REVIEW

CURRENT
OPINION Respiratory pathogen panels in the hospital:
good or unnecessary?
Kelly A. Cawcutt a, Paul D. Fey b, and Andre C. Kalil a

Purpose of review
We aim to review the epidemiology of respiratory viral infections and the strengths and limitations of
multiplex respiratory pathogen panels that are currently available along with their respective features and
differences.
Recent findings
We give particular emphasis to the pathogens included on each test and evaluate their performance in the
hospital setting.
Summary
We conclude with a discussion on the evidence for the clinical utility of respiratory pathogen multiplex
panels in hospitalized patients, including the potential for coinfection with viral and bacterial pathogens.
Keywords
bacterial, pneumonia, respiratory panel, viral

INTRODUCTION pathogens do not have a specific antiviral therapy,

Respiratory illnesses are major causes of morbidity
and mortality throughout the world [1–4]. Viral
respiratory illnesses, specifically, are pervasive in
all types of hosts, age ranges and healthcare settings
[1,5–7]. One of the classic clinical conundrums of a
respiratory viral illness is that presentations and
symptoms are rarely pathogen specific, thus result-
&
ing in a broad differential diagnosis [8 ]. This is
further complicated by potential difficulty discern-
ing between bacterial and viral respiratory illnesses,
thus leaving clinicians making empiric decisions on
need for antiviral, antibacterial therapy or both, and
waiting for microbiologic results that may not be
available for several days to guide further therapy
&
decisions [1,8 ,9]. If we were able to rapidly identify
the specific pathogens of respiratory illnesses, this
could also impact infection prevention control
interventions to reduce further spread of infection
in both inpatient and outpatient settings [2,3,5,10].
Over recent years, multiplex polymerase chain
reaction panels for detection of respiratory viral
pathogens and some respiratory bacterial pathogens
have been approved by the Food and Drug Admin-
istration. These multiplex platforms have the poten-
tial to simplify microbiologic testing algorithms
and provide faster diagnostic results for both patient
and clinicians [2,3,10,11]. However, unfortunately,
faster results may not always result in a more rapid
initiation of treatment as many of the viral
thus raising concerns as to whether these panels
improve clinical care or simply add further cost [10].
Herein, we discuss the epidemiology of respir-
atory viral infections and review the multiplex
panels that are currently available along with their
respective features and differences, particularly
regarding the pathogens included on each test.
Finally, we conclude with a discussion on the evi-
dence for the clinical utility of respiratory viral
pathogen multiplex panels in hospitalized patients,
including the potential for coinfection with both
viral and bacterial pathogens.
EPIDEMIOLOGY OF RESPIRATORY VIRAL
INFECTIONS
Although viral respiratory pathogens typically
mediate disease in the upper respiratory tract, it is
becoming increasingly recognized that they also
cause community-acquired pneumonia (CAP) in
a
Division of Infectious Diseases, Department of Internal Medicine and
b
Department of Pathology and Microbiology, University of Nebraska
Medical Center, Omaha, Nebraska, USA
Correspondence to Andre C. Kalil, MD, MPH, Division of Infectious
Diseases, Department of Internal Medicine, University of Nebraska
Medical Center, 985400 Nebraska Medical Center, Omaha, NE
68198, USA. E-mail: akalil@unmc.edu
Curr Opin Infect Dis 2017, 30:226–230
DOI:10.1097/QCO.0000000000000357

