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A Case of Hypercalcemia Secondary to Hot Tub LungA Case of Hypercalcemia Secondary to Hot Tub Lung FREE TO VIEW

Jessica Donato, MD; Colin T. Phillips, MD; Adam W. Gaffney, MD; Paul A. VanderLaan, MD, PhD; Majd Mouded, MD
Author and Funding Information

From the Department of Medicine (Drs Donato and Phillips), Department of Pulmonary and Critical Care Medicine (Drs Gaffney and Mouded), and Department of Pathology (Dr VanderLaan), Beth Israel Deaconness Medical Center; and Department of Pulmonary Medicine (Dr Mouded), Harvard Vanguard Medical Associates, Boston, MA.

CORRESPONDENCE TO: Colin T. Phillips MD, Beth Israel Deaconess Medical Center, Department of Medicine, 330 Brookline Ave, Boston, MA 02215; e-mail: ctphilli@bidmc.harvard.edu


Drs Donato and Phillips contributed equally to this work.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(6):e186-e189. doi:10.1378/chest.14-0350
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Published online

Hypersensitivity pneumonitis (HP) is a diffuse granulomatous lung disease resulting from inhalation of an antigen to which an individual has been previously sensitized. Hot tub lung is an increasingly common form of HP associated with inhalation of water aerosols containing Mycobacterium avium complex organisms that contaminate hot tub water. Granulomatous lung disorders, most classically sarcoidosis, have been associated with unregulated 1-α-hydroxylase expression by macrophages present in the granulomas, causing conversion of 25-OH-vitamin D to the active form of vitamin D, 1,25(OH)2 vitamin D, and, thus, hypercalcemia. To our knowledge, this is the first confirmed case of hypercalcemia secondary to elevated 1,25(OH)2 vitamin D levels associated with HP.

Figures in this Article

Granulomatous lung diseases are known to cause hypercalcemia due to activated macrophages converting vitamin D to its active form, 1,25(OH)2 vitamin D (OH2-D).1-6 Here, we describe a case of hot tub lung with resultant hypercalcemia treated successfully with prednisone.

A 70-year-old man with history of stage 3 chronic kidney disease secondary to hypertension was admitted for evaluation of progressive dyspnea. The patient reported 9 months of progressive dyspnea on exertion with mild dyspnea at rest. He was a lifelong nonsmoker. Social history was notable for exposure to horses, hay, and molds from his home in rural New England, as well as a hot tub, which he had been using more frequently to alleviate symptoms as his dyspnea progressed. He was hypoxemic on presentation, requiring 2 L supplemental oxygen to saturate at 96%. His pulmonary examination was notable for diffuse inspiratory crackles. There was no edema or clubbing.

Initial laboratory investigations revealed a WBC count of 6.4 K/μL, calcium level of 10.7 mg/dL, and baseline creatinine level of 1.9 mg/dL. The patient’s chest radiograph was notable for diffuse bilateral ground-glass opacities (Fig 1), and a noncontrast CT scan of the chest further elucidated a pattern of peripheral and upper-lobe-predominant reticular and ground-glass opacities along with multiple small (< 7 mm) pulmonary nodules (Fig 2). His calcium level ultimately peaked at 11.9 mg/dL, with other laboratory data revealing a low-normal parathyroid hormone level of 15 pg/mL, 25-OH-vitamin D level of 30 ng/mL, albumin level of 3.5 g/dL, and phosphorous level of 4 mg/dL. His OH2-D level was elevated at 76 pg/mL (normal range: 18-72 pg/mL). Other values are reported in Table 1.

Figure Jump LinkFigure 1 –  Initial chest radiograph with diffuse, bilateral ground-glass opacities with increased interstitial markings.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, B, CT scans of the chest at the level of the aortic arch (A) and the carina (B). Both demonstrate fine, increased interstitial density with faint ground-glass densities and multiple small (< 7 mm) pulmonary nodules.Grahic Jump Location
Table Graphic Jump Location
TABLE 1 ]  Blood Test Results at Baseline, Presentation, Hospitalization, and Posttreatment Follow-up

ACE = angiotensin-1 converting enzyme; EGFR = estimated glomerular filtration rate; PTH = parathyroid hormone; PTHrP = parathyroid hormone-related peptide.

a 

8 mo prior to presentation.

b 

1 mo posttreatment.

