Risk factors and containment of respiratory syncytial virus outbreak in a hematology and transplant unit

Abstract

Respiratory syncytial virus (RSV) usually causes self-limiting upper respiratory tract infections, but can be associated with severe lower respiratory tract infection disease (LRTID) in infants and in patients with hematologic malignancies. We have analyzed the risk factors and the measures for containment within an outbreak of nosocomial RSV infections in a hematology and SCT unit. A total of 56 patients were affected (53 RSV-A and 3 RSV-B) including 32 transplant patients (16 allogeneic and 16 autologous). Forty (71%) of the 56 patients suffered from LRTID and 14 (35%) of the patients with LRTID subsequently died. However, because of concomitant infections with fungal and bacterial pathogens, the impact of RSV on the fatal outcome was difficult to assess. Multivariate analysis showed that low levels of IgG were significantly associated with fatal outcome (P=0.007), treatment with oral ribavirin represented a protective factor (P=0.02). An extremely protracted viral shedding was observed in this cohort of patients (median=30.5 days, range: 1-162 days), especially pronounced in patients after allogeneic transplantation (P=0.002). Implementation of rigorous isolation and barrier measures, although challenged by long-term viral carriers, was effective in containment of the outbreak.Bone Marrow Transplantation advance online publication, 1 July 2013; doi:10.1038/bmt.2013.94.

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OPEN
ORIGINAL ARTICLE
Risk factors and containment of respiratory syncytial virus
outbreak in a hematology and transplant unit
N Lehners
1
, P Schnitzler
2
, S Geis
2
, J Puthenparambil
1
, MA Benz
2
, B Alber
1
, T Luft
1
, P Dreger
1
, C Eisenbach
1
, C Kunz
3
,
A Benner
3
, U Buchholz
4
, E Aichinger
4,5
, U Frank
2
, K Heeg
2
,ADHo
1
and G Egerer
1
Respiratory syncytial virus (RSV) usually causes self-limiting upper respiratory tract infections, but can be associated with severe
lower respiratory tract infection disease (LRTID) in infants and in patients with hematologic malignancies. We have analyzed the risk
factors and the measures for containment within an outbreak of nosocomial RSV infections in a hematology and SCT unit. A total of
56 patients were affected (53 RSV-A and 3 RSV-B) including 32 transplant patients (16 allogeneic and 16 autologous). Forty (71%) of
the 56 patients suffered from LRTID and 14 (35%) of the patients with LRTID subsequently died. However, because of concomitant
infections with fungal and bacterial pathogens, the impact of RSV on the fatal outcome was difficult to assess. Multivariate analysis
showed that low levels of IgG were significantly associated with fatal outcome (P¼0.007), treatment with oral ribavirin represented
a protective factor (P¼0.02). An extremely protracted viral shedding was observed in this cohort of patients (median ¼30.5 days,
range: 1–162 days), especially pronounced in patients after allogeneic transplantation (P¼0.002). Implementation of rigorous
isolation and barrier measures, although challenged by long-term viral carriers, was effective in containment of the outbreak.
Bone Marrow Transplantation (2013) 48, 1548–1553; doi:10.1038/bmt.2013.94; published online 1 July 2013
Keywords: allogeneic transplantation; RSV; risk factors; outbreak; containment
INTRODUCTION
Respiratory syncytial virus (RSV) is an enveloped single-stranded
RNA virus of the family Paramyxoviridae. It is a common pathogen
in children and might induce severe lower respiratory tract
infection disease (LRTID), especially in infants. Nearly all children
have been infected by the age of 2, yet no lasting immunity is
acquired.
1
RSV is rapidly transmitted by inhalation of droplets and
can stay viable for up to 6 h outside of the patient.
2
The diagnostic
gold standard is viral culture, however, detection of viral RNA in
respiratory specimens by reverse transcription PCR represents a
faster and more sensitive approach.
