International Journal of Infectious Diseases 51 (2016) 25–26

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International Journal of Infectious Diseases

jou rnal homepage: www.elsevier.com/locate/ijid

Case Report

Candida in an immunocompetent patient detected through (1!3)-beta-D-glucan

a,b, a,b a,b a,b a,b

Mark K. Farrugia *, Evan P. Fogha , Abdul R. Miah , Joel Yednock , H. Carl Palmer , a,b

John Guilfoose

a

West Virginia University School of Medicine, Morgantown, West Virginia, USA

b

Department of Medicine, West Virginia University Health Sciences Center, PO Box 91601, Medical Center Dr., Morgantown, WV 26506, USA

A R T I C L E I N F O S U M M A R Y

Article history: A 44-year-old female presented with a 3-month history of headache, dizziness, nausea, and vomiting.

Received 29 July 2016

Her past medical history was significant for long-standing intravenous drug abuse. Shortly after

Received in revised form 23 August 2016

admission, the patient became hypertensive and febrile, with fever as high as 38.8 8C. The lumbar

Accepted 24 August 2016

puncture profile supported an infectious process; however multiple cultures of blood and cerebrospinal

Corresponding Editor: Eskild Petersen,

fluid (CSF) did not initially show growth of organisms. Finally after 9 days of incubation, a CSF culture

Aarhus, Denmark

showed evidence of a few colonies of . To confirm the diagnosis, preserved CSF from that

sample was tested for (1!3)-b-D-glucan, showing levels >500 pg/ml. This report illustrates a rare

Keywords: complication of intravenous drug use in an immunocompetent patient and demonstrates the utility of

Intravenous drug abuse

(1!3)-b-D-glucan testing in possible Candida meningitis.

Candida

ß 2016 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

Meningitis

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- (1!3)-b-D-glucan nc-nd/4.0/). Fungal

Cerebrospinal fluid

Case report tomography (CT) of the brain without contrast showed a

disproportionate prominence of the ventricles relative to the

A 44-year-old white female presented with a 3-month history cortical sulci, raising the question of possible normal pressure

of headache, dizziness, nausea, and vomiting. Her past medical hydrocephalus; magnetic resonance imaging (MRI) of the brain

history was significant for hypertension, intravenous drug abuse revealed similar findings. A chest X-ray showed no focal infiltrates,

(IVDA), and chronic hepatitis C. The symptoms had started with and HIV antibody testing, as well as PCR testing, was negative. The

daily, intermittent headaches for roughly 3 months before her patient was admitted with a suspicion of normal pressure

admission. The headaches could be exacerbated by light or hydrocephalus.

screaming, and ibuprofen partially relieved the pain. About a After admission, the patient spiked episodic fevers as high as

month following the onset of headaches, she developed gait 38.8 8C. Blood and urine cultures were drawn. The following day,

instability. She ultimately decided to come to the hospital after the patient continued to have episodic fever and also became

developing severe nausea, vomiting, and dizziness. On further hypertensive with a BP of 190/90 mmHg. A subsequent lumbar

questioning, she denied any fever, chills, incontinence, sputum puncture demonstrated an opening pressure of 310 mmHg, and

production, hemoptysis, or cough. The patient had a 26-year cerebrospinal fluid (CSF) studies showed glucose of 7 mg/dl,

6 6

history of IVDA. A urine drug screen performed on admission was protein of 357 mg/dl, 2 10 red blood cells/l, and 203 10 white

positive for buprenorphine, benzodiazepine, and opiates. blood cells/l, with >50% neutrophils. Gram staining did not reveal

On arrival, the patient was afebrile and had a blood pressure any organisms and CSF cultures were initiated. CSF flow cytometry

(BP) of 126/92 mmHg and heart rate of 111 bpm. Laboratory test showed no evidence of acute leukemia or lymphoma. Additional

results, including the complete blood profile and basic metabolic CSF assays evaluating possible tuberculosis, syphilis, Epstein–Barr

profile, were grossly normal. A physical examination demonstrat- virus, cytomegalovirus, enterovirus, herpes simplex virus 1 and 2,

ed photophobia, but was otherwise unremarkable. Computed and were negative. Furthermore, tests for

and were also negative. The blood

cultures drawn on admission showed no growth in 4 days. She was

then started on empiric vancomycin and piperacillin/tazobactam

* Corresponding author.

