A previously healthy 5-year-old girl was admitted to the first hospital on January 17, 2018, with symptoms of abdominal pain, vomiting, and new-onset refractory status epilepticus (NORSE) that had lasted for 4 h. The results of a cranial computed tomography (CT) performed by the emergency department were normal. She was transferred to our hospital 6 h after onset, demonstrating signs of coma, tachypnea, and tachycardia. Her past medical history was negative. Upon admission, her body temperature was 36.3 °C, her heart rate was 155 beats/min, her respiratory rate was 50 breaths/min, her blood pressure was 102/67 mmHg, and the Glasgow Coma Scale score (GCS) was E1V1M3. Hypermyotonia was observed in both limbs, and the Babinski sign was positive bilaterally. Other findings from the systemic physical examinations were unremarkable. Percutaneous oxygen saturation measured by pulse oximetry (SpO2) was 93–95% on 25% FiO2. A series of blood tests showed the white blood cell (WBC) count to be 15.98 × 109/L, neutrophils 91.3%, lymphocytes 4.8%, red blood cells 4.99 × 1012/L, platelets 264 × 109/L, CRP 2.5 mg/L, procalcitonin (PCT) 55.77 ng/mL, ferritin 120 ng/ml, coagulant function (fibrin 1.53 g/L, D-Dimer 0.27 mg/L, prothrombin time (PT) 12.2 s, activated partial thromboplastin time (APTT) 24.9 s, INR 1.04, ACT 85%), serum enzymes (CKMB 24 U/L, CK 298 U/L, LDH 797 U/L, aspartate transaminase (AST) 65 IU/L, alanine transaminase (ALT), 38 IU/L), creatinine 40.7 μmol/L, and BUN 4.34 mmol/L. Brain magnetic resonance imaging (MRI) was performed quickly when the patient was admitted to our hospital. The diffusion-weighted imaging (DWI) scan of the patient’s brain on admission showed symmetric areas with high signal intensity in the periventricular white matter involving the centrum semiovale and the corona radiate. The patient had rapid clinical deterioration that developed to hyperferritinemic sepsis with multiple organ dysfunction syndrome (MODS) 15 h after onset, including exhibiting a worsening mental status (GCS E1V1M1), fever (40.6 °C), hypotension (60/47 mmHg), tachycardia (heart rate: 178 beats/min), and tachypnea (respiratory rate: 70 breaths/min). She was intubated, and a vasopressor was quickly given to maintain blood pressure. A repeat blood test showed a WBC count of 9.09 × 109/L, neutrophils 71.4%, lymphocytes 18.8%, red blood cells 4.49 × 1012/L, platelets 27 × 109/L, ferritin 22,579.1 ng/ml, coagulant dysfunction (fibrin 1.5 g/L, D-dimer, 4.7 mg/L, PT 31.4 s, APTT 74.1 s, INR2.79, ACT 20.2%,), serum enzymes (CKMB 55 U/L, CK 1529 U/L, LDH 2550 U/L, AST 295 IU/L, ALT 114 IU/L), creatinine 134.3 μmol/L, and BUN 10.82 mmol/L. Blood cultures did not identify any pathogens. Serum viral studies (influenza A and B viruses, respiratory syncytial virus, adenoviruses, cytomegalovirus, Epstein–Barr virus, hepatitis C virus, hepatitis B virus, and human immunodeficiency virus) and serology tests for syphilis, Mycoplasma pneumonia and Mycobacterium tuberculosis were all negative. Lumber punctures were performed 3 times, and showed increased intracranial pressure (the highest was over 300 mm H2O). Cerebrospinal fluid (CSF) tests revealed that protein levels and glucose levels were normal without pleocytosis. CSF PCRs for enterovirus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, and tuberculosis were all negative. CSF bacterial and fungal cultures were also negative. The echocardiographic results showed that the left ventricular ejection fraction was 52%. The electrocardiograph (ECG) showed tachycardia. The electroencephalography examination demonstrated diffuse, generalized and slow background activity. X-ray imaging showed the presence of bronchitis. Hyperferritinemic sepsis was diagnosed after ruling out haemophagocytic lymphohistiocytosis (HLH) since the diagnostic criteria for HLH were not fulfilled in this girl. SAE was also diagnosed by ruling out encephalitis, meningitis, acute necrotizing encephalopathy, acute disseminated encephalomyelitis, Guillain-Barre syndrome, cerebral vasculitis, and metabolic encephalopathy, according to laboratory tests and imaging features. Integrated treatment was initiated on admission, which included anti-infection treatments (meropenem, vancomycin, and voriconazole), anti-inflammation treatments (methylprednisolone, 15 mg/kg/day × 3 days), intravenous immunoglobulin (1 g/kg/day × 2 days), and frozen plasma as well as the administration of other medicines for hepatic and myocardial protection. The symptoms were not relieved, and the fulminant development of MODS indicated that hyperinflammation or an autoimmune response might be involved. Membrane-based therapeutic plasma exchange (TPE) was started on day 3 since it can eliminate pro-inflammatory cytokines rapidly and can modulate the sepsis cascade. The exchange volume was 1.5-fold the patient’s plasma volume. Plasma volume was estimated as follows: plasma volume (in liters) = 0.07 × weight (kg) × (1-hematocrit) []. The removed plasma was substituted with fresh frozen plasma at a 1:1 ratio in our patient. The first three TPEs were performed daily. After the second TPE, the patient needed less vasopressor. By the third TPE treatment, liver enzymes had decreased. The patient was extubated and regained full consciousness on day 10, with mild remaining disseminated intravascular coagulation (DIC), acute kidney injury (AKI) and capillary leak syndrome (CLS). The last two TPEs were followed by continuous vena-venous hemofiltration (CVVH) 2 times to remove creatinine and BUN, to prevent liquid overload and to maintain coagulation function. After these integrated treatments, clinical and laboratory improvement were monitored in the patient. Echocardiography showed that left ventricular systolic function was normalized, with a left ventricular ejection fraction (LVEF) of 62%. The ECG was normal. Her muscle strength gradually improved, showing increased movements, and she was able to walk short distances 17 days after onset. At this point, repeated brain MRI showed that the lesions were reduced, and T2/FLAIR scans indicated diffuse high signal intensity in the white matter of the occipital and parietal regions. The patient was transferred to a rehabilitation center 21 days after onset. She had regained full independence in activities of daily living at 55 days after onset. A repeat brain MRI showed that the lesions had completely disappeared in the white matter regions.