Article Type : Case Report
Authors : Buttar R, Zhenhui Lee S, Tousif Syed M and Kumar P
Keywords : Immunoglobulin; Lymphoplasmocytic infiltrate; Storiform fibrosis
Immunoglobulin
G4-related disease (IgG4-RD) is an immune fibro-inflammatory condition. It is
characterized by tumor like organ swelling, storiform fibrosis, infiltrative
CD4 T cells, lymphoplasmocytic infiltrate and an elevated serum IgG4. The
disease lends itself to a multisystem disorder and isolated organ manifestation
can also occur. Common findings of IgG4-RD include autoimmune pancreatitis,
sialadenitis, sclerosing cholecystitis, tubulointerstitial nephritis, orbital
disease, lymphadenopathy and retroperitonal fibrosis and lymphadenopathy. However,
IgG4 related disease of the lung is particularly novel. It manifests as lung
nodules, fibrosis and scarring of the lung tissue. In 2015 the international
consensus reviewed and re-established a consensus the diagnosing IgG 4. A
criterion for the diagnosis of IgG4-RD encompasses a set of clinical,
pathological and serological features in conjunction with specific criteria for
organ specific involvement. Recognizing and differentiating IgG4-RD to other
similar pathologies is essential for managing the underlying condition,
preventing long-term complications and necessary for appropriate treatment.
Immunoglobulin G4-related
disease is an immune mediated condition resulting in disease in various organs
of the body such as the pancreas, kidneys, salivary glands, lung, liver, lymph
nodes, biliary tract and orbits of the eyes. The disease is recognized by a
characteristic pattern of pathological, serological or clinical features shared
amongst the organs system that are involved. In some cases, IgG4-RD can mimic
malignant, infectious or inflammatory disorders and therefore distinguishing
the disease is crucial [1].
The international
consensus statement on IgG4-RD established bases for the diagnosis IgG4-RD from
findings in multiple organs. The definitive algorithm for diagnosing IgG4-RD
includes: (1) organ swelling (enlargement, mass or nodular lesions) or organ
dysfunction in one or more organs on physical examination; hematological
studies showing a serum IgG4+ concentration of ? 135 mg/dL; histopathology
indicating marked lymphocyte and plasmacyte infiltration with fibrosis and IgG4
+ plasma cell infiltration (IgG4+/total IgG+ cells > 40% AND > 10 IgG4+
cells on high power field) [2].
As discussed in
literature, the etiology of if IgG4-RD remains to be completely understood.
However, increasing evidence suggests an autoimmune picture with involvement of
CD4+ T cells and T follicular helper cells (Tfh). IgG4 antibodies are currently
thought to be non-pathogenic and arise due to a down regulatory response to an
underlying process [3].
Cases of IgG4-RD are rare
with contributing factors being poor recognition, understanding and
under-reporting. Majority cases are found in middle aged. Variation in organ
manifestation appears to vary with gender. In males, there is increased
tendency to affect the pancreas, causing autoimmune pancreatitis type 1 as well
as retroperitoneal fibrosis and tubulointerstitial nephritis. Higher prevalence
for head and neck involvement is seen in females causing sialadenitis,
dacryoadenitis and thyroiditis according to a study [4].
Multisystem disease
accounts for the majority of IgG4-RD cases and isolated single organ disease is
less common. The involvement of the lung in patients with IgG4-RD is becoming
increasingly recognized [5]. In three large case series conducted by Chen at
al, Fernandez Codina et al and Inner et al, lung involvement was accounted for
in 32%, 9% and 13% of cases respectively [6]. Another study reported 13% of AIP
with IgG4 lung involvement. Isolated cases of IgG4 lung disease were reported
in 20% of cases, while the remaining 80% had multi-organ involvement. It also
stated IgG4-RD of the lung was the seventh most common manifestation [7].