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


KEY POINTS
 A positive respiratory panel may obviate the
unnecessary use of antibiotics and may decrease the
use of more invasive sample collection methods;
however, many of the pathogens do not have
available therapy.
 A negative multiplex respiratory pathogen panel
consistently provides higher sensitivity than traditional
culture methods, but a negative nasopharyngeal swab
may be followed by a positive bronchoalveolar lavage
in critically ill patients.
 A positive test alone cannot distinguish colonization
versus active infection, thus a positive test from
colonization may miss the true cause in cases of
coinfection with bacteria and fungi.
 Cost-effectiveness studies are needed for different
clinical settings.
 More evidence is required for these panels in the
immunocompromised patient and in the adult
patient population.
both the general and immunocompromised popu-
lations [1,4–7,9]. Rates of viral infection among those
admitted to the hospital or ICU with CAP may range
upwards of at least 20% [1,4,6,7,9,12]. There are over
20 identified viral causes of respiratory infection
among the general population, most frequently
including (but not limited to) influenza, respiratory
syncytial virus (RSV), rhinovirus, enterovirus, coro-
navirus, human metapneumovirus, adenovirus and
parainfluenza [1,5,7,9]. Many of these are not rou-
tinely attributed to severe infection requiring hospi-
talization or ICU level stay, but our understanding of
the clinical implications of these viruses is evolving
and with it, our recognition of their role in severe
respiratory illnesses. When considering the immu-
nocompromised population, other viruses, particu-
larly those of the Herpes virus family, such as herpes
simplex and cytomegalovirus, may play an import-
ant clinical role and are not included in the current
multiplex panels; therefore, clinicians must be aware
of their absence and consider alternative diagnostics
if considering these viruses. In addition, evolving
viral illnesses, endemic, or rare, geographically
limited viral infections including Middle East Respir-
atory Syndrome-Coronavirus, Sin Nombre and some
Hantan virus are also not included in such multiplex
PCR tests; thus again, clinicians are required to
consider full differential diagnoses and utilize
additional diagnostics as needed based on their
regional epidemiology.
Treatment for viral infections is limited and has
largely focused on antivirals for influenza [1,9].
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Respiratory pathogen panels in the hospital Cawcutt et al.
There are some treatments available for Respiratory
syncytial virus (RSV); however, these are generally
reserved for specific subpopulations, for example
children and the immunocompromised. Herpes
virus infections, such as Herpes simplex virus
(HSV), Varicella zoster virus (VZV) and Cytomega-
lovirus (CMV), have antiviral options, but are not
the focus of the pathogen panels.
PATHOGEN PANELS: WHAT IS
AVAILABLE?
There are several respiratory viral pathogen plat-
forms currently approved by the United States Food
and Drug Administration (Table 1). All platforms are
FDA approved for use with nasopharyngeal swab
specimens; however, clinical laboratories may inde-
pendently verify other potential specimens includ-
&
ing bronchoalveolar lavage samples [2,8 ]. Each
platform is highly sensitive for all targets; however,
significant differences have been observed in some
studies between detection of influenza and adeno-
&
virus specifically [8 ,13–15]. Other differences
include work flow, hands on time, test run time,
throughput and random access. Although outside
the scope of this review, laboratories should consult
with clinical partners to identify the platform that
best fits their clinical needs and test volume. From
an epidemiologic standpoint, the Luminex NxTAG
(ThermoFisher Scientific, Pittsburgh, PA, USA) and
Biofire FilmArray (BioMérieux, Inc., Durham, NC,
USA) are the most comprehensive with 20 separate
targets detected. The NxTag does not include influ-
enza A subtype 2009 H1N1 or Bordetella pertussis but
does include human bocavirus and RSV A and B (the
FilmArray does not differentiate between RSV A and
B) (Table 1).
In regard to concordance with epidemiology,
this continues to evolve; however, the majority of
viruses implicated in viral CAP have been influenza,
RSV and rhinovirus. Other viruses such as human
metapneumovirus, coronaviridae and human boca-
virus have had been documented as causes of illness
(although the prevalence of actual pneumonia
caused by these viruses remains unknown), includ-
ing the evolving syndromes of both community-
acquired and hospital-acquired viral and bacterial
coinfection. No single study is able to comprehen-
sively determine all causes of bacterial and viral
respiratory infections, but if only one test for influ-
enza is available, the decision of whether subtype
2009 H1N1 is of concern, will define which test to
choose. Further, for more difficult-to-culture bac-
terial pathogens without an alternative molecular
test, there may be an increased value for Chlamydo-
phila and Mycoplasma testing.
www.co-infectiousdiseases.com 227
Respiratory infections

