PERSPECTIVES

Intravenous Immunoglobulin as Potential Adjunct Therapy

for Interstitial Lung Disease
Robert W. Hallowell1, Diana Amariei2, and Sonye K. Danoff3
1
Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts; 2Department of Internal Medicine, Johns Hopkins Hospital, Baltimore, Maryland; and 3Division of Pulmonary and Critical
Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

Abstract autoimmune disorders and connective tissue diseases, and the

Intravenous Ig (IVIg) is a pooled plasma product consisting primarily
of monomeric IgG. For the past several decades, the use of IVIg
has expanded to include the treatment of various autoimmune
and inflammatory disorders, including Kawasaki’s disease,
antineutrophil cytoplasmic antibody–associated vasculitis, systemic
lupus erythematosis, and the inflammatory myopathies. IVIg is
thought to exert its immunomodulatory effects through a variety of
mechanisms: neutralization of pathogenic autoantibodies; alteration
of immune cell effector function; suppression of cytokine and
chemokine activity; and interference with complement activation.
Interstitial lung disease (ILD) is a frequent complication of
presence of ILD is associated with significant morbidity and
mortality. Although there are currently no large studies to support the
use of IVIg in the treatment of ILD, it is being used off-label with
increasing frequency for refractory cases that have failed to respond
to standard immunosuppression. Although associated with less
systemic toxicity and global immunosuppression than traditional
agents, IVIg is much more costly. Therefore, although the routine use
of IVIg to treat ILD is not currently recommended, future studies to
determine its role in pulmonary disease are warranted.
Keywords: intravenous Ig; dermatomyositis; polymyositis;
antisynthetase syndrome; interstitial lung disease

(Received in original form March 11, 2016; accepted in final form July 29, 2016 )
Correspondence and requests for reprints should be addressed to Robert W. Hallowell, M.D., 330 Brookline Avenue, Boston, MA 02215.
E-mail: rhallowe@bidmc.harvard.edu
Ann Am Thorac Soc Vol 13, No 10, pp 1682–1688, Oct 2016
Copyright © 2016 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201603-179PS
Internet address: www.atsjournals.org

Interstitial pneumonia frequently
complicates the various connective tissue
diseases and remains a leading cause of
morbidity and mortality (1–4). Therapies
aimed at controlling the underlying
connective tissue disease are often effective
at treating the associated pneumonitis;
however, all too frequently, physicians
encounter patients with progressive
interstitial lung disease (ILD) that fails
to respond to high doses of prednisone
combined with other forms of
conventional immunosuppression. In
such cases, lung transplantation or a
palliative approach is often the only
option. Furthermore, even when effective,
the standard immunosuppressive agents
are associated with numerous side effects,
including a significant risk of infection,
renal and hepatic toxicity, direct
pulmonary toxicity, and exacerbations of
pneumonitis (5–7).
As such, alternative, less toxic therapies
to treat challenging cases of ILD are needed.
Although the pathophysiology driving
pulmonary involvement in these conditions
is not entirely understood, abnormalities
in immune cell function, the presence of
autoantibodies, and an inappropriate
cytokine response have all been implicated
in the development of parenchymal lung
disease (8). As discussed subsequently
here, each of these mechanisms has been
suggested as a potential target for therapy
with intravenous Ig (IVIg).
IVIg has been used for over 70 years
and has well established antiinflammatory
and immunomodulatory properties that
make it a potentially attractive candidate
for the treatment of refractory ILD. IVIg
is a preparation comprised of the pooled
plasma from up to 20,000 donors. It
primarily contains intact monomeric IgG
with only trace amounts of IgA, IgM, and
IgE, and the distribution of IgG subclasses
and antibody specificities approximate
the range found in normal human serum
(9, 10).
Igs were first used in the 1940s to
treat infections, such as measles, mumps,
and pertussis. In 1952, the first case of
primary immunodeficiency was treated with
subcutaneous gammaglobulin, and in the
years to follow, immune serum globulin
became the standard treatment for the
antibody deficiency syndromes (11). Over
the course of several decades, the use of
IVIg has expanded to include various
inflammatory and autoimmune conditions,
including Kawasaki’s disease (12),

