C
American Journal of Transplantation 2015; 15: 560–564 Wiley Periodicals Inc.
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13002
Case Report
Dramatic Improvement of Severe Cryptococcosis-Induced Immune Reconstitution Syndrome With Adalimumab in a Renal Transplant Recipient A. Scemla1,*, S. Gerber2, A. Duquesne1, P. Parize3, F. Martinez1, D. Anglicheau1, R. Snanoudj1, M. Zuber4, M.-E. Bougnoux5, C. Legendre1 and O. Lortholary3,6,* 1
Service de Ne´phrologie et Transplantation Adulte, Hoˆpital Necker Enfants Malades, Assistance PubliqueHoˆpitaux de Paris, Universite´ Paris Descartes Sorbonne Paris Cite´, RTRS Centaure, Paris, France 2 Service de Radiologie, Hoˆpital Saint-Joseph, Universite´ Paris Descartes Sorbonne Paris Cite´, Paris, France 3 Universite´ Paris Descartes, Hoˆpital Necker Enfants Malades, Assistance Publique-Hoˆpitaux de Paris, Centre d’Infectiologie Necker Pasteur, IHU Imagine, Paris, France 4 Service de Neurologie et Neurovasculaire, Hoˆpital SaintJoseph, Universite´ Paris Descartes Sorbonne Paris Cite´, Paris, France 5 Service de Mycologie Parasitologie, Hoˆpital Necker Enfants Malades, Assistance Publique-Hoˆpitaux de Paris, Universite´ Paris Descartes Sorbonne Paris Cite´, Paris, France 6 Institut Pasteur, Centre National de Re´fe´rence Mycoses Invasives et Antifongiques, Paris, France Corresponding authors: Anne Scemla, [email protected], and Olivier Lortholary, [email protected]
Received 15 April 2014, revised 07 August 2014 and accepted for publication 23 August 2014
Introduction In solid organ transplant (SOT) recipients, cryptococcosis is the third most common cause of invasive fungal infection after Candida spp and Aspergillus spp infections, with an overall incidence of 0.3–5% (1,2). Most of the cases are disseminated with central nervous system involvement in up to 62% of the cases whose lumbar puncture is performed and are associated with a high mortality rate (3,4). Cryptococcosis-related immune reconstitution inflammatory syndrome (IRIS) affects up to 30% of HIV-infected patients (4) and may result in neurological worsening and increased mortality. Thus far, only a few reports have described IRIS after tapering immunosuppressive drugs in the context of SOT (5–8). Here, we describe a case of severe cryptococcal meningo-encephalitis-related IRIS occurring after immunosuppressive regimen reduction, which was resistant to highdose steroids but dramatically improved as early as 2 weeks after anti-TNF-a therapy (adalimumab) initiation (Figure 1).
Case In solid organ transplant recipients, immune reconstitution inflammatory syndrome (IRIS) is a rare complication of cryptococcosis, which may require steroids in its most severe forms. Here, we report the case of a renal transplant recipient who developed severe cryptococcal meningitis-associated IRIS 1 week after immunosuppression reduction. Highdose steroids failed to improve the disease. Finally, a recombinant human monoclonal tumor necrosis factor-a (TNF-a) antagonist, adalimumab, was prescribed, and the patient rapidly experienced dramatic neurological improvement. No IRIS relapse occurred within 14 months following adalimumab discontinuation. Abbreviations: CNS, central nervous system; IRIS, immune reconstitution inflammatory syndrome; TNFa, tumor necrosis factor a 560
A 43-year-old woman received a kidney from a living donor in 2004 for end-stage renal failure related to an IgA nephropathy. Induction and maintenance of immunosuppressive (IS) therapy consisted of basiliximab induction, steroids, tacrolimus and mycophenolate mofetil. She developed new-onset diabetes after transplantation. Fiftythree months after kidney transplantation (KT), norovirusrelated acute gastroenteritis was diagnosed and resolved spontaneously without immunosuppression tapering. Three months later, she complained of headache and fatigue. Her blood pressure was 137/86 mmHg, and brain magnetic resonance imaging (MRI) was normal. Two months later, she was admitted for acute dizziness and confusion. Neurological examination found marked disorientation, nystagmus and cerebellar ataxia. Brain MRI (Figures 2 and 3: A1, A2, A3, A4) showed ventriculomegaly
Anti-TNF Therapy in Cryptococcal IRIS IRIS diagnosis Adalimumab SC -----every 2 weeks
Right CSF derivaon
Clinical management
Le CSF derivaon LAmB and 5FC
Tac 6mg/d
200mg/d
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IV CyA, 30mg/d
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800 500 370 380
d1
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d12
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Figure 1: Evolution of immunosuppressive therapy, CSF protein levels and antifungal therapy. LAmB, liposomal amphotericin; 5FC, flucytosine; MMF, mycophenolate mofetil; SMD, solumedrol; Tac, tacrolimus; CyA, cyclosporine; d, day; Pred, prednisone; DXM, dexamethasone; FCZ, fluconazole; CSF, cerebrospinal fluid; SC, subcutaneous; Right and left derivations, right and left lateral ventricles.
