Medical Services
Tuberculosis & Sarcoidosis
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 1
Medical Services
Document control
Version history
Version Date
Comments
1a Draft
October 2008
Initial Draft
1b (rev)
March 2009
Reformatted and re-ordered
1c (rev)
April 2009
Inter author review
1d with int. QA May 2009
Dr Gill Buchanan’s comments incorporate
1e draft
Jan 2010
External review comments by Dr Munro
1 Final
14 October 2010
Signed off by CMMS
Changes since last version
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 2
Medical Services
A. TUBERCULOSIS
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 3
Medical Services
Introduction
Definition
Tuberculosis is a chronic, progressive infection with a period of latency
following initial infection. It occurs most commonly in the lungs. Pulmonary
symptoms include productive cough, chest pain, and dyspnoea. Diagnosis is
by sputum culture and smear. Treatment is with multiple antimicrobial agents.
Tuberculosis (TB) is an infectious disease caused by the bacterium
Mycobacterium tuberculosis, also known as 'the tubercle bacillus'.
TB commonly affects the lungs, but can reach any part of the body.
It is usually spread by the coughs or sneezes of an infected person, but is
not highly contagious.
Prolonged close contact with a person with TB, for example, living in the
same household is usually necessary for infection to be passed on.
It may take many years before someone infected with TB develops the full
disease.
Tuberculosis is a ‘Notifiable Disease’ under the Public Health (Infectious
Diseases) Regulations 1988 and must be reported to the Health Protection
Agency.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 4
link to page 3 link to page 3
Medical Services
Description
Epidemiology
Tuberculosis (TB) has been identified in human remains more than 9,000 years
old.
It is the leading infectious cause of morbidity and mortality in adults worldwide,
killing about 2 million people every year.
About 1.6 billion are infected worldwide. Of these, only 15 million have active
disease at any given time. Case rates vary widely by country, age, race, sex,
and socioeconomic status.
According to WHO figures 26 of the 30 countries with the greatest TB load are
in Africa, and many of these have a prevalence 10 times more than the 40
cases per 100,000 per year figure required to qualify as a ‘high load country’.
HIV infection is the greatest single medical risk factor because
cell-mediated immunity, which is impaired by HIV, is essential for defence
against TB; other immunosuppressive illnesses (e.g. diabetes) or therapies
(e.g. corticosteroids) are risks but less so than HIV.
TB is still a major problem in many countries. It has been on the increase in the
developed world in recent years, probably because of increased air travel and
movement of people from areas where it is common.
In the UK from September 2005, a new targeted programme of BCG
vaccination was introduced. Only those people at high risk of contracting TB
will be vaccinated, as opposed to all school children.
Prevalence
TB worldwide is a massive problem and large numbers die annually.
In England cases fell progressively until the mid-1980s but started to rise again
in the early 1990s.
In 2006, there were 8497 cases of TB reported in the UK (14.0 per 100,000)
and the London region accounted for 40% of cases (44.8 per 100,000). TB is
potentially curable with a course of specific antibiotics taken for at least 6
months.
About 8000 new cases of TB are currently reported each year in the United
Kingdom. Most cases occur in major cities, particularly in London
1.
The most important part of controlling TB is identifying and treating those who
already have the disease, to shorten their infection and to stop it being passed
on to others.
2
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 5
link to page 3 link to page 3
Medical Services
Aetiology
TB properly refers only to disease caused by Mycobacterium tuberculosis (M.
tuberculosis).
Similar disease occasionally results from
M. bovis,
M. africanum, and
M. microti.
In the United Kingdom TB occurs almost exclusively from inhalation of droplet
nuclei containing
M. tuberculosis. They disperse primarily through coughing,
singing, and other forced respiratory manoeuvres by a person with active
pulmonary disease.
People with cavitating pulmonary lesions are especially infectious. Droplet
nuclei containing tubercle bacilli may float on room-air currents for several
hours, increasing the chance of spread. About 25% of household contacts
acquire infection. Healthcare practitioners who have close contact with active
cases have increased risk.
Transmission is enhanced by overcrowding; thus, people living in poverty or in
institutions are at particular risk. Once effective treatment begins, however,
cough rapidly decreases, and after two weeks, TB is no longer contagious.
Fomites (e.g. clothes or bedding) do not appear to facilitate spread.
Pathophysiology3
Tubercle bacilli initially produce a primary infection, followed by a latent
(dormant) phase and then, in some cases, by active disease. Infection is not
transmissible in the primary and latent phases.
Primary infection:
Airborne droplet nuclei lodge in sub-pleural terminal airspaces, predominantly
in the lower lung, usually in only one site. Tubercle bacilli replicate inside
macrophages, ultimately killing them. Inflammatory cells are attracted to the
area, causing a tubercle to form and in some cases pneumonitis. In the early
weeks of infection, some infected macrophages are carried to regional lymph
nodes (eg, hilar, mediastinal). Haematogenous spread to any part of the body,
particularly the apical-posterior portion of the lungs, epiphyses of the long
bones, kidneys, vertebral bodies, and meninges, may occur.
In 95% of cases, after about 3 weeks of uninhibited growth, the immune system
suppresses bacillary replication. This may happen before symptoms or signs
develop. Foci of infection in the lung or other sites resolve into epithelioid cell
granulomas, which may have caseous and necrotic centres; tubercle bacilli can
survive in this material for years, the host's resistance determining whether the
infection ultimately resolves without treatment, remains dormant, or becomes
active.
Foci may leave nodular scars in the apices of one or both lungs (Simon foci),
calcified scars from the primary infection (Ghon foci), or calcified hilar lymph
nodes. The tuberculin skin test is positive.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 6
Medical Services
Rarely, the primary focus immediately progresses especially in infants or young
children with other debilitating diseases, causing acute, potentially fatal, illness
with pneumonia, pleural effusion, and marked mediastinal or hilar lymph node
enlargement (which in children may compress bronchi). Small pleural effusions
are predominantly lymphocytic, typically contain few organisms, and clear
within a few weeks.
Primary extra-pulmonary TB at any site can sometimes present without
evidence of lung involvement. While TB lymphadenopathy is the most common
extra-pulmonary presentation, meningitis is the most feared because of its high
mortality in the very young and very old.
Active disease:
In about 10% of patients overall, latent infection develops into active disease,
although the percentage varies significantly depending on age and other risk
factors. In 50 to 80% of those who develop active disease, TB reactivates
within the first 2 years, but it can occur decades later. Any organ initially
seeded may be a site of reactivation, but reactivation occurs most often in the
lung apices, where O2 tension is highest.
Ghon foci and affected hilar lymph nodes are much less likely to be sites of
reactivation.
Conditions that facilitate activation include:
impaired immunity (particularly HIV infection)
certain immunosuppressant drugs (eg, corticosteroids, infliximab and other
tumour necrosis factor blockers (TNF antagonists)
gastrectomy, jejunoileal bypass surgery, silicosis, renal insufficiency,
stress, diabetes, head or neck cancer,
Adolescence, and advanced age (> 70 yr).
