Cough and Difficulty of Breathing

Tuberculosis, Idiopathic Pulmonary Fibrosis,

Sarcoidosis, Pneumoconiosis

Course: Introductions to Clinical Medicine

Prepared/Modified by Dr. Tetiana Hliebova
Summer 2018
Prepared/modified by Dr. Tetiana Hliebova, MD
 Intended Learning Objectives
by the end of this lecture you will be able to:

Know the following related to Tuberculosis and Interstitial Lung Disease:

• risk factors
• pathogenesis
• types
• etiology
• clinical features
• investigation
• treatment
• complications
• prevention

Prepared/modified by Dr. Tetiana Hliebova, MD

Tuberculosis

Prepared/modified by Dr. Tetiana Hliebova, MD

• Mycobacterium tuberculosis is Tuberculosis
responsible for most cases of
tuberculosis, acid-fast stain +!
• Reservoir: humans with active
tuberculosis.
• Milk contaminated with M.
bovis (unpasteurized milk).
• Epidemiology: 1.7 billion
individuals worldwide, with 8 to
10 million new cases and 1.6
million deaths each year.
• 14,000 new cases of active
tuberculosis in the United States
annually (half of which occur in
foreign-born people).
Prepared/modified by Dr. Tetiana Hliebova, MD
 Risk Factors for Pulmonary TB

Unlike the risk of acquiring

infection with M. tuberculosis, the
risk of developing disease after
being infected depends largely on
endogenous factors, such as the
individual’s innate immunologic
and nonimmunologic defenses and
the level at which the individual’s
cell-mediated immunity is
functioning.

Prepared/modified by Dr. Tetiana Hliebova, MD

 From Exposure to Infection
• M.tuberculosis is the most
commonly transmitted from a
person with infectious pulmonary
TB by droplet nuclei, which are
aerosolized by coughing,
sneezing or speaking.
• The tiny droplets dry rapidly; the
smallest may remain suspended
in the air for several hours.
• There may be as many as 3000
infectious nuclei per cough.
• Other routes of transmission of
tubercle bacilli (e.g., through the
skin or the placenta) are
uncommon and of no
epidemilogic significance.

Prepared/modified by Dr. Tetiana Hliebova, MD

 M. Tuberculosis Infection vs Disease

• Infection is the presence of organisms, which may or may not cause

clinically significant disease.
• In most people primary tuberculosis is asymptomatic, although it may
cause fever and pleural effusion.
• Fibrocalcific nodule at the site of the infection the only
evidence of infection. Viable organisms may remain dormant lesions for
decades until immune defenses are lowered.

Prepared/modified by Dr. Tetiana Hliebova, MD

Administration of Tuberculin Skin Test

• The TST is performed by injecting 0.1 ml

of tuberculin purified protein derivative
(PPD) into the inner surface of the forearm.
• The injection should be made with a
tuberculin syringe, with the needle bevel
facing upward.
• The TST is an intradermal injection. When
placed correctly, the injection should
produce a pale elevation of the skin (a
wheal) 6 to 10 mm in diameter.

Prepared/modified by Dr. Tetiana Hliebova, MD

 Reading of Tuberculin Skin Test
• The skin test reaction should
be read between 48 and 72
hours after administration.
• A patient who does not return
within 72 hours will need to be
rescheduled for another skin
test.
• The reaction should be
measured in millimeters of the
induration (palpable, raised,
hardened area or swelling)
NB:
• If there is no induration, the result should be recorded as 0 mm.
• The area of erythema should not be measured, just the
induration. Horizontally measured***