Table 1. Comparisons of multiplex respiratory pathogen panels

Biofire FilmArray Luminex NxTAG Luminex Verigene GenMark eSensor

Number of targets 20 20 16 14
VIRAL targets
  
Adenovirus

Adenovirus B/E

Adenovirus C
 
Coronavirus HKU1
 
Cornoavirus NL63
 
Coronavirus 229E
 
Coronavirus OC43
   
Metapneumovirus
 
Rhinovirus/Enterovirus
 
Rhinovirus
   
Influenza A
   
Influenza A/H1
   
Influenza A/H3
 
Influenza A/H1-2009
   
Influenza B
   
Parainfluenza virus 1
   
Parainfluenza virus 2
   
Parainfluenza virus 3
  
Parainfluenza virus 4

Respiratory syncytial virus
  
Respiratory syncytial virus A
  
Respiratory syncytial virus B

Bocavirus
BACTERIAL targets
 
Bordetella pertussis
 
Chlamydophila pneumoniae
 
Mycoplasma pneumoniae

Bordetella parapertussis/bronchiseptica

Bordetella holmesii

From literature including both upper (nasophar-
yngeal swab) and lower (BAL) specimens, discordant
results have been reported, and this may be of
particular interest among hospitalized and critically
ill patients. Upper airway testing may be negative or
represent viral colonization or shedding, whereas
lower respiratory tract samples may be more indica-
tive of actual infection, but this needs further
&
research evaluation [4,16 ].
UTILIZATION OF MULTIPLEX
RESPIRATORY PATHOGEN PANELS
(2) The ability to perform a multiplex panel on a
Pros
(1) There are several positive aspects to utilization
of multiplex respiratory pathogen panels. These
include a simplification of both diagnostic test
ordering for clinicians and laboratory work flow
as one test can provide results on multiple
pathogens that would otherwise have required
specific microbiological laboratory techniques
for identification based on historical standards
&
[2,8 ,10]. These panels also have increased diag-
nostic yield given that they are able to identify
pathogens not easily identified by traditional
&
laboratory techniques [2,3,8 ,10]. Further, there
is increased sensitivity of a PCR-based test as
opposed to culture or other microbiologic test-
&
ing techniques [1,3,8 ,10,11].
nasopharyngeal swab specimen may limit the
need for invasive procedures such as broncho-
scopy with bronchial alveolar lavage for some

