Hypercalcemia Associated with Infection by Cryptococcus neoformans and Coccidioides immitis

Hypercalcemia Associated with Infection by Cryptococcus neoformans and Coccidioides immitis M. Y. ALI, MD;

K. V. GOPAl, MD;

L. A. llERENA, MD;

H. C. TAYLOR, MD

ABSTRACT: Background: Of the 13 reported cases of hypercalcemia associated with fungal infection, 1 was caused by Cryptococcus neoformans and probably mediated by increased levels of 1,25-dihydroxyvitamin 0 [1,25(OH)2D]. Eight others were associated with Coccidioides immitis, of which only 2 had measured 1,25(OHbD levels; in both, they were diminished. We report a patient with human immunodeficiency virus infection and simultaneous C immitis and C neoformans pneumonia and C immitis fungemia associated with hypercalcemia. Methods: Consecutive measurements of serum total and ionized calcium, phosphorous, blood urea nitrogen, creatinine, 25(OH)D, l,25(OHbD, parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrp) and albumin were performed over a period of 46 months. Results: While the patient was

hypercalcemic, intact serum PTH and PTHrp were undetectable, serum 25(OH)D levels were normal, and serum 1,25(OHbD levels were in the high normal range. Successful treatment of the C immitis and C neoformans infections resulted in resolution of the hypercalcemia and increase of PTH and PTHrp to the normal range. Conclusion: In some patients with HIV infection, coincident hypercalcemia, and severe fungal infection, the responsible factor may be 1,25(OHbD. Although total serum levels of this compound may not be frankly elevated, they are inappropriately high for the circumstances. Free 1,25(OH)2D levels should be determined in this situation. KEY INDEXING TERMS: Hypercalcemia; HIV; Cryptococcus neoformans; Coccidioides immitis [Am J Med Sci 1999;318(6):419-23.]

H

ioides immitis and Cryptococcus neoformans in a patient with HN infection. Concurrent with the pneumonia was cryptococcal fungemia, the second such recorded example associated with hypercalcemia. 5 We demonstrate suppressed values of parathyroid hormone (PI'H) and parathyroid hormone-related protein (PI'Hrp) and high normal values of serum 1,25(OH)2D, and we discuss the perturbations of 1,25(OH)2D in HN infection and its therapy, which may spuriously decrease circulating 1,25(OH)2D levels.

ypercalcemia as a consequence of granulomatous disease is a well recognized phenomenon. Most frequently, the responsible disorders are sarcoidosis1 and, to a lesser extent, tuberculosis. 2,3 Much less common, although documented, is the occurrence of hypercalcemia in the granulomatoses of a subgroup of these disorders, fungal infection.4-11 Whereas the mechanism of the calcium elevation in sarcoid and tuberculosis has been shown to be consistent with increased concentration of serum total1,25-dihydroxyvitamin D [1,25(OH)2D),1-3 the mechanism of fungal hypercalcemia is much less clear. To date, only 13 patients have been described with fungal infection and hypercalcemia;4-12 of these, in 3, the mechanism was plausibly shown to be increased concentration of serum total 1,25(OH)2D.4,5,12 We present the fourteenth case of hypercalcemia associated with fungal infection, a pneumonia caused by combined infection with CoccidDivision of Infectious Disease and Endocrinology, Fairview General Hospital, Cleveland Clinic Health System (MYA, LAL, KVG), and Department of Clinical and Molecular Endocrinology (RCT), Case Western Reserve University School of Medicine, Cleveland, Ohio. Submitted January 4, 1999; accepted in revised form April 23, 1999. Correspondence: Harris C. Taylor M.D., FACP, FACE, Lutheran Hospital, 1730 W.25'h Street, Cleveland, Ohio 44113. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

Case Report A 40-year-old white man presented on October 16, 1995, with a I-month history of increasing dyspnea, fever, chills, profuse sweating, headache, generalized weakness, and a 20-pound weight loss. He denied cough or chest pain. His medical history was insignificant. He had been a resident of Arizona and had moved to Cleveland 10 years before. Although sexually promiscuous, he denied homosexual contact, smoking, or intravenous drug use. On physical examination, the temperature was 37°C, pulse was 100 beats/min., blood pressure 140/80 mm Hg, and respiration was 241min. He was in moderate respiratory distress, exhibited oral thrush, and had decreased breath sounds associated with bilateral diffuse rales but no rhonchi. The remainder of the examination was normal. His hemoglobin was 12.8 g/dL, white cell count was 9800/i."L, and platelet count was 353 k/JLL. Except for a slightly increased lactate dehydrogenase of 323 UIL, the rest of his routine serum chemistries were normal. Blood pH

