Sarajevo Medical School

Student: Lamija, Med year 4

Subject: Clinical Immunology
Student assignment- January, 2019

Interstitial pneumonia
Methods: This seminar work is done by researching through relevant medical literature and
databases. It provides a brief insight into the topic and key points.

Introduction

Interstitial lung diseases represent a large number of conditions that involve the inflammation and
scarring of the parenchymal tissue of the lung—the alveoli, the alveolar epithelium, the
capillary endothelium, and the spaces between those structures—as well as the perivascular and
lymphatic tissues. The disorders in this heterogeneous group are classified together because of
similar clinical, imaging, physiologic, or pathologic manifestations. Oxygen passes from the
alveoli to the blood vessels through the tissue called interstitium. It is the portion of the lung
parenchyma lying between the epithelial and endothelial basement membranes (Figure 1).

ILDs have been difficult to classify because >200 known individual

diseases are characterized by diffuse parenchymal lung involvement (sometimes the term ILD is
used simultaneously with DPLD- diffuse parencymal lung disease), either as the primary condition
or as a significant part of a multiorgan process, as may occur in the connective tissue diseases like
Rheumatoid arthritis, and their classification is becoming increasingly complex, without uniform
international consensus.
One useful approach to classification is to separate the ILDs into two groups based on the major
underlying histopathology: (1) those associated with predominant inflammation and fibrosis and
(2) those with a predominantly granulomatous reaction in interstitial or vascular
areas. Those two major histopathologic patterns predominate in ILDs. Each of these groups can
be subdivided further according to whether the cause is known or unknown.

Figure 1: ILD (Source: Geisinger Health)

PATHOGENESIS

The ILDs are nonmalignant disorders and are usually not caused by identified infectious agents.
In case they are, the cause are usually viruses, who initially affect the alveolar epithelium and
result in a mononuclear infiltrate in the interstitium of the lung. Sometimes bacteria Mycoplasma
pneumoniae and fungi may cause interstitial pneumonia. However, the precise pathway(s) leading
from injury to fibrosis is not known, because it results from chronic inflammation.
Pathophysiologic changes may include interstitial and alveolar wall thickening and
increased collagen bundles in the interstitium. Lung tissue becomes iniltrated by lymphocytes,
macrophages, and plasma cells. Persistent alveolitis may lead to obliteration of alveolar capillaries,
reorganization of the lung parenchyma, and irreversible fibrosis. These changes
in turn lead to the formation of large air-illed sacs (cysts) accompanied by dilated terminal and
respiratory bronchioles.
Another sign of end-stage injury that follows fibrosis is patchy, honeycomb appereance seen in
high-resolution CT scan.

Inflammation and Fibrosis

The initial insult is an injury to the epithelial surface that causes inflammation in the air spaces and
alveolar walls. If the disease becomes chronic, inflammation spreads to adjacent portions
of the interstitium and vasculature and eventually causes interstitial
fibrosis. Important histopathologic patterns found in the ILDs include usual interstitial pneumonia
(UIP), nonspecific interstitial pneumonia, respiratory bronchiolitis/desquamative interstitial
pneumonia, organizing pneumonia, diffuse alveolar damage (acute or organizing), and
lymphocytic interstitial pneumonia.
Chronic inflammation by definition is associated with, or will result in, tissue damage and the
tissue will try to repair itself. Even though there is a diverse range of potentially damaging agents,
lung response is relatively limited and as such similar patterns of response may be seen clinically
and pathologically in patients with differing aetiologies. The end-stage of tissue damage, scarring
or fibrosis has no possibility of returning back to normal, is irreversible.
The development of fibrosis of alveolar walls, airways, or vasculature is the most feared outcome
in all of these conditions because it is often progressive and leads to significant defect of ventilatory
function and gas exchange.

