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How I Treat
How I treat respiratory viral infections in the setting of intensive
chemotherapy or hematopoietic cell transplantation
Alpana Waghmare,1-3 Janet A. Englund,1,2 and Michael Boeckh1,3
1
University of Washington, Seattle, WA; 2Seattle Children’s Hospital, Seattle, WA; and 3Fred Hutchinson Cancer Research Center, Seattle, WA
The widespread use of multiplex molecular diagnostics has led to a significant
increase in the detection of respiratory
viruses in patients undergoing cytotoxic
chemotherapy and hematopoietic cell
transplantation (HCT). Respiratory viruses
initially infect the upper respiratory tract
and then progress to lower respiratory tract
disease in a subset of patients. Lower
respiratory tract disease can manifest
itself as airflow obstruction or viral
pneumonia, which can be fatal. Infection
in HCT candidates may require delay of
transplantation. The risk of progression
differs between viruses and immunosuppressive regimens. Risk factors for progression and severity scores have been
described, which may allow targeting
treatment to high-risk patients. Ribavirin
is the only antiviral treatment option for
noninfluenza respiratory viruses; however, high-quality data demonstrating its
efficacy and relative advantages of the
aerosolized versus oral form are lacking.
There are significant unmet needs, including data defining the virologic characteristics and clinical significance of
human rhinoviruses, human coronaviruses, human metapneumovirus, and human bocavirus, as well as the need for new
treatment and preventative options.
(Blood. 2016;127(22):2682-2692)
Clinical significance
The epidemiology of respiratory virus infections among hematopoietic cell transplantation (HCT) recipients and patients undergoing
cytotoxic chemotherapy closely parallels the occurrence of infections in the community, although infections in immunocompromised
hosts are notable for prolonged viral shedding, higher rates of
pneumonia, late airflow obstruction, and mortality.1,2 These effects
are well documented for respiratory syncytial virus (RSV), parainfluenzaviruses (PIVs), influenza viruses, and, to some extent, human
metapneumovirus (HMPV), whereas less information is available on
human rhinoviruses (HRVs), human coronaviruses (HCoVs), and
human bocavirus (HBoV). Other viruses can manifest as pulmonary
infection; however, management of these viruses is beyond the scope
of this article.
One key feature of respiratory viruses in immunocompromised
patients is higher rates of progression from upper respiratory tract
infection (URTI) to lower respiratory tract infection (LRTI).
Assessing risk factors for progression has been a focus of recent
research to identify subjects who may benefit from early treatment.
The best data exist for RSV, where lymphopenia, smoking history,
high-dose total body irradiation (TBI), recipient age, APACHE II
score, and presence of copathogens are significant risk factors for
progression.3,4 Recently, scores have been proposed to increase the
precision of severity predictions for RSV and influenza viruses5-7;
however, these scores have not yet been validated. A meta-analysis
of risk factors for progression of PIV identified cytopenias and highdose steroids, among other factors.8 Limited data on risk factors for
progression of HMPV, HCoV, HRV, or HBoV exist.
LRTI can manifest as viral pneumonia and/or an airflow obstruction syndrome1,9; risk factors for mortality and airflow obstruction
have been examined for RSV, PIV, influenza, and HMPV.2,10
Mortality rates for LRTI with respiratory viruses range from 15%
to 40%; mortality-associated risk factors include stem cell source,
oxygen requirement, high-dose steroid use, APACHE II score, and
cytopenias.11-16 Prolonged shedding, lasting for weeks or months, is a
hallmark of respiratory virus infections in immunocompromised
patients.17,18 Prolonged shedding may result in continued risk for virus
transmission and is a rationale for continued isolation.19,20
Submitted January 29, 2016; accepted March 5, 2016. Prepublished online as
Blood First Edition paper, March 11, 2016; DOI 10.1182/blood-2016-01634873.
The online version of this article contains a data supplement.
2682
Case 1
A 10-year-old boy with relapsed T-cell acute lymphoblastic
leukemia presented for evaluation 14 days prior to a prescheduled
second unrelated matched cord blood transplant. A nasal respiratory
swab was sent for multiplex viral polymerase chain reaction (PCR)
for routine pretransplant evaluation documented HRV with a cycle
threshold (CT) of 27. The patient was asymptomatic, and chest
computed tomography was normal. On day 26, the patient began
conditioning with treosulfan and fludarabine; TBI (200 cGy) was
completed on day 21. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine (day 23) and mycophenolate
mofetil (day 0). On day 21, he developed a dry cough without other
symptoms; lung examination was normal. On day 0, his cough
worsened and nasal congestion developed, although his lungs
remained clear with normal oxygen saturations. Cells were infused,
but the patient developed respiratory distress 15 minutes into
infusion necessitating transfer to the intensive care unit and eventual
intubation. Chest radiography showed interval development of
diffuse bilateral patchy pulmonary opacities concerning for pulmonary
edema. Echocardiogram demonstrated acute systolic cardiac failure.
