指南概述

• 目的：更新2013年美国胸科学会（ATS）婴幼儿chILD综合征指南，纳入临床实践中基因检测、影像、肺活检、肺移植转诊及多学科护理的变化。
• 适用人群：2岁以下有chILD综合征的婴幼儿。

定义

• chILD综合征：符合以下四项标准中至少三项，且排除较常见弥漫性肺病病因的婴幼儿，标准为呼吸症状、体征、低氧血症、胸部影像学弥漫性异常；排除病因包括囊性纤维化、先天性或获得性免疫缺陷等。
• chILD疾病：符合chILD综合征标准并明确具体病因（如基因、免疫介导等）的婴幼儿。

推荐建议

基因检测

• 强烈推荐：对2岁以下有chILD综合征和呼吸衰竭、疑似致命性chILD疾病的婴幼儿进行快速和广泛的基因检测。
• 建议：在有创诊断干预前进行基因检测；对已进行肺活检且组织病理学特征提示单基因chILD疾病的婴幼儿进行基因检测。

胸部CT

• 建议：胸部CT作为2岁以下有chILD综合征婴幼儿诊断评估的一部分。

外科肺活检

• 建议：其他诊断检查未明确特定chILD疾病且临床状况未改善时，进行外科肺活检。
• 强烈推荐：临床急需明确特定chILD疾病，且基因检测不可行、无结论或不及时时，进行活检以识别组织病理“可治疗特征”或辅助决策。

肺移植评估转诊

• 强烈推荐：对有可预测预后不良的特定单基因chILD疾病的婴幼儿进行早期肺移植评估转诊。
• 建议：对有需要机械通气或ECMO、进行性肺动脉高压或有特定chILD疾病且有进行性呼吸症状或即将呼吸衰竭的婴幼儿进行早期转诊。

重复胸部CT

• 建议：对2岁前诊断为chILD综合征的婴幼儿进行重复胸部CT，以辅助决策、评估预后和/或改变治疗。

证据分析

基因检测

• 背景：基因检测方法进步，改变了诊断模式，可避免有创检查，辅助预后和家庭规划。
• 证据基础：对9项chILD注册研究的回顾显示，基因检测诊断特定单基因chILD疾病的阳性率为26%，大多数儿童接受单基因或基因面板检测；不同类型基因检测和特定chILD疾病的诊断阳性率不同。
• 证据确定性：证据准确性的信心非常低，主要因多为回顾性研究，但因部分疾病严重且致命，推荐建议1A强度从有条件升级为强烈。
• 益处：可明确特定chILD疾病，减少住院费用，避免肺活检，为靶向治疗提供依据等。
• 不良影响：涉及基因信息隐私、保险和家族成员影响等问题，结果解读也存在专业人员不足等担忧。
• 其他考虑：基因型 - 表型相关性不明确，检测时机难评估，成本受多种因素影响。
• 合理性：至少25%的婴幼儿可通过基因检测明确单基因chILD疾病，部分可避免有创检查。
• 实施：考虑检测方法、成本和资源等因素，建议配备遗传咨询师。

胸部CT

• 背景：胸部X光诊断和指导肺活检部位选择有限，此前推荐高分辨率胸部CT，现评估其是否仍适用。
• 证据基础：对50项研究的评估涉及多种chILD疾病，总结了常见胸部CT模式。
• 证据确定性：因研究存在患者年龄、诊断标准等差异，缺乏随机临床试验，CT成像预测特定chILD疾病的价值有限。
• Benefits
  • Suggest specific disease or category via identifiable CT pattern
  • Guide treatment for various diagnoses
  • Establish baseline for parenchymal disease and monitor progression/response
  • Complement or support genetic testing
  • Identify lung biopsy sites
  • Provide info on concurrent lung conditions and comorbidities
• Undesirable Effects
  • Some radiologic patterns non - diagnostic
  • Findings confounded by acute illness or prolonged ventilation
  • Dependent on protocol
  • Risks: radiation exposure, need for anesthesia, transporting critically ill child
  • May be unrecognized by inexperienced radiologists
• Values
  • Most caregivers willing, but concerned about radiation and anesthesia
• Other Considerations
  • Consider transport risk for critically ill patients
  • Inequity in diagnosis time, radiation exposure, and cost for some
  • Higher risk of hematologic malignancy from radiation
  • Use pediatric protocols to limit radiation
  • Choice between controlled ventilation and free breathing scans depends on institution and patient
• Justification
  • Radiologic pattern supports diagnosis and guides treatment
  • CT may not be necessary for children with established genetic diagnoses but useful for surveillance, etc.
• Implementation
  • Refer to pediatric - centered institutions with experienced radiologists
  • Acceptable protocols (controlled or free breathing) should minimize motion artifact
  • Contrast agents not always needed but useful in specific scenarios
  • Refer to experienced center if initial facility can't perform high - quality CT
  • Transfer existing CT images if patient is referred

