, Volume 192, Issue 6, pp 841–847 | Cite as

Calcified Granulomatous Disease: Occupational Associations and Lack of Familial Aggregation

  • Robert M. Reed
  • Anthony Amoroso
  • Salman Hashmi
  • Seth Kligerman
  • Alan R. Shuldiner
  • Braxton D. Mitchell
  • Giora Netzer



The acute host response to histoplasma capsulatum infection varies according to exposure and susceptibility. Late sequelae include calcifications in the lung, thoracic lymphatics, and spleen. Determinants of calcified granuloma formation are poorly studied and may differ from those affecting acute response. We examined the occupational associations and familial aggregation of radiographic calcified granulomatous disease to characterize the determinants of calcified granuloma formation.


We analyzed prospectively collected cross-sectional data including computed tomograms from 872 adult members of the Old Order Amish of Lancaster County.


Granulomas were present in 71 % of participants. Granulomas were present in the lung of 57 % of participants, in the hilar or mediastinal lymph nodes of 55 % of participants, and in the spleen of 29 % of participants. No significant differences were observed in the presence of granulomas between men and women. Each year of age was associated with 4 % higher odds of splenic calcifications, and a primary occupation of farming was associated with an 84 % higher odds of splenic calcifications. A compelling pattern of familial aggregation was not observed.


Calcified granulomatous disease does not appear to aggregate in families. Determinants influencing patterns of granulomatous disease include occupation, age, and geographic location.


Calcified granuloma  Occupational lung disease Farming lung disease Old Order Amish Amish Familial aggregation Histoplasma Granulomatous lung disease 

Abbreviations list


Confidence interval


Computed tomography


Interquartile range


Old Order Amish


Odds ratio


Pittsburgh Lung Screening Study



This work was supported by research grants R01 HL69313 and U01 HL72515 and the University of Maryland General Clinical Research Center (Grant M01 RR 16500), General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health, and the Baltimore Veterans Administration Geriatric Research and Education Clinical Center. Dr. Reed is supported in part by the Flight Attendants Medical Research Institute. Dr. Netzer is supported in part by the Clinical Research Career Development Award from the National Institutes of Health (NIH), Bethesda, MD (5K12RR023250-03). We would like to thank Drs. David O. Wilson and Joel Weissfeld for their contribution of data from PLuSS. We would like to thank the Amish community members of Lancaster County for their ongoing participation in our studies.

Conflict of Interest

No author reports any potential conflict of interest.