Prepared/modified by Dr. Tetiana Hliebova, MD

 Interpreting TST Reactions
Skin test interpretation depends on the measurement of the induration and the individual’s risk of being infected
with TB or progression to disease if infected.
An induration of 5 or more An induration of 10 or more millimeters is ✓ An induration of 15 or more
millimeters is considered positive in: considered positive in: millimeters is considered
✓ HIV-infected person ✓ Recent immigrants (< 5 years) from high- positive in any person,
✓ A recent contact of a person with prevalence countries including persons with no
TB disease ✓ Injection drug users known risk factors for TB.
✓ Persons with fibrotic changes on ✓ Residents and employees of high-risk However, targeted skin
chest radiograph consistent with congregate settings testing programs should only
prior TB ✓ Mycobacteriology laboratory personnel be conducted among high-
✓ Patients with organ transplants ✓ Persons with clinical conditions that place risk groups.
✓ Persons who are them at high risk
immunosuppressed for other ✓ Children < 4 years of age
reasons (e.g., taking the ✓ Infants, children, and
equivalent of >15 mg/day of adolescents exposed
prednisone for 1 month or longer, to adults in high-risk
taking TNF-a antagonists) categories

Prepared/modified by Dr. Tetiana Hliebova, MD

 False Positives, False Negatives
The TST is a valuable tool, but it is not perfect. Several factors can lead to false-positive and
false-negative skin test reactions.

False-positive reaction may be caused by: False-negative reaction may be caused by:

• Nontuberculous mycobacteria • Cutaneous anergy (inability to react to a skin test)

• BCG vaccination
• Incorrect interpretation
• Administration of incorrect antigen
• Recent TB infection
• Very young age (<6 months old)
• Recent live-virus vaccination (including smallpox)
• Overwhelming TB disease
• Some viral illnesses (e.g., measles, chickenpox)
• Incorrect method of administration
• Too little antigen
• Subcutaneous injection
• Incorrect interpretation

Prepared/modified by Dr. Tetiana Hliebova, MD

 What is the next step?

• Next step is to obtain a chest x-ray:

Normal CXR (lalent TB): isonazid (INH) therapy for 9 months (12 mo for HIV
patients)
Abnormal CXR (TB) – next step is sputum stain!!!! If sputum +, then
• Treatment: 6-month course:
• Isoniazid 6mo (add B6!)
• Rifampin 6mo (orange urine)
• Pyrizinomide 2mo (hyperuricemea)
• Ethambutol 2mo (optic neuritis)

Prepared/modified by Dr. Tetiana Hliebova, MD

 Clinical Features of Primary Tuberculosis

• Primary tuberculosis resembles an

acute bacterial pneumonia, with lower
and middle lobe consolidation, hilar
adenopathy, and pleural effusion.

• Lymphohematogenous dissemination
may result in the development of
tuberculous meningitis or miliary
tuberculosis

Prepared/modified by Dr. Tetiana Hliebova, MD

 Clinical Features of Secondary Tuberculosis

• Secondary Tuberculosis Involves the apex of the upper lobes of one or both lungs.
• Lung tissue cavitation occurs more readily.
• Systemic symptoms are due to cytokines released by activated macrophages (e.g., TNF and IL-1) : malaise, anorexia,
weight loss, and fever.
• Fever is low grade and remittent (appearing late each afternoon and then subsiding), and night sweats occur.
• Cough with increasing amounts of sputum, at first mucoid and later purulent.
• Hemoptysis is present in about half of all cases of pulmonary tuberculosis.
• Pleuritic pain may result from extension of the infection to the pleural surfaces.
• Extrapulmonary manifestations of tuberculosis are depend on the organ system involved.

Prepared/modified by Dr. Tetiana Hliebova, MD

 HIV and Tuberculosis
• All stages of HIV infection are associated with an increased risk of tuberculosis.
• HAART therapy reduces risk of aquiring TB
• The manifestations of tuberculosis differ depending on the degree of
immunosuppression:
• CD4+ T-cell counts >300 cells/mm3- apical disease with cavitation
• CD4+ T-cell counts <200 cells/mm3 - resembles progressive primary tuberculosis, 50%
cases extrapulmonary Tb
• Increased frequency of false-negative sputum smears and tuberculin tests (the latter due
to “anergy”),
(The increased frequency of sputum smear-negativity (the absence of bronchial wall
destruction due to reduced T-cell–mediated hypersensitivity results in the excretion of
fewer bacilli in the sputum)

Prepared/modified by Dr. Tetiana Hliebova, MD

Morphology of Primary Tuberculosis (Lungs)

• Almost always begins in the lungs.

