Clinical impact of human metapneumovirus infections before and during the COVID-19 pandemic.

BACKGROUND: The first outbreak of coronavirus disease 2019 (COVID-19) occurred in March 2020 in Europe, which is normally the peak incidence period of human metapneumovirus (HMPV) infections, implying cocirculation and potentially causing competition between them. METHODS: We investigated differences in clinical characteristics and outcomes of HMPV infections in hospitalized patients before (January 2016-28 February, 2020) and HMPV and COVID-19 during part of the COVID-19 pandemic (28 February, 2020-1 April, 2020). RESULTS: A total of 239 HMPV patients and 303 COVID-19 patients were included. Incidence of HMPV peaked in March. Despite a 324% increase in HMPV testing during the COVID-19 outbreak, incidence of HMPV remained stable. Clinical characteristics showed 25 (11%) ICU admissions and 14 (6%) deaths. History of myocardial infarction, higher age and lower BMI were independently associated with increased 30-day mortality. Clinical characteristics of HMPV-infected patients did not differ between the non-COVID-19 period and the examined COVID-19 period except for length of hospital stay (7 vs. 5 days). HMPV infection and COVID-19 shared many clinical features but HMPV was associated with female gender, elderly patients and chronic conditions (COPD and chronic heart failure). Clinical outcomes did not differ between the viruses during the COVID-19 period. CONCLUSIONS: The clinical impact of HMPV infection did not change during the COVID-19 outbreak in terms of incidence and/or disease severity; hence, HMPV and SARS-CoV-2 are probably co-circulating independently. Despite the current clinical focus on the COVID-19 pandemic, clinicians should keep in mind that HMPV-infection may mimic COVID-19 and is also associated with serious adverse outcomes.

Stenotrophomonas maltophilia ventilator-associated pneumonia. A retrospective matched case-control study.

BACKGROUND: Stenotrophomonas maltophilia is increasingly identified in critically ill patients, but it is considered a pathogen with limited pathogenicity and it is therefore infrequently targeted. This study explores whether S. maltophilia may cause ventilator-associated pneumonia (VAP) and whether it affects intensive care unit (ICU) mortality and 28-day mortality when compared to VAP caused by other Gram-negative bacilli. METHODS: Retrospective analysis of a 19-year prospectively collected database. Stenotrophomonas maltophilia as a cause was considered in VAP-suspected cases when S. maltophilia growth of ≥10(4) cfu/ml was detected in bronchoalveolar lavage fluid analysis. Cases were matched on hospital, gender, age and acute physiology and chronic health evaluation II score in a 1:3 ratio with controls from the same database suffering from VAP caused by other Gram-negative bacilli. RESULTS: Eight cases met the inclusion criteria, of which three were labelled as 'probable' SM-VAP and three as 'possible' SM-VAP. These six patients constitute 1.8% of all VAPs in the studied period. No significant differences in baseline characteristics and duration of mechanical ventilation (p = 0.68), length of stay in the ICU (p = 0.55) and hospital (p = 0.84) between cases and controls were identified between cases and controls. Intensive care unit mortality odds ratio was 1.7 (p = 0.55; 95% CI 0.3-10.5) and 28-day mortality odds ratio was 1.4 (p = 0.70; 95% CI 0.2-9.1). CONCLUSIONS: Stenotrophomonas maltophilia is a possible, yet infrequent cause of VAP. No outcome differences were found when compared to matched VAP caused by other Gram-negative bacilli.

Ventilator-associated Pneumonia caused by commensal oropharyngeal Flora; [corrected] a retrospective Analysis of a prospectively collected Database.

