Review article

Risks and prevention of severe RS virus infection among children with

immunodeciency and Down's syndrome
Masaaki Mori
a, *
, Tomohiro Morio
b
, Shuichi Ito
c
, Akira Morimoto
d
, Setsuo Ota
e
,
Koichi Mizuta
f
, Tsutomu Iwata
g
, Toshiro Hara
h
, Tsutomu Saji
i
a
Yokohama City University Medical Center, Pediatrics, Japan
b
Tokyo Medical and Dental University, Department of Pediatrics, Japan
c
National Center for Child Health and Development, Renal, Rheumatism, Collagen Department, Japan
d
Jichi Medical University, Department of Pediatrics, Japan
e
Teikyo University Medical Center, Department of Pediatrics, Japan
f
Jichi Medical University, Department of Transplant Surgery, Japan
g
Tokyo Kasei University, Pediatrics, Japan
h
Kyushu University, Graduate School of Medical Sciences, Department of Pediatrics, Japan
i
Toho University, Medical Center, Omori Hospital, Department of Pediatrics, Japan
a r t i c l e i n f o
Article history:
Received 28 April 2014
Accepted 5 May 2014
Available online 11 June 2014
Keywords:
Respiratory syncytial virus
Immunodeciency
Down's syndrome
Additional indications
Palivizumab
a b s t r a c t
By the age of two years, almost all infants are infected with the Respiratory syncytial virus (RSV). One of
the main causes of hospitalizations for bronchiolitis and pneumonia at this age is RSV infection. In
addition to well-known risks for severe RSV disease, such as prematurity, bronchopulmonary dysplasia
and congenital heart disease, immunodeciencies, chromosomal abnormalities such as Down's syn-
drome or neuromuscular diseases have also been identied as risks. While the medical needs for RSV
prevention in these risk groups are high, clinical evidence to support this is limited. Palivizumab was
recently approved in Japan for prophylaxis in children with immunodeciency or Down's syndrome. A
clinical guidance protocol for the prevention of RSV infection using Palivizumab in these risk groups is
provided here on the basis of a review of the available literature and on expert opinion. Thus, the present
article reviews the published literature related to RSV infections in infants and children with immuno-
deciencies or Down's syndrome in order to outline the risks, pathology and physiology of severe RSV
disease in these patient groups. The purpose of this article is to facilitate understanding of the medical
scientic bases for the clinical guidance.
2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.
1. Introduction
Respiratory syncytial virus (RSV) is one of the pathogens most
frequently identied as causing lower respiratory tract infections in
infants and children. In particular, prematurity, bronchopulmonary
dysplasia and congenital heart disease are well known risk factors
for severe RSV infection. In addition, it has been shown that pa-
tients with other conditions such as immunodeciencies, Down's
syndrome and neuromuscular diseases are also at signicant risk of
severe RSV disease according to a nationwide survey on the status
of RSV infections in Japan conducted by Mori et al. [1], which is in
agreement with other reports outside Japan [2,3]. Both the innate
and adoptive immune systems, and respiratory function in terms of
anatomical, histological and physiological factors, inuence the
course of RSV infection in such high risk groups in a complex
manner. The humanized monoclonal antibody Palivizumab specic
for an epitope in the A antigenic site of the F protein of RSV was
approved in Japan for prevention of severe RSV infections in pre-
mature babies, bronchopulmonary dysplasia and congenital heart
disease, but at that time other high risk groups such as patients
with immunodeciencies, neuromuscular disorders, or chromo-
somal abnormalities were not included. Therefore, an application
for additional indications for Palivizumab use in immunocompro-
mised children and Down's syndrome was submitted to the
* Corresponding author. Yokohama City University Medical Center, Pediatrics
General Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama-shi, Kanagawa
Prefecture 232-0024, Japan. Tel.: 81 045 261 5656; fax: 81 045 243 3886.
E-mail address: mmori@med.yokohama-cu.ac.jp (M. Mori).
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy
j ournal homepage: ht t p: / / www. el sevi er. com/ l ocat e/ j i c
http://dx.doi.org/10.1016/j.jiac.2014.05.001
1341-321X/ 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
J Infect Chemother 20 (2014) 455e459
Ministry of Health, Labour and Welfare. After examination by the
Review Conference on Unlicensed and Adapted Medicine Highly
Necessary for Medical Care, this application was endorsed and a
clinical trial was conducted. In August 2013, two new indications
for Palivizumab use in children with immunocompromised condi-
tions and Down's syndrome were approved.