• An inhaled bacilli implant in the lower part of the upper lobe or the upper part
of the lower lobe, close to the pleura.

• A 1 to 1.5cm area of gray-white inflammation - Ghon focus (the center may be

caseous necrosis).

• Bacilli drain to the regional nodes and form caseating necrosis area.

• Combination of parenchymal lung lesion and nodal lesion = Ghon complex

Prepared/modified by Dr. Tetiana Hliebova, MD

Morphology of Primary
Tuberculosis
1. Ghon focus 1+2=Ghon complex
1 2. Hilar Lymph node

2 1

Prepared/modified by Dr. Tetiana Hliebova, MD

Prepared/modified by Dr. Tetiana Hliebova, MD
 Secondary Tuberculosis
I. Progressive pulmonary
tuberculosis:
1.Cavitary fibrocaseous
tuberculosis (apical and
advanced)
2. Miliary pulmonary disease
3. Tuberculous
bronchopneumonia
II. Systemic miliary tuberculosis
III. Isolated tuberculosis

The caseous necrosis is extensive, and

cavitation is prominent.
Such patients can be highly contagious
Prepared/modified by Dr. Tetiana Hliebova, MD
Prepared/modified by Dr. Tetiana Hliebova, MD
An 18-year-old man with no clinically significant medical history presented with a six-month history of an increasing mass on the
left side of his back (Panel A). About three days before seeking medical attention, the patient had noticed serous drainage from a
sore on the left lateral wall of his chest (Panel B). Chest radiography showed multiple left-sided pleural nodules with a
consolidation in the left lower lobe. Computed tomography of the chest showed numerous pleural nodules encasing the left lung
and a large collection of fluid in the musculature of the left back (Panel C), which was consistent with empyema necessitatis, in
which pus can escape toward the chest wall. Although the results of the pleural biopsy were culture-negative, the pleural-fluid
culture was positive for Mycobacterium tuberculosis. The test for infection with the human immunodeficiency virus was negative.
Since the mycobacteria were fully susceptible to all antimycobacterial agents, the patient began treatment with a standard
antituberculosis regimen, and his condition slowly improved

Tuberculous empyema - represents a chronic, active infection of the pleural space that contains a large number of
tubercle bacilli. Most commonly is a result of rupture of a subpleural caseous focus into the pleural space
Empyema necessitatis is defined by the extension of an empyema through the parietal pleura, into surrounding tissue

Prepared/modified by Dr. Tetiana Hliebova, MD

 Morphology of Isolated Tuberculosis

• Appears in any of the organs or tissues (hematogenously)

• Most common organs: the meninges (tuberculous meningitis), kidneys (renal
tuberculosis), adrenals (formerly an important cause of Addison disease), bones
(osteomyelitis), and fallopian tubes (salpingitis). Spine, KD, bones, reproductive = kd
• When the vertebrae are affected, the disease is called Pott disease. Paraspinal
“cold” abscesses in these patients may track along tissue planes and present as an
abdominal or pelvic mass.
• Lymphadenitis usually occurring in the neck region (“scrofula”). HIV-positive
people, almost always have multifocal process
• Intestinal tuberculosis contracted by the drinking of contaminated milk, swallowing
of coughed-up infective material in patients with advanced pulmonary disease.
Granulomatous inflammation of mucosal lymphoid nodules can lead to ulceration
particularly in the ileum.
Prepared/modified by Dr. Tetiana Hliebova, MD
 scrofula

tuberculous meningitis Pott disease

tuberculous infiltrates of the choroid Prepared/modified by Dr. Tetiana Hliebova, MD

Prepared/modified by Dr. Tetiana Hliebova, MD
Prepared/modified by Dr. Tetiana Hliebova, MD
Interstitial Lung Disease

