显微镜下多血管炎患者继发弥漫性肺泡出血和肺间质病的临床特征及预后分析

doi:10.24920/004067

摘要/Abstract

摘要：

目的评估继发于显微镜下多血管炎（microscopic polyangiitis，MPA）的弥漫性肺泡出血和/或肺间质病患者的临床特征以及预后相关因素。
方法回顾性分析2002年至2012年于北京协和医院内科住院的MPA患者，根据肺受累类型不同分为单纯肺间质病组、单纯弥漫性肺泡出血组、弥漫肺泡出血合并肺间质病组和无肺受累组。比较各组患者人口学资料、全身症状、脏器受累情况、实验室检查、治疗与预后。采用Logistic回归和Cox分析患者早期与晚期死亡的危险因素。
结果共181例MPA患者纳入研究，其中单纯肺间质病组96例、单纯弥漫性肺泡出血组19例、弥漫肺泡出血合并肺间质病组18例、无肺受累组48例。随访时间的中位数为67个月（范围：1~199个月）。单纯弥漫性肺泡出血组肾脏受累最严重（血肌酐中位值：449 μmol/L，显著高于单纯肺间质病组（123 μmol/L，Nemenyi = -35.215，P = 0.045）和弥漫肺泡出血合并肺间质病组（359 μmol/L，Nemenyi = -43.609，P = 0.007）。单纯肺间质病组患者年龄大于单纯弥漫性肺泡出血组（中位年龄：69比57岁；Nemenyi = 43.853，P = 0.005）。弥漫肺泡出血合并肺间质病组患者融合了两种单纯亚型患者的临床特点，并且死亡率最高（死亡率72.2%）。MPA患者总的5年生存率为51.9%。外周血白细胞升高（1月内死亡风险评估：OR = 1.103，95%CI：1.008-1.207，P = 0.032；1年内死亡风险评估：OR = 1.103，95%CI：1.026-1.186，P = 0.008）是MPA患者早期死亡的高危因素。高龄（HR = 1.044，95%CI：1.023-1.066，P < 0.001）、肾功能严重受损（HR = 1.001，95%CI：1.000-1.002，P = 0.032）及心血管受累（HR = 2.093，95%CI：1.195-3.665，P = 0.010）是MPA患者晚期死亡的高危因素。在诊断后1年内共有49例患者发生过肺部感染。肺部感染是MPA患者最主要的死亡原因（38/54），以肺间质病患者尤为明显。
结论不同肺受累模式的MPA患者具有完全不同的临床特征，提示不同肺受累模式的MPA可能存在不同的发病机制。因此，对继发于MPA的弥漫性肺泡出血和肺间质病应按照不同的临床亚型分别研究。

关键词: 显微镜下多血管炎, 弥漫性肺泡出血, 肺间质病, 死亡率, 危险因素

Abstract:

Objective To evaluate the clinical characteristics and prognostic predictors of patients with diffuse alveolar hemorrhage (DAH) and/or interstitial lung disease (ILD) secondary to microscopic polyangiitis (MPA) in a Chinese general hospital.
Methods We retrospectively reviewed the medical records of MPA patients admitted to internal medicine departments between the year 2002 and 2012. The patients were divided into the ILD, DAH, DAH combined with ILD (DAHILD), and no pulmonary involvement (NPI) groups according to pulmonary involvement patterns. The clinical characteristics at diagnosis were analyzed. The risk factors associated with short-term death and long-term death were identified with Logistic regression and Cox analysis.
Results Of 193 newly diagnosed MPA patients, 181 patients were enrolled in the research, of which 19 had DAH alone, 96 had ILD alone, 18 had DAH and DAH concurrently, and 48 had NPI. The median of serum creatine level in the DAH group was 449 μmol/L, significantly higher than that in the ILD group (123 μmol/L, Nemenyi = -35.215, P = 0.045) and DAHILD group (359 μmol/L, Nemenyi = -43.609, P = 0.007). The median follow-up time was 67 (range: 1-199) months. Patients in the ILD group were older than those in the DAH group (median: 69 years vs. 57 years, Nemenyi = 43.853, P= 0.005). The patients with both DAH and ILD had combined features of the two subtypes, and the highest mortality (72.2% at the end of follow-up). The elevated white blood cell count was a risk factor for short-term death (OR = 1.103, 95%CI: 1.008-1.207, P = 0.032 for one month; OR = 1.103, 95%CI: 1.026-1.186, P = 0.008 for one year). Old age (HR= 1.044, 95%CI: 1.023-1.066, P < 0.001), cardiovascular system involvement (HR = 2.093, 95%CI: 1.195-3.665, P = 0.010), poor renal function (HR = 1.001, 95%CI: 1.000-1.002, P = 0.032) were risk factors for long-term death. Pulmonary infections (38/54) were the leading causes of death, especially for the patients with ILD. Besides, 49 patients suffered from pulmonary infections in the first year after diagnosis.
Conclusions MPA patients who presented with different pulmonary involvement patterns have completely different clinical features. These subtypes probably have different pathogenesis and should be studied separately.

