Human Metapneumovirus — An Important New Respiratory Virus
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《新英格兰医药杂志》
Physicians who have an interest in infectious diseases know well that many infections cannot be assigned a microbial cause. This gap between what we observe and what we can explain is particularly obvious in the realm of respiratory infections. The article on human metapneumovirus infections by Williams and colleagues in this issue of the Journal (pages 443–450) represents substantial progress in bridging that gap.
Our assumption has been that the gap is attributable to a combination of the insufficient sensitivity of our diagnostic tests and the existence of several as-yet-undiscovered microbes. Both of these assumptions turn out to be correct. The sensitivity gap was considerably narrowed when the polymerase-chain-reaction (PCR) technique was applied to the diagnosis of viruses. A good example is the rhinoviruses, in which PCR is several times as sensitive as tissue culture in the detection of virus in clinical samples. The diagnostic use of PCR has widened our concepts of the role of rhinovirus in respiratory disease, particularly in wheezing children.
Gaps due to undiscovered microbes have been slower to be filled. In the 1960s, there was hope that coronaviruses would account for some of these microbes, but before the advent of the severe acute respiratory syndrome (SARS), the only gaps that had been filled by coronaviruses were related to minor illnesses of the upper respiratory tract. In contrast, the human metapneumovirus, first described in the Netherlands, has been found in many cases of more serious lower respiratory tract illnesses. Accumulating evidence from Europe, North America, and Australia, including the careful 25-year study by Williams and coworkers, indicates that human metapneumovirus is, with a few differences, a kid brother or sister to respiratory syncytial virus (RSV) that, particularly in young children, accounts for a very substantial proportion of cases previously relegated to the "undiagnosed" category.
The metapneumovirus genus is a member of the larger Pneumovirinae subfamily (containing, among other viruses, RSV), which, in turn, is a member of the Paramyxoviridae family (see Figure). The first metapneumovirus to be discovered was turkey rhinotracheitis virus, now called avian pneumovirus, and the avian pneumoviruses have been classified into four genotypes, one of which, type C, is closely related to human metapneumovirus. Metapneumoviruses differ from the true pneumoviruses (RSV, for example) in two respects: they are missing two nonstructural proteins that are present in the pneumoviruses, and they have a slightly different gene order. Human metapneumoviruses, unlike the SARS coronavirus, have almost certainly been around for many decades but have escaped detection because they are difficult to grow in the laboratory from clinical specimens.
Figure. Classification of Viral Pathogens of the Paramyxoviridae Family That Infect Humans.
Among these pathogens, human metapneumovirus is most closely related to respiratory syncytial virus. Not shown is avian pneumovirus, a member of the metapneumovirus genus that is genetically quite similar to human metapneumovirus.
With the discovery of any new microorganism, there are several questions we would like to answer right away. How common is it? What sorts of diseases does it cause? How does it stack up against other known viruses? How does it spread? Is it seasonal? There are also questions about how to treat it and whether it can be prevented by vaccines. The article by Williams et al. adds much to our knowledge, and we are now in a position to begin to answer many of these questions.
How common is human metapneumovirus infection? On the basis of the data collected by Williams et al., as well as by others, we can say that infection in the major target population — namely, previously normal young infants — is somewhat less common than infection with RSV but more common than parainfluenza virus infection. It is difficult to make such comparisons with any certainty, however, since they depend on the relative sensitivity of the detection systems. PCR, the standard diagnostic method for metapneumoviruses, is probably more sensitive than other detection methods for most viruses. Nevertheless, we can say with some certainty that human metapneumovirus infection in this age group is a very important medical problem.
What sorts of diseases does it cause? This question is more difficult to answer, since a causal role is not easy to prove. People frequently invoke Koch's postulates, but on the one hand, even the satisfaction of these postulates (which human metapneumovirus does fulfill) does not prove a causal relationship. On the other hand, we sometimes fully accept a causal relationship despite the fact that Koch's postulates have not been fulfilled; a notable example is human immunodeficiency virus (HIV) and AIDS. So, with moderate confidence but with some residual skepticism, we can say that human metapneumovirus is a cause of bronchiolitis and pneumonia in infants and is probably also a cause of some cases of lower respiratory tract disease in elderly adults. There is a difference of opinion about its role in exacerbations of asthma in children. Although human metapneumovirus appears to infect normal young adults frequently, it is not clear what sort of symptoms it causes in such hosts.
How does it stack up against other known viruses? The diseases caused by human metapneumovirus are most similar to those caused by RSV. A number of surveys have compared human metapneumovirus with RSV, and the relative frequency with which they are found during clinically significant illness varies from close to 1:1 (in the study by Williams et al.) to about 1:5. Infection with human metapneumovirus is probably somewhat less likely in infants younger than two months of age, and overall it is probably somewhat less severe than infection with RSV. The frequency and severity of disease in the elderly are still not well delineated.
Is it seasonal? Yes, it has a seasonality similar to that of RSV (i.e., winter epidemics), with variation in severity from year to year. How does it spread? Unknown. How can we treat or prevent it? Also unknown. Both treatment and prevention raise important questions about serotypes and about cross-protection between various strains of virus. In this era of rapid sequencing, it is easier to study genetic variation than antigenic variation (a case in point being HIV). Although we know that there are two genetic groups of human metapneumovirus, we do not yet know whether infection with one provides protection against infection with the other. Vaccine development will depend on the answers to these questions.
Human metapneumovirus should quickly be given a prominent position on the list of respiratory pathogens. This means that we should make widely available the tools that allow the virus to be detected in patients with serious respiratory infections; learn more about its role in disease, particularly in hosts other than children, and about its spread in the community and in hospitals; and as soon as possible, develop the means to prevent and treat human metapneumovirus infection.
