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Original article

Septic state in the differential diagnosis of fever of unknown origin

Luka Ilić1, Aleksandar Jeremić2
  • Institute for Orthopedic Surgery „Banjica”, Belgrade, Serbia
  • Clinical Hospital Center „Zvezdara”, Belgrade, Serbia

ABSTRACT

Introduction: In the modern world, fever of unknown origin is becoming an increasingly common entity with varied etiologies. Septic condition has a significant role as an etiological factor of fever of unknown origin, often being overlooked or treated late.

Objective: To determine the frequency of sepsis, to establish demographic characteristics, clinical presentation of the disease, to identify the proportion of proven pathogens and their distribution by type, and to present laboratory analyses of patients diagnosed with sepsis upon admission and discharge from the hospital.

Materials and Methods: The study included patients treated at the Clinic for Infectious and Tropical Diseases of the Clinical Center of Serbia, in the Department of Clinical Pharmacotherapy, from December 1, 2014, to December 31, 2017, with documented sepsis during the investigation of the etiology of FUO.

Results: Among 420 patients studied, sepsis was documented in 50 (11.9%). The study included 29 (58%) women and 21 (42%) men, with an average age of 63.76 ± 13.6 (24-90) years. The causative agent of the disease was detected in blood cultures in 40 (80%) patients, while not in 10 (20%). Elevated body temperature occurred in 49 (98%) patients, whilst 24 (47%) experienced chills and shivering, 13 (25.5%) nausea, and 16 (31.4%) vomiting. Headache occurred in 8 (16%) patients, while diarrhea, urinary symptoms, and altered consciousness were observed in 11 (21.6%) patients. By comparing the median values of biochemical analyses of patients obtained upon admission and discharge from the hospital, a statistically significant difference (p<0,01) was found, indicating a decrease in laboratory parameter values such as erythrocyte sedimentation rate, C-reactive protein, total leukocyte count, and percentage of segmented leukocytes.

Conclusion: In the observed sample, sepsis occurs relatively frequently (11.9%) as an etiological factor of FUO. In the differential diagnosis of fever of unknown origin, despite significant progress and development of sophisticated diagnostic procedures, one should always consider potential systemic infection as a possible cause, among which septic condition occupies an important place, even when initial examinations do not lead to such a conclusion.


INTRODUCTION

Fever of unknown origin denotes the presence of body temperature >38.3°C recorded on multiple occasions lasting longer than 3 weeks, with no diagnosis established despite adequate investigation including basic biochemical tests, chest radiographs, abdominal ultrasound examination, throat swab culture, urine culture, and gynecological examination in women, or urological examination in men, conducted during three visits to the doctor or after three days of hospital stay [1],[2],[3].

Septic condition signifies a systemic inflammatory response (SIRS - “systemic inflammatory response syndrome”) of proven or probable microbial etiology, regardless of whether microorganisms are disseminated in the blood, which commonly occurs, or remain in a local focus. SIRS is the immune-metabolic reaction of the body to various, including biological, agents attacking it, characterized by at least two of the following clinical signs:

  • fever (> 38°C) or hypothermia (< 36°C)
  • tachypnea (> 24 breaths/min)
  • tachycardia (> 90 beats/min)
  • leukocytosis (> 12x109 /L), leukopenia (< 4x109 /L), or more than 10% immature forms of leukocytes

Given that it involves dysregulation of the immune response to infectious agents and is often characterized by disturbances in body temperature, timely consideration of this condition is of utmost importance [4],[5],[6].

In the modern world, fever of unknown origin is an increasingly common entity with diverse etiology. Sepsis significantly participates as an etiological factor of fever of unknown origin, often overlooked, i.e., treatment is initiated late. This study aimed to determine the frequency of sepsis, present demographic characteristics, clinical presentation of the disease, proportion of proven pathogens, and their distribution by types, and to present laboratory analyses of patients diagnosed with sepsis upon admission and discharge from the hospital.

