Sex: M
Vaccine: FLUX, PPV
Symptoms: Chest X-ray normal, Complement factor C3, Complement factor C4 decreased, Cryoglobulinaemia, Cryoglobulins present
Clinical narrative: Type II mixed cryoglobulinemia/IgM kappa (k) monoclonal cryoglobulinemia with polyclonal IgG cryoglobulinemia; Leukocytoclastic vasculitis; Cyanosis of the Toes and Fingers; Flu-like symptoms; nonpalpable, purpuric lesions on his toes and fingers/acral purpuric lesions; Necrosis of the distal finger; Acral pain; Digital ischemia/acral ischemic symptoms; livedo reticularis of both plantar surfaces; anorexia; Night sweats; Myalgias; Fatigue; Arthralgia; This case was reported in a literature article and described the occurrence of acrocyanosis in a 76-year-old male patient who received Flu Seasonal TIV Dresden (Flu trivalent vaccine) for prophylaxis.    Co-suspect products included PNEUMOCOCCAL VACCINE for prophylaxis.   The patient's past medical history included coronary artery disease (bypass surgery), hypercholesterolemia and gastroesophageal reflux disease.   On an unknown date, the patient received Flu trivalent vaccine at an unknown dose and PNEUMOCOCCAL VACCINE at an unknown dose. On an unknown date, 5 days after receiving Flu trivalent vaccine, the patient experienced acrocyanosis, cryoglobulinemia (serious criteria GSK medically significant), leukocytoclastic vasculitis (serious criteria GSK medically significant), influenza-like symptoms, purpura, digital necrosis, pain localized, peripheral ischemia, livedo reticularis, anorexia, night sweat, myalgia, fatigue and arthralgia. The patient was treated with prednisone, rituximab and cyclophosphamide. On an unknown date, the outcome of the acrocyanosis, cryoglobulinemia, leukocytoclastic vasculitis, influenza-like symptoms, purpura, digital necrosis, pain localized, peripheral ischemia, livedo reticularis, anorexia, night sweat, myalgia, fatigue and arthralgia were unknown.   The reporter considered the acrocyanosis, cryoglobulinemia, leukocytoclastic vasculitis, influenza-like symptoms, purpura, digital necrosis, pain localized, peripheral ischemia, livedo reticularis, anorexia, night sweat, myalgia, fatigue and arthralgia to be probably related to Flu trivalent vaccine.  Additional details were provided as follows: This case was reported in a literature article and described the occurrence of type II mixed cryoglobulinemia, leukocytoclastic vasculitis and flu-like symptoms in a 76-year- old male patient, who was vaccinated with unspecified trivalent influenza vaccine and unspecified pneumococcal vaccine (manufacturer unknown for both) for prophylaxis. The patient's medical history included coronary artery disease, bypass surgery, hypercholesterolemia, and gastroesophageal reflux disease. The patient had no prior immunologic disease. No information on patient's family history or concomitant medication was provided. On an unspecified date, the patient received unspecified trivalent influenza vaccine and unspecified pneumococcal vaccine (administration route and site unspecified, dosage unknown; batch number not provided for both). The age of vaccination was not provided but it could be 75 or 76 years. On an unspecified date, at the age of 76 years, 5 days after the vaccinations, the patient presented with flu-like symptoms and cyanosis of the toes and fingers. The patient had nonpalpable, purpuric lesions on his toes and fingers (necrosis of the distal finger) along with acral pain. The patient progressively had worsening purpura and digital ischemia along with livedo reticularis of both plantar surfaces. Within 4 weeks, the patient had anorexia, night sweats, myalgias, fatigue, and arthralgias. A biopsy was offered and discussed with the patient, but the patient refused initially.  Laboratory evaluation found a normal complete blood count, normal urinalysis, comprehensive metabolic panel, negative antinuclear antibodies, antineutrophil cytoplasmic antibodies, anticardiolipin antibodies, immunofixation electrophoresis, hepatitis A antibody, hepatitis B surface antigen, and hepatitis C antibody. The following test results were abnormal: rheumatoid factor: 24 (normal range: less than 20 IU/mL); total hemolytic complement level [CH50]: 28 (normal range: 60-185); complement component 3 (C3) level: 75.50 (normal range: more than 78 mg/dL); C4 level: less than 1.67 (normal range: more than 16 mg/dL); Westergren erythrocyte sedimentation rate: 48 (normal range: less than 20 mm/h), high sensitive C-reactive protein: 5.24 (normal range: less than 4.0 mg/dL); antiphosphatidylserine Immunoglobulin G (IgG): 19 (normal range, less than 11) and antiphosphatidylserine(IgM: 64 (normal range: less than 25). A chest radiograph and Doppler studies of blood flow of the extremities were also normal. Initial testing for cryoglobulins was negative. Two weeks later, the patient's rheumatoid factor was 54 IU/mL. The patient was initially treated with oral prednisone, 20 mg daily, which