外科肺活检

• Recommendations
  • 3A: Suggest for those with non - diagnostic investigations and non - improving condition (conditional, very low certainty)
  • 3B: Recommend for those with clinical urgency, when genetic testing is not feasible, etc. (strong, very low certainty)
• Background
  • Genetic testing and imaging facilitate non - biopsy diagnoses, but not always available or diagnostic
  • Useful for determining biopsy necessity and timing when genetic results are unclear
  • Some patients benefit from biopsy for 'treatable traits'
• Evidence Base
  • Timing of Lung Biopsy
    • Limited info on biopsy sequence in diagnostic algorithm
    • Variable use of biopsy depending on suspected disorder
    • Some studies reported unclassified patients with/without biopsy
    • Some studies had unavailable or unobtainable genetic testing before biopsy
  • Diagnostic Yield, Management Changes, and Safety
    • High diagnostic rates in some studies
    • 57 - 86% of patients had management changes after biopsy
    • Complications reported in 6 studies, no mortality
    • Higher complication risk in ECMO - supported patients (not significant)
    • VATS has equivalent diagnostic yield with few complications in stable patients
• Certainty of Evidence
  • Very low due to study limitations (single - center, retrospective, etc.)
• Benefits
  • Narrow differential diagnosis
  • Provide evidence for 'treatable traits'
  • Establish prognosis and guide treatment decisions
  • Store biopsy material for future studies
• Undesirable Effects
  • Mortality (low), pneumothorax, hemorrhage, pain, increased ICU stay
  • Risk of unclassifiable biopsy
  • Decisions on biopsy type not well - established
  • Results may complicate transplant decisions
• Values
  • Caregivers value diagnosis certainty, treatment options, and prognosis
• Other Considerations
  • Some hospitals lack pediatric surgical expertise
  • Biopsy timing affected by concurrent surgery
  • Travel for biopsy can be a hardship
  • Clinical course factors may affect biopsy interpretation
• Justification
  • Strong recommendation for urgent cases due to potential benefits
  • Conditional recommendation for non - urgent cases
• Implementation
  • Obtain biopsy at experienced center
  • Consider timing relative to other treatments
  • Follow established biopsy protocols
  • Submit separate microbiology specimen if needed
  • Review by an expert pathologist

肺移植评估转诊

• Recommendations
  • 4a: Recommend early referral for specific monogenic chILD disorders with poor outcomes (strong, very low certainty)
  • 4b: Suggest early referral for those with ventilation/ECMO need, progressive PH, or specific disorder with respiratory symptoms (conditional, very low certainty)
• Background
  • Lung transplant or palliative care are options for fatal monogenic chILD disorders
  • Early referral may reduce evaluation time and increase acceptance likelihood
  • Some disorders have multi - organ involvement for transplant evaluation
  • Referring physicians should consider indications early
• Evidence Base
  • Timing of Lung Transplant Referral
    • No studies on timing; younger age associated with shorter listing - to - death time
  • Alternative Outcomes
    • ECMO and mechanical ventilation at transplant associated with higher mortality
    • Other risk factors for post - transplant mortality identified
    • Younger patients have fewer rejection episodes and BOS
  • Monogenic Variants
    • Biallelic loss - of - function ABCA3, SFTPB variants associated with poor outcomes
    • Some FLNA variants and ACDMPV may require early referral
• Certainty of Evidence
  • Very low due to indirect outcomes, imprecision, and bias; 4a upgraded to strong
• Benefits
  • Access specialized services, treatment options, and research
  • Time for assessment, intervention, and building trust
• Undesirable Effects
  • Low - volume procedure, long - distance travel
  • Unnecessary transfers and increased costs
• Values
  • Early referral improves trust and provides transplant education
• Other Considerations
  • Strong recommendation for high - fatality disorders
  • Suggest referral for others with significant symptoms
  • Access may be inequitable for some families
• Implementation
  • Create a pediatric lung transplant referral pathway

