Vidaur et al. Ann. Intensive Care (2019) 9:86 https://doi.org/10.1186/s13613-019-0559-y RESEARCH Open Access Human metapneumovirus as cause of severe community‑acquired pneumonia in adults: insights from a ten‑year molecular and epidemiological analysis Loreto Vidaur1,3*, Izarne Totorika1, Milagrosa Montes2, Diego Vicente2,4, Jordi Rello3,5 and Gustavo Cilla2 Abstract Background: Information on the clinical, epidemiological and molecular characterization of human metapneu- movirus in critically ill adult patients with severe community-acquired pneumonia (CAP) and the role of biomarkers identifying bacterial coinfection is scarce. Methods: This is a retrospective epidemiological study of adult patients with hMPV severe CAP admitted to ICU dur- ing a ten-year period with admission PSI score ≥ 3. Results: The 92.8% of the 28 patients with severe CAP due to human metapneumovirus were detected during the first half of the year. Median age was 62 years and 60.7% were male. The genotyping of isolated human metapneumo- virus showed group B predominance (60.7%). All patients had acute respiratory failure. Median APACHE II and SOFA score were 13 and 6.55, respectively. The 25% were coinfected with Streptococcus pneumoniae. 60.7% of the patients had shock at admission and 50% underwent mechanical ventilation. Seven patients developed ARDS, three of them younger than 60 years and without comorbidities. Mortality in ICU was 14.3%. Among survivors, ICU and hospital stay were 6.5 and 14 days, respectively. Plasma levels of procalcitonin were higher in patients with bacterial coinfection (18.2 vs 0.54; p < 0.05). The levels of C-reactive protein, however, were similar. Conclusion: Human metapneumovirus was associated with severe CAP requiring ICU admission among elderly patients or patients with comorbidities, but also in healthy young subjects. These patients often underwent mechani- cal ventilation with elevated health resource consumption. While one out of four patients showed pneumococcal coinfection, plasma procalcitonin helped to implement antimicrobial stewardship. Keywords: Severe community-acquired pneumonia, Human metapneumovirus, Acute respiratory distress syndrome, Biomarkers Background Based on genetic and antigenic variability, hMPV strains Human metapneumovirus (hMPV) is a worldwide dis- have been classified in two groups or lineages (A and tributed enveloped virus with a RNA genome closely B) and four sublineages (A1, A2, B1 and B2) [1–3]. The related to respiratory syncytial virus. hMPV belongs to virus has been reported as a common respiratory patho- the Paramyxoviridae family, in the genus Metapneu- gen in childhood, associated mainly with upper but also movirus, first identified in the Netherlands in 2001 [1]. with lower respiratory tract infections [2, 4]. During the annual epidemics, hMPV has been associated with a sig- nificant number of hospital admissions in young children *Correspondence: loretovidaurtello@gmail.com [4–7]. 1 Critical Care Department, Donostia University Hospital-Biodonostia Respiratory tract infections caused by hMPV during Health Research Institute, San Sebastian, Guipuzcoa, Spain Full list of author information is available at the end of the article adulthood are less prevalent and less serious than those © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Vidaur et al. Ann. Intensive Care (2019) 9:86 Page 2 of 6 in childhood. However, the presence of hMPV has been radiographic opacities and hypoxemia not fully explained detected in 2–4% of adult patients admitted due to a by cardiac failure or fluid overload following the Berlin community-acquired pneumonia (CAP) [8, 9] and has criteria [21]. Exclusion criteria: subjects with nosocomial been associated with asthma and chronic obstructive pneumonia or admitted due to non-respiratory infec- pulmonary disease exacerbation [10–12]. The same as tion (non-severe coincidental infection) and patients with other common respiratory viruses, hMPV is usu- with pneumonia during the preceding 2 months (persis- ally associated with non-severe pneumonia, whereas tence of viral RNA in respiratory samples). Patients were risk factors like immunosuppression, specific comorbidi- recruited from the computerized records of the Microbi- ties—chronic lung disease, heart disease, blood disor- ology department, and the medical records were revised ders— elderly and living in long-term care facilities are by two clinical investigators (IT, LV). The recorded clini- associated with a higher risk of severe viral pneumonia cal variables were socio-demographic (age and sex), [13, 14]. Nevertheless, recent studies suggest that hMPV comorbidities, the Charlson comorbidity score and infection is an underappreciated cause of critical