BACKGROUND: The significance of commensal oropharyngeal flora (COF) as a potential cause of ventilator-associated pneumonia (VAP) is scarcely investigated and consequently unknown. Therefore, the aim of this study was to explore whether COF may cause VAP. METHODS: Retrospective clinical, microbiological and radiographic analysis of all prospectively collected suspected VAP cases in which bronchoalveolar lavage fluid exclusively yielded ≥ 10(4) cfu/ml COF during a 9.5-year period. Characteristics of 899 recent intensive care unit (ICU) admissions were used as a reference population. RESULTS: Out of the prospectively collected database containing 159 VAP cases, 23 patients were included. In these patients, VAP developed after a median of 8 days of mechanical ventilation. The patients faced a prolonged total ICU length of stay (35 days [P < .001]), hospital length of stay (45 days [P = .001]), and a trend to higher mortality (39 % vs. 26 %, [P = .158]; standardized mortality ratio 1.26 vs. 0.77, [P = .137]) compared to the reference population. After clinical, microbiological and radiographic analysis, COF was the most likely cause of respiratory deterioration in 15 patients (9.4 % of all VAP cases) and a possible cause in 2 patients. CONCLUSION: Commensal oropharyngeal flora appears to be a potential cause of VAP in limited numbers of ICU patients as is probably associated with an increased length of stay in both ICU and hospital. As COF-VAP develops late in the course of ICU admission, it is possibly associated with the immunocompromised status of ICU patients.

Alternative diagnosis in the putative ventilator-associated pneumonia patient not meeting lavage-based diagnostic criteria.

BACKGROUND: The clinical picture of ventilator-associated pneumonia (VAP) can be mimicked by other infectious and non-infectious diseases. The aim of this study was to determine the alternative diagnoses and to develop a diagnostic flow chart for patients suspected of having VAP not meeting the diagnostic broncho-alveolar lavage (BAL) criteria. METHODS: Adult intensive care patients with a clinical suspicion of VAP and negative BAL results were included. The clinical suspicion of VAP was based on the combination of clinical, radiological, and microbiological criteria. BAL was considered positive if cell differentiation revealed ≥ 2% cells with intracellular organisms and/or quantitative culture results of ≥ 10(4) cfu/ml. The most likely alternative diagnosis of fever and pulmonary densities was retrospectively determined by two authors independently. RESULTS: In all, 110 of 207 patients with suspected VAP did not meet the diagnostic BAL criteria and required further diagnostic evaluation. In 67 patients an alternative diagnosis for fever could be found. In 51 patients an alternative diagnosis of both fever and pulmonary densities could be established. In almost 40% of patients no alternative diagnosis could be provided. Non-bacterial pneumonia was diagnosed in 10 patients with Herpes simplex virus 1 (HSV-1) as the most common pathogen. In eight patients non-infectious pneumonitis was diagnosed. CONCLUSION: Due to the wide range of alternative diagnoses and applied tests the diagnostic work-up proved to be necessarily individualized and guided by repeated clinical assessment. The most frequently found alternative diagnoses were viral pneumonia and non-infectious pneumonitis.

Endotracheal aspirate and bronchoalveolar lavage fluid analysis: interchangeable diagnostic modalities in suspected ventilator-associated pneumonia?

Authoritative guidelines state that the diagnosis of ventilator-associated pneumonia (VAP) can be established using either endotracheal aspirate (ETA) or bronchoalveolar lavage fluid (BALF) analysis, thereby suggesting that their results are considered to be in accordance. Therefore, the results of ETA Gram staining and semiquantitative cultures were compared to the results from a paired ETA-BALF analysis. Different thresholds for the positivity of ETAs were assessed. This was a prospective study of all patients who underwent bronchoalveolar lavage for suspected VAP in a 27-bed university intensive care unit during an 8-year period. VAP was diagnosed when ≥ 2% of the BALF cells contained intracellular organisms and/or when BALF quantitative culture revealed ≥ 10(4) CFU/ml of potentially pathogenic microorganisms. ETA Gram staining and semiquantitative cultures were compared to the results from paired BALF analysis by Cohen's kappa coefficients. VAP was suspected in 311 patients and diagnosed in 122 (39%) patients. In 288 (93%) patients, the results from the ETA analysis were available for comparison. Depending on the threshold used and the diagnostic modality, VAP incidences varied from 15% to 68%. For the diagnosis of VAP, the most accurate threshold for positivity of ETA semiquantitative cultures was moderate or heavy growth, whereas the optimal threshold for BALF Gram staining was ≥ 1 microorganisms per high power field. The Cohen's kappa coefficients were 0.22, 0.31, and 0.60 for ETA and paired BALF Gram stains, cultures, and BALF Gram stains, respectively. Since the ETA and BALF Gram stains and cultures agreed only fairly, they are probably not interchangeable for diagnosing VAP.