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Hypercalcemia and Fungal Infection

A

Figure 1. Diffuse nodular, interstitial, and alveolar infiltrates are noted throughout both lung fields.

was 7.52, P0 2 was 67 mm H 20, and Pco 2 was 28 mm of H 20 in room air. Chest radiographs revealed bilateral patchy infiltrates (Fig 1.) The results of the enzyme-linked immunosorbent assay for HN were positive and the CD4 count was 0/mm3 • A preSl!IDptive diagnosis of AIDS with Pneumocystis carinii pneumonia was made, and the patient was begun on intravenous (N) trimethoprimlsulfamethoxazole (TMP/SMX). Because of the lack of clinical improvement after 1 week of TMP/SMX, a bronchoalveolar lavage was performed on October 24, 1995. Bronchial washings revealed the presence of C immitis and C neoformans (Figure 2, A-C), confirmed by cultures. Blood cultures revealed the presence of cryptococcal fungemia and serum cryptococcal antigen titer was positive at 1:128. IV amphotericin was begun, TMP/ SMX was discontinued, and zidovudine and zalcitabine instituted for treatment of his HN infection. Because of continued deterioration, a daily oral dose of 400 mg of itraconazole was added with subsequent improvement. He was discharged on December 12, 1996, taking itraconazole, rifabutin, TMP/SMX, zidovudine and zalcitabine. On January 3, 1996, he returned with complaints of dyspnea, nausea, vomiting, and lethargy for 10 days. Physical examination was unchanged except for dehydration. Serum Ca was 13.3 mgt dL, albumin was 2.3 gldL, phosphorus was 5.9 mg/dL, blood urea nitrogen was 28 mg/dL, and creatinine was 1.6 mgldL (Table 1). TSH was 2.5 /A-IU/mL and free thyroxine index 1.9 (normal, 1.0-4.6), whereas the immunochemiluminescent intact molecule PTH was <5 pgldL (normal, 12-72 pglmL), PTHrp was <0.3 pmollL (normal, 0.5-1.5 pmollL), and 25(OH)D was 18 ngldL (normal, 15--57 nglmL). A cosyntropin stimulation test showed a normal rise in serum cortisol from 12.6 to 30.3 /A-gldL. The patient was treated with rehydration, 100 mg ofN hydrocortisone every 8 hours and 90 mg of N pamidronate. Repeat bronchoscopy reconfirmed the presence of C immitis. After decrease of serum calcium to 8.5 mgldL, he was discharged on January 8, 1996, taking the same medication as before. The patient continued to manifest asymptomatic ionized hypercalcemia during the next 7

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Figure 2. (A) Large and small arrows demonstrating spherule of C immitis and yeast form of C neoformans respectively [Gomori methenamine silver (GMS) stain, original magnification, 400xJ. (B) Mucicarmine stain (original magnification, 400X) demonstrating C neoformans (large arrowhead) and spherule of C immitis (small arrowhead). (C) Pap stain (original magnification, 400X) demonstrating spherules of C immitis (black arrow) and C neoformans (white arrow). months, with serum ionized calcium ranging from 1.38 to 1.44 mmollL (normal, 1.15-1.35 mmollL), whereas his renal function and serum P remained within the normal range. Serum 25(OH)D ranged from 22 to 50 ngldL and 1,25(OH)2D ranged from 30 to 46 pglmL (normal, 15-50 pglmL), with 1 isolated elevated value of 56 pglmL. Intact PTH continued to be suppressed, and a repeat December 1999 Volume 318 Number 6

Ali, Gopal, and Taylor

Table 1. Sequential Determinations of Analytes Related to Calcium Homeostasis in a Patient with Hypercalcemia and HIV, C immitis, and C neoformans Infection