3
Although RSV is usually a self-limiting disease causing only mild
symptoms of upper respiratory tract infection disease (URTID) or no
symptoms at all,
4
it may be associated with severe LRTID in elderly
or immunocompromised adults.
5,6
Morbidity and mortality rates
reported in the literature are heterogeneous, the relevance of RSV
infections in terms of outcome for patients undergoing autologous
or allogeneic SCT ranging from none
7,8
to a mortality rate of up to
78%.
9–14
The impact of RSV on fatal outcome in this often multi-
morbid patient population might be difficult, if not impossible, to
assess. Aerosolized ribavirin is the only Food and Drug
Administration-approved drug for the treatment of severe RSV
infection in children.
15,16
The use of aerosolized ribavirin to treat
RSV infection in adults has remained controversial and clinical trials
are lacking. Even fewer data are available regarding oral ribavirin.
However, a recent pooled analysis suggests some efficacy.
17
Several nosocomial outbreaks of RSV infections on pediatric
wards
18–20
as well as in adult hematology and transplantation
units
13,21–25
have been described in the literature.
Here we report an outbreak of nosocomial RSV infections
in an oncology and SCT unit from December 2011 to March 2012,
which affected a total of 56 patients. The virological aspects of this
outbreak have been recently published by Geis et al.
26
We now
present an analysis from a clinical point of view and aim to identify
risk factors for LRTID and fatal outcome, to evaluate the
contribution of RSV infection to the fatal cases observed and to
define strategies for management as well as containment of RSV
infections in immunocompromised patients.
MATERIALS AND METHODS
Study site, RSV diagnostics and treatment
The medical center of the University of Heidelberg is a tertiary care referral
center. The Department of Hematology–Oncology consists of two inpatient
wards where normal and high-dose chemotherapy including autologous
blood SCT are performed, one intensive care ward for critically ill patients not
requiring mechanical ventilation and an allogeneic transplant unit. In 2011, a
total of 1825 cases were treated, 227 autologous and 114 allogeneic SCTs
were performed.
Before the described outbreak, screening for RSV infections was not
standard and RSV was only tested for if specifically requested by the
physician. Diagnosis of RSV infection was performed via reverse
transcription PCR amplification of specific viral RNA in respiratory
specimens, that is, nasal or throat swabs, tracheal secretions or broncho-
alveolar lavage, and was characterized as either RSV-A or RSV-B. In the
majority of patients, the RSV strain was further characterized by
sequencing of the second variable region of the G gene. Details on
reverse transcription PCR and sequencing are provided by Geis et al.
26
During the outbreak, throat swabs were established as standard
1
Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany;
2
Department of Infectious Diseases, University of Heidelberg, Heidelberg, Germany;
3
Division
of Biostatistics, German Cancer Research Center, Heidelberg, Germany;
4
Department of Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany and
5
State Health
Office of Baden-Wuerttemberg, Stuttgart, Germany. Correspondence: Professor AD Ho, Department of Internal Medicine, University of Heidelberg, Im Neuenheimer Feld 410,
Heidelberg 69120, Germany.
E-mail: anthony_dick.ho@urz.uni-heidelberg.de
Received 18 January 2013; revised 10 May 2013; accepted 14 May 2013; published online 1 July 2013
Bone Marrow Transplantation (2013) 48, 1548– 1553
&
2013 Macmillan Publishers Limited All rights reserved 0268-3369/13
www.nature.com/bmt

diagnostic material for screening purposes, being readily obtainable and
practicable.
No standard treatment existed for RSV infections in adults. At the peak
of the outbreak, a 2 week course of oral ribavirin in a weight adapted
dosage (o65 kg body weight: 800 mg daily; 65–80 kg body weight:
1000 mg daily; 480 kg body weight: 1200 mg daily; total daily dose
administered in two divided doses) was recommended for all patients,
independently of the presence of LRTID. Aerosolized ribavirin was not used
for safety reasons because of its suspected teratogenicity for the
surroundings.
27
During ribavirin therapy, patients were checked twice
weekly for signs of hemolytic anemia as the major reported side-effect.