TB damages tissues through delayed hypersensitivity, typically producing:
Granulomatous necrosis with a caseous histological appearance.
Cavitating Lung lesions
Pleural effusions. This is less common than in progressive primary TB but
may occur from direct extension or haematogenous spread.
Rupture of a large tuberculous lesion into the pleural space may produce
empyema with or without broncho-pleural fistula; it sometimes causes
pneumothorax.
The course varies greatly, depending on the virulence of the organism and the
state of host defences. The course may be rapid among African Americans,
Afro-Caribbeans and American Indians who have not had as many centuries of
selective pressure to develop innate or natural immunity.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 7
link to page 3 link to page 3
Medical Services
Diagnosis4
Symptoms and Signs
In active pulmonary TB, even with moderate or severe disease, the patient
may have no symptoms except ‘not feeling well’ or may have more specific
symptoms.
Cough is most common.
At first, it may be minimally productive of yellow or green sputum, usually
on rising, but cough may become more productive as the disease
progresses.
Drenching night sweats are a classic symptom but are neither common in
nor specific for TB.
Dyspnoea may result from lung parenchymal involvement, spontaneous
pneumothorax, or pleural involvement with effusion.
Haemoptysis occurs only with cavitating TB.
Weight Loss
Recommended investigations
Latent TB
To diagnose latent TB:
Mantoux testing should be performed
Those with positive results (or in whom Mantoux testing may be less
reliable) should then be considered for interferon-gamma immunological
testing, if available.
If testing is inconclusive, the person should be referred to a TB specialist.
Active TB
To diagnose active respiratory TB:
a posterior–anterior chest X-ray should be taken; chest X-ray
appearances suggestive of TB should lead to further diagnostic
investigation
multiple sputum samples (at least three, with one early morning
sample) should be sent for TB microscopy and culture for suspected
respiratory TB before starting treatment if possible or, failing that,
within 7 days of starting
spontaneously produced sputum should be obtained if possible.
Otherwise induction of sputum (by inhalation of saline) or
bronchoscopy and lavage should be used
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 8
Medical Services
in children unable to expectorate sputum, induction of sputum should
be considered if it can be done safely, with gastric washings
considered as third line
If there are clinical signs and symptoms consistent with a diagnosis of TB,
treatment should be started without waiting for culture results. The standard
recommended regimen should be continued in patients whose subsequent
culture results are negative
Samples may be sent for TB culture from autopsy samples if respiratory TB is a
possibility
Active non-respiratory TB:
The advantages and disadvantages of both biopsy and needle aspiration
should be discussed with the patient, with the aim of obtaining adequate
material for diagnosis.
If non-respiratory TB is a possibility, part or all of any of the following samples
should be placed in a dry pot (and not all placed in formalin) and sent for TB
culture:
lymph
node
biopsy
pus aspirated from lymph nodes
pleural
biopsy
any surgical sample sent for routine culture
any radiological sample sent for routine culture
histology sample
aspiration sample (from pleural or pericardial effusions)
autopsy
sample
TB culture should routinely be performed on the above samples.
The appropriate treatment regimen should be started without waiting for
culture results if the histology and clinical picture are consistent with a
diagnosis of TB.
All patients with non-respiratory TB should have a chest X-ray to exclude
or confirm co-existing respiratory TB
The appropriate drug regimen should be continued even if subsequent
culture results are negative.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 9
Medical Services
Table 1 Suggested site-specific investigations in the diagnosis and
assessment of non-respiratory TB
Site Imaging
Biopsy
Culture
Lymph node
Node
Node or aspirate
Bone/joint
Plain X-ray and
Site of disease
Biopsy or
computed tomography
paraspinal
(CT)
abscess
Magnetic resonance
Site or joint fluid
imaging (MRI)
Gastrointestinal
Ultrasound
Omentum
Biopsy
CT abdomen
Bowel
Ascites
Genitourinary
Intravenous urography
Site of disease
Early morning
Ultrasound
urine (x3)
Site of disease
Endometrial
curettings
Disseminated
High-resolution CT
Lung
Bronchial wash
thorax
Liver
Liver
Ultrasound abdomen
Bone marrow
Bone marrow
Blood
Central nervous
CT brain
Tuberculoma
Cerebrospinal
system
MRI
fluid
Skin
Site of disease
Site of disease
Pericardium
Echocardiogram
Pericardium
Pericardial fluid
Cold/liver
Ultrasound
Site of disease
Site of disease
abscess
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 10
link to page 8
Medical Services
Treatment
Management of respiratory TB4
Respiratory TB is defined as active TB that is affecting any of the following:
lungs
pleural cavity
mediastinal lymph nodes
larynx
Drug treatment
Once a diagnosis of active TB is made, the clinician responsible for care should refer
the person with TB to a physician with training in, and experience of, the specialised
care of people with TB.
TB in children should be managed either by a paediatrician with experience and
training in the treatment of TB, or by a general paediatrician with advice from a
specialised physician.
A 6-month, four-drug initial regimen (6 months of Isoniazid and Rifampicin
supplemented in the first 2 months with Pyrazinamide and Ethambutol) should be
used to treat active respiratory TB in:
adults not known to be HIV-positive
adults who are HIV-positive
children
This regimen is referred to as ‘standard recommended regimen’.
Fixed-dose combination tablets should be used as part of any TB treatment
regimen.
Cure is possible in Multi-drug Resistant T B (MDRTB) using prolonged
treatment with less effective, more expensive and more toxic drugs. However,
further resistance may develop and there is a high risk of treatment failure.
Infection control
All patients with TB should have risk assessments for drug resistance and for
HIV.
A significant proportion of patients with TB do not require to be admitted to
hospital. Others require admission because they are seriously ill or require
inpatient investigations. In addition admission may be indicated for socio-
economic reasons perhaps where there are doubts about drug compliance
due to learning difficulties or severe mental health problems including
addictions.
If admitted to hospital, patients with suspected respiratory TB should be
given a single room.
Patients with respiratory TB should be separated from immuno-
compromised patients, either by admission to a single room on a
separate ward, or to a negative-pressure room on the same ward.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 11
Medical Services
Any visitors to a child with TB in hospital should be screened as part of
contact tracing, and kept separate from other patients until they have
been excluded as the source of infection.
Smear-positive TB patients without risk factors for Multi-Drug Resistant
TB (MDR TB) should be cared for in a single room, until:
they have completed 2 weeks of the standard recommended regimen, or
they are discharged from hospital
Aerosol-generating procedures such as bronchoscopy, sputum induction or
nebuliser treatment should be carried out in an appropriately engineered and
ventilated area for:
all patients on an HIV ward, regardless of whether a diagnosis of TB has
been considered
all patients in whom TB is considered a possible diagnosis, in any setting
Healthcare workers caring for people with TB should not use masks, gowns or
barrier nursing techniques unless:
MDR TB is suspected
aerosol-generating procedures are being performed
When such equipment is used, the reason should be explained to the
person with TB.