Known causes, mostly for interstitial inflammatory and fibrotic diseases are:

 Asbestos
 Talc
 Coal dust, or various other metal dusts from working in mining
 Grain dust from farming
 Bird proteins (such as from exotic birds, chickens, or pigeons)
 Drugs : antibiotics, amiodarone, gold
 Chemotherapy drugs
 Radiation
 Aspiration pneumonia
In Granulomatous Lung Disease, the process is characterized by an accumulation of T
lymphocytes, macrophages, and epithelioid cells organized into discrete structures (granulomas)
in the lung parenchyma.
The granulomatous lesions can progress to fibrosis. Many patients with granulomatous lung
disease remain free of severe impairment of lung function or, when symptomatic, improve after
treatment. The main differential diagnosis is between sarcoidosis and
hypersensitivity pneumonitis.
Common causes for granulomatous lung diseases are: organic dusts (hypersensitivity
pneumonitis) and inorganic dusts like beryllium and silica.

(Source: “What Rheumatologists Need to Know about Diagnosing and Managing Interstitial Lung Disease (ILD)”. Aryeh
Fischer, MD, and Jeff Swigris, DO, MS. The Rheumatologist)

Because there are many different forms and manifestations of IPs (Table 1), only the most
common ones will be here described. The most broad category includes those with unknown and
multifactorial cause.
IDIOPATHIC INTERSTITIAL PNEUMONIA (IIP) – symptoms and signs

Idiopathic interstitial pneumonia is one subclass of diffuse interstitial lung diseases, and by
epidemiology is the most common. The IIPs are further subdivided into 8 categories: usual
interstitial pneumonia, idiopathic pulmonary fibrosis, desquamative interstitial pneumonia,
respiratory bronchiolitis interstitial lung disease, acute interstitial pneumonia, cryptogenic
organizing pneumonia, nonspecific interstitial pneumonia (NSIP), and lymphocytic interstitial
pneumonia. Idiopathic pulmonary fibrosis is the most lethal amongst the interstitial lung diseases
and presents high heterogeneity in clinical behaviour. IIP might be seen in HIV patients, in forms
of lymphoid interstitial pneumonitis
(LIP) more oftenly found in children, and nonspecific interstitial pneumonitis (NSIP). All types
cause cough and shortness of breath and affect the lungs similarly. Patients usually complain about
chest discomfort, hemoptysis, wheezing, dyspnea, non-productive cough and fever.
From the obvious clinical signs, most seen are nail clubbing and crackling sound in auscultation
and restrictive pulmonary function. Anorexia, weight loss and cyanosis may be found on the
physical exam when the disease has progressed.

Histologically, interstitial infiltrates of lymphocytes and plasma cells in a perivascular and

peribronchial are present. In blood, antinuclear antibodies and anti-immunoglobulin antibodies
(rheumatoid factors) are identified in some patients, even in the absence of a defined CTD.

USUAL INTERSTITIAL PNEUMONIA (UIP)

UIP is one of the most common types of interstitial pneumonia, with an annual incidence of 6 to
14.6 cases per 100,000 persons. It has a slight male predominance and a mean age at onset of 50
to 60 years. UIP is characterized by ongoing inflammation of the alveolar walls, injury and
architectural collapse, so it unsuprisingly leads to interstitial pulmonary fibrosis (IPF) with
extensive scarring. The prevalence of IPF in different series ranges from 6-14.6 per 100,000
persons, but in those older than 75 years, the prevalence may exceed 175 per 100,000.

Pathogenesis
The etiology of UIP is unknown, but viral, genetic, and immunologic factors are thought to play a
role. A viral etiology is favored by a history of flu-like illness in some patients. A genetic role is
suggested by cases of familial UIP and the association of UIP-like diseases in patients with
inherited disorders such as neurofibromatosis. It is remarkable that
collagen vascular diseases and autoimmune diseases such as rheumatoid arthritis, systemic lupus
erythematosus, and progressive systemic sclerosis may also occur in about 20% of cases. UIP also
follows other autoimmune
disorders, and frequently circulating autoantibodies (e.g., antinuclear antibodies and
rheumatoid factor), immune complexes in circulation are found in lab results, although the antigen
has not been identified.
Those immune complexes and molecules are thought to be responsible for fibrosis development,
as macrophages ingest them, after which they release cytokines for neutrophils recruitment.
Neutrophils in turn damage alveolar walls. (Figure 2)
However, before IPF develops, UIP has better prognosis and chances of treatment in patients with
CTDs.
Patchy chronic inflammation with honeycomb cystic change is found in the pathologic result.
There are also some vascular changes like intimal fibrosis and tunica media thickening, that is
why pulmonary hypertension may be a complication.