28
In
cases of significant hypogammaglobulinemia, patients might additionally
receive polyvalent Ig preparations (0.2–0.4 g/kg body weight) at the
discretion of the attending physician.
Outbreak management
RSV-infected patients were isolated in single rooms or cohort isolated. They
were considered infectious until three consecutive throat swabs were tested
negative covering a period of 2 weeks. Contact patients were isolated in
single rooms until they tested negative at the end of the 2–8 days incubation
period.
29
RSV-negative inpatients were regularly screened for RSV infections.
Infected patients were repeatedly retested in order to monitor viral shedding.
Barrier measures were severely reinforced. Disposable gowns, gloves and
filtering facepieces (FFP2) were to be worn when entering patient rooms.
Health-care staff with respiratory symptoms were suspended from work until
anegativeRSVtestwasobtained.
Retrospective analysis
Charts of all RSV-infected hematologic inpatients from 1 September 2011 to
30 March 2012 were thoroughly reviewed. Patients were categorized as either
asymptomatic/URTID or LRTID according to the adapted criteria by the
European Centre for Disease Prevention and Control applied in the recent
guidelines by the 4th European Conference on Infections in Leukaemia
(ECIL-4).
30
Aplasia was defined as total leukocyte count o1000/mL,
hypogammaglobulinemia as polyclonal IgG o6g/L. Time to RSV clearance
was calculated from first to last positive RSV test, patients who were only
tested once were excluded for analysis of this end point. Patient movements
and bed occupancies were analyzed to identify a possible chain of infection.
Statistical analysis of potential risk and protective factors in regard to
respiratory disease, fatal outcome and duration of RSV positivity was
performed. Single risk/protective factors (delineated in Table 3) for
development of LRTID as well as for fatal outcome were analyzed using
univariate w
2
tests for binary variables and univariate Wilcoxon tests for
continuous variables. Possible influence factors regarding duration of RSV
positivity were analyzed by Kruskal–Wallis tests in the case of binary
variables and by Spearman’s rstatistics in the case of continuous variables.
For multivariate analysis, a reduced set of potential influence factors
was considered: age (X65 years versuso65 years), allogeneic versus
autologous transplantation, pre-existing respiratory disease, duration of
aplasia (4versus p10 days), hypogammaglobulinemia and treatment
with ribavirin. Penalized logistic regression models
31
were adapted for the
outcomes LRTID, fatal disease and RSV positivity. The outcome RSV
positivity was dichotomized in 4or p1 week in the multivariate model.
In all tests, P-valueso0.05 were regarded as significant.
RESULTS
Outbreak and monitoring of RSV
From 30 December 2011 to 22 March 2012 an outbreak of
nosocomial RSV infections occurred at the Department of
Hematology–Oncology of the University of Heidelberg. RSV-A RNA
was detected in bronchial specimens of two patients with LRTID on
two different wards on 30 December. During the first 2 weeks of
January, systematic RSV screening of all inpatients and personnel was
performed revealing further 16 RSV-infected patients, 14 of them
with signs of LRTID and 1 infected physician out of 209 employees.
Barrier measures were reinforced and elective admissions were
suspended. Over the following weeks, the number of newly
diagnosed RSV infections decreased with the last infection occurring
on 22 March.
Systematic review of virological test results as well as
retrospective tests of stored respiratory specimens identified
10 patients with RSV infection before the recognition of the
outbreak (2 in November and 8 in December), 1 of them was
infected as early as 12 November. Retrospectively, this might
represent the actual index case. In summary, 56 inpatients were
diagnosed with RSV infection from November 2011 to March
2012, 53 with RSV-A and 3 with RSV-B.
The strict criteria of a nosocomial case, that is, diagnosis of RSV
infection X3 days after hospital admission taking into account the
2–8 days incubation period,
29
were met by 40 patients. However, a
further eight patients had a prior stay on one of the hematologic
wards or were treated at the chemotherapy day care unit within
4 weeks of the recent admission. A timeline of new cases is given
in Figure 1.