重复胸部CT

• Recommendation
  • Suggest repeat CT for decision - making, prognosis, and targeting 'treatable traits' (conditional, very low certainty)
• Background
  • Chest CT is key for initial diagnosis
  • Repeat CT shows disease progression/remission and guides therapy
• Evidence Base
  • Humidifier Disinfectant - Associated Lung Disease (HD - ILD)
    • 53 patients had repeat CT
    • CT findings categorized into stages
    • Resolution of certain findings associated with better outcomes
  • Other disorders (NEHI, PIBO, etc.) also studied, but details not fully summarized
• 不同疾病重复CT时间
  • NEHI：4 - 72个月
  • PIBO：1 - 6年
  • 肺间质糖原沉积症：3 - 12年
  • 遗传性表面活性物质功能障碍疾病：3个月 - 18年
• 不同疾病重复CT表现
  • NEHI：部分或完全解决磨玻璃影（GGOs），CT改善与临床改善相关，与特定治疗无关
  • PIBO：74%改善，18%无变化，8%恶化，进展表现为支气管扩张或继发并发症
  • 肺间质糖原沉积症：多数儿童GGOs减少或消失，出现实质带增加等，缺乏放射学与临床结局关联
  • 遗传性表面活性物质功能障碍疾病：多数表现为进行性结构扭曲，部分GGOs减少与临床改善相关，部分无关
• 益处
  • 识别与原诊断不一致特征
  • 发现初始CT未充分认识的影像学特征
  • 识别可治疗特征
  • 评估治疗反应
  • 完善预后或提示肺移植评估
• 不良影响
  • 辐射和麻醉风险
  • 偶然发现
  • 儿童和家庭负担
  • 医疗资源成本
• 价值
  • 患者、护理人员和提供者认为是必要工具，当潜在益处大于风险且有专业知识时更受重视
• 其他考虑
  • 涉及广泛协调，依赖机构资源
  • 最佳频率未知，满足临床标准可考虑
  • 临床‘Fan’评分3分及以上可每三年考虑
  • 近期呼吸道感染建议等待6 - 8周
  • 相对整体护理成本，重复CT成本较小
• 理由
  • 文献和专家共识支持用于评估非典型疾病进展、治疗反应等，证据确定性低
• 实施
  • 标准化扫描协议，减少辐射暴露，优化图像质量
  • 儿科肺科医生、放射科医生和麻醉科医生协作
  • 咨询chILD中心或专家

研究优先级

常见优先级

• 多中心和国际合作
• 标准化检测、成像、病理评估和移植转诊方法
• 识别非侵入性生物标志物

遗传学

• 确定最适合和成本效益高的基因检测方法
• 开发数据库和生物样本库
• 改进确定基因变异致病性的方法
• 确定重新检测或分析基因组数据的最佳时机和方法

胸部成像

• 改善放射学与病理学特征关联
• 优化CT协议，避免镇静
• 评估替代成像方式

组织病理学

• 标准化肺活检组织处理协议
• 评估活检样本充分性

移植评估转诊

• 跟踪移植前患者
• 建立标准化转诊方法
• 扩大远程医疗能力

重复胸部成像

• 验证重复CT标准
• 改善可治疗特征识别和关联
• 监测疾病进展
• 改进儿科放射学 - 组织病理学关联研究

结论

• 提供基因检测、胸部成像、肺活检和肺移植评估的循证建议
• 促进多学科护理
• 为未来研究提供基础
• 国际合作和注册对疾病特征化和临床试验至关重要