HMPV in Immunocompromised Patients: Frequency and Severity in Pediatric Oncology Patients

Cancer is the first cause of death by disease in childhood globally. The most frequent types of cancers in children and adolescents are leukemias, followed by brain and central nervous system tumors and lymphomas. The recovery rate of cancer in children is around 80% in developed countries and up to 30% in developing countries. Some of the main causes of complications in children and adolescents with cancer are respiratory viral infections, mainly in bone marrow-transplanted patients. Respiratory viruses have been detected in the bronchoalveolar lavage or nasal wash specimens from cancer patients with or without respiratory illness symptoms. Human metapneumovirus (HMPV) is within the ten most common viruses that are encountered in samples from pediatric patients with underlying oncology conditions. In most of cases, HMPV is found as the only viral agent, but co-infection with other viruses or with bacterial agents has also been reported. The discrepancies between the most prevalent viral agents may be due to the different populations studied or the range of viral agents tested. Some of the cases of infection with HMPV in cancer patients have been fatal, especially in those who have received a hematopoietic stem cell transplant. This review seeks to show a general view of the participation of HMPV in respiratory illness as a complication of cancer in childhood and adolescence.


Frequency of Human Metapneumovirus in Pediatric Patients
HMPV has been associated with 6.0-40.0% of acute respiratory illness in children, as was summarized by Shafagati and collaborators, with data from 2003 to 2013 [8]. Research recently performed in Belgium aimed at determining the frequency of HRSV and HMPV in samples from children and adults placed HMPV as the second most prevalent virus in respiratory samples, accounting for 7.3%, behind HRSV, which was encountered in 18% of the samples [11].
There have been studies with more extended search of viruses that have placed HMPV within the ten most prevalent viruses. In a study performed in Brazil, HMPV was found as the seventh most frequent causing agent of community-acquired pneumonia in children from 0.3 to 10 years old (12%) [12]; in the same way, analyses performed in China have situated HMPV as the eighth most frequent cause (5%) of severe acute respiratory infection in hospitalized children [13], the seventh most frequent cause (2.1%) of acute lower respiratory tract infection in children who were admitted to a pediatric intensive care unit [14], and the ninth (2.8%) most frequent virus in pediatric patients hospitalized with acute respiratory illness [15].
Patients going through an infection of HMPV usually have a favorable outcome; however, fatal cases have been reported in children without underlying medical conditions. Recently, two deaths due to HMPV infection were reported: the death of a 2.7 years old girl suffering from acute respiratory distress syndrome [16] and the death of a two-year-old old girl who suffered respiratory failure [17].
This review summarizes the cases of infection or death by HMPV in children and adolescents who have cancer as a basal medical condition.

Distribution of Respiratory Viruses in Pediatric Cancer
The distribution of respiratory viral pathogens in children and adolescents with cancer is summarized in Table 1. The types of cancer included in these studies were restricted to hematological malignancies and solid tumors, except for the work by Fazekas et al. [18], who additionally included inherited genetic disorders and primary immunodeficiencies in their study. The exact type of cancer of each study is shown in Table 2. Samples analyzed more frequently were nasopharyngeal aspirates, nasopharyngeal swabs, and bronchoalveolar lavages.
Rhinovirus is the leading cause of respiratory diseases in oncology patients. It is detected in 10-62.7% of cases. Second to rhinovirus, the most represented virus is HRSV, found in 2.1-46% of cases. HMPV has been found in 3.3-13.5% of cases, being classified as the third [19], fourth [18,[20][21][22][23], fifth [24] and tenth [25,26] most frequent respiratory virus, according to the literature reviewed. Interestingly, HMPV has been reported as the only viral agent that was responsible for an outbreak in a pediatric oncology population [27] (Table 1).   Herpes simplex virus  -----------Varicella zoster virus  -----------Codetection of more than one Table 1 shows evidence of the place that HMPV takes in respect to other viral agents. However, there have been reports that only investigated the frequency of HMPV, and the most important information from these research works is condensed in Table 2.

Frequency of HMPV Infection in Pediatric Oncology
We previously mentioned that HMPV has been found in 3.3-13.5% of acute respiratory infection (ARI) episodes (Table 1); nevertheless in febrile and neutropenia episodes, HMPV infection frequency has been found to be 0.4-44% (Table 2).
Co-infections were reported in most of the papers reviewed, but, in some cases, HMPV has been found as the only agent that caused respiratory illness in pediatric cancer patients, being 2.0-7.4% of the total virus distribution [25,[28][29][30]. In some cases, bacteria or other pathogens have been detected along with HMPV [21,26,[30][31][32] (Table 2).
Co-infections were described in detail in work by Torres and collaborators, who showed that HMPV is the sixth most frequent pathogen in sole infections, the fourth most frequent in mixed viral infections, and the sixth most frequent in virus-bacteria mixed infections [30].

