Corresponding Author: Fachri
Setiawan
Email: [email protected]
INTRODUCTION
Interstitial lung disease is a
lung disease that has vast variations. There are more than 200 disorders that
fall into the group of interstitial lung diseases. Interstitial lung disease
includes areas with various cell types such as fibroblasts, myofibroblasts,
macrophages, and many matrix components such as collagen, elastin, and
proteoglycans. These
matrix components lie between the alveolar epithelium and the vascular
endothelium. Interstitial lung disease is a
rare disease. The most common interstitial lung disease is idiopathic pulmonary
fibrosis (IPF). This disease has a low survival rate (Putra et al., 2017).
Interstitial lung disease has
several classifications. As seen in Figure 1, the classification currently used
divides interstitial lung disease into five groups, namely autoimmune-related
interstitial lung disease, idiopathic interstitial pneumonia, hypersensitivity
pneumonitis, sarcoidosis, and other forms of interstitial lung disease. One
form of interstitial lung disease is pulmonary sarcoidosis (Cottin et al., 2018) . In this literature review, the author will discuss the
epidemiology, definition, clinical picture, diagnosis, and management of
sarcoidosis.
Figure 1.
Classification of Interstitial Lung Disease
Based on the background above, the objective
of this research is to understand the characteristics of interstitial lung
disease, specifically sarcoidosis. This study is expected to provide a deeper
understanding of the variations in clinical symptoms, possible causes, and
diagnostic methods of this disease. With a better understanding of sarcoidosis,
it is hoped to improve the ability to diagnose and manage this condition, as
well as to benefit patients through increased effectiveness of therapy and care.
METHOD
The method used
involves a literature review to gather current information on interstitial lung
disease, particularly sarcoidosis, including variations in clinical symptoms,
possible causes, and diagnostic methods used. This is based on data sources
from both online and offline references, including books, journals, and
articles related to the topic.
RESULTS AND DISCUSSION
Sarcoidosis
is a systemic disease characterized by the formation of noncaseating granulomas
involving the lungs. Lung involvement can reach 90%, while other organs that
can be affected include the lymphatic system, skin, and eyes. The clinical
manifestations of sarcoidosis vary widely, ranging from asymptomatic to causing
severe symptoms with an undetermined prognosis (Sikj�r et al., 2021). Sarcoidosis was first identified by
Jonathan Hutchinson in 1869 in a 58-year-old coal dock worker (Spagnolo, 2015). Sarcoidosis has an acute, subacute, and
chronic onset and can attack various organs, especially the lungs (Sikj�r et al., 2021).
Several other
organs can be involved in this disease, including the lymphatic system, skin,
eyes, liver, spleen, nervous disorders, and heart. The proportion of
involvement of other organs can be seen in Table 1 (Polverino et al., 2020). Sarcoidosis is very difficult to diagnose
because it often resembles various diseases, including infections, vasculitis,
drug reactions, and malignancies. Sarcoidosis is generally benign, and most
patients do not require treatment. Complete resolution occurs in almost 50% of
cases, and only a third of cases of this disease develop into chronic and
progressive disease (Bernardinello et al., 2021).
Table 1. Organ Involvement in
Sarcoidosis
|
Organ
|
Frequency (%)
|
|
Lungs
|
90
|
|
Skin (excluding erythema nodosum)
|
16
|
|
Erythema nodosum
|
8
|
|
I measured
|
12
|
|
Extrathoracic lymph node
|
15.2
|
|
Liver
|
12
|
|
Spleen
|
7
|
|
Nerve
|
5
|
|
Heart
|
2
|
Epidemiologist
Sarcoidosis occurs worldwide and
most commonly affects young and middle-aged people of all races and genders.
The incidence of this disease is most common in Scandinavian countries. Data in
Sweden shows the incidence of this disease reached 11.5 per 100,000 population.
This data is higher than that of the United States, which reached 8-11 per
100,000 people, and Canada's 6.8 per 100,000 people. The incidence of this
disease in the East Asian region is lower. Data in South Korea shows the
incidence of this disease reaches 0.5-1.3 per 100,000 population. The incidence and prevalence of this
disease can be seen in Table 2 (Arkema & Cozier,
2020).
Table 2. Incidence and Prevalence of
Sarcoidosis
|
Country
|
Prevalence per 100,000
|
Incidence per 100,000 per year
|
|
Australia
|
|
4.7
|
|
Belgium
|
2
|
0.3
|
|
Canada
|
143
|
6,8
|
|
Croatia
|
|
3.3
|
|
Czech Republic
|
63.1
|
4.4
|
|
Denmark
|
|
7.2
|
|
Finland
|
28
|
11.4
|
|
French
|
30
|
4.9
|
|
Greece
|
5.9
|
1.07
|
|
Ireland
|
28
|
|
|
Italy
|
49
|
|
|
Japan
|
3.7
|
1
|
|
Poland
|
6.5
|
5.9
|
|
Saudi Arabia
|
13
|
|
|
South Korea
|
4.69
|
0.48
|
|
Sweden
|
160
|
11.5
|
|
Switzerland
|
121
|
7
|
|
Taiwan
|
2,2
|
|
|
T�rkiye
|
|
4
|
|
English
|
11
|
|
|
United States of America
|
60
|
8.3
|
Etiology
The leading cause of sarcoidosis
has not yet been found, but several researchers have hypothesized that it can
cause sarcoidosis. Sarcoidosis develops due to complex immune interactions with
environmental exposures and a person's genetic factors. Several hypotheses that
can cause this disease include genetic factors, environmental exposure,
infection, and autoimmune. Sarcoidosis is frequently reported in patients with
autoimmune thyroid disease, Sjogren's syndrome, and systemic sclerosis. This
disease is also often found in patients with airway diseases such as asthma and
chronic obstructive pulmonary disease (Jain et al., 2020).
