Diagnostic utility of sepsis screening tools, procalcitonin, and C-reactive protein in nosocomial fever of unknown origin

Table 1 Spectrum of nosocomial fever of unknown origin (n = 80)

Etiologies	n (%)
Infectious disorders	34 (42.5)
Pneumonia	21 (26.2)
Ventilator-associated pneumonia1	17
Hospital-acquired pneumonia2	4
Bloodstream infections	9 (11.2)
Bacteraemia with unknown primary site3	6
Catheter-related blood stream infection4	3
Intra-abdominal Infections	3 (3.75)
Clostridioides difficile diarrhea	1
Peritonitis	1
Gall bladder perforation with peritonitis and intra-abdominal collections	1
Catheter-associated urinary tract infection5	1 (1.3)
Multi-site infections	2 (2.5)
Ventilator-associated pneumonia and pressure ulcer6	1
Ventilator-associated pneumonia7 and catheter-related blood stream infection8	1
Non-infectious disorders	31 (38.7)
Central fever	6 (7.5)
Thrombophlebitis	6 (7.5)
Pneumonitis without infection	4 (5)
Acute pancreatitis	3 (3.8)
Rhabdomyolysis	3 (3.8)
Venous thromboembolism	2 (2.5)
Drug fever	2 (2.5)
Alcohol withdrawal syndrome	1 (1.3)
Central pontine demyelination	1 (1.3)
Transfusion reaction	1 (1.3)
Acute hemolysis	1 (1.3)
Atelectasis	1 (1.3)
Undiagnosed	15 (18.8)

¹Acinetobacter baumannii (n = 12), Klebsiella pneumoniae (n = 1), Pseudomonas aeruginosa (n = 1), coinfection of Acinetobacter baumannii and Klebsiella pneumoniae (n = 1), coinfection of Acinetobacter baumannii and Pseudomonas aeruginosa (n = 1), and Staphylococcus aureus (n = 1).

²Acinetobacter baumannii (n = 3) and Proteus mirabilis (n = 1).

³Pseudomonas stutzeri (n = 2), Acinetobacter baumannii (n = 1), Escherichia coli (n = 1), coinfection of Acinetobacter baumannii and Providencia stuartii (n = 1), and Enterococcus faecium (n = 1).

⁴Pseudomonas stutzeri (n = 1), coinfection of Acinetobacter baumannii and Providencia stuartii (n = 1), and Enterococcus faecium (n = 1).

⁵Enterococcus faecium.

⁶Acinetobacter baumannii.

⁷Burkholderia cenocepacia.

⁸Enterococcus faecium.

Table 2 Sociodemographic profile, pre-existing conditions, and acute medical disorders, n (%)

Parameter	Total (n = 80)	Infectious (n = 34)	Non-infectious (n = 31)	P value
Age (years), mean ± SD	42.9 ± 16.5	39.2 ± 17.4	45.8 ± 14.1	0.098
Male gender	64 (80)	26 (76.5)	26 (83.9)	0.456
Pre-existing comorbidities
Any	48 (60)	21 (61.8)	20 (64.5)	0.818
Diabetes	19 (23.8)	7 (20.6)	8 (25.8)	0.618
Hypertension	14 (17.5)	7 (20.6)	4 (12.9)	0.409
Chronic kidney disease	8 (10)	2 (5.9)	4 (12.9)	0.413
Epilepsy	8 (10)	5 (14.7)	3 (9.7)	0.711
Coronary artery disease or heart failure	7 (8.8)	3 (8.8)	4 (12.9)	0.701
Miscellaneous1	11 (13.8)	5 (14.7)	5 (16.1)	-
Charlson comorbidity index, median (IQR)	0 (0-2)	0 (0-1.25)	0 (0-2)	0.719
Age-adjusted Charlson comorbidity index, median (IQR)	0 (0-2)	0 (0-2)	1 (0-2)	0.389
Substance use disorders2	20 (25)	5 (14.7)	9 (29)	0.161
Medical emergencies
Neurological disorders3	32 (40)	14 (41.2)	16 (51.6)	0.399
Toxicological disorders4	19 (23.7)	6 (17.6)	9 (29)	0.277
Gastro-intestinal disorders5	7 (8.75)	3 (8.8)	1 (3.2)	0.615
Renal disorders6	6 (7.5)	2 (5.9)	2 (6.5)	1.000
Miscellaneous7	16 (20)	9 (26.5)	3 (9.7)	-

¹Chronic liver disease (n = 4), bronchial asthma (n = 1), interstitial lung disease (n = 1), post-tuberculosis lung abnormalities (n = 1), parkinsonism (n = 1), major depressive disorder (n = 1), renal stone disease (n = 1), and Down’s syndrome (n = 1).

