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Churg-StraussSyndrome
by
C. Thomas
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Prof. Dr. Carlos Thomas
former director of the Medical Centre for
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Churg-Strauss Syndrome (CSS)
History
– The pattern of inflammation is not always granulomatosis.The disease can also manifest histologically as necrotising or exclusively as eosinophilic cell infiltration.
– Polyangiitis is only present in a (rather small) proportion
of patients with Churg-Strauss syndrome, and only in
the third stage of the disease.
– It is incomprehensible why the names of the first describers should not be used.
In 1951 the pathologists Jacob Churg and Lotte Strauss described a clinical picture which was characterised by the histomorphological findings of a thrombosing inflammation
of the small blood vessels. Clinical pictures had been described even earlier which one would today assign to CSS,
but which were then considered to be variants of polyarteritis nodosa.
In the Chapel Hill proposal (2013) the authors explicitly
point out that it is intended only for the nomenclature of the
vasculitides and not for the systematics. Nevertheless, it is
used by numerous authors as a subclassification of the
vasculitides. However, this does not take into account the
fact that several diseases (thromboangiitis obliterans,
various cutaneous vasculitides) are not enumerated in the
Chapel Hill proposal 27, 32.
Definition of terms
Churg-Strauss syndrome (ICD-10 M30.1) belongs to the
spectrum disorderof immunologically-mediated diseases
(autoimmune disease). It progresses in stages with very characteristic symptomatology. Only in the third and final stage
do the typical changes to the small blood vessels occur – in
the form of vasculitis – and justify the designation vasculopathy. It is typical that CSS is always accompanied by bronchial asthma which is known clinically several years or
decades before the CSS.
The International Coding of Diseases (ICD 10) is also problematic: Churg-Strauss syndrome is – under ICD-10 M
30.1 – counted as one of the systemic connective tissue
disorders (including autoimmune diseases). However, the
two disease designations are problematic: polyarteritis with
lung involvement and allergic granulomatosis.
Nomenclature - Synonyms - Coding
Numerous designations have been proposed for ChurgStrauss syndrome, but these do not apply to all cases: allergic granulomatosis with vasculitis, granulomatous angiitis,
allergic vasculitis, eosinophilia granulomatosis with polyangiitis (EGPA) and others. The disease is still best characterised by the name of the first people to describe it. Even in
the case of other vasculitides, the Chapel Hill Consensus
Conference did not adopt the names of the first describers
for the nomenclature of the vasculitides (2013):27.32:
Level of awareness of Churg-Strauss syndrome
With the exception of pulmonologists, allergists and rheumatologists, the disease is not known in detail in the clinical field. This also applies to gastroenterologists, neurologists and dermatologists. Similarly, pathologists only rarely
arrive at the correct diagnosis: In most cases this is "eosinophilic enteritis" or "atypical Crohn's disease". Disease
progressions lasting years and decades – without diagnosis
and with a corresponding loss of quality of life – are therefore the rule. This low level of awareness is explained –
certainly without justification – by the rarity of the disease.
Wegener's granulomatosis → Granulomatosis with polyangiitis (GPA)
Churg-Strauss syndrome → eosinophilic granulomatosis
with polyangiitis (EGPA)
Purpura Henoch-Schönlein → IgA vasculitis
Goodpasture's syndrome → Anti-GBM disease.
Clinicopathological literature references
After the original publication by Churg and Strauss, the
following details are repeatedly emphasised in textbooks
and relevant publications:
1 The modern designation is "eosinophilic granulomatosis
with polyangiitis" (EGPA)27, 32
2 Churg-Strauss syndrome is a vasculopathy (or vasculitis) 43, 44
3 Churg-Strauss syndrome is included in the spectrum disorder of the ANCA-associated vasculopathies44
4 With an incidence of 1 to 2 diseases per 1 million inhabitants per year, the disease is very rare22.
5 The diagnosis has to be made histologically by means of
a biopsy. Here, confirmation of vasculitis is crucial.
6 Blood eosinophilia is always present.
Criticism. The names of diseases and syndromes are determined by the rules of general pathology. The disease designations should be
– internationally known and recognised,
– of pathological-anatomical, diagnostic, prognostic and
therapeutic relevance.
– cover the entire course of the disease.
– In the case of a disease (Morbus), a particular cause must
be identifiable. If the pathogenesis is polyaetiological,
one then speaks of a syndrome.
These requirements are not fulfilled by the new proposal
for Churg-Strauss syndrome. The objection relates to the
following aspects of the designation eosinophilic granulomatosis with polyangiitis:
3
Churg-Strauss-Syndrome
ment of existing bronchial asthma are also discussed. In
most cases, however, these are individual observations
which it has not been possible to convincingly confirm.
7 The typical changes to the skin include small reddish lesions that are considered to be palpable haemorrhaging47, 65.
These statements should today be considered only partially
correct or even wrong. At least they are debatable.
Formal pathogenesis
The various findings in CSS can be attributed with respect
to their formal pathogenesis to two mechanisms:
– the toxic effect of the eosinophils and
– vasculitis.
Evaluation of statistical data
In the literature there are numerous examples of cumulative
statistics on the topic of Churg-Strauss syndrome. These
provide information on frequencies, e.g. incidence, age and
sex distribution, the observed findings, prognosis and treatment outcomes. The problem with these lists is that no
details are provided of the composition of the collective
analysed. In the introduction to the publications, CSS is
defined as vasculitis, but the stage of the disease and the
ANCA determination are not highlighted. One therefore
has to ask oneself if only stage 3 (only in this stage of the
disease is vasculitis present) or whether all patients with
Churg-Strauss syndrome were evaluated. For this reason it
is only possible in most cases to compare the figures of the
evaluated findings with one another. Details of absolute
values are not possible, however.
■ The eosinophilic granulocytes migrate – after stimulation of the haematopoietic eosinophilic series by the cytokine IL-5 – into the surrounding tissue (tissue eosinophilia). Here they survive – until disintegration of the cells –
for four weeks. Due to the breakdown of the cell, the specific eosinophilic granules are released. Their subsequent
destruction forms various proteins (major basic protein,
eosinophilic peroxidase, eosinophil-derived neurotoxin
[EDN] and eosinophilic cationic protein)50.