This article reviews the literature related to RSV infections in
immunodeciencies and Down's syndrome and outlines risk
assessment for severe RSV infections. Based on this review, clinical
guidance for prevention of RSV infections through the use of Pal-
ivizumab were formulated by expert opinion consensus for the
purpose of determining the appropriate use of Palivizumab.
Because of the heterogeneous nature and complexity of immuno-
deciency disorders, however, these guidelines may not fully cover
all of them equally well. Thus, it is necessary to personalize pro-
phylaxis for the prevention of RSV infections based on the indi-
vidual child's immunity, risk of exposure to RSV, and anatomical
and physiological condition of the respiratory system.
2. Clinical guidance
2.1. Indications
Children with Down's Syndrome or immunocompromised
newborn babies, infants and children under the age of 24 months at
the beginning of the RSV season have been recently added to those
with an indication for the use of prophylactic Palivizumab. Here, we
describe these new indications in the following sections. In addi-
tion, respiratory conditions such as underlying respiratory disease
and chest deformity, as well as the risk of exposure to RSV (assessed
by prevalence in the geographical region or incidence in that
particular the hospital, and the presence or absence of siblings),
should also be taken into account.
2.1.1. Immunodeciencies
2.1.1.1. Congenital/acquired immunodeciencies. For high risk in-
fants and children 24 months of age at the beginning of the RSV
season having the following congenital or acquired immunode-
ciencies, the prevention of severe RSV disease using Palivizumab
may be considered as follows:
Primary immunodeciencies with predominantly T-cell dys-
functions including, but not limited to, SCID, DiGeorge syn-
drome, WiskotteAldrich syndrome, Ataxia Telangiectasia, etc.
Acquired T cell dysfunctions such as those caused by HIV
infection, use of steroids/immunosuppressive drugs etc.
T-cell dysfunctions include decrease in T-lymphocytes, T-cell
functions (such as decreased proliferative responses to PHA) or
marked lymphopenia. The following diseases and conditions are
not included: auto-inammatory diseases which do not require
medication, abnormality of granulocytes or the complement sys-
tem, and mild T-cell dysfunction (in the absence of lymphopenia or
T-lymphcoytopenia).
For systemic wasting diseases such as HIV infection, general
physical conditions should also be considered.
2.1.1.2. Hematological malignancies, solid tumors, bone marrow de-
ciencies, hematopoietic stem cell transplantation and organ trans-
plants. Inpatients with these diseases and conditions, some reports
of fatal cases of severe RSV infection have appeared. For infants and
children 24 months of age at the beginning of the RSV season
having the following conditions and diseases, the prevention of
severe RSV disease using Palivizumab may be considered:
Allogeneic hematopoietic stem cell transplantation (HSCT)
Autologous HSCT before hematological recovery
Recipients of and candidates for chemotherapy causing signi-
cant bone marrow suppression
Bone marrowfailure accompanied by immunosuppression, such
as in aplastic anemia
Organ transplants. There have been reports of severe RSV in-
fections in solid organ transplant (SOT) recipients. For infants and
children 24 months of age at the beginning of the RSV season
receiving solid organ transplants, the prevention of severe RSV
disease using Palivizumab may be considered:
Both recipients of and candidates for HSCT or SOT with signi-
cant organ dysfunction or immunosuppression are included in the
above criteria. These patients are considered at high risk of severe
RSV infection even though they are hospitalized.
2.1.1.3. Use of immunosuppressive medications for kidney diseases,
rheumatic/inammatory diseases. For infants and children 24
months of age at the beginning of the RSV season having either (1)
or (2) below, the prevention of severe RSV disease using Pal-
ivizumab may be considered:
(1) Use of corticosteroids, immunosuppressants, or biologics
#1
for the following diseases:
Rheumatic diseases (juvenile idiopathic arthritis, systemic
lupus erythematosus and juvenile dermatomyositis etc),
auto-inammatory syndrome, inammatory bowel dis-
ease, so on.
Nephrotic syndrome, chronic glomerulonephritis, etc.