A repeat nasal swab documented HRV (CT 5 17). Despite initial
© 2016 by The American Society of Hematology
BLOOD, 2 JUNE 2016 x VOLUME 127, NUMBER 22
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BLOOD, 2 JUNE 2016 x VOLUME 127, NUMBER 22
improvements in respiratory status, his cardiac dysfunction deteriorated and he died on day 113 posttransplant with multiorgan failure.
Case 2
A 77-year-old female, 6 years after allogeneic HCT for acute
myeloid leukemia, presented to the emergency room with 3 days of
fever and upper respiratory symptoms, 1 day of shortness of breath,
and a new oxygen requirement (5 L/min via nasal cannula). On
physical examination, she had diminished and coarse breath sounds
and was slightly tachypneic. The patient had chronic GVHD treated
with prednisone (,0.5 mg/kg per day) and sirolimus. Absolute
lymphocyte count was 0.86 3 109/L and neutrophil count was
5.26 3 109/L. The patient had a smoking history. A nasal swab was
positive for RSV with a CT of 22.7. A chest radiograph was normal,
whereas chest computed tomography showed scattered foci of
ground glass infiltrates and centrilobular nodules. BAL was positive
for RSV with a CT of 27.2, and the patient was started on 2 g aerosolized ribavirin every 8 hours. She improved after 2 days and was
back on room air on hospital day 5, at which point she was switched to
oral ribavirin (600 mg 3 times a day) for an additional 7 days. She was
discharged on hospital day 6 and continues to do well as an outpatient.
These 2 cases present real clinical challenges in the management
of HCT candidates and recipients with respiratory viral infections.
The first case is relatively common and highlights our limited
understanding of risk factors for disease severity in HRV infection,
the impact of pretransplant infection on posttransplant outcomes, and
the risks of asymptomatic shedding. The second case raises several
important questions, including the impact of RSV LRTI very late
after allogeneic HCT compared with what we know about RSV
infection early after transplant and the correlation between radiographic
findings and outcomes. These issues are discussed further in the text.
Diagnostic considerations
Multiplex PCR testing is rapidly replacing conventional diagnostic
platforms such as viral culture and direct fluorescent antibody tests.
PCR is rapid, sensitive, and specific and can potentially quantify
viral load, although most commercial assays provide only
qualitative results. In the cases presented, CT values are inversely
related to viral load. Respiratory viruses are typically detected in
samples obtained from the upper respiratory tract (nasal wash
or swab) from symptomatic patients. Viruses can, however, be
detected in asymptomatic patients, as in case 1.21,22 Once clinical and/or radiographic evidence of LRTI is documented, we
routinely perform a bronchoalveolar lavage (BAL) to reliably
establish lower respiratory tract involvement and facilitate targeted
treatment of the virus and potential copathogens23,24 (supplemental
Table 1, available on the Blood Web site). Detection of virus in the
lower respiratory tract is associated with poorer outcome.13 In case 1,
the rapid clinical deterioration suggested multiple etiologies for
respiratory failure but a BAL was never performed to confirm HRV
LRTI, highlighting the limitations of empiric management and
lack of specific treatments. In case 2, the BAL was positive for RSV with
discrepant findings on chest imaging. It is not known how radiographic
presentation correlates with outcome. In case 2, infection occurred late
posttransplant, emphasizing the importance of primary care physicians
in obtaining a full diagnostic workup and considering consultation with a
transplant and/or infectious disease specialist.
HOW I TREAT RESPIRATORY VIRAL INFECTIONS
2683
Treatment
Several strategies exist for prevention and treatment of respiratory
viruses in HCT recipients and hematologic malignancy patients
(Figure 1). Here, we outline our center’s recommendations for
treatment of confirmed respiratory viral infections at the URTI and
LRTI stage.
