哮喘控制不佳时应考虑真菌感染的可能性

旧金山(EGMN)——潜在的肺部真菌定植或感染可能是部分儿童重度哮喘对常规治疗应答不充分的原因所在。

人们最近才开始认识真菌致敏的重度哮喘（SAFS）。在成人中，研究者已发现SAFS对口服伊曲康唑有应答（Am. J. Respir. Crit. Care Med. 2009;179:11-8）。

纽约Cohen儿童医疗中心的Alfin G. Vicencio 博士在美国胸科学会(ATS)年会上指出，SAFS也可发生在儿童中。

研究者招募了41例患有重度哮喘的儿童、青少年和年轻成人（年龄2~21岁），这些患者均曾接受4级或更高级别联合抗哮喘治疗而失败。研究者发现其中17例（41.5%）患者的血清真菌IgE水平高于100 IU/ml并且有真菌致敏的放射过敏原吸附或皮肤点刺试验证据，提示为SAFS。

11例（65%）患者对1种以上真菌敏感。曲霉菌是最常见的相关种类，其次是链格孢菌、念珠菌、枝孢菌、毛霉菌和青霉菌。

男孩和女孩患病率相似，但SAFS患者倾向于年龄较大、肺功能检查（PFT）结果交差，其第1秒用力呼气量（FEV1）为预测值的73.33%，而同龄的非SAFS患者为91.60%。有些孩子不符合SAFS诊断标准，虽然IgE水平高但没有真菌致敏的证据，或者有真菌致敏证据而IgE水平正常。

 “真菌在儿童哮喘控制不良中的作用很可能被低估了，同理，可能有不少能从抗真菌治疗中获益的患儿却未获得这一治疗。”

迄今为止，Vicencio 博士已采用伊曲康唑治疗了十余例儿科SAFS患者。“大约一半患儿治疗效果良好，其哮喘得到了更有效控制，我们还观察到了一些肺功能改善。他们的IgE水平是可变的，有些急剧下降，有些则没有。总体而言，真菌致敏是重度难治性哮喘的一个危险因素，我们相信抗真菌药物对某些患者是有益的。”

总的来说，“它看起来像是真菌致敏是一个危险因素，严重的持续性疾病。我们相信，将有一个作用，抗真菌剂在某些特定人群，”他说。

这项仍在进行中的研究已招募了大约60例难以控制的重度哮喘患儿，“其中可能有多达60%实际上存在真菌致敏”。

研究者计划对受试者进行痰或支气管肺泡灌洗检查，以了解年轻SAFS患者的肺部是否确实存在真菌。

基因分型也在进行中，以了解这些患者是否存在CHIT1基因突变，CHIT1是一种编码壳三糖酶的基因，而壳三糖酶是在哺乳动物中发现的一种天然抗真菌物质。在Vicencio博士此前已发表的一项系列病例研究中，6例儿科SAFS患者被发现携带这一突变。在3例接受伊曲康唑治疗的患儿中，2例应答良好，1例应答“极好”（Pediatrics 2010;126:e982-5）。

一般人群中约1/3的人携带这一突变，而绝大多数携带者并没有发病。不过，对于某些患有哮喘或有真菌暴露的人，“我们相信突变可能导致严重哮喘”。

Vicencio博士报告称无相关利益冲突。

爱思唯尔  版权所有

BY M. ALEXANDER OTTO
Elsevier Global Medical News
Breaking News

SAN FRANCISCO (EGMN)–Underlying pulmonary fungal colonization or infection may be the reason that some children with severe asthma don’t respond fully to conventional treatments.

Severe asthma with fungal sensitization (SAFS) has been recognized only recently. In adults, SAFS has been found to respond to oral itraconazole (Am. J. Respir. Crit. Care Med. 2009;179:11-8).

SAFS also occurs in children, according to Dr. Alfin G. Vicencio, chief of pediatric pulmonology and cystic fibrosis at Cohen Children’s Medical Center in New Hyde Park, New York, and his colleagues.

The researchers looked at 41 children, teens, and young adults (aged 2-21 years) with severe asthma who were failing level 4 or greater combination asthma therapy, and found that 17 (41.5%) had serum fungal IgE levels above 100 IU/mL and evidence of fungal sensitization on radioallergosorbent or skin-prick tests, indicating SAFS.

Eleven (65%) of those patients were sensitive to more than one fungal species. Aspergillus was the most commonly implicated species, followed by Alternaria, Candida, Cladosporium, Setomelanomma, Mucor, and Penicillium, Dr. Vicencio said at an international conference of the American Thoracic Society.

Boys and girls were affected equally, but SAFS patients tended to be older and have worse results on pulmonary function tests (PFTs) than their peers did, with forced expiratory volume in 1 second (FEV1) at 73.33% of predicted, for instance, compared with 91.60% in those without SAFS. Some of the children who didn’t meet the criteria for SAFS diagnosis had high IgE levels but no evidence of fungal sensitization, or evidence of fungal sensitivity but normal IgE levels.

“The contribution of fungi to poorly controlled asthma in children is likely to be underestimated, as is the number of patients who might benefit from antifungal therapy,” Dr. Vicencio said.

So far, he’s treated about a dozen pediatric SAFS patients with itraconazole. “About half of them have done very well. Their asthma is better controlled. We have documented some PFT improvements. Their IgE levels are variable; some of them are dropping dramatically, and some are not,” he said.

Overall, “what it looks like is that fungal sensitization is a risk factor for severe persistent disease. We do believe that there is going to be a role for antifungal agents in certain select populations,” he said.

The ongoing series now includes about 60 children with severe, poorly controlled asthma. “Something on the order of 60% actually have fungal sensitization,” Dr. Vicencio said.

Sputum testing or bronchoalveolar lavage is planned to see if young SAFS patients actually have fungus in their lungs.

Genotyping is also underway to see if these patients have a mutation in the CHIT1 gene, which encodes for chitotriosidase, a kind of natural antifungal found in mammals. Dr. Vicencio has published a case series in which the mutation was present in six pediatric SAFS patients tested for it. Of the three treated with itraconazole, two responded well and one responded “dramatically” (Pediatrics 2010;126:e982-5).

About a third of the general population has the mutation, and it doesn’t cause disease in most. However, in someone with asthma and fungal exposure, “we believe the mutation” might cause “a perfect storm for asthma,” he said.

Dr. Vicencio said he has no relevant disclosures.