The CATALINA Study

A composite outcome measure defined as:

1. New hospitalization for respiratory reasons
2. 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:

1. Prolongation of systemic corticosteroids >5 days administered for the index acute exacerbation or first readmission for respiratory reasons
2. Upgrade of antibiotics administered for the index exacerbation or first readmission for respiratory reasons
3. New course of systemic corticosteroids for respiratory reasons
4. New course of antibiotics for respiratory reasons

A composite outcome measure defined as:

1. All-cause mortality
2. Step-up in hospital care for respiratory reasons
3. 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:

1. All-cause mortality
2. 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:

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

The time to the following outcomes will be measured:

1. All-cause mortality
2. First hospital readmission for respiratory reasons
3. Hospital care intensification for respiratory reasons
4. Treatment intensification for respiratory reasons
5. Treatment failure
6. 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:

1. 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