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&
patients [16 ]. This could be a significant benefit
both from safety and cost perspectives for the
patient. The institutional cost of respiratory
pathogen panels as compared with prior multi-
faceted diagnostic algorithms have demon-
strated a range of potential cost savings [10,11].
(3) There may be other downstream benefits,
including improved outcomes, from using the
multiplex panels, although data are lacking
& &&
[8 ,17 ]. A more rapid diagnosis has been shown
to decrease inpatient length of stay for patients
&&
with positive viral test results [10,11,17 ]. There
may be other outcome benefits such as improved
antimicrobial stewardship with fewer antibiotics
prescribed and shorter treatment courses
&&
[10,11,17 ]. Earlier implementation of appropri-
ate isolation for positive viral illnesses may mit-
igate the risk of potential spread of infection to
other patients, visitors and healthcare workers
[3,5,9,10]. Finally, there may be additional cost
benefits, such as the cost reduction due to the
shorter hospital length of stay and antimicrobial
courses, despite the increased cost of the tests
&&
[17 ].
(4) From a public health perspective, there may be
benefits to defining which viral pathogens are
circulating in the community for epidemiologic
study and implementation of public health
practices as needed [3].
(5) There is also the inherent value for both the
physician and patient of ‘knowing’ the diagno-
sis. Defining the pathogen responsible for the
syndrome provides a sense of fulfilment of the
patient–clinician experience and a sense of clo-
sure. The lack of a clinical diagnosis can result in
further testing or treatment that may be
unnecessary in some settings.
Cons
(1) As with any test, the positives may be counter-
balanced by potential negative implications of
these tests. Clinicians may not have a clear
algorithm provided that details the appropriate
clinical situation to order multiplex pathogen
panels. As these are expensive tests, this could
result in significantly increased cost without
improvement of patient outcome. This raises
the question as to the cost–benefit ratio from
an institutional standpoint. Which specific
patient populations should be tested? Is it
actually cost-effective? Do institutions need to
develop individualized diagnostic algorithms
for utilization of such platforms?
(2) From the laboratory standpoint, the tests may
be easy to complete but may carry a higher risk
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Respiratory pathogen panels in the hospital Cawcutt et al.
of contamination if not handled properly. This
could result in potentially increased risk of false
&
positive test results [3,8 ].
(3) In a patient with chronic pulmonary disease,
immunocompromising condition or critically
ill patients with respiratory failure requiring
invasive mechanical ventilation, the nasophar-
yngeal swab test results may not provide accu-
rate diagnostics and add additional cost if the
ultimate decision is to proceed with broncho-
& &
scopy and bronchoalveolar lavage [8 ,16 ].
(4) For patients who have been hospitalized for
many days, these panels are often considered
to be of little diagnostic assistance because the
most likely respiratory pathogens are from noso-
comial sources. However, it is possible that even
in this population, there may be an under-
recognized presence of concomitant viral infec-
tions [4,18].
(5) Another potential concern, particularly in hos-
pitalized patients, is that these panels may not
indicate presence of bacterial or fungal coinfec-
tion or superinfection. The literature of coinfec-
tion continues to evolve and may portend
significant clinical importance as we move for-
ward [1,4,7,9]. A classic example of this are
hospitalized patients with concurrent infections
such as influenza and methicillin-resistant
Staphylococcus aureus pneumonia [6,12]. In
addition, viral or bacterial organisms can be
colonizers or pathogens, so discerning what to
treat may be more difficult. Some have advo-
cated the use of rapid diagnostics, procalcitonin
and cultures to assist with such complex de-
cisions [1,4,6,19,20]. Further, there are little
data on the ability of these panels to detect
more than one pathogen simultaneously.
(6) Beyond diagnosis of presumed infection, some
results may be positive but not clinically signifi-
cant by representing the presence of a viral shed-
ding or colonization [1,4,7]. Without knowledge
of the pathogenicity and presentations of the
viruses included on the panels, clinicians could
be misled into treating a viral pneumonia and
missing the bacterial pneumonia.
WHAT REMAINS UNCLEAR?
Pros and cons have been discussed regarding the
multiplex respiratory pathogen panels, yet there are
still specific areas in which we lack information.
First, there is a little overall knowledge of the respir-
atory ‘virome’ and how colonization and/or viral
shedding within particular patient populations
complicates test interpretation. Second, although
some outcome data exist, ongoing research is
www.co-infectiousdiseases.com 229
Respiratory infections
necessary to answer how best to implement and
manage the use of respiratory pathogen panels
within hospitalized patients. We also lack adequate
data on the best specimens to collect in varying
clinical settings, including many subgroup popu-
lations such as immunocompromised populations,
as well as on the number of patients who have
multiple concurrent infections such as viral and
bacterial respiratory infections as well as outcome-
related metrics [2–4]. Third, from a workflow status,
physician and laboratory satisfaction in test results
are poorly documented. Do physicians trust the
results enough to alter their management plans?
Or are we continuing to order excess testing for fear
of missing something? Lastly, this discussion begs
the question of whether we really need to know the
viral cause? If the majority of the pathogens
included in a multiplex panel would not result in
clinical intervention that would impact outcome,
does the cost outweigh the benefit?
CONCLUSION
Respiratory viral illnesses are ubiquitous in the
population and continue to demand clinician atten-
tion. The development of multiplex respiratory viral
pathogen panels for rapid detection of various
potential pathogens is appealing for clinical situ-
ations. However, the benefit of a rapid diagnostic
panel that cannot differentiate active infection from
colonization, or presence of coinfection, limits the
level of confidence clinicians can place in the util-
ization of such tests. Further, there is a paucity of
adult and specific population (e.g. immunocompro-
mised patients) data to drive robust evidence-based
decisions on the appropriate utilization of these
tests. Further research is needed to determine their
clinical utility. In the meantime, providers require
education on the potential benefits and risks of
relying on the results of these panels.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
230 www.co-infectiousdiseases.com
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