Download Infectious Complications With the Use of Biologic Response

CLINICAL REPORT
Guidance for the Clinician in Rendering Pediatric Care
Infectious Complications With
the Use of Biologic Response
Modifiers in Infants and Children
H. Dele Davies, MD, FAAP, COMMITTEE ON INFECTIOUS DISEASES
Biologic response modifiers (BRMs) are substances that interact with
and modify the host immune system. BRMs that dampen the immune
system are used to treat conditions such as juvenile idiopathic arthritis,
psoriatic arthritis, or inflammatory bowel disease and often in combination
with other immunosuppressive agents, such as methotrexate and
corticosteroids. Cytokines that are targeted include tumor necrosis factor
α; interleukins (ILs) 6, 12, and 23; and the receptors for IL-1α (IL-1A) and
IL-1β (IL-1B) as well as other molecules. Although the risk varies with the
class of BRM, patients receiving immune-dampening BRMs generally are
at increased risk of infection or reactivation with mycobacterial infections
(Mycobacterium tuberculosis and nontuberculous mycobacteria), some viral
(herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, hepatitis B)
and fungal (histoplasmosis, coccidioidomycosis) infections, as well as other
opportunistic infections. The use of BRMs warrants careful determination
of infectious risk on the basis of history (including exposure, residence,
and travel and immunization history) and selected baseline screening test
results. Routine immunizations should be given at least 2 weeks (inactivated
or subunit vaccines) or 4 weeks (live vaccines) before initiation of BRMs
whenever feasible, and inactivated influenza vaccine should be given
annually. Inactivated and subunit vaccines should be given when needed
while taking BRMs, but live vaccines should be avoided unless under special
circumstances in consultation with an infectious diseases specialist. If the
patient develops a febrile or serious respiratory illness during BRM therapy,
consideration should be given to stopping the BRM while actively searching
for and treating possible infectious causes.
abstract
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Clinical reports from the American Academy of Pediatrics benefit from
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reviewers. However, clinical reports from the American Academy of
Pediatrics may not reflect the views of the liaisons or the organizations
or government agencies that they represent.
The guidance in this report does not indicate an exclusive course of
treatment or serve as a standard of medical care. Variations, taking
into account individual circumstances, may be appropriate.
All clinical reports from the American Academy of Pediatrics
automatically expire 5 years after publication unless reaffirmed,
revised, or retired at or before that time.
DOI: 10.1542/peds.2016-1209
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The author has indicated he does
not have a financial relationship relevant to this article to
disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The author has indicated
he has no potential conflicts of interest to disclose.
INTRODUCTION
Biologic response modifiers (BRMs) refer to substances that interact
with the host immune system and modify it. Several BRMs, such
To cite: Davies HD and AAP COMMITTEE ON INFECTIOUS
DISEASES. Infectious Complications With the Use of Biologic
Response Modifiers in Infants and Children. Pediatrics.
2016;138(2):e20161209
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PEDIATRICS Volume 138, number 2, August 2016:e20161209
FROM THE AMERICAN ACADEMY OF PEDIATRICS
as cytokines, chemokines, and
antibodies, occur naturally in
the body and help to protect
against infections. Depending on
the condition, synthetic BRMs
mimicking natural cytokines or
inhibitors, including humanized
monoclonal antibodies against
a cytokine or its receptor, have
been used in treatment to restore,
boost, or dampen the host immune
response. The focus of this clinical
report is on cytokine-inhibiting
BRMs that dampen the immune
response and treat immunemediated conditions, such as
juvenile idiopathic arthritis (JIA),
inflammatory bowel disease, graftversus-host disease associated with
hematopoietic stem cell transplant
(HSCT), and scleritis. Cytokines
that have been targeted include
tumor necrosis factor (TNF) α;
interleukins (ILs) 6, 12, and 23;
and the receptors for IL-1α (IL1A) and IL-1β (IL-1B) as well as
other molecules described below.
These medications are increasingly
being used in pediatric populations
in combination with other
immunosuppressive agents, such as
methotrexate and corticosteroids.
Although they have been very
effective in treating the symptoms
of the underlying immune-mediated
conditions and lessening disability,
the immunosuppressive effect of the
cytokine-inhibiting BRMs can persist
for weeks to months after the last
dose.1 There is strong evidence of an
association of the use of these drugs
with an elevated risk of infection
with viral and mycobacterial
pathogens and weaker evidence
for fungal and other intracellular
pathogens.2–4
This clinical report aims to
summarize the infectious disease
complications associated with
BRMs to guide subspecialists and
to familiarize pediatricians, family
physicians, and other primary care
practitioners who may care for,
diagnose, and manage infections
e2
in children treated with BRMs. A
summary of key points for primary
care providers is given in Table 1.
It should be noted that experience
with the use of BRMs varies by
product, with infliximab having the
most data available for its use. Data
for children are mostly extrapolated
from studies in adults,5–9 with
mostly small case series and cohort
studies reported,2,10–15 and thus
suggested practices are consensus
driven on the basis of knowledge of
the impact of BRMs on the immune
system. Finally, patients are usually
prescribed BRMs in conjunction
with other immunosuppressive
agents, such as methotrexate
and prednisone, which also have
immunomodulatory effects that
must be considered when the data
are being reviewed. In general, the
combinations should be considered
at least as immunosuppressive
as the most immunosuppressive
agent in the combination. Table
2 summarizes the BRMs that are
currently approved by the US Food
and Drug Administration (FDA)
along with their mechanisms of
action, route of administration,
half-lives, and indications. There
are also several other products
under consideration or in clinical
trials. Some currently licensed BRMs
are being tested for many new
indications, and unlicensed BRMs
are also being tested for various
indications either as sole agents or
in combinations.
FDA-APPROVED BRMS
TNF-α Blockers
Two classes of TNF-α blocking
agents are currently used in
managing rheumatologic conditions:
(1) monoclonal anti-TNF antibodies
(includes infliximab [Remicade;
Janssen Biotech, Horsham, PA],21,37–39
adalimumab [Humira; AbbVie, North
Chicago, IL],38,40–43 golimumab
[Simponi; Janssen Biotech, Horsham,
PA],24,44,45 and certolizumab pegol
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[Cimzia; UCB, Smyrna, GA]25)
and (2) soluble TNF receptors
(etanercept [Enbrel; Immunex,
Thousand Oaks, CA]).22,46,47
Infliximab, the first to be licensed in
its class, is a chimeric mouse/human
protein, and the other monoclonal
anti-TNF agents are fully composed
of human amino acid sequences.
Certolizumab pegol is unique
in also being pegylated, which
improves its pharmacokinetics
and bioavailability.48 Etanercept
is composed of 2 extracellular
domains of human TNF-R2 fused
to the fragment-crystallizable (Fc)
fragment of human immunoglobulin
(Ig) G1 (Fig 1).48
Non–TNF-α Blockers
The other classes of BRMs consist
of monoclonal antibodies and other
proteins that antagonize IL-1, IL-6,
IL-12, and IL-23 or other molecules,
which are important in the
inflammatory cascade.
Monoclonal Antibodies
Tocilizumab (Actemra [IL-6];
Genentech, South San Francisco, CA),
ustekinumab (Stelara [IL-12 and
IL-23]; Janssen Biotech, Horsham,
PA), and canakinumab (Ilaris
[IL-1B]; Novartis Pharma, Basil,
Switzerland) are all humanized
monoclonal antibodies against the
interleukins noted. Natalizumab
(Tysabri, Biogen, Cambridge, MA) is
a recombinant human monoclonal
antibody against the cell adhesion
molecule α-4-integrin, which acts
by preventing the adhesion of
leukocytes to endothelial cells.
