Sirolimus is an effective therapy for children with kaposiform hemangioendothelioma with or without the Kasabach-Merritt phenomenon. We report the case of a child with kaposiform hemangioendothelioma and the Kasabach-Merritt phenomenon who developed Pneumocystis carinii pneumonia (PCP) while on sirolimus and a prednisolone taper, after lack of adequate response to prednisolone, propranolol, and vincristine. He had a prompt positive clinical and laboratory response to sirolimus, but 4 weeks after starting it, at the age of 4 months, he developed PCP. This led to respiratory failure, which required extracorporeal membrane oxygenation. Sirolimus was temporarily discontinued, and he was successfully treated for PCP with sulfamethoxazole-trimethoprim and methylprednisolone. He was restarted on sirolimus 3 weeks after discharge and given sulfamethoxazole-trimethoprim prophylaxis. At the age of 22 months, while still on sirolimus, the lesion continued to improve with test results revealing stable hemoglobin and platelet counts. PCP is a rare but life-threatening side effect of sirolimus therapy, especially in the setting of concurrent steroid treatment. Pneumocystis prophylaxis should be considered for patients receiving sirolimus.
- ECMO —
- extracorporeal membrane oxygenation
- KHE —
- kaposiform hemangioendothelioma
- KMP —
- Kasabach-Merritt phenomenon
- mTOR —
- mammalian target of rapamycin
- PCP —
- Pneumocystis carinii pneumonia
- SOT —
- solid organ transplant
Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), is an effective therapy for children with kaposiform hemangioendothelioma (KHE). A recent clinical trial revealed a high response rate to sirolimus in patients with KHE with or without the Kasabach-Merritt phenomenon (KMP), as well as some other complicated vascular anomalies, with manageable toxicities.1 Pneumocystis jirovecii is an opportunistic pathogen that is a well-known cause of pneumonia in immunocompromised individuals. Pneumocystis carinii pneumonia (PCP) has been reported in patients receiving sirolimus for solid organ transplants (SOTs).2–4 Here, we report PCP in a child being treated with sirolimus for KHE with KMP.
A term male infant was noted at birth to have an area that looked like a bruise on his left lower trunk and abdomen. The lesion slowly enlarged, darkened, and became firm. At age 2 months, a complete blood cell count showed a normocytic anemia (hemoglobin: 8.0 g/dL) and thrombocytopenia (platelets: 55 000/μL). The white blood cell count was 6400 per μL, the absolute neutrophil count was 960 per μL, and absolute lymphocyte count was 492 per μL. Additional laboratories showed a fibrinogen level of 74 mg/dL (reference range: 180–363 mg/dL), a prothrombin time of 14.8 seconds (reference range: 8.9–12.1 seconds), and a partial thromboplastin time of 34.8 seconds (reference range, <30 seconds). An ultrasound revealed a subcutaneous hypervascular soft tissue mass extending from the anterior abdominal wall to the left flank, with multiple vascular channels and surrounding soft tissue edema. There were no abnormalities noted on the ultrasound examinations of the head or abdominal viscera, including the liver. On the basis of clinical and radiographic features, he was diagnosed with KHE complicated by KMP. The lesion was not biopsied because of concern about a bleeding complication.
Therapy was initiated at age 2 months with prednisolone (2 mg/kg per day) and propranolol (escalated to 3 mg/kg per day). After 2 weeks, minimal clinical response was noted and an intravenous vincristine dose of 0.025 mg/kg once a week was initiated. After 3 weeks of vincristine, progressive worsening of the lesion was noted (Fig 1A) without any improvement in his laboratory values. Vincristine and propranolol were discontinued; at age 3 months, on the basis of previous case reports,5–7 he was started on sirolimus at 0.05 mg/kg per dose twice a day with a trough goal of 8 to 15 ng/mL. The lesion showed prompt improvement with smaller size, lighter color, and softer texture. His hemoglobin and platelet count normalized by the third week of sirolimus therapy (Fig 2). A taper of prednisolone was started.