The most important component is the eosinophilic cationic
protein, which is secreted particularly in inflammation.
This compound has a local cytotoxic effect on certain bacteria (anti-bacterial) and on some parasites (anthelmintic),
but also on the body's own cells (especially in the respiratory tract). The toxic effect on the body's own tissue manifests as a local inflammatory reaction (neutrophilic granulocytes and lymphocytes are also present), as cell and tissue
necrosis, as well as fibrosis of the interstitial tissue (especially in the myocardium). Tissue eosinophilia is a typical
manifestation in the second stage of CSS. The density of
the eosinophilic cell infiltrates does not correlate with the
severity of the organ damage.
General information on frequencies
CSS is quoted as being very rare, with an incidence of 1 to
2 cases among 1 million inhabitants per year. The stated
values can only hold true for the third stage of the disease
(approximately 3 to 5 years), the course of which is considerably shorter, and not for all forms of CSS. If one evaluates the obligatory concomitant disease bronchial asthma as
a collective, a significantly higher incidence can be expected (according to literature references 64 CSS cases/1 million asthmatics/year) 41, 44, 53, 57, 67.
■ ´Vasculitis is a typical finding that only manifests itself
in the third stage of CSS. It affects the small blood vessels
(in particular the venules) throughout the organism. The
main areas affected during this phase of the disease are the
CNS and coronary arteries, as well as the pulmonary vessels. The thrombosising inflammation of the vessels leads
to poor blood flow in the periphery: the consequences are
heart attacks, which ultimately represent the cause of death
of inadequately treated CSS. These changes can be detected
histopathologically (e.g. by means of an endomyocardial
biopsy), as well as with imaging techniques: computed
tomography of the lungs shows the formation of foci.
Age distribution
The age of the patients afflicted by this disease fluctuates
between 7 and 70 years, with a mean average age of 40. In
these figures it should be taken into account that the prodromal disease stage 1 is largely asymptomatic. The beginning of CSS can therefore only be guessed in most cases. It
is also striking that in some publications, the incidence collective is specified as 100,000 inhabitants4.18.
Gender distribution
Here too, the details available are not uniform. The sex
ratio fluctuates in the relevant publications between 1 to 3
men to 1 woman.
Pathology
Causal pathogenesis (aetiology)
In various organs, changes can occur which are the consequence of an allergic aetiology. These range from tissue
eosinophilia to the severest form of damage, allergic vasculitis with its sequelae (circulatory disorders, infarct). In
addition, other tissue damage occurs (e.g. in the skin, lungs
or the peripheral nervous system), which is fairly characteristic of CSS.
Churg-Strauss syndrome (CSS) is an immunological disease (autoimmune disease). The causal pathogenesis (aetiology) is largely unknown. As with many allergic diseases, a
multifactorial aetiology can be assumed for this syndrome
as well. In the relevant literature, various toxic, drug or
inflammatory causes are described. Changes in the treat-
4
Pathology
■ Eosinophilia
In medical routine, this designation refers to an increase in
the eosinophilic granulocytes in the peripheral blood in
veins or capillaries. Histomorphologically, two further typical findings occur in the second phase of the disease:
– Tissue eosinophilia. In the interstitial tissue of various
organs, focal accumulations of eosinophilic granulocytes
are found. As a result of the decay of these cells, an inflammatory reaction may be reinforced: the consequence of this is that other blood or inflammatory cells (neutrophilic granulocytes, lymphocytes, plasma cells, histiocytes) are found in the infiltrate. Occasionally, a granulomatous reaction dominates the morphological picture. A typical feature of the change in the intestine ("eosinophilic enteritis") is tissue eosinophilia (cardinal findings of CSS).
– Central blood eosinophilia. This finding is only rarely
considered in histopathological routine histology. This is
blood eosinophilia, which can be detected in the capillaries of organs and therefore represents a precursor stage
of tissue eosinophilia. Tissue eosinophilia and central
blood eosinophilia are of diagnostic relevance, as they
are very common in Churg-Strauss syndrome and are
not suppressed by the long-term treatment of bronchial
asthma. In some organs (e.g. in the urinary bladder),
chronic infections are very common and may mask tissue eosinophilia. The central blood eosinophilia is still
identifiable in these cases and allows a reliable diagnosis to be made.
1 Nasal cavities and paranasal sinuses
During an active phase of the disease, a serous or seromucous inflammation is the predominant feature. Granulomas
are rare. The mucous membrane shows a proliferation of
the goblet cells. The stroma displays oedematous loosening
and is infiltrated with eosinophilic granulocytes. Typical of
the allergic genesis is the band-shaped, homogeneous,
eosin-red thickening of the basal membrane of the mucosa.
After a protracted course of the disease, polyps develop,
which largely change the position of the lumen of the nasal
cavity. These changes (which are often combined in the
literature as ENT findings) occur as the earliest signs of
CSS. The findings already occur in the first phase of the
disease (prodromal phase). Furthermore, they are an early
sign of relapse in the remission phase.
2 Pulmonary changes
Changes in the lungs are typical of CSS, although they differ in the second and third stage of the disease. They are
accompanied by the typical histomorphological changes of
bronchial asthma.
In the second stage the eosinophilic cell infiltration of lung
parenchyma and pulmonary alveoli are the predominant
features. This finding corresponds radiologically to
Löffler's syndrome. In the thoracic image one sees a discreet, diffuse cloudiness. Bronchioalveolar lavage shows a
strong increase (up to 65%) in the eosinophilic granulocytes.
Vasculitis can be detected in the third stage. The formation
of foci occurs, which can be identified particularly impressively by unenhanced computed tomography. These may be
infarcts or confluent granulomas. The latter consist of circumscribed collections of various inflammatory cells (neutrophilic granulocytes, lymphocytes, plasma cells, epithelioid cells), as well as central necroses31, 65.