Morbidity and mortality
A total of 16 of the 56 RSV-infected patients were asymptomatic or
showed only minor signs of URTID. Forty patients developed a
LRTID, 13 of them had progressed from prior URTID, whereas 27
had already symptoms of LRTID at the time of RSV diagnosis. The
patients’ characteristics are summarized in Table 1. Oral ribavirin
was administered to 36 patients. Treatment with oral ribavirin was
generally well tolerated and no side effects requiring medical
intervention or dose reduction were observed. At the discretion of
the attending physician, 14 patients received i.v. Ig preparations in
addition.
Of all RSV-infected patients, 32 underwent SCT (16 allogeneic
and 16 autologous). RSV infection was diagnosed in 24 patients
after engraftment, 8 patients were infected during aplasia. The
median time to leukocyte recovery (that is, leukocytes 41000/mL)
was 13.5 days (range 0–27) and 14.5 days (range 10–47) for post-
and pre-engraftment infected patients, respectively.
Among the 40 patients with LRTID, 14 patients died 1 to 134
days (median 15 days) after diagnosis of RSV. Six underwent SCT
(three allogeneic and three autologous), two of them were
infected before engraftment. Concomitant infections with fungal,
bacterial and other viral pathogens were present in 11 patients. In
addition, a high proportion of these patients suffered from
advanced, resistant disease or from severe comorbidities such as
steroid-refractory GVHD. The details are delineated in Table 2. At
the time of death, one patient had already cleared the virus (that
is, tested repeatedly negative) but still required mechanical
ventilation and two tested negative once.
We have performed a retrospective analysis to determine if the
development of LRTID as well as fatal outcome was associated
with any of an extensive list of possible influence factors.
Univariate analysis showed that duration of aplasia was
52 4 8
Calendar week
0
2
4
6
8
10
12
14
Patients
Community acquired
Nosocomial
46 48 50 2 6 1210
Figure 1. Epidemiology of RSV cases. The number of newly
diagnosed patients with RSV infection is given for each calendar
week November 2011 to March 2012 with nosocomial cases shaded
in light grey, community acquired cases in dark grey.
RSV infections in hematology and transplant unit
N Lehners et al
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significantly associated with development of LRTID (P¼0.0001).
Hypogammaglobulinemia was a significant risk factor for fatal
outcome (P¼0.03), whereas therapy with ribavirin was a protective
factor (P¼0.02). Details of univariate analysis are given in Table 3.
Multivariate analysis confirmed hypogammaglobulinemia to be
a risk factor (P¼0.007) and treatment with ribavirin a protective
factor against fatal outcome (P¼0.02). In addition, a negative
trend for fatal outcome was seen for pre-existing respiratory
disease (P¼0.08). Age and transplant status remained without
significant influence. In regard to development of LRTID, no factor
reached statistical significance, but a trend was seen for aplasia
410 days (P¼0.08). For details on multivariate analysis refer to
Table 4.
An extensively protracted viral shedding was noted in this
group of patients. The median duration of positive RSV detection
using PCR was 30.5 days (range: 1–162 days) in 51 patients who
were tested at least twice. The risk factors that were significantly
associated with duration of RSV positivity in univariate analysis
were hypogammaglobulinemia (P¼0.01) and allogeneic trans-
plantation (P¼0.04). In multivariate analysis, allogeneic transplan-
tation correlated significantly (P¼0.002) with duration of RSV
positivity by 41 week. Interestingly, therapy with ribavirin was
also associated with prolonged viral shedding (P¼0.01). Details of
multivariate analysis are given in Table 5.
DISCUSSION
This is the largest outbreak of RSV infections documented in the
literature, affecting a total of 56 patients. Several smaller outbreaks
have been reported from adult hematology or transplant
units
13,21–25
as well as from pediatric wards and neonatal
intensive care units.
