PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Infect Dis Clin North Am. Author manuscript; available in PMC 2014 March 1.
Published in final edited form as:
PMCID: PMC3572787
NIHMSID: NIHMS422075

What is the Role of Respiratory Viruses in Community Acquired Pneumonia; What is the Best Therapy for Influenza and Other Viral Causes of CAP?

Synopsis

Respiratory viruses including influenza have long been appreciated as a cause of community acquired pneumonia (CAP), particularly among children, people with serious medical co-morbidities and military recruits. They are increasingly recognized as a cause of CAP among adults, particularly older adults. Polymerase chain reaction-based testing has allowed detection of newer agents (e.g. human metapneumovirus, coronavirus HKU1 and NL63) as well as improved the ability to detect “old” viral infections such as influenza virus and rhinovirus. When PCR is used, viruses have been detected in 45–75% of children and 15–54% of adults with CAP. Co-infection with viruses and bacteria is common and it remains challenging to determine which patients have only viral infection as the cause of CAP. Treatment for influenza with neuraminidase inhibitors should be started promptly for patients with CAP when influenza is suspected or documented, regardless of evidence of bacterial co-infection. Better ways to diagnose viral CAP and to integrate detection into management are urgently needed, as well as better treatment options for non-influenza respiratory viral infections.

Keywords: Respiratory viruses, respiratory viral infections, influenza, antiviral agents, viral pneumonia

Respiratory viruses including influenza have long been appreciated as a cause of community acquired pneumonia, particularly among children, people with serious medical co-morbidities and military recruits. Recent advances in molecular virology have led to the discovery of previously unrecognized respiratory viruses, including human metapneumovirus, parainfluenza virus 4, human coronaviruses HKU1 and NL-63, and human bocavirus. Polymerase chain reaction-based testing has allowed detection of newer agents as well as improved the ability to detect “old” viral infections such as influenza virus and rhinovirus. (Table 1) Widespread use of newer vaccines against Streptococcus pneumoniae and Haemophilus influenzae has changed the epidemiology of childhood and adult pneumonia. These changes have led to recognition of the greater and more widespread role of respiratory viruses in CAP in all age groups. Although not addressed in this review, respiratory viruses are a very important cause of severe pneumonia and respiratory failure in immunocompromised patients, particularly hematopoietic stem cell transplant recipients.1,2

Table 1
Viruses associated with pneumonia. Asterisks indicate those recently discovered or recently appreciated as associated with pneumonia. The role of all Bocavirus and Parechovirus has not been clearly established

One challenge is that respiratory viruses in patients with CAP can be the sole cause of a viral pneumonia (often referred to as primary viral pneumonia), can be present as a co-infection (virus- bacteria or virus-virus), and can act as a predisposing factor to facilitate or worsen bacterial pneumonia. Moreover, detection of some viruses in the upper respiratory tract of asymptomatic patients is relatively common and therefore may indicate convalescent shedding or asymptomatic infection.3.

There are a number of critical questions. What is the role of individual viruses in pneumonia? What is the prevalence of specific viruses among patients of CAP Which patients are most likely to have viral pneumonia? What does the detection of a respiratory virus from a patient with CAP tell us about the etiology? How should viral detection effect clinical management and when can antibiotics be avoided or stopped?

Specific viruses

Respiratory Syncytial virus

Respiratory syncytial virus (RSV) is a paramyxovirus that causes URI and bronchiolitis in children but is also associated with a substantial proportion CAP among children (see below). RSV has been detected in 3 to 31% of children hospitalized with CAP. The incidence and severity varies with age; younger children are generally more likely to have RSV-associated pneumonia and are the most severely effected. Important studies in the mid 1990’s demonstrated that RSV was an important cause of CAP in adults.4,5 Dowell studied non-institutionalized adults admitted to two Ohio hospitals and found that 53(4.4%) of 1195 adults admitted during the RSV seasons and 4 (1.0%) of 390 in the off-season had serologic evidence of RSV infection.5 RSV has been identified in 4–7% of adults with CAP.69 RSV-associated CAP appears to be more common and severe among older adults.10 Using viral surveillance, hospitalization and mortality data, Zhou and colleagues from CDC estimated that the rate of hospitalization for RSV for persons >65 was 86/100,000 persons per year, compared to a hospitalization rate for influenza of 309/100,000 in that age group.11 RSV was listed in the discharge codes in fewer than 2% of the hospitalizations for RSV among older persons was, suggesting marked under recognition. RSV causes substantial mortality as well. Thompson and colleagues estimated that during the 1990s, RSV was associated with an average of more than than 11,000 deaths each year in the United States.12 The majority of these deaths were in persons over 65.

In studies comparing adults with RSV and pneumonia to those with influenza or other causes, wheezing is more common5, but clinical characteristics cannot reliably differentiate those with RSV.13

Influenza virus

Pneumonia was recognized as a complication of influenza during the pandemic of 1918–1919, long before the virus was identified. During the “Asian influenza” pandemic of 1957–58, Louria and others codified the concept that influenza could cause a primary viral pneumonia or lead to bacterial pneumonia with each having distinct pathologic appearance. 14 Animal studies are beginning to yield insights into the nature of the complex and synergistic interaction in the lung between influenza and S. pneumoniae and Staphylococcus aureus,15,16 which is thought to be responsible for much of the mortality during pandemics.17

Among patients hospitalized with influenza, radiographic pneumonia has been reported in 16–55%, with lower rates in studies among children.1821 Patients admitted with influenza who have pneumonia are more likely to be admitted to ICU or die.19,22 Differentiating viral pneumonia due to influenza from bacterial co-infection or super-infection is not always clear. The classical presentation of super-infection is biphasic, with typical influenza like illness that begins to resolve over several days followed by acute deterioration with the development of chest pain and new infiltrates, and bacteriologic evidence of infection, but this represents a minority.

Human metapneumovirus

Dutch researchers first described human metapneumovirus (hMPV] in 2001 in children with bronchiolitis.23 Subsequent studies identified it as an important cause of acute respiratory infections in children and adults, with a worldwide distribution.24,25 hMPV is a paramyxovirus in the sub-family pneumovirineae that includes RSV, but hMPV is most closely related to avian pneumovirus. In temporal climates, infection occurs predominantly in the winter months, and there is significant year-to-year variation. Clinical manifestations of hMPV infection include asymptomatic infections, colds, febrile seizures, bronchiolitis, asthma exacerbations, COPD exacerbations, pneumonia and respiratory failure. Symptomatic infection occurs in all age groups,2430 but pneumonia is most commonly seen among younger children, older adults, and those with underlying medical conditions.23,31 In prospective studies of adults hospitalized in Rochester, New York, and Nashville Tennessee with acute respiratory illness, the prevalence of hMPV infection and clinical characteristics of patients were similar to patients with influenza and RSV.29,30 Using prospective surveillance in central Tennessee, Widmer estimated the incidence of hospitalization for hMPV among persons >65 years old was 220/100,000 compared to 254/100,000 and 123/100,000 for RSV and influenza virus respectively.30

