key: cord-1043678-w5l2gfk6
authors: Evans, Scott E.; Jennerich, Ann L.; Azar, Marwan M.; Cao, Bin; Crothers, Kristina; Dickson, Robert P.; Herold, Susanne; Jain, Seema; Madhavan, Ann; Metersky, Mark L.; Myers, Laura C.; Oren, Eyal; Restrepo, Marcos I.; Semret, Makeda; Sheshadri, Ajay; Wunderink, Richard G.
title: Nucleic Acid–based Testing for Noninfluenza Viral Pathogens in Adults with Suspected Community-acquired Pneumonia. An Official American Thoracic Society Clinical Practice Guideline
date: 2021-05-01
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202102-0498st
sha: 917a92e0d893f3968448aa62317b83a16e1a1c97
doc_id: 1043678
cord_uid: w5l2gfk6

Background: This document provides evidence-based clinical practice guidelines on the diagnostic utility of nucleic acid–based testing of respiratory samples for viral pathogens other than influenza in adults with suspected community-acquired pneumonia (CAP). Methods: A multidisciplinary panel developed a Population–Intervention–Comparison–Outcome question, conducted a pragmatic systematic review, and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations. Results: The panel evaluated the literature to develop recommendations regarding whether routine diagnostics should include nucleic acid–based testing of respiratory samples for viral pathogens other than influenza in suspected CAP. The evidence addressing this topic was generally adjudicated to be of very low quality because of risk of bias and imprecision. Furthermore, there was little direct evidence supporting a role for routine nucleic acid–based testing of respiratory samples in improving critical outcomes such as overall survival or antibiotic use patterns. However, on the basis of direct and indirect evidence, recommendations were made for both outpatient and hospitalized patients with suspected CAP. Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was not addressed in the literature at the time of the evidence review. Conclusions: The panel formulated and provided their rationale for recommendations on nucleic acid–based diagnostics for viral pathogens other than influenza for patients with suspected CAP.

Community-acquired pneumonia (CAP) is a heterogeneous illness caused by a wide range of respiratory pathogens. There is increasing recognition that respiratory viruses are frequent causative agents of CAP (1) . CAP is typically diagnosed on the basis of clinical signs and symptoms, often with notable reliance on radiographic findings. In recent years, a number of additional diagnostic technologies have been introduced into clinical practice that are intended to aid clinicians in the identification of CAP-causing pathogens. The American Thoracic Society (ATS) and Infectious Diseases Society of America clinical practice guideline on the diagnosis and management of CAP was updated in 2019 (2) . The revised guideline includes the recommendation that adults with CAP should have a respiratory sample tested for influenza virus at the time of diagnosis. The recommendation specifically endorses rapid influenza molecular assays such as influenza nucleic acid amplification tests (NAATs) over rapid antigen tests when influenza viruses are in circulation in the community. However, no recommendation is made regarding the role of testing for noninfluenza viruses.

Given the important etiologic contributions to CAP of noninfluenza respiratory viruses and the expanding commercial availability of multiplex testing for these viruses, the ATS commissioned the current document to provide an evidencebased clinical practice guidance regarding the pertinence of nucleic acid-based testing of respiratory samples for noninfluenza respiratory viruses in adults with suspected CAP.

At the time of document development, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was not a recognized CAP-causing pathogen. As such, the systematic literature review did not consider this virus, and no related recommendations are made. However, as SARS-CoV-2 has been well established as an important cause of CAP since the time of the literature review, discussions of how these recommendations may relate to viruses like SARS-CoV-2 are offered.

NAATs first emerged in the 1980s for HIV and Chlamydia trachomatis and were eventually adapted for other microorganisms, including respiratory viral infections. The breadth of respiratory infections detectable by NAATs has drastically increased over the past several years, largely supplanting other diagnostic modalities as the principal means of respiratory viral testing. The role of NAATs in respiratory viral diagnosis was recently emphasized by the dependence of healthcare institutions on NAATs to detect SARS-CoV-2 infections in response to the coronavirus disease (COVID- 19) pandemic. NAATs for the detection of noninfluenza respiratory viruses may be developed for use by individual clinical laboratories (laboratory-developed assays) or by private companies (commercially available assays). Within the United States, NAAT-based assays for respiratory viruses are classified as medical devices by the Food and Drug Administration (FDA). Therefore, all commercially available respiratory viral assays are subject to FDA approval and oversight to provide reasonable quality assurance and reliability. At the time of this writing, FDA approval is not required for laboratory-developed assays, though guidelines to assist in establishing performance specifications are routinely published by the Clinical and Laboratory Standards Institute; current legislation (Verifying Accurate and Leading-Edge In Vitro Clinical Test Development Act) proposes to enforce more stringent regulation (3) . Assays may be designed for use in a central laboratory or at the point of care (POC). Many POC tests in the United States are Clinical Laboratory Improvement Amendments of 1988 waived, indicating that they are of low complexity, requiring little operator expertise and having a low potential for errors (4) .