18–20
A unique aspect of this retrospective
analysis was the fact that all inpatients were repeatedly screened
for the presence of RSV infection. In addition, retrospective
analysis of stored respiratory specimens covering a time period of
over 6 months was performed enabling us to provide a detailed
Table 1. Characteristics of RSV-infected patients
RSV-infected patients (n¼56)
Age (median (range)) 57.5 (18–78) years
Male:female 31:25
Underlying disease
AML/MDS 17
ALL/LBL 4
NHL/HL 12
MM 16
Other 7
Transplant status
Allogeneic 16
Autologous 16
Abbreviations: HL ¼Hodgkin’s lymphoma; LBL ¼lymphoblastic lymphoma;
MDS ¼myelodysplastic syndrome; MM ¼multiple myeloma;
NHL ¼non-Hodgkin lymphoma.
Table 2. Characteristics of fatal cases
Case Age
(years)
Sex Underlying
disease
Disease
control
Transplant
status
Days after
transplant
Days
of
aplasia
Initial
site of
infection
Pneumonia
on CT scan
RSV
therapy
Presumed
cause of
death
Co-infections
1 73 F AML PD — — 41 LRTID Yes Ribavirin Progressive
leukemia
None
2 67 F CLL PD — — 0 LRTID Yes IgG Pneumonia None
3 56 M CNS B-NHL PR Autologous 12 8 LRTID Yes — Pneumonia HSV (BL), E. coli (BC)
4 77 F Amyloidosis PD — — 0 LRTID No — Heart and
renal failure
None
5 47 M MCL CR Allogeneic 1191 0 LRTID Yes Ribavirin,
IgG
Pneumonia,
wasting
Candida krusei (BL),
E. coli (S), P.
aeruginosa (S)
6 61 F MM PR Autologous 2 6 LRTID Yes Ribavirin,
IgG
Aspergillus
pneumonia
HSV (BL), Aspergillus
spp. (BL)
7 70 M AML PD — — 46 URTID Yes Ribavirin Gram-
negative
sepsis
P. aeruginosa (BL, BC),
Citrobacter freundii (BL)
8 64 F AML PD — — 19 URTID Yes — Pneumonia HSV (BL)
9 42 M T-NHL CR Allogeneic 191 0 URTID Yes — Pulmonary
GVHD
BKV (urine), CMV (B),
EBV (TS) E. faecium
(BC)
10 58 F DLBCL PD — — 10 LRTID Yes IgG Aspergillus
pneumonia
Aspergillus fumigatus
(BL), HSV (BL)
11 61 F AML PD — — 13 LRTID Yes — Pneumonia Stenotrophomonas
maltophilia (BL, BC),
M. luteus (BC)
12 51 M AML CR Allogeneic 126 4 LRTID Yes IgG Pneumonia EBV (B), HSV (BL)
13 58 M MDS CR Allogeneic 20 51 LRTID Yes Ribavirin,
IgG
Myocardial
infarction,
lung
hemorrhage
Achromobacter
xylosoxidans (BL), CMV
(B, BL), EBV (B), E.
faecalis (BC), HSV (BL),
VZV (BL)
14 48 M MM PD Autologous 15 12 LRTID Yes — Pericardial
tamponade
HSV (oral swab)
Abbreviations: B¼blood; BC ¼blood culture; BKV ¼BK virus; BL ¼bronchoalveolar lavage; CNS B-NHL ¼central nervous system B-cell non-Hodgkin
lymphoma; CR ¼complete response (that is, 100% reduction in tumor mass); DLBCL ¼diffuse large B-cell lymphoma; E. coli ¼Escherichia coli; F¼female;
HSV ¼Herpes simplex virus; LRTID ¼lower respiratory tract infection disease; M ¼male; MDS ¼myelodysplastic syndrome; MCL ¼mantle cell lymphoma;
MM ¼multiple myeloma; PD ¼progressive disease (that is, uncontrolled disease); PR ¼partial response (that is, at least 50% reduction in tumor mass);
RSV ¼respiratory syncytial virus; S ¼sputum; T-NHL ¼T-cell non-Hodgkin lymphoma; TS ¼tracheal secretion; URTID ¼upper respiratory tract infection
disease; VZV ¼varicella zoster virus. Clinical characteristics on the 14 fatal cases, all of whom showing signs of RSV LRTID before their death, are given. Namely,
age (years), sex, underlying hemato–oncologic disease, control of that disease, transplant status and number of days passed after transplantation at the time
of RSV diagnosis, days of aplasia during RSV infection, site of infection at initial RSV diagnosis, presence of pneumonia on CT scan during course of infection,
RSV therapy given, presumed cause of death and presence of co-infections as well as their infection sites.