RSV
Ribavirin is a broad-spectrum nucleoside analog with activity against
many RNA and DNA viruses that is available in an aerosolized, oral, or
IV form. Several retrospective studies, including a pooled analysis,
have identified ribavirin in any form as protective against disease
progression from URTI to LRTI and mortality in HCT recipients.4,25
In patients with leukemia, multivariate models demonstrated similar
effects.26 However, conclusive proof of efficacy from randomized
trials remains elusive.27 Oral and IV ribavirin showed promising
results in smaller case series28,29 and in a larger study of patients
receiving chemotherapy or transplant.30 A recent meta-analysis of
nonrandomized studies suggested a possible effect of oral ribavirin;
however, lack of randomized controls was a limitation in all studies.31
A randomized trial comparing oral and aerosolized ribavirin in HCT
recipients is ongoing.32
In HCT recipients with confirmed RSV LRTI, use of aerosolized
ribavirin was associated with decreased mortality, with a lower effect
seen with oral or IV ribavirin.11 Efficacy of ribavirin in hematologic
malignancy patients with LRTI has also been demonstrated,33,34
although larger studies are lacking. Current international guidelines
recommend aerosolized or systemic (oral or IV) ribavirin with IVIG in
patients with RSV URTI undergoing allogeneic HCT, allogeneic HCT
recipients with risk factors for progression to LRTI, and allogeneic
HCT patients with LRTI.20 Lymphopenia is a specific risk factor that
has been associated with progression to LRTI in several studies.3,5,35,36
At our institution, ribavirin is given to HCT recipients with RSV URTI
who have lymphopenia; additional risk factors, such as smoking history
and use of high-dose TBI, could be used to further risk-stratify patients.3
Given significant cost increases in aerosolized ribavirin in the United
States from $6105 per day in January 2013 to $29 953 per day in
September 2015 (average wholesale price)37 and lack of conclusive
evidence that aerosolized ribavirin is superior,11 we currently consider
the use of oral ribavirin in adults (;$25 per day depending on dosing
strategy). Using an immunodeficiency scoring index developed at the
MD Anderson Cancer Center, the patient in case 2 would have
moderate risk of LRTI and mortality and potentially an intermediate
benefit of ribavirin treatment.5 Interestingly, the patient presented
late (.5 years) after transplantation, and the benefit of treatment
(including ribavirin) is poorly studied in the late period. In a large MD
Anderson Cancer Center analysis, the latest death occurred ;4 years
after HCT,4 but it is unclear how complete the data capture was in this
very late posttransplant period. Our patient was transitioned from
aerosolized to oral ribavirin as soon as respiratory status improved.
Whether such moderate-risk patients or pediatric patients can be treated
with oral ribavirin alone is presently poorly defined.
The additional benefit of immunoglobulin products remains controversial. One retrospective review of 280 HCT recipients with RSV
URTI or LRTI showed benefit when used with ribavirin4; another study
in LRTI did not.11 The use of RSV-specific monoclonal antibody
palivizumab also appears to have variable efficacy and is very costly
in adults. A small nonrandomized unadjusted analysis in pediatric cancer
patients with RSV LRTI suggested a beneficial effect of adjunctive
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2684
BLOOD, 2 JUNE 2016 x VOLUME 127, NUMBER 22
WAGHMARE et al
Upper respiratory tract infection
Specimen: Nasal wash/swab
Diagnostic test: Multiplex PCR
Pre-emptive therapy
Lower respiratory tract infection
Figure 1. Therapeutic strategies for respiratory viral
infections posttransplant. *See supplemental Table 1.
Specimen: BAL fluid
Diagnostic test: Multiplex PCR +
diagnostic panel*
Treatment of disease
palivizumab or IVIG.38 In larger studies of HCT recipients with RSV
LRTI, we were unable to demonstrate improved outcomes with
adjunctive palivizumab11,12; we are not currently utilizing palivizumab
for treatment of RSV infection in any immunocompromised patients.
Influenza
Several guidelines have outlined the importance of early influenza
treatment in immunosuppressed patients.19,39 Shifting susceptibility
patterns of influenza viral strains have now rendered M2 inhibitors
(amantadine and rimantadine) ineffective, and neuraminidase inhibitors
(NAIs) are now first line for prophylaxis and treatment of influenza.
