Case Report

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American Journal of Emergency Medicine

journal homepage: www. elsevier. com/ locate/ajem

Hypercalcemia as a primary manifestation of cryptococcal immune reconstitution syndrome-a rare presentation?,??,?,??

Abstract

Hypercalcemia has been well documented in neoplastic and granu- lomatous diseases. However, it is a distinctly uncommon manifestation of fungal infections. We report a rare case of an acquired immunodefi- ciency syndrome patient who was admitted with constipation and an- orexia and was found to be having severe hypercalcemia and acute kidney injury with low vitamin D levels. diagnostic work up of etiology of hypercalcemia revealed recurrent cryptococcal meningitis that responded favorably to medical therapy with normalization of serum calcium and kidney function over next few days. The exact mechanism of hypercalcemia in these patients remains unclear, although few have hypothesized immune reconstitution syndrome to be a probable cause in previously reported cases

In human immunodeficiency virus individuals who are started on highly active Antiretroviral therapy (HAART), one might see immune re- constitution inflammatory syndrome (IRIS) as a consequence. Immune reconstitution inflammatory syndrome is a group of inflammatory dis- orders that are associated with paradoxical worsening of preexisting in- fectious processes [1,2]. It is estimated that approximately 15% to 25% of patients receiving HAART develop IRIS of varying severity [3,4]. We present a unique case of hypercalcemia due to cryptococcal meningitis leading to IRIS.

Our patient is a 24-year-old man with history of hypertension and acquired immunodeficiency syndrome who presented with headache, constipation, poor appetite, generalized weakness, and unintentional weight loss of 30 lbs in 3 weeks. He was on atazanavir, emtricitabine, tenofovir, and ritonavir. He was an active smoker and engaged in un- protected sex with multiple female sexual partners. He was recently treated for cryptococcal meningitis when his CD4 T lymphocyte count (CD4) was 56, and a positive serum cryptococcal antigen was seen at a titer of 1:320. Physical examination was pertinent for poor dental hygiene and anicteric sclera. He had no Nuchal rigidity. Rest of the ex- amination was unremarkable. blood work showed white blood cell of 7300/uL and an absolute CD4 count of 125; the rest of blood cell counts

? Authors declare no conflicts of interest.

?? Authors declare that no financial assistance was taken from any source.

? Authors declare that they have no commercial or proprietary interest in any drug,

device, or equipment mentioned in the submitted article.

?? Informed consent has been taken from the patient for presentation/publication of

this case.

were within normal limits. The basic metabolic profile revealed blood urea nitrogen of 32 mg/dL; serum creatinine, 2.4 mg/dL; and calcium of 16.1 mg/dL with ionized calcium of 1.98. Hepatic function revealed alkaline phosphatase, 210 u/L and albumin of 3.6 g/dL. Electrocardio- gram showed first-degree heart block. For management of hypercalce- mia, he was hydrated with normal saline and received a dose of intravenous pamidronate. With minimal success and continued work- up, further evaluation revealed low parathyroid hormone (9 gm/mL), low 25-hydroxyvitamin D (10 ng/mL), low 1,25-dihydroxyvitamin D (11 pg/mL), and a normal PTH related peptide level. We ruled out any pertinent malignancy with a negative serum protein electrophoresis and urine protein electrophoresis and a negative chest X-ray for any suspicious mass. Cerebral workup with a magnetic resonance imaging (with contrast) of the brain revealed abnormal signal intensity within the right and left basal ganglia and the right maxillary sinus that was consistent with inflammation (Figure). Lumbar puncture revealed high cerebrospinal fluid (CSF) opening pressure 380 mm of water, 200 mononuclear cells, elevated protein, normal glucose, and positive cryp- tococcal antigen on immunofluorescence with titer of 1:128. Cerebro- spinal fluid cultures were negative at 14 days. With all other causes ruled out, the diagnosis of recurrent cryptococcal meningitis with hy- percalcemia likely due to immune reconstitution syndrome was

Figure. Enhancement in bilateral basal ganglia.

0735-6757/

established. Patient responded extremely well with ambisome, 5-fluorouracil, and steroids to treat his meningitis and IRIS. His hypercal- cemia and acute kidney injury resolved as well with proper treatment.

Although hypercalcemia is a common occurrence in neoplasms and granulomatous diseases, very few cases have been reported hy- percalcemia as a consequence of active cryptococcal meningitis in the setting of acquired immunodeficiency syndrome. Immune recon- stitution inflammatory syndrome has been hypothesized as a mech- anism, but the physiology is still unclear and under debate. Cryptococcal IRIS can have a varied array of presentations [5] Jenny-Avital and Abadi [6] described 5 cases of cryptococcal IRIS in 10 patients who were treated with HAART. Two patients developed Aseptic meningitis, 1 developed intrathoracic lymphadenopathy with hypercalcemia, and the other 2 developed cavitary pneumonia and supraclavicular abscesses. These events occurred 2 to 11 months after initiation of HAART [6].

Presentation of cryptococcal IRIS is similar to cryptococcal meningi- tis except that the former patients were found to have higher CSF open- ing pressures, CSF white cell counts, and CD4 counts in blood all with sterile CSF cultures [6,7]. As our case highlights, inadequate treatment or reactivation of the initial infection appears to be the main trigger [4]. Other factors that can predispose to IRIS include lower initial CD4 cell counts (b 100) and higher level of viremia [1,3,4,8]. The mechanism of IRIS is thought to be increased T-lymphocyte proliferation after initi- ation of HAART with immune activation leading to pathogen-specific delayed hypersensitivity. This theory is also supported by the observa- tion that IRIS manifests as a granulomatous inflammation; this can explain why most of the documented cases of hypercalcemia with IRIS are associated with elevated levels of 1,25-dihydoxyvitamin D [7,9-11]. However, in contrast to previously reported cases, our patient had suppressed levels of all forms of vitamin D along with a low para- thyroid hormone.

Although IRIS is a self-limited process, long-term sequelae and fatal outcomes may occur. Patients may present with an acute neurologic complaint that can make diagnosing difficult. The treatment of IRIS is with corticosteroids or nonsteroidal antiinflammatory drugs being the mainstay treatment to minimize systemic inflammation [12-14]. Our patient responded favorably to Steroid therapy and was an excellent ex- ample of IRIS.

The incidence of IRIS is increasing with widespread use of HAART. Clinicians should be aware of the atypical presentation of IRIS such as neurologic involvement. Early recognition and treatment of IRIS can prevent major complications, thereby significantly decreasing the mor- bidity and mortality.

Nidhi Bansal, MBBS

Department of Endocrinology, SUNY Upstate Medical University

Syracuse, NY, USA 13210 E-mail address: [email protected]

Rushikesh Shah, MBBS?

Arpan Patel, MD Gaurand Vaidya, MBBS Pramod Pantangi, MBBS

Department of Internal Medicine, SUNY Upstate Medical University

Syracuse, NY, USA 13210

?Corresponding author. Department of Internal Medicine SUNY Upstate Medical University, Syracuse, NY, USA 13210

Tel.: +1 972 375 3932

E-mail addresses: [email protected] (R. Shah)

[email protected] (A. Patel)

Divey Manocha, MD

Department of Gastroenterology, SUNY Upstate Medical University

Syracuse, NY, USA 13210

http://dx.doi.org/10.1016/j.ajem.2014.08.065

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