Successful Treatment of Lomentospora Prolificans Infection Following Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report and Literature Review

Introduction

Due to neutropenia, immunosuppressive treatments, and suboptimal reconstruction of immunity, allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are vulnerable to invasive fungal infections (IFIs), which represent a leading cause of non-relapse mortality and prolonged hospitalization in this population.^1–3 IFIs are predominantly caused by Candida spp., Aspergillus spp. or Mucorales.⁴ However, as an emerging opportunistic fungal pathogen with a high mortality rate, Lomentospora prolificans has been increasingly reported in immunocompromised individuals over the past three decades. Cases have been documented in the United States, Australia, and several European countries, particularly Spain.^5–8 Lomentospora prolificans can cause disseminated infections involving multiple organs with fungemia, as well as localized infections such as pulmonary or cerebral invasive mycosis and osteoarticular infections.⁶ Previous studies have demonstrated that Lomentospora prolificans exhibits intrinsic resistance to most conventional antifungal agents, including triazoles and amphotericin B.⁹ Moreover, breakthrough infections have been observed even in patients receiving antifungal prophylaxis, often with poor clinical outcomes.^10,11 Therefore, identifying optimal therapeutic strategies for Lomentospora prolificans infections is of critical importance. Current consensus guidelines recommend voriconazole as the first-line treatment,^12,13 and a retrospective study by Jenks et al has highlighted the efficacy of voriconazole-terbinafine combination therapy.¹⁴ Here, we report the first successfully treated case of post-HSCT Lomentospora prolificans infection in China using a combination of voriconazole and terbinafine. To our knowledge, this represents the longest survival reported among all documented cases of Lomentospora prolificans infection, which contributes valuable clinical data and insights into the diagnosis and management of Lomentospora prolificans infections.

Case Report

A 27-year-old male was admitted to the hospital in October 2019 with a persistent fever. Subsequent bone marrow analysis confirmed a diagnosis of acute myelomonocytic leukemia (AML-M4). On June 15, 2020, the patient underwent matched sibling donor (MSD) allo-HSCT due to poor response to chemotherapy and recurrent relapses. The patient had an ECOG performance status of grade 2 and a Karnofsky Performance Status (KPS) score of 80 prior to HSCT, with a Hematopoietic Cell Transplantation–Comorbidity Index (HCT-CI) of 2. Neutrophils and platelets successfully engrafted on day +12 (day+12 means the twelfth day after the day of stem cell infusion). After HSCT, He received Cyclosporine A(CsA) for GVHD prevention while CsA was tapered and discontinued by day+90. Due to persistent MRD positivity, a prophylactic donor lymphocyte infusion (DLI) was administered on day+30 and a preemptive treatment with interferon-α was administered on day +128 to prevent relapse.^15,16 By day +144, he developed severe cGVHD and methylprednisolone was used as first-line therapy, followed by second-line ruxolitinib and CsA. It is worth noting that the patient received posaconazole oral suspension for antifungal prophylaxis starting on day −9 (the first day of the conditioning regimen). Therapeutic drug monitoring (TDM) confirmed that posaconazole plasma concentrations were consistently maintained above the effective threshold (≥1.0 μg/mL).

He developed fever and cough with yellow-green sputum on day+151 (Figure 1). Chest computed tomography (CT) revealed mild inflammation in the bilateral lower lung lobes (Figure 2A). Multiple sputum bacterial cultures obtained between days +151 and +183 identified Klebsiella pneumoniae producing extended-spectrum beta-lactamases (ESBLs). Cefoperazone-Sulbactam and subsequently Imipenem were administered. By day +161, CT showed improvement (Figure 2B). Then he developed cytomegalovirus viremia and subsequent ganciclovir treatment was administrated. The patient then developed neutropenia on day +168. On day +171, his symptoms, including cough and expectoration, worsened, and chest CT revealed multiple infections in both lungs, showing progression compared to previous scans (Figure 2C).

Figure 1 Timeline of the episodes of Lomentospora prolificans infection involving therapeutic interventions and diagnostic hallmarks.

