Abstract
Hypercalcaemia-induced rhinovirus has only been reported in a single study in children. Here, we report a case of hypercalcaemia in an adult who tested positive for rhinovirus. This patient underwent an extensive evaluation of hypercalcaemia, and it was found to be mediated by an increase in 1,25 hydroxy-vitamin D that could not be attributed to a cause. Their hypercalcaemia responded to standard treatment with intravascular expansion, bisphosphonates and calcitonin. Serum 1,25 OH vitamin D levels returned to normal with recovery from rhinovirus infection.
Keywords: Metabolic disorders, Calcium and bone, Infectious diseases
Background
Rhinovirus is a common cause of upper respiratory illness that is typically managed supportively. As it does not involve hospitalisation, there are limited data on electrolyte abnormalities that could be associated with rhinovirus infection. Hypercalcaemia is a common clinical problem with many differential diagnoses. The association of rhinovirus with hypercalcaemia has been reported in a single paper in children but none with adults.1 This case identifies rhinovirus infection as a possible cause of transient hypercalcaemia.
Case presentation
A woman in her 60s presents with problems of generalised weakness and dyspnoea for the past 2 weeks. She has a medical history of autosomal dominant polycystic kidney disease status post living donor kidney transplant 10 years prior. The patient followed closely with clinic since her transplant and all her medications were prescribed by physicians in our system. These include prednisone 5 mg one time a day, tacrolimus 3 mg two times a day, mycophenolate 750 mg two times a day, calcium carbonate-vitamin d 600–400 mg two tablets one time a day, and torsemide 20 mg one time a day. Family history was negative for any known form of hypercalcaemia. Social history was unrevealing. On physical examination, the patient was noted to be hypoxic requiring 2 L of nasal cannula. Lungs were clear to auscultation. The abdomen was diffusely tender to palpation without guarding or rebound. Chest X-ray showed bilateral pulmonary opacities. Initial laboratory blood test results were significant for elevated creatinine of 3.40 mg/dL (reference range 0.40–0.99 mg/dL) and calcium of 12.3 mg/dL (reference range 8.6–10.4 mg/dL). Respiratory panel swab was obtained, and patient tested positive for rhinovirus PCR only. Sputum cultures were negative. The patient was subsequently admitted for concerns of atypical pneumonia and workup for new hypercalcaemia.
Investigations
Further laboratory blood test results shown in table 1 were obtained to investigate the source of the patient’s new diagnosis of hypercalcaemia. Imaging including CT of the head, chest and abdomen demonstrated bilateral interstitial pneumonia in keeping with rhinovirus infection but was negative for lymphadenopathy or bony lesions. Serum and urine immunofixation along with free light chain assay were negative. The patient also underwent bronchoscopy with bronchoalveolar lavage and transbronchial biopsy due to suspicion of interstitial lung disease, results of both were unremarkable. A lung biopsy was obtained as well, which showed focal interstitial fibrosis with no evidence of malignancy.
Table 1.
Initial laboratory blood test results during first admission and subsequent laboratory blood test results 3 months later
| At initial presentation | Three months later | Reference range | |
| Sodium (mmol/L) | 136 | 135 | 135–145 |
| Potassium (mmol/L) | 4.2 | 4.0 | 3.3–4.6 |
| Total carbon dioxide (mmol/L) | 25 | 21 | 21–29 |
| Serum calcium (mg/dL) | 12.3 | 8.0 | 8.6–10.4 |
| Phosphorous (mg/dL) | 4.5 | 5.0 | 2.1–4.3 |
| Creatinine (mg/dL) | 3.40 | 2.74 | 0.50–0.99 |
| Albumin (g/dL) | 3.50 | Not obtained | 3.60–5.10 |
| Ionised calcium (mmol/L) | 1.65 | 1.00 | 1.09–1.32 |
| PTH (pg/mL) | 9 | 104 | 16–65 |
| PTH-rp (pmol/L) | <2.0 | Not obtained | <2.0 |
| 25-OH-vitamin-D (ng/mL) | 42.20 | Not obtained | 12–52 |
| 1,25-vitamin-D (pg/mL) | 210.4 | 23.4 | 19.9–79.3 |
| TSH (miU/L) | 1.370 | Not obtained | 0.270–4.200 |
PTH, parathyroid hormone; PTH-rP, parathyroid hormone-related protein; TSH, thyroid-stimulating hormone.