1682 AnnalsATS Volume 13 Number 10 | October 2016

 PERSPECTIVES
Guillain-Barre syndrome (13), systemic
lupus erythematosis (9, 14–16), the
antineutrophil cytoplasmic antibody–
related vasculitides (9, 17–21), and systemic
sclerosis (22, 23). More recently, IVIg has
also shown promise in the treatment of
polymyositis (PM) and dermatomyositis
(DM) (24–26). Anecdotal evidence and
several case series have also highlighted its
usefulness as adjunct treatment for ILD,
emphasizing the need for further awareness
and research into the use of IVIg in the
appropriate patient population.
Mechanism of Action
There is evidence that IVIg exerts
antiinflammatory and immunomodulatory
effects through multiple mechanisms,
depending on the disease process being
treated: modulation of macrophage Fc
receptor expression and function; alteration
of T cell and B cell function; inhibition
of pathogenic autoantibodies; inhibition of
inflammatory cytokines, chemokines,
or neurodegenerative molecules; and
inhibition of complement activation
(Table 1) (10, 27). Given that aberrant
immune response and heightened
inflammation are hallmarks of ILD, IVIg
could potentially alter the course of
pulmonary disease through some of
these mechanisms.
IVIg Regulates Immune Cells
Abnormalities in both innate and adaptive
immunity have been implicated in the
development of ILD, and there is
growing evidence that IVIg may possess
antiinflammatory properties through an
ability to alter the function of immune
effector cells. Lavage fluid from patients
with fibrotic lung disease demonstrates
Table 1. Intravenous Ig mechanisms of
action
Mechanisms
Inhibition of pathogenic autoantibodies
(27, 45, 46, 82, 83)
Modulation of macrophage Fc receptor
expression and function (30).
Inhibition of inflammatory cytokines,
chemokines, or neurodegenerative
molecules (45, 46, 50–53)
Inhibition of complement activation (84–87)
Alteration of T cell and B cell function (38, 88)
Perspectives
an increase in alternatively polarized
macrophages, and these macrophages are
believed to participate in a positive-feedback
loop involving lung fibroblasts and
increased collagen production (28, 29). In a
murine model of antibody-mediated
immune thrombocytopenia, the injection
of IVIg Fc fragments seemed to be
protective through up-regulation of an
inhibitory Fc-g receptor IIB on
macrophages (30).
Similarly, the presence of T cells and
abnormalities in T cell function are also
associated with parenchymal lung disease
(31–37). As an example, T cell polarization
to a Th2 phenotype has been associated
with the presence of active ILD and worse
pulmonary function in patients with
scleroderma (34). Furthermore, in one
study, lavage fluid from patients with
myositis-associated ILD demonstrated an
increased number of lymphocytes in addition
to an increase in T cell clonality when
compared with healthy control subjects (31).
In patients with chronic inflammatory
demyelinating polyneuropathy, there is
evidence that IVIg might regulate T cell
clonality and function by reducing the
oligoclonal expansion of T cell receptors in
both the CD41 and CD81 populations (38).
As such, the ability of IVIg to influence the
function of immune cells implicated in
pulmonary inflammation might make it an
effective immunomodulatory agent for the
treatment of ILD.
IVIg Interacts with Autoantibodies
The presence of specific autoantibodies
predicts the development of ILD in a variety
of connective tissue diseases. Antibodies
targeting citrullinated proteins are
associated with the presence of ILD in
patients with rheumatoid arthritis (39, 40),
whereas antibodies against ribonucleoprotein,
topoisomerase I (Scl-70), and transfer
RNA synthetases are associated with the
presence of ILD in other connective tissue
diseases, including systemic sclerosis,
systemic lupus erythematosis, and the
inflammatory myopathies (39–44). Igs in
IVIg preparations can bind the idiotype
of autoantibodies. For example, F(ab9)2
fragments have demonstrated a high
frequency of binding to the variable region
of naturally occurring IgG and IgM
autoantibodies secreted from B cell lines
of healthy patients. In addition, the
antibodies in IVIg have demonstrated
in vitro neutralization of autoantibodies
associated with known autoimmune
diseases: anti-cardiolipin antibodies, anti–
neutrophil cytoplasmic antigen antibodies,
and anti-DNA antibodies (45). As such,
IVIg has the ability to inhibit
autoantibody–antigen interaction and the
subsequent autoimmune response
escalation (27, 46).
Levy and colleagues (16) demonstrated
that, in patients with systemic lupus
erythematosis, titers of anti-nuclear, anti–
double-stranded DNA, anti–Sjögren’s
syndrome–related antigen A (SSA), and
anti-SSB antibodies decreased after treatment
with IVIg. Furthermore, those patients
demonstrating a clinical response were
more likely to have elevated levels of these
autoantibodies before the initiation of IVIg
treatment. Although causality between
autoantibodies and ILD in patients with
connective tissue disease has not been securely
established, it is conceivable that, by inhibiting
autoantibodies and the subsequent immune
response, IVIg therapy could lead to a
decrease in pulmonary inflammation.
IVIg Down-Regulates the Expression
of Chemokines
A number of inflammatory cytokines
have been implicated in the development
of ILD. For instance, serum levels of IL-6,
IL-8, TNF-a, and IFN-g–induced protein
10 were all elevated in patients with
myopathy-associated ILD compared with
myopathy control subjects that did not
have pulmonary involvement, and these
levels decreased after immunosuppression
(47). Furthermore, in vitro studies, animal
models, and human research indicate that
transforming growth factor (TGF)-b is
involved in promoting epithelial damage,
activation and proliferation of
myofibroblasts, and the subsequent
development of pulmonary fibrosis (48, 49).
There is evidence that IVIg may exert its
immunomodulatory effects by decreasing
both circulating levels and tissue expression
of various inflammatory cytokines,
chemokines, chemokine receptors, and
adhesion molecules, including: IFN-a, IL-1a,
IL-6, IL-10, granulocyte/macrophage
colony–stimulating factor, and TGF-b
(45, 46, 50–53). In a murine model of
scleroderma using subcutaneous injections
of bleomycin, the administration of IVIg
inhibited both the development of fibrotic
skin changes and the expression of TGF-b1
(51). Furthermore, in a study involving
patients with DM, monthly IVIg treatments
1683