Clinical features
suggestive of pulmonary involvement include cough, shortness of breath,
hemoptysis, pleurisy, chest pain and fevers [8]. Patients may be asymptomatic
until significant organ involvement. Lymphadenopathy appears to be a common
occurrence across IgG4-RD cases. Asthma or allergy presents in up-to 40% of all
cases [9]. With reference to imaging findings, literature describes four
particular patterns of respiratory involvement including solid nodular,
bronchovascular, alveolar interstitial and round shaped ground glass opacities
[10]. Other presentations of lung related IgG4-RD include interstitial
pneumonia, primary lung cancer, sarcoidosis, lymphoproliferative disease and
obliterative phlebitis and storiform fibrosis [10]. Confirmation of IgG4-RD
with respiratory involvement requires diagnostic criteria established through a
collection of serological, imaging and histopathology studies. A set of
criteria for recognizing individual organ involvement was proposed by the Study
Group of Intractable Disease from the Ministry of Health, Labour and Welfare
(MHLW) in Japan and is increasing in acceptance [11]. Referred to as diagnostic
criteria for IgG4 related respiratory disease (RRD) [Image A], the diagnostic
criteria includes chest imaging findings showing intrathoracic lesions;
serology of elevated series IgG4 concentration of ?135 mg/dl; and significant
histopathology obtained from biopsy of the sample from intrathoracic tissue. It
is also important to exclude conditions with similar presentation features such
Castleman disease, Wegeners granuloma, Churg-Strauss Syndrome, Sarcoidosis,
Rosai-Dorfman disease, respiratory infections and tumors [11]. In this study,
we report a case of persistant cough later diagnosed with IgG4-RD upon
serological, histological and imaging findings.
A
51 year
Caucasian
female
was
referred
to
the
respiratory
out-patient clinic for evaluation of chronic cough.
Asthma
was
diagnosed
as
an
adolescent
and
reported
to
be
well
controlled
under control.
She
has
since
then
presented
to
hospital
on
one
occasion
with
exacerbation
of
the
asthma
and
reports
exacerbation
3 to
4 times
a
year
with
suboptimal
asthma
control
and
notable
increase
following
cyclone
in
2017. She
has
had
6 exacerbations
of
asthma
in
the
last
12 months
but
no
admissions
to
ICU.
She
reports
a
long
history
of
a
chronic
dry
cough
which
is
triggered
by
cold
air,
respiratory
infections
and
becomes
productive
with
tenacious
green
sputum.
There
is
no
history
of
sputum
plugs.
The
cough
is
associated
with
a
wheeze,
SOB,
chest
tightness,
throat
clearing,
globus
sensation
and
gradually
progressive
decline
in
exercise
tolerance
(18-month
history
with
MRC
grade
1). The
ongoing
cough
is
also
worse
at
night
and
when
supine,
often
waking
her
up
from
sleep.
There
no
symptoms
suggestive
of
cardiac
failure.
Nocturnal
cough
resolves
with
PRN
salbutamol.
No
history
of
anorexia,
fever
of
night
sweats.
A patient wakes
up
numerously
at
night
due
to
nocturia
or
coughing.
She
is
a
shift
worker
and
sleeps
at
9 am
with
a
latency
of
20 minutes.
No
reported
apnea
or
choking
episodes
due
to
no
collateral
history.
She
experiences
occasional
morning
headache
and
feeling
unrefreshed
at
5am
but
no
xerostomia.
There
often
daytime
somnolence
and
naps,
scoring
an
Epworth
sleep
scale
of
10, though
no
reported
falling
asleep
while
at
the
wheel.
Patient
has
background
history
of
gastroesophageal
reflux
disease
(GORD),
seasonal
allergic
rhinitis,
sinusitis
with
postnasal
drip,
hay
fever
with
childhood
eczema
and
Bronchiectasis.
Medications
included
Esomeprazole,
Symbicort
200/6, Spiriva
Respimat
2.5, Ventolin,
Rhinocort,
Citalopram
and uses
Ventolin
when
required
3-4 times
weekly
when
well.
