GI bleeding; Hemophagocytic Lymphohistiocytosis; Intense Epigastric pain; Nausea; Vomiting; Diarrhea; Myalgias; Weight loss; Oral aphthous ulcers; Fever 104.6 F; Abdominal pain; Leukocytosis; Lactic acidosis; sepsis, likely secondary to viral etiology and rhabdomyolysis; sepsis, likely secondary to viral etiology and rhabdomyolysis; Refractory shock\ shock; Acute kidney injury due to rhabdomyolysis\ acute renal failure; Bicytopenia; Hyperferritinemia; Hypertriglyceridemia; low NK cell cytotoxicity; Erythema of eyelids; Oral petechiae on a background of pale mucosa; Oral petechiae on a background of pale mucosa; Nonpruritic petechial rash over his anterior chest; epigastric tenderness; Thrombocytopenia; Transaminitis; Myoglobinuria; possible viral infection complicated by rhabdomyolysis; unresponsive; Severe Metabolic acidosis; Hyperkalemia; Muscle damage; Severe acute respiratory distress syndrome (ARDS); positive rhinovirus; Epstein-Barr virus DNA positive; CMV IgG positive; Peptic ulcer; Hypogammaglobulinemia; Hepatitis; This case was reported in a literature article and described the occurrence of gastrointestinal bleeding in a 38-year-old male patient who received Flu unspecified (Influenza vaccine) for prophylaxis.  The patient's past medical history included systemic lupus erythematosus (Family History) (notable for several family members) and inflammatory arthritis (Family History).   On an unknown date, the patient received Influenza vaccine. On an unknown date, unknown after receiving Influenza vaccine, the patient experienced gastrointestinal bleeding (serious criteria hospitalization, GSK medically significant and life threatening), hemophagocytic lymphohistiocytosis (serious criteria hospitalization and GSK medically significant), epigastric pain (serious criteria hospitalization), nausea (serious criteria hospitalization), vomiting (serious criteria hospitalization), diarrhea (serious criteria hospitalization), myalgia (serious criteria hospitalization), weight loss (serious criteria hospitalization), ulcer aphthous oral (serious criteria hospitalization), fever (serious criteria hospitalization), abdominal pain (serious criteria hospitalization), leukocytosis (serious criteria hospitalization), lactic acidosis (serious criteria hospitalization and GSK medically significant), viral sepsis (serious criteria hospitalization and GSK medically significant), rhabdomyolysis (serious criteria hospitalization and GSK medically significant), refractory shock (serious criteria hospitalization and GSK medically significant), acute renal failure (serious criteria hospitalization and GSK medically significant), bicytopenia (serious criteria hospitalization and GSK medically significant), hyperferritinemia (serious criteria hospitalization), hypertriglyceridemia (serious criteria hospitalization), cell-mediated cytotoxicity (serious criteria hospitalization), erythema eyelid (serious criteria hospitalization), oral mucosal petechiae (serious criteria hospitalization), pale mucous membrane (serious criteria hospitalization), petechial rash (serious criteria hospitalization), tenderness epigastric (serious criteria hospitalization), thrombocytopenia (serious criteria hospitalization and GSK medically significant), transaminitis (serious criteria hospitalization), myoglobinuria (serious criteria hospitalization), viral infection (serious criteria hospitalization and GSK medically significant), unresponsive to stimuli (serious criteria hospitalization and GSK medically significant), metabolic acidosis (serious criteria hospitalization and GSK medically significant), hyperkalemia (serious criteria hospitalization and GSK medically significant), muscle damage (serious criteria hospitalization), acute respiratory distress syndrome (serious criteria hospitalization and GSK medically significant), rhinovirus infection (serious criteria hospitalization), epstein-barr virus infection (serious criteria hospitalization), cytomegalovirus infection (serious criteria hospitalization and GSK medically significant), peptic ulcer (serious criteria hospitalization and GSK medically significant), hypogammaglobulinemia (serious criteria hospitalization and GSK medically significant) and hepatitis (serious criteria hospitalization and GSK medically significant). The patient was treated with corticosteroid nos (Corticosteroids (Drug