Rituximab (Rituxan; Genentech,
South San Francisco, CA) is a
chimeric monoclonal antibody
against the CD20 protein, primarily
found on the surface of B cells, which
acts by inducing B-cell destruction
through mechanisms that could
include complement-dependent
cytotoxicity, apoptosis, or antibodydependent cytotoxicity. Belimumab
(Benlysta; GlaxoSmithKline,
Rockville, MD) is a human IgG1-λ
FROM THE AMERICAN ACADEMY OF PEDIATRICS
TABLE 1 Summary of Suggested Screening/Immunizations Before and After BRM Therapy
Suggested screening/immunizations before BRM started
Thorough history
Document previous vaccines, antibody testing when indicated (routine antibody testing not recommended for varicella)
Query about possible exposure and epidemiologic risk factors for histoplasmosis and coccidioidomycosis
Query about history of recurrent HSV
Consider serologic testing for EBV
Screen for past hepatitis B and determine need for vaccine (Table 3)
Routine immunizations
Follow current AAP, Centers for Disease Control and Prevention, and American Academy of Family Physicians guidelines16,17
Give recommended vaccines, inactivated, or subunit vaccines 2 weeks before initiation of BRM
Consider safety of giving live vaccine; if appropriate, give 4 weeks before initiating BRM18
TB
Test for latent TB and manage based on result (see ref 19 for algorithm)
Suggested screening/immunizations after BRM started
Routine immunizations
May still receive routine inactivated, polysaccharide, recombinant, or subunit vaccinea
Give annual inactivated influenza vaccine18
Avoid live vaccines, unless under special circumstances with help of infectious diseases specialist18
Immunizing immunocompetent household contacts (before or during treatment)?
Follow AAP guidelines for immunizing household contacts of immunocompromised patients18
Risk of listeriosis
Avoid unpasteurized milk and milk products, uncooked meats20
Febrile or serious respiratory illness during BRM therapy
Consider stopping BRM and actively search for infections including bacterial, mycobacterial, and opportunistic infections
Suggested screening/immunizations after BRM stopped
Routine immunizations
May still receive routine inactivated, polysaccharide, recombinant, or subunit vaccinea
Timing of giving live vaccines after stoppage of BRM ± other immunosuppressive agents?
Consult infectious diseases specialist
These are suggestions only. Each situation should be guided by clinical scenario, and the help of an infectious diseases consultant may be sought.
a If receiving rituximab, may not respond.
monoclonal antibody against soluble
human B lymphocyte stimulator
protein (BLyS; also known as BAFF
and TNFSF13B). It does not bind B
cells directly but blocks the binding
of soluble BLyS to its receptors on
B cells, thereby inhibiting B-cell
survival and differentiation into
immunoglobulin-producing plasma
cells.34
Fusion Proteins
rilonacept (Arcalyst; Regeneron
Pharmaceuticals, Tarrytown, NY)
are both fusion proteins composed
of Fc regions of IgG1 fused with
another molecule. Abatacept is
a fusion protein of the Fc region
of IgG1 fused to the extracellular
domain of cytotoxic T-lymphocyte
antigen 4. Abatacept has strong
affinity and binds to the B7 protein
on the antigen-presenting cells,
which would normally bind to the
CD28 protein on T cells, preventing
the antigen-presenting cells from
delivering the costimulatory signals
needed to fully activate the T cells.
Rilonacept (Arcalyst; Regeneron
Pharmaceuticals, Tarrytown, NY) is
a dimeric fusion protein made of the
Fc region of human IgG1 that binds
IL-1 linked to the ligand binding
domains of the extracellular portions
of human IL-1R1 and the IL-1R
accessory protein (IL-1RAcP).
Abatacept (Orencia; Bristol
Myers Squibb, Princeton, NJ) and
Tofacitinib (Xeljanz; Pfizer, New
York, NY) is an oral, small-molecule
Recombinant IL1 Antagonist
Anakinra (Kineret; Swedish Orphan
Biovitrum AB, Stockholm, Sweden)
is a recombinant, nonglycosylated
human IL-1 receptor (IL-1R)
antagonist that blocks the biologic
activity of both IL-1A and IL-1B
by competitively inhibiting IL-1
binding to the IL-1 type 1 receptor
found in a wide range of organs and
tissues.
PEDIATRICS Volume 138, number 2, August 2016
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protein kinase inhibitor of the
enzyme Janus kinase (JAK) 3 and
1 (JAK3 and JAK1, respectively)
that interferes with the JAKSTAT signaling pathway, which
transmits extracellular information
into the cell nucleus, influencing
DNA transcription. Functionally,
tofacitinib affects both innate and
adaptive immune responses by
inhibiting pathogenic T helper (Th)
17 cells and Th-1 and Th-2 cell
differentiation (Table 2).49–52
INFECTIONS ASSOCIATED WITH THE
USE OF BRMS
Overall Rate of Serious Infections
BRM use has been associated with
an increased risk of developing
certain infections. In addition to the
immunosuppressive effects of these
agents, concomitant use of other
immunosuppressive agents, such as
steroids and methotrexate, and the
e3
TABLE 2 FDA-Approved BRMs and Indications
Generic Name (Year[s] FDA
Approved for Indications)
Trade Name
Infliximab (1999, 2009)
Remicade21
Etanercept (1998)
Enbrel22
Adalimumab (2002)
Humira23
Golimumab (2009)
Simponi24
Certolizumab pegol (2009)
Cimzia25
Abatacept (2005, 2009)
Orencia26
Anakinra (2001)
Kineret27
Rituximab (2006)
Tocilizumab (2010)
Rituxan28
Actemra29
Ustekinumab (2013)
Stelara30
Canakinumab (2009, 2013)
Ilaris31,32
Natalizumab (2008, 2013)
Tysabri33
Belimumab (2011)
Benlysta34
Rilonacept (2008, orphan
drug)
Tofacitinib (2012)
Arcalyst35
Xeljanz36
Mechanism of Action
TNF-α inhibitor (anti–TNF-α
chimeric monoclonal
IgG1κ antibody)
TNF-α inhibitor (soluble
TNF-α receptor fusion
protein)
TNF-α inhibitor (anti–TNF-α
humanized monoclonal
IgG1 antibody)
TNF-α inhibitor (anti–TNF-α
IgG1κ antibody)
TNF-α inhibitor (PEGylated
human Fab antigen
binding)
Anti-CTLA4 selective T-cell
costimulation modulator
protein (blocks TNF-α,
IL-2, and interferon-γ
production)
Recombinant anti-IL-1
receptor antagonist
Anti-CD20 therapy
Anti-IL-6 humanized
monoclonal antibody
Anti-IL-12 and IL-23
humanized monoclonal
antibody
Anti-IL-1B human monoclonal
antibody
Humanized anti–integrin
α 4 subunit monoclonal
antibody (reduces
leukocyte adhesion and
transmigration)
Human IgG1λ monoclonal
antibody against soluble
human B lymphocyte
stimulator protein
IL-1 receptor fusion protein
Small molecule protein
kinase inhibitor of JAK3
and JAK1
FDA-Approved Indicationa
Usual Route,
Half-life
IV, 7.5–9.5 d
SQ, 70–132 h
Crohn disease [RA, plaque psoriasis, psoriatic
arthritis, ankylosing spondylitis, ulcerative
colitis]
JIA [RA, plaque psoriasis, psoriatic arthritis,
ankylosing spondylitis]
SQ, 10–20 d
JIA [RA, plaque psoriasis, psoriatic arthritis,
ankylosing spondylitis, Crohn disease]
SQ, 7–20 d
[RA, psoriatic arthritis, ankylosing spondylitis]
SQ, 14 d
[RA, Crohn disease]
IV or SQ, 8–25 d
JIA [RA]
SQ, 4–6 h
[RA]
IV, 14–62 d
IV, 8–14 d
[RA, non-Hodgkin’s lymphoma]
[RA]
SQ, 20–24 d
[Psoriatic arthritis, plaque psoriasis]
SQ, 26 d
CAPS, JIA
IV, 11 d
[Crohn disease, multiple sclerosis]
IV, 19 d
[Systemic lupus erythematosus]
SQ, 8.6 d
CAPS
Oral, 3 h
[RA]
CAPS, cryopyrin-associated periodic syndromes (consisting of familial cold autoinflammatory syndrome and Muckle-Wells syndrome); IV, intravenous; SQ, subcutaneous.