Adenovirus

Shortly after the discovery of adenovirus in 1953, it was recovered from military personnel with acute respiratory disease, thus making it one of the first viruses clearly linked with pneumonia.32 Adenoviruses are lytic non-enveloped DNA viruses, which contrasts with the majority of respiratory viruses that are RNA viruses. More than 50 serotypes have been described. Adenoviruses cause a wide variety of infections, including conjunctivitis, epidemic keratoconjunctivitis, pharyngitis, URI, pneumonia, meningitis, hepatitis and gastroenteritis. Conjunctivitis, pharyngitis or rash may be present with pneumonia and provide a clue to the etiology, but this is uncommon. Serotypes differ in tissue tropism and their tendency to cause severe respiratory disease, although the mechanisms for this are poorly understood. Severe respiratory disease is associated with adenovirus serotypes 5, 7, 14, and 21. Historically, adenovirus pneumonia has been primarily documented among children, immunocompromised adults,33 and outbreaks in hospitalized patients34,35 and healthy adults in closed settings such as military recruits.3638 However severe disease can occur in immunocompetent adults.39 The genetic diversity genetic diversity of adenoviruses has limited the sensitivity of culture and PCR-based diagnostics, so the true rate of adenoviral pneumonia may be underestimated.

Adenovirus vaccine was used in the U.S. military for more than 2 decades, resulting in a marked decrease in adenoviral pneumonia among recruits. When the sole manufacturer ceased production there was a marked resurgence in adenoviral disease.36,40 Beginning in 2005, a new variant of serotype 14 emerged as a cause of severe lower respiratory tract disease in immunocompetent adults in the community41 and in the military.42

Parainfluenza virus

Parainfluenza viruses (PIV) are paramyxovirus that are antigenically divided in to 4 serotypes PIV1-4).43 They are common causes of acute respiratory infections including URI, croup, bronchiolitis, and pneumonia.44,45 Seasonal outbreaks occur in the fall and spring. Most infections are mild, but in a prospective surveillance study of children in 3 regions, Weinberg found that parainfluenza viruses were associated with an average annual rate of 100 hospitalizations/100,000 persons younger than 5 years or roughly 23,000 hospitalizations per year.45 Similar population based estimates for adults are not available. In one study, Marx used serology to detect parainfluenza virus type 1 (PIV1) from 2.5% of 721 and PIV3 from 3.1% of 705 adults hospitalized with lower respiratory tract infection.46 However, they predominantly tested patients hospitalized during “the parainfluenza season.”

Most pneumonia associated with parainfluenza viruses occurs in infants, young children and immunocompromised hosts. However, parainfluenza virus has been detected in 0–8% of adults with community acquired pneumonia.69,47,48 Parainfluenza type 3 is more commonly associated with pneumonia than other types, although fewer studies have systematically sought parainfluenza type 4.

Non-SARS Coronaviruses

Human coronaviruses (HCoV) 229E and OC43 have been long recognized as causes of viral URI and were linked to pneumonia in children and immunocompromised adults.49 Two novel human coronaviruses, NL6350 and HKU151 were identified in the past decade. All four human coronaviruses show distinct winter seasonality. They are associated with both upper and lower respiratory tract infections in all age groups.5254 In a prospective study from Scotland that included a control group of patients with no respiratory symptoms, HCoV HKU1, HCoV NL63 and HCoV OC43 were isolated significantly more often from patients with lower respiratory tract infections than from controls, supporting the etiologic role of these viruses.52 In a prospective study of hospitalized patients with pneumonia in Thailand, coronaviruses were detected by PCR in 5.9% of 734 patients in year 1 of the study. However, in the second year when a control group was included, coronaviruses were detected in only 1.8% of 1156 patients and were detected in 2.1% of controls.55 Thus, this study did not demonstrate an epidemiologic association of coronaviruses with pneumonia, but it is unclear if this was due to variation in intensity of the season. In a prospective study of patients with severe pneumonia undergoing bronchoalveolar lavage about half of whom were transplant recipients, coronaviruses were detected in 5.8%, mostly as the sole pathogen.56 Thus, the role of coronaviruses in pneumonia has not been completely clarified but it seems clear that they cause some cases of CAP in normal hosts and cause severe pneumonia in transplant patients.

Rhinovirus

Rhinoviruses are among the most common cause of respiratory infections in people of all ages. However elucidating their role in pneumonia has proven complex.57 The use of PCR and sequencing has greatly enhanced detection of rhinoviruses in severely ill patients and led to the recognition of a third rhinovirus species, genogroup C.58 Many rhinovirus PCR assays also detect other picornaviruses, particularly enterovirus which complicates the literature. Rhinoviruses were long known to cause common colds, otitis media, asthma exacerbations and exacerbations of COPD, but lower respiratory tract infections were thought to be rare, perhaps because of the belief that rhinoviruses grow poorly at 37 degrees. Recent data clearly demonstrate that rhinoviruses can replicate at body temperature59 and infect cells of the lower respiratory tract.60 Rhinovirus infection of respiratory endothelium induces potent inflammatory responses, but, in contrast in several other respiratory viruses does not induce cell lysis.61

Studies using PCR consistently identify rhinoviruses in nasopharyngeal or pharyngeal specimens from children and adults with lower respiratory tract infections.6265 Rhinovirus has also been detected in 4–45% of children6670 and 2–17% of adults with CAP.69,47,48 (Tables 2 and and3)3) Determining whether rhinovirus has a causal role in any single case of CAP is particularly problematic because of the high rate of co-detection of rhinovirus with other viruses and bacteria, and because of the detection of rhinovirus in asymptomatic patients, representing convalescent shedding or asymptomatic infection. Shedding generally does not persist beyond 2–3 weeks, but few studies have done careful molecular subtyping, making it difficult to separate shedding from re-infection. The rates of rhinovirus detection in asymptomatic patients are generally substantially lower than among patients with lower respiratory tract infection or pneumonia. In a review of published studies of viral detection in asymptomatic subjects, Jartti found a mean rate of rhinovirus/enterovirus detection by PCR of 15%, with higher rates among children and very low rates (2%) among the elderly.3 In preliminary results from the CDC Etiology of Pnemonia in the Community (EPIC) Study, rhinovirus was detected in 31% of 1320 children hospitalized with CAP and 22% of 442 control children who were undergoing elective surgery.

Table 2
Etiology of community acquired pneumonia in hospitalized children and role of viruses in 6 recent studies
Table 3
Etiology of community acquired pneumonia in hospitalized adults and role of viruses in 6 recent studies

It appears likely that rhinovirus is a cause of CAP, but questions remain. Are some rhinovirus strains more likely to cause CAP? Are higher viral loads in the nasopharynx better predictors of lower respiratory tract infecton and rhinovirus pneumonia? Does co-infection with rhinovirus facilitate infection with a second viral or bacterial pathogen and does rhinovirus co-infection increase the severity?

