FROM THE AMERICAN ACADEMY OF PEDIATRICSPEDIATRICS Volume 138 , number 2 , August 2016 :e 20161209

Infectious Complications With the Use of Biologic Response Modifiers in Infants and ChildrenH. Dele Davies, MD, FAAP, COMMITTEE ON INFECTIOUS DISEASES

This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have fi led confl ict of interest statements with the American Academy of Pediatrics. Any confl icts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.

Clinical reports from the American Academy of Pediatrics benefi t from expertise and resources of liaisons and internal (AAP) and external reviewers. However, clinical reports from the American Academy of Pediatrics may not refl ect 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 reaffi rmed, 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 fi nancial relationship relevant to this article to

disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The author has indicated

he has no potential confl icts of interest to disclose.

abstractBiologic response modifi ers (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 infl ammatory 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 infl uenza 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.

CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

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 Modifi ers in Infants and Children. Pediatrics.

2016;138(2):e20161209

by guest on August 7, 2019www.aappublications.org/newsDownloaded from

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 immune-

mediated conditions, such as

juvenile idiopathic arthritis (JIA),

inflammatory bowel disease, graft-

versus-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 (IL-

1A) 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

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

[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 antibody-

dependent cytotoxicity. Belimumab

(Benlysta; GlaxoSmithKline,

Rockville, MD) is a human IgG1-λ

e2 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

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

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.

Fusion Proteins

Abatacept (Orencia; Bristol

Myers Squibb, Princeton, NJ) and

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).

Tofacitinib (Xeljanz; Pfizer, New

York, NY) is an oral, small-molecule

protein kinase inhibitor of the

enzyme Janus kinase (JAK) 3 and

1 (JAK3 and JAK1, respectively)

that interferes with the JAK-

STAT 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 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 guidelines 16, 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 BRM 18

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 infl uenza vaccine 18

Avoid live vaccines, unless under special circumstances with help of infectious diseases specialist 18

Immunizing immunocompetent household contacts (before or during treatment)?

Follow AAP guidelines for immunizing household contacts of immunocompromised patients 18

Risk of listeriosis

Avoid unpasteurized milk and milk products, uncooked meats 20

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.

by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

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,

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

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

e4

TABLE 2 FDA-Approved BRMs and Indications

Generic Name (Year[s] FDA

Approved for Indications)

Trade Name Mechanism of Action Usual Route,

Half-life

FDA-Approved Indicationa

Infl iximab (1999, 2009) Remicade 21 TNF-α inhibitor (anti–TNF-α

chimeric monoclonal

IgG1κ antibody)

IV, 7.5–9.5 d Crohn disease [RA, plaque psoriasis, psoriatic

arthritis, ankylosing spondylitis, ulcerative

colitis]

Etanercept (1998) Enbrel 22 TNF-α inhibitor (soluble

TNF-α receptor fusion

protein)

SQ, 70–132 h JIA [RA, plaque psoriasis, psoriatic arthritis,

ankylosing spondylitis]

Adalimumab (2002) Humira 23 TNF-α inhibitor (anti–TNF-α

humanized monoclonal

IgG1 antibody)

SQ, 10–20 d JIA [RA, plaque psoriasis, psoriatic arthritis,

ankylosing spondylitis, Crohn disease]

Golimumab (2009) Simponi 24 TNF-α inhibitor (anti–TNF-α

IgG1κ antibody)

SQ, 7–20 d [RA, psoriatic arthritis, ankylosing spondylitis]

Certolizumab pegol (2009) Cimzia 25 TNF-α inhibitor (PEGylated

human Fab antigen

binding)

SQ, 14 d [RA, Crohn disease]

Abatacept (2005, 2009) Orencia 26 Anti-CTLA4 selective T-cell

costimulation modulator

protein (blocks TNF-α,

IL-2, and interferon-γ

production)

IV or SQ, 8–25 d JIA [RA]

Anakinra (2001) Kineret 27 Recombinant anti-IL-1

receptor antagonist

SQ, 4–6 h [RA]

Rituximab (2006) Rituxan 28 Anti-CD20 therapy IV, 14–62 d [RA, non-Hodgkin’s lymphoma]

Tocilizumab (2010) Actemra 29 Anti-IL-6 humanized

monoclonal antibody

IV, 8–14 d [RA]

Ustekinumab (2013) Stelara 30 Anti-IL-12 and IL-23

humanized monoclonal

antibody

SQ, 20–24 d [Psoriatic arthritis, plaque psoriasis]

Canakinumab (2009, 2013) Ilaris 31, 32 Anti-IL-1B human monoclonal

antibody

SQ, 26 d CAPS, JIA

Natalizumab (2008, 2013) Tysabri 33 Humanized anti–integrin

α 4 subunit monoclonal

antibody (reduces

leukocyte adhesion and

transmigration)

IV, 11 d [Crohn disease, multiple sclerosis]

Belimumab (2011) Benlysta 34 Human IgG1λ monoclonal

antibody against soluble

human B lymphocyte

stimulator protein

IV, 19 d [Systemic lupus erythematosus]

Rilonacept (2008, orphan

drug)

Arcalyst 35 IL-1 receptor fusion protein SQ, 8.6 d CAPS

Tofacitinib (2012) Xeljanz 36 Small molecule protein

kinase inhibitor of JAK3

and JAK1

Oral, 3 h [RA]

CAPS, cryopyrin-associated periodic syndromes (consisting of familial cold autoinfl ammatory syndrome and Muckle-Wells syndrome); IV, intravenous; SQ, subcutaneous.a For underlined conditions, safety and effi cacy have been established in children <18 y; for bracketed indications, safety and effi cacy have only been shown in adults. Infl iximab, etanercept,

and adalimumab have been used off-label for scleritis, but none are FDA approved for this condition.

by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

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

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 infliximab 12, 31, 61, 67 – 70 and

adalimumab 38, 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,

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

FIGURE 1Structures 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.

by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

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

were ear, nose, and throat (14%)

as well as skin (11%) infections.

Four cases of herpetic infections

were also reported among the mild

infections.