Vaccinations
are reported
to
be
up
to
date.
The
patient
has
no significant
family
history.
The
patient
is
an
ex-smoker with a 5.5-year pack history for which she ceased smoking
20 years
ago
and
consumes
alcohol
once
weekly.
Patient
also
reported
THC
use,
last
reported
in
2018. She
lives
in
a
split-level home and is independent with ADLs. Work history includes hostel manager and tourism work on boats. There may be possible exposure to asbestos and mould during work at in produce but details are unknown.
No
reported
exposure
to
coal,
dust,
birds
or
tuberculosis.
On
review
the
patient
reported
an
improving
cough
with
less
phlegm,
nil
worsening
of
wheeze
and
Epworth
sleep
score
of
10. No
decrease
in
exercise
tolerance
while
she
is
able
to
walk
long
distance
and
upstairs
without
dyspnea.
She
reports
2 pillow
orthopnea
and
paroxysmal
nocturnal
dyspnea.
Her
appetite
has
been
normal
although
reported
weight
gain
of
12kg
in
18 months.
She
also
states
low
energy
and
tiredness.
Sleep
was
described
to
be
disturbed
and
reports
snoring
loudly.
Clinical examination were within the normal
limts
Cardiovascular,
neurological
and
abdominal
examinations
were
un-remarkable.
Full
blood
count,
renal
function
and
liver
function
were
unremarkable.
Immunoglobulin
subclass
screen
revealed:
·
IgG of 17g/l,
·
IgG4 of 2.97g/L
·
ESR of 232
·
RAST A. fumigatus was positive
Vasculitis screen was unremarkable.
Chest X-ray revealed large volume lungs. A persisting nodule measuring up to 13mm was again noted in the right upper lobe and resolving focal patchy ground glass changes in the left upper lobe. Spirometry results were as follows: FEV1 2.45 (81%), FVC 3.49 (91%), FEV1/ FVC 88%, DLCO 96.1%, KCO 86.9 and these parameter were within the normal limits.
BAL
was unremarkable and histology
demonstrated degree of lymphoplasmacytic infiltrates with some degree of
fibrosis.
A.
Diagnostic factors |
I. Chest
imaging |
Imaging
findings include any of the following intrathoracic lesions, Hilar/mediastinal
lymphadenopathy Bronchial
wall/Broncho vascular bundle thickening, interlobular septal wall thickening, Nodular shadow infiltrative
shadow, pleural thickening and/or effusion. |
II.
Serology |
Elevated serum IgG4 concentration of ?135
mg/dl |
III.
Histology |
Two or more of the following items are
required from intrathoracic organ tissues. |
a: ?3 Items; b: 2 items |
(1) Marked
lymphoplasmacytic cell infiltration into interstitium of peribronchovascular
sheath, interlobular septal wall, and/or pleura. (2) IgG4/IgG-positive
cell ratio >40% and/or >10 IgG4-positive cells/high power field. (3) Obliterative
phlebitis or obliterative arteritis. (4) Storiform
fibrosis or fibrosis consisting of proliferating spindle-shaped cells around
infiltrating lymphocytes. |
B. Diagnosis |
1.
Definite
diagnosis (definite): I+II+IIIa, or I+II+IIIb+IV Histological definite
diagnosis [definite (histological)]: I+all four items of III 2.
Probable
diagnosis (probable): I+II+IV, or I+II +IIIb+V 3.
Possible
diagnosis (possible): I+II+IIIb |
Overall, a diagnosis of IgG4
related disease of the lung was considered. It became evident following
findings from the clinical features, spirometry, blood results, radiographic
reports and histopathology of lung tissue. The presentation is consistent with
a rare case of isolated IgG4 related lung disease, presenting as chronic cough.
Based on history and clinical presentation, our patient had allergic
hypersensitivity with features of poorly controlled recurrent asthma. IgG4-RD
with ear, nose, throat manifestation could also be suggested [12-19].
