Chinese Medical Sciences Journal ›› 2022, Vol. 37 ›› Issue (2): 134-141.doi: 10.24920/003975
• Original Article • Previous Articles Next Articles
Changyi Liu1, Xiaoqing Liu2, 3, 4, Xiaochun Shi2, 3, *()
Received:
2021-07-29
Accepted:
2022-01-11
Published:
2022-06-30
Online:
2022-04-26
Contact:
Xiaochun Shi
E-mail:shixch7722@163.com
Changyi Liu, Xiaoqing Liu, Xiaochun Shi. Clinical Features of Spontaneous Remission in the Classic Fever of Unknown Origin: A Retrospective Study[J].Chinese Medical Sciences Journal, 2022, 37(2): 134-141.
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Figure 1.
Diagnosis and treatment process of classic FUO. FUO: fever of unknown origin; LDH: lactate dehydrogenase; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; Ig: immunoglobulin; CMVDNA: cytomegalovirus DNA; EBVDNA: Epstein-Barr virus; BST: blood serologic test; TB-IGRA: interferon-gamma release assay for Mycobacterium tuberculosis; ANA: antinuclear antibody; ENA: extractable nuclear antigen; ANCA: antineutrophil cytoplasmic antibody; RF: rheumatoid factor; anti-CCP: anti-cyclic citrullinated peptide; CT: computed tomography; PDCs: potential diagnostic clues; SACE: serum angiotensin converting enzyme; TEE: trans esophageal echocardiography; PET/CT: positron emission tomography/computed tomography; NSAIDs: nonsteroidal antiinflammatory drugs."
Table 1.
Etiological diagnosis of 119 classic FUO cases"
Items | Case number (%) |
---|---|
Infectious diseases | 30 (25.2) |
Bacterial infections | 21 (17.6) |
Tuberculosis | 8 (6.7) |
Infective endocarditis | 5 (4.2) |
Osteomyelitis | 5 (4.2) |
Disseminated nontuberculous mycobacteria infection | 3 (2.5) |
Viral infections | 9 (7.6) |
Epstein-Barr virus infection | 7 (5.9) |
Cytomegalovirus infection | 2 (1.7) |
Connective tissue diseases | 28 (23.5) |
Adult-onset Still’s disease | 16 (13.4) |
Polymyalgia rheumatica | 3 (2.5) |
Rheumatoid arthritis | 2 (1.7) |
Systemic vasculitis | 2 (1.7) |
Takayasu arteritis | 1 (0.8) |
Nodular feverish non-suppurative panniculitis | 1 (0.8) |
Systemic lupus erythematosus | 1 (0.8) |
Undifferentiated connective tissue diseases | 2 (1.7) |
Malignant tumors | 8 (6.7) |
Castleman’s disease | 2 (1.7) |
Colonic sarcoma | 1 (0.8) |
Prostate cancer | 1 (0.8) |
Renal carcinoma | 1 (0.8) |
Gastric carcinoma | 1 (0.8) |
Undifferentiated carcinoma | 2 (1.7) |
Miscellaneous other diseases | 6 (5.0) |
Hemophagocytic syndrome | 3 (2.5) |
Necrotizing lymphadenitis | 2 (1.7) |
Drug induced fever | 1 (0.8) |
Undiagnosed: follow up results | 47 (39.5) |
Spontaneous remission | 41 (34.5) |
Recurrent fever | 6 (5.0) |
Table 2.