Specifi c 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

100 000 88 to 24.4 per 100 000. 4 In

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 cohort 92

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

e6 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

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 reports 88, 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

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

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 al 63

described 3 patients (ages 13, 10,

and 8 years) with primary VZV

among 58 children (ages 4–17 years)

enrolled in a North American open-

label 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 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

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

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

identified 3, 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

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

e8 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

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, Epstein-

Barr virus [EBV]), 111 protozoal

(Pneumocystis), 4, 111 and bacterial

(Listeria 125– 127 and Legionella 128, 129)

during postmarketing surveillance 47

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

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 database 141 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 immune-

mediated condition, including Crohn

disease and graft-versus-host disease

after HSCT should be considered

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 graft-

versus-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 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

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 age 16 (available at:

http:// aapredbook. aappublications.

org/ site/ resources/ IZSchedule.

pdf 144). 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 measles-

mumps-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

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

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 live-

attenuated 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 vaccine-

preventable 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

e10 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

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

appropriate treatment should be

initiated 155 – 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

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 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

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

following 122, 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

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 histoplasmosis 122, 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 live-

virus vaccine it should be given at

least 4 weeks before the initiation of

BRM therapy. 165

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

HBsAb 166 ( 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

e12 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

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 false-

positive 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.

e13

TABL

E 3

Scr

een

ing

Test

s fo

r H

BV

Infe

ctio

n, I

nte

rpre

tati

on, a

nd

Rec

omm

end

atio

ns

Bef

ore

BR

M T

her

apy

HB

V In

fect

ion

HB

sAg

HB

sAb

HB

cAb

HB

cIgM

Abn

orm

al L

FTs

and

/or

Sym

pto

ms

Add

itio

nal

Tes

tin

gM

anag

emen

tC

omm

ents

Un

infe

cted

,

non

imm

un

e

––

––

–N

ot n

eed

edS

afel

y tr

eat

wit

h B

RM

Adm

inis

ter

hep

atit

is B

vac

cin

e b

efor

e

BR

M t

her

apy

Vacc

inat

ed–

+–

––

Not

nee

ded

Saf

ely

trea

t w

ith

BR

MFo

r H

BsA

b <

10 m

IU/m

L, s

ugg

est

HB

V

boo

ster

Acu

te+

–+

++

Not

nee

ded

Def

er B

RM

th

erap

y

Ch

ron

ic+

–+

–+

/–H

BeA

g, H

BeA

b,

HB

V D

NA

Trea

t w

ith

BR

M in

con

sult

atio

n w

ith

ID

con

sult

ant

or h

epat

olog

ist

Res

olve

d–

++

––

HB

V D

NA

Trea

t w

ith

BR

M in

con

sult

atio

n w

ith

ID

con

sult

ant

or h

epat

olog

ist

Occ

ult

––

+–

–H

BV

DN

ATr

eat

wit

h B

RM

in c

onsu

ltat

ion

wit

h ID

con

sult

ant

or h

epat

olog

ist

Adap

ted

wit

h p

erm

issi

on f

rom

ref

117

. HB

cIgM

, hep

atit

is B

cor

e Ig

M a

nti

bod

y; H

BeA

b, h

epat

itis

B c

ore

e an

tib

ody;

HB

eAg,

hep

atit

is B

cor

e e

anti

gen

; ID

, in

fect

iou

s d

isea

ses;

–, n

egat

ive;

+, p

osit

ive.

by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

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,

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 Lynfi eld, 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 Offi ce

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

Jeffrey R. Starke, MD, FAAP – American Thoracic

Society

STAFF

Jennifer M. Frantz, MPH

e14

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 Administra-

tion

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 leu-

koencephalopathy

RA:  rheumatoid arthritis

TB:  tuberculosis

Th:  T helper

TNF:  tumor necrosis factor

TST:  tuberculin skin test

VZV:  varicella-zoster virus

by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

REFERENCES

1. Saag KG, Teng GG, Patkar NM, et al;

American College of Rheumatology.

American College of Rheumatology

2008 recommendations for the use

of nonbiologic and biologic disease-

modifying antirheumatic drugs in

rheumatoid arthritis. Arthritis Rheum.

2008;59(6):762–784

2. Toussi SS, Pan N, Walters HM,

Walsh TJ. Infections in children and

adolescents with juvenile idiopathic

arthritis and infl ammatory bowel

disease treated with tumor necrosis

factor-α inhibitors: systematic review

of the literature. Clin Infect Dis.

2013;57(9):1318–1330

3. Giles JT, Bathon JM. Serious infections

associated with anticytokine therapies

in the rheumatic diseases. J Intensive

Care Med. 2004;19(6):320–334

4. Keane J, Gershon S, Wise RP, et

al. Tuberculosis associated with

infl iximab, a tumor necrosis factor

alpha-neutralizing agent. N Engl J Med.

2001;345(15):1098–1104

5. Ford AC, Peyrin-Biroulet L.

Opportunistic infections with anti-

tumor necrosis factor-α therapy

in infl ammatory bowel disease:

meta-analysis of randomized

controlled trials. Am J Gastroenterol.

2013;108(8):1268–1276

6. Lichtenstein GR, Feagan BG, Cohen

RD, et al. Serious infections and

mortality in association with

therapies for Crohn’s disease: TREAT

registry. Clin Gastroenterol Hepatol.

2006;4(5):621–630

7. Rahier JF, Ben-Horin S, Chowers Y,

et al; European Crohn’s and Colitis

Organisation. European evidence-

based consensus on the prevention,

diagnosis and management

of opportunistic infections in

infl ammatory bowel disease. J Crohn’s

Colitis. 2009;3(2):47–91

8. Rahier JF, Yazdanpanah Y, Colombel

JF, Travis S. The European (ECCO)

consensus on infection in IBD: what

does it change for the clinician? Gut.

2009;58(10):1313–1315

9. Viget N, Vernier-Massouille G, Salmon-

Ceron D, Yazdanpanah Y, Colombel JF.

Opportunistic infections in patients

with infl ammatory bowel disease:

prevention and diagnosis. Gut.

2008;57(4):549–558

10. Beukelman T, Patkar NM, Saag KG,

et al. 2011 American College of

Rheumatology recommendations for

the treatment of juvenile idiopathic

arthritis: initiation and safety

monitoring of therapeutic agents for

the treatment of arthritis and systemic

features. Arthritis Care Res (Hoboken).

2011;63(4):465–482

11. Beukelman T, Xie F, Baddley JW, et al;

SABER Collaboration. Brief report:

incidence of selected opportunistic

infections among children with juvenile

idiopathic arthritis. Arthritis Rheum.

2013;65(5):1384–1389

12. Hyams J, Walters TD, Crandall W, et

al. Safety and effi cacy of maintenance

infl iximab therapy for moderate-to-

severe Crohn’s disease in children:

REACH open-label extension. Curr Med

Res Opin. 2011;27(3):651–662

13. Le Saux N; Canadian Paediatric Society,

Infectious Diseases and Immunization

Committee. Biologic response

modifi ers to decrease infl ammation:

focus on infection risks. Paediatr Child

Health. 2012;17(3):147–154

14. Veereman-Wauters G, de Ridder L,

Veres G, et al; ESPGHAN IBD Porto

Group. Risk of infection and prevention

in pediatric patients with IBD: ESPGHAN

IBD Porto Group commentary.

J Pediatr Gastroenterol Nutr.

2012;54(6):830–837

15. Woerner A, Ritz N. Infections in children

treated with biological agents. Pediatr

Infect Dis J. 2013;32(3):284–288

16. Centers for Disease Control and

Prevention, Advisory Committee

on Immunization Practices;.

Recommended immunization

schedules for persons aged 0 through

18 years—United States, 2013. MMWR

Morb Mortal Wkly Rep. 2013;62(1):2–8

17. Centers for Disease Control and

Prevention, Advisory Committee on

Immunization Practices; American

Academy of Pediatrics; American

Academy of Family Physicians.

