{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:48:14Z","timestamp":1760240894004,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,2]],"date-time":"2019-10-02T00:00:00Z","timestamp":1569974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Ninety percent of patients with scrub typhus (SC) with vasculitis-like syndrome recover after mild symptoms; however, 10% can suffer serious complications, such as acute respiratory failure (ARF) and admission to the intensive care unit (ICU). Predictors for the progression of SC have not yet been established, and conventional scoring systems for ICU patients are insufficient to predict severity. We aimed to identify simple and robust indicators to predict aggressive behaviors of SC. We evaluated 91 patients with SC and 81 non-SC patients who were admitted to the ICU, and 32 cases from the public functional genomics data repository for gene expression analysis. We analyzed the relationships between several predictors and clinicopathological characteristics in patients with SC. We performed gene set enrichment analysis (GSEA) to identify SC-specific gene sets. The acid-base imbalance (ABI), measured 24 h before serious complications, was higher in patients with SC than in non-SC patients. A high ABI was associated with an increased incidence of ARF, leading to mechanical ventilation and worse survival. GSEA revealed that SC correlated to gene sets reflecting inflammation\/apoptotic response and airway inflammation. ABI can be used to indicate ARF in patients with SC and assist with early detection.<\/jats:p>","DOI":"10.3390\/jcm8101580","type":"journal-article","created":{"date-parts":[[2019,10,2]],"date-time":"2019-10-02T08:17:54Z","timestamp":1570004274000},"page":"1580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Higher Acid-Base Imbalance Associated with Respiratory Failure Could Decrease the Survival of Patients with Scrub Typhus during Intensive Care Unit Stay: A Gene Set Enrichment Analysis"],"prefix":"10.3390","volume":"8","author":[{"given":"Kyoung Min","family":"Moon","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung 25440, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4757-9211","authenticated-orcid":false,"given":"Kyueng-Whan","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi-Hye","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung 25440, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong-Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Departments of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9299-5476","authenticated-orcid":false,"given":"Byoung Kwan","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Eulji Hospital, Eulji University School of Medicine, Seoul 01830, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8750-9843","authenticated-orcid":false,"given":"Youngha","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woonyong","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mijung","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"O-Yu","family":"Kwon","sequence":"additional","affiliation":[{"name":"Departments of Medical Science and Anatomy and Cell Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S145","DOI":"10.1086\/339908","article-title":"The past and present threat of rickettsial diseases to military medicine and international public health","volume":"34","author":"Kelly","year":"2002","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S203","DOI":"10.1086\/596576","article-title":"Scrub typhus: The geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi","volume":"48","author":"Kelly","year":"2009","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1148\/rg.271065074","article-title":"Scrub typhus: Clinical, pathologic, and imaging findings","volume":"27","author":"Jeong","year":"2007","journal-title":"Radiographics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S1286-4579(00)01352-6","article-title":"Orientia tsutsugamushi infection: Overview and immune responses","volume":"3","author":"Seong","year":"2001","journal-title":"Microbes Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3346\/jkms.2000.15.3.343","article-title":"Acute respiratory distress syndrome associated with scrub typhus: Diffuse alveolar damage without pulmonary vasculitis","volume":"15","author":"Park","year":"2000","journal-title":"J. Korean Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"668","DOI":"10.3346\/jkms.2004.19.5.668","article-title":"Clinical role of interstitial pneumonia in patients with scrub typhus: A possible marker of disease severity","volume":"19","author":"Song","year":"2004","journal-title":"J. Korean Med. Sci."},{"key":"ref_7","first-page":"780","article-title":"Septic shock secondary to scrub typhus: Characteristics and complications","volume":"33","author":"Thap","year":"2002","journal-title":"Southeast Asian J. Trop. Med. Public Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.4269\/ajtmh.2007.76.1148","article-title":"Acute respiratory distress syndrome in scrub typhus","volume":"76","author":"Wang","year":"2007","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"634","DOI":"10.3109\/00365549709035911","article-title":"Scrub typhus associated with multiorgan failure: A case report","volume":"29","author":"Chi","year":"1997","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"480","DOI":"10.4103\/0972-5229.188206","article-title":"Acute respiratory failure in scrub typhus patients","volume":"20","author":"Sahoo","year":"2016","journal-title":"Indian J. Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"497","DOI":"10.4103\/0972-5229.138145","article-title":"Profile of organ dysfunction and predictors of mortality in severe scrub typhus infection requiring intensive care admission","volume":"18","author":"Griffith","year":"2014","journal-title":"Indian J. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s10157-012-0753-9","article-title":"Acute kidney injury in scrub typhus","volume":"17","author":"Attur","year":"2013","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"484","DOI":"10.4269\/ajtmh.2009.81.484","article-title":"Risk factors leading to fatal outcome in scrub typhus patients","volume":"81","author":"Lee","year":"2009","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_14","first-page":"367","article-title":"Death and other complications of emergency airway management in critically ill adults a prospective investigation of 297 tracheal intubations","volume":"82","author":"Schwartz","year":"1995","journal-title":"Anesthesiol. J. Am. Soc. Anesthesiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/2110-5820-3-22","article-title":"Role of biomarkers in the management of antibiotic therapy: An expert panel review: I-currently available biomarkers for clinical use in acute infections","volume":"3","author":"Dupuy","year":"2013","journal-title":"Ann. Intensive Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1097\/CCM.0b013e3181a02afc","article-title":"Biomarkers of sepsis","volume":"37","author":"Marshall","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0140-6736(04)17667-8","article-title":"Septic shock","volume":"365","author":"Annane","year":"2005","journal-title":"Lancet (Lond. Engl.)"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Joseph, P.V., Wang, Y., Fourie, N.H., and Henderson, W.A. (2018). A computational framework for predicting obesity risk based on optimizing and integrating genetic risk score and gene expression profiles. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0197843"},{"key":"ref_19","unstructured":"Wang, L.Y., and Tu, Z. (September, January 30). Lung tumor diagnosis and subtype discovery by gene expression profiling. Proceedings of the International Conference of the IEEE Engineering in Medicine and Biology Society, New York, NY, USA."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/978-1-4939-3578-9_5","article-title":"The Gene Expression Omnibus Database","volume":"1418","author":"Clough","year":"2016","journal-title":"Methods Mol. Biol. (Cliftonn. J.)"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.resuscitation.2012.12.016","article-title":"The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death","volume":"84","author":"Smith","year":"2013","journal-title":"Resuscitation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1097\/00003246-198510000-00009","article-title":"APACHE II: A severity of disease classification system","volume":"13","author":"Knaus","year":"1985","journal-title":"Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/BF01709751","article-title":"The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction\/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine","volume":"22","author":"Vincent","year":"1996","journal-title":"Intensive Care Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tantibhedhyangkul, W., Prachason, T., Waywa, D., El Filali, A., Ghigo, E., Thongnoppakhun, W., Raoult, D., Suputtamongkol, Y., Capo, C., and Limwongse, C. (2011). Orientia tsutsugamushi stimulates an original gene expression program in monocytes: Relationship with gene expression in patients with scrub typhus. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001028"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Paris, D.H., Phetsouvanh, R., Tanganuchitcharnchai, A., Jones, M., Jenjaroen, K., Vongsouvath, M., Ferguson, D.P., Blacksell, S.D., Newton, P.N., and Day, N.P. (2012). Orientia tsutsugamushi in human scrub typhus eschars shows tropism for dendritic cells and monocytes rather than endothelium. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001466"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wee, I., Lo, A., and Rodrigo, C. (2017). Drug treatment of scrub typhus: A systematic review and meta-analysis of controlled clinical trials. Trans. R. Soc. Trop. Med. Hyg.","DOI":"10.1093\/trstmh\/trx066"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1001\/archinte.167.15.1655","article-title":"Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study","volume":"167","author":"Kellum","year":"2007","journal-title":"Arch. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"465","DOI":"10.4269\/ajtmh.2005.72.465","article-title":"Activation of cytotoxic lymphocytes in patients with scrub typhus","volume":"72","author":"Chierakul","year":"2005","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1378\/chest.103.2.565","article-title":"Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality","volume":"103","author":"Pinsky","year":"1993","journal-title":"Chest"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1159\/000346689","article-title":"Cytokine secretion and markers of inflammation in relation to acidosis among chronic hemodialysis patients","volume":"35","author":"Ori","year":"2013","journal-title":"Blood Purif."