IgG4-RD has a precedence to
affect the middle aged male population according to literature but in this case
the patient was female, making the case unique. Physical examination was
largely unremarkable. Findings on CT imaging revelased bronchiectatic changes,
peribronchial centrilobular ground-glass opacities. Manifestations of IgG4-RD
were not evident in other systems of the body including liver, bile duct or
pancreas.
Laboratory data showed an
IgG4 level of 297 mg/dL (17g/L, reference range: 2.4 - 121.0 mg/dL) which
fulfills the serological criteria, Section A Part II of the diagnostic criteria
required IgG4-RD. Blood test revealed an elevated ESR of 232 (reference range)
as well positive RAST A. fumigatus. Spirometry indicated normal lung function
and results were unremarkable for this patient, although reversibility was not
recorded.
Tissue biopsy remains gold
standard for the diagnosis of organ specific involvement of IgG4-RD, thus
bronchoscopy was conducted in the light of a definitive diagnosis. Despite,
optimal samples were difficult to obtain through brushings to assess cytology,
microscopy and sputum. From brushings of the right lower lobe, microscopy
showed bronchial epithelial cells, alveolar macrophages and leukocytes.
However, no significant eosinophilia or plasmacytosis was observed.
Histology demonstrating the degree of lymphoplasmacytic infiltrates and there was no comment on the CD4 T cells + plasma B cells levels or eosinophil infiltration. Some degrees of fibrotic changes were noted as well.
Systemic manifestations
IgG4-RD can virtually effect
any organ system of the body. It has a variety of clinical presentations and
manifestations that may not be mutually exclusive. In the absence of
significant clinical suspicion, tests for IgG4-RD are not recommended as
diagnostic [20,21]. Multiple organs are affected in 60 to 90% of incidences of
IgG4-RD [17,19]. Due to the extent of organ involvement, one study looked at 2
cross-sectional studies in the attempt to categories types of IgG4-RD. It
comprised of 765 cases and identified four groups with distinct patterns of
organ involvement and manifestations using latent class analysis (LCA). IgG4-RD
was classified into 4 groups: Group 1, Pancreato-Hepato-Biliary disease (31%);
Group 2, Retroperitoneal Fibrosis and/or Aortitis (24%); Group 3, Head and
Neck-Limited disease (24%) and Group 4 (22%), classic Mikulicz syndrome with
systemic involvement [22]. Conditions previously considered as
single entities are now regarded as manifestations of IgG4-RD [2].
Lymphadenopathy
IgG4 disease effects the
lymph nodes causing lymphadenopathy in 41% of patients with multiple organ
involvement [12]. Presenting symptoms relate to the mass effect of the lymph
nodes and the lymphadenopathy itself tends to be non-tender. It can occur in
isolation or along with other manifestations. Multiple groups of lymph nodes
may be involved including hilar, intraabdominal, mediastinal and axillary.
Biopsies have poor specificity for diagnosis and may not reflect the extent of
disease in other organs [13]. Histopathology shows features of storiform
fibrosis, IgG4+ plasma cells, eosinophilic infiltration consistent with
classical IgG4-RD [14,15].
Autoimmune pancreatitis
Of the two subtypes of
autoimmune pancreatitis only one has been associated with IgG4-RD. The most
common and typical form is Type 1 (IgG4-related) autoimmune pancreatitis (AIP),
also referred to as lymphoplasmacytic sclerosing pancreatitis [17]. Presentation
includes painless obstructive jaundice making distinguishing AIP from
pancreatic cancer difficult but essential so that surgery can be avoided in
unnecessary. Patients may also experience secondary diabetes mellitus as seen
in 50% of cases [13,16]. Though likely to be an underestimation, AIP from
IgG4-RD has a prevalence of 0.82 in 100,00 in Japan in early studies [18]. Characteristically
on CT imaging, an enlarged “sausage shaped” pancreas with surrounding edema is
highly suggestive of AIP. Diagnostic criteria for AIP resulting from IgG4-RD
requires combined ductal and parenchymal imaging, serum IgG4 concentration,
pancreatic histology, presence of extra-pancreatic disease and response to
glucocorticoids. Endoscopic ultrasounds, MRCP and PET scans may aid diagnosis
[13].