E-mail address: [email protected] (M.K. Farrugia). for possible bacterial meningitis.

http://dx.doi.org/10.1016/j.ijid.2016.08.020

1201-9712/ß 2016 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

26 M.K. Farrugia et al. / International Journal of Infectious Diseases 51 (2016) 25–26

On hospital day 4, the patient continued to experience episodic In 2012, several patients developed CNS complications due to

fever and uncontrolled hypertension. The patient also became the contamination of methylprednisolone epidural injections with

3

confused and would regularly only be oriented to person and/or C. albicans. From this outbreak, researchers evaluated the utility of

place. An ophthalmological examination revealed papilledema. the BDG assay to improve upon the diagnostic limitations of

Multiple escalations of her blood pressure regimen failed to traditional culture methods. BDG is a fungal cell wall component

achieve control. Ultimately, she was given an anti-hypertensive highly enriched in C. albicans, , and other fungal species.

regimen consisting of metoprolol 50 mg, clonidine 0.1 mg twice Notably, BDG is not highly expressed in Cryptococcus fungi. The

daily, clonidine 0.1 mg as needed, lisinopril 20 mg daily, and test was initially developed for blood sampling, with levels <60 pg/

3

hydralazine 5 mg every 6 hours as needed; her blood pressure ml negative, 60–80 pg/ml indeterminate, and >80 pg/ml positive.

continued to measure between 154/104 and 224/136 mmHg. According to Viracor, a BDG assay manufacturer, there is no

Repeat serology and CSF studies for possible organisms determined reference range for CSF. Despite this fact, physicians

continued to be negative. Gram staining and India ink staining have evaluated the utility of BDG testing of CSF with impressive

did not show any organisms. Repeat CSF cultures, including results.

bacterial, acid-fast bacilli, and fungal, were started. Serum (1!3)- One study demonstrated that a cut-off level of 138 pg/ml

b-D-glucan (BDG) was low at 48 pg/ml. revealed Candida meningitis with a sensitivity of 98% and

As no organism could be identified, the patient continued to specificity of 100%, whereas another showed that a cut-off level

receive empiric treatment for bacterial meningitis and supportive as low as 66 pg/ml had 91% sensitivity and 92% specificity in the

3,4

care. Fungal meningitis remained high on the differential given the setting of probable meningitis. Others have reported that a CSF

chronic presentation and findings of hydrocephalus. However, due BDG cut-off value of 110 pg/ml can diagnose CNS fungal infections

5

to the morbidity associated with amphotericin B treatment, with a sensitivity of 100% and specificity of 96%. Furthermore,

empiric antifungal treatment was not started. The patient another study found BDG levels to be useful for evaluating the

remained hypertensive and experienced episodic fever, requiring response to therapy, as physicians monitored serial CSF BDG

therapeutic large-volume lumbar punctures every 3–4 days. Other measurements in patients with fungal meningitis receiving

6

studies, including West Nile virus serum and CSF PCR, as well as treatment until they eventually fell below 31 pg/ml.

Lyme’s disease serology, were negative. Repeat imaging demon- In the current case, only one out of four fungal CSF cultures grew

strated only small focal enhancement within the midbrain, which C. albicans, and only sparsely. This is consistent with previous

could not be sampled. observations and demonstrates the poor sensitivity of this

th 3,4

On her 16 day in the hospital, the fungal culture from the diagnostic approach. Furthermore, serum BDG testing was

second performed on hospital day 7 grew fewer consistently negative, in agreement with prior reports on serum

7

than five colonies of Candida albicans. While it was encouraging to BDG levels in CNS fungal infections. On the other hand, BDG

obtain a potential causative agent, there was concern over possible testing of the CSF revealed levels >500 pg/ml, which is well above

contamination given the small yield. To confirm the diagnosis, BDG reported cut-off values for this assay.