Prepared/modified by Dr. Tetiana Hliebova, MD

 Interstitial Lung Disease

• Interstitial lung disease (ILD) is a group of

heterogeneous diseases and includes more than 100
disorders.
• ILD is characterized by chronic inflammation and
fibrosis of the interstitium and lung parenchyma.
• The interstitium of the lung (supporting structure) is
the area in and around the small blood vessels and
alveoli where the exchange of oxygen and carbon
dioxide takes place.
• Inflammation and scarring of the interstitium (and
eventually extension into the alveoli) will disrupt
normal gas exchange.
• Although the progression of ILD may be variable
from one disease to another, there are common
clinical, radiographic, and spirometric findings.
Prepared/modified by Dr. Tetiana Hliebova, MD
 Interstitial Lung Disease
• All patients with ILD develop exertional dyspnea
(the most common complaint that brings them to the
physician) and nonproductive cough.
• Examination shows the typical coarse crackles,
evidence of pulmonary hypertension (increased
pulmonic sound, right heart failure), and clubbing
(not always).
• Chest x-ray is consistent with reticular or
reticulonodular pattern (“groundglass” appearance).
• PFTs show evidence of intrapulmonary restrictive
pattern.
• Diagnostic evaluation should include high-
resolution CT scan and, eventually, biopsy via
bronchoscopy or open lung biopsy.
Causes include:
• Idiopathic pulmonary fibrosis
• Sarcoidosis
• Pneumoconiosis and occupational lung disease
• Connective tissue or autoimmune disease–
related pulmonary fibrosis
• Hypersensitivity pneumonitis
• Eosinophilic granuloma (a.k.a. Langerhans cell
histiocytosis)
• Chronic eosinophilic pneumonia
• Wegener granulomatosis
• Idiopathic pulmonary hemosiderosis
• Bronchiolitis obliterans
• Lymphangioleiomyomatosis
Prepared/modified by Dr. Tetiana Hliebova, MD
 Case 1

A 55-year-old man comes for evaluation of exercise

intolerance over the past 6 months. He has no
significant past medical history. He informs you that
over the past week he cannot walk across the room
without getting “short of breath.” He takes no
medications and has never smoked. The physical
exam is significant for a respiratory rate of 24/min,
jugular venous distention ~8 cm, coarse crackles on
auscultation, clubbing, and trace pedal edema on
both legs. The chest x-ray reveals diffuse reticular
disease.

Prepared/modified by Dr. Tetiana Hliebova, MD

 Idiopathic Pulmonary Fibrosis (IPF)
• Idiopathic pulmonary fibrosis (IPF) is an inflammatory lung disease of unknown origin that causes lung
fibrosis and restrictive lung disease.
• It characteristically involves only the lung and has no extrapulmonary manifestations except clubbing.
• Typically seen in decade 5 of life, it affects men and women equally.
• Clinical Presentation. Progressive exercise intolerance and dyspnea are seen most commonly. There are
coarse dry crackles on auscultation.
• Chest x-ray reveals reticular or reticulonodular disease. High-resolution CT may show ground-glass
appearance. As IPF progresses, imaging will show extensive fibrosis with honeycomb pattern.
• A restrictive intrapulmonary process is evident on PFTs.
• Bronchoalveolar lavage will show nonspecific findings, specifically increased macrophages.
• Lung biopsy will exclude other causes with similar findings, e.g., vasculitis, infections, cancer.
• Treatment. Pharmacologic treatment includes pirfenidone, a new small-molecule compound that has
antifibrotic effects (shown to significantly reduce a decline in lung function and IPF disease progression).
Non-pharmacologic treatment for eligible patients includes lung transplantation (shown to reduce the risk of
death by 75% as compared with those who remain on the waiting list).
Prepared/modified by Dr. Tetiana Hliebova, MD
 Case 2

A 27-year-old woman comes to your office with painful erythematous

papules that occurred yesterday. She has no other complaints except joint
swelling and pain that occurred 3 days ago. Physical examination
discloses low-grade fever, symmetric swelling of the knees, PIP
(proximal interphalangeal) and MCP (metacarpophalangeal) joints,
and well demarcated, 3- to 4-cm papules over the anterior aspect of her
legs.
What is the next step in confirming the likely diagnosis?