Genetic factors
Various studies show that genetic
factors play an essential role in determining the risk and clinical development
of sarcoidosis. Eleven loci associated with the risk of sarcoidosis have been
identified, namely butyrophilin like 2 (BTNL2), human leukocyte antigen B
(HLA-B), human leukocyte antigen beta chain 1 (HLA-DPB1), annexin A11 (ANXA11),
interleukin 23 receptor (IL -23R), SH2 adapter protein 3 (SH2B3), ataxin 2
(ATXN2), IL-12B, nuclear factor kappa B subunit 1 (NFKB1/MANBA), family with
sequence similarity 177 member B (FAM177B), chromosome 11q13.1 and ras-related
protein (RAB 23). A study showed that familial sarcoidosis occurred in 17% of
African Americans, and only 1.4% of Spaniards showed the same risk. Granuloma-encoding genetic variations also
play a role in this process (Jain et al., 2020).
In a Case Control
Etiologic Study of Sarcoidosis (ACCESS) research, there is a family history factor in this disease. Siblings
have five times the risk of developing sarcoidosis, and monozygotic siblings
have an 80-fold higher risk of developing sarcoidosis. Genomic studies also
show that several HLA and non-HLA alleles are associated with the development
of this disease. Transforming growth factor beta (TGF- b), tumor necrosis factor-alpha (TNF- a), toll-like receptor 4 (TLR-4), and the
subgenre HLA-DRB1*0301/DQB1*0201 are considered significant indicators for
susceptibility to sarcoidosis (Jain et al. al., 2020).
Environmental factor
Various
environmental factors, such as exposure to wood stoves, soil, tree pollen,
inorganic particulates, insecticides, and nanoparticles, are thought to be
associated with an increased risk of sarcoidosis. In addition, marines,
firefighters, and some workers involved in plantation materials, building
supplies, and metalwork are susceptible to sarcoidosis. Exposure to silica dust
is also associated with this disease. This hypothesis is strengthened by
reports that workers at the World Trade Center, especially firefighters,
experienced an increase in the incidence of sarcoid-like diseases (Newman & Newman,
2012).
Infection
Several
other studies have also identified infectious agents that trigger the immune
response in sarcoidosis, namely Leptospira sp, Mycoplasma sp, herpes viruses,
retroviruses, Chlamydia pneumoniae, Borrelia burgdorferi, Pneumocystis
jirovecii, Mycobacterium tuberculosis, and Propionibacterium sp. Mycobacterium
tuberculosis infection is considered to be one of the causes of sarcoidosis.
This is because granuloma production is a critical factor in the immune
response to this agent. Isolation of these bacterial proteins, mainly the early
secreted antigenic target 6 (ESAT6), catalase-peroxidase (KatG), and superoxide
dismutase A (SoD A) proteins from sarcoidosis patient tissue, shows that these
bacteria are the strongest candidates for sarcoidosis. Other studies also show
that hepatitis C patients who receive interferon alpha (IFN- a) therapy can develop sarcoidosis.
Administration of IFN-γ therapy will increase the expression of gamma
interferon (IFN- g) and IL-2, which stimulate granuloma formation and
increase the incidence of sarcoidosis (Jain et al., 2020).
Autoimmune
Autoimmunity
may help explain the immunopathogenesis of sarcoidosis, especially sarcoid
etiology. Major histocompatibility complex (MHC) class II molecules on
antigen-presenting cells have autoantigens that are recognized by T cell
receptors in sarcoidosis patients. There is a strong association between MHC
class II alleles and the T cell receptor subfamily in the clinical course of
sarcoidosis. Vimentin, an MHC class II peptide, can function as an antigen and
activate T cells in sarcoidosis patients. T cells carrying the TCR V a2.3/V b22 chain accumulate in the lungs of
patients with Lofgren's syndrome (Zissel &
M�ller-Quernheim, 2016).
Pathogenesis
Natural immune response
The natural immune system provides
the first protection against invading microbes, as seen in Figure 2. Host cells
will express receptors on the cell surface, endosomal membrane, or in the
cytoplasm to recognize pathogen-associated molecular patterns (PAMP) found in
bacteria, viruses, fungi, and protozoa. One of the receptors expressed is
nucleotide-binding oligomerization domain and leucine-rich repeat-containing
receptors (NLRs). This receptor is one of the inflammatory components of the
NLRP-inflammasome. This inflammatory component is a large multiprotein complex
consisting of adapter proteins such as caspase-1. The formation of this protein
results in the activation of caspase-1, which activates IL-1 band IL-18 (Lee et al., 2020).
