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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2017  |  Volume : 28  |  Issue : 6  |  Page : 1435-1439
Disseminated cryptococcosis as a complication of lupus nephritis


Department of Nephrology, La Rabta Hospital, Tunis, Tunisia

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Date of Web Publication18-Dec-2017
 

   Abstract 


Cryptococcus neoformans is an opportunistic fungal infection affects predominately the central nervous system in HIV patients and patients with other immunocompromised states. It has rarely been described in immunocompetent patients. It is a serious infection with a high of mortality rate. We describe a case of a 48-year-old patient diagnosed with lupus nephritis treated with corticosteroids and mycophenolate mofetil who developed central nervous cryptococcosis complicated by septicemia. She died despite the use of antifungals. Cryptococcal infection is an uncommon, but often a fatal complication of systemic lupus erythematosus. Timely diagnosis and effective antifungal therapy could improve its prognosis.

How to cite this article:
Beji S, Hajji M, El Kateb H, Kosai I, Jebali H, Kheder R, Fatma LB, Rais L, Laameri L, Krid M, Zouaghi K. Disseminated cryptococcosis as a complication of lupus nephritis. Saudi J Kidney Dis Transpl 2017;28:1435-9

How to cite this URL:
Beji S, Hajji M, El Kateb H, Kosai I, Jebali H, Kheder R, Fatma LB, Rais L, Laameri L, Krid M, Zouaghi K. Disseminated cryptococcosis as a complication of lupus nephritis. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Dec 8];28:1435-9. Available from: http://www.sjkdt.org/text.asp?2017/28/6/1435/220874



   Introduction Top


Cryptococcus neoformans is an opportunistic fungal pathogen of global distribution, which grows predominately in the form of yeast and has a polysaccharide capsule that differentiates this microorganism from other pathogenic fungi. Cryptococcosis is prevalent in individuals with T-cell deficiencies, such as those infected with HIV. It is rarely described in immunocompetent patients.[1],[2] The clinical features and physical signs of the infection are often nonspecific and may present a problem of diagnosis with other infections, especially tuberculosis, Martinez-Longoria et al[3] had reported a rare case of central nervous system (CNS) co-infection in a child with systemic lupus erythematosus (SLE). This shows the importance of considering various etiologic possibilities when an immunocompromised patient presents to the emergency room. Cryptococcosis is associated with significant morbidity and mortality. It can present as meningoencephalitis, pneumonia, and cryptococcemia in immunocompromised hosts. Outcome and treatment failure are usually associated with underlying conditions, a delay in diagnosis, and absence of a fungicidal drug.[4],[5] We report a case of disseminated cryptococcosis occurring in a patient with lupus nephritis receiving long-term corticosteroid and immunosuppressive treatment.


