Post-COVID-19-Associated Asymptomatic Sarcoidosis with Hypercalcemia and Renal Dysfunction: A Case Report and Literature Review

Introduction

Sarcoidosis is a systemic granulomatous disease of unknown etiology that commonly affects the lungs, lymph nodes, skin, eyes, and heart [1]. It is histologically identified by the presence of non-caseating granulomas in the involved organs [2]. The clinical presentation is diverse, ranging from asymptomatic radiographic findings to severe multisystem involvement. Diagnosis is often challenging due to the rarity of the disease, broad differentials, and the absence of pathognomonic features. It relies on a combination of clinical, radiologic, and histopathologic findings, after exclusion of other infectious or malignant etiologies [3].

We present a diagnostically challenging case of sarcoidosis in a patient with persistent anosmia following COVID-19 infection 6 months earlier, who developed persistent hypercalcemia, anemia, and renal impairment in the absence of typical respiratory symptoms or radiographic features. This case is particularly noteworthy given the growing body of literature suggesting a potential immunologic link between SARS-CoV-2 infection and granulomatous diseases such as sarcoidosis [4]. To our knowledge, this is the first report of asymptomatic post-COVID-19 sarcoidosis presenting predominantly with metabolic and renal abnormalities, adding a novel dimension to the evolving spectrum of post-viral immune-mediated conditions.

Case Report

A 60-year-old Black woman with a history of hypertension and osteoarthritis presented for a routine follow-up. She reported a history of COVID-19 infection 6 months earlier with persistent anosmia. Since then, she was self-administering over-the-counter zinc (50 mg daily), vitamin D (1000 units daily), and calcium supplements. Her other medications included amlodipine 2.5 mg daily. She denied any tobacco, alcohol, or substance use. No personal or family history of autoimmune diseases was reported, and she had no known history of occupational or environmental exposures.

She denied any fatigue, shortness of breath, dry mouth, constipation, or bone pains. Laboratory testing revealed hypercalcemia (serum calcium 12.2 mg/dL), anemia (hemoglobin 9.6 g/dL), and elevated creatinine (2.0 mg/dL). Hence, her supplements were discontinued. Further workup demonstrated suppressed parathyroid hormone (15 pg/ml) and normal 25-hydroxy vitamin D levels (55 pg/mL). Serum and urine protein electrophoresis did not show any evidence of monoclonal gammopathy. Chest X-ray (Figure 1) and mammogram were normal. Renal ultrasound showed bilaterally small kidneys, consistent with chronic kidney disease.

One week later, she was hospitalized due to worsening hypercalcemia (13.3 mg/dL) and persistent anemia (Table 1). On admission, she was hemodynamically stable and asymptomatic. Physical examination and electrocardiogram (ECG) were unremarkable. Urinalysis revealed a pH of 7.0, specific gravity of 1.020, 1+ protein, with negative glucose, ketones, and nitrate. Urinary calcium testing was not performed.

She was treated with intravenous (IV) hydration (2 liters of normal saline on day 1 followed by 1 liter of normal saline on days 2 and 3) and furosemide (40 mg IV daily on days 1 and 2), with only mild improvement of calcium levels (12.3 mg/dL). She received a 4-mg dose of IV zoledronic acid on day 4, resulting in normalization of calcium levels (9.6 mg/dL) and improved creatinine (1.5 mg/dL) by day 6. Alkaline phosphatase was mildly elevated. Ferritin, vitamin B12, and folic acid levels were normal. The 1,25-dihydroxy vitamin D level was markedly elevated at 108 pg/mL. The QuantiFERON-TB test result was negative. A bone scan showed no evidence of lytic lesions. Computed tomography (CT) of the chest, abdomen, and pelvis revealed nonspecific pulmonary nodules (Figure 2A). She was discharged on day 6 to continue outpatient workup.

Three weeks later, ultrasound of the neck revealed 2 enlarged left supraclavicular lymph nodes, not previously seen on the CT (Figure 3). She underwent a positron emission tomography (PET) CT scan, which revealed multiple small fluorodeoxyglucose (FDG) avid pulmonary nodules, diffuse uptake involving multiple lymph node chains (bilateral hilar, mediastinal, left internal mammary, left axillary, and left subpectoral nodes), diffuse activity in the liver, spleen, and abdominopelvic lymph nodes, and multiple FDG-avid osseous lesions. No increased uptake was noted in the kidneys (Figure 4A). Core-needle biopsy of a 1-cm left supraclavicular lymph node demonstrated non-caseating granulomas (Figure 5). No acid-fast bacilli, fungi, or malignant cells were detected. The markedly elevated 1,25-dihydroxy vitamin D in the context of suppressed PTH, persistent hypercalcemia, and biopsy-confirmed non-caseating granulomas strongly supported sarcoidosis as the unifying diagnosis.

