Article Type : Case Report
Authors : Zhenhui Lee S, Poots I and Kumar P
Keywords : Granulomatosis; Polyangiitis; Anti-neutrophil cytoplasmic antibody
Granulomatosis with
polyangiitis (GPA) is a rare primary systemic vasculitic condition, affecting
small to medium sized vessels. It is associated with a raised anti-neutrophil
cytoplasmic antibody (ANCA) count with diagnosis confirmed via histological
findings. This report is centered on a rare occurrence of pulmonary GPA in an
80 year-old female patient with a, elevated atypical ANCA level.
Granulomatosis with
polyangiitis (GPA) is a subtype of systemic vasculitides, often proving
difficult to diagnose due its variety of clinical presentations. These can
range from respiratory complaints, to dermatological or ophthalmological
manifestations, depending on the location of the blood vessels affected [1]. GPA
is commonly associated with an elevated anti-neutrophil cytoplasmic antibody
(ANCA) count; with cytoplasmic ANCA (C-ANCA) raised in 80-90% of patients and
perinuclear-stained ANCA (P-ANCA) elevated in 10% [2]. The patient being
discussed in this report is an 80-year-old female who presents with a rare case
of pulmonary GPA. When investigated she was found to have a raised atypical
ANCA with negative C-ANCA and P-ANCA levels.
The patient being
presented is an 80-year-old female, with a past medical history of atrial
fibrillation, hypertension, gastro-oesophageal reflux disorder (GORD) and
breast cancer. She presented to a rural hospital with increasing shortness of
breath, a productive cough and intermittent fevers which had been ongoing for
two weeks. Initially treated for a suspected pneumonia, the patient was
prescribed intravenous fluids and treated with Ceftriaxone and Doxycycline.
Despite this, her shortness of breath worsened and she had an increasing oxygen
requirement with saturations of just 92% while on six litres of oxygen via
nasal prongs. Her antibiotic regime was later altered to consist of Meropenem
and Azithromycin, and she was transferred to our hospital for further management.
Upon arrival in the
emergency department, she was noted to have ongoing shortness of breath with a
respiratory rate of 33 breaths per minute and oxygen saturations of 97% on six
litres of oxygen. Her blood pressure was stable at 132/105, her temperature was
38 degrees celsius, she was tachycardic at 115 beats per minute and her pulse
was irregularly irregular. On examination, she had left basal crepitations, but
otherwise exhibited no signs of respiratory distress and was haemodynamically
stable. She was initially managed with 10 litres of oxygen via a Hudson’s mask,
nebulised Salbutamol, IV frusemide and her electrolytes were optimised. Her
investigations showed an elevated white cell count of 20, a potassium level of
2.7, a creatinine of 104 and an estimated GFR of 44. She also tested positive
for Influenza A RNA and a chest X-ray revealed left lower zone consolidation
suggestive of a left lower lobe pneumonia (Figure 1A).
Due to worsening
shortness of breath, she was placed on high flow nasal prongs at 40L/minute
with an FiO2 of 0.40 and was admitted to the high dependency unit
(HDU) for management of Influenza A pneumonia, complicated by type 1
respiratory failure requiring non-invasive ventilatory support. On day five of
admission, following improvement of her respiratory symptoms, she was stepped
down to the medical ward for ongoing management and was discharged 2 days
later.
Following discharge, she
was reviewed in the respiratory outpatient clinic, where she complained of
persistent productive cough and as a result she underwent a CT scan of her
chest. This revealed a large left lower lobe lesion, initially raising concerns
of a lung malignancy, particularly in the context of her past history of right
breast cancer (Figure 1B). She then underwent a CT-guided core biopsy to
characterize the lesion, which showed a necrotising granulomatous inflammation
with no evidence of malignant cells (Figure 1C). The differential diagnoses
considered for this lesion included: malignancy, a lung abscess following her
influenza infection, tuberculosis, a pulmonary fungal infection and finally
autoimmune conditions including sarcoidosis and GPA. A bronchoscopy was
performed and an endobronchial biopsy was negative for malignancy and there was
no evidence of fungal elements or acid-fast bacilli (AFB) on bronchoscopy
washings (Figures 1D and 1E). Further investigations revealed a raised C -
reactive protein (CRP) of 6.9, an atypical ANCA level of more than 2560, a
negative P-ANCA, a negative C-ANCA, and negative Angiotensin-Converting Enzyme
(ACE).
Based on her clinical
presentation, positive ANCA level, and histological evidence, she was diagnosed
with GPA. A pulmonary function test was performed which showed mild airflow
limitation, small airway obstruction with gas trapping, and a mild decrease in
the corrected diffusion deficit, which is consistent with an interstitial lung
disease pattern. She was given oral prednisolone 25 mg daily, oral methotrexate
5mg weekly and oral folic acid 0.5mg daily. On review in clinic two weeks
later, her persistent cough resolved.