Name Unknown)), intravenous immunoglobulin, anakinra, intravenous fluid, cardiovascular system drugs (Vasopressor (Nos)), methylprednisolone and dexamethasone. On an unknown date, the outcome of the gastrointestinal bleeding, hemophagocytic lymphohistiocytosis, epigastric pain, nausea, vomiting, diarrhea, myalgia, weight loss, ulcer aphthous oral, fever, abdominal pain, leukocytosis, viral sepsis, rhabdomyolysis, refractory shock, acute renal failure, bicytopenia, hyperferritinemia, hypertriglyceridemia, cell-mediated cytotoxicity, erythema eyelid, oral mucosal petechiae, pale mucous membrane, petechial rash, tenderness epigastric, thrombocytopenia, transaminitis, myoglobinuria, viral infection, unresponsive to stimuli, metabolic acidosis, hyperkalemia, muscle damage, acute respiratory distress syndrome, rhinovirus infection, epstein-barr virus infection, cytomegalovirus infection, peptic ulcer, hypogammaglobulinemia and hepatitis were recovering/resolving and the outcome of the lactic acidosis was recovered/resolved.   The reporter considered the gastrointestinal bleeding, hemophagocytic lymphohistiocytosis, epigastric pain, nausea, vomiting, diarrhea, myalgia, weight loss, ulcer aphthous oral, fever, abdominal pain, leukocytosis, lactic acidosis, viral sepsis, rhabdomyolysis, refractory shock, acute renal failure, bicytopenia, hyperferritinemia, hypertriglyceridemia, cell-mediated cytotoxicity, erythema eyelid, oral mucosal petechiae, pale mucous membrane, petechial rash, tenderness epigastric, thrombocytopenia, transaminitis, myoglobinuria, viral infection, unresponsive to stimuli, metabolic acidosis, hyperkalemia, muscle damage, acute respiratory distress syndrome, rhinovirus infection, epstein-barr virus infection, cytomegalovirus infection, peptic ulcer, hypogammaglobulinemia and hepatitis to be related to Influenza vaccine.     Additional Information: GSK Receipt Date: 29-APR-2022 Author comment: The previously health patient was evaluated for intense epigastric pain, nausea, vomiting, and diarrhea one week after he received an inactivated influenza virus vaccination. He also developed myalgia, oral aphthous ulcers, and a weight loss of 5 kg during that period. He denied recent sick contacts or travel outside of New England and has not started any new medications. He identified himself as men who have sex with men (MSM). His last sexual contact was four months ago, and recent HIV testing was negative. His family history was notable for several family members who had systemic lupus erythematosus and inflammatory arthritis. Initial assessment revealed a normal body temperature, heart rate of 140/minute, respiratory rate of 20/minute, blood pressure of 170/130 mm Hg, and oxygen saturation of 100% on room air. Physical exam showed erythema of eyelids, oral aphthous ulcers, oral petechiae on a background of pale mucosa, nonpruritic petechial rash over his anterior chest, and mild-to-moderate epigastric tenderness. The rest of the physical examination was unremarkable. The patient was started on IV fluids with improvements of his vital signs and clearance of lactic acid. Lab work showed markedly elevated CK levels and myoglobinuria on microscopic urine analysis, consistent with rhabdomyolysis. Although he was initially afebrile, he eventually spiked a fever up to 104.6 F. His presentation with systemic illness manifested with GI symptoms, oral ulcers, generalized aches, and rhabdomyolysis was suggestive of possible viral infection complicated by rhabdomyolysis. During his hospitalization, he has rapidly deteriorated. On hospital day 3, he was found unresponsive. Arterial blood analysis showed severe metabolic acidosis (PH 7.20, HCO3 11 mmol/L). He was intubated and transferred to the ICU. Soon after the transfer, he developed shock, requiring multiple vasopressor agents despite ongoing aggressive IV fluid resuscitation. The subsequent laboratory work-up showed progressive elevation of CK levels acute renal failure, and hyperkalemia. Unfortunately, ongoing muscle damage and kidney failure caused persistent hyperkalemia despite hemodialysis. The patient required continuous veno-venous hemofiltration. The underlying cause of the patient's presentation was unclear. He had an extensive infectious work-up. Repeated blood cultures were negative. A viral blood panel was only positive for Epstein- Barr virus (EBV) DNA. EBV IgG was positive but IgM was negative, consistent with past infection. A respiratory viral panel by nasopharyngeal swab showed positive rhinovirus. A CT of the abdomen and pelvis didn't reveal any pathology. Due to ongoing severe acute respiratory distress syndrome (ARDS), the patient's serum was also tested for ß-d-glucan, which appeared to be positive. Subsequently, aspergillus antigen was obtained and was negative. Further work-up of ß-d-glucan warranted bronchoscopy, which was negative for Pneumocystis jiroveci infection. Extensive rheumatological work-up was unrevealing. Extensive infectious work-up showed positive EBV and CMV IgG. Given that his clinical picture could also be triggered by an immune disorder, he underwent additional testing as autoimmune serologies including antinuclear antibody (ANA), rheumatoid factor, and antineutrophil cytoplasmic antibodies (ANCA), which were negative. Complement levels were normal as well. Given severe muscle injury, the patient was also worked up for possible autoimmune myopathies. Anti-PL-7, anti-PL-12, and anti-Mi-2 were all negative. Although ferritin level was initially normal, it has significantly risen, as well as C-reactive protein. Notably, his inflammatory markers spiked on hospital days 6-7 as well as CK level. Fasting lipid profile showed hypertriglyceridemia (triglycerides level peaked at 568 mg/dl). Marked hyperferritinemia in the context of severe systemic inflammatory response raised the suspicion of possible secondary HLH, especially given the recent immunogenic trigger of influenza vaccine and/or possible active viral infection. In addition to elevated C-reactive protein and ferritin, the immunologic panel revealed elevated soluble interleukin-2 receptors (sCD25) and depressed NK cell function, which was pathognomonic for HLH. HLH was confirmed based on HLH-2004 diagnostic criteria, fulfilling six out of the eight criteria and the HLH-probability calculator. For further work-up for HLH, after extended infectious and immunological work-up, flow cytometry revealed absolute CD19+ B-cell lymphopenia as well as absolute CD3+ T-cell lymphopenia, which are nonspecific findings. However, there was no evidence of monoclonal B-cell lymphoproliferative disease. Given that a genetic component might have contributed to the patient's clinical therapy, extended gene testing was done with no evidence of HLH triggering genes. It was thought that HLH had probably developed secondary to an inactivated influenza vaccine. The patient was started on directed therapy according to the HLH protocol. He received pulse dose methylprednisolone 1000 mg for three days followed by a slow steroid taper. Given hypogammaglobulinemia, he was started on intravenous immunoglobulin (IVIG) 10 g weekly to maintain IgG above 700 mg/dL. IgG levels were monitored weekly with slow improvement back to baseline. Unfortunately, he developed severe complications with prolonged steroid use, including life-threatening GI bleed from peptic ulcer and steroids were quickly tapered, he was started on anakinra, a steroid-sparing agent resulting in the slow gradual improvement of clinical status and inflammatory markers trend. After two months, he was discharged to a rehabilitation center where he continued to receive IVIG monthly and daily anakinra. Conclusion:  HLH is a severe immune disorder characterized by dysregulation of the natural killer T-cell function, causing macrophage and lymphocyte activation with a subsequent cytokine storm that leads to organ failure and death. HLH can be familial or can be triggered by stimuli, mostly infections, malignancies, rheumatological diseases, or post-vaccination. The presentation includes fairly nonspecific symptoms such as fever, cytopenias, or liver dysfunction. HLH should be suspected in patients with those symptoms, especially in the setting of cytopenia and markedly elevated ferritin levels. The H-score helps predict the probability of HLH. Evidence of hemophagocytosis in bone marrow biopsy increases the likelihood of the diagnosis, but its absence does not rule it out. If suspected, early initiation of HLH targeted therapy with immunosuppressants including steroids may prevent irreversible organ damage and subsequent death.  Additional Supportive Information: This article is not available for regulatory reporting due to copyright restriction.