Other viruses

Table 1 shows the range of viruses associated with CAP. Human bocavirus is a recently described parvovirus that has been frequently detected in respiratory secretions of children with respiratory tract infection.71,72 The role of bocavirus in CAP remains unclear. Interpretation of human bocavirus detection has been complicated by relatively common detection in asymptomatic children and prolonged detection after infection. However, in a study of Thai patients hospitalized with pneumonia, Fry and colleagues found that compared to control patients, detection of human bocavirus was associated with hospitalization for pneumonia.73 Four patients with human bocavirus and pneumonia were older than 65. However, 83% of pneumonia patients with human bocavirus had coinfection with another pathogen. Brieu detected human bocavirus in 10.8% of 508 children hospitalized with respiratory illness and none of 68 controls.72 Pneumonia was diagnosed in 4 of the children with human bocavirus. Most bocavirus-infected children had a co-infection, but viral loads were higher in the mono-infected children. Christenson detected bocavirus in 10% of 1154 children with respiratory tract infection and a similar proportion of controls.74 Of those with bocavirus, a second virus was detected in 75%. Bocavirus viral load > 106 copies/mL was not associated with respiratory infection, viral loads > 2 × 108/mL was only seen in ill patients. Thus, the exact role of bocavirus in pneumonia remains unclear.

Varicella zoster virus, herpes simplex virus, cytomegalovirus and measles virus can cause severe pneumonia immunocompromised hosts, but can cause pneumonia in otherwise normal hosts. Parechoviruses are rapidly emerging as important causes of sepsis and meningitis in infants. Parechoviruses have been occasionally isolated from children with pneumonia. 75,76 The systematic investigation of parechovirus infections are just beginning and their true role in CAP is unknown.

Respiratory viruses in CAP in children

Viral infections are the most common cause of CAP in children in recent studies where sensitive molecular methods were used.6670,77,78 It is challenging to compare individual studies because of differences in populations studied (age, severity of illness), seasons, samples obtained, agents sought and the technologies used (e.g. viral culture, viral and/or bacterial PCR, viral and/or bacterial serology). Moreover, the introduction of conjugate vaccines for H. influenza and S. pneumonia has decreased the incidence of these important pathogens compared to older studies.79,80 Several recent studies of hospitalized children with CAP which employ PCR to enhance viral detection are summarized in Table 2. A virus was detected in 45–77% of children and a potential bacterial etiology in 2–60%. It is important to note the frequency of co-infection, ranging from 22–33%. Mixed bacterial viral infections were found in 28–33% and viral-viral infections in 8–14%.66,69,70 In general, viral infections are more predominant among infants and children younger than 5 years old compared to older children.

RSV (3–30%), influenza virus (4–22%), and rhinovirus (4–45%) were the viruses most commonly detected. The highly variable rates of detection of hMPV (1–13%) and PIV (1–13%) may reflect differences in the populations studied or year-to-year variation in the epidemiology of these infections. The ongoing CDC EPIC study67 when finished will encompass approximately 2400 children over two and one half years and include population-based data from 3 cities. This will provide more detailed and stable estimates of the role of viruses in CAP among children.

It is remarkable that no pathogen can be identified in 14–23% of pediatric CAP in recent studies, suggesting the need for improved diagnostics and the possibility of unrecognized pathogens.

Respiratory viruses in CAP in adults

It is likely that the epidemiology of CAP in adults has also changed in recent years because of the indirect impact of pneumococcal conjugate vaccine in children and the increasing age of the population. In four recent studies of adult patients hospitalized with CAP that used at a minimum blood and sputum culture plus urinary antigen detection, S. pneumoniae was detected in 7–38%.6,7,8,47 The highest proportion of S. pneumoniae (38%) was in the study of Johansson7, that included the use of PCR to detect S. pneumoniae in sputum. The apparently lower proportion of S. pneumoniae has led to speculation that viruses now cause an increasing proportion of CAP in adults. It is hard to determine if this is true or reflects recent advances in viral diagnosis, the difficulty of establishing the etiology of pneumonia and the prevalence of dual infections.

Table 3 summarizes 6 prospective studies that included viral PCR to determine the etiology of CAP in 1762 hospitalized adults (a small number of outpatients are included in the study by Templeton48). At least one virus was detected in 15–54%. In the 5 studies that reported bacterial etiologies, bacterial pathogens were detected in 20–58% and co-infection was detected in 4–30%. Viral infection are generally a more prominent cause of CAP among older adults.81 Johnstone reported that patients with viral infections were significantly older than those without viral infections (median age, 76 vs 64 years), and were more likely to have underlying cardiac disease (66% vs 32%) and to be frail.8 Influenza virus was among the most commonly detected viruses in adults hospitalized with CAP, detected in 4–12%. RSV was detected in 2–7% of adults. Both influenza and RSV detection were highly seasonal. Detection of rhinovirus/enterovirus varied from 2–17%, but these viruses were often detected as a co-infection. Parainfluenza and coronaviruses were detected at variable rates, (0–8% and 2–13%, respectively). HMPV and adenovirus were somewhat less commonly detected (0–4% and <1–4%, respectively). A putative pathogen could not be detected in 24–61% of patients in these studies despite the use of multiple methods including PCR for detection of viruses. This proportion is considerably higher than in studies of CAP in children, but the reasons are unclear. Possible explanations include a greater role of bacterial infection for which current diagnostics remain inadequate, the greater role of viral infection and co-infection in children, greater incidental detection of viral shedding in children, or lower viral copy number in the nasopharynx of adults with viral infections of the lower respiratory tract, making detection more difficult.

Questions

What is the Role of Mixed Infections in CAP?

When sophisticated diagnostic tests are applied, more than one pathogen can be identified in 23–33% of children and 4–30% of adults in prospective studies of CAP. (Table 2 and and3)3) This raises several important questions. What proportion of patients in whom a virus is detected by PCR truly have a bacterial co-infection? Does viral-bacterial co-infection influence the course of illness?

The clinical interaction between influenza and S. pneumoniae and S. aureus has long been appreciated, and is a major contributor to influenza mortality.16,17,82 Several pathologic mechanisms have been proposed including epithelial damage, changes in airway function, up-regulation of receptors, and changes in the innate immune reponse.16 It is becoming clear that similar interactions may occur with other respiratory viruses, including RSV, human metapneumovirus, and possibly rhinovirus and parainfluenza virus.83,84

Clinical evidence from prospective studies on the role of co-infection on severity is somewhat conflicting. There is a suggestion that viral-bacterial co-infection is associated with more severe disease among adults. Johansson found that compared to those with only bacterial infections, adults with co-infection were much more likely to have pneumonia severity index (PSI) scores of IV or V (62% vs 26%; OR 4.6, P <0.001) and had longer length of stay (7 vs 4 days; P = 0.002).7,85 Templeton reported that age older than 60, rhinovirus in mixed infection, and mixed infection were all associated with PSI score classes IV and V.48 Similarly, Jennings reported that rhinovirus infection with pneumococcal infection was independently associated with more severe disease by either PSI or CURBAge criteria.6 In contrast, Charles reported similar 30-day mortality among those with co-infection and single infection (8.0 vs 5.4%)47

What Findings Differentiate Viral Pneumonia from Mixed or Bacterial Pneumonia?