Normal values Date 10/16/95 10/28/95 11/1/95 11/05/95 11/11195 11/17/95 11/21/95 12/14/95 12/22/95 113/96 114/96 1122196 2/14196 3/6/96 3/22/96 4122/96 6/28/96 7/10/96 9/18/96 12/9/96 1/23/97 9/30/97 12/2/97 8/19/98 8/18/99

Total calcium

Ionized calcium

P

BUN/Cr

25(OH)D

8.5-10.5 mgidL

1.15-1.35 mmollL

2.2-4.6 mgidL

7-18/0.6-1.3 mgidL

15-57 ngidL

8.5 10.7 9.6 9.6 9.9 10.9 10.9 10.9 11.6 13.3 11.8 9.9 10.3 10.9 10.1 11.0 10.1 10.2 9.8 9.3 9.5 10.5 9.8 9.5 9.5

1.44 1.39 1.43 1.38 1.25 1.20 1.17 1.25 1.27 1.24

2.7 2.2 3.2 4.5 8.3 9.6 2.2 2.9 5.0 5.9 3.7 3.9 4.1 3.8 4.0 4.4 4.9 4.0 3.8 3.9 4.3 3.6 4.1 3.7

15/1.3 36/1.0 22/1.3 25/1.4 53/22 67/2.8 36/1.0 - /1.0 23/1.6 28/1.6 24/1.2 12/0.9 11/0.7 8/0.8 1110.6 13/0.7 15/1.1 10/1.1 14/0.9 13/0.8

15-50 pg/mL

18

PTH

PTHrp

Alb

12-72 pgimL

0-1.5 pmollL

3-5 g/dL

<0.3

3.8 2.2 1.6 2.3 2.5 2.5 2.6 2.6 2.6 2.3 1.9 2.5 2.4 2.8 3.4 3.9 3.9 3.9 4.2 4.2 4.4

<5

30 22 50

43 46 40 30

<5 <5 2 (11-54)

29 38 36

56 28 40

11 (11-54) 14 26

48

44

0.5

13/1.0 15/1.5

BUN, blood urea nitrogen; Cr, creatinine; Alb, albumin.

PTHrp was 0.5 pmollL. A CT scan of the chest and abdomen revealed no underlying malignancy. With clinical and radiological improvement of his pulmonary infection (Figure 3), his serum ionized calcium levels returned to normal (1.17-1.25 mmollL) and have remained so over the past 33 months as have 25(OH)D and 1,25(OH)2D levels, whereas PTH has gradually risen to 26 pg/mL. Table 1 depicts the sequential changes in calcium, vitamin D, and PTH homeostasis.

Discussion

Interest in hypercalcemia associated with fungal infection has heightened as the incidence of severe systemic fungal infections increases in the wake of the HIV pandemic. However, despite this, the incidence of fungus-induced hypercalcemia remains very low. Increased production of 1,25(OH)2D has been implicated in. the pathogenesis of hypercalcemia associated with a number of chronic granulomatous processes, such as sarcoidosis,l silicone-induced granulomas,13 Wegener granulomatosis,14,15 lipoid pneumonitis,16,17 tuberculosis,2,3 leprosy, 18 and plasma cell granuloma.1 9 Its role in fungal infection hypercalcemia, however, is less clear. In 1977, Lee et al reported for the first time the association of hypercalcemia with disseminated coccidioidomycosis. 11 Since then, 7 additional cases of hypercalcemia with coccidioidomycosis have been reported. 6,7,9,11 In 1 patient, 1,25(OH)2D was found to be suppressed, THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

Figure 3. Diffuse areas of fibrosis in both lungs with improvement in nodular infiltrates.

