Favorable outcome of Lasiodiplodia theobromae keratomycosis : a clinical case and systematic review

Abstract

Backroud

Keratitis caused by Lasiodiplodia theobromae is rare and typically associated with a poor prognosis. Current literature lacks sufficient evidence on effective management of patients with this condition.

Case presentation

A 74-year-old former agricultural worker presented with a red right eye, discomfort, and decreased visual acuity, progressing over three days without treatment. Examination revealed type 2 diabetes and a non-perforating, spiculated corneal abscess with a hypopyon in the right eye. Initial treatment included a triple antibiotic therapy and supportive care. Direct mycological examination identified numerous septate mycelial filaments. Antifungal treatment with natamycin and voriconazole, both topically and orally, was initiated. Cultures confirmed Lasiodiplodia theobromae. The patient showed significant improvement. Treatment continued for eight weeks, with a final visual acuity of 20/50 due to a stromal scar.

Conclusion

An extensive literature review conducted in November 2023, using databases such as PubMed and Google Scholar with the keywords “lasiodiplodia” and “keratitis” yielded no previous cases of this specific condition being managed solely with the combined use of natamycin and voriconazole. This antifungal combination is commonly included in most management protocols for fungal keratitis. Factors such as the use of corticosteroids and delayed diagnosis were noted to adversely affect the prognosis. This case and this systematic review underscores the potential for non-surgical management options in severe fungal keratitis.

Backround

Fungal keratitis, in general, are rare infections with a poor prognosis, particularly affecting developing areas and tropical regions [1]. Due to their unusual nature, adequate treatment is generally only initiated after a certain delay, which contributes to the poor outcomes often encountered. These are mainly filamentous fungi in tropical climates, foremost among which is Fusarium and Aspergillus [2].

Lasiodiplodia theobromae is a black fungus, often food in tropical regions, where it contributes to the rot of bananas, sugar cane, cocoa and other plants. It was first described as a cause of fungal keratitis by Puttanna in 1967 in India [3].

Since then, only 68 observations of ocular infections by this germ have been recorded in the literature, with mostly unfortunate outcomes. We present a case of Lasiodiplodia theobromae keratitis with a favorable outcome under medical treatment with a combination of natamycin and voriconazole.

Case presentation

A 74-year-old man presented to the Department of Ophthalmology, University Hospital of Martinique, Fort de France, France (French West Indies) with a red right eye, sensation of “discomfort,” no significant pain, associated with decreased visual acuity and progressing for 3 days without any initiated treatment. There was no history of trauma or foreign bodies, but the patient, a former agricultural worker living in a rural area, often worked in a banana plantation and had several animals. He had no known medical history, had not received medical follow-up and appeared to be in good general health. During his hospitalization, examinations revealed previously unknown type 2 diabetes. No other abnormalities were found in the general clinical examination.

The examination revealed a visual acuity of “counting fingers” at one meter on the right, unimprovable, and 20/25 Parinaud 2 on the left eye with correction. In the anterior segment, a large (5 mm diameter), non-perforating, spiculated corneal abscess with epithelial haze and a barely visible millimetric hypopyon in the anterior chamber were noted on the right. On the left eye, there was only a cortico-nuclear cataract (Fig. 1). The ocular pressure was measured at 15mmHg on the left with a pachymetry of 517 μm, and 13mmHg on the right. The fundus was inaccessible on the right eye; B-scan ultrasound revealed no signs of posterior segment involvement.

Fig. 1

Clinical photography of the first examination

We began local antibiotic treatment immediately after collecting corneal scrapings. The patient was given an antibiotic triple therapy with gentamicin, piperacillin, and vancomycin eye drops. Additionally, we administered atropine and moisturizers, along with paracetamol for pain management. The corneal scraping was performed under oxybuprocaine anesthesia. This procedure took place in a sterile room using a microscope. Following the scraping, cultures were promptly initiated by a biologist. The next day, a direct mycological examination showed numerous septate and branched mycelial filaments. These filaments, which were turoloid with intercalary chlamydospores, were visible with May Grunwald Giemsa staining (Fig. 2). Based on these findings, we prescribed antifungal treatment. This included 5% natamycin eye drops, voriconazole eye drops, and an oral dose of voriconazole at 400 mg/day. In addition to antifungals, we used a bi-antibiotic therapy (ciprofloxacin and tobramycin eye drops). We continued antibiotic treatment until bacteriological samples returned negative results.

Fig. 2

Photography of Lasiodiplodia Theobromae petri dish (A) and of direct examination of MGG-stained scrapings (B)

The culture allowed the isolation of a filamentous fungus, grey, with abundant aerial mycelium, without fruiting bodies. Identification of Lasiodiplodia theobromae was made by mass spectroscopy. Those microbiological analysis were performed by the Mycology Department at CHU Fort de France. The strains were also sent to the CNRMA at the Institut Pasteur (Paris, France) for diagnostic confirmation by molecular biology.

The clinical picture improved favorably, allowing discharge from the hospital on the thirteenth day under natamycin eye drops and voriconazole eye drops and orally. The patient’s condition improved favorably, and the treatment was maintained at full dose for 8 weeks, with a gradual decrease leading to a complete cessation of treatment around the third month. At the end of the treatment, the patient achieved a visual acuity of 20/50 due to the presence of a stromal scar in the visual axis (Fig. 3).