The equipment should meet the standards of the Health and Safety Executive.
TB patients admitted to a setting where care is provided for HIV-positive or
other immunocompromised patients should be considered infectious and
should stay in a negative-pressure room until:
(a) For people who were sputum smear positive at admission:
1.
they have had had at least 2 weeks of appropriate multiple drug
therapy, and
2. if moving to accommodation (inpatient or home) with HIV-positive or
immunocompromised patients, have had at least three negative
microscopic smears on separate occasions over a 14-day period, and
3. are showing tolerance to the prescribed treatment and an ability and
agreement to adhere to treatment,
and either
4. any cough has resolved completely, or
5. there is definite clinical improvement on treatment, for example remaining
afebrile for a week
(b) For people who were sputum smear negative at admission (that is, three
negative samples were taken on separate days; samples were spontaneously
produced sputum if possible, or obtained by bronchoscopy or lavage if sputum
samples were not possible):
all of 1, 2, 3 and 5 above should apply.
Inpatients with smear-positive respiratory TB should be asked (with
explanation) to wear a surgical mask whenever they leave their room until
they have had 2 weeks of drug treatment.
Management of non-respiratory TB - See Appendix A
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 12
Medical Services
Prognosis
In immuno-competent patients with drug-susceptible pulmonary TB, even
severe disease and large cavities usually heal if appropriate therapy is
instituted and completed.
TB still causes or contributes to death in about 10% of cases, often in those
who are debilitated for other reasons.
Disseminated TB and TB meningitis may be fatal in up to 25% of cases despite
optimal treatment. TB is much more aggressive in immuno-compromised
patients and, if not properly and aggressively treated, may be fatal in as little as
2 months from its initial symptom. This is especially true of Multi-Drug Resistant
TB (MDR- TB), in which mortality can approach 90%.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 13
link to page 6
Medical Services
Main Disabling Effects
Severe disability is uncommon unless the claimant has been ineffectively
treated or is immunocompromised but can arise e.g. following TB affecting the
CNS, pericardium or urogenital tracts.
Respiratory TB
Even in active pulmonary TB with moderate disease, the patient may have few
symptoms and only very minimal disability due to a general malaise.
Occasionally there may be a cough and/or night sweats which affect sleep and
so add to the general malaise.
Dyspnoea may result from lung parenchymal involvement and in this situation
disability is unlikely to be more than mild to moderate.
Spontaneous pneumothorax may give rise to an acute episode of
breathlessness but should resolve with the appropriate treatment.
Pleural involvement with effusion is likely to produce the longest period of
breathlessness while any significant effusion is present.
Pulmonary TB would normally be expected to respond to the anti-tuberculous
medication with progressive reduction and complete resolution of symptoms
over a period of 3 months.
Non-respiratory TB
Lymph Nodes
Affected nodes are swollen and may be mildly tender or drain. Adjacent nodes
sometimes coalesce into an irregular mass. Usually the hilar lymph nodes are
involved. Other nodes generally are not involved unless disease is poorly
contained, allowing organisms to reach the thoracic duct, where they
disseminate into the bloodstream. Most infected nodes heal, but reactivation
commonly occurs. Infection in supraclavicular nodes may inoculate anterior
cervical nodes, eventually resulting in Scrofula - TB lymphadenitis in the neck.
TB peritonitis:
Symptoms may be mild, with fatigue, abdominal pain, and tenderness, or
severe enough to mimic acute abdomen.
The “doughy abdomen” referred to in old textbooks is rarely present.
TB pericarditis:
Pericardial infection may develop from foci in mediastinal lymph nodes or from
pleural TB. In some high incidence parts of the world, TB pericarditis is a
common cause of heart failure.
In Africa TB pericarditis is a common feature of AIDS.
Constrictive pericarditis or tamponade may occur, producing dyspnoea, neck
vein distension, paradoxical pulse, muffled heart sounds, and possibly
hypotension
.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 14
Medical Services
TB of bones and joints Symptoms include progressive or constant pain in involved bones and chronic
or subacute arthritis (usually monoarticular). In Pott's disease, spinal cord
compression produces neurological deficits, including paraplegia; paravertebral
swelling may result from an abscess. Weight-bearing joints are most
commonly involved, but bones of the wrist, hand, and elbow also may be
affected, especially after injury.
Gastrointestinal TB:
Gastrointestinal TB is usually caused by swallowing infected sputum. Intestinal
invasion generally produces hyperplasia and an inflammatory bowel syndrome
with pain, diarrhoea, obstruction, and melaena. It may also mimic appendicitis.
Ulceration and fistulae are possible.
TB of the liver: Liver infection is common with advanced pulmonary TB and widely
disseminated or miliary TB. However, the liver generally heals without sequelae
when the principal infection is treated. TB in the liver occasionally spreads to
the gallbladder, leading to obstructive jaundice
TB meningitis:
Meningitis often occurs in the absence of infection at other extra-pulmonary
sites. At any age, meningitis is the most serious form of TB and has high
morbidity and mortality. It is the one form of TB believed to be prevented in
childhood by vaccination with BCG.
Symptoms are low-grade fever, unremitting headache, nausea, and
drowsiness, which may progress to stupor and coma.
Kernig's and Brudzinski's signs may be positive.
Stages are:
clear sensorium with abnormal CSF,
drowsiness or stupor with focal neurological signs, and
Coma.
Stroke may develop due to thrombosis of a major cerebral vessel. Focal
neurological symptoms suggest a tuberculous mass intracranial lesion
(tuberculoma).
Genitourinary TB:
Infection of the kidney may present as pyelonephritis (e.g. fever, back pain,
pyuria) without the usual urinary pathogens on routine culture (“sterile pyuria”).
Infection commonly spreads to the bladder and, in men, to the prostate,
seminal vesicles, or epididymis, causing an enlarging scrotal mass. Infection
may spread to the perinephric space and down the psoas muscle, sometimes
causing an abscess on the anterior thigh.
In women, salpingo-oophoritis can occur after menarche, when the fallopian
tubes become vascular. Symptoms include chronic pelvic pain and sterility or
ectopic pregnancy from tubal scarring.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 15
Medical Services
Miliary TB:
Also known as generalized haematogenous TB, miliary TB occurs when a
tuberculous lesion erodes into a blood vessel, disseminating millions of
tubercle bacilli into the bloodstream and throughout the body. The lungs and
bone marrow are most often affected, but any site may be involved.
Miliary TB is most common in children under 4 years old, immuno-
compromised people, and the elderly.
Symptoms include fever, chills, weakness, malaise, and often progressive
dyspnoea. Intermittent dissemination of tubercle bacilli may lead to a prolonged
PUO (Pyrexia of Unknown Origin). Bone marrow involvement may produce
anaemia, thrombocytopenia, or a leukaemoid reaction.
