Transcript Wegener`s Granulomatosis

Clinical Pathological Conference
三軍總醫院
小兒科部
R2 田炯璽 / 洪志興 醫師
Present Illness
A 15-year-old boy with history of allergic rhinitis
had fever and epistaxis developed this March.
(Two months before present)
Bilateral markedly enlarged exudative tonsillitis was
also present, which was improved after treatment
with Amoxicillin-clavulanic acid (Augmentin).
However, one week later, arthralgias developed in
the ankles and subsequently in the knees and
hands.
Night sweating was noted, however, no joint swelling
or erythema.
Present Illness
Soon, cough developed, and it was occasionally
associated with thick, whitish, blood-streaked
sputum and postnasal drip with bloody nasal
discharge.
The patient coughed frequently but appeared well.
Past, Personal History
A case of allergic rhinosiusitis.
Suffered from paranasal sinusitis since 10 years old.
Sinus surgery was performed at another hospital in
this January.
Pathological result revealed acute and chronic
rhinosinusitis with stromal eosinophils.
Laboratory Data
CBC:
WBC: 9000/ul
Neutrophils:
63%
Lymphocytes: 17%
Monocytes:
8%
Eosinophils:
11% (990/ul)
Basophils:
1%
HCT:
44%
PLT: 391000/ul
Biochemistry:
No abnormalities including serum BUN, creatinine,
AST, ALT, uric acid, LDH, and glucose levels.
Laboratory Data
ESR: 22 mm/hr (child: 4 ~ 20 mm/hr)
ANA: negative
Rheumatoid factor: negative
Urine routine:
Protein: (+)
RBC: 2~4/ Hpf
(30mg/dl)
Radiological Findings
Chest film:
Bilateral ill-defined, rounded, patchy opacities, none
of them larger than 2cm in diameters.
No lymphadenopathy, no pleural effusion.
CT of chest:
Multiple ground-glass opacities throughout both
lungs, some had a rounded shape, and some had a
central radiolucency, a feature consistent with
cavitation.
Bronchoscopic Examination
Normal airway with no abnormal secretion.
Broncho-alveolar lavage:
A few acid-fast bacilli.
Cytology: negative for malignant cells.
Microbiological Examinations
Ordinary culture for lavage : negative
Fungus culture for lavage : negative
Legionelle culture for lavage : negative
PPD test for the patient: negative.
Hospital course
After the examinations performed which was
described previously, a regimen of isonizid,
rifampin, and pyrazinamide was begun.
Two weeks later, another CT scan of chest showed
no change in the bilateral opacities and no new
lesions.
The examination of a stained sputum revealed no
acid-fast bacilli. Then the anti-TB regimen was
discontinued.
Problems
Major Problems
Productive cough with blood-streaked
sputum. (Hemoptysis?)
Positive findings on chest film and chest CT
scan.
Bloody nasal discharge (Epistaxis)
Eosinophilia
Minor Problems
Previous exudative tonsillitis
Night sweating
Arthralgias
Elevated ESR
Mild proteinuria, and RBC in urine.
Acid-fast bacilli found in bronchoalveolar lavage
History of allergic rhinosinusitis.
Questions to be asked:
Any specific contact history? Living on a farm or near a coal
mine? Drug history?
History of asthma?
Any other positive findings of physical examinations? Skin rash
or purpura? Hepatosplenomegaly? Other palpable
lymphadenopathy?
Any other examinations of immunology? Serum immunoglobulin
level (especially IgE) ?
Did ANCA test performed? Which form is predominant?
cANCA or pANCA?
Serum angiotensin-converting enzyme level?
Hemoptysis
The expectoration of blood or blood tinged sputum.
Bleeding can occur from disruption of the
pulmonary or bronchial vessels.
First it must be determined if a child is truly
experiencing hemoptysis, because blood from the
nose or GI tract may appear similar to bleeding
from the pulmonary system.
The blood in hemoptysis is generally bright red and
frothy, has an alkaline pH, may contain sputum, and
may be accompanied by a cough.
