"Science means constantly walking a tight rope" Heinrich Rohrer, physicist, 1933. Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease worldwide and disproportionately affects older adults and children. In high-income countries, pneumonia is one of the most common reasons for hospitalisation and (when recurrent) is associated with a risk of developing chronic pulmonary conditions in adulthood. Pneumococcal pneumonia is particularly prevalent in older adults, and here, pneumonia is still associated with significant mortality despite the widespread use of pneumococcal vaccination in middleand high-income countries and a low prevalence of resistant organisms. In older adults, 11% of pneumonia survivors are readmitted within months of discharge, often with a further pneumonia episode and with worse outcomes. In children, recurrent pneumonia occurs in approximately 10% of survivors and therefore is a significant cause of healthcare use. Current antibiotic trials focus on short-term outcomes and increasingly shorter courses of antibiotic therapy. However, the high requirement for further treatment for recurrent pneumonia questions the effectiveness of current strategies, and there is increasing global concern about our reliance on antibiotics to treat infections. Novel therapeutic targets and approaches are needed to improve outcomes. Neutrophils are the most abundant immune cell and among the first responders to infection. Appropriate neutrophil responses are crucial to host defence, as evidenced by the poor outcomes seen in neutropenia. Neutrophils from older adults appear to be dysfunctional, displaying a reduced ability to target infected or inflamed tissue, poor phagocytic responses and a reduced capacity to release neutrophil extracellular traps (NETs); this occurs in health, but responses are further diminished during infection and particularly during sepsis, where a reduced response to granulocyte colony-stimulating factor (G-CSF) inhibits the release of immature neutrophils from the bone marrow. Of note, neutrophil responses are similar in preterm infants. Here, the storage pool is decreased, neutrophils are less able to degranulate, have a reduced migratory capacity and are less able to release NETs. Less is known about neutrophil function from older children, but theoretically, impaired functions might increase susceptibility to infections. Targeting these blunted responses may offer a new paradigm for treating CAP, but modifying neutrophil behaviour is challenging; reducing their numbers or inhibiting their function is associated with poor clinical outcomes from infection. Uncontrolled activation and degranulation can cause significant host tissue damage. Any neutrophil-based intervention must walk the tightrope described by Heinrich Rohrer, facilitating necessary phagocytic functions while preventing bystander host damage, and this is a significant challenge which this review will explore.

中文翻译：

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社区获得性肺炎中的中性粒细胞：极端年龄时功能障碍的相似之处

“科学意味着不断地走紧绳索”，物理学家 Heinrich Rohrer，1933 年。社区获得性肺炎 (CAP) 是全球传染病死亡的主要原因，对老年人和儿童的影响尤为严重。在高收入国家，肺炎是最常见的住院原因之一，并且（当复发时）与成年后患慢性肺部疾病的风险有关。肺炎球菌性肺炎在老年人中尤为普遍，尽管在中等和高收入国家广泛使用肺炎球菌疫苗，并且耐药菌的流行率很低，但肺炎仍然与显着死亡率相关。在老年人中，11% 的肺炎幸存者在出院数月内重新入院，通常伴有进一步的肺炎发作和更糟糕的结果。在儿童中，大约 10% 的幸存者会出现复发性肺炎，因此是使用医疗保健的重要原因。目前的抗生素试验侧重于短期结果和越来越短的抗生素治疗疗程。然而，对复发性肺炎进一步治疗的高要求质疑当前策略的有效性，全球越来越关注我们对抗生素治疗感染的依赖。需要新的治疗靶点和方法来改善结果。中性粒细胞是最丰富的免疫细胞，也是感染的第一反应者。适当的中性粒细胞反应对于宿主防御至关重要，中性粒细胞减少症的不良结果就是证明。来自老年人的中性粒细胞似乎功能失调，表现出针对受感染或发炎组织的能力降低、吞噬反应差以及释放中性粒细胞胞外陷阱 (NET) 的能力降低；这发生在健康中，但在感染期间反应会进一步减弱，尤其是在败血症期间，对粒细胞集落刺激因子 (G-CSF) 的反应降低会抑制骨髓中未成熟中性粒细胞的释放。值得注意的是，早产儿的中性粒细胞反应相似。在这里，存储池减少，中性粒细胞脱粒能力降低，迁移能力降低，释放 NETs 的能力降低。对年龄较大的儿童的中性粒细胞功能知之甚少，但理论上，功能受损可能会增加对感染的易感性。针对这些迟钝的反应可能会为治疗 CAP 提供新的范式，但改变中性粒细胞行为具有挑战性；减少它们的数量或抑制它们的功能与感染的不良临床结果有关。不受控制的活化和脱粒会导致严重的宿主组织损伤。任何基于中性粒细胞的干预措施都必须像 Heinrich Rohrer 所描述的那样走钢丝，促进必要的吞噬功能，同时防止旁观者宿主受损，这是本综述将探讨的一项重大挑战。