Other sites:
Rarely, TB may develop on abraded skin in a patient with cavitating pulmonary
TB. TB may infect the wall of a blood vessel and has even ruptured the aorta.
Adrenal involvement, leading to Addison's disease, formerly was common but
now is rare. Trauma to a tendon sheath may cause tuberculous tenosynovitis in
a patient with tuberculous involvement of any organ.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 16
Medical Services
B. SARCOIDOSIS
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 17
Medical Services
Introduction
Definition
Sarcoidosis is characterized by non-caseating granulomas in one or more
organs and tissues and is of unknown aetiology.
The lungs and lymphatic system are most often affected, but sarcoidosis may
affect any organ.
Diagnosis usually is first suspected because of pulmonary involvement and is
confirmed by chest x-ray, biopsy, and exclusion of other causes of
granulomatous inflammation.
First-line treatment is corticosteroids.
Prognosis is excellent for limited disease but poor for more advanced
disease.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 18
link to page 3 link to page 3
Medical Services
Description
Epidemiology
Sarcoidosis primarily affects people aged 20 to 40 but occasionally affects
children and older adults.
Prevalence 2, 4
Worldwide, prevalence is greatest in black Americans and northern Europeans,
especially Scandinavians, who have one of the highest incidence rates at 64
cases per 100,000 population. This contrasts with Poland, where the incidence
is reported as 3 cases per 100,000 population.
The disease is rare in Eskimos, Southeast Asians, New Zealand Maoris, and
native Canadian populations.
Disease presentation varies widely by racial and ethnic background, with black
Americans and Puerto Ricans demonstrating more frequent extra thoracic
manifestations.
Sarcoidosis is slightly more prevalent in women.
Incidence increases in winter and early spring, for unknown reasons.
Although sarcoidosis can appear at any age, a bimodal age distribution is seen,
which peaks between ages 25-35 and 45-65 years.
Aetiology5
The cause of sarcoidosis remains obscure. One hypothesis is that sarcoidosis
is an inflammatory response to an environmental agent (including infectious)
which occurs in a susceptible host. Susceptibility is influenced by genetic
predisposition.
Several potential infectious agents have been proposed as causes of
sarcoidosis. Although non-caseating, the granulomatous reaction reminds
many of tuberculosis, and much effort has been expended trying to identify a
mycobacterial cause. Several studies using polymerase chain reaction (PCR)
and similar molecular biological techniques have been employed, but there is
still no convincing evidence that Mycobacterium tuberculosis causes most
cases of sarcoidosis. It may lead to an occasional case of sarcoid-like reaction.
Other mycobacteria have been identified in some cases. Cell wall-deficient
mycobacteria have been grown from the blood of patients with sarcoidosis.
However, a recently completed control trial failed to demonstrate a difference in
the incidence of cell wall-deficient mycobacteria between those with
sarcoidosis and controls.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 19
link to page 19
Medical Services
Pathophysiology
Sarcoidosis is defined by its immunological reaction, the granuloma.
Original immunological studies stressed a lack of systemic immune response
by the patient with sarcoidosis. This includes anergy, the lack of reaction to any
skin test, which is a common feature of active sarcoidosis. A reduction in
circulating leucocytes, especially lymphocytes, is an important feature of the
disease.
In the 1970s, new techniques helped in the understanding of sarcoidosis. The
most important tool introduced at the time was bronchoalveolar lavage, which
provided a sample of the inflammatory cells in the lower respiratory tract. In
normal lavage fluid, alveolar macrophages are the usual resident inflammatory
cell retrieved; lymphocytes and neutrophils are found much less frequently. In
lavage fluid from patients with active sarcoidosis, the preponderance of T
lymphocytes is usually increased. These lymphocytes are often T-
helper/inducer cells (CD4+), and the ratio of CD4 to CD8 lymphocytes is
increased from that normally found in the blood (0.8 to 2.2), often to greater
than 3.5.
The CD4 lymphocyte is a crucial cell in cell-mediated immunity. The CD4
lymphocytes are activated and release several cytokines, including interleukin
2 (IL-2) and γ-interferon. The T lymphocyte can mount either a TH1 or TH2
response. The TH1 response is associated with granuloma formation, while
TH2 is associated with an eosinophilic response and fibrosis. The initial
response of sarcoidosis follows a TH1 pattern. The lymphocytes release IL-2
spontaneously, and γ-interferon is released by both lymphocytes and
macrophages. An increase in IL-12 and lower levels of IL-10 have also recently
been described, consistent with a TH1 response.
The resolution of sarcoidosis has also been studied with serial lavages. The T
lymphocytes remain elevated for some time, but the proportion of CD4 to CD8
decreases to the normal ratio found in blood (0.8 to 2.2). The amount of
cytokines released also decreases. This return to normal of the inflammatory
response has been shown to occur during treatment of sarcoidosis with
corticosteroids or methotrexate.
Genetic factors
Familial clustering of cases has been reported. Monozygotic twins are
2-4 times as likely to have the disease as dizygotic twins.
Certain HLA associations have been demonstrated; the most
common allele found in sarcoidosis is HLA-B8. Other associated
alleles include HLA-A1 and HLA-DR3.
Affected organs
Commonly affected organs include the lung, skin, and eyes.
Less commonly, the liver, heart, and brain are affected by the disease.
Individual organ involvement by sarcoidosis can be proved by a biopsy
showing non-caseating granuloma.
Presumed organ involvement is assumed if certain criteria are met.
Table 2 lists some of the criteria suggested for definite or probable organ
involvement for some of the more commonly affected organs in sarcoidosis.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 20
Medical Services
Lung
Radiological evidence of respiratory involvement has been described in more
than 90 per cent of patients. The lung involvement includes both the lymph
nodes and the lung parenchyma.
Scadding and Wurm independently described four stages of the chest
radiograph:
stage 1 is hilar adenopathy alone,
stage 2 is adenopathy and parenchymal disease,
stage 3 is parenchymal disease alone, and
stage 4 is fibrosis
Fibrotic changes due to sarcoidosis are usually in the upper lobe, with
retraction.
The staging system has proved useful in standardizing reports of pulmonary
level of involvement. It has also proved a useful prognostic measure.
Patients with stage 1 disease have a 90 per cent rate of resolution within 2 to
3 years, while patients with stage 3 disease possess only a 30 per cent chance
of resolution.
However, it does not predict the degree of extra-pulmonary disease. The
choice of the term ‘stage’ is therefore unfortunate. However, it is so standard
that it will not be easily replaced.
The use of the CT scan has changed our evaluation of many interstitial lung
diseases.
In sarcoidosis, peribronchial thickening is often seen in the upper lobe.
Adenopathy is usually seen in sarcoidosis, making the staging system only
applicable for plain radiographs. The CT scan may identify adenopathy in a
patient with possible extra-pulmonary sarcoidosis. This may help in deciding
where to proceed with a tissue diagnosis (lung biopsy or mediastinoscopy).