Figure 2: Consecutive cerebral MRIs, Ax FLAIR WIs. Initial MRI (A1, A2) shows the occurrence of ventricular dilatation involving both supra tentorial and 4th ventricles. High signal T2 FLAIR of periventricular white matter reflects the trans-ependymal resorption. Partitioning of the ventricles is observed on the 2nd MRI (B1, B2) as increased hydrocephalus. Secondary damages of the periventricular white matter are observed as extended high signal FLAIR. Slight decrease of white matter involvement is noted on the last MRI (C1, C2) especially close to the 4th ventricle.
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Figure 3: Cerebral MRIs: 3D SPGR T1 with Gd-DTPA injection WIs. Contrast enhancement of the ventricle walls, initially missing (A3, A4), is associated with intraventricular enhanced septa and lobulations on the 2nd MR (B3, B4); on the control MR (C3, C4), decreased enhancement of the partitioned ventricles attests to the regression of the inflammatory process. Laminar necrosis of the frontal cortical ribbon observed as high signal T1 (white arrow on B4) occurs as a vascular complication, decreasing on control MR (C4).
with diffuse and extensive periventricular areas of hypersignal on T2 weighted images, involving white matter along ventricular margins compatible with trans-ependymal resorption. Slight contrast enhancement of the ventricular margins was noted without clear leptomeningeal enhancement. Similar abnormalities were observed in the posterior fossa. Immunosuppression consisted of prednisone (10 mg/day), tacrolimus (11 mg/day) and mycophenolate mofetil (500 mg bid). A lumbar puncture was performed: cerebral spinal fluid (CSF) opening pressure was 15 cm H2O; white blood cell count: 145 cells/mm3, 96% lymphocytes; glucose: 50 mg/dL (peripheral glucose: 140 mg/dL); and total protein level: 380 mg/dL with positive India ink staining. CSF and serum cryptococcal antigen (CRAG) (Premier cryptococcal antigen, Meridian, Biosciences, Cincinnati, OH) titers were 271 and 125, respectively. A CSF culture yielded Cryptococcus neoformans, while urinary and blood fungal cultures were negative. Chest computed tomography was normal. Liposomal amphotericin B (3 mg/kg/day) and flucytosine (50 mg/kg/day adapted to renal function, with serum creatinine level: 160 mmol/L, 1.8 mg/dL) were initiated on day 1. One day after the cryptococcosis diagnosis, mycophenolate mofetil was discontinued, 562
tacrolimus was reduced to 6 mg/day and prednisone was reduced to 7.5 mg/day. On day 8 after antifungal therapy initiation, her neurological condition worsened (Glasgow coma scale score: 10/15). Repeated CSF analyses revealed unchanged opening pressure (15 cm H2O), an increase in protein level up to 800 mg/dL on day 19, with a white blood cell count: 8 cells/mm3, glucose level: 22 mg/dL (peripheral glucose: 110 mg/dL) with negative bacterial and fungal cultures. CSF and serum CRAG titers decreased to 41 and 8, respectively, on day 8. Brain MRI (Figures 2 and 3: B1, B2, B3, B4) showed slightly increased hydrocephalus, with the appearance of inflammatory septations and lobulations of the ventricles. In addition, ependymal contrast enhancement markedly increased, and high signal FLAIR of periventricular white matter expanded. Laminar necrosis involving the right frontal cortex appeared as a high signal ribbon on T1WIs and as hypo-intensity on T2 star gradient echo weighted images. Two ventricular shunts were placed on days 8 and 12, but no improvement was noted (Glasgow coma scale score: 8/15). A short course of highdose steroid therapy (prednisone, 1 mg/kg/day) was administered from day 19 to day 27 but failed to improve her neurological condition. Antifungal therapy was switched to fluconazole on day 69. After a complete diagnostic procedure (including repeated blood cultures, American Journal of Transplantation 2015; 15: 560–564
Anti-TNF Therapy in Cryptococcal IRIS