Molecular epidemiology of Pneumocystis jiroveci in human immunodeficiency virus-positive and -negative immunocompromised patients in The Netherlands.

Pneumocystis jiroveci infections can cause pneumocystis pneumonia (PCP) or lead to colonization without signs of PCP. Over the years, different genotypes of P. jiroveci have been discovered. Genomic typing of P. jiroveci in different subpopulations can contribute to unravelling the pathogenesis, transmission and spread of the different genotypes. In this study, we wanted to determine the distribution of P. jiroveci genotypes in immunocompetent and immunocompromised patients in The Netherlands and determine the clinical relevance of these detected mutations. A real-time PCR targeting the major surface glycoprotein gene (MSG) was used as a screening test for the presence of P. jiroveci DNA. Samples positive for MSG were genotyped based on the internal transcribed spacer (ITS) and dihydropteroate synthase (DHPS) genes. Of the 595 included bronchoalveolar lavage fluid samples, 116 revealed the presence of P. jiroveci DNA. A total of 52 of the 116 samples were ITS genotyped and 58 DHPS genotyped. The ITS genotyping revealed 17 ITS types, including two types that have not been described previously. There was no correlation between ITS genotype and underlying disease. All ITS- and DHPS-genotyped samples were found in immunocompromised patients. Of the 58 DHPS-genotyped samples, 50 were found to be WT. The other eight samples revealed a mixed genotype consisting of WT and type 1. The majority of the latter recovered on trimethoprim-sulfamethoxazole suggesting no clinical relevance for this mutation.

Surveillance cultures in intensive care units: a nationwide survey on current practice providing future perspectives.

PURPOSE: To explore the extent of surveillance culture (SC) implementation underlying motives for obtaining SC and decision making based on the results. MATERIALS AND METHODS: A questionnaire was distributed to Heads of Department (HODs) and microbiologists within all intensive care departments in the Netherlands. RESULTS: Response was provided by 75 (79%) of 95 HODs and 38 (64%) of 59 laboratories allied to an intensive care unit (ICU). Surveillance cultures were routinely obtained according to 55 (73%) of 75 HODs and 33 (87%) of 38 microbiologists. Surveillance cultures were obtained in more than 80% of higher-level ICUs and in 58% of lower-level ICUs (P < .05). Surveillance cultures were obtained twice weekly (88%) and sampled from trachea (87%), pharynx (74%), and rectum (68%). Thirty (58%) of 52 HODs obtained SC to optimize individual patient treatment. On suspicion of infection from an unknown source, microorganisms identified by SC were targeted according to 87%. One third of HODs targeted microorganisms identified by SC in the case of an infection not at the location where the SC was obtained. This was significantly more often than microbiologists in case of no infection (P = .02) or infection of unknown origin (P < .05). CONCLUSIONS: Surveillance culture implementation is common in Dutch ICUs to optimize individual patients' treatment. Consensus is lacking on how to deal with SC results when the focus of infection is not at the sampled site.

Surveillance cultures in healthcare-associated pneumonia: sense or nonsense?

PURPOSE OF REVIEW: This review explores the usefulness of surveillance cultures in healthcare-associated pneumonia (HCAP). RECENT FINDINGS: The definition of HCAP is controversial. Causative micro-organisms of HCAP resemble those found in hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Some types of surveillance cultures have proven useful in hospitalized patients. Whereas numerous studies have investigated the role of surveillance cultures in VAP, one may wonder whether surveillance culture implementation should belong in HCAP management guidelines. SUMMARY: Studies exploring the usefulness of obtaining surveillance cultures in VAP are numerous, but are mostly retrospective, observational and/or quasi-experimental in nature. Surveillance cultures may be useful for antibiotic guidance, but positive predictive value and specificity of surveillance cultures are low, obviously negatively impacting on cost effectiveness, especially in the large population at risk for HCAP. On the other hand, multidrug-resistance is increasing and surveillance cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci in ICU-admitted patients appeared useful and cost-effective. Furthermore, surveillance cultures for the presence of multidrug-resistant Gram-negative bacilli might be useful for antibiotic guidance. Currently, neither community-acquired pneumonia, HCAP, HAP nor VAP guidelines incorporate surveillance cultures. In the future, surveillance cultures in populations at risk for HCAP may be able to differentiate HCAP from other kinds of pneumonia and authorize its reason for existence.