Pulmonary function studies in patients with sarcoidosis classically demonstrate
a restrictive pattern, with reduction of lung volumes. The transfer factor is
usually reduced out of proportion to the loss of lung volume, as one would
expect in an interstitial lung disease.
In advanced cases, the oxygen level will be reduced, especially during
exercise.
Obstructive disease can also occur in sarcoidosis. This can be due to airway
involvement by the sarcoidosis or associated with cough, a common complaint
in the condition.
Skin
The skin is the second most commonly affected organ in sarcoidosis. There are
six major manifestations.
Hyperpigmentation, hypopigmentation, and keloid reaction may demonstrate
granulomas on biopsy. However, their appearance is not always specific.
Waxy, maculopapular lesions, which occur on the extremities, back, and face,
are usually raised, with the majority less than 2 cm in diameter.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 21
Medical Services
When these occur on the face, especially on the cheeks and nose, they are
called lupus pernio.
Erythema nodosum (red nodular lesions on the extremities which are acutely
tender) usually involves the legs. The constellation of erythema nodosum,
arthritis (in the ankles), hilar adenopathy, and uveitis is referred to as Lofgren’s
syndrome and is a diagnostic manifestation of sarcoidosis. It is associated with
a good prognosis. Interestingly, the skin lesions from erythema nodosum do
not contain granulomas, but are considered to be due to circulating immune
complexes from the disease.
Eye
The eye can be affected in more than 20 per cent of patients with sarcoidosis.
The most common findings are uveitis and lacrimal gland involvement.
Anterior uveitis is often self-limiting, and can be treated topically; however,
posterior uveitis is a more chronic form of the disease and may require
injections of corticosteroids or systemic therapy.
Sicca (dry eyes) and glaucoma are long-term complications which are
encountered in patients often years after other sarcoidosis symptoms have
resolved. They are consequences of the fibrotic changes in the lacrimal glands
and eye. They do not respond to anti-inflammatory therapy.
Optic nerve involvement can be seen with sarcoidosis, with idiopathic disease
and multiple sclerosis being the other major causes of this sight-threatening
complication.
Retinal disease has also been reported.
Fortunately, blindness from sarcoidosis is rare, and usually a consequence of
untreated uveitis, retinitis, or optic neuritis.
Neurological
Neurological disease from sarcoidosis includes cranial nerve, central nervous
system, and peripheral nerve involvement.
Bell’s palsy (seventh cranial nerve) is a common complaint in neurosarcoidosis.
Central nervous system lesions can lead to a lymphocytic meningitis.
Hypothalamic involvement is a characteristic finding, with diabetes insipidus as
a resulting complaint.
The use of contrast-enhanced magnetic resonance imaging is the most
sensitive method for detecting central nervous system disease. The lumbar
puncture is complementary, with increased protein and lymphocytes often seen
in active disease. Detection of angiotensin-converting enzyme in the spinal fluid
is suggestive but not diagnostic of neurosarcoidosis.
Other manifestations
Liver and spleen involvement may be found in over half of patients with
sarcoidosis. However, symptomatic disease occurs in less than 10 per cent of
patients. Often, elevated liver function tests (especially the alkaline
phosphatase and γ-glutamyl transferase) are seen, suggesting an obstructive
pattern. Hyperbilirubinaemia is relatively rare, but implies extensive disease
and is usually an indication for therapy. Massive splenomegaly can occur, and
occasionally splenectomy is performed to avoid rupture.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 22
Medical Services
Hypercalcaemia and hypercalcinuria are seen with sarcoidosis.
The mechanism is related to the effect of the granuloma on vitamin D3.
The granuloma itself converts the vitamin D3 to the biologically active form
1,25-D3. This form of the vitamin has immunological activity as well as
enhancing calcium absorption from the gastrointestinal tract. In some patients
with sarcoidosis, the 1,25-D3 can leak into the bloodstream and produce a
systemic effect. Increased sunlight exposure also increases the levels of 1,25-
D3.
In America, hypercalcaemia is far more common in Caucasian than African-
American individuals. Because of the effect of increased calcium absorption,
urolithiasis may also be seen in patients with sarcoidosis. Recently, it has been
rwecognised to be a marker for chronic disease.
A less common, but serious complication of sarcoidosis is cardiac involvement.
Direct involvement of the heart can lead to arrhythmias such as heart block and
ventricular ectopy. This can lead to sudden death. If the problem is recognized,
the use of an implanted defibrillator may reduce this risk.
Cardiomyopathy is also seen, and cardiac sarcoidosis should be considered in
a young patient who presents with unexpected heart failure. Endomyocardial
biopsy rarely makes a diagnosis, since the granulomas are patchy. The
technetium scan showing non-segmental fixed defects is the most sensitive
test. Gallium uptake of the heart is more specific than a thallium scan.
Sarcoidosis granulomas can involve virtually any organ of the body. Rare
manifestations include bone cysts, usually in the distal portion of the fingers,
sinus invasion, pleural disease, breast disease, and ovarian or testicular
masses.
The multi-organ involvement of sarcoidosis distinguishes it from other
diseases. Lymphoma and tuberculosis are two diseases often considered in
the differential diagnosis of patients with possible sarcoidosis.
Table 2
Organ
Suggestive features
Possible features
Lung
Positive biopsy of lung
Lymphocytic alveolitis by bronchoalveolar
lavage
Chest radiograph characteristic for sarcoidosis (hilar
Any other pulmonary infiltrate
adenopathy, diffuse infiltrates, or upper lobe fibrosis)
Pulmonary function tests showing restriction
Isolated reduction of DLCO
Skin
Positive biopsy of skin
Macular/papular lesion
Lupus pernio
New nodules (including subcutaneous)
Erythema nodosum
Annular lesion
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 23
Medical Services
Eyes
Positive biopsy of eye
Blindness
Lacrimal gland swelling
Uveitis
Optic neuritis
Liver
Positive biopsy of liver
Compatible CT scan
Liver function tests more than 3 times normal
Elevated alkaline phosphatase
Neurological
Positive biopsy of nerve tissue
Other abnormalities on MRI
MRI with gadolinium uptake in meninges, brainstem, or
Unexplained neuropathy
mass lesion
Cerebral spinal fluid with increased lymphocytes or protein
Positive electromyogram
Organ
Possible features
Suggestive features
Diabetes insipidus
Neurological
(con’d
Cranial seventh nerve paralysis
Other cranial nerve dysfunction
Cardiac
Positive cardiac biopsy
Cardiomyopathy or ventricular arrhythmias
without other cardiac problems
Treatment-responsive cardiomyopathy
ECG showing intraventricular or nodal block
Positive thallium scan
Positive gallium scan of heart
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 24
link to page 3
Medical Services
Diagnosis
Symptoms and Signs6
Patients with sarcoidosis may have a variety of presentations.
