key: cord-0764916-65m09pmg
authors: Husain, M; Valayer, S; Poey, N; Rondinaud, E; d’Humières, C; Visseaux, B; Lariven, S; Lescure, FX; Deconinck, L
title: Pulmonary bacterial infections in adult patients hospitalized for COVID-19 in standard wards
date: 2021-12-09
journal: Infect Dis Now
DOI: 10.1016/j.idnow.2021.12.001
sha: 6dcef3177d822bc8f16c70c1a7ddc7df34339e25
doc_id: 764916
cord_uid: 65m09pmg

Objectives. During the COVID-19 pandemic, antibiotic use was very common. However, bacterial co-/secondary infections with coronaviruses remain largely unknown in standard wards. We aimed to investigate the characteristics of pulmonary bacterial infections associated with COVID-19 in hospitalized patients. Methods. A retrospective monocentric observational study was conducted in Bichat hospital, France, between February 26 and April 22, 2020. All patients hospitalized in standard wards with COVID-19 (positive nasopharyngeal PCR and/or typical aspect on CT scan) and diagnosed with pulmonary bacterial infection (positive bacteriological samples) were included. Bacteriological and clinical data were collected from the microbiology laboratories and patient's medical records. Results. Twenty-three bacteriological samples from 22 patients were positive out of 2,075 screened samples (1.1%) from 784 patients (2.8%). Bacterial infection occurred within a median of 10 days after COVID-19 onset. Diagnosis of pulmonary bacterial infection was suspected on increase of oxygen requirements (20/22), productive cough or modification of sputum aspect (17/22), or fever (10/22). Positive samples included 13 sputum cultures, one FilmArray® assay on sputum samples, one bronchoalveolar lavage, six blood cultures, and two pneumococcal urinary antigen tests. The most frequent bacteria were Pseudomonas aeruginosa (6/23), Staphylococcus aureus (5/23), Streptococcus pneumoniae (4/23), Enterococcus faecalis (3/23), and Klebsiella aerogenes (3/23). No Legionella urinary antigen test was positive. Four out of 496 nasopharyngeal PCR tests (0.8%) were positive for intracellular bacteria (two Bordetella pertussis and two Mycoplasma pneumonia). Conclusions. Pulmonary bacterial secondary infections and co-infections with SARS-CoV-2 are uncommon. Antibiotic use should remain limited in the management of COVID-19.

Over the last century, the emergence of new viral respiratory tract infections with high epidemic potential has received global attention [1, 2] . From the Spanish flu to the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), each of these modern pandemics are responsible for numerous deaths [3, 4] . Pulmonary bacterial infections ─ a key factor in the potential severity of viral infections [5] ─ are still poorly documented in case of association with Human coronaviruses. Few studies investigated the co-infection and secondary infection rates. One study reported a rate up to 10% for J o u r n a l P r e -p r o o f Mycoplasma, Legionella, and Streptococcus pneumonia in severe acute respiratory syndrome (SARS) [6] and 1% for Mycoplasma, Legionella, and Chlamydia spp. in Middle East respiratory syndrome (MERS) [7] . Recent studies focusing on COVID-19 reported highly variable rates of bacterial infection, up to 45% [9, 10] . However, most studies focused on intensive care patients and ventilator-associated pneumonia [11, 12] .

Antibiotics have been extensively used during the first wave of the COVID-19 pandemic [9, 13] . The main reasons were symptom similarities between COVID-19 and pulmonary bacterial infections, severity of SARS-CoV-2 pneumonia, and lack of knowledge of the virus pathogenicity. Based on early data reported on COVID-19, it is time to question whether the broad use of antibacterial agents is warranted, especially in the context of rising antibiotic resistance.

Thus, a retrospective study of documented pulmonary bacterial co/secondary infections in COVID-19 patients hospitalized in standard wards was conducted. The aim of this study was to investigate the characteristics of pulmonary bacterial infections associated with COVID-19 in hospitalized patients.

A monocentric retrospective observational study was conducted in Bichat University Hospital in Paris, France, during the SARS-CoV-2 outbreak between February 26 and April 22, 2020. All departments in charge of SARS-CoV-2-infected patients, except for intensive care units, participated in the study. We used two data collection methods: the microbiological database of the bacteriological ward was screened to identify positive respiratory tract secretion sample (sputum samples, bronchial aspirations, and bronchoalveolar lavages), J o u r n a l P r e -p r o o f urinary antigen (pneumococcal and Legionella) tests, and blood cultures from hospitalized SARS-CoV-2-infected patients; and a second database (hospital activity-based payment registry) was used to recover positive bacterial nasopharyngeal PCR test (QIAstat-Dx® or BIOFIRE® RP2.1+) of all patients diagnosed with COVID-19, hospitalized during the same period. Microbiological investigations and biological samples were obtained as part of the routine patient care, at the discretion of the treating physician.

Sputum cultures were considered positive regardless of the culture threshold if one or several bacteria were isolated from quality sample, defined by >10 leukocytes/field and <25 epithelial cells/field. FilmArray® testing on sputum samples, bronchial aspirations, and bronchoalveolar lavages were included if one or several bacteria were found, regardless of the threshold. Data collection was further completed using the hospital electronic medical records of identified patients.

The authors evaluated the likelihood of pulmonary origin for each positive blood culture based on clinical examination, context, imaging and microbiological investigations.

An acute bacterial infection was defined as either co-infection at symptom onset or secondary infection occurring during the course of illness or hospitalization [14] .

All patients meeting the following criteria were included: Patients were excluded if they met the following criteria:

invasive ventilation prior to the documented bacterial examination;

positive blood culture with presumed extra-pulmonary origin or considered as contamination;

positive respiratory tract sample considered as colonization. Depending on the viral infection severity, patients were treated according to the local guidelines at the time of screening and according to ongoing trial knowledge, using highdose glucocorticoids (dexamethasone) and immunomodulators (anakinra or tocilizumab).