   Case Report Top


A 48-year-old woman presented with a three-week history of dull frontal headache, malaise and a low-grade fever. Three years previously, she had been diagnosed with SLE based on seven of the American College of Rheumatology criteria which are malar rash, photosensibility, oral ulcers, pleuritis, positive anti-nuclear antibodies and the presence of anti-ds DNA antibody, renal failure with a serum creatinine level at 40 mg/L (creatinine clearance at 17 mL/min), 24 h proteinuria at 6 g and class IV glomerulonephritis associated to thrombotic microangiopathy in renal biopsy. She was treated with methylprednisolone at the dose of 1 g/day for three days followed by prednisone at the dose of 1 mg/Kg/day and iv monthly cyclophosphamide pulses (1 g/1.73 m2) followed by Mycophenolate Mofetil 2 g/day. There was no relapse with a stable renal function (serum creatinine level at 30 mg/L, creatinine clearance at 21 mL/min). She had never received dialysis. During the current admission, she was drowsy suffering from a headache with no other symptoms. On clinical examination, she had normal blood pressure (130/80 mm Hg), a Glasgow coma scale (15/15), no meningial signs, an extensor planter response on the right with normal osteotendinous reflexes and sensitivity level. Routine laboratory tests showed, normal leucocyte numeration [6000 white blood cell (WBC/mm3)] associated to lympho-penia (310 L/mm3), raised C-reactive protein (CRP)-concentration up to 39 mg/L, anemia with a Hb level at 9.6 g/dL and a stable creatinine level at 30 mg/L. Computed tomography (CT) and magnetic resonance imaging of the brain were normal. A lumbar puncture produced clear cerebrospinal fluid (CSF) containing WBC 32/mm3 (80% lymphocytes), normal protein, and glucose level, respectively: 0.4 g/L and 0.52 g/L, fungal and bacterial cultures were negative, and no oligoclonal bands were detected. Serologic studies for cytomegalovirus, Eptein–Barr virus, rickettsiae, toxoplasma, borrelia, and measles were negative. Immunologic studies showed positive antinuclear antibodies titer 1/1600 (homogeneous pattern), anti-ds DNA antibodies and anti-Sm antibodies while serum complement (C3, C4, CH50) levels were normal. A lupus relapse was suspected, and the patient received oral corticosteroids (1 mg/kg/day). The headache improved but she acutely developed fever up to 40°C, raised CRP up to 178 mg/L and kidney function had gradually worsened with serum creatinine between 52 and 60 mg/L. She required three sessions of hemodialysis and she received an antibiotherapy based on imipinem, vancomycine and amikacine. A second lumbar puncture was performed. A Gram-stain showed scanty yeast cells, which on an Indian ink preparation revealed the presence of encapsulated C. neoformans, later confirmed by culture. Serum and CSF cryptococcal antigen titer was 1/1600 by latex agglutination method. Blood cultures and urine culture were positive to C. neoformans. Voriconazole (800 mg/day) was started. One week later, she developed melanodermia with a widespread vesiculobullous rash predominant in axillary and neck folds with an acute cholestatic hepatitis. Voriconazole was discontinued and we started Fluconazole with a daily dose of 400 mg. Three days later, her level of consciousness had fallen and became febrile and dyspneic. A third lumbar punction produced clear CSF containing 12 WBC/mm3, the cytobacteriological examination revealed the presence of Cryptococcus and cryptococcal antigen titer was 1/400. The chest radiograph showed a left basal pneumonitis. The cerebral CT scan was normal, but the fundus revealed a hemorrhagic bilateral papilledema. She died in a context of multiple organ failure despite the use of nonspecific antibiotherapy.