Increased NLRP-inflammasome and
caspase-1 were found in the granulomas of patients with cardiac sarcoidosis.
This study also showed an increase in IL-1 released by alveolar macrophages and
unstimulated monocytes from sarcoidosis patients. In addition to caspase-1, the
transcription factor hypoxia-inducible factor 1-alpha (HIF-1 a) also increases the production of IL-1 band IL-17 because HIF-1 is expressed in the central granulomatous
tissue and giant cells in pulmonary sarcoidosis patients. Shamaei et al.'s
research also showed an increase in type 2 (M2) macrophages in the lymph nodes
and non-lymphatic tissue of sarcoidosis patients (Lee et al., 2020).
In the research, Matsuyama et al.
also showed a decrease in the expression of mucosal-associated invariant
T-cells (MAIT) in the peripheral blood of sarcoidosis patients, which produce
pro-inflammatory cytokines including IFN- gand TNF- a. Increased expression of programmed cell death (PD-1) was also
found in this study. In addition, researchers also reported an increase in the
number and frequency of MAIT cells in the bronchoalveolar cavities in
sarcoidosis patients with lung parenchymal involvement. A decrease in natural
immune cells, such as natural killer (NK) cells, was also found in sarcoidosis
patients (Lee et al., 2020).
Figure 2. Natural and Adaptive
Immune Responses in Granuloma Formation
Adaptive immune response
In addition to macrophages and
dendritic cells, the sarcoid granulomas that form consist of infiltrating T
cells and B cells. Analysis of lymphocyte profiles in lymph nodes taken from
endobronchial ultrasound-guided transbronchial needle aspiration shows an
increased ratio of CD4 + T cells/CD8 + T cells compared to
accumulating. bronchoalveolar sarcoidosis patients. Several recent studies have
demonstrated an essential role for adaptive immune system cells in the
development of sarcoidosis. The increase in adaptive immune cells in
sarcoidosis patients can be seen in Table 3 (Lee et al., 2020).
Table 3.
Adaptive Immune Responses in Sarcoidosis
|
Sample
|
Findings
|
|
Blood, bronchoalevolar smear
|
Increased T helper 1 (Th1) cytokines, decreased
proliferation, increased apoptosis and PD-1 expression in CD4 T cells,
increased percentage of chemokine receptor 4 (CCR4 + ) CD4 + T
cells, increased TGF production by PD-1 +, CD4 + T cells and
helper T cells 17, increased T-reg cells, increased percentage of na�ve B
cells, decreased percentage of memory B cells.
|
|
Serum
|
Increased chemokine ligand 9 (CXCL9), CXCL10 and
CXCL11, Increased vimentin antibody levels, increased B cell activation
factor
|
|
Lymph nodes
|
Increased percentage of Th cells 17.1
|
Granuloma Formation in Sarcoidosis
Granuloma is a differentiation of
immune cells with a lymphoid-like structure. Sarcoid granulomas are often found
in the lungs, lymph nodes, eyes, and skin. The process of granuloma formation
begins when aggregated macrophages are converted into epithelioid cells, which
then form immature granulomas. Inflammatory signals cause macrophages and
monocytes or dendritic cells to fuse to form multinucleated giant cells.
Macrophages will then activate and attract T lymphocyte cells to the site of
inflammation to form mature granulomas. Granuloma formation occurs due to the
failure of antigen elimination. Granulomas function to protect antigens from
spreading. The structure of sarcoid granuloma consists of two segments, namely
the core and the crust. The granuloma core consists of groups of macrophages,
epithelioid cells, and multinucleated giant cells, while the crust area
consists of high levels of T lymphocytes and few B lymphocytes (Sakthivel & Bruder, 2017).
In the process of chronic
granuloma formation, as seen in Figure 3, alveolar macrophages will present
antigens to MHC class II thereby converting CD4 + T cells. na�ve to
activated CD4 + T cells . CD4 + T cells will release IFN-
and migrate to the site of inflammation guided by the chemokine receptor CXCR3.
Apart from CXCR3, these cells also excrete the cytokine tumor necrosis
factor-like cytokine 1A (TLA1) to interact with death receptor 3 (DR3) and produce
high amounts of matrix metalloproteinase-9. This will make macrophages
increasingly activated, thereby releasing TLR9. Activation of TLR9 will
increase CXCL10 so that it will attract more Th 1 lymphocytes to the granuloma.
Activated macrophages will also increase the regulation of interleukin-1
receptor-associated kinase 1 (IRAK-1) and receptor-interacting protein 2 (RIP
2) expression, which will increase the production of IL-1 band IL-6. This cytokine is used for the differentiation of Th 17
lymphocytes. The accumulation of Th 17 produces the cytokines IL-17 and IL-22 (Sakthivel & Bruder, 2017).
In the process of acute granuloma
formation that occurs in Lofgren's syndrome, alveolar macrophages present
vimentin to class II HLA-DR3 molecules, thereby activating CD4 T lymphocytes
that carry the Va2.3/Vb22 TCR chain. These specific T lymphocytes secrete high
amounts of IL-17 and IL-22 and glow amounts of IFN-. In addition, Treg cells that accumulate in
granulomas will show increased levels of inducible costimulator (ICOS), thereby
increasing IL-10 secretion by Tregs and creating an immunosuppressive state. B
lymphocyte cells also have a role in the formation of acute granulomas. This is
indicated by an increase in Propionibacterium acnes-specific immunoglobulin A
antibodies in Lofgren syndrome patients (Sakthivel & Bruder, 2017).
