以纵隔淋巴结肿大为突出表现的儿童肺隐球菌病3例报告

Abstract

In this study, we report on three immunocompetent children with pulmonary cryptococcosis presenting mediastinal lymphadenopathy as the prominent manifestation. All three children were otherwise healthy previously. Two children had a history of exposure to pigeons and poultry. All three presented persistent fever accompanied by mild cough. There were no obvious positive signs in the lungs. One patient had enlarged cervical lymph nodes. All three had elevated levels of white blood cells, neutrophil count, and C-reactive protein (CRP). The levels of IgG, IgM, IgA, IgE and T cell subsets were normal in all cases, and they were all tested negative for HIV antibody. Two children were tested positive for serum cryptococcal antigen (sCRAG). The chest X-ray and pulmonary CT findings of the three patients all demonstrated marked enlargement of mediastinal lymph nodes, and one patient had nodules in the parenchyma. Surgical biopsies of mediastinal lymph nodes were performed in two children and large numbers of capsule spores were found in the histological examination. In the three cases, definitive diagnosis of pulmonary cryptococcosis were made in two patients, and clinical diagnosis was made in the third patient. Two patients were treated with fluconazole alone. The other patient whose condition was complicated with spleen infection was treated with fluconazole combined with amphotericin B for the first month, and was then given fluconazole for maintenance treatment. The overall treatment course lasted 5-9 months and all three were cured eventually. In conclusion, immunocompetent children with pulmonary cryptococcosis may present mediastinal lymphadenopathy as a prominent or isolated manifestation, which should be considered in differential diagnosis. Treatment with fluconazole alone or in combination with amphotericin B when it was necessary showed good therapeutic outcomes.

隐球菌是一种环境腐生菌，鸽子是其天然宿主，鸽粪污染的土壤是主要传播媒介，其它家禽和猫狗等宠物也可携带隐球菌。肺隐球菌病是由吸入空气中的隐球菌孢子引起的一种肺部真菌病，常见于免疫功能低下，尤其是细胞免疫功能低下患者。近年关于免疫功能正常患者肺隐球菌病的报道不断增多，其临床表现具有一定的特征性^[1-4]。在免疫功能正常的患者，临床症状相对较轻，最常见肺部影像表现为单发或多发结节或团块^[1-6]，但目前尚未见以纵隔淋巴结肿大为突出表现的肺隐球菌病报道。本文对3例以纵隔淋巴结肿大为主要表现的儿童肺隐球菌病进行报道，旨在进一步提高对儿童肺隐球菌病的认识。

1. 病例资料

一般资料：3例患儿中男2例，女1例，年龄分别为3岁、7岁和10岁，既往均体健，无反复感染病史，生长发育好。1例邻居家饲养鸽子，1例家中饲养牛和鸡，1例否认动物接触史。临床表现：3例患儿均持续或者间断发热3～6周，中～高热，1例在确诊前体温逐渐恢复正常；均伴轻咳，以干咳为主，无咯血、气促等。肺部查体均未见明显异常，肝脾无肿大，例2伴颈部淋巴结肿大，直径2 cm×2 cm，质地硬，无红肿，活动度差。辅助检查：3例患儿白细胞计数（12.4×10⁹～23.7×10⁹L^－1）、中性粒细胞比例（67%～82%）及血清C反应蛋白（C-reactive protein, CRP）均升高（40～160 mg/L，正常<8 mg/L）。1例伴嗜酸细胞升高（18%）。2例患儿血新隐球菌荚膜多糖抗原阳性（正常<1∶8），分别为1∶16和1∶64；3例患儿结核菌素试验均阴性；支气管灌洗液抗酸染色、细菌培养、真菌培养均阴性。3例均行脑脊液检查，墨汁染色及隐球菌荚膜多糖抗原检测均阴性。1例患儿腹部B超脾脏可见小低密度灶，脾脏无肿大。3例患儿体液免疫（IgA，IgM，IgG，IgE）及淋巴细胞亚群均正常，人类免疫缺陷病毒（HIV）抗体检测均阴性。肺部影像学表现：3例患儿胸片及肺CT均显示明显的纵隔淋巴结肿大，多发，甚至融合团块，增强后轻度环形强化，1例伴肺内散在结节，见图1。

图 1.

Pulmonaryimaging findings

肺部影像表现

A: Markedly enlarged mediastinal lymph nodes; B: Multiple enlarged mediastinal lymph nodes with slight ring enhancement; C: Scattered nodules in parenchyma.

