Background: Cryptococcus gattii is known to be an etiologic agent of human cryptococcosis, particularly in immunocompetent persons. C. gattii infection usually involves the central nervous system, the respiratory tract, or may be disseminated. Here we report an atypical manifestation of C. gattii infection in a patient who had C. gattii meningitis complicating the ventriculoperitoneal (VP) shunt infection and concurrent infected intraabdominal VP shunt pseudocyst. Case presentation: A 66-year-old Thai female was initially diagnosed with normal pressure hydrocephalus (NPH) and underwent programmable VP shunt placement. However, she still suffered from recurrent communicating hydrocephalus with in-place VP shunt, and later developed recurrent gait impairment, chronic abdominal pain and abdominal mass. Radiological studies demonstrated recurrent hydrocephalus and a very large intraabdominal VP shunt pseudocyst. C. gattii was isolated from both the cerebrospinal fluid and the pseudocyst aspiration. C. gattii meningitis complicating the VP shunt infection and concurrent infected intraabdominal VP shunt pseudocyst was diagnosed. Prolonged antifungal therapy, removal of the infected VP shunt with subsequent implant of a new shunt provided a good outcome. Conclusion: Chronic C. gattii meningitis should be aware in a patient presenting with normal pressure hydrocephalus. Under-diagnosed cryptococcal meningitis following VP shunt insertion for treating the hydrocephalus can render a complicated VP shunt infection including infected VP shunt pseudocyst. Keywords: Cryptococcus gattii, Cryptococcal meningitis, Ventriculoperitoneal shunt infection, Infected ventriculoperitoneal shunt pseudocyst Background capsules, namely serotypes A, B, C and D [1, 3]. C. neofor- Cryptococcosis is one of the more common systemic fungal mans was categorized into serotypes A and D whereas C. infections caused by two main species, Cryptococcus neofor- gattii was classified into the serotypes B and C. Inhalation mans and Cryptococcus gattii. Cryptococcus is a spore form- of spores is a primary route of infection that mainly affects ing, environmental encapsulated fungus [1, 2]. Formerly, immunocompromised persons, such as HIV-infected pa- human Cryptococcus had been grouped into 4 major sero- tients, organ transplant recipients, and patients receiving types based on antigenic differences of the polysaccharide corticosteroid or immunosuppressive agents. However, several published reports have demonstrated C. gattii to be * Correspondence: email@example.com frequently associated with cryptococcosis in patients with Division of Infectious Diseases and Tropical Medicine, Department of no known immunodeficiency [4–6]. Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dhitinanmuang et al. BMC Infectious Diseases (2018) 18:257 Page 2 of 7 In recent years, the prevalence of C. gattii infection diagnosed with normal pressure hydrocephalus (NPH) has increased since a major outbreak on Vancouver Is- and underwent programmable VP shunt placement to land . Similar to C. neoformans, central nervous sys- relieve her symptoms. One year later, the gait difficulty tem (CNS) and respiratory tract infections are the most and dizziness resumed. A brain CT showed recurrent common presentations [1–4]. However, C. gattii infec- communicating hydrocephalus. The neurological deficits tion occurs more frequently in immunocompetent per- were reduced after adjusting the VP shunt pressure. Six sons and more often results in CNS complications, such months following adjustment of the shunt pressure, the as hydrocephalus, and large cryptococcoma with delayed patient developed abdominal discomfort with a palpable treatment response [1, 2, 7]. Few studies of C. gattii in- mass at the right paraumbilical region. The patient did fection in Thailand have been published. A molecular not feel feverish and did not have nausea or vomiting. typing study of 498 Cryptococcus spp. isolates from clin- Prior to this admission, gait difficulty and dizziness in- ical, animal and environmental sources from Thailand cluding diffuse