Figure 3.
Granuloma Formation in Sarcoidosis
Resolution and Persistence of Granulomas
in Sarcoidosis
The
granuloma that forms can undergo resolution or be persistent, as seen in Figure
4. Exposure to an unknown antigen can cause the resolution or progression of
the granuloma. Granuloma resolution occurs when peptide antigens are presented
by HLA-DR3 molecules on dendritic cells or macrophages and recognized by
specific T cell receptors segment variable chain 8 (TRBV8), a-chain variable 2.3 (TRAV 2.3 )
and CD4 + TRAV 2.3+TRBV22+ T cells. The
resulting immune response is so efficient that the antigen can be eliminated,
and the granuloma is resolved. On the other hand, granuloma development occurs
if antigen recognition does not occur properly. This could be due to the
peptide antigen not being presented by the HLA-DR3 molecule or T cell
inactivation (Grunewald et al., 2019).
Figure 4.
Process of Resolution and Persistence of Granuloma in Sarcoidosis
Pathology
A diagnosis of sarcoidosis can be made by
looking at clinical and radiological images. However, pathological images can
also support this diagnosis. Based on pathology, a non-caseating granuloma can
be found on biopsy, as seen in Figure 5. Granuloma
is an area of inflammation formed by epithelioid cells, lymphocytes,
leukocytes, and plasma cells. Epithelioid cells can fuse to form multinucleated
giant cells located at the edges and center of the granuloma. Giant cells can reach a diameter of 50
microns, consist of abundant cytoplasm, and contain more than 20 small cell
nuclei. The nuclei of these small cells
will be scattered at the edges and are called Langerhans-type giant cells.
Apart from that, it can also be spread in the cytoplasm in so-called giant
cells similar to foreign objects. These granulomas can be found in various
organs. The choice of organ biopsy must consider the risks and complications
that may occur (Tana et al., 2022).
Figure 5.
Histopathology of Granulomas in Sarcoidosis
Clinical Features
The
clinical manifestations of sarcoidosis are very diverse because the disease
affects various organs. The onset of this disease can be acute, subacute, or
chronic. Based on the hypothesis, this difference is due to different
immunological features. Based on clinical and immunological features,
sarcoidosis is divided into Lofgren's syndrome and non-Lofgren's syndrome. In
most cases, this disease can heal spontaneously within two years. The number of
recoveries decreases if the disease occurs for five years, so in its
development, this disease can be divided into acute onset, namely for two
years, and chronic for three to five years (Polverino et al., 2020).
Lofgren's syndrome
Lofgren's
syndrome is characterized by symptoms of fever, erythema nodosum, arthritis,
and bilateral hilar lymphadenopathy with an acute onset. This syndrome is strongly associated with the HLA B8 serotype
HLA-B*. The acute onset of the disease is associated with spontaneous
resolution and an excellent prognosis. In patients in Europe and Sweden, this syndrome has a good prognosis
even without therapy. In general, patients with Lofgren's syndrome will improve
after administering corticosteroids. Apart from Lofgren's syndrome, acute-onset
sarcoidosis can also be found in Heerfordt-Waldenstrom syndrome. This syndrome
is a rare form of sarcoidosis. This rare form of sarcoidosis is characterized
by typical symptoms such as parotitis, facial paralysis, anterior uveitis, and
fever. Radiological images show typical enlargement of the parotid glands and
enlarged lymph nodes (Polverino et al., 2020).
NonLofgren's syndrome
NonLofgren's syndrome is another
form of sarcoidosis with a subacute to chronic onset. This form is more
heterogeneous. The clinical features of this disease are cough, shortness of
breath, arthralgia, fatigue, chest pain, muscle pain, night sweats, and weight
loss. Fatigue is a widespread complaint in patients. This complaint is felt by
50-70% of patients, which causes a decrease in quality of life and disability.
Chronic sarcoidosis is associated with an increased risk of developing
fibrosis, pulmonary arterial hypertension, and permanent loss of lung function,
affecting quality of life. Extrapulmonary manifestations associated with a poor
prognosis are lupus pernio, chronic uveitis, chronic hypercalcemia,
nephrocalcinosis, cystic bone lesions, and myocardial involvement. An overview of the clinical manifestations
of sarcoidosis can be seen in Table 4 (Polverino et al., 2020).
Table 4.
Clinical Features of Sarcoidosis Based on Organs Affected
|
Organ
|
Clinical picture
|
|
Lungs
|
Dry cough, wheezing, shortness
of breath, fatigue.