Clinical characteristics of classic FUOs with different causes"
Items | Classic FUO | Spontaneous remission | Infections | Autoimmune diseases | Malignancies | Others | Recurrent FUO |
---|---|---|---|---|---|---|---|
n | 119 | 41 | 30 | 28 | 8 | 6 | 6 |
Age (yrs, mean±SD) | 43±17 | 43±17 | 43±19 | 42±17 | 48±13 | 37±16 | 45±13 |
Gender [n (%)] | |||||||
Male | 66 (55.5) | 22 (53.7) | 19 (63.3) | 11 (39.3) | 6 (75.0) | 3 (50.0) | 5 (83.3) |
Female | 53 (44.5) | 19 (46.3) | 11 (36.7) | 17 (60.7) | 2 (25.0) | 3 (50.0) | 1 (16.7) |
Tmax [n (%)] | |||||||
≤ 39℃ | 41 (34.5) | 15 (36.6) | 12 (40.0) | 7 (25.0) | 4 (50.0) | 2 (33.3) | 1 (16.7) |
39°C-41°C | 77 (64.7) | 26 (63.4) | 18 (60.0) | 20 (71.4) | 4 (50.0) | 4 (66.7) | 5 (83.3) |
> 41℃ | 1 (0.8) | 0 | 0 | 1 (3.6) | 0 | 0 | 0 |
Rash [n (%)] | 40 (33.6) | 8 (19.5) | 7 (23.3) | 19 (67.9) | 1 (12.5) | 5 (83.3) | 0 |
Arthritis [n (%)] | 22 (18.5) | 5 (12.2) | 2 (6.7%) | 12 (42.9) | 0 | 1 (16.7) | 2 (33.3) |
Lymphadenopathy [n (%)] | 45 (37.8) | 10 (24.4) | 10 (33.3) | 17 (60.7) | 2 (25.0) | 4 (66.7) | 2 (33.3) |
Spleno/hepatosplenomegaly [n (%)] | 51 (42.9) | 12 (29.3) | 15 (50.0) | 13 (46.4) | 2 (25.0) | 4 (66.7) | 3 (50.0) |
Digestive system involvement [n (%)] | 5 (4.2) | 0 | 1 (3.3) | 0 | 3 (37.5) | 1 (16.7) | 0 |
Renal involvement [n (%)] | 8 (6.7) | 2 (4.9) | 1 (3.3) | 2 (7.1) | 3 (37.5) | 0 | 0 |
Respiratory system involvement [n (%)] | 7 (5.9) | 1 (2.4) | 1 (3.3) | 3 (10.7) | 1 (12.5) | 0 | 1 (16.7) |
Neural system involvement [n (%)] | 5 (4.2) | 1 (2.4) | 3 (10.0) | 1 (3.6) | 0 | 0 | 0 |
Cardiovascular involvement [n (%)] | 4 (3.4) | 0 | 3 (10.0) | 1 (3.6) | 0 | 0 | 0 |
WBC (×109/L, mean±SD) | 8.45±4.90 | 6.94±3.84 | 8.26±5.20 | 10.8±5.61 | 10.07±4.28 | 6.60±3.98 | 8.28±4.67 |
NEUT [×109/L, median (IQR)] | 5.29 (2.96, 7.94) | 3.82 (2.49, 6.28) | 5.26 (2.48, 7.95) | 6.48 (4.69, 12.4) | 6.46 (5.29, 7.84) | 3.86 (2.45, 5.49) | 5.77 (3.23, 10.44) |
NEUT% (mean±SD) | 69.4±15.3 | 63.8±15.9 | 69.9±17.0 | 75.0±12.4 | 72.9±9.1 | 63.8±15.0 | 80.1±8.1 |
HB (g/L, mean±SD)a | 108±20 | 112±15 | 110±23 | 103±21 | 92±18 | 110±21 | 112±19 |
PLT (×109/L, mean±SD)b | 293±132 | 309±116 | 244±150 | 332±114 | 304±145 | 251±70 | 267±198 |
Anemia [n (%)]a | 70 (60.9) | 19 (51.4) | 18 (60.0) | 19 (67.9) | 7 (87.5) | 4 (66.7) | 3 (50.0) |
Liver damage [n (%)] | 23 (19.3) | 9 (22.0) | 8 (26.7) | 3 (10.7) | 1 (12.5) | 2 (33.3) | 0 |
Hypoproteinemia [n (%)] | 65 (54.6) | 20 (48.8) | 18 (60.0) | 15 (53.6) | 7 (87.5) | 3 (50.0) | 2 (33.3) |
ALB (g/L, mean±SD) | 34±6 | 35±6 | 34±5 | 33±5 | 29±5 | 34±3 | 35±4 |