Eosinophilic granulocytes can also be part of an inflammatory (Crohn's disease) or neoplastic disease (Hodgkin's
lymphoma) – combined with other cells (lymphocytes,
plasma cells, macrophages, epithelioid cells and giant
cells). In most cases these are only isolated eos.
■ Allergic vasculitis
3 Intestinal changes
Histologically, diffuse infiltration of the intestinal wall with
eosinophilic granulocytes is seen. Granulomas, such as
those found in Crohn's disease, are absent. This morphological finding is the correlate to the cardinal symptom of
CSS: treatment-resistant diarrhoea47, 63.
The detection of allergic vasculitis in CSS occurs only in
the third stage and forms part of the spectrum disorder of
allergic microangiopathies (including Wegener's granulomatosis and polyarteritis nodosa). The changes occur in the
small blood vessels (especially the venules). Accordingly,
all organs can be affected.
4 Skin changes
As with any allergic genesis, various changes occur in the
skin. Typical of CSS is the detection of small red spots
which are rich in blood on the cut surface. Histologically
this is not – as described in the literature – palpable punctate haemorrhaging, but circumscribed sub-epidermal
capillary proliferations. Eosinophilic granulocytes are
absent or found to be very sparse. Furthermore, other cutaneous findings occur which indicate an allergic genesis,
but which occur not only in CSS: granulomas, vascular
changes of the type found in leucocytoclastic vasculitis,
small itchy skin infiltrates, urticaria-type changes etc 46.
The histopathological picture shows a transmural inflammatory infiltration with eosinophilic granulocytes, as well
as isolated epithelioid cells, multinucleated giant cells and
neutrophilic granulocytes. Fibrin exudates or fibrinoid wall
necroses – as in polyarteritis nodosa – do not belong to the
typical CSS changes.
The inflammatory infiltrate spreads to the lumen and the
immediately adjacent interstitial tissue. As a result of the
relocation of the vessel lumen, organ necroses occur which
can subsequently coalesce and centrally liquefy37, 60, 61.
5
Churg-Strauss-Syndrome
present. Impressive black-and-white images can be found
in the original work by Churg and Strauss.
5 Changes in the nervous system
Peripheral nerves display mildly inflamed infiltration in the
semi-thin section, as well as signs of demyelination. These
changes represent the morphological correlate to clinical
mono- or polyneuropathy. In 60% of cases, inflammation
of the vasa nervorum is detected. In the third stage of the
disease, inflammatory changes occur in the small blood
vessels (angiitis) of the central nervous system, which are
associated with relocation of the lumen. Minor infarcts
occur as a consequence42, 54, 55.
Clinical presentation and course
Various organs display changes that indicate an allergic
genesis. These range from tissue eosinophilia to allergic
vasculitis. Furthermore, changes occur which are organospecific, for example in the skin and nervous system.
1. Disease stage (prodromal phase)
During this stage, the CSS is masked by the long-term therapy of bronchial asthma with corticosteroids. It therefore
remains clinically unrecognised. The onset and duration are
usually unknown. The cardinal symptoms which are characteristic of the second stage of the disease are absent. In
most cases there is only serous inflammation of the mucosa
of the nasal cavities and paranasal sinuses ("wet nose").
6 Heart changes
In the third stage of the disease, the following cardiac
changes occur:
– coronaritis with the described histomorphological picture of allergic vasculitis. The changes can lead to the formation of a coronary aneurysm20. 45.
– inflammatory infiltration of the myocardium. In the early phase there are large amounts of eosinophilic granulocytes in the interstitial tissue. Interstitial fibrosis occurs
at a later stage30.48,62
The changes to the heart can be very pronounced and lead
directly to death.
2. Disease stage (eosinophilic cell phase)
During this phase, patients with bronchial asthma display
the typical findings (cardinal symptoms) which indicate
CSS. As an expression of an immunological disease, eosinophilic cell infiltrates dominate the morphological picture.
While tissue eosinophilia is very characteristic, blood eosinophilia – as the consequence of the long-term therapy of
the bronchial asthma with corticosteroids – may be absent.
The tissue eosinophilia remains unaffected by the generally
low-dose cortisone therapy. The duration of this stage of
the disease may be years or even decades. Tissue eosinophilia can occur in virtually every organ during this phase;
however, some are affected more than others and induce the
classical cardinal symptoms of CSS 43.
7 Urinary system
The kidneys are only rarely affected. They occur in 47% of
patients with ANCA-positive CSS. Morphologically, this is
progressive intracapillary glomerulonephritis (ANCAassociated glomerulonephritis). Antibodies are present
which are directed against neutrophilic granulocytes.
Furthermore, pANCA (against myeloperoxidase) occur,
which can be depicted in the immunofluorescence. The kidney changes may be associated with pulmonary haemorrhaging (Goodpasture's syndrome).
■ Pulmonary findings. The involvement of the lungs is
one of the most common findings of CSS. Initially this is
usually a volatile infiltrate of the lungs during the second
stage of the disease which is detected with imaging techniques. It is often referred to by the term Löffler infiltrate
(ICD-10 J82). Histologically, eosinophilic cell infiltration
of the interstitial lung tissue is present. In the x-ray or noncontrasted computed tomography, a rapidly changing
image with diffuse clouding is seen 5, 9, 69.
One little-known aspect is that the urinary bladder can also
be affected in the form of irritable bladder. The typical
changes (pronounced focal infiltration of eosinophilic granulocytes) occur predominantly in the tunica muscularis
propria. This section of the urinary bladder wall is, however, only rarely biopsied. In the mucous membrane the
eosinophilic granulocytes are mostly masked by the presence of chronic, non-specific inflammation with lymphocytes
and plasma cells. In these cases, the detection of central
eosinophilia is diagnostically relevant.
■ Intestinal findings. Focal eosinophilic cell infiltrates
are found in the various wall layers of the small and large
intestine. A granulomatous structure is rare ("atypical
Crohn's disease"). Among the clinical findings, chronic
refractory diarrhoea predominates. This results in severe
impairment of the quality of life 47.