a For underlined conditions, safety and efficacy have been established in children <18 y; for bracketed indications, safety and efficacy have only been shown in adults. Infliximab, etanercept,
and adalimumab have been used off-label for scleritis, but none are FDA approved for this condition.
underlying inflammatory disease
likely contribute to increased
infectious risk.47,53,54
A 2011 Cochrane review examined
adverse events identified in
randomized controlled trials,
controlled clinical trials, and
open-label extension studies
involving >60 000 participants
(primarily adults) receiving 9
BRMs (adalimumab, certolizumab,
etanercept, golimumab, infliximab,
e4
anakinra, tocilizumab, abatacept,
and rituximab) for treatment of
either rheumatoid arthritis (RA) or
cancer.55 Serious infections were
defined as infections associated
with death, hospitalization, and/
or use of intravenous antibiotics.
The review identified an overall
increased risk of serious infections
(odds ratio [OR]: 1.37; 95%
confidence interval [CI]: 1.04–1.82)
among participants receiving
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BRMs compared with placebo
recipients.55 The drugs most
commonly associated with serious
infection were certolizumab (OR:
4.75; 95% CI: 1.52–18.5) and
anakinra (OR: 4.05; 95% CI: 1.22–
16.8). Overall, patients receiving
TNF-α inhibitors had a greater risk
of developing a serious infection
versus patients receiving other
BRMs (OR: 1.4; 95% CI: 1.13–1.75).
However, patients receiving any
FROM THE AMERICAN ACADEMY OF PEDIATRICS
FIGURE 1
Structures of the TNF-α antagonists. (Adapted from Wallis RS. Biologics and infections: lessons from tumor necrosis factor blocking agents. Infect Dis Clin
North Am. 2011;25(4):896, with permission from Elsevier Limited.) Fab, Fragment antibody binding; mAb, monoclonal antibody; sTNFR, soluble TNF receptor.
of the other BRMs also had an
increased overall risk of serious
infection when compared with
those receiving placebo. There was
evidence of an increased risk of
reactivation of tuberculosis (TB)
among patients receiving BRMs
compared with those receiving
placebo (see section titled “TB”).
Although the risk of serious
infections is increased, there is no
clear evidence of overall increased
risk of bacterial infections, other
than mycobacteria, with the use
of BRMs. Before the BRM era, the
rate of serious bacterial infections
requiring hospitalization or
parenteral antibiotics in patients
with RA (primarily adults) was
reported to be between 0.02
and 0.12 per patient-year.56,57 In
contrast, the incidence of infection
noted for patients with RA treated
with etanercept has ranged from
0.017 to 0.050 per patient-year, a
rate that is not significantly different
from the general population.58 One
hypothesis would be that even
though BRMs temporarily increase
the risk of serious infections, their
PEDIATRICS Volume 138, number 2, August 2016
profound positive effects on the
underlying disease counterbalances
this effect.
In head-to-head trials, the rates of
upper respiratory infections (20%)
were similar among recipients of
etanercept and control patients
with RA.47 Among studies involving
children alone, etanercept has not
been shown to increase the risk of
serious nonmycobacterial infection
compared with etanercept plus
conventional disease-modifying
antirheumatic drugs (DMARDs)
such as methotrexate,22,46,59–66
with rates ranging from 0.007 to
0.035 per patient-year. Children
receiving infliximab12,31,61,67–70 and
adalimumab38,42,43,64,71 had higher
rates of serious nonmycobacterial
infections, ranging from 0.027 to
0.086 per patient-year, but there
were no data presented to suggest
that these rates were higher
than those observed for patients
receiving DMARDs alone or DMARDs
in combination with the BRMs.
Infections related to these BRMs
were primarily lower respiratory
tract and gastrointestinal infections,
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sepsis, and abscesses. Although
there is no clear increased risk
compared with patients receiving
DMARDs alone, case reports of
sepsis and even death among
patients receiving these drugs
necessitate caution in instituting
therapy in patients who have active
infections.
Studies involving children treated
with the other classes of BRMs (IL-1
[anakinra], IL-6 [tocilizumab], and
T-cell costimulation [abatacept]
inhibitors) are limited and generally
showed few serious infections.
Similarly, infection rates have been
low in adult patients treated with
ustekinumab, canakinumab, and
rilonacept. When infections are
identified, they have primarily been
viral, gastrointestinal tract, or skin
infections. However, there are no
data to suggest that the overall
incidence of infection is increased
compared with the incidence in
patients taking DMARDs alone. More
studies are needed on the rates of
infections for patients receiving these
classes of BRMs.
e5
Rituximab-Associated Neutropenia
Rituximab-associated neutropenia
is prolonged neutropenia described
during or after the completion of
therapy, primarily in adult patients
being treated for lymphomas.72–80
The incidence ranges mostly from
0.02% to 6%, although it has been
described to be as high as 25% in 1
series and has involved admission
to the hospital with fever and
neutropenia and sometimes sepsis
with bacterial pathogens including
Pseudomonas species. The duration
of the neutropenia has ranged from
4 days to 1 year. The mechanism is
unknown, but circulating antibodies
against neutrophils were postulated
in 1 study.80 In 1 open-label cohort
study in which rituximab was used
to treat JIA in 55 children who had
failed to respond to infliximab and
other DMARDs, 8 serious infections,
all lower respiratory tract infections
including Pneumocystis jirovecii
and Mycoplasma pneumonia,
were identified during a 96-week
follow-up period.81 Of interest,
neutropenia occurred in 17 (31%)
of these patients between weeks 6
and 28 of treatment. The neutrophil
count did not exceed 1500 per μL in
9 (16%) of the patients, was <1000
per μL in 5 (9%) of the patients, and
was <500 per μL in 3 (6%) of the
patients. All patients were treated
with granulocyte-macrophage
colony–stimulating factor (5 μg/kg),
and no cases of sepsis or febrile
neutropenia were described. Not
surprisingly given the mechanism
of action (anti-CD20 monoclonal
antibody), 80% of the patients had
a complete depletion of their B
cells (CD20+ cells), which remained
low throughout the 96 weeks of
follow-up, but the level or duration
of depletion did not correlate with
any specific infection. Eleven (20%)
patients also had a reduction in their
serum immunoglobulin (IgM and
IgG) levels below the age-related
lower limits of normal. The most
common (mild) infections noted
e6
were ear, nose, and throat (14%)
as well as skin (11%) infections.
Four cases of herpetic infections
were also reported among the mild
infections.
Specific Infections
TB
Reactivation infections caused by
organisms in the Mycobacterium
tuberculosis complex have been
associated with use of TNF
inhibitors. TNF-α has been shown
in mouse models to contribute
to granuloma formation and to
induce and maintain latency of TB
infection.82 In contrast, blockage
of this cytokine results in failure to
control bacillary growth and form
protective granulomata.83–86 In the
Cochrane review by Singh et al,55 the
overall OR of TB reactivation was 4.7
(95% CI: 1.2–18.6) among patients
receiving BRMs compared with those
receiving placebo, with the absolute
risk measured at 20 cases per 10 000
compared with 4 per 10 000 patients
receiving placebo. However, there
were insufficient data in that study
to compare risk of TB activation in
patients receiving 1 BRM versus
another.