(2) Children who have the following kidney diseases, regardless
of medications:
Congenital nephrotic syndrome
#2, #3
Chronic peritoneal dialysis, hemodialysis
#2
#1
: Including high-dose corticosteroid therapy (0.5 mg/kg
prednisolone every other day for approximately four weeks or
longer, excluding local treatments of inhalation, topical use or joint
injection), immunosuppressants (azathioprine, methotrexate,
mizoribine, mycophenolate mofetil, cyclophosphamide, cyclo-
sporine, tacrolimus, everolimus, rapamycin, etc), and biologics
(including cytokine inhibitors).
#2
: Pharmacokinetics and effectiveness of Palivizumab may
differ in individual cases.
Optimal doses and intervals between them should be decided
individually.
#3
: The drug may be lost through urine. No effectiveness data for
Palivizumab in this group is available. The risks of exposure to, and
severe disease from RSV, should be carefully assessed when
administering Palivizumab.
2.1.2. Down's syndrome
Down's syndrome itself has been shown to be a risk factor for
severe RSV infection, even in the absence of congenital heart dis-
ease. For infants and children with Down's syndrome 24 months
of age at the beginning of the RSV season, the prevention of severe
RSV disease using Palivizumab may be considered when the patient
suffered any of following past or present complications, or has
abnormal laboratory test results:
Anatomical, physiological or functional abnormalities of the
respiratory system: Airway obstruction and/or associated apnea
due to marked megaloglossia, glossoptosis, respiratory tract
malacia, or other airway abnormalities, pulmonary hyperten-
sion, pulmonary hypoplasia/dysplasia, or emphysematous lung.
M. Mori et al. / J Infect Chemother 20 (2014) 455e459 456
Previous severe respiratory diseases or viral infections: History
of hospitalizations due to viral infections/respiratory infections
Abnormal laboratory tests of immunological function: Low
lymphocyte or T-lymphocyte counts*
* Although the normal values vary depending on the months of
age, one suggestion would be 2000/mm
3
or lower and 1000/mm
3
or lower for lymphocyte counts and T-lymphocytes, respectively.
2.2. Precautions
(1) If patients have a tendency to bleed due to thrombocytopenia
(such as because of WiskotteAldrich syndrome and mye-
loablation) or other coagulopathy, or they are receiving an-
ticoagulants and/or antiplatelet drugs, bleeding resulting
from an intramuscular injection of Palivizumab may be
serious. It is recommended that Palivizumab be carefully
given to such patients, for example, with application of
pressure to the injection site for an appropriate length of
time to ensure hemostasis.
(2) Effectiveness of Palivizumab in treating RSV infection has not
been established.
(3) The latest package insert and the published guidelines for
prematurity and congenital heart diseases should also be
referred to.
2.3. Importance of basic infection control
It is important to employ strict infection control measures even
when using Palivizumab. It is particularly important to educate
guardians, since their cooperation is essential in managing high-risk
children. It is also important to provide instructions not only for RSV
infection, but also for other pathogens causing respiratory tract in-
fections. In addition, guardians should understand that adhering to
the administration schedule is critical to maximize the effectiveness.
3. Comments
3.1. Congenital/acquired immunodeciency diseases
Recent medical advances have improved the lives of immuno-
compromised patients, but as a result, the chance of exposure to
and infection by RSV among these high risk patients has increased.
Severe RSV infections in immunodeciency disorders such as SCID
have long been recognized, at least since the 1980s [2,4,5]. Hall et al.
examined the immunological status of 608 infants under the age of
ve who were hospitalized with an RSV infection over a ten year
period [2]. They identied 47 patients with immunologic abnor-
malities, including those receiving chemotherapy (20 cases) or
steroids (22 cases) and those with primary immunodeciency
syndrome (5 cases). The frequency of nosocomial infections, as well
as the rates of infection in the lower respiratory tract, admissions to
the ICU and mortality was compared with immunologically normal
children. Nosocomial infections accounted for 25 cases including
one with primary immunodeciency. Lower respiratory tract in-
fections developed in all patients with immunodeciency syn-
dromes and in those receiving chemotherapy, with high rates of 80
and 60% admission to the ICU and 40 and 15% mortality in the
syndrome and chemotherapy groups, respectively. More than half
of the patients who received steroids developed LRTI (12 of 22), but
with no cases of mortality and two requiring ICU admission (9%).