MATERIALS AND METHODS

The study included patients treated at the Clinic for Infectious and Tropical Diseases of the Clinical Center of Serbia, in the Department of Clinical Pharmacotherapy, from December 1, 2014, to December 31, 2017, who were diagnosed with sepsis during the investigation of the etiology of fever of unknown origin. During the observation period, 420 patients were examined, among whom sepsis was confirmed in 50 individuals. Persons under 18 years old were not included in the study, as the Department of Clinical Pharmacotherapy within the Clinic for Infectious and Tropical Diseases of the Clinical Center of Serbia does not treat pediatric patients. Standard biochemical methods were used in the diagnosis, including non-specific inflammation factors (CRP, ESR), complete blood count (WBC, % granulocytes, RBC, platelets, Hgb), examination of significant enzymes (AST, ALT, LDH, CPK), and microbiological methods involving blood and urine sampling for isolation and cultivation of potentially infectious agents, as well as antibiotic susceptibility testing to guide or adjust therapy.

Statistical Methods

SPSS (Statistical Package for the Social Sciences) and EZR (Easy R) programs were used for statistical analysis of the data. Student’s t-test and Wilcoxon’s test were used to assess the statistical significance of the difference in mean values of two independent samples. A criterion of statistical significance was applied with p < 0.01.

RESULTS

The results of this study showed that among the 420 examined patients during the given period, sepsis was confirmed in 50 (11.9%) cases (Graph 1).

Figure 1. The frequency of sepsis within the examined group of patients

Figure 1. The frequency of sepsis within the examined group of patients

Among the patients included in the study, there were 29 (58%) females and 21 (42%) males (Graph 2). The average age of the patients was 63.76 ± 13.6 (24- 90) years.

Figure 2. Demographic display of patients diagnosed with sepsis

Figure 2. Demographic display of patients diagnosed with sepsis

In 40 (80%) patients, the causative agent of the disease was identified from blood culture, while in 10 (20%) patients it was not (Table 1).

Table 1. Proportion of proven and unproven microbiological pathogens of septic conditions

Table 1. Proportion of proven and unproven microbiological pathogens of septic conditions

Among patients with positive blood cultures, the majority had isolated bacterial pathogens, with urosepsis-causing agents such as Escherichia coli occurring in 17 (34%) and Klebsiella spp. in 8 (16%) subjects. All other infectious agents are presented in the appendix (Table 2).

Table 2. Display of pathogens of septic condition according to frequency of occurrence

Table 2. Display of pathogens of septic condition according to frequency of occurrence

Monitoring the basic clinical manifestations of the disease and the main complaints reported by patients upon admission to the hospital, the results of the presented study show that elevated body temperature occurred in 49 (98.04%) patients. Additionally, 24 (47%) experienced chills and shivering, 13 (25.5%) had nausea as a symptom of the disease, and 16 (31.4%) experienced vomiting. Headache occurred in 8 (16%) patients, while diarrhea, urinary symptoms, and altered consciousness were reported in 11 (21.6%) patients (Table 3).

Table 3. Clinical characteristics of patients diagnosed with sepsis

Table 3. Clinical characteristics of patients diagnosed with sepsis

By comparing the median values of routine biochemical analyses of patients diagnosed with sepsis upon admission and upon discharge from the hospital, a statistically significant difference (p<0.01) was found, indicating a decrease in the values of the following laboratory parameters: erythrocyte sedimentation rate (78.6 / 55.16), C-reactive protein (344.6 / 30.6), total leukocyte count (13.77 / 7.56), percentage of segmented leukocytes (82.6 / 67.2) (Table 4).