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Hypercalcemia and Fungal Infection

on 2 separate occasions, to 3.4 pg/mL and undetectable (normal, 25-75 pg/mL), with a suppressed PTH leveL9 Westphal's patient6 is the only other recorded example of hypercalcemia with coccidioidomycosis in which 1,25(OH)2D was measured. It was diminished to 14 pg/mL (normal, 15-60) when the serum calcium was 13.4 mg/dL and PTH was <1.4 pg/mL (normal, 11-54). On the other hand, Spindel et al reported a patient with HIV who had ionized and total hypercalcemia in association with C neoformans infection. Serum 1,25(OHhD was elevated to 67 pg/mL (normal, 15-50 pg/mL) with a suppressed serum PTH of 2.0 pg/mL (normal, 10-55 pg/ml). This improved after therapy of his fungal infection, consistent with 1,25(OH)2D as the cause of the hypercalcemia. 5 Two previously reported patients with histoplasmosis and hypercalcemia contained no measurements of serum 1,25(OH)2D.8,lO However, Kantarjian's patient with disseminated candidiasis and hypercalcemia manifested elevated levels of total serum 1,25(OH)2D that returned to normal, as did the serum calcium, with resolution of the candidiasis. 4 A similar clinical picture of elevated serum 1,25(OH)2D and hypercalcemia in a patient infected with HIV with P carinii infection was reported by Ahmed and J aspan. 12 Both abnormalities resolved with resolution of the P carinii pneumonia. Our patient demonstrated total and ionized hypercalcemia over 9 months, associated with an undetectable or suppressed serum PTH, normal to elevated serum phosphorous, and impaired to normal renal function. There was no evidence of malignancy as demonstrated by (1) normal CT scan of the thorax and abdomen (except for the pneumonia), (2) an absence of PTHrp, and (3) improving health over the ensuing 40 months. There was no indication of primary adrenal insufficiency as evidenced by the normal cosyntropin test. During his period of hypercalcemia, he continued to demonstrate a high normal serum level of 1,25(OH)2D (mean of 39.75 pg/mL; normal, 15-50 pg/ mL). It was inappropriately elevated for the suppressed PTH and normal to high-normal phosphorous levels, thereby suggesting inappropriately elevated production or decreased clearance of 1,25(OH)2D. Our patient's hypercalcemia was treated only during the symptomatic phase with N pamidronate and hydrocortisone, after which he remained asymptomatic from the point of view of his hypercalcemia. With improvement in his general physical condition and his pulmonary infection, as indicated by his follow-up chest radiographs, his hypercalcemia normalized despite the single elevated value of 1,25(OH)2D of 56 pg/mL. We hypothesize that several factors may account for the lack of frank elevation of 1,25(OH)2D levels. First, we measured only total 1,25(OH)2D rather than the free values and/or vitamin D binding protein to calculate a free calcitriol index. It is known that 85% of calcitriol is bound to vitamin D binding protein, 0.4% is free, and the rest is bound to albu-

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min.20 A decrease in vitamin D binding protein (paralleling and together with the decreased albumin) may have contributed to a spuriously low total 1,25(OH)2D leveL This hypothesis loses some of its attraction by the recent demonstration of Haug et al that circulating levels of vitamin D binding protein in 54 patients with HN did not differ significantly among those whose 1,25(OH)2D levels were normal, low, or undetectable. 21 However, Shaker et al reported a patient with Wegener's granulomatosis, hypercalcemia, suppressed PTH, and a baseline normal level of 1,25(OH)2D with a modestly decreased level of vitamin D binding protein.1 5 The 33% increase in the percentage of free 1,25(OH)2D consequent to this decreased level would have been sufficient to elevate the absolute free 1,25(OH)2D level above normaL Such a level of vitamin D binding protein could be approximated in patients with HIV given the lowest inferred levels from Haug's median and 25th and 75th percentile levels in 54 patients with HIV.21 Save for our lack of measurement of vitamin D binding protein, the pattern in Shaker's patient is quite similar to that of our patient. Second, Haug et aI, in a study of 53 HIV-positive patients, demonstrated significantly lower serum levels of total 1,25(OH)2D in symptomatic patients with HN compared with their asymptomatic peers. Furthermore, serum levels of 1,25(OH)2D correlated positively with the CD4 cell count in the blood. 22 Our patient presented with stage IV HIV infection with a CD4 count of zero. This would suggest the likelihood of a lower serum 1,25(OH)2D apart from other factors. Other studies have documented the high turnover rate of CD4 lymphocytes in HN infection. 23 Given the role of 1,25(OH)2D in immune system cellular differentiation,24 as Haug et al point out, "it is not inconceivable that increased need for 1,25(OH)2D for maturation of lymphocytes may account for at least part of the decreased levels of 1,25(OHhD in immune activated, rapidly proliferating T cells."21 In short, there may be accelerated clearance of 1,25(OH)2D. These observations likewise may help explain the lower-than-expected increased levels of total 1,25(OHhD in our patient. Third, ketoconazole has been shown to suppress mitochondrial cytochrome P450-linked enzymes such as la-hydroxylase. Adams et al demonstrated a dosedependent in vivo and in vitro suppression of 1,25(OH)2D production with ketoconazole in hypercalcemic patient with sarcoidosis. 25 Glass and Eil reconfirmed these findings in their study of 15 hypercalcemic patients and showed a fall in the levels of 1,25(OH)2D by a mean of 43 ± 6%, which is similar to the 44 ± 6% fall they noted when ketoconazole was given to 9 healthy men. 26,27 In both studies, there was only a mild reduction in the level of total calcium, and no change was noted in the levels of serum ionized calcium, phosphate, PTH, 25(OH)D, or urinary cAMP excretion. Our patient's fungal infections were treated with itracon-