illness, clinical symptoms at admission [22]. Radiological and also in previously healthy patients [15–18]. analytic findings at admission and during the evolution, Severe community-acquired pneumonia (SCAP) is a coinfections, antibiotic therapy, the presence of shock known infectious complication of respiratory viruses or need of mechanical ventilation, ICU and hospital stay including hMPV. In these cases, clinical presentation, were also recorded. evolution and treatment differ depending on the patho- The detection of hMPV in respiratory samples was gens involved, hMPV alone or hMPV coinfected with a made by reverse transcription polymerase chain reac- bacteria. Some biomarkers have been studied as diag- tion (RT-PCR), in house monoplex until July 2010 [5], nostic markers to discriminate between viral or bacterial real-time commercial multiplex (Luminex xTAG Res- Anyplex™ II RV16/Allplex™ Respiratory Panel [Republic pneumonias and help physicians to decide not to start or piratory viral panel [USA]) until July 2013 and Seegene when to withdraw the antibiotic therapy [19, 20]. The main objective of this study was to describe the of Korea] since then. The extraction of nucleic acids was clinical and epidemiological characteristics of adults made using an automatic BioRobot1 M48 extractor (Qia- ­NucliSENS® Easy-Mag platform (bio-Mèrieux SA, Marcy with severe pneumonia caused by hMPV who required gen GmbH, Hilden, Germany) until July 2009 and the intensive care unit (ICU) admission, over a long period of time. Secondary objectives were to characterize the l’Etoile, France) from that date. The genotyping of hMPV epidemiological and molecular viral diversity and to was performed with a RT-PCR followed by sequenc- compare the value of C-reactive protein (CRP) and proc- ing [23]. Blood cultures, Streptococcus pneumoniae and alcitonin in identifying bacterial coinfections. Legionella pneumophila antigenuria (Alere BinaxNOW, Scarborough, ME, USA), and pharyngeal exudates with Methods viral transport media to evaluate respiratory viruses were This is a ten-year, retrospective epidemiological study assessed in all the patients included in the study. Coinfec- with inclusion of patients with CAP due to hMPV admit- tion was considered when hMPV was isolated with other ted in a 48-bed ICU in the North of Spain. In 2017, this viral or bacterial pathogens at the same time. ICU assisted a referral population of 545,227 inhabitants Discrete variables were expressed as counts (percent- older than 14 years. age) and continuous variables as medians and 25–75% All patients older than 14 years from July 2007 to interquartile ranges (IQRs). Differences in continuous June 2017 admitted in the ICU by CAP with admis- variables were analyzed by the Mann–Whitney U test or sion PSI score ≥ 3 were considered eligible. During the the Kruskall–Wallis test when appropriate. Qualitative first 2 years of the study, samples to detect respiratory variables were analyzed by the Chi-square test with Yate’s viruses were obtained occasionally in patients with CAP. correction when necessary. The threshold for clinical sig- However, it turned the standard of care in the ICU after nificance was p < 0.05. Data analysis was performed using 2009 influenza pandemic. To be included, cases meet SPSS for Windows 21.0.0 (SPSS, Chicago, IL, USA). The two of the following three criteria upon admission: (a) obtained clinical samples and the medical intervention of severe acute respiratory failure (paO2/FiO2 < 250), (b) the patients were ordered by the clinician attending each multilobar radiological involvement or (c) systolic arte- patient. The study was approved by the ethics commit- rial pressure < 90 mmHg. Acute respiratory distress syn- tee for clinical research of the health area of Gipuzkoa drome (ARDS) was diagnosed as an acute diffuse lung (Spain). Informed consent was waived due to the retro- injury with increased vascular permeability, bilateral spective nature of the study. Vidaur et al. Ann. Intensive Care (2019) 9:86 Page 3 of 6 Results Table 1 Annual epidemic peaks of influenza virus and human During the study period, 1942 respiratory samples were metapneumovirus infections, and temporal distribution sent from the ICU to the Microbiology Service to study of isolates in patients with severe community-acquired viral etiology, hMPV being identified in 33 patients pneumonia due to human metapneumovirus infection (Gipuzkoa, Spain, 2008–2017) (1.7%). Studied samples were mainly pharyngeal exudates (77.3%), but also tracheal aspirates (7.5%), bronchoaspi- Year Flu epidemic peak hMPV SCAP hMPV rates (5.8%), bronchoalveolar lavages (5.6%) and sputum epidemic peak (4.2%), where bacterial culture was also performed. Five patients with hMPV were