Evaluation of direct inoculation of the BD PHOENIX system from positive BACTEC blood cultures for both Gram-positive cocci and Gram-negative rods.

BACKGROUND: Rapid identification (ID) and antibiotic susceptibility testing (AST) of the causative micro-organism of bloodstream infections result in earlier targeting of antibiotic therapy.In order to obtain results of ID and AST up to 24 hours earlier, we evaluated the accuracy of direct inoculation of the Phoenix system from positive blood cultures (BACTEC) by using Serum Separator Tubes to harvest bacteria from positive blood cultures. Results were compared to those of standard Phoenix procedure. Discrepancies between the two methods were resolved by using the API system, E-test or microbroth dilution. RESULTS: ID with the direct method was correct for 95.2% of all tested Enterobacteriaceae (n = 42) and 71.4% of Pseudomonas aeruginosa strains (n = 7).AST with the direct method showed a categorical agreement for Gram-negative rods (GNR) of 99.0%, with 0.7% minor errors, 0.3% very major errors and no major errors. All antibiotics showed an agreement of >95%.The direct method for AST of Staphylococcus (n = 81) and Enterococcus (n = 3) species showed a categorical agreement of 95.4%, with a minor error rate of 1.1%, a major error rate of 3.1% and a very major error rate of 0.4%. All antibiotics showed an agreement of >90%, except for trimethoprim-sulfamethoxazole and erythromycin. CONCLUSIONS: Inoculation of Phoenix panels directly from positive blood cultures can be used to report reliable results of AST of GNR a day earlier, as well as ID-results of Enterobacteriaceae. For Staphylococcus and Enterococcus species, results of AST can also be reported a day earlier for all antibiotics, except for erythromycin and trimethoprim-sulfamethoxazole.

Positive cultures from cardiopulmonary bypass: prevalence and relevance regarding postoperative infection.

OBJECTIVE: Postoperative infections due to cardiopulmonary bypass (CPB) are associated with high morbidity and mortality. The value of positive cultures taken from CPB priming fluid and CPB blood samples, however, is unclear. This study investigates the epidemiology of positive cultures from CPB and their relation to the occurrence of postoperative infection. METHODS: The study was conducted at the Maastricht University Medical Centre, a 715-bed teaching hospital with 900-1000 surgeries requiring CPB annually. From 1 January 1998 until 31 March 2010, all patients with positive CPB cultures drawn either from priming fluid or blood were retrospectively studied. Second, 335 patients with a positive CPB culture were compared with 335 randomly assigned patients who underwent cardiovascular surgery using CPB and had negative CPB cultures. Patients with active endocarditis were excluded. Demographic data and perioperative parameters were documented. Outcome measures were: a relevant infection (acute infectious valve endocarditis, wound infection, intravascular catheter-related infection, and bloodstream infection), occurrence of fever of unknown origin, and 30-day mortality. RESULTS: A total of 21840 cultures were analyzed, half being priming fluid and half CPB blood cultures. As many as 111 out of 10920 (1.0%) priming fluid cultures and 598 out of 10920 (5.6%) blood cultures tested positive. Gram-positive cocci predominated both priming fluid and blood cultures. Relevant postoperative infections within 30 days after surgery were seen in 47/663 (7.1%) of patients overall, in 27/330 in the CPB-culture-positive group (8.2%) and 20/333 in the CPB-culture-negative group (6.0%), p=0.275. As many as 38 out of 363 patients (5.7%) were affected by fever of unknown origin (CPB-culture-positive group 4.5%, and CPB-culture-negative 6.9%; p=0.191). The 30-day mortality was 16/330 (4.8%) in the CPB-culture-positive group and 13/333 (3.9%) in the CPB-culture-negative group (p=0.552). CONCLUSIONS: Positive cultures from both CPB priming fluid and CPB blood samples were not a rarity and mainly involved skin bacteria, arguing that contamination may have played a role. The risk of postoperative infection within 30 days after surgery was not increased in CPB-culture-positive patients. Therefore, no evidence was found to support routine culturing of CPB samples in patients undergoing cardiothoracic surgery.