Differential Diagnosis of Hemoptysis
Infection
Tracheobronchitis
Pneumonia
Bacterial
TB
Fungal (e.g., aspergillosis)
Parasitic
Tracheostomy-related
Bronchiectasis
Cystic fibrosis
Ciliary dyskinesia
Immunodeficiency
Foreign body
Congenital heart disease
(mainly with pulmonary
vascular obstructive disease)
Pulmonary arteriovenous
malformation
Trauma
Alveolar hemorrhage syndromes
Connective tissue
disease/vasculitis
(e.g., Goodpasture syndrome,
Wegener granuloma)
Primary pulmonary
hemosiderosis (e.g., idiopathic,
Heiner syndrome)
Pulmonary thromboembolism
Tumor
Bronchial adenoma
Metastasis
DDx Flowchart of Hemoptysis
DDx Flowchart of Hemoptysis
Differential Diagnosis of
Rhinorrhea/Nasal Congestion
Seasonal allergic rhinitis
Perennial allergic rhinitis
Non-allergic rhinitis with eosinophilia
Rhinitis medicamentosa
Drugs/medication (prazosin, guanethidine,
reserpine, cocaine)
Mechanical/anatomic obstruction
Cerebrospinal fluid rhinorrhea
Pregnancy
Hypothyroidism
Wegener’s granulomatosis
Sinusitis (viral, bacterial, fungal)
Conditions that may mimic symptoms of rhinitis
A. Structural/mechanical factors
1. Deviated septum/septal wall anomalies
2. Hypertrophic turbinates
3. Adenoidal hypertrophy
4. Foreign bodies
5. Nasal tumors
a. Benign
b. Malignant
6. Choanal atresia
B. Inflammatory/immunologic
1. Wegener’s granulomatosis
2. Sarcoidosis
3. Midline granuloma
4. Systemic lupus erythematosus
5. Sjogren’s syndrome
6. Nasal polyposis
C. Cerebrospinal fluid rhinorrhea
Eosinophilia
Eosinophils regulate and moderate mast-celldependent immediate hypersensitivity
reactions
Major function is as a cytotoxic cell, especially
against helminthic infection.
Absolute eosinophil count > 0.7 X 109/uL(700/ul)
 Eosinophilia
Differential Diagnosis of Eosinophilia
Allergic disorder
Gastrointestinal disorder
Infectious diseases
Immunodificiency disease
Allergic rhinitis
Asthma
Acute urticaria
Hypersensitivity drug reaction
Tissue-invasive helminth infection
Pneumocystic carinii
Toxoplasmosis
Amebiasis
Malaria
Bronchopneumonia aspergillosis
Coccidiodomycosis
Scabies
Malignant disorder
Brain tumors
Hodgkins disease
T cell lymphoma
AML
Myeloproliferative disorder
Inflammatory bowel disease
Peritoneal dialysis
Eosinophilic gastroenteritis
Milk precipitin disease
Hyper IgE syndrome
Wiskott-Aldrich syndrome
GVHD
Pulmonary disease
Löffler syndrome
Eosinophilic leukemia
Hypersensitivity pneumonitis
Miscellaneous
Thrombocytopenia with absent radii
Vasculitis
Histiocytosis with cutaneous
involvement
Hypereosinophilic syndrome
Differential Diagnosis of Eosinophilia
Differential Diagnosis of Night Sweats
Pulmonary Tuberculosis
The most specific confirmation of pulmonary tuberculosis
is isolation of M. tuberculosis.
Unfortunately, three consecutive morning gastric aspirates
yield the organism in less than 50%. The culture yield
from bronchoscopy is even lower.
For most children, the presence of a positive tuberculin
test, and abnormal chest radiograph consistent with
tuberculosis, and a history of exposure is adequate
proof that tuberculosis is present.
Acid-fast Stain
The Ziehl-Neelsen technique employed for identification of
acid-fast bacteria.
Acid-fast bacteria includes those cause tuberculosis, nontuberculosis mycobacteria infection, and Norcardia.
Miliary Tuberculosis
Erosion of a parenchymal focus of primary tuberculosis
into blood or lymphatic vessels may result in
dissemination of the bacilli and a miliary pattern.
Usually complicates the primary infection, occurring within
2-6 months of the initial infection.
Lesions are often larger and more numerous in the lungs,
spleen, liver, and bone marrow.
More often, the onset is insidious with early systemic signs,
including anorexia, weight loss, and low-grade fever.
Within several more weeks, the lungs may be filled with
tubercles, and dyspnea, cough, rales, or wheezing occurs.
The resolution of miliary TB is slow, even with proper
treatment. The chest radiographic abnormalities may
not resolve for many months.
Miliary Tuberculosis
Diagnosis of disseminated tuberculosis can be difficult.
Early sputum or gastric aspirate cultures have a low
sensitivity.
The tuberculin skin test is non-reactive in up to 40% of
patients.
Biopsy of the liver or bone marrow with appropriate
bacteriologic and histologic exams more often yields an
early diagnosis.
The most important clue is usually history of recent
exposure to an adult with infectious tuberculosis.
Treatment: the AAP and CDC have endorsed a regimen of
6 months of INH + RIF supplemented during the first
two months by PZA as standard therapy of intrathoracic
tuberculosis.
Lymphoma (Non-Hodgkin)
Lymphoblastic (T cell) lymphoma often presents as an
intrathoracic tumor, usually a mediastinal mass, and is
associated with dyspnea, chest pain, dysphagia, pleural
effusion and superior vena cava syndrome.
Cervical or axillary lymphadenopathy is present in up to
80% of patient at diagnosis.
