Hospitalized acute exacerbations of chronic obstructive pulmonary disease: which patients may have a negative clinical outcome?

KEYWORDS:

• COPD
• acute exacerbation
• hospitalization
• outcome
• failure

1. Introduction

Hospitalization for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) increases the disease-related mortality risk [1], and so a tailored approach to the management of the disease is required [2]. At admission, early identification of risk factors for negative outcomes may help physicians to decide whether to maximize treatment for the current exacerbation or whether to apply close in-hospital or early discharge monitoring in order to prevent subsequent worse events.

In this editorial, we focus on patients with a severe AECOPD needing hospitalization in whom a negative clinical outcome is likely. Negative clinical outcome is defined as failure of treatment, failure of non-invasive mechanical ventilation (NIMV), prolonged hospital stay, and a higher rate of short-term mortality or early readmission.

2. Patients with a high risk of treatment failure

The failure of a pharmacological treatment, defined by the persistence or worsening of disease symptoms [3], occurs in around 15% of AECOPD patients treated with both antibiotics and systemic steroids [4]. The choice of initial treatment is a useful guide to the patient’s subsequent clinical course [5]. Day-to-day evaluation of patient-reported symptoms in hospitalized AECOPD found the absence of improvement on the Clinical COPD Questionnaire (a 10-item health status scale measuring symptoms, functional status and mental state) to be a predictor of treatment failure (Hazard ratios [HR] 0.636; 95% confidence interval [CI] 0.427 to 0.947) [6]. Similarly, a high early inflammatory response at admission to hospital, measured by C-reactive protein (CRP) levels (+1 mg/dL odds ratios [OR] 1.07; 95% CI 1.01 to 1.13) and the choice of antibiotic (penicillins or cephalosporins, OR 5.63; 95% CI 1.26 to 25.07) were independently associated with an increased risk of treatment failure [4]. A good lung function value (assessed by the forced expiratory volume in the first second [FEV₁] HR 0.949; 95% CI 0.907 to 0.993) [6] and the presence of cough symptoms at admission (OR 0.20; 95% CI 0.05 to 0.75) [4] were associated with a lower risk of failure. This latter protective risk factor, evaluated only by clinical observation, is probably related to a defense mechanism of the airways with improved mucus clearance and better treatment efficacy [4].

3. Patients with a high risk of non-invasive mechanical ventilation failure

In AECOPD patients who develop respiratory fatigue with hypercapnia and acute respiratory acidosis, non-invasive mechanical ventilation (NIMV) is strongly recommended [2]. The need for endotracheal intubation (ETI) is taken as a definition of NIMV failure [2,7]. NIMV failure is divided into immediate (occurring within one hour), early (within 48 hours), and late (after 48 hours) [7]. A weak cough reflex with/without the presence of excessive secretions, reduced level of consciousness, and psychomotor agitation also causing patient-ventilator asynchrony have been reported as common risk factors for immediate NIMV failure [7]. The severity of hypercapnia and acidosis at admission (pH < 7.25) or an increased respiratory rate (RR >35 breaths/min) are associated with early NIMV failure [7]. Specific risk charts reporting these relevant variables together during an AECOPD, reflect the probability of NIMV failure [8]: patients with a Glasgow Coma Score (GCS) <11, an acute physiology and chronic health evaluation (APACHE) II ≥ 29, a RR ≥ 30 breaths/min, and a pH at admission <7.25 have a predicted risk of failure >70% [8]. Close monitoring of the arterial blood gas analysis, and in particular of pH, is therefore necessary to identify early NIMV failure, in which case an ETI should be requested immediately [2,7]; ETI should never be delayed in patients with severe AECOPD, because this would worsen prognosis [2,7,8]. In the context of NIMV failure that occurs in the late period, sleep disturbances or functional limitations before admission may be recognized as important causes [7]. Recently, in patients hospitalized for AECOPD, ultrasound evaluation of diaphragmatic dysfunction (DD) accurately identified patients at higher risk of NIMV failure [9]. Moreover, change in diaphragm thickness predicted NIMV failure better than pH value at admission or change in both pH and partial arterial carbon dioxide pressure (PaCO₂) after the start of NIMV [9].