Differentiating viral pneumonia from infection with bacteria alone or mixed viral-bacterial infection could significantly decrease antibiotic use with the associated risk of adverse reactions and the selective pressure for the development of resistance. However, developing clinical and laboratory tools to differentiate has been challenging.

Viral pneumonia is more likely during fall, winter, and early spring when outbreaks of respiratory viruses are occurring.6,8,86 Age less than 2 years87 or older age among adults8 are associated with an increased likelihood of viral pneumonia. Wheezing in children78 and adults5 has been significantly associated in some studies with viral pneumonia compared to mixed or bacterial infection. High temperature69, rigors6, and chest pain8 are significantly more common on presentation in patients with bacterial or mixed infection. Significant overlap limits the utility of these findings.

There has been significant interest in the ability of inflammatory markers to discriminate between viral and bacterial etiology in CAP.88 In children, procalcitonin and C-reactive protein are consistently higher among children with bacterial infection69,89,90, but it is unclear if specific cut offs can be identified. Toikka found that procalcitonin (median 2.09 ng/ml vs. 0.56 ng/ml, P = 0.019) and CRP concentrations (96 mg/l vs. 54 mg/l, P = 0.008) were significantly higher in children with bacterial CAP than those with sole viral etiology, but there was substantial overlap.90 Nascimento-Carvalho though reported that a cutoff of procalcitonin < 2.0 ng/mL had a negative predictive value of 95% for excluding bacterial infection.89 In adults, procalcitonin levels are also higher in bacterial pneumonia.91 Procalcitonin values are not static however; they increase rapidly during bacterial infection and fall during appropriate therapy. To get around the limitations of a single cutoff value, treatment algorithms using sequential procalcitonin levels have been studied in a number of randomized trials as a way to guide therapy.88,92,93 For a complete discussion see Niederman M and XXX [agree, can add later] in this issue.

Chest radiographs are only moderately useful in discriminating viral from bacterial CAP.86,87,94,95 Interstitial infiltrates with a patchy distribution are typical of viral pneumonia, while alveolar infiltrates, particularly with a lobar pattern are suggestive of bacterial infection. However, there is marked overlap. In one study, 72% of 134 children with bacterial infection had alveolar infiltrates, as did 49% of 81 children with only viral infection (P = 0.001). Exclusively interstitial infiltrates were present in 28% of children with bacterial infection and 49% of those with viral infection.87 The presence of pleural effusions was predictive of bacterial infection in several studies.69,78

It is tempting to hypothesize that the use of sensitive PCR assays in conjunction with biomarkers such as procalcitonin could lead to diagnostic algorithms with adequate predictive value to improve the use antibiotics in CAP, but this has not been adequately studied.

What is the Best Treatment of influenza Virus in CAP?

Effective antiviral therapy may prevent the development of CAP, and treatment of patients with influenza-associated pneumonia may improve outcomes. However, the evidence base is not optimal. Two classes of drugs are available for the treatment of influenza virus infection – the adamantanes (amantadine and rimantidine) and neuraminidase inhibitors (oseltamivir [Tamiflu] and zanamivir [Relenza]). Widespread and stable resistance to the adamantanes has rendered this class of limited use.96 Oseltamivir and zanamivir were initially studied in randomized controlled trials among adults and children with uncomplicated influenza.97 These studies demonstrated reductions in the time to the primary endpoint of resolution of all symptoms of approximately 1.25 days when neuraminidase inhibitors were begun within 48 hours of symptom onset; larger benefits were seen for return to functional status. Few patients with risk factors for complications were enrolled in these studies and with low rate of event the individual studies did not demonstrate reductions in hospitalizations or pneumonia. Kaiser performed a pooled analysis of oseltamivir clinical trials including 1340 patients, and reported statistically significant reductions in the development of lower respiratory tract infections resulting in antibiotic use and in hospitalizations and a non significant reduction in pneumonia.98 Although statistically significant, the absolute risk reductions in generally healthy patients were relatively modest.

A critical question is whether treatment is beneficial among patients at high risk of complications, those with more severe disease requiring hospitalization, or with lower respiratory tract infections due to influenza (with or without bacterial co-infection). A large body of carefully conducted but observational studies in both seasonal99101 and pandemic 2009 H1N1 influenza19,22,102109 demonstrated improved outcomes among hospitalized patients treated with neuraminidase inhibitors including decreased ICU admission and mortality. Benefits were independently demonstrated among children108, pregnant women104, and critically ill patients.109 A formal meta-analysis by Hsu and colleagues concluded that among high risk patients, oral oseltamivir may reduce mortality, hospitalization, and duration of symptoms, but the quality of the evidence was deemed low.110 Earlier initiation of therapy is associated with the greatest benefit, but among hospitalized patients, benefits were observed when oseltamivir was started as late as 5 days after symptom onset compared to no therapy.

Bacterial co-infection is an important cause of severe pneumonia and mortality in patients with influenza and pneumonia. In studies among critically ill children111 and adults82 with pandemic 2009 H1N1 influenza, bacterial infection, particularly with MRSA, was associated with mortality. It is not possible from existing data to conclusively demonstrate that oseltamivir in addition to appropriate antibiotic therapy improves outcomes in patients with documented bacterial co-infection, but animal data15,16 and limited observational data suggest an independent benefit of antiviral therapy.

Thus, antiviral therapy with neuraminidase inhibitors should be started empirically in all hospitalized patients in whom influenza is suspected without waiting for laboratory confirmation, including those with CAP.96,112 Influenza testing and empiric antiviral therapy in addition to antibiotic therapy is appropriate for patients at increased risk of influenza complications who present with signs of CAP during outbreaks of seasonal influenza. It is important to remember that current rapid antigen based influenza tests have relatively low sensitivity and a negative test does not rule out influenza.113,114

Resistance to oseltamivir became widespread among seasonal strains of H1N1 influenza in 2008 the H275Y mutation in the neuraminidase gene115,116, and sporadic resistance to oseltamivir has emerged on therapy and been transmitted in other strains, including pandemic 2009 H1N1 influenza.117119 These strains remain sensitive to zanamivir, but it is only available as a dry powder for inhalation which is not appropriate for treatment of children younger than 5 years old and is not recommended for those with asthma or COPD because of the risk of bronchospasm. Continued spread of oseltamivir resistance would greatly reduce our ability to treat influenza associated CAP.

What is the Best Treatment for Other Respiratory Viruses in CAP

Although effective therapy exists for influenza-related CAP in children and adults, options for the treatment of other viruses are extremely limited. Ribavirin has broad antiviral activity in vitro that includes RSV, hMPV, parainfluenza virus and influenza, but there are scarce data to demonstrate clinical utility. Observational studies of inhaled ribavirin for RSV demonstrated limited benefits among severely immunocompromised patients120 but the single randomized trial was underpowered.121 Among other populations, the benefits are questionable and the costs and risks limit the use of inhaled ribabirin.122 Palivizumab, a monoclonal antibody directed against the fusion glycoprotein of RSV is recommended for the prevention of RSV hospitalization in specific subgroups of premature infants and infants with some types of congenital heart disease or chronic lung disease. Unfortunately, it has not demonstrated any value in the treatment of RSV disease.