Commercially available assays for the detection of noninfluenza respiratory viruses employ several methodologies, including 1) real-time RT-PCR, 2) multiplex microarray competitive DNA hybridization, 3) nested multiplex RT-PCR, 4) isothermal nucleic acid amplification, 5) loop-mediated isothermal DNA amplification, and 6) RT-PCR followed by microarray hybridization. The most common approved specimen for testing is a nasopharyngeal swab, but other approved specimens may include nasal swabs, nasal aspirates, nasal washes, and throat swabs. Most assays are not approved for testing on BAL fluid, with some exceptions (e.g., FilmArray Pneumonia Panel [BioFire Diagnostics]) (5) .

Both single-target and multiplex assays are available to detect noninfluenza respiratory virus targets. These can be divided into five categories: 1) multiplex PCR assays (generally >4 targets) for influenza and noninfluenza respiratory viruses plus select atypical bacterial pathogens (e.g., FilmArray Pneumonia Panel and FilmArray Respiratory Panel by BioFire Diagnostics; ePlex Respiratory Pathogen Panel by GenMark Diagnostics); 2) multiplex PCR assays (generally >4 targets) for influenza and noninfluenza respiratory viruses only (e.g., eSensor Respiratory Viral Panel by GenMark Diagnostics); 3) multiplex PCR assays (3 targets) for influenza A/B plus respiratory syncytial virus (RSV) (e.g., Xpert Flu/RSV XC by Cepheid); 4) multiplex PCR assays (generally 2-3 targets) for noninfluenza viruses only (e.g., Solana RSV 1 human metapneumovirus assay by Quidel; Panther Fusion Paraflu Assay by Hologic); and 5) single-target assays for noninfluenza viruses (e.g., Alere I RSV by Abbott Laboratories) (5) .

Upper respiratory tract testing for influenza using molecular panels is not sufficiently sensitive to exclude lower tract infections, particularly in critically ill and immunocompromised patients, nor is it sufficiently sensitive to exclude some strains of influenza (e.g., H1N1 and H5N1) that preferentially infect the lower respiratory tract (6) (7) (8) (9) (10) . Relevant data for other respiratory viruses are sparser. It is well established that rhinoviruses, coronaviruses, and adenoviruses infect both upper and lower respiratory tract epithelia. Moreover, cases of children infected with rhinovirus, adenovirus, and bocavirus have been documented to have positive testing in the lower respiratory tract but negative testing in the upper respiratory tract (11) . In infants and immunocompromised adults with RSV, progression of infection from the upper to the lower respiratory tract often portends higher morbidity and mortality. In one study of immunocompromised adults with RSV, testing of lower respiratory tract specimens was significantly more sensitive than testing of upper respiratory tract specimens (nasal wash: 15%; endotracheal aspirate: 71.4%; BAL: 88.9%) (12) . In another study of adult hematopoietic stem cell transplant (HSCT) recipients, high rates of discordance between upper and lower respiratory tract specimens were reported for adenovirus (100%), human metapneumovirus (44%), rhinovirus (34%), and parainfluenza virus type 3 (28%), whereas testing for RSV was highly concordant (92%) (13) .

Given the variable diagnostic performance and clinical impact of multianalyte NAATs for different viruses and in difference clinical contexts, together with the lack of guidance from the most recent CAP guideline on this topic, the ATS initiated a project to investigate the role of molecular testing for noninfluenza viruses in the setting of suspected CAP.

A multidisciplinary, international panel of experts in respiratory infections convened to develop a single Population-Intervention-Comparison-Outcome (PICO) question regarding the use of nucleic acid-based viral diagnostic testing for viral pathogens (other than influenza) in patients with suspected CAP. The PICO question was finalized after multiple rounds of discussions via teleconference. Subsequently, we performed a systematic review of the literature and applied the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to evaluate quality of evidence and inform our recommendations. The detailed guideline-development methodology and conflict-of-interest management strategies are included in the online supplement. GRADE standards were used to determine the designation of the quality of evidence as high, moderate, low, or very low. On the basis of the quality of the evidence and committee discussions, recommendations were assigned as being strong or conditional. Recommendations based on a low or very low quality of evidence and that were not believed to represent standards of care were labeled as being conditional. The guideline document was subjected to expert peer review and was approved by the Board of Directors of the ATS. It will be reevaluated in 3-5 years to determine whether updating is necessary.

The PICO guideline co-chairs (S.E.E. and C.S.D.C.) were selected by the ATS. They led all aspects of project management and selected the panelists, who included 12 clinicians and researchers with experience in pneumonia. Two (B.C. and R.G.W.) participated in the initial design and discussions of the PICO questions and evidence but were not involved in the formulation of the recommendations or writing of the guideline. With the assistance of a librarian (A.M.), three methodologists (A.L.J., L.C.M., and E.O.) identified, collected, and synthesized the evidence; constructed the evidence profiles; and ensured that all methodological requirements were met. The methodologists presented the evidence to the co-chairs and panelists, who then formulated and finalized the recommendations. All panel members were required to disclose conflicts of interest on an ongoing basis throughout the process.

