key: cord-0872252-5zojihzh
authors: Martin, D.; Hönemann, M.; Liebert, U.G.
title: Dynamics of nosocomial parainfluenza virus type 3 and influenza virus infections at a large German University Hospital between 2012 and 2019
date: 2020-10-17
journal: Diagn Microbiol Infect Dis
DOI: 10.1016/j.diagmicrobio.2020.115244
sha: 996a5c881f228eb595004cd51e01c2446ca4d11e
doc_id: 872252
cord_uid: 5zojihzh

Nosocomial virus infections cause significant morbidity and mortality. Besides influenza viruses, the disease burden of parainfluenza virus type 3 (PIV-3) is comparatively high among hospitalized patients and severe disease courses can occur. PIV-3 showed the highest rates of nosocomial infections of a panel of respiratory viruses. Therefore, a retrospective observational study was conducted among patients with either PIV-3 or influenza viruses, which served as reference pathogen. The aim was to compare the seasonal dynamics and clinical characteristics of nosocomial infections with these highly transmittable viruses. Nosocomial infection occurred in 15.8% (n = 177) of all influenza cases, mainly in the first half of a season. 24.3% (n = 104) of the PIV-3 cases were nosocomial and occurred mainly in the second half of a season. Both nosocomial rates of influenza and nosocomial rates of PIV-3 varied between the seasons. Community acquired and nosocomial cases differed in underlying medical conditions and immunosuppression. Knowledge of the baseline rates of nosocomial infections could contribute to the implementation of appropriate infection control measures.

Human parainfluenza virus type 3 (PIV-3) is a common pathogen that may cause severe respiratory symptoms particularly in young children, the elderly, and in immunosuppressed patients [1] [2] [3] [4] [5] .It is the most frequently detected type of the four human parainfluenza viruses [6, 7] and is among the most common pathogens causing acute respiratory infections (ARI) and influenza-like illness (ILI) [8] [9] [10] [11] [12] . Furthermore PIV-3 is also known to cause nosocomial infection [2, 4, 8, 13, 14] . The disease burden and the magnitude of nosocomial infection rates across consecutive respiratory seasons, however, are poorly understood. A reason might be the underestimation of the clinical impact in comparison to influenza viruses. Influenza is a seasonal disease that is caused by influenza virus A(H3N2), influenza virus A(H1N1)pdm09, and influenza B viruses [15] . For both PIV-3 and influenza virus, the severity of infections varies and the spectrum of symptoms can range from asymptomatic to severe pneumonia [8, 11, 16] . Besides community-acquired infections, nosocomial influenza is increasingly deemed an important health risk and recognized as causing significant morbidity and mortality. All influenza types are known to cause nosocomial outbreaks and recent studies found nosocomial rates of 4.3 to 35.5% in hospitals across Germany, Spain, Canada, USA and Australia [17] [18] [19] [20] [21] [22] [23] [24] . Most studies, however, focus on a single season, warranting further research on long-term nosocomial infection rates. Medical records were reviewed of patients with confirmed PIV-3 or influenza virus infection. If a patient was hospitalized several times independently, each stay was included as a separate case.

Patients' medical histories were assessed for co-morbidities. Co-morbidities that were looked for are any history of malignant neoplasia (further divided into blood malignancy and solid cancer), chronic renal failure, chronic heart failure, asthma, chronic obstructive pulmonary disease (COPD), obesity, and immunosuppression. Patients with any of the following were considered immunocompromised: receiving active chemotherapy for cancer, severe chronic neutropenia, receiving steroids or other immunomodulatory medications over a prolonged period, aplasia of the thymus gland, or reported HIV infection.

An infection was classified as nosocomial when respiratory symptoms were not present on admission and the beginning of ARI symptoms (fever >38° C or self-reported, new onset of cough, new onset of dyspnoea) occurred at least 72 hours after admission, or readmission with symptoms of ARI within 48 hours after discharge from UKL.

Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 25.0 (Armonk, NY: IBM Corp.). Continuous values were expressed as median (interquartile range) and categorical data as frequencies (percentages). Chi square test and Mann-Whitney U-test were performed as appropriate. A p-level of < 0.05 was considered significant.

Absolute numbers of respiratory virus detections and the nosocomial infection rate is presented in table 1. PIV-3 showed the highest rate for nosocomial infections of all analysed viral pathogens, followed by the three influenza types B, A(H3N2), and A(H1N1)pdm09, respectively. Therefore, a further analysis was focused on PIV-3 in relation to influenza virus infections.

During the study period, 428 patients were tested positive for PIV-3 and 1117 for any influenza virus 

Differences were noted for the symptoms of patients with community-acquired infections. Patients with influenza suffered more frequently from fever while PIV-3 cases presented more often with dyspnoea. Differences between nosocomial and community-acquired infections were mainly identified in the frequency of underlying health conditions (Table 3A and 3B). Patients with nosocomial infections were older and had higher rates of malignancies, immunosuppression, in the influenza group also higher rates of chronic heart failure, and chronic kidney disease. Reported neuraminidase inhibitor treatment was higher in cases with nosocomial influenza virus infection.

Between nosocomial PIV-3 and influenza virus infections, there were no significant differences in severe outcome parameters, i.e. development of acute respiratory distress syndrome, admission the ICU, or death. When compared to nosocomial influenza virus infections, nosocomial PIV-3 cases had a lower median age (P < 0.001), a lower rate of COPD (p = 0.042), chronic heart failure (p = 0.001), and chronic kidney disease (p = 0.001), longer hospital stays (P < 0.001), a higher rate of haematological malignancies (P < 0.001), and a higher rate of immunosuppression (P < 0.001). Furthermore, the findings demonstrate that nosocomial infections with both PIV-3 and influenza viruses occur more often in the context of certain pre-existing medical conditions, such as malignancies, immunosuppression, and obesity. For influenza, it was additionally chronic renal insufficiency and heart failure, while this was not observed in the PIV-3 group. The patient population in a hospital thus profoundly impacts the type and the amount of nosocomial infections that are detected. The higher rates of malignancies and immunosuppression are consistent with previous studies highlighting the susceptibility of immunocompromised patients for ARI [1, [26] [27] [28] [29] , while the higher rates of chronic renal insufficiency and heart failure observed in the group of nosocomial influenza might be due to higher age. The hospital stay was longer for patients with hospital acquired infection, indicating an increased risk for nosocomial infection or a protracted stay in hospital due to the infection [30] [31] [32] . However, a case control group would be needed to better assess the influence of length of hospital stay on the probability of nosocomial infection.

There were several limitations in this study. The chosen timeframe for nosocomial infection with onset of symptoms >72 hours after admission might be too narrow for PIV-3. Although there is only limited data, the median incubation period is estimated to be 2.6 days [33] . 97.1 % of the nosocomial PIV-3 patients in this study had an onset of symptoms after 5.2 days, more than two times the estimated incubation period. This suggests the chosen timeframe to be a robust cut-off for the study of nosocomial PIV-3 virus infections.

Additionally, the clinical outcomes might be biased towards a higher severity in the communityacquired influenza group due to UKL being a reference centre for ARDS. Ninety out of 95 cases of ARDS in influenza are classified as community-acquired. Sixty-six of them were referred from outside hospitals relying on UKL expertise in treating these severely ill patients. Thus, the data set might not be representative in the comparison of outcome parameters between the two patient groups. If these transferred patients are excluded, there is no longer a difference in the occurrence of ARDS (2.3% for nosocomial influenza vs. 2.9% for community-acquired influenza).

