Bacterial and Fungal Infections in Critically Ill Patients with Covid-19 Pneumonia: An Observational Study - Juniper Publishers

 Anesthesia & Intensive Care Medicine - Juniper Publishers

Abstract

Objectives: The aim of this study is describe and analyse bacterial and/or fungal infections in critically ill patients with coronavirus diseases 2019 (COVID-19) pneumonia during the first pandemic period and compared them with historic cohort of influenza pneumonia patients. Design: Multicentre, observational, and retrospective. Setting: Three ICUs of Spain Patients: Critically ill patients with COVID-19 and influenza pneumonia which required ICU admission were recruited from October 2018 to April 30th, 2020. We described population, distribution of infections/microorganisms and risk factors related. Main variables of interest: Exposure: COVID-19 infection. Outcome: Superinfection, Overall mortality 90 days Measurements and Main Results: 58 critical care patients with COVID-19 and a further 48 patients with influenza pneumonia were included. COVID-19 patients had significantly less respiratory co-infection (3 vs 29; p˂0.001). Superinfections were not significantly higher in patients with COVID-19 (46 vs 29%; p=0.06). Gram negative bacteria were significantly higher than in influenza pneumonia patients (48 vs 27; p=0.02) and Pseudomonas aeruginosa (27%), and lower respiratory infections (42 vs 25; p=0.07) were the most frequent aetiology and source of superinfection in COVID-19 patients. In adjusted analysis, days of invasive mechanical ventilation (OR 1.08; CI 1.01-1.16; p=0.04) and SOFA score at admission (OR 1.48; CI 1.13-1.95; p=0.04) were statistically associated with superinfection. Superinfection (HR 4.76; CI 1.63-13.91; p=0.004) was related in crude analysis with overall mortality at 90 days. Conclusion: The incidence of coinfections is low in critically ill patients with COVID-19 pneumonia and significantly less frequent than in patients with influenza pneumonia. Empirical treatment at admission should be closely revaluated. Incidence of superinfection is high, if is suspected, empirical antipseudomonal treatment should be considered specially in lower respiratory infections, considering local flora. Severity of illness and supportive treatments seems to be the clearer factors related to superinfections.

Keywords: Coronavirus infection, Pneumonia, Infection, Coinfection, Superinfection, Critical care

Introduction

Information about bacterial and fungal infections in critical patients with Coronavirus disease 2019 (COVID-19) is increasing after one year of the pandemic outbreak. Some explanations of this fact are the most immediate priorities for hospitals providing acute medical care (intensivist have habilitated up to 300% more critical patients’ beds in hospitals), keeping critically ill patients alive, protecting staff, and optimizing care of critically ill non-COVID patients in this context [1-3].

Coinfection in patients with COVID-19 seems to be low according to published data, but complications with superinfections in these critically ill patients shows important variability in different studies [4]. While some reports show low incidence of hospital acquired pneumonia of 11%, others show an increase of incidence of more than 50% of lower respiratory infections or high incidence of blood stream infections in these patients [5,6].

The aim of this study is to describe bacterial and/or fungal coinfections and superinfections in critically ill patients with COVID-19 pneumonia, compare them with critical care patients with influenza pneumonia and evaluate the risk factors associated. This knowledge may be useful to improve management of these patients, optimize antibiotics policy and to adapt initial protocols.

Patients and Methods

This is an observational, retrospective, cohort study carried out at 3 hospitals in the south of Spain. We evaluated all adult patients with viral pneumonia due to SARS-VoV-2 and influenza who required ICU admission from October 2018 to April 30th, 2020. Eligibility criteria included were age ≥18 years old, confirmed laboratory test of SARS-COV-2 or influenza (A or B) infection, and compatible chest X ray or computed tomography infiltrates. Patients with limited therapeutic effort at admission and ICU hospitalization duration lasting ˂48 hours were excluded.