Recommended immunization

schedules for persons aged 0 through

18 years--United States, 2013. MMWR

Morb Mortal Wkly Rep. 2013;62(1):1–19

18. American Academy of Pediatrics.

Immunization in special clinical

circumstances. In: Pickering LK, Baker

CJ, Kimberlin DW, Long SS, eds. Red

Book: 2012 Report of the Committee on

Infectious Diseases. Elk Grove Village,

IL: American Academy of Pediatrics;

2012:69–109

19. Starke JR; Committee on Infectious

Diseases. Interferon-γ release assays

for diagnosis of tuberculosis infection

and disease in children. Pediatrics.

2014;134(6). Available at: www.

pediatrics. org/ cgi/ content/ full/ 134/ 6/

e1763

20. American Academy of Pediatrics.

Listeria monocytogenes infections

(listeriosis). In: Pickering LK, Baker

CJ, Kimberlin DW, Long SS, eds. Red

Book: 2012 Report of the Committee on

Infectious Diseases. Elk Grove Village,

IL: American Academy of Pediatrics;

2012:471–474

21. Remicade (infl iximab) [package

insert]. Horsham, PA: Janssen Biotech;

2013. Available at: www. remicade. com/

shared/ product/ remicade/ prescribing-

information. pdf. Accessed October 22,

2014

22. Horneff G, De Bock F, Foeldvari I, et

al; German and Austrian Paediatric

Rheumatology Collaborative

Study Group. Safety and effi cacy

of combination of etanercept and

methotrexate compared to treatment

with etanercept only in patients

with juvenile idiopathic arthritis

(JIA): preliminary data from the

German JIA Registry. Ann Rheum Dis.

2009;68(4):519–525

23. Humira (adalimunab) [package

insert]. North Chicago, IL: AbbVie; 2013.

Available at: www. rxabbvie. com/ pdf/

humira. pdf. Accessed October

22, 2014

24. Simponi (golimumab) [package

insert]. Horsham, PA: Jannsen Biotech;

2013. Available at: www. simponiaria.

com/ shared/ product/ simponiaria/

prescribing- information. pdf. Accessed

October 22, 2014

25. Cimzia (certolizumab pegol) [package

insert]. Smyrna, GA: UCB; 2012.

Available at: www. cimzia. com/ assets/

pdf/ Prescribing_ Information. pdf.

Accessed October 22, 2014

e15 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

26. Orencia (abatacept) [package

insert]. Princeton, NJ: Bristol Myers

Squibb; 2013. Available at: http://

packageinserts. bms. com/ pi/ pi_

orencia. pdf. Accessed October 22, 2014

27. Kineret (anakinra) [package insert].

Stockholm, Sweden: Swedish Orphan

Biovitrum AB; 2013. Available at: www.

kineretrx. com/ fi leadmin/ user_ upload/

kineretus/ documents/ Kineret_ Full_

Prescribing_ Information. pdf. Accessed

October 22, 2014

28. Rituxan (rituximab) [package insert].

South San Francisco, CA: Genentech;

2013. Available at: www. gene. com/

download/ pdf/ rituxan_ prescribing. pdf.

Accessed October 22, 2014

29. Actemra (tocilizumab) [package

insert]. South San Francisco, CA:

Genentech; 2013. Available at: www.

gene. com/ download/ pdf/ actemra_

prescribing. pdf. Accessed October 22,

2014

30. Stelara (ustekinumab) [package

insert]. Horsham, PA: Janssen Biotech;

2013. Available at: www. stelarainfo.

com/ pdf/ PrescribingInform ation. pdf.

Accessed October 22, 2014

31. Ruperto N, Lovell DJ, Cuttica R,

et al; Paediatric Rheumatology

International Trials Organisation;

Pediatric Rheumatology Collaborative

Study Group. A randomized, placebo-

controlled trial of infl iximab plus

methotrexate for the treatment

of polyarticular-course juvenile

rheumatoid arthritis. Arthritis Rheum.

2007;56(9):3096–3106

32. Ilaris (canakinumab) [package

insert]. East Hanover, NJ: Novartis;

2013. Available at: www. pharma. us.

novartis. com/ product/ pi/ pdf/ ilaris. pdf.

Accessed October 22, 2014

33. Tysabri (natalizumab) [package

insert]. Cambridge, MA: Biogen Idec;

2013. Available at: www. tysabri. com/

pdfs/ I61061- 13_ PI. pdf. Accessed

October 22, 2014

34. Benlysta (belimumab) [package

insert]. GlaxoSmithKline, Mississauga,

Ontatrio, Canada; 2014. Available

at: www. gsksource. com/ gskprm/

en/ US/ adirect/ gskprm? cmd=

ProductDetailPage & product_ id=

1300455676143& featureKey= 602522&

tab= tab1& footer= yes& pTab=

one#nlmhighlights . Accessed October

22, 2014

35. Arcalyst (rilonacept) [package

insert]. Tarrytown, NY: Regeneron

Pharmaceuticals; 2013. Available

at: www. arcalyst. com/ images/ pdf/

ARCALYST- fpi. pdf? phpMyAdmin=

e99e09ae33c1fdbba fd69c8883f97963.

Accessed October 22, 2014

36. Xeljanz (tofacitinib) [package insert].

New York, NY: Pfi zer; 2014. Available

at: http:// labeling. pfi zer. com/

ShowLabeling. aspx? id= 959. Accessed

October 22, 2014

37. Bray V. The safety of infl iximab

(Remicade(R)) infusion in clinical

practice [abstract 153]. Arthritis

Rheum. 2001;(suppl 9):S83

38. Hyams JS, Griffi ths A, Markowitz J, et

al Safety and effi cacy of adalimumab

for moderate to severe Crohn's

disease in children. Gastroenterology.

2012;143(2):365.e2–374.e2

39. Lipsky PE, van der Heijde DM, St Clair

EW, et al; Anti-Tumor Necrosis Factor

Trial in Rheumatoid Arthritis with

Concomitant Therapy Study Group.

Infl iximab and methotrexate in the

treatment of rheumatoid arthritis. N

Engl J Med. 2000;343(22):1594–1602

40. Furst D, Schiff M, Fleischmann

R, et al. Safety and effi cacy of

adalimumab (D2E7), a fully human

anti-TNF-alpha monoclonal antibody,

given in combination with standard

antirheumatic therapy: safety trial of

adalimumab in rheumatoid arthritis

(RA) [abstract]. Arthritis Rheum.

2002;46(suppl):S572

41. Keystone E, Kavanaugh A, Sharp J,

et al. Adalimumab (D2E7), a fully human

anti-TNF-alpha monoclonal antibody,

inhibits the progression of structural

joint damage in patients with active

RA despite concomitant methotrexate

therapy [abstract]. Arthritis Rheum.

2002;46(suppl 9):S205

42. Lovell DJ, Ruperto N, Goodman

S, et al; Pediatric Rheumatology

Collaborative Study Group; Pediatric

Rheumatology International Trials

Organisation. Adalimumab with or

without methotrexate in juvenile

rheumatoid arthritis. N Engl J Med.

