key: cord-0825413-64p990kt
authors: Ilonze, Onyedika J.; Giovannini, Marina; Jones, Mark A.; Rao, Roopa; Ballut, Kareem; Guglin, Maya
title: Calcineurin-Inhibitor Induced Pain Syndrome in a Heart Transplant Patient
date: 2021-09-02
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2021.08.014
sha: f4c7c8f4914caa218a0eacef176afb1ccf71b773
doc_id: 825413
cord_uid: 64p990kt

Calcineurin-inhibitor induced pain syndrome (CIPS) also called the “symmetrical bone syndrome” is a condition describing reversible lower extremity pain in patients after organ transplantation who are receiving calcineurin inhibitors, especially tacrolimus. We present a case of CIPS after orthotopic heart transplant complicated with concurrent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We emphasize the presentation; diagnostic evaluation, and findings. We then discuss the proposed pathophysiologic mechanisms of CIPS and conclude with discussion of management strategies. Additionally, we present a table to guide clinicians in assessing posttransplant bone pain syndromes. To our knowledge, this is the first article to describe a case of CIPS with concurrent SARS-CoV-2 infection.

C ALCINEURIN-INHIBITOR induced pain syndrome (CIPS) also called the "symmetrical bone syndrome" is a condition describing reversible lower extremity pain in patients after organ transplantation who are receiving calcineurin inhibitors (CNIs), especially tacrolimus and cyclosporine. This clinical syndrome was first described in 1989 by Bouteiller et al based on symptoms in transplant patients treated with cyclosporine [1] . The term CIPS was first used by Grotz et al in 2001 , who recognized that tacrolimus and not just cyclosporine played a central role in the pathogenesis of CIPS [2] . CIPS occurs in solid organ as well as bone marrow transplant recipients treated with either tacrolimus or cyclosporine [3] . The exact frequency of CIPS after transplantation is variable and unknown owing to underdiagnosis, however a range of 1.5% to 14% has been suggested [4] . Most cases are diagnosed empirically based on clinical suspicion, but a radiologic criteria for imaging CIPS was suggested by Chapin et al in 2013 [5] .

Awareness of CIPS in the heart transplant literature remains poor and thus it is severely underdiagnosed.

We present a case of CIPS after orthotopic heart transplant complicated with concurrent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conclude with a discussion of the differential diagnosis considered and management strategies.

To our knowledge, this is the first article to describe a case of CIPS with concurrent SARS-CoV-2 infection.

A 51-year-old man with medical history of systemic hypertension, obstructive sleep apnea, diabetes mellitus, and neuropathy underwent orthotopic heart transplant (OHT) for end stage heart failure secondary to nonischemic dilated cardiomyopathy.

Postoperative induction therapy was with thymoglobulin, and he was started on tacrolimus and mycophenolate mofetil (MMF). He required high doses of tacrolimus up to 16 mg twice daily to maintain a target trough level of 10 to 15 ng/mL.

Posttransplant course was unremarkable with no significant acute cellular or antibody mediated rejection. Two months after OHT, he developed severe malaise, diffuse pain, and myalgias all over all over the body. He had declined the SARS-CoV-2 vaccine for unclear reasons.

He was evaluated twice in the emergency room 7 and 9 months after OHT with diffuse body aches including bilateral leg pain. During both emergency room visits he reported that his myalgias and pain were debilitating enough to interfere with daily activities. Muscles were tender to the touch and that he had associated fatigue.

Initial rheumatologic evaluation was unremarkable including negative erythrocyte sedimentation rate and high-sensitivity Creactive protein. Creatine kinase was unremarkable and he had negative imaging of all joints.

Atorvastatin was stopped but there was no relief; tacrolimus was suspected to be contributory, but because he was less than a year posttransplant the target level was decreased to 8 ng/mL and the transplant team felt that discontinuing CNIs was premature.

Despite these changes, he was admitted a month later (10 months after OHT) with soreness and pain worse in bilateral lower extremities, right hip, lower abdomen, and generalized myalgias. On physical examination, he had an unremarkable neurologic examination and notably full strength of his lower extremities. Laboratory findings now revealed elevated inflammatory markers-erythrocyte sedimentation rate 55 and C-reactive protein 4.5.

An x-ray of the lumbar spine showed possible right sacroiliitis. MRI abdomen and pelvis (Siemens, Germany) and SPECT (scintigraphy Technetium 99) bone scan (Siemens, Germany) were both unremarkable (Fig 1) .

Rheumatology evaluation also was negative. Hydralazine induced vasculitis, drug-induced lupus, and avascular necrosis were all considered but work-up was negative.

CIPS or diabetic neuropathy exacerbated by tacrolimus was suspected. We started weaning tacrolimus to run a lower target level and added sirolimus with a combined goal therapeutic level of 10. MMF was decreased owing to leucopenia and thrombocytopenia with SARS-CoV-2 and bacterial super infection (Table 1) . Home diltiazem was switched to amlodipine and gabapentin dosing was increased.

Owing to atypical features of green productive cough, diarrhea, and myalgias, he tested positive for SARS-CoV-2. Computed tomography chest revealed bilateral infiltrates left worse than right likely from SARS-CoV-2 infection. He also had a secondary infection with Moraxella pneumonia and completed a 5-day course of ceftriaxone. Because he did not become hypoxic and never required supplemental oxygen throughout hospitalization, he was not treated with dexamethasone or remdesivir.

Pain improved but did not resolve and he was discharged home on a short course of analgesics. He eventually had to be taken off tacrolimus and continued sirolimus and MMF for immunosuppression in addition to amlodipine. Table 1 shows the immunosuppression strategies employed. He has not had any more pain episodes or admissions 3 months after discharge.