Question: In adults with suspected CAP, should routine diagnostics include nucleic acid-based testing of respiratory samples for viral pathogens other than influenza? Recommendation 1. In outpatients with suspected CAP, we suggest not performing routine nucleic acid-based testing of respiratory samples for viral pathogens other than influenza (conditional recommendation, very-low-quality evidence). Recommendation 2. In hospitalized patients with suspected CAP, we suggest nucleic acid-based testing of respiratory samples for viral pathogens other than influenza only in patients who meet one of the following conditions (conditional recommendation, very-low-quality evidence):

d Patients with severe CAP (i.e., patients with >1 major or >3 minor criteria [2] ) and d Immunocompromised patients (including those with neutropenia, those undergoing active cancer therapy, those with a history of solid-organ or bloodcomponent transplantation, those with advanced HIV disease, or those with a history of chronic use of immunosuppressive medications, including systemic corticosteroids). Summary of the evidence. There is limited evidence regarding the relationship between nucleic acid-based testing of respiratory samples for noninfluenza viral pathogens and patient-centered outcomes, specifically among patients with suspected or confirmed CAP. Few studies compare testing with "no testing" when assessing these associations (14, 15) . Given the limited number of studies with a true comparison of testing with no testing, we also reviewed studies that compare a positive viral test result with a negative viral test result (16) (17) (18) . In addition, we included studies that evaluated tests involving both viral and bacterial assays, if comparisons related to viral testing were reported (19) (20) (21) (22) (23) . Most of the evaluated studies are observational in nature, and of the studies that involved clinical trials (14, 19, 20) , data related to our question consist of comparisons other than the primary intervention versus the control.

Overall, available evidence is of very low quality because of methodological issues, most notably risk of bias and imprecision. Study findings and GRADE assessments for prespecified patientcentered outcomes are detailed in Tables 1  and 2 . The evidence does not support a clinically significant relationship between testing for noninfluenza viral pathogens and antimicrobial treatment (14, 15, 17, 18) . Once antibiotics are initiated, identification of viral pathogens using a NAAT may reduce the duration of antibiotic use (19, 20, 22) , but this finding is not consistent (14, 15, 17) . When viral PCR results become available to clinicians, most patients with positive test results continue to receive antibiotics (16, 18, 20, 21, 23) . 

Lastly, the hospital length of stay does not differ significantly between hospitalized patients who undergo viral testing or have a positive viral test result and those who do not have tests performed or whose test results are negative (14, 17) .

To supplement the evidence most directly informing our recommendations, we also provide a narrative summary of studies identified in our literature review that include patients with non-CAP respiratory illnesses, such as acute exacerbations of chronic obstructive pulmonary disease or bronchiectasis, in addition to patients with suspected or confirmed CAP; these studies are detailed in Tables 3-8 . Although these findings are indirect, as our population of interest is individuals with suspected CAP, they include important data about outpatient testing and the use of NAATs in critically ill and immunocompromised individuals (24) (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) .

Limited evidence of altered antibiotic use with viral testing. Although the panel anticipated that changes in antibiotic use would be among the most substantial effects of testing, there is little current evidence supporting the supposition that the use of nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in patients with suspected or confirmed CAP impacts antibiotic management. In theory, identification of viruses without concomitant bacteria might prompt clinicians to withhold antibiotics for CAP. However, possibly because of time lags in obtaining results of the respiratory virus panel even with POC tests, no studies have found that these tests are associated with a significant decrease in the initiation of antibiotic therapy. Among patients hospitalized with CAP, over 95% received antibiotics, regardless of whether they were found to be respiratory virus panel positive Definition of abbreviations: CAP = community-acquired pneumonia; ED = emergency department; HAP = hospital-acquired pneumonia; HCAP = health care-associated pneumonia; ILI = influenza-like illness; LOS = length of stay; RTI = respiratory tract infection.

or negative (17) . Most of the literature addressing this issue focuses on the inpatient setting, so the panel extrapolates these reports to outpatients, in whom antibiotic use is presumed to be less prevalent.

Alternately, identification of respiratory viruses but not bacteria could support discontinuation of antibiotics. Yet in studies of patients with acute respiratory illness, only a minority have had antibiotics discontinued, despite the lack of identification of bacterial pathogens and positive respiratory virus panel NAAT results. The rate of antibiotics discontinuation has been reported to range from 12.5% to 32% of viruspositive/bacteria-negative patients, even when accompanied by a low procalcitonin concentration (16, 19) . One study reported that pathogen identification using multiplex PCR resulted in changes to antibiotic treatment in only 22% of the patients, who were mostly in the ICU (21) . Although identification of influenza is clearly associated with modifications in antibiotic and antiviral management, significant differences in the discontinuation of antibiotics have not generally been observed between patients who had only noninfluenza respiratory viruses isolated and patients who had only bacterial or mixed bacterial and viral infections (18) . Other factors, such as clinician suspicion of pneumonia based on radiographic findings may be more important drivers of continuation of antibiotics than respiratory virus panel results (18) .