Table 4. Median values of routined biochemical analyses of patients diagnosed with sepsis upon admission and discharge from the hospital

Table 4. Median values of routined biochemical analyses of patients diagnosed with sepsis upon admission and discharge from the hospital

DISCUSSION

Based on available data from the Centers for Disease Control and Prevention (CDC) in the United States, over 1.5 million cases of septic conditions are registered an nually, resulting in approximately 250,000 fatalities. Sepsis is proven in one out of three hospitalized patients with a fatal outcome. The most common sources of infection leading to the development of septic conditions in adults include respiratory infections (35%), urinary tract and kidney infections (25%), gastrointestinal infections (11%), and skin infections (11%) [7],[8].

According to data obtained from large cohort studies conducted in five developed countries (the United Kingdom, France, the United States, Australia, and New Zealand), the annual incidence of sepsis significantly varies from 51 (the United Kingdom) to 300 (the United States) cases per 100,000 population, with an increasing incidence trend (8-13%) over the past two decades. This trend is attributed to population aging, prolonged lifespan of patients with chronic diseases and infections (such as tumors, type 2 diabetes mellitus, AIDS), widespread use of antimicrobial drugs, glucocorticoids, indwelling catheters, mechanical devices, and mechanical ventilation [9],[10],[11],[12],[13].

If we focus solely on individual regions of Europe, a significant retrospective analysis conducted in Catalonia, an autonomous region of Spain, reports an incidence of sepsis or septic conditions of 1.72% annually. Of the total number of cases, 56.1% were male, with an average age of 71.2 ± 19.7 years among patients diagnosed with sepsis. The most common sources of infection leading to the development of septic conditions include urinary tract infections (37.2%) and respiratory system infections (32.5%). The study results indicate that the causative agent was identified from blood culture in 84.2% of patients, while it was not in 15.8% of subjects. The most frequently isolated infectious agents include Escherichia coli (8%), Streptococcus spp. (7%), coagulase-negative Staphylococcus spp. (6%), and Staphylococcus aureus (6%) [14],[15].

At the Clinic for Infectious and Tropical Diseases of the Clinical Center of Serbia, in the Department of Clinical Pharmacotherapy, among the 420 examined patients from December 1, 2014, to December 31, 2017, sepsis occurred in 50 (11.9%) patients. Among them, 29 (58%) were female and 21 (42%) were male, with an average age of 63.76 ± 13.6 (24-90) years. The study results also showed that the most commonly isolated etiological agents in patients with positive blood cultures were bacteria, namely Escherichia coli occurring in 17 (34%) and Klebsiella spp. in 8 (16%) subjects. Other isolates, such as Staphylococcus aureus (6%), Streptococcus gallolyticus (6%), and Streptococcus pneumoniae (2%), support bacterial microorganisms as the most common causative agents of this condition. A fungal etiology (Candida parapsilosis) was confirmed in one patient (2%).

Comparing these results with those of previous studies, a higher frequency of septic conditions and a lower average patient age are observed. Significant deviations regarding the percentage of positive blood cultures and isolated pathogens are not noted.

Sepsis can be a response to an infection caused by any type of microorganism. Although gram-negative and gram-positive bacteria are the most common infectious agents underlying SIRS, sepsis can also be caused by fungi, mycobacteria, protozoa [16].

Sepsis can be easily suspected in patients with a local infection who suddenly develop elevated body temperature, fever, tachycardia, tachypnea, altered consciousness, and hypotension. However, the septic response can develop much more slowly and have subtler manifestations. In one study, 36% of patients with sepsis were afebrile, 44% had normal consciousness, 60% were eupneic, and 10% had heart rates within physiological limits. Absence of fever is most common in older individuals, patients with uremia, or alcoholics [17],[18],[19].

Basic clinical manifestations of the disease and main complaints reported by patients upon hospital admission included elevated body temperature in 98% of respondents, chills and shivering in 47%, nausea in 25.5%, vomiting in 31.4%, headache in 16%, while diarrhea, urinary symptoms, and altered consciousness were reported in 21.6% of patients.

