Interstitial Granulomatous Pneumonitis associated with Sirolimus in a Child after Liver Transplantation

Sirolimus (SRL, rapamycin, Rapamune, Wyeth-Ayerst, Philadelphia, PA) is a recent addition to the immune-suppression protocols for pediatric solid organ transplantation (1–4). SRL blocks signal 3 of T-cell activation and prevents T-cell proliferation by inhibiting the mammalian target of rapamycin (mTOR) (5,6). Common adverse effects of SRL include hyperlipidemia and myelosuppression (7–9), both of which are dose dependent and generally responsive to dose reduction. We describe a pediatric orthotopic liver transplant (OLTx) recipient in whom interstitial granulomatous pneumonitis developed while on SRL. Interstitial pneumonitis associated with SRL treatment has been reported in adults after solid organ transplantation (10–13). However, this is the first report of interstitial granulomatous pneumonitis secondary to SRL in the pediatric OLTx population. CASE REPORT An 8-year-old female who underwent an orthotopic liver transplantation for extrahepatic biliary atresia at one year of age, developed fatigue and decreased appetite. There was no history of fever, gastrointestinal, or respiratory symptoms. Medical history included recurrent Epstein-Barr virus (EBV) hepatitis, and early infectious mononucleosis-like post-transplant lymphoproliferative disease (PTLD) of the tonsils with no other organ involvement. Treatment of PTLD including tonsillectomy, led to its resolution. Because of chronically elevated EBV viral load after treatment (from 100-1000 to >1000 viral genome copies per 106 peripheral blood mononuclear cells (PBMC) by semiquantitative PCR), she remained on PTLD prophylaxis using acyclovir and a low dose of cyclosporine (target trough level 50-100 μg/L). Therapy with SRL (0.12-0.18 mg/kg/day) in conjunction with tapering and then discontinuation of cyclosporine, was started 9 months before admission. Indications for SRL treatment were previous PTLD, calcineurin inhibitor mediated nephrotoxicity (creatinine 65 μmol/L, urea 8.5 mmol/L, and glomerular filtration rate of 44 mls/min/1.73sq.m), and biopsy-proven recurrent acute rejection episodes while on low dose cyclosporine therapy. SRL trough levels were maintained at 8 to 12 ng/ml for the first 5 months and later decreased to 4 to 6 ng/ml due to the development of SRL-induced leukopenia and mouth ulcers. On admission, physical examination and vital signs were normal. Laboratory testing included normal complete blood count, serum electrolytes, liver enzymes, and renal function tests. The trough level of SRL was 5 ng/ml. Despite the lack of respiratory symptoms at the time of presentation, a chest radiograph demonstrated increased bilateral interstitial marking. Computed tomography of the chest showed multiple parenchymal nodular opacities in the lung (Fig. 1). Pulmonary function tests (PFTs) revealed a forced expiratory volume in 1-second (FEV-1) of 91% of predicted normal values. Blood cultures, nasopharyngeal cultures, serologic tests for human herpes virus-6/7, herpes simplex virus-1/2, and varicella-zoster virus were negative. Evaluation for Mycobacterium tuberculosis, including Mantoux testing and repeated gastric aspirates, were negative. Semiquantitative EBV PCR was positive at 100 to 1000 viral genome copies per 106 peripheral blood mononuclear cells, but this value was unchanged compared with previous values. An infectious pneumonia was the initial working diagnosis and empiric treatment was initiated with cefu roxime and azithromycin. Despite antibiotic treatment, the patient developed dyspnea and tachypnea. Repeated radiographic imaging of the chest showed no improvement. An open lung biopsy was performed. Histologic examination of lung tissue revealed two pathologic processes. The first was diffuse pneumonitis with alveolar proteinosis and two well-formed granulomas with multinucleated giant cells (Fig. 2). The second was mucosal lymphoid hyperplasia along the bronchiolo-vascular bundles with positive EBV encoded RNA (EBER) stain and positive anti-CD-20 stain consistent with EBV positive PTLD of the benign lymphoid hyperplasia subtype. EBER stain of the granulomas was negative. Cultures and immunohistologic assessment of lung tissue for bacteria, fungi, Pneumocystis carinii, Mycobacterium tuberculosis, cytomegalovirus, adeno-virus, human herpes virus-6/7, herpes simplex virus-1/2, and varicella-zoster virus were negative.FIG. 1.: Computed tomography scan of the chest revealing diffuse parenchymal abnormalities with multiple bilateral lung parenchymal micronodular opacities. Areas of consolidation or collapse were not detected.FIG. 2.: Histopathologic sections showing a well-formed non-necrotic granuloma containing multi-nucleated giant cells, with no infective agents identifiable (stain, hematoxylin-eosin; original magnification, ×200).The patient was thought to have two concurrent pathologic processes—a drug reaction causing interstitial granulomatous pneumonitis and PTLD. Therefore, SRL was stopped and low-dose tacrolimus (trough level- 3.5-4.5 μg/L) was initiated. In addition, treatment for PTLD, including ganciclovir (10 mg/kg/d) and CytoGam (150 mg/kg/dose every other day) was instituted. Because of increasing dyspnea, hypoxia (blood oxygen saturation of 90% in room