In conclusion, nosocomial infections account for a substantial proportion of infections with PIV-3 and influenza in a hospital setting with immunocompromised or chronically ill patients. Intensified infection control management that addresses the culture of "working while sick" among healthcare workers [34] [35] [36] and increased influenza vaccination rates might be able to lower the rates of nosocomial infections [35, 37, 38] . For PIV-3 however, neither a vaccination nor specific antiviral agents are available. Due to the various sources of nosocomial infections -visitors, patients and healthcare workers-it is not possible to prevent all nosocomial infections. Therefore, the assessment of baseline rates for nosocomial infections facilitates the re-evaluation of hygiene measures should nosocomial infections start to increase.

Study design: UGL 

Parainfluenza virus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review

Human parainfluenza virus infection after hematopoietic stem cell transplantation: Risk factors, management, mortality, and changes over time

Impact of parainfluenza virus infection in pediatric cancer patients

Nosocomial transmission of parainfluenza 3 virus in hematological patients characterized by molecular epidemiology

Respiratory virus infection among hematopoietic cell transplant recipients: evidence for asymptomatic parainfluenza virus infection

Epidemiology of parainfluenza infection in England and Wales, 1998-2013: any evidence of change?

Human parainfluenza virus in patients with influenzalike illness from Central and South America during

Parainfluenza Virus in the Hospitalized Adult

Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults

Community-acquired pneumonia requiring hospitalization among U.S. children

Parainfluenza Viruses

Epidemiology and clinical impact of parainfluenza virus infections in otherwise healthy infants and young children < 5 years old

A molecular epidemiological study of human parainfluenza virus type 3 at a tertiary university hospital during 2013-2015 in Catalonia, Spain

Hospital-Acquired Respiratory Viral Infections: Incidence, Morbidity, and Mortality in Pediatric and Adult Patients

The evolution of seasonal influenza viruses

The Role of Human Parainfluenza Virus Infections in the Immunopathology of the Respiratory Tract

Retrospective analysis of clinical and virological parameters of influenza cases at four university hospitals in Germany

Characteristics and management of patients with influenza in a German hospital during the 2014/2015 influenza season

Characterisation of nosocomial and community-acquired influenza in a large university hospital during two consecutive influenza seasons

Healthcare-associated influenza in Canadian hospitals from

Hospital-acquired influenza in an Australian sentinel surveillance system

Characteristics of patients with hospitalacquired influenza A (H1N1)pdm09 virus admitted to the intensive care unit

Nosocomial influenza in a pediatric hospital: Comparison of rates of seasonal and pandemic 2009 influenza A/H1N1 infection

Influenza B virus infections in Western Saxony, Germany in three consecutive seasons between

RKI (Arbeitsgemeinschaft Influenza): Saisonberichte

Respiratory viruses in transplant recipients: more than just a cold. Clinical syndromes and infection prevention principles

Management of respiratory viral infections in hematopoietic cell transplant recipients

The characteristics and outcomes of parainfluenza virus infections in 200 patients with leukemia or recipients of hematopoietic stem cell transplantation

Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies

Estimating excess length of stay due to healthcareassociated infections: a systematic review and meta-analysis of statistical methodology

Nosocomial infection, length of stay, and timedependent bias

Landmark prediction of nosocomial infection risk to disentangle short-and long-stay patients

Incubation periods of acute respiratory viral infections: A systematic review

Reasons Why Physicians and Advanced Practice Clinicians Work While Sick: A Mixed-Methods Analysis

European journal of clinical microbiology & infectious diseases : official publication of the

Health care workers causing large nosocomial outbreaks: a systematic review

Effect of influenza vaccination of healthcare personnel on morbidity and mortality among patients: systematic review and grading of evidence

Influenza vaccination of healthcare workers in acute-care hospitals: a case-control study of its effect on hospital-acquired influenza among patients

with n/N being the number of nosocomial cases / total cases of that virus in the respective season

Analysed categories are displayed on the column to the left and either given as frequencies [%], median and range [median (range)] or median and interquartile range [median(IQR)]. (n/total) indicates the respective cases of the total amount of available data. A comparison was done for the whole study period and a p-value <0.05 was considered significant