RSV infections in hematology and transplant unit
N Lehners et al
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Bone Marrow Transplantation (2013) 1548 – 1553 &2013 Macmillan Publishers Limited

and comprehensive review of the outbreak. Systematic analysis of
risk factors in this special cohort of patients revealed
hypogammaglobulinemia to be a significant risk factor for RSV-
associated morbidity and mortality, whereas treatment with oral
ribavirin might provide a protective effect. Protracted viral
shedding was frequently observed, especially affecting patients
after allogeneic transplantation.
We have shown that RSV is highly contagious—especially
among immunocompromised patients and direct patient-to-
patient contact was revealed as the most likely chain of infection.
In all, 95% of cases were infected with RSV-A. Sequence analysis of
the RSV G-protein was performed in some patients infected
with RSV-A and showed by the majority an identical virus strain
type GA2.
26
Univariate and multivariate analysis showed that hypogamma-
globulinemia was a significant risk factor for fatal outcome.
However, treatment with polyvalent Ig preparations was not able
to reverse this association. In contrast, treatment with ribavirin had
a significant impact on mortality. Pre-existing pulmonary condi-
tions might also have an influence but the difference was
statistically not significant.
In a retrospective analysis, Khanna et al.
32
reported that severe
immunosuppression was associated with mortality. This is
consistent with our observation that hypogammaglobulinemia
was associated with fatal outcome. Other risk factors, such as
age
33
or RSV infection pre-engraftment,
32,34,35
were not
statistically significant in our univariate or multivariate analysis.
We also did not find any significant difference in median time to
Table 3. Factors associated with LRTID and fatal outcome on univariate analysis
Factor LRTID Fatal outcome
OR (95% CI) P-value OR (95% CI) P-value
Age 1.16 (0.77; 1.74) 0.77 1.13 (0.72; 1.79) 0.91
Sex (male) 0.45 (0.13; 1.55) 0.24 0.75 (0.22; 2.52) 0.76
Underlying disease
AML/MDS 0.94 (0.27; 3.31) 1.00 2.11 (0.60; 7.47) 0.31
ALL/LBL 1.22 (0.12; 12.64) 1.00 0.00 (0.00; 4.61) 0.56
NHL/HL 1.26 (0.29; 5.41) 1.00 2.78 (0.71; 10.84) 0.26
MM 0.83 (0.24; 2.96) 1.00 0.33 (0.07; 1.70) 0.30
Other 1.00 (0.17; 5.77) 1.00 0.46 (0.05; 4.21) 0.67
Transplantation
Allogeneic 0.83 (0.24; 2.96) 1.00 1.00 (0.26; 3.81) 1.00
Autologous
a
5.69 (0.67; 48.35) 0.15 1.00 (0.23; 4.37) 1.00
Engraftment status
Pre-engraftment N(0.48; N) 0.15 1.07 (0.16; 7.06) 1.00
Post-engraftment 0.00 (0.00; 2.10) 0.15 0.94 (0.14; 6.20) 1.00
GVHD 0.56 (0.06; 4.76) 1.00 1.00 (0.10; 9.61) 1.00
Co-infections 3.10 (0.93; 10.30) 0.08 3.67 (0.89; 15.06) 0.13
Uncontrolled disease 0.90 (0.28; 2.89) 1.00 2.40 (0.69; 8.40) 0.22
Respiratory disease
b
3.37 (0.67; 17.08) 0.19 1.78 (0.48; 6.55) 0.48
Diabetes 0.23 (0.03; 1.52) 0.14 0.73 (0.07; 7.14) 1.00
BMI430 kg/m
2