Lung Symptoms
Shortness of breath
An unproductive cough
Wheezing
Pain in the middle of the chest that gets worse when breathing
deeply or coughing (rare).
Lymph Node Symptoms
Enlarged and sometimes tender lymph nodes—most often those in
the neck and chest but sometimes those under the chin, arm pits,
or in the groin.
Skin Symptoms
Various types of bumps, ulcers, or, rarely, flat areas of discoloured
skin, that appear mostly near the nose, eyes, back, arms, legs,
and scalp. They usually itch but aren't painful. They may last a
long time.
Painful bumps that usually appear on the ankles and shins and
can be warm, tender, red or purple-to-red in colour, and slightly
raised (
erythema nodosum). These bumps may be associated
with fever and swollen ankles and joint pain.
Disfiguring skin sores that may affect the nose, nasal passages,
cheeks, ears, eyelids, and fingers (lupus pernio). The sores tend to
be ongoing and can return after treatment is over.
Eye Symptoms
Burning, itching, tearing, pain
Red eye
Sensitivity to light
Dryness
Floaters (i.e., seeing black spots)
Blurred vision
Reduced colour vision
Reduced visual acuity
Blindness (in rare cases).
Heart Symptoms
Shortness of breath
Swelling in the legs
Wheezing
Coughing
Irregular heartbeat,
Sudden loss of consciousness
Sudden death.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 25
Medical Services
Joint and Muscle Symptoms
Joint stiffness or swelling—usually in the ankles, feet, and hands.
Joint pain.
Myalgia.
Muscle pain, a mass in a muscle, or muscle weakness.
Painless arthritis that can last for months or even years. It should
be treated.
Bone Symptoms
Painless holes in the bones.
Painless swelling, most often in the fingers.
Anaemia from granulomas affecting the bone marrow. This usually
requires treatment.
Liver Symptoms
Fatigue
Itching
Pain in the upper right quadrant of the abdomen, under the right
ribs
Enlarged liver.
Parotid and Other Salivary Gland Symptoms
Swelling
Excessive dryness in the mouth and throat.
Blood, Urinary Tract, and Kidney Symptoms
Increased calcium in the blood or urine, which can lead to kidney
stones
Confusion
Polyuria which may be due to hypercalcaemia/renal impairment or
diabetes insipidus
Nervous System Symptoms
Headaches.
Vision problems.
Weakness or numbness of an arm or leg.
Coma (rare).
7th nerve palsy. This can be confused with
Bell's palsy, a disorder
that may be caused by a virus.
Paralysis of the arms or legs, from spinal cord involvement.
Weakness, pain, or parasthesia in areas where many nerves are
affected.
Pituitary Gland Symptoms (Rare)
Headaches
Vision problems
Weakness or numbness of an arm or leg
Coma (rare).
Other Symptoms
Nasal obstruction or frequent bouts
of sinusitis.
Enlarged spleen, which leads to a decrease in platelets in the
blood and splenic pain.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 26
link to page 6
Medical Services
Sarcoidosis may also cause more general symptoms, including:
Uneasiness, feeling sick (malaise), an overall feeling of ill health
Tiredness, fatigue, weakness
Loss of appetite or weight
Fever
Night sweats
Sleep problems
(All these general symptoms are often caused by other conditions.)
Differential Diagnosis of Sarcoidosis
Infectious
Bacterial
o Mycobacterial
o TB
o
Atypical mycobacteria
o Syphilis
Fungal
o Aspergillosis
o Blastomycosis
o Coccidioidomycosis
o Cryptococcal
infection
o Histoplasmosis
Other
o Brucellosis
o
Cat-scratch disease (lymph nodes only)
o Mycoplasmal
infection
o
Pneumocystis jiroveci (formerly P. carinii)
Rheumatological
o Juvenile
RA
o
Kikuchi's lymphadenitis (lymph nodes only)
o Sjögren's
syndrome
o Wegener's
granulomatosis
Haematological malignancy
o Hodgkin
lymphoma
o Non-Hodgkin
lymphoma
o Splenic
lymphoma
Hypersensitivity
Occupational metals
o Aluminium,
Berylliosis
o Titanium
o Zirconium
Organic antigens producing hypersensitivity pneumonitis
o Actinomycetes
o Atypical
mycobacterial
antigens
o
Fungi Mushroom spores
o
Other bio aerosols
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 27
link to page 19
Medical Services
Inorganic antigens producing hypersensitivity pneumonitis
o Isocyanates
o Pyrethrins
o Drug
reaction
Other
o
Inflammatory bowel disease
o
foreign body aspiration or inoculation
o granulomatous
hepatitis
o
granulomatous lesion of unknown significance
o
lymphoid interstitial pneumonia
Investigations
Because the cause of sarcoidosis is unknown, one can never be absolutely
confident of the diagnosis, which is always one of exclusion. However, the
finding of non-caseating granulomas in two or more organs is considered
diagnostic. Cultures and special stains for tuberculosis and deep-seated fungal
infections should be taken to rule out infection as the cause of granulomas.
Close examination should also be made for foreign bodies and malignancy,
both of which can lead to a granulomatous reaction.
Serum angiotensin-converting enzyme (ACE) levels
In 1976, Lieberman reported that ACE level was elevated in the blood of some
patients with sarcoidosis.
Determining the significance of the ACE level in sarcoidosis can be difficult for
a variety of reasons.
Sixty per cent of patients with acute disease will have elevated values, whilst
only 10 per cent of patients with disease for more than 2 years will continue to
have an elevated level.
The ACE level will decrease in response to treatment or disease resolution,
and it has therefore been proposed as a marker for disease activity.
Tests of the lung
Bronchoalveolar lavage: findings can be characteristic in sarcoidosis. The
finding of increased lymphocytes, especially an increased CD4 to CD8 ratio,
has been interpreted by some groups as enough to make the diagnosis of
sarcoidosis, and in a patient with a compatible clinical history and no evidence
for infection or malignancy, the lavage findings may be considered sufficient.
Bronchoscopy: includes a transbronchial biopsy showing non-caseating
granulomas. In over 60 per cent of patients with a stage 1 chest radiograph the
biopsy should be positive, rising to 80 per cent in patients with stage 2 or 3
disease.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 28
Medical Services
Transbronchial needle aspiration: has recently been used to sample hilar
lymph nodes, but raises the problem of incomplete sampling in patients with a
malignancy and granulomatous response to the lesion.
Mediastinoscopy and video-assisted thoracoscopy provide a minimally
invasive method to obtain more tissue.
Gallium scan can reveal increased activity in patients with sarcoidosis.
Unfortunately, interpreting the uptake in the lung may be difficult as it is non-
specific and occurs with other inflammatory lung diseases. It also rapidly
returns to normal with corticosteroid therapy. On the other hand, the uptake in
the parotid and conjunctiva (the ‘panda’ sign) and the uptake in the hilar nodes
(the ‘lambda’ sign) are fairly characteristic for sarcoidosis and are useful
confirmation in difficult cases.