Though early therapy is associated with better outcomes,40 there may
be benefits even with delayed treatment.14,41 Available NAIs available
in the United States include oral oseltamivir, inhaled zanamivir, and IV
peramivir. Several reports in patients with leukemia or HCT recipients
demonstrate clinical efficacy with either oseltamivir or inhaled
zanamivir.14,42-45 Many mutations causing oseltamivir and peramivir
resistance, including the common H275Y mutation in A(H1N1)pdm09
influenza, do not lead to zanamivir resistance46; inhaled zanamivir has
been used to treat these resistant strains.47,48 IV peramivir used during
the 2009 pandemic in severely ill patients was well tolerated, with
evidence of recovery in most patients.49 In a randomized trial
comparing IV peramivir to oral oseltamivir, clinical outcomes were
similar.50 The drug is approved as a single dose; however, this is likely
inadequate in immunocompromised hosts, and the optimal duration of
therapy has not been determined. Longer treatment courses (10 days)
with oseltamivir or zanamivir have also been suggested given the
potential for recurrence and the median time for progression from
URTI to LRTI.40,51,52
Several case reports describe multidrug resistant strains in
immunocompromised patients53,54 and combination therapy has been
proposed. Triple-combination antiviral therapy with amantadine,
ribavirin, and oseltamivir was given to patients with severe influenza
A with oseltamivir or amantadine resistance.55-57 A randomized trial
is comparing triple-combination antiviral therapy with oseltamivir
alone in high-risk adults.58 Interestingly, a randomized trial in
hospitalized patients using oseltamivir/zanamivir combination showed
poorer outcomes than with monotherapy oseltamivir.59
Parainfluenza
In several retrospective studies, ribavirin had no impact on viral
shedding, symptom and hospitalization length, progression to LRTI,
or mortality in patients with PIV.60,61 Our own experience with
aerosolized ribavirin suggested a moderate reduction in overall
mortality, but not in death due to respiratory failure.13 A recent
systematic review evaluated aerosolized or systemic ribavirin in 10
retrospective studies of HCT recipients and hematologic malignancy
patients and found no difference in PIV-associated mortality or in
progression to LRTI.8 Given lack of evidence of clinical efficacy, we
currently do not use ribavirin for PIV infections. The impact of IVIG
alone remains to be determined, although IVIG in PIV LRTI cases
did not reduce mortality.13
Other respiratory viruses
The management of other respiratory viral infections in immunosuppressed patients is generally supportive (Table 1). Ribavirin has
shown efficacy against HMPV in vitro62 and in BALB/c mice,63 with
anecdotal reports describing ribavirin use in severe infection in
immunocompromised hosts (with and without IVIG).64-68 Lack of
controlled studies of ribavirin for HMPV therapy and the known
toxicities of therapy, including hemolytic anemia, limits its recommendation for use in immunocompromised hosts. The largest
nonrandomized series to date did not find an effect of ribavirin for
mortality, although a treatment bias cannot be excluded.16 Currently,
no approved antiviral agents exist for treatment of HCov, HRV,
HBoV, or enteroviruses, although some investigational agents are in
the pipeline (Figure 2). The use of IVIG has not been evaluated and is
not recommended. In case 1, the patient was presumed to have HRV
LRTI given the clinical circumstances; however, no specific
therapies directed at HRV could be offered.
Respiratory viruses in transplant candidates
Identification of respiratory viral infection pretransplantation raises
difficult management questions, as in case 1. International guidelines
recommend the deferral of conditioning therapy in patients with
respiratory infections in the setting of planned allogeneic HCT
transplants,19,20 with low strength of evidence. The decision to delay
transplant may be impacted by concern for underlying disease
progression and donor availability. Small retrospective studies have
provided limited data on the impact of transplant delay for viral
infections.69-72 A large prospective study evaluated clinical outcomes
associated with respiratory virus detection prior to allogeneic HCT.22
Various respiratory viruses were detected in 116 of 458 HCT patients
prior to transplantation; viral detection was associated with prolonged
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BLOOD, 2 JUNE 2016 x VOLUME 127, NUMBER 22
HOW I TREAT RESPIRATORY VIRAL INFECTIONS
2685
Table 1. Principles of prevention and treatment recommendations for HCT recipients
Virus
RSV
Prophylaxis
• Infection control procedures
Asymptomatic
shedding
Isolation
• Palivizumab for children #2 y
(during season)
URTI
LRTI
• Isolation
• Isolation
• Ribavirin for high-risk
• Low-risk situations: oral ribavirin†
situations*,†
• High-risk situations: aerosolized ribavirin
initially followed by oral†
• Supportive care
Influenza virus
• Infection control procedures
• Isolation
• Isolation
• Isolation
• Vaccination of contacts
• Oseltamivir
• Oseltamivir or zanamivir
• Oseltamivir or zanamivir
• Vaccination 2-3 weeks before
• Consider combination therapy with rimantadine
or zanamivir
transplant in recipients of
(only Influenza A) and/or ribavirin
• Consider IV peramivir if mechanically ventilated
nonmyeloablative conditioning‡
• Vaccination of HCT recipients as early as
• Supportive care
possible, depending on timing of flu season
Parainfluenza virus
Infection control procedures
Isolation
• Isolation
• Isolation
• Consider reduction of
• Supportive care
steroid dose
Metapneumovirus
Infection control procedures
Isolation
Isolation
• Consider ribavirin if mechanically ventilated†
• Isolation
• Supportive care
• Consider ribavirin if mechanically ventilated†
Rhinovirus
Infection control procedures
Isolation
Isolation
• Isolation
Coronavirus
Infection control procedures
Isolation
Isolation
• Isolation
Bocavirus
Infection control procedures
Isolation
Isolation
• Isolation
• Supportive care
• Supportive care
• Supportive care
Recommendations from the Fred Hutchinson Cancer Research Center, University of Washington, and Seattle Children’s Hospital (the Seattle Cancer Care Alliance).