The study was approved by the local Ethics Committee of the Reina Sofía University Hospital of Córdoba (Code 4706), which were exempted from the need to seek written informed consent due to the observational and retrospective nature of the study. STROBE recommendations for observational studies were followed and checked (Supplementary Table 1) [7]

Clinical data was recorded in a standardized protocol and anonymized in a database. Variables evaluated were: (i) demographics, (ii) previous conditions, (iii) clinical characteristics, (iv) severity of illness (APACHE II and SOFA score) (v) analytic and microbiological studies, (vii) pharmacologic and support therapy, (viii) and outcome variables (microbiologically confirmed coinfection and superinfection during ICU stay, type of infection, microbiology characteristics, overall mortality at 30 and 90 days and died with active infection). Corticosteroids when administered were given at maximum doses of 1mg/kg/day of methylprednisolone. All patients admitted during this period were followed until ICU discharge and overall mortality 90 day was assessed by phone call in discharge patients.

To standardize the classification of an infection as present on admission (co-infection) or a healthcare-associated infection (superinfection), we used the CDC/NHSN criteria. Superinfection is defined as localized or systemic condition resulting from an adverse reaction to the presence of an infectious agent(s) or its toxin(s) that was not present on or after the 3rd hospital day (day of hospital admission is day 1) [8]. Diagnosis of lower respiratory infection was based on two of the next criteria: temperature up to 38.5 ˚C or leucocyte account (≥12.000 or ˂4.000 cells per μL), and purulent secretions. Episodes need microbiological confirmation with isolation in the endotracheal aspirate. Ventilator associated pneumonia was defined with the above criteria and the presence of new or progressive infiltrates on radiological explorations after 48 hours of mechanical ventilation [6]. ICU bloodstream infection for typical skin contaminants (e.g. coagulase-negative Staphylococcus) were included only if ≥2 blood cultures showed the same phenotype on separate occasions, or 1≥ blood cultures for clinical sepsis and no other infectious process; catheter related bloodstream infections were documented by quantitative tip culture [9]. All episodes and criteria were critically reviewed by two investigators (A.M and J.R.G).

SARS-COV-2 testing was performed at Microbiology Reference Laboratory (Reina Sofía University Hospital/IMIBIC). VIASURE SARS-CoV-2 Real Time PCR Detection Kit (CerTest Biotec), a multiplex real-time PCR detecting ORF1ab and N genes, was used for diagnosis. Influenza A/B virus were also investigated using GeneXpert® (Cepheid) or the BioFire® FilmArray® Respiratory 2 plus Panel (Biomerieux).

Continuous variables were compared using the Mann- Whitney U or T Test of Student Test and categorical variables were compared using the Chi Square Test or Fisher’s Exact Test as appropriate. Ventilator associated pneumonia and blood stream infections incidence rate were calculated as the number of events per 1000 patient-days at risk; the 95% confidence interval (CI) for the incidence rate estimate was obtained using mid-P exact test. In patients with COVID-19, multivariate analyses were performed using logistic regression for study variables related with superinfection and Cox regression for overall mortality 90 days. In logistic regression for variables related to superinfection, each multivariate analysis included one variable for every ten events; they were selected those with p˂0.1 (model 1) or those with clinical interest (model 2 and 3). Due to prolonged length of ICU stays of COVID-19 patients we decide overall 90 days mortality over overall 30 mortality. In Cox regression analysis for overall mortality 90 days, superinfection variable was included as time-dependent; patients have an additional transient state before superinfection event, not taking timing, this time, into account would cause time-depending bias [10].

Results

Description of patients with COVID19 and Influenza pneumonia

During the study period 116 patients were evaluated. 62 patients with highly suspected COVID-19 pneumonia were identified; 58 met inclusion criteria, 3 patients with COVID-19 disease like symptoms were not confirmed in laboratory RT-PCR of SARS-COV-2 and 1 patient with limited therapeutic effort at admission was excluded. There were 48 influenza pneumonia patients evaluated and all of them were legible without exclusion criteria.