Acute: pleural effusion,
pericardial effusion, pneumothorax, lymph nodes
Chronic: pulmonary fibrosis and
respiratory failure
|
|
Lymph gland
|
Peripheral lymphadenopathy,
swollen and painless lymph nodes.
|
|
Endocrine (thyroid and parotid
glands)
|
Thyroid dysfunction,
enlargement of the parotid gland, affects the hypothalamic-pituitary axis,
causing diabetes insipidus.
|
|
Skin
|
Erythema nodosum, nodules, paul
and plaque
|
|
Eye
|
Pain, photophobia, and
hyperemia are often associated with Lofgren's syndrome.
|
|
Bone
|
Osteoporosis, osteopenia,
arthritis, arthralgia, and cystic lesions.
|
|
Upper respiratory tract
|
Regarding the larynx, pharynx,
and nose
|
|
Kidney
|
Nephrocalcinosis, interstitial nephritis,
and renal failure.
|
|
Heart
|
Heart failure, arrhythmia, and
syncope
|
|
Nerve
|
Facial weakness, meningeal
inflammation, encephalopathy, vasculopathy, seizures and hydrocephalus.
|
|
Liver and spleen
|
Enlarged liver and spleen,
intrahepatic cholestasis, portal hypertension, changes in liver function.
|
Radiological Features
Lung
imaging is essential to help establish the diagnosis in all patients with
suspected sarcoidosis. Chest X-rays are routinely used to evaluate patients
with suspected sarcoidosis. Chest X-rays often reveal bilateral hilar lymph
node enlargement, which occurs in 50-85% of patients, and parenchymal changes,
which occur in 25-60% of patients. In the 1960s, Guy Scadding developed a sarcoidosis staging system based
on chest radiographs. The staging system based on Scadding is shown in Figure 6
and Table 5 (Bernardinello et al., 2021; Jain
et al., 2020; S�ve et al., 2021).
Figure 6. Scadding staging system
chest x-ray. (A) Stage I bilateral hilar lymph node enlargement (white arrow),
(B) Stage II bilateral hilar lymph node enlargement and left upper lobe
infiltrate (white arrow), (C) Stage III pulmonary infiltrate without lymph node
enlargement, (D) Stage IV pulmonary fibrosis
Table 5. Scadding Staging System
|
Staging
|
Radiological picture
|
|
0
|
There are
no abnormalities
|
|
I
|
Bilateral hilar lymph node enlargement
|
|
II
|
Bilateral hilar lymph node enlargement and parenchymal
infiltrates
|
|
III
|
Parenchymal infiltrate without
hilar lymph node enlargement on regular chest X-ray
|
|
IV
|
Advanced fibrosis with distortion of the normal lung,
especially in the middle and upper lobes, with evidence of bronchiectasis,
hilar retraction, bullae, cysts, and rarely honeycombing.
|
Another imaging that can be used
to help diagnose sarcoidosis is thoracic high-resolution computed tomography
(HRCT). This imaging has a higher sensitivity for detecting abnormalities in
the hilus, mediastinum, and parenchyma. Based on this imaging, typical lesions
of sarcoidosis include micronodules scattered along the veins, bronchi,
vasculature, and pleura. Micronodules can turn confluent, causing
conglomeration images such as masses and distortion of the lung parenchyma. The
appearance of this conglomerated mass is sometimes surrounded by many
micronodules resembling a galaxy sign. The appearance of thoracic HRCT abnormalities can also be divided into
typical and atypical, as shown in Table 6, figures 7 and 8 (Bernardinello et al.,
2021; Cozzi et al., 2018).
Table 6.
Typical and Atypical Features of Sarcoidosis on HRCT
|
Typical picture
|
Atypical picture
|
|
Nodules with lymphatic spread
in the peri broncho vascular interstitial spaces and interlobular septa
|
Atypical picture of isolated,
unilateral, enlarged lymph nodes with calcification
|
|
Bilateral hilar lymph node
enlargement
|
Pulmonary masses and nodules
|
|
Fibrotic changes: linear and
reticulated opacities, thickening of interlobular septa, traction
bronchiectasis, and reduction in lung volume
|
Interstitial fibrosis: bullae,
cysts, honeycomb-shaped opacities in the upper and middle lobes of the lung,
emphysema
|
|
Predominant in the upper and
middle lobes of the lung
|
Ground-glass opacity
|
|
|
Pleural involvement:
pneumothorax, effusion, and pleural thickening
|
|
|
Linear opacity: thickening of
the interlobular septa
|
|
|
Hello Sign
|
|
|
Airway involvement:
atelectasis, mosaic-attenuation, tracheobronchial changes
|
Figure 7. Typical sarcoidosis lesions, (C)
bilateral hilar lymph node enlargement, (D) cystic fibrosis with traction
bronchiectasis in the perihilar upper lobe
Figure 8.
Atypical lesions, (a) and (b) peripheral consolidation with air bronchogram in
the lower lobe of the right lung resembling a mass in malignancy and organizing
pneumonia
Diagnosis
The
diagnosis of sarcoidosis is a challenge for every clinician. This is due to the
involvement of many organs, causing various clinical manifestations. Physical
and radiological examinations supported by biopsy results of noncaseating
granulomas can confirm the diagnosis of sarcoidosis. In patients with clear
clinical manifestations such as Lofgren's syndrome and Heerfordt's syndrome,
diagnosis based on clinical examination and chest x-ray is considered
sufficient. In other cases, the diagnosis of sarcoidosis must be confirmed
histologically. There is an algorithm that can be used to help diagnose
sarcoidosis, as shown in Figure 9 (Spagnolo et al., 2018).
