Isolated aortitis: a rare cause of febrile illness

Abstract

Febrile illness often presents a challenge for the clinician. The main causes of febrile illness are infections, solid or haematological malignancies and connective tissue disorders, including vasculitis. A 49-year-old woman sought medical attention because of intermittent fever that lasted 2 weeks. She presented no further symptoms or physical signs to suggest the aetiology. The epidemiological context was irrelevant. Analyses revealed anaemia of chronic disease and significant elevations of inflammatory parameters. A comprehensive study was performed, which revealed presence of an aortitis. Investigation of infectious and immunological causes was negative. We arrived at the definitive diagnosis of isolated aortitis. She was treated with corticosteroid and methotrexate, with resolution of symptoms and clinical abnormalities.

Background

Fever is a common reason for seeking medical care. Usually, the cause is easily identifiable with patient observation, but in a minority of cases, it represents a clinical challenge.^{1 2} Possible causes of febrile illness are multiple. The most frequent are infections, solid or haematological malignancies and conjunctive tissue diseases,^{1 2} including vasculitis.

Vasculitis can manifest with symptoms related to local vascular inflammation, or simply with fever and constitutional symptoms.³ Therefore, their diagnosis is dependent on careful clinical suspicion. The aorta can be affected by the inflammatory process in the course of a large vessel vasculitis, and in some cases, this can be the only location of disease. The most important diagnoses to consider are Takayasu’s arteritis (TA) and giant cell arteritis (GCA).³

We present a case of isolated aortitis that manifested with fever in a patient who presents no further symptoms or diagnostic criteria for TA or GCA.

Case presentation

A 49-year-old woman sought medical attention because of intermittent fever that lasted 2 weeks.

She had no respiratory, neurological, gastrointestinal or urinary symptoms, and also denied arthralgia.

She had a history of transient malar rash and gastro-oesophageal reflux treated with omeprazole.

She lived in an urban area and worked in an office. She denied recent travel, animal contact or consumption of unpasteurised products. She had no significant family history.

On examination, she presented a good general condition; she was eupnoeic and normotensive. She had no localised signs of infection, such as nuchal rigidity, alterations in cardiopulmonary auscultation or in abdominal palpation, and no costovertebral angle tenderness or lymphadenopathy.

Laboratory tests showed normocytic anaemia (haemoglobin (Hb) 9.6 g/dL, mean corpuscular volume 79.9 fL), increased inflammatory parameters with 12 200 leucocytes/µL with normal formula and sedimentation rate of 120 mm/h, C reactive protein (CRP) 196.8 mg/L. Renal function, coagulation, hepatic enzymology, lactate dehydrogenase and summary urine analyses were normal (table 1). Chest radiograph showed no pulmonary or mediastinal changes.

Table 1.

Baseline laboratory values

Haemoglobin (11.5–15.5×10 g/L)	9.6
Mean corpuscular volume (78–96 fL)	79.9
Leucocytes (4.5–11.0×109/L)	12.20
Neutrophils (40–75%)	68.29
Eosinophils (0.0–6.0%)	0.41
Basophils (0.0–1.0%)	0.24
Lymphocytes (15.0–45.0%)	23.96
Monocytes (2.0–11.0%)	7.10
Platelets (150–540×109/L)	499
Sedimentation rate (<20 mm/h)	120
C reactive protein (<5.0 mg/L)	196.8
Urea (15.0–40.0 mg/dL)	22
Creatinine (0.51–0.95 mg/dL)	0.80
Sodium (136–145 mEq/L)	139
Potassium (3.50–5.10 mEq/L)	4.1
Chlorine (98–106 mEq/L)	99
Calcium (8.8–10.8 mg/dL)	9.8
Proteins (66–83 g/L)	84.6
Albumin (35–52 g/L)	37.0
Bilirubin (0.3–1.2 mg/dL)	0.44
Aspartate aminotransferase (<35 U/L)	17
Alanine aminotransferase (<35 U/L)	16
Creatine kinase (<145 U/L)	60
Iron (60–180 μg/dL)	12
Lactate dehydrogenase (<247 U/L)	182
Ferritin (11–307 ng/mL)	160
Transferrin (2.00–3.60 g/L)	1.93

Investigations

Blood cultures and urine culture were sterile. Serologies for HIV infection (fourth generation test), hepatitis virus, Coxiella and Brucella were also negative. Investigation of anaemia revealed normal ferritin, no vitamin deficits, normal thyroid function and negative Coombs’ test.