The patient was started on prednisone 15 mg daily in the setting of persistent hypercalcemia and renal dysfunction to prevent further organ injury. She tolerated it well and a follow-up chest CT 2 months later showed interval improvement of pulmonary nodules (Figure 2B). Pulmonary function testing after 7 months of prednisone therapy revealed mild restrictive physiology and mildly reduced diffusion capacity. A repeat PET-CT at 7 months showed significant improvement of the widespread FDG-avid lesions (Figure 4B). She continues to follow up at 3-month intervals for monitoring of renal function and calcium levels. No evidence of disease recurrence or flare-ups has been observed to date. The prednisone dose was gradually tapered down to a daily maintenance dose of 5 mg. Repeat laboratory test results at 12 months showed improved creatinine (1.2 mg/dL) and normalization of calcium (9.5 mg/dL) and hemoglobin levels (12.6 g/dL). Notably, the results 1 year prior to her COVID-19 infection revealed normal hemoglobin (12.2 g/dL), creatinine (0.9 mg/dL), and calcium levels (9.5 mg/dL) (Table 2).

Discussion

Sarcoidosis is a granulomatous disease of unknown etiology that affects individuals across diverse demographics, with a higher prevalence in females and certain ethnic groups [1]. Most cases occur in adults between 20 to 50 years of age [3]. The disease is hypothesized to result from an exaggerated immune response to an unidentified antigen in genetically susceptible individuals [1]. Potential triggers include infectious agents (eg, Mycobacterium, Cutibacterium acnes, Borrelia, fungi, viruses) and non-infectious substances (eg, aluminum, pollen) [4,5].

The hallmark of sarcoidosis is the formation of non-caseating granulomas in the affected tissues, most commonly seen in the lungs and hilar lymph nodes [1,2]. Classic clinical presentations include cough, dyspnea, fatigue, or systemic symptoms such as fever and weight loss. Variants like Löfgren syndrome, an acute form of sarcoidosis, presents with a triad of erythema nodosum, hilar lymphadenopathy, and polyarthritis [6]. Another rare variant, Heerfordt syndrome, presents with uveitis, parotid gland enlargement, facial nerve palsy, and low-grade fever [7]. Diagnosis becomes challenging when patients present without typical findings. Diagnosis requires compatible clinical and radiologic findings, exclusion of other granulomatous diseases and, when necessary, biopsy of the accessible affected tissue.

In our case, the diagnostic challenge stemmed from the absence of respiratory symptoms or classic radiographic findings such as bilateral hilar lymphadenopathy. The patient’s initial presentation with persistent hypercalcemia, anemia, and renal dysfunction was suspicious for multiple myeloma. Serum and urine protein electrophoresis showed no monoclonal spike and no lytic lesions were noted on the bone scan, effectively ruling out multiple myeloma. Subsequent workup based on the PET scan raised a concern for metastatic malignancy or non-Hodgkin’s lymphoma due to involvement of the lymph nodes, liver, spleen, and bone marrow; however, she had no systemic B symptoms and the histopathology was negative.

The diagnosis was surprising after a supraclavicular lymph node biopsy revealed non-caseating granulomas, which in conjunction with elevated 1,25-dihydroxy vitamin D, suppressed PTH, and persistent hypercalcemia favored a granulomatous disease like sarcoidosis [8]. Hypercalcemia occurs in 10% to 20% of sarcoidosis cases, caused by increased 1,25-dihydroxy vitamin D production by macrophages [8]. The QuantiFERON-TB test result was negative and no acid-fast-bacilli were noted on histopathology, ruling out tuberculosis. No fungal organisms or malignant cells were noted, ruling out fungal causes or malignancy as the cause of granulomas.

The recent literature has reported a growing number of sarcoidosis cases emerging after COVID-19 infection, raising important questions about post-viral immune dysregulation as a potential disease trigger [9]. Most cases have involved symptomatic pulmonary or extrapulmonary organ involvement [9–16] (Table 3). For instance, Capaccione et al reported pulmonary sarcoidosis with dyspnea and bilateral hilar lymphadenopathy [10], while Rodrigues et al described cutaneous and pulmonary lesions [15]. Other reports have highlighted cardiac [17] and neurological involvement [18]. In contrast, our patient remained entirely asymptomatic and presented with extrapulmonary features – persistent hypercalcemia, anemia, and renal dysfunction – without classic pulmonary symptoms or radiographic findings. A review of recent reports reveals that most post-COVID-19 sarcoidosis cases occurred within 1–6 months after infection, and very few provided data on metabolic abnormalities or prior baseline laboratory test results.

