自发缓解的经典型不明原因发热的临床特征

doi:10.24920/003975

摘要/Abstract

摘要：

目的总结自发缓解的经典型不明原因发热（FUO）的临床特征。
方法回顾性分析2018年1月~2018年6月北京协和医院住院诊治的符合经典型FUO诊断标准的121例患者的临床资料,对出院时诊断未明的患者进行为期2年的随访。总结这些患者的临床特征和结果,并采用多因素logistic回归分析FUO自发缓解的相关因素。
结果除外失访的2例患者,最终119例FUO患者的病因构成为：感染性疾病30例（25.2%）、结缔组织病28例（23.5%）、肿瘤性疾病8例（6.7%）、其他疾病6例（5.0%）、诊断未明的47例（39.5%）。出院时仍诊断未明的51例患者中,41例患者的发热自发缓解（起病至缓解的时间为4~39周,中位时间为9周）。单因素分析显示皮疹和淋巴结肿大在非自发缓解FUO患者组比自发缓解FUO组更为常见;炎症指标中白细胞计数、中性粒细胞计数、中性粒细胞比例、C反应蛋白、IL-8和铁蛋白水平在非自发缓解FUO组比自发缓解FUO组更高;淋巴细胞亚群分析显示自发缓解组FUO患者外周血淋巴细胞比例比非自发缓解组FUO患者更高,而非自发缓解组FUO患者CD8阳性T淋巴细胞表达CD38的比例高于自发缓解FUO组。多因素logistic回归分析结果显示白细胞计数（OR：0.545,95%CI：0.306~0.971,P = 0.039）、中性粒细胞计数（OR：2.074,95%CI：1.004~4.284,P = 0.049）和中性粒细胞比例（OR：0.928,95%CI：0.871~0.990,P = 0.022）为FUO能否自发缓解的独立预测因素。
结论有限的数据表明：出院时仍诊断未明的经典型FUO患者大多数会自发缓解,因此,对临床情况稳定的患者随访观察是最佳处理策略。部分炎症相关指标有可能成为FUO自发缓解预测因子。

关键词: 不明原因发热, 随访, 自发缓解, 诊断

Abstract:

Objective To summarize the clinical features of spontaneous remission in classic fever of unknown origin (FUO).
Methods Medical records of 121 patients diagnosed with FUO at admission in Peking Union Medical College Hospital between January 2018 and June 2018 were reviewed retrospectively. Patients who were discharged without etiological diagnoses were followed for 2 years. The clinical features and outcomes of these patients were summarized. Multivariate logistic regression was used to analyze related factors of spontaneous remission of FUO.
Results After excluding 2 patients who lost to follow-up, the etiology of 119 FUO patients were as follows: infectious diseases in 30 (25.2%) cases, connective tissue diseases in 28 (23.5%) cases, tumor diseases in 8 (6.7%) cases, other diseases in 6 (5.0%) cases, and unknown diagnoses in 47 (39.5%) cases. Totally, 41 patients experienced spontaneous remission of fever (the median time from onset to remission was 9 weeks, ranging from 4 to 39 weeks). In patients with spontaneous remission in FUO, lymphadenopathy was less common clinical manifestation, the levels of inflammatory markers including leukocyte count, neutrophil count, neutrophil ratio, C-reactive protein, and ferritin were lower, and the proportion of CD8 positive T lymphocytes expressing CD38 was lower. Multivariate logistic regression analysis of factors with a P-value < 0.05 in univariate analysis shown that white blood cell count (OR: 0.545, 95%CI: 0.306-0.971, P = 0.039), neutrophil count (OR: 2.074, 95%CI: 1.004-4.284, P = 0.049), and proportion of neutrophils (OR: 0.928, 95%CI: 0.871-0.990, P = 0.022) were independent significant factors associated with spontaneous remission in FUO.
Conclusions This study suggested that most patients discharged with undiagnosed classic FUO would remit spontaneously. Thus, for patients with stable clinical conditions, follow-up and observation could be the best choice. Patients with lower level of some inflammatory factors may have a high likelihood of spontaneous remission in classic FUO.

Key words: fever of unknown origin, follow-up, spontaneous remission, diagnosis

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.

图/表 5

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)
T_max [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)

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

参考文献 12.

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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)

Study	Number of FUO^a	Follow-up time	Patients with spontaneous remission [n (%)]	Deaths [n (%)]
Knockaert et al.^[4]	61	5 years	41 (67.2)	6/2^b(3.2)
Vanderschueren et al.^[5]	95	574 (125-2052) days	63 (66.3)	3 (3.2)
Zenone^[8]	37	/	29 (78.4)	1 (2.7)
Bleeker-Rovers et al.^[6]	37	12 (6-23) months	21 (56.8)	1 (2.7)
Mansueto et al.^[7]	29	2 years	13 (44.8)	4 (13.8)
Tan et al.^[9]	58	518 (0.4-830) weeks	35 (60.3)	10/9^c(15.5)

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