ESR (mm/h, mean±SD) | 73±38 | 69±37 | 58±39 | 90±32 | 106±27 | 51±36 | 62±33 |
CRP [mg/L, median (IQR)] | 56.69 (23.66, 115.55) | 32.40 (17.1, 108.2) | 37.85 (21.64, 97.77) | 91.96 (57.40, 136.55) | 133.56 (73.85, 236.32) | 50.59 (27.63, 83.02) | 46.10 (24.27, 97.98) |
Ferritin [ng/ml, median (IQR)]c | 551 (253, 1,570) | 380 (103, 601) | 576 (253, 1,675) | 2501 (581, 7,459) | 382 (255, 1,534) | 1126 (567, 3,674) | 272 (101, 445) |
PET/CT positive [ratio (%)]d | 42/51 (82.4) | 8/12 (66.7) | 9/10 (90.0) | 13/16 (81.3) | 5/5 (100) | 4/4 (100) | 3/4 (75.0) |
Antibiotic treatment [n (%)] | 116 (97.5) | 40 (97.6) | 30 (100) | 28 (100) | 8 (100) | 5 (83.3) | 5 (83.3) |
Antivirus treatment [n (%)] | 12 (10.1) | 4 (9.8) | 4 (13.3) | 3 (10.7) | 0 | 0 | 1 (16.7) |
Diagnostic anti-tuberculosis treatment [n (%)] | 14 (11.8) | 2 (4.9) | 7 (23.3) | 3 (10.7) | 0 | 0 | 2 (33.3) |
Glucocorticoid treatment [n (%)] | 46 (38.7) | 10 (24.4) | 8 (26.7) | 20 (71.4) | 1 (12.5) | 4 (66.7) | 3 (50.0) |
Table 3.
Univariate analysis of related factors of spontaneous remission in FUO patients"
Items | Spontaneous remissions in FUO (n=41) | Non-spontaneous remission in FUO (n=78) | OR (95%CI) | P-value |
---|---|---|---|---|
Age (yrs, mean±SD) | 43±17 | 43±17 | 1.002 (0.980-1.025) | 0.876 |
Gender [n (%)] | 0.895 (0.419-1.913) | 0.774 | ||
Male | 22 (53.7) | 44 (56.4) | ||
Female | 19 (46.3) | 34 (43.6) | ||
Rash [n (%)] | 8 (19.5) | 31 (39.7) | 0.426 (0.179-1.015) | 0.054 |
Arthritis [n (%)] | 5 (12.2) | 17 (21.8) | 0.498 (0.169-1.466) | 0.206 |
Lymphadenopathy [n (%)] | 10 (24.4) | 35 (44.9) | 0.396 (0.171-0.919) | 0.031 |
Splenomegaly/hepatosplenomegaly [n (%)] | 12 (29.3) | 37 (47.4) | 0.459 (0.205-1.027) | 0.058 |
Liver damage [n (%)] | 9 (22.0) | 14 (17.9) | 1.286 (0.503-3.287) | 0.600 |
WBC (×109/L, mean±SD) | 6.94±3.84 | 9.24±5.22 | 0.892 (0.811-0.981) | 0.019 |
NEUT [×109/L, median (IQR)] | 3.82 (2.49, 6.28) | 5.93 (3.74, 8.62) | 0.884 (0.794-0.994) | 0.024 |
NEUT% (mean±SD) | 63.8±15.9 | 72.3±14.3 | 0.967 (0.941-0.995) | 0.018 |
HB (g/L, mean±SD)a | 112±15 | 106±21 | 1.016 (0.995-1.037) | 0.136 |
PLT (×109/L, mean±SD)b | 309±116 | 285±139 | 1.001 (0.999-1.004) | 0.331 |
ALB (g/L, mean±SD) | 35±6 | 33±5 | 1.058 (0.989-1.133) | 0.101 |
ESR (mm/h, mean±SD) | 69±37 | 74±39 | 0.997 (0.987-1.007) | 0.551 |
CRP [mg/L, median (IQR)] | 32.40 (17.1, 108.2) | 72.2 (32.2, 117.2) | 0.993 (0.986-1.000) | 0.049 |
Ferritin [(ng/ml, median (IQR)]c | 380 (103, 601) | 760 (331, 3476) | 1.000 (0.999-1.000) | 0.063 |