Figure 2
(Source: Essentials of Rubin's pathology 5th edition. Emanuel Rubin, Howard M. Reisner)

Clinical Features: UIP begins insidiously, with the gradual onset of dyspnea on exertion and dry
cough, usually over a period of 1 to 3 years. Patients with UIP usually present in the sixth or
seventh decade of life with slowly progressive dyspnea and nonproductive cough that does not
respond well to to antitussive agents. Sometimes they come in acute exacerbation of IPF. The
classic auscultatory finding is late inspiratory crackles and fine vesicular rales at the lung bases.
Another symptoms are usually tachypnea at rest, cyanosis, and cor pulmonale especially in late
stage. The prognosis is bleak, with a mean survival of 4 to 6 years. HRCT shows basal and
peripheral gradual reticular opacities with honeycomb or cobblestone changes. (Figure 3)
 Figure 3, UIP HRCT scan (Source: Radiopedia)

ACUTE INTERSTITIAL PNEUMONIA (HAMMAN-RICH SYNDROME)

AIP, synonymous with Hamman-Rich syndrome is defined as rapidly progressive respiratory

failure occurring in patients without pre-existing lung disease or extrathoracic disorders known to
be associated with lung involvement Acute interstitial pneumonia (AIP) and acute exacerbations
of idiopathic pulmonary fibrosis (AEIPF) are similar respiratory disorders characterized by the
rapid development of progressive dyspnea, fever and cough.A prodromal illness, usually lasting
7–14 days before presentation, is common Most patients are older than 40 years. Both natural killer
cells and chemokines such as interleukin-18 and interleukin-2 may play important roles in the
evolution of acute cell injury into unremitting fibrosis specifically through abnormal wound repair.

Diagnosis: Since AIP clinically resembles to acute respiratory distress syndrome, at least imaging,
then lung biopsy are needed for diagnosis. The diagnosis is confirmed when other causes of acute
lung injury are excluded and consistent findings are found with computed tomography (CT) and
lung biopsy, if done. Plain chest radiographic studies of AIP reveal a diffuse, bilateral, air-space
opacification pattern, and high-resolution-computed tomography (HRCT) of the chest shows
bilateral, patchy, symmetric areas of ground glass attenuation. Exudate is common.
Histopathologic findings are: edema, hyaline membranes, acute interstitial inflammation, loose
organizing fibrosis, mostly within alveolar septa and type II pneumocyte hyperplasia.
NONSPECIFIC INTERSTITIAL PNEUMONIA (NSIP)

This condition defines a subgroup of the idiopathic interstitial pneumonias that can be
distinguished clinically and pathologically from other defined types of ILD like IPF, AIP, DLID,
COP. NSIP presents a heterogenous group of disorders with different clinical courses being
recognized, but whose features and pathological patterns are still not uniformly described. Onset
begins in 40s and 50s, and in contrast to IPF may occur in children. It also has a more favorable
prognosis than IPF.
There are two primary forms of NSIP - cellular and fibrotic. The cellular form is defined mainly
by inflammation of the cells of the interstitium. The fibrotic form is defined by thickening and
scarring of lung tissue. Remarkably, many patients with NSIP histopathologic pattern have
underlying disorder, most commonly of autoimmune origin, CTD, drug-induced ILD, chronic
hypersensitivity pneumonitis, or HIV infection where NSIP was firstly recognised in 1980s.
NSIP may be the presenting manifestation that could predict diagnosis of collagen vascular disease
by several months or several years.

