American Journal of Emergency Medicine 33 (2015) 124.e1-124.e4

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American Journal of Emergency Medicine

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Case Report

Acute respiratory distress attributed to sirolimus in solid organ transplant recipients?

Abstract

pulmonary toxicity has frequently been recognized as a potentially serious complication associated with sirolimus therapy. It consists of a wide spectrum of syndromes most characterized by the presence of lymphocytic alveolitis and lymphocytic interstitial pneumonitis. The most commonly presenting symptoms are fever and dyspnea. chest computed tomography generally reveals bilateral, patchy, or diffuse alveolointerstitial infiltrates. The discontinuation or dose reduction of sirolimus usually leads in most cases to a good outcome with complete clinical and radiologic resolution. However, to establish a diagnosis is difficult because of the absence of specific diagnostic criteria, and in rare cases, it could be fatal or life threatening when the diagnosis was delayed. Here, we reported 2 severe cases of acute respiratory distress attributed to the therapy of sirolimus in solid organ transplant recipients. Although the diagnostic course was difficult, withdrawal of sirolimus and temporary administration of steroids eventually resulted in a rapid recovery in both 2 patients. In addition, possible mechanisms, clinical characteristics, approach to diagnosis, and treatment strategies of sirolimus-induced pulmonary toxicity were also discussed in this article.

Sirolimus is a powerful immunosuppressive agent usually used in renal transplantation often as an alternative to calcineurin inhibitor therapy to reduce renal toxicity. And recently, it has also been increasingly used in other solid organ transplantation. However, sirolimus does have its own side effect and toxicity profile. The drug has been shown to cause thrombocytopenia, hyperlipidemia, and anemia as well as delayed wound healing [1,2]. It is noteworthy that the literature has frequently associated sirolimus with important pulmonary complications since Singer et al [3] first reported 3 cases in 2000. According to the literature, this kind of complication has been reported to develop in a wide range of 1 to 51 months after the initiation of sirolimus therapy [4-8], and it consists of a broad spectrum of syndromes most characterized by the presence of lymphocytic alveolitis [3,4,6-9] and lymphocytic interstitial pneumo- nitis [3,9]. Other types of histologic features have also been described, including organizing pneumonia [4], pulmonary alveolar proteinosis [10], or diffuse alveolar hemorrhage [11]. The most commonly presenting symptoms are fever and dyspnea, other symptoms such as cough, fatigue, and hemoptysis have also been reported [4-8]. Chest computed tomography usually reveals bilateral, patchy, or diffuse alveolointerstitial infiltrates [7,8]. The pathogenic mechanism

? This work was supported in part by National High-tech Researching and Developing Plan (plan 863): Establishing Integrated Organ Preserving and Recovering System In Vitro as well as Evaluating and Screening Criteria of DCD donors (No. 2012AA021001).

has not been clearly known, but an autoimmune response was suggested because of the findings of lymphocytosis in the broncho- alveolar lavage (BAL) from the affected patients [4,9,11,12]. Although fatal case has been described in a heart transplant recipient [13], in most cases, drug discontinuation or dose reduction usually results in clinical and radiologic improvement. Herein, 2 cases of life-threaten- ing pulmonary complications attributed to sirolimus in solid organ transplant recipients are detailed. Unlike previous reports, both 2 patients presented with a very Severe form of acute respiratory distress. Most notably, when the diagnosis was established, it resolved quickly and completely with drug withdrawal and temporary steroids treatment. Furthermore, in this article, we further discussed the possible mechanisms, clinical characteristics, approach to diagnosis, and treatment strategies of sirolimus-induced pulmonary toxicity.