Four weeks after starting sirolimus therapy and near the end of his prednisolone taper (at age 4 months), he presented with fever, tachypnea, and hypoxia. A sirolimus trough level 5 days before admission was 16.2 ng/mL. On the day of admission, a complete blood cell count revealed a white blood cell count of 10.700 per μL, an absolute neutrophil count of 5029 per μL, and an absolute lymphocyte count of 4922 per μL. A chest radiograph revealed symmetric lung hyperinflation with diffuse interstitial prominence (Fig 3). The results of a respiratory viral panel were negative. Sirolimus was held to reduce immunosuppression. His respiratory condition worsened and he required intubation and mechanical ventilation. A tracheal aspirate was positive by direct fluorescent antibody for P jirovecii. He was treated with sulfamethoxazole-trimethoprim and methylprednisolone, as well as azithromycin, cefepime, and vancomycin.
Despite aggressive treatment, including high-frequency oscillator ventilation, his respiratory condition worsened, and on hospital day 4, he was placed on extracorporeal membrane oxygenation (ECMO). He tolerated ECMO well and showed gradual improvement of his lung aeration. ECMO was discontinued after 7 days of treatment (hospital day 11). He completed a 21-day course of sulfamethoxazole-trimethoprim and methylprednisolone for PCP. Sedation and ventilator settings were gradually weaned and he was discharged on day 32 of hospitalization. For PCP prophylaxis, he was continued on sulfamethoxazole-trimethoprim 3 days a week. Three weeks after discharge, the lesion was darkening and the platelet count was dropping, so he was restarted on sirolimus, to which the lesion again responded favorably. At age 11 months, the KHE lesion showed continued improvement (Fig 1B), with normal hemoglobin and platelet counts. This improvement continued at least until age 22 months, while the patient was still on sirolimus.
KHE is a rare vascular tumor that typically presents during infancy as a large, violaceous plaque. KHE is often associated with KMP, consisting of microangiopathic hemolytic anemia, thrombocytopenia, and consumptive coagulopathy in the setting of an enlarging vascular lesion.
Steroid therapy with or without vincristine has been successful in treating KHE, as has propranolol.8 Our patient’s KHE and KMP had only minimal response to prednisolone, propranolol, and vincristine. When sirolimus was started, there was prompt and encouraging clinical and laboratory improvement. Sirolimus (dosed at 0.8 mg/m2 per dose twice a day) has recently shown promise for treating KHE with or without KMP.1 Currently, a phase II clinical trial comparing vincristine and sirolimus is underway for patients with high-risk vascular tumors (ClinicalTrials.gov identifier NCT02110069).
Sirolimus (also known as rapamycin) is an inhibitor of mTOR, a protein kinase that promotes protein synthesis and cell growth, including angiogenesis, and is dysregulated in some cancers and vascular anomalies. Other mTOR inhibitors, such as temsirolimus and everolimus, are used to treat certain rare cancers.9 Sirolimus is mostly used as a second-line or adjuvant immunosuppressant to prevent rejection after SOT (most commonly renal transplant). The literature on the use and side effects of sirolimus in the pediatric population at this time is limited, especially outside the setting of renal transplant.
PCP is a classic infection associated with HIV infection and drug-associated immunosuppression, with or without lymphopenia.10 PCP has been reported in adults receiving everolimus for renal cell carcinoma,11,12 and sirolimus as part of immunosuppression after SOT.3 At least 1 pediatric patient developed PCP while receiving sirolimus after SOT.2 Steroids are also considered a risk factor for PCP.4,13 One pediatric patient with KHE and KMP developed PCP while receiving prednisolone and after radiation therapy, pulse methylprednisolone, interferon-α, vincristine, dactomycin, and cyclophosphamide.14 In contrast, our patient had been on sirolimus for 1 month and was nearly off prednisolone when he developed PCP. Our patient did not have lymphopenia at the time of PCP diagnosis. PCP has also been documented in pediatric patients with infantile hemangioma during treatment with prednisolone ranging from 5 weeks to 5 months.15,16 It is thus possible, if not likely, that steroid therapy was a contributing factor to the development of PCP in our patient.
This case supports sirolimus as an effective therapy for KHE with KMP but highlights the risk of PCP with sirolimus therapy, especially in the setting of concurrent steroid treatment. Pneumocystis prophylaxis should be considered in children receiving sirolimus for vascular anomalies and other indications.
- Accepted June 21, 2017.
- Address correspondence to Thomas W. McLean, MD, Department of Pediatrics, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-2919.
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- Copyright © 2018 by the American Academy of Pediatrics