2008;359(8):810–820

43. Trachana M, Pratsidou-Gertsi P,

Pardalos G, Kozeis N, Badouraki M,

Kanakoudi-Tsakalidou F. Safety and

effi cacy of adalimumab treatment in

Greek children with juvenile idiopathic

arthritis. Scand J Rheumatol.

2011;40(2):101–107

44. Hsia EC, Cush JJ, Matteson EL, et al.

Comprehensive tuberculosis screening

program in patients with infl ammatory

arthritides treated with golimumab,

a human anti-tumor necrosis factor

antibody, in phase III clinical trials.

Arthritis Care Res (Hoboken).

2013;65(2):309–313

45. Pérez-Alvarez R, Díaz-Lagares C,

García-Hernández F, et al; BIOGEAS

Study Group. Hepatitis B virus

(HBV) reactivation in patients

receiving tumor necrosis factor

(TNF)-targeted therapy: analysis of

257 cases. Medicine (Baltimore).

2011;90(6):359–371

46. Giannini EH, Ilowite NT, Lovell DJ, et al;

Pediatric Rheumatology Collaborative

Study Group. Long-term safety and

effectiveness of etanercept in children

with selected categories of juvenile

idiopathic arthritis. Arthritis Rheum.

2009;60(9):2794–2804

47. Enbrel (etanercept) [package insert].

Thousand Oaks, CA: Immunex; 2013.

Available at: http:// pi. amgen. com/

united_ states/ enbrel/ derm/ enbrel_ pi.

pdf. Accessed October 22, 2014

48. Wallis RS. Biologics and infections:

lessons from tumor necrosis factor

blocking agents. Infect Dis Clin North

Am. 2011;25(4):895–910

49. Cutolo M. The kinase inhibitor

tofacitinib in patients with rheumatoid

arthritis: latest fi ndings and clinical

potential. Ther Adv Musculoskelet Dis.

2013;5(1):3–11

50. Ghoreschi K, Laurence A, O’Shea JJ.

Selectivity and therapeutic inhibition

of kinases: to be or not to be? Nat

Immunol. 2009;10(4):356–360

51. Ghoreschi K, Laurence A, O’Shea

JJ. Janus kinases in immune

cell signaling. Immunol Rev.

2009;228(1):273–287

52. Riese RJ, Krishnaswami S, Kremer J.

Inhibition of JAK kinases in patients

with rheumatoid arthritis: scientifi c

rationale and clinical outcomes.

e16 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

Best Pract Res Clin Rheumatol.

2010;24(4):513–526

53. Bongartz T, Sutton AJ, Sweeting

MJ, Buchan I, Matteson EL, Montori

V. Anti-TNF antibody therapy in

rheumatoid arthritis and the risk of

serious infections and malignancies:

systematic review and meta-

analysis of rare harmful effects in

randomized controlled trials. JAMA.

2006;295(19):2275–2285

54. Thompson AE, Rieder SW, Pope JE.

Tumor necrosis factor therapy and

the risk of serious infection and

malignancy in patients with early

rheumatoid arthritis: a meta-analysis

of randomized controlled trials.

Arthritis Rheum. 2011;63(6):1479–1485

55. Singh JA, Wells GA, Christensen R,

et al. Adverse effects of biologics: a

network meta-analysis and Cochrane

overview. Cochrane Database Syst Rev.

2011;2:CD008794

56. Doran MF, Crowson CS, Pond GR,

O’Fallon WM, Gabriel SE. Predictors

of infection in rheumatoid arthritis.

Arthritis Rheum. 2002;46(9):2294–2300

57. Jeurissen ME, Boerbooms AM, van de

Putte LB, et al. Methotrexate versus

azathioprine in the treatment of

rheumatoid arthritis: a forty-eight-

week randomized, double-blind trial.

Arthritis Rheum. 1991;34(8):961–972

58. Immunex Corporation. Enbrel:

serious and opportunistic infection

rates. Thousand Oaks, CA: Immunex;

2013. Available at: www. enbrel. com/

RheumPro/ infection- rates. jspx.

Accessed October 22, 2014

59. Beukelman T, Xie F, Chen L, et al; SABER

Collaboration. Rates of hospitalized

bacterial infection associated with

juvenile idiopathic arthritis and

its treatment. Arthritis Rheum.

2012;64(8):2773–2780

60. Bracaglia C, Buonuomo PS, Tozzi

AE, et al. Safety and effi cacy of

etanercept in a cohort of patients

with juvenile idiopathic arthritis

under 4 years of age. J Rheumatol.

2012;39(6):1287–1290

61. Gerloni V, Pontikaki I, Gattinara M,

Fantini F. Focus on adverse events

of tumour necrosis factor alpha

blockade in juvenile idiopathic arthritis

in an open monocentric long-term

prospective study of 163 patients. Ann

Rheum Dis. 2008;67(8):1145–1152

62. Lovell DJ, Giannini EH, Reiff A, et al;

Pediatric Rheumatology Collaborative

Study Group. Etanercept in

children with polyarticular juvenile

rheumatoid arthritis. N Engl J Med.

2000;342(11):763–769

63. Lovell DJ, Giannini EH, Reiff A, et al;

Pediatric Rheumatology Collaborative

Study Group. Long-term effi cacy

and safety of etanercept in children

with polyarticular-course juvenile

rheumatoid arthritis: interim results

from an ongoing multicenter, open-

label, extended-treatment trial.

Arthritis Rheum. 2003;48(1):218–226

64. Lovell DJ, Reiff A, Ilowite NT, et al;

Pediatric Rheumatology Collaborative

Study Group. Safety and effi cacy

of up to eight years of continuous

etanercept therapy in patients with

juvenile rheumatoid arthritis. Arthritis

Rheum. 2008;58(5):1496–1504

65. Lovell DJ, Reiff A, Jones OY, et al;

Pediatric Rheumatology Collaborative

Study Group. Long-term safety and

effi cacy of etanercept in children

with polyarticular-course juvenile

rheumatoid arthritis. Arthritis Rheum.

2006;54(6):1987–1994

66. Prince FH, Twilt M, ten Cate R, et al.

Long-term follow-up on effectiveness

and safety of etanercept in juvenile

idiopathic arthritis: the Dutch

national register. Ann Rheum Dis.

2009;68(5):635–641

67. Hyams J, Damaraju L, Blank M, et

al; T72 Study Group. Induction and

maintenance therapy with infl iximab

for children with moderate to severe

ulcerative colitis. Clin Gastroenterol

Hepatol. 2012;10(4):391–399.e1

68. Ruperto N, Lovell DJ, Cuttica R, et al;

Paediatric Rheumatology INternational

Trials Organization (PRINTO); Pediatric

Rheumatology Collaborative Study

Group (PRCSG). Long-term effi cacy and

safety of infl iximab plus methotrexate

for the treatment of polyarticular-

course juvenile rheumatoid arthritis:

fi ndings from an open-label

treatment extension. Ann Rheum Dis.

