**6. Management**

**5.3. Radiology**

**5.4. Biomarkers**

after an AECOPD.

in clinical practice.

A chest X-ray is mainly useful for excluding other pathology like pneumothorax, pleural fluid, congestive heart failure or otherwise. It may reveal consolidations or other pathology. In the acute phase a chest CT-scan has no additive value in the tract of diagnosing an exacerbation of COPD. It can be performed if doubts exist about the presence of pulmonary embolisms as an explanation for dyspnea and/or desaturation. In a patient with recurrent airways infections

Biomarkers can be used as indicators of a physiological state in which a patient is or may become, it can help in diagnosis, aetiology and prognosis. In theory, biomarkers could be used to predict exacerbations, to determine if a patient has increased inflammation, to distinguish type of inflammation (bacterial or viral infection or otherwise) or to predict clinical outcome

Many biomarkers have been researched of which many of them are of little clinical use. At this moment the most important biomarkers in AECOPD are CRP, serum IL-6, 8-isoprostane, H2O2 and procalcitonin (ProCT). These biomarkers are closely related to oxidative stress and inflammation. C-reactive protein is momentarily the most widely used marker of inflammation

In patients with frequent exacerbations, both CRP and serum IL-6 levels are increased during a stable phase but also during the recovery period of an AECOPD [58, 59] compared to patients with infrequent exacerbations. Interleukin-6 is a cytokine which is widely expressed and produced in the body, and is not specific to the lung. Serum IL-6 has no additional value above CRP in clinical decision making. Interleukin-6 levels in sputum may be of use to predict therapy response [58], although more research is needed before clinical decisions can be made based on this biomarker. Similarly, there is a lack of studies which investigate the use of exhaled biomarkers 8-isoporstane and H2O2 for clinical purposes. Procalcitonin may be a biomarker which can discriminate in aetiology of an exacerbation but may also be used as therapeutic response parameter. Procalcitonin is the precursor of calcitonin and is released in response to a bacterial infection by many tissues under stimulation of several cytokines. Procalcitonin levels are minimally raised in viral infections [60], making it a relative specific diagnostic tool for bacterial infections. Most research has been performed in patients with community acquired pneumonia (CAP) [61]. It is suggested that ProCT could become a useful tool in clinical decision making regarding antibiotic therapy. There have been several trials to assess the utility of ProCT in AECOPD. In general ProCT-guided antibiotic therapy compared to standard management in AECOPD showed no differences in death from any cause, rates of intensive care unit (ICU) admission for any reason, duration of ICU stay, improvement of symptoms, difference in the quality-of-life score, re-exacerbation and readmission [62]. Procalcitonin-guided antibiotic therapy showed reduction in antibiotic prescription [62] and in one study [63] also reduction in antibiotic therapy duration, which in turn decreases the patient's exposure to antibiotics and related side effects, lowers the burden of antibiotic use and the risk of antimicrobial resistance. Procalcitonin is not yet being implemented in standard

a CT-thorax can be performed to investigate whether bronchiectasis is present.

82 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

The treatment of an AECOPD consists of supportive therapy, maximal bronchodilation, steroids to reduce the inflammation and treatment of the cause.

#### **6.1. Supportive therapy**

Oxygen delivery is one of the first supportive therapies which can be provided for a patient. Oxygen saturation should be at least 90% though in some cases lower saturations may also be accepted. Too much oxygen may cause hypercapnia as the drive to breathe in some COPD patients may rely on arterial O2 pressure. Symptoms of acute hypercapnia are somnolence, headache, drowsiness, confusion, flushed skin or agitation. Physiotherapy during an admis‐ sion for an AECOPD can prevent deterioration in skeletal muscle function and improve exercise capacity [64, 65]. Because an AECOPD is accompanied by an impaired energy balance due to a decreased dietary intake and an increased resting energy expenditure, nutritional support may also benefit the patient in terms of general well-being and prevention of muscle wasting [66-68].

