The clinical picture on admission was dominated by neurological deficits. Physical examination revealed diminished knee reflexes and profound motor weakness, with muscle strength graded just 1 out of 5 in the upper extremities and 2 out of 5 in the lower extremities. The straight-leg-raise test was positive on both sides, and the patient displayed bilateral digital clubbing, a finding often associated with chronic pulmonary disease. Lumbar tenderness was present at the L4 to L5 level, yet strikingly, there were no external signs of inflammation such as redness or swelling over the affected area. Electromyography and nerve conduction studies pointed to chronic bilateral L5-S1 radiculopathy along with moderate C5-C6 root involvement, and the pattern initially raised suspicion for an underlying paraneoplastic process, sending the diagnostic workup in a direction that would soon prove misleading.

Magnetic resonance imaging of the central nervous system became the turning point. Brain MRI was unremarkable, but cervical and lumbar imaging told a different story. The scans revealed an epidural abscess at the L5-S1 level causing severe spinal canal stenosis, a paravertebral abscess, and destruction of the vertebral endplates and anterior portions of the vertebral bodies accompanied by bone marrow edema at the S1-S2 level, findings consistent with spondylodiscitis. The absence of local inflammatory signs suggested a so-called cold abscess, a classic feature of tuberculous infection of the spine, also known as Pott’s disease. Given the characteristic imaging, the patient’s history of smoking and methadone use, and his recent migration from Afghanistan, a country where tuberculosis remains endemic, spinal tuberculosis moved to the top of the differential diagnosis. Surgeons recommended urgent decompression and abscess drainage, but the patient declined operative intervention and opted for conservative management, a decision that would shape the entire course of his hospitalization.

The search for the source of infection quickly extended to the chest. A plain radiograph revealed bilateral diffuse patchy opacities suggestive of active pulmonary tuberculosis, predominantly involving the upper lobes and perihilar regions. High-resolution computed tomography went further, demonstrating diffuse micronodular and interstitial infiltrates consistent with miliary tuberculosis, the disseminated form of the disease in which tiny seedlings of infection spread throughout both lungs. Supporting evidence accumulated rapidly: a purified protein derivative skin test produced an induration of 30 millimeters, and sputum smear microscopy was positive for acid-fast bacilli. After informed consent was obtained, surgical aspiration of the spinal abscess was performed, and polymerase chain reaction analysis of the aspirated material confirmed the presence of Mycobacterium tuberculosis. Standard four-drug anti-tuberculosis therapy, combining isoniazid, rifampin, pyrazinamide, and ethambutol, was initiated for the intensive two-month phase of treatment. Following aspiration and the start of therapy, the patient’s neurological status improved, and he regained the ability to walk with assistance.

But the story did not end there. During hospitalization, the patient experienced recurrent episodes of fever and agitation, prompting a sepsis workup. Follow-up imaging revealed new pulmonary lesions, and auscultation detected diminished breath sounds with expiratory wheezing. A low procalcitonin level of 0.196 nanograms per milliliter argued against bacterial sepsis, so the existing antimicrobial regimen was continued. Because chronic pulmonary aspergillosis was suspected, a serum galactomannan assay was performed and returned a positive result. Histopathological examination of the aspirated abscess material had already demonstrated septate hyaline hyphae, morphologically suggestive of Aspergillus species. In response, the treatment regimen was expanded to include liposomal amphotericin B, voriconazole at 200 milligrams every twelve hours, and adjunctive antibiotics. The diagnostic picture, however, remained incomplete: no fungal culture or molecular identification was obtained, so the aspergillosis could not be confirmed with certainty, a limitation the authors openly acknowledge.

The most dramatic and therapeutically stubborn feature of this case was the patient’s blood calcium. On the first day of admission, serum calcium measured 12.08 milligrams per deciliter, already well above the normal range, and it climbed to 13.24 within twelve hours. The usual suspects were systematically excluded. Primary hyperparathyroidism, the most common cause of hypercalcemia in outpatient practice, was ruled out by a suppressed parathyroid hormone level of 1.66 picograms per milliliter alongside a phosphorus level of 4.26 milligrams per deciliter. Malignancy, the dominant cause among hospitalized patients, was considered but computed tomography revealed no evidence of an underlying neoplastic process. The patient’s symptoms, including constipation and myalgia, were attributed to the elevated calcium, and electrocardiography showed ST-segment depression and prominent U waves, electrocardiographic changes consistent with the metabolic disturbance, though no immediate cardiac intervention was required.