Figure 2 Representative CT scans of the patient’s lungs at different time points post-HSCT. (A) Day +151; (B) Day +161; (C) Day +171, first sputum culture identified as Lomentospora prolificans; (D) Day +178; (E) Day +189; (F) Day +197, (G) Day +203, last sputum culture identified as Lomentospora prolificans; (H) Day +210, (I) Day +231, (J) Day +274, outpatient, (K) Day +318, (L) Day +367.

The first sputum culture identified Lomentospora prolificans, with subsequent cultures consistently detecting the same pathogen from day +171 to day +197. Incubated at 28°C for 5–7 days, colonies on SCDA medium appeared flat, spreading, black, and velvety (Figure 3A). On SDA medium, colonies were flat, spreading, olive-gray, and suede-like in texture (Figure 3B). Lactophenol cotton blue staining followed by observation under a fluorescence microscope at 400× magnification reveals the characteristic morphological features of the fungus. Lomentospora prolificans produces conidia through annellidic conidiogenesis, distinguished by annellations on the conidiogenous cells. The conidia are single-celled, hyaline to light brown, ovoid to pyriform in shape, with a thin, smooth cell wall. They are arranged in small clusters in an acropetal fashion on flask-shaped conidiogenous cells, which exhibit basal swelling where they connect to the hyphae (Figure 3C and D). Antifungal susceptibility testing was performed using the E-test method (bioMérieux, France) in adherence to the manufacturer’s protocol and Aspergillus flavus ATCC^® 204304 was employed as the quality control (QC) strain to monitor the reliability of the antifungal susceptibility testing. The result indicated that Amphotericin B, Itraconazole, Caspofungin, and Voriconazole all had a minimum inhibitory concentration (MIC) exceeding 32 μg/mL, suggesting high-level resistance.

Figure 3 Morphological characteristics of Lomentospora prolificans. (A) colonies on SCDA medium; (B) On SDA medium; (C and D) Lactophenol cotton blue staining.

On day +172, He was administered with voriconazole (0.2g q12h) and oral terbinafine (0.25g q12h) for Lomentospora prolificans eradication. During day +177 to day +197, the β-D-glucan (BDG) test fluctuated between 97 and 123 pg/mL and voriconazole plasma concentration was maintained around 2.0 μg/mL. On day +197, he developed high fever and dyspnea. A CT scan revealed further exacerbation of the lung infection, characterized by an increased number of infectious lesions and an expanded affected area (Figure 2C–F). Then he received combination antibacterial therapy with meropenem for five days, after which his body temperature returned to normal. Sputum cultures converted to negative for Lomentospora prolificans from day +198. Additionally, chest CT showed gradual improvement starting from day +203. After being discharged on day +215, he continued oral voriconazole and terbinafine. Pulmonary CT continued to show sustained improvement up to one-year post-transplant, and at the last follow-up, he remained alive at 58 months post-allo-HSCT (Figure 2G–L).

Literature Review

Methods

We conducted a PubMed keyword-based search search using the term “((((Scedosporium prolificans) OR (Lomentospora prolificans)) OR (Scedosporium inflatum)) AND (infection)) AND (transplant)”, including articles published up to March 2025. Case reports or articles concerning Lomentospora prolificans infection in HSCT recipients were included, while studies that concerning Lomentospora prolificans infection in solid organ transplantation was excluded. After screening and data extraction, 24 studies were selected, encompassing a total of 37 reported cases of Lomentospora prolificans infection after HSCT (Table 1).

Table 1 Characteristics of Reported Cases of Post-HSCT Lomentospora Prolificans Infections

Baseline Data

The 37 reported cases came from nine countries, with Australia (11 cases, 29.7%) and Spain (10 cases, 27%) having the most. Among the patients, 19 (51.4%) were male, and the mean age was 43 years (±16; range: 3–67).

The most common underlying disease was acute myeloid leukemia (AML; 11 cases, 29.7%), followed by chronic myeloid leukemia (CML; 7 cases), multiple myeloma (MM; 5 cases), and lymphoma (5 cases: 4 non-Hodgkin lymphoma [NHL], 1 Hodgkin lymphoma [HL]). Other diseases included acute lymphoblastic leukemia (ALL; 2 cases), aplastic anemia (1 case), myelofibrosis (1 case), myelodysplastic syndrome (1 case), breast cancer (1 case), neuroblastoma (1 case), and X-linked chronic granulomatous disease (1 case). Underlying diseases were unreported in two cases.