Clinical characteristics of COVID-19 and influenza pneumonia cohorts are described in Table 1. Critically ill patients with COVID-19 pneumonia were median age 64 years old. Only 10% (6) of patients did not have comorbidities while the most frequent were hypertension and obesity with 56% (33) and 37% (22) respectively. At admission, laboratory results showed the median of D Dimer of 1096 ng/ml, median of 347 cell/ μL of CD4 and 47 pg/mL of IL6.

Patients with COVID-19 in comparison with those with influenza pneumonia were significantly older (64 vs 55; p=0.004), with higher incidence of hypertension (56 vs 37; p=0.04), more days from onset of symptoms to ICU admission (9 vs 4; p˂0.001), treated with corticosteroids (43 vs 16%; p=0.002), but have less APACHE II score (12 vs 19; p˂0.001).

Co-infection and superinfections

Patients with COVID-19 pneumonia, in comparison, had significantly less frequent respiratory co-infection (3 vs 29; p˂0.001) (Table 2). 96% of patients with COVID-19 were treated with antibiotics at admission. There were 3 cases of Coagulase Negative Staphylococcus in COVID-19 patients at ICU admission.

Superinfections were not significantly higher in patients with COVID-19 (46 vs 29%; p=0.06). The most frequent microorganisms isolated in this cohort was Pseudomonas aeruginosa (27%), and Gram-negative bacteria were significantly higher than in influenza pneumonia patients (48 vs 27; p=0.02) (Table 2). Lower respiratory infections were the most frequent superinfections in COVID-19 patients, and they were not significantly higher than influenza pneumonia patients (42 vs 25; p=0.07); gram negative (77%) and Pseudomonas aeruginosa (41%) were the most frequent microorganisms related in this infection. (Supplementary Table 2) Incidence rate of ventilator associated pneumonia was not significantly higher in this group with 13.2 (CI95% 7.24-21.8) per 1000-days-ventilated COVID-19 patients in comparison with 7.1 (CI 1.9-18.3) per 1000-days-ventilated patients in influenza pneumonia cohort (p=0.28). ICU blood stream superinfections were similar in both cohorts (40 vs 47%; p=0.47) with and incidence rate (including secondary bacteraemia) of 25.8 (CI95% 18.1-35.8) in COVID-19 patients and 24,3 (CI95% 15.1-37.2) per 1000-days-at risk in influenza pneumonia cohort (p=0.84). Grampositive bacteria and Coagulase-negative Staphylococcus were in both cohorts the most frequent bacteria (Supplementary Table 2). The rate of blood stream candidemia was 5 and 14%.

Variables related with bacterial and/or fungal superinfection in critical care patients with COVID-19

The crude and adjusted analysis of the association between selected variables and superinfection in COVID-19 patients is shown in Table 3. In the crude analysis, variables statically significant related to superinfection were the severity of the illness at admission, SOFA score (Odds Ratio (OR) 1.48; CI 1.13- 1.95; p=0.005), interleukin 6 (OR 3.33; CI 1.03-10.74; p=0.04) and days of invasive mechanical ventilation (OR 1.11; CI 1.03- 1.20; p=0.005). In adjusted analysis, days of invasive mechanical ventilation (OR 1.08; CI 1.01-1.16; p=0.04) and SOFA score at admission (OR 1.48; CI 1.13-1.95; p=0.04) were statistically associated with superinfection. Treatments with tociluzumab (OR 1.21; CI 0.36-4.10; p=0.75) or corticosteroids (OR 0.49; CI 0.14- 1.67; p=0.25) failed to show any relation in the crude and adjusted analysis.

Prognosis in COVID19 patients: Impact of superinfection

Patients with COVID-19 showed higher overall mortality 90 day but there were not statistical differences in comparison with patients with influenza infections (29 vs 18%; p=0.20). Eleven patients died in treatment with active infection in COVID-19 cohort. Survival analysis of 90-day overall mortality did not show differences between COVID-19 and influenza pneumonia (p=0.20). (Supplementary Figure 1)

Table 4 shows that variables that were related in crude analysis with overall mortality at 90 days were severity of illness, APACHE II score (HR 1.07; CI 1.008-1.14; p=0.02), SOFA score at 72 hours (HR 1.19; CI 1.04-1,37; p=0.01) and superinfection (HR 4.76; CI 1.63-13.91; p=0.004) when was explored as timedependent variable.