What followed defied the typical behavior of tuberculosis-associated hypercalcemia. In most reported cases, hypercalcemia in tuberculosis is mild and asymptomatic, detected incidentally on routine laboratory testing, and it generally resolves as the underlying infection is treated. Studies cited in the report suggest that roughly 88 percent of tuberculosis patients with hypercalcemia experience only mild elevations, and even in the setting of granulomatous disease and bone destruction, serum calcium rarely exceeds 13 milligrams per deciliter. This patient’s calcium, by contrast, continued to rise despite aggressive intravenous hydration, reaching a peak of 18.01 milligrams per deciliter on the eighth day of hospitalization, a level associated with risk of life-threatening cardiac, renal, and neurological complications. The mechanism believed to underlie granulomatous hypercalcemia involves activated macrophages within granulomas ectopically producing 1,25-dihydroxyvitamin D3, the hormonally active form of vitamin D, which drives increased intestinal calcium absorption. Both tuberculosis and certain fungal infections are recognized causes of this pathway, and local bone destruction from vertebral infection may have contributed further.

Treatment escalation became necessary. Three liters of normal saline over twenty-four hours followed by one liter every six hours failed to control the rising calcium. Calcitonin, administered in both injectable and intranasal formulations, also proved inadequate. After consultation with the nephrology team, only liposomal amphotericin B was continued among the antifungal agents to minimize the risk of electrolyte disturbances. When the serum calcium still failed to decline significantly, intravenous pamidronate, a bisphosphonate that inhibits osteoclast-mediated bone resorption, was administered at 90 milligrams on two consecutive days. Only then did the calcium begin a gradual decline, reaching a corrected level of 11.12 milligrams per deciliter by discharge. The patient was sent home with instructions to continue treatment on an outpatient basis and to attend close follow-up, but he never returned, and his ultimate clinical outcome could not be determined.

The case raises intriguing questions about why the hypercalcemia was so unusually severe. The authors note that risk factors for severe hypercalcemia in tuberculosis include elevated serum creatinine, renal failure, diuretic use, severe anemia, disseminated tuberculosis, diabetes mellitus, hypertension, and HIV infection. Of these, only disseminated tuberculosis and mild anemia were present in this patient, and crucially, HIV status was never assessed, an omission the authors identify as a significant limitation given that the World Health Organization strongly recommends HIV testing for all tuberculosis patients and that both HIV infection and invasive fungal infection raise the possibility of underlying immunosuppression. A comparable case reported by Spindel and colleagues in 1995 involved an HIV-positive patient with an opportunistic fungal infection and persistent hypercalcemia that ultimately normalized after roughly four weeks of intravenous hydration, underscoring how difficult these cases can be to manage.

Perhaps the most important takeaway from this report is epidemiological. The prevalence of tuberculosis-Aspergillus co-infection has been estimated at approximately 14.7 percent in Asia, and pulmonary tuberculosis is considered the single most important risk factor for chronic pulmonary aspergillosis, because cavitary lung damage and immune dysregulation create a favorable environment for Aspergillus fumigatus to colonize and proliferate. Despite this substantial overlap, routine screening for Aspergillus is not commonly incorporated into the diagnostic evaluation of tuberculosis patients. Whether a synergistic interaction between the two infections drove the extreme, treatment-resistant hypercalcemia in this patient cannot be determined with certainty, and the authors are careful not to overclaim. What the case does demonstrate is that in patients with disseminated tuberculosis, particularly when fungal co-infection is suspected, clinicians should monitor calcium levels closely, recognize that severe hypercalcemia can develop abruptly and resist standard therapy, and be prepared to escalate to bisphosphonates when hydration and calcitonin fall short.

Subject of Research: Hypercalcemia associated with spinal tuberculosis and Aspergillus co-infection

Article Title: Hypercalcemia in a Patient With Spinal Tuberculosis and Aspergillus Co‐Infection: A Case‐Report

Article References: Parsa, N., Amlelshahbaz, A., & Soltani, H. (2026). Hypercalcemia in a Patient With Spinal Tuberculosis and Aspergillus Co‐Infection: A Case‐Report. Immunity, Inflammation and Disease, 14(9), Article e70508. https://doi.org/10.1002/iid3.70508

Image Credits: AI Generated

DOI: 10.1002/iid3.70508

Keywords: tuberculosis, spinal tuberculosis, Pott's disease, Aspergillus, hypercalcemia, miliary tuberculosis, granulomatous disease, vitamin D metabolism, pamidronate, chronic pulmonary aspergillosis, case report, co-infection