The report by Hung described a renal transplant recipient with Pneumocystis carinii pneumonia who presented with hypercalcemia and concluded that this entity should be considered in the differential diagnosis of transplant recipients with pneumonia (1). Two additional points with regards to this observation deserve mention. First, hypercalcemia may be observed not only with Pneumocystis jiroveci, but also with other granulomatous infections such as Mycobacterium tuberculosis and invasive mycoses e.g., Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis (2). Endogenous overproduction of 1, 25-dihdroxyvitamin D (1,25[OH2]D3) by disease activated macrophages is the proposed underlying mechanism of hypercalcemia in such cases (2, 3).
Second, hypercalcemia may not be present at the onset of infection, but develop after the treatment is employed. Granuloma formation is a delayed type hypersensitivity reaction with Th1 cytokines e.g., interferon-gamma (IFN-γ) being its initial mediators (4). IFN-γ and Th1 cytokines are also the targets of immunosuppressive drugs, particularly calcineurin-inhibitor agents employed in transplant recipients (4). Receipt of these agents in transplant recipients may be associated with impaired granulomatous host responses. Reduction of immunosuppression, in conjunction with appropriate antimicrobial therapy has the potential to cause a rebound in IFN-γ, which promotes granuloma formation and facilitates the eradication of infection (5). In addition to its role in granulomatous responses, IFN-γ enhances human monocytic cell induced synthesis of 1,25(OH2) D3 by 30-fold, blocks 1,25(OH2) D3 related suppression of its synthesis, and reduces its degradation (2). Care providers should be aware that hypercalcemia may not be present at the onset of infection and may be a manifestation of immune reconstitution or restoration of granulomatous host responses in the evolution of opportunistic infections in transplant recipients.
Infectious Disease Section
University of Pittsburgh
VA Medical Center
1. Hung Y-M. Pneumocytis carinii
pneumonia with hypercalcemia and suppressed parathyroid hormone levels in a renal transplant patient. Transplantation
2006; 81: 639.
2. Dusso AS, Kamimura S, Gallieni M, et al. γ- Inteferon-induced resistance to 1, 25-(ΟΗ)2
in human monocytes and macroophages: a mechanism for the hypercalcemia of various granulomatoses. J Clin Endocrinol Metabol
1997; 7: 2222.
3. Lawn SD, Macallan DC. Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person. Clin Infect Dis
2004; 38: 154.
4. Summers SA, Dorling A, Boyle JJ, Shaunak S. Cure of disseminated cryptococcal infection in a renal allograft recipient after the addition of γ-interferon to antifungal therapy. Am J Transplantation
2005; 5: 2067.
5. Singh N, Lortholary O, Alexander BD, et al. An “immune reconstitution syndrome”-like entity associated with Cryptococcus neoformans
infections in organ transplant recipients. Clin Infect Dis
2005; 40: 1756.