Risk or Predisposing Factors

All 37 patients underwent HSCT, with 24 (64.7%) receiving allo-HSCT and 7 (18.9%) undergoing auto-HSCT. Post-HSCT immunosuppressants were used for GVHD prophylaxis or treatment.

Among 30 patients with available risk factor data (81.1%), neutropenia was most common (19 patients, 63.3%). Acute GVHD (aGVHD) occurred in 6 patients (20%), chronic GVHD (cGVHD) in 7 (35%), and immunosuppressants were recorded in 13 (43.3%).

Origin of the Isolate and Location of Infection

Lomentospora prolificans infection was diagnosed via culture from blood (25/37, 67.6%), bronchoalveolar lavage (10/37, 27.0%), sputum (8/37, 21.6%), skin (5/37, 13.5%), and urine (8/37, 21.6%). Four cases (10.8%) were diagnosed postmortem by autopsy.

Disseminated infection was most common (31/37, 83.8%). Lung was most frequently affected (18/37, 48.6%), followed by the central nervous system (CNS; 8 cases, 21.6%, including 3 meningitis cases). Ocular involvement occurred in 7 cases (18.9%, with 4 endophthalmitis cases). Other sites included skin (3/37, 8.1%), bone and joints (4/37, 10.8%), and one endocarditis case, with Lomentospora prolificans cultured from endocardial vegetation.

Antifungal Treatment

Treatment records were available for 33 patients, with 26 (78.8%) receiving combination antifungal therapy and 7 (21.2%) receiving monotherapy. The most common combination was amphotericin B (AMB) plus a triazole (13/26), especially AMB + itraconazole (8/13). Voriconazole (VZ) combined with terbinafine (TBF) was used in 8 patients. Monotherapy consisted of either AMB or a triazole.

Lomentospora prolificans was tested for antifungal susceptibility in 9 studies (Table 2). According to CLSI guidelines, MIC was used for triazoles and AMB, while minimum effective concentration (MEC) was used for echinocandins. For geometric mean calculations of MIC, MEC, and FICI, out-of-range values were adjusted to the next highest concentration.

Geometric mean MIC values were: voriconazole (5.04 μg/mL), itraconazole (24.66 μg/mL), posaconazole (21.11 μg/mL), isavuconazole (22.63 μg/mL), amphotericin B (14.67 μg/mL), and terbinafine (2.83 μg/mL). For echinocandins, geometric mean MEC values were 5.66 μg/mL for micafungin and 4.00 μg/mL for caspofungin.

Table 2 Susceptibility Testing of Lomentospora Prolificans

Synergy testing was performed in four studies (Table 3), with three showing synergistic effects of VZ + TBF combination. Synergy was defined as FICI ≤0.5, no interaction as 0.5 < FICI ≤ 4.0, and antagonism as FICI > 4.0.⁴⁰

Table 3 Synergistic Test of Voriconazole and Terbinafine Combination Therapy

Clinical Outcome of Patients

Among the 37 patients, only 5 (13.5%) survived, resulting in an overall mortality rate of 86.5%. Four survivors received combination antifungal therapy, while only one survived with monotherapy. Survival rates were 12.5% for AMB + triazoles and 23.1% for VZ + TBF. Of the five survivors, two had localized infections, one underwent debridement surgery, and one had breast cancer. Three received Granulocyte Colony-Stimulating Factor (G-CSF) during the neutropenic phase.

Discussion

Our case is characterized by a patient with relapsed acute myeloid leukemia (AML) who underwent allo-HSCT while in a minimal residual disease (MRD)-positive state. Post-transplant, the recurrence of MRD further exposed him to the risk of cGVHD. During both first-line and second-line treatment for cGVHD, he received posaconazole prophylaxis according to guideline recommendations, with therapeutic drug monitoring confirming effective plasma concentrations. However, this prophylaxis proved ineffective against Lomentospora prolificans. Upon diagnosis, we promptly adjusted antifungal therapy to a combination of voriconazole and terbinafine, ultimately achieving successful clearance of the Lomentospora prolificans infection. Remarkably, the patient maintained MRD-negative remission for nearly five years post-transplant. To the best of our knowledge, this represents the longest survival reported among all documented cases of Lomentospora prolificans infection.