were associated with decreased expression
of muscle TGF-b1 mRNA, and this effect was
most pronounced in those demonstrating a
clinical response to therapy (50). Given that
inflammatory cytokines, and in particular,
TGF-b, have been implicated in the
development of pulmonary fibrosis (48, 49),
the ability of IVIg to alter the expression
and circulating levels of such cytokines may
have implications for its use in the treatment
of ILD.
The Use of IVIg as Adjunct
Treatment for Myositis-
Associated ILD
The notion of using IVIg to treat ILD
originated from observations involving its
utility in the treatment of DM and PM, two
conditions associated with a high incidence
of pulmonary involvement. Over the past
few decades, numerous case reports, larger
case series, and retrospective studies focusing
on muscle strength, creatinine kinase
levels, and skin lesions have described a
favorable response to IVIg therapy in patients
with severe myositis refractory to traditional
immunosuppression (24, 54–63).
Subsequently, randomized trials have
demonstrated the ability of IVIg to improve
the rash, muscle strength, and neurological
symptoms in patients with steroid-resistant
myositis (25, 26).
ILD frequently complicates both
PM and DM, and its presence is associated
with increased morbidity and mortality
(4, 64). Although IVIg seems to be effective
at treating the muscular manifestations of
DM, it is unclear whether the pathological
mechanisms leading to myopathy are also
responsible for the concurrent pulmonary
disease, or if IVIg would also be effective
at treating ILD in these patients. Over
the past 10 years, emerging anecdotal
evidence has suggested that IVIg might
be contributing to the pulmonary
improvement seen in patients receiving
this form of immunosuppression for
inflammatory myositis with associated ILD.
Murota and colleagues (65) described
the case of a man with DM and ILD
in a radiographic pattern consistent with
nonspecific interstitial pneumonia.
Although his pulmonary disease progressed
despite therapy with steroids and
cyclosporine, there was a significant
decrease in dyspnea, oxygen requirements,
and radiographic abnormalities after the
1684
initiation of both cyclosphosphamide and
IVIg. Unfortunately, it is impossible to
discern the separate contribution that each
of these agents made to his clinical
improvement, as cyclophosphamide itself
is a potent immunosuppressant and may
have been solely responsible for the noted
clinical improvement.
Diot and colleagues (66) describe a
man with PM-associated ILD who failed to
respond to high-dose steroids, with further
clinical worsening after a dose of
cyclophosphamide. However, after three
monthly courses of IVIg, there was a
marked improvement in both muscle and
pulmonary function, as measured by total
lung capacity and diffusion capacity for
carbon monoxide. The authors also
reported regression of fibrotic changes seen
on computed tomography (CT) scan,
although the comparative images were not
published. In addition, Bakewell and Raghu
(67) published another case of severe
PM-associated ILD without clinical
improvement after high-dose steroids, but a
significant improvement in symptoms and
diffusion capacity for carbon monoxide
after IVIg 2 g/kg monthly for 3 months.
The initial CT scan demonstrated ground
glass opacities with subtle honeycombing
consistent with nonspecific interstitial
pneumonia. These findings resolved
completely, and, 2 years after therapy, the
patient still had no supplemental oxygen
requirement.
Suzuki and colleagues (68) conducted
a review of five patients with refractory
and rapidly progressive ILD in association
with either PM or amyopathic DM. Each
patient presented with treatment failure
despite high-dose prednisone and
cyclosporine, and, in each case, CT imaging
demonstrated ground glass opacities or
consolidations without the presence of
honeycombing. After a course of IVIg
(0.4 g/kg/d for 5 d), two patients survived,
and two had an initial positive response,
followed by a subsequent decline and death.
Although, at first glance, this outcome may
seem disappointing, the rapidly progressive
form of ILD in patients with idiopathic
myopathy often carries a dismal prognosis,
with reported 6-month mortality rates
ranging from 60 to 72% (64, 69).
In a review of 197 patients with either
DM or PM, of which 69 had associated
ILD, a combination of IVIg and
corticosteroids was used in 36 cases.
The mortality rate among those receiving
AnnalsATS Volume 13 Number 10 | October 2016
PERSPECTIVES
IVIg was 41.6%, similar to that of those
patients receiving either cyclophosphamide
or azathioprine, but higher than those
receiving mycophenolate or methotrexate.
However, the study was retrospective, the
number of patients in each of the other
treatment groups was small (ranging from
2 to 23), and the severity of ILD in each
of the groups was not reported (70).
Additional studies and case series focusing
on myositis-related ILD have reported only
a handful of other patients that have
received IVIg (41).
IVIg as Adjunct Therapy for
Other Forms of ILD
Published evidence supporting the use of
IVIg in myositis-associated ILD remains
limited, and there are even fewer published
cases involving the treatment of other forms
of ILD. Matsubara and colleagues (71)
reported on a woman with common
variable immunodeficiency-associated
lymphoid interstitial pneumonia who was
treated successfully with a combination of
IVIg and steroids. The authors noted a
significant radiographic improvement,
although the benefit of IVIg remains
unclear, as steroids have traditionally been
used as effective monotherapy for the
treatment of lymphoid interstitial
pneumonia. Another group reported the
case of a woman with CT findings
consistent with NSIP in the setting of a
myositis/systemic sclerosis overlap
syndrome and a positive anti–PM-Scl
antibody. After a flare of her muscular
disease, she was also noted to have
progression of her ILD on CT imaging
with a FVC of 53% predicted. She was
treated with a combination of monthly IVIg
and azathioprine, and, after six infusions,
her FVC normalized and the subpleural
ground glass opacities and septal thickening
completely resolved (72).
More recently, IVIg has been used
as adjunct therapy in the treatment of
idiopathic pulmonary fibrosis (IPF)
flares. Donahoe and colleagues (73)
reported 11 consecutive cases of acute
IPF exacerbations treated with plasma
exchange and rituximab, and these patients
had significantly better mortality rates
and subsequent pulmonary function than
historical control subjects. The last four
patients in the study also received IVIg
therapy, and they demonstrated a more
 PERSPECTIVES

