The CATALINA Study

Death from any cause

A composite outcome measure defined as:

• New hospitalization for respiratory reasons
• Hospital care intensification from baseline (ie. within 24h from hospital admission) for respiratory reasons, including:

• 2.1 Non-invasive respiratory therapy (oxygen by mask or nasal flow)
• 2.2 Non-invasive respiratory therapy (oxygen by NIV or high flow)
• 2.3 Invasive respiratory therapy (intubation and mechanical ventilation)
• 2.4 Physiological support with inotropes

A composite outcome measure defined as:

• Prolongation of systemic corticosteroids >5 days administered for the index acute exacerbation or first readmission for respiratory reasons
• Upgrade of antibiotics administered for the index exacerbation or first readmission for respiratory reasons
• New course of systemic corticosteroids for respiratory reasons
• New course of antibiotics for respiratory reasons

A composite outcome measure defined as:

• All-cause mortality
• Step-up in hospital care for respiratory reasons
• Treatment intensification for respiratory reasons

As intensification of drug treatment regimens and treatment intensifications are country/region-specific and not always related to failure of disease control, severe treatment failure (STF) will be defined as the composite of:

• All-cause mortality
• Step-up in hospital care for respiratory reasons

Readmission of the patient to the hospital for a severe COPD exacerbation

New admission of the patient to the hospital for respiratory reasons

A composite outcome measure defined as:

• Non-invasive respiratory therapy (oxygen by mask or nasal flow)
• Non-invasive respiratory therapy (oxygen by NIV or high flow)
• Invasive respiratory therapy (intubation and mechanical ventilation)
• Physiological support with inotropes

The time to the following outcomes will be measured:

• All-cause mortality
• First hospital readmission for respiratory reasons
• Hospital care intensification for respiratory reasons
• Treatment intensification for respiratory reasons
• Treatment failure
• Severe treatment failure

The implementation of a new or changed DNR code during study participation will be measured.

• DNR 0: do not restrict therapy (i.e. explicit statement not to withhold any life-sustaining interventions)
• DNR 1: do not resuscitate, further specified as:

DNR 1a: No CPR DNR 1b: No CPR + no intubation + NIV to be considered

• DNR 2: do not extend therapy (i.e. no CPR + no intubation + no NIV)
• DNR 3: discontinue therapy (i.e. no CPR + no intubation + no NIV + withdrawal of current treatment°)

Abbreviations: CPR, cardiopulmonary resuscitation; NIV, non-invasive ventilation; °, treatment of disabling symptoms to be prioritised, however, no life-prolonging interventions are to be continued

The total dose of systemic corticosteroids administered during study participation will be measured.

Total number of days spent in a hospital during study participation will be measured.

The change in the following patient reported outcome measures (PROM) will be measured:

modified Medical Research Council (mMRC): a dyspnea scale

• scale: 0 to 4
• interpretation: higher scores indicate worse outcome

The change in the following patient reported outcome measures (PROM) will be measured:

COPD Assessment Test (CAT): a COPD impact scale

• scale: 0 to 40
• interpretation: higher scores indicate worse outcome

The change in the following patient reported outcome measures (PROM) will be measured:

Patient Health Questionnaire-9 (PHQ-9): a depression scale

• scale: 0 to 29
• interpretation: higher scores indicate worse outcome

The change in the following patient reported outcome measures (PROM) will be measured:

Generalized Anxiety Disorder-7 (GAD-7): a anxiety scale

• scale: 0 to 21
• interpretation: higher scores indicate worse outcome

The change in the following PREM will be measured:

• Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS): measuring patients' perceptions of their hospital experience

-interpretation: higher scores indicate better outcome

Changes in baseline comorbidies (ie. the appearance of new or worsening of existing) will be measured

Eotaxin-3 is a small cytokine belonging to the CC chemokine family (called CCL26, Chemokine (C-C motif) ligand 26). Eotaxin-3 is chemotactic for eosinophils and basophils and elicits its effects by binding to the cell surface chemokine receptor CCR3.

Interleukin-5 (IL-5) acts on mature eosinophils, leading to proliferation, activation, differentiation, and survival; playing a critical role in the host immune response to infections.

Interleukin-33 (IL-33) is described as an inducer of type 2 immune responses, activating T helper 2 cells and mast cells.

Monocyte chemotactic protein 4 (MCP-4), also called CCL13, is a major chemo-attractant for eosinophils, basophils, monocytes and T lymphocytes

Thymus and activation regulated chemokine (TARC), also known as CCL17, is a chemokine that induces chemotaxis of Type 2 T helper (Th2) cells.

Interferon gamma-induced protein 10 (IP-10 (CXCL10)) chemoattracts Th1 lymphocytes and monocytes, and inhibits cytokine-stimulated hematopoietic progenitor cell proliferation.

Interleukin 1 alpha (IL1A) stimulates the activity of genes involved in inflammation and immunity

Interleukin 8 (IL-8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells; which attracts and activates neutrophils in inflammatory regions

Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates proliferation and/or activation of monocytes, macrophages, neutrophils and eosinophils