Methods and analysis
This prospective observational study was performed at the Unit of Pediatric Hematology and Oncology in Catania between March and June 2020, at the beginning of the spread of the Covid-19 epidemic in Italy. It was used as a complementary technique to the physical examination, with the aim of limiting daily out-patient access or in-ward admission and transfer of patients to other departments to perform tests. All admitted cancer patients undergoing therapy (steroid, chemotherapy, radiotherapy) with suspected infection in progress, participated in the study. As a case-control, a similar number of patients, with no signs of infection, randomly picked, underwent LUS. The procedures performed were in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments (2013). Informed consent was obtained from all participants.
The inclusion criteria were age 0-18 years, diagnosis of leukemia or solid tumor, therapy in progress. Patients with the following features were excluded: ongoing asthma crisis, cystic fibrosis, bronchodysplasia, congenital cardio-pulmonary malformations, primary and metastatic pleuro-pulmonary tumor localization.
Infection was defined as: body temperature (T) greater than or equal to 38°C and increased c-reactive protein (CRP) (normal range 0-5mg/dl) and/or procalcitonin (normal range 0-01 ng/ml), with or without respiratory signs and symptoms (cough, tachydispnea, SaO2 <96%, rales, reduction of vesicular murmur (VM)).
For each patient we assessed age, gender, underlying cancer, the absolute number of white blood cells and neutrophils at the time of the LUS, distinguishing the patients in
- neutropenic, (neutrophils less than or equal to 1000/mmc)
- non-neutropenic (neutrophils greater than 1000/mmc).
We reported the presence or absence of fever considering as T greater than or equal to 38°C, respiratory symptoms and signs, the results of hematological tests for infection. CXR and/or chest CT scans were also recorded.
CXR and chest CT were evaluated with radiologists and considered positive in the presence of pulmonary thickening or marked accentuation of the bronchovascular texture.
Chest CT scans were considered positive in the presence of pulmonary thickening or ground glass.
These tests were performed only if considered useful and appropriate for diagnostic purposes and clinical management.
LUS was always performed by two operators: a pediatrician with a six-month ultrasound training, and an expert sonographer pediatrician who reviewed all exams with a 5-10 MHz linear probe. The probe was placed perpendicularly, oblique and parallel to the ribs in the anterior, lateral and posterior thorax as described by Copetti & Cattarossi with the patient supine and seated to scan the posterior thorax. (17) The sonographer was unaware of the CRX results.
Pneumonia was diagnosed in the presence of lung consolidation, air or fluid bronchograms in the sub-pleural region >1 cm, multiple air or fluid bronchograms, air bronchogram<1 cm with multiple B lines in the neighboring sites, confluent B lines or white lung as previously classified. (2,18,19)
All ultrasound examinations represented by A-lines only, rare B-lines (less than 3 per ultrasound scan) or single and isolated aerial bronchogram<1 cm were considered normal.
In cases of positive LUS a control ultrasound was repeated to evaluate the evolution of the described picture after 3 and 7 days. In cases with persistent positive LUS, a monthly sonography was performed.
The compliance of children during the ultrasound examination by assigning a score from 0 to 2 was also evaluated:
- 0 if he was uncooperative (if the patient cries or refuses to undergo the exam),
- 1 if he was indifferent during the exam,
- 2 if he was proactive (takes the exam as a game, participates curiously in the exam).
We divided the recruited patients into 4 groups:
1. non-infected non-neutropenic patients are patients with absolute number of neutrophils greater than or equal to 1000/mmc without fever and with normal value of CRP and/or procalcitonin,
2. non-infected neutropenic patients are patients with absolute number of neutrophils less than or equal to 1000/mmc without fever and with normal value of CRP and/or procalcitonin,
3. infected non-neutropenic patients are patients with absolute number of neutrophils greater than or equal to 1000/mmc with fever and with high level of CRP and/or procalcitonin,
4. infected neutropenic patients are patients with absolute number of neutrophils less than or equal to 1000/mmc with fever and with high level of CRP and/or procalcitonin,
Patients of the first two groups did not show signs of ongoing infection and ultrasound results were analyzed in order to identify if there was an increase in false positives related to the underlying disease, the treatments administered for cancer or the number of white blood cells and neutrophils in patients without infection signs. Groups 3 and 4 include the cases with suspected infection.
LUS results in the third and fourth groups were analyzed with the aim of evaluating the sensitivity of LUS compared to CXR and CT images.