a

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Ali, Gopal, and Taylor

azole, a congener of ketoconazole. To our knowledge, there is no published information addressing whether the aforementioned effect of ketoconazole is shared by itraconazole in vivo. If it is, it may also have contributed to the lower-than-anticipated elevated levels of totall,25(OH)2D. However, in vitro data indicate that itraconazole "shows low, if any affinity for adrenal, testes, lung and liver P450s ... this is further proved by its low, if any, effect on the I-hydroxylation of 25-hydroxyvitamin D3 in kidney mitochondria."28 Regrettably, the serum level of 1,25(OH)2D was not recorded in our patient before institution ofitraconazole. Finally, interleukin 6, tumor necrosis factor, interferon-y, or other as-yet-unidentified cytokines, produced as a response to malignancy or infections, have been shown to be associated with hypercalcemia29,30 or, in the case of interferon-y, to induce lahydroxylase in macrophages. 31 Although we cannot eliminate the first 2 of these factors as being responsible for the hypercalcemia in our patient, we think it less likely given the inappropriately high normal 1,25(OH)2D levels. Obviously, implication of interferon-y would require measurements of this cytokine. In summary, we report an exceedingly rare cause of hypercalcemia, fungal infection with C neoformans and C immitis. Our duration of follow-up, nearly 4 years without recrudescence of the hypercalcemia, is much longer than previously reported in such patients and supports the fungal etiology. Finally, we demonstrate consistently high normal levels of 1,25(OH)2D, despite several potential and recognized factors that should otherwise severely reduce the circulating levels of this compound. This supports the hypothesis that the hypercalcemia may be mediated by inappropriately high levels of 1,25(OH)2D. References 1. Bell NH, Stern PH, Pantzer E, et al. Evidence that increased circulating 1a,25-dihydroxy-vitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest 1979;64:218-25. 2. Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25 dihydroxyvitamin D levels in a patient with end-stage renal disease and active tuberculosis. N Engl J Med 1984;311:1683-5. 3. Bell NH, Shary J, Shaw S, et aI. Hypercalcemia associated with increased circulating 1,25 dibydroxyvitamin D in a patient with pulmonary tuberculosis. Calcif Tissue Int 1985;37:588-91. 4. Kantarjian HM, Saad MF, Estey EH, et al. Hypercalcemia in disseminated candidiasis Am J Med 1983;74:721-4. 5. Spindel SJ, Hamill RJ, Georghiou PR, et al. Case report: vitamin D-mediated hypercalcemia in fungal infections. Am J Med Sci 1995;310:71-6. 6. Westphal SA. Disseminated coccidioidomycosis associated with hypercalcemia. Mayo Clin Proc 1998;73:893-4. 7. Walter RM Jr, Lawrence RM. Total ionized serum calcium and parathyroid hormone levels in patients with disseminated coccidioidomycosis. Am J Med Sci 1981;281:97-9. 8. Murray JJ, Heim CR. Hypercalcemia in disseminated histoplasmosis. Aggravation by vitamin D. Am J Med 1985;78:881-4. 9. Parker MS, Dokoh S, Woolfenden JM, et al. Hypercalcemia in coccidioidomycosis. Am J Med 1984;76:341-4.

