key: cord-324148-bllyruh8
authors: Loubet, Paul; Mathieu, Pauline; Lenzi, Nezha; Galtier, Florence; Lainé, Fabrice; Lesieur, Zineb; Vanhems, Philippe; Duval, Xavier; Postil, Deborah; Amour, Sélilah; Rogez, Sylvie; Lagathu, Gisèle; L'Honneur, Anne-Sophie; Foulongne, Vincent; Houhou, Nadhira; Lina, Bruno; Carrat, Fabrice; Launay, Odile
title: Characteristics of human metapneumovirus infection in adults hospitalized for community-acquired influenza-like illness in France, 2012-2018: a retrospective observational study
date: 2020-04-10
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.04.005
sha: 
doc_id: 324148
cord_uid: bllyruh8

OBJECTIVES: To describe the prevalence, clinical features and complications of human metapneumovirus (hMPV) infections in a population of adults hospitalized with influenza-like illness (ILI). METHODS: This was a retrospective, observational, multicenter cohort study using prospectively collected data from adult patients hospitalized during influenza virus circulation, for at least 24h, for community-acquired ILI (with symptom onset <7 days). Data were collected from five French teaching hospitals over six consecutive winters (2012-2018). Respiratory viruses were identified by multiplex RT-PCR on nasopharyngeal specimens. hMPV+ patients were compared to hMPV– patients, influenza+ and respiratory syncytial virus (RSV)+ patients using multivariate logistic regressions. Primary outcome was the prevalence of hMPV in patients hospitalized for ILI. RESULTS: Among the 3148 patients included (1449 (46%) women, 1988 (63%) aged 65 and over; 2508 (80%) with chronic disease), at least one respiratory virus was detected in 1604 (51%, 95%CI [49-53]), including 100 cases of hMPV (100/3148, 3% 95%CI [3, 4]), of which 10 (10%) were viral co-infection. In the hMPV+ patients, mean length of stay was 7 days, 62% (56/90) developed a complication, 21% (14/68) were admitted to intensive care unit and 4% (4/90) died during hospitalization. In comparison with influenza+ patients, hMPV+ patients were more frequently > 65 years old (aOR=3.3, 95%CI[1.9-6.3]) and presented more acute heart failure during hospitalization (aOR=1.8, 95%CI[1.0-2.9]). Compared to RSV+ patients, hMPV+ patients had less cancer (aOR=0.4, 95%CI[0.2-0.9]) and were less likely to smoke (aOR=0.5, 95%CI[0.2-0.9]) but had similar outcomes especially high rate of respiratory and cardiovascular complications. CONCLUSIONS: Adult hMPV infections mainly affect the elderly and patients with chronic conditions and are responsible for frequent cardiac and pulmonary complications similar to those of RSV infections. At-risk populations would benefit from the development of antivirals and vaccines targeting hMPV.

During winter, community-acquired influenza-like illness (ILI), mostly caused by respiratory 74 viruses, is very common. The most frequent viruses seen in primary care are influenza 75 viruses A/B, rhinovirus, coronavirus, respiratory syncytial virus (RSV) and human 76 metapneumovirus (hMPV) [1, 2] . In the hospital setting, adults with ILI are commonly tested 77 only for influenza, resulting in limited data concerning other respiratory viruses. The use of 78 multiplex RT-PCR allows identification of multiple viruses simultaneously but remains a 79 second-line test in non-immunocompromised patients in emergency departments because of 80 its cost and the limited therapeutic options [3] . 81

Human MPV, discovered in 2001, is phylogenetically similar to RSV and has been frequently 82 found associated with respiratory tract illnesses [1, 4, 5] . Its circulation occurs with a seasonal 83 distribution from January to March in the Northern hemisphere, often overlapping or following 84 RSV infection season [6, 7] . Human MPV is a major pediatric respiratory pathogen at least one of the following respiratory symptoms: cough, sore throat or dyspnea. Patient 105 with contra-indication for influenza immunization, those who had previously tested positive 106 for influenza virus in the same season and those without French social security affiliation 107 were excluded. Each participant was interviewed, and nasopharyngeal samples were 108

obtained at enrolment to screen for influenza and other respiratory viruses. 109

In the present study, we included all the patients from the first six FLUVAC seasons 110 (2012/13, 2013/14, 2014/15, 2015/16, 2016/17, 2017/18) Patients with multiple viral infections were excluded from the analyses. Univariate analysis 143 was used to asses risk factors for the detection of hMPV infection, influenza infection, RSV 144 infection and acute heart failure. We performed two multivariate analyses using a backward 145 stepwise logistic regression model using hMPV test result (positive/negative) and acute heart 146 failure (yes/no) as the dependent variable in the first and second model respectively. 147