Although results are mixed, several studies suggest that identification of respiratory viruses may be associated with a shorter duration of antibiotic therapy. Patients who were found to have only respiratory viruses, when compared with patients with bacterial or mixed pathogens, had fewer days of antibiotics (15, 19, 20) and were more likely to receive a single dose of antibiotics or receive antibiotics for Definition of abbreviations: CI = confidence interval; ED = emergency department; LOS = length of stay.

48 hours or fewer (14, 17) . There is concern that these results may be more driven by patients with asthma and chronic obstructive pulmonary disease exacerbations after secondary analyses of the data (40) . In a retrospective study of hospitalized patients with CAP, the average duration of antibiotics was also shorter for the group with a viral pathogen detected by using NAATs than for those who did not have a viruses detected (4.9 vs. 8.3 d) (22) . However, in other studies, detection of respiratory viruses by using NAATs was not associated with any significant difference in antibiotic treatment or the median duration of therapy (17, 23) . Data on the influence of respiratory viral NAAT results used to inform antibiotic management in patients with CAP are limited by the number of studies and methodological concerns. Limitations Antimicrobial prescription rates differed when comparing the three following groups: positive for influenza virus (n = 105), positive for a noninfluenza virus pathogen (n = 109), and negative for all pathogens tested (n = 81); antibiotic prescription rates were 29.5%, 48.6%, and 49.3%, respectively (P = 0.005), and oseltamivir prescription rates were 81.0%, 5.5%, and 2.5%, respectively (P , 0.001). There was no significant difference in antibiotic prescription rates between individuals who tested positive for a noninfluenza virus and those who tested negative (48.6% and 49.3%, respectively; P = 1.0). Tang 

include small sample sizes, retrospective study designs, challenges in implementation of respiratory virus panel testing and obtaining results in a rapid manner, communicating findings in a standardized and consistent way to treating clinicians, inclusion of mixed populations of patients with acute respiratory illness not restricted to CAP, and a primary focus on elderly patients. As a result, the panel was unable to recommend the routine use of NAAT-based testing for noninfluenza viral pathogens in patients with suspected CAP in the outpatient or the inpatient setting because of very-low-quality evidence. Substantial work Among adults, the decrease in antibiotic prescriptions was more common in the multiplex group than in the IFA group in a multivariable model (OR, 15.52; 95% CI, 1.99 to 120.8; P = 0.009). In unadjusted analysis, a change from intention to treat with oseltamivir to a final decision not to treat occurred in 12% of influenza A/B-negative adults tested by using multiplex PCR vs. 9% of influenza A/B-negative adults tested by using IFA (P = 0.042).

(Continued )

remains to be done to address this question. Future studies should consider implementation strategies that combine viral NAATs with measurements of biomarkers, such as procalcitonin, and antibiotic stewardship practices in an effort to have a meaningful impact on antibiotic management of CAP. The panel further recognizes that factors related to local test availability may impact adherence to the suggestion not to routinely test for noninfluenza viral pathogens while routinely performing guideline-compliant testing for influenza in patients with CAP. For instance, some hospitals may only offer influenza testing as part of a multiplex panel that also includes noninfluenza virus targets. In such cases, the panel offers no guidance regarding the composition of the multiplex assay and must defer to individual institutional judgment as to whether the avoidance of occasional unnecessary testing justifies the cost of purchasing influenzaonly tests.

Limited evidence of changes in other clinical outcomes. Although antibiotic use and hospital length of stay were identified as critically important outcomes, the panel also sought evidence to suggest that the use of such testing could impact other important clinical outcomes, such as mortality and hospital or ICU admission rates. No highquality data were identified to conclusively support an association between routine testing for noninfluenza viruses and these outcomes. The panel did not identify evidence that routine use of nucleic acid-based testing for noninfluenza respiratory viruses improved the survival rate of patients with suspected CAP, nor did it demonstrably reduce hospitalization, the use of ICU services, or the time to clinical stability. The absence of data supporting such benefits may result from studies that largely focused on other questions and were thus underpowered to detect these effects. Nonetheless, the panel did not find that there was sufficient evidence of improvement in these patientcentered outcomes to recommend routine testing for viruses other than influenza in patients with suspected CAP.