excluded because admission 2008 January (2nd week) March None causes were other than respiratory infection. Cases were 2009 December (2008) January April (n = 1) detected every year except in 2008 (n = 0–5). The highest (50th week) July (n = 1) prevalence was in 2015 and 2017 (Fig. 1). Twenty-six of 2010 October (2009) Pandemia March March (n = 3) (42th week) the 28 patients with respiratory infection due to hMPV 2011 January (1st week) March March (n = 2) (92.9%) were detected during the first half of the year April (n = 1) and 16 (57.1%) in March–April. HMPV circulated every 2012 February (7th week) March June (n = 2) year later than influenza virus, being the epidemic peak 2013 February (7th week) March May (n = 1) of both infections separated by a period of 1–2 months. July (n = 1) In fact, the 75% of cases (21/28) of hMPV infections in 2014 January (3rd week) March January 2014 (n = 1) patients admitted to ICU occurred out of the influenza April 2014 (n = 1) epidemic period (Table 1). 2015 February (5th week) March January (n = 1) March (n = 1) Genotyping of hMPV was performed in 27 cases, being April (n = 2) ten cases of hMPV group A (39.3%) and 17 of hMPV May (n = 1) group B (60.7%). The viral strains belonged to subline- 2016 January (4th week) March March (n = 3) ages A2 (n = 10; 39.3%), B1 (n = 11; 39.3%) and B2 (n = 6; 2017 January (3rd week) March January (n = 2) 21.4%). Group A strains predominated until 2011 (72.7%), February (n = 1) March (n = 2) while later, the most frequent was genotype B (79%). After excluding seven patients with bacterial coinfection, hMPV human metapneumovirus, SCAP severe community-acquired pneumonia there were not significant differences in the genotype of hMPV between six patients who developed ARDS (60% than two comorbidities). The 60.7% (n = 17) of the genotype B) and 15 who did not (67% genotype B). patients were male. Main symptoms at admission were At ICU admission, all patients had acute respiratory cough (89.3%), dyspnea (71.4%), fever (67.9%) and puru- failure and received empiric antibiotic therapy. Median lent respiratory secretions (67.8%). Nineteen patients APACHE II score was 13 [IQR 11.2–20], and median (67.9%) had major comorbidities such as immune com- SAPS III and SOFA scores were 58.5 [IQR 47.2–70.7] promise (n = 7), asthma (n = 3) or chronic respiratory and 6.5 [IQR 3.5–9.5], respectively. Median age of the disease (n = 3) (Table 2). Seven patients (none died) included patients was 62 years [25–75% IQR 49.7–75.7], had coinfection with Streptococcus pneumoniae. Three and 60.7% of them were under 65 years old (9 with less episodes were coinfected with viral pathogens: human parainfluenza virus type 3 (hPIV3), human rhinovirus and cytomegalovirus (last one in an immunosuppressed patient). 6 Predominant radiologic pattern in patients with hMPV Not typed 5 Genotype B infection and without coinfection was the interstitial Genotype A alveolar pattern (47.6%), while in the patients with Strep- tococcus pneumoniae coinfection, the alveolar pattern Cases detected (Nº) 4 3 was predominant (85.7%). Eight patients had pleural effu- sion at admission, and two more developed it during the 2 ICU stay. Pleural effusion was bilateral in four patients 1 and massive (> 2 L) in three cases. Seventeen (60.7%) patients had shock at admission, 0 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 fourteen (50%) underwent invasive mechanical venti- Fig. 1 Cases of severe community-acquired pneumonia associated lation (median 5.5 days [IQR 5–14.2]) due to acute res- with human metapneumovirus infection, hospitalized in the Intensive piratory failure and four were tracheostomized due to Care Unit of a large regional hospital (San Sebastián, North of Spain) prolonged mechanical ventilation. Severe complications Vidaur et al. Ann. Intensive Care (2019) 9:86 Page 4 of 6 Table 2 Demographic characteristics of the study immunocompromised, died during the ICU stay due to population complications of respiratory failure. Among survivors, Total n Bacterial Without ICU and hospital median stay were 6.5 [IQR 5–11.7] and (%) coinfection bacterial 14 [IQR 10–23.3] days, respectively. Survival rate after (n) coinfection hospital discharge at 3 and 6 months was 97.1% (n = 23) (n) and 87.5% (n = 21), respectively. Study patients (n) 28 (100) 7 21 The median CRP and procalcitonin plasma levels at Male 17 (60.7) 5 12 ICU admission in the 28 hMPV-infected patients with Age (years) median [ICR] 62 [50 to 62 [61 to 83] 62 [48 to 75] CAP were 125 [44.6–305.9] mg/L and 1.3 [0.2–9.3] ng/ 76] mL, respectively. The values of CRP were similar between Comorbidities patients with bacterial coinfection and those without COPD 3 (10.7) 1 2 (median 231.4 [IQR 84.0–407.5] vs 110.2 [38–281.7] Asthma 3 (10.7) 0 3 mg/L; p = 0.29). In contrast, the plasma levels of procal- Heart failure 2 (7.1) 1 1 citonin were higher in the patients with bacterial coinfec- Alcoholism 3 (10.7) 0 3 tion than in those without (median, 18.2 [IQR 8.4–57.6] vs Immunosuppression 7 (25.0) 2 5 0.54 [0.1–1.9] ng/mL, p < 0.005). All patients with bacterial No comorbidities 11 (39.3) 3 8 coinfection had procalcitonin > 1 ng/mL at ICU admission. Clinical manifestations Fever 19 (67.9) 6 13 Discussion Cough 25 (89.3) 6 19 Our study gives new insights on the molecular epi- Purulent secretions 19 (67.9) 5 14 demiology of hMPV pneumonia admitted to the ICU Dyspnea 20 (71.4) 5 15 over 10 years. HMPV was consistently detected in CAP Radiologic pattern admitted to the ICU, with an annual incidence rang- Alveolar 15 (53.6) 6 9 ing 0.5–1 case/100,000 inhabitants older than 14 years Interstitial 3 (10.7) 1 2 per year. Molecular characterization of hMPV revealed Interstitial alveolar 10 (35.7) 0 10 group dominance of subgroup B. HMPV infection pre- Bilateral 17 (60.7) 2 15 sented seasonal distribution, with 2/3 of cases detected in Pleural effusion 8 (28.6) 2 6 late winter-early spring each year. The 32% of the stud- Complete blood count ied patients were younger than 65 years without comor- Leukopenia/leukocy- 16 (57.1) 4 12 bidities. HMPV CAP often presented as acute respiratory tosis/mm3 (< 4000 failure with bilateral opacities and half of ICU subjects year > 11,000) underwent mechanical ventilation. Lymphocytopenia Thrombocytopenia/ 9 (32.1) 4 5 mm3 (< 150,000) and pleural effusion were common at admission. Plasma Lymphopenia/mm3 23 (82.1) 6 17 procalcitonin was a sensitive tool to identify coinfection (< 1000) with bacteria (25%), which contributes to antimicrobial COPD chronic obstructive pulmonary disease stewardship. These findings suggest the need to imple- ment hMPV diagnosis tests in subjects with CAP devel- were frequent, highlighting acute renal failure in 12 oping acute respiratory failure. patients (42.8%), of which two required renal replace- Two out of three patients of this study had shock at ment therapy; cardiac failure or cardiogenic shock in admission, half of them underwent mechanical venti- eight patients (28.5%); and ARDS in seven cases (25%) lation, one out of four developed ARDS and one out of (two of them in patients with bacterial coinfection) seven died during the clinical course, suggesting that (Table 2). Three patients who developed ARDS were hMPV is responsible for SCAP in adults. These data are younger than 60 years (38, 47 and 54 years, respectively) concordant to that observed in the only study with a wide without major comorbidities or bacterial coinfection. All range of patients with hMPV infection in critically ill of them underwent invasive mechanical ventilation due patients, in which 55% of the patients required mechani- to acute respiratory failure (one had coinfection with cal ventilation, 48% developed ARDS and the mortal- hPIV3). The main clinical and epidemiological charac- ity was 18% [18]. Moreover, there are sporadic reports teristics of the patients are summarized in the Supple- of 3–6 patients with hMPV infection acquired in the mentary material (Additional file 1: Table S1, Additional community and acute respiratory failure who required file 2: Table S2). The majority of the patients (83.3%) had ICU admission [15–17]. In a large prospective study of lymphocytopenia (< 1000/mL) at admission (Table 2). ICU patients requiring invasive mechanical ventilation, Four patients (average age 68.5 years), three of them hMPV was more frequently detected in patients admitted Vidaur et al. Ann. Intensive Care (2019) 9:86 Page 5 of 6 by severe respiratory infection than in patients with other infection was diagnosed by oropharyngeal swab sam- causes, suggesting a causal role of HMPV in the develop- ples more than in low respiratory tract samples, mainly ment of severe respiratory infection [24]. in non-intubated patients. The detection of a viral path- Most of the patients of this study had major comorbidi- ogen in respiratory samples of a patient with acute res- ties at admission, mainly chronic respiratory failure and piratory infection can be coincident and not related to immunosuppression, being those patients and the elderly ICU admission. The retrospective design of the study the most susceptible to develop severe hMPV infections can underestimate the actual incidence of hMPV infec- [2, 10, 14]. However, 60% of the patients were younger tion because some patients admitted because of acute than 65 years old and one out of three did not have major respiratory infection could not be investigated for viral comorbidities, being similar to CAP related to other