Prepared/modified by Dr. Tetiana Hliebova, MD

• Sarcoidosis is a systemic disease of Sarcoidosis
unknown cause, characterized histologically
by the presence of nonspecific
noncaseating granulomas in the lung and
other organs.
• There is an increased incidence among
patients age 20–40, especially Afro-
American females.
• Sarcoidosis can involve almost any organ
system, but pulmonary involvement is most
common.
• Ocular, cutaneous, myocardial,
rheumatologic, GI, and neurologic
manifestations can also occur.
• Dermatologic manifestations occur in 25%
of patients with sarcoidosis; they include
lupus pernio, erythema nodosum, non-
scarring alopecia, and papules.
• Commonly, sarcoidosis is discovered in a
completely asymptomatic patient, usually
Prepared/modified by Dr. Tetiana Hliebova, MD
in the form of hilar adenopathy on
 Sarcoidosis

There are 2 distinct sarcoid syndromes with acute presentation:

Löfgren syndrome includes: Heerfordt-Waldenstrom syndrome:

love green – anywhere else. (Her forehead) – face infection related
• erythema nodosum • fever
• arthritis • parotid enlargement
• hilar adenopathy • uveitis
• facial palsy

Prepared/modified by Dr. Tetiana Hliebova, MD

Prepared/modified by Dr. Tetiana Hliebova, MD
 Sarcoidosis

Lung involvement in sarcoidosis occurs in 90% of patients at some time in their

course. Hilar and left paratracheal adenopathy is the most common presentation.

Chest x-ray findings can show 4 stages of disease (the stages are not progressive):
1. • Bilateral hilar adenopathy
2. • Hilar adenopathy with reticulonodular parenchyma
3. • Reticulonodular parenchyma alone
4. • Honeycombing of bilateral lung fields with fibrosis

Prepared/modified by Dr. Tetiana Hliebova, MD

 Sarcoidosis

Stage I
Bilateral hilar adenopathy

Prepared/modified by Dr. Tetiana Hliebova, MD

 Sarcoidosis

Stage II

Hilar adenopathy with

reticulonodular parenchyma

Prepared/modified by Dr. Tetiana Hliebova, MD

 Sarcoidosis

Stage III

Reticulonodular parenchyma

Prepared/modified by Dr. Tetiana Hliebova, MD

 Sarcoidosis

Stage IV

Honeycombing of bilateral lung fields with fibrosis

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Prepared/modified by Dr. Tetiana Hliebova, MD
Clinical presentation includes:
Sarcoidosis
• Hypercalcemia or hypercalciuria
due to increased circulation of vitamin
D produced by macrophages.
• Elevated angiotensin-converting
enzyme (ACE) (60% of patients);
ACE levels are nonspecific but can be
used to follow the course of the
disease
• Abnormalities in LFTs (30% of
patients with liver involvement, with
90% of patients being symptomatic)
• Skin anergy
• PFTs normal or showing a restrictive
pattern
• Uveitis and conjunctivitis (>25% of
patients) (give all patients with
suspected sarcoidosis an
ophthalmologic examination)
Prepared/modified by Dr. Tetiana Hliebova, MD

✓ The definitive diagnosis of sarcoidosis rests
on biopsy of suspected tissues, which show
noncaseating granulomas
NB: If a patient is asymptomatic
and has bilateral hilar adenopathy on
routine chest x-ray, assume it is
sarcoidosis and follow with imaging.
Sarcoidosis
• Treatment:
• There is no evidence that any therapy alters
the course of disease.
• Generally in the setting of organ impairment,
a trial of steroids may be used, giving a high
dose for 2 months followed by tapering the
dose over 3 months.
• There are certain scenarios in which steroids
are mandatory: uveitis, sarcoidosis involving
the CNS and heart, and patients who develop
• hypercalcemia.
Prepared/modified by Dr. Tetiana Hliebova, MD
Pneumoconiosis

Prepared/modified by Dr. Tetiana Hliebova, MD

 Definition

• The pneumoconioses are occupational lung

diseases in which inhalation of certain fibers
initiates an inflammatory process and
History is of primary
eventually leads to fibrosis of the lung.
importance in assessing
• Usually, pneumoconiosis appears 20–30 years possible occupational
after constant exposure to offending agents lung diseases.
(metal mining of gold, silver, lead, copper),
but it can develop in <10 years when dust
exposure is extremely high.