A transthoracic echocardiogram revealed no signs of endocarditis or valvular disease.

As there was no evidence of infection after the first stage of investigation, we directed our study to possible immunological and neoplastic causes.

The patient had positive antinuclear antibody (ANA; 1/160, granular pattern) without specificity in an ELISA study, without complement consumption, negative antidouble stranded DNA, negative antiphospholipid antibodies, negative antineutrophil cytoplasmic antibody or negative rheumatoid factor. Electrophoresis of protein was normal and there was no proteinuria in 24 h urine collection.

CT of the thorax and abdomen was performed, which excluded the presence of abnormal lymph nodes or other signs of lymphoproliferative disease or tuberculosis. Since of an abnormally thickened aortic wall, the study was complemented with angio-CT, confirming regular concentric wall thickening of the entire aorta, from the aortic valve to the iliac bifurcation (figure 1). There was no involvement of the major branches of the aorta, and no stenosis or aneurysmal dilatations. These findings were suggestive of aortitis.

Figure 1.

Angio-CT of the aorta, coronal (left) and transversal (right) view: thoracic and abdominal aorta with regular continuous concentric thickening of the vascular wall (white arrows).

Differential diagnosis

The differential diagnoses of isolated aortitis include infectious and autoimmune aetiologies.^3–5 Infectious aetiologies include acute bacterial infections, syphilis, tuberculosis and HIV infections.^{3 6} Autoimmune aetiologies include large vessel vasculitis, such as TA, GCA and Behçet's disease.^{3 7}

Acute bacterial infection and HIV were excluded by the earlier examinations. Imaging studies did not find any sign of tuberculosis, and blood culture directed to mycobacteria was negative (BACTEC system). Venereal Disease Research Laboratory test was negative.

Behçet's disease was not probable without other signs of disease such as arthralgia, skin lesions, oral–genital ulcerations or uveitis.

We checked for other signs of large vessel vasculitis but the patient had no tenderness or thickening in temporal arteries or changes of peripheral pulses. Carotid and vertebral Doppler were normal. Retinal disease was excluded by ophthalmological examination.

We arrived at the definitive diagnosis of isolated (idiopathic) aortitis; the patient presented no further symptoms or diagnostic criteria suggestive of TA or GCA; it is remarkable that her age was intermediate between the typical age presentations of these two entities.

Biopsy was not performed because there was no involvement of peripheral vessels. It was not possible to perform a fluorodeoxyglucose positron emission tomography before beginning treatment.

Treatment

The patient began treatment with prednisolone 1 mg/kg/day with good clinical and laboratory response. Fever and malaise disappeared in the first 48 h and laboratory abnormalities normalised in 2 weeks. Methotrexate 15 mg/week was added as corticoid sparing agent and corticosteroids were tapered progressively.

Outcome and follow-up

After 6 months of treatment, the patient is taking 7.5 mg/day of prednisolone and continues methotrexate. She has no symptoms and blood tests are normal, with Hb 13 g/dL, sedimentation rate 13 mm/h and CRP 2.0 mg/L.

Unfortunately, the patient experienced adverse effects from corticosteroids, including weight gain, hypertrichosis and anxiety.

Discussion

Febrile illness can be a challenging clinical situation and, in rare cases, data from clinical history, physical examination and blood tests is not sufficient for diagnosis. In this particular case, CT scan was key in establishing the diagnosis.

Aortitis is an inflammation of the aortic wall and may have various causes, including infectious and non-infectious.^3–5 When it is caused by common bacteria such as Staphylococcus or Salmonella, it is said to be pyogenic, and courses with acute septic disease and positive blood cultures.⁶ There are more insidious infectious causes, such as tuberculosis, syphilis or HIV,^{3 6} all excluded during the investigation.

Within the inflammatory causes, we should consider vasculitis of large vessels, such as TA, GCA and Behçet's disease.^{3 7} The patient did not present symptoms or diagnostic criteria suggestive of systemic lupus erythematosus.

Behçet's disease is associated with vasculitis in vessels of various sizes, including the aorta.⁸ Diagnosis is based on the classical clinical signs such as oral–genital ulceration, uveitis, arthralgia and cutaneous lesions,⁸ which were absent in this case.