Rationale for noninfluenza virus testing recommendation in hospitalized patients with severe CAP. Although there is little high-quality evidence to strongly support the use of molecular testing for noninfluenza respiratory virus testing in any setting, the panel identified certain situations in which the potential benefit of testing is perceived to be greater. The recommendation to routinely use nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in patients with severe CAP is based on increasing recognition that noninfluenza viruses cause severe CAP and the panel's assertion that detection of these viruses may have important impacts on patient management as well as hospital antiinfective practices. Highly sensitive and specific NAATs allow improved detection of respiratory viruses, enhancing our understanding of the epidemiology and ecology of severe CAP (1, (41) (42) (43) (44) (45) (46) (47) . Noninfluenza viruses are detected in a substantial proportion of severe CAP cases and have been associated with important complications in hospitalized adults, including the increased need for mechanical ventilation, the increased need for prolonged intensive-care support, and increased mortality (48) . In fact, some series indicate that noninfluenza respiratory viruses have been associated with greater inpatient mortality than influenza (49) . Furthermore, noninfluenza viruses have been reported to cause more severe CAP than influenza in patients with advanced age, chronic respiratory diseases, malignancy, and/or immunosuppression (49) . The yield of NAATs for respiratory viruses in reported series of adults with severe CAP ranges between 9% and 41%, although these numbers are influenced by the inclusion of influenza virus in these data sets (1, (41) (42) (43) (44) (45) (46) (47) . Mixed viral and bacterial Definition of abbreviations: CI = confidence interval; ED = emergency department; IFA = immunofluorescence assay; ILI = influenza-like illness; IQR = interquartile range; IRR = incidence rate ratio; LOS = length of stay; LRTI = lower respiratory tract illness/infection; OR = odds ratio; RTI = respiratory tract infection.

infections are detected in about 12% of CAP cases, and rapid recognition of all contributing pathogens is critical for patients with severe CAP (41) , for whom delays in appropriate antibiotic and antiviral selections can have serious consequences. The panel agreed that detection of noninfluenza viruses or mixed viral and bacterial infections in patients with severe CAP can promote appropriate antibiotic use and/or allow deescalation to prevent overuse of antimicrobial agents in the ICU, where antimicrobial use is significantly higher than in other settings (50) . We explicitly support the stratification of patients on the basis of disease severity as outlined in the 2007 (and endorsed in the 2019) Infectious Diseases Society of America/ATS severe CAP criteria (Table 9) (2) rather than on the basis of hospital care setting or unit type, as this may vary among hospitals and practices.

Rationale for testing recommendation in hospitalized immunocompromised patients. Immunocompromised patients are at particularly high risk for death after developing an infectious pneumonia syndrome (51) . This population may include patients with inherited or acquired immune deficiency or drug-induced neutropenia, such as patients actively receiving cancer chemotherapy, patients with HIV infection and CD4 counts ,500 cells/mm 3 , and solid organ transplant or HSCT recipients.

Certain immunocompromised populations, such as HSCT recipients, have a high annual incidence of respiratory viral infections (52) , and the rate of progression from upper respiratory viral infection to fatal pneumonia is markedly higher than that in nonimmunocompromised hosts (53) . Similarly, lung transplant recipients are at high risk of progression from upper respiratory tract infection to severe pneumonia (54, 55) . Even in symptomatic, immunocompromised patients, the yield of causative pathogens from BAL fluid using culture-based techniques for bacterial pathogens remains low (56, 57) . Because of the risk of progression or death after respiratory viral infection in immunocompromised hosts, early detection of viral infection may be useful for clinicians providing treatment. Although prospective, randomized studies are needed to draw better conclusions, noninfluenza respiratory viruses such as RSV and adenovirus have enhanced pathogenic potential in immunocompromised patients, potentially warranting more invasive testing if initial upper respiratory tract testing results are negative.

Thus, the panel supports routine testing for noninfluenza respiratory viruses in the immunocompromised population. Such testing in these patients has the further potential to enhance our understanding of the viral epidemiology in a population that is susceptible to uncommon and unusual pathogens. However, this recommendation is made while recognizing that the utility of viral testing in this population may be limited by certain key observations. First, despite the use of cidofovir for the treatment of adenovirus (58) and oral or inhaled ribavirin for the treatment of RSV pneumonia (59) , only antiinfluenza medications have FDA-approved indications in immunocompromised adults with respiratory viral infection (60) . Second, prolonged periods of viral shedding in immunocompromised hosts may lead to overdiagnosis and overtreatment in cases in which viral inflammation is inactive or minimal (61) . Finally, in the absence of lower respiratory PCR panels that detect bacterial infection, clinicians may not be comfortable with stopping antibiotics after a negative bacterial culture from BAL fluid samples because of the low diagnostic yield (62) . As in nonimmunocompromised patients, there is no current evidence demonstrating that viral respiratory PCR panels alter prescribing patterns of antimicrobial agents in immunocompromised hosts (29, 39) . In light of these limitations, the consensus opinion of the committee was to recommend that nucleic acid-based testing of respiratory samples for viral pathogens other than influenza be considered in certain immunocompromised patients at high risk for death of respiratory viral infection, but the utility of this test will depend heavily on the development of novel effective antiviral therapies. It is further acknowledged that identifying viral pathogens in immunocompromised outpatients via nucleic acid-based testing may also provide important benefits, but the absence of even indirect evidence from that population limits the panel's capacity to suggest testing in that context.