2010;69(4):718–722

69. Stephens MC, Shepanski MA, Mamula

P, Markowitz JE, Brown KA, Baldassano

RN. Safety and steroid-sparing

experience using infl iximab for Crohn’s

disease at a pediatric infl ammatory

bowel disease center. Am J

Gastroenterol. 2003;98(1):104–111

70. Tschudy J, Michail S. Disseminated

histoplasmosis and pneumocystis

pneumonia in a child with Crohn

disease receiving infl iximab. J Pediatr

Gastroenterol Nutr. 2010;51(2):221–222

71. Imagawa T, Takei S, Umebayashi H,

et al. Effi cacy, pharmacokinetics, and

safety of adalimumab in pediatric

patients with juvenile idiopathic

arthritis in Japan. Clin Rheumatol.

2012;31(12):1713–1721

72. Chaiwatanatorn K, Lee N, Grigg A,

Filshie R, Firkin F. Delayed-onset

neutropenia associated with

rituximab therapy. Br J Haematol.

2003;121(6):913–918

73. Dunleavy K, Hakim F, Kim HK, et al.

B-cell recovery following rituximab-

based therapy is associated with

perturbations in stromal derived

factor-1 and granulocyte homeostasis.

Blood. 2005;106(3):795–802

74. Fukuno K, Tsurumi H, Ando N, et al.

Late-onset neutropenia in patients

treated with rituximab for non-

Hodgkin’s lymphoma. Int J Hematol.

2006;84(3):242–247

75. Hofer S, Viollier R, Ludwig C. Delayed-

onset and long-lasting severe

neutropenia due to rituximab. Swiss

Med Wkly. 2004;134(5-6):79–80

76. Mitsuhata N, Fujita R, Ito S, Mannami

M, Keimei K. Delayed-onset neutropenia

in a patient receiving rituximab as

treatment for refractory kidney

transplantation. Transplantation.

2005;80(9):1355

77. Nitta E, Izutsu K, Sato T, et al. A high

incidence of late-onset neutropenia

following rituximab-containing

chemotherapy as a primary treatment

of CD20-positive B-cell lymphoma: a

single-institution study. Ann Oncol.

2007;18(2):364–369

78. Terrier B, Ittah M, Tourneur L,

et al. Late-onset neutropenia

following rituximab results from a

hematopoietic lineage competition

due to an excessive BAFF-induced

B-cell recovery. Haematologica.

2007;92(2):e20–e23

79. Voog E, Morschhauser F, Solal-

Céligny P. Neutropenia in patients

e17 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

treated with rituximab. N Engl J Med.

2003;348(26):2691–2694; discussion:

2691–2694

80. Weissmann-Brenner A, Brenner B,

Belyaeva I, Lahav M, Rabizadeh E.

Rituximab associated neutropenia:

description of three cases and

an insight into the underlying

pathogenesis. Med Sci Monit.

2011;17(11):CS133–CS137

81. Alexeeva EI, Valieva SI, Bzarova TM,

et al. Effi cacy and safety of repeat

courses of rituximab treatment

in patients with severe refractory

juvenile idiopathic arthritis. Clin

Rheumatol. 2011;30(9):1163–1172

82. Flynn JL, Goldstein MM, Chan J, et

al. Tumor necrosis factor-alpha is

required in the protective immune

response against Mycobacterium

tuberculosis in mice. Immunity.

1995;2(6):561–572

83. Wagner TE, Huseby ES, Huseby JS.

Exacerbation of Mycobacterium

tuberculosis enteritis masquerading

as Crohn’s disease after treatment

with a tumor necrosis factor-alpha

inhibitor. Am J Med. 2002;112(1):67–69

84. Fallahi-Sichani M, Schaller MA,

Kirschner DE, Kunkel SL, Linderman

JJ. Identifi cation of key processes

that control tumor necrosis factor

availability in a tuberculosis

granuloma. PLOS Comput Biol.

2010;6(5):e1000778

85. Marino S, Myers A, Flynn JL, Kirschner

DE. TNF and IL-10 are major factors

in modulation of the phagocytic cell

environment in lung and lymph node

in tuberculosis: a next-generation two-

compartmental model. J Theor Biol.

2010;265(4):586–598

86. Mata-Espinosa DA, Mendoza-Rodríguez

V, Aguilar-León D, Rosales R, López-

Casillas F, Hernández-Pando R.

Therapeutic effect of recombinant

adenovirus encoding interferon-

gamma in a murine model of

progressive pulmonary tuberculosis.

Mol Ther. 2008;16(6):1065–1072

87. Salgado E, Gómez-Reino JJ. The risk

of tuberculosis in patients treated

with TNF antagonists. Expert Rev Clin

Immunol. 2011;7(3):329–340

88. Mohan AK, Coté TR, Block JA, Manadan

AM, Siegel JN, Braun MM. Tuberculosis

following the use of etanercept, a

tumor necrosis factor inhibitor. Clin

Infect Dis. 2004;39(3):295–299

89. Dixon WG, Hyrich KL, Watson KD, et al;

BSRBR Control Centre Consortium;

BSR Biologics Register. Drug-specifi c

risk of tuberculosis in patients with

rheumatoid arthritis treated with anti-

TNF therapy: results from the British

Society for Rheumatology Biologics

Register (BSRBR). Ann Rheum Dis.

2010;69(3):522–528

90. Fleischmann R, Yocum D. Does safety

make a difference in selecting the

right TNF antagonist? Arthritis Res

Ther. 2004;6(suppl 2):S12–S18

91. Dye C, Scheele S, Dolin P, Pathania

V, Raviglione MC. Global burden of

tuberculosis: estimated incidence,

prevalence, and mortality by country

[consensus statement]. WHO Global

Surveillance and Monitoring Project.

JAMA. 1999;282(7):677–686

92. Dixon WG, Watson K, Lunt M, Hyrich

KL, Silman AJ, Symmons DP; British

Society for Rheumatology Biologics

Register. Rates of serious infection,

including site-specifi c and bacterial

intracellular infection, in rheumatoid

arthritis patients receiving anti-tumor

necrosis factor therapy: results from

the British Society for Rheumatology

Biologics Register. Arthritis Rheum.

2006;54(8):2368–2376

93. Tubach F, Salmon D, Ravaud P, et

al; Research Axed on Tolerance

of Biotherapies Group. Risk of

tuberculosis is higher with anti-

tumor necrosis factor monoclonal

antibody therapy than with soluble

tumor necrosis factor receptor

therapy: the three-year prospective

French Research Axed on Tolerance

of Biotherapies Registry [published

correction appears in Arthritis Rheum.

2009;60(8):2540. Arthritis Rheum.

2009;60(7):1884–1894

94. Imperato AK, Smiles S, Abramson

SB. Long-term risks associated with

biologic response modifi ers used

in rheumatic diseases. Curr Opin

Rheumatol. 2004;16(3):199–205

95. Gómez-Reino JJ, Carmona L, Angel

Descalzo M; Biobadaser Group. Risk of

tuberculosis in patients treated with

tumor necrosis factor antagonists

due to incomplete prevention of

reactivation of latent infection.