Prepared/modified by Dr. Tetiana Hliebova, MD

 Pathology

Alveolar macrophages engulf

offending agents, causing
inflammation and fibrosis
of the lung parenchyma in
pneumoconiosis.

Respiratory insufficiency is
the ultimate consequence of
the pneumoconioses.

Prepared/modified by Dr. Tetiana Hliebova, MD

 Diagnosis

Signs and symptoms include:

• PFTs show a restrictive pattern with a decreased DLCO.
• dyspnea
• Hypoxemia is evident with an increased PAo2-Pao2 gradient.
• shortness of breath
• Chest x-ray findings include small irregular opacities,
• cough, sputum production interstitial densities, ground glass appearance, and
• cor pulmonale honeycombing.
• clubbing

Prepared/modified by Dr. Tetiana Hliebova, MD

 Asbestosis

• Asbestosis is an occupational lung disease

caused by prolonged inhalation of asbestos
dust.
• The result is lung parenchymal fibrosis which
results in respiratory compromise.
• Asbestos fiber exposure may be seen in
mining, milling, foundry work, shipyards, or
the application of asbestos products to pipes,
brake linings, insulation, and boilers.

• History of exposure to asbestos is needed to

consider the diagnosis.

Prepared/modified by Dr. Tetiana Hliebova, MD


Signs and symptoms include:
• exertional dyspnea and reduced exercise
tolerance
• cough and wheezing (especially among
smokers)
• chest wall pain
• ultimately respiratory failure
Asbestosis
✓ Pleural effusions are commonly seen, and the interstitial
lung process associated with asbestosis usually involves the
lower lung fields.
✓ The most common cancer associated with asbestosis is
bronchogenic carcinoma (adenocarcinoma or squamous cell
carcinoma).
✓ Pleural or peritoneal mesotheliomas are also associated with
asbestos exposure but are not as common as bronchogenic
cancer.
✓ For diagnosis, a lung biopsy is usually needed; the
classic barbell-shaped asbestos fiber is found.
✓ No specific treatment is offered. Patients with asbestos
exposure should strongly be advised to stop smoking since
their risk of lung cancer is 75 times higher than that of the
normal population.
Prepared/modified by Dr. Tetiana Hliebova, MD
 Asbestosis

On chest x-ray:
• diffuse or local
pleural thickening
• pleural plaques
• calcifications at
the level of the
diaphragm

Prepared/modified by Dr. Tetiana Hliebova, MD

 Silicosis
• Silicosis is an occupational lung disease caused by inhalation
of silica dust.
• It is seen in individuals who work in mining, quarrying,
tunneling, glass and pottery making, and sandblasting.
• Silicosis causes similar symptoms to asbestosis (or any other
pneumoconiosis) except the acute form of silicosis, which is
caused by massive exposure that causes lung failure in
months.
• Pathology. Silica causes inflammatory reactions with
pathologic lesions being the hyaline nodule.
• Chest X-Ray. In silicosis there are nodules (1–10 mm) seen
throughout the lungs that are most prominent in the
upper lobes. A characteristic finding is eggshell
calcifications (rare). In progressive massive fibrosis,
densities are 10 mm or more and coalesce in large masses.
• Diagnosis is made with lung biopsy.
• There is no effective therapy for silicosis. Death occurs
usually because of progressive respiratory insufficiency.
NB: High association with TB!!! Prepared/modified by Dr. Tetiana Hliebova, MD
Coal miner’s Lung / Coal worker’s Pneumoconiosis
• Patients clinically present as they would with any
other occupational lung disease.
• On chest x-ray, small round densities are seen in
the parenchyma, usually involving the upper half
of the lungs.
• Complicated or progressive massive fibrosis is
diagnosed by the presence of larger densities
from 1 cm in diameter to the entire lobe.
• Increased levels of IgA, IgG, C3, antinuclear
antibodies (ANA), and rheumatoid factor are
also seen.

Caplan’s syndrome
=
pneumoconoisis + rheumatoid
arthritis
Prepared/modified by Dr. Tetiana Hliebova, MD
Questions?

Prepared/modified by Dr. Tetiana Hliebova, MD