Infectious Diseases, 2015; Early Online: 1–4
BRIEF REPORT
Paradoxical response preceding control of Scedosporium apiospermum mycetoma with posaconazole treatment
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GUILLAUME BÉRAUD1, NICOLE DESBOIS2, CAROLINE COYO3, DANIÈLE QUIST4, BENOIT ROZÉ5, LUC SAVORIT6 & ANDRÉ CABIÉ5 From the 1Internal Medicine and Infectious Disease H8, University Hospital of Poitiers, Poitier, France, 2Microbiology Laboratory, 3Hospital Pharmacy, 4Dermatology Department, and 5Infectious Disease Department, University Hospital of Martinique, Fort de France, Martinique, and 6Clinique Saint-Paul, Fort de France, Martinique
Abstract Mycetoma is a chronic granulomatous infection that is difficult to treat, notably when due to fungi such as Scedosporium apiospermum. Recent antifungal agents could be an option, but cases are rarely reported, and none with posaconazole. Paradoxical responses, defined as initial clinical worsening despite appropriate treatment, are common in tuberculosis but rare in deep mycoses in non-immunocompromised hosts. Hence, paradoxical responses in context other than mycobacterial infection in an immunocompromised host could provide insights into the pathophysiology and the optimal strategy for treatment. We report the first case of a mycetoma caused by S. apiospermum with bone involvement treated with posaconazole, and the paradoxical response observed at the beginning of the treatment. As with mycobacterial infections, a paradoxical response in deep mycosis could represent the earliest marker of therapeutic efficacy.
Keywords: Mycetoma, Scedosporium apiospermum, paradoxical reaction, posaconazole
Introduction Scedosporium apiospermum is a saprophytic fungus frequently isolated from soil and water. It causes visceral infections in immunocompromised patients, and soft tissue infections in immunocompetent hosts. Mycetoma is a chronic granulomatous infection that is usually localized, causing nodule formation, draining sinuses, and discharge of ‘grain.’ It could be due either to fungus (eumycetoma) or to bacteria (actinomycetoma). While a bacterial mycetoma can be effectively managed by antibacterial therapy alone, a fungal mycetoma frequently requires a combination of antifungal therapy and surgery. S. apiospermum mycetoma is difficult to treat and usually requires limb amputation when bones are involved. Paradoxical responses, defined as clinical worsening despite appropriate anti-infectious treatment, were initially described in patients with tuberculosis [1] or leprosy [2]. They have been widely reported as the immune reconstitution inflammatory syndrome (IRIS) occurring in human immunodeficiency virus (HIV)-positive patients after initiation of highly
active antiretroviral therapy (HAART) [3]. However, they have rarely been described in deep endemic mycoses in the non-immunosuppressed host [4], and never for a mycetoma of a saprophytic fungus such as S. apiospermum. Paradoxical response in infections other than mycobacteria in the immunosuppressed host could provide insights into the pathophysiology and the optimal strategy for treatment. We report a case with a mycetoma caused by S. apiospermium with bone involvement in an immunocompetent patient presenting a paradoxical response after initiating a treatment with posaconazole. Case presentation A 40-year-old man from Martinique (French West Indies), of African descent, consulted the Infectious and Tropical Diseases Department of the University Hospital of Fort de France in 2007 for a mycetoma of the right foot that had been evolving for 15 years.
Correspondence: Guillaume Béraud, Infectious Disease H8, University Hospital of Poitiers, 2, rue de la Milétrie, BP 577 86021 Poitiers Cedex, France. Tel: ⫹ 33 (0) 6 82 75 27 26. E-mail: [email protected] (Received 12 February 2015 ; accepted 9 June 2015) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/23744235.2015.1062535
Infect Dis Downloaded from informahealthcare.com by University of Otago on 07/30/15 For personal use only.
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G. Béraud et al.
His past medical history was notable for a minor wound on his left foot by a nail 20 years earlier. In 1993, he first developed a mycetoma in the left foot. As no microorganisms were isolated and antibiotics were ineffective, fungal etiology was suspected and led to treatment with ketoconazole for 3 months and with itraconazole for 1 year without any improvement. In 1997 and 1998, all infected tissues were removed surgically. Secondarily, a skin graft was done, combined with terbinafine. No improvement was observed. In 2002, caspofungin combined with voriconazole was administered through a central venous catheter. Some improvement was observed, but a catheter infection required extraction and antibiotics. After 2.5 months of antifungal therapy and 2.5 months without, oral voriconazole was reintroduced in November 2003. Despite an increased dose after the first 3 months of oral voriconazole, the mycetoma progressed, joint and bone were involved, and numerous fistulas appeared and produced yellow ‘grain’ that was finally identified as S. apiospermum. After 8 months of ineffective therapy, in June 2004 the patient decided to discontinue voriconazole. On examination in 2007, his left foot was extremely painful and sensitive, with severe edema and numerous fistulas excreting yellow grains (Figure 1). S. apiospermum was cultured from these grains. CT scan confirmed chronic osteitis of the metatarsus and tibio-tarsus joint while magnetic resonance imaging showed diffuse inflammation of the foot (Figure 2). Laboratory tests showed no systemic inflammation, with normal white blood cell count (WBC) and C-reactive protein (CRP). The patient requested an amputation, but we proposed a final attempt at medical treatment with posaconazole. Posaconazole was given at 400 mg bid and was well tolerated. But after 2 weeks, inflammation and pain increased with abscess formation. Some fistulas began excreting even though they had been ‘dry’
Figure 1. Fistulas of the left foot.
Figure 2. (A) CT scan and (B) magnetic resonance imaging (MRI) of the left foot.
before treatment. Laboratory findings showed WBC and CRP of 10 600/mm3 and 60 mg/L, respectively. Pain was no longer controlled with non-steroidal anti-inflammatory drugs, but required oral morphine. Posaconazole was continued at the same dosage. Within a month, however, the patient’s condition dramatically improved. After 3 months, there was no more clinical inflammation, and the slight pain was controlled with occasional use of paracetamol alone, and half of the fistulas were closed. Edema nonetheless persisted and WBC was 10 900/mm3 and CRP 73 mg/L. After 4 and 6 months, only three nonproductive fistulas persisted, with no more inflammation, and slight mechanical pain only after a long walk. Edema was easily controlled by compression stockings. We had planned to maintain posaconazole
Scedosporium apiospermum and paradoxical response therapy for 18 months. After 1 year, the patient left Martinique and was lost to follow-up.
Infect Dis Downloaded from informahealthcare.com by University of Otago on 07/30/15 For personal use only.
Discussion Paradoxical response (initial worsening before improvement) is well known in the treatment of tuberculosis [5], notably in patients who are immunocompromised, e.g. IRIS after HAART initiation. To the best of our knowledge, it has not been described for other microorganisms in immunocompetent patients, with the notable exception of Mycobacterium ulcerans. M. ulcerans is an interesting model for paradoxical reaction, as the microorganism produces an immunosuppressive toxin known as mycolactone. An antibiotic-induced recovery of cellular immunity by the wash-out of mycolactone has been suggested [6]. We are not including in the spectrum of paradoxical response the Herxheimer reaction in syphilis and release of lipopolysaccharide (LPS) due to cell wall lysis in typhoid fever. In such cases, the pathophysiology (similar to the Mazzotti reaction with antiparasitic agents) is due not to immunologic changes, as with mycobacteria, but rather to the release of cell wall proteins. It should be noted that while a Mazzoti-like reaction occurs on the first day of treatment, reactions involving mycobacteria manifest after 1 or 2 months. Most of what we know about pathophysiology in paradoxical responses comes from cases where IRIS occurred after HAART initiation. Although the pathophysiology and predisposing factors of paradoxical responses are poorly understood, a common characteristic is that tuberculosis, leprosy, and mycoses are all chronic granulomatous diseases. Paradoxical response is considered as an exaggerated reaction to persistent microbial antigens revealed when disease-related immunosuppressive mechanisms are impaired. When the disease-related immune defect lasts for months or years, its partial restoration may lead to such exaggerated reactions. In fact, the patients with a paradoxical response in paracoccidioidomycosis [4] were treated after many years of evolution. Moreover, the major risk factor for an IRIS among HIV patients is the degree of immunodepression [3]. Consequently, one of the risk factors for a paradoxical reaction may be the restoration of a severe and/or prolonged immunodepression. Our patient had no systemic immunodepression but we could hypothesize that the mycetoma could result in impaired local immunity. Although no such mechanism has been described in vivo for S. apiospermum, ex vivo experiments showed a dose-dependent inhibition of phagocytosis induced by soluble α-glucan. This phenomenon was removed by pretreatment with α-amyloglucosidase [7]. Consequently, we suggest
3
that down-regulation of local immunity induced by α-glucan could be removed by antifungal treatment. Similarly to M. ulcerans, this could explain the paradoxical reaction observed in our patient [8]. Corticosteroid therapy has been proposed and used for IRIS, tuberculosis, and paracoccidioidomycosis. Of note, in a study on lymph node tuberculosis, corticosteroids did not affect the duration of the paradoxical reaction [9]. Successful medical treatment of mycetoma with voriconazole has been reported [10]. One article reported a case of brain abscess caused by S. apiospermum treated with posaconazole in a patient with leukemia [11]. No cases of either chronic infection or mycetoma with bone involvement treated with posaconazole have been reported in the literature. One explanation for failure of voriconazole could be the variable pharmacokinetics, notably in immunocompromised patients, where plasma level measurements are required to adjust dosage [12]. Although posaconazole must be administered with high-fat meal, between subjects its pharmacokinetics is remarkably stable. Even though healing can be considered complete only if no relapse occurs during the year after the end of treatment, the spectacular improvement experienced by our patient suggests that posaconazole could be an interesting option for treatment of S. apiospermum mycetoma with bone involvement. As a potentially efficient treatment, posaconazole could have restored local immunity and favored a paradoxical response. Hence, paradoxical response could be considered as an early marker of efficiency. Moreover, differentiating paradoxical reaction from treatment failure is crucial, to avoid unnecessary aggressive intervention such as amputation. Declaration of interest: The authors declare that they have no conflicts of interest.
Acknowledgment We wish to thank Jeffrey Arsham, an American medical translator, for reviewing our original English language text.
References [1] Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J Infect 1987;15:1–3. [2] Ridley DS, Radia KB. The histological course of reactions in borderline leprosy and their outcome. Int J Lepr Mycobact Dis 1981;49:383–92. [3] French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis 2009;48: 101–7.
Infect Dis Downloaded from informahealthcare.com by University of Otago on 07/30/15 For personal use only.
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G. Béraud et al.
[4] Gryschek RCB, Pereira RM, Kono A, Patzina RA, Tresoldi AT, Shikanai-Yasuda MA, et al. Paradoxical reaction to treatment in 2 patients with severe acute paracoccidioidomycosis: a previously unreported complication and its management with corticosteroids. Clin Infect Dis 2010;50: e56–8. [5] Cheng VCC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PCY, et al. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21:803–9. [6] Nienhuis WA, Stienstra Y, Abass KM, Tuah W, Thompson WA, Awuah PC, et al. Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis 2012;54:519–26. [7] Bittencourt VCB, Figueiredo RT, da Silva RB, Mourão-Sá DS, Fernandez PL, Sassaki GL, et al. An alphaglucan of Pseudallescheria boydii is involved in fungal phagocytosis and Toll-like receptor activation. J Biol Chem 2006;281:22614–23.
[8] Roilides E, Simitsopoulou M, Katragkou A, Walsh TJ. Host immune response against Scedosporium species. Med Mycol 2009;47:433–40. [9] Hawkey CR, Yap T, Pereira J, Moore DAJ, Davidson RN, Pasvol G, et al. Characterization and management of paradoxical upgrading reactions in HIV-uninfected patients with lymph node tuberculosis. Clin Infect Dis 2005;40:1368–71. [10] Porte L, Khatibi S, Hajj LE, Cassaing S, Berry A, Massip P, et al. Scedosporium apiospermum mycetoma with bone involvement successfully treated with voriconazole. Trans R Soc Trop Med Hyg 2006;100:891–4. [11] Mellinghoff IK, Winston DJ, Mukwaya G, Schiller GJ. Treatment of Scedosporium apiospermum brain abscesses with posaconazole. Clin Infect Dis 2002;34:1648–50. [12] Schaenman JM, DiGiulio DB, Mirels LF, McClenny NM, Berry GJ, Fothergill AW, et al. Scedosporium apiospermum soft tissue infection successfully treated with voriconazole: potential pitfalls in the transition from intravenous to oral therapy. J Clin Microbiol 2005;43:973–7.
BRIEF REPORT
Paradoxical response preceding control of Scedosporium apiospermum mycetoma with posaconazole treatment
Infect Dis Downloaded from informahealthcare.com by University of Otago on 07/30/15 For personal use only.
GUILLAUME BÉRAUD1, NICOLE DESBOIS2, CAROLINE COYO3, DANIÈLE QUIST4, BENOIT ROZÉ5, LUC SAVORIT6 & ANDRÉ CABIÉ5 From the 1Internal Medicine and Infectious Disease H8, University Hospital of Poitiers, Poitier, France, 2Microbiology Laboratory, 3Hospital Pharmacy, 4Dermatology Department, and 5Infectious Disease Department, University Hospital of Martinique, Fort de France, Martinique, and 6Clinique Saint-Paul, Fort de France, Martinique
Abstract Mycetoma is a chronic granulomatous infection that is difficult to treat, notably when due to fungi such as Scedosporium apiospermum. Recent antifungal agents could be an option, but cases are rarely reported, and none with posaconazole. Paradoxical responses, defined as initial clinical worsening despite appropriate treatment, are common in tuberculosis but rare in deep mycoses in non-immunocompromised hosts. Hence, paradoxical responses in context other than mycobacterial infection in an immunocompromised host could provide insights into the pathophysiology and the optimal strategy for treatment. We report the first case of a mycetoma caused by S. apiospermum with bone involvement treated with posaconazole, and the paradoxical response observed at the beginning of the treatment. As with mycobacterial infections, a paradoxical response in deep mycosis could represent the earliest marker of therapeutic efficacy.
Keywords: Mycetoma, Scedosporium apiospermum, paradoxical reaction, posaconazole
Introduction Scedosporium apiospermum is a saprophytic fungus frequently isolated from soil and water. It causes visceral infections in immunocompromised patients, and soft tissue infections in immunocompetent hosts. Mycetoma is a chronic granulomatous infection that is usually localized, causing nodule formation, draining sinuses, and discharge of ‘grain.’ It could be due either to fungus (eumycetoma) or to bacteria (actinomycetoma). While a bacterial mycetoma can be effectively managed by antibacterial therapy alone, a fungal mycetoma frequently requires a combination of antifungal therapy and surgery. S. apiospermum mycetoma is difficult to treat and usually requires limb amputation when bones are involved. Paradoxical responses, defined as clinical worsening despite appropriate anti-infectious treatment, were initially described in patients with tuberculosis [1] or leprosy [2]. They have been widely reported as the immune reconstitution inflammatory syndrome (IRIS) occurring in human immunodeficiency virus (HIV)-positive patients after initiation of highly
active antiretroviral therapy (HAART) [3]. However, they have rarely been described in deep endemic mycoses in the non-immunosuppressed host [4], and never for a mycetoma of a saprophytic fungus such as S. apiospermum. Paradoxical response in infections other than mycobacteria in the immunosuppressed host could provide insights into the pathophysiology and the optimal strategy for treatment. We report a case with a mycetoma caused by S. apiospermium with bone involvement in an immunocompetent patient presenting a paradoxical response after initiating a treatment with posaconazole. Case presentation A 40-year-old man from Martinique (French West Indies), of African descent, consulted the Infectious and Tropical Diseases Department of the University Hospital of Fort de France in 2007 for a mycetoma of the right foot that had been evolving for 15 years.
Correspondence: Guillaume Béraud, Infectious Disease H8, University Hospital of Poitiers, 2, rue de la Milétrie, BP 577 86021 Poitiers Cedex, France. Tel: ⫹ 33 (0) 6 82 75 27 26. E-mail: [email protected] (Received 12 February 2015 ; accepted 9 June 2015) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/23744235.2015.1062535
Infect Dis Downloaded from informahealthcare.com by University of Otago on 07/30/15 For personal use only.
2
G. Béraud et al.
His past medical history was notable for a minor wound on his left foot by a nail 20 years earlier. In 1993, he first developed a mycetoma in the left foot. As no microorganisms were isolated and antibiotics were ineffective, fungal etiology was suspected and led to treatment with ketoconazole for 3 months and with itraconazole for 1 year without any improvement. In 1997 and 1998, all infected tissues were removed surgically. Secondarily, a skin graft was done, combined with terbinafine. No improvement was observed. In 2002, caspofungin combined with voriconazole was administered through a central venous catheter. Some improvement was observed, but a catheter infection required extraction and antibiotics. After 2.5 months of antifungal therapy and 2.5 months without, oral voriconazole was reintroduced in November 2003. Despite an increased dose after the first 3 months of oral voriconazole, the mycetoma progressed, joint and bone were involved, and numerous fistulas appeared and produced yellow ‘grain’ that was finally identified as S. apiospermum. After 8 months of ineffective therapy, in June 2004 the patient decided to discontinue voriconazole. On examination in 2007, his left foot was extremely painful and sensitive, with severe edema and numerous fistulas excreting yellow grains (Figure 1). S. apiospermum was cultured from these grains. CT scan confirmed chronic osteitis of the metatarsus and tibio-tarsus joint while magnetic resonance imaging showed diffuse inflammation of the foot (Figure 2). Laboratory tests showed no systemic inflammation, with normal white blood cell count (WBC) and C-reactive protein (CRP). The patient requested an amputation, but we proposed a final attempt at medical treatment with posaconazole. Posaconazole was given at 400 mg bid and was well tolerated. But after 2 weeks, inflammation and pain increased with abscess formation. Some fistulas began excreting even though they had been ‘dry’
Figure 1. Fistulas of the left foot.
Figure 2. (A) CT scan and (B) magnetic resonance imaging (MRI) of the left foot.
before treatment. Laboratory findings showed WBC and CRP of 10 600/mm3 and 60 mg/L, respectively. Pain was no longer controlled with non-steroidal anti-inflammatory drugs, but required oral morphine. Posaconazole was continued at the same dosage. Within a month, however, the patient’s condition dramatically improved. After 3 months, there was no more clinical inflammation, and the slight pain was controlled with occasional use of paracetamol alone, and half of the fistulas were closed. Edema nonetheless persisted and WBC was 10 900/mm3 and CRP 73 mg/L. After 4 and 6 months, only three nonproductive fistulas persisted, with no more inflammation, and slight mechanical pain only after a long walk. Edema was easily controlled by compression stockings. We had planned to maintain posaconazole
Scedosporium apiospermum and paradoxical response therapy for 18 months. After 1 year, the patient left Martinique and was lost to follow-up.
Infect Dis Downloaded from informahealthcare.com by University of Otago on 07/30/15 For personal use only.
Discussion Paradoxical response (initial worsening before improvement) is well known in the treatment of tuberculosis [5], notably in patients who are immunocompromised, e.g. IRIS after HAART initiation. To the best of our knowledge, it has not been described for other microorganisms in immunocompetent patients, with the notable exception of Mycobacterium ulcerans. M. ulcerans is an interesting model for paradoxical reaction, as the microorganism produces an immunosuppressive toxin known as mycolactone. An antibiotic-induced recovery of cellular immunity by the wash-out of mycolactone has been suggested [6]. We are not including in the spectrum of paradoxical response the Herxheimer reaction in syphilis and release of lipopolysaccharide (LPS) due to cell wall lysis in typhoid fever. In such cases, the pathophysiology (similar to the Mazzotti reaction with antiparasitic agents) is due not to immunologic changes, as with mycobacteria, but rather to the release of cell wall proteins. It should be noted that while a Mazzoti-like reaction occurs on the first day of treatment, reactions involving mycobacteria manifest after 1 or 2 months. Most of what we know about pathophysiology in paradoxical responses comes from cases where IRIS occurred after HAART initiation. Although the pathophysiology and predisposing factors of paradoxical responses are poorly understood, a common characteristic is that tuberculosis, leprosy, and mycoses are all chronic granulomatous diseases. Paradoxical response is considered as an exaggerated reaction to persistent microbial antigens revealed when disease-related immunosuppressive mechanisms are impaired. When the disease-related immune defect lasts for months or years, its partial restoration may lead to such exaggerated reactions. In fact, the patients with a paradoxical response in paracoccidioidomycosis [4] were treated after many years of evolution. Moreover, the major risk factor for an IRIS among HIV patients is the degree of immunodepression [3]. Consequently, one of the risk factors for a paradoxical reaction may be the restoration of a severe and/or prolonged immunodepression. Our patient had no systemic immunodepression but we could hypothesize that the mycetoma could result in impaired local immunity. Although no such mechanism has been described in vivo for S. apiospermum, ex vivo experiments showed a dose-dependent inhibition of phagocytosis induced by soluble α-glucan. This phenomenon was removed by pretreatment with α-amyloglucosidase [7]. Consequently, we suggest
3
that down-regulation of local immunity induced by α-glucan could be removed by antifungal treatment. Similarly to M. ulcerans, this could explain the paradoxical reaction observed in our patient [8]. Corticosteroid therapy has been proposed and used for IRIS, tuberculosis, and paracoccidioidomycosis. Of note, in a study on lymph node tuberculosis, corticosteroids did not affect the duration of the paradoxical reaction [9]. Successful medical treatment of mycetoma with voriconazole has been reported [10]. One article reported a case of brain abscess caused by S. apiospermum treated with posaconazole in a patient with leukemia [11]. No cases of either chronic infection or mycetoma with bone involvement treated with posaconazole have been reported in the literature. One explanation for failure of voriconazole could be the variable pharmacokinetics, notably in immunocompromised patients, where plasma level measurements are required to adjust dosage [12]. Although posaconazole must be administered with high-fat meal, between subjects its pharmacokinetics is remarkably stable. Even though healing can be considered complete only if no relapse occurs during the year after the end of treatment, the spectacular improvement experienced by our patient suggests that posaconazole could be an interesting option for treatment of S. apiospermum mycetoma with bone involvement. As a potentially efficient treatment, posaconazole could have restored local immunity and favored a paradoxical response. Hence, paradoxical response could be considered as an early marker of efficiency. Moreover, differentiating paradoxical reaction from treatment failure is crucial, to avoid unnecessary aggressive intervention such as amputation. Declaration of interest: The authors declare that they have no conflicts of interest.
Acknowledgment We wish to thank Jeffrey Arsham, an American medical translator, for reviewing our original English language text.
References [1] Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J Infect 1987;15:1–3. [2] Ridley DS, Radia KB. The histological course of reactions in borderline leprosy and their outcome. Int J Lepr Mycobact Dis 1981;49:383–92. [3] French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis 2009;48: 101–7.
Infect Dis Downloaded from informahealthcare.com by University of Otago on 07/30/15 For personal use only.
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G. Béraud et al.
[4] Gryschek RCB, Pereira RM, Kono A, Patzina RA, Tresoldi AT, Shikanai-Yasuda MA, et al. Paradoxical reaction to treatment in 2 patients with severe acute paracoccidioidomycosis: a previously unreported complication and its management with corticosteroids. Clin Infect Dis 2010;50: e56–8. [5] Cheng VCC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PCY, et al. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21:803–9. [6] Nienhuis WA, Stienstra Y, Abass KM, Tuah W, Thompson WA, Awuah PC, et al. Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis 2012;54:519–26. [7] Bittencourt VCB, Figueiredo RT, da Silva RB, Mourão-Sá DS, Fernandez PL, Sassaki GL, et al. An alphaglucan of Pseudallescheria boydii is involved in fungal phagocytosis and Toll-like receptor activation. J Biol Chem 2006;281:22614–23.
[8] Roilides E, Simitsopoulou M, Katragkou A, Walsh TJ. Host immune response against Scedosporium species. Med Mycol 2009;47:433–40. [9] Hawkey CR, Yap T, Pereira J, Moore DAJ, Davidson RN, Pasvol G, et al. Characterization and management of paradoxical upgrading reactions in HIV-uninfected patients with lymph node tuberculosis. Clin Infect Dis 2005;40:1368–71. [10] Porte L, Khatibi S, Hajj LE, Cassaing S, Berry A, Massip P, et al. Scedosporium apiospermum mycetoma with bone involvement successfully treated with voriconazole. Trans R Soc Trop Med Hyg 2006;100:891–4. [11] Mellinghoff IK, Winston DJ, Mukwaya G, Schiller GJ. Treatment of Scedosporium apiospermum brain abscesses with posaconazole. Clin Infect Dis 2002;34:1648–50. [12] Schaenman JM, DiGiulio DB, Mirels LF, McClenny NM, Berry GJ, Fothergill AW, et al. Scedosporium apiospermum soft tissue infection successfully treated with voriconazole: potential pitfalls in the transition from intravenous to oral therapy. J Clin Microbiol 2005;43:973–7.