IL-6 [pg/ml, median (IQR)]d | 10.1 (2.0, 21.5) | 21.0 (6.3, 45.2) | 0.980 (0.947-1.014) | 0.244 |
IL-8 [pg/ml, median (IQR)]d | 58 (42, 120) | 108 (57, 372) | 0.996 (0.990-1.001) | 0.151 |
IL-10 [pg/ml, median (IQR)]d | 5.0 (5.0, 5.0) | 5.0 (5.0, 10.5) | 0.826 (0.552-1.235) | 0.351 |
TNF-α[pg/ml, median (IQR)]d | 24.4 (9.2, 39.9) | 25.1 (18.1, 44.2) | 0.979 (0.938-1.023) | 0.343 |
Lymphocyte [×109/L, median (IQR)]e | 1266 (873, 1629) | 1189 (874, 1720) | 1.000 (0.999-1.000) | 0.482 |
Lymphocyte percentage [median (IQR)] | 21.2 (15.9, 31.1) | 16.6 (11.5, 23.7) | 1.034 (0.999-1.070) | 0.058 |
B lymphocyte [×106/L, median (IQR)] | 76 (40, 132) | 65 (42, 105) | 1.002 (0.996-1.007) | 0.508 |
B lymphocyte percentage [median (IQR)] | 6.9 (3.5, 9.8) | 5.2 (2.8, 8.1) | 1.037 (0.940-1.144) | 0.472 |
NK cell [×106/L, median (IQR)] | 142 (62, 196) | 116 (61, 194) | 1.001 (0.998-1.005) | 0.407 |
NK cell percentage [median (IQR)] | 10.7 (6.2, 14.5) | 9.0 (6.4, 13.9) | 1.023 (0.966-1.085) | 0.434 |
T lymphocyte [×106/L, median (IQR)] | 1042 (712, 1278) | 976 (683, 1329) | 1.000 (0.999-1.000) | 0.338 |
T lymphocyte percentage [median (IQR)] | 81.6 (77.4, 84.7) | 82.8 (76.2, 88.5) | 0.981 (0.936-1.029) | 0.433 |
CD4+ T lymphocyte [×106/L, median (IQR)] | 552 (374, 725) | 480 (328, 689) | 1.000 (0.999-1.001) | 0.698 |
CD4+ T lymphocyte percentage [median (IQR)] | 44.6 (33.8, 50.8) | 43.7 (33.8, 47.9) | 1.017 (0.979-1.057) | 0.383 |
CD8+ T lymphocyte [×106/L, median (IQR)] | 382 (228, 473) | 356 (238, 647) | 0.999 (0.998-1.000) | 0.189 |
CD8+ T lymphocyte percentage [median (IQR)] | 29.9 (21.8, 38.9) | 30.7 (24.9, 38.5) | 0.983 (0.948-1.019) | 0.344 |
CD8+HLA-DR+/CD8+ percentage [median (IQR)] | 45.0 (26.9, 57.6) | 53.8 (32.0, 73.8) | 0.983 (0.965-1.002) | 0.076 |
CD8+CD38+/CD8+ percentage [median (IQR)] | 67.0 (43.5, 78.8) | 73.1 (55.4, 87.0) | 0.977 (0.956-0.997) | 0.028 |
PET-CT positive [n (%)]f | 8 (66.7) | 34 (87.2) | 0.294 (0.064-1.350) | 0.115 |
Table 4.
Outcomes of FUO patients undiagnosed at discharge in literatures"
Study | Number of FUOa | Follow-up time | Patients with spontaneous remission [n (%)] | Deaths [n (%)] |
---|---|---|---|---|
Knockaert et al.[ | 61 | 5 years | 41 (67.2) | 6/2b (3.2) |
Vanderschueren et al.[ | 95 | 574 (125-2052) days | 63 (66.3) | 3 (3.2) |
Zenone[ | 37 | / | 29 (78.4) | 1 (2.7) |
Bleeker-Rovers et al.[ | 37 | 12 (6-23) months | 21 (56.8) | 1 (2.7) |
Mansueto et al.[ | 29 | 2 years | 13 (44.8) | 4 (13.8) |
Tan et al.[ | 58 | 518 (0.4-830) weeks | 35 (60.3) | 10/9c (15.5) |
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