Clara cell protein in bronchoalveolar lavage fluid: a predictor of ventilator-associated pneumonia?

INTRODUCTION: Clara cell protein 10 (CC-10) has been associated with inflammatory and infectious pulmonary diseases. This study evaluates CC-10 concentrations in bronchoalveolar lavage (BAL) fluid as a potential marker of ventilator-associated pneumonia (VAP). METHODS: Between January 2003 and December 2007, BAL fluid samples obtained from critically ill patients at the intensive care unit of the Maastricht University Medical Centre clinically suspected of having VAP were included. Patients were divided into two groups: (1) microbiologically confirmed VAP (the VAP group) and (2) microbiologically unconfirmed VAP (the non-VAP group). The concentration of CC-10 was measured by means of a commercially available enzyme-linked immunosorbent assay kit, and retrospective analysis was performed. Areas under the curve of receiver operating characteristic curves were calculated for CC-10 concentrations. RESULTS: A total of 196 patients (122 men, 74 women) were included. A total of 79 (40%) of 196 cases of suspected VAP were microbiologically confirmed. The median CC-10 concentration in the VAP group was 3,019 ng/mL (range, 282 to 65,546 ng/mL) versus 2,504 ng/mL (range, 62 to 30,240 ng/mL) in the non-VAP group (P = 0.03). There was no significant difference in CC-10 concentrations between patients treated with or without corticosteroids (P = 0.26) or antibiotic therapy (P = 0.9). The CC-10 concentration did not differ significantly between patients with Gram-positive versus Gram-negative bacteria that caused the VAP (P = 0.06). However, CC-10 concentrations did differ significantly between the late-onset VAP group and the non-VAP group. CONCLUSIONS: The CC-10 concentration in BAL fluid yielded low diagnostic accuracy in confirming the presence of VAP.

Role of microorganisms in interstitial lung disease.

PURPOSE OF REVIEW: To review the role of microorganisms in interstitial lung disease (ILD) and to emphasize their importance in initiation and course of ILD. RECENT FINDINGS: ILD can be idiopathic but often causality such as drugs or connective tissue disease can be found. Multiple microorganisms have been associated with ILD. On the one hand, pulmonary infection can cause extensive pulmonary damage with patterns of an ILD. On the other hand, microorganisms can trigger the immune system and provoke an abnormal response- not directed against the causative pathogen- that may result in ILD. Moreover, patients with ILD often are susceptible to infection, and infections can importantly influence the course of ILD. Furthermore, not only an infection but also its treatment can result in a drug-induced pneumonitis, eventually resulting in long-term lung damage. SUMMARY: Microorganisms can initiate and/or influence the course of ILD. Early recognition, adequate diagnostic evaluation and therapy are essential to prevent permanent damage. Prevention of infection in patients with established ILD is strongly recommended.

Herpes simplex virus load in bronchoalveolar lavage fluid is related to poor outcome in critically ill patients.

OBJECTIVE: To evaluate the relationship between the HSV-1 and -2 loads in BAL fluid (BALF) and clinical outcome. DESIGN: Retrospective study. SETTING: The general intensive care unit of the University Hospital Maastricht. PATIENTS: Five hundred and twenty-one BALF samples from 462 patients were included. Patients were divided into three groups; (1) patients admitted to the hospital <48 h before lavage (Community), (2) patients admitted to the ICU >48 h before lavage (ICU) and (3) the remaining patients (non-ICU group). INTERVENTIONS: No additional interventions were conducted. MEASUREMENTS AND RESULTS: HSV-1 and HSV-2 loads were determined by real-time polymerase chain reaction (PCR). HSV-1 DNA was detected in 4.3% (4/92) of samples in the community group, 15% (18/121) in the non-ICU group and in 32% (99/308) of the ICU group. In the age group <50 years HSV-1 DNA was less frequently isolated compared to the age group >or=50 years (16/129 (12%) versus 187/376 (25%), respectively, OR = 2.6; P < 0.001). HSV-1 loads of >10(5) genome equivalents (ge)/ml were associated with an increased 14-day in-hospital mortality compared to patients with a HSV-1 load 10(5) ge/ml enforces its clinical relevance and necessitates to start randomized medical intervention studies.

