Age: 76.0
Sex: M
Vaccine: PPV, UNK
Symptoms: Blood immunoglobulin G, Blood immunoglobulin M increased, C-reactive protein increased, Cardiolipin antibody negative, Chest X-ray normal
Clinical narrative: Type 2 mixed cryoglobulinemia; Leukocytoclastic vasculitis; This is a literature case, initially received from physician on 11-Nov-2019, concerning a 76-year-old, male patient.  The patient's historical conditions included bypass surgery. The patient's current conditions included hypercholesterolemia, coronary artery disease and gastroesophageal reflux disease. The patient's concomitant medications were not reported.  On an unspecified date, the patient was administered unspecified Flu Vaccine [Influenza virus vaccine trivalent; anatomical location, route of administration, dose, batch number and expiration date: not reported] for an unknown indication.   On an unspecified date, the patient was administered co-suspect unspecified pneumococcal vaccine [pneumococcal vaccine; anatomical location, route of administration, dose, batch number and expiration date: not reported] for an unknown indication.  On an unspecified date, reported as 5 days after vaccination, the patient experienced flu-like symptoms and cyanosis. The patient developed non-palpable, purpuric lesions on his toes and fingers along with acral pain. He progressively had worsening purpura and digital ischemia along with livedo reticularis of both plantar surfaces.  On an unspecified date, within 4 weeks, the patient developed anorexia, night sweats, myalgias, fatigue and arthralgias. The patient refused biopsy. Laboratory evaluation found a normal complete blood count, normal urinalysis, normal comprehensive metabolic panel, negative antinuclear antibodies, negative antineutrophil cytoplasmic antibodies, negative anticardiolipin antibodies, negative immunofixation electrophoresis, negative hepatitis A antibody, negative hepatitis B surface antigen, and negative hepatitis C antibody. The following test results were abnormal: rheumatoid factor was 24 IU/mL (reference range less than 20); total hemolytic complement level [CH50] was 28, units unspecified (reference range 60-185); C3 level was 75.50 mg/dL (reference range more than 78); C4 level was less than 1.67 mg/dL (reference range more than 16); Westergren erythrocyte sedimentation rate was 48 mm/h (reference range less than 20), high sensitive C-reactive protein was 5.24 mg/dL (reference range less than 4); anti-phosphatidylserine IgG was 19, units unspecified (reference range less than 11); and anti-phosphatidylserine IgM was 64, units unspecified (reference 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. The patient was treated with oral prednisone at the dose of 20 mg, daily.  On an unspecified date, two weeks later, the patient's rheumatoid factor was 54 IU/mL. The dose for the prednisone was increased at the dose of 40 mg, administered once per day. The patient continued to develop new acral purpuric lesions and had increasing acral pain.   On an unspecified date, 6 weeks into his course, the patient was administered treatment medication rituximab intravenously, at a dose of 375 mg/mm2, weekly for a total of 4 infusions. Because of the limited clinical change, an additional 2 infusions of rituximab were given monthly.  On an unspecified date, at the end of fourth infusion of rituximab, cryoglobulins were detected for the first time.  On an unspecified date, roughly 3 months after last rituximab infusion, the patient's acral lesions healed. Prednisone at the dose of 40 mg, daily was continued throughout the first 3 months of the course and then slowly tapered and stopped 4 months after his last infusion of rituximab. His cryoglobulin level continued to be detectable.  On an unspecified date, 18 months after initial presentation, the patient had increasing acral ischemic symptoms. 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 this time found leukocytoclastic vasculitis, while direct immunofluorescence microscopy found IgG in the vessel walls. The patient was treated with oral prednisone at the dose of 40 mg daily, which was tapered and stopped over 3 weeks and his 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 k monoclonal cryoglobulinemia with polyclonal IgG cryoglobulinemia. A bone marrow biopsy finding was normal.   On an unspecified date, twenty months after initial presentation, the patient began therapy with oral cyclophosphamide at the dose of 100 mg daily, and oral prednisone at the dose of 10 mg daily. His symptoms and clinical findings have been controlled with this regimen.  On an unspecified date, 3 years after the presentation, doses for the treatment medications were decreased to cyclophosphamide at the dose of 50 mg every other day, and prednisone at the dose of 5 mg daily. Although his symptoms and physical findings have remained controlled, his low level of C4 has persisted, and the patient was recovering from the events.  The case was assessed as serious.   The reporter assessed the event of type 2 mixed cryoglobulinemia as related to unspecified Flu vaccine while the causality assessment for the event of leukocytoclastic vasculitis was not reported. It was reported that it was not possible to ascertain which vaccine was responsible for the patient's disease, but it was more likely caused by viral vaccination. Although a causal link with the influenza vaccination cannot be proved by reporter's observation, they could speculate that based on the timing of the vaccination, constellation of symptoms, and positive laboratory results, influenza virus-induced cryoglobulinemia was the most probable cause of patient's symptoms.  Company comment: The patient has experienced cryoglobulinaemia and hypersensitivity vasculitis associated with the suspect product - INN Flu Vaccine. Chronology seems plausible. It was reported that it was not possible to ascertain which vaccine was responsible for the patient's disease, but it was more likely caused by viral vaccination. Although a causal link with the influenza vaccination cannot be proved by reporter's observation, they could speculate that based on the timing of the vaccination, constellation of symptoms, and positive laboratory results, influenza virus-induced cryoglobulinemia was the most probable cause of patient's symptoms. The patient's concomitant medications were not reported. Leucocytoclastic vasculitis is seen in cryoglobulinaemia and infection is a very important cause of this disease and parasites (toxoplasmosis, malaria), bacteria (streptococcus, syphilis, Lyme disease) and fungi (coccidiomyocosis) have all been associated with this disease. Viruses such as cytomegalovirus (CMV), HIV, Epstein-Barr virus (EBV) and in particular; hepatitis A, B, and C (or chronic liver disease) are also important causes. With information presented causality is assessed as probable for cryoglobulinaemia  and unlikely to hypersensitivity vasculitis.; Sender's Comments: The patient has experienced cryoglobulinaemia and hypersensitivity vasculitis associated with the suspect product - INN Flu Vaccine. Chronology seems plausible. It was reported that it was not possible to ascertain which vaccine was responsible for the patient's disease, but it was more likely caused by viral vaccination. Although a causal link with the influenza vaccination cannot be proved by reporter's observation, they could speculate that based on the timing of the vaccination, constellation of symptoms, and positive laboratory results, influenza virus-induced cryoglobulinemia was the most probable cause of patient's symptoms. The patient's concomitant medications were not reported.  Leucocytoclastic vasculitis is seen in cryoglobulinaemia and infection is a very important cause of this disease and parasites (toxoplasmosis, malaria), bacteria (streptococcus, syphilis, Lyme disease) and fungi (coccidiomyocosis) have all been associated with this disease. Viruses such as cytomegalovirus (CMV), HIV, Epstein-Barr virus (EBV) and in particular; hepatitis A, B, and C (or chronic liver disease) are also important causes. With information presented causality is assessed as probable for cryoglobulinaemia  and unlikely to hypersensitivity vasculitis.