Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of uncontrolled immune activation.Incidence in the adult population remains unclear. Primary HLH is caused by genetic mutations affecting the cytotoxic function of T lymphocytes and natural killer (NK) cells and typically presents in young children. Secondary HLH occurs in the setting of infectious, malignant, rheumatologic, or metabolic conditions. Various infections have been described as triggers. The diagnosis of HLH is particularly challenging, as many features overlap with other causes of severe illness including sepsis and hematologic malignancy. Background 53-years-old male patient presented to a hospital elsewhere with complaints of fever, dysuria and malaise for 1 week. On evaluation, he was diagnosed as bilateral pyelonephritis with right sided emphysematous pyelonephritis,with urosepsis, acute kidney injury (AKI) on chronic kidney disease (CKD). Due to severe azotaemia and acidosis, patient required dialytic support (SLED) on 2 occasions. Subsequently, patient underwent bilateral DJ stenting, right renal papilla extraction and optical urethrotomy.Due to persistent fever and not improving general wellbeing patient was shifted to Star hospital for further management. Course in hospital Patient presented with severe sepsis and empiric antibiotic therapy started after sending appropriate cultures (date of admission 18.7.19). As cultures were suggestive of CRBSI, dialysis catheter removed and antibiotics continued. He improved initially, however he again had high-grade intermittent fever,then right sided PCNL and drainage of perinephric collection was done. Post procedure patient developed septic shock, hyperkalemia and acidemia. Left IJV dialysis catheter was placed and initiated on SLED. He underwent right nephrectomy and left DJ stent exchange in view of persistent fever despite using broad spectrum antibiotics and antifungals. X-ray chest showed pulmonary edema and 2D echo revealed global hypokinesia. Patient further deteriorated, vasopressor requirement increased and required intubation and mechanical ventilation on 1.8.19. Patient received GM-CSF in view of leukopenia. To look for other causes of non-responding sepsis, serum ferritin and interleukin 6 (IL-6) were tested. Ferritin was 4532 ng/ml& IL-6 was 531 pg/ml as on 1.8.19. Bone marrow aspiration and biopsy (3.8.19) revealed acquired hemophagocytosis,hence he was started on corticosteroids (1 mg/kg/day prednisolone equivalent) and other appropriate antibiotics continued. Gradually fever subsided and hemodynamic improved. As patient showed adequate respiratory attempts and acceptable oxygenation, he was extubated on 9.8.19. Patient remained on alternate day haemodialysis. Patent was discharged from hospital on 19.8.19 with tunnelled right IJV catheter for haemodialysis. Corticosteroids (prednisolone) tapered off gradually over a period of 8 weeks. After 8 weeks; patient remains dialysis dependant but back to work and routine life. Conclusion In events of non-responding sepsis, immunological disorders could be screened for and treated accordingly. Seemingly, treating immunological disorders and sepsis is seen antagonistic but might be mutually complementary as is seen in this particular case with acquired HLH where patient responded to immune suppression with corticosteroid. In literature search, we could not find association of HLH with emphysematous pyelonephritis. Hence, this could be a unique case of immune activation in a patient with complicated UTI, AKI and resulting in dialysis dependency. Moreover, antibiotic resistance and scarcity of new antibiotics are two more reasons to search for immune dysregulation in sepsis. As many of these cases could be immune dysregulation and not infection per se.