Immune reconstitution associated hypercalcemia

Case Report

Immune reconstitution associated hypercalcemia Abstract

The emergence of Highly active antiretroviral therapy using combinations of reverse transcriptase and Protease inhibitors ushered the dawn of a new era in management of human immunodeficiency virus infection. Immune recon- stitution inflammatory syndrome is an adverse consequence of the restoration of pathogen-specific immune responses during the early phase of antiretroviral therapy. Pre-existing subclinical or opportunistic infections become apparent or even “worse” as host immunological inflammatory responses are “switched on”. Major reductions in plasma viral load were associated with substantial increases in circulating CD4 T-cell lymphocyte counts and restoration of immune function. The rapid reversal in immune function gives rise to paradoxical therapeutic reaction by rebuilding host immune responses. Herein, a hidden culprit responsible for tuberculosis- associated immune reconstitution characterized by severe hypercalcemia and acute renal failure is reported, illustrating the compounded therapeutic strategy in AIDS patients.

A 41-year-old homosexual man presented was referred to the emergency department due to acute renal failure. He had a 5-year history of silent human immunodeficiency virus -1 infection and reported no illicit drug use, trauma, or other medical history. Two months previously, unexplained weight loss developed, and his plasma virus load increased to 1,200,190 RNA copies/mL with a CD4 T-cell count of 42 cells/uL. Accordingly, highly active antiretroviral therapy (HAART) with stavudine, lamivudine, and efavirenz was commenced, resulting in satisfactory response without Major adverse events. On admission, he was alert and his blood pressure was 150/90 mm Hg, pulse rate was 78 beats per minute, respiratory rate was 22/min, and body temperature was 36.2?C. Laboratory studies showed hemoglobin level of

11.2 g/dL, platelet count of 215 x 109/L, and leukocyte count of 7.6 x 109/L. His CD4 T-cell count was elevated (285 cells/ uL) with considerably reduced viral load (890 copies/mL). Serum biochemistries revealed sodium, 133 mmol/L; potassium, 4.9 mmol/L; chloride, 101 mmol/L; blood urea nitrogen, 62 mg/dL; creatinine level, 2.4 mg/dL; and metabolic acidosis. Further workup revealed hypercalcemia

(ionized calcium, 6.7 mg/dL) with hypercalciuria (urinary fraction excretion of calcium, 4.8%), a high serum level of 1,25(OH)2D3 (251 pmol/L), and suppressed intact parathyr- oid hormone (6.8 pg/mL), necessitating interrogation for primary foci of absorptive hypercalcemia. Consistent with contrast-enhanced computed tomographic scan of the abdo- men (Fig. 1), microbiological and histopathologic analyses confirmed Mycobacterium tuberculosis splenic abscess. The newly developed hypercalcemia of tuberculosis infection after starting HAART suggests that these clinical features were attributable to Immune reconstitution inflammatory syndrome (IRIS). Aggressive intravenous volume repletion with concurrent corticosteroids institution yielded rapid normalization of serum calcium without compromise of renal function. Standard quadruple drug antituberculous regimen with surgical drainage achieved complete resolution of splenic tuberculosis.

Immune reconstitution inflammatory syndrome is recog- nized as a paradoxical worsening of preexisting or smolder- ing opportunistic infections in patients with HIV on HAART due to the recuperating of immune system. The temporal association between initiation of HAART and the

Fig. 1 Contrast-enhanced computed tomographic scan of the abdomen showing a wedge-shaped low-attenuation lesion located at the anterior aspect of the spleen with surrounding fat stranding (arrow).

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development of an unusual manifestation often provides a strong evidence of IRIS. Immune reconstitution inflamma- tory syndrome is not a new phenomenon nor is it limited to HIV-infected populations receiving HAART. Indeed, the potential for IRIS exists whenever patients who have been severely immunocompromised have rapid revitalization of immune function. Immune reconstitution inflammatory syndrome is most frequently reported in patients with HIV infection on HAART, and in such patients, it has been described with a wide variety of opportunistic infections. Notably, the pathogens involved in IRIS reflect the spectrum of opportunistic infections in association with the specific form of immunosuppression [1].

The risk of paradoxical treatment reactions is strongly associated with starting HAART within the first 2 months of antituberculosis treatment. Other factors associated with IRIS include extrapulmonary and disseminated tuberculosis, a lower CD4 lymphocyte count and higher viral load before commencing HAART, and a greater reduction in viral load and greater expansion of CD4 T-cell during HAART [2]. Development of IRIS is associated with a preceding increase in CD4 lymphocyte count in most patients. However, a rise in blood CD4 lymphocyte count per se is not always indicating the ongoing improvement of immunopathologic responses. Conversely, lack of a rise in CD4 lymphocyte count does not denote that there has been no restoration of functional T lymphocyte [1]. In fact, IRIS can occur within the first few weeks of HAART before any rise in blood CD4 lymphocyte count. Of note, a positive response to HAART heralded by a paralleled reduction of viral load is fairly invariable, which might be a more practical surrogate for IRIS. Generally, a reduction in plasma viral load of more than 90% occurs within the first 1 to 2 weeks of HAART, and associated rapid rise in the number of circulating CD4 lymphocytes can usually be detected within 1 to 2 weeks of starting HAART and extends for several months after treatment.

