【Cochrane简语概要】六个月前第一次注射全细胞百日咳疫苗能预防儿童过敏性疾病吗？

什么是过敏性疾病？

过敏性疾病是儿童最常见的顽固性疾病之一。这类疾病是由免疫系统对食物和花粉等无害物质的异常反应引起的。食物过敏日益引起人们的关注，因为在过去30年中，一些高收入国家报告的病例数量似乎有所增加。

（图片来自qld.gov.au）

我们为什么要做本Cochrane系统综述？

在婴儿饮食中早期引入花生和鸡蛋是唯一被证实的预防食物过敏的策略。然而，最近的一项研究发现，在婴儿早期接种一剂或多剂全细胞（wP）百日咳疫苗的儿童中，食物过敏的发生率似乎低于仅接种非细胞（aP）百日咳疫苗的儿童。由于疫苗不是随机分配的，该研究无法确定过敏风险明显降低是因为wP疫苗，还是因为接种wP疫苗和ap疫苗的儿童之间存在其他潜在差异。因此，需要Cochrane系统综述来确定wP作为食物过敏预防策略的尽可能的证据。

我们做了什么？

我们检索了对6个月以下婴儿接种wP和aP疫苗进行比较的研究。我们对接种wP疫苗的婴儿与接种aP疫苗的婴儿在以下方面进行的比较感兴趣：

1.有多少婴儿患上了食物过敏、哮喘或严重的（可能危及生命的）过敏反应；

2.接种疫苗后发生严重意外事件的人数；以及，

3.有多少人患有脑病，这是一种严重但不常见的影响大脑的疾病。

为了比较脑病和其他严重意外事件的发生率，我们寻找了婴儿随机接种wP或aP疫苗的研究（随机对照临床试验（randomised controlled trials, RCTs））。比较过敏性疾病的发生率，我们还寻找了非随机接种wP或aP疫苗的研究（干预的非随机研究（non-randomised studies of interventions, NRSIs））。在这两种情况下，研究至少持续了六个月。

检索日期

我们纳入了截至2020年9月发布的证据。

我们发现了什么

调查研究1

我们发现在瑞典（一项）、澳大利亚（两项）和英国（一项）进行的四项研究（7333名儿童）观察了百日咳疫苗对过敏性疾病的影响。由于我们找到的关于接种百日咳疫苗后食物过敏风险的可靠数据较少，我们决定研究任何过敏性疾病的风险。在接种百日咳疫苗（1项RCT）的2.5年内，37/137名接种wP的儿童和114/360名接种aP的儿童被诊断至少患有一种过敏性疾病。在同一时期，15/137接种wP和38/360接种aP被诊断为哮喘。没有研究评估严重或潜在危及生命的过敏反应。

调查研究2和3

所有组（15项研究，38,072名儿童）都报告了少量的严重不良影响。每1000名接种第一剂wP的婴儿中，就有11名婴儿至少有一种严重的不良影响。接种aP疫苗的风险为12名儿童至少有一种严重的不良影响。两组均未发现脑病病例（7项研究，115,271名儿童）。

这些调查结果有多可靠？

一项关于百日咳疫苗和过敏性疾病的随机对照临床试验报告纳入了少数儿童，并在一个过敏性疾病水平较低的国家进行。因此，第一剂wP是否能降低过敏性疾病的风险仍然非常不确定。

很少有儿童经历过严重的不良反应。我们不确定与aP相比，接种第一剂wP的儿童发生严重不良反应的风险是否存在差异，但任何差异都可能很小。未报告接种疫苗后发生脑病的病例。由于这是一个严重的结局，因此证据被评定为低质量证据。

关键信息

正在进行的和未来的研究可能会改变我们的结论，并提供更明确的证据。系统综述的数据表明，wP是安全的，并支持那些仍推荐将wP用于预防百日咳的国家继续使用。

作者结论: 

有极低质量的证据表明，与第一剂aP相比，在婴儿早期给予第一剂wP会影响儿童患特应性疾病的风险。wP和aP疫苗接种者的全因严重不良事件发生率较低，没有脑病病例报告。对于证据质量等级，全因性SAEs被判定为中等级别质量证据，脑病被判定为低级别质量证据。

未来的研究应该使用与临床相关的敏感性和特异性终点指标，并且应该在IgE介导的食物过敏高流行的环境中进行。安全终点指标应优先考虑常见疫苗反应、父母可接受性、SAEs及其与给药剂量的潜在相关性。

作者：Perez Chacon G, Ramsay J, Brennan-Jones CG, Estcourt MJ, Richmond P, Holt P, Snelling T；译者：黄颖娟，武汉大学；审校：靳英辉，武汉大学中南医院循证与转化医学中心；编辑排版：索于思，北京中医药大学循证医学中心

相关文章链接

【Cochrane Plain Language Summary】Can a first dose of whole-cell whooping cough vaccine given before six months old prevent allergic diseases in childhood?