   Discussion Top


Cryptococcal meningoencephalitis had been described as a rare complication of SLE.[6] However, Hung et al[7] have reported that cryptococcal meningoencephalitis played the major role in CNS infections of patients with SLE. Headache is the most common symptom, but patients may also present with meningeal signs, confusion, seizures, blurred vision, and, rarely, focal deficits. Fever and nuchal rigidity may be mild or absent.[8] Sivalingam et al[9] have reported that normal neurological and CSF examinations did not exclude cryptococcal meningoencephalitis in a patient with SLE, as in our patient. Cryptococcal meningoencephalitis should be considered as a differential in SLE patients presenting nonspecific symptoms of headache, fever, nausea, or vomiting. In a Chinese study including 631 patients with SLE, six patients with cryptococcal meningitis were identified. The most common presentations of CM were a headache and fever.[10] Conti et al described a case of a 47-year-old woman with SLE and Sjögren Syndrome who developed an acute longitudinal myelitis concurrently with a Cryptococcus laurentii pneumonia.[11] The non consideration of this diagnosis in the first place can lead to delayed diagnosis as in our case. Lumbar puncture is a useful initial diagnostic test that shows increased CSF pressure and may show mild-to-moderate leukocytosis, decreased glucose levels, and elevated protein levels. The India ink test is more specific and helps in diagnosing the fungus. This exam was performed secondly in our patient as she didn't improve after anti-biotherapy. The level of antigen titer corresponds to the severity of disease.[12] Besides the immune status of the patient, the size of the inoculum is considered to be an important factor in determining the pathogenesis of this disease.[13] CNS infection can be either meningeal or parenchymal. Infection usually starts as meningitis. Parenchymal involvement is seen as cryptococcomas (also known as toruloma), dilated Virchow-Robin spaces, or enhancing cortical nodules[14] which was not seen in our case. It is difficult to identify the intrinsic immunological abnormality as the risk for cryptococcal meningoencephalitis development in SLE patients other than immunosuppressive therapy. Host resistance to C. neoformans depends primarily on cell-mediated immunity. CD4 lymphocytes, cytotoxic lymphocytes, natural killer cells, activated macrophages, and various cytokines are implicated in successful host responses to C. neoformans.[15] Decreased CD4 lymphocyte count, natural killer cell activity, and T-cell cytotoxicity are related to SLE clinical activity.[16] Ecevit et al[17] described nine nonimmunosuppressed patients with CNS cryptococcosis. Pappas et al[18] reported that 47 of 157 HIV-negative patients had cryptococcus meningoencephalitis without underlying conditions. As SLE patients have intrinsic abnormalities of cell-mediated immunity and receive immunosuppressive therapy, indefinite maintenance therapy with fluconazole is recommended in SLE patients with cryptococcosis.[19] Shapiro et al[20] reported the importance of C3 in defense against cryptococcus infection by demonstrating increased susceptibility for genetically deficient C3 knockout mice. Complement levels in our case were normal. The recommended therapy for cryptococcal meningoencephalitis in HIV-negative and nontransplant patients includes induction therapy with amphotericin B deoxycholate (0.7–1.0 mg/kg daily) plus flucytosine (100 mg/kg daily) for at least four weeks, followed by a consolidation therapy with fluconazole (400–800 mg daily) for eight weeks and another six to 12 months of reduced-dose of fluconazole (200 mg daily) for maintenance therapy.[21] If toxic side effects of amphotericin B develop, fluconazole plus flucytosine regimen might be considered. In our case, we did not use amphotericin B due to the presence of renal failure. We used voriconazole which is a synthetic derivative of fluconazole, a broad-spectrum triazole antifungal. It demonstrates excellent in vitro activity against C. neoformans[22]'[23] and achieves good levels in CSF.[24] In a study by Perfect et al, voriconazole therapy resulted in a 39% response rate in 18 patients with refractory cryptococcal meningoencephalitis.[25],[26] This treatment was discontinued in our patient due to side effects


   Conclusion Top


Cryptococcal meningitis is a recognized complication of SLE, with high mortality rates, particularly in those treated with immunosuppressive agents.[27],[28] To the best of our knowledge, our case represents the eighth case report of a patient diagnosed with disseminated cryptococcosis. Earlier diagnosis and effective antifungal therapy can improve the prognosis of cryptococcal meningitis in SLE patients. Strategies for the treatment of patients with this complication are discussed.

Conflict of interest: None declared.



 
   References Top

1.
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Martinez-Longoria CA, Rubio-Perez NE, Rios-Solis JE, Garcia-Rodriguez F. Severe meningoencephalitis co-infection due to Cryptococcus neoformans and Mycobacterium tuberculosis in a child with systemic lupus erythematosus. Int J Infect Dis 2015;33:106-8.  Back to cited text no. 3
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Dromer F, Bernede-Bauduin C, Guillemot D, Lortholary O, French Cryptococcosis Study Group. Major role for amphotericin B-flucytosine combination in severe cryptococcosis. PLoS One 2008;3:e2870.  Back to cited text no. 5
    
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Hung JJ, Ou LS, Lee WI, Huang JL. Central nervous system infections in patients with systemic lupus erythematosus. J Rheumatol 2005;32:40-3.  Back to cited text no. 7
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Harris DE, Enterline DS. Neuroimaging of AIDS. I. Fungal infections of the central nervous system. Neuroimaging Clin N Am 1997;7:187-98.  Back to cited text no. 8
    