*Due to recent price increases, restrictions have been put in place for the use of aerosolized ribavirin.
†Benefit and dosing of oral ribavirin in pediatric patients is not clearly understood.
‡Exceptions may be made in certain immunodeficiencies.
hospitalization and lower survival at day 100. Interestingly, this risk
was also present in patients with HRV alone, contrary to smaller
studies suggesting pretransplant HRV detection does not impact
outcomes.73 Symptomatic patients with viruses detected had an
increased risk of mortality compared with those without a virus
detected; this risk was not seen in asymptomatically infected patients.
These data support delay of allogeneic transplantation in symptomatic
patients, even those with less “pathogenic” viruses such as HRV. The
number of HCoV and HBoV cases in this study was too small to
determine an effect. These data should ideally be validated in larger,
multicenter studies. The impact of other factors such as a viral-specific
risk scores and viral load need to be evaluated. Our current practice is
to perform respiratory viral diagnostics on all symptomatic HCT
candidates and recommend delay of transplantation if feasible
(Table 2). In pediatric patients, diagnostic PCR is done on all
transplant candidates regardless of symptoms due to higher rates of
virus acquisition and shedding in children. Whether asymptomatic
shedding requires delay of transplantation requires further study;
case 1 demonstrates a problematic situation in which asymptomatic
infection was associated with cardiopulmonary death. Though death
was likely due to multiple factors, the respiratory infection could
have contributed.
Effect of steroid therapy
We generally recommend reduction of immunosuppressive therapy
as allowed by the particular clinical situation. However, the relative
contribution of steroids and the dose effect may vary by virus
(Table 3).3,11,13,14,16,45,74 Interestingly, an inverse relationship
between steroid therapy (.1 mg/kg per day) and need for mechanical
ventilation for influenza may exist; this observation has not been
validated.14 Overall, low doses of steroids (,1 mg/kg per day) may
not significantly impact progression to LRTI and/or mortality. The
patient presented developed complications of HRV infection early
posttransplant and thus was not on steroids for GVHD. If steroids had
been initiated, without specific data on HRV, we would recommend
lowering the dose to ,1 mg/kg per day.
Prevention strategies
Infection control practices
Several consensus guidelines outline specific recommendations for
the prevention of respiratory viral infections through infection
prevention and control practices.19,20,39,75 Patients with suspected
respiratory viral infections (based on presence of symptoms) should be
empirically placed on contact plus droplet precautions and diagnostic
testing promptly initiated. Hand hygiene is extremely important, as
most respiratory viruses are transmitted through direct contact.
