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.