Subjects
Approximately 14,000 out-patients a year are treated at Saitama Medical University Hospital's Dept. of General Internal Medicine. The potential 362 subjects for this study consisted of 191 males and 171 females, who were either inpatients or outpatients, with a primary complaint of fever during a 5-year period from August 1 2012 to July 31 2017 (Table 1).
Table 1
Distribution of patients’ demographic data (n=362)
Demographics
|
|
Age, median (IQR), y
|
67 (47–76)
|
Females, n (%)
|
171 (47%)
|
Symptoms, n (%)
|
Fever
|
90 (24.8%)
|
Dyspnea
|
25 (0.069%)
|
Presyncope
|
16 (0.044%)
|
Hemoptysis
|
2 (0.0055%)
|
Headache
|
3 (0.0083%)
|
Joint swelling
|
2 (0.0055%)
|
Backpain
|
10 (0.028%)
|
Abdominal distention
|
3 (0.0083%)
|
Muscle weakness
|
3 (0.0083%)
|
Abdominal pain
|
26 (0.072%)
|
Nausea
|
7 (0.019%)
|
Diarrhea
|
10 (0.028%)
|
Cough
|
39 (0.11%)
|
Sputum
|
3 (0.0083%)
|
Edema
|
9 (0.025%)
|
Pulmonary opacity
|
12 (0.033%
|
Lower limb pain
|
6 (0.017%)
|
Anorexia
|
6 (0.017%)
|
Vomiting
|
2 (0.0055%)
|
Arthralgia
|
15 (0.041%)
|
Rash
|
3 (0.0083%)
|
Adenopathy
|
7 (0.019%)
|
Anemia
|
2 (0.0055%)
|
Malaise
|
7 (0.019%)
|
Chest pain
|
10 (0.028%)
|
Neck pain
|
2 (0.0055%)
|
Hand swelling
|
2 (0.0055%)
|
Sore throat
|
9 (0.025%)
|
Weight loss
|
2 (0.0055%)
|
Chills
|
2 (0.0055%)
|
Pedal swelling
|
3 (0.0083%)
|
Other
|
24 (0.067%)
|
Medical history
|
Risk factors
|
Smoking
|
Never
|
158
|
Brinkman index
|
0–499
|
44
|
500–999
|
36
|
1000–1499
|
21
|
1500–1999
|
9
|
2000–
|
6
|
Total
|
11
|
Unknown
|
88
|
Alcohol consumption
|
Never
Standard drink per week
|
243
|
0–14
|
34
|
15–28
|
7
|
29–35
|
5
|
36–
|
2
|
Total
|
48
|
Unknown
|
171
|
The potential subjects were diagnosed with reference to their medical admission records, and the 205 analysis subjects were those whose final diagnoses were infectious diseases, malignancies, collagen diseases, and benign tumors, consisting of 176, 12, 11 and 6 subjects, respectively. The breakdown of infectious diseases by number of subjects was as follows: pyelonephritis: 33; bacterial pneumonia: 62; phlegmon: 14; cystitis: 12; cholecystitis: 8; abscesses: 11; acute upper respiratory inflammation: 17; nontuberculous mycobacterial infection: 4; appendicitis: 3; peritonitis: 2; infectious mononucleosis: 4; pulmonary tuberculosis: 2; pseudomembranous enterocolitis: 2; and mycoplasma pneumonia: 2. The remaining patients were excluded from the analysis, consisting of 150 patients with whom the final diagnosis was merely symptoms such as headache, or was a condition not covered by internal medicine, such as traumas; and 7 patients whose diagnoses were unknown (Figure 1).
In terms of the backgrounds of the 205 subjects, the age range was 17 to 98, and the median age was 66, and they included 105 males and 100 females.
Urinary tract infection was defined as the condition in which, with no other clear bacterial source found, the concentration of pathogenic bacteria is 103 or higher in midstream urine and/or 105 or higher in catheter urine, as determined by the quantitative culture method. Urinary tract infection was taken to be pyelonephritis when signs such as costovertebral angle tenderness, and/or increased perirenal fat concentration shown by computed tomography (CT), were present, and was taken to be cystitis when such signs were absent [9].
Subjects were taken to have bacterial pneumonia when both of the following conditions were met:
1. Alveolar infiltrative opacity found by thoracic X-radiography and/or thoracic CT.
2. At least two of the following: (i) fever at 37.5ºC or higher; (ii) abnormally high CRP; (iii) peripheral WBC count of at least 9000 cells/µL; and (iv) airway symptoms such as sputum accumulation [10].
Subjects were taken to have acute upper respiratory inflammation if they showed respiratory symptoms such as sputum accumulation, but no signs were found by imaging, and no noise was found by stethoscopy.
The diagnostic criteria for cholecystitis were as in "Tokyo Guidelines 2018: Initial management of acute biliary infection and flowchart for acute cholangitis" [11].
Subjects were taken to have phlegmon when they had fever, and redness and pain on the same area of the skin, but no other bacterial source was found.
Subjects were taken to have malignant tumors when pathological signs of malignancy were found.
Before initiation of the study, approval of the Ethics Committee was obtained; IRB: Institutional Review Board of Saitama Medical University Hospital (Ethical approval number 17-067-1). Informed consent was waived due to the retrospective nature of the study. The study was entered on the hospital homepage so as to be made public.
Procalcitonin measurement:
0.4 mL of serum of the patient was collected intravenously at our hospital. Both inpatients and outpatients received the tests on the first visit day to our hospital. The test was performed in the central laboratory, and assay time was within 1 hour. The test was performed in time of AM 8:30 to PM 5:00 from Monday to Saturday. The Brahms Procalcitonin kit (Roche Diagnostics Co., Ltd.) was utilized to measure procalcitonin levels, and the measurement range was 0.02 to 100 ng/mL. For blood culture, two samples were collected from different limbs into a BD Bactec blood culture bottle (Becton, Dickinson and Company, Ltd.) was used.
Statistical analysis:
Evaluation 1
Multiple comparisons of four groups of subjects (with infectious diseases, malignant tumors, collagen diseases, and benign tumors), were carried out using the Kruskal-Wallis test and Steel-Dwass test.
Evaluation 2
In the subjects with infectious diseases and high procalcitonin levels, multiple comparisons between the types of disease affecting large numbers of subjects, that is, bacterial pneumonia, pyelonephritis, acute upper respiratory inflammation, phlegmon, cystitis, and cholecystitis, were carried out using the Kruskal-Wallis and Steel-Dwass tests. Abscesses were excluded from this evaluation, because abscess characteristics are considered to vary between different affected sites.
Evaluation 3
In the case of infectious diseases that affected large numbers of subjects (pyelonephritis, bacterial pneumonia, cholecystitis, and phlegmon), with those subjects with whom blood culture was carried out, the mortality rate for each disease was tested using Fisher's exact test. A total of six tests was carried out (₄C₂), so, with correction by the Bonferroni method, the p-value was taken to be 0.0083.
This evaluation included a large number of subjects, but those with whom blood culture was not carried out, and those with cystitis or acute upper respiratory inflammation, were excluded.
Evaluation 4
Multiple regression analysis was carried out with all 205 subjects, on the basis of the hematology test results, with procalcitonin level as the objective variable, and CRP, WBC count, creatinine, and alanine aminotransferase (ALT) as the explanatory variables, so as to test the relationships between procalcitonin level and the hematology test results.