Notably, our patient’s laboratory results 1 year prior to her COVID-19 diagnosis showed normal renal function, calcium, and hemoglobin levels. This temporal contrast supports a potential link between post-COVID-19 immune dysregulation and the subsequent development of sarcoidosis with associated biochemical abnormalities. Although our patient remained asymptomatic, prednisone therapy was initiated because of renal dysfunction and persistent hypercalcemia with elevated 1,25-dihydroxy vitamin D levels. In sarcoidosis, these biochemical abnormalities reflect granulomatous inflammation and if left untreated can contribute to progressive organ damage. Therefore, the primary rationale for corticosteroid therapy was to prevent further organ injury [19].

Importantly, ACE (angiotensin-converting enzyme) levels were within normal limits in our patient. While elevated ACE is often associated with sarcoidosis, it is seen in 30% to 80% of sarcoidosis cases, with reported sensitivity around 60% and specificity between 70% and 90%, depending on the population and disease activity [20]. Therefore, a normal ACE level does not exclude the diagnosis, and should be interpreted in the broader clinical and histopathologic context.

Corticosteroids remain the first-line treatment for symptomatic sarcoidosis or when organ function is at risk [1,21,22]. The decision to initiate a 15-mg daily dose of prednisone was made to balance efficacy against the risk of adverse effects associated with high-dose corticosteroids [1]. The dose and duration of prednisone therapy can vary depending on the extent of organ involvement, disease severity, and treatment response [19]. Our patient responded well, with normalization of calcium and hemoglobin levels, improved renal function, and significant radiographic improvement on follow-up PET-CT. These outcomes support the initial decision to initiate corticosteroid therapy. Follow-up in such cases typically involves monitoring for sarcoidosis flare-ups or treatment-related complications [19]. Spontaneous remission is common in mild cases, while second-line agents such as methotrexate and hydroxychloroquine are considered when corticosteroids are insufficient or contraindicated.

Although sarcoidosis can be asymptomatic or incidentally detected, notably, no cases of asymptomatic sarcoidosis have been reported thus far in the context of post-COVID-19-associated presentations. This highlights an underrecognized asymptomatic presentation in this emerging clinical setting. Mechanistically, it is plausible that the hyperinflammatory milieu of COVID-19, characterized by cytokine release, macrophage activation, and immune dysregulation lowers the threshold for granuloma formation in susceptible individuals [23]. Persistent antigenic stimulation from viral components or unregulated immune repair pathways may further contribute to this. However, the exact pathophysiology linking COVID-19 to sarcoidosis remains poorly understood and warrants further investigation.

Cases of COVID-19-associated sarcoidosis may be underreported, as sarcoidosis is frequently asymptomatic and most individuals recovering from COVID-19 do not routinely undergo post-infection imaging [23]. While this case demonstrates a potential link between these 2 conditions and proposes a plausible immunopathologic mechanism, it remains a single-patient observation. Therefore, causality cannot be inferred despite the close temporal association. Importantly, the possible association between COVID-19 and sarcoidosis is not conclusive – given the large proportion of the global population infected by SARS-CoV-2, some cases of sarcoidosis may have arisen spontaneously. Additionally, although a tissue diagnosis remains the standard method for sarcoidosis, various infections can elicit granulomatous responses that mimic sarcoidosis histologically. None of the existing case reports, including ours, have systematically evaluated sarcoidosis incidence before and during the pandemic. More detailed longitudinal studies on larger cohorts are required to better establish any causal relationship.

Overall, this case contributes to the evolving understanding of post-COVID-19 sarcoidosis and underscores the need for further research into the underlying immunopathologic mechanisms. Larger case series and systematic registries are needed to clarify causality, identify at-risk populations, and determine long-term outcomes in this unique patient subgroup.

Conclusions

This case illustrates an atypical presentation of post-COVID-19 sarcoidosis, manifesting primarily with hypercalcemia and renal impairment without any symptoms or classic pulmonary findings. Elevated 1,25-dihydroxy vitamin D and tissue biopsy were pivotal to the diagnosis, and a thorough, persistent diagnostic approach enabled successful management with corticosteroids. Clinicians should maintain a high index of suspicion for post-COVID-19 sarcoidosis in patients with unexplained metabolic or systemic abnormalities, as early recognition and treatment can significantly improve outcomes.

While this case suggests a possible link between COVID-19 and sarcoidosis, the association remains speculative, as causality cannot be established from a single case report. Given the global prevalence of SARS-CoV-2 infection, some cases of sarcoidosis may have arisen coincidentally. Larger, longitudinal studies are needed to clarify potential relationships and better define at-risk populations.