Vasculitides are a
diverse group of autoimmune diseases, characterized by blood vessel wall
inflammation and a subsequent impediment of oxygen delivery to affected organs,
causing ischemia and damage [3]. GPA, formerly known as Wegener’s
granulomatosis, is a rare pauci-immune member of the vasculitides family, which
predominantly affects small and medium-sized vessels [4-6].
Epidemiologically, it has
a higher incidence in Europe (up to 14.3 cases/million people) in comparison to
Asian countries (2.1 cases/million) [7]. Although it can present in any age
group, it is most commonly diagnosed in adults from 40 to 70 years old (with a
peak incidence in the group over 55) and exhibits no specific gender preference
[7,8]. The pathogenesis of GPA is not well understood, however, it is believed
that there are genetic associations with HLA-DPB1*0401, RXRB, RING, SEMA6A and
SERPINA, all of which have been found in affected individuals [9,10]. Some
known triggers for GPA include infection, environmental exposures and some
drugs.
GPA is associated with
varied clinical presentations primarily consisting of organ-damage specific to
the location of vessel wall injury. In a report by Comarmard and Cacoub, two clinical
phenotypes of GPA were identified; limited and systemic forms [6]. The
localized type predominantly presents as recurrent respiratory tract infections
and is associated with a Th1 lymphocytic response, coupled with granuloma formation
visualised on histology [6]. The systemic variant typically has a more severe
presentation and may involve the kidneys or other vital organ systems,
resulting in musculoskeletal, visual, dermatological or neurological complaints
(Table 1) [1,3,6,11-20]. Patients affected by the systemic form of GPA develop
constitutional symptoms such as fever, weight loss, night sweats, fatigue and
arthralgia [5]. It is associated with a predominant Th2 lymphocytic response
and is noted to demonstrate vasculitic lesions on histology [6].
Table 1: Clinical presentation of
GPA.
|
History |
Physical
Examination |
Ref: |
Respiratory
|
·
Upper
respiratory tract: nasal
congestion/discharge, nose bleeds, sinus tenderness. ·
Lower
respiratory tract: cough,
haemoptysis, shortness of breath. ·
Other symptoms:
Chronic cough, pleuritic chest pain. |
·
Purulent or
bloody nasal discharge ·
Saddle nose
deformity ·
Respiratory
distress ·
Decreased
breath sounds, inspiratory crepitations ·
Hypoxia with
respiratory failure |
[1,5,6,12-15] |
Renal |
·
Fatigue ·
Frothy urine |
·
Proteinuria on
dipstick examination |
5,13,15 |
Dermatological |
·
Skin rash |
·
Palpable
purpura ·
Tender
subcutaneous nodules ·
Ulcers |
1,3,16 |
Rheumatological |
·
Joint pain ·
Muscle aches |
·
Muscle
weakness |
1,6,17 |
Neurological |
·
Chronic
headache ·
Ataxia ·
Seizures ·
Impaired motor
and/or sensory function |
·
Cranial and
peripheral nerves deficits |
5,14,15,18 |
Auditory |
·
Hearing loss |
·
Middle ear
swelling, erythema and effusion ·
Conductive
hearing loss |
12,15,19 |
Visual |
·
Eye erythema
and pain ·
Foreign body
sensation ·
Blurred vision |
·
Cataracts ·
Diplopia ·
Conjunctival
hyperemia ·
Episcleritis ·
Scleritis |
1,5,14,20 |
Cardiac |
·
Chest pain ·
Arrhythmias |
·
ECG
abnormalities ·
Features of
heart failure |
14,15,19 |
Constitutional |
·
Fever ·
Malaise ·
Anorexia ·
Lethargy |
·
Fevers ·
Weight loss |
12,15,19 |
A well-known
classification system for the identification of GPA is the American College of
Rheumatology (ACR) classification criteria which mandates the patient
fulfilling of at least two of the four criteria for diagnosis. The criteria
include: 1) the presence of nasal or oral inflammation; 2) radiographic
abnormality; 3) abnormal urinary sediment on urinalysis; 4) histological
evidence of granulomatous inflammation [18].
When performing
investigations, it is important to consider laboratory testing, imaging and
histology (Table 2).
Table 2: Investigations for GPA.