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10. Walker JV, Baran D, Yakub YN, et al. Histoplasmosis with hypercalcemia, renal failure and papillary necrosis. Confusion with sarcoidosis. JAMA 1977;237:1350-2. 11. Lee JC, Catanzaro A, Parthemore JG, et aI. Hypercalcemia in disseminated coccidioidomycosis. N Engl J Med 1977;297:431-3. 12. Ahmed B, Jaspan JB, Hypercalcemia in a patient with AIDS and Pneumocystis carinii pneumonia. Am J Med Sci 1993;306:313-6. 13. Kozeny GA, Barbato AL, Bansal VK, et al. Hypercalcemia associated with silicone-induced granulomas. N Eng J Med 1984;311:1103-5. 14. Bosch .x, Lopez-Soto A, Morello A, et aI. Vitamin D mediated hypercalcemia in Wegener's granulomatosis. Mayo Clin Proc 1997;72:440-4. 15. Shaker JL, Redlin KC, Warren GV, et al. Case report: hypercalcemia with inappropriate 1,25-dihydroxyvitamin D in Wegener's granulomatosis. Am J Med Sci 1994;308:115-8. 16. Rolla AR, Granfone A, Balogh K, et al. Granuloma-related hypercalcemia in lipoid pneumonia. Am J Med Sci 1986;292:313-6. 17. Greenaway TM, Caterson ID. Hypercalcemia and lipoid pneumonia. Aust NZ J Med 1989;19:713-5. 18. Hoffman VN, Korzeniowski OM. Leprosy, hypercalcemia and elevated serum calcitriollevels. Ann Intern Med 1986;105:890-1. 19. Hellikson MA, Havey AD, Zerwekh JE, et al. Plasma-cell granuloma producing calcitriol and hypercalcemia. Ann Intern Med 1986;105:379-81. 20. Bikle DD, Gee E, Halloran B, et aI. Free 1,25 dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects and subjects with liver disease. J Clin Invest 1984;74:1966-71. 21. Haug CH, Aukrust P, Haug E, et aI. Severe deficiency of 1,25-dihydroxy vitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab 1998;83:3832-8. 22. Haug CH, Muller F, Aukrust P, et al. Subnormal serum concentration of 1,25 vitamin D in human immunodeficiency virus infection. Correlation with degree of immune deficiency and survival. J Infect Dis 1994;169:889-93. 23. Ho DD, Neumann, AV, Perelson AS, et al. Rapid turnover of plasma virions and DC4 lymphocytes in HN-1 infection. Nature 1995;373:123-6. 24. Lemire JM. Immunomodulatory rate of 1,25 dihydroxyvitamin D3. J Cell Biochem 1992;49:26-31. 25. Adams JS, Sharma OP, Diz MM, et aI. Ketoconazole decreases the serum 1,25 dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia. J Clin Endocrinol Metab 1990;70:1090-5. 26. Glass AR, Ell C. Ketoconazole-induced reduction in serum 1,25 dihydroxyvitanIin D. J Clin Endocrinol Metab 1986;63:766-9. 27. Glass AR, Eil C. Ketoconazole-induced reduction in serum 1,25 dihydroxyvitamin D and total serum calcium in hypercalcemic patients. J Clin Endocrinol Metab 1988;66:934-8. 28. Vanden Bossche H, Heeres J, Bacloc LJJ, et al. Discovery, chemistry, mode of action and selectivity ofitraconazole. In: Rippon JW, Fromtling RA, editors. Cutaneous antifungal agents. New York: Marcel Dekker; 1993. p. 263-83. 29. Yoneda T, Nakai M, Moriyama K, et al. Neutralizing antibodies to human interleukin 6 reverses hypercalcemia associated with a human squamous carcinoma. Cancer Res 1993;53:737-40. 30. Yoneda T, Alsina M, Chavez J, et al. Evidence that tumor necrosis factor plays a pathogenic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice. J Clin Invest 1991;87:977-85. 31. Koeffier HP, Reichel H, Bishop JE, et aI. Gamma interferon stimulates production of 1,25-dihydroxy vitamin D3 by normal human macrophages. Biochem Biophys Res Commun 1985;127:596-603.

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