Fatal Recurrent Disseminated Lomentospora prolificans Infection during Autologous Hematopoietic Stem Cell Transplantation — A Case Report and Review, and Discussion on the Importance of Prolonged Neutropenia
Vanessa Gow-Lee MD, Justin T. Moyers MD, Daniel K. Rogstad MD PhD
Acknowledgements: Dr. John Wong (Loma Linda University, Loma Linda, CA), Dr. James Ito (City of Hope, Duarte, CA)
[email protected] 200 1st St SW
Rochester, MN 55901
Manuscript Type: Case Report Abstract Words: 122
Manuscript Words: 1725
Running Title: Recurrent Disseminated L. prolificans
Infections with Scedosporium and Lomentospora species, in particular Lomentospora (previously Scedosporium) prolificans, are nearly universally fatal and rapidly-progressive in the transplant population. We report a case of a patient with diffuse large B-cell lymphoma undergoing myelosuppressive chemotherapy who developed disseminated L. prolificans infection which afterward persisted in his knee joint. The infection was treated with early empiric triple antifungal therapy tailored to synergy studies, growth factors to quickly resolve neutropenia, and aggressive debridement (where possible) of infection sites, including amputation. He achieved an 11-month remission until undergoing autologous hematopoietic stem cell transplantation with deep myelosuppression, wherein recrudescent L. prolificans infection occurred, causing death. We highlight the importance of early treatment, synergy studies, and especially recovery of neutropenia in treating this devastating condition.
Keywords: Scedosporium, scedosporiosis, Lomentospora prolificans, disseminated, hematologic malignancy, lymphoma, DLBCL, immunocompromised, neutrophil, neutropenia, surgical, antifungal, voriconazole, terbinafine, micafungin, echinocandin, azoles, survival, remission, transplant, g-cs
Scedosporium species are environmental fungi often found in soil and in polluted waters.1 The two medically-relevant species in humans are Scedosporium apiospermum (whose teleomorph is known as Pseudallescheria boydii) and Scedosporium prolificans, which has recently been reclassified as Lomentospora prolificans, and will be referred to as such. Although originally found mostly in soft-tissue infections, they have become increasingly identified as the cause of serious infections in the immunocompromised host.1 These fungi are now known to cause three disease categories in humans: local infections (mycetoma infections vs. nonmycetoma infections such as sinopulmonary, CNS, bone/joint), saprophytic colonization (e.g., pulmonary colonization in cystic fibrosis patients), and disseminated disease.1 Disseminated infections usually occur in immunocompromised patients, particularly patients with hematologic malignancies, who comprise up to 80% of disseminated cases in a study of 162 patients with L. prolificans infection.2
While both species have typically been found to be highly resistant to most systemically active antifungals, most studies of medical management have focused on the use of voriconazole, as
S. apiospermum has some susceptibility to the azoles.3 L. prolificans, however, thus far seems to be resistant to any single antifungal and only occasionally seems to respond to combination therapy (usually an azole plus terbinafine and/or an echinocandin). Even among cases of apparent response to this antifungal regimen, surgical intervention was often also employed.4, 5 Accordingly, the mainstay of treatment for both L. prolificans and S. apiospermum is moving more toward surgical debridement, with antifungal regimens and optimization of the patient’s immune status as adjunct therapy.
Poor prognostic factors are the species of fungus (with L. prolificans portending a worse prognosis than S. apiospermum), malignancy, neutropenia, CNS symptoms, and disseminated infection.2, 6, 7 Surgical debridement and recovery from any aplasia have been shown to decrease the risk of mortality, but because of anti-fungal resistance and the inability to surgically manage some infections, the prognosis of patients with systemic disease is poor, with mortality rates up to 85% in disseminated L. prolificans.2 Herein, we report a case of a patient with disseminated L. prolificans who gained temporary remission through rapid empiric antifungals, quick restoration of neutrophil count, and surgical management (including amputation). The patient ultimately died from recurrent disseminated infection after heavy immunosuppression was reintroduced during autologous stem- cell transplantation, despite our prior aggressive attempts of pathogen eradication. We present this case to especially highlight the importance of correcting immunosuppression where possible.
Our patient is a 63-year-old Hispanic male with a history of stage IV Diffuse Large B-cell Lymphoma (DLBCL). He was treated with 8 cycles of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) and had a residual biopsy-negative mesenteric mass which was irradiated. Three years after initial diagnosis, he was found to have enlarging cervical lymph nodes and a biopsy confirmed recurrent DLBCL. At that time, he was begun on R-IVAC (Rituximab, Ifosfamide, Vincristine, Doxorubicin, and Cyclophosphamide) with intrathecal methotrexate for neuraxial prophylaxis in high-risk disease.
