Human metapneumovirus (hMPV) was first identified in 2001, the Netherlands from a pediatric patient who had symptoms similar to those of respiratory syncytial virus (RSV) infection. It is a member of the paramyxovirus family and is genetically similar to RSV [1]. Typically hMPV infections occur between March and April, and account for 7% of respiratory tract infections [2].

A hMPV infection commonly occurs in children less than 2 years old and manifests as mild flu-like symptoms, similar to RSV [3]. Furthermore, hMPV is a major contributor to the burden of wintertime respiratory illness in older adults that is peak incidence at 65 years of age and immunocompromised individuals [2,4,5]. hMPV infections in children are usually mild and self-limiting, but in elderly and immunocompromised patients, the clinical course can progress to acute respiratory distress syndrome (ARDS) [6]. Studies of patients with hMPV who develop severe illness have focused on children; few have involved adults [7,8]. Nosocomial infection has been reported in several studies as a mode of transmission [5,9-11]. Nosocomial hMPV infection of adults occurs predominantly in human immunodeficiency virus-infected persons [12].

There are few studies on hMPV infection of adults in Korea. And the number of immunocompromised patients is increasing in hospitals. These patients are also vulnerable to previously neglected pathogens. Therefore, we designed a retrospective review of hMPV-infected adults. The clinical characteristics of the patients—including demographic data, comorbidities, presence of pneumonia or ARDS, acquisition site (community-acquired or nosocomial), and risk factors for ARDS—were reviewed.

This study was a retrospective review of medical records; institutional review board approval was obtained (No. GAIRB2016-179). We identified all patients at Gachon University Gil Medical Center, a tertiary referral hospital, with a laboratory-confirmed hMPV infection as diagnosed by positive multiplex real time-polymerase chain reaction (mRT-PCR) between January 2012 and April 2016. Nasopharyngeal or oropharyngeal samples were obtained in the emergency department, in an inpatient setting, or in an outpatient setting. All diagnostic testing was performed at the Gil Medical Center Laboratory Department. Multiplex real time-PCR was performed using Anyplex II RV16 Detection kit (Seegene, Seoul, Korea). This kit detected in parallel for the following 16 respiratory viruses: human bocavirus, human enterovirus, influenza virus A and B, parainfluenza virus 1, 2, 3, and 4, RSV A and B, coronavirus OC43, 229E, NL63, human rhinovirus A/B/C, and metapneumovirus. A total of 652 cases of hMPV infection were identified by mRT-PCR from nasopharyngeal or oropharyngeal swabs among patients. We collected hospitalized adult patients over 18 years with positive hMPV mRT-PCR assay result among 652 patients. The 110 of hospitalized adult patients with hMPV infection were included in the primary analysis.

Demographic, comorbidity, and hospitalization data of 110 adult patients were collected. The data included chronic respiratory disease, cardiac disease, immunocompromised state, end-stage renal disease (ESRD) requiring dialysis, cirrhosis, corticosteroid use, and immunosuppressive therapy. Viral co-infection was defined as identification by mRT-PCR from a nasopharyngeal or oropharyngeal swab. Patients who had either a positive blood culture or a positive sputum culture from a satisfactory specimen were identified as having bacterial co-infection. We reviewed the medical records of the patients to identify those admitted to the intensive care unit (ICU) with a nosocomial infection and who met the criteria for ARDS using the Berlin definition [13]. The incubation period is estimated to be 4 to 6 days [14]. Nosocomial infection was defined as an infection that occurred up to 5 days after discharge or more than 5 days in admission. Death information of patients was confirmed using hospital medical record and obliterated information of national health insurance service which means death.

Clinically relevant parameters were identified on the day of execution of mRT-PCR and admission to the ICU or ward; these included temperature, respiratory rate, applied fraction of inspired oxygen, partial pressure of arterial oxygen, white blood cell count, blood urea nitrogen (BUN)/creatinine, total bilirubin, C-reactive protein (CRP) level, and procalcitonin level. The patients were divided into non-ARDS and ARDS groups, and the risk factors and laboratory values for ARDS were assessed.

Our study is the first to characterize ARDS and mortality in the adult patients with hMPV infections in Korea. This study evaluated the clinical features of 110 hospitalized adults with a positive hMPV mRT-PCR assay result at a tertiary referral hospital in South Korea from 2012 to 2016. This was a retrospective study of hMPV-infected adults and provided detailed clinical data, including comorbidities, radiologic findings, and laboratory findings, as well as the demographic data of the subjects. Most of the adults with hMPV infection had pneumonia on chest X-ray, and 20% had ARDS. The in-hospital mortality rate of ARDS patients was 36.4%, and 10.9% of all patients died during hospitalization. Nosocomial infection occurred in 39.1% of the subjects. Other study shows forty-eight percent of ICU patient is ARDS and mortality is 18% [8]. Although the scope of the studies, it is necessary to focus on high ARDS incidence and high mortality rates.