Key words: microscopic polyangiitis, diffuse alveolar hemorrhage, interstitial lung disease, mortality, risk factors

Yu Gu, Ting Zhang, Min Peng, Juhong Shi. Characteristics and Prognosis of Microscopic Polyangiitis Patients with Diffuse Alveolar Hemorrhage and Interstitial Lung Disease[J].Chinese Medical Sciences Journal, 2022, 37(4): 293-302.

图/表 7

Variable	DAH	DAH+ILD	ILD	NPI	Statistic	P value
No. of patients [n (%)]	19 (10.5)	18 (9.9)	96 (53.0)	48 (26.5)
Age at diagnosis [yrs, median (range)]	57 (47-65)^a	64 (59-75)	69 (60-74)^a	65 (53-74)	H = 12.13	0.007
Male [n (%)]	7 (36.8)	8 (44.4)	50 (52.1)	20 (41.7)	χ²= 2.378	0.498
Follow-up time [months, median (range)]	54 (5-105)	31 (3-78)	50 (15-100)	78 (57-112)	H = 2.545	0.058
BVAS [score, median (range)]	22 (18-28)	21 (12-25)	21 (15-27)	21 (15-29)	H = 1.955	0.582
FFS2009 [score, mean±SD]	2.01±0.97	2.22±0.81	1.88±0.77	1.81±0.76	H = 3.356	0.340
Fever [n (%)]	4 (21.1)	6 (33.3)	25 (26.0)	14 (29.2)	Fisher’s exact χ²=0.927	0.831
Weight loss [n (%)]	6 (31.6)	9 (50.0)	48 (50.0)	26 (54.2)	χ²= 2.863	0.413
Organ involvement [n (%)]
Renal	18 (94.7)	18 (100)	83 (86.5)	43 (89.6)	Fisher’s exact χ²=2.951	0.398
Nervous system	5 (26.3)	3 (16.7)	40 (41.7)	21 (48.3)	χ²= 5.791	0.122
ENT	2 (10.5)	1 (5.6)	14 (14.6)	12 (25.0)	Fisher’s exact χ²=4.263	0.235
Skin	4 (21.1)	3 (16.7)	10 (10.4)	8 (16.7)	Fisher’s exact χ²=2.702	0.433
Cardiovascular system	4 (21.1)	3 (16.7)	8 (8.3)	3 (6.3)	Fisher’s exact χ²=4.589	0.171
Eyes	1 (5.3)	0	5 (5.2)	5 (10.4)	Fisher’s exact χ^?=2.294	0.467
Abdomen	3 (15.8)	1 (5.6)	2 (2.1)	3 (6.3)	Fisher’s exact χ²=6.237	0.064
Laboratory findings
WBC [×??⁹/L, median (range)]	10.1 (8.1-18.0)	9.4 (7.9-13.7)	10.0 (7.4-13.7)	9.6 (6.8-12.8)	H = 2.510	0.473
HGB (g/L, mean±SD)^*	88±30^b	92±22	107±22^b,c	96±19^c	F = 5.952	0.001
PLT (×10⁹/L, median (range))	291 (209-429)	228 (132-308)	278 (194-363)	260 (230-405)	H = 5.387	0.146
ESR (mm/h, mean±SD)^*	78 ± 40	73 ± 42	75±31	77±31	F = 0.144	0.933
CRP (mg/L, median (range))	39 (18-70)	21 (13-73)	45 (10-91)	58 (14-127)	H = 0.902	0.825
Creatinine [μmol/L, median (range)]	449 (126-523)^d,e	357 (156-640)^e	123 (81-230)^d	170 (104-385)	H = 16.572	0.001
ANA [n (%)]	28 (29.2)	7 (38.9)	7 (36.8)	16 (33.3)	χ²= 0.990	0.825
ANCA [n (%)]					Fisher’s exact χ²=10.309	0.185
PR3/c-ANCA	5 (5.3)	0	2 (2.1)	2 (4.2)		>0.05
MPO/p-ANCA	17 (89.5)	16 (88.9)	92 (95.8)	44 (91.7)		>0.05
MPO/p-ANCA+PR3/c-ANCA positive	0	2 (11.1)	1 (1.0)	2 (4.2)		>0.05
MPO/p-ANCA+PR3/c-ANCA negative	1 (5.3)	0	1 (1.0)	0		>0.05
Treatments
p-GC/h-GC/n-GC (n)	8/11/0	8/10/0	20/73/3	17/31/0	Fisher’s exact χ²=8.867	0.129
iv-CTX/po-CTX/n-CTX (n)	11/4/4	11/4/3	53/33/10	25/15/8	Fisher’s exact χ²=3.848	0.704
IVIG [n (%)]	2 (10.5)	5 (27.8)^g	3 (3.1)^g	3 (6.3)	Fisher’s exact χ²=11.062	0.005
PE [n (%)]	3 (15.8)	5 (27.8)^h	1 (1.0)^h,i	1 (2.1)ⁱ	Fisher’s exact χ²=18.792	<0.001
Prognosis [n (%)]
Pulmonary infections in one year	4 (8.2)	4 (8.2)	34 (69.4)	7 (14.3)	Fisher’s exact χ²=7.590	0.051
Deaths in one year	8 (42.1)	7 (38.9)	22 (22.9)	9 (18.8)	Fisher’s exact χ²=5.870	0.115
Deaths overall	11 (57.9)	13 (72.2)	58 (60.4)	20 (41.7)	χ²= 6.715	0.082