prolonged response than those receiving
plasma exchange and rituximab alone.
However, these same patients also received
additional plasma exchange sessions.
As such, although IVIg may have worked
either alone or synergistically with the
baseline therapy to mitigate autoantibody
rebound, it is also possible that the
more enduring response of the last four
patients was simply the result of having
received addition plasma exchange
sessions.
In another small, prospective study,
10 patients with progressive IPF received IVIg
for either 5 consecutive days (5-day group),
or once monthly for 5 consecutive months
(5-month group), with a cumulative dose
totaling 2 g/kg in both groups. In the 5-day
group, respiratory symptoms were improved
in two patients and stable in the other
four; although the vital capacity initially
improved in five of six patients, this effect
waned after 3 months. In the 5-month group,
symptoms were improved in two out of four
patients; vital capacity increased in three
patients; percent diffusion capacity for carbon
monoxide increased in three patients; and
HRCT abnormalities were improved in two
patients. In contrast to the 5-day group, these
changes were sustained at 6 months, and
there was a rapid decline in pulmonary
function test parameters after the cessation of
IVIg (74). The dose of IVIg used in this
study was significantly lower than that
used to treat other inflammatory disorders,
where 2 g/kg is typically infused on a
monthly basis. As such, although the results
of such a small study should not justify the
use of IVIg in the treatment of IPF, they
should spark interest in larger, randomized,
controlled trials.
Possible Advantages to Using
IVIg in the Treatment of ILD
IVIg has yet to be established as an
appropriate adjunct therapy for ILD.
However, if future studies demonstrate
convincing evidence of its efficacy, then its
monthly administration and favorable side
effect profile would make IVIg an attractive
option for patients with refractory disease.
Traditional immunomodulatory agents,
such as corticosteroids, methotrexate,
azathioprine, mycophenolate, and
cyclophosphamide, are associated with
significant side effects and toxicity,
including an increased risk of opportunistic
infection (75). It is postulated that IVIg may
be less immunosuppressive than these
traditional agents, and therefore carry a
lower infection risk.
Furthermore, IVIg is generally well
tolerated (Table 2), with minor side effects,
such as headache, fever, nausea, or
myalgias, occurring in 0.5–7.3% of patients.
More serious side effects, such as DVT,
stroke, or aseptic meningitis, are seemingly
rare (76, 77). Wittstock and colleagues (76)
prospectively analyzed 117 patients with
various neurological diseases who received
a combined total of 1,361 courses of IVIg
therapy. In their study, deep venous
thrombosis occurred in two patients (1.7%),
with headaches, fevers, or chills occurring
in eight patients (6.8%). Four patients
(3.4%) reported either urticarial or palmar
itching, and these symptoms lasted an
average of 2 weeks. They calculated an
overall adverse event rate of 4% of
treatment courses, and no patients had a
permanent termination of therapy. In our
experience, the development of allergic
reactions (itching, rash) after repeated
infusions can be ameliorated by changing
the brand of IVIg, slowing the infusion rate,
or prehydrating with normal saline; a
discontinuation of therapy is rarely
necessary.
Challenges to the Use of IVIg in
the Treatment of ILD
Despite its relatively favorable side-effect
profile, there are currently several
