient presented an eye lesion swab culture from December 6, 2018, that was positive for Sporothrix sp. Itraconazole was started at 200 mg/day. The patient showed significant improvement of the eye injury, and after 10 weeks the ITZ dosage was reduced to 100 mg/day and maintained until completing 4 months of treatment. She was discharged on June 10, 2019, after an ophthalmology evaluation that confirmed the complete resolution of the eye lesion on biomicroscopy.

DISCUSSION

We examined a series of seven cases of ocular sporotrichosis with involvement of the adnexa, and in three of these cases, the presence of Parinaud’s oculoglandular syndrome was described.^12–14 Our findings corroborate the predominance of female cases, with five of our seven cases occurring in female patients.^15–17 The involvement in this case series of patients with a mean age of 23.6 years emphasizes the importance of ocular sporotrichosis among children and young adults, who are more exposed to the fungus due to greater “face-to-face” contact with sick animals (Table 1).^6,18

Table 1.

Demographic, clinical, mycological, and antifungal treatment data of seven patients diagnosed with sporotrichosis in ocular adnexa from January to December 2018 in Paraíba, Northeast Brazil

Patient ID	Sex/age (years)	Occupation	Exposure	Mycological examination	PCR identification	Type of lesion	Treatment and dosage	Treatment (months)
Patient 1	F/15	Student	Contact with cat without injury	Sporothrix sp.	Sporothrix brasiliensis	Nodulation in the lower eyelid and tarsal conjunctiva of the right eye with granulomatous appearance	ITZ 200 mg/day (2 cap/day)*	3
Patient 2	M/13	Student	Contact with exudate from a cat skin lesion without injury	Sporothrix sp.	S. brasiliensis	Lesion in the tarsal conjunctiva of the right eye	ITZ 100 mg/day (1 cap/day)	3
Patient 3	F/28	Housewife	Contact with cat wounds without injury	Sporothrix sp.	S. brasiliensis	Lesion on the left hand accompanied by subcutaneous nodules on the left forearm + lesion in the tarsal and bulbar conjunctiva of the right eye and nodular lesion in upper eyelid	ITZ 200 mg/day (2 cap/day)	3
Patient 4	M/24	Public service worker	Scratching by cat on left forearm	Sporothrix sp.	Not performed	Ulcer and painful lymphatic nodules on the left forearm + submandibular and left cervical lymphadenopathy + nodule in the region of the lachrymal gland, painful on palpation, and inflammation + arthralgias	ITZ 400 mg/day (4 cap/day)†	3
Patient 5	F/8	Student	Cat without injury	Sporothrix sp.	Not performed	Hyperemia and granulomas in the superior and inferior tarsal conjunctiva + preauricular adenomegaly	Concentrated potassium iodide solution (1 g/mL), 2.25 g/day	3
Patient 6	F/50	Housewife	Cat without injury	Sporothrix sp.	Not performed	Hyperemia with tarsal conjunctival secretion and granuloma in the lower eyelid	ITZ 200 mg/day (2 cap/day)	6
Patient 7	F/27	Unemployed	Without contact with animals or trauma	Sporothrix sp.	Not performed	Granulomatous lesion in the lower eyelid of the right eye + pre-auricular and cervical lymphadenomegaly	ITZ 200 mg/day (2 cap/day)‡	4

ITZ = itraconazole; PCR = polymerase chain reaction.

^*Daily.

^†Reduced to 200 mg/day in the first visit at the infectious disease outpatient clinic.

^‡Reduced to 100 mg/day after 10 weeks.

The geographic expansion of zoonotic sporotrichosis by S. brasiliensis, mainly through the cat, has been experienced in South and Southeast Brazil in the last decades.¹⁹ The emergence of the epidemic has occurred in the Brazilian Northeast,^4,20 and it has made it possible to identify cases of extracutaneous sporotrichosis that are considered rare, such as ocular sporotrichosis.^7,9 Although zoonotic transmission of sporotrichosis is related to biting and scratching by infected cats,^3,21 none of the patients in this study had a previous history of ocular trauma, leading us to hypothesize that autoinoculation may occur, in addition to handling skin lesions in other areas of the body. The presence of the lymphocutaneous form in patients 3 and 4 may favor ocular infection. Moreover, the identification of S. brasiliensis in the cases with genomic characterization emphasizes the possibility of nontraumatic inoculation of the fungus.²²

Ocular sporotrichosis can present as an intraocular infection or an infection of the eye adnexa when it affects the eyelids, the conjunctiva, and the lacrimal system.^7,23 In granulomatous conjunctivitis, yellowish nodules with a smooth and shiny surface are clustered, involving the tarsal and/or bulbar conjunctiva, associated with conjunctival hyperemia and/or purulent exudate,¹⁷ which was found in six of the seven patients. Initially, the nodular lesions caused by granulomatous conjunctivitis may be confused with hordeolum or chalazion, as presented in patient 1, delaying diagnosis and appropriate therapy.^17,24 When granulomatous conjunctivitis is accompanied by ipsilateral preauricular and submandibular adenomegaly, as observed in patients 4, 5, and 7, Parinaud’s oculoglandular syndrome is characterized.¹² Although Parinaud’s oculoglandular syndrome is classically associated with infection by Bartonella henselae,²⁵ the diagnosis of ocular sporotrichosis may be facilitated in sporotrichosis-endemic areas.