was increased 2 weeks later to 40 mg daily. However, the patient continued to develop new acral purpuric lesions and had increasing acral pain. Therefore, 6 weeks into this course, intravenous rituximab, 375 mg/mm2, was administered weekly for a total of 4 infusions. Because of limited clinical change, an additional 2 infusions of rituximab were given monthly. Cryoglobulins were detected for the first time at the end of his fourth infusion of rituximab. The patient's acral lesions healed (healing of toes and fingers) roughly 3 months after the patient's last rituximab infusion. Prednisone, 40 mg daily, was continued throughout the first 3 months of his course and then slowly tapered and stopped 4 months after his last infusion of rituximab. The patient's cryoglobulin level continued to be detectable, and 18 months after his initial presentation, he had increasing acral ischemic symptoms, and an elevated IgM level and low C4 level led to plans for another 4 rituximab infusions. However, before the second set of infusions, palpable purpura developed on his legs. Biopsy at that time found leukocytoclastic vasculitis, and direct immunofluorescence microscopy found IgG in the vessel walls. At that time, the patient was treated by service with oral prednisone, 40 mg daily, which was tapered and stopped over 3 weeks and the patient's hematologist administered another 4 weekly infusions of intravenous rituximab. The patient was seen at clinic (hematology), and a type II cryoglobulin was identified and characterized as IgM kappa (k) monoclonal cryoglobulinemia with polyclonal IgG cryoglobulinemia. A bone marrow biopsy finding was normal. Twenty months after the patient's initial presentation, he began therapy with oral cyclophosphamide, 100 mg daily, and oral prednisone, 10 mg daily. The patient's symptoms and clinical findings had been controlled with this regimen, and 3 years after his presentation, his doses had been decreased to cyclophosphamide, 50 mg every other day, and prednisone, 5 mg daily. Although the patient's symptoms and physical findings had remained controlled, his low level of C4 had persisted. The authors commented, "The mechanisms of vasculitis and cryoglobulinemia induced by the influenza or pneumococcal vaccination remain unknown. It was not possible to ascertain which vaccine responsible for this patient's disease, but it we propose that it was more likely caused by the viral vaccination. Mixed cryoglobulinemia was commonly associated with viral infections including hepatitis C virus (HCV), hepatitis B virus, or Epstein-Barr virus. The mechanism of viral-induced cryoglobulinemia is not completely understood but was postulated to be caused by cryoglobulin formation induced by cytokine or chemokine-mediated immune response to the HCV infection. It was not clear why cryoglobulins were produced as a response to a viral antigen was triggered in response to a vaccination. Studies have shown that mixed cryoglobulinemia can persist or recur after successful treatment of hepatitis C virus (HCV) without detectable hepatitis C virus ribonucleic acid (HCV RNA) in the serum yet detectable in the cryoprecipitate. Although a causal link with the influenza vaccination cannot be proved by our observation, we can speculate that based on the timing of the vaccination, constellation of symptoms, and positive laboratory results, influenza viruses induced cryoglobulinemia was the most probable cause of our patient's symptoms. Induction of cryoglobulin after viral stimulation may result in a prolonged disease. Early recognition and treatment can improve patients' long-term outcome. Further research was necessary to explore the possible immunopathogenic link due to the sequential nature of the disease following vaccinations."      Lab Comments: Lab tests done on an unknown date. Laboratory evaluation found a normal complete blood count, normal urinalysis, comprehensive metabolic panel, negative antinuclear antibodies, antineutrophil cytoplasmic antibodies, anticardiolipin antibodies, immunofixation electrophoresis, hepatitis A antibody, hepatitis B surface antigen, and hepatitis C antibody. The following test results were abnormal: rheumatoid factor: 24 (normal range: less than 20 IU/mL); total hemolytic complement level [CH50]: 28 (normal range: 60-185); complement component 3 (C3) level: 75.50 (normal range: more than 78 mg/dL); C4 level: less than 1.67 (normal range: more than 16 mg/dL); Westergren erythrocyte sedimentation rate: 48 (normal range: less than 20 mm/h), high sensitive C-reactive protein: 5.24 (normal range: less than 4.0 mg/dL); antiphosphatidylserine Immunoglobulin G (IgG): 19 (normal range, less than 11) and antiphosphatidylserine(IgM: 64 (normal range: less than 25). A chest radiograph and Doppler studies of blood flow of the extremities were also normal. Initial testing for cryoglobulins was negative. Two weeks later, the patient's rheumatoid factor was 54 IU/mL.