air), and deterioration of the FEV-1 to 48% of predicted normal values, additional therapy for PTLD with anti CD-20 monoclonal antibody (Rituximab) and prednisone (3 mg/kg/d) was started. There was a gradual improvement in respiratory distress after these changes in therapy. Four months later, EBV viral load had dropped to 10 to 100 viral genome copies per 106, the FEV-1 was 74% of predicted normal values and a CT scan of the chest showed an improvement in the micronodular pattern. DISCUSSION This is the first reported case of interstitial granulomatous pneumonitis caused by SRL in a child following liver transplantation. The clinical, radiographic, and pathologic findings were consistent with the combination of SRL associated granulomatous pneumonitis and PTLD of the lungs. Currently, SRL is not widely used following liver transplantation. However, small case series report its use for indications including primary immunosuppressive therapy in conjunction with low doses of calcineurin inhibitor (9,14,15); PTLD (1); hepatocellular carcinoma before transplantation (9); calcineurin inhibitor mediated toxicity or treatment failure (1,16,17); renal failure documented before liver transplantation (16); and rescue therapy for chronic rejection (4). The use of SRL in children after liver transplantation is less common than in adults. It is used mainly to treat calcineurin inhibitor toxicity and PTLD (1–4). Therapy with SRL was initiated in our patient because of her history of PTLD, recurrent acute rejection episodes while on cyclosporine treatment, and calcineurin inhibitor mediated nephrotoxicity. Following the introduction of SRL, GFR improved from 44 to 63 mls/min/1.73sq.m in the 4 months after discontinuation of cyclosporine. The patient experienced only one acute rejection episode in 4 months compared with 3 episodes during the same period of time before SRL initiation. On the other hand, despite the potential inhibitory effect of SRL on proliferation of EBV positive B-cells (18), the patient had a recurrence of PTLD. This case emphasizes that the occurrence of new or rare adverse effects following introduction of a new medication is not merely a theoretical risk. In the field of transplantation, such events may occur even more frequently due to ongoing development of new drugs and immunosuppressive protocols. In many cases, unknown adverse events mimic common symptoms and signs, and physicians must consider a drug reaction in the differential diagnosis when confronted with common symptoms and signs amidst an unusual clinical course. A diagnosis of SRL toxicity in our patient with the non-specific symptoms of dyspnea and fatigue was based on the four criteria for confirming the diagnosis of methotrexateinduced pneumonitis described by Henry et al. (19). These criteria include exposure to the drug before the onset of pulmonary symptoms, exclusion of infection or alternative pulmonary disease, histopathology consistent with drug-induced lung pathology, and new or evolving pulmonary infiltrates on chest radiographs. While we are not aware of reports describing PTLD-induced granulomas with diffuse pneumonitis, interstitial pneumonitis with granulomas has been reported in adult patients treated with SRL after solid organ transplantation (10–13). Morelon et al. (10) reported interstitial lymphocytic infiltrates, bronchiolitis obliterans with organizing pneumonia (BOOP), and non-necrotizing granulomas in lung biopsies obtained from two adults with kidney transplantation receiving SRL. The striking similarities between these biopsies and the biopsy in our patient led us to conclude that our patient's condition was at least in part related to SRL toxicity. The mechanism of SRL induced interstitial granulomatous pneumonitis is unknown. Some investigators have suggested that a dose dependent toxicity induces an autoimmune response resulting in interstitial pneumonitis (10). However, in our case the patient trough levels of SRL (4-6 ng/ml) were relatively low, suggesting that the effect may not be dose dependent. Treatment for drug-induced toxicity includes immediate discontinuation of the drug and, in severe or life-threatening cases, consideration of high-dose steroid therapy. In three small case series, SRL withdrawal led to improvement of pneumonitis in some of the patients (10,12,13). However, our patient did not improve after withdrawal of SRL and her respiratory status improved only after the initiation of steroid treatment (3 mg/kg/d) and anti-CD-20 antibody. Although this treatment was intended to target the PTLD, the steroids may have had an adjunctive effect on the SRL-induced pneumonitis. Monitoring of respiratory status by repeated pulmonary function tests is an important tool in the evaluation and follow-up of patients with interstitial pneumonitis (20). The most sensitive indicator of our patient's respiratory status was her PFTs while changes in blood oxygen saturation, physical examination, and radiographic studies were subtle or delayed. PFTs, measured before and during SRL treatment may be a sensitive marker for the development of SRL-induced pneumonitis in the asymptomatic patient. Acknowledgments: The authors thank Dr. Philip Sherman for his critical review of this manuscript.

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