This was a 51-year-old man who received renal transplantation for end-stage renal disease in August 2006. He had received calcineurin inhibitor, which was switched to sirolimus due to new-onset diabetes one and a half years after transplantation. The patient maintained normal graft function with careful monitoring of sirolimus levels on regular follow-up visits. In October 2013, the patient presented with fever approximately 37.5?C with no cough or sputum, no painful, urgent or frequent urination, no vomiting or diarrhea. After 3 days intake of acetaminophen at home, fever continued to increase up to 40?C. The patient was treated with cefuroxime during the next 2 days for presumed pneumonia and again with no improvement. On fever day 5, he was admitted to the kidney transplant ward for further evaluation. At the time of admission, he was receiving sirolimus (1 mg daily), mycophenolate mofetil (500 mg twice daily), and prednisone (5 mg daily), which had not been changed over the previous years. His other medications were aspirin, nitroglycerin, and ?-blocker because of coronary artery disease. The patient had no smoking or drinking history. At the time of admission, body temperature was 40.5?C, blood pressure was 115/70 mm Hg, heart rate was 115 beats per minute, and respiratory rate was 24 breaths per minute. Physical examination revealed no signs of hypoxemia. The lungs were clear to auscultation bilaterally, without any wheeze, rales, or rhonchi. Laboratory results revealed an increased neutrophil fraction of 85.5%, high C-reactive protein level of 26.4 mg/dL, and also increased procalcitonin level of 12.52 ng/mL in blood samples. Plasma 1-3-?-D glucan measurement was normal, and polymerase chain reactions (PCRs) for Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in both blood and sputum samples were negative. However, the trough level of sirolimus was unexpectedly high, increasing from a baseline of approximately 6 ng/mL to 15.7 ng/mL. A chest CT showed the presence of regional infiltrates in the right lower lob. Empirical antibiotic therapy with intravenous cefoperazone and sulbactam was started. However, the fever was not controlled, and other symptoms

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of cough and dyspnea appeared. And quickly, the patient progressed to acute respiratory distress, combined with acute cardiac insuffi- ciency on hospital day 4. He was transferred to the Intensive care units and required emergent intubation and mechanical ventilation. In the ICU, the patient was treated with both diuretics and antimicrobial agents including those against atypical pneumonia pathogens and CMV. Furthermore, dose of sirolimus was decreased down to 0.5 mg daily because of the high trough level. His heart function improved with the treatment, and the level of N-terminal probrain natriuretic peptide gradually decreased. However, hypox- emia continued to deteriorate. The concentration of inhaled oxygen had to be increased up to 100% to maintain the saturation in the level of 90%. Furthermore, the patient needed sedatives to decrease the oxygen consumption. Another series of tests for causes of pneumonia, including CMV, EBV, respiratory viruses, fungi, and tuberculosis were all negative. Serologic tests including cytoplasmic antinuclear antibody

(c-ANCA), perinuclear antibody (p-ANCA), antiglomerular basement membrane antibody, and antinuclear antibody were all unremarkable. Furthermore, the PCT level decreased down to the reference range. Fibrotic bronchoscopy was performed, which again failed to reveal any infectious agents including Pneumocystis carinii pneumonia, and the cytology of BAL showed lymphocytic alveolitis. Another chest CT showed a bilateral, diffuse interstitial and alveolar infiltrates (Fig. 1). Both BAL and CT were suggestive of sirolimus-associated pulmonary toxicity. Then, the treatment of sirolimus and antibiotics were discontinued. Furthermore, steroids (methylprednisolone 60 mg daily, intravenously) were added because of the Severity of disease. This resulted in dramatic improvement of clinical condition and progressive resolution of radiologic findings. Oxygen concentration was rapidly decreased down to 45% over the next 2 days, and the patient was weaned off the ventilator on day 10 of steroids therapy, which was tapered over weeks to a maintenance dosage of 10 mg prednisone daily. Repeated chest CT on day 20 after diagnosis showed the most absorption of interstitial and alveolar infiltrates but persistent diffuse ground-glass parenchymal opacification of residual (Fig. 2). During the whole disease course, the renal graft function was maintained in a reference range. And at the time of writing, the patient was doing well with no recurrence of any pulmonary symptoms, 6 months after diagnosis.