Symptomatic health care workers should be restricted from patient
contact and symptomatic visitors should be actively excluded from
visitation until symptoms are completely resolved.76 Importantly,
prolonged shedding frequently occurs in immunocompromised
individuals17,21,77-79; thus, guidelines for HCT recipients recommend appropriate isolation be maintained for at least the duration
of clinical illness, hospitalization, or viral shedding to prevent
transmission.19
Influenza vaccination
Inactivated influenza vaccine (IIV) is recommended for all patients
$6 months of age with hematologic malignancies, although
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2686
BLOOD, 2 JUNE 2016 x VOLUME 127, NUMBER 22
WAGHMARE et al
Table 2. Recommendations for respiratory viral infections before
transplantation
Virus
Recommendation for URTI
Recommendation for LRTI
RSV
Delay transplant, if possible;
Delay transplant; consider
if not possible to delay,
ribavirin if delay is not
consider oral ribavirin*
Influenza virus
feasible (anecdotal data)*
Delay transplant if possible
Delay transplant and treat†
and treat†
If not possible to delay, treat†
Parainfluenza virus
Delay transplant if possible
Delay transplant; consider
If not possible to delay,
ribavirin if delay is not
supportive care
Metapneumovirus
feasible (anecdotal data)*
Delay transplant if possible
Delay transplant; no data on
ribavirin
Rhinovirus
of various pathogens including influenza.87-89 Influenza vaccination is
also recommended for all family members, close contacts, and health
care workers caring for immunocompromised patients. LAIV is not
recommended for household contacts of HCT recipients ,2 months
posttransplant or with severe immunosuppression due to GVHD.80
However, if LAIV is given to persons caring for severely immunosuppressed patients, Centers for Disease Control and Prevention guidelines
recommend avoidance of contact for 7 days following vaccination.90
Delay transplant if possible;
Delay transplant, if feasible
no data for autologous
transplant
Coronavirus
No data
No data
Bocavirus
No data
No data
*Benefit and dosing of oral ribavirin in pediatric patients is not clearly understood.
†See influenza treatment section in Table 1.
Infectious Diseases Society of America guidelines do not recommend vaccination in patients receiving intensive chemotherapy such
as induction or consolidation chemotherapy for acute leukemia
or those who have received anti–B-cell antibodies in the last
6 months.39,80 Though immune responses are generally lower in
children with malignancies,81 a recent Cochrane review demonstrated reductions in respiratory infections and hospitalization;
however, the quality of evidence is low.82 In adults with cancer,
vaccination is associated with lower mortality, although data are
observational and randomized trials are lacking.83,84 Patients .65
years of age may demonstrate reduced antibody responses to
influenza vaccination and use of high-dose IIV formulations reduced
laboratory-confirmed influenza in a large multicenter trial.85 We
offer high-dose IIV to patients .65 years; of note, data in
immunosuppressed patients are limited. Live attenuated influenza
vaccine (LAIV) should not be used for immunosuppressed patients.19,80
One exception would be in an outbreak setting in which LAIV is
determined to be a more effective option due to strain type. We offer
quadrivalent vaccine when available.
Timing of influenza vaccination following HCT depends on local
epidemiology, but immune responses are likely more effective later
after HCT. HCT recipients aged $6 months should receive IIV
annually starting 6 months after transplant or starting 4 months after
transplant during a community outbreak of influenza80,86 with second
doses recommended for children and considered for many adults,
depending on time from transplant. Pretransplant vaccination may be
appropriate in reduced-intensity HCT, where host immunity is
expected to extend into the early transplant period; several studies
have shown protective antibody levels with pretransplant vaccination
Influenza chemoprophylaxis
Postexposure chemoprophylaxis with NAIs should be considered in
immunosuppressed patients who are in close contact with confirmed
influenza cases or during influenza outbreaks.19 In outbreak settings,
HCT recipients should receive vaccine immediately if $4 months
posttransplant, and chemoprophylaxis with oseltamivir or zanamivir
should be initiated for 2 weeks after vaccination while immunity
develops.19 Chemoprophylaxis is also recommended for patients
,24 months after HCT or who are $24 months post-HCT and
substantially immunocompromised, regardless of vaccination
history.91,92 Oseltamivir resistance may emerge when using widespread prophylaxis93,94; drug resistance patterns of circulating strains
should be considered when initiating prophylaxis and/or preemptive
therapy.
Palivizumab. Palivizumab is approved for prevention of RSV
bronchiolitis in high-risk immunocompetent infants (age #2 years).95
Palivizumab may be considered in pediatric HCT recipients #2 years
during RSV season; prophylaxis is not indicated in older children or
adults.19,20 Palivizumab can be considered in outbreak settings96,97 but
would come at substantial cost, especially in adults.