8 Further organ changes
In various organs, eosinophilic cell infiltrates and symptoms of vasculitis can occur. It is not well known that the
teeth can also be affected. In these cases there is an increased susceptibility to caries, as well as radiographically
detectable homogenisation of the dentin layer. Severe toothache and tooth loss can be the consequence. In addition
to the histomorphological changes of allergic vasculitis,
vessel-independent granulomas with necroses can also be
■ Nervous system. The peripheral nervous system is particularly affected in the form of symmetrical polyneuropathy (mononeuritis is less common). In most cases the nerve
changes manifest in the lower extremities. Patients complain of numbness which is initially plantar and propagates
in the direction of the knees. Shooting pains are less com-
6
Disease Stage
mon. In addition, these findings may occur in the fingertips
and oral cavity.
are also found in other systemic diseases and are especially
typical of Wegener's granulomatosis in an advanced stage
of the disease. The clinical findings include a severe chronic cough with small quantities of mucoid sputum31, 34, 64.
A further clinical manifestation (which is rarely assigned to
CSS, however) is muscle cramps. These are often confused with the classic nocturnal leg cramps, but display certain peculiarities. They occur not only at night and are not
restricted to the calf region. As a rule, the cramps are triggered by strains on the muscles. It is also very characteristic
that they are not affected by the administration of magnesium. Very typical are the cramps of the thumb muscles,
which are associated with characteristic contraction
("obstetrician's hand") – as in hypocalcaemia tetany. Other
locations, such as cramps of the abdominal wall muscles,
are not unusual.
■ Central nervous system. Each CNS region can be
affected by vasculitis. Accordingly, the clinical findings are
varied and uncharacteristic3, 7.
■ Cardiac changes. During this phase of the disease, two
particularly typical changes are found in the heart: coronaritis and interstitial myocarditis. As a sign of heart muscle
disease that has existed for some time, interstitial fibrosis
with heart failure is a clinical correlate. Due to the relocation of the lumen of the coronary arteries caused by inflammation, it is possible that a myocardial infarction may
occur. Evidence of cardiac involvement should be seen as
an unfavourable prognostic sign which – especially in the
case of insufficient therapy – results in death after a relatively short period of just a few months16, 23, 24, 29, 30, 48.
■ Skin changes. These also belong to the classic cardinal
symptoms in the second stage of the disease. In addition to
a wide range of uncharacteristic skin efflorescences (e.g.
urticaria-like images), typical findings occur, although
these usually remain pathogenetically undetected.
Relatively sharply demarcated reddish changes occur,
which are approximately 2 cm in size and are found mainly
on the extremities. Histologically, these are not – as often
described in the literature – haemorrhages, but subepidermal capillary proliferations. The spots remain unchanged
over a prolonged period or become slightly brighter or take
on a brownish-red colour8, 47, 65.
■ Kidney changes. Changes to this organ only occur in
ANCA-positive CSS patients. This is glomerulonephritis.
All age groups can be affected, usually the fifth decade of
life. The renal changes are usually considered to be clinically mild: slight haematuria and albuminaemia are common. A percutaneous renal biopsy shows focal-segmental
or diffuse, necrotising glomerulonephritis. In the interstitial
tissue an oedema is found with cellular infiltration. These
are – in addition to isolated lymphocytes, neutrophilic granulocytes and plasma cells – eosinophilic granulocytes.
Tubule changes are minor and not specific36.
■ Changes to the urinary tract.
Glomerulonephritis is known, although it occurs only in
pANCA-positive patients. One aspect which is not described is irritable bladder caused by Churg-Strauss syndrome
(overactive urinary bladder/OAB syndrome: urge incontinence, frequent micturition [pollakisuria]). This is characterised by a strong urge to urinate which cannot be treated
with the usual methods (parasympatholytics [darifenacin],
Botox, Gepan).
■ Rarer organ findings often remain unconsidered in the
relevant literature. Indications are usually only found
among the details of the patients in the self-help groups. To
quote just a few examples:
3. Disease stage (vasculitic phase)
Only in this phase do the classic changes to the small blood
vessels (usually venules) occur in the form of vasculopathy.
Each organ can be affected, although the vascular changes
are found particularly frequently in the lungs, central nervous system and heart. The disease leads to death after a
few years if the therapy is insufficient or no therapy is carried out. Lethal causes are changes to the heart (coronaritis,
myocarditis) or necroses in the central nervous system 43.
■ Urinary system. The rare urological and nephrological
findings include an irritable bladder. An infected urinary
bladder leads to pronounced urgency with very frequent
micturition. These findings cannot be treated by the usual
therapeutic measures (Emselex, Gepan, Botox) and lead to
a significant impairment of the patient's quality of life 69.
■ Dental changes. Increased susceptibility to caries and
pulp necroses may result in severe toothache.
Radiographically, homogenisation of the dentin layer is
observed 69.
■ Ocular changes. All parts of the eyes – albeit very rarely – can be affected. There are descriptions of occlusion of
the retinal artery and an orbital pseudotumour 1.
■ Pulmonary changes. In the third stage of the disease,
the clinical and computed tomography detection of pulmonary infiltrates predominates. Opacities – some of which
are isolated, others of which are confluent – with central
necroses develop. These are the consequence of vasculitides with peripheral circulatory disorders (infarcts).
Laboratory findings. These include haematological and
immunoserological investigations, as well as the detection
of general inflammation parameters (erythrocyte sedimentation rate and C-reactive protein are increased).
Haematological analyses show mild anaemia and leucocytosis. The number of eosinophilic granulocytes is often greatly increased (1,500 to 29,000 eosinophilic
If kidney changes occur at the same time, one speaks of
pulmorenal syndrome. Goodpasture's syndrome also
belongs to this spectrum disorder. Pulmonary vasculitides
7
Churg-Strauss-Syndrome
granulocytes/µl). Among the immunoserological findings,
the detection of neutrophilic antibodies (pANCA) is of particular relevance. These represent a sub-classification criterion of the vasculitides (ANCA-asociated vasculitis), but
are only detectable in 40% of CSS cases 34, 20, 49, 56.
(morphological correlate of diarrhoea). In the case of polyneuropathy, the examination of nerves (peroneal nerve)
shows an inflammatory infiltration of the vasa nervorum,
as well as demyelination and axonal degeneration. Other
typical features are the skin changes (subepidermal proliferated capillaries) 37, 42, 61, 63.