Two weeks after cycle 1, he presented with headache, fever, and vomiting and was found to be severely neutropenic, with absolute neutrophil count (ANC) <0.5 bil/L for seven days. Due to recurring fevers, a broad work-up included a CT chest which illustrated multiple new focal nodular consolidations of both lungs and an area of cavitation, concerning for invasive fungal species (see Figure 1). Voriconazole and micafungin were empirically started, in addition to GM-CSF, and eventually bronchoscopic cultures grew both Aspergillus species (versicolor and tereus) and L. prolificans, and one blood culture grew L. prolificans. Soon after, he developed new left knee pain and a joint aspiration showed 22,900 nucleated cells (94% neutrophils) and uric acid crystals. He underwent prompt incision and drainage of the knee after fungal growth was seen on the synovial culture, which was identified eventually as L. prolificans. An MRI brain showed two small bifrontal parenchymal ring-enhancing lesions consistent with metastatic infection, but no biopsy was performed for culture (see Figures 2 and 3). Culture and susceptibility data, including synergistic studies done by checkerboard analysis, are summarized in Table 1.
He was febrile only five more days in the following month and his only symptoms were an intermittent dry cough and knee pain, with no neurologic symptoms. Three follow-up blood cultures were all negative, repeat chest CT ten days after the antifungals were started showed improvement of the lesions, and MRI brain at 21 days of antifungal treatment was stable. Terbinafine was added to the treatment regimen because of his persistent knee pain and due to hope of potential synergy with voriconazole, and he was discharged home with voriconazole, micafungin, and terbinafine on hospital day 41 while synergy studies were still pending.
Due to good clinical response from one cycle of chemotherapy, he was monitored clinically for progression of his malignancy while his disseminated infection was treated with antifungals.
Subsequent imaging showed continued improvement in his brain and pulmonary lesions and repeat fungal blood cultures as an outpatient were negative. However, his knee pain and inflammation persisted and worsened within two months after discharge. Arthrocentesis with culture showed persistent L. prolificans infection. He underwent two more arthroscopic surgeries and was continued on voriconazole and terbinafine, although susceptibility studies showed resistance to micafungin and no demonstrable synergy with the voriconazole/terbinafine combination. Approximately five months after diagnosis of scedosporiosis, he underwent an above-the-knee amputation of the left lower extremity to ensure clearance of infection, as he was being worked up for recurrent lymphoma and would need more chemotherapy followed possibly by stem-cell transplant.
Repeat biopsy of an enlarging parotid mass showed persistent diffuse large B-Cell lymphoma. Repeat bronchoscopic cultures did not show Aspergillus nor Lomentospora/Scedosporium species. Given he had undergone amputation of the residual site of infection and blood and pathologic cultures had been clear for three months after the amputation, he underwent four cycles of R-GemOx (Rituximab, Gemcitabine, Oxaliplatin) with growth factor support. He achieved a complete response to therapy and was referred for autologous hematopoietic stem cell transplant. Ten months after contracting scedosporiosis, he underwent BEAM conditioning and was engrafted with stem cells. One week after engraftment during a prolonged neutropenic phase, he developed renal and respiratory failure requiring intubation.
Bronchoscopic studies were positive for galactomannan antigen and he was treated with voriconazole, micafungin, and liposomal amphotericin B for presumptive invasive pulmonary Aspergillosis. Blood cultures ultimately grew L. prolificans, but before the results were available, our patient died on day 28 after engraftment.
Our patient with a history of DLBCL had several poor prognostic factors: disseminated infection with L. prolificans fungemia and involvement of lungs, knee, and possibly brain; underlying malignancy; neutropenia; and an inability to surgically debride all the foci of infection (although knee amputation was performed to address the joint infection). Although he was quickly started on empiric anti-fungals, it is unclear if the initial combination of voriconazole and micafungin or the later combination of voriconazole and terbinafine had a profound effect on the organism, since the eventual synergy studies could not demonstrate any significant synergy (although the MICs were lowered somewhat with combination testing – see Table 1). Since he also had lung infection with multiple Aspergillus species, this may be the reason for the improved chest imaging findings while on voriconazole and micafungin.
Ultimately, our patient died of disseminated scedosporiosis after stem cell transplantation. Interestingly, however, his death was 11 months after he first developed disseminated infection and he experienced clinical remission of the infection (with clearing of fungemia and radiographic improvement of pulmonary and CNS lesions). Although there are a few reports of immunocompromised, neutropenic patients with severe L. prolificans infections with prolonged survival (see Table 2), these infections typically exhibit a quickly deteriorating clinical course. In one study of 55 patients with L. prolificans bloodstream infection, the mean survival time was only 22 days.6 It is unlikely that our patient’s overall course was influenced significantly by surgical intervention or antifungals, given the inability to surgically debride all foci of infection and based on the synergy studies, which did not suggest much if any benefit to combination therapy. But in both our case and in several of these other reported cases, G-CSF was employed in patients to reduce the length of neutropenia. There were two cases reported of prolonged survival without G-CSF, but in one case, the infection was limited to a cellulitis alone and seems to have been successfully controlled with source control, and in another case of fungemia, the patient was not neutropenic.8, 9 This clinical association of recovery from neutropenia with better outcomes is supported by in vitro findings of neutrophil activity against L. prolificans and the success of combined G-CSF and antifungals in murine models.10, 11
Given these findings, the resolution of our patient’s profound neutropenia within three days of pathogen discovery combined with the use of G-CSF was likely key to his prolonged survival. To further ensure clinical resolution, he also underwent knee amputation and was monitored for about two months off all anti-fungals, in order to proceed with treatment of his DLBCL. Although he was clinically judged to be cleared of any residual infection prior to transplantation and all pretransplant surveillance cultures and microbiologic data were consistent with this, his infection recurred after he underwent BMT. This recurrence during a time of severe neutropenia after months of clinical stability further supports the clinical importance of recovery from neutropenia as being perhaps the most important factor in his initial clinical improvement.