testing of saved CSF from the positive culture showed levels This case report demonstrates a rare complication of IVDA and

>500 pg/ml. Repeat serum BDG testing was still negative. The supports CSF BDG testing as a viable option for the diagnosis of

patient began treatment with liposomal amphotericin B; flucyto- Candida meningitis.

sine was held due to low blood counts. After starting treatment, the Funding: There was no declared funding source for this report.

patient’s blood pressure and mentation began to improve. Follow- Ethical approval: No identifying material was used, therefore

up ophthalmological examinations demonstrated resolving papil- approval was not required.

ledema and she was consistently afebrile. After 14 days of Conflict of interest: The authors declare no conflicts of interest,

liposomal amphotericin B treatment, the patient was discharged financial or otherwise.

home on an indefinite course of fluconazole 800 mg.

Discussion

References

Fungal meningitis is associated with individuals who are

1. Sanchez-Portocarrero J, Perez-Cecilia E, Corral O, Romero-Vivas J, Picazo JJ. The

immunocompromised, prolonged antibiotic use, serious burns, central nervous system and infection by Candida species. Diagn Microbiol Infect

Dis 2000;37:169–79.

direct inoculation, intravascular catheters, neonates, or those with

1 2. Lyons JL, Erkkinen MG, Vodopivec I. Cerebrospinal fluid (1,3)-beta-D-glucan in

intracranial devices such as shunts. Cryptococcus meningitis is a

isolated Candida meningitis. Clin Infect Dis 2015;60:161–2.

common complication of HIV-induced immunosuppression, while 3. Litvintseva AP, Lindsley MD, Gade L, Smith R, Chiller T, Lyons JL, et al. Utility of (1-

3)-beta-D-glucan testing for diagnostics and monitoring response to treatment

Candida meningitis is more frequently observed in neonates and

during the multistate outbreak of fungal meningitis and other infections. Clin

individuals with intracranial instrumentation. In the current case,

Infect Dis 2014;58:622–30.

the patient lacked any of these known risk factors. Only her history 4. Malani AN, Singal B, Wheat LJ, Al SO, Summons TA, Durkin MM, et al. (1,3)-beta-

D-glucan in cerebrospinal fluid for diagnosis of fungal meningitis associated with

of IVDA provides any rationale as to how she developed this

contaminated methylprednisolone injections. J Clin Microbiol 2015;53:799–803.

infection. In fact, Candida meningitis within an immunocompetent

5. Lyons JL, Thakur KT, Lee R, Watkins T, Pardo CA, Carson KA, et al. Utility of

2

patient with a history of IVDA has been documented recently. measuring (1,3)-b-D-glucan in cerebrospinal fluid for diagnosis of fungal central

The diagnosis of Candida meningitis can be challenging. Fungal nervous system infection. J Clin Microbiol 2015;53:319–22.

6. Salvatore CM, Chen TK, Toussi SS, DeLaMora P, Petraitiene R, Finkelman M, et al.

cultures of CSF have a poor sensitivity and can take weeks to grow.

(1!3)-b-D-glucan in cerebrospinal fluid as a biomarker for Candida and Asper-

Furthermore, unlike Cryptococcus infections, there is currently no

gillus infections of the central nervous system in pediatric patients. J Pediatr

widely accepted molecular-, antigen-, or nucleic acid-based testing Infect Dis 2016;5:277–86.

7. Ceccarelli G, Ghezzi MC, Raponi G, Brunetti G, Marsiglia C, Fallani S, et al.

method to expedite identification of the organism, thus delaying

Voriconazole treatment of meningitis: persistence of (1,3)-

proper treatment. Such limitations necessitate the development of

b-D-glucan in the cerebrospinal fluid is a marker of clinical and microbiological

improved diagnostic assays for involvement of the CNS by Candida. failure: a case report. Medicine (Baltimore) 2016;95:e4474.