Dacryocystitis is an infection of the lacrimal system. However, this infection due to sporotrichosis is infrequent.⁷ In a recent retrospective study of 120 cases of ocular sporotrichosis from 2007 to 2017 in the state of Rio de Janeiro, Brazil, dacryocystitis was identified in 7.5% of cases.¹⁸ It may present with other clinical manifestations, such as conjunctivitis and lymphocutaneous,^24,26 and may evolve with sequelae.²⁷ Even though patient 4 had a nodular lesion in the lacrimal region, he did not progress to the classic picture of dacryocystitis characterized by erythema, edema, and pain in a hardened area over the nasolacrimal sac just below the anatomical limit of the medial canthal ligament.²⁶

Hypersensitivity reactions in the sporotrichosis is associated with zoonotic transmission of S. brasiliensis and can manifest as erythema nodosum, erythema multiforme, Sweet’s syndrome, and reactive arthritis.^2,28 Reactive arthritis often disappears with specific treatment of sporotrichosis, but the use of corticosteroids may be necessary in other hypersensitivity reactions.^18,28,29 We noted probable reactive arthritis in Patient 4, in whom polyarthralgia and enthesitis of the left calcaneus were evident but soon disappeared with the use of itraconazole.

Laboratory diagnosis of sporotrichosis includes direct and histopathological examination, mycological culture, and molecular identification of the species.³⁰ Like other clinical presentations, in ocular sporotrichosis the gold standard for diagnosis is the conventional culture of clinical specimens, such as tissue fragments and secretion from lesions, from which it is possible to observe delicate conidiophores and conidia arranger sympodially with floral appearance (Figure 1J). Although the histopathological slides are used, biopsy is an invasive procedure that is prone to complications, and the histopathological findings may be nonspecific and mimic other granulomatous conditions.^15,24,30,31 In our study, patients 2, 3, 4, 5, and 7 underwent swab collection of secretion or ocular lesion, whereas patients 1 and 6 underwent collection of a fragment of lesion of the bulbar and tarsal conjunctiva, respectively, to seed on culture, and in samples all Sporothrix sp. were isolated.

Despite the molecular identification of the Sporothrix species having important implications for the choice of antifungal therapy,³² this approach has gained special attention in the current spread of sporotrichosis to the northeast region of Brazil.^1,20,33 Nevertheless, it is not available in most hospitals.²⁴ The identification of S. brasiliensis in three of our patients (patients 1, 2, and 3) corroborates recent literature data that implicate this species as a main cause of human sporotrichosis in the states of Pernambuco and Rio Grande do Norte, neighboring the state of Paraíba, the homeland of all patients in this series of cases.

Like cutaneous sporotrichosis, the treatment of ocular sporotrichosis is performed orally, and in the same doses with ITZ, terbinafine, or SSKI. Itraconazole is the treatment of choice at a dosage of 100–400 mg/day, usually for 3–6 months, despite its high cost.^15,34 Saturated solution of potassium iodide shows good results, but its main disadvantages are adverse effects and low tolerability.^18,24 When there is intraocular involvement, amphotericin B administered parenterally alone or in combination with oral antifungal agents is the most commonly used treatment.⁷ In our case series, six patients were treated with ITZ, and only one 8-year-old child was treated with SSKI, unlike the study by Ramírez-Soto,³⁵ where 20 out of 21 patients were treated with SSKI. Our patient had the dosage of SSKI reduced after the appearance of adverse events, which did not impair the treatment and promoted clinical cure of the eye lesion. The ITZ dosage ranged from 100 to 200 mg/day, and only one of the patients started treatment with 400 mg/day, which was reduced to 200 mg/day during outpatient follow-up.

Despite the limited number of patients, healing without ocular sequelae in all the patients is quite encouraging. On the other hand, Arinelle et al.¹⁸ identified sequelae in 22.5% in a series of 120 cases of ocular sporotrichosis.

Even though antifungal susceptibility tests are still limited, this knowledge becomes increasingly necessary because Sporothrix clinical strains have shown the ability to develop resistance to conventional antifungals.³⁶ The high inhibitory concentrations against fluconazole and voriconazole among the three genetically identified strains emphasizes the guidance not to use them in the treatment of sporotrichosis. However, the susceptibility to ITZ and terbinafine of the same strains points to the maintenance of these antifungals as first-line therapeutic agents for the treatment of ocular sporotrichosis, in agreement with the literature.^1,4 Although Sporothrix clinical strains showed low minimal inhibitory concentrations to cetoconazole (Table 2), its bioavailability is lower than ITZ. Furthermore, the detection of resistance to amphotericin B in one of these strains is noteworthy. Nevertheless, the role of this resistance in vitro needs to be better understood.

Table 2.

Minimal inhibitory concentration in µg/mL of three Sporothrix brasiliensis related to ocular sporotrichosis, and identified by calmodulin partial sequencing, against antifungals drugs

Case (isolate)	GenBank accession number	Amph B	ITZ	FLZ	VRZ	CTZ	TBF
Patient 1	OP094679	4	1	≥ 64	4	0.125	0.125
Patient 2	OP094680	0.5	0.06	32	2	0.125	0.125
Patient 3	OP094681	0.06	0.25	≥ 64	4	0.25	0.125

Amph B = amphotericin B; CTZ = cetoconazole; FLZ = fluconazole; ITZ, itraconazole; TBF = terbinafine; VRZ, voriconazole.

CONCLUSION

Sporotrichosis is a broad-clinical-spectrum fungal infection that displays a behavioral polymorphism. Uncommon manifestations of the disease may be challenging in the medical assistance. Therefore, this study recommends that sporotrichosis should be considered as diagnostic hypothesis in granulomatous conjunctivitis. Although there are usually no long-term ocular sequelae if ocular sporotrichosis is treated in a timely manner, it can cause prolonged eye discommodity and require several medical appointments.