Covariates with a p-value <0.2 in univariate analysis were tested in the multivariate model. 148

Results from regression models are expressed as crude odds ratios (OR) and adjusted ORs 149 (Figure 1 and Table S1 ). Ten of the 100 hMPV infections (10%) were co- and 41% (37/90) hospitalized in the 12 months preceding the study (Table 1) . 174

The median time from symptom onset to admission was similar between hMPV+ and hMPV-175 patients (2 days (IQR, 1-3)) as well as the main symptoms at inclusion except for 176 weakness/malaise that was less frequent in hMPV+ patients (13/90 (14%) vs 27%, p<.007). 177

There was no difference between hMPV+ and hMPV-groups in terms of median length of 178 stay, number of complications during hospitalization, intensive care unit (ICU) admission and 179 death. However, hMPV+ patients were more likely to have an acute heart failure during 180 hospitalization (25% (22/89) vs 14% (377/2722), p<.004). 181

There was no difference in sociodemographic characteristics, clinical presentation or 182 outcomes between hMPV and viral coinfection and patients with hMPV infections alone. 183

In the multivariate analysis, when comparing hMPV+ patients to all hMPV-patients, age > 65 184 years (aOR 95% CI 3.3 [1.9;6.1], p<0.001) was significantly associated with hMPV detection. 185

In contrast, the sudden onset of symptoms, defined as the occurrence of malaise/weakness, 186 was associated with the absence of hMPV infection (aOR 95% CI 0.4 [0.2;0.8], p=0.008) 187 (Table 1) . 188

After adjustment for chronic heart disease, age, gender, smoking status and influenza 189 vaccination, hMPV infection was significantly associated with occurrence of acute heart 190 failure during hospitalization (aOR 95% CI 1.8 [1.1;3.0], p=0.02). 191

In univariate analysis, in comparison to influenza+ patients, hMPV+ patients were older 193 

In our post-hoc analysis of 3148 hospitalized adult patients with community-acquired ILI, 211 hMPV was found in 3% of the samples. These patients were older, had chronic conditions, 212 frequent respiratory and cardiac chronic diseases, and frequently presented complications. 213

This prevalence is consistent with several studies that found hMPV in 3 to 6% of adult 214 patients with lower respiratory tract infection in primary care [1, [14] [15] [16] and in 6% of patients 215 hospitalized for acute respiratory infection (ARI) [17] . This frequency may vary according to 216 the inclusion criteria, especially temperature cut-off, as hMPV infection frequently causes 217 non-febrile illness [5] . 218

Our hospitalized hMPV+ adults were mostly older and/or high risk patients as previously 219 described in the literature [5, 10, [18] [19] [20] . Complications were frequent (62%), as well as ICU 220 admission (17%) and death (4%). These rates were similar to those of the 91 hospitalized 221 patients with hMPV from the Walsh et al. study in 2008 in the USA [10], but lower than those 222 of the 128 critically ill adults with hMPV infection (31% required ICU admission and 8% died) 223 from the Hasvold et al. study in 2016 [20] . 224

The majority of hMPV+ patients presented several respiratory signs (cough, dyspnea), 225

whereas sudden onset of symptoms was associated with the absence of hMPV infection. 226

There were differences in clinical presentation between hMPV+ patients and influenza+ 227 patients (less frequent constitutional symptoms (headache, weakness, myalgia) but more 228 dyspnea) but not between hMPV+ patients and RSV+ patients. These points emphasize the 229 difficulty of distinguishing respiratory viruses based on clinical signs alone and question the 230 relevance of the current ILI definition to detect hMPV infection. 231

Interestingly, we also found that hMPV+ patients were older and presented more chronic 232 cardiac conditions and acute heart failure during the hospitalization than influenza+ patients. 233

Although, influenza [21] and RSV [22] are known to worsen heart failure, no study has 234 specifically assessed hMPV [21, 22] 

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Onset of symptoms > 7 days: n=124No consent obtained n=6)