Sclerosing cholangitis
Sclerosing cholangitis from
IgG4-RD is often associated with type 1 AIP as the commonest extra-pancreatic
manifestation in more than 70% of cases. To note, it is distinct from primary
sclerosing cholangitis and cholangiocarcinoma and definitively excluding these
conditions may require endoscopic transpapillary biops [13,19]. Tissue biopsy
of IgG4-RD sclerosing cholangitis reveals dense IgG4+ plasma infiltrates,
transmural fibrosis, obliterative phlebitis and elevated IgG4 serum levels [13].
Salivary and lacrimal glands
Mikulicz’s disease and
Küttner tumor are now considered subcategories of IgG4-related sialadenitis and
are often seen in conjunction with AIP [23,24]. IgG4-RD can affect both major
and minor salivary glands. Mikulicz’s presents with dacryoadenitis (lacrimal)
along with enlargement of the submandibular and parotid gland. Enlargement of
the submandibular gland is a form of sclerosing sialadenitis, which is known as
a Küttner tumor. This varies in contrast to Sjo?gren’s syndrome where parotid
gland involvement s predominates [13]. IgG4-related sialadenitis and
dacryoadenitis demonstrates typical IgG4-RD characteristics obtained from
tissue samples as seen in other organ sites.
Orbital
Common ophthalmic
manifestations of IgG4-RD include frank proptosis and orbital swelling often
involving the lacrimal gland (dacryoadenitis). Orbital myositis and orbital
pseudotumours due to IgG4-RD may also present as proptosis. Less commonly
scleritis, nasolacrimal duct obstruction and nerves surrounding the orbits can
be compressed. Of patient with IgG4-RD, ophthalmic disease is accounted for in
estimated 17-23% of cases [13,25,26].
Chronic periaortitis and retroperitoneal
fibrosis
Up to two thirds of cases of
idiopathic retroperitoneal fibrosis are as result of IgG4-RD. It is one of the
most common manifestations of IgG4-RD. Previously known an Ormond’s disease,
the classification of chronic periortitis currently incorporates 3
manifestations; IgG4-RD related retroperitoneal fibrosis, IgG4-related
abdominal aortitis, and IgG4-related perianeurysmal fibrosis. Three broad
regions are known to effect in chronic periaortitis, which include the
periaortic/arterial, periureteral and retroperitoneum. Chronic periaortitis can
present with non-specific back, flank, lower abdominal, lower limb pain or
oedema and obstructive uropathy which may cause delay in diagnosis [27,28].
IgG4 related retroperitoneal
fibrosis tends to present with fibrotic and chronic inflammatory changes
affecting the infra-renal aorta, iliac arteries and regional tissue. In the
laboratory, the IgG4+ plasma cell to total plasma
cells ratio that is obtained from tissue sample, provides a useful tool for
diagnosis. Often storiform fibrosis and obliterative phlebitis are also present
and consistent with classic IgG4-RD characteristics [13,29,30].
Thoracic aorta, branches of aorta and coronary
lesions
Non-infectious aortitis is
known to be caused by IgG4-RD [31]. Aneurysms and dissections of the thoracic
aorta are common findings in IgG4 related aortitis, though primary aortic
branches are spared unlike in Giant Cell and Takayasu’s arteritis. Medium
size vessels and coronary arteries can also be effected by IgG4-RD [13]. Radiographic
findings of primary vessel disease showing inflammation of vessel walls was
found in 8.1 percent of patients with IgG4-RD [32].