What are allergic diseases?

Allergic diseases are among the most common persistent illnesses in children. They are caused by the immune system reacting abnormally to otherwise harmless substances such as foods and pollens. Food allergies are of increasing concern as the number of cases reported in a number of high-income countries over the past 30 years appears to have increased.

Why we did this Cochrane Review?

The only proven preventive strategy against food allergies is early introduction of peanut and egg into the infant diet. However, a recent study found that food allergies appeared less common in children who had received one or more doses of whole-cell (wP) whooping cough vaccine in early infancy than in those who had received acellular (aP) whooping cough vaccines only. That study could not determine whether the apparently lower risk of allergy was because of the wP vaccine, or whether it was because of other potential differences between wP and aP-vaccinated children, as the vaccines were not randomly assigned. Therefore, a Cochrane Review was required to identify any evidence of wP as a food allergy prevention strategy.

What did we do?

We searched for studies that compared wP versus aP vaccination in babies younger than six months. We were interested in comparing babies vaccinated with wP vaccines and those vaccinated with aP vaccines, with respect to:

1. how many went on to develop food allergy, asthma or serious (and potentially life-threatening) allergic reactions;

2. how many had serious unwanted events following vaccination; and,

3. how many had encephalopathy, a serious yet uncommon condition affecting the brain.

To compare rates of encephalopathy and other serious unwanted events, we looked for studies in which babies were given wP or aP vaccines at random (randomised controlled trials (RCTs)). To compare rates of allergic diseases, we also looked for studies where wP or aP vaccines were not given at random (non-randomised studies of interventions (NRSIs)). In either case, studies lasted for at least six months.

Search date

We included evidence published up to September 2020.

What we found

Investigation 1

We found four studies (7333 children) carried out in Sweden (one), Australia (two) and the UK (one) that looked at the effect of whooping cough vaccines on allergic diseases. As we found little reliable data about the risk of food allergy after whooping cough vaccine, we decided to look at the risk of any allergic disease. Within 2.5 years of receiving a whooping cough vaccine (one RCT), 37/137 children vaccinated with wP, and 114/360 vaccinated with aP were diagnosed with at least one allergic disease. During the same period 15/137 vaccinated with wP and 38/360 vaccinated with aP were diagnosed with asthma specifically. No studies assessed serious or potentially life-threatening allergic reactions.

Investigations 2 & 3

Low numbers of serious unwanted effects were reported for all groups (15 studies, 38,072 children). For every 1000 babies vaccinated with a first dose of wP, 11 had at least one serious unwanted effect. The risk for those who received aP vaccines was 12 children. No cases of encephalopathy were identified in either group (seven studies, 115,271 children).

How reliable are these findings?

One RCT reporting on whooping cough vaccines and allergic diseases included few children, and was carried out in a country with low levels of allergic disease. Therefore, it remains very uncertain whether a first dose of wP does or does not decrease the risk of allergic diseases.

Very few children experienced serious unwanted effects. We are uncertain whether there is a difference in the risk of serious unwanted effects in children vaccinated with a first dose of wP, compared with aP, but any difference is likely to be small. No cases of encephalopathy following vaccination were reported. Because this is a serious outcome, the certainty of the evidence was judged to be low.

Key messages

Ongoing and future studies may change our conclusions and provide more definitive evidence. The data reviewed suggest that wP is safe and support its continued use in countries where it is still recommended for preventing whooping cough.

Authors' conclusions: 

There is very low-certainty evidence that a first dose of wP given early in infancy, compared to a first dose of aP, affects the risk of atopic diseases in children. The incidence of all-cause SAEs in wP and aP vaccinees was low, and no cases of encephalopathy were reported. The certainty of the evidence was judged as moderate for all-cause SAEs, and low for encephalopathy.

Future studies should use sensitive and specific endpoints of clinical relevance, and should be conducted in settings with high prevalence of IgE-mediated food allergy. Safety endpoints should prioritise common vaccine reactions, parental acceptability, SAEs and their potential relatedness to the dose administered.

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