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1378\/chest.130.4.962","article-title":"Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis","volume":"130","author":"Kellum","year":"2006","journal-title":"Chest"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1186\/cc2900","article-title":"Science review: Extracellular acidosis and the immune response: Clinical and physiologic implications","volume":"8","author":"Kellum","year":"2004","journal-title":"Crit. Care"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1079\/PNS2003259","article-title":"Energy balance in critical illness","volume":"62","author":"Plank","year":"2008","journal-title":"Proc. Nutr. Soc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1258\/0007142991902204","article-title":"Manipulating the metabolic response to injury","volume":"55","author":"Griffiths","year":"1999","journal-title":"Br. Med. Bull."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s001340051352","article-title":"Base excess and lactate as prognostic indicators for patients admitted to intensive care","volume":"27","author":"Smith","year":"2001","journal-title":"Intensive Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"289","DOI":"10.5414\/CN108760","article-title":"An unexpected cause of acute kidney injury in a patient with ANCA associated vasculitis","volume":"85","author":"Choudhry","year":"2016","journal-title":"Clin. Nephrol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1001\/archinte.1985.00360020091016","article-title":"Systemic necrotizing vasculitis seen initially as hypertensive crisis","volume":"145","author":"Kubrusly","year":"1985","journal-title":"Arch. Intern. Med."},{"key":"ref_39","first-page":"334","article-title":"MELAS masquerading as a systemic vasculitis","volume":"13","author":"Carroll","year":"2007","journal-title":"J. Clin. Rheumatol. Pract. Rep. Rheum. Musculoskelet. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1177\/0961203314546018","article-title":"Fulminant systemic vasculitis in systemic lupus erythematosus. Case report and review of the literature","volume":"23","author":"Medina","year":"2014","journal-title":"Lupus"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1097\/ADM.0000000000000290","article-title":"Unexpected Complication of Cocaine-Associated Anti-Neutrophil Cytoplasmic Antibody Vasculitis Related to Persistent In-Hospital Cocaine Use","volume":"11","author":"Olives","year":"2017","journal-title":"J. Addict. Med."},{"key":"ref_42","first-page":"252","article-title":"[Mechanical ventilation monitoring: Gas analysis and acid base balance]","volume":"59","year":"2003","journal-title":"An. Pediatr. (Barc. Spain 2003)"},{"key":"ref_43","first-page":"7950374","article-title":"Elevated Admission Base Deficit Is Associated with a Complex Dynamic Network of Systemic Inflammation Which Drives Clinical Trajectories in Blunt Trauma Patients","volume":"2016","author":"Vodovotz","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1590\/S1807-59322006000100009","article-title":"Evolutive standard base excess and serum lactate level in severe sepsis and septic shock patients resuscitated with early goal-directed therapy: Still outcome markers?","volume":"61","author":"Park","year":"2006","journal-title":"Clinics (Sao Paulobrazil)"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1097\/00005373-199811000-00005","article-title":"Base deficit in the elderly: A marker of severe injury and death","volume":"45","author":"Davis","year":"1998","journal-title":"J. Trauma"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1001\/archsurg.1990.01410160084019","article-title":"Early physiologic predictors of injury severity and death in blunt multiple trauma","volume":"125","author":"Siegel","year":"1990","journal-title":"Arch. Surg. (Chic. III 1960)"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1097\/00005373-199209000-00014","article-title":"Base deficit stratifies mortality and determines therapy","volume":"33","author":"Rutherford","year":"1992","journal-title":"J. Trauma"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0196-0644(05)81423-4","article-title":"Base deficit as an indicator of significant abdominal injury","volume":"20","author":"Davis","year":"1991","journal-title":"Ann. Emerg. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1001\/archsurg.1989.01410070063013","article-title":"Intra-abdominal injury following blunt trauma. Identifying the high-risk patient using objective risk factors","volume":"124","author":"Mackersie","year":"1989","journal-title":"Arch. Surg. (Chic. III 1960)"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1097\/00005373-199611000-00001","article-title":"Admission base deficit predicts transfusion requirements and risk of complications","volume":"41","author":"Davis","year":"1996","journal-title":"J. Trauma"},{"key":"ref_51","first-page":"332","article-title":"[Acute respiratory failure in chronic obstructive lung disease. Effective weaning and excess base]","volume":"41","author":"Boix","year":"1994","journal-title":"Rev. Esp. Anestesiol. Reanim."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.3109\/0886022X.2013.828257","article-title":"Scrub typhus associated acute kidney injury\u2014A study from a tertiary care hospital from western Himalayan State of India","volume":"35","author":"Vikrant","year":"2013","journal-title":"Ren. Fail."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/10\/1580\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:53Z","timestamp":1760189213000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/10\/1580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,2]]},"references-count":52,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["jcm8101580"],"URL":"https:\/\/doi.org\/10.3390\/jcm8101580","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2019,10,2]]}}}