Test |
Components |
Findings |
Significance |
CBE |
White cell count |
Elevated white cell count |
Inflammation |
Haemoglobin |
Normocytic-normochromic anemia |
Anaemia of chronic disease, or, reduced
EPO function secondary to kidney disease |
|
Platelets |
Elevated platelet count |
Inflammation |
|
EUC |
Urea, Creatinine |
Normal |
Kidneys not affected |
Elevated |
May suggest renal involvement |
||
eGFR |
Current renal function |
Baseline renal function and for
prognostication |
|
Electrolytes |
Normal or Deranged |
Affected electrolytes secondary to renal
involvement |
|
Inflammatory
markers |
CRP, ESR |
Elevated |
Inflammation |
Autoimmune
Screen |
ANCA |
Positive or Negative ·
PR3-ANCA or C-ANCA (common) ·
MPO-ANCA or P-ANCA (less common) |
Positive suggests GPA, MPA, EGPA or
inflammatory bowel disease |
ANA |
Negative |
To assess for differential diagnoses |
|
RF |
Negative |
To assess for differential diagnoses |
|
Imaging |
CXR |
Pulmonary nodules, consolidation, or
effusion |
To assess for pulmonary involvement and
determine progression of disease |
CT Chest |
Ground-glass opacity and consolidation |
Diffuse alveolar haemorrhage |
|
Septal thickening |
Resolving phase following diffuse
alveolar haemorrhage |
||
Subglottic trachea narrowing |
Suggestive of tracheal involvement |
||
Pleural effusion, nodules or thickening |
Suggestive of pleural involvement |
||
Urine
|
Urinalysis |
Dysmorphic RBCs, RBC casts and/or WBC
casts, urinary sediment |
To assess for glomerular disease and
determine progression |
Histology |
Biopsy of affected tissue |
1.
Granulomatous inflammation 2.
Necrotising vasculitis |
Definitive diagnosis for GPA |
*ANA: antinuclear antibody, ANCA:
antineutrophilic cytoplasmic antibodies, CBE: complete blood examination,
CRP: C-reactive protein, CXR: chest X-ray, eGFR: estimated glomerular
filtration rate, EGPA: eosinophilic granulomatosis with polyangiitis, EPO:
erythropoietin, ESR: erythrocyte sediment ratio, EUC: electrolytes, urea and
creatinine, MPA: microscopic polyangiitis, MPO: myeloperoxidase, PR3:
proteinase 3, RBCs: red blood cells, RF: rheumatoid factor. |
Figure 1: A: Chest X-ray showing left lower zone consolidation suggestive of a left lower lobe pneumonia; B: CT Chest demonstrating a triangular opacity in the left lower lobe measuring 51 x 33mm with vessels present within it and a central area of necrosis measuring 18 x 21mm corresponding with the previous CXR findings; C: Gathering histological samples of the left lower lobe CT-guided core biopsy showing necrotising granulomatous inflammation; D: Biopsy of left lower lobe lesion on Bronchoscopy; E: Post-biopsy bleed on Bronchoscopy.
Routine laboratory
testing should include a complete blood count, erythrocyte sedimentation rate
(ESR) and CRP to assess for features of inflammation [8,16]. A specific
autoimmune panel also includes ANCA, which is a good screening test for small
vessel necrotising vasculitis, including GPA, microscopic polyangiitis (MPA),
and eosinophilic granulomatosis with polyangiitis (EGPA) [12]. A positive ANCA
can be one of 3 types: cytoplasmic, perinuclear or atypical. A recent study on
GPA patients concluded that 85% were C-ANCA positive, 10% were P-ANCA positive,
and 5% were ANCA negative [14]. Atypical ANCA is rarely seen in patients with
systemic small-vessel vasculitis, but has been reported in hepatobiliary
diseases including chronic inflammatory bowel disease, primary sclerosing
cholangitis, primary biliary cirrhosis and autoimmune hepatitis [12,22-23]. Other
autoimmune screening tests include antinuclear antibody (ANA), rheumatoid
factor (RF) and ACE which can aid in excluding other differential diagnoses [12,19].
Recommended imaging
assessment includes a chest radiograph for a baseline image and to monitor
disease progression. Additionally, a CT scan of the chest may better elicit the
severity of disease and aid as a guide for biopsy and/or intervention purpose [16,24].
Histological assessment
of GPA is the gold-standard investigation. There are two predominant
histological patterns seen in this condition: necrotic granulomatous inflammation
and vasculitic inflammation [17]. The case discussed above depicts the
localized form of GPA whereby our patient presented with ongoing respiratory
symptoms, an elevated atypical ANCA level and a histological finding of
necrotising granulomatous inflammation.
The mainstay of treatment
for GPA is steroids and immunosuppressive agents. For the induction of
remission, immunosuppressive agents including cyclophosphamide or methotrexate,
and monoclonal antibodies such as Rituximab are commonly used [25,26]. Current
guidelines suggest that the maintenance therapy duration should be at least 2
years at which time the patient should be reassessed to determine whether treatment
cessation is appropriate [26].
In conclusion, this report has focused on a
patient who, following an Influenza A pneumonia, presented with persistent
respiratory symptoms for more than two months duration. Following investigation
with laboratory testing, imaging and histological assessment, it was concluded
that the patient had an atypical ANCA-positive GPA. On reviewing articles and
case reports previously conducted on this topic, it is understood that this
patient’s condition, which involved only her respiratory system and spared all
other organs, is very rare. The patient was successfully treated following prompt
assessment and management with steroids and immunosuppressive agents
The corresponding author is the guarantor of
submission.
None ?
Written informed consent
was obtained from the patient for publication of this case report.
Authors declare no
conflict of interest.