The
clinical diagnosis of sarcoidosis can be made in patients based on clinical and
radiological findings. Another supporting examination that can be used is a
biopsy. If the biopsy results show granulomatous inflammation and there are
still alternative diagnoses, the diagnosis of sarcoidosis cannot be made.
However, if an alternative diagnosis is not available, then sarcoidosis may be
diagnosed. The results of the biopsy examination did not show granulomatous
inflammation. However, there were additional suggestive features, which
included a negative tuberculin test, serum angiotensin converting enzyme more
than twice the standard limit, bronchoalveolar lymphocytosis more than twice
the average value, CD4+ /CD8+ ratio more than 3.5 in
bronchoalveolar calculi and hypercalciuria make the diagnosis of sarcoidosis
possible (Spagnolo et al., 2018).
The
extensive involvement of the lungs in this disease means that the role of
bronchoscopy is vital to help confirm the diagnosis. A cobblestone appearance
can be found in the mucosa of patients with sarcoidosis. Apart from that,
another action that can be taken is cellular analysis of bronchoalveolar
smears. On cellular analysis examination, an increase in the number of
lymphocytes > 25% and an increase in the CD4+ /CD8+
ratio are often found. An increase in the CD4+ /CD8+
ratio > 3.5 has a specificity of 93-96%, even though the sensitivity is only
53-59%. However, in other studies, an increase in the CD4+/CD8+
ratio > 10 has a specificity value of > 99% for diagnosing sarcoidosis (Bernardinello et al .,
2021).
Figure 9.
Sarcoidosis Diagnosis Flow
Another
modality that can be used to help confirm the diagnosis is transbronchial
needle aspiration (TBNA) using endobronchial ultrasonography (USG) guidance
(EBUS-TBNA). This modality can be used to sample the enlarged hilar lymph nodes
frequently found in sarcoidosis patients. This modality has a success rate of
84% in helping to diagnose stage I sarcoidosis and 77% in stage II. The use of
EBUS-TBNA is superior when compared to transbronchial lung biopsy (TBLB). In
patients with suspected sarcoidosis, sampling is recommended from lymph nodes
in different locations. This influences the positivity rate for sarcoidosis
diagnosis. The recommended location for lymph node sampling is in the suitable
subcarinal and paratracheal regions (Bernardinello et al.,
2021; Crouser et al., 2020).
In
sarcoidosis with parenchymal involvement, transbronchial lung biopsy can be an
option to help confirm the diagnosis. The TBLB procedure has a success rate of
50-75% in sarcoidosis patients with parenchymal involvement. This success rate
decreases to 12% if this modality is used to diagnose stage I sarcoidosis
patients. Sampling using this method must be carried out based on the results
of the patient's chest CT scan. This is to avoid sampling lung parenchyma that
has minimal abnormalities, namely in the lower lobes. 8-10 biopsies must be
taken to increase the positivity rate. The procedure is relatively safe but
carries risks such as bleeding and pneumothorax (Bernardinello et al.,
2021).
Alternative diagnosis
Alternative
diagnoses of sarcoidosis are diverse. This is due to the absence of a gold
standard and specific etiology for this disease, so the diagnosis of
sarcoidosis remains one of exclusion. In addition, features of granulomatous
inflammation can also be found in various conditions, including bacterial,
mycobacterial, and fungal infections, and occupational lung diseases such as
chronic beryllium disease and silicosis. Granulomatous inflammation can also
occur as a result of an immunological response to antigens or the use of
malignant drugs. Alternative diagnoses of
sarcoidosis are listed in Table 7 (Bernardinello et al., 2021)
Table 7. Alternative Diagnosis of Sarcoidosis
|
|
Sarcoidosis
|
Tuberculosis
|
Chronic beryllium disease and silicosis
|
Sarcoid-like reactions
|
|
Clinical manifestations
|
Often asymptomatic, dry cough, shortness of breath,
weight loss and fever
|
Weight loss, cough, purulent phlegm, coughing up blood,
fever
|
Dry cough and shortness of breath
|
Often asymptomatic
|
|
Exposure history
|
Not known
|
Travel history to endemic countries, history of contact
with TB patients
|
History of exposure to beryllium or silica
|
Drugs, malignancy, or implantation of medical devices
|
|
Radiological findings
|
Symmetrical and bilateral enlargement of hilar lymph
nodes, perilymphatic and peri broncho vascular nodules, cavities (rare)
|
Enlarged hilar lymph nodes are usually asymmetrical,
cavitary (often), randomly distributed nodules.
|
Enlarged bilateral hilar lymph nodes, egg-shell
appearance of the lymph nodes
|
Depends on the underlying cause
|
|
Laboratory
|
Hypercalcemia and hypercalciuria, increased serum
angiotensin-converting enzyme, increased soluble interleukin-2 receptor
(sIL-2R), and peripheral lymphopenia.
|
Mantoux test: positive, Interferon-gamma release assay
(IGRA): positive, increased serum angiotensin-converting enzyme
|
Mantoux test: negative, increased serum
angiotensin-converting enzyme
|
Depending on the underlying cause, possible increase in
serum angiotensin-converting enzyme, Mantoux test: negative
|
|
Histopathology
|
Noncaseating granuloma
|
Caseous granuloma
|
Noncaseating granulomas, sclerotic nodules, silica
particles
|
It can be differentiated from sarcoid granuloma
|
|
Bronchoscopy and bronchoalveolar sampling
|
Lymphocytosis, CD4 + /CD8 + ratio >
3.5
|
Mycobacterium tuberculosis culture was positive
|
Lymphocytosis, Beryllium
lymphocyte proliferation test: positive
|
Depends on the underlying cause
|
Management
Management
of sarcoidosis differs depending on the patient's condition. Not all sarcoidosis patients require hospital treatment.