More recently, a population-based cohort study of RSV infections in
Denmark identied congenital immunodeciency as a signicant
risk factor, among others including Down's syndrome [3].
In general, cellular immune functions are considered important
in controlling virus infection. RSV-specic CD8

and CD4

T cells
can be found in adult peripheral blood, which suggests a persis-
tently important role for cellular immunity against RSV [6e9].
Mbawuike reported that infants possessing CTL activity against RSV
during their rst year of life were less likely to have LRTI in their
second year [10], indicating the importance of CTL activity.
Human Immunodeciency Virus (HIV) infects CD4

T cells and
causes immunodeciencies. In recent years, comprehensive mea-
sures to prevent mother-to-child transmission (MCT) have been
widely and successfully implemented in Japan, and the frequency
of new occurrences of MCT is fortunately as low as only one every
few years. Nevertheless, according to reports from Africa, where
MTC is still a signicant public health problem, there is a higher rate
of lower respiratory tract infection and mortality in children
infected with HIV compared to those uninfected [11].
Overall, the available literature indicates the importance of
cellular immunity to control RSV infection. Nonetheless, the hu-
moral response is also important for controlling RSV infection, as
immunoglobulin is effective in preventing severe RSV infections.
However, there is insufcient available information to be included
in this guidance.
3.2. Malignant tumors, hematopoietic stem cell transplants, and
organ transplants
Severe RSV infections have been widely reported in those with
hematological malignancy and HSCT. Generally, younger patients,
lymphocytopenia and neutropenia, infection prior to or early after
transplantation, high doses of steroids, and failure to treat with
ribavirin have all been reported as risks for severe RSV infection
[12e15]. Allogeneic HSCT recipients are considered to be at
particularly high risk of severe infection and suffer high mortality
rates [13,16,17]. In addition, there have been reports of severe RSV
infection in malignant diseases without HSCT [13,18,19], indicating
that underlying diseases and bone marrow suppression due to
anticancer treatments are also risks for severe RSV infections. On
the other hand, there have also been reports that the frequency of
RSV infection and severity is not high, and that deaths are rare in
these patient groups [20,21].
Severe RSV infections have also been reported in solid organ
transplant patients. From reports of a high frequency of severe
infection of 50e80% [22,23], there are also reports that it is only
around 20% [24,25]. There are also reports of mortality [23,25].
According to a survey at organ transplant centers in the United
States, of those facilities that responded, nearly half reported that
they took some form of measure to prevent RSV infection [26]. In
that study, it was also reported that 27% (17/62) of institutions had
seen RSV LRTI infection during the previous season and that of
those who received Palivizumab 4% required hospitalization (4 of
109), whereas of those who did not it was 11% (22 of 195) (p 0.03).
3.3. Use of steroids/immunosuppressive drugs, and kidney and
rheumatic diseases
In adult patients with rheumatoid and autoimmune diseases,
cases of severe RSV infections including fatality have been reported
[27,28]. Furthermore, in some reports, exacerbation of the under-
lying diseases [29], and rejection of the transplanted kidney [1] or
even death [24] have been reported.
3.4. Down's syndrome
Chromosomal abnormality and congenital malformations are
regarded as risks for severe RSV infections in infants [3,30], for
M. Mori et al. / J Infect Chemother 20 (2014) 455e459 457
which it is speculated that immunologic abnormalities and
anatomical abnormalities in the lungs and airways are responsible.
Pulmonary hypertension is a common complication accompanying
congenital heart disease in about half of Down's syndrome patients.
On the other hand, Down's syndrome itself without congenital
heart disease is also a risk factor for severe RSV infections [31,32].
Bronchomalacia and tracheomalacia is frequently seen in persons
with Down's syndrome [33,34], as well as lung hypoplasia and
emphysematous changes [34]. There are also reported cases of
aspiration pneumonia and obliterating bronchiolitis associated
with RSV infections [32,34,35]. In addition to the aforementioned
anatomical and histological abnormalities, Down's syndrome pa-
tients are known to have small thymi. A measure of the release of
newT-cells fromthe thymus, the amount of T-cell receptor excision
circles (TRECs), is low in Down's syndrome [36], and the peripheral
blood nave CD4

T cell count, as well as the overall T-cell count,

and the B-cell count, are all decreased [37], which may also be
related to susceptibility to severe respiratory viral infections. Thus,
in Down's syndrome, these anatomical and histological abnormal-
ities, as well as quantitative and qualitative abnormalities in
immunological parameters, should be taken into account when
assessing the risk of severe RSV infections.