He was initially treated with IV fluids for stabilization and underwent video-assisted thorascopic surgery with right upper, middle, and lower lobe wedge biopsies. Lung pathology revealed numerous nonnecrotizing, loose to moderately formed granulomas with negative fungal, bacterial, and mycobacterial stains (Fig 3). The constellation of pathologic findings was most consistent with a diagnosis of hypersensitivity pneumonitis (HP). Both BAL and biopsy-obtained tissue ultimately grew Mycobacterium avium complex (MAC) organisms. Independent home evaluation confirmed MAC in the patient’s home water. The pathology along with presence of MAC confirmed the diagnosis of hot tub lung.3,7 He was initiated on prednisone, 60 mg/d, with immediate resolution of his hypercalcemia. He was weaned over 3 months with significant resolution of his clinical and radiographic abnormalities. Calcium levels remained normal 1 month after completing his prednisone course.

Figure Jump LinkFigure 3 –  A, B, Histologic sections from the lung wedges at original magnification × 2 (A) and original magnification × 20 (B) demonstrate a diffuse, moderately formed, nonnecrotizing granulomatous process with a somewhat airway-centric distribution, characteristic of hot tub lung (hematoxylin and eosin stain).Grahic Jump Location

Here, we report the first confirmed case, to our knowledge, of hypercalcemia secondary to elevated OH2-D levels associated with HP. Hypercalcemia secondary to granulomas is classically associated with sarcoidosis, where discrete, well-formed, interstitial granulomas consist of activated macrophages expressing 1-α-hydroxylase, which converts vitamin D to its active form OH2-D, with the resultant hypercalcemia.5,6,8-10 Expression of 1-α-hydroxylase in granulomatous disease is typically unregulated, and the elevated calcium level suppresses parathyroid hormone.6,10

Sarcoid granulomas are well-formed, nonnecrotizing granulomas that follow a lymphatic distribution. This differs from typical HP histopathology, where the granulomas are small, nonnecrotizing, loosely formed, poorly circumscribed, and follow an interstitial and generally bronchiolocentric distribution.8,9,11 In contrast to other hypersensitivities, classic hot tub lung histopathology shows larger granulomas that range from loose to more well formed.8,9,12 Despite the histologic differences, the disparate granulomas can result in hypercalcemia via the same mechanism of elevated OH2-D. This case implicates a common pathway whereby the activation of macrophages to form granulomas can also lead to their production of OH2-D.

Hypercalcemia in other granulomatous diseases has been reported, including TB, leprosy, and granulomatosis with polyangiitis.13 Although a case presumed secondary to farmer’s lung has previously been reported, the diagnosis was not confirmed and the mechanism was not elucidated.14 Here, we have both confirmed the diagnosis pathologically and demonstrated similar pathophysiology to the more classic granulomatous diseases.

Regarding treatment of mycobacterial diseases, literature demonstrates that MAC disease severity and presentation can vary depending on mycobacterial species.15 How this influences hot tub lung is currently unknown. In addition, the clinical and radiographic findings along with improvement following contact avoidance and prednisone are all consistent with hypersensitivity and not infection. Furthermore, antimicrobacterial therapy in hot tub lung has not shown clear or additional benefit.1,3

In our case, the degree of hypercalcemia necessitated treatment and not mere avoidance of the hot tub. Prednisone suppresses the inflammatory process involved in granuloma formation, reducing the granuloma burden. Prednisone also decreases 1-α-hydroxylase enzyme activity, which reduces OH2-D levels, thus correcting the hypercalcemia by both reducing the number of granulomas and by preventing formation of OH2-D.5,6 This case illustrates how granulomas in hot tub lung specifically, and HP more generally, can cause increased 1-α-hydroxylase activity, elevated OH2-D, and hypercalcemia, which can be successfully treated with glucocorticoids.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

HP

hypersensitivity pneumonitis

MAC

Mycobacterium avium complex

OH2-D

1,25(OH)2 vitamin D

Lacasse Y, Girard M, Cormier Y. Recent advances in hypersensitivity pneumonitis. Chest. 2012;142(1):208-217. [CrossRef] [PubMed]
 
Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol. 2001;108(5):661-670. [CrossRef] [PubMed]
 
Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot tub lung: presenting features and clinical course of 21 patients. Respir Med. 2006;100(4):610-615. [CrossRef] [PubMed]
 
Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin Proc. 2007;82(7):812-816. [CrossRef] [PubMed]
 
Hamzeh N. Sarcoidosis. Med Clin North Am. 2011;95(6):1223-1134. [CrossRef] [PubMed]
 
Zhang JT, Chan C, Kwun SY, Benson KA. A case of severe 1,25-dihydroxyvitamin D-mediated hypercalcemia due to a granulomatous disorder. J Clin Endocrinol Metab. 2012;97(8):2579-2583. [CrossRef] [PubMed]
 
Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416. [CrossRef] [PubMed]
 
Mukhopadhyay S, Gal AA. Granulomatous lung disease: an approach to the differential diagnosis. Arch Pathol Lab Med. 2010;134(5):667-690. [PubMed]
 
Khoor A, Leslie KO, Tazelaar HD, Helmers RA, Colby TV. Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol. 2001;115(5):755-762. [CrossRef] [PubMed]
 
