Short summary

Respiratory tract infection is a serious condition resulting in high hospitalization and mortality. Specimens from the lower respiratory tract is important to support clinical decisions in order to direct the antibiotic treatment, but successful sputum sample collection and good quality samples are challenging. Consequently, identification of optimal sputum collecting method to increase the quality of the samples, and investigation of an alternative sputum analyses is needed to improve specimens' suitability in order to identify the etiology and aid value to management of respiratory infections.

Rationale

Multi-resistant bacteria (MRB) are associated with high antibiotic consumption and designated by WHO as one of the major threats to the world. In Denmark, the incidence of MRB is generally increasing, and every 20th patient admitted to Danish Emergency Department (ED), are infected with resistant bacteria. Respiratory tract infection is a serious condition, with 3 million death worldwide every year, and about 20-40% of the patients with community-acquired pneumonia need hospitalization. Data from the ED at Hospital Sonderjylland shows that 6% of the patients are registered with a respiratory tract infection, including pneumonia.

Treatment of pneumonia should be initiated within a few hours, therefore early and precise diagnostic is extremely important. Imprecisely or delayed diagnostic will often result in over consumption of broad-spectrum antibiotics, contributing to the increase development of MRBs and thereby threatens future treatments possibilities. Pneumonia diagnosis is currently primary based on clinical symptoms as cough, expectoration, chest pain, fever or breathlessness, combined with x-ray of the lungs, relevant blood tests and microbiological analyses of sputum samples. X-ray is however an imprecisely diagnostic tool, and sputum test responses are available after 2 days. Thus, the diagnostic is challenged by unspecific symptoms, unsure diagnostic methods and the waiting time for results up to several days.

Sputum can be cultivated to determine bacterial agent. However, the sputum samples are often of poor quality and many patients cannot deliver a sample (11). A recently published Danish study shows, that only half of the patients at the ED have sputum samples collected for culturing and none of them had the antibiotic treatment adjusted based on the microbiological results of the sputum. In addition, different microbiological analysis methods are used to detect bacteria or virus causative to pneumonia, but common to the methods is that a representative specimen from the lower respiratory tract is crucial for optimal sensitivity and specificity. Consequently, identification of optimal sputum collecting method and investigation of an alternative sputum analyses assessment is needed to improve specimens' suitability in order to identify the etiology of pneumonia.

Clinical experience indicates that an inhalation mask with saline solution can induce sputum facilitating in sputum sampling. Tracheal suction is often used on intubated patients at the intensive care unit to collect sputum and this method has become the standard procedure at several EDs. The profit of the two methods have not been investigated in an ED context nor compared to each other to investigate quality of the collected sputum samples and its relevance for clinical practice.

Ensuring an optimal sputum collection is even more relevant in relation to the Covid-19 pandemic. An optimal sputum collection is important to be able to determine if the pneumonia is caused by SARS-CoV-2 or a bacterium - especially in situations where the swab from throat or pharynx present a negative results, as the method is not sensitive enough to rule out Covid-19 in patients with pneumonia.

Accordingly, the Health Board in Denmark recommends tracheal suction of patients admitted with suspected Covid-19 in case of symptoms of the lower respiratory tract, and only in cases the symptoms originates from the upper airways a swab can be performed.

The hypotheses is, that by inducing the sputum the patient will be able to deliver an equally representative specimen from the lower respiratory tract as by tracheal suction.

The purpose of this study is to determine the most optimal method for obtaining high quality sputum samples. Following research questions will be explored:

1. What is the difference between the conventional sampling by tracheal suction comparing to induced sputum in relation to the proportion of suitable sputum samples

2. What is the difference between washed sputum technique and quantitative analyses comparing to conventional semi quantitative sputum analyses

3. Identification of possibly adverse events regarding to sputum collections methods

Description of the cohort

This study design is a randomized controlled trial (RCT). It is a single center study and will run at a 50-bed ED at Hospital Sønderjylland, Aabenraa with a hospital coverage of approximately150.000 inhabitants. The study will run from the 19.October 2020 to 1. Marts 2021.

All patients arriving at the ED with suspected with respiratory tract infecton are invited to participate in the project.

Inclusion criteria:

 - Patients admitted with suspected respiratory infection

 - Patients > 18 years old

 - One of the following pulmonary symptoms: dyspnea, cough, expectoration, chest pain or fever

Exclusion criteria:

 - Patients transferred directly to ICU

 - If the attending physician considers that participation will delay a life-threatening treatment

 - Patients with severe immuno-deficiencies treated with prednisolone 20mg/d over 2 days

 - Patient which consent cannot be obtained

Right after consent, the patient will be randomized in two groups:

Group 1 (tracheal suction): The standard procedure is tracheal suction of secretions from the lower respiratory tract using local described procedure.

Group 2 (forced expiratory technique + induced sputum): The intervention is based on the patient's own attempt to deliver a sputum sample after instructions of proper huff forced exhalation and coughing technique. After an attempt to deliver a sputum sample the patient will receive a 0, 9% isotonic saline by an inhalation mask to induce the sputum, thereafter the patient will again make an effort to expectorate a sputum sample repeating the forced expiratory technique. In the case of unsuccessful sample collection, specimen will be collected by the standard procedure tracheal suction.

Additionally, to identify possibly adverse effects in relation to collecting methods, following measures there are routinely used in the ED will be registered at baseline and 10 minutes after the intervention:

1. Patient clinical symptoms (cough, expectoration, chest pain or dyspnea)

2. Patient experience report based on Borg CR10 scale

3. Oxygen saturation

4. Respiratory Rate

Data and biological material

Sputum samples will be collected and quality assessed by two methods

1. A washing technique where a pus-filled part of the specimen is mechanically purified, Gram stained and quantitative cultured

2. A conventional procedure where the remaining part of the specimen is directly Gram stained and semi quantitative cultured

Collaborating researchers and departments

Focused Research Unit in Emergency Medicine, Hospital of South Jutland

• Associate Professor, M.Sc.Pharm., PhD Helene Skjøt-Arkil
• Professor, PhD, MHM, Christian Backer Mogensen

Department of Clinical Microbiology, Odense University Hospital

• Chief Physician Flemming Rosenvinge

Department of Clinical Microbiology, Hospital of South Jutland

• Senior Consultant Steen Lomborg

Publications associated with the project

Cartuliares, M.B., Skjøt-Arkil, H., Rosenvinge, F.S. et al. Effectiveness of expiratory technique and induced sputum in obtaining good quality sputum from patients acutely hospitalized with suspected lower respiratory tract infection: a statistical analysis plan for a randomized controlled trial. Trials 22, 675 (2021). https://doi.org/10.1186/s13063-021-05639-1