Respiratory viral pathogens other than influenza cause a significant burden of disease and lead to poor outcomes in high-risk patients. Although the standard of care for patients infected with these pathogens is generally limited to supportive management, some patients may be candidates for antiviral therapy or passive immunization with virus-specific immunoglobulins, supporting our recommendation for testing viral pathogens in high-risk patients.

For example, human RSV is a common cause of acute upper respiratory tract illness that often leads to more severe disease and hospitalization in older adults and in those with compromised immunity (63) . Although there are no formal guidelines for therapy of RSV in adults, off-label use of aerosolized ribavirin has been used to treat RSV infections in HSCT or lung transplant recipients, on the basis of mainly observational data (52) . Treatment with oral ribavirin, which is significantly less 

expensive and easier to administer than the aerosolized compound, may be an effective alternative in reducing progression to lower respiratory tract infection and mortality (59) . Several new antiviral agents (presatovir, ALS-008176, and RSV604), as well as monoclonal antibodies to prevent acquisition of RSV, are currently at different phases of preclinical or clinical development (64) . Human adenoviruses (HAdVs) typically cause short-lived upper respiratory tract manifestations in adults, but some species have been associated with severe viral pneumonia in outbreak settings. Furthermore, HAdVs are capable of establishing latent infections with subsequent reactivation during periods of immune suppression, allowing development of pneumonia and disseminated disease (65) . Clinical experience with antivirals is limited, but cidofovir has been used to treat severe HAdV disease on the basis of in vitro activity and observational data (66, 67) ; trials for the safety and efficacy of brincidofovir are underway (68) .

Other respiratory viruses, such as human metapneumovirus, parainfluenza types 1-4, rhinovirus/enterovirus, or human coronaviruses, may also cause severe pneumonia in adult patients, although agents with activity against them are not clinically available (69, 70) . In such cases, their detection may become more relevant as effective antivirals become available.

Although the focus of this guideline is testing for viral pathogens, the panel recognizes the clinical importance and diagnostic challenges related to detection of nonviral pathogens in CAP. Development and adoption of rapid molecular tests for nonviral pathogens may improve etiologic diagnosis and appropriate selection of antimicrobials (23) . "Atypical" bacterial pathogens (e.g., Legionella spp, Mycoplasma pneumoniae, and Chlamydophila pneumoniae) are common causes of CAP (1, 71) with distinct antimicrobialsusceptibility profiles. In endemic regions and high-risk patients, rapid molecular testing of Mycobacterium tuberculosis likely improves diagnostic accuracy and informs infection prevention interventions (72) . Specific fungal pathogens can be common causes of CAP in endemic regions (e.g., coccidiomycosis in the American Southwest [73] and histoplasmosis and blastomycosis in the Mississippi and Ohio River valleys [74, 75] ). Specific recommendations regarding their implementation are beyond the scope of the current document, but the panel notes that these organisms may also be detected by some NAAT arrays and thus recognizes that a potential further benefit may exist.

Role in infection control and outbreak management. Rapid nucleic acid-based tests for viral pathogens other than influenza could result in faster and more efficient infection-control measures in hospital settings through detection and prevention of nosocomial outbreaks. Alternately, when respiratory viral infections are suspected, rapid tests with a short turnaround time could provide economic benefit due to a reduced number of isolation days (39) . A recent single-center study confirmed significant reductions in the mean number of days in isolation, mean number of days under contact precautions, and mean number of days under droplet precaution measures upon introduction of a rapid RT-PCR test for influenza (76) . It is suspected that similar results might be observed for other respiratory viral infections, such as RSV.

Indeed, significant reductions in admissions to isolation facilities and the time of isolation have been described after implementation of a rapid PCR-based viral respiratory panel test targeting several respiratory viruses (39, 77) . The impact on isolation use appears to relate mainly to the accelerated turnaround time for newly implemented POC test results. Thus, although it seems likely that nucleic acid-based tests for respiratory viruses other than influenza will improve infection control and outbreak measures while saving costs, studies confirming this in different healthcare settings are needed before such testing is recommended. Underscoring this potential, NAATs are the cornerstone of the CDC's U.S. SARS-CoV-2 Surveillance Plan, with NAAT data being used to characterize the spread of disease and inform pandemic management strategies. Furthermore, the U.S. FDA has issued emergency use authorizations for rapid nucleic acid amplification platforms on the basis of the expectation that reduced turnaround times will improve patient care and better contain viral spread.