Based on anecdotal experience, intravenous ribavirin may have a potential role for overwhelming viral pneumonia in severely immunocompromised patients due to RSV, hMPV, or parainfluenza virus.123 Cidofovir has potent activity against adenovirus and case reports suggest clinical benefit in immunocompromised patients with adenovirus infection.124,125 Cidofovir should be considered for patients with overwhelming adenovirus pneumonia including adenovirus type 14.126 Because of the toxicity and difficulty with administration, cidofovir is not appropriate for CAP in immunocompetent hosts. An orally available prodrug of cidofovir, CMX001 is in advanced development and may prove useful for a wider array of patients with adenovirus pneumonia.127 Pleconaril, a drug with activity against picornaviruses including rhinovirus, inhibits viral uncoating. A clinical trial showed reduction in the duration of symptoms for naturally occurring colds.128 Pleconaril is no longer in development but this class of agents could be useful in lower respiratory tract disease due to picornaviruses.

Because of the ubiquity of respiratory viruses, most pools of intravenous immunoglobulin (IVIG) have significant titers of antibody, including neutralizing antibody against common respiratory viruses. IVIG should be considered for hypogammaglobulinemic and severely immunocompromised patients with viral pneumonia.

Unanswered questions and future directions

Much remains to be learned about viral infections in CAP and how to translate the knowledge into improved patient care.

How can we determine if the detection of a virus in in the upper airway in a patient with CAP indicates a causal role? This problem is common to interpreting prospective studies and tests in individual patients. The problem is more difficult for rhinovirus and coronaviruses that have been detected in 2–45% and 0–6% of asymptomatic subjects respectively by PCR than for influenza and hMPV, which are rarely detected in the absence of symptoms.3 Some studies have shown higher viral loads in patients with pneumonia, suggesting that quantitative assays might increase the specificity.74,129132

Which patients with CAP should be tested for viral infections and how should it alter clinical care? Detection of influenza infection can clearly lead to use of antivirals and in most cases limit the use of antibiotics. The use of sensitive and specific influenza tests is appropriate for children and adults with CAP during influenza season, and is recommended in recent guidelines.133,134 In younger children with moderate to severe CAP and immunocompromised patients viral pneumonia is common and testing for an array of viral causes of pneumonia can direct therapy and improve infection control. However, additional studies are needed to determine the impact of viral testing in other groups. The combined use of biologic markers and viral testing holds the promise of correctly identifying patients who whom antibiotic exposure can be safely limited. Tests that can accurately detect multiple viruses with rapid turnaround time and can be deployed in a variety of settings would improve facilitate this.

There is a critical need for influenza antivirals that will be effective for viruses resistant to oseltamivir. Moreover, effective treatments, including antiviral agents, immunomodulatory agents or siRNA are needed for respiratory viruses other than influenza. RSV and hMPV are particularly attractive targets, since an effective drug could decrease morbidity, hospitalization and mortality in many young children, older adults and immunocompromised patients. Targets have been identified, but clinical development has been slow.135,136 Effective vaccines against respiratory viruses could have a substantial impact on CAP, both by preventing primary viral pneumonia and preventing secondary bacterial infections.

Key Points

  • Respiratory viruses particularly influenza and RSV are a common cause of CAP.
  • Respiratory viruses are detected in 45–75% of children and 15–54% of adults hospitalized with CAP.
  • Co-infection with viruses and bacteria is common: 22–33% of children and in 4–30% of adults hospitalized with CAP.
  • The role of Streptococcus pneumonia relative to viral causes of CAP may have decreased due to widespread use of pneumococcal conjugate vaccines in children.
  • Neuraminidase inhibitors reduce ICU admission and mortality among patients hospitalized with influenza, including those with pneumonia and should be started when influenza is susptected.
  • Differentiating viral CAP from mixed infection and bacterial CAP remains challenging, but better approaches could reduce antibiotic overuse.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