N(0.48; N) 0.17 3.55 (0.63; 20.09) 0.32
Bortezomib therapy
a
1.08 (0.25; 4.74) 1.00 0.61 (0.12; 3.24) 0.71
Steroid therapy
c
4.38 (0.66; 29.22) 0.14 1.37 (0.14; 13.38) 1.00
Duration of aplasia 38.09 (3.22; 450.07) 0.0001 1.70 (1.00; 2.88) 0.14
Hypogammaglobulinemia 2.86 (0.81; 10.14) 0.12 9.50 (1.09; 82.72) 0.03
Ig therapy 3.00 (0.59; 15.29) 0.30 2.04 (0.54; 7.61) 0.47
Ribavirin therapy 1.62 (0.49; 5.30) 0.54 0.20 (0.05; 0.72) 0.02
Abbreviations: BMI ¼body mass index; CI ¼confidence interval; HL ¼Hodgkin’s lymphoma; LBL¼lymphoblastic lymphoma; LRTID ¼lower respiratory
tract infection disease; MDS¼myelodysplastic syndrome; MM¼multiple myeloma; NHL¼non-Hodgk in lymphoma; OR ¼odds ratio;
RSV ¼respiratory syncytial virus.
a
Within 6 months before RSV diagnosis.
b
Pre-existing.
c
Within 3 months before RSV diagnosis.
Table 4. Factors associated with LRTID and fatal outcome on multivariate analysis
Factor LRTID Fatal outcome
OR (95% CI) P-value OR (95% CI) P-value
Hypogammaglobulinemia 2.93 (0.68; 12.54) 0.12 11.76 (1.38; 100.26) 0.007
Ribavirin therapy 1.11 (0.25; 12.54) 0.88 0.14 (0.02; 0.92) 0.02
Respiratory disease
a
2.72 (0.48; 15.49) 0.22 5.21 (0.74; 36.71) 0.08
Age X65 years 1.21 (0.26; 5.71) 0.80 0.73 (0.07; 2.87) 0.35
Aplasia 410 days 3.40 (0.75; 15.35) 0.08 0.80 (0.13; 5.03) 0.80
Allogeneic transplant 1.55 (0.31; 7.65) 0.57 1.14 (0.17; 7.62) 0.89
Autologous transplant
b
4.61 (0.55; 38.47) 0.11 0.81 (0.09; 7.39) 0.84
Abbreviations: CI ¼confidence interval; LRTID ¼lower respiratory trac t infection disease; OR ¼odds ratio; RSV ¼respiratory syncytial virus.
a
Pre-existing.
b
Within 6 months before RSV diagnosis.
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leukocyte recovery in patients infected before versus after
engraftment, as found by others.
11,22
However, the numbers of
patients in these subgroups in our study were relatively small.
The impact of RSV on morbidity and mortality for transplant and
oncology patients has been controversial. Although RSV has been
associated with fatal pneumonia without evidence of super-
infections by other pathogens,
10
other groups have provided
evidence that RSV positivity in immunocompromised patients was
not associated with any adverse outcome.
7,8
It is indeed difficult to
assess to what extent the fatal outcome could be attributed to the
RSV infection in our cohort, because this particular population
typically suffers from several comorbidities and co-infections. The
fatal cases in the outbreak described here showed that the majority
(11/14 patients) had co-infections with other viral (BK virus, CMV, EBV,
Herpes simplex virus—in one case acyclovir resistant), bacterial (for
example, multi-drug resistant Pseudomonas aeruginosa) or fungal
(Aspergillus fumigatus) pathogens. A significant contribution of RSV to
the fatal outcome was clinically suspected in several patients; in
addition, RSV might have contributed to susceptibility for
other pathogens by damage to the mucous lining of the bronchial
system.