Of diagnostic relevance is the determination of the ribonuclease eosinophilic cationic protein (ECP), which is released as the result of the degranulation of the disintegrating
eosinophilic granulocytes.
Further findings. In the second and third stages of the disease, findings may be present which are not CSS-specific:
fatigue, general weakness, tiredness, sub-febrile temperatures, muscle pain (myalgia), joint pain (arthralgia) and
others 36.
A further granular product of the eosinophilic granulocytes
is glycosilated eosinophilic protein x (EPX). This indicates
the degree of activation and degranulation of eosinophilic
granulocytes in the gastrointestinal tract. The determination
is carried out on a stool sample. Values above 15 µg/l are
considered to be pathological. EPX is cytotoxic and results
in local necroses and inflammation. The most important clinical indication of the determination is the classification of
food allergies and intolerances.
Diagnosis – Differential Diagnosis
The diagnosis is based on the detection of the cardinal
symptoms of Churg-Strauss syndrome, which are determined in a patient with a long history of bronchial asthma in
his or her anamnesis. In this process, clinical (cardinal
symptoms), laboratory-chemical (haematological analyses,
ANCA determination), imaging (non-contrasted computed
tomography of the lungs) and histopathological methods
(evidence of tissue eosinophilia and vasculitis) should be
evaluated by an investigator. It is important to note that the
findings in the case of ANCA-positive and ANCA-negative
patients can be different.
Imaging techniques. For the detection of pulmonary changes, the use of non-contrasted computed tomography is the
analytical method of choice. It is able to detect pulmonary
changes in the second stage of the disease (diffuse eosinophilic cell infiltration) and in the third stage of the disease
(vasculitis with the formation of foci) 5, 9.
In the differential diagnosis, the cardinal findings of the
CSS should be considered in particular:
1. Eosinophilia (blood and tissue eosinophilia). Blood eosinophilia is typical of allergic diseases, parasitic diseases (ascariasis, ancylostomiasis) and – in rare cases –
neoplastic disorders (eosinophilic leukaemia).
Histopathological examination. With this method, the
two main findings of CSS are determined: tissue eosinophilia and vasculitis. Through the fine-tissue examination of
an intestinal biopsy it is possible to detect a diffuse infiltration of the intestinal wall with eosinophilic granulocytes
Clinical Findings
ANCA-positive
Airways
Sinusitis
75.0%
Rhinitis
46.9%
Nasal polyposis
34.4%
Bronchial asthma
>90.0%
Pulmonary infiltrates, nodes
65.5%
Pulmonary haemorrhaging
25.0%
Cardiovascular
Peri- and myocarditis
3.1%
Cardiomyopathy
0.0%
Vaskulitis
56.3%
Peripheral nervous system
Mono/polyneuritis
34.4%
Central nervous system
Foci
15.6%
Gastrointestinal tract
Diarrhoea, tissue eosinophilia
21.9%
Skin
Efflorescences
56.3%
Blood eosinophilia
96.9%
Tissue eosinophilia (general)
87.5%
Kidney (glomerulonephritis)
47.0%
ANCA-negative
80.0%
51.7%
53.3%
>93.0%
70.0%
8.3%
21.7%
13.3%
80.0%
30.0%
11.7%
30.0%
53.3%
93.3%
88.3%
0%
8
Table: 1. Clinical findings in Churg-Strauss syndrome depending on ANCA. Modified 52
Diffrential Diagnosis – Prognosis – Therapy
– Clonal eosinophilia: acute leukaemia, myeloproliferative syndromes as classic MPD (polycythaemia) or atypical MPD (eosinophilic cell leukaemia), mastocytosis,
chronic myelomonocytic leukaemia) should be discussed.
1.1 Loeffler's syndrome (ICD-10: I42.3). This is a diffuse eosinophilic cell reaction of the lungs. It occurs in the
interstitial tissue and in the alveolar lumens. The x-ray
image shows slight diffuse opacification. This change
was initially described as a consequence of a pulmonary
passage of parasitic larvae (Ascaris lumbricoides, Ankylostoma duodenale). Today, Loeffler's syndrome is interpreted as being a local immunological reaction and is attributed to several causes.
1.2 Hypereosinophilic syndrome (HES). This clinical
picture displays a certain degree of similarity with CSS in
clinical and morphological terms, but can nevertheless be
distinguished from CSS. Clinically, the patient has no history of asthma. Histopathologically, tissue eosinophilia is
present without vasculitis. The nasal cavities, lungs and intestine are particularly affected. Other organ locations are
only rarely diagnosed due to the difficulty of obtaining
biopsy material. Here, mention should be made of the cardiac changes in particular. The bone marrow displays a distinct increase in the cells of the eosinophilic series. The
diagnosis of HES is made taking into account the findings
listed by Chusid et al 12:
– eosinophilia with more than 1,500 cells/µl that lasts longer than 6 months
– fleeting pulmonary infiltrates
– changes in the intestinal tract
– cardiac changes
– polyneuropathy
– there are no parasitic diseases or allergy.
The differential diagnostic delineation between HES and
CSS can be difficult. It is important to remember that bronchial asthma does not necessarily accompany HES. A further difference is the frequency of PNS damage (polyneuropathy) of the skin and kidneys. Confirmed vasculopathy
excludes the diagnosis of HES 58, 70.
Course. Approximately 4 to 5 months after appropriate
therapy, remission occurs. During the subsequent course,
however, there may be relapses, albeit much less often than
in CSS.
1.3 Tissue eosinophilia. This is responsible for further
cardinal symptoms:
– Diarrhoea with eosinophilic cell infiltration of the intestinal walls. A distinction is to be made between various infectious forms of diarrhoea, as well as ulcerative
colitis and Crohn's disease.
– Pulmonary findings: in these cases, various chronic
lung diseases (e.g. chronic obstructive pulmonary disease) must be considered.
– Polyneuropathy: consideration should be given to various neurological and metabolic diseases (diabetes).