Discussion

We found that in our cohort of critically ill patients with COVID19 pneumonia, patients experienced low coinfection rate (3%) and high incidence of superinfections (46%). Gram negative infections were significantly higher in comparison with those with influenza pneumonia and lower respiratory infections and Pseudomonas aeruginosa were the most frequent source and microorganism related.

Microbiologically confirmed respiratory co-infection of COVID-19 patients of our cohort was significantly lower (3%) than patients with influenza pneumonia. Similar findings are noted in other studies, so we could suggest that coinfection is unlikely to be common in patients with COVID-19 upon admission to the ICU [11,12]. On the other hand, we are aware that coinfection could be influenced by seasonal factors and it is unknown if these results could change during other periods. Considering the low coinfection rate, empiric antibiotic treatment should be closely revaluated once bacterial and/or fungal bacterial infections has been ruled out to reduce resistant emergence. We found 3 cases at admission of bloodstream infections by Coagulase-negative Staphylococcus; in the context of fulfil bloodstream infection criteria and clinical systemic inflammatory response they were treated. We could not rule out that those results as contaminations.

The published incidence of superinfections in critical care patients with COVID-19 is highly variable. While some reports show low incidence of lower respiratory infections less than 30%, other studies point to SARS-CoV-2 as an independent risk factor and to increase its´ incidence (˃50%) [5,6,13,14]. In our study, the incidence of lower respiratory infection is elevated (42% of lower respiratory infection and 21% of ventilator associated pneumonia) and higher than those patient with influenza pneumonia. Even though we found lower incidence rate of ICU bloodstream infection than other reports like Giacobbe et al. [15] study (47 vs 28 episodes per 1000 patients-days at risk in our COVID-cohort), and was not significantly higher than influenza patients, still remains high with up to 20% incidence of catheter related blood stream infections [15].

Some reasons that could explain this high variability between studies may be: different pressure of ICU admissions and its´ impact in quality care, publication bias (tend to report good results), different severity of illness and patients characteristics, the effect of mortalities differences in superinfection incidence (competitive risk bias) and exclusion in some studies of patients that are still admitted to hospital or ICU at the end of the studies follow up, which could corresponded with long term patients with high rate of complications [12-14,16].

Critical COVID-19 patients are exposed to important risk factors for superinfection that can explain the high rate established like advanced age, underlying systemic diseases, acute respiratory distress syndrome, mechanical ventilation, catheters and prolonged hospital and ICU stays [17,18]. In our case we found that the severity of presentation (SOFA score at admission) interleukin 6 and supportive treatment (days of invasive mechanical ventilation) showed to be more important factors associated with superinfections in that of critical care patients with COVID-19. Even though we were unable to assess if immunomodulatory treatment was related, the study is not powdered enough to test this hypothesis; published data shows controversial findings related corticosteroids and tociluzumab: the balance of the result of theatrically reduction of supports with immunomodulatory treatment (e.g. mechanical ventilation and prognosis) and the increase of the exposure to superinfections is still unknown [9]. Some studies point to SARS-COV-2 as an independent risk factor for exposure to lower respiratory and blood stream infections. Suggested explanations for this hypothesis are endothelial dysfunction, widespread thrombosis, histologic findings of acute fibrinous and organizing pneumonia and gut biota disruption [6,9].

In some papers increasing Pseudomonas aeruginosa superinfections in COVID-19 patients were noted [6,19]. In our case, Pseudomonas aeruginosa was too the main pathogen isolated (27%). Future studies will assess if COVID-19 clinical evolution and its´ histopathology lung damage/ADRS may predispose to these kinds of infections; despite this, we found that gram negative infections were significantly higher in COVID-19 patients in comparison with influenza pneumonia, local flora may play an important role in this issue.