Controversies prevail over the management of symptomatic RSV
infections among adult immunocompromised patients. Although
some authors have reported a mild and self-limiting course of
infection without any specific treatment, even in transplant
patients,
7,8
a recent pooled analysis by Shah and Chemaly
17
comparing different treatment regimens for RSV infection in SCT
patients showed a significantly improved outcome in patients
treated with ribavirin, regardless of modality of administration. The
recent ECIL-4 guidelines recommended aerosolized or systemic
ribavirin therapy for RSV-infected patients undergoing allogeneic
transplantation.
30
A joint report of several societies for BMT, including
the American Society and the European Group for Blood and Marrow
Transplantation, also proposed aggressive therapy of RSV infection in
allogeneic transplant recipients, however, without opting for any
specific treatment strategy.
36
For patients with other hematologic–
oncologic conditions, there is even less evidence on the role of
antiviral therapy.
Univariate and multivariate analysis in our cohort showed that
treatment with oral ribavirin might be a significant protective factor
against fatal outcome. The mortality rate among patients with RSV
LRTID was 69% for untreated and 23% for treated patients. Although
the former almost exactly matches the mortality rate of 70% for
untreated HSCT patients with RSV-associated LRTID as reported by
Shah and Chemaly
17
, the mortality rate was estimated to be 54% for
patients who received systemic ribavirin treatment in this pooled
analysis. The lower mortality rate of 23% in our cohort might be due
to improved supportive care, taking into account the fact that some
of the studies covered in the meta-analysis went back as far as 1993.
An important observation in this outbreak was the protracted
viral shedding and hence the RSV carrier status of the patients
affected. Although this finding has been discussed in detail from a
virological point of view by Geis et al.,
26
we tried to identify clinical
risk factors for prolonged RSV positivity. In multivariate analysis,
allogeneic transplantation was significantly associated with viral
shedding for 41 week. In all, 6 of the 10 patients with viral
shedding for 450 days were allogeneic transplant recipients,
5 of whom were transplanted within the previous 3 months.
Thus, intensive immunosuppression following allogeneic trans-
plantation might represent a significant risk factor for protracted
RSV infection. Interestingly, treatment with ribavirin showed also a
trend toward longer viral shedding, maybe attributable to the
lower mortality rate in the treated cohort.
As this study is a retrospective analysis, it is associated with a
number of limitations. The major limitation may be the relatively
small number of patients limiting the statistical power. Further-
more, the study population does not constitute a completely
homogenous group in regard to various aspects: before or early
during the outbreak patients were tested for RSV because of
clinically manifest respiratory symptoms or only identified retro-
spectively, whereas later on many patients were diagnosed with
RSV infection during the systematic screenings; a treatment
recommendation to administer oral ribavirin was first established
at the height of the outbreak; optional therapies such as Ig
preparations were given mainly at the discretion of the attending
physician; finally both transplant and non-transplant patients were
included. However, we think that the data presented in this
retrospective analysis, being one of the largest of its kind and one
of the few reporting on oral ribavirin to treat RSV infection,
17
might prove helpful to the clinician, especially considering the lack
of randomized controlled trials in adults.
In conclusion, this report shows that RSV is highly contagious in
immunocompromised patients. Patients with severe hypogam-
maglobulinemia as a consequence of underlying disease and of
immunosuppressive treatment have a significantly higher pro-
pensity to suffer fatal complications. Treatment with oral ribavirin
might positively influence the outcome of RSV infections.
Prolonged viral shedding, in particular after allogeneic transplan-
tation, poses a major challenge among immunocompromised
patients. Awareness of RSV, early recognition of infected patients
and rigorous isolation of RSV-infected patients are the only
effective measures in the containment of an RSV outbreak.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
We thank the nurses and physicians working at the Department of Hematology–
Oncology at the University of Heidelberg for their commitment in containing this
outbreak of RSV infections.
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