Hospitalization of sarcoidosis patients depends on disease progression
characterized by decreased functional status and worsening chest radiographs or
HRCT imaging. Worsening clinical conditions and a significant reduction in
quality of life are the two main indications for starting treatment. Treatment of sarcoidosis patients should
include the mental, emotional, and physical. The first-line therapy is
corticosteroids. Corticosteroids function to inhibit the activation of
macrophages and lymphocytes and modulate cytokines that play a role in
granulomatous inflammation. Corticosteroids have been proven to relieve
symptoms and restore organ function, although the use of corticosteroids has
many risks (Jain et al., 2020;
Polverino et al., 2020).
Corticosteroid
treatment begins with prednisolone 0.5-0.75 mg/kg BW every day for 4 weeks. It
is tapered off to 10 mg every 4 weeks, depending on the disease response. This
therapy takes 6-12 months and can be measured by improvements in lung function.
This treatment can be started in patients who have mild clinical features such
as skin lesions, anterior uveitis, or cough. Most patients who require systemic
treatment will recover, and only a small group will experience chronic
disorders for up to two to five years (Jain et al., 2020).
Immunosuppressants
can be given to patients if corticosteroid administration does not give good
results, relapses, or they cannot tolerate the side effects of corticosteroids.
This treatment is the recommended second line. Methotrexate is an antimetabolite,
immunosuppressant, and anti-inflammatory recommended in patients. In several
studies, methotrexate was safely given to sarcoidosis patients with involvement
of the lungs, eyes, skin, and central nervous system. The dose of methotrexate
that can be given is 5-7.5 mg per week and can be increased every week (Polverino et al., 2020).
Methotrexate
can be given orally or intramuscularly. This drug has a slow onset, so
treatment evaluation can be carried out after being given for six months.
Methotrexate has several side effects, including toxicity in the liver and
lungs, increased risk of infection, and myelosuppression. Therefore, 5 mg folic
acid supplementation every week and checking blood, liver, and kidney function
must be carried out periodically. Other immunosuppressants that can be used as
a substitute for methotrexate are mycophenolate mofetil, azathioprine, and
leflunomide. However, their effectiveness is still far below that of
methotrexate (Polverino et al., 2020).
The third
line of treatment that can be given to sarcoidosis patients is TNF-antagonist
biological therapy a. This therapy is given to patients who have
progressive, life-threatening disease despite corticosteroids and at least one
second-line immunosuppressant agent. Infliximab is a monoclonal antibody that
functions to neutralize TNF-a. In research study, the administration of
infliximab could increase 2.5% forced vital capacity and improve lung
parenchyma. Infliximab is well tolerated by
patients who have features of progressive sarcoidosis (Polverino et al., 2020).
CONCLUSION
Sarcoidosis is a
systemic disease characterized by the formation of noncaseating granulomas that
primarily involve the lungs and other organs. The cause of sarcoidosis is still
unclear, but several hypotheses explain that several things, including genetic
factors, environmental factors, infection, and autoimmune can cause it. The
pathogenesis of sarcoidosis is the formation of noncaseating granulomas
involving the innate and adaptive immune systems. Based on the clinical
picture, sarcoidosis can be divided into two, namely Lofgren's syndrome and
non-Lofgren's syndrome. Based on radiological images, sarcoidosis has a typical
appearance, namely bilaterally symmetrical enlargement of the hilar lymph
nodes, predominance in the upper and middle fields of the lung,
peribronchovascular nodules, and pulmonary fibrosis at an advanced stage. The
diagnosis of sarcoidosis can be made based on clinical, radiological, and
biopsy images, with histopathological images showing noncaseating granulomas.
Several diseases can resemble sarcoidosis, including tuberculosis and chronic
beryllium disease. Treatment for sarcoidosis can be given according to the severity
of the symptoms, and administration of corticosteroids is still the primary
choice. In progressive sarcoidosis, immunosuppressants and TNF-α
antagonist biological therapy can be considered.
REFERENCES
Arkema, E. V., & Cozier, Y. C.
(2020). Sarcoidosis epidemiology:
Recent estimates of incidence, prevalence and risk factors. Current Opinion
in Pulmonary Medicine, 26(5), 527�534.
https://doi.org/10.1097/MCP.0000000000000715
Bernardinello, N., Petrarulo, S., Balestro, E., Cocconcelli,
E., Veltkamp, M., & Spagnolo, P. (2021). Pulmonary sarcoidosis: Diagnosis
and differential diagnosis. Diagnostics, 11(9), 1�14.
https://doi.org/10.3390/diagnostics11091558
Cottin, V., Hirani, N. A., Hotchkin, D. L., Nambiar, A. M.,
Ogura, T., Otaola, M., Skowasch, D., Park, J. S., Poonyagariyagorn, H. K.,
& Wuyts, W. (2018). Presentation, diagnosis and clinical course of the
spectrum of progressive-fibrosing interstitial lung diseases. European
Respiratory Review, 27(150).