eti- etiology. However, from the 2009 influenza pandem- ologies. Interestingly, three patients (10.7%) were young ics, nasopharyngeal swab samples with respiratory viral adult patients without comorbidities and without bacterial detection are routine of care being collected in the 90% coinfection that developed ARDS pointing out a main role of patients with SCAP admitted to ICU. Finally, three dif- of hMPV in the etiology of severe respiratory infections ferent molecular techniques were used, with potential requiring mechanical ventilation. In the cohort of patients selection bias due to the differences in sensitivity of these of Hasvold et al. [18], 15% of the patients had only minor techniques. comorbidities and were not immunosuppressed. One out of four episodes of severe acute respiratory infection was coinfected with bacteria, similar to that Conclusion observed in other series [17, 18]. Streptococcus pneu- In conclusion, our study confirms that hMPV, a res- moniae, one of the bacterial species most frequently piratory virus causing bronchiolitis and pneumonia involved in post-viral super-infections [25], was the main in children, was associated with severe CAP requiring isolated bacterial pathogen. In these episodes, procal- ICU admission among elderly patients or patients with citonin has been reported to discriminate between viral comorbidities, but also in healthy young subjects. These episodes and those with bacterial coinfection [26], in patients often underwent mechanical ventilation with contrast with CRP. Some studies have recommended dif- long ICU and hospital stays, associated with elevated ferent cutoff points of procalcitonin to discontinue early health resource consumption. The results of this study antibiotic therapy in patients with community-acquired agree with recent observations [13] suggesting a shift in therapy, being 0.25 ng/mL and, mainly 0.1 ng/mL the the paradigm of severe pneumonia, recommending that most recommended [27, 28]. None of the patients with viral infection (and specifically hMPV) should be ruled documented bacterial coinfection in this study had a pro- out when complicated with acute respiratory failure. calcitonin level lower than 1 ng/mL which supports the While one out of four patients showed pneumococcal early discontinuation of antibiotic therapy in this group coinfection, plasma procalcitonin levels helped to imple- of patients with low plasma levels of procalcitonin. The ment antimicrobial stewardship. results of this study, about procalcitonin plasma determi- nations, could help to develop personalized medicine in patients with CAP, helping physicians to early discrimi- Additional files nation between viral or bacterial pneumonia and antimi- crobial stewardship [29]. Additional file 1: Table S1. Main characteristics of immunocompe- Three different genotypes of hMPV were associated tent adult patients admitted to the Intensive Care Unit due to a severe with severe CAP requiring ICU admission, which sup- community-acquired pneumonia associated with human metapneumovi- rus infection (Guipuzcoa, Basque Country, Spain, 2007–2017). ports that all of them are able to cause severe infections in adult patients. The low number of cases of the three differ- Additional file 2: Table S2. Main characteristics of immunosuppressed adult patients admitted to the Intensive Care Unit due to a severe ent hMPV lineages, the presence of coinfections and the community-acquired pneumonia associated with human metapneumovi- retrospective nature of the study made impossible to ana- rus infection (Guipuzcoa, Basque Country, Spain, 2007–2017). lyze the clinical pattern and the evolution of the patients based on the genotype of the infecting hMPV. However, Abbreviations to date, there are no significant differences in the evolu- ARDS: acute respiratory distress syndrome; APACHE II: acute physiology and chronic health evaluation II; CAP: community-acquired pneumonia; COPD: tion or clinical manifestation between different genotypes chronic obstructive pulmonary disease; CRP: C-reactive protein; hMPV: human of HMPV in adults in the outpatient setting [30]. metapneumovirus; ICU: intensive care unit; PSI Score: Pneumonia Severity This study has some limitations and therefore, the Index; SAPS III: simplified acute physiology score III; SCAP: severe community- acquired pneumonia; SOFA: sequential organ failure assessment. results should be evaluated cautiously. The hMPV Vidaur et al. Ann. Intensive Care (2019) 9:86 Page 6 of 6 Authors’ contributions 10. Walsh EE, Peterson DR, Falsey AR. Human metapneumovirus infec- LV made substantial contribution to the conception and design of the work, tions in adults: another piece of the puzzle. 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