Takayasu’s arteritis in an adolescent with fever of unknown origin: the contribution of PET–CT in the diagnosis

Abstract

Finding the cause of fever of unknown origin can sometimes be a real challenge. We present an adolescent whose diagnosis was achieved after 4 months of fever onset by performing a positron emission tomography (PET)–CT. A young woman presented with prolonged, intermittent fever along with inflammatory and iron deficiency anaemia, loss of weight and abdominal and chest pain. First investigational studies showed high-titre positive antinuclear antibodies, extractable nuclear antibodies and anti-Sjögren's-syndrome-related antigen a autoantibodies (anti-SSA), and mild pericardial effusion and aortic regurgitation, but without meeting criteria for systemic lupus erythematosus. She had maxillary sinusitis that did not resolve with antibiotics. Further study displayed elevated calprotectin in faeces. After normal abdominal ultrasound and CT, an intestinal MRI showed thickening of the terminal ileum, orienting towards an inflammatory bowel disease. A colonoscopy showed only minor macroscopic changes. A PET–CT scan was finally requested, which exhibited a diffuse increase in metabolism in the wall of the thoracic and abdominal aortas, suggesting Takayasu’s arteritis.

Background

Takayasu’s arteritis (TAK) is an idiopathic, granulomatous, chronic, large-vessel vasculitis affecting the wall of the larger arteries, mainly the aorta and its major branches, which can lead to the development of stenosis, obstruction or aneurysms.¹ Young women are typically affected, and the incidence changes greatly between regions, being more frequent in Eastern countries.

The symptoms are varied, from being asymptomatic to prolonged fever, weight loss, cardiovascular problems, blood pressure difference between extremities, dizziness and syncope. Diagnosis is difficult and often late, so treatment is started in advanced stages of the disease. Due to the wide spectrum of symptoms, the diagnosis is usually made by elevation of acute-phase reactants in blood studies, image studies performed for other reasons or as a casual finding.

TAK is a chronic and complicated disease which usually needs lifelong corticosteroids and immunosupressants. A delayed diagnosis can make the disease progress and produce irreversible changes.

We report the case of a teenager with prolonged, intermittent fever of unknown origin (FUO) who was admitted to the hospital several times, taking more than 4 months to reach a proper diagnosis, which was finally achieved by performing a positron emission tomography (PET)–CT.

Case presentation

A teenage girl with a history of iron deficiency anaemia attributed to menstrual losses undergoing treatment with oral iron was admitted for study due to 2 week-long FUO along with tiredness, intermittent nausea, headache, chest and abdominal pain with constipation, and 2 kg weight loss. The anaemia had worsened, requiring intravenous iron, and she displayed elevation of acute-phase reactants.

On physical examination, she looked pale, with normal blood pressure and heart rate, and had some small palpable cervical lymphadenopathies. The rest of the examination was unremarkable.

During admission, fever decreased spontaneously. Very mild pericardial effusion was found that did not require treatment. A left maxillary sinusitis was found in head MRI, and she was discharged 7 days later with a 14-day treatment with oral amoxicillin–clavulanate and nasal corticoids. As outpatient, asthenia worsened and she continued with low-grade fever. Two months later, pericardial effusion increased and she received a cycle of ibuprofen with effusion resolution. A CT scan of the sinuses showed persistence of the maxillary sinusitis, and she received a second cycle of antibiotics with moxifloxacin with secondary diarrhoea. Abdominal CT scan did not reveal any sign of TAK. An assessment was requested by the ear, nose and throat service that programmed a nasal endoscopic surgery 1 month later that was not carried out in the end. Subsequently, calprotectin in faeces, mildly elevated on first admission, was repeated, showing an important increase (table 1). Suspecting that she might have an inflammatory bowel disease, an intestinal MRI was requested, which showed thickening of the terminal ileum. A colonoscopy was programmed but had to be postponed because she developed an acute gastroenteritis due to Campylobacter jejuni needing a hospital admission for a second time for treatment with IV fluids and azithromycin. After resolution of the diarrhoea a week later, the colonoscopy showed minimal macroscopic changes but some inflammatory changes in microscopy suggesting a possible Crohn’s disease. Because she did not show major changes in colonoscopy but continued with low-grade fever, asthenia and worsening analytical data, she was admitted for a third time to continue the study and assess the response to corticoids. A PET–CT was performed showing inflammation of great vessels (table 1), suggesting TAK. The vessel changes shown in an angio-MRI confirmed the diagnosis. An ultrasonography was not performed in this patient.

Table 1.

Main performed investigations

	First admission	Outpatient	Second admission	Third admission
From symptom onset	2–3 weeks	9–12 weeks	13 weeks	15 weeks
Haematology tests
Leucocytes (×109/L)	10.8	12.4	6.9–10.0	10.6–13.0
Haemoglobin (g/L)	7*7	10.7	10.9	8.2
MCV (fL)	63.2	69.7	70.8	71.7
ESR (mm/hour)	80
Biochemistry tests
CRP (mg/L) (N <3)	137		124–138	243
Ferritin (ng/mL)	146	553		541
Fe (µg/dL)	14	22		13
TSI (%)	6.3–9.2	11.2		10.1
LDH (IU/L) (N 135–235)				141–164
TSH (µU/mL)	1.89
ANAs	+ (citoplasmic pattern)
ENAs	++
Anti-SSA Ab	+++
ANCAs	–
C3 (mg/dL) (N 75–140)	163			151
Faeces
Calprotectin (ng/g) (N <30)	274	2411
Occult blood (×3)	–
Urinalysis	N		N
Microbiology tests
Serologies	–
Leishmania PCR	–
Blood, urine cultures	–		–	–
Stool culture	–		Campylobacter jejuni
IGRA	–
Clostridium difficile Ag			–
Image studies
Chest X-ray	N
Abdominal ultrasound	N
Echocardiography	Mild pericardial effussion		Mild pericardial effusion/aortic regurgitation
Gastrointestinal transit	N
Abdominal CT	N
Brain MRI	Left maxillary sinusitis	Left maxillary sinusitis
Intestinal MRI		Thickening of the terminal ileum
MR angiography				Inflammation of the wall of the thoracic and abdominal aorta and supra-aortic trunks
PET–CT				Increase in metabolism in thoracic and abdominal aorta
Colonoscopy				Macroscopy: minimal changes in the terminal ileum Microscopy: compatible with Crohn’s disease

*IV iron administered.

ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; CRP, C reactive protein; ENA, extractable nuclear antibody; ESR, erythrocyte sedimentation rate; IGRA, interferon-gamma release assay; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; MR, magnetic resonance; N, normal; PET, positron emission tomography; TSH, thyroid-stimulating-hormone; TSI, transferrin saturation index.

The most representative images of the PET–CT are shown in figures 1 and 2.

Figure 1.

Young woman with fever of unknown origin for 4 months. Fluorodeoxyglucose F 18 (18F-FDG) PET and PET/CT show diffuse and extensive uptake in ascending (A, A’) and descending (B, B’) thoracic aorta, suggestive of vasculitis. PET, positron emission tomography.

Figure 2.

18F-FDG uptake involving the abdominal aorta. Axial (A), sagittal (B) and coronal (C) 18F-FDG positron emission tomography views.

Investigations

The principal investigations that were performed in the patient throughout the three admissions and outpatient follow-up are shown in table 1.

Differential diagnosis

She was admitted to the hospital for the first time due to FUO, constitutional syndrome, inflammatory and iron deficiency anaemia, and elevation of acute-phase reactants. Causes of FUO are shown in table 2.

Table 2.

Causes of fever of unknown origin in children

Causes
Infections
Generalised infections.
Common causes. Tuberculosis. Salmonella. Cat-scratch disease. Malaria.* Viral infection (EBV, CMV, adenovirus and parvovirus). Less common causes. Toxoplasmosis. Visceral leishmaniosis. Brucellosis. Leptospirosis. Other rare causes (tularemia, fungal infections, rickettsioses, etc).
Localised infections.
Infective endocarditis Intra-adbominal. Osteomyelitis and septic arthritis. Upper respiratory infection (sinusitis, peritonsillar abscess, etc). Urinary tract infection.
Rheumatological diseases
Juvenile idiopathic arthritis. Systemic lupus erythematosus. Mixed connective tissue disease. Vasculitis.
Malignancies
Leukaemia. Lymphoma. Other less common (sarcoma, hepatoma and neuroblastoma).
Miscellaneous
Inflammatory bowel disease. Haemophagocytic lymphohistiocytosis. Central nervous system dysfunction. Diabetes insipidous. Ectodermal dysplasia. Periodic fevers. Pancreatitis.	Thyrotoxicosis.  Familial dysautonomia.  Factitious fever.  Kikuchi disease.  Sarcoidosis.  Serum sickness.  Drug hypersensitivity.

CMV, Cytomegalovirus; EBV, Epstein-Barr Virus.

Serological studies, bacterial cultures and interferon-gamma release assay study ruled out the main generalised infectious causes in our environment. A possible localised infectious origin was the subacute–chronic maxillary sinusitis, and she received amoxicillin–clavulanic acid for this without improvement.

Because of her anaemia of chronic disease, pericardial effusion and positive autoimmune laboratory tests, a rheumatological cause was suspected, but diagnostic criteria for connective tissue diseases were not met. Sinusitis can be a manifestation of granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), but she had negative ANCA studies and a normal urinalysis. HLAB52 was not studied in this patient. A possible autoinflammatory syndrome was also considered, but it produces periodic/recurrent fever usually of shorter duration (an exception is tumour necrosis factor receptor-associated periodic syndrome) accompanying the clinical symptoms, with frequent joint and skin involvement, absent in our patient. These syndromes have asymptomatic periods with no acute-phase reactants in laboratory tests between fever episodes,² and they do not display autoantibodies, as it happened in our patient.

Due to the repeated elevation of calprotectin in the stool, together with the symptoms of constitutional syndrome and intermittent diarrhoea, the diagnosis of inflammatory bowel disease was raised. However, the minimal macroscopic changes at the colonoscopy supported neither the persistence of clinical symptoms nor the worsening of analytical data. Laboratory tests supported an inflammatory cause rather than an occult malignancy. However, as a definite diagnosis was not yet met, a PET–CT was finally performed that led to the diagnosis of TAK.

Treatment

Boluses of methyl-prednisolone were administrated at 1 g/day for 3 consecutive days; later, oral prednisone at high doses and subcutaneous methotrexate were prescribed. Two months later, adalimumab was associated, and methotrexate was subsequently taken orally but had to be suspended due to poor gastrointestinal tolerance.

Outcome and follow-up

Two years later, the patient is currently undergoing treatment with adalimumab 40 mg every 28 days subcutaneously, with great clinical improvement. Currently, she is completely asymptomatic and leads a normal life as a student.

Discussion

FUO can be a diagnostic challenge due to the many causes involved (table 2). In children, infections are the main aetiology (59% bacterial; 7% viral, especially Ebstein-Barr virus infection; and 10% parasitic, mainly visceral leishmaniosis in low-income countries but also in Spain).^