CIPSis a well-known syndrome in posttransplant patients that presents with reversible lower extremity pain. The pain typically presents bilaterally and symmetrically in weight-bearing joints, commonly in the knees, ankles, and feet after organ transplantation in patients treated with tacrolimus or cyclosporine [4] .

The pathophysiology of CIPS remains unclear but potential mechanisms have been described. The first mechanism involves, increased vascular permeability resulting in increased osseous pressure and marrow edema. This is thought to be similar to the effects of CNI in posterior reversible encephalopathy syndrome, and the proposed pathophysiologic mechanism includes autoregulatory failure, hypertension, and endothelial dysfunction leading to vasogenic edema typically with subsequent abnormalities in the posterior brain on MRI. These effects on vasculature could manifest in the bone marrow in CIPS as well. The second mechanism is related to alterations in bone metabolism with increased bone turnover [2] . Thirdly, the role of CNIs as nociceptor modulators, which can induce facilitation of pronociceptive processes by interrupting glial function and by inhibition of nuclear factor-activated T-cells, has been postulated [6] . Fourthly, the manifestation of CIPS-like symptoms in patients with human herpes virus 6 reactivation [7] suggests a possible role for human herpes virus 6 in the pathogenesis althogh this has not been confirmed.

Diagnosis of CIPS is usually confirmed by MRI or a radionuclide bone scan that identifies areas of marrow edema or hyperemia often associated with soft tissue swelling and joint effusions [2] . However, as was seen in our index patient, some cases of CIPS have normal radionuclide scans [8] . Possible reasons for the negative imaging include the fact that the pain syndrome was present for 4 months before imaging and/or that tacrolimus dose and target level was already being reduced before imaging.

Pain may be associated with higher trough levels of tacrolimus and improves as marrow edema recedes. Although it has been suggested that the onset of pain syndrome may correlate with the tacrolimus level, this was not present in our case. However, we saw a correlation between onset and severity of symptoms and a >5 ng/mL rise in tacrolimus level within a 24-hour period. CIPS may be sometimes difficult to distinguish from conditions such as osteoporosis with fragility fractures, gout, hyperparathyroidism, or osteonecrosis. The bilateral and symmetrical nature of the pain distinguishes it from osteonecrosis. Table 2 shows a list of important differential diagnosis of bone pain to consider in posttransplant patients.

Effective therapy for CIPS involves adjustment of the immunosuppressive regimen with reduction of CNI dose and/or target level, slow conversion to alternative noncalcineurin agent such as target of rapamycin inhibitors, and introduction of dihydropyridine calcium channel blockers such as amlodipine [9] . In our index patient, relief of symptoms was seen after reducing and eventually stopping tacrolimus and initiation of sirolimus and conversion from diltiazem to amlodipine.

Adjunctive therapies include, elevation of extremities [2] , GABA analogs such as pregabalin or gabapentin, and bisphosphonates such as intravenous pamidronate [10] . The efficacy of these therapies remains uncertain, because they have almost always been used in conjunction with immunosuppression strategy change and calcium channel blocker use.

The concurrent infection with SARS-CoV-2 with bacterial superinfection was unexpected but reflects part of the growing reality of post-transplant care in the era of the coronavirus disease 2019 pandemic. Notably, the patient was transplanted 4 months after the World Health Organization declared the coronavirus disease 2019 a pandemic. Despite typical chest radiographic findings for SAR-CoV-2 infection, there was no hypoxia and indicated treatment was intravenous cephalosporin without supplemental oxygen. Owing to concurrent leucopenia and thrombocytopenia on admission with the suspected CIPS, MMF and tacrolimus was reduced but sirolimus was added. Because of the lack of hypoxia with SARS-CoV-2 infection we did not use steroids.

With an increase in the number of patients receiving solid organ and hematopoietic stem cell transplants and, hence, more CNI use, the early recognition of this syndrome is important. Pain burden associated with CIPS is severe and debilitating, responds poorly to conventional analgesics, and is responsive only to strong narcotic analgesics.

The differential diagnosis of severe bilateral lower extremity pain in solid organ transplant patients should include CIPS owing to tacrolimus or cyclosporine. A high index of suspicion is critical and can guide early imaging to confirm the diagnosis typically with MRI of affected extremities and bone scintigraphy. Diagnostic utility is helpful if imaging is done in the early phases of suspected diagnosis. A strategy of reducing CNI use and/or adding mammalian target of rapamycin inhibitors, augmenting neuro-modulating therapies can be life-changing for affected patients. Whole body skeletal bone scan showing increased uptake within the sternum, consistent with sternotomy and mildly increased radiotracer uptake at wrists, elbows, shoulders, knees, and ankles.

Syndrome algique polyarticulaire probablement induit par la ciclosporine (SAPPIC) chez trois transplantes renaux et un transplant e cardiaque

Calcineurin inhibitor induced pain syndrome (CIPS): a severe disabling complication after organ transplantation

Clinical features of calcineurin inhibitorinduced pain syndrome after allo-SCT

Tacrolimus pain syndrome in renal transplant patients: report of two cases

Case report: Imaging features in a renal transplant patient with calcineurin inhibitorinduced pain syndrome (CIPS)

Calcineurin as a nociceptor modulator

High incidence of human herpes virus 6-associated encephalitis/myelitis following a second unrelated cord blood transplantation

Bone pain in transplant recipients responsive to calcium channel blockers

Calcineurin-inhibitor pain syndrome

From marrow oedema to osteonecrosis: common paths in the development of posttransplant bone pain

Validation of proposed diagnostic criteria (the "Budapest Criteria") for complex regional pain syndrome