Arthritis Rheum. 2007;57(5):756–761

96. Myers A, Clark J, Foster H. Tuberculosis

and treatment with infl iximab. N Engl J

Med. 2002;346(8):623–626

97. Armbrust W, Kamphuis SSM, Wolfs

TWF, et al. Tuberculosis in a nine-

year-old girl treated with infl iximab

for systemic juvenile idiopathic

arthritis. Rheumatology (Oxford).

2004;43(4):527–529

98. Askling J, Fored CM, Brandt L, et al.

Risk and case characteristics of

tuberculosis in rheumatoid arthritis

associated with tumor necrosis factor

antagonists in Sweden. Arthritis

Rheum. 2005;52(7):1986–1992

99. Ayaz NA, Demirkaya E, Bilginer Y, et al.

Preventing tuberculosis in children

receiving anti-TNF treatment. Clin

Rheumatol. 2010;29(4):389–392

100. Winthrop KL, Daley CL, Griffi th D.

Nontuberuclous mycobacterial

disease: updated diagnostic criteria

for an under-recognized infectious

complication of anti-tumor necrosis

factor therapy. Nat Clin Pract

Rheumatol. 2007;3(10):E1

101. Winthrop KL, Yamashita S, Beekmann

SE, Polgreen PM; Infectious Diseases

Society of America Emerging Infections

Network. Mycobacterial and other

serious infections in patients receiving

anti-tumor necrosis factor and other

newly approved biologic therapies:

case fi nding through the Emerging

Infections Network. Clin Infect Dis.

2008;46(11):1738–1740

102. Winthrop KL, Chang E, Yamashita

S, Iademarco MF, LoBue PA.

Nontuberculous mycobacteria

infections and anti-tumor necrosis

factor-alpha therapy. Emerg Infect Dis.

2009;15(10):1556–1561

103. Cullen G, Baden RP, Cheifetz AS.

Varicella zoster virus infection in

infl ammatory bowel disease. Infl amm

Bowel Dis. 2012;18(12):2392–2403

104. Strangfeld A, Listing J, Herzer P, et

al. Risk of herpes zoster in patients

with rheumatoid arthritis treated

with anti-TNF-alpha agents. JAMA.

2009;301(7):737–744

105. Smitten AL, Choi HK, Hochberg MC, et

al. The risk of herpes zoster in patients

e18 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

with rheumatoid arthritis in the

United States and the United Kingdom.

Arthritis Rheum. 2007;57(8):1431–1438

106. Galloway JB, Mercer LK, Moseley

A, et al. Risk of skin and soft tissue

infections (including shingles) in

patients exposed to anti-tumour

necrosis factor therapy: results from

the British Society for Rheumatology

Biologics Register. Ann Rheum Dis.

2013;72(2):229–234

107. Winthrop KL, Baddley JW, Chen L, et al.

Association between the initiation of

anti-tumor necrosis factor therapy

and the risk of herpes zoster. JAMA.

2013;309(9):887–895

108. Wolfe F, Michaud K, Chakravarty EF.

Rates and predictors of herpes zoster

in patients with rheumatoid arthritis

and non-infl ammatory musculoskeletal

disorders. Rheumatology (Oxford).

2006;45(11):1370–1375

109. Bradford RD, Pettit AC, Wright PW,

et al. Herpes simplex encephalitis

during treatment with tumor necrosis

factor-alpha inhibitors. Clin Infect Dis.

2009;49(6):924–927

110. Justice EA, Khan SY, Logan S,

Jobanputra P. Disseminated cutaneous

herpes simplex virus-1 in a woman

with rheumatoid arthritis receiving

infl iximab: a case report. J Med Case

Reports. 2008;2:282

111. Salmon-Ceron D, Tubach F, Lortholary

O, et al; RATIO Group. Drug-specifi c

risk of non-tuberculosis opportunistic

infections in patients receiving anti-

TNF therapy reported to the 3-year

prospective French RATIO registry. Ann

Rheum Dis. 2011;70(4):616–623

112. Sciaudone G, Pellino G, Guadagni I,

Selvaggi F. Education and imaging:

gastrointestinal: herpes simplex

virus-associated erythema multiforme

(HAEM) during infl iximab treatment

for ulcerative colitis. J Gastroenterol

Hepatol. 2011;26(3):610

113. van der Klooster JM, Bosman

RJ, Oudemans-van Straaten HM,

van der Spoel JI, Wester JP, Zandstra

DF. Disseminated tuberculosis,

pulmonary aspergillosis and

cutaneous herpes simplex infection

in a patient with infl iximab and

methotrexate. Intensive Care Med.

2003;29(12):2327–2329

114. Checchin D, Buda A, Sgarabotto D,

Sturniolo GC, D’Incà R. Successful

prophylaxis with valaciclovir for

relapsing HSV-1 in a girl treated with

infl iximab for moderate Crohn’s

disease. Eur J Gastroenterol Hepatol.

2009;21(9):1095–1096

115. Carroll MB. The impact of biologic

response modifi ers on hepatitis B

virus infection. Expert Opin Biol Ther.

2011;11(4):533–544

116. Zachou K, Sarantopoulos A,

Gatselis NK, et al. Hepatitis B virus

reactivation in hepatitis B virus

surface antigen negative patients

receiving immunosuppression: a

hidden threat. World J Hepatol.

2013;5(7):387–392

117. Motaparthi K, Stanisic V, Van Voorhees

AS, Lebwohl MG, Hsu S; Medical

Board of the National Psoriasis

Foundation. From the Medical

Board of the National Psoriasis

Foundation: recommendations for

screening for hepatitis B infection

prior to initiating anti-tumor necrosis

factor-alfa inhibitors or other

immunosuppressive agents in patients

with psoriasis. J Am Acad Dermatol.

2014;70(1):178–186

118. Tsiodras S, Samonis G, Boumpas DT,

Kontoyiannis DP. Fungal infections

complicating tumor necrosis factor

alpha blockade therapy. Mayo Clin

Proc. 2008;83(2):181–194

119. Ampel NM. Coccidioidomycosis: a

review of recent advances. Clin Chest

Med. 2009;30(2):241–251

120. Bergstrom L, Yocum DE, Ampel

NM, et al. Increased risk of

coccidioidomycosis in patients

treated with tumor necrosis factor

alpha antagonists. Arthritis Rheum.

2004;50(6):1959–1966

121. Taroumian S, Knowles SL, Lisse JR, et al.

Management of coccidioidomycosis

in patients receiving biologic response

modifi ers or disease-modifying

antirheumatic drugs. Arthritis Care

Res (Hoboken). 2012;64(12):

1903–1909

122. Hage CA, Bowyer S, Tarvin SE,

Helper D, Kleiman MB, Wheat LJ.

Recognition, diagnosis, and treatment

of histoplasmosis complicating tumor

necrosis factor blocker therapy. Clin

Infect Dis. 2010;50(1):85–92

123. Winthrop KL, Chiller T. Preventing

and treating biologic-associated

opportunistic infections. Nat Rev

Rheumatol. 2009;5(7):405–410

124. Lee JH, Slifman NR, Gershon SK, et

al. Life-threatening histoplasmosis

complicating immunotherapy

with tumor necrosis factor

alpha antagonists infl iximab and

etanercept. Arthritis Rheum.

