**3.3. Non-eosinophilic asthma: Neutrophilic, Th2-low asthma**

#### *3.3.1. Anti-tumor necrosis factor-α monoclonal antibodies*

Unfortunately, for patients belonging to severe asthma phenotypes other than eosinophilic asthma, current therapeutic options are scarce, and many of these patients are steroiddependent and even steroid-resistant [2]. Clinical trials with anti-tumour necrosis factor (TNF) α mAbs (such as infliximab, adalimumab, and golimumab) have been performed with discouraging results. A study including 309 patients with severe persistent asthma, random‐ ized to receive placebo or three different doses of golimumab (50, 100, and 200 mg), showed no significant improvement in any of the efficacy variables [64]. More importantly, the trial had to be prematurely discontinued due to serious adverse events (SAEs), namely infections and malignancies, in the golimumab group. A post-hoc analysis suggested that patients with a prestudy history of sinusitis and FEV1 reversibility (≥12%) who received golimumab (100 and 200 mg) had fewer severe asthma exacerbations, apparently associated with a dose– response effect. Perhaps, if biomarkers were developed for predicting response to anti-TNFα agents, then they could be used for selected subgroups of patients with severe asthma, but the contradictory efficacy results and especially the potential safety concerns have prevented the performance of any additional clinical trials so far.

#### *3.3.2. Bronchial thermoplasty*

cally significant. Significant differences in favor of dupilumab in the time until the first exacerbation and in the risk of exacerbations were also recorded. In the dupilumab patient group, both the morning peak expiratory flow (PEF) and the asthma symptoms evaluated by the ACQ5 improved significantly. Nocturnal awakenings and the use of short-acting beta-2

Regarding adverse effects, more local reactions at the injection site, nasopharyngitis, nausea, and headache were reported in patients on active treatment, and there was one case of angioedema. The authors of this study emphasize the effect of dupilumab on the reduced frequency of exacerbations, even after withdrawal of ICS and LABA. Nevertheless, they admit that the definition of "exacerbation" used in their protocol does not coincide with that usually employed in clinical practice and, accordingly, recommend that larger studies should be

As we have seen, most new mAbs under development are directed against different targets of the Th2 pathway [62]. A summary of all these drugs is found in Table 3. Figure 2 briefly sketches the allergic inflammatory cascade, so that we might easily visualize these therapeutic targets.

agonists were also reduced.

128 Asthma - From Childhood Asthma to ACOS Phenotypes

further performed [63].

**Figure 2.** Therapeutic targets within the allergic cascade.

Thermoplasty is a bronchoscopic procedure that reduces the bronchial smooth muscle layer by applying heat by radiofrequency. The results of the studies showed, in patients with moderate and severe asthma, a significant improvement in their quality of life, increased disease control, and a reduction of exacerbations. These results persist for years after the procedure, without medium- to long-term secondary effects [65–67]. While new evidence is needed to identify the ideal candidate, it is currently considered to be preferably indicated in patients with severe uncontrolled asthma, with chronic airflow limitation (FEV1 > 50% and <80%), and without bronchial hypersecretion. Likewise, its application is recommended to be performed in centers with experienced and sufficiently trained endoscopists [2].

### **4. Conclusions and future perspectives**

We are witnessing the rapid development of new molecules and also of promising new combinations in terms of efficacy, safety, and dosage for the treatment of asthma, except perhaps for treatment for a subgroup of patients with severe non-eosinophilic asthma, in which therapeutic options still remain limited. Given the heterogeneity of the disease, we consider it is important to establish the phenotype or endotype as a first step on the road to the "person‐ alized" medicine in asthma.

From a practical point of view, in Table 4 we present the personal opinion of the authors of this chapter on the individualized" utility of the new asthma treatments, already existing or proximally available.


*AERD = aspirin-exacerbated respiratory disease (or Samter's triad); ICS = inhaled corticosteroids; IL = interleukin; LABA = longacting beta-2-agonists; LAMA = long-acting muscarinic antagonists; NERD = non-steroidal anti-inflammatory drugs-exacerbated respiratory disease; Th2 = helper type 2 lymphocyte; TNF = tumour necrosis factor \* Clinical trials with anti-TNF agents (infliximab, adalimumab, and golimumab) had to be suspended prematurely due to the*

**Table 4.** The path to personalized treatment of asthma insufficiently controlled with ICS/LABA: Present and future.