Fig. 3

Clinical photography at M3

Discussion

While fungal keratitis is estimated at 1.5 million cases per year globally [3], Lasiodiplodia theobromae keratitis remains understudied. An extensive literature review in November 2023, utilizing databases such as PubMed and Google Scholar with the keywords “lasiodiplodia” and “keratitis”, revealed no previous instances of Lasiodiplodia theobromae keratitis being managed with only this specific antifungal regimen.

The analysis of the literature was complicated by several factors. Firstly, there are few experimental studies in this field, but mostly descriptive studies, mainly case reports, which limits the scientific conclusions. Moreover, some fungi can be saprophytic in the flora of the eyelids and conjunctiva, particularly in individuals working outdoors in conditions of high heat and humidity. It is also sometimes difficult to identify the fungal strain, and some misclassifications may occur. This underscores the importance of collaborating with competent microbiological analysis services in centers treating serious ocular infectious pathologies.

Only 68 ocular infection cases are described in the literature, including one in French Guiana [4] and one in Martinique [5], comprising 65 keratitis cases and 3 endophthalmitis cases (Table 1). This contrasts with over 5000 references for Fusarium keratitis and more than 4000 for Aspergillus keratitis [6].

Table 1 Previous Lasiodiplodia theobromae ocular infection cases

The geographic distribution of these infections mirrors of other fungal germs, being rare in Western countries and more frequent in hot and humid climates (Fig. 4) [3]. In addition, there is a diversity of genera and species of molds that can be involved in ocular infections given the significant fungal biodiversity in tropical countries [7]. This partly explain why it’s complicated to have validated therapeutic protocols. Also, most reported cases lack information on patient management and outcomes. Only 30 patient’s management details are known, without always specifying the antifungals used, and among them, the final outcomes of 19 patients are known (Table 1).

Fig. 4

Map showing reported cases of L. theobromae ocular infections

Excluding endophthalmitis cases, which all resulted in evisceration, 11 out of 27 patients required a corneal transplant. 9 out of 19 recovered with a visual acuity (VA) less than 20/40. 7 out of 19 recovered with a visual acuity (VA) more than 20/40, and 3 patients lost their eyeball (Table 1). These keratitis cases have a terrible prognosis, comparable to the worst series in the literature for fungal keratitis [8].

Regarding risk factors, we discussed the geographical distribution favoring hot and humid climates. In published observations, keratitis primarily occurs in traumatized eyes with a context of contamination by soil or plants [9,10,11,12]. Additionally, diagnostic delays of several months are sometimes evident [11]. There are also notions of prescribing topical corticosteroids by primary care providers [9, 11,12,13,14,15]. It is concerning that topical corticosteroids are sometimes prescribed without the benefit of a thorough slit-lamp examination, a practice that may lead to severe consequences. This highlights the importance of proper training and preventive measures for healthcare providers.

Given the rarity of these infections, there is little information on the in vitro sensitivity of this germ. But in these papers the germ was sensitive to amphotericin B and voriconazole but resistant to other azoles (Table 2). It should be noted that, for our case, the sensitivity profile could not be carried out neither in our laboratory nor at the CNRMA of the Pasteur Institute due to the absence of fruiting bodies of the fungus (it is a fungus which does not fruit on the usual culture media) [16].

Table 2 Reports of in vitro sensitivity of Lasiodiplodia theobromae when involved in keratitis

Details of the medical treatments initiated are available for 13 patients for whom outcome data are available (Table 3). The results in these observations are very disappointing: the success of medical treatment alone was only found in 7 patients [9, 12, 15]. It is observed that all patients who received corticosteroid treatment had to undergo a corneal transplant or lost their eyeball [5, 9, 11, 13]. No treatment combination seems satisfactory. Even though all patients who received amphotericin B and natamycin without prior corticosteroids did not require surgery, they also had a very short care delay of less than 72 h [9]. A recent study by Konwar et al. documents a series of cases successfully treated with Voriconazole monotherapy, notably without the prior administration of corticosteroids. However, the precise duration between the onset of symptoms and the initiation of treatment was not disclosed [12]. Overall it is observed that patients with delayed care more often resorted to transplantation [11, 14].

Table 3 13 patients for whom detailed treatment and final outcome data are available

So, to our knowledge, this was the first favorable evolution of keratitis with a germ known for poor prognosis with the combination of natamycin and voriconazole, a combination found in most management protocols for fungal keratitis in the literature [17, 18, 23]. All this during rapid management without diagnostic wandering, and no previous administration of corticosteroid. The combination of Natamycin and Voriconazole could be considered a possible treatment for Lasiodiplodia theobromae keratitis as it has proven effective in the management of other fungal keratitis [19]. However, more robust studies are needed to support this hypothesis, but they are improbable due to the rarity of the infection.

In this analysis, we omitted a case report of Lasiodiplodia pseudotheobromae keratitis, a closely related organism, which had shown significant evolutionary adaptation when treated with a combination of natamycin and voriconazole, initiated one week following the onset of symptoms without prior exposure to corticosteroid therapy [20].

Conclusion

In summary, although no universally accepted treatment protocol for Lasiodiplodia theobromae keratitis exists due to generally poor outcomes and limited in vitro sensitivity data, our case report is one of the few demonstrating a favorable outcome of this infection. We have also conducted the most comprehensive synthesis of all published cases of keratitis caused by this organism. Critically, it seems that the rapid initiation of antifungal therapy—in the absence of prior corticosteroid use—significantly contributed to a favorable outcome. This underscores the importance of early diagnosis and prompt treatment initiation.