The development of this document revealed a paucity of high-quality data related to the impact of diagnosing noninfluenza viral infections on patient outcomes in suspected CAP. This underscores the urgent need for prospective studies to determine the influence of nucleic acid-based viral diagnostics in the management of outpatient and inpatient CAP, including pragmatic and implementation studies. Studies are specifically needed to determine the clinical impact of these diagnostics on treatment decisions in patients with severe CAP and in those who are immunocompromised. Such studies may reveal the impact of turnaround time using NAAT technologies to diagnose viral pneumonias on important patient outcomes. Studies are also needed to better assess the impact of multiplex NAAT panel target composition. This can allow insight into the clinical benefit of differently sized panels, as well as into those that include pathogens that are often separately targeted (e.g., influenza viruses or SARS-CoV-2) or those that include nonviral pathogens (e.g., atypical bacteria).

Improved clinical identification of common respiratory viral pathogens may promote the development of novel therapies to manage and prevent these infections. Studies demonstrating efficacy of such viral agents could subsequently improve antimicrobial stewardship practices. Relatedly, health system-integrated clinical reminders after viral testing may further enhance NAAT impacts on antibiotic use patterns, although this also requires formal evaluation. Nucleic acid amplification testing has infection-control implications in the hospital setting, especially where patients with severe CAP are managed, and this should be formally investigated. Welldesigned pragmatic clinical trials will be instrumental in informing the use of NAATs for noninfluenza viral pathogens. The SARS-CoV-2 pandemic has highlighted the importance of molecular diagnostics in the diagnosis, management, and surveillance of viral respiratory infections. Studies to assess the impact of such testing on patient outcomes and pandemic management are ongoing.

This guideline constitutes a rigorous PICOguided evaluation of relevant and available literature for scientific evidence regarding recommendations pertaining to the use of nucleic acid-based diagnostics testing for noninfluenza viral pathogens in CAP for the outpatient and inpatient setting. On the basis of GRADE criteria, the quality of evidence on this topic was rated as being very low, with few studies assessing the effect of noninfluenza viral diagnoses on key patient-centered outcomes. The use of nucleic acid-based diagnostics for viral pathogens other than influenza only was not clearly associated with patterns of antibiotic use. The panel examined and discussed the role of nucleic acid-based viral diagnostics for hospitalized patients and believed their use for the routine evaluation of suspected CAP should be considered only for patients with severe disease or those with immunocompromising conditions. Neither of the recommendations in this guideline is considered to be an appropriate target for a performance measure. n This official clinical practice guideline was prepared by an ad hoc subcommittee of the ATS Assembly on Pulmonary Infection and Tuberculosis.

Members of the subcommittee are as follows:

CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among U.S. adults

Diagnosis and treatment of adults with community-acquired pneumonia: an official clinical practice guideline of the

Diagnostics reform and harmonization of clinical laboratory testing

Detection of influenza A and B viruses and respiratory syncytial virus by use of Clinical Laboratory Improvement Amendments of 1988 (CLIA)-waived point-of-care assays: a paradigm shift to molecular tests

Laboratory diagnosis of respiratory tract infections in children -the state of the art

Viral clearance and inflammatory response patterns in adults hospitalized for pandemic 2009 influenza A(H1N1) virus pneumonia

Preferential lower respiratory tract infection in swine-origin 2009 A(H1N1) influenza

Severe Influenza A Task Force. Segregation of virulent influenza A(H1N1) variants in the lower respiratory tract of critically ill patients during the 2010-2011 seasonal epidemic

Diagnosis of influenza from lower respiratory tract sampling after negative upper respiratory tract sampling

Lung cancer mortality associated with smoking and smoking cessation among people living with HIV in the United States

Respiratory virus detection in nasopharyngeal aspirate versus bronchoalveolar lavage is dependent on virus type in children with chronic respiratory symptoms

Rapid diagnosis of respiratory syncytial virus infections in immunocompromised adults

Predictive value of respiratory viral detection in the upper respiratory tract for infection of the lower respiratory tract with hematopoietic stem cell transplantation

Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial

Clinical diagnosis, viral PCR, and antibiotic utilization in community-acquired pneumonia

No impact of early real-time PCR screening for respiratory viruses on length of stay and use of antibiotics in elderly patients hospitalized with symptoms of a respiratory tract infection in a single center in Norway

Impact of respiratory virus molecular testing on antibiotic utilization in community-acquired pneumonia

Multiplex respiratory virus testing for antimicrobial stewardship: a prospective assessment of antimicrobial use and clinical outcomes among hospitalized adults

The potential of molecular diagnostics and serum procalcitonin levels to change the antibiotic management of community-acquired pneumonia

The clinical impact of the detection of potential etiologic pathogens of communityacquired pneumonia

Impact on the medical decision-making process of multiplex PCR assay for respiratory pathogens

The impact of molecular testing for pathogens of community-acquired pneumonia on antibiotic utilization

The extent of microbiological testing is associated with alteration of antibiotic therapy in adults with community-acquired pneumonia

Clinical utility of on-demand multiplex respiratory pathogen testing among adult outpatients

Contribution of the FilmArray Respiratory Panel in the management of adult and pediatric patients attending the emergency room during 2015-2016 influenza epidemics: an interventional study

Utility of flexible bronchoscopy with polymerase chain reaction in the diagnosis and management of pulmonary infiltrates in allogeneic HSCT patients

Impact of early detection of respiratory viruses by multiplex PCR assay on clinical outcomes in adult patients

Multiplex PCR point of care testing versus routine, laboratory-based testing in the treatment of adults with respiratory tract infections: a quasi-randomised study assessing impact on length of stay and antimicrobial use

Stewardship opportunities in viral pneumonia: why not the immunocompromised?