2002;46(10):2565–2570

125. Bodro M, Paterson DL. Listeriosis in

patients receiving biologic therapies.

Eur J Clin Microbiol Infect Dis.

2013;32(9):1225–1230

126. Peña-Sagredo JL, Hernández MV,

Fernandez-Llanio N, et al; Biobadaser

Group. Listeria monocytogenes

infection in patients with rheumatic

diseases on TNF-alpha antagonist

therapy: the Spanish Study Group

experience. Clin Exp Rheumatol.

2008;26(5):854–859

127. Slifman NR, Gershon SK, Lee JH,

Edwards ET, Braun MM. Listeria

monocytogenes infection as a

complication of treatment with

tumor necrosis factor alpha-

neutralizing agents. Arthritis Rheum.

2003;48(2):319–324

128. Lanternier F, Tubach F, Ravaud P, et

al; Research Axed on Tolerance of

Biotherapies Group. Incidence and

risk factors of Legionella pneumophila

pneumonia during anti-tumor necrosis

factor therapy: a prospective French

study. Chest. 2013;144(3):990–998

129. Tubach F, Ravaud P, Salmon-Céron D,

et al; Recherce Axée sur la Tolérance

des Biothérapies Group. Emergence

of Legionella pneumophila pneumonia

in patients receiving tumor necrosis

factor-alpha antagonists. Clin Infect

Dis. 2006;43(10):e95–e100

130. Torre-Cisneros J, Del Castillo M, Castón

JJ, Castro MC, Pérez V, Collantes E.

Infl iximab does not activate replication

of lymphotropic herpesviruses in

patients with refractory rheumatoid

arthritis. Rheumatology (Oxford).

2005;44(9):1132–1135

131. Balandraud N, Guis S, Meynard JB,

Auger I, Roudier J, Roudier C. Long-

term treatment with methotrexate

or tumor necrosis factor alpha

inhibitors does not increase

e19 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

FROM THE AMERICAN ACADEMY OF PEDIATRICS

Epstein-Barr virus load in patients with

rheumatoid arthritis. Arthritis Rheum.

2007;57(5):762–767

132. Fritzsche C, Riebold D, Munk-Hartig A,

Klammt S, Neeck G, Reisinger E. High

prevalence of Pneumocystis jirovecii

colonization among patients with

autoimmune infl ammatory diseases

and corticosteroid therapy. Scand J

Rheumatol. 2012;41(3):208–213

133. Mekinian A, Durand-Joly I, Hatron

PY, et al. Pneumocystis jirovecii

colonization in patients with systemic

autoimmune diseases: prevalence,

risk factors of colonization and

outcome. Rheumatology (Oxford).

2011;50(3):569–577

134. Mori S, Cho I, Sugimoto M. A cluster of

Pneumocystis jirovecii infection among

outpatients with rheumatoid arthritis.

J Rheumatol. 2010;37(7):1547–1548

135. Lund FE, Hollifi eld M, Schuer K,

Lines JL, Randall TD, Garvy BA. B

cells are required for generation of

protective effector and memory CD4

cells in response to Pneumocystis

lung infection. J Immunol.

2006;176(10):6147–6154

136. Martin-Garrido I, Carmona EM,

Specks U, Limper AH. Pneumocystis

pneumonia in patients treated with

rituximab. Chest. 2013;144(1):258–265

137. Mori S, Cho I, Sugimoto M. A followup

study of asymptomatic carriers

of Pneumocystis jiroveci during

immunosuppressive therapy for

rheumatoid arthritis. J Rheumatol.

2009;36(8):1600–1605

138. Specks U. Biologic agents in the

treatment of granulomatosis with

polyangiitis. Cleve Clin J Med.

2012;79(suppl 3):S50–S53

139. Besada E, Nossent JC. Should

Pneumocystis jiroveci prophylaxis

be recommended with rituximab

treatment in ANCA-associated

vasculitis? Clin Rheumatol.

2013;32(11):1677–1681

140. Green H, Paul M, Vidal L, Leibovici

L. Prophylaxis of Pneumocystis

pneumonia in immunocompromised

non-HIV-infected patients: systematic

review and meta-analysis of

randomized controlled trials. Mayo

Clin Proc. 2007;82(9):1052–1059

141. Kaur N, Mahl TC. Pneumocystis jiroveci

(carinii) pneumonia after infl iximab

therapy: a review of 84 cases. Dig Dis

Sci. 2007;52(6):1481–1484

142. Tanaka M, Sakai R, Koike R, et al.

Pneumocystis jirovecii pneumonia

associated with etanercept treatment

in patients with rheumatoid arthritis:

a retrospective review of 15 cases

and analysis of risk factors. Mod

Rheumatol. 2012;22(6):849–858

143. Watanabe K, Sakai R, Koike R, et

al. Clinical characteristics and

risk factors for Pneumocystis

jirovecii pneumonia in patients

with rheumatoid arthritis receiving

adalimumab: a retrospective review

and case-control study of 17 patients.

Mod Rheumatol. 2013;23(6):1085–1093

144. Rubin LG, Levin MJ, Ljungman P, et

al; Infectious Diseases Society of

America. 2013 IDSA clinical practice

guideline for vaccination of the

immunocompromised host. Clin Infect

Dis. 2014;58(3):309–318

145. American Academy of Pediatrics.

Testing for Mycobacterium

tuberculosis infection. In: Pickering

LK, Baker CJ, Kimberlin DW, Long SS,

eds. Red Book: 2012 Report of the

Committee on Infectious Diseases. Elk

Grove Village, IL: American Academy of

Pediatrics; 2012:39

146. Elkayam O, Bashkin A, Mandelboim

M, et al. The effect of infl iximab and

timing of vaccination on the humoral

response to infl uenza vaccination in

patients with rheumatoid arthritis and

ankylosing spondylitis. Semin Arthritis

Rheum. 2010;39(6):442–447

147. Glück T, Müller-Ladner U. Vaccination

in patients with chronic rheumatic or

autoimmune diseases. Clin Infect Dis.

2008;46(9):1459–1465

148. Moses J, Alkhouri N, Shannon A, et al.

Hepatitis B immunity and response to

booster vaccination in children with

infl ammatory bowel disease treated

with infl iximab. Am J Gastroenterol.

2012;107(1):133–138

149. Visvanathan S, Keenan GF, Baker DG,

Levinson AI, Wagner CL. Response to

pneumococcal vaccine in patients with

early rheumatoid arthritis receiving

infl iximab plus methotrexate or

methotrexate alone. J Rheumatol.

2007;34(5):952–957

150. Bingham CO III, Looney RJ, Deodhar

A, et al. Immunization responses

in rheumatoid arthritis patients

treated with rituximab: results from

a controlled clinical trial. Arthritis

Rheum. 2010;62(1):64–74

151. Crnkic Kapetanovic M, Saxne T,

Jönsson G, Truedsson L, Geborek

P. Rituximab and abatacept but not

tocilizumab impair antibody response

to pneumococcal conjugate vaccine

in patients with rheumatoid arthritis.