Reference List

  1. 1.
    Kauffman CA (2007) Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 20:115–132PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    McKinsey DS, McKinsey JP (2011) Pulmonary histoplasmosis. Semin Respir Crit Care Med 32:735–744CrossRefPubMedGoogle Scholar
  3. 3.
    Cano MV, Hajjeh RA (2001) The epidemiology of histoplasmosis: a review. Semin Respir Infect 16:109–118CrossRefPubMedGoogle Scholar
  4. 4.
    Brown K, Mund DF, Aberle DR, Batra P, Young DA (1994) Intrathoracic calcifications: radiographic features and differential diagnoses. Radiographics 14:1247–1261CrossRefPubMedGoogle Scholar
  5. 5.
    Cobat A, Gallant CJ, Simkin L et al (2010) High heritability of antimycobacterial immunity in an area of hyperendemicity for tuberculosis disease. J Infect Dis 201:15–19CrossRefPubMedGoogle Scholar
  6. 6.
    Orru V, Steri M, Sole G et al (2013) Genetic variants regulating immune cell levels in health and disease. Cell 155:242–256CrossRefPubMedGoogle Scholar
  7. 7.
    Spagnolo P, Grunewald J (2013) Recent advances in the genetics of sarcoidosis. J Med Genet 50:290–297CrossRefPubMedGoogle Scholar
  8. 8.
    Kondratieva E, Logunova N, Majorov K, Averbakh M, Apt A (2010) Host genetics in granuloma formation: human-like lung pathology in mice with reciprocal genetic susceptibility to M. tuberculosis and M. avium. PLoS One 5:e10515PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Giachelli CM, Steitz S (2000) Osteopontin: a versatile regulator of inflammation and biomineralization. Matrix Biol 19:615–622CrossRefPubMedGoogle Scholar
  10. 10.
    O’Regan AW, Hayden JM, Body S et al (2001) Abnormal pulmonary granuloma formation in osteopontin-deficient mice. Am J Respir Crit Care Med 164:2243–2247CrossRefPubMedGoogle Scholar
  11. 11.
    O’Regan AW, Chupp GL, Lowry JA, Goetschkes M, Mulligan N, Berman JS (1999) Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro. J Immunol 162:1024–1031PubMedGoogle Scholar
  12. 12.
    Hunter GK (2013) Role of osteopontin in modulation of hydroxyapatite formation. Calcif Tissue Int 93:348–354CrossRefPubMedGoogle Scholar
  13. 13.
    Kraybill DB, Johnson-Weiner KM, Nolt SM (2013) The Amish. The Johns Hopkins University Press, BaltimoreGoogle Scholar
  14. 14.
    Post W, Bielak LF, Ryan KA et al (2007) Determinants of coronary artery and aortic calcification in the Old Order Amish. Circulation 115:717–724PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Sorkin J, Post W, Pollin TI, O’Connell JR, Mitchell BD, Shuldiner AR (2005) Exploring the genetics of longevity in the Old Order Amish. Mech Ageing Dev 126:347–350CrossRefPubMedGoogle Scholar
  16. 16.
    Wilson DO, Weissfeld JL, Fuhrman CR et al (2008) The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan. Am J Respir Crit Care Med 178:956–961PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Weissfeld JL (2014) Frequency of calcified granulomas found in the PLUSS cohort. Ref Type: Personal CommunicationGoogle Scholar
  18. 18.
    Mettler FA Jr, Bhargavan M, Faulkner K et al (2009) Radiologic and nuclear medicine studies in the United States and worldwide: frequency, radiation dose, and comparison with other radiation sources–1950–2007. Radiology 253:520–531CrossRefPubMedGoogle Scholar
  19. 19.
    Polonsky TS, McClelland RL, Jorgensen NW et al (2010) Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA 303:1610–1616PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Aberle DR, Adams AM, Berg CD et al (2011) Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395–409CrossRefPubMedGoogle Scholar
  21. 21.
    U.S. Preventive Services Task Force (2014) Screening for Lung Cancer: Draft Recommendation Statement. AHRQ Publication No. 13-05196-EF-3. Accessed 06 Mar 2014. Ref Type: Online Source
  22. 22.
    Diederich S, Wormanns D, Semik M et al (2002) Screening for early lung cancer with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology 222:773–781CrossRefPubMedGoogle Scholar
  23. 23.
    Smith MA, Battafarano RJ, Meyers BF, Zoole JB, Cooper JD, Patterson GA (2006) Prevalence of benign disease in patients undergoing resection for suspected lung cancer. Ann Thorac Surg 81:1824–1828CrossRefPubMedGoogle Scholar
  24. 24.
    MacMahon H, Austin JH, Gamsu G et al (2005) Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 237:395–400CrossRefPubMedGoogle Scholar
  25. 25.
    Knox KS, Hage CA (2010) Histoplasmosis. Proc Am Thorac Soc 7:169–172CrossRefPubMedGoogle Scholar
  26. 26.
    Gurney JW, Conces DJ (1996) Pulmonary histoplasmosis. Radiology 199:297–306CrossRefPubMedGoogle Scholar
  27. 27.
    Edwards LB, Acquaviva FA, Livesay VT (1973) Further observations on histoplasmin sensitivity in the United States. Am J Epidemiol 98:315–325PubMedGoogle Scholar
  28. 28.
    Edwards LB, Acquaviva FA, Livesay VT, Cross FW, Palmer CE (1969) An atlas of sensitivity to tuberculin, PPD-B, and histoplasmin in the United States. Am Rev Respir Dis 99:Suppl-132Google Scholar
  29. 29.
    Taylor ML, Perez-Mejia A, Yamamoto-Furusho JK, Granados J (1997) Immunologic, genetic and social human risk factors associated to histoplasmosis: studies in the State of Guerrero, Mexico. Mycopathologia 138:137–142CrossRefPubMedGoogle Scholar
  30. 30.
    Fernandez Andreu CM (2010) Martinez MG, Illnait Zaragozi MT, Perurena Lancha MR, Gonzalez L. [Outbreaks of occupational acquired histoplasmosis in La Habana province]. Rev Cubana Med Trop 62:68–72PubMedGoogle Scholar
  31. 31.
    Huhn GD, Austin C, Carr M et al (2005) Two outbreaks of occupationally acquired histoplasmosis: more than workers at risk. Environ Health Perspect 113:585–589PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Stobierski MG, Hospedales CJ, Hall WN, Robinson-Dunn B, Hoch D, Sheill DA (1996) Outbreak of histoplasmosis among employees in a paper factory–Michigan, 1993. J Clin Microbiol 34:1220–1223PubMedCentralPubMedGoogle Scholar
  33. 33.
    Suarez HM, Fernandez Andreu CM, Estrada OA, Cisneros DE (1992) Histoplasmin reactivity in poultry farm workers in the province of Ciego de Avila, Cuba. Rev Inst Med Trop Sao Paulo 34:329–333Google Scholar
  34. 34.
    Cermeno JR, Hernandez I, Cermeno JJ et al (2004) Epidemiological survey of histoplasmine and paracoccidioidine skin reactivity in an agricultural area in Bolivar state, Venezuela. Eur J Epidemiol 19:189–193CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Robert M. Reed
    • 1
  • Anthony Amoroso
    • 2
  • Salman Hashmi
    • 1
  • Seth Kligerman
    • 3
  • Alan R. Shuldiner
    • 4
    • 5
    • 6
  • Braxton D. Mitchell
    • 4
    • 5
    • 6
  • Giora Netzer
    • 1
    • 6
  1. 1.Division of Pulmonary and Critical Care MedicineUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Division of Infectious DiseaseUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Department of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland School of MedicineBaltimoreUSA
  4. 4.Division of Endocrinology, Diabetes, and NutritionUniversity of Maryland School of MedicineBaltimoreUSA
  5. 5.Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore Geriatric Research Education and Clinical Center (GRECC)BaltimoreUSA
  6. 6.Department of Epidemiology and Public HealthUniversity of Maryland School of MedicineBaltimoreUSA

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