A 51-year-old man underwent an orthotopic liver transplantation

for hepatitis B cirrhosis in September 2007. His perioperative course was uneventful, and he was discharged from the hospital on day 15 after transplant with an immunosuppressive regimen consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone. He did well until postoperative year 5, when he was readmitted for a new

Fig. 1. Chest CT scan before diagnosis demonstrates a bilateral, diffuse interstitial and alveolar infiltrates.

Fig. 2. Chest CT scan, performed on day 20 of sirolimus withdrawal and steroids administration, shows the most absorption of interstitial and alveolar infiltrates but persistent diffuse ground-glass parenchymal opacification of residual.

onset of jaundice and an elevation of Liver enzymes. An allograft biopsy revealed the presence of drug-induced organ liver damage. Tacrolimus was presumed as the culprit agent and was converted to sirolimus (1 mg daily). His other immunosuppressive agents were mycophenolate mofetil (750 mg twice daily) and methylprednisolone (8 mg daily). On day 3 after the conversion, the patient developed fever up to 38?C with productive cough of white secretions. Over the next 4 days, he continued to develop daily fevers up to 39?C to 40?C, although Intravenous antibiotic therapy had initiated with cefuroxime for 2 days followed by intravenous cefoperazone and sulbactam for the other 2 days. And oxygen by nasal channel was prescribed for increasing dyspnea. Chest CT scan was performed on fever day 5, and it revealed diffuse multifocal interstitial and alveolar infiltrates. Ganciclovir and caspofungin were added for empirical CMV and fungal coverage. However, the clinical condition of the patient continued to decline, and he was transferred to the ICU on fever day 8 because of severe hypoxemia. At the time of transferring, he was noted to desaturate to 75% on 15 L/min of nasal cannula oxygen. He immediately received high-flow nasal cannula oxygen therapy with oxygen concentration of 70%, and the saturation was gradually increased up to 90%. Subsequent arterial blood gases showed severe Respiratory insufficiency (pH 7.52, PO2 58 mm Hg, PCO2 26 mm Hg, HCO^- 21.2 mmol/L, fraction of inspired oxygen, 70%). Physical examination revealed no signs of heart failure. The patient’s body temperature was 38.5?C, blood pressure was 125/78 mm Hg, heart rate was 120 beats per minute, and respiratory rate was 30 breaths per minute. Auscultation of the lungs revealed bilateral basal coarse crackles. Cultures of blood, sputum, and Urine samples taken before the initial antibiotic therapy failed to reveal any infectious organisms. Furthermore, repeated plasma levels of PCT and 1-3-?-D glucan were in the reference range, and PCRs for CMV, EBV, and tuberculosis in both blood and sputum samples were all negative. Serologic tests including atypical pneumonia pathogens, respiratory viruses as well as c-ANCA and p-ANCA were unremarkable. The blood levels of sirolimus were in the recommended range of 4.6 to 7.6 ng/mL. Given no response to antibiotic therapy and no evidence of infectious agents, sirolimus-induced pulmonary toxicity was suspected. Fibrotic bronchoscopy was indicated for distinguishing between opportunistic infection and sirolimus-induced pneumonitis. However, the patient refused to accept this kind of invasive procedure. Then, sirolimus was empirically discontinued, and he also received intravenous steroids therapy for acute respiratory distress. Methylprednisolone was initiated with a dosage of 40 mg twice daily for 3 days followed by 20 mg twice daily for 2 days and then 20 mg daily, which was tapered over weeks to a maintenance dosage of 4 mg methylprednisolone daily. The treatment of broad spectrum antibiotics combined with ganciclovir and caspofungin was continued over the next week, considering the

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high risk for new acquired infection challenging under the large dosage of steroids. The clinical symptom of dyspnea gradually improved, and the patient was stopped the oxygen therapy and transferred back to the ward with normal saturation on day 15 of steroids therapy. Retrospective chart review revealed that all sputum and blood cultures on multiple occasions were persistently negative during the whole disease course, which mostly supported the diagnosis of sirolimus-induced pulmonary toxicity.