headache recurred. Recurrent hydroceph- found only 13 isolates (2.6%) were C. gattii, but clinical alus was suspected and the patient was admitted for data have not been reported . Another study de- further investigation. scribed Tsunami survivors from Thailand who suffered The patient was afebrile and had a very large, from primary cutaneous cryptococcosis caused by C. ill-defined mass with cystic consistency and smooth sur- gattii . Here we report atypical C. gattii infection in a face at the right paraumbilical region. Neurological patient who had chronic C. gattii meningitis complicat- examination revealed a magnetic gait, no neck stiffness ing a ventriculoperitoneal (VP) shunt infection and con- and otherwise normal findings. The brain CT revealed current infected intraabdominal VP shunt pseudocyst. communicating hydrocephalus with appropriate in-place VP shunt as shown in Fig. 1a. The abdominal CT identi- Case presentation fied a well-defined rounded cystic mass measuring ap- A 66-year-old Thai female with underlying hypertension proximately 9.6 × 11.3 × 15 cm at the inframesocolic was admitted to Siriraj Hospital, Bangkok, Thailand on space. This cystic mass encased the distal end of the VP September 26, 2016 to evaluate the function of an im- shunt, suggestive of a CSF pseudocyst (Fig. 1b). CSF was planted VP shunt and identify the cause of an abdominal collected by lumbar puncture and returned a WBC mass. Two years earlier, she had progressive memory count of 12 cells/mm with 94% lymphocytes, 20 mg/dL impairment, dizziness, and difficulty walking for protein, and a ratio of CSF/serum glucose of 46/106 mg/ 4 months. Computed tomography (CT) of the brain re- dL (0.43). Ultrasonography-guided aspiration of the vealed communicating hydrocephalus without leptomen- intraabdominal VP shunt pseudocyst was also per- ingeal enhancement or abnormal enhancing lesion. formed. A total of 360 mL of clear yellow fluid was ob- Initial cerebrospinal fluid (CSF) showed a white blood tained and examined. The WBC count was 20 cell/mm cell (WBC) count of 54 cells/mm with 96% lympho- with 97% lymphocytes, 472 mg/dL protein, and a ratio cytes, a protein 165 mg/dL, and a ratio of CSF/serum of CSF/serum glucose of < 4.32/120 mg/dL (< 0.03). An glucose of 25/126 mg/dL (0.2). The patient was India ink preparation of the CSF taken from the Fig. 1 a) Computed tomography of brain revealed recurrent communicating hydrocephalus with appropriate in-place VP shunt, b) Computed tomography of whole abdomen with contrast revealed a large well-defined cystic mass at inframesocolic space, approximately 9.6 × 11.3 × 15 cm in diameter which it encased the distal limb of VP shunt (arrow) Dhitinanmuang et al. BMC Infectious Diseases (2018) 18:257 Page 3 of 7 pseudocyst and from the lumbar puncture revealed a communicating hydrocephalus similar to other reports few encapsulated budding yeasts. Cryptococcal antigen [1, 2, 4, 6, 8]. However, this patient was initially misdiag- testing of the serum and the CSF was positive at the ti- nosed with normal pressure hydrocephalus requiring VP ters of 1:8 and of > 1:1024, respectively. The yeasts grew shunt placement, although the CSF culture completed 2 well on saboraud dextrose agar without cycloheximide. yrs earlier had revealed the presence of C. gattii infec- The isolate was identified as C. gattii by biochemical tion. Chronic, undiagnosed C. gattii meningitis following testing and a conversion to blue color on the VP shunt placement lead to multiple recurrent com- L-canavanine-glycine bromothymol blue (CGB) agar. A municating hydrocephalus, and eventually resulted in a molecular typing using the restriction fragment length cryptococcal intraabdominal VP shunt pseudocyst. A polymorphism (RFLP) of URA5 determined the isolate summary of nine case reports of cryptococcal VP shunt to be compatible with C. gattii molecular type VGI. An- infection including the present case is provided in tifungal susceptibility testing by the broth microdilution Table 1 [9–14]. Only three patients had immunodefi- method was performed and showed minimal inhibitory cient