²Alcohol use (n = 11), smoking (n = 2), opioid use (n = 2), and multi-substance use (n = 5).

³Cerebrovascular disorders (n = 13), Guillain-Barré syndrome (n = 8), status epilepticus (n = 6), metabolic encephalopathy (n = 2), delirium (n = 2), and autoimmune encephalitis (n = 1).

⁴Pesticide toxicity (n = 7), drug overdose (n = 3), unknown poisoning (n = 4), snake envenomation (n = 3), and alcohol withdrawal syndrome (n = 2).

⁵Acute pancreatitis (n = 4), decompensated chronic liver disease (n = 2), and acute liver failure (n = 1).

⁶Chronic kidney disease complications (n = 5) and rapidly progressive renal failure (n = 1).

⁷Expanded dengue syndrome (n = 5), acute exacerbations of chronic respiratory disorders (n = 3), heart failure (n = 2), diabetic ketoacidosis (n = 2), Sjögren’s syndrome with hypokalemic paralysis (n = 2), immune thrombocytopenia with bleeding (n = 1), and mediastinal mass (n = 1).

IQR: Interquartile range.

Table 3 Clinical and laboratory characteristics at fever onset

Parameter	Total (n = 80)	Infectious (n = 34)	Non-infectious (n = 31)	P value
Time to fever onset post-hospitalization (days), median (IQR)	5 (3-8)	5 (3.75-9)	5 (3-7)	0.229
Temperature (F), mean ± SD	101.6 ± 0.7	101.7 ± 0.8	101.5 ± 0.7	0.714
Pulse rate (per minute), mean ± SD	104.2 ± 20.6	109.0 ± 23.4	100.0 ± 16.0	0.079
Tachycardia, n (%)	36 (45)	18 (52.9)	12 (38.7)	0.250
Systolic blood pressure (mmHg), mean ± SD	127.9 ± 21.9	128.8 ± 23.6	126.3 ± 21.2	0.655
Diastolic blood pressure (mmHg), mean ± SD	76.8 ± 12.9	79.5 ± 14.5	74.4 ± 11.2	0.118
Mean arterial pressure (mmHg), mean ± SD	93.8 ± 14.6	95.9 ± 16.3	91.67 ± 13.7	0.262
Glasgow coma scale, median (IQR)	10 (8-11)	10 (8-14.3)	9 (7.0-11.0)	0.185
Intensive organ support requirement
Mechanical ventilation, n (%)	64 (80)	28 (82.4)	24 (77.4)	0.619
Vasopressor therapy, n (%)	11 (13.8)	5 (14.7)	4 (12.9)	1.000
Hemodialysis, n (%)	8 (10)	5 (14.7)	0 (0)	0.054
In-situ catheters or tubes, n (%)
Urinary catheters	72 (90)	31 (91.2)	29 (93.5)	1.000
Endotracheal tubes	64 (80)	28 (82.4)	24 (77.4)	0.619
Nasogastric tubes	64 (80)	29 (85.3)	24 (77.4)	0.414
Central lines	25 (31.3)	9 (26.5)	5 (16.1)	0.311
Non-tunnelled dialysis catheters	7 (8.8)	4 (11.8)	0 (0)	0.115
Percutaneous catheters	6 (7.5)	3 (8.8)	1 (3.2)	0.614
Laboratory investigations
Hemoglobin (g/L), mean ± SD	110.7 ± 27.4	109.0 ± 28.2	109.6 ± 28.1	0.933
Platelet count (per μL), median (IQR)	165500 (109250-230250)	168000 (125500-237250)	198000 (110000-254000)	0.590
Total leucocyte count (per μL), median (IQR)	12640 (10005-18842)	12490 (9500-19165)	14420 (1.280-23400)	0.123
Leukocytosis, n (%)	54 (67.5)	22 (64.7)	23 (74.2)	0.408
Neutrophils (%), mean ± SD	82.7 ± 7.0	82.2 ± 6.4	84.3 ± 6.2	0.199
Lymphocytes (%), mean ± SD	8.2 ± 4.4	8.2 ± 4.1	7.8 ± 4.4	0.610
Neutrophil to lymphocyte ratio, median (IQR)	10.6 (7.2-20.7)	10.5 (6.5-18.7)	12.0 (7.4-23.7)	0.470
Sodium (mmol/L), mean ± SD	141.0 ± 8.2	140.2 ± 7.2	142.0 ± 8.7	0.368
Blood urea (mmol/L), median (IQR)	8.7 (5.1-15.4)	6.8 (4.4-11.2)	9.2 (5.0-16.3)	0.164
Creatinine (mol/L), median (IQR)	91.1 (61.9-209.7)	97.2 (57.5-296.1)	92.9 (61.9-210.4)	0.478
Bilirubin (mol/L), median (IQR)	13.5 (6.8-23.6)	12.6 (8.6-27.4)	13.5 (6.7-20.0)	0.454
Aspartate transaminase (U/L), median (IQR)	45.7 (25.9-87.8)	44.5 (28.3-85.9)	49.5 (23.0-102.0)	0.984
Alanine transaminase (U/L), median (IQR)	32.1 (17.5-69.3)	35.1 (19.8-57.0)	29.2 (16.2-74.0)	0.778
Alkaline phosphatase (U/L), median (IQR)	101 (75.3-132.8)	92.5 (71-123.3)	103 (75.5-133.5)	0.711
Total protein (g/L), mean ± SD	63.9 ± 10.3	62.2 ± 9.7	64.4 ± 11.5	0.418
Albumin (g/L), mean ± SD	31.6 ± 5.8	31.2 ± 5.7	31.4 ± 5.6	0.863