Thyroid disease
IgG4-RD of the thyroid gland
manifests as rare form of thyroiditis, called Riedel's thyroiditis. A hard
goiter is noted along with symptoms such as dyspnea, dysphagia and hoarseness
as a result of correlating compression of surrounding structures. Features of
IgG4-RD that are observed on tissue biopsy include storiform fibrosis,
obliterative phlebitis and elevated IgG4: IgG ratio. Cytology may not be
conclusive thus diagnosis is often made following resection of the thyroid, for
symptomatic treatment and/or ruling out malignancy [33].
Kidney
Tubulointerstitial nephritis is the most common
finding of IgG4 related renal disease often seen in middle-aged and older
males. Histology remains consistent with features observed in other organs and
type 1 AIP [34]. Though notably
low concentrations of complement (hypocomplementaemia) are demonstrated in IgG4
related tubulointerstitial nephritis compared to other organ manifestations of
IgG4-RD. Patient may develop advanced to end stage renal failure, proteinuria
and atrophy of kidney despite responsiveness to therapy. CT Imaging may reveal
hypodense lesions and an enlarged kidney in relation to the disease. Nodular
lesions can mimic renal cell carcinoma in some cases [34,35]. TIN
secondary to IgG4 related was observed in 15% of cases from a retrospective
study in Japan involving 153 cases of suspected IgG4-RD [34]. Membranous
glomerulonephropathy is a less common manifestation of renal IgG4 disease
though it is often seen in conjunction with TIN [36].
Ear, nose and throat
Many IgG4-RD patients are
not atopic but a considerable proportion present with allergic features
relating to the ear, nose and throat. Before the IgG4-RD phenotype is known,
patients may suffer from long standing allergic rhinitis, nasal polyps, asthma,
sinusitis, obstruction or rhinorrhea. Elevated levels of leukocyte count,
mild-moderate peripheral eosinophilia, IgE concentrations above 10-fold are
common [37]. In some cases, disease process causes inflammation of the pharynx,
hypopharynx, Waldeyer’s ring, vocal cords and trachea, with some occurrences of
mass lesions [38,39].
Other involved organs and tissues
IgG4-RD can occur in various
other forms and organs of the bodies in much rarer instances [13]. Several
cases of skin involvement have been reported presenting with erythematous
papules typically affecting the head and neck [40]. In the CNS, IgG4-RD affects
the brain parenchyma most often resulting in hypertrophic pachymenigiits.
Hypophysitis with hypopituitarism is another less common manifestation [41]. Within
the mesentery and mediastinum IgG4-RD has been associated with sclerosing
lesions causing compression of adjacent vital structures [42]. Liver
manifestations if IgG4-RD may resemble autoimmune-hepatitis or hepatic
inflammatory pseudotumors [43]. While in the prostate, benign prostatic
hypertrophic and prostatitis have been observed [44].
In some cases of asymptomatic IgG4-RD with no
presence of organ dysfunction treatment may not be necessary. However, patients
should be monitored closely with adequate follow-up by managing teams. IgG4-RD
is treated with glucocorticoid as first-line therapy. The dose and regime are
based on findings in AIP cases. Typically, prednisolone 0.6mg/kg/day for 2-4
weeks is used an induction and the tapering of corticosteroid is occurs over
3-6 months. A maintenance dose of 2.5-5mg/day may be required for up to 3
years. In refractory or complication IgG4-RD disease, steroid-sparing agents
such as azathioprine, mycophenolate mofetil, and methotrexate can be
considered. Rituximab may aid B cell depletion refractory disease.
Additionally, surgery may be considered on a case to case bases [6,13].
IgG4-RD is a relatively poorly understood condition
with unknown definitive aetiology. Cases in the current population are
underestimated and undervalued. IgG4-RD may often be overlooked and therefore
should be considered by clinicians as an important differential if multiple
features are present. The diagnostic criteria outlined in literature should aid
definitive diagnosis of IgG4 RD. If suspected, IgG4-RD manifestations in other
organs should also be investigated so that appropriate and optimal an treatment
can be administered to the patient.
The corresponding author
is the guarantor of submission.
None
Written informed consent was obtained from the
patient for publication of this case report.
Authors declare no conflict of interest.