Arthritis Res Ther. 2013;15(5):R171

152. Nazi I, Kelton JG, Larché M, et

al. The effect of rituximab on

vaccine responses in patients with

immune thrombocytopenia. Blood.

2013;122(11):1946–1953

153. van Assen S, Holvast A, Benne CA, et

al. Humoral responses after infl uenza

vaccination are severely reduced in

patients with rheumatoid arthritis

treated with rituximab. Arthritis

Rheum. 2010;62(1):75–81

154. van der Kolk LE, Baars JW, Prins MH,

van Oers MH. Rituximab treatment

results in impaired secondary humoral

immune responsiveness. Blood.

2002;100(6):2257–2259

155. Centers for Disease Control and

Prevention. Latent tuberculosis

infection: a guide for primary health

care providers. Atlanta, GA: Centers

for Disease Control and Prevention;

2013. Available at: www. cdc. gov/

tb/ publications/ ltbi/ diagnosis. htm.

Accessed October 22, 2014

156. Centers for Disease Control and

Prevention. TB guidelines, treatment.

Atlanta, GA: Centers for Disease

Control and Prevention; 2013. Available

at: www. cdc. gov/ tb/ publications/

guidelines/ treatment. htm. Accessed

October 22, 2014

157. Mazurek GH, Jereb J, Vernon A,

LoBue P, Goldberg S, Castro K; IGRA

Expert Committee; Centers for

Disease Control and Prevention.

Updated guidelines for using

interferon gamma release assays to

detect Mycobacterium tuberculosis

infection—United States, 2010. MMWR

Recomm Rep. 2010;59(RR-5):1–25

158. American Academy of Pediatrics.

Tuberculosis. In: Pickering LK, Baker

CJ, Kimberlin DW, Long SS, eds. Red

Book: 2012 Report of the Committee on

Infectious Diseases. Elk Grove Village,

IL: American Academy of Pediatrics;

2012:736–759

e20 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 138 , number 2 , August 2016

159. Chamany S, Mirza SA, Fleming JW,

et al. A large histoplasmosis outbreak

among high school students in

Indiana, 2001. Pediatr Infect Dis J.

2004;23(10):909–914

160. National Institute for Occupational

Safety and Health. Histoplasmosis,

protecting workers at risk. Atlanta,

GA: National Institute for Occupational

Safety and Health, Department of

Health and Human Services; 2004.

Available at: www. cdc. gov/ niosh/ docs/

2005- 109/ . Accessed October 22, 2014

161. Jassal MS, Bishai WR. The risk of

infections with tumor necrosis factor-

alpha inhibitors. J Clin Rheumatol.

2009;15(8):419–426

162. Chiller TM, Galgiani JN, Stevens DA.

Coccidioidomycosis. Infect Dis Clin

North Am. 2003;17(1):41–57, viii

163. Crum NF, Lederman ER, Stafford

CM, Parrish JS, Wallace MR.

Coccidioidomycosis: a descriptive

survey of a reemerging disease—

clinical characteristics and current

controversies. Medicine (Baltimore).

2004;83(3):149–175

164. Rosenstein NE, Emery KW, Werner

SB, et al. Risk factors for severe

pulmonary and disseminated

coccidioidomycosis: Kern County,

California, 1995-1996. Clin Infect Dis.

2001;32(5):708–715

165. American Academy of Pediatrics.

Varicella-zoster infections. In:

Pickering LK, Baker CJ, Kimberlin

DW, Long SS, eds. Red Book: 2012

Report of the Committee on Infectious

Diseases. Elk Grove Village, IL:

American Academy of Pediatrics;

2012:774–789

166. Centers for Disease Control and

Prevention. Hepatitis B information

for health professionals. Atlanta,

GA: Centers for Disease Control and

Prevention; 2013. Available at: www.

cdc. gov/ hepatitis/ hbv/ hbvfaq. htm.

Accessed October 22, 2014

167. Carroll MB, Bond MI. Use of tumor

necrosis factor-alpha inhibitors in

patients with chronic hepatitis B

infection. Semin Arthritis Rheum.

2008;38(3):208–217

168. Kato M, Atsumi T, Kurita T, et al.

Hepatitis B virus reactivation by

immunosuppressive therapy in

patients with autoimmune diseases:

risk analysis in hepatitis B surface

antigen-negative cases. J Rheumatol.

2011;38(10):2209–2214

169. Lok AS, McMahon BJ. Chronic hepatitis

B. Hepatology. 2007;45(2):507–539

170. Post A, Nagendra S. Reactivation of

hepatitis B: pathogenesis and clinical

implications. Curr Infect Dis Rep.

2009;11(2):113–119

171. Yeo W, Chan PK, Zhong S, et al.

Frequency of hepatitis B virus

reactivation in cancer patients

undergoing cytotoxic chemotherapy: a

prospective study of 626 patients with

identifi cation of risk factors. J Med

Virol. 2000;62(3):299–307

172. Yeo W, Johnson PJ. Diagnosis,

prevention and management of

hepatitis B virus reactivation during

anticancer therapy. Hepatology.

2006;43(2):209–220

173. Rahier JF, Moutschen M, Van Gompel

A, et al. Vaccinations in patients with

immune-mediated infl ammatory

diseases. Rheumatology (Oxford).

2010;49(10):1815–1827

174. Hunt D, Giovannoni G. Natalizumab-

associated progressive multifocal

leucoencephalopathy: a practical

approach to risk profi ling

and monitoring. Pract Neurol.

2012;12(1):25–35

e21 by guest on August 7, 2019www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2016-1209 originally published online July 18, 2016; 2016;138;Pediatrics 

H. Dele Davies and COMMITTEE ON INFECTIOUS DISEASESand Children

Infectious Complications With the Use of Biologic Response Modifiers in Infants

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/138/2/e20161209including high resolution figures, can be found at:

Referenceshttp://pediatrics.aappublications.org/content/138/2/e20161209#BIBLThis article cites 147 articles, 21 of which you can access for free at:

Subspecialty Collections

bhttp://www.aappublications.org/cgi/collection/infectious_diseases_suInfectious Diseaseous_diseaseshttp://www.aappublications.org/cgi/collection/committee_on_infectiCommittee on Infectious Diseaseshttp://www.aappublications.org/cgi/collection/current_policyCurrent Policyfollowing collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtmlin its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or

Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

by guest on August 7, 2019www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2016-1209 originally published online July 18, 2016; 2016;138;Pediatrics 

H. Dele Davies and COMMITTEE ON INFECTIOUS DISEASESand Children

Infectious Complications With the Use of Biologic Response Modifiers in Infants

http://pediatrics.aappublications.org/content/138/2/e20161209located on the World Wide Web at:

The online version of this article, along with updated information and services, is

1073-0397. ISSN:60007. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print

the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

by guest on August 7, 2019www.aappublications.org/newsDownloaded from