Elevated or decreased leukocyte count, as well as the presence of young forms of granulocytes, are part of the definition of SIRS, within which sepsis is encompassed. Leukocytosis, with a marked predominance of polymorphonuclear cells, is most commonly encountered in the early stage of sepsis caused by gram-positive bacteria, while leukopenia is more characteristic of sepsis caused by gram-negative bacteria. Elevated erythrocyte sedimentation rate, increased fibrinogen level, C-reactive protein, and alpha 2-globulin are nonspecific indicators of inflammation and are typically present in sepsis [6],[7],[8],[9].

During the examination of patients upon admission to the institution, leukocytosis with an increase in segmented leukocyte percentage, accelerated erythrocyte sedimentation rate, and elevated C-reactive protein level were recorded in most cases. Statistical analysis of biochemical parameters upon discharge from the hospital revealed a significant decrease in these parameters.

In the modern world, fever of unknown origin becoming increasingly common entities with diverse etiologies. Septic conditions significantly contribute as an etiological factor in fever of unknown origin, often overlooked, i.e. leading to delayed treatment.

Based on the results, we can conclude that the percentage of individuals affected by this infectious condition is higher among the participants in the presented study due to the poorer socio-economic conditions of our country and the healthcare system in general. These conditions lead to poorer primary diagnostic results compared to healthcare systems in developed countries. Additionally, this can be justified by a higher prevalence of infectious diseases in our environment, as well as a higher percentage of working individuals who, due to poor medical culture, tend to seek medical attention later.

CONCLUSION

In the observed sample, sepsis emerges relatively frequently as an etiological factor in a fever of unknown origin (11.9%). Based on the results of this study, it is concluded that females are more often affected (58%), particularly those of older age, with Escherichia coli (34%) and Klebsiella spp. (16%) being the most commonly isolated pathogens, indicating that the most common origin of infection is the urinary tract. The main symptoms may not necessarily be specific, thus systemic infection should be considered in the differential diagnosis of prolonged fever.

Despite significant advancements and the development of sophisticated diagnostic procedures, differential diagnosis of fever of unknown origin should always include the consideration of potential systemic infection, among which septic conditions hold a significant position, even when initial investigations do not suggest such a conclusion.

  • Conflict of interest:
    None declared.

Informations

March 2024

Pages 56-63
  • Keywords:
    sepsis, SIRS, fever of unknown origin, infectious diseases
  • Received:
    27 November 2023
  • Revised:
    29 December 2023
  • Accepted:
    12 February 2024
  • Online first:
    25 March 2024
  • DOI:
  • Cite this article:
    Ilić L, Jeremić A. Septic state in the differential diagnosis of fever of unknown origin. Serbian Journal of the Medical Chamber. 2024;5(1):56-63. doi: 10.5937/smclk5-47932
Corresponding author

Luka Ilić
Institute for Orthopedic Surgery „Banjica”
28 Mihaila Avramovića Street, 11000 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


1. Arnow PM, Flaherty JP. Fever of unknown origin. Lancet. 1997 Aug 23;350(9077):575-80. doi: 10.1016/S0140-6736(97)07061-X. [CROSSREF]

2. Gelfand J. A. Fever of unknown origin. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL. editors. Harrison’s Principles of Internal Medicine, 15th edition. New York, NY: McGraw-Hill; 2001. p. 125.

3. Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years on. J Intern Med. 2003 Mar;253(3):263-75. doi: 10.1046/ j.1365-2796.2003. 01120.x. [CROSSREF]

4. Astiz ME, Rackow EC. Septic shock. Lancet. 1998 May 16;351(9114):1501-5. doi: 10.1016/S0140-6736(98)01134-9. [CROSSREF]

5. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013 Mar 2;381(9868):774-5. doi: 10.1016/S0140-6736(12)61815-7. [CROSSREF]

6. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530- 8. doi: 10.1007/s00134-003-1662-x. [CROSSREF]

7. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. [CROSSREF]

8. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al; CDC Prevention Epicenter Program. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017 Oct 3;318(13):1241-9. doi: 10.1001/jama.2017.13836. [CROSSREF]

9. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003 Apr 17;348(16):1546-54. doi: 10.1056/NEJMoa022139. [CROSSREF]

10. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012 Jun;10(6):701-6. doi: 10.1586/eri.12.50. [CROSSREF]

11. Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med. 2003 Sep;31(9):2332-8. doi: 10.1097/01.CCM.0000085141.75513.2B. [CROSSREF]

12. Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J. Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med. 2004 Apr;30(4):589-96. doi: 10.1007/s00134-004-2157-0. [CROSSREF]

13. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul;29(7):1303-10. doi: 10.1097/00003246-200107000-00002. [CROSSREF]

14. Ferrer R, Artigas A, Levy MM, Blanco J, González-Díaz G, Garnacho-Montero J, et al; Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008 May 21;299(19):2294-303. doi: 10.1001/jama.299.19.2294. [CROSSREF]

15. Yébenes JC, Ruiz-Rodriguez JC, Ferrer R, Clèries M, Bosch A, Lorencio C, Rodriguez A, et al; SOCMIC (Catalonian Critical Care Society) Sepsis Working Group. Epidemiology of sepsis in Catalonia: analysis of incidence and outcomes in a European setting. Ann Intensive Care. 2017 Dec;7(1):19. doi: 10.1186/s13613-017-0241-1. [CROSSREF]

16. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af. [CROSSREF]

17. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990 Aug 1;113(3):227-42. doi: 10.7326/0003-4819-113-3-227. [CROSSREF]

18. Marx JA, Hockberger RS, Walls RM. Rosen’s emergency medicine: concepts and clinical practice. 7th edition. Philadelphia, PA: Mosby/Elsevier; 2010.

19. Rumbus Z, Matics R, Hegyi P, Zsiboras C, Szabo I, Illes A, et al. Fever Is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials. PLoS One. 2017 Jan 12;12(1): e0170152. doi: 10.1371/journal.pone.0170152. [CROSSREF]


REFERENCES

1. Arnow PM, Flaherty JP. Fever of unknown origin. Lancet. 1997 Aug 23;350(9077):575-80. doi: 10.1016/S0140-6736(97)07061-X. [CROSSREF]

2. Gelfand J. A. Fever of unknown origin. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL. editors. Harrison’s Principles of Internal Medicine, 15th edition. New York, NY: McGraw-Hill; 2001. p. 125.

3. Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years on. J Intern Med. 2003 Mar;253(3):263-75. doi: 10.1046/ j.1365-2796.2003. 01120.x. [CROSSREF]

4. Astiz ME, Rackow EC. Septic shock. Lancet. 1998 May 16;351(9114):1501-5. doi: 10.1016/S0140-6736(98)01134-9. [CROSSREF]

5. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013 Mar 2;381(9868):774-5. doi: 10.1016/S0140-6736(12)61815-7. [CROSSREF]

6. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530- 8. doi: 10.1007/s00134-003-1662-x. [CROSSREF]

7. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. [CROSSREF]

8. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al; CDC Prevention Epicenter Program. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017 Oct 3;318(13):1241-9. doi: 10.1001/jama.2017.13836. [CROSSREF]

9. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003 Apr 17;348(16):1546-54. doi: 10.1056/NEJMoa022139. [CROSSREF]

10. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012 Jun;10(6):701-6. doi: 10.1586/eri.12.50. [CROSSREF]

11. Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med. 2003 Sep;31(9):2332-8. doi: 10.1097/01.CCM.0000085141.75513.2B. [CROSSREF]

12. Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J. Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med. 2004 Apr;30(4):589-96. doi: 10.1007/s00134-004-2157-0. [CROSSREF]

13. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul;29(7):1303-10. doi: 10.1097/00003246-200107000-00002. [CROSSREF]

14. Ferrer R, Artigas A, Levy MM, Blanco J, González-Díaz G, Garnacho-Montero J, et al; Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008 May 21;299(19):2294-303. doi: 10.1001/jama.299.19.2294. [CROSSREF]