In our case we can show that superinfection was independently associated with overall mortality at 90 days in crude analysis, but future studies will clear the complex relationship between severity of illness, superinfection, treatments, and mortality.

Our study has obvious limitations. Its´ observational design is exposed to certain biases by its nature, even though we tried to minimize them by applying strict definitions and following STROBE recommendations for observational studies. We are aware of the important limitation of sample size; that is important in the precision of our estimate, so it must be taken with caution. Epidemiology may be influenced by local flora. This cohort of critical care patients with COVID-19 were admitted to ICU before RECOVERY trial results, so more than one half of patients did not receive corticosteroids, it can impact in the future patients and superinfections events [20]. But considering the context of the high variable data reports, these results in this critical care cohort specifically focused on bacterial and/or fungal infection in COVID-19 patients may be useful discussing issues such as the co-infection and superinfection, it´s impact and epidemiology and treatment approach.

Conclusion

The incidence of coinfections is low in critically ill patients with COVID-19 pneumonia and significantly less frequent than in patients with influenza pneumonia. Empirical treatment at admission should be closely revaluated. Incidence of superinfection is high, if is suspected, empirical antipseudomonal treatment should be considered specially in lower respiratory infections, considering local flora. Severity of illness and supportive treatments seems to be the clearer factors related to superinfections.

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Legionellosis- A Mini Review - Juniper publishers

Journal of Case Studies - Juniper Publishers

Mini Review

Legionellosis is the term used to describe clinical manifestations of infection caused by the Legionella bacteria. It includes Legionnaires disease (LD), focal non-pulmonary infections and Pontiac fever. LD is a type of bacterial pneumonia, while Pontiac fever is a several days long non-pneumonic, febrile, influenza like illness associated with exposure to Legionella spp. That resolves spontaneously. Legionnaires disease was first described during an outbreak at a convention of the American legion in Philadelphia in 1976 [1]. Twenty-nine of 182 cases were fatal. Extensive epidemiologic work led to identification of the bacterium.

The legionella spp. is small gram-negative rods with fastidious growth requirements. More than 58 different Legionella spp. have been described, about half of which have been reported to infect humans [2]. Legionella pneumophila (Lp) is the most commonly encountered species. Lp contains at least 16 different serogroups. Lp serogroup 1 is the most common clinical isolate. The most common non Lp species isolated from humans are L.longbeachae, L.micdadei, L.bozemanae, and L.dumoffii [3]. These constitute less than 5% of culture -proven cases in North America. This bacteria needs special growth medium which contains Iron, L-cysteine, α-ketoglutarate, and charcoal-containing yeast extract agar buffered with an organic buffer (BCYEα agar).

Legionella bacteria are found in natural aqueous environment, in lakes, streams and costal oceans. Warm water (25°C-40°C) supports its growth [4]. Free living amoebas in the same waters support the intracellular growth and survival of Legionella. Almost all cases of LD results from this bacteria growing in water heaters, warm water baths, warm water plumbing systems and air conditioning and other types of cooling towers. Rain puddles in tropical regions, tsunami related water exposure, and windshield viper fluid are few other reported sources of infection. One exception to water as risk factor is that Llb, which is mainly transmitted through soil contact, especially from potting soil. LD is initiated by inhalation of aerosolized Legionella bacteria. After bacteria enter lung they are phagocytosed by alveolar macrophages. Bacteria prevents fusion of phagosome to lysosomes or endosomes, thus avoiding acidification and degradative enzymes. After sufficient intracellular replication, the bacteria kill the macrophage and then rephagocytosed by other macrophage. This process recruits other inflammatory cells leading to pneumonia [5].