CSF bacterial and mycobacterial cultures, blood and CSF CMV, JC virus, Adenovirus, HHV6, HHV8, VZV and HSV PCR, blood and CSF galactomannan, beta-glucan and Aspergillus real time PCR), other neurological opportunistic infections were ruled out, and a diagnosis of cryptococcosis-associated IRIS was considered. QuantiFERON1-TB Gold test and tuberculosis interferon-g ELISPOT results were negative. High-dose intravenous dexamethasone was thus administered from 0.4 g/kg/day on day 52 to 0.1 g/kg/day on day 81 without any improvement in the neurological condition or the cerebral MRI findings. On day 95, as her neurological condition remained unchanged, a TNF-a blockade was started with subcutaneous adalimumab 40 mg every 2 weeks. Ten days later, the patient spoke, fed herself and rapidly walked outside her room. Brain MRI performed 21 and 60 days after adalimumab initiation (Figures 2 and 3: C1, C2, C3, C4) showed slight decreasing of supra tentorial white matter lesions. No progression of hydrocephalus was noted. Under a prednisone (10 mg/day) and low-dose tacrolimus immunosuppressive regimen, graft function worsened, with serum creatinine level reaching 260 mmol/L (2.94 mg/ dL). Rejection was assumed, but no kidney biopsy was performed as an increase in immunosuppression was avoided due to a concern for additional opportunistic infections. The patient did not develop any other opportunistic infections. Adalimumab treatment was administered for 7 months. At adalimumab discontinuation, immunosuppressive regimen consisted of prednisone 10 mg/day and tacrolimus 4 mg/day. At last follow-up, 14 months after adalimumab cessation, the patient is still on fluconazole, continues to experience improvement in her neurological condition and has regained her autonomy for normal daily activities, despite the persistence of mild amnesia. Followup cerebral MRI and serum creatinine levels remain unchanged (263 mmol/L, 2.98 mg/dL).
Discussion Central nervous system cryptococcosis accounts for 54– 62% of all cryptococcal disease in SOT recipients and is associated with increased mortality (9). It occurs later than nonCNS cryptococcosis, at a median time of 25 months after transplantation (10). While tacrolimus might have antifungal activity and be protective against CNS cryptococcosis (3,11), patients with mycophenolate mofetil appear more prone to develop CNS lesions (10). Cryptococcus neoformans-associated IRIS has been well described in HIV patients receiving HAART with rapid lymphocyte CD4þ cell count recovery. In SOT recipients, IRIS associated with C. neoformans infection is rare, being estimated to affect 4.8% of organ transplant recipients with cryptococcosis in the only series to date (5). Because the clinical presentation of IRIS may be similar to that of C. neoformans meningitis, CSF negative fungal culture, American Journal of Transplantation 2015; 15: 560–564
increase in CSF white blood cell counts, decrease in CSF CRAG titers associated with an increase in inflammatory lesions on MRI are parts of an IRIS diagnosis (12). In SOT recipients, CD4þ T helper dysregulation may contribute to cryptococcosis pathogenesis. Indeed, tacrolimus and corticosteroids are associated with a decrease in IFN-g and TNF-a levels. In patients with cryptococcal meningitis, CSF IFN-g/IL-10 ratios are also lower compared with patients without meningitis (13). Antifungal therapies and the reduction of immunosuppressive drugs are associated with a rebound in Th1 inflammatory response that facilitates fungal eradication but might lead to a subsequent increase in IFN-g and TNF-a secretion and then IRIS (8). Thus, it is recommended to delay immunosuppression reduction (12) after cryptococcosis diagnosis. IRIS management is still debated. Consistent with IRIS occurring in HIV-infected patients, good results have been observed with steroid therapy for transplant recipients. Lanternier et al previously reported in the Journal a case of aseptic cellulitis revealing cryptococcosis-IRIS for which high-dose prednisolone resulted in dramatic improvement with a complete resolution in 6 days (7). In HIV patients with steroid-dependent refractory IRIS, resolution has been reported with thalidomide, an oral immunomodulator also acting on TNF-a (14). Considering IRIS mechanisms and their prompt antiinflammatory properties, anti-TNF blockers might also be a promising treatment of severe neurological IRIS. Furthermore, infliximab and adalimumab