Infectious Diseases Case of the Month Case #42

A thirty-four year old white male heterosexual with HIV/AIDS was admitted to the hospital for hypercalcemia and acute renal failure.

AIDS had been diagnosed two months previously when he had presented with diffuse pneumonitis secondary to Pneumocystis jirovecii. At the time of his diagnosis his CD4 count was 22 and HIV viral load was 7,900,000 copies/ml. His respiratory illness responded readily to anti-pneumocystis therapy and prednisone. A rash to TMP/SMX necessitated change to dapsone for secondary prophylaxis of pneumocystis. He was begun on antiviral therapy of HIV with Atripla (tenofovir, emtricitabine, efavirenz) and prophylaxis for Mycobacterium avium complex (MAC) with weekly azithromycin.

Two or three weeks subsequent to his initial clinical improvement he began to experience headaches. A lumbar puncture was performed with normal results including CSF VDRL, cryptococcal antigen, and cultures for bacteria, fungi, and AFB. A Quantiferon Gold test (gamma interferon release assay) was negative. He then began to experience fevers, malaise, back, and abdominal pain. Eventually, a blood culture was positive for Mycobacterium avium complex. The patient was begun on therapeutic doses of azithromycin, ethambutol, and rifabutin.

He developed severe nausea and vomiting and was unable to tolerate his oral medications (except for Atripla) even with the aid of anti-emetics. When his abdominal pain worsened, he presented to the emergency room where he was discovered to be hypercalcemic (CA 14.1) and in renal failure (creatinine 2.1). An abdominal CT scan (see left and click here for larger images) showed extensive lymphadenopathy of the mesentery and retroperitoneum.

The patient was admitted to the hospital. At the time of his admission he appeared dehydrated. He had no cutaneous lesions nor abnormal peripheral lymphadenopathy. A CD4 count was 94 (it had been as high as 223 one month earlier). His HIV viral load was 8,350 copies/ml. He was treated for his hypercalcemia and renal failure. Upper GI endoscopy findings were notable for bile gastritis. Therapy with sucralfate eliminated his nausea and vomiting.

A biopsy was performed of a retroperitoneal lymph node.

What was the cause of this patient's lymphadenopathy and hypercalcemia?
Diagnosis: Mycobacterium avium complex

The intra-abdominal lymphadenopathy was secondary to disseminated Mycobacterium avium complex infection. The granulomatous inflammatory response to infection with this organism was responsible for elaboration of excessive 1,25 dihydroxyvitamin D3 (calcitriol) leading to hypercalcemia and renal insufficiency. Immune reconstitution inflammatory syndrome (IRIS) likely contributed to the extent of his illness.

Photomicrographs of the patient's biopsy are at left. An H&E stain (upper left) showed sheets of histiocytes. At lower left is an AFB stain of the biopsy demonstrating the tissue to be loaded with mycobacteria.

Granulomatous disease is a well described cause of hypercalcemia having been observed in diseases such as sarcoidosis, tuberculosis, berylliosis, coccidioidomycosis, histoplasmosis, and Wegener's granulomatosis. The mechanism is most completely understood in the case of sarcoidosis. In normal subjects, the conversion of 25-hydroxyvitamin D (calcidiol) to calcitriol occurs via hydroxylation in the kidney proximal tubule that is under the physiologic control of parathyroid hormone (PTH), fibroblast growth factor 23, and the serum phosphate concentration. Hypercalcemia normally suppresses the release of PTH and therefore the production of calcitriol, but in sarcoidosis and other granulomatous diseases, activated mononuclear cells (particularly macrophages) in diseased tissues produce calcitriol from calcidiol independent of PTH

In the case described the patient's 1,25 dihydroxyvitamin D3 level was 125 pg/ml (normal range 15-75) and his parathormone level was 3.9 pg/ml (normal range 15-65). His hypercalcemia responded readily to rehydration, zoledronic acid, and corticosteroids. His renal failure likewise resolved over succeeding weeks. He was maintained on azithromycin and ethambutol for Mycobacterium avium.

The patient had had a very large burden of intra-abdominal lymphadenopathy due to disseminated Mycobacterium avium complex disease. Given the severity of his related abdominal pain and constitutional symptoms (fever, prostration) and the onset of these symptoms shortly after initiation of highly active antiretroviral therapy (HAART), it is likely that the immune reconstitution inflammatory syndrome (IRIS) was present, perhaps also contributing to the development of hypercalcemia.

IRIS in persons infected with HIV is an incompletely understood severe inflammatory reaction to recognized or previously unrecognized existing co-infections in persons recently initiated on HAART. It appears to represent a dysregulated "reawakening" of the immune system to the presence of pathogens (click here for a schematic proposed mechanism). Risk factors for the development of IRIS associated with several HIV associated conditions may include very low CD4 count at initiation of HAART and the rapidity of immunologic and virologic response to HAART. IRIS can be life threatening. Anti-inflammatory therapy with corticosteroids may be beneficial in cases of severe IRIS.

Several of the other diagnostic choices in the preceding vignette can also have associated extensive intra-abdominal lymphadenopathy and/or hypercalcemia. Non hodgkin's lymphoma is certainly a diagnostic possibility in persons with AIDS and could have associated paraneoplastic hypercalcemia. Milk-alkali syndrome is a cause of hypercalcemia associated with excessive calcium carbonate intake but would not cause lymphadenopathy. Yersinia enterocolitica is a cause of mesenteric lymphadenitis. HHV8 is a causative agent of Kaposi's Sarcoma and Castleman's Disease. In the former it would be unlikely to cause intra-abdominal lymphadenopathy; in the latter it could.

Ref: Wilson, E.M.P and Sereti, I, Immune restoration after antiretroviral therapy: the pitfalls of hasty or incomplete repairs, Immunological Reviews 2013, 254:343-354.


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