Pulmonary complication is relatively common and sometimes life threatening in organ transplant recipients treated with sirolimus, which has been shown to effectively prevent acute graft rejection without adversely affecting the renal function. The literature has reported a frequency of this complication of 2.9% to 16.7% [4-8]. It may begin with fever, fatigue, cough, and dyspnea and often nonspecific signs. Several histopathologic features of pulmonary damage have been recognized, including lymphocytic interstitial pneumonitis, lymphocytic alveolitis, organizing pneumonia, pulmonary alveolar proteinosis, or diffuse alveolar hemorrhage. The presentation of our cases was different from that detailed in previous reports in the literature. Both 2 patients presented with a very severe form of pulmonary damage, and the condition rapidly progressed to acute respiratory distress within 10 days after the onset of symptoms, and they need high oxygen concentration of 70% to 100% to maintain the saturation in the range of 90% to 92%. However, when the diagnosis was established, the patients achieved a good outcome with the discontinuation of sirolimus and administration of steroids.

The exact pathogenic mechanism of sirolimus-associated pulmo- nary toxicity is not well understood. The possible mechanism may be an autoimmune response. This hypothesis is supported by the findings of striking lymphocytic alveolitis with a majority of CD4- positive cells and a significantly increased number of eosinophils and mast cells [4,9,11,12]. The possible explanation is that sirolimus, as a potent antiproliferative agent, hampers the repairment of alveolar epithelium damage, leading to the exposure of pulmonary autoanti- gen and further initiation of an immune response. In addition, Pham et al [12] speculate that T cell-mediated, delayed hypersensitivity may be an alternative pathogenic mechanism. Sirolimus, combined with plasma proteins, acquires immunogenic as a hapten, which is processed by antigen presenting cells, then evokes the immune response with the subsequent T-cell recognition and differentiation.

The existence of a dose-dependent effect was also presumed because most cases showed an association of the pulmonary toxicity with high plasma concentrations, and the clinical and radiologic condition improved dramatically after sirolimus dose reduction or drug withdrawal [3,4]. In the case series of Champion et al [4], sirolimus trough levels in patients who experienced sirolimus pneumonitis were higher than those usually maintained in patients having renal transplantation. However, in some cases, the drug levels were in the recommended range [5-7,12,14,15]. In the report of Rehm et al [15], sirolimus trough levels of patients were between 5 and 12 mg/mL without the evidence of sirolimus overdosage. In one of our cases, both the concentration and dosage of sirolimus were in the recommended range. The other patient presented a high trough level of sirolimus concentration at the time of admission, but discontinu- ation of sirolimus therapy did not lead to the improvement of clinical status. The possible explanation is that the patient had used sirolimus for a very long time (more than 66 months), leading to severe damage of the repairment function and further persistent immune reaction. However, the mean time from the initiation of sirolimus to the onset of symptoms was diverse, ranged from 1 to 51 months according the literature. Furthermore, the patient of liver transplant in our report presented with pulmonary symptoms on the third day after the sirolimus conversion from tacrolimus. The different trough levels on the onset of pulmonary complications and the broad range of the time course after the initiation of sirolimus suggest an idiosyncratic mechanism rather than dose-dependent or time-dependent toxicity.