In other studies conducted in
adults, the risk of TB reactivation
appeared to be related to the class
of TNF inhibitor. TNF antibodies
(eg, infliximab and adalimumab)
are associated with the highest
risk, whereas soluble TNF receptor
antibodies (eg, etanercept) appear
to have the lowest risks.87 One study
counted the rates of opportunistic
infections associated with infliximab
use by analysis of the Adverse
Event Reporting System (AERS) of
MedWatch, a spontaneous reporting
system of the FDA.4 Although the
baseline rate of TB in adults was
estimated at 6.2 per 100 000, the
rate among the estimated 147 000
patients receiving infliximab was
found to range from ∼10 per
100 00088 to 24.4 per 100 000.4 In
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contrast, there were many fewer
cases of TB reported in relation to
etanercept, with 9 cases identified
among ∼102 000 patients treated in
the same database. Similar results
were reported by Dixon et al,89
based on analysis of 10 712 patients
treated with anti-TNF BRMs (3913
etanercept, 3295 infliximab, 3504
adalimumab). The rates of TB were
much higher in patients receiving
either of the monoclonal antibodies
(adalimumab: 144 events per
100 000 person-years; infliximab:
136 per 100 000 person-years)
versus those taking etanercept (39
per 100 000 person-years). Other
data suggest that adalimumab is
associated with TB in patients with
RA in a dose-related manner, with
higher doses associated with greater
risk.90
Although the risk appears to be
lower with etanercept, since its
approval many cases of TB have been
described among patients receiving
the drug. The estimated incidence
noted in studies of 10 to 14.3 cases
per 100 000 etanercept-treated
patients is more than the Centers
for Disease Control and Prevention–
estimated rate of TB in the general US
population of 6.2 per 100 000.88,90,91
Most cases have localized disease,
although disseminated infections
have been reported. Other cohort92
and case-control93,94 studies noted
rates of 6 to 39 cases of TB for
etanercept, compared with 71 to 100
cases for infliximab and adalimumab
per 100 000 patient-years.
Risk of Extrapulmonary and
Disseminated TB Of note is the
significant increase in the incidence
of extrapulmonary and disseminated
disease among the TB cases detected
in adult patients receiving BRMs,
with many cases requiring an
invasive procedure for diagnosis.95
For example, in the Keane et al
study,4 56% of patients receiving
infliximab who developed TB had
FROM THE AMERICAN ACADEMY OF PEDIATRICS
extrapulmonary TB, and 24% had
disseminated disease, compared
with an expected background rate
of 18% and 2%, respectively, in
patients with non–HIV-related TB.
Similarly, in the study by Dixon
et al,89 62% of all cases were
extrapulmonary TB, with 28%
with disseminated disease. A high
proportion of patients do not develop
granulomas, which is consistent
with diminished host response
against the mycobacteria. In general,
the median time to presentation is
fastest with infliximab (12 weeks)
versus adalimumab (30 weeks) and
etanercept (46 weeks), suggesting
different pharmacokinetics or
pharmacodynamics or different
levels of modulation of the immune
system for each medication.94
Although there are fewer data
available in children, the increased
risk of TB reactivation with
infliximab and etanercept has
been corroborated in several
case reports88,96,97 and at least 1
randomized controlled trial.31,68
However, it is important to note that
the risk of TB reactivation associated
with the underlying autoimmune/
inflammatory conditions alone
without medications has been
estimated to be twice the baseline
rate for the normal population.98
Screening to Reduce TB Infections
During BRM Therapy There is fair
evidence that screening for TB
and treating before starting BRMs
substantially reduces the risk of TB
reactivation. In a small case series,
36 children from Turkey with JIA
were treated with etanercept for
a median duration of 11.5 months
after careful screening with the use
of chest radiography, tuberculin
skin test (TST), clinical histories,
family screening, and physical
examination.99 It was noted that
Turkey has a moderate baseline
prevalence of TB of 27 per 100 000
population. Patients with TST results
of >10 mm who had received bacille
PEDIATRICS Volume 138, number 2, August 2016
Calmette-Guérin (BCG) vaccine or
those suspected of having latent
TB for other reasons underwent
computed tomography of the chest
and/or had cultures performed if
specimens were available. Those
identified as having only latent
TB (no evidence of abnormalities
on computed tomography and/
or sputum specimens) received
4 to 8 weeks of “treatment
doses” of isoniazid followed by
9 months of “lower prophylactic
doses.” The investigators did not
indicate the actual doses used
for either isoniazid treatment or
prophylaxis, and North American
authorities do not normally make
a distinction between prophylaxis
and treatment doses. Treatment
with etanercept was started only
during the “prophylaxis stage” of
the treatment in 7 of the 36 children
meeting the criteria, and none of the
36 developed active TB. Similarly,
among 2210 adult patients with
different rheumatologic conditions
who were treated worldwide
with golimumab, no cases of TB
developed among the 317 who were
assessed and treated for latent TB
with isoniazid, whereas 5 cases
developed in patients not assessed
and treated by week 52.44
Nontuberculous Mycobacteria
Although M tuberculosis has
received the most attention,
some reports suggest that
nontuberculous mycobacteria
(NTM) may be twice as common
as TB in adult patients receiving
BRMs.100–102 With the use of the
FDA MedWatch database, 239
patients with NTM were identified
among patients taking BRMs.102
Although pulmonary disease was
most common (56%), a substantial
number of presentations were
extrapulmonary (44%), which
is similar to the cases seen for
patients developing TB while
receiving BRMs. Most of the
cases occurred during treatment
with infliximab (75%), but this
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finding may be more indicative
of the overall usage of this agent
compared with the others.
Mycobacterium avium was the
organism most commonly isolated.
Actual rates of disease could not be
calculated from the data presented
because the total numbers of
patients in the database were not
reported. Even though NTM may be
common, there is no consensus on
baseline screening, because there is
no accurate (sensitive and specific)
screening test.102 Furthermore, the
treatment of NTM is not as clearly
delineated as for TB.
Varicella and Herpes Zoster Infections
Varicella-zoster virus (VZV)
infections (primary or reactivated)
are a frequently reported
complication among patients
receiving BRMs. For patients
receiving anti–TNF-α BRMs,
reactivation of VZV is the most
common infection.2,60,63,103
However, primary VZV
infections have also been
reported.Varicella.
In a retrospective cohort study of
etanercept use among 25 Italian
children younger than 4 years treated
for a mean period of 23 months, 2
unimmunized patients developed
primary VZV infections at 40 and 24
months, respectively,60 with 1 case
being complicated with necrotizing
fasciitis. Similarly, Lovell et al63
described 3 patients (ages 13, 10,
and 8 years) with primary VZV
among 58 children (ages 4–17 years)
enrolled in a North American openlabel trial of treatment of JIA with
etanercept. Although there was no
report of their immunization status,
all 3 were antibody negative at the
time of diagnosis and seroconverted
after infection, suggesting that these
were primary wild-type infections.
One of these 3 patients’ courses was
complicated by aseptic meningitis,
but all 3 recovered with acyclovir
therapy and discontinuation of
etanercept. These data support the
e7
importance of appropriate varicella
immunization and the recognition
of exposures in patients taking all
BRMs.
Herpes Zoster There is mixed
evidence of an increase in zoster
infections with the use of BRMs. The
data for this evidence are almost
exclusively from adult patients. In
a large German registry in which
5040 patients receiving anti–TNF-α
BRMs or DMARDs were enrolled
prospectively to monitor their
outcomes, there was a significant
increase in the risk of herpes zoster
infections in patients treated with
monoclonal antibodies (infliximab
or adalimumab) but no increase
noted for those receiving etanercept
or DMARDs.104 Similarly, Smitten
et al,105 Galloway et al,106 and
Winthrop et al,107 analyzing large
databases in the United States
and United Kingdom, found an
increased risk of VZV reactivation
in patients receiving BRMs
compared with those receiving
DMARDs alone. In contrast,
another study108 involving the
National Data Bank for Rheumatic
Diseases did not find an increased
risk of zoster for infliximab,
etanercept, or adalimumab.