Hodgkin Disease
Painless, firm, cervical or supraclavicular lymphadenopathy
is the most common presenting sign.
B symptoms: unexplained fever, weight loss, or night
sweats.
Pulmonary Metastasis
Metastatic lesions are the most common forms of
pulmonary malignancy in children.
Primary process including Wilm’s tumor, osteogenic
sarcoma, soft tissue sarcoma, and hepatoblastoma.
Pulmonary tumors may present as fever, hemoptysis,
wheezing, cough, pleural effusion, chest pain, dyspnea,
recurrent pneumonia, or atelectasis.
The prognosis varies and depends on the type of tumor
involved.
Histiocytosis
Mainly referred as Langerhan’s cell histiocytosis.
Bone lesions are the commonest manifestation(78%),
second commonest: skin and mucous membrane (40%).
Pulmonary involvement (25~30%): diffused cystic changes,
nodular infiltrates, or extensive fibrosis can occur. The
radiographic apearance may resemble miliary
tuberculosis.
Multi-system disease is frequent with patient’s
presentation(40%), with single bone involvement
mostly(53%). Pulmonary involvement is less frequently
(6%).
Painful bone lesion affecting hematopoeitically active
bones are common.
Löffler Syndrome
(Eosinophilic Lung Diseases)
Synonym: Simple pulmonary eosinophilia.
Characterized by migrating pulmonary infiltrates
accompanies by peripheral eosinophilia but minimal
respiratory symptoms.
The name “Löffler syndrome” is rarely used today.
Chronic cough, intermittent fever, dyspnea, wheezing , and
occasionally abdominal pain and weight loss.
Patients present with nonspecific interstitial, alveolar or
mixed pulmonary infiltrates, which tend to be bilateral
and diffused.
Often patients would have allergic reaction to parasites
(c.g. heminthiasis), or drugs(c.g. ampicillin, ibuprofen).
Extrinsic Allergic Alveolitis
(Hypersensitivity Pneumonitis)
Typically an adult disease, but have been reported in
children.
Caused by inhalation of a variety of organic antigens.
The chronic form shows further progression of the
granulomatous alveolitis resulting in interstitial fibrosis
and honeycombing. Chest radiographs show coarse
reticulonodular infiltrates and bronchiectasis.
Patients with chronic disease may present as dyspnea,
severe cough, weight loss, weakness, hypoxemia
Lab findings: leukocytosis with neutrophilia; modest ESR
elevation; serum immunoglobulins(IgM, IgA, IgG) are
often elevated.
Bronchoalveolar lavage fluid typically shows marked
lymphocytosis and may also contains higher levels of
immunoglobulins.
Sarcoidosis
Chronic, multi-system granulomatous disease of unknown
cause.
Manifestations: peripheral lymphadenopathy, arthritis,
uveitis, skin rash, hepatosplenomegaly
Acute  fever, erythema nodosum, iritis, polyarthritis.
Insidious  including weight loss, cough, fatique, bone and
joint pain, and anemia.
Pulmonary involvement is variable: parenchymal infiltrates,
miliary nodules, and hilar and paratracheal
lymphadenopathy occurs.
Typical symptoms with pulmonary involvement are dyspnea
with exercise, and a dry cough. Hemoptysis is rare, as is
production of sputum.
Sarcoidosis
Lab findings: elevated ESR; eosinophilia; hyperproteinemia,
hypercalcemia, hypercalciuria.
Serum angiotensin-converting enzyme level is elevated in
about 2/3 of patients.
Definite diagnosis: tissue biopsy (mostly lung )
– mononuclear cell granulomatous inflammatory process.
Collegen Vascular Disease
Primarily suggesting systemic lupus erythematosus,
which consists a variety of clinical manifestation.
Characterized by fever, weight loss, rash, hematologic
abnormalities, arthritis, and involvement of heart,
lung, CNS, and kidney.
Restrictive interstitial lung disease is the commonest
form of parenchymal involvement. The chest
radiograph is usually normal but may present “platelike” atelectasis or interstitial fibrosis with
“ honeycombing”.
May also present the radiographic manifestation of
vasculitis.
It may be asymptomatic.
Wegener’s Granulomatosis
A necrotizing granulomatous angiitis affecting small and
medium-size arteries and veins.
The three major areas of involvement are the upper
respiratory tract, the lung parenchyma, and the
kidney.
Upper airway: Acute and chronic sinusitis, often with
secondary infection, occurs in over 80% of patients.
Nasal ulcers, mucosal inflammation with nasal
obstruction, septal perforation, and necrosis of nasal
cartilage with “saddle nose”.
Lower airway: Pulmonary infiltrates, pulmonary nodules
(which may cavitate), and pulmonary hemorrhage.
Renal: glomerulonephritis—80%, and half develop renal
insufficiency.