drawbacks to the use of IVIg in the treatment
of ILD (Table 3). Although the treatments
are monthly, they are administered over
3–5 days and require intravenous access.
For some patients, this may prove
logistically difficult. Furthermore, if
repeatedly obtaining intravenous access is
challenging, the placement of an infusion
port may be necessary. In addition, IVIg
therapy remains costly. For example, a
dose of IVIg for a 70-kg patient (2 g/kg)
has an average cost ranging from $14,000
to $21,840 per month; conversely, the
monthly cost for a standard dose of
azathioprine, mycophenolate, or oral
cyclophosphamide ranges from $118 to
$1,542 (78–81). Finally, experience with IVIg
for the treatment of ILD remains relatively
limited, and, to date, no convincing data
supporting its use in this context have been
published.
Table 2. Intravenous Ig side effects
Side Effects
Common side effects
Headache
Fever
Chills
Nausea
Myalgias
Arthralgias
Rash
Pruritis
Fatigue
Hypertension
Rare side effects
Aseptic meningitis
Deep venous thrombosis
Stroke
Acute kidney injury
Anaphylaxis*
See References 46, 76, and 77.
*Risk is increased in patients with underlying IgA
deficiency.
Current Use and
Future Directions
As previously discussed, evidence
supporting IVIg for the treatment of ILD
is limited to case series and anecdotal
reports. As such, it remains largely
experimental, and has been used
primarily as salvage therapy when
traditional immunosuppression has
either failed or been poorly tolerated.
Multiple trials have already demonstrated
the efficacy of IVIg in the treatment of
inflammatory and autoimmune disorders,
although, to date, there is no conclusive
Table 3. The pros and cons of
intravenous Ig therapy in the treatment of
interstitial lung disease
Pros and Cons
Pros
Alternative mechanisms of action compared
with traditional immunotherapy
Less immunosuppression and risk of
infection compared with traditional
immunotherapy
Favorable side-effect profile
Proven safe and effective for the
treatment of various other disorders
Cons
Expensive
Requires serial visits to an infusion center
Currently no adequate data to support its use

Perspectives 1685
 PERSPECTIVES

evidence to support its routine use in the
treatment of ILD, regardless of the
underlying cause. However, the need for
alternative therapies in a subset of patients
with ILD, combined with the favorable
safety profile of IVIg, makes the use of this
agent an attractive topic for future clinical
trials. As such, the true efficacy of IVIg
should be determined and compared with
more traditional forms of
immunosuppression, with steroid dose
reduction, pulmonary function tests,
radiographic improvement, and quality of
life scores being predefined outcomes.
Conclusions
IVIg has been used for decades to treat a
wide array of infectious, inflammatory, and
autoimmune conditions, and its mechanism
of action likely varies in conjunction with
the disease being treated. In recent years,
there has been anecdotal evidence and
limited reports suggesting the utility of IVIg
in the treatment of various forms of ILD.
However, although IVIg is relatively well
tolerated, it is much more expensive than
traditional therapies, and there are currently
not adequate data to support its routine use
in this context. As such, clinical trials are
necessary to determine if IVIg has a role in
the treatment of ILD. n
Author disclosures are available with the text
of this article at www.atsjournals.org.

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AnnalsATS Volume 13 Number 10 | October 2016