Encephalitis and meningitis
attributable to herpes simplex
virus (HSV) and VZV have also
been described in postmarketing
surveillance of patients receiving
natalizumab.33
Herpes Simplex Although uncommon,
HSV encephalitis, disseminated
cutaneous HSV, and localized
disease have been described
primarily in case series as a
complication of treatment with
TNF-α inhibitors.5,109–113 There
is at least 1 case report in which
infliximab was successfully used
along with valacyclovir prophylaxis
in a girl with Crohn disease who had
relapsing peribuccal herpes labialis
attributable to HSV type 1.114
e8
Hepatitis B
There have been reports of an
increased risk of hepatitis B
reactivation for patients receiving
BRMs.115,116 As expected, the risk
is greatest in patients who are
hepatitis B surface antigen (HBsAg)
positive. However, the presence of
hepatitis B core antibody (HBcAb) in
HBsAg-negative patients (indicating
immunity on the basis of infection
rather than vaccine) has been
associated with HBV reactivation
in some patients up to 2 years after
immunosuppression with BRMs.117
In 1 study involving 257 patients
infected with hepatitis B and treated
with TNF inhibitors, 39% of patients
who were HBsAg positive and 5%
of those who were HBcAb positive
had reactivation of hepatitis B.45
Increased risk of reactivation
correlates with low levels of hepatitis
B surface antibody (HbsAb) for
patients taking rituximab or TNF-α
antagonists,115,116 suggesting that
reactivation is a direct result of the
BRM decreasing antibody levels.
Endemic Mycoses and Other Fungi
Fungal infections (Aspergillus,111,113,118
Coccidioides,119–121 Histoplasma,
Cryptococcus, Sporothrix, and
Candida)3,5,70,101,111,118,122–124
have been noted, primarily in case
reports or series during treatment
with BRMs. Histoplasma is the most
common invasive fungal organism
identified3,122,123 and is especially
important to diagnose, because
the symptoms, signs, and chest
radiography findings are virtually
indistinguishable from those of
acute TB (cough, fever, chills,
night sweats, weight loss, and
possible skin or mouth lesions).
In at least 1 series, histoplasmosis
was diagnosed 3 times more
commonly than TB among recipients
of BRMs.101 The presentation
of histoplasmosis generally
includes fever of unknown origin
with disseminated disease in
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approximately three-fourths of
patients, and pulmonary disease
is less common. Because the signs
and symptoms are nonspecific,
diagnosis is usually more challenging.
Furthermore, the case fatality
rate of patients with disseminated
disease receiving BRMs is very
high (50%).122 Pancytopenia and
liver dysfunction are often noted.
Antigen detection in urine and serum
is most useful for diagnosis, although
culture of bone marrow could be
considered.
Other fungi are less common. In an
observational study of AERS data
by Keane et al,4 although actual
incidence rates were not given,
there were 12 patients with
P jirovecii pneumonia (PCP), 7 with
histoplasmosis, 6 with aspergillosis,
and 7 with severe Candida infections
in association with infliximab
treatment among the cohort of
∼147 000 patients treated.
HIV
There have been no studies showing
an increased rate of HIV infections
among patients receiving BRMs.
Progressive Multifocal
Leukoencephalopathy
Progressive multifocal
leukoencephalopathy (PML), an
opportunistic viral infection of the
brain associated with JC virus (a
human polyomavirus named after
the initials of the first patient in
whom it was identified) infection
in immunocompromised hosts, has
been reported in adult patients
receiving natalizumab, either as
monotherapy or in conjunction
with other immunomodulators
or immunosuppressors.33 Risk
factors associated with the
development of PML include the
duration of therapy, previous use of
immunosuppressants, and presence
of anti–JC virus antibodies. For this
reason, natalizumab is only available
FROM THE AMERICAN ACADEMY OF PEDIATRICS
through a restricted distribution
program that also involves close
monitoring known as the TOUCH
prescribing program (https://www.
touchprogram.com/TTP/).33
Other Infections
Other opportunistic-type
infections that have been noted
(mostly case reports or case
series) during treatment with
BRMs used alone or with other
immunosuppressive agents include
viral (cytomegalovirus, EpsteinBarr virus [EBV]),111 protozoal
(Pneumocystis),4,111 and bacterial
(Listeria125–127 and Legionella128,129)
during postmarketing surveillance47
or in national or regional databases.
In studies in which EBV or
cytomegalovirus viral load was
measured or polymerase chain
reaction assay was performed
before and during infliximab
treatment over a period of 6 weeks
to 5 years, there was no evidence
of viral reactivation.130,131 In the
adult US population older than
60 years, the annual risk of Listeria
was identified as 43 per 1 000 000
among people receiving anti-TNF
regimens versus 13 million in the
general population.127 Similarly,
a Spanish registry identified rates
of 26.5 per 100 000 patient-years
versus 0.34 per 100 000 patient-years
in the general population.126
P jirovecii colonization has been
identified in 16% to 29% of adult
patients with systemic autoimmune
inflammatory diseases.132–134
In mouse models, B cells play
an antibody-independent role
in clearing a murine form of
Pneumocystis (Pneumocystis carinii
f sp muris) by presenting antigen to
CD4 T cells.135 Rituximab depletes
B cells, and there have been reports
of an increased risk of PCP in the
population of patients receiving
this BRM, primarily those patients
receiving it for hematologic
malignancies.136 Despite this
report, the benefit of using induced
PEDIATRICS Volume 138, number 2, August 2016
sputum to screen for P jirovecii or
chemoprophylaxis for PCP in patients
receiving rituximab is unclear.133,137
Although some experts have
recommended PCP prophylaxis in
the setting of rituximab therapy,138
there are concerns that the PCP
risk is lower than the target of 3.5%
for the benefits to outweigh the
adverse effects of chemoprophylaxis
in non–HIV-infected patients.139,140
PCP infections have also been
identified in 84 patients receiving
infliximab identified through the
AERS database141 and in those
receiving other BRMs.142,143
However, virtually all of the patients
were also receiving concomitant
immunosuppressive agents that
included methotrexate, prednisone,
azathioprine, 6-mercaptopurine, and
cyclosporine. As a result, it is unclear
whether there is an increased risk for
PCP beyond that attributable to the
underlying DMARDs.
INFECTIOUS CONSIDERATIONS FOR
PATIENTS BEFORE INITIATION AND
WHILE RECEIVING BRMS
General Precautions
The indications for intervening
with biologics are often to reverse
a serious clinical condition. Thus,
deferring BRMs to provide protection
against vaccine-preventable
diseases often involves trading
risks. Although, at times, it is clearly
appropriate to defer BRMs so the
patient can receive an immunization,
it may not always be the case, and
deferral of BRMs should generally
be undertaken in consultation with
the relevant specialist managing
the patient (eg, rheumatologist,
gastroenterologist, dermatologist).
However, some basic principles
can be applied to reduce the risk of
serious infections for patients taking
BRMs. All patients with a newly
diagnosed rheumatologic or immunemediated condition, including Crohn
disease and graft-versus-host disease
after HSCT should be considered
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as a current or future candidate for
a BRM and should be screened for
potential opportunistic infections at
the time of diagnosis before initiation
of any immunosuppressive agents.
Although the guidelines in this
statement are applicable, patients
with HSCT with or without graftversus-host disease generally need
to have several other considerations
before and after their transplantation
that are beyond the scope of this
statement, and consultation with
an infectious diseases specialist is
warranted. These agents should
not be given to any patients while
they have clinically significant acute
infections. Furthermore, restraint
should be shown in prescribing BRMs
to children who are being treated
for chronic infections, those with a
history of recurrent infections, or
those with conditions (including HIV
infection) that predispose them to
such infections.89 For such children,
it is prudent to involve an infectious
diseases specialist to help guide and
advocate that all risks are assessed
and that appropriate screening tests
before treatment and monitoring
during and after treatment occur.