Gardner DG. Hypercalcemia and sarcoidosis—another piece of the puzzle falls into place. Am J Med. 2001;110(9):736-737. [CrossRef] [PubMed]
 
Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity pneumonitis. Am J Surg Pathol. 2006;30(2):201-208. [CrossRef] [PubMed]
 
Marras TK, Wallace RJ Jr, Koth LL, Stulbarg MS, Cowl CT, Daley CL. Hypersensitivity pneumonitis reaction toMycobacterium aviumin household water. Chest. 2005;127(2):664-671. [CrossRef] [PubMed]
 
Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med. 2000;6(5):442-447. [CrossRef] [PubMed]
 
Zawada ET Jr, Sanderson EW, Rossing D, Ohrt D, Simmons J. Hypercalcemia and acute renal insufficiency in a 24-year-old white male with lung disease. Am J Nephrol. 1986;6(2):152-157. [CrossRef] [PubMed]
 
Koh W-J, Jeong B-H, Jeon K, et al. Clinical significance of the differentiation betweenMycobacterium aviumandMycobacterium intracellulareinM aviumcomplex lung disease. Chest. 2012;142(6):1482-1488. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Initial chest radiograph with diffuse, bilateral ground-glass opacities with increased interstitial markings.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, B, CT scans of the chest at the level of the aortic arch (A) and the carina (B). Both demonstrate fine, increased interstitial density with faint ground-glass densities and multiple small (< 7 mm) pulmonary nodules.Grahic Jump Location
Figure Jump LinkFigure 3 –  A, B, Histologic sections from the lung wedges at original magnification × 2 (A) and original magnification × 20 (B) demonstrate a diffuse, moderately formed, nonnecrotizing granulomatous process with a somewhat airway-centric distribution, characteristic of hot tub lung (hematoxylin and eosin stain).Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Blood Test Results at Baseline, Presentation, Hospitalization, and Posttreatment Follow-up

ACE = angiotensin-1 converting enzyme; EGFR = estimated glomerular filtration rate; PTH = parathyroid hormone; PTHrP = parathyroid hormone-related peptide.

a 

8 mo prior to presentation.

b 

1 mo posttreatment.

References

Lacasse Y, Girard M, Cormier Y. Recent advances in hypersensitivity pneumonitis. Chest. 2012;142(1):208-217. [CrossRef] [PubMed]
 
Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol. 2001;108(5):661-670. [CrossRef] [PubMed]
 
Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot tub lung: presenting features and clinical course of 21 patients. Respir Med. 2006;100(4):610-615. [CrossRef] [PubMed]
 
Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin Proc. 2007;82(7):812-816. [CrossRef] [PubMed]
 
Hamzeh N. Sarcoidosis. Med Clin North Am. 2011;95(6):1223-1134. [CrossRef] [PubMed]
 
Zhang JT, Chan C, Kwun SY, Benson KA. A case of severe 1,25-dihydroxyvitamin D-mediated hypercalcemia due to a granulomatous disorder. J Clin Endocrinol Metab. 2012;97(8):2579-2583. [CrossRef] [PubMed]
 
Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416. [CrossRef] [PubMed]
 
Mukhopadhyay S, Gal AA. Granulomatous lung disease: an approach to the differential diagnosis. Arch Pathol Lab Med. 2010;134(5):667-690. [PubMed]
 
Khoor A, Leslie KO, Tazelaar HD, Helmers RA, Colby TV. Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol. 2001;115(5):755-762. [CrossRef] [PubMed]
 
Gardner DG. Hypercalcemia and sarcoidosis—another piece of the puzzle falls into place. Am J Med. 2001;110(9):736-737. [CrossRef] [PubMed]
 
Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity pneumonitis. Am J Surg Pathol. 2006;30(2):201-208. [CrossRef] [PubMed]
 
Marras TK, Wallace RJ Jr, Koth LL, Stulbarg MS, Cowl CT, Daley CL. Hypersensitivity pneumonitis reaction toMycobacterium aviumin household water. Chest. 2005;127(2):664-671. [CrossRef] [PubMed]
 
Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med. 2000;6(5):442-447. [CrossRef] [PubMed]
 
Zawada ET Jr, Sanderson EW, Rossing D, Ohrt D, Simmons J. Hypercalcemia and acute renal insufficiency in a 24-year-old white male with lung disease. Am J Nephrol. 1986;6(2):152-157. [CrossRef] [PubMed]
 
Koh W-J, Jeong B-H, Jeon K, et al. Clinical significance of the differentiation betweenMycobacterium aviumandMycobacterium intracellulareinM aviumcomplex lung disease. Chest. 2012;142(6):1482-1488. [CrossRef] [PubMed]
 
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