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Background: Leptospira is an uncommon pathogen for adult severe community-acquired pneumonia and its nonspecific manifestations and limited diagnostic tests make it difficult to identify. Although conventional penicillin remains efficacious to treat leptospirosis, failure in early diagnosis and treatment can lead to progression into a deadly syndrome with multiple organ dysfunction. Next generation sequencing is of great value to understand cases with infection of unknown cause, which could help in the diagnosis of uncertain Leptospira infection., Case Summary: We recently managed a patient with fever, cough and dyspnea on admission that progressed into persistent adult respiratory distress syndrome, hemoptysis and hematuria after admission. In this case, the rare Leptospira infection was clouded by the positive influenza tests at admission, delaying early Leptospira -targeted antibiotics administration. Next generation sequencing, a novel molecular diagnostic tool, provided a key hint to uncover the crucial pathogen, Leptospira interrogans , further supported by the possible occupational exposure history. Subsequent conventional penicillin and mechanical respiratory support were administrated to cure the patient successfully without any sequela., Conclusion: Clinicians must pay attention to possible exposure history and keep uncommon Leptospira in mind when managing pneumonia with unknown causes., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)