Risks associated with potential
opportunistic infections that are
endemic in the area of residence (eg,
histoplasmosis, coccidioidomycosis,
etc) should be thoroughly considered
before starting a BRM. Part of the
consideration for such children
will include the determination of
underlying previous exposure to the
infectious agent and associated risk
of reactivation or infection during
treatment with the BRM. If a decision
is made to treat such children with
a BRM, close monitoring will be
required, ideally in conjunction with
an infectious diseases specialist.
Special consideration should always
be given to the risk of TB. The
development of symptoms suggestive
of an opportunistic infection should
lead to immediate cessation of the
BRM pending confirmation of the
infection, appropriate management
of the infection, and resolution of
e9
symptoms. Serum neutrophil counts
should be monitored regularly
(weekly) in patients receiving
rituximab, and episodes of recurrent
ear, nose, or throat infections in these
patients should lead to measurement
of serum immunoglobulin
concentrations.
Screening for and Facilitating
Adequacy of Immunizations
Immunization Before a BRM Is Started
Immunizations of children about
to receive a BRM should follow the
current recommendations of the
American Academy of Pediatrics
(AAP), Centers for Disease Control and
Prevention, and American Academy
of Family Physicians for persons 0
through 18 years of age16 (available at:
http://aapredbook.aappublications.
org/site/resources/IZSchedule.
pdf144). Before the initiation of BRM
therapy, a thorough history should be
taken for documentation of previous
receipt of appropriate inactivated and
live vaccines or history of having had
the disease, with testing for specific
antibody concentrations where
documentation is inadequate. For
varicella, if there is a reported history
of vaccination but not confirmed by
documentation, serologic testing
is not indicated and vaccination is
recommended if there is sufficient
time to safely administer it (4 weeks
minimum) before initiating the BRM
(Table 2).
All recommended inactivated
vaccines should be given at least 2
weeks before the initiation of BRMs
to enhance immunogenicity. Live
vaccines (rotavirus, live-attenuated
influenza, varicella, measles, mumps,
and rubella) should be given a
minimum of 4 weeks in advance
of beginning BRMs. The measlesmumps-rubella (MMR) vaccine can
be given on the same day as a TST
is administered. If the MMR vaccine
is given before administering the
TST, the latter should be delayed for
4 to 6 weeks because of temporary
e10
suppression of the TST test by
the MMR vaccine.145 Inactivated
vaccines, polysaccharide vaccines,
and recombinant or subunit vaccines
and toxoids do not interfere with TST
interpretation. The determination
of which vaccines are safe to give
for patients receiving steroids
should be made in concert with an
infectious diseases specialist. The
Committee on Infectious Diseases
of the AAP recommends that
children who have diseases such
as systemic lupus erythematosus,
which are, in themselves, considered
to be suppressive of the immune
system, and/or who are receiving
immunosuppressive medications
other than corticosteroids and who
are receiving systemic or locally
administered corticosteroids should
not be given live-virus vaccines
except in special circumstances.18
Patients receiving higher doses
of steroids (≥2 mg/kg per day of
prednisone or its equivalent
or ≥20 mg/day for ≥14 days for
those weighing >10 kg) should
not receive any live-virus vaccines
until corticosteroid therapy has
been discontinued for at least
1 month.18
Immunization After a BRM Is Started
If the patient is already receiving
a BRM, he or she may still receive
any inactivated, polysaccharide,
recombinant, or subunit vaccine that
is due. There is evidence that adult
patients receiving BRM therapy
develop a diminished but adequate
response to such vaccines, including
the annual inactivated influenza
immunizations.146–149 A possible
exception to this may be if the child
is receiving rituximab, which has
been shown to significantly impair
antibody response, especially to
pneumococcal vaccines.150–154
These impairments may persist
for up to 6 months after the
discontinuation of rituximab
and highlight the importance of
immunizing such patients who
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are to receive this or other BRMs
before they begin BRM therapy.
Where there is a test available
for a known antibody correlate
of protection in patients who are
immunized while receiving a BRM,
specific postimmunization serum
antibody titers can be measured
4 to 6 weeks after immunization
to assess immune response and to
guide further immunization and
management of future exposures.18
All children receiving BRMs should
receive annual immunization with
inactivated influenza vaccine.
Live vaccines, including the liveattenuated influenza vaccines, should
not be given to any patients receiving
BRMs or other immunosuppressive
drugs during treatment because
of the risk of dissemination and
adverse outcomes, except in special
circumstances as recommended by
an infectious diseases specialist.18
Immunization After a BRM is Stopped
Because patients receiving BRMs
may have prolonged periods of
immunosuppression after the
discontinuation of the agent, there
are currently no clear data to guide
how soon a live vaccine may be
administered, and studies of duration
of suppression are needed.18 Any
consideration for giving a live vaccine
after the cessation of a BRM should
be made in consultation with an
infectious diseases specialist.
Immunizing Immunocompetent
Household Contacts of Patients
Receiving BRMs
The immunization history of
household members of patients
receiving BRMs should also be
assessed, because they may pose
a risk of transmitting vaccinepreventable conditions. Household
members should all be up to
date with the recommended
inactivated vaccines. The principles
of vaccination of household
contacts of patients receiving
BRMs should follow the same
FROM THE AMERICAN ACADEMY OF PEDIATRICS
principles recommended by the
AAP for household contacts of
immunocompromised patients.18
All household contacts aged
≥6 months should also receive
influenza immunization annually.18
With regard to live vaccines, oral
polio vaccine (no longer given
in the United States) should not
be administered to household
contacts of persons receiving BRMs.
However, susceptible household
contacts can and should receive
both MMR and rotavirus vaccines,
because the vaccine-strain viruses
are rarely transmitted. Similarly,
varicella vaccine should be given
to susceptible household contacts,
because vaccine-strain virus is also
rarely transmitted. In the event
a household contact of a patient
receiving a BRM who is thought to
be susceptible to VZV develops a
vesicular rash after receiving the
varicella vaccine, efforts should be
made to separate him or her from
the person receiving a BRM for
the duration of the rash. However,
because the risk of transmission of
the vaccine strain is very low and
disease associated with the virus
is expected to be mild, VariZIG
(varicella-zoster immune globulin)
is not indicated if contact does
occur. For further guidance on
immunizing parents and other
household contacts in the pediatric
office setting, including medico-legal,
financial, and logistic considerations,
please see the AAP’s technical report
“Immunizing Parents and Other
Households Contacts in the Pediatric
Office Setting” (http://pediatrics.
aappublications.org/content/129/
1/e247.full; accessed September
10, 2015).
Screening and Treatment
Recommendations for TB
As soon as a patient is diagnosed with
a rheumatologic or inflammatory/
autoimmune condition for which
BRMs may be later needed for
treatment, TB screening and
PEDIATRICS Volume 138, number 2, August 2016
appropriate treatment should be
initiated155–157 using the principles
outlined as follows:
• All patients, regardless of specific
TB risk factors, who will be taking
an immunomodulating biologic
agent should be tested for latent
TB infection (LTBI) before starting
the therapy.
• There are 2 options that should
be considered for screening,
depending on the clinical scenario:
either TST or use of an interferon-γ
release assay (IGRA) or both.