conditions such as HIV infection (2) and diabetes concentrations (MICs) of amphotericin B deoxycholate mellitus with liver cirrhosis (1), while the six cases left (ABD) of 0.5 μg/mL, 5-fluorocytosine (5-FC) of 0.5 μg/ had no apparent immunodeficient states. Previous stud- mL, fluconazole of 1 μg/mL, itraconazole of ≤ 0.015 μg/ ies tentatively found an association among human leuco- mL, voriconazole of 0.015 μg/mL, posaconazole of cyte antigen (HLA) subtypes and fungal infections such 0.03 μg/mL and all echinocandins (caspofungin, mica- as histoplasmosis , paracoccidioidomycosis . A fungin and anidulafungin) of > 8 μg/mL. Unfortunately, study conducted in Papua New Guinea revealed patients when NPH was initially diagnosed 2 yrs earlier the CSF conferred HLA B*5601 were likely susceptible to C. gat- culture had grown C. gattii, but the result was over- tii infection . However, a relation of HLA and gen- looked. Chest radiography found no pulmonary nodules etic susceptibility to fungal infections is still inconclusive or infiltrations. Complete blood count showed and requires more studies. In Asian population including hemoglobin of 12.4 g/dL, hematocrit of 39.4%, WBC Thai patients, anti-IFN- autoantibodies have associ- counts of 10,930/mm (neutrophil 70%, lymphocyte ated with disseminated infection secondary to several 25%, monocyte 5%) and platelet counts of 385,000/mm . opportunistic organisms, such as nontuberculous myco- Blood urea nitrogen (BUN), creatinine, and liver func- bacteria, Salmonella non-Typhi, Varizella-zoster virus tion tests were within normal limits. Anti-HIV testing and fungi . In addition, high level of anti-GM-CSF was negative. Immunological studies revealed CD Tcell autoantibodies was associated with cryptococcal menin- counts of 842 cells/mm (51.8%), CD T cell counts of gitis [19, 20] and disseminated cryptococcosis in 361 cells/mm (22.2%), IgG 1170 mg/dL, IgA 255 mg/dL HIV-negative patients who had no previously apparent and IgM 141 mg/dL. Anti-interferon gamma (anti-- IFN- ) and anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF) autoantibodies were both negative. During hospitalization, the patient received daily intra- venous amphotericin B deoxycholate 40 mg (0.7 mg/kg/ day) combined with oral fluconazole 800 mg/day. The VP shunt was removed after 14 days of antifungal treat- ment. After discharge to home, the patient received long-term oral fluconazole for consolidation and main- tenance therapy according to the IDSA recommendation . Reimplantation of the VP shunt was performed after 8 weeks of antifungal treatment. The follow-up CSF cul- ture was sterile. Brain CT following shunt reimplanta- tion demonstrated significantly decreased ventricular dilatation (Fig. 2). After 6 months of antifungal treat- ment, the gait abnormality, dizziness and diffuse head- ache resolved, and the abdominal mass was no longer detectable. Discussion Fig. 2 Computed tomography of brain following the shunt This patient without apparent immunodeficiency pre- reimplantation exhibited significantly decreased ventricular dilatation sented with cryptococcal meningitis complicating Dhitinanmuang et al. BMC Infectious Diseases (2018) 18:257 Page 4 of 7 Table 1 Summary of case reports of cryptococcal meningitis complicating ventriculoperitoneal (VP) shunt infection with or without concurrent infected intraabdominal VP shunt pseudocyst Case Author Age Underlying Onset Clinical manifestations Findings Cryptococcus Managements Outcomes (year) (yrs)/ conditions (mo- species Sex yrs) 1–3 Mangham 22/M – 1 yr Rapidly declined CT brain: hydrocephalus C. ABD, 5-FC, shunt removal Dead et al.  (1983) consciousness with frontal headache Brain necropsy: basilar meningitis with neoformans yeast like organisms seen 58/M – 9 mo Progressive headache and memory CT brain: hydrocephalus C. ABD, 5-FC, shunt removal Recovery deficit Intact shunt function neoformans 55/M CLD, DM, 4 mo Memory deficit and gait difficulty CT brain: hydrocephalus C. ABD, 5-FC Dead NPH Brain necropsy: fibrous and thickening neoformans leptomeninges with yeast like organisms seen 4 Crum-Cianflone 34/M HIV, TB 1 yr Abdominal distention CT abdomen: intraabdominal CSF C. LAB, 5-FC then oral FLU and 5-FC, Recovery et al.  (2008) meningitis VP shunt pseudocyst, sized 26 cm neoformans cyst aspiration and shunt removal Cyst fluid CRAG titers of 1:64 5 Viereck et al. 65/M NPH 20 yrs Difficult ambulation and confusion Intact shunt function C. ABD, 5-FC, shunt removal and Recovery  (2014) Radiographic findings: no data neoformans reimplant 6 Lee et al.  80/M NPH 10 yrs Abdominal pain and diarrhea CT abdomen: large intraperitoneal CSF C. ABD, 5-FC and shunt removal Recovery, no (2016) VP shunt pseudocyst neoformans residual pseudocyst 7 Foong et al. 52/M NPH 1 yr Fever, lethargy, confusion CT brain: hydrocephalus with possible C. LAB, 5-FC then oral FLU, shunt re Recovery  (2016) shunt malfunction neoformans moval and reimplant 8 Genebat et al. 36/F HIV, TB 1 yr Abdominal mass CT abdomen: subcutaneous CSF VP C. LAB, 5-FC then oral FLU, and Recovery, no  (2017) meningitis shunt pseudocyst, sized 7 cm neoformans shunt removal residual pseudocyst 9 The present 66/F HT 2 yrs Gait difficulty, dizziness, headache, CT brain: hydrocephalsCT abdomen: C. gattii ABD, FLU then oral FLU, shunt Recovery, no case abdominal mass intraabdominal CSF removal and reimplant residual pseudocyst VP shunt pseudocyst, sized 15 cm Cyst fluid CRAG titers of > 1:1024 Temporal onset of infection following VP shunt implant Abbreviations: ABD amphotericin B deoxycholate, CLD chronic liver disease, cm centimeter. CRAG cryptococcal antigen, CSF, cerebrospinal fluid, CT computed tomography, DM diabetes mellitus, 5-FC 5-flucytosine, F female, FLU fluconazole, HIV human immunodeficiency virus, HT hypertension, LAB liposomal amphotericin B, M male, mo month, NPH normal pressure hydrocephalus, TB tuberculosis, yrs. years Dhitinanmuang et al. BMC Infectious Diseases (2018) 18:257 Page 5 of 7 immunodeficiencies. The present case had negative re- The present case had a CNS infection caused by the rare sults of the both autoantibodies. Unfortunately, informa- VGI strain. The insidious onset and slow progression of tion on the immunological studies of the previous cases the CNS infection we observed might be associated with in the Table 1 have been unknown. From the Table 1, the less virulent VGI strain. The MICs of antifungal cryptococcal VP shunt infection may be separated into agents, such as ABD, 5-FC and azoles were active early onset, within several months to a few years post against the C. gattii isolated from our patient. However, implant, and late onset more than 10 years post implant. the standard breakpoint of antifungal susceptibility test- We postulate that an undiagnosed Cryptococcus infec- ing for Cryptococcus spp. is still not available. Flucona- tion might be the primary cause of neurological deficits zole resistance is uncommon among C. gattii although in patients who presented with early onset infection. increasing fluconazole MICs of C. gattii VGII has been These patients received VP shunt placements to relieve reported [27–29]. Thus, molecular typing and antifungal their symptoms, but an occult Cryptococcus infection susceptibility testing may affect treatment outcomes in subsequently causes a shunt infection soon after. Crypto- C. gattii infection. coccus can also cause a sporadic VP shunt infection in Most of the case reports received a combination of patients who had the shunt implant several years earlier. conventional or liposomal amphotericin with 5-FC, Of nine cases, three also had concurrent infected ab- which is the first line antifungal therapy for treating se- dominal pseudocysts and one had a subcutaneous vere cryptococcal infection . In the present case, high pseudocyst following the VP shunt infections. Clinical dose fluconazole was substituted because 5-FC is re- manifestations such as abdominal distention, abdominal stricted use and not widely available in Thailand. Flu- pain, or abdominal mass were comparable among these conazole is an alternative agent used for combination patients. The infected pseudocysts were moderate to with amphotericin when treating