#### **6.2. Pharmacotherapy**

An exacerbation is the result of increased inflammation causing increased flow limitation. Treatment should be directed towards controlling this exacerbated inflammation and maxi‐ mizing bronchodilation. Short acting agents like salbutamol and ipratropium are mostly used for maximal bronchodilation, usually delivered by nebulizer. Many patients may not be able to generate the flows required to use other devices during an exacerbation. Corticosteroids have been proven to reduce time to recovery and treatment failure, increase FEV1 and arterial hypoxemia [8]. Treatment schemes have been reported varying from 30 mg prednisolone orally to 60 mg intravenous, ranging from 5 days to two weeks. Studies showed that there is no difference in clinical outcome if a patient is treated with oral steroids compared to parenteral steroids [69]. Antibiotic treatment can be initiated when a bacterial infection is suspected. With the Anthonisen criteria [70] one can decide whether antibiotic treatment is necessary or not. These criteria are derived from a randomized placebo-controlled crossover trial which has been performed in the '80s where patients with COPD exacerbations were treated with antibiotics or placebo. The cardinal symptoms of infection in this study were increased sputum volume and purulence in combination with increased dyspnea. An exacerbation with all the previous 3 symptoms is called a type 1 exacerbation; two out of three symptoms have to be present for a type 2 exacerbation; one out of three and at least one other "minor symptom" (see table 2) have to be present for it to be a type 3 exacerbation. Patients with type 1 and type 2 exacerbations are most likely to benefit from antibiotic therapy. In Spain a pilot study was performed with hospitalized patients with AECOPD, where antibiotic therapy was given to patients with self-reported purulent sputum and withheld in patients with non-purulent sputum [71]. There was no difference between the two groups in treatment failure on day 3, suggesting patient reported non-purulent sputum may be a valid criterion to withhold antibiotics [71]. A Dutch study showed that addition of doxycycline to the treatment regimen with glucocorticoids of a patient with an exacerbation was superior on day 10 but equivalent on day 30 in terms of clinical success and clinical cure compared to glucocorticoids alone, even in patients not showing signs of infection [72]. Most recently Spanish investigators performed a multicenter trial where they suggested that treatment of a mild to moderate exacerbation with amoxicillin/clavulanate, independent of glucocorticoids treatment, might give better clinical cure after 10 days compared to placebo [73]. In this study the median time to next exacerbation was also increased in patients receiving antibiotics compared to placebo. Unfortunately, because of recruitment problems this study did not reach the calculated amount of patients needed, so that definite conclusions cannot be made from the results of this study.

patients with COPD. Investigation on this subject is ongoing. Of the non-pharmacologic interventions, pulmonary rehabilitation is the most effective in reducing hospital admissions and mortality and improving health-related quality of life in COPD patients who have recently

Acute Exacerbations of Chronic Obstructive Pulmonary Disease

http://dx.doi.org/10.5772/54867

85

Long-acting bronchodilators can be divided in two groups: long acting muscarinic receptor antagonists (LAMAs) and long acting β-agonists (LABAs). Both have proven to show a positive effect on exacerbation reduction and improvement in quality of life [75-79]. An overview of

Of the long-acting bronchodilators, indacaterol and glycopyrronium are the most recent additions for the treatment of COPD. Indacaterol is proven to be superior to formoterol, salmeterol and tiotropium in terms of use of rescue medication, dyspnoea score and health related quality of life. Compared to salmeterol and formoterol it is also superior in improving spirometry values. Indacaterol is non-inferior to tiotropium but when added to tiotropium therapy it is superior compared to tiotropium alone [80]. Indacaterol also lowers the risk of AECOPD compared to placebo [78, 81, 82]. Glycopyrronium has been approved in 2012 as therapy for COPD. It provides significant improvements in lung function, dyspnoea, health status, exacerbation frequency and rescue medication use versus placebo, and is comparable to tiotropium [83, 84]. The combination of glycopyrronium and indacaterol has shown superiority in bronchodilation compared to indacaterol alone [85]. Glycopyrronium has not

Inhalation corticosteroids (ICS) can be given to patients with high risk of exacerbations. In several studies ICS provided a reduction of symptoms (dyspnea, cough) and reduced the frequency of exacerbations [86-88]. The GOLD guidelines advise treatment for high exacerba‐ tion risk patients with few symptoms (group C) with a combination of ICS/LABA or a LAMA alone, or a combination of LABA and LAMA [8]. For high exacerbation risk patients who have many symptoms (group D) the same treatment is advised as for group C, also a combination

suffered an exacerbation of COPD [74].

the long-acting bronchodilators is given in table 3.

**LABA LAMA** Formoterol Tiotropium Arfomoterol Glycopyrronium

**Table 3.** An overview of available long-acting bronchodilators.

been compared to other LABAs yet.

of all three classes of inhalation drugs is possible [8].

**7.3. Inhalation corticosteroids**

**7.2. Long-acting bronchodilators**

Salmeterol Indacaterol


**Table 2.** Classification of acute exacerbations of COPD according to Anthonisen criteria [70]