Other tests
The
Kveim–Siltzbach agent is a suspension of spleen tissue from a patient
with confirmed sarcoidosis. Six weeks after an intradermal injection of the
agent, the site is inspected for a reaction, which will occur in over 60 per cent of
patients with acute sarcoidosis. On biopsy, the reaction will show non-
caseating granulomas, consistent with sarcoidosis. Properly prepared Kveim–
Siltzbach agent has a less than 1 in 500 chance of causing a false positive.
However, because of the difficulties in preparing the agent and concerns
regarding the risk of transmission of an infectious agent, the test is rarely used
except in those centres with a well established reagent.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 29
link to page 19
Medical Services
Management
The natural course of sarcoidosis is unclear, since corticosteroids are
normally used to treat symptomatic patients. For the patient with no
symptoms on presentation, the prognosis is often good and no treatment
is indicated. This also applies to patients in whom spontaneous resolution
can be anticipated. Spontaneous resolution commonly occurs within a
year or two of diagnosis, but the disease can also take a chronic form,
with symptoms for many years. The concept of acute disease, which lasts
for less than 2 years, as opposed to chronic disease has been a useful
method for considering patients, especially in terms of therapy.
The table below lists several factors associated with resolution within 2 to
5 years as well as those predicting chronic disease.
Table 3
Organ
Acute
Chronic
Chest radiograph
Stage 1
Stage 4
Skin
Erythema nodosum
Lupus pernio
Eyes
Anterior uveitis
Posterior uveitis
Pars planitis
Joint involvement
Bone cysts
Calcium metabolism
Hypercalcaemia
Renal stones
Cardiac
Cardiomyopathy
Neurological
Cranial seventh nerve palsy
Central nervous system mass
Sinus
Sinus involvement
The major indication for therapy in sarcoidosis is symptoms.
Hypercalcaemia should be treated, even if the patient is asymptomatic.
An eye examination should be performed in all patients with sarcoidosis.
Uveitis may be misdiagnosed as sicca (dry eyes). The former will require
anti-inflammatory agents, while the latter will only need a wetting agent.
If possible, treatment should be topical. Corticosteroid creams and eye
drops are effective if inflammation is superficial.
It is not clear whether corticosteroids change the natural course of the
disease. Early randomized trials found no difference in the long-term
outcome of patients who received corticosteroids compared with controls.
A British Thoracic Society randomized study did demonstrate a small
benefit for corticosteroids over placebo for patients with persistent, but
not severe, disease. One of the difficulties in assessing this and other
trials is that the more severely affected patients were treated with
corticosteroids and excluded from the study.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 30
Medical Services
Once systemic steroids are initiated a prolonged course is usually
necessary.
In the beginning, doses may be changed every 1 to 3 months, but after a
patient remains stable on a lower dose (equivalent to less than 10 mg of
prednisolone per day), tapering may be prolonged. The use of alternate-
day corticosteroids is strongly advocated by some, but others are less
enthusiastic. Rarely will alternate-day therapy be sufficient for initial
control of the disease.
The toxicity of corticosteroids is well known. Unfortunately, most patients
will require more than a year of treatment.
Several alternatives to systemic corticosteroids have been proposed over
the years.
Table 4
Drug
Dosage
Efficacy
Toxicity
Usage
(%)
Prednisone/
5–40 mg/day
90
Weight gain, diabetes, hypertension,
Acute, chronic,
osteoporosis, psychiatric
refractory
prednisolone
Methotrexate
10–25 mg once a week
60–80
Haematological, gastrointestinal, Chronic,
lung, hepatic, mutagenic
refractory
Hydroxychloroquine
200–400 mg/day
30–50
Gastrointestinal, retinal
Acute, chronic
Azathioprine
50–200 mg/day
50–80
Haematological, gastrointestinal, Chronic,
carcinogenic, mutagenic
refractory
Pentoxyfylline
400 mg three times a
50
Gastrointestinal
Acute
day
Cyclophosphamide
50–150 mg/day orally,
80
Gastrointestinal, haematological,
Chronic,
refractory
500–2000 mg every 2
carcinogenic, bladder, teratogenic
weeks intravenously
Thalidomide
50–100 mg/day
80
Teratogenic, somnolence, peripheral
Chronic,
neuropathy
refractory
The commonly prescribed antimalarial agents
chloroquine and hydroxychloroquine possess anti-inflammatory activity with their major
toxicities being eye and gastrointestinal. Because hydroxychloroquine,
especially at 400 mg a day or less, is unlikely to cause eye toxicity, it is
more frequently prescribed. However, some experts feel chloroquine is a
more effective agent. These drugs concentrate in the skin and are most
efficacious for skin disease and hypercalcaemia. They are less
successful in the treatment of pulmonary disease.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 31
Medical Services
In sarcoidosis,
methotrexate has been most studied as a treatment for
chronic disease. This probably reflects the fact that it may require 6
months for the drug to become effective. The usual dose is 10 to 15 mg
orally each week, adjusted if this proves toxic. Acute toxicity including
mucositis and nausea can be minimized with supplements of folic acid at
1 mg/day. The long-term toxicity of methotrexate can include
hypersensitivity pneumonitis and cirrhosis. The latter is a concern,
because 50 per cent of patients with chronic disease will have sarcoid
granulomas in a liver biopsy, and thus liver biopsies are recommended
every 2 years for patients requiring the drug long term.
The response rate to methotrexate in chronic sarcoidosis is 60 to 80 per
cent. Most patients who respond can be treated with methotrexate alone.
Approximately 20 per cent of patients will require additional low-dose
corticosteroids. In most patients skin lesions can be easily controlled with
methotrexate, but studies have also reported benefit for disease in the
lungs, eyes, and nervous system.
Azathioprine has been used for many years as an immunosuppressant
for patients receiving solid-organ transplants and those with idiopathic
pulmonary fibrosis. However, its use in sarcoidosis has been more
sporadic, usually reserved for chronic cases. Its major side-effects are
gastrointestinal and haematological.
Other drugs have been used for refractory sarcoidosis.
Cyclophosphamide is used in the treatment of many
vasculitic diseases and has been reported as very useful in
neurological and cardiac sarcoidosis, but it has more
gastrointestinal, haematological, and bladder toxicity than
methotrexate or azathioprine.
Cyclosporin has been used with limited success in some
neurological cases. A recent randomized trial failed to show
additional benefit over corticosteroids alone in patients with
pulmonary sarcoidosis. The drug is relatively expensive,
causes hypertension and renal failure, and requires blood
levels to be monitored.
Pentoxyfylline has been shown by one centre to provide
some benefit in acute sarcoidosis. It is associated with
significant gastrointestinal toxicity, which is dose dependent.
There is no single treatment for all patients with sarcoidosis.
It is important to determine whether the patient requires treatment.