TA is a rare disease primarily affecting women in the second and third decades of life.^{9 10} It is a panarteritis that affects the aorta and its branches, as well as the pulmonary artery.¹⁰ Chronic inflammation induces fibrosis and vascular fragility, with consequent development of stenosis or aneurysm.¹⁰ It manifests as constitutional symptoms of systemic inflammation and by local vascular complications such as ischaemia or aneurysm rupture.¹⁰

GCA affects older ages, typically during the seventh and eigth decades of life.³ It often affects the branches of the external carotid artery, including the ophthalmic artery. It is generally associated with osteomuscular pain (polymyalgia rheumatica).³ It can be associated with vasculitis of the aorta and its branches, manifesting similarly to TA.³

No specific serological tests exist for TA and GCA,^9–11 rendering definitive diagnosis difficult. The diagnosis is based on suggestive clinical findings and imaging tests.^9–11 When there is disease in superficial vessels, a biopsy can confirm the diagnosis. The American College of Rheumatology established classification criteria for both diseases in 1990 (box 1).

Box 1. Criteria for the classification of large vessel vasculitis, American College of Rheumatology in 1990^{9 11}.

Criteria for the classification of Takayasu arteritis*

1. Age at disease onset <40 years

2. Claudication of extremities

3. Decreased brachial artery pulse

4. Difference of >10 mm Hg in systolic blood pressure between arms

5. Bruit over subclavian arteries or aorta

6. Arteriogram abnormality (narrowing or occlusion of the entire aorta, its primary branches or large arteries in the proximal upper or lower extremities)

Criteria for the classification of giant cell (temporal) arteritis†

1. Age at disease onset ≥50 years

2. New headache

3. Temporal artery tenderness to palpation or decreased pulsation

4. Elevated erythrocyte sedimentation rate

5. Abnormal artery biopsy (vasculitis characterised by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells)

* 3 of 6 criteria are needed for classification as Takayasu arteritis

† 3 of 5 criteria are needed for classification as giant cell arteritis

Angiography is considered the gold standard diagnostic test; however, it only shows changes of the vascular lumen but not of the vessel wall and, therefore, gives little information regarding activity of disease.^3–5 Current CT and MR equipment permit observation of the thickness of the vascular wall, which is a marker of inflammation, and therefore has greater diagnostic accuracy with less risk.^3–5

The recently described IgG4-related disease has been associated with aortitis. This finding comes from reports of operated aortas with unexpected infiltration of lymphocytes and plasma cells with histological characteristics typical of this disease.¹² Unlike this case, in IgG4-related disease there is no significant systemic inflammatory response.

Isolated aortitis can be the sole or initial manifestation of a large vessel vasculitis such as TA or GCA.¹³ Cases of isolated aortitis without other vascular lesions are described in the literature.^13–15 Most are diagnosed incidentally or after a complication, for example, an aortic aneurysm.^14–16 These entities do not normally manifest systemic symptoms, they can be benign with generally good outcomes, despite the absence of anti-inflammatory therapy.^{14 15} Indications for treatment in this situation is controversial.^{14 17} In our case, systemic manifestation predominates the clinical picture, which suggests an active inflammatory disease and an insidious process, typical of TA or CGA. For this reason we decided to start systemic immunosuppressor treatment.

Regarding treatment, TA and GCA have similar approaches. Since the amount of observational studies and clinical trials is limited, treatment is based mainly on expert experience.¹⁸

The first-line treatment is systemic corticosteroids in a dose of 1 mg/kg/day of prednisone (or equivalent).^{3 10 18} In severe cases, cyclophosphamide is used.^{10 18}

Corticosteroids should be progressively weaned to doses below 10 mg/day after approximately 3 months.¹⁸ The disease tends to evolve by flares, and therefore some experts suggest adding an immunosuppressor to reduce the cumulative dose of corticosteroids. The most commonly used immunosuppressants are methotrexate and azathioprine.^{10 18}

Some cases of refractory disease responsive to novel biotechnological drugs have been reported, especially using tocilizumab (anti-interleukin 6).^19–21

Monitoring of large vessel vasculitis is another controversial issue since there are no validated activity scores.¹⁰ Clinical signs and routine inflammatory markers, although useful, are not sufficiently good indicators of vascular inflammation, since it is demonstrated that vasculitis may remain active even after normalisation of inflammatory parameters.¹⁰

Learning points.

• Persistent fever alone can be the manifestation of an occult severe disease.

• Knowledge about rare diseases facilitates the diagnosis in subtle cases.

• Development of imaging technology has improved diagnosis accuracy, especially when the clinical signs are insufficient.

• Isolated aortitis may be the sole manifestation of large vessel vasculitis such as Takayasu's arteritis or giant cell arteritis.