Source Information
From the Division of Infectious Diseases (K.M.) and the Department of Laboratory Medicine (A.J.M.), Children's Hospital and Harvard Medical School, Boston.(Kenneth McIntosh, M.D., a)
Our assumption has been that the gap is attributable to a combination of the insufficient sensitivity of our diagnostic tests and the existence of several as-yet-undiscovered microbes. Both of these assumptions turn out to be correct. The sensitivity gap was considerably narrowed when the polymerase-chain-reaction (PCR) technique was applied to the diagnosis of viruses. A good example is the rhinoviruses, in which PCR is several times as sensitive as tissue culture in the detection of virus in clinical samples. The diagnostic use of PCR has widened our concepts of the role of rhinovirus in respiratory disease, particularly in wheezing children.
Gaps due to undiscovered microbes have been slower to be filled. In the 1960s, there was hope that coronaviruses would account for some of these microbes, but before the advent of the severe acute respiratory syndrome (SARS), the only gaps that had been filled by coronaviruses were related to minor illnesses of the upper respiratory tract. In contrast, the human metapneumovirus, first described in the Netherlands, has been found in many cases of more serious lower respiratory tract illnesses. Accumulating evidence from Europe, North America, and Australia, including the careful 25-year study by Williams and coworkers, indicates that human metapneumovirus is, with a few differences, a kid brother or sister to respiratory syncytial virus (RSV) that, particularly in young children, accounts for a very substantial proportion of cases previously relegated to the "undiagnosed" category.
The metapneumovirus genus is a member of the larger Pneumovirinae subfamily (containing, among other viruses, RSV), which, in turn, is a member of the Paramyxoviridae family (see Figure). The first metapneumovirus to be discovered was turkey rhinotracheitis virus, now called avian pneumovirus, and the avian pneumoviruses have been classified into four genotypes, one of which, type C, is closely related to human metapneumovirus. Metapneumoviruses differ from the true pneumoviruses (RSV, for example) in two respects: they are missing two nonstructural proteins that are present in the pneumoviruses, and they have a slightly different gene order. Human metapneumoviruses, unlike the SARS coronavirus, have almost certainly been around for many decades but have escaped detection because they are difficult to grow in the laboratory from clinical specimens.
Figure. Classification of Viral Pathogens of the Paramyxoviridae Family That Infect Humans.
Among these pathogens, human metapneumovirus is most closely related to respiratory syncytial virus. Not shown is avian pneumovirus, a member of the metapneumovirus genus that is genetically quite similar to human metapneumovirus.
With the discovery of any new microorganism, there are several questions we would like to answer right away. How common is it? What sorts of diseases does it cause? How does it stack up against other known viruses? How does it spread? Is it seasonal? There are also questions about how to treat it and whether it can be prevented by vaccines. The article by Williams et al. adds much to our knowledge, and we are now in a position to begin to answer many of these questions.
How common is human metapneumovirus infection? On the basis of the data collected by Williams et al., as well as by others, we can say that infection in the major target population — namely, previously normal young infants — is somewhat less common than infection with RSV but more common than parainfluenza virus infection. It is difficult to make such comparisons with any certainty, however, since they depend on the relative sensitivity of the detection systems. PCR, the standard diagnostic method for metapneumoviruses, is probably more sensitive than other detection methods for most viruses. Nevertheless, we can say with some certainty that human metapneumovirus infection in this age group is a very important medical problem.
What sorts of diseases does it cause? This question is more difficult to answer, since a causal role is not easy to prove. People frequently invoke Koch's postulates, but on the one hand, even the satisfaction of these postulates (which human metapneumovirus does fulfill) does not prove a causal relationship. On the other hand, we sometimes fully accept a causal relationship despite the fact that Koch's postulates have not been fulfilled; a notable example is human immunodeficiency virus (HIV) and AIDS. So, with moderate confidence but with some residual skepticism, we can say that human metapneumovirus is a cause of bronchiolitis and pneumonia in infants and is probably also a cause of some cases of lower respiratory tract disease in elderly adults. There is a difference of opinion about its role in exacerbations of asthma in children. Although human metapneumovirus appears to infect normal young adults frequently, it is not clear what sort of symptoms it causes in such hosts.
How does it stack up against other known viruses? The diseases caused by human metapneumovirus are most similar to those caused by RSV. A number of surveys have compared human metapneumovirus with RSV, and the relative frequency with which they are found during clinically significant illness varies from close to 1:1 (in the study by Williams et al.) to about 1:5. Infection with human metapneumovirus is probably somewhat less likely in infants younger than two months of age, and overall it is probably somewhat less severe than infection with RSV. The frequency and severity of disease in the elderly are still not well delineated.
Is it seasonal? Yes, it has a seasonality similar to that of RSV (i.e., winter epidemics), with variation in severity from year to year. How does it spread? Unknown. How can we treat or prevent it? Also unknown. Both treatment and prevention raise important questions about serotypes and about cross-protection between various strains of virus. In this era of rapid sequencing, it is easier to study genetic variation than antigenic variation (a case in point being HIV). Although we know that there are two genetic groups of human metapneumovirus, we do not yet know whether infection with one provides protection against infection with the other. Vaccine development will depend on the answers to these questions.
Human metapneumovirus should quickly be given a prominent position on the list of respiratory pathogens. This means that we should make widely available the tools that allow the virus to be detected in patients with serious respiratory infections; learn more about its role in disease, particularly in hosts other than children, and about its spread in the community and in hospitals; and as soon as possible, develop the means to prevent and treat human metapneumovirus infection.
Source Information
From the Division of Infectious Diseases (K.M.) and the Department of Laboratory Medicine (A.J.M.), Children's Hospital and Harvard Medical School, Boston.(Kenneth McIntosh, M.D., a)