3.5. Other considerations
There are various factors complicating immunodeciencies and
Down's syndrome that can aggravate RSV infections. Of these, there
are some important conditions in common, such as a decline in the
number and function of T-lymphocytes, including marked lym-
phopenia, mentioned specically above for congenital and acquired
immunodeciency and others. Steroids, tacrolimus, biological
preparations and other such treatments cause functional impair-
ment. A numerical decline is seen in recipients of chemotherapy
and HSCT. Severe bone marrowaplasia such as in aplastic anemia is
included in these conditions. The number of lymphocytes, T-cells
and PHA responsiveness are examples of parameters useful for the
evaluation of cell-mediated immunity and T-cell-related functions
at bedside. However, abnormalities may not always be detected
through such tests in all diseases, such as those involving STAT
malfunctions, so caution is necessary [38]. In addition, immuno-
deciencies in which T-cell dysfunction is not important (eg.
autoinammatory diseases, polymorph abnormalities, comple-
ment abnormalities, slight T-cell immunodeciency) were omitted
from the list of indications for Palivizumab use, but as research
progresses and risks for aggravated RSV infection are claried, it
will be necessary to review these current guidance again.
In general, in the early recovery stages after transplantation and
chemotherapy, when the level of immunosuppression and myelo-
suppression is still high, it may be thought that the risk of RSV
exposure is low during hospitalization. On the other hand, if RSV
does happen to be transmitted to patients in such an advanced
immunocompromised state, the risk of severe disease even to the
point of death is considerable. In addition, most RSV infections in
adults present with mild or even no symptoms, so the risk of
infection froman adult during times when it is prevalent cannot be
completely prevented. That is why a section on preventing RSV
infection during hospitalization was included in this guidance
above. Therefore, it is important to be thorough in taking basic
measures to prevent infection, considering the risk of infection,
regional prevalence of RSV and the conditions and numbers or
visitors, and to formulate a prevention plan.
At the present time, while the prevention of RSV using Pal-
ivizumab in those with immunodeciencies and Down's syndrome
has been approved in Japan before anywhere else in the world,
there is currently insufcient evidence of efcacy and safety of its
use. Thus, the importance of collecting information on Palivizumab
use and reporting our experience with this antibody in our country
to the international community cannot be overemphasized.
Acknowledgments
I would like to express my deepest gratitude to the following
doctors for their expert advice in preparing these guidelines. Dr.
Katsuhiro Asonuma, Kumamoto University Hospital, Trans-
plantation Department; Dr. Shinya Okamoto, Kyoto University
Hospital, Pediatrics; Dr. Atsushi Kikuta, Fukushima Medical Uni-
versity Hospital, Clinical Tumor Center, Pediatrics Oncology
Department; Dr. Katsuyoshi Yasu, Saitama Children's Medical
Center, Hematology and Oncology Department; Dr. Akihiko Saito,
Niigata University Medical & Dental Hospital, General Research,
Pediatrics; Dr. Shinichi Takatsuki, Toho University, Medical Center,
Omori Hospital, Pediatrics; Dr. Mizue Tanaka, National Center for
Global Health and Medicine Center Hospital, Pediatrics; Dr. Masao
Togawa, Osaka City General Hospital, Pediatric Medical Care Center,
Pediatric Emergency Medicine; Dr. Hideki Nakayama, Fukuoka
Higashi Medical Center, Pediatrics; Dr. Yoshinori Hara, Yokohama
City University Hospital, Pediatrics; Dr. Akiya Fukuda, National
Center for Child Health and Development, OrganTransplant Center;
Dr. Mizuka Miki, Hiroshima University Graduate School of
Biomedical & Health Sciences, Pediatrics; Dr. Hiromasa Yabe, Tokai
University, School of Medicine, Base Medical Treatment Studies
System, Regenerative Medical Science; Dr. Tetsushi Yoshikawa,
Fujita Health University, School of Medical, Pediatrics. We also
thank Dr. Yo Hoshino, Abbvie G.K. for providing suggestions and
reviewing this article.
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