The decision to treat is usually based on the patient’s symptoms.
The clinician needs to determine the extent of the symptomatic disease
and whether the disease is acute or chronic. Asymptomatic or minimally
symptomatic patients with hypercalcaemia, cardiac, or central nervous
system disease may require therapy to prevent life-threatening
complications.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 32
Medical Services
The use of systemic therapy usually means corticosteroids first. However,
over time, the patient and the physician may need to seek alternatives.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 33
Medical Services
Prognosis
The course of sarcoidosis is variable, ranging from self-limiting acute
disease to a chronic debilitating disease that may result in death.
the majority of cases will resolve within 2 to 5 years
Approximately 25 per cent of patients will develop residual fibrosis
10-30% of patients have a more chronic or progressive course.
For the patient with chronic disease, treatment can usually palliate the
symptoms. However, organ failure, including eye, liver, cardiac, or
respiratory, can occur as a result of disease.
The mortality rate is 1-6%.
Sarcoidosis can lead to death from severe involvement of lung
parenchyma leading to pulmonary fibrosis and respiratory failure and
from myocardial involvement leading to arrhythmias and cardiac
failure
Organ transplantation has been performed successfully in patients with
sarcoidosis. Although sarcoidosis lesions can occur in the new organ,
organ failure due to recurrent sarcoidosis is unlikely.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 34
Medical Services
Main Disabling Effects
Respiratory disease
As 90% of cases involve the lungs the common disabilities arising from
sarcoidosis are due to impaired lung function.
Shortness of breath
A dry cough that doesn't bring up phlegm, or mucus
Wheezing
Pain in the middle of the chest that gets worse when breathing
deeply or coughing (rare).
However as only in advanced cases will the oxygen levels be reduced by
exercise the level of disability due to pulmonary sarcoidosis itself, in the
majority of patients means significant disability is unlikely.
Where the patient is requiring treatment for more advanced or symptomatic
disease any disability is likely to arise either from the treatment or any extra
pulmonary manifestation of the disease.
Sarcoidosis may cause general symptoms, including:
Uneasiness, feeling sick (malaise), an overall feeling of ill health
Tiredness, fatigue, weakness
Loss of appetite or weight
Fever
Night sweats
Sleep problems
Non - Respiratory
Ocular involvement occurs in 25% of cases with uveitis being the most
common manifestation causing blurred vision and photobia.
Arthritis is reported in 25 – 50% with ankle, knee, wrist and elbow involvement
being most common. Chronic arthritis can occur.
Skin involvement may cause itching, tender nodules (erythema nodosum) or
sores on the nose, nasal passages, cheeks, ears, eyelids, and fingers in
lupus pernio.
While most other systems (including gastro-intestinal, bone, neurological
renal and cardiac can be involved in general they are relatively rare (5%) and
their effects have to be considered on an individual basis.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 35
Medical Services
Appendix A Management of non-respiratory TB
Meningeal TB
Patients with active meningeal TB should be offered:
a treatment regimen, initially lasting for 12 months, comprising
isoniazid, pyrazinamide, rifampicin and a fourth drug (for example,
ethambutol) for the first 2 months, followed by isoniazid and
rifampicin for the rest of the treatment period
a glucocorticoid at the normal dose range
adults – equivalent to prednisolone 20–40 mg if on rifampicin,
otherwise 10–20 mg
children – equivalent to prednisolone 1–2 mg/kg, maximum
40 mg
with gradual withdrawal of the glucocorticoid considered, starting
within 2–3 weeks of initiation.
Clinicians prescribing treatment for active meningeal TB should
consider as first choice:
a daily dosing schedule
using combination tablets
Peripheral lymph node TB
For patients with active peripheral lymph node tuberculosis, the first
choice of treatment should be the standard recommended regimen:
use a daily dosing schedule
include combination tablets
Patients with active peripheral lymph node TB who have had an affected
gland surgically removed should still be treated with the standard
recommended regimen.
Drug treatment of peripheral lymph node TB should normally be stopped
after 6 months, regardless of the appearance of new nodes, residual
nodes or sinuses draining during treatment.
Bone and joint TB: drug treatment
The standard recommended regimen should be planned and started in
people with:
active spinal TB
active TB at other bone and joint sites
Clinicians prescribing treatment for active bone and joint tuberculosis
should consider as first choice:
a daily dosing schedule
using combination tablets
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 36
Medical Services
A computed tomography (CT) or magnetic resonance (MR) scan should
be performed on patients with active spinal TB who have neurological
signs or symptoms. If there is direct spinal cord involvement (for example,
a spinal cord tuberculoma), management should be as for meningeal TB
Bone and joint TB: routine therapeutic surgery
In patients with spinal TB, anterior spinal fusion should not be
performed routinely.
In patients with spinal TB, anterior spinal fusion should be
considered if there is spinal instability or evidence of spinal cord
compression.
Pericardial TB
For patients with active pericardial TB, the first choice of treatment should
be:
the standard recommended regimen use a daily dosing schedule
include combination tablets
In addition to anti-TB treatment, patients with active pericardial TB should
be offered:
for adults, a glucocorticoid equivalent to prednisolone at
60 mg/day
for children, a glucocorticoid equivalent to prednisolone
1mg/kg/day (maximum 40 mg/day)
with gradual withdrawal of the glucocorticoid considered, starting within
2–3 weeks of initiation.
Disseminated (including miliary) TB
For patients with disseminated (including miliary) TB, the first choice of
treatment should be the standard recommended regimen
use a daily dosing schedule
include combination tablets
Treatment of disseminated (including miliary) TB should be started even
if initial liver function tests are abnormal. If the patient’s liver function
deteriorates significantly on drug treatment, advice on management
options should be sought from clinicians with specialist experience of
these circumstances.
Patients with disseminated (including miliary) TB should be tested for
central nervous system (CNS) involvement by:
brain scan (CT or MRI) and/or lumbar puncture for those with CNS
signs or symptoms
lumbar puncture for those without CNS signs and symptoms.
If evidence of CNS involvement is detected, treatment should be the
same as for meningeal TB.
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 37
Medical Services
Other sites of infection
For patients with:
active genitourinary TB, or
active TB of any site other than:
respiratory system
CNS (typically meninges)
peripheral lymph nodes
bones and joints
pericardium
disseminated (including miliary) disease
the first choice of treatment should be the standard recommended
regimen
use a daily dosing schedule
include combination tablets
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 38
Medical Services
References
1 Health Protection Agency
2 Department of Health
3
erck Manual
M
4
NICE Guidelines 033 Clinical diagnosis and management of tuberculosis, and measures for
its prevention and control March 2006
5 Oxford Textbook of Medicine
6 http://www.nhlbi.nih.gov/health/dci/Diseases/sarc/sar_signsandsymptoms.html
EBM – Tuberculosis and Sarcoidosis
Version 1 Final
MED/S2/CMEP~0053 (k)
Page 39
Document Outline