1. Ison MG, Michaels MG. RNA respiratory viral infections in solid organ transplant recipients. Am J Transplant. 2009;9 (Suppl 4):S166–72. [PubMed]
2. Kim YJ, Boeckh M, Englund JA. Community respiratory virus infections in immunocompromised patients: hematopoietic stem cell and solid organ transplant recipients, and individuals with human immunodeficiency virus infection. Semin Respir Crit Care Med. 2007;28:222–42. [PubMed]
3. Jartti T, Jartti L, Peltola V, Waris M, Ruuskanen O. Identification of respiratory viruses in asymptomatic subjects: asymptomatic respiratory viral infections. 2008;27:1103–7. [PubMed]
4. Falsey AR, Cunningham CK, Barker WH, et al. Respiratory syncytial virus and influenza A infections in the hospitalized elderly. J Infect Dis. 1995;172:389–94. [PubMed]
5. Dowell SF, Anderson LJ, Gary HE, Jr, et al. Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis. 1996;174:456–62. [PubMed]
6. Jennings LC, Anderson TP, Beynon KA, et al. Incidence and characteristics of viral community-acquired pneumonia in adults. Thorax. 2008;63:42–8. [PubMed]
7. Johansson N, Kalin M, Tiveljung-Lindell A, Giske CG, Hedlund J. Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods. Clin Infect Dis. 2010;50:202–9. [PubMed]
8. Johnstone J, Majumdar SR, Fox JD, Marrie TJ. Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation. Chest. 2008;134:1141–8. [PubMed]
9. Lieberman D, Shimoni A, Shemer-Avni Y, Keren-Naos A, Shtainberg R. Respiratory viruses in adults with community-acquired pneumonia. Chest. 2010;138:811–6. [PubMed]
10. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med. 2005;352:1749–59. [PubMed]
11. Zhou H, Thompson WW, Viboud CG, et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993–2008. Clin Infect Dis. 2012;54:1427–36. [PMC free article] [PubMed]
12. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179–86. [PubMed]
13. Walsh EE, Peterson DR, Falsey AR. Is clinical recognition of respiratory syncytial virus infection in hospitalized elderly and high-risk adults possible? J Infect Dis. 2007;195:1046–51. [PubMed]
14. Louria D, Blumenfeld H, Ellis J, Kilbourne E, Rogers D. Studies on influenza in the pandemic of 1957–58. II. Pulmonary complications of Influenza. J Clin Invest. 1959;38:213–65. [PMC free article] [PubMed]
15. Iverson AR, Boyd KL, McAuley JL, Plano LR, Hart ME, McCullers JA. Influenza virus primes mice for pneumonia from Staphylococcus aureus. J Infect Dis. 2011;203:880–8. [PMC free article] [PubMed]
16. McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev. 2006;19:571–82. [PMC free article] [PubMed]
17. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis. 2008;198:962–70. [PMC free article] [PubMed]
18. Ampofo K, Gesteland PH, Bender J, et al. Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection. Pediatrics. 2006;118:2409–17. [PubMed]
19. Jain S, Benoit SR, Skarbinski J, Bramley AM, Finelli L. Influenza-associated pneumonia among hospitalized patients with 2009 pandemic influenza A (H1N1) virus--United States, 2009. Clin Infect Dis. 2012;54:1221–9. [PubMed]
20. Lee N, Chan PK, Lui GC, et al. Complications and outcomes of pandemic 2009 Influenza A (H1N1) virus infection in hospitalized adults: how do they differ from those in seasonal influenza? J Infect Dis. 2011;203:1739–47. [PubMed]
21. Murata Y, Walsh EE, Falsey AR. Pulmonary complications of interpandemic influenza A in hospitalized adults. J Infect Dis. 2007;195:1029–37. [PubMed]
22. Louie JK, Acosta M, Winter K, et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA. 2009;302:1896–902. [PubMed]
23. Schildgen V, van den Hoogen B, Fouchier R, et al. Human Metapneumovirus: lessons learned over the first decade. Clin Microbiol Rev. 2011;24:734–54. [PMC free article] [PubMed]
24. Falsey AR, Erdman D, Anderson LJ, Walsh EE. Human metapneumovirus infections in young and elderly adults. J Infect Dis. 2003;187:785–90. [PubMed]
25. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med. 2004;350:443–50. [PMC free article] [PubMed]
26. Foulongne V, Guyon G, Rodiere M, Segondy M. Human metapneumovirus infection in young children hospitalized with respiratory tract disease. Pediatr Infect Dis J. 2006;25:354–9. [PubMed]
27. Caracciolo S, Minini C, Colombrita D, et al. Human metapneumovirus infection in young children hospitalized with acute respiratory tract disease: virologic and clinical features. Pediatr Infect Dis J. 2008;27:406–12. [PubMed]
28. Falsey AR. Human metapneumovirus infection in adults. Pediatr Infect Dis J. 2008;27:S80–3. [PubMed]
29. Walsh EE, Peterson DR, Falsey AR. Human metapneumovirus infections in adults: another piece of the puzzle. Arch Intern Med. 2008;168:2489–96. [PMC free article] [PubMed]
30. Widmer K, Zhu Y, Williams JV, Griffin MR, Edwards KM, Talbot HK. Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults. J Infect Dis. 2012;206:56–62. [PMC free article] [PubMed]
31. Hamelin ME, Cote S, Laforge J, et al. Human metapneumovirus infection in adults with community-acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. Cin Infect Dis. 2005;41:498–502. [PubMed]
32. Hilleman MR, Werner JH. Recovery of new agent from patients with acute respiratory illness. Proc Soc Exp Biol Med. 1954;85:183–8. [PubMed]
33. Ison MG. Adenovirus infections in transplant recipients. Clin Infect Dis. 2006;43:331–9. [PubMed]
34. Gerber SI, Erdman DD, Pur SL, et al. Outbreak of adenovirus genome type 7d2 infection in a pediatric chronic-care facility and tertiary-care hospital. Clin Infect Dis. 2001;32:694–700. [PubMed]
35. Sanchez MP, Erdman DD, Torok TJ, Freeman CJ, Matyas BT. Outbreak of adenovirus 35 pneumonia among adult residents and staff of a chronic care psychiatric facility. J Infect Dis. 1997;176:760–3. [PubMed]
36. Gray GC, Goswami PR, Malasig MD, et al. Adult adenovirus infections: loss of orphaned vaccines precipitates military respiratory disease epidemics. For the Adenovirus Surveillance Group. Clin Infect Dis. 2000;31:663–70. [PubMed]
37. Dudding BA, Top FH, Jr, Winter PE, Buescher EL, Lamson TH, Leibovitz A. Acute respiratory disease in military trainees: the adenovirus surveillance program, 1966–1971. Am J Epidemiol. 1973;97:187–98. [PubMed]
38. van der Veen J, Oei KG, Abarbanel MF. Patterns of infections with adenovirus types 4, 7 and 21 in military recruits during a 9-year survey. J Hyg (Lond) 1969;67:255–68. [PMC free article] [PubMed]
39. Hakim FA, Tleyjeh IM. Severe adenovirus pneumonia in immunocompetent adults: a case report and review of the literature. Eur J Clin Microbiol Infect Dis. 2008;27:153–8. [PubMed]
40. Potter RN, Cantrell JA, Mallak CT, Gaydos JC. Adenovirus-associated deaths in US military during postvaccination period, 1999–2010. Emerg Infect Dis. 2012;18:507–9. [PMC free article] [PubMed]
41. Lewis PF, Schmidt MA, Lu X, et al. A community-based outbreak of severe respiratory illness caused by human adenovirus serotype 14. J Infect Dis. 2009;199:1427–34. [PubMed]
42. Metzgar D, Osuna M, Kajon AE, Hawksworth AW, Irvine M, Russell KL. Abrupt Emergence of Diverse Species B Adenoviruses at US Military Recruit Training Centers. J Infect Dis. 2007;196:1465–73. [PubMed]
43. Henrickson KJ. Parainfluenza viruses. Clin Microbiol Rev. 2003;16:242–64. [PMC free article] [PubMed]
44. Iwane MK, Edwards KM, Szilagyi PG, et al. Population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children. Pediatr. 2004;113:1758–64. [PubMed]