The clinical presentation of sirolimus-induced pneumonary toxic- ity is heterogeneous; dyspnea is a relatively common feature of this complication. The other symptoms are fever, fatigue, cough, and hemoptysis. But all these symptoms are unspecific. Chest CT images commonly describe bilateral, patchy, and interstitial opacities with a predilection for the lower lobes [7,8]. Diagnosis of sirolimus-induced pulmonary toxicity is difficult because it is essentially a diagnosis of exclusion. Usually, a possible relationship between pulmonary disease and sirolimus administration should be suggested, when patients presented pulmonary symptoms in lack of response to empirical antibiotic treatment and the absence of infection or alternative pulmonary disease and exhibited improved symptoms after dose reduction or withdrawal of the drug. Furthermore, to achieve a correct diagnosis, BAL should be performed, although nonspecific. Broncho- alveolar lavage cytology generally shows an increased number of lymphocytes. In addition, BAL is extremely useful to rule out infectious processes in these Immunocompromised patients. In some cases, lung biopsy was performed [3,9]. Usually, the pathology pattern may include several histologic features such as lymphocytic alveolitis, lymphocytic interstitial pneumonitis, organizing pneumo- nia, or diffuse alveolar hemorrhage. Champion et al [4] offered the following criteria for the definitive diagnosis of sirolimus-induced lung toxicity: (i) exposure to sirolimus preceding the onset of pulmonary symptoms; (ii) exclusion of infection or alternative pulmonary disease (eg, vasculitis and other drug toxicity); (iii) bronchiolitis obliterans-organizing pneumonia on chest CT and lymphocytic infiltrates on BAL, new or evolving infiltrates on chest radiography; and (iv) clinical improvement after drug withdrawal.

Risk factors for sirolimus-associated pulmonary toxicity have not

been clearly evaluated. High dose, high trough level, late conversion, and male sex have been suggested as risk factors according the literature [4,5,16]. Morath et al [16] reviewed the literature and analyzed 84 solid organ transplant recipients with suspected sirolimus-associated inter- stitial pneumonitis, including 63 kidney, 4 liver, 4 lung, 11 heart, 1 heart- lung, and 1 islet cell transplant. They identified that possible risk factors for the development of sirolimus-associated interstitial pneumonitis are high sirolimus dose (ie, N 5 mg/day), high sirolimus trough level (ie, N 15 ng/mL), administration of loading dose, prior increase of sirolimus dose or trough level, late sirolimus exposure (compared with de novo treatment), allograft dysfunction, hypervolemia, male sex, and higher age.

The treatment of these pulmonary complications is variable, in most cases, dose reduction or withdrawal of sirolimus could be sufficient to control symptoms and avoid Disease progression. In some cases, sirolimus should be permanently stopped because the recur- rence with continued low-dose treatment or readministration of the drug has been observed [4,5,9]. Treatment with steroids has been proposed in several reports [4,6,7,14]. In the cases of Haydar et al [14], corticosteroid showed to accelerate the course of recovery from pulmonary insufficiency. Especially in patients who developed moderate-to-severe symptoms, mostly presenting as diffuse alveolar hemorrhage, therapy of steroids showed rapid improvement of clinical conditions and radiologic findings and acquired favorable outcomes [7]. However, the benefit of steroids remains unclear and need to be further evaluated.

In conclusion, sirolimus-associated pulmonary complication should be taken into account as an alternative to the diagnosis of an opportunistic infection in patients who are being administered this drug. Dyspnea and fever are common symptoms. Chest CT changes are predominantly seen in the lower lobes and commonly presented as bilateral, patchy, or diffuse interstitial opacities. The presence of marked lymphocytosis in BAL and Histologic findings as described support the diagnosis of sirolimus-induced toxicity in patients with treatment of this drug. Discontinuation or dose reduction of sirolimus always leads in most of the cases to the complete and lasting resolution of symptoms. The effect of steroids therapy for the

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treatment of this form of pulmonary toxicity has not been adequately analyzed. However, in patients who develop severe respiratory insufficiency, steroids could be a theoretically rational therapy.

Wei Li Wang, MD? Li Xin Yu, MD

Intensive Care Unit of Organ Transplantation Department Tianjin First Central Hospital, Tianjin, China, 300192

?Corresponding author.

E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2014.05.047

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