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Variables	Death in one year			Death in one month
Variables	OR	95%CI	P value	OR	95%CI	P value
Age	1.047	1.009, 1.086	0.016	1.066	0.995, 1.142	0.080
Male	0.993	0.465, 2.121	0.905	0.537	0.113, 2.333	0.866
Fever	1.775	0.690, 4.566	0.302
DAH	2.164	0.864, 5.418	0.078	4.358	1.277, 14.877	0.019
Cardiovascular system	2.013	0.661, 6.129	0.145
Skin/mucosa				5.110	1.392, 18.758	0.014
Abdomen				3.744	0.419, 33.492	0.272
WBC	1.103	1.026, 1.186	0.008	1.103	1.008, 1.207	0.032
HGB				0.978	0.944, 1.014	0.240
Creatinine	1.002	1.000, 1.003	0.011	1.001	0.998, 1.004	0.430

Variables	Cox regression			Logistic regression
Variables	HR	95%CI	P value	OR	95%CI	P value
Age	1.044	1.023, 1.066	<0.001	1.061	1.030, 1.094	< 0.001
Male	0.803	0.539, 1.196	0.314	0.761	0.387, 1.497	0.366
ILD	1.389	0.904, 2.134	0.145	1.623	0.792, 3.324	0.185
Cardiovascular system	2.093	1.195, 3.665	0.010	6.216	1.260, 30.664	0.025
WBC	1.040	1.002, 1.079	0.039	1.024	0.955, 1.098	0.503
HGB				1.021	1.004, 1.038	0.016
Creatinine	1.001	1.000, 1.002	0.032	1.003	1.001, 1.005	0.003

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