IQR: Interquartile range.

Table 4 Sepsis screening tools and biomarkers at fever onset

Parameter	Total (n = 80)	Infectious (n = 34)	Non-infectious (n = 31)	P value
Sepsis screening tools
SIRS, median (IQR)	3 (3-4)	3 (3-4)	3 (3-4)	0.949
SIRS ≥ 2, n (%)	78 (97.5)	33 (97.1)	31 (100)	1.000
qSOFA, median (IQR)	2 (1-2)	2 (1-2)	2 (1-2)	0.957
qSOFA ≥ 2, n (%)	57 (71.3)	25 (73.5)	21 (67.7)	0.608
SOFA, median (IQR)	6 (4-8)	6.5 (4-8.3)	6 (3-8)	0.736
NEWS, median (IQR)	12 (9-14)	12.5 (9.5-8.3)	12 (8-14)	0.726
NEWS ≥ 7, n (%)	67 (83.8)	28 (82.4)	27 (87.1)	0.736
qNEWS, median (IQR)	6 (3-6)	5 (3-6)	6 (3-6)	0.496
MEWS, median (IQR)	6 (4.25-8)	7 (5-8)	6 (5-8)	0.863
Sepsis biomarkers
Procalcitonin (μg/L), median (IQR)	1.9 (0.5-12.1)	2.8 (0.8-25.9)	1.0 (0.5-4.6)	0.156
C- reactive protein (mg/L), median (IQR)	123.0 (55.9-225.6)	107.2 (50.5-209.0)	136.5 (51.9-245.3)	0.566

SIRS: Systemic inflammatory response syndrome; qSOFA: Quick Sequential Organ Failure Assessment; SOFA: Sequential Organ Failure Assessment; NEWS: National Early Warning Score; qNEWS: Quick National Early Warning Score; MEWS: Modified Early Warning Score; IQR: Interquartile range.

Table 5 Diagnostic performance of serum procalcitonin and combined sepsis screening tools and procalcitonin

Parameters	PCT 0.85 μg/L	PCT 0.50 μg/L	qSOFA 2 + PCT 0.85 μg/L	SIRS 2 + PCT 0.85 μg/L
Sensitivity	77% (58-90)	77% (58-90)	72% (51-88)	76% (56-90)
Specificity	48% (28-69)	24% (9-45)	44% (22-69)	48% (28-69)
False negative rate	23% (10-42)	23% (10-42)	28% (12-49)	24% (10-44)
False positive rate	52% (31-72)	76% (55-91)	56% (31-78)	52% (31-72)
Positive likelihood ratio	1.47 (0.96-2.26)	1.01 (0.75-1.36)	1.30 (0.80-2.09)	1.46 (0.95-2.24)
Negative likelihood ratio	0.49 (0.23-1.05)	0.97 (0.38-2.52)	0.63 (0.28-1.42)	0.50 (0.23-1.08)
Diagnostic odds ratio	3.03 (0.96-9.62)	1.04 (0.30-3.69)	2.06 (0.57-7.36)	2.90 (0.91-9.23)
Youden’s index	0.25 (0.00-0.49)	0.01 (-0.22 to 0.23)	0.16 (-0.12 to 0.45)	0.24 (-0.01 to 0.49)

Values are given in percentage (95% confidence interval) or ratio (95% confidence interval). PCT: Procalcitonin; qSOFA: Quick Sequential Organ Failure Assessment; SIRS: Systemic inflammatory response syndrome.