45. Weinberg GA, Hall CB, Iwane MK, et al. Parainfluenza virus infection of young children: estimates of the population-based burden of hospitalization. J Pediatr. 2009;154:694–9. [PubMed]
46. Marx A, Gary HE, Jr, Marston BJ, et al. Parainfluenza virus infection among adults hospitalized for lower respiratory tract infection. Clin Infect Dis. 1999;29:134–40. [PubMed]
47. Charles PG, Whitby M, Fuller AJ, et al. The etiology of community-acquired pneumonia in Australia: why penicillin plus doxycycline or a macrolide is the most appropriate therapy. Clin Infect Dis. 2008;46:1513–21. [PubMed]
48. Templeton KE, Scheltinga SA, van den Eeden WC, Graffelman AW, van den Broek PJ, Claas EC. Improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction. Clin Infect Dis. 2005;41:345–51. [PubMed]
49. Pene F, Merlat A, Vabret A, et al. Coronavirus 229E-related pneumonia in immunocompromised patients. Clin Infect Dis. 2003;37:929–32. [PubMed]
50. van der Hoek L, Pyrc K, Jebbink MF, et al. Identification of a new human coronavirus. Nat Med. 2004;10:368–73. [PubMed]
51. Woo PC, Lau SK, Chu CM, et al. Characterization and complete genome sequence of a novel coronavirus HKU1 from patients with pneumonia. J Virol. 2005;79:884–95. [PMC free article] [PubMed]
52. Gaunt ER, Hardie A, Claas EC, Simmonds P, Templeton KE. Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method. J Clin Microbiol. 2010;48:2940–7. [PMC free article] [PubMed]
53. Kuypers J, Martin ET, Heugel J, Wright N, Morrow R, Englund JA. Clinical disease in children associated with newly described coronavirus subtypes. Pediatr. 2007;119:e70–6. [PubMed]
54. van der Hoek L, Ihorst G, Sure K, et al. Burden of disease due to human coronavirus NL63 infections and periodicity of infection. J Clin Virol. 2010;48:104–8. [PubMed]
55. Dare RK, Fry AM, Chittaganpitch M, Sawanpanyalert P, Olsen SJ, Erdman DD. Human coronavirus infections in rural Thailand: a comprehensive study using real-time reverse-transcription polymerase chain reaction assays. J Infect Dis. 2007;196:1321–8. [PubMed]
56. Garbino J, Crespo S, Aubert JD, et al. A prospective hospital-based study of the clinical impact of non-severe acute respiratory syndrome (Non-SARS)-related human coronavirus infection. Clin Infect Dis. 2006;43:1009–15. [PubMed]
57. Mackay IM. Human rhinoviruses: the cold wars resume. J Clin Virol. 2008;42:297–320. [PubMed]
58. Arden KE, Mackay IM. Newly identified human rhinoviruses: molecular methods heat up the cold viruses. Rev Med Virol. 2010;20:156–76. [PubMed]
59. Papadopoulos NG, Sanderson G, Hunter J, Johnston SL. Rhinoviruses replicate effectively at lower airway temperatures. J Med Virol. 1999;58:100–4. [PubMed]
60. Papadopoulos NG, Bates PJ, Bardin PG, et al. Rhinoviruses infect the lower airways. J Infect Dis. 2000;181:1875–84. [PubMed]
61. Kennedy JL, Turner RB, Braciale T, Heymann PW, Borish L. Pathogenesis of rhinovirus infection. Curr Opin Virol. 2012;2:287–93. [PMC free article] [PubMed]
62. Falsey AR, Walsh EE, Hayden FG. Rhinovirus and coronavirus infection-associated hospitalizations among older adults. J Infect Dis. 2002;185:1338–41. [PubMed]
63. Cheuk DK, Tang IW, Chan KH, Woo PC, Peiris MJ, Chiu SS. Rhinovirus infection in hospitalized children in Hong Kong: a prospective study. Pediatr Infect Dis J. 2007;26:995–1000. [PubMed]
64. Miller EK, Lu X, Erdman DD, et al. Rhinovirus-associated hospitalizations in young children. J Infect Dis. 2007;195:773–81. [PubMed]
65. Louie JK, Roy-Burman A, Guardia-Labar L, et al. Rhinovirus associated with severe lower respiratory tract infections in children. Pediatr Infect Dis J. 2009;28:337–9. [PubMed]
66. Cevey-Macherel M, Galetto-Lacour A, Gervaix A, et al. Etiology of community-acquired pneumonia in hospitalized children based on WHO clinical guidelines. Eur J Pediatr. 2009;168:1429–36. [PubMed]
67. Jain S, Ampofo K, Arnold SR, et al. Etiology of community-acquired pneumonia among hospitalized children in the United States: Preliminary data from the CDC Etiology of Pneumonia in the Community (EPIC) Study. Infectioius Diseases Society of America 49th Annual Meeting; 2011 October 20–23, 2011; Boston, MA. 2011. p. Abst 168.
68. Juven T, Mertsola J, Waris M, et al. Etiology of community-acquired pneumonia in 254 hospitalized children. Pediatr Infect Dis J. 2000;19:293–8. [PubMed]
69. Michelow IC, Olsen K, Lozano J, et al. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatr. 2004;113:701–7. [PubMed]
70. Tsolia MN, Psarras S, Bossios A, et al. Etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections. Clin Infect Dis. 2004;39:681–6. [PubMed]
71. Allander T. Human bocavirus. 2008;41:29–33. [PubMed]
72. Brieu N, Guyon G, Rodiere M, Segondy M, Foulongne V. Human bocavirus infection in children with respiratory tract disease. Pediatr Infect Dis J. 2008;27:969–73. [PubMed]
73. Fry AM, Lu X, Chittaganpitch M, et al. Human bocavirus: a novel parvovirus epidemiologically associated with pneumonia requiring hospitalization in Thailand. J Infect Dis. 2007;195:1038–45. [PubMed]
74. Christensen A, Nordbo SA, Krokstad S, Rognlien AG, Dollner H. Human bocavirus in children: mono-detection, high viral load and viraemia are associated with respiratory tract infection. J Clin Virol. 2010;49:158–62. [PubMed]
75. Harvala H, Wolthers KC, Simmonds P. Parechoviruses in children: understanding a new infection. Curr Opin Infect Dis. 2010;23:224–30. [PubMed]
76. Abed Y, Boivin G. Human parechovirus types 1, 2 and 3 infections in Canada. Emerg Infect Dis. 2006;12:969–75. [PMC free article] [PubMed]
77. McCracken GH. Diagnosis and management of pneumonia in children. Pediatr Infect Dis J. 2000;19:924–8. [PubMed]
78. Garcia-Garcia ML, Calvo C, Pozo F, Villadangos PA, Perez-Brena P, Casas I. Spectrum of respiratory viruses in children with community-acquired pneumonia. Pediatr Infect Dis J. 2012;31:808–13. [PubMed]
79. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201:32–41. [PubMed]
80. Ampofo K, Pavia AT, Stockmann CR, et al. Evolution of the epidemiology of pneumococcal disease among Utah children through the vaccine era. Pediatr Infect Dis J. 2011;30:1100–3. [PubMed]
81. Falsey AR, Walsh EE. Viral pneumonia in older adults. Clin Infect Dis. 2006;42:518–24. [PubMed]
82. Rice TW, Rubinson L, Uyeki TM, et al. Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United States. Crit Care Med. 2012;40:1487–98. [PMC free article] [PubMed]
83. Ampofo K, Bender J, Sheng X, et al. Seasonal invasive pneumococcal disease in children: role of preceding respiratory viral infection. Pediatrics. 2008;122:229–37. [PubMed]
84. Talbot TR, Poehling KA, Hartert TV, et al. Seasonality of invasive pneumococcal disease: temporal relation to documented influenza and respiratory syncytial viral circulation. Am J Med. 2005;118:285–91. [PubMed]
85. Johansson N, Kalin M, Hedlund J. Clinical impact of combined viral and bacterial infection in patients with community-acquired pneumonia. Scand J Infect Dis. 2011;43:609–15. [PubMed]
86. Ruuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia. Lancet. 2011;377:1264–75. [PubMed]
87. Virkki R, Juven T, Rikalainen H, Svedstrom E, Mertsola J, Ruuskanen O. Differentiation of bacterial and viral pneumonia in children. Thorax. 2002;57:438–41. [PMC free article] [PubMed]
