Diagnosing the Treatment

Lymphoma would appear to be the most likely diagnosis as it accounts for most of the clinical findings observed in the patient and is a fairly common disorder. Sarcoidosis is also reasonably common and would explain the laboratory abnormalities but is not usually associated with weight loss and frailty. Disseminated infections, such as tuberculosis, histoplasmosis, and coccidioidomycosis, are all possible, but the patient lacks key risk factors for these infections. A complication of iBCG is the most intriguing possibility and could account for many of the patient’s clinical findings, including the septic episode, which is an event not clearly accounted for by the other diagnostic possibilities. However, disseminated BCG and hypersensitivity reactions to BCG leading to hypercalcemia are rare. When asked to choose between the most interesting possibility and the most common possibility, the most common will usually be the best (and safest) bet. Nonetheless, the effects of prior BCG treatment, including disseminated infection or diffuse immune-mediated granulomatous disease, would be near the top of the differential diagnosis in this case.

The bone survey was normal, the renal ultrasound examination showed nodular wall thickening of the bladder with areas of calcification, and the CT scan of the chest, abdomen, and pelvis showed an area of calcification in the superior portion of the bladder but no evidence of lymphadenopathy or masses to suggest lymphoma. Aerobic and anaerobic blood and urine cultures were sterile. The patient was discharged 12 days after admission with plans for further outpatient diagnostic evaluation. At this time, his serum calcium had stabilized at 10.5 mg/dL with pamidronate, diuretics, and aggressive oral hydration.

Hypercalcemia is a common finding in both hospital and ambulatory settings. The classic symptoms associated with hypercalcemia are aptly summarized with the mnemonic “bones, stones, abdominal groans, and psychiatric overtones” (to represent the associated skeletal involvement, renal disease, gastrointestinal symptoms, and effects on the nervous system). However, the severity and type of symptoms vary depending on the degree of hypercalcemia, acuity of onset, and underlying etiology. The vast majority (90%) of hypercalcemia cases are due to primary hyperparathyroidism and malignancy.³ Measuring the PTH level is a key step in the diagnostic evaluation process. An isolated elevation of PTH confirms the presence of primary or possibly tertiary hyperparathyroidism. Low PTH concentrations (<20 pg/mL) occur in the settings of PTHrP or vitamin-D-mediated hypercalcemia such as hypervitaminosis D, malignancy, or granulomatous disease.

Elevated PTHrP occurs most commonly in squamous cell, renal, bladder, and ovarian carcinomas.^3,4 Elevated levels of 25-hydroxy vitamin D can occur with excessive consumption of vitamin D-containing products and some herbal supplements. In this case, neither PTHrP nor 25-hydroxy vitamin D level was elevated, leading to an exhaustive search for other causes. Although iBCG treatment is a rare cause of hypercalcemia, 2 previous reports indicated the presence of hypercalcemia secondary to granuloma formation in treated patients.^5,6

The finding of an elevated 1,25-dihydroxy vitamin D level was unexpected. As the discussant mentioned, this finding is associated with lymphoma and with granulomatous disorders that were not initially strong diagnostic considerations in the patient. A variety of granulomatous diseases can cause hypercalcemia. Sarcoidosis and tuberculosis are the most common, but berylliosis, fungal infections, Crohn’s disease, silicone exposure, and granulomatosis with polyangiitis may also be associated with hypercalcemia.⁷ The mechanism for hypercalcemia in these situations is increased intestinal calcium absorption mediated by inappropriately increased, PTH-independent, extrarenal calcitriol (1,25-dihydroxy vitamin D) production. Activated monocytes upregulate 25(OH)D-alpha-hydroxylase, converting 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D. Concurrently, the elevated levels of gamma-interferon render macrophages resistant to the normal regulatory feedback mechanisms, thereby promoting the production and inhibiting the degradation of 1,25-dihydroxy vitamin D.⁸

The tuberculosis vaccine BCG is an attenuated form of M. bovis and was originally developed by Albert Calmette and Camille Guérin at the Pasteur Institute in Paris in the early 20^th century. In addition to its use as a vaccine against tuberculosis, BCG can protect against other mycobacterial infections, help treat atopic conditions via stimulation of the Th1 cellular immune response, and has been used as an antineoplastic agent. To date, BCG remains the most effective agent available for intravesical treatment of superficial bladder cancer.^9,10 Although iBCG therapy is considered relatively safe and well-tolerated, rare complications do occur. Localized symptoms (bladder irritation, hematuria) and/or flu-like symptoms are common immediately after instillation and thought to be related to the cellular immune response and inflammatory cascade triggered by mycobacterial antigens.¹¹ Other adverse effects, such as infectious and noninfectious complications, may occur months to years after treatment with BCG, and the associated symptoms can be quite nonspecific. Infectious complications include mycobacterial prostatitis, orchiepididymitis, balantitis, pneumonia, hepatitis, nephritis, septic arthritis, osteomyelitis, infected orthopedic and vascular prostheses, endocarditis, and bacteremia. Traumatic catheterization is the most common risk factor for infection with BCG.^11-13 Noninfectious complications include reactive arthritis, hypersensitivity pneumonitis, hemophagocytic lymphohistiocytosis (HLH), and sterile granulomatous infiltration of solid organs.

The protean and nonspecific nature of the adverse effects of iBCG treatment and the fact that complications can present weeks to years after instillation can make diagnosis quite challenging.¹⁴ Even if clinical suspicion is high, it may be difficult to definitively identify BCG as the underlying etiology because acid fast staining, culture, and even PCR can lead to falsely negative results.^14,15 For this reason, biopsy and tissue culture are recommended to demonstrate granuloma formation and identify the presence of M. bovis.

Although no prospective studies have been conducted to assess the optimal therapy for BCG infection, opinion-based recommendations include cessation of BCG treatment, initiation of at least 3 tuberculostatic agents, and treatment for 3-12 months depending on the severity of the complications.^11,14 M. bovis is susceptible to isoniazid, rifampin, and ethambutol as well as to fluoroquinolones, clarithromycin, aminoglycosides, and doxycycline; however, this organism is highly resistant to pyrazinamide due to single-point mutation.^11,16Interestingly, imipenem is used to treat other nontuberculous mycobacterial diseases, such as those caused by M. abscessus, thereby raising the possibility that the patient’s exposure to meropenem during treatment for his prior sepsis may have partially treated an acute infection due to M. bovis.

Although treatment with steroids is a standard approach for management of hypercalcemia in other granulomatous disorders and leads to rapid reduction in circulating levels of 1,25-dihydroxy vitamin D and serum calcium., specific evidence has not been established to support its efficacy and effectiveness in treating hypercalcemia and other complications due to M. bovis.¹⁷ Nevertheless, some experts recommend the use of steroids in conjunction with a multidrug tuberculostatic regimen in cases of septicemia and multiorgan failure due to M. bovis.^12,14,18-20

In summary, this case illustrates the importance of making room in differential diagnosis to include iatrogenic complications. That is, when faced with an unclear diagnosis, the provider should consider common and uncommon immediate and delayed side effects of prior therapies.