The increasing availability and broadened scope of viral respiratory polymerase chain reaction panels helps our understanding of viral pathogens. The mRT-PCR assay had a sensitivity and specificity higher than 88% and 98.6%. And the mRT-PCR could detect co-infecting respiratory viruses, even at low viral loads that cannot be detected using culture techniques [15].

During the study period, the peak incidence of hMPV infection was in April, after that of influenza which had peak in February. A study in a similar area conducted from 2000 to 2005 reported a peak incidence of hMPV infection in January to March [16], and another in March to April [17]. In this study, 17% of the subjects had viral co-infections, most frequently with influenza virus (Table 4). This is in agreement with a previous report [4]. These co-infections may be due to the overlap of the periods of peak incidence of these viruses. hMPV infections occur between March and April. And RSV infection is in December and Influenza is in January and February (Supplementary Figure 1). A high percentage (90% to 100%) of children in 5–10 years old have been infected. 78%, under 5 years of age in this study (Supplementary Figure 2).

The mean age of the adult patients was 61.4 years, and all but five had comorbidities such as diabetes, malignancy, airway obstructive diseases, ESRD, and heart failure. Such comorbidities and old age can result in an immunocompromised state, possibly leading to the development of severe viral infections such as pneumonitis or ARDS. hMPV infections in healthy adults usually show mild clinical features from asymptomatic to upper respiratory symptoms, similar to RSV infection [18]. However, frail elderly patients with an hMPV infection could progress to pneumonitis, ARDS, or death [8,12,18]. In this study, severe hMPV infection was associated with a risk of pneumonia, ARDS, and mortality in immunocompromised elderly patients. The findings of this study suggest that 20% of hospitalized adults with an hMPV infection will develop ARDS. The risk factor for hMPV-associated ARDS was congestive heart failure. It is known that viral infection is one of the risk factors for aggravation of congestive heart failure. When patients with congestive heart failure are infected by hMPV, they have risks both aggravation of congestive heart failure and ARDS [8]. The patients with ARDS and congestive heart failure may also have had pulmonary edema; however, this could not be determined because of the limitations inherent to a retrospective study. The patients with ARDS among hMPV-infected adults showed lymphocytopenia, higher levels of BUN, creatinine, and CRP and lower levels of albumin compared to non-ARDS patients. In-hospital mortality of severe ARDS (OR, 9.48) was higher than ARDS (OR, 5.24). The in-hospital mortality rate of the patients with hMPV infection was 10.9%. The in-hospital mortality rate of the ARDS group (36.4%) was significantly higher than that of the non-ARDS group (5.7%). The risk factors for hMPV-associated ARDS should be considered as congestive heart failure. These results suggest that hMPV is an important and previously underappreciated cause of ARDS in adult patients. Severe clinical manifestations such as ARDS should be considered when hMPV infection is diagnosed in adult patients with congestive heart failure.

The hMPV infection has been reported in immunocompromised patients, including lung transplant and hematopoietic stem cell transplant recipients [3,19]. Moreover, outbreaks in healthcare facilities have been reported [2,9]. When considering the implications of these findings, it should be noted that the risk of nosocomial hMPV infection is on the rise among patients with blood cancer or patients with a solid tumor [20] who were recently admitted for chemotherapy. The additional analysis showed that immunosuppressive therapy is interaction variable with cancer. A patient with liver cirrhosis was not explained as risk factor of nosocomial infection because small cases and a further research is needed. Such patients typically reside in shared rooms containing four to six patients. Therefore, the possibility of hMPV infection should be considered in long-term immunocompromised patients residing in shared rooms. Droplet respiratory precautions are appropriate for preventing the transmission of hMPV, particularly in immunocompromised patients.

This study has multiple limitations. Whether hMPV was the pathogen in all patients enrolled in this study was unclear. However, the mRT-PCR assay used has high sensitivity and specificity. Also, the rate of co-infection with other pathogens was not high (Table 5). Future studies should assess the clinical features of hMPV infection in adults, determine the clinical potential of the virus as a respiratory pathogen to induce severe ARDS, and develop novel antiviral agents or vaccines.

In conclusion, this study suggests that hMPV is an important respiratory pathogen that causes pneumonia/ARDS in elderly, immunocompromised individuals and that it is transmitted via the nosocomial route. Clinicians need to consider mMPV virus and sufficient attention is required.