88. File TM., Jr New diagnostic tests for pneumonia: what is their role in clinical practice? Clin Chest Med. 2011;32:417–30. [PubMed]
89. Nascimento-Carvalho CM, Cardoso M-RA, Barral A, et al. Procalcitonin is useful in identifying bacteraemia among children with pneumonia. Scand J Infect Dis. 2010;42:644–9. [PubMed]
90. Toikka P, Irjala K, Juven T, et al. Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr Infect Dis J. 2000;19:598–602. [PubMed]
91. Gilbert DN. Use of plasma procalcitonin levels as an adjunct to clinical microbiology. J Clin Microbiol. 2010;48:2325–9. [PMC free article] [PubMed]
92. Gilbert DN. Procalcitonin as a biomarker in respiratory tract infection. Clin Infect Dis. 2011;52 (Suppl 4):S346–50. [PubMed]
93. Schuetz P, Briel M, Christ-Crain M, et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis. 2012;55:651–62. [PMC free article] [PubMed]
94. Franquet T. Imaging of pulmonary viral pneumonia. Radiology. 2011;260:18–39. [PubMed]
95. Guo W, Wang J, Sheng M, Zhou M, Fang L. Radiological findings in 210 paediatric patients with viral pneumonia: a retrospective case study. Br J Radiol. 2012 [PMC free article] [PubMed]
96. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM. Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP) 2011;60:1–24. [PubMed]
97. Hayden FG, Pavia AT. Antiviral management of seasonal and pandemic influenza. J Infect Dis. 2006;194 (Suppl 2):S119–26. [PubMed]
98. Kaiser L, Wat C, Mills T. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med. 2003;163:1667. [PubMed]
99. Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis. 2009;200:492–500. [PubMed]
100. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis. 2007;45:1568–75. [PubMed]
101. Lee N, Choi KW, Chan PK, et al. Outcomes of adults hospitalised with severe influenza. Thorax. 2010;65:510–5. [PubMed]
102. Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med. 2009;361:1935–44. [PubMed]
103. Bautista E, Chotpitayasunondh T, Gao Z, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med. 2010;362:1708–19. [PubMed]
104. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA. 2010;303:1517–25. [PubMed]
105. Yu H, Feng Z, Uyeki TM, et al. Risk factors for severe illness with 2009 pandemic influenza A (H1N1) virus infection in China. Clin Infect Dis. 2011;52:457–65. [PMC free article] [PubMed]
106. Yang SG, Cao B, Liang LR, et al. Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1) virus. PLoS One. 2012;7:e29652. [PMC free article] [PubMed]
107. Louie JK, Yang S, Acosta M, et al. Treatment With Neuraminidase Inhibitors for Critically Ill Patients With Influenza A (H1N1)pdm09. Clin Infect Dis. 2012 [PubMed]
108. Eriksson CO, Graham DA, Uyeki TM, Randolph AG. Risk factors for mechanical ventilation in U.S. children hospitalized with seasonal influenza and 2009 pandemic influenza A. Pediatr Crit Care Med. 2012 [PubMed]
109. Kumar A, Zarychanski R, Pinto R, et al. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA. 2009;302:1872–9. [PubMed]
110. Hsu J, Santesso N, Mustafa R, et al. Antivirals for Treatment of Influenza: A Systematic Review and Meta-analysis of Observational Studies. Ann Intern Med. 2012 [PubMed]
111. Randolph AG, Vaughn F, Sullivan R, et al. Critically ill children during the 2009–2010 influenza pandemic in the United States. Pediatrics. 2011;128:e1450–8. [PMC free article] [PubMed]
112. Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1003–32. [PubMed]
113. Ginocchio CC, Zhang F, Manji R, et al. Evaluation of multiple test methods for the detection of the novel 2009 influenza A (H1N1) during the New York City outbreak. J Clin Virol. 2009;45:191–5. [PubMed]
114. Uyeki TM, Prasad R, Vukotich C, et al. Low sensitivity of rapid diagnostic test for influenza. Clin Infect Dis. 2009;48:e89–92. [PubMed]
115. Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA. 2009;301:1034–41. [PubMed]
116. Moscona A. Global transmission of oseltamivir-resistant influenza. N Engl J Med. 2009;360:953–6. [PubMed]
117. Fry AM, Gubareva LV. Understanding influenza virus resistance to antiviral agents; early warning signs for wider community circulation. J Infect Dis. 2012;206:145–7. [PubMed]
118. Hayden FG, de Jong MD. Emerging influenza antiviral resistance threats. J Infect Dis. 2011;203:6–10. [PMC free article] [PubMed]
119. Hurt AC, Hardie K, Wilson NJ, et al. Characteristics of a widespread community cluster of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza in Australia. J Infect Dis. 2012;206:148–57. [PMC free article] [PubMed]
120. Krilov LR. Respiratory syncytial virus disease: update on treatment and prevention. Expert Rev Anti Infect Ther. 2011;9:27–32. [PubMed]
121. Boeckh M, Englund J, Li Y, et al. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clin Infect Dis. 2007;44:245–9. [PubMed]
122. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. Cochrane Database Syst Rev. 2007:CD000181. [PubMed]
123. Shachor-Meyouhas Y, Ben-Barak A, Kassis I. Treatment with oral ribavirin and IVIG of severe human metapneumovirus pneumonia (HMPV) in immune compromised child. Pediatr Blood Cancer. 2011;57:350–1. [PubMed]
124. Refaat M, McNamara D, Teuteberg J, et al. Successful cidofovir treatment in an adult heart transplant recipient with severe adenovirus pneumonia. J Heart Lung Transplant. 2008;27:699–700. [PubMed]
125. Doan ML, Mallory GB, Kaplan SL, et al. Treatment of adenovirus pneumonia with cidofovir in pediatric lung transplant recipients. J Heart Lung Transplant. 2007;26:883–9. [PubMed]
126. Darr S, Madisch I, Heim A. Antiviral activity of cidofovir and ribavirin against the new human adenovirus subtype 14a that is associated with severe pneumonia. Clin Infect Dis. 2008;47:731–2. [PubMed]
127. Toth K, Spencer JF, Dhar D, et al. Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model. Proc Natl Acad Sci U S A. 2008;105:7293–7. [PubMed]
128. Hayden FG, Herrington DT, Coats TL, et al. Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: results of 2 double-blind, randomized, placebo-controlled trials. Clin Infect Dis. 2003;36:1523–32. [PubMed]
129. DeVincenzo JP, El Saleeby CM, Bush AJ. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J Infect Dis. 2005;191:1861–8. [PubMed]
130. Fodha I, Vabret A, Ghedira L, et al. Respiratory syncytial virus infections in hospitalized infants: association between viral load, virus subgroup, and disease severity. J Med Virol. 2007;79:1951–8. [PubMed]
131. Gerna G, Piralla A, Rovida F, et al. Correlation of rhinovirus load in the respiratory tract and clinical symptoms in hospitalized immunocompetent and immunocompromised patients. J Med Virol. 2009;81:1498–507. [PubMed]
132. Martin ET, Kuypers J, Heugel J, Englund JA. Clinical disease and viral load in children infected with respiratory syncytial virus or human metapneumovirus. Diagn Microbiol Infect Dis. 2008;62:382–8. [PubMed]
133. Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53:e25–76. [PubMed]
134. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 (Suppl 2):S27–72. [PubMed]
135. Abed Y, Boivin G. Treatment of respiratory virus infections. Antiviral Res. 2006;70:1–16. [PubMed]
136. Nichols WG, Peck Campbell AJ, Boeckh M. Respiratory viruses other than influenza virus: impact and therapeutic advances. Clin Microbiol Rev. 2008;21:274–90. [PMC free article] [PubMed]