Age: 69.0
Sex: F
Vaccine: FLUX
Symptoms: Fungal test negative, Fungal test positive, Giardia test negative, Haemoglobin decreased, Haemophagocytic lymphohistiocytosis
Clinical narrative: This is a literature case, initially received on 06-May-2019, concerning a 69-year-old, elderly female patient. The patient's current conditions included rheumatoid arthritis (RA), hypertension and hyperlipidemia. The patient concomitant medications included methotrexate and prednisone for rheumatoid arthritis, triamterene and hydrochlorothiazide for hypertension and fenofibrate for hyperlipidemia. It was reported that the patient had travelled recently but had no international travel or animal exposures. The patient had exposure to endemic fungi by living in certain location and traveling. The patient did not use tobacco, drugs, or alcohol. The patient had no recent abdominal trauma or procedures. The patient had reported being in a monogamous relationship. The patient had no recent illnesses or sick contacts. On an unspecified date, the patient was administered INN Flu Vaccine Seasonal (dose, route of administration, anatomical location, batch number, expiry date, trade name and manufacturer: not reported) for an unknown indication. On an unspecified date after vaccination, the patient experienced new-onset fever, acute severe epigastric abdominal pain as well as several weeks of fatigue and decreased exercise tolerance. She had an average of 3 loose stools per day. The patient experienced a flare of her RA with increasingly painful rheumatic nodules, a few months before the current presentation. The patient's methotrexate dose was increased from 10 mg to 15 mg weekly and prednisone dose remained at 5 mg/d. On an unspecified date, the patient was admitted to the hospital. Review of vital signs revealed a temperature of 39.4 degree Celsius, heart rate of 102 beats/min, blood pressure 116/48 mm Hg, respiratory rate of 31 breaths/min, and oxygen saturation greater than 90 percent while breathing 2 L of supplemental oxygen through a nasal cannula. On physical examination, the patient appeared ill and had epigastric and right upper quadrant abdominal tenderness. The location of pain also was not typical. Murphy sign was absent, and there was no rebound or guarding. She had RA joint changes without active synovitis. On an unspecified date, the patient experienced rash, hypertension, and oedema. No lymphadenopathy was noted, and skin examination revealed no rash, petechiae, or xanthomas. Cardiopulmonary examination findings were normal. The patient's antibody screen results were negative at initial admission. Further laboratory evaluation of her sepsis revealed the following (reference ranges provided parenthetically): white blood cell count was 15.5 x 10E9/L; haemoglobin was 8.7 g/dL, platelets was 43 x 10E9/L, alkaline phosphatase was 140 U/L, alanine aminotransferase was 109 U/L; aspartate aminotransferase was 150 U/L, total bilirubin was 1.3 mg/dL, direct bilirubin was 0.9 mg/dL, international normalized ratio was 1.2, creatinine was 2.2 mg/dL, C-reactive protein was 357.7 mg/L, lipase was 1355 U/L, ferritin was 4652 micro gram/L, triglycerides was 223 mg/dL and calcium was 9.3 mg/dL. Stool studies were negative for C difficile, Cryptosporidium, Giardia, cytomegalovirus (CMV), leukocytes, and blood. However, previous stool testing was negative for leukocytes and multiple pathogens. Abdominal computed tomography (CT) revealed inflammatory changes of the pancreatic body. Gallbladder ultrasonography was negative for any abnormalities. Chest radiography revealed bilateral patchy infiltrates. It was reported that at this point in her care, with evidence of cytopenias, elevated ferritin and triglyceride levels, and fever, there was concern for hemophagocytic lymphohistiocytosis (HLH) as well. The patient's urine antigen testing was low positive for both Blastomyces (1.15 ng/mL) and histoplasma (<0.6 ng/mL). The patient was treated with liposomal amphotericin B for 7 days and then transitioned to oral itraconazole. Methotrexate was withheld for 6 months, but low-dose prednisone was continued. At the follow up of 4 months later, the yeast CF titre was 1:32, and results of serum mycelial testing were negative. Bone marrow biopsy findings were thus consistent with infection caused by Histoplasma capsulatum. Subsequently, blood cultures also grew H capsulatum. It was reported that the patient's clinical picture and CT findings were most consistent with acute pancreatitis. Clinical manifestations, lipase level, and inflammatory markers improved. Follow-up urine Histoplasma antigen was undetectable. The patient discontinued itraconazole at month 9 of the planned 12 months of treatment because of rash, hypertension, and oedema. It was reported that the patient was well 7 years later (recovered). The reporter assessed the case as serious (hospitalization) and concluded that the case presented diagnostic challenges with a broad differential diagnosis because the initial clinical picture resembled cholangitis but quickly evolved with imaging and laboratory findings consistent with acute pancreatitis. Histoplasmosis can be diagnosed by cultures, serologies, and urine and serum antigen tests. Treatment varies based on severity and the presence of disseminated disease. Reporter's Comments: A 69-year-old female patient with concurrent condition rheumatoid arthritis and hypertension on concomitant medication methotrexate experienced flare up of rheumatoid arthritis with increasingly painful rheumatic nodules, unspecified period after receipt of INN flu vaccine seasonal. Due to the lack of information important for the causality assessment, such as onset latency between the vaccination and reported event, company assessed the causality as unassessable. The patient was diagnosed with acute pancreatitis due to Histoplasma capsulatum infection, lung infilteration and hemophagocytic lymphohistiocytosis, unspecified period post vaccination and multiple lab investigations supported these diagnoses. Despite the lack of onset latency, considering the infective origin (Histoplasma capsulatum) of the event acute pancreatitis and Histoplasma capsulatum infection are assessed as not related to suspect vaccine. The event hemophagocytic lymphohistiocytosis assessed as not related as the event can be alternately explained as the complication of acute infective pancreatitis. The event oxygen saturation decreased assessed as not related, as it can be explained as complication (severity) of acute pancreatitis. The methotrexate therapy is considered as a known risk factor. The patient was treated with itraconazole which was later discontinued after 7 months due to hypertension, oedema and rash. Considering the implausible temporal relationship between vaccination and these reported events, the causality assessed as not related. Itraconazole is considered as confounding factor and alternative etiology. The company assessed the events acute pancreatitis, hemophagocytic lymphohistiocytosis, infection by histoplasma capsulatum and rheumatoid arthritis flare up as serious (medically significant).