Disseminated infection due to L. prolificans typically carries a poor prognosis, due to its inherent resistance to antifungals and the frequent inability to adequately surgically remove foci of infection. Our patient with underlying DLBCL and disseminated L. prolificans infection remained unusually clinically stable for many months despite several poor prognostic factors, likely due to the short duration (i.e., one week) of his initial neutropenia at the time of dissemination. Despite great efforts to ensure clearance of infection and a clinical course that strongly suggested resolution of disease, he had a recurrence of disseminated scedosporiosis after stem cell transplantation when he was severely neutropenic once again. Rather than representing an encouraging response to therapy, therefore, our patient’s case more likely represents the importance of recovery from underlying neutropenia in the prognosis of L. prolificans infections. Additionally, this insight into our patient’s course and ultimate outcome should serve as a cautionary tale regarding repeating heavy immunosuppression in patients with a history of disseminated L. prolificans infection, even if the infection has been deemed clinically resolved.
1. Cortez KJ, Roilides E, Quiroz-Telles F, et al. Infections caused by Scedosporium spp. Clin Microbiol Rev. 2008;21(1):157–197. doi: 10.1128/CMR.00039-07
2. Rodriguez-Tudela JL, Berenguer J, Guarro J, et al. Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases. Med Mycol. 2009;47(4):359–379. doi: 10.1080/13693780802524506
3. Troke P, Aguirrebengoa K, Arteaga C, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother. 2008;52(5):1743-1750.
4. Whyte M, Irving H, O’Regan P, et al. Disseminated Scedosporium prolificans infection and survival of a child with acute lymphoblastic leukemia. Pediatr Infect Dis J. 2005;24(4):375– 377.
5. Howden BP, Slavin MA, Schwarer AP, et al. Successful control of disseminated Scedosporium prolificans infection with a combination of voriconazole and terbinafine. Eur J Clin Microbiol Infect Dis. 2003;22(2):111–113. doi: 10.1007/s10096-002-0877-z
6. Seidel D, Meißner A, Lackner M, et al. Prognostic factors in 264 adults with invasive Scedosporium spp. and Lomentospora prolificans infection reported in the literature and FungiScope(R). Crit Rev Microbiol. Jan 2019:1–21. doi: 10.1080/1040841X.2018.1514366.
7. Lamaris GA, Chamilos G, Lewis RE, et al. Scedosporium infection in a tertiary care cancer center: a review of 25 cases from 1989-2006. Clin Infect Dis. 2006; 43(12):1580-1584. doi: 10.1086/509579
8. Cooley L, Spelman D, Thursky K, et al. Infection with Scedosporium apiospermum and S. prolificans, Australia. Emerg Infect Dis. 2007; 13(8):1170–1177. doi: 10.3201/eid1308.060576
9. Tong S, Peleg A, Yoong J, et al. Breakthrough Scedosporium prolificans infection while receiving voriconazole prophylaxis in an allogeneic stem cell transplant recipient. Transpl Infect Dis. 2007; 9(3):241–243. doi: 10.1111/j.1399-3062.2007.00203.x
10. Gil-Lamaignere C, Maloukou A, Rodriguez-Tudela JL, et al. Human phagocytic cell responses to Scedosporium prolificans. Med Mycol. 2001;39(2):169–175.
11. Ortoneda M, Capilla J, Pastor FJ, et al. Interaction of granulocyte colony-stimulating factor and high doses of liposomal amphotericin B in the treatment of severe murine scedosporiosis. Diagn Microbiol Infect Dis. 2004;50(4):247–251. doi: 10.1016/j.diagmicrobio.2004.07.011
12. Bouza E, Munoz P, Vega L, et al. Clinical resolution of Scedosporium prolificans fungemia associated with reversal of neutropenia following administration of granulocyte colony stimulating factor. Clin Infect Dis. 1996; 23: 192193.
13. Johnson LS, Shields RK, Clancy CJ. Epidemiology, clinical manifestations, and outcomes of Scedosporium infections among solid organ transplant recipients. Transpl Infect Dis. 2014;16(4):578–587. doi: 10.1111/tid.12244