Age: 10.0
Sex: F
Vaccine: DTAP, PPV
Symptoms: Blood culture negative, Blood fibrinogen decreased, Chest X-ray normal, Clostridium test negative, Culture stool negative
Clinical narrative: This subject was enrolled in a clinical trial using sirolimus as a study drug. Sirolimus Regimens: Regimen 1, 0.13 mg twice daily, from 25Sep2010 till unknown. Regimen 2, 0.32 mg twice daily, from unknown till 22Jun2011. Regimen 3, 0.32 mg twice daily, from 29Jun2011 to ongoing. This case was forwarded to GSK by another manufacturer (Pfizer). Pneumococcal 7-valent conjugate vaccine and DTPA vaccine are concomitant vaccines used in this sirolimus study. Past medical history included a clostridium difficile infection. Medical conditions at the time of the event included exposure to chicken pox (exposure to communicable disease), kaposiform hemangioendothelioma with Kasabach-Merritt Syndrome (hemangioma-thrombocytopenia syndrome). Concomitant medications included BACTRIM. On 20 June 2011, 9 months after starting sirolimus at a dose of 0.13 mg twice daily and an unspecified number of days after switching to sirolimus at a dose of 0.32 mg twice daily, and 4 days after receiving a 2nd dose of pneumococcal 7-valent conjugate vaccine (NON-GSK concomitant vaccine), and 4 days after a 1st dose of DTPA concomitant vaccine, this 10 month-old female subject developed lymphatic edema limb. The subject was hospitalised. The subject was treated with cefdinir, clindamycin, acyclovir, oxycodone and steroid. Treatment with sirolimus was discontinued. The event improved on an unspecified date. The investigator considered that there was a reasonable possibility that the lymphatic edema limb may have been caused by sirolimus and that the event was possibly due to the concomitant vaccines, pneumococcal 7-valent conjugate vaccine (NON-GSK, taken for: routine immunization) and DTPA vaccine (Unknown manufacturer, taken for: routine immunization). This is a report from a non-Pfizer sponsored interventional study. A 10-month-old female patient was enrolled in the sirolimus clinical trial, starting sirolimus on 25Sep2010 at 0.13 mg twice daily for Kaposiform hemangioendothelioma (KHE) with Kasabeck-Merritt Syndrome (Haemangioma-thrombocytopenia syndrome). At the time of the event she was receiving 0.32 mg twice daily. Additional suspect medication included pneumococcal 7-valent conjugate vaccine, dose number 2 on 16Jun2011 at 1 dose form and diphtheria, tetanus and acellular pertussis (DTAP, "DT/TD") at 1 dose form on 16Jun2011. Relevant medical history included a previous history of clostridium difficile infection and exposure to chicken pox in Jun2011 prior to the event. Relevant concomitant medication included BACTRIM oral since 25Sep2010 for infection prophylaxis. The subject suffered from Kaposiform Hemangioendothelioma with Kasabach-Merritt phenomenon (Hemangioma-thrombocytopenia syndrome) since birth, extending from her foot all the way up into her inguinal area and lower abdomen, back and buttocks. Due to her significant Kasabach-Merritt phenomenon, her baseline issues included decreased platelets, haemoglobin, fibrinogen and increased D-dimers. On 16Jun2011, the subject received immunizations. The following day, she was seen by her primary care physician due to increased fussiness and fever of 102F. The physician prescribed OMNICEF for supposed acute suppurative otitis media and possible immunization reaction. On 19Jun2011, the subject was noted by parents to have increased swelling of the right leg. She remained afebrile. On 20JUn2011, she was brought to the emergency department, where an ultrasound and labs were performed. The ultrasound showed normal appearance of the major veins of the right leg without evidence of thrombus. The subject was discharged from the emergency department with instructions to loosely wrap and ace bandage around the affected leg. On 21Jun2011, the subject's right leg continued to be swollen. On 22Jun2011, it was noted that she had increased swelling now into her foot, as well as increased fussiness. She reported to the emergency department where she was admitted for possible cellulitis, though there was no erythema or increased temperature. Her sirolimus was held as of 22Jun2011 PM dose. A dose of intravenous CLEACIN 120 mg every 4 hours was administered. Chest X-ray was normal. Blood and urine cultures had no growth. On 23Jun2011, she remained afebrile. A dose of intravenous CLEOCIN 120 mg every 4 hours was administered. On 24Jun2011 she remained afebrile. MRI of right leg was performed which showed diffuse edema associated with the malformation. A dose of intravenous clindamycin 120 mg every 4 hours was administered. On 25Jun2011, the subject was transferred to the Hospital. There was no evidence of cellulitis but since intravenous clindamycin treatment was already started, the decision was made to continue treatment for 7 days. There was a new discovery of exposure to chicken pox 11 days previous. Due to varicella exposure and immunosuppression from sirolimus, the subject was treated with 6 days of intravenous and 1 day of oral ZOVIRAX per infectious disease. On 26Jun2011, she remained afebrile, but received a dose of oxycodone overnight due to fussiness. Stool cultures including Clostridium difficile were negative; the subject had a previous history of C. Difficile infection. Lab work included white blood cell count 26Jun2011 5.6 K/mcl; haemoglobin 24Jun2011, 10.2 Gm/dl. On 27Jun2011, the subject remained afebrile, but received three doses of oxycodone overnight due to fussiness. Right leg swelling had decreased in regards to twice daily girth measurements. On 28Jun2011, the subject remained afebrile, but received a dose of oxycodone overnight due to fussiness. Her edema had improved, the KHE lesion was still purpuric and taut; thus treatment needed to be continued. In addition, one dose of steroids was given due to worsening of KHE lesion. No signs of varicella to date. On 29Jun2011, the subject remained afebrile and was restarted on sirolimus 0.32 mg orally twice daily. On 30Jun2011, she remained afebrile and leg was softer in upper thigh area. Intravenous clindamycin was discontinued. Since swelling decreased during hospital stay, she was discharged from the hospital on oral ZOVIRAX on 01Jul2011. At the time of the report, the subject was recovering. Study drug action due to the event was withdrawn temporarily. Per the investigator, there is not a reasonable possibility that the event was related to study drug or to a clinical trial procedure. It was felt that the lymphedema was secondary to pneumococcal 7-valent conjugate vaccine and diphtheria, tetanus, and acellular pertussis vaccination response and not secondary to sirolimus, as edema has occurred in KHE lesion after immunizations. Additionally resolution of edema is lengthy due to underlying KHE. Follow-up (27Jul2011): Additional information received from the site. The subject received the following immunizations on 16Jun2011: pneumococcal conjugate vaccine (PCV) number 2 and DTAP (Diphtheria and tetanus toxoids and acellular pertussis vaccine) "(DT/TD)". The immunizations were just prior to increased swelling reaction. Per the investigator, edema has been known to occur in KHE lesions after immunizations. In agreement with the investigator, the company (Pfizer) assesses there is not a reasonable possibility the event is causally related to sirolimus therapy.