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Sivalingam SK, Saligram P, Natanasabapathy S, Paez AS. Covert cryptococcal meningitis in a patient with systemic lupus erythematous. J Emerg Med 2012;42:e101-4.  Back to cited text no. 9
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Zhong Y, Li M, Liu J, Zhang W, Peng F. Cryptococcal meningitis in Chinese patients with systemic lupus erythematosus. Clin Neurol Neurosurg 2015;131:59-63.  Back to cited text no. 10
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Conti F, Spinelli FR, Colafrancesco S, et al. Acute longitudinal myelitis following Cryptococcus laurentii pneumonia in a patient with systemic lupus erythematosus. Lupus 2015;24: 94-7.  Back to cited text no. 11
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Everett BA, Kusske JA, Rush JL, Pribram HW. Cryptococcal infection of the central nervous system. Surg Neurol 1978;9:157-63.  Back to cited text no. 12
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Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS–100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev 1995;8:515-48.  Back to cited text no. 13
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Tien RD, Chu PK, Hesselink JR, Duberg A, Wiley C. Intracranial cryptococcosis in immunocompromised patients: CT and MR findings in 29 cases. AJNR Am J Neuroradiol 1991;12:283-9.  Back to cited text no. 14
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Horwitz DA, Gray JD. The interaction of T-cells with cells of the innate immune system and B cells in the pathogenesis of SLE. In: Wallace DJ, Hahn BH, eds. Dubois' Lupus Erythematosus. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 133-60.  Back to cited text no. 16
    
17.
Ecevit IZ, Clancy CJ, Schmalfuss IM, Nguyen MH. The poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: A call for better disease recognition and evaluation of adjuncts to antifungal therapy. Clin Infect Dis 2006;42: 1443-7.  Back to cited text no. 17
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Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis 2001;33:690-9.  Back to cited text no. 18
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González LA, Vásquez G, Restrepo JP, Velásquez M, Ramírez LA. Cryptococcosis in systemic lupus erythematosus: A series of six cases. Lupus 2010;19:639-45.  Back to cited text no. 19
    
20.
Shapiro S, Beenhouwer DO, Feldmesser M, et al. Immunoglobulin G monoclonal antibodies to Cryptococcus neoformans protect mice deficient in complement component C3. Infect Immun 2002;70:2598-604.  Back to cited text no. 20
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Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis 2010;50:291-322.  Back to cited text no. 21
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22.
Hoban DJ, Zhanel GG, Karlowsky JA. In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from blood cultures of neutropenic patients. Antimicrob Agents Chemother 1999;43:1463-4.  Back to cited text no. 22
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23.
Pfaller MA, Zhang J, Messer SA, et al. In vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of Cryptococcus neoformans from the United States and Africa. Antimicrob Agents Chemother 1999;43:169-71.  Back to cited text no. 23
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24.
Schwartz S, Milatovic D, Thiel E. Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia. Br J Haematol 1997;97:663-5.  Back to cited text no. 24
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25.
Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 2003;36:1122-31.  Back to cited text no. 25
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van Duin D, Cleare W, Zaragoza O, Casadevall A, Nosanchuk JD. Effects of voriconazole on Cryptococcus neoformans. Antimicrob Agents Chemother 2004;48:2014-20.  Back to cited text no. 26
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Gladman DD, Hussain F, Ibañez D, Urowitz MB. The nature and outcome of infection in systemic lupus erythematosus. Lupus 2002;11: 234-9.  Back to cited text no. 27
    
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Matsumura M, Kawamura R, Inoue R, et al. Concurrent presentation of cryptococcal meningoencephalitis and systemic lupus erythematosus. Mod Rheumatol 2011;21:305-8.  Back to cited text no. 28
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Correspondence Address:
Meriam Hajji
Department of Nephrology, La Rabta Hospital, Tunis
Tunisia
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DOI: 10.4103/1319-2442.220874

PMID: 29265061

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    Abstract
   Introduction
   Case Report
   Discussion
   Conclusion
    References
 

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