sirolimus and Pneumonia--Pneumocystis

Initially developed as immunosuppressive agents, mammalian target of rapamycin (mTOR) inhibitors are currently used widely in the management of vascular malformations and tumors. The incidence of infectious complications in the vascular anomalies (VA) population is not well defined. The goal of this systematic review was to better define the types and severity of reported infectious complications in patients with VAs treated with mTOR inhibition.. This was a systematic review conducted following PRISMA guidelines evaluating all research articles focused on infectious complications in patients with VAs treated with sirolimus or everolimus. Thirty articles including 1182 total patients and 316 infections (in 291 unique patients) were ultimately included.. The majority of infections were viral upper respiratory (n = 137, 54%), followed by pneumonia (n = 53, 20%), and cutaneous infections (n = 20, 8%). There were six total infection-related fatalities, which all occurred in patients younger than 2 years. Two cases of Pneumocystis jirovecii pneumonia (PJP) were reported. These were infants with kaposiform hemangioendothelioma (KHE) who were also treated with steroids and did not receive PJP prophylaxis. Almost one-third (n = 96, 32%) of infectious complications were graded 3-4 according to Common Terminology Criteria for Adverse Events (CTCAE) criteria. Details of patient age, subtype of VA, and timing of infection were lacking from many reports.. Most infectious complications reported in patients with VA on mTOR inhibitors were viral respiratory infections and non-severe. Bacteremia, infectious fatalities, and PJP are exceedingly rare. Future studies are needed to clarify the spectrum of infectious risks in VA patients and to provide guidance for infection prevention.

Topics: Everolimus; Humans; Immunosuppressive Agents; Infant; Pneumonia, Pneumocystis; Sirolimus; TOR Serine-Threonine Kinases; Vascular Malformations

Hematopoietic cell transplantation (HCT) offers long-term cure against early morbidity and mortality of hemoglobinopathies, such as sickle cell disease (SCD) and beta-thalassemia. Following HCT, sirolimus is an immunosuppressant used to prevent graft-versus-host disease (GVHD) while receiving trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jirovecii prophylaxis and other antimicrobial agents (including acyclovir). One rare adverse event associated with both drugs is rhabdomyolysis, defined as creatine kinase (CK) elevation at least 5 to 10 times the upper limit of normal. This study was conducted to evaluate the rate of and risk factors for developing rhabdomyolysis in the post-HCT setting. Across 4 haploidentical and matched related donor (MRD) nonmyeloablative protocols, CK levels were prospectively monitored and patients were retrospectively identified for rhabdomyolysis. The rhabdomyolysis was graded based on the severity of CK elevation and other organ injury. At diagnosis, patients were queried for concurrent medication use (ie, sirolimus, TMP-SMX, acyclovir, or statins), sex, age, donor genotype, and time from transplantation. Among 127 patients with mostly SCD, rhabdomyolysis occurred in 22 (17%), including 2 recipients of haploidentical donor HCT and 20 recipients of MRD HCT. The time to the development of rhabdomyolysis was 61 and 73 days for the 2 recipients of haploidentical HCT and a median of 73 days for the MRD HCT recipients. Among the 22 patients who developed rhabdomyolysis, 20 (91%) were receiving sirolimus (2 haploidentical HCT recipients and 18 MRD HCT recipients), and 14 (64%) were also receiving TMP-SMX (all in the MRD HCT group). Seventy-five percent of the haploidentical donors and 69% of the MRDs had sickle cell trait. All but 2 patients with rhabdomyolysis were male. No patients who developed rhabdomyolysis were receiving statins at any point. Higher-than-expected rates of rhabdomyolysis were found post-transplantation for patients with SCD and beta-thalassemia. Contributing risk factors included immunosuppression with sirolimus, TMP-SMX, male sex, and sickle trait donor. These factors differ from the excessive muscle strain or injury, seizures, infections, or HMG-CoA inhibitors typically identified in non-HCT recipients.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Male; Pneumonia, Pneumocystis; Retrospective Studies; Rhabdomyolysis; Sirolimus; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Hemangioendothelioma; Humans; Immunocompromised Host; Kasabach-Merritt Syndrome; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Risk Assessment; Sarcoma, Kaposi; Sirolimus; Vincristine