Pathogenesis of Pontiac fever is not known with certainty. It is believed that PF is caused by inhalation of disease causing environmental aerosol derived from water containing microorganisms including Legionella bacteria. The incubation period of LD is between 2-10 days and for PF 4 hours- 3 days [1]. Person-to-person transmission of either LD or Pontiac fever does not occur. Legionella spp. is ubiquitous in environment. However, disease is not that common. Legionella is causative organism of only 0.5-10% hospitalized cases of community acquired pneumonia, an average value is probably 2% even in the geographic regions with excellent diagnostic capabilities [6]. Male gender, cigarette smoking, chronic heart or lung disease, diabetes, end stage renal failure, organ transplantation, immunosuppression, some forms of cancer and old age are well known host risk factors. Also important are environmental and bacterial factors such as relative bacterial virulence, bacterial aerosol stability, organism growth conditions and factors that facilitate the spread of bacterium from contaminated water to host, such as wind direction, relative humidity and aerosol formation.

LD is one of cause of bacterial pneumonia. Sometimes it is characterized by fever with pulse-temperature dissociation, myalgia, few pulmonary symptoms, nonproductive cough, diarrhea, confusion, hyponatremia, hypophosphatemia, and elevated liver enzymes. This symptom complex, however, is neither specific nor frequent enough to allow differentiation of LD from other common causes of community acquired pneumonia [7]. LD starts with prodrome of headache, muscle aches, and anorexia. Fever accompanies these symptoms. Cough may develop hours to days after onset of prodrome. Careful examination always demonstrates findings of pneumonia including focal rales and patchy infiltrate to dense focal consolidation on Chest X ray.

Diagnosis of LD requires high degree of suspicion and keen consideration of epidemiology. Various laboratory tests can be sued including sputum culture, urine antigen testing, immunofluorescent microscopy, paired serum antibody and molecular amplification techniques. Culture requires special media; hence laboratory needs to be informed about this. Yield of sputum culture varies between 20%-95%. Many clinical laboratories have neither expertise nor ability to properly perform these specialized cultures. Urine antigen testing has revolutionized the diagnosis. It is easy to perform and has fast turnaround time. The average sensitivity of this test is in the range of 70% to 80% [8]. Big caveat in using urine antigen is that it detects Lp serogroup 1 and poorly sensitive for other Lp serogroups. Hence negative test should be taken with grain of salt. Urine antigen test can be positive for months after the initial infection.

Legionella bacteria are intracellular, this means antimicrobials which are concentrated intracellularly are going to be more efficacious. The macrolides, quinolones, and tetracyclines all meet these criteria. Prospective, adequately sized clinical trials of antimicrobial therapy for LD have not been performed. In absence of these, decisions about antimicrobials must be made on the basis of experimental animal and cell culture studies [9]. For mild pneumonia in immunocompetent host first choice antibiotics include: Azithromycin 500mg daily for 3-5 days, Levofloxacin 500mg daily for 7-10 days, ciprofloxacin 500 twice a day for 7-10 days, moxifloxacin 400mg daily for 7-10 days or clarithromycin 500mg twice a day for 10- 14 days. Second choice for these patients will be Doxycycline 200mg loading dose followed by 100mg twice a day for 10-14 days or Erythromycin 500mg four times a day for 10-14 days [9,10].

In severe cases or immunocompromised host treatment of LD includes using Azithromycin 500mg daily for 5-7 days or levofloxacin 500mg daily for 7-10 days or 750mg daily for 5-7 days. Second lie drugs for these severe cases include Ciprofloxacin 750mg twice daily for 14 days or moxifloxacin 400mg daily for 14 days or Erythromycin 750-1000mg IV four times a day for 3-7 days followed by 500mg four times a day for total of 21 days or Clarithromycin 500mg IV twice a day for 3-7 days followed by 500mg twice a day for total of 21 days. Failure to respond to specific therapy for LD should bring into question the validity of the diagnosis, the possibility of coinfection or superinfection. No human vaccine exists for LD, and prior infection does not prevent reinfection [11]. Antibiotic prophylaxis prevents LD and should be considered during nosocomial epidemics and for high-risk population before control of an epidemic. Engineering modifications and maintenance of water supply systems is important to prevent contamination of water with Legionella. Disinfection of water distribution systems and surveillance for Legionella contamination should be a routine practice to prevent disease transmission from contaminated water. 

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