On October 13, 2020, a 64-year-old woman was referred to our hospital with fatigue, low blood pressure, arthralgia, and myalgia, for 1 week. She had a history of untreated hydronephrosis for 4 years and was positive for hepatitis B surface antigen for several decades. She did farm work in the mountain without personal protection 1 week prior to admission to a local hospital.
Her laboratory findings on admission were as follows: white blood cell (WBC) count 15.3 x 109/L; platelet (PLT) level 10 x 109/L; albumin level 22.7 g/L; alanine transaminase (ALT) level 79 U/L; aspartate aminotransferase (AST) level, 134 U/L; total bilirubin (TBI) level 105.3 mumol/L; direct bilirubin (DBI) level 60.6 mumol/L; creatinine level 87.3 mumol/L; blood urea nitrogen level 16.68 mmol/L; prothrombin time (PT), 18.6 s; activated partial thromboplastin time (APTT) 41.9 s; and D-dimer level 6,320 mug/L. Her blood pressure (120/73 mmHg) and breathing was stable.
Four days later, her blood pressure fell dramatically to 84/58 mmHg, jaundice appeared, and renal function deteriorated despite symptomatic treatment. Subsequently, she was transferred to our hospital and complained of generalized pain without fever and jaundice on the entire body. Physical examination revealed thickened wet rales in both lungs, abdominal distention, and edema in both lower limbs. Neurological examination was negative. Other signs were normal. The Glasgow Coma Scale score was 15/15 and blood pressure was 100/80 mmHg and pulse rate 98 beats/min (on noradrenaline maintenance) in the supine position. Laboratory parameters were markedly elevated: white blood cell count 57.0 x 109/L; total bilirubin 254.5 mumol/L; creatinine 263 mumol/L; procalcitonin 10.73 ng/mL; and C-reactive protein 59.3 mg/L. Chest radiography revealed obvious patchy shadows in both lungs. Supportive care included infusion of thrombocytes and plasma, liver protection, and relief of jaundice by high-flow oxygen therapy (60 L/min). Under an initial diagnosis of pneumonia, meropenem (1.0 g three times per day) was prescribed in combination with continuous renal replacement therapy.
On days 2-4 of hospitalization, the patient's condition worsened, and we commenced noninvasive assisted ventilation under high-flow oxygen (60 L/min). The patient's maximum body temperature was 37.2 C. Tracheoscopy revealed extensive hemorrhage in both airways. Brain computed tomography (CT) findings were normal (Figure 1A1). Chest CT revealed bilateral patchy shadows and diffuse infiltration and extensive consolidation in the right lung (Figure 1B1). Etiological cultures of blood, sputum, urine, and feces samples were performed; serum antibodies against dengue, leptospirosis, and epidemic hemorrhagic fever were tested for, considering the patient's history of farm work in the mountains. Bone marrow puncture was performed due to obviously abnormal blood routine examinations. Samples of sputum, urine, and feces were collected to detect Leptospira IgM and IgG antibodies, which were both negative. Multidisciplinary diagnosis and treatment were carried out by the Departments of Hematology, Infectious Disease, Pneumology, and Organ Transplantation, as well as the Intensive Care Unit. PCR was conducted using the diagnostic reagent kits based on the guidelines of the Center for Disease Control (CDC) of Zhejiang Province. Next-generation sequencing (NGS) of blood and sputum samples was also conducted. Supportive organ therapy was initiated. The patient developed multiple organ failure, but the cause was unclear. Entecavir (25 mg per day) and ornithine aspartate (40 mg per day) were administered to lower the high blood ammonia level. Her liver cirrhosis with ascites was evident on abdominal CT, possibly due to the patient's long history of hepatitis B surface antigen-positivity.
NGS revealed Leptospira interrogans (four different sequences of leptospires DNA, Supplementary Material 1) in blood on day 4 of hospitalization. Two family members who had engaged in farm work also underwent antibody test for leptospirosis, which revealed negative results. Her red blood cell count was decreased, and the free iron level was very high; chronic anemia was apparent. Meropenem was terminated and penicillin was initiated (four injections of 800,000 units per day) combined with dexamethasone (20 mg per day) to prevent the Hector reaction. Repeat chest CT indicated hydrothorax and relief of bilateral exudation (Figure 1B2).
On days 5-13 of hospitalization, The test of bone marrow puncture showed no obvious abnormality. However, the patient's liver function deteriorated; she was sedated under non-invasive assisted ventilation and administered continuous renal replacement therapy. Considering the severe jaundice and inflammatory response caused by the pulmonary infection and activation of hepatitis B virus, as well as liver failure, plasmapheresis was performed to remove inflammatory factors and improve liver function on days 8, 9, and 10. Piperacillin-tazobactam (4.5 g three times per day) was commenced because Pseudomonas aeruginosa was detected in sputum on day 10. Further sputum cultures revealed Aspergillus fumigatus; chest CT revealed improvement of the infiltrates in both lungs except for new patchy shadows in the right upper lung (Figure 1B3). Voriconazole (200 mg twice a day) was prescribed as antifungal therapy. The priorities at this time were symptomatic treatments including venous nutritional support, adjustment of the acid-base balance and circulatory parameters, prevention of gastrointestinal bleeding, and protection of organ parenchymae. On day 14, the patient suddenly vomited blood (200 mL) and then lost consciousness; her Glasgow Coma Scale score was suddenly decreased to 3/15. Emergency brain CT revealed hematoceles in both lateral ventricles and hemorrhage in the right paraoccipital lobe that had ruptured the lateral ventricle (Figure 1A2). Chest CT was also repeated (Figure 1B4). We communicated with the family members about the patient's condition and explained that no further treatment options were available. The patient died 5 h later.