Clinical Manifestations: Patients with idiopathic NSIP have clinical, serologic, radiographic, and
pathologic characteristics that go with a picture of autoimmune disease and meet the criteria for
undifferentiated CTD. It is often associated with a febrile illness and environmental exposure.
Crackles, predominantly in basal lobes and inspiratory squeaks are typically heard on auscultation.
Cough and dyspnea are present for months to years. CT scans of patients with NSIP show a
bilateral, subpleural, typical "ground glass" pattern that represents interstitial inflammation
(increased lymphocytes in bronchoalveolar lavage in 50% of cases), and is usually seen in the
cellular form. Scarring, or fibrosis, will be seen in the fibrotic form. Honeycombing is less
commonly found, but there is lower lobes volume loss.

TREATMENT FOR INTERSTITIAL PNEUMONIA

Treatment for all ILDs is similar. Above all, the patients should be encouraged to avoid tobacco
use and environmental exposure to the irritants. Primary therapy
consists of administration of antiinlammatory and immunosuppressive
agents. Glucocorticoids/corticosteroids are needed to fight inflammation. Immunosuppressive
agents have been useful in reducing the dosage of corticosteroids required. Mycophenolate mofetil
can be given in combination with corticosteroids, because it is an inhibitor of lymphocyte
proliferation that is often used in the treatment of systemic rheumatic disease and has shown
efficacy in the treatment of interstitial lung disease with scleroderma.

Most patients have moderate to severe hypoxemia and develop respiratory failure. Oxygen therapy
is needed in patients with hypoxemia. Mechanical ventilation is often required. ECG and heart
controls are important, since right-sided cardiomegaly with right ventricular
hypertrophy seen on electrocardiogram. Lung transplantation is also an option. Supportive therapy
is of a great importance.
Conclusion: These disorders require special medical attention, because of their complicated
etiology, progress and treatment. The biggest issue are their considerable rates of morbidity and
mortality, and there is little concensus regardind the best management, especially with so many
different forms of ILD. Each patient should be examined and approached individually, since the
triggers for disease development are multiple, not well understood and environmental agents have
to be identified. The foundation is injury to the alveolar epithelial or capillary endothelial cells,
and immune reaction that follows. Underlying diseases like autoimmune diseases, HIV infection
or neoplastic diseases are common finding. Therefore, a multidisciplinary approach—requiring
close communication between clinicians of different specialties, radiologist, pathologist—is often
required to make the diagnosis. The patient’s whole anamnesis should be thorougly taken, and
based on those data and risks for comorbidities, appropriate lab test should be done. ILDs are hard
to treat and significantly affect the quality of life, so the patient must ensure that he avoids
environmental and pro-inflammatory triggers. Frequent control exams are important, to prevent
complications on time.

References:
1. Harrison’s principles of Internal Medicine, 19th Edition
2. “American Thoracic Society/European Respiratory Society International Multidisciplinary
Consensus Classification of the Idiopathic Interstitial Pneumonias”. AMERICAN JOURNAL OF
RESPIRATORY AND CRITICAL CARE MEDICINE.VOL 165 – 2002.
3. “Interstitial lung disease”.Katerina M. Antoniou, George A. Margaritopoulos, Sara
Tomassetti, Francesco Bonella, Ulrich Costabel, Venerino Poletti. European Respiratory Review
2014
4. “Nonspecific Interstitial Pneumonia (NSIP): Management and Treatment”. Cleveland Clinic
5. Bruminhent J., Yassir S., Pippim J. Acute interstitial pneumonia (Hamman-Rich syndrome) as
a cause of idiopathic acute respiratory distress syndrome. Case Rep. Med. 2011:2011.
6. “Nonspecific Interstitial Pneumonia”. Joyce Lee. Msd Manual Professional version, 2018
7. “Pathology of Usual Interstitial Pneumonia”.Eunhee (Joanne) S Yi, Philip T Cagle. Medscape,
2014.
8. “Treatment and prognosis of nonspecific interstitial pneumonia”. Kevin R Flaherty. UptoDate,
2017.