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

Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Drug Therapy, Combination; Hemangioendothelioma; Humans; Immunosuppressive Agents; Infant; Kasabach-Merritt Syndrome; Male; Pneumocystis carinii; Pneumonia, Pneumocystis; Prednisolone; Propranolol; Respiratory Insufficiency; Sarcoma, Kaposi; Sirolimus; Vincristine

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Nephrectomy; Pneumocystis carinii; Pneumonia, Pneumocystis; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases

A 76-year-old female with advanced renal cell carcinoma had been treated with everolimus for 3 months. She visited our hospital because of a cough and fever lasting a few days. Chest X-rays showed bilateral infiltrative shadows, and a chest computed tomography scan showed homogeneous ground-glass opacities with mosaic patterns, especially in the apical region. The laboratory results revealed a decreased white blood cell count with lymphocytopenia and high levels of lactate dehydrogenase, C-reactive protein and KL-6. Pneumonitis was suspected and, therefore, everolimus therapy was interrupted. At that time, the pneumonitis was thought to be drug-induced interstitial lung disease. However, it was not possible to rule out pneumocystis pneumonia, because the patient was immunocompromised and the computed tomography findings suggested the possibility of pneumocystis pneumonia. The pneumonitis progressed rapidly and the patient developed respiratory failure, so we performed bronchoalveolar lavage to make a definitive diagnosis, and simultaneously started treatment with prednisolone and trimethoprim-sulfamethoxazole to cover both interstitial lung disease and pneumocystis pneumonia. A polymerase chain reaction assay of the bronchoalveolar lavage fluid was positive for Pneumocystis carinii DNA, and the serum level of β-d-glucan was significantly elevated. Thus, the patient was diagnosed with pneumocystis pneumonia, which was cured by the treatment. Interstitial lung disease is a major adverse drug reaction associated with everolimus, and interstitial lung disease is the first condition suspected when a patient presents with pneumonitis during everolimus therapy. Pneumocystis pneumonia associated with everolimus therapy is rare, but our experience suggests that pneumocystis pneumonia should be considered as a differential diagnosis when pneumonitis is encountered in patients receiving everolimus therapy.

Topics: Aged; Anti-Infective Agents; Antineoplastic Agents; Bronchoalveolar Lavage; Carcinoma, Renal Cell; Diagnosis, Differential; Drug Administration Schedule; Everolimus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Neoplasms; Lung Diseases, Interstitial; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Respiratory Insufficiency; Sirolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

To report 3 separate cases of wound dehiscence in liver transplant recipients receiving sirolimus for immunosuppressive therapy.. Three patients who had received liver transplants experienced a delay in wound granulation and healing after being placed on an immunosuppressive regimen containing sirolimus and steroids. Each patient was admitted and treated for wound dehiscence, at which time sirolimus was discontinued. When other immunosuppressive agents were substituted for sirolimus, each incisional wound granulated and closed without complication.. Sirolimus is an important adjunctive immunosuppressant used to prevent acute rejection episodes in patients who have undergone transplant, particularly when nephrotoxic effects from first-line calcineurin inhibitors become problematic. The unique ability of sirolimus to inhibit smooth muscle cell proliferation and intimal thickening by blocking important growth factors may subsequently become a significant feature to prevent the development of chronic rejection. Theoretically, by this same mechanism, sirolimus may play a role in forestalling wound healing and may even promote dehiscence.. These case reports describe patients who underwent liver transplant who developed wound dehiscence possibly secondary to sirolimus therapy. Although the cases were complicated by acute rejection, wound infections, and comorbidities, wound granulation and healing began after discontinuation of sirolimus. Substitution with another immunosuppressant may be necessary for patients who experience wound dehiscence after transplant.

Topics: Adult; Anti-Inflammatory Agents; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Pneumonia, Pneumocystis; Prednisone; Reoperation; Sirolimus; Surgical Wound Dehiscence; Tacrolimus

Topics: Animals; Dexamethasone; Humans; Immunosuppressive Agents; Mycophenolic Acid; Pneumonia, Pneumocystis; Rats; Sirolimus; Tacrolimus