Wegener’s Granulomatosis
Musculoskeletal: myalgias and arthralgias in 70% of
patients, which a third develop a true nondeforming,
nonerosive arthritis.
Cutaneous: palpable purpura, cutaneous ulcers, pyoderma
gangrenosum, and Raynaud’s phenomenon.
Neurologic: Mononeuritis multiplex, peripheral
symmetric polyneuropathy, cranial neuropathy,
infarction, subdural or subarachinoid hemorhage,
seizures, or cerebritis.
GI tract: abdominal pain, diarrhea, and intestinal ulcers
with or without bleeding.
Cardiac: 10% of patients. Including pericarditis,
coronary arteritis, cardiomyopathy, and conduction
defects.
Wegener’s Granulomatosis
Lab findings:
Elevated ESR;
Normocytic anemia, leukocytosis, thrombocytosis.
Rheumatoid factor (+): 50%
ANCA(+), cytoplasmic pattern: 90% in active stage
and 40% in remission.
RBC and RBC casts in urinalysis.
Rising creatinine indicates renal failure.
Diagnosis: Biopsy evidence of vasculitis. The most tru
reliable disgnostic tissue is obtained by open lung
biopsy.
Treatment: Cyclophosphamide for the mainstay of
treatment. Corticosteroid for initial therapy.
Churg-Strauss Syndrome
(Allergic Granulomatosis and Angiitis)
A necrotizing, granulomatous, small-vessel vasculitis
associated with asthma, sinusitis, and eosinophilia.
Pulmonay involvement is the cardinal feature of it.
Patients generally have a long history of upper
respiratory allergies, asthma, and eosinophilia before
the onset of syndrome.
Increased levels of IgE and peripheral eosinophilia are
common in untreated patients, and asthma, sinusitis,
and allergic rhinitis are major manifestation of the
disease.
Pulmonary: Adult-onset asthma is most common,
affecting nearly all patients; Patchy infiltrates seen
in half of the patients, are generally evanescent, and
may sometimes associated with pleural effusion.
Churg-Strauss Syndrome
(Allergic Granulomatosis and Angiitis)
Constitutional symptoms - Malaise, fatigue, flulike
symptoms, weight loss (70%), fever (57%), myalgias
(52%) ,arthralgias (40%)
Skin manifestations (49%): Purpura, skin nodules,
urticarial rash, necrotic bullae, digital ischemia
Cardiac manifestations – congestive heart failure,
restrictive cardiomyopathy, and pericarditis.
Gastrointestinal symptoms (31%) - Symptoms related to
GI vasculitis and GI bleeding
Peripheral neuropathy - Mononeuritis multiplex (most
frequent form, occurring in as many as 77% of
patients)
Renal: FSGN 50%
Churg-Strauss Syndrome
(Allergic Granulomatosis and Angiitis)
Lab findings:
Elevated ESR;
Anemia, eosinophilia;
Elevated IgE level.
ANCA(+): 70%, perinuclear pattern.
Rheumatoid factor (+): 50%
RBC, RBC casts and proteinuria in urinalysis.
Churg-Strauss Syndrome
(Allergic Granulomatosis and Angiitis)
Diagnosis:
6 criteria proposed by the American College of Rheumatology in
1990:
(1) asthma
(2) peripheral eosinophilia of 10% or higher on differential
leukocyte count
(3) mononeuropathy (including multiplex) or polyneuropathy
(4) paranasal sinus abnormality
(5) nonfixed pulmonary infiltrates
(6) biopsy-proven extravascular eosinophila
The presence of 4 or more of these criteria distinguished
CSS from other vasculitides, with a sensitivity of 85% and
a specificity of 99.7%
Biopsy confirmation of vasculitis is mandatory, however,
the most fruitful biopsy sites are nerve, skin, lung and
kidney.
Anti-neutrophil Cytoplasmic Antibody
(ANCA)
Antibodies directed against certain proteins in the
cytoplasm of neutrophils.
Two major categories of ANCA based on different targets
for the antibodies: cytoplasmic (cANCA) and perinuclear
(pANCA).
cANCA are found primarily in patients with Wegener’s
granulomatosis (90%), microscopic polyarteritis, and
active glomerulonephrtis.
pANCA occurs in various vasculitis disorder, such as
polyarteritis nodosa(PAN), Churg-Struss syndrome,
polyangiitis overlaping syndrome, Goodpasture’s
syndrome, and inflammatory bowel disorder(ulcerative
colitis). 80% of patients in whom pANCA are found has
evidences of vasculitis or disorders mentioned above.
Impression
Wegener’s Granulomatosis
or
Churg-Strauss Syndrome
Or
Miliary tuberculosis
Diagnostic Procedure
Thoracoscopic or open-lung biopsy
&
ANCA test
Thanks for Your Attention