Novel therapies
Antivirals
Several antivirals are in development for treatment of RSV infection,
including in immunocompromised patients and infants (Figure 2). GS5806 is an oral RSV entry inhibitor that demonstrated reductions in viral
load and clinical severity in phase 1 studies.98-100 Phase 2 trials are
underway in hospitalized and adults transplant recipients.101-104 ALS8176, a nucleoside analog targeting RSV polymerase, demonstrated
reduction of viral load and decreased disease severity in a human
challenge model.105 Studies in hospitalized infants are underway.106
ALN-RSV01, a small interfering RNA, was effective in a challenge
model107 and reduced cumulative daily symptom scores in lung
transplant recipients.108,109
Influenza antivirals continue to be an important area of
investigation.110 IV zanamivir used under the US Food and Drug
Administration (FDA) eIND may be useful in strains with H275Y
Table 3. Role of corticosteroid treatment in progression of respiratory viral illnesses
Progression
Mortality
Virus
Steroid dose per day
Risk
HR (95% CI)
P value
Steroid dose per day
Risk
HR (95% CI)
P value
RSV
.2 mg/kg
1/2
1.4 (0.4-5.2)
.193
.2 mg/kg
111
3.3 (1.7-6.3)
,.00111
Influenza
$1 mg/kg
1/2
0.8 (0.2-2.4)
.6045
$1 mg/kg
1/2
1.1 (0.3-3.5)
.8745
PIV
.2 mg/kg
111
4.6 (1.2-17.0)
.0274
.2 mg/kg
111
3.2 (1.5-7.2)
.00413
Any steroids
111
5.0 (1.8-14)
.00216
$1 mg/kg
1111
7.1 (2.3-22)
,.00116
HMPV or RSV
Not reported in the combined cohort
CI, confidence interval; HR, hazard ratio.
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BLOOD, 2 JUNE 2016 x VOLUME 127, NUMBER 22
HOW I TREAT RESPIRATORY VIRAL INFECTIONS
Figure 2. Ongoing clinical trials for treatment of
respiratory viral infections on selected agents.
*Studies ongoing in patients with hematologic malignancy or HCT recipients.
Preclinical
Phase I
Phase II
2687
Phase III
GS-5806 (Presatovir)* GILEAD
ALS-8176 ALIOS
RSV
ALN-RSV01 ALNYLAM
MEDI8897 mAb MEDIMMUNE
PIV
DAS181 (Fludase)* ANSUN
IV Zanamivir GlaxoSmithKline
Favipiravir TOYOMA CHEMICAL
Nitazoxanide ROMARK
IV Hyperimmune Immunoglobulin NIH
Anti-Influenza Immune Plasma NIH
Influenza
Laninamivir BIOTA
DAS181 (Fludase) ANSUN
MHAA4549A mAb GENENTECH
CR6261 mAb JANSSEN
MEDI8852 mAb MEDIMMUNE
TCN-032 mAb THERACLONE
Rhinovirus
Enterovirus
oseltamivir resistance.111 In healthy individuals, an open-label phase
2 study demonstrated good safety and a reduction in viral load 112;
a randomized trial comparing efficacy to oseltamivir is nearing
completion.113 Laninamivir (prodrug laninamivir octanoate) is a
single-dose inhaled agent approved in Japan; in a large randomized
trial, laninamivir octanoate reduced time to illness alleviation
and was effective against oseltamivir resistant virus.114 Phase 3
results of favipiravir, an inhibitor of the RNA-dependent RNA
polymerase complex, are forthcoming. 115 Nitazoxanide reduced
symptom duration in phase 2b/3 trials in adults and adolescents with
uncomplicated influenza116; a phase 3 trial is underway.117
DAS181 is a recombinant fusion protein that cleaves sialic acid
residues from respiratory epithelial cell surfaces and prevents influenza
viral fusion and entry.118-121 A phase 2 trial demonstrated reduction in
influenza viral load in healthy adults122; no data for immunocompromised hosts exist. DAS181 is also active against PIV and was used to
treat several immunocompromised patients with PIV infection.123-126
A phase 2 randomized trial of DAS181 in immunocompromised hosts
with PIV LRTI is underway.127
Several agents have shown efficacy against HRV and enteroviruses.
Oral pleconaril, a capsid binder, was effective in 2 randomized trials128;
however, its future development remains unclear after initial FDA
Vapendavir BIOTA
Omalizumab (Xolair) GENENTECH
rejection due to concerns regarding viral resistance and reduced
effectiveness of oral contraceptives.129 Vapendavir, another capsid
binder, decreased HRV viral load in an experimental infection model
in healthy volunteers130 and decreased symptom severity in mild
asthmatics131; a trial in moderate to severe asthmatics with HRV
is underway.132 Some studies suggest HRV-C species be inherently
resistant to capsid binders,133,134 which may have implications for
drug development.