The imaging classification of the present study was based on the SARS-CoV-2 classification system of the French Society of Radiology: mild (<10%), moderate (10-25%), extended (25- J o u r n a l P r e -p r o o f 50%), severe (50-75%), and critical (>75%) [15] . Patients were treated by the attending physicians from participating wards, who decided whether it was an actual infection requiring antibacterial treatment.

All continuous variables were either expressed as medians and interquartile ranges or means and confidence intervals. Categorical variables were expressed as numbers and percentages. Paired samples t-test was used to compare continuous variables among patients at various time points. All statistical analyses were performed using Excel® sheets.

A total of 784 patients were hospitalized with COVID-19 during the inclusion period with 22 patients (2.8%) identified as having secondary pulmonary infections. Twenty-three samples among 2,075 collected (1.1%) were positive for bacteria and considered as pathogens ( Figure 1 ). Patients' characteristics are presented in Table 1 Table 2 .

The mean level of neutrophil count before bacterial infection was 7,905/mm 3 , 9,546/mm 3 on the day of infection, and 8,056/mm 3 after (Figure 2A ). Differences were nonsignificant between mean level of neutrophil count before and on the day of infection Similarly, the same study suggested an association of regular coronavirus, parainfluenza virus, and RSV infections with Acinetobacter spp. and Klebsiella spp. The previously described meta-analysis mainly reported M. pneumoniae (42%), P. aeruginosa (12%), and [27] . The proportion of M. pneumoniae was surprisingly high and very likely overestimated because the authors relied on IgM serology [28] . Most included studies were from Asian countries, which might explain the relatively high proportion of Acinetobacter infections. Other reports showed more similarities with the present study [16, 18, 19] .

Findings from the present study highlighted diagnostic difficulties. Clinical features leading to pulmonary bacterial infection suspicion can be easily confused with the usual signs of a progressing SARS-CoV-2 infection [29] . Although sputum production seems to be an interesting sign, it has been reported in one third of SARS-CoV-2-infected patients and remains non-specific of bacterial infection [30] . Additionally, bacterial infection occurrence within the COVID-19 timeframe, around Day 10 after symptom onset, corresponds to the usual worsening of COVID-19 symptoms [31, 16] , which adds to the difficult identification of a bacterial infection. Furthermore, in the studied population, biological features did not show any difference between a potential bacterial infection and the underlying evolution of COVID-19. Imaging benefits should be further investigated to contribute to bacterial infection diagnosis. No distinctive marker has been highlighted in COVID-19 yet. In their study, Wang et al. found that white blood cell count, neutrophil count, and CRP on admission were significantly higher in patients with bacterial co-infections [22] . Huang and colleagues [32] described PCT blood levels on admission in SARS-CoV-2 patients showing 75% of PCT >0.5 ng/mL in confirmed secondary infections, whereas 69% of the other patients had a PCT level <0.1 ng/mL. In contrast to the previous findings, Wan et al. [33] found that CRP and PCT levels on admission were significantly higher in severe patients than in the mild patient group, with no difference in documented bacterial infection rate. PCT levels could not be assessed in the present study because of missing data.

The final outcome was positive in only 62% of selected patients, with a third requiring intensive care before being discharged. Because of the study design, we could not confirm that poor outcome in this population was the consequence of secondary bacterial infections.

In the study by Wang et al. there was no difference in ICU admission or 30 day all-cause mortality in patients with and without bacterial co-infection [22] . However, this J o u r n a l P r e -p r o o f ascertainment seems otherwise consistent with the literature [17, 34] , and might mainly involve patients with bacteremia [18] .

The design of the present study was retrospective. Database screenings were conducted using two methods for PCR and bacteriological sample data collection to optimize extraction quality and to limit a potential selection bias. Despite the authors' endeavor, both extraction methods showed some flaws and resulted in additional exclusions during the selection process. Though all patient results were thoroughly described and analyzed, there were missing data, especially for PCT levels and CT scans, preventing further analyses.

In order to identify all potential secondary infections, no threshold was held for There is growing evidence suggesting the global overestimation of pulmonary bacterial infections in SARS-CoV-2-infected patients, resulting in the overuse of antibiotics and its consequences, mainly an increase of bacterial resistance [35] . This work supports the low prevalence of co-infections and secondary infections in non-ICU hospitalized patients with COVID-19. Empirical use of antibiotics are unlikely to provide significant benefit to COVID-19 patients. Systematic use of antibiotics, especially fluoroquinolones or macrolides on admission, does not seem justified as suggested by the French guidelines [36] . To support these findings, prospective studies are required to collect further data on the actual prevalence of bacterial infections in COVID-19 patients. Future research needs to focus on the role of antibiotics in SARS-CoV-2-infected patients, to guide its use in daily care and hopefully reduce the adverse consequences of its overuse.

Pulmonary bacterial secondary and co-infections with SARS-CoV-2 are uncommon. Their diagnosis is difficult due to similarities with the natural course of the disease. Cough with sputum around Day 10 might be a sign of bacterial infection. There is a balanced ratio between Gram-positive and Gram-negative bacteria. Systematic use of antibiotics does not seem justified in COVID-19 management.

All authors contributed to the study conception and design. ER, CD, and BV extracted the data from the various databases. MH and SV collected and analyzed the data. MH and SV wrote the manuscript. NP and LD supervised the study. All authors read and approved the final version of the manuscript. Total number of pathogens exceeds total number of samples because more than one isolate was identified in a single culture (with a maximum of three bacteria).

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IQR: interquartile range, COPD: chronic obstructive pulmonary disease