C-reactive protein and procalcitonin concentrations in bronchoalveolar lavage fluid as a predictor of ventilator-associated pneumonia.

BACKGROUND: Diagnosis of ventilator-associated pneumonia (VAP) is difficult. The usefulness of high-sensitivity procalcitonin (ProCa-S) and high-sensitivity C-reactive protein (CRPH) in bronchoalveolar lavage (BAL) fluid and serum in the prediction of VAP was determined. METHODS: The study was conducted over a 28-month period (November 1999-June 2002) at the University Hospital Maastricht. BAL fluid samples were collected from patients admitted to the intensive care unit. Differential cell count and quantitative culture of BAL fluid were performed. C-reactive protein (CRP) and procalcitonin (PCT) on BAL fluid were determined by means of two high-sensitivity kits (CRPH and ProCa-S, respectively). Since both kits were designed for use on serum, validation for use on BAL fluid was performed. RESULTS: A total of 117 patients were included. 43.6% (51/117) had microbiologically confirmed VAP. Both CRPH and ProCa-S showed good matrix effect, linearity and intra- and inter-assay variation. No significant differences in PCT and CRP concentrations in serum and BAL fluid were found between the VAP and the non-VAP group. CONCLUSIONS: Both the ProCa-S and the CRPH kits can be used for assessing the concentration of PCT and CRP in BAL fluid, respectively. PCT and CRP concentrations in BAL fluid appeared to be of no additional value in the diagnosis of VAP.

Influence of antibiotic therapy on the cytological diagnosis of ventilator-associated pneumonia.

OBJECTIVE: To assess the influence of antibiotics on the value of various cytological parameters, and their combinations, in diagnosing ventilator-associated pneumonia (VAP). DESIGN: Prospective study. SETTING: The general intensive care unit (17 beds) of the University Hospital Maastricht. PATIENTS: Three hundred and thirty-five episodes of clinically suspected VAP (defined by the clinical and radiological criteria previously described by Bonten et al.) in 282 patients were studied. INTERVENTIONS: No additional interventions were conducted. MEASUREMENTS AND RESULTS: Bronchoalveolar lavage fluid cytology included a total cell count per millilitre, differential cell count and the percentage of infected cells (cells containing phagocytised organisms). Antibiotic therapy from 72 h prior to lavage was recorded. Areas under the curve (AUCs) of receiver operating characteristic curves were calculated for various cytological parameters and their combinations, in patients with and without antibiotic therapy. In 126 episodes (37.6%) in 106 patients, VAP was confirmed. There was no difference in AUCs between patients with and without antibiotic therapy for any parameter studied. The most prominent AUCs were (for patient groups with and without antibiotics combined): total cell count, 0.65; percentage polymorphonuclear neutrophils, 0.71; and percentage infected cells, 0.90. The combination of percentage infected cells with any other cytological parameter did not increase the AUC. CONCLUSION: Antibiotic therapy did not influence the predictive value of the percentage infected cells in BALF in diagnosing VAP.

Inter-laboratory comparison of three different real-time PCR assays for the detection of Pneumocystis jiroveci in bronchoalveolar lavage fluid samples.

Pneumocystis jiroveci pneumonia (PCP) is an opportunistic infection affecting immunocompromised patients. While conventional diagnosis of PCP by microscopy is cumbersome, the use of PCR to diagnose PCP has great potential. Nevertheless, inter-laboratory validation and standardization of PCR assays is lacking. The aim of this study was to evaluate the inter-laboratory agreement of three independently developed real-time PCR assays for the detection of P. jiroveci in bronchoalveolar lavage fluid samples. Therefore, 124 samples were collected in three tertiary care laboratories (Leiden University Medical Center, Maastricht Infection Center and Radboud University Nijmegen Medical Centre) and were tested by both microscopy and real-time PCR. Of 41 samples positive for P. jiroveci by microscopy, 40 were positive in all three PCR assays. The remaining sample was positive in a single assay only. Out of 83 microscopy-negative samples, 69 were negative in all three PCR assays. The other 14 samples were found positive, either in all three assays (n=5), in two (n=2) or in one of the assays (n=7). The data demonstrate high inter-laboratory agreement among real-time PCR assays for the detection of P. jiroveci.