There are 2 choices for IGRA, the
QuantiFERON-TB Gold In-Tube
assay (Cellestis/Qiagen, Carnegie,
Australia) and the T-SPOT.TB assay
(Oxford Immunotec, Abingdon,
United Kingdom). Both are
considered acceptable.19,157
• For children without risk factors
for LTBI (previous history of TB,
previous history of positive TST
result, history of exposure to
someone with active TB, travel to
an area with endemic TB in the
past 12 months, or foreign-born
patient or parents from area with
endemic TB) and without any
symptoms suggestive of TB, the
decision as to which screening
method to use at baseline should
be based on age. Children younger
than 5 years, in general, should
be screened with TST, whereas an
IGRA is preferred for children older
than 5 years.19
• For patients with any risk factor
for LTBI (previous history of TB,
previous history of positive TST
result, history of exposure to
someone with active TB, or travel
to an area with endemic TB in the
past 12 months) or any symptoms
suggestive of TB, both the TST and
an IGRA should be performed and
appropriate treatment of LTBI
should be started if either test
result is positive once TB disease
has been ruled out.19 Most experts
do not currently use an IGRA
when testing for LTBI for children
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younger than 2 years because of
a lack of data for this age group
and a high risk of progression
to disease but will still use an
IGRA in children 2 years or older,
especially if they have received a
bacille Calmette-Guerin vaccine.19
Although most of the data available
are for children 5 years and older,
there are increasing data also
available for children 2 to 5 years
of age.19
• Patients with a positive TST or an
IGRA result or any risk factor as
stated previously for LTBI should
also have chest radiography
(postanterior and lateral)
performed.
• Routine annual TST or IGRA is not
recommended, but patients should
be asked at least annually about TB
symptoms and risk factors.
• If there is a change in risk or
new symptoms suggestive of
TB infection while receiving
treatment, there should be further
evaluation and risk assessment,
including a repeat of both
TST and IGRA (if the baseline
was negative) as well as chest
radiography.
• If LTBI is diagnosed, the patient
needs treatment to prevent TB
disease.155,156
• Patients suspected of having active
TB should have their BRM and
other immunosuppressive agents
discontinued until TB is ruled out
or under control. Guidance from
an infectious diseases specialist
is recommended in this setting
for possible isolation precautions
and management. Risk factors
for drug-resistant TB (previous
history of treatment of TB disease,
contact with a patient with known
drug-resistant TB, country of
origin or current residence in
geographic area with a high
prevalence of drug-resistant TB,
or contact with a source case
who has positive smears for
acid-fast bacilli or cultures after
e11
2 months of appropriate anti-TB
therapy) should be considered in
formulating empirical therapy.158
There will need to be an intensive
investigation to examine for
disseminated or extrapulmonary
disease guided by an expert in TB
management.
NTM
There are no recommendations or
tests at the present time for screening
for NTM. However, NTM should
be considered in the differential
diagnosis of patients receiving BRMs
with febrile illnesses, cervical or
unexplained lymphadenitis, or other
focal infections or anytime TB is
being considered.
Screening for Histoplasmosis and
Other Fungi
All patients should be queried
about possible exposure and
epidemiologic risk factors for
potentially invasive fungal
infections, especially histoplasmosis
and coccidioidomycosis, which
have symptoms and signs that
significantly overlap with TB. The
main epidemiologic determinants of
risk for histoplasmosis include the
following122,124,159–161: geographic
location of residence near river
beds (Mississippi River Valley,
Ohio River Valley, Chesapeake
Bay area, eastern Oklahoma, and
eastern Texas). Anyone who lives in
a histoplasmosis belt is potentially
infected; estimates are that 90% of
residents acquire histoplasmosis
and self-resolve before adulthood;
thus, routine laboratory screening
is not indicated. Furthermore,
negative serologic test results
before the initiation of BRMs does
not predict patients at risk of
development of histoplasmosis,
especially among patients
already receiving DMARDs.122
Immunosuppression and extremes
of age are also major risk factors.
Residence in geographic areas
where coccidioidomycosis is
endemic (eg, southwestern
e12
United States and southern
California) is an epidemiologic
risk factor for developing
coccidioidomycosis,119,120,161–164
and Filipino, Hispanic, black,
American Indian, and Asian persons
and pregnant women during the
third trimester and women in the
immediate postpartum period are
at risk for more severe disease. Any
form of immunosuppression also
leads to an increased risk of invasive
and disseminated disease. Up to
2% of patients receiving BRMs will
develop coccidioidomycosis if they
reside in an at-risk region.
Patients suspected of having signs
or symptoms compatible with
acute histoplasmosis122,124,159,160
or coccidioidomycosis119–121,162–164
during therapy with BRMs should
have the BRM discontinued
immediately and require evaluation
with a combination of chest
radiography and serologic, antigen
detection, and culture tests. These
tests and treatment options are best
conducted in consultation with an
infectious diseases expert.
Screening for HSV, VZV, EBV,
Hepatitis B, and PML
VZV and HSV
As noted previously in the
immunization section, all patients
should be screened by history,
immunization, and possibly
laboratory serologic records to
facilitate documentation that they are
either immune or have received the
age-appropriate dose(s) of varicella
vaccine at presentation. Routine
testing for VZV is not recommended
because of the variability in
sensitivity of the assays, particularly
in assessing immunity after VZV
immunization; and where there is
doubt about immunity on the basis
of history or inadequacy of records,
vaccination is recommended. If VZV
vaccine is needed, because it is a livevirus vaccine it should be given at
least 4 weeks before the initiation of
BRM therapy.165
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Patients suspected of having VZV
or HSV infection during BRM
therapy should stop taking the BRM.
Diagnosis should be sought by a
combination of clinical, serologic, and
polymerase chain reaction tests from
skin lesions (ie, vesicles or papules),
and acyclovir or valacyclovir
therapy should be started pending
confirmation of diagnosis. Patients
with recurrent HSV who are being
considered for BRM therapy
should be given consideration for
prophylaxis with valacyclovir or
acyclovir.
EBV
Consideration should be given
to baseline serologic testing for
EBV at the time of diagnosis of the
underlying rheumatologic condition.
Further serologic testing should be
considered if the patient develops
signs or symptoms that have been
associated with EBV, including
mononucleosis-like illness or
excessive fatigue.
Hepatitis B
Patients being considered for
BRM therapy should be screened
for past hepatitis B infection with
both immunization records and
serologic testing for HBsAg, HbcAb
(total and IgM), and quantitative
HBsAb166 (Table 3). It is advisable
to obtain baseline liver function
tests (LFTs) at the same time.167–172
Patients who are negative for HBsAg,
HBcAb, and HBsAb are considered
uninfected and nonimmune. They
should be immunized with the first
dose of hepatitis B vaccine at least
2 weeks before initiation of the
BRM.173 Consideration of whether
the full series of HBV vaccinations
is given before initiation of the BRM
should be made in conjunction with
the specialist initiating the BRM,
weighing the risks and benefit of
delaying BRM therapy. Patients
who are only HBsAb positive are
likely immune and can be safely
treated with BRMs. If their antibody
FROM THE AMERICAN ACADEMY OF PEDIATRICS
Adapted with permission from ref 117. HBcIgM, hepatitis B core IgM antibody; HBeAb, hepatitis B core e antibody; HBeAg, hepatitis B core e antigen; ID, infectious diseases; –, negative; +, positive.