15. Yébenes JC, Ruiz-Rodriguez JC, Ferrer R, Clèries M, Bosch A, Lorencio C, Rodriguez A, et al; SOCMIC (Catalonian Critical Care Society) Sepsis Working Group. Epidemiology of sepsis in Catalonia: analysis of incidence and outcomes in a European setting. Ann Intensive Care. 2017 Dec;7(1):19. doi: 10.1186/s13613-017-0241-1. [CROSSREF]

16. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af. [CROSSREF]

17. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990 Aug 1;113(3):227-42. doi: 10.7326/0003-4819-113-3-227. [CROSSREF]

18. Marx JA, Hockberger RS, Walls RM. Rosen’s emergency medicine: concepts and clinical practice. 7th edition. Philadelphia, PA: Mosby/Elsevier; 2010.

19. Rumbus Z, Matics R, Hegyi P, Zsiboras C, Szabo I, Illes A, et al. Fever Is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials. PLoS One. 2017 Jan 12;12(1): e0170152. doi: 10.1371/journal.pone.0170152. [CROSSREF]

1. Arnow PM, Flaherty JP. Fever of unknown origin. Lancet. 1997 Aug 23;350(9077):575-80. doi: 10.1016/S0140-6736(97)07061-X. [CROSSREF]

2. Gelfand J. A. Fever of unknown origin. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL. editors. Harrison’s Principles of Internal Medicine, 15th edition. New York, NY: McGraw-Hill; 2001. p. 125.

3. Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years on. J Intern Med. 2003 Mar;253(3):263-75. doi: 10.1046/ j.1365-2796.2003. 01120.x. [CROSSREF]

4. Astiz ME, Rackow EC. Septic shock. Lancet. 1998 May 16;351(9114):1501-5. doi: 10.1016/S0140-6736(98)01134-9. [CROSSREF]

5. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013 Mar 2;381(9868):774-5. doi: 10.1016/S0140-6736(12)61815-7. [CROSSREF]

6. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530- 8. doi: 10.1007/s00134-003-1662-x. [CROSSREF]

7. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. [CROSSREF]

8. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al; CDC Prevention Epicenter Program. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017 Oct 3;318(13):1241-9. doi: 10.1001/jama.2017.13836. [CROSSREF]

9. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003 Apr 17;348(16):1546-54. doi: 10.1056/NEJMoa022139. [CROSSREF]

10. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012 Jun;10(6):701-6. doi: 10.1586/eri.12.50. [CROSSREF]

11. Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med. 2003 Sep;31(9):2332-8. doi: 10.1097/01.CCM.0000085141.75513.2B. [CROSSREF]

12. Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J. Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med. 2004 Apr;30(4):589-96. doi: 10.1007/s00134-004-2157-0. [CROSSREF]

13. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul;29(7):1303-10. doi: 10.1097/00003246-200107000-00002. [CROSSREF]

14. Ferrer R, Artigas A, Levy MM, Blanco J, González-Díaz G, Garnacho-Montero J, et al; Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008 May 21;299(19):2294-303. doi: 10.1001/jama.299.19.2294. [CROSSREF]

15. Yébenes JC, Ruiz-Rodriguez JC, Ferrer R, Clèries M, Bosch A, Lorencio C, Rodriguez A, et al; SOCMIC (Catalonian Critical Care Society) Sepsis Working Group. Epidemiology of sepsis in Catalonia: analysis of incidence and outcomes in a European setting. Ann Intensive Care. 2017 Dec;7(1):19. doi: 10.1186/s13613-017-0241-1. [CROSSREF]

16. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af. [CROSSREF]

17. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990 Aug 1;113(3):227-42. doi: 10.7326/0003-4819-113-3-227. [CROSSREF]

18. Marx JA, Hockberger RS, Walls RM. Rosen’s emergency medicine: concepts and clinical practice. 7th edition. Philadelphia, PA: Mosby/Elsevier; 2010.

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