4. Patients with a high risk of prolonged stay

Length of hospital stay (LOS) for AECOPD has a major impact on the costs of disease management [10]. Although common reasons impacting upon protracted hospital lengths of stay include social issues at home or bed blocking at post-discharge facilities [10], the early identification of patients with a higher risk of a prolonged LOS could help to target specific interventions. Some clinical variables [11] such as the presence of cor pulmonale (OR 2.19; 95% CI 1.27 to 3.78), the respiratory rate at admission (OR 1.09; 95% CI 1.03 to 1.14) or the hospitalization in the weekend (OR 4.17; 95% CI 2.42 to 7.18) increase the risk of prolonging hospital stay beyond three days [11]. A recent observational Spanish study [12] aimed to identify predictors of prolonged LOS found that a dyspnea score ≥ 2 in the modified Medical Research Council [mMRC] scale (OR 2.24; 95% CI 1.34 to 3.74) and the presence of acute respiratory acidosis (OR 2.75; 95% CI 1.49 to 5.05), both measured at admission, were independent predictors of hospital stay beyond seven days [12]. Another very recent study [13] in severe AECOPD patients, which evaluated the role of microorganisms resistant to conventional treatment using microbiological data from respiratory cultures, demonstrated that the presence of these germs (mainly Pseudomonas aeruginosa) does not increase mortality but prolongs hospital stay [13].

5. Patients with a high risk of short-term mortality

In hospitalized AECOPD, short-term mortality (defined as death in a period ≤ 90 days after admission and including in-hospital mortality) had a cumulative incidence varying from 1.8 to 20.4% [14]. A meta-analysis of mortality predictors [14] identified 12 variables increasing the risk of short-term mortality. Significant variables were related to patients’ demographic data (age, male sex, low body mass index [BMI]), associated comorbidities (cardiac or renal failure), COPD severity (use of long-term oxygen therapy, lower limb edema, very severe airflow obstruction and presence of cor pulmonale), and acute derangements (respiratory acidosis, confusion, and elevated plasma troponin level) [14]. Similarly, in the context of heart involvement during AECOPD, a recent study reported a significant negative role of intensive care unit admission or in-hospital mortality of pulmonary arterial enlargement defined by a pulmonary artery to aorta ratio >1 on chest computed tomography scan if associated with an increased troponin level (>0.01 ng/mL) [15]. Surprisingly, considering baseline characteristics as confounders using a propensity score matching method, the risk of death was similar in hospitalized AECOPD with and without bronchiectasis [16]. As for NIMV failure, non-invasive evaluation of DD at admission may also be a significant predictor of short-term mortality [9].

6. Patients with a high risk of early readmission

Readmission shortly after discharge (≤ 30 days),which occurs in 18% of hospitalized AECOPD [17], is associated with a subsequent progressive increase in mortality risk [17] and for this reason is regarded as a marker of severity [18]. Although several predictors of readmission have been reported in the literature [19], a recent prospective found that a combination of three parameters – high inflammatory status at discharge (CRP ≥ 7.6 mg/L, OR 7.46; 95% CI 1.34 to 40.91), probably reflecting a non-resolving exacerbation, together with the presence of diabetes (OR 11.03; 95% CI 1.77 to 68.54) and one or more previous hospitalizations (OR 8.04; 95% CI 1.61 to 40.17) – could accurately predict early readmission after discharge [20], with a positive predictive value of 1.00 and a negative predictive value of 1.00. However, this ability was confirmed only in 24 AECOPD patients (prevalence 0.208) in whom the three risk factors were present at the same time [20].

Concluding, in hospitalized AECOPD patients several variables related to the complexity and severity of acute event may increase the risk of having a negative clinical outcome. Although this information derived from observational studies, all these aspects may influence the clinical progression and prognosis of patients, but also the economic burden of disease. At admission to hospital, every effort need to be required to physicians to identify the negative predictors. The early identification of at-risk patients using these markers of severity, in fact, could be useful for the planning of tailored interventions during and after hospitalization.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.