Evaluation of a molecular point-of-care testing for viral and atypical pathogens on intravenous antibiotic duration in hospitalized adults with lower respiratory tract infection: a randomized clinical trial

Serum procalcitonin measurement and viral testing to guide antibiotic use for respiratory infections in hospitalized adults: a randomized controlled trial

Access to a polymerase chain reaction assay method targeting 13 respiratory viruses can reduce antibiotics: a randomised, controlled trial

Optimizing treatment of respiratory tract infections in nursing homes: nurse-initiated polymerase chain reaction testing

Clinical impact of rapid molecular detection of respiratory pathogens in patients with acute respiratory infection

Impact of rapid detection of viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection

Evaluating the impact of the multiplex respiratory virus panel polymerase chain reaction test on the clinical management of suspected respiratory viral infections in adult patients in a hospital setting

Impact of viral multiplex real-time PCR on management of respiratory tract infection: a retrospective cohort study

Respiratory virus of severe pneumonia in South Korea: prevalence and clinical implications

More targeted use of oseltamivir and inhospital isolation facilities after implementation of a multifaceted strategy including a rapid molecular diagnostic panel for respiratory viruses in immunocompromised adult patients

Impact of point-of-care testing for respiratory viruses on antibiotic use in adults with exacerbation of airways disease

Incidence of respiratory viral infections detected by PCR and real-time PCR in adult patients with community-acquired pneumonia: a metaanalysis

Viral infection in patients with severe pneumonia requiring intensive care unit admission

An international perspective on hospitalized patients with viral community-acquired pneumonia

Community-acquired polymicrobial pneumonia in the intensive care unit: aetiology and prognosis

The burden of viruses in pneumonia associated with acute respiratory failure: an underappreciated issue

Burden and viral aetiology of influenza-like illness and acute respiratory infection in intensive care units

Respiratory viruses in invasively ventilated critically ill patients: a prospective multicenter observational study

Impact of bronchoalveolar lavage multiplex polymerase chain reaction on microbiological yield and therapeutic decisions in severe pneumonia in intensive care unit

FLUVAC Study Group. Non-influenza respiratory viruses in adult patients admitted with influenza-like illness: a 3-year prospective multicenter study

Antibiotic stewardship in the intensive care unit: an official American Thoracic Society workshop report in collaboration with the AACN, CHEST

Pneumonia during remission induction chemotherapy in patients with acute leukemia

Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies

Immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with RSV infections

Disease burden of the most commonly detected respiratory viruses in hospitalized patients calculated using the disability adjusted life year (DALY) model

Respiratory syncytial virus-and human metapneumovirus-associated emergency department and hospital burden in adults

Role of bronchoalveolar lavage in the diagnosis of pulmonary infiltrates in immunocompromised patients

Diagnostic utility of bronchoscopy in adults with acute myeloid leukemia and other high-grade myeloid neoplasms

Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the infectious diseases working party of the European group for blood and marrow transplantation

Oral versus aerosolized ribavirin for the treatment of respiratory syncytial virus infections in hematopoietic cell transplant recipients

Epidemiology, diagnosis, treatment, and prevention of influenza infection in oncology patients

Initial high viral load is associated with prolonged shedding of human rhinovirus in allogeneic hematopoietic cell transplant recipients

Performance of a standardized bronchoalveolar lavage protocol in a comprehensive tcancer center: a prospective 2-year study

Respiratory syncytial virus infection in elderly and high-risk adults

Role of chitinase 3-like-1 in interleukin-18-induced pulmonary type 1, type 2, and type 17 inflammation; alveolar destruction; and airway fibrosis in the murine lung

Adenoviruses in immunocompromised hosts

Prospects for adenovirus antivirals

Adenovirus infections in transplant recipients

Disseminated adenovirus infection after allogeneic stem cell transplant and the potential role of brincidofovir: case series and 10 year experience of management in an adult transplant cohort

Respiratory virus infections in hematopoietic cell transplant recipients

Expanding the armamentarium against respiratory viral infections: DAS181

Comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia

The health-system benefits and cost-effectiveness of using Mycobacterium tuberculosis direct nucleic acid amplification testing to diagnose tuberculosis disease in the United States

Coccidioidomycosis as a common cause of community-acquired pneumonia

Histoplasmosis: up-todate evidence-based approach to diagnosis and management

Reduction in total patient isolation days with a change in influenza testing methodology

Impact of a rapid respiratory panel test on patient outcomes