Cozzi, D., Bargagli, E., Calabr�, A. G., Torricelli, E.,
Giannelli, F., Cavigli, E., & Miele, V. (2018). Atypical HRCT
manifestations of pulmonary sarcoidosis. Radiologia Medica, 123(3),
174�184. https://doi.org/10.1007/s11547-017-0830-y
Crouser, E. D., Maier, L. A., Baughman, R. P., Abston, E.,
Bernstein, R. C., Blankstein, R., Bonham, C. A., Chen, E. S., Culver, D. A.,
Drake, W., Drent, M., Gerke, A. K., Ghobrial, M., Govender, P., Hamzeh, N.,
James, W. E., Judson, M. A., Kellermeyer, L., Knight, S., � Wilson, K. C.
(2020). Diagnosis and Detection of Sarcoidosis An Official American Thoracic
Society Clinical Practice Guideline. American Journal of Respiratory and
Critical Care Medicine, 201(8), 26�51.
https://doi.org/10.1164/RCCM.202002-0251ST
Grunewald, J., Grutters, J. C., Arkema, E. V., Saketkoo, L.
A., Moller, D. R., & M�ller-Quernheim, J. (2019). Sarcoidosis. Nature
Reviews Disease Primers, 5(1), 1�22.
https://doi.org/10.1038/s41572-019-0096-x
Jain, R., Yadav, D., Puranik, N., Guleria, R., & Jin, J.
O. (2020). Sarcoidosis: Causes, diagnosis, clinical features, and treatments. Journal
of Clinical Medicine, 9(4), 1�21. https://doi.org/10.3390/jcm9041081
Lee, S., Birnie, D., & Dwivedi, G. (2020). Current
perspectives on the immunopathogenesis of sarcoidosis. Respiratory Medicine,
173(August), 106�161. https://doi.org/10.1016/j.rmed.2020.106161
Newman, K. L., & Newman, L. S. (2012). Occupational
causes of sarcoidosis. Current Opinion in Allergy and Clinical Immunology,
12(2), 145�150. https://doi.org/10.1097/ACI.0b013e3283515173
Polverino, F., Balestro, E., &
Spagnolo, P. (2020). Clinical
presentations, pathogenesis, and therapy of sarcoidosis: State of the art. Journal
of Clinical Medicine, 9(8), 1�17. https://doi.org/10.3390/jcm9082363
Putra, A. C., Andarini, S. L., Susanto, A. D., Damayanti, T.,
Samoedro, E., Priyonugroho, G., Septiyanti, D., Fajriwan, & Bernida, I.
(2017). Penyakit paru interstisial.pdf (A. C. Putra & S. L. Andarini
(eds.)). Perhimpuan Dokter Paru Indonesia.
Sakthivel, P., & Bruder, D. (2017). Mechanism of
granuloma formation in sarcoidosis. Current Opinion in Hematology, 24(1),
59�65. https://doi.org/10.1097/MOH.0000000000000301
S�ve, P., Pacheco, Y., Durupt, F., Jamilloux, Y.,
Gerfaud-Valentin, M., Isaac, S., Boussel, L., Calender, A., Androdias, G.,
Valeyre, D., & El Jammal, T. (2021). Sarcoidosis: A clinical overview from
symptoms to diagnosis. Cells, 10(4), 1�33.
https://doi.org/10.3390/cells10040766
Sikj�r, M. G., Hilberg, O., Ibsen, R., & L�kke, A.
(2021). Sarcoidosis: A nationwide registry-based study of incidence, prevalence
and diagnostic work-up. Respiratory Medicine, 187(July), 1�8.
https://doi.org/10.1016/j.rmed.2021.106548
Spagnolo, P. (2015). Sarcoidosis: a Critical Review of
History and Milestones. Clinical Reviews in Allergy and Immunology, 49(1),
15�19. https://doi.org/10.1007/s12016-015-8480-0
Spagnolo, P., Rossi, G., Trisolini, R., Sverzellati, N.,
Baughman, R. P., & Wells, A. U. (2018). Pulmonary sarcoidosis. The
Lancet Respiratory Medicine, 6(5), 389�402.
https://doi.org/10.1016/S2213-2600(18)30064-X
Tana, C., Donatiello, I., Caputo, A.,
Tana, M., Naccarelli, T., Mantini, C., Ricci, F., Ticinesi, A., Meschi, T.,
Cipollone, F., & Giamberardino, M. A. (2022). Clinical features, histopathology and differential diagnosis
of sarcoidosis. Cells, 11(1), 1�16.
https://doi.org/10.3390/cells11010059
Zissel, G., & M�ller-Quernheim, J.
(2016). Specific antigen(s) in
sarcoidosis: A link to autoimmunity? European Respiratory Journal, 47(3),
707�709. https://doi.org/10.1183/13993003.01791-2015