–
–
–
–
Occult
+
–
–
+
–
Resolved
+
HBV DNA
Defer BRM therapy
Treat with BRM in consultation with ID
consultant or hepatologist
Treat with BRM in consultation with ID
consultant or hepatologist
Treat with BRM in consultation with ID
consultant or hepatologist
Not needed
HBeAg, HBeAb,
HBV DNA
HBV DNA
+
+/–
+
–
+
+
+
+
Acute
Chronic
–
–
+
–
–
–
–
Not needed
Safely treat with BRM
Administer hepatitis B vaccine before
BRM therapy
For HBsAb <10 mIU/mL, suggest HBV
booster
Safely treat with BRM
Not needed
–
–
–
–
–
Uninfected,
nonimmune
Vaccinated
Comments
Management
Additional Testing
Abnormal LFTs and/or
Symptoms
HBcIgM
HBcAb
HBsAb
HBsAg
HBV Infection
TABLE 3 Screening Tests for HBV Infection, Interpretation, and Recommendations Before BRM Therapy
PEDIATRICS Volume 138, number 2, August 2016
titer is low (<10 mIU/mL), strong
consideration should be given to
giving a booster dose of hepatitis
B vaccine before initiation of
treatment.148,166 Recent receipt
of Immune Globulin Intravenous
(IGIV) may be associated with a
transiently positive serologic test
result. Patients who have acute
HBV infection (HBsAg positive, total
HBcAb positive, hepatitis B core
IgM positive, and elevated LFTs)
should not receive a BRM. Patients
who show evidence of chronic
HBV infection (HBsAg positive,
HBcAb positive, hepatitis B core
IgM negative, and persistently or
intermittently high LFT results)
should be evaluated by either an
infectious diseases specialist or
a hepatologist for further testing
to determine their status.169 This
testing will likely involve measuring
HBV DNA levels to determine
the likelihood of clearance with
antiviral treatment. In general,
chronic carriers with a high viral
load (HBV DNA >105 copies per
mL) and abnormal LFTs will
need to be treated with antiviral
agents effective against HBV, but
guidance by an infectious diseases
specialist or hepatologist is strongly
recommended. Patients who are
HBsAg negative, HBsAb positive,
and HBcAb positive are considered
to have “resolved HBV infection”
and can likely be treated with close
monitoring by an infectious diseases
expert or hepatologist. In this
scenario, it is advisable to first obtain
a baseline HBV DNA quantitative
level as well as LFTs that can be
monitored in follow-up. Finally, some
patients will only be positive for
HBcAb and are generally considered
to have “occult HBV.” Some of these
patients may also have a falsepositive test result or may have
resolving infection. They may or
may not be at risk of HBV
reactivation. Most can be treated
with the BRM under the guidance
of an infectious diseases expert or a
hepatologist.
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e13
Long-term Monitoring for HBV
All patients at risk of HBV
reactivation (chronic, resolved,
or occult) should have regular
(every 1–3 months, depending
on underlying HBV infection)
monitoring of their LFTs, HBsAg,
hepatitis B e antigen, and HBV DNA
counts. This monitoring should
continue for at least 6 months after
termination of the BRM.
PML
All patients receiving natalizumab
should be monitored regularly (3 and
6 months after the first infusion and
every 6 months after and for at least
6 months after discontinuation) for
PML, and the medication should be
withheld immediately with any signs
or symptoms of the condition.174
Diagnosis of PML involves a
gadolinium-enhanced MRI brain
scan and cerebrospinal fluid analysis
for JC viral DNA when indicated. An
algorithm has been proposed for risk
profiling and management of PML for
patients receiving natalizumab.174
CONCLUSIONS
BRMs have become an important
component of effective management
of patients with a variety of
autoimmune/inflammatory
conditions. However, there is an
increased risk of certain serious
and opportunistic infections for
patients receiving these biologic
agents, especially the risks of TB
and viral infections. It is important
for pediatricians, family physicians,
and other primary care practitioners
managing patients who receive these
important treatments to be aware of
the potential infections complications
and to practice anticipatory
guidance between visits to reduce
the risk of occurrence or of negative
outcomes if the complications do
occur. In most scenarios, a close
working relationship among the
pediatrician, the pediatric medical
subspecialist prescribing the BRM,
e14
and an infectious diseases specialist
is warranted.
COMMITTEE ON INFECTIOUS DISEASES,
2015–2016
Carrie L. Byington, MD, FAAP, Chairperson
Yvonne A. Maldonado, MD, FAAP, Vice Chairperson
Elizabeth D. Barnett, MD, FAAP
H. Dele Davies, MD, FAAP
Kathryn M. Edwards, MD, FAAP
Ruth Lynfield, MD, FAAP
Flor M. Munoz-Rivas, MD, FAAP
Dawn L. Nolt, MD, FAAP
Ann-Christine Nyquist, MD, MSPH, FAAP
Mobeen H. Rathore, MD, FAAP
Mark H. Sawyer, MD, FAAP
William J. Steinbach, MD, FAAP
Tina Q. Tan, MD, FAAP
Theoklis E. Zaoutis, MD, MSCE, FAAP
FORMER COMMITTEE MEMBERS
Dennis L. Murray, MD, FAAP
Gordon E. Schutze, MD, FAAP
Rodney E. Willoughby, MD, FAAP
EX OFFICIO
Henry H. Bernstein, DO, MHCM, FAAP – Red Book
Online Associate Editor
Michael T. Brady, MD, FAAP – Red Book Associate
Editor
Mary Anne Jackson, MD, FAAP, Red Book Associate
Editor
David W. Kimberlin, MD, FAAP – Red Book Editor
Sarah S. Long, MD, FAAP – Red Book Associate
Editor
H. Cody Meissner, MD, FAAP – Visual Red Book
Associate Editor
LIAISONS
Douglas Campos-Outcalt, MD, MPH – American
Academy of Family Physicians
Karen M. Farizo, MD – Food and Drug
Administration
Marc Fischer, MD, FAAP – Centers for Disease
Control and Prevention
Bruce Gellin, MD, MPH – National Vaccine
Program Office
Richard L. Gorman, MD, FAAP – National Institutes
of Health
Natasha B. Halasa, MD, MPH, FAAP – Pediatric
Infectious Diseases Society
Joan L. Robinson, MD – Canadian Paediatric
Society
Marco Aurelio Palazzi Safadi, MD – Sociedad
Latinoamericana de Infectologia Pediatrica
Jane F. Seward, MBBS, MPH, FAAP – Centers for
Disease Control and Prevention
Geoffrey Simon, MD, FAAP – Committee on
Practice Ambulatory Medicine
Downloaded from by guest on April 29, 2017
Jeffrey R. Starke, MD, FAAP – American Thoracic
Society
STAFF
Jennifer M. Frantz, MPH
ABBREVIATIONS
AAP: American Academy of
Pediatrics
AERS: Adverse Event Reporting
System
BRM: biologic response modifier
CI: confidence interval
DMARD: disease-modifying
antirheumatic drug
EBV: Epstein-Barr virus
Fc: fragment-crystallizable
FDA: Food and Drug Administration
HBcAb: hepatitis B core antibody
HBsAb: hepatitis B surface
antibody
HBsAg: hepatitis B surface
antigen
HBV: hepatitis B virus
HSCT: hematopoietic stem cell
transplant
HSV: herpes simplex virus
Ig: immunoglobulin
IGRA: interferon-γ release assay
IL: interleukin
JAK: Janus kinase
JIA: juvenile idiopathic arthritis
LFT: liver function test
LTBI: latent tuberculosis
infection
MMR: measles-mumps-rubella
NTM: nontuberculous
mycobacteria
OR: odds ratio
PCP: Pneumocystis jirovecii
(previously carinii)
pneumonia
PML: progressive multifocal leukoencephalopathy
RA: rheumatoid arthritis
TB: tuberculosis
Th: T helper
TNF: tumor necrosis factor
TST: tuberculin skin test
VZV: varicella-zoster virus
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Infectious Complications With the Use of Biologic Response Modifiers in Infants
and Children
H. Dele Davies and COMMITTEE ON INFECTIOUS DISEASES
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
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and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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Infectious Complications With the Use of Biologic Response Modifiers in Infants
and Children
H. Dele Davies and COMMITTEE ON INFECTIOUS DISEASES
Pediatrics 2016;138;; originally published online July 18, 2016;
DOI: 10.1542/peds.2016-1209
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/138/2/e20161209.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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