诊断：2例为确诊，这2例行纵隔淋巴结活检示肉芽肿性炎，PAS染色和六胺银染色找到大量隐球菌孢子（图2），同时例1患儿血隐球菌抗原阳性，诊断为纵隔淋巴结隐球菌病，例2伴有颈部淋巴结播散（未做活检，但治疗后消失）。例3患儿血隐球菌抗原阳性，伴脾脏播散，两性霉素B联合氟康唑治疗有效，为临床诊断。治疗及转归：例1和例2患儿分别予氟康唑治疗9个月和6个月，例3患儿存在脾播散，初始两性霉素B联合氟康唑治疗1个月，之后予氟康唑维持治疗4个月。例2和例3在治疗后48～72 h后体温正常，例1在确诊前体温已正常，3例患儿均在治疗2～4周时复查纵隔淋巴结肿大吸收好转，颈部淋巴结明显缩小，治疗5～9个月最终病变均完全消失。治疗过程中，患儿对药物耐受好，未见明显不良反应。

图 2.

Mediastinal lympha node biopsy. ×40

纵隔淋巴结病理。 ×40

Abundant fungal yeasts with capsules were seen in PAS staining (A) and GMS staining (B) of mediastinal lymph node biopsy.

2. 讨论

儿童肺隐球菌病较成人相对少见，多见于免疫功能低下患儿，隐球菌的孢子很小，被吸入后可达到终末细支气管及肺泡腔。在免疫功能正常患者，隐球菌孢子被肺泡巨噬细胞吞噬，引起血管周围大量炎性细胞浸润，形成炎性肉芽肿，在肺CT上表现为单发或多发结节样病变，为免疫功能正常成人肺隐球菌病的最常见影像学表现，儿童肺隐球菌病的临床和影像学表现与成人类似，但以纵隔淋巴结肿大为独立或者突出表现者未见报道^{[1-3, 5-6]}。

病理组织找到新型隐球菌孢子和/或无菌呼吸道标本直接镜检或培养阳性是确诊隐球菌病“金标准”；血或呼吸道标本隐球菌荚膜多糖抗原阳性，结合肺部影像表现及抗真菌治疗有效，可临床诊断^{[5, 7]}。文中例1和例2患儿纵隔淋巴结活检组织病理均找到新型隐球菌为确诊病例。例3患儿可疑脾播散，血新型隐球菌抗原显著升高（1∶64），两性霉素B联合氟康唑治疗有效，为临床诊断。本文报道的这3例肺隐球菌病以多发纵隔淋巴结肿大为突出表现，临床均表现为长期发热、轻咳，呈亚急性和慢性病程，白细胞和CRP轻度到明显升高，脾脏播散者，CRP明显升高，这些表现均无特异性。影像学特点为肿大淋巴结分布广泛，累及前中后纵隔，可融合呈团块，增强CT可呈轻度强化。由于上述临床和影像学表现特点，极易误诊为淋巴瘤和肺结核。本文3例均先后考虑结核病和淋巴瘤，鉴别点为病原学检查和病理检查。隐球菌病的诊断依靠病原学培养阳性或者墨汁涂片阳性和/或隐球菌荚膜多糖抗原检测，一般认为血隐球菌荚膜多糖抗原阳性对隐球菌病诊断的特异性很高，但在单纯肺隐球菌病患儿的敏感性相对较低^[5]，阳性多提示播散性感染，本文3例患儿中2例隐球菌抗原阳性，2例分别存在颈部淋巴结播散和脾播散。3例患儿支气管-肺泡灌洗液虽墨汁染色未做，但真菌培养均阴性，考虑与以纵隔淋巴结侵犯为主，而无或者轻微肺内病变有关。

所有患儿未做基因检测，但体液免疫（IgA，IgM，IgG，IgE）及淋巴细胞亚群均正常，HIV抗体检测均阴性，提示无明显免疫功能缺陷。

虽然在免疫功能正常成人肺隐球菌病有自发缓解的倾向，但儿童免疫功能发育相对不成熟，有潜在播散的可能，因此儿童肺隐球菌病应积极予抗真菌治疗。氟康唑生物利用度高，副作用小，价格相对便宜，推荐为免疫功能正常儿童孤立性肺隐球菌病的首选用药^[8]。因例3发生脾脏播散，加用两性霉素B治疗，3例患儿均治愈，随访2年左右，无复发。

总之，在儿童纵隔淋巴结肿大的鉴别诊断中，应考虑到肺隐球菌病可能，予积极行血隐球菌荚膜抗原检测。单用氟康唑或者必要时加用两性霉素效果良好。

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