Paradoxical reactions in tuberculosis-associated IRIS are constitutionally pertaining to intensification of cell-mediated immunity s and may be associated with conversion of pre- HAART immune anergy to a positive response after antituberculosis treatment. Human immunodeficiency virus and mycobacteria coinfection disrupts cell-mediated immune responses by impairing both the recruitment and function of the effective macrophages and CD4 T lymphocytes [3]. Interleukin 2-mediated CD4 lymphocyte activation and proliferation are inhibited along with the unregulated imbalance of type 1 and type 2 cytokine secretions. These changes drive the humoral arm of the immune system and dampened cell-mediated immunity. Through these defects, progressive HIV-associated immunodeficiency results in abrogation of granuloma formation and unbridled mycobac- teria in infected tissues. Subsequently, patients with AIDS may develop active infection with very high mycobacteria burden, but only have few clinical symptoms [4].

The homeostasis of calcium is complex because the bone, gastrointestinal tract, and kidney are all implicated in the

Table 1 Differential diagnosis of hypercalcemia

I. Low urine calcium excretion (FECa b2%)

  • Renal reabsorption bundle (reabsorption hypercalcemia) Thiazide, chronic

Lithium, chronic

Inactivating mutations in the CaSR Familial hypocalciuric hypercalcemia Acquired hypocalciuric hypercalcemia

II. High urine calcium excretion (FECa N2%)

  • Bony resorption bundle (resorptive hypercalcemia) High serum iPTH

Primary hyperparathyroidism Tertiary hyperparathyroidism Metabolic acidosis, chronic Low serum iPTH

Malignancy (osteolytic, humoral)

Multiple myeloma, breast carcinoma, solid cancers (PTHrP), antioestrogen (Tamoxifen flare)


Hyperthyroidism, Adrenal insufficiency, pheochromocytoma, VIPoma

Immobilization Adynamic bone disease

  • Gastrointestinal absorption bundle (absorptive hypercalcemia)

High serum 1,25(OH)2D3 Exogenous

vitamin D intoxication Endogenous Granulomatous diseases

Sarcoidosis, tuberculosis, silicosis Fungal infections


Low serum 1,25(OH)2D3 Total parenteral nutrition Milk-alkali syndrome Vitamin A intoxication

CaSR indicates calcium sensing receptor; FECa, urinary fraction excretion of calcium; iPTH, intact parathyroid hormone; PTHrP, parathyroid hormone-related peptide.

balance of calcium. As a result, hypercalcemia can be divided basically into 3 bundles as follows: accelerated bony calcium resorption, increased enteral/parenteral calcium absorption, and enhanced renal calcium reabsorption (Table 1). Measure- ment of urinary calcium excretion, serum intact parathyroid hormone, and 1,25(OH)2D3 is very useful in the differentia- tion of these 3 categories. Hypercalcemia per se can induce acute renal failure via afferent glomerular arteriolar vasocon- striction, Volume depletion due to diuresis, and nephrocalci- nosis and then in turn, compromise calcium excretion and accentuate the degree of hypercalcemia [5]. Irreversible attrition of renal function supervenes if the diagnosis and treatment are delayed. In this patient, hypercalcemia with resultant acute renal failure during tuberculosis-associated IRIS provides further indirect evidence that HAART restores the ability to form functioning granulomas [6]. The restora- tion of the granulomatous host response during HAART is

Case Report

incriminated in overproduction of active 1,25(OH)2D3 resulting from increased macrophagic 1?-hydroxylase activ- ity in granulomatous lesions, leading to hypercalcemia [7]. Corticosteroids are the mainstay of therapy for disordered calcium homeostasis in the presence of excess active vitamin D metabolites and also a treatment of choice for IRIS.

Most tuberculosis-associated IRIS develop within the first 3 months of HAART. Tuberculosis-associated IRIS typically occurs in patients with profound immunodefi- ciency, usually a nadir CD4 lymphocyte count of less than 100 cells/uL (median, b50cells/uL), a viral load of more than 105 copies/mL, and with a rapid response to combination antiretroviral treatment after a median of 4 weeks of HAART [8]. To date, Mycobacterium tubercu- losis, the most common pathogen associated with IRIS, still presents a great challenge to antiretroviral programs because it could be easily overlooked in terms of protean manifestations in extrapulmonary tuberculosis spreading. Besides, the limited sensitive diagnostic tests for tubercu- losis when applied to patients with advanced immunode- ficiency further compounds the therapeutic strategy. Hypercalcemia secondary to tuberculosis-associated IRIS should be kept in mind to obviate unnecessary intervention, preserve renal function, and achieve better outcomes.

Yu-Tzu Tsao MD Division of Nephrology Department of Medicine

Tri-Service General Hospital National Defense Medical Center

Taipei 114, Taiwan E-mail address: [email protected]

Yi-Chang Wu MD, PhD

National Defense Medical Center

Taipei 114, Taiwan Department of Medicine Gangshan Armed Forced Hospital

Kaohsiung 820, Taiwan


Cheng-Shu Yang MD Department of Medicine Gangshan Armed Forced Hospital

Kaohsiung 820, Taiwan

Ying-Tsun Lin MD Department of Medicine Gangshan Armed Forced Hospital

Kaohsiung 820, Taiwan



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