Differential diagnosis
The PTH was found to be suppressed which points to a PTH independent cause of hypercalcaemia. PTH-rp levels were within normal limits; thus, humoral hypercalcaemia of malignancy was ruled out. The elevated level of 1,25-vitamin-D raised suspicion for lymphoma or granulomatous disease; however, extensive imaging was negative for evidence of either disease. Additional multiple myeloma testing was unrevealing, thus effectively ruling it out. One plausible diagnosis considered was exogenous overconsumption of calcium; however, she had been taking calcium carbonate for years prior without any evidence of hypercalcaemia. In addition, this would not explain her serum 1,25 OH vitamin D level which was almost three times the upper limit of normal. The overconsumption of calcitriol was another possibility, but the patient denied usage and no record of a calcitriol prescription was present. In addition, adrenal insufficiency was also ruled out as the cause as the patient remained haemodynamically stable the whole admission and no laboratory values were suggestive of it.2
Treatment
The patient was initially treated with intravenous isotonic saline. In addition to fluids, she received 60 mg of pamidronate. Despite this, her calcium continued to uptrend and peaked at 15.0 mg/dL. She received another dose of pamidronate with the addition of calcitonin. With this regimen, her calcium returned to normal limits.
Outcome and follow-up
The patient received an empiric course of antibiotics for atypical pneumonia although the only aetiology found for infection was a positive nasal PCR for rhinovirus. She was then discharged with instructions to follow-up with her primary care physician and nephrology. Three months after discharge, her serum calcium and ionised calcium returned to normal limits. In addition, her serum PTH and 1,25 OH vitamin D levels returned to normal as shown in table 1.
Discussion
Hypercalcaemia is a commonly encountered clinical problems with a broad differently diagnosis and because of this, an algorithm was established to ensure detailed stepwise workup for hypercalcaemia. The most commonly identified causes include primary hyperparathyroidism, hypercalcaemia of malignancy, granulomatous diseases and multiple myeloma. However, if the algorithm fails to identify the cause, other sources must be considered. In this case, we hypothesised that the cause of her transient hypercalcaemia was mediated by an increase in serum 1,25 OH vitamin D. The patient had resolution of hypercalcaemia and serum 1,25 OH vitamin D levels returned to normal with recovery from rhinovirus infection. Furthermore, she had no reoccurrence of hypercalcaemia during her subsequent follow-up. Our hypothesis is further supported as extensive workup excluded all other causes of hypercalcaemia. It is once again worth noting that this patient follows very closely with our outpatient nephrologist since her transplant; thus, her medication list was tightly monitored. A thorough review of her electronic medical record shows that no calcitriol was ever prescribed, and the patient strongly denied taking any other over the counter medications, other than the ones listed on our records.
There is limited literature describing the association of hypercalcaemia with rhinovirus. In one study in children, about half of the subjects with rhinovirus were noted to have significant elevations in their calcium (> 10.5 mg/dL).1 The mechanism of rhinovirus inducing hypercalcaemia remains unknown. We can speculate that in this case it is mediated by extrarenal production of 1,25-vitamin-D based on initial laboratory values. Several case reports have noted vitamin D-mediated hypercalcaemia as a complication of fungal infections, most notably candidiasis, cryptococcus and pneumocystis.3 4 In another case report, cytomegaloviral (CMV) infection was also noted to be in association with hypercalcaemia. Their proposed route of mechanism is direct osteoclastic stimulation increasing osteoclastic bone resorption as a result of a reaction to CMV infection.5 Additionally, what all of these cases have in common is that these patients have an active infection; thus, another aetiology to consider is macrophages-mediated production of 1,25-vitamin-D during proinflammatory states.6 In general, infections leading to hypercalcaemia is a rare phenomenon. Case reports have only described the association without a clear idea of the mechanism of action. Additional studies are required to distinguish this finding of hypercalcaemia in viral infections as simply a correlation or causation.
Patient’s perspective.
“Oh I thought I just had the common cold, I wasn’t sure why I was feeling so terrible.”
Learning objectives.
To describe the association of hypercalcaemia with rhinovirus and as a rare cause of elevated serum calcium.
To review the stepwise approach in differentiating the causes of hypercalcaemia.
To review various treatment approaches inpatient hypercalcaemia.
Footnotes
Twitter: @abhz_karan
Contributors: All authors contributed equally to the production of this manuscript. HJG and AKaran contributed to the body of the manuscript. AKiamos and VJ contributed to the review of the manuscript. All authors are in agreement of the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Ethics statements
Patient consent for publication
Consent obtained directly from patient(s)
References
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