therapies proved effective in treating, respectively neurotuberculosis steroidresistant IRIS in a nonHIV-infected patient and cryptococcosis-associated IRIS after steroid tapering in a HIVinfected patient (15,16). Here, we report the first case of anti-TNF antibody efficacy in a SOT recipient with steroid-resistant cryptococcosisassociated IRIS. The question as why our patient didn’t respond to steroid therapy remains unclear. We postulated that high levels of TNF-a characterized the inflammatory immune response and that steroids may have been insufficiently specific. Thus, we considered specific TNFa blockade and our patient successfully received adalimumab, a recombinant human immunoglobulin G1 monoclonal antibody specific for human TNF-a. When making the selection of adalimumab in the present case, infliximab and etanercept were also considered. Etanercept, a soluble TNF receptor, has never been reported to be effective as IRIS therapy. Adalimumab and infliximab have been successfully described for IRIS therapy. However, infliximab has never been used as cryptococcosis-associated IRIS therapy. Despite previous reports of cryptococcosis with adalimumab (17), more cryptococcosis cases and more fungal infections have been reported with infliximab (18). Although the optimal duration of such a therapy remains unknown, we administered it for 7 months. Interestingly, adalimumab was well tolerated, and no 563
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relapse occurred after adalimumab withdrawal with a subsequent follow-up of 14 months. 7.
However, clinicians should be aware of adalimumab and other TNF-blockers side effects, as they predispose to severe opportunistic infections. Tuberculosis has been more frequently reported, but risks of fungal, parasitic and bacterial infections are also increased (19). The FDA recommends to test patients for latent tuberculosis before TNF blockers use and to initiate treatment in case of latent tuberculosis (20). In our patient, we obtained a serum quantiferon MTb gold assay and ELISPOT prior to adalimumab use.
8.
9.
10.
In conclusion, anti-TNF-a monoclonal antibodies may be considered in the setting of severe cryptococcosis-associated neurological steroid-refractory IRIS occurring in SOT recipients.
11.
Disclosure
12.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
13.
References 1. Singh N, Dromer F, Perfect JR, Lortholary O. Cryptococcosis in solid organ transplant recipients: Current state of the science. Clin Infect Dis 2008; 47: 1321–1327. 2. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 2010; 50: 1101–1111. 3. Osawa R, Alexander BD, Lortholary O, et al. Identifying predictors of central nervous system disease in solid organ transplant recipients with cryptococcosis. Transplantation 2010; 89: 69–74. 4. Singh N, Alexander BD, Lortholary O, et al. Cryptococcal Collaborative Transplant Study Group. Cryptococcus neoformans in organ transplant recipients: Impact of calcineurin-inhibitor agents on mortality. J Infect Dis 2007; 195: 756–764. 5. Singh N, Lortholary O, Alexander BD, et al. An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis 2005; 40: 1756–1761. 6. Legris T, Massad M, Purgus R, et al. Immune reconstitution inflammatory syndrome mimicking relapsing cryptococcal menin-
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gitis in a renal transplant recipient. Transpl Infect Dis 2011; 13: 303–308. Lanternier F, Chandresris MO, Poiree S, et al. Cellulitis revealing a Cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient. Am J Transplant 2007; 7: 2826– 2828. Sun HY, Singh N. Opportunistic infection-associated immune reconstitution syndrome in transplant recipients. Clin Infect Dis 2011; 53: 168–176. Wu G, Vilchez RA, Eidelman B, Fung J, Kormos R, Kusne S. Cryptococcal meningitis: An analysis among 5521 consecutive organ transplant recipients. Transpl Infect Dis 2002; 4: 183–188. Singh N, Lortholary O, Dromer F, et al. Central nervous system cryptococcosis in solid organ transplant recipients: Clinical relevance of abnormal neuroimaging findings. Transplantation 2008; 5: 647–651. Cruz MC, Del Poeta M, Wang P, et al. Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin. Antimicrob Agents Chemother 2000; 44: 143–149. Baddley JW, Forrest GN. AST Infectious Diseases Community of Practice. Cryptococcosis in solid organ transplantation. Am J Transplant 2013; 13: 242–249. Singh N, Husain S, Limaye AP, et al. Systemic and cerebrospinal fluid T-helper cytokine responses in organ transplant recipients with Cryptococcus neoformans infection. Transpl Immunol 2006; 16: 69–72. Brunel AS, Reynes J, Tuaillon E, et al. Thalidomide for steroiddependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012; 26: 2110–2112. Blackmore TK, Manning L, Taylor WJ, Wallis RS. Use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. Clin Infect Dis 2008; 47: 83–85. Sitapati AM, Kao CL, Cachay ER, Masoumi H, Wallis RS, Mathews C. Treatment of HIV-related inflammatory cerebral cryptococcoma with adalimumab. Clin Infect Dis 2010; 50: e7–e9. Iwata T, Nagano T, Tomita M, et al. Adalimumab-associated pulmonary cryptococcosis. Ann Thorac Cardiovasc Surg 2011; 17: 390–393. Tsiodras S, Samonis G, Boumpas DT, Kontoyiannis DP. Fungal infections complicating tumor necrosis factor alpha blockade therapy. Mayo Clin Proc 2008; 83: 181–194. Novosad SA, Winthrop KL. Beyond tumor necrosis factor inhibition: The expanding pipeline of biologic therapies for inflammatory diseases and their associated infectious sequelae. Clin Infect Dis 2014; 58: 1587–1598. US Food and Drug Administration. Highlights of adalimumab prescribing informations. Revised May 2013. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/ 125057s310lbl.pdf.
American Journal of Transplantation 2015; 15: 560–564
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American Journal of Transplantation 2015; 15: 560–564 Wiley Periodicals Inc.
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13002
Case Report
Dramatic Improvement of Severe Cryptococcosis-Induced Immune Reconstitution Syndrome With Adalimumab in a Renal Transplant Recipient A. Scemla1,*, S. Gerber2, A. Duquesne1, P. Parize3, F. Martinez1, D. Anglicheau1, R. Snanoudj1, M. Zuber4, M.-E. Bougnoux5, C. Legendre1 and O. Lortholary3,6,* 1
Service de Ne´phrologie et Transplantation Adulte, Hoˆpital Necker Enfants Malades, Assistance PubliqueHoˆpitaux de Paris, Universite´ Paris Descartes Sorbonne Paris Cite´, RTRS Centaure, Paris, France 2 Service de Radiologie, Hoˆpital Saint-Joseph, Universite´ Paris Descartes Sorbonne Paris Cite´, Paris, France 3 Universite´ Paris Descartes, Hoˆpital Necker Enfants Malades, Assistance Publique-Hoˆpitaux de Paris, Centre d’Infectiologie Necker Pasteur, IHU Imagine, Paris, France 4 Service de Neurologie et Neurovasculaire, Hoˆpital SaintJoseph, Universite´ Paris Descartes Sorbonne Paris Cite´, Paris, France 5 Service de Mycologie Parasitologie, Hoˆpital Necker Enfants Malades, Assistance Publique-Hoˆpitaux de Paris, Universite´ Paris Descartes Sorbonne Paris Cite´, Paris, France 6 Institut Pasteur, Centre National de Re´fe´rence Mycoses Invasives et Antifongiques, Paris, France Corresponding authors: Anne Scemla, [email protected], and Olivier Lortholary, [email protected]
Received 15 April 2014, revised 07 August 2014 and accepted for publication 23 August 2014
Introduction In solid organ transplant (SOT) recipients, cryptococcosis is the third most common cause of invasive fungal infection after Candida spp and Aspergillus spp infections, with an overall incidence of 0.3–5% (1,2). Most of the cases are disseminated with central nervous system involvement in up to 62% of the cases whose lumbar puncture is performed and are associated with a high mortality rate (3,4). Cryptococcosis-related immune reconstitution inflammatory syndrome (IRIS) affects up to 30% of HIV-infected patients (4) and may result in neurological worsening and increased mortality. Thus far, only a few reports have described IRIS after tapering immunosuppressive drugs in the context of SOT (5–8). Here, we describe a case of severe cryptococcal meningo-encephalitis-related IRIS occurring after immunosuppressive regimen reduction, which was resistant to highdose steroids but dramatically improved as early as 2 weeks after anti-TNF-a therapy (adalimumab) initiation (Figure 1).
Case In solid organ transplant recipients, immune reconstitution inflammatory syndrome (IRIS) is a rare complication of cryptococcosis, which may require steroids in its most severe forms. Here, we report the case of a renal transplant recipient who developed severe cryptococcal meningitis-associated IRIS 1 week after immunosuppression reduction. Highdose steroids failed to improve the disease. Finally, a recombinant human monoclonal tumor necrosis factor-a (TNF-a) antagonist, adalimumab, was prescribed, and the patient rapidly experienced dramatic neurological improvement. No IRIS relapse occurred within 14 months following adalimumab discontinuation. Abbreviations: CNS, central nervous system; IRIS, immune reconstitution inflammatory syndrome; TNFa, tumor necrosis factor a 560
A 43-year-old woman received a kidney from a living donor in 2004 for end-stage renal failure related to an IgA nephropathy. Induction and maintenance of immunosuppressive (IS) therapy consisted of basiliximab induction, steroids, tacrolimus and mycophenolate mofetil. She developed new-onset diabetes after transplantation. Fiftythree months after kidney transplantation (KT), norovirusrelated acute gastroenteritis was diagnosed and resolved spontaneously without immunosuppression tapering. Three months later, she complained of headache and fatigue. Her blood pressure was 137/86 mmHg, and brain magnetic resonance imaging (MRI) was normal. Two months later, she was admitted for acute dizziness and confusion. Neurological examination found marked disorientation, nystagmus and cerebellar ataxia. Brain MRI (Figures 2 and 3: A1, A2, A3, A4) showed ventriculomegaly
Anti-TNF Therapy in Cryptococcal IRIS IRIS diagnosis Adalimumab SC -----every 2 weeks
Right CSF derivaon
Clinical management
Le CSF derivaon LAmB and 5FC
Tac 6mg/d
200mg/d
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IV CyA, 30mg/d
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d1
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d12
d19
d27
d41
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d69
d81
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d110 d125 d140
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Figure 1: Evolution of immunosuppressive therapy, CSF protein levels and antifungal therapy. LAmB, liposomal amphotericin; 5FC, flucytosine; MMF, mycophenolate mofetil; SMD, solumedrol; Tac, tacrolimus; CyA, cyclosporine; d, day; Pred, prednisone; DXM, dexamethasone; FCZ, fluconazole; CSF, cerebrospinal fluid; SC, subcutaneous; Right and left derivations, right and left lateral ventricles.
Figure 2: Consecutive cerebral MRIs, Ax FLAIR WIs. Initial MRI (A1, A2) shows the occurrence of ventricular dilatation involving both supra tentorial and 4th ventricles. High signal T2 FLAIR of periventricular white matter reflects the trans-ependymal resorption. Partitioning of the ventricles is observed on the 2nd MRI (B1, B2) as increased hydrocephalus. Secondary damages of the periventricular white matter are observed as extended high signal FLAIR. Slight decrease of white matter involvement is noted on the last MRI (C1, C2) especially close to the 4th ventricle.
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Figure 3: Cerebral MRIs: 3D SPGR T1 with Gd-DTPA injection WIs. Contrast enhancement of the ventricle walls, initially missing (A3, A4), is associated with intraventricular enhanced septa and lobulations on the 2nd MR (B3, B4); on the control MR (C3, C4), decreased enhancement of the partitioned ventricles attests to the regression of the inflammatory process. Laminar necrosis of the frontal cortical ribbon observed as high signal T1 (white arrow on B4) occurs as a vascular complication, decreasing on control MR (C4).
with diffuse and extensive periventricular areas of hypersignal on T2 weighted images, involving white matter along ventricular margins compatible with trans-ependymal resorption. Slight contrast enhancement of the ventricular margins was noted without clear leptomeningeal enhancement. Similar abnormalities were observed in the posterior fossa. Immunosuppression consisted of prednisone (10 mg/day), tacrolimus (11 mg/day) and mycophenolate mofetil (500 mg bid). A lumbar puncture was performed: cerebral spinal fluid (CSF) opening pressure was 15 cm H2O; white blood cell count: 145 cells/mm3, 96% lymphocytes; glucose: 50 mg/dL (peripheral glucose: 140 mg/dL); and total protein level: 380 mg/dL with positive India ink staining. CSF and serum cryptococcal antigen (CRAG) (Premier cryptococcal antigen, Meridian, Biosciences, Cincinnati, OH) titers were 271 and 125, respectively. A CSF culture yielded Cryptococcus neoformans, while urinary and blood fungal cultures were negative. Chest computed tomography was normal. Liposomal amphotericin B (3 mg/kg/day) and flucytosine (50 mg/kg/day adapted to renal function, with serum creatinine level: 160 mmol/L, 1.8 mg/dL) were initiated on day 1. One day after the cryptococcosis diagnosis, mycophenolate mofetil was discontinued, 562
tacrolimus was reduced to 6 mg/day and prednisone was reduced to 7.5 mg/day. On day 8 after antifungal therapy initiation, her neurological condition worsened (Glasgow coma scale score: 10/15). Repeated CSF analyses revealed unchanged opening pressure (15 cm H2O), an increase in protein level up to 800 mg/dL on day 19, with a white blood cell count: 8 cells/mm3, glucose level: 22 mg/dL (peripheral glucose: 110 mg/dL) with negative bacterial and fungal cultures. CSF and serum CRAG titers decreased to 41 and 8, respectively, on day 8. Brain MRI (Figures 2 and 3: B1, B2, B3, B4) showed slightly increased hydrocephalus, with the appearance of inflammatory septations and lobulations of the ventricles. In addition, ependymal contrast enhancement markedly increased, and high signal FLAIR of periventricular white matter expanded. Laminar necrosis involving the right frontal cortex appeared as a high signal ribbon on T1WIs and as hypo-intensity on T2 star gradient echo weighted images. Two ventricular shunts were placed on days 8 and 12, but no improvement was noted (Glasgow coma scale score: 8/15). A short course of highdose steroid therapy (prednisone, 1 mg/kg/day) was administered from day 19 to day 27 but failed to improve her neurological condition. Antifungal therapy was switched to fluconazole on day 69. After a complete diagnostic procedure (including repeated blood cultures, American Journal of Transplantation 2015; 15: 560–564
Anti-TNF Therapy in Cryptococcal IRIS
CSF bacterial and mycobacterial cultures, blood and CSF CMV, JC virus, Adenovirus, HHV6, HHV8, VZV and HSV PCR, blood and CSF galactomannan, beta-glucan and Aspergillus real time PCR), other neurological opportunistic infections were ruled out, and a diagnosis of cryptococcosis-associated IRIS was considered. QuantiFERON1-TB Gold test and tuberculosis interferon-g ELISPOT results were negative. High-dose intravenous dexamethasone was thus administered from 0.4 g/kg/day on day 52 to 0.1 g/kg/day on day 81 without any improvement in the neurological condition or the cerebral MRI findings. On day 95, as her neurological condition remained unchanged, a TNF-a blockade was started with subcutaneous adalimumab 40 mg every 2 weeks. Ten days later, the patient spoke, fed herself and rapidly walked outside her room. Brain MRI performed 21 and 60 days after adalimumab initiation (Figures 2 and 3: C1, C2, C3, C4) showed slight decreasing of supra tentorial white matter lesions. No progression of hydrocephalus was noted. Under a prednisone (10 mg/day) and low-dose tacrolimus immunosuppressive regimen, graft function worsened, with serum creatinine level reaching 260 mmol/L (2.94 mg/ dL). Rejection was assumed, but no kidney biopsy was performed as an increase in immunosuppression was avoided due to a concern for additional opportunistic infections. The patient did not develop any other opportunistic infections. Adalimumab treatment was administered for 7 months. At adalimumab discontinuation, immunosuppressive regimen consisted of prednisone 10 mg/day and tacrolimus 4 mg/day. At last follow-up, 14 months after adalimumab cessation, the patient is still on fluconazole, continues to experience improvement in her neurological condition and has regained her autonomy for normal daily activities, despite the persistence of mild amnesia. Followup cerebral MRI and serum creatinine levels remain unchanged (263 mmol/L, 2.98 mg/dL).
Discussion Central nervous system cryptococcosis accounts for 54– 62% of all cryptococcal disease in SOT recipients and is associated with increased mortality (9). It occurs later than nonCNS cryptococcosis, at a median time of 25 months after transplantation (10). While tacrolimus might have antifungal activity and be protective against CNS cryptococcosis (3,11), patients with mycophenolate mofetil appear more prone to develop CNS lesions (10). Cryptococcus neoformans-associated IRIS has been well described in HIV patients receiving HAART with rapid lymphocyte CD4þ cell count recovery. In SOT recipients, IRIS associated with C. neoformans infection is rare, being estimated to affect 4.8% of organ transplant recipients with cryptococcosis in the only series to date (5). Because the clinical presentation of IRIS may be similar to that of C. neoformans meningitis, CSF negative fungal culture, American Journal of Transplantation 2015; 15: 560–564
increase in CSF white blood cell counts, decrease in CSF CRAG titers associated with an increase in inflammatory lesions on MRI are parts of an IRIS diagnosis (12). In SOT recipients, CD4þ T helper dysregulation may contribute to cryptococcosis pathogenesis. Indeed, tacrolimus and corticosteroids are associated with a decrease in IFN-g and TNF-a levels. In patients with cryptococcal meningitis, CSF IFN-g/IL-10 ratios are also lower compared with patients without meningitis (13). Antifungal therapies and the reduction of immunosuppressive drugs are associated with a rebound in Th1 inflammatory response that facilitates fungal eradication but might lead to a subsequent increase in IFN-g and TNF-a secretion and then IRIS (8). Thus, it is recommended to delay immunosuppression reduction (12) after cryptococcosis diagnosis. IRIS management is still debated. Consistent with IRIS occurring in HIV-infected patients, good results have been observed with steroid therapy for transplant recipients. Lanternier et al previously reported in the Journal a case of aseptic cellulitis revealing cryptococcosis-IRIS for which high-dose prednisolone resulted in dramatic improvement with a complete resolution in 6 days (7). In HIV patients with steroid-dependent refractory IRIS, resolution has been reported with thalidomide, an oral immunomodulator also acting on TNF-a (14). Considering IRIS mechanisms and their prompt antiinflammatory properties, anti-TNF blockers might also be a promising treatment of severe neurological IRIS. Furthermore, infliximab and adalimumab therapies proved effective in treating, respectively neurotuberculosis steroidresistant IRIS in a nonHIV-infected patient and cryptococcosis-associated IRIS after steroid tapering in a HIVinfected patient (15,16). Here, we report the first case of anti-TNF antibody efficacy in a SOT recipient with steroid-resistant cryptococcosisassociated IRIS. The question as why our patient didn’t respond to steroid therapy remains unclear. We postulated that high levels of TNF-a characterized the inflammatory immune response and that steroids may have been insufficiently specific. Thus, we considered specific TNFa blockade and our patient successfully received adalimumab, a recombinant human immunoglobulin G1 monoclonal antibody specific for human TNF-a. When making the selection of adalimumab in the present case, infliximab and etanercept were also considered. Etanercept, a soluble TNF receptor, has never been reported to be effective as IRIS therapy. Adalimumab and infliximab have been successfully described for IRIS therapy. However, infliximab has never been used as cryptococcosis-associated IRIS therapy. Despite previous reports of cryptococcosis with adalimumab (17), more cryptococcosis cases and more fungal infections have been reported with infliximab (18). Although the optimal duration of such a therapy remains unknown, we administered it for 7 months. Interestingly, adalimumab was well tolerated, and no 563
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relapse occurred after adalimumab withdrawal with a subsequent follow-up of 14 months. 7.
However, clinicians should be aware of adalimumab and other TNF-blockers side effects, as they predispose to severe opportunistic infections. Tuberculosis has been more frequently reported, but risks of fungal, parasitic and bacterial infections are also increased (19). The FDA recommends to test patients for latent tuberculosis before TNF blockers use and to initiate treatment in case of latent tuberculosis (20). In our patient, we obtained a serum quantiferon MTb gold assay and ELISPOT prior to adalimumab use.
8.
9.
10.
In conclusion, anti-TNF-a monoclonal antibodies may be considered in the setting of severe cryptococcosis-associated neurological steroid-refractory IRIS occurring in SOT recipients.
11.
Disclosure
12.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
13.
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American Journal of Transplantation 2015; 15: 560–564
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