HIV-infected patients large in size, and cyst fluid tested for cryptococcal anti- with severe C. neoformans infection . Although gens from two patients showed high titers. amphotericin B in combination with fluconazole The present case is unique for several reasons. First, showed in vitro antagonistic interaction , several this patient was initially misdiagnosed as NPH for clinical studies demonstrated the combined two-drug 2 years. The reasons of slow progression in this patient regimen provided favorable outcomes for treating may be from the released CSF by VP shunt at the onset HIV-infected patients with cryptococcal meningitis of NPH, an ability to produce biofilm formation and a where 5-FC was not available or contraindicated [31– variation of virulence based on strain typing. Previous 33] However, clinical studies of cryptococcal meningitis experimental studies elucidated C. neoformans exhibited in non-HIV infected individuals have been limited. All exopolymeric matrices including capsular polysaccharide cases listed in Table 1 that survived continued the oral promoting adherence to VP shunt  and plastic sur- fluconazole therapy for several weeks. Following the in- face , and was resistant to host immune response duction of combined antifungal agents, patients who causing persistent infection. Second C. gattii was the have cryptococcal infection require long term flucona- only pathogen isolated from CSF and fluid from the zole therapy to prevent relapse . Neurological com- pseudocyst in the present case while C. neoformans was plications such as increased intracranial pressure or the principle etiologic agent in the other cases. Third, hydrocephalus, must be managed by CSF drainage pro- intraabdominal VP shunt pseudocyst infection caused by cedures. The present case initially received a VP shunt C. gattii has not been previously reported. Molecular to reduce hydrocephalus though the first CSF culture typing of the isolate identified C. gattii VGI strain, an was positive for C. gattii at the onset. It is possible that uncommon type. According to the molecular typing placement of the VP shunt may have prevented a rapid studies, C. gattii VGII is the most common molecular deterioration in neurological status. Of the nine re- type distributed in Thailand and other countries [3, 4]. ported cases, eight had the VP shunt removal, and three Of 386 Cryptococcus isolates from Thailand, 12 (3.1%) of these including the present case subsequently had a were C. gattii VGII and only 1 (0.3%) was a VGI strain shunt reimplant. All of these patients had neurological . Interestingly, multi-locus sequence typing (MLST) recovery and no recurrence following the reimplanta- revealed all but 1 of the C. gattii VGII had an identical tion. Thus, in patients with cryptococcal meningitis linkage to the genotype of Vancouver outbreak strains complicating VP shunt infection, shunt removal . Clinical manifestation from each molecular type followed by a reimplant is considered safe and provides were not significantly different, but most of the con- a good outcome. Four patients who had concurrent firmed cases who died had an infection caused by the infected abdominal pseudocysts required no surgical subtyped VGIIa (67%) and the subtyped VGIIb (27%) excision. Simple aspiration of the infected pseudocyst . Several studies demonstrated that the subtyped and prolonged antifungal therapy provided a favorable VGIIa was more virulent than other strains [2, 24–26]. outcome. Dhitinanmuang et al. BMC Infectious Diseases (2018) 18:257 Page 6 of 7 Conclusion Received: 5 September 2017 Accepted: 25 May 2018 C. gattii infection should be considered in patients who develop normal pressure hydrocephalus without appar- ent cause. VP shunt implant is usually performed to re- References 1. Perfect JR. Cryptococcosis (Cryptococcus neoformans and Cryptococcus lieve neurological deficits. An undiagnosed cryptococcal gattii). In: Bennett JE, Dolin R, Blaser MJ, editors. 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Published: Jun 4, 2018
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