Antibody-based therapy
High-titer RSV immunoglobulin was evaluated in phase 2 trials in
immunocompromised adults with RSV URTI and LRTI135,136; further
study is needed to determine efficacy. Motavizumab, a humanized
IgG1 monoclonal antibody with higher affinity for RSV than
palivizumab, failed to show a reduction of viral load or illness
severity in hospitalized infants with RSV LRTI137 but reduced health
care attended visits in healthy infants.138 MEDI8897 is a monoclonal
antibody and promising prophylactic agent with an extended half-life
currently in phase 1b/2a trials in healthy preterm infants.139
Several monoclonals are under investigation for influenza with
and without concomitant oseltamivir (Figure 2).140-143 IV hyperimmune
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WAGHMARE et al
immunoglobulin increased hemagglutination inhibition antibody
responses,144 and a phase 3 trial is underway.145 High- versus low-titer
anti-influenza plasma for treatment of severe influenza A is also under
evaluation.146
Omalizumab, an anti-IgE monoclonal antibody FDA approved for
treatment of moderate to severe allergic asthma, is in phase 2 trials in an
HRV challenge model.147
HCT and non-HCT immunosuppressed patients. Validation of
proposed severity scores, identification of laboratory biomarkers for
progressive disease, and more data on the impact of pretransplant
infections are critically important for respiratory viruses. Additionally, the mechanisms of acquisition and determinants of transmission
need further study, and these will inform infection prevention
strategies. Finally, development of new therapeutics and vaccines
and systematic evaluation of new and existing treatments are needed.
Vaccines
Several candidate vaccines for RSV and PIV are being evaluated
in infants, children, healthy and pregnant women, and older
adults,27,148-152 including bivalent RSV/PIV vaccines.153,154 RSV
vaccine trials are underway in healthy women and older adults.149
Several vaccine candidates are being evaluated in animals and
humans for HMPV. 155 Both donor and recipient vaccination
strategies should be studied in the HCT setting based on encouraging
results herpesvirus vaccines.156-159
Adoptive T-cell therapy
Adoptive T-cell therapy with pathogen-specific T cells is an emerging
field.160,161 Recent evidence of broad-spectrum T cells for treatment of
multiple herpes-group viruses has been described.162 As cell processing
and expansion technology improves, this therapy has the potential to
impact outcomes in HCT recipients with respiratory viral infections.
Future directions
Diagnostic information of respiratory virus infections is dramatically
increasing due to widespread availability of multiplex PCR
testing, resulting in better characterization of disease burden while
simultaneously creating new challenges for clinicians as demonstrated in the cases. Although most infections are mild and selflimited, severe clinical disease causing hospitalization, critical
illness, chronic lung disease, and death can occur. Although these
complications are well characterized for RSV, PIV, and influenza
after HCT, further study is needed for other respiratory viruses in
Acknowledgments
The authors thank Lisa Chung and Ryan Owens for their graphic
design support, and Steve Pergam for additional infection prevention input.
This work was supported in part by the National Institutes of
Health (NIH) National Institute of Allergy and Infectious Diseases
(K23AI114844), and the NIH National Heart, Lung, and Blood
Institute (K24HL03294).
Authorship
Contribution: A.W., J.A.E., and M.B. researched the topic and wrote
the paper.
Conflict-of-interest disclosure: J.A.E. received research support
from Gilead Sciences, Alios BioPharma, GlaxoSmithKline, Pfizer
Inc., Roche, and Chimerix Inc., and served as consultant for Pfizer
Inc. and Gilead Sciences. M.B. received research support from
Gilead Sciences, Ansun Biopharma, GlaxoSmithKline, and Chimerix Inc., and served as a consultant for Gilead Sciences, Biota
Pharmaceuticals, Chimerix Inc., Humab Biomed, and Pulmocide
Ltd. A.W. declares no competing financial interests.
Correspondence: Michael Boeckh, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, Mailstop E4-100, Seattle,
WA 98109; e-mail: [email protected].
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2016 127: 2682-2692
doi:10.1182/blood-2016-01-634873 originally published
online March 11, 2016
How I treat respiratory viral infections in the setting of intensive
chemotherapy or hematopoietic cell transplantation
Alpana Waghmare, Janet A. Englund and Michael Boeckh
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