Fatal Cases Due to HMPV Infection in Pediatric Patients with an Underlying Oncology Condition
Fatal cases in pediatric patients with no underlying medical condition due to HMPV are known [17,45]; HMPV has also been related to a fatal case of encephalitis [46]. Though rare, some fatal cases due to HMPV infection have been reported for pediatric cancer patients (Table 2) and for those who are recipients of a hematological cell transplant ( Table 3).
As a result of this review, we found 17 cases of death that were positive for HMPV; in nine cases, HMPV was the only pathogen found [31,35,40,44]. However, some of these investigations considered children and adults [31,39] or children without cancer [33]. Excluding these investigations, we counted 3233 cases of children and adolescents with cancer who showed a respiratory disease or fever and neutropenia episodes. Out of the 3233 cases, 227 children were positive for HMPV (7%). Three deaths were reported, which means that 0.09% (3/3233) of the total patients succumbed and 1.3% (3/227) of the patients infected with HMPV succumbed ( Table 2).
It is important to mention that at least in one piece of research, the authors tested HMPV in pediatric hematopoietic stem cell transplant patients, but they found nothing [47].
Of note, three out of the five patients who were treated with ribavirin plus intravenous immunoglobulin survived [41][42][43]; the other two did not [35]. The mentioned treatment has also been proven to reduce the risk of mortality for HRSV in hematopoietic stem cell-transplanted patients [48].
Cases of death in adult patients who have received a transplant of hematopoietic stem cells due to onco-hematological conditions, ascribable undoubtfully or presumably to HMPV, have been reported [49][50][51][52]. A systematic review by Shah and collaborators gathered 4208 cases of hematologic malignancy in children and adults who received a hematopoietic cell transplant. In that review, they showed that 34% of the analyzed cases of lower respiratory tract infection (LRTI) were due to HMPV, and 6% were fatal [6].

Conclusions
Pediatric oncology patients are more susceptible infections due, in most cases, to the neutropenia that results from medication.
HMPV infections in patients with hematological conditions have been documented, but their impact in childhood is not clear because the research has involved children and adults or only adults. This review shows the respiratory viral infections that can be originated to HMPV infection exclusively in pediatric oncology patients. The distribution of HMPV among other viruses in otherwise healthy children and adolescents is reported to be 6-40% [8], which is greater than that of the pediatric population with underlying cancer, whose HMPV distribution is 3.3-13.5% (as seen in this review). These data should be taken carefully because the combined number of patients in the cancer group was small (n = 3867), and the number of HMPV infections may have been underestimated. Interestingly, in pediatric oncology patients, 2.9-10% of the HMPV infections were detected in episodes of ARI; however in children going through febrile episodes, HMPV infection was found in up to 44% [37] and 51% [38] of cases. This difference is probably because HMPV infections could be asymptomatic because about 60% of the fever episodes in neutropenic patients do not show other signs or symptoms [59].
HMPV has become more relevant because outbreaks of infection in pediatric [27] and adult cancer patients [60] have occurred with fatalities. Some deaths attributable to HMPV infection have been reported in the pediatric oncology population, with and without a hematopoietic stem cell transplant [31,35,40,44,55,58]. According to the analyzed information, 1.3% of pediatric patients with cancer have been found to be positive for an HMPV infection and had a fatal outcome; meanwhile, 2.3% of the pediatric cancer patients who were recipients of a transplant have been found to be positive for HMPV had death.
The management of patients with HMPV is mainly supportive. The treatment of two patients with ribavirin and intravenous immunoglobulin in three cases of Burkitt lymphoma [41,42] and one case of acute lymphoblastic leukemia (ALL) [43] has been to be effective against infection with HMPV; this treatment has also been shown to be effective in the cases of two adults with ribavirin following hematopoietic stem cell transplantation (HSCT) [61] and lung transplant [62]. Though the previously described treatment has been proved to be effective, no randomized clinical trials have been performed to support these results. Actually, the treatment with ribavirin and intravenous immunoglobulin (IVIG) had an unfavorable outcome in other cases [35]. The lack of an approved treatment for HMPV infection has increased the possibility of fatal outcomes in a population at risk, and so research to find efficient treatments or vaccines for HMPV should be encouraged.
It is important to note that HMPV infections are frequently accompanied by other viral or bacterial infections. One third of the children with cancer who present viral infections are co-infected with bacteria, and children with viral infections stay for fewer days in the hospital than children with mixed virus-bacterial infections [30]. The question of where HMPV infections contribute to the progress of other infections needs to be explored, especially in immunodeficient children.
Research regarding HMPV infections exclusively in the pediatric cancer population is available, but the estimations made from this research have limitations, mainly due to the number of analyzed patients. Thus, more work in this field is imperative to have a better understanding of the impact of HMPV and other respiratory viruses in populations at risk.

Methodology
Two researchers (C.M.R. and M.R.B.L) independently performed a search in PubMed with different combinations of the terms HMPV, metapneumovirus, and respiratory viral infection, as well as cancer children, leukemia children, and pediatric oncology. As a result, a total of 811 papers were found. A second search with the terms HMPV, metapneumovirus, and transplant cancer retrieved 61 papers. After reading the abstracts, reviews and duplicates were eliminated. Papers in which the subjects of the studies were only adults and those in which HMPV was not surveyed were also eliminated. Papers written in English and Spanish were all considered. In the end, the number of papers that met the established characteristics was 30. During the process of writing of the review, four more papers were included.
Each researcher designed different tables for gathering the most critical data out of the papers while trying to keep as much common information as possible. Afterwards, the researchers shared and compared their found information; as a result, three tables were obtained.