Bacterial infections
As previously mentioned, the most common secondary infections in critically ill patients with COVID-19 are VAP and BSIs. The diagnosis is made when the patient shows clinical symptoms and signs of infection and a new pathogen is detected in a biological specimen.
VAP is defined as the association of persistent pulmonary infiltrates on radiological imaging and positive microbiological cultures from a lower respiratory tract specimen with clinical suspicion of new onset pneumonia in a patient that has received at least 48 h of invasive mechanical ventilation [
35‐
37]. Scores, such as the Clinical Pulmonary Infection Score (CPIS) [
38] (based on six variables: temperature, blood leukocytes, aspect of tracheal secretions, oxygenation, radiographic infiltrates, and Gram stain on tracheal aspirates), have been developed to help clinicians diagnose VAP, but the most recent guidelines [
36,
39] highlight the role of clinical signs of infection (i.e., new onset of fever, purulent secretion from the air-way, leukocytosis or leukopenia, worsening of blood oxygenation, increased need for inotropic and vasoactive agents) rather than the use of a score. Imaging techniques, such as chest X-ray [
37], chest computed tomography, and, more recently, lung ultrasound [
40,
41], tailored to detect new pulmonary infiltrates, and markers of inflammation (e.g., C-reactive protein, procalcitonin) can support the clinical diagnosis.
Adequate and specific antibiotic therapy, however, requires a microbiological diagnosis based on culture examinations and tests (e.g., Gram stain, biomarkers, rapid diagnostic assay, polymerase chain reaction [PCR]) to enable identification of the involved bacteria. Samples can be obtained from the distal airway in a more invasive way using bronchoscopy (i.e., bronchoalveolar lavage [BAL], protected specimen brush [PSB]), in a ‘less-invasive’ way (i.e., blind mini-BAL, blind PSB) or from the proximal airway (endotracheal aspirate); a recent meta-analysis [
42] comparing cultures from proximal and distal airways showed no differences in patient outcome, but it should be remembered that sampling from the distal airway may be associated with an increased risk for the patient (i.e., hypoxemia, bleeding). Furthermore, invasive procedures are associated with potential exposure to aerosolized viral particles, which represents a risk for healthcare personnel.
BSI in critically ill patients is defined as the onset of signs and symptoms of infection within 24 h of a positive blood culture. Blood cultures and identification of specific bacteria represent the gold standard for the diagnosis, but a single positive culture is not suggestive of infection when a typical human skin contaminant is involved; in this case, the diagnosis requires at least two positive blood cultures for the microorganism within 48 h.
Fungal infections
COVID-19-associated pulmonary aspergillosis should be suspected in all patients with COVID-19 who present with refractory fever lasting more than 3 days after an initial 48-h period of defervescence (following appropriate antibiotic therapy), worsening of gas exchange, onset of hemoptysis, or new pleural rubs [
29]. A complete and accurate algorithm for diagnosing COVID-19-associated pulmonary aspergillosis is still lacking but it would be useful to search for
Aspergillus spp. in respiratory samples (e.g., bronchoalveolar lavage, tracheal aspirate) and to use serologic biomarkers such as galactomannan on respiratory samples and serum. Other tests that may help in diagnosing COVID-19-associated pulmonary aspergillosis are aspergillus PCR and serum (1→3)-β-
d-glucan.