Among malignancies, leukemia and lymphoma are the primary contributing risk factors for Lomentospora prolificans infection.^5,6,41 For patients with hematological malignancies who had HSCT, neutropenia and immunosuppressive therapy were also unavoidable. Seidel et al also demonstrated that allo-HSCT is an independent risk factor associated with poor outcomes in patients infected with Lomentospora prolificans.⁴² Husain et al demonstrated that Lomentospora prolificans infection was more prevalent in HSCT patients than in solid organ transplantation (SOT) patients (39.1% vs 16.9%, P = 0.045). Moreover, HSCT patients were more frequently affected by fungemia,⁴³ and Lomentospora prolificans infection was frequently disseminated and significantly associated with higher rate of 1-month mortality (HR = 6.87, P < 0.001).⁴⁴ According to Konsoula et al, although Lomentospora prolificans infection is rare in immunocompromised patients, the overall mortality rate is relatively high, reaching 87.3% in cases of disseminated infection. In our review, the overall mortality rate of Lomentospora prolificans infection in HSCT patients was 86.5%, markedly higher than the reported mortality rates of post-HSCT invasive fungal infections, which range from 13.7% to 47%.^45–48

Currently, many antifungal agents are largely ineffective in eradicating Lomentospora prolificans infections. In our case, the isolated strain exhibited resistance to amphotericin B, itraconazole, caspofungin, and voriconazole, with all agents demonstrating a minimum inhibitory concentration (MIC) of ≥32 μg/mL. However, many studies have found that combination therapy can possibly improve treatment outcomes. Terbinafine and triazoles target different stages of fungal ergosterol biosynthesis, suggesting potential synergy. Terbinafine (an allylamine) inhibits squalene epoxidase, causing squalene accumulation and defective ergosterol production. Triazoles inhibit 14α-demethylase, blocking lanosterol methylation, a key step in ergosterol synthesis. This complementary action may enhance antifungal efficacy and improve outcomes.⁴⁹ Several in vitro studies have demonstrated the efficacy of voriconazole plus terbinafine combination therapy. In 2000, Meletiadis et al reported that itraconazole plus terbinafine showed in vitro synergy against nearly all Lomentospora prolificans isolates after 48 and 72 hours.^50,51 Subsequently, they applied a modified MIC analysis method and a novel statistical model, which further demonstrated that voriconazole also exhibited significant in vitro synergistic effects when combined with terbinafine.⁵² In 2003, Howden et al successfully treated disseminated Lomentospora prolificans infection with voriconazole and terbinafine.²⁴ In 2020, Jenks et al conducted a retrospective study of 41 cases of invasive Lomentospora prolificans infections, revealing that the voriconazole plus terbinafine combination therapy was associated with significantly improved overall survival.¹⁴

Apart from the synergistic antifungal effects of voriconazole and terbinafine, several other factors may have contributed to the successful control of Lomentospora prolificans infection. Including the recovery of innate and adaptive immunity following the rapid cessation of immunosuppressive agents, resolution of prolonged neutropenia through the administration of G-CSF, and the potential benefit of adjunctive debridement surgery in reducing fungal burden.^24,44,45 These supportive interventions likely played a crucial role in improving treatment outcomes in patients with Lomentospora prolificans infection.

Finally, it is worth mentioning that our case represents a single patient experience, and factors such as the patient’s relatively young age, specific immune reconstitution profile, or the early initiation of combination therapy may not be generalizable to all immunocompromised hosts with Lomentospora prolificans infection. Future multi-center prospective registries, collaborative studies, better therapies and rapid diagnostic tools are pressingly needed.

Conclusions

This case highlights the importance of early recognition and prompt initiation of synergistic antifungal therapy (voriconazole-terbinafine) for Lomentospora prolificans infection in immunocompromised patients. The sustained remission achieved in this patient underscores the importance of combination antifungal strategies. However, the persistently high mortality rate (86.5% in HSCT recipients) emphasizes the critical need for novel antifungals and improved diagnostic tools for Lomentospora prolificans infection.