– The skin changes in CSS should be distinguished from
one another in terms of their primary and secondary efflorescences.
The expected incidence is approximately 10 cases/1 million
inhabitants/year. The male sex is affected nine times more
often than the female. The age fluctuates between 20 and
50. From the formal pathogenetic aspect, the increased production of eosinophils by interleukin 5 and a prolonged survival time of these cells is debated. In the early phase, the
clinical picture is uncharacteristic (fatigue, cough, fever,
myalgia and skin exanthemas). During the subsequent
course, more or fewer characteristic signs of organ damage
in the lungs (eosinophilic cell alveolitis), intestine (diarrhoea with local tissue eosinophilia) and polyneuropathies
as a consequence of the release of the eosinophil-derived
neurotoxins occur. Skin changes also occur. In the case of
cardiac involvement, parietal thromboses (cause of thromboembolic scattering, which is the most common cause of
death) may form. Other cardiac complications are interstitial myocardial infiltrates, which can result in restrictive
cardiomyopathy 34.
1.4 Vasculitis. The differential diagnosis should exclude
other vasculitides of the medium-sized and small vessels10, 66:
▪ Polyarteritis nodosa 10,40
– ANCA-negative vasculitis
– Incidence 7 to 18 cases/million inhabitants/year. Men affected three times more often.
– Fibrinoid necrosis of medium-sized and small arteries.
Arterioles, capillaries and venules are not affected.
– Focal (segmental) involvement of the arterial wall (nodous), which at this point occupies the entire arterial
wall (panarteritis).
– Multiorgan involvement (rheumatoid arthritis), in particular the kidneys, skin, liver, gastrointestinal tract and
other organs.
– The clinical symptoms depend on the organ affected.
During the course of the disease, further findings and clinical pictures can occur, for example sinusitis, rhinitis, bronchial asthma, myalgias, arthralgias and various forms of
allergies. HES is an exclusion diagnosis:
– Conditions to be excluded are secondary eosinophilia
in parasitic infections or allergies. CSS, polyarteritis nodosa, aspergillosis, dermatitis herpetiformis should also
be considered in the differential diagnosis.
▪ Microscopic form of polyarteritis nodosa
– Necrotising inflammation of the small blood vessels (arterioles, capillaries and venules). No granulomatous reaction.
– pANCA-positive vasculitis
– Predominant involvement of the kidneys (glomerulonephritis) and lungs.
9
Grundlagen der klinischen Medizin
The daily cortisone dose can be reduced by concomitant
immunosuppressive therapy. The minimum dosage for azathioprine is 2 mg/kg/day; this is approximately 150 mg/day.
A remission is often achieved with a daily dose of 100
mg/day. If the classical forms of treatment are not sufficiently effective or tolerated, interferon therapy is suggested.
▪ Wegener's granulomatosis 6, 61, 62
– Incidence 9 cases/million inhabitants/year
– cANCA-asociated vasculitis (up to 90% positive)
– Predominant involvement of the upper respiratory tract
(granulomatous rhinitis/sinusitis) and kidneys (glomerulonephritis). Also involvement of the lungs in the advanced stage of the disease.
The typical complications of chemotherapy include changes to the blood count (leukopenia, agranulocytosis, thrombocytopenia). If chemotherapy is administered over a period of 6 years, the risk of lymphoma is increased. Long-term
treatment with cyclophosphamide can lead to the development of urinary bladder cancer.
Prognosis
The prognosis of CSS depends on early appropriate therapy
(corticosteroids, immunosuppressants) 21, 23. The prognosis is described as good if the CSS is diagnosed in the first
and second stage of the disease and is adequately treated. In
the third stage of the disease, more aggressive treatment has
to be initiated: a higher dosage of the immunosuppressive
therapy. In this way it is possible to achieve permanent remission at this stage of the disease as well.
CSS progression during the course of
the therapy
Appropriate and effective treatment should – particularly
in the second stage of the disease – result in remission.
However, in most cases this does not mean that the typical
CSS findings can no longer be detected.
– Neurological findings. Symmetrical polyneuritis, which
is a typical symptom of CSS, represents irreversible damage to the peripheral nervous system (numbness in the
plantar region and the fingertips). However, during treatment the changes to the nerves do not continue to spread.
– Intestinal findings. There is partial regression of the
severe cases of diarrhoea. Defecation is usually reduced
to 3 stools/day. The stool is mostly mushy and is accompanied by a slight urge to defecate.
– Skin findings. The skin efflorescences that occur do not
disappear even after several years: they only fade and take on a slightly brownish colour. No new efflorescences
occur during therapy.
– Pulmonary findings. Extensive pulmonary infiltrates
regress after appropriate therapy. Often a slight cough
with mucoid sputum remains.
With the Five-Factor Score, 5 prognostically unfavourable
findings are listed:
– Serum creatinine above 140 µg/L
– Proteinuria of more than 1 g/day
– Cardiomyopathy
– Gastrointestinal involvement
– CNS involvement.
Further studies have shown that the age of the patient (over
65) is also a prognostically unfavourable finding. On the
other hand, the so-called ENT findings (sinusitis, rhinitis)
are considered to be prognostically favourable.
Therapy
There are several proposals for the treatment of ChurgStrauss syndrome. The selection depends on the stage of the
disease, the severity of the disease and the organ concerned.
The medications of first choice include corticosteroids. The
treatment is usually carried out as part of the long-term therapy of bronchial asthma. However, in many cases it is too
low for the treatment of the CSS. In the case of significant
organ damage (lungs, intestines), a daily dose of 20 mg of
prednisolone/day and up brings about remission. Initial treatment can also be initiated with corticosteroid pulse therapy: on 3 consecutive days an intravenous dose of 1 g of
prednisone is administered 14, 15, 17, 19, 38, 39.
Comments on the literature references to ChurgStrauss syndrome referred to in the introduction
1. The designation "eosinophilic granulomatosis with
polyangiitis" refers only to the third stage of the disease.
2. During the first two stages of the disease, Churg-Strauss
syndrome is not vasculopathy/vasculitis, but an immunologically induced autoimmune disease. The vasculopathy
occurs only in the third stage of the disease. If this finding
is absent, then only stage 2 of the disease is present.
Disease stages 2 and 3 differ significantly from one another
in terms of their clinical picture, prognosis and therapy. In
the evaluation of a CSS collective, the two stages of the
disease should therefore be precisely defined.
Complications of corticosteroid therapy. The most
important complication of long-term corticosteroid therapy
with prednisolone is atrophy of the adrenal cortex. The consequences – if hormonal substitution is not sufficient – are
acute or chronic adrenal gland insufficiency (Addison's
disease). The threshold dose of iatrogenic Cushing is
approximately 7.5 mg of prednisolone/day. A further complication of long-term corticosteroid treatment is aseptic
bone necroses, which in their most extreme form can result
in necrosis of the entire femoral head. The knee and hip
joints are predominantly affected.
3. CSS is only ANCA-positive in 40% of cases..
10
Churg-Strauss-Syndrome
4. It is very likely that CSS is not such a rare disease (in the
literature, 2 to 3 cases/million inhabitants/year are stated).
These values probably apply to the third stage of the disease, but not to its second stage. If the frequency of the bronchial asthma which is always associated with it is taken into
account, it can be assumed that CSS occurs significantly
more often in the second stage of the disease.
Conclusions
The disease designation eosinophilic granulomatosis with
polyangiitis (EGPA) proposed by the Chapel Hill
Consensus Conference for the nomenclature of vasculitides
(2013) only applies to a small proportion of CSS patients!
Only the designation Churg-Strauss syndrome covers all of
the clinical manifestations (stages of the disease).
5. CSS is not primarily diagnosed histopathologically.
Only in the third stage of the disease is the detection of
vasculopathy/vasculitis diagnostically conclusive. In the
second stage of the disease, bronchial asthma, cardinal
symptoms and a test therapy form the basis of the diagnosis.
CSS should be classified as immunopathy and only designated as vasculitis in the third stage of the disease.
In every patient with chronic bronchial asthma, a search
should be undertaken for the cardinal symptoms of ChurgStrauss syndrome: diarrhoea, eosinophilia, pulmonary
changes in the computed tomography, characteristic skin
efflorescences and mononeuritis/polyneuropathy.
6. Peripheral blood eosinophilia is not an obligatory finding in CSS. The long-term therapy of bronchial asthma
with cortisone can suppress the blood eosinophilia: the Eos
values are then normal or even low.
Important: all of the findings of the various medical disciplines should be collated by one examiner.
7. The typical skin changes are not palpable skin haemorrhages, but corial capillary proliferation.
In a statistical evaluation of CSS, the stage of the disease
and the ANCA findings should always be stated.
The diagnosis of Churg-Strauss syndrome and its appropriate treatment during the second stage of the disease can
greatly improve the quality of life, whereas in the third
stage of the disease it can save the life of the patient!
11
Churg-Strauss-Syndrome
Classification of the vasculitides 32, 66
1
Vasculitis of the large vessels (LVV)
1.1
Takayasu's arteritis (TAK)
1.2
Giant cell arteritis (GCA)
1.3
Aortitis
1.4
Endangiitis obliterans (thromboangiitis obliterans)
2
Vasculitis of the medium-sized vessels (MVV)
2.1
Polyarteritis nodosa (PAN)
2.2
Cutaneous polyarteritis
2.2
Kawasaki disease (KD)
3
Vasculitis of the small vessels (SVV)
ANCA-asociated vasculitis (AAV)
3.1
Microscopic polyangiitis (MPA)
3.2
Wegener's granulomatosis (GPA: granulomatosis with polyangiitis)
3.3
Churg-Strauss syndrome (EGP: eosinophilic cell granulomatosis with polyangiitis)
Immune complex small-vessel vasculitis
3.4
Goodpasture's syndrome (anti-GBR: anti-basal glomerular disease)
3.5
Cryoglobulinaemic vasculitis (CV)
3.6
Henoch-Schönlein vasculitis (IGAV: IgA vasculitis) in children and adults
3.7
Hypocomplementaemic urticaria vasculitis (HUV)
3.8
Erythema elevatum et diutinum
3.9
Granuloma faciale
3.10
Lupus erythematosus vasculitis
3.11
Rheumatoid vasculitis
3.12
Sjögren's Syndrome vasculitis
4
Variable vessel vasculitis (VVV) (This affects small and medium-sized vessels)
4.1
Behçet's disease (BV)
4.2
Cogan's syndrome (CS)
4.3
Nodular vasculitis (erythema induratum Bazin)
4.4
Erythema nodosum leprosum
5
Single-organ vasculitis (SOV)
5.1
Cutaneous leucocytoclastic vasculitis
5.2
Cutaneous arteritis
5.3
Primary vasculitis of the CNS
5.4
Isolated aortitis
6
Vasculitis associated with systemic diseases (collagenosis)
6.1
Secondary acral vasculitis in systemic lupus erythematosus
6.2
Vasculitis in rheumatoid arthritis
6.3
Sarcoid vasculitis
7
Secondary vasculitis with a (probably) confirmed aetiology
7.1
Hepatitis C infections
7.2
Hepatitis B infections
7.3
Syphilis (Mesaortitis luica)
7.4
Other infections that predominantly involve the vessels (mycosis)
7.5
Drug-associated immune complex vasculitis
7.6
Drug-associated ANCA vasculitis
7.7
Prescription drug-induced vasculitis
7.8
Vasculitis in malignant tumours (paraneoplastic vasculitis)
7.9
Vasculitis in the rejection of transplanted organs
12
Appendix
8
8.1
8.2
9
9.1
9.2
9.3
10
Capillaritis
Capillaritis in small vessel vasculitis
Isolated capillaritis (e.g. in glomerulonephritis, septicopyaemia)
Phlebitis
Primary and secondary phlebitis
Phlebitis in small vessel vasculitis
Special forms (e.g. organ-related phlebitis)
Lymphangiitis (in infectious diseases)
13
Atlas of Churg-Strauss-Syndrome
Atlas of Churg-Strauss-Syndrome
capillary
small arteries
venules
large and mediumsized arteries
veins
cutaneous leucocytoclastic angiitis
Henoch-Schönlein
syndrome cryoglobulinaemic angiitis
microscopic polyangiitis
giant cell arteritis
Takayasu's disease
Wegener's granulomatosis – Churg-Strauss syndrome
Polyarteritis nodosa
Kawasaki disease
Fig. 1. Vasculitis diseases depending on the size of the vessel affected. Modified according to 32.
Fig. 2: Example of tissue eosinophilia. Between the smooth
muscle fibres of tunica muscularis propria of the large intestine there are dense accumulations of eosinophilic granulocytes. These cells are easy to identify in the HE stain. The cytoplasm includes coarse orange-red granules. A typical feature
is also the nucleus, which consists of two segments connected
by a soft bridge.
14
Atlas of Churg-Strauss-Syndrome
Fig. 3 and 4. Vasculitis. The images show a diffuse inflammatory infiltration of all layers of the vessel wall.The
inflammation is also spreading to the surrounding tissue. The lumen is displaced due to the exudate. A typical
feature of Churg-Strauss vasculitis is the detection of numerous eosinophilic granulocytes in the inflammatory
infiltrate. HE-stain
15
Churg-Strauss-Syndrome
Fig. 5. Churg-Strauss syndrome in the lungs. Small pulmonary vessels show a dense inflammatory infiltration of
all layers of the wall with displacement of the lumen. The arrow indicates an accumulation of eosinophilic granulocytes in the surroundings of the vessel. The change is typical of the third stage of the disease. HE-stain
Fig. 6. Churg-Strauss syndrome in the lungs. In the Elastica van Gieson stain the original structure of the pulmonary vein is still clearly visible. The lumen is displaced. All layers of the vascular wall display inflammatory
infiltrations. The Tunica adventitia is affected.
16
Atlas of Churg-Strauss-Syndrome
Fig. 7. Churg-Strauss syndrome in the lungs. The lumen of the vein is displaced by a large cell granulomatous infiltrate. The arrow shows remnants of
the Tunica elastica interna. Elastica van Gieson stain
Fig. 8. Churg-Strauss syndrome in the small intestine. The micro-villi
show – in addition to lymphocytes and plasma cells – small focal infiltrates
of eosinophilic granulocytes. These can be selectively detected in the Giemsa stain by their eosin-red granules in the cytoplasm.
17
Churg-Strauss-Syndrome
a
b
Fig. 9a-c. Churg-Strauss syndrome in the intestinal
wall. a: In the muscular wall of the small intestine (terminal ileum) there are eosinophilic granulocytes, lymphocytes and plasma cells. b: at a higher magnification,
the eosinophilic granulocytes are particularly easy to
identify. c: eosinophilic granulocytes can also be selectively detected in the Goldner stain. Here the cellular
infiltration is located in the area of the tunica adventitia.
c
18
Atlas of Churg-Strauss-Syndrome
b
a
d
Fig. 10a-d. Skin efflorescences in Churg-Strauss syndrome. Figures a and b show the typical efflorescences of ChurgStrauss syndrome. These mainly occur on the extremities. In
the early stage they are red in colour, but turn brown after
months and years. In the biopsy the cut surface
c
19
Churg-Strauss-Syndrome
Fig. 11 Cardiac changes in Churg-Strauss syndrome. These
mainly occur during the third stage of the disease. Initially, an
inflammatory infiltration with eosinophilic granulocytes is
seen. This is located in the interstitial tissue of the myocardium.
During the subsequent course of the disease, myocardiocytes
are destroyed (vacuolisation of the cytoplasm) and replaced by
fibrosis. HE stain of an endomyocardial biopsy.
Fig. 12. Urinary bladder changes in Churg-Strauss syndrome (irritable bladder). In the biopsy of the urinary bladder
mucosa, a dense inflammatory infiltrate of round cells with
scattered, interspersed eosinophilic granulocytes is found. These are mostly masked by the non-specific inflammatory infiltrate, so that they are often overlooked. HE-stain
20
Atlas of Churg-Strauss-Syndrome
Fig. 13. Urinary bladder changes in Churg-Strauss syndrome. A typical feature is the detection of central blood eosinophilia in the affected organ. In the lumen of the capillaries,
increased numbers of eosinophilic granulocytes are found (see
arrow). This local blood eosinophilia does not correlate with
the number of eosinophilic granulocytes in the peripheral
blood. HE-stain
Abb. 14. Harnblasenveränderungen beim Churg-StraussSyndrom. Diagnostisch relevant ist dagegen der Nachweis von
herdförmigen Ansammlungen von eosinophilen Granulozyten zwischen den Muskelfasern der Tunica muscularis propria. Oft sieht man
sie in der unmittelbaren Nachbarschaft von Gefäßen. Diese für ein
Churg-Strauss-Syndrom typische feingewebliche Veränderung lässt
sich nur nachweisen, wenn die Biopsie auch die tiefer gelegene Wand
aus glatten Muskelfasern erfasst (hier ein OP-Präparat). HE-Fbg.
21
Churg-Strauss-Syndrome
Fig. 15. Pulmonary changes in Churg-Strauss syndrome. In the second stage of the disease the lungs display a
fleeting diffuse infiltrate in the radiograph. No foci are detected. The radiographic findings correspond to Loeffler's
syndrome.
Fig. 16. Pulmonary changes in Churg-Strauss syndrome. The pulmonary changes in the third stage of the
disease can be detected in particular in non-contrasted computed tomography. Foci of different sizes, some of
them confluent, are a consequence of vasculitis.
22
Atlas of Churg-Strauss-Syndrome
Fig. 17. Dental changes in Churg-Strauss syndrome. In rare cases the teeth are also affected by the disease. In addition to
changes to the pulp (necroses, vasculitis), homogenisation of the dentin layer can also be detected in the radiograph image
(loss of the typical canals).
Fig. 18. Detection of ANCA. With immunofluorescence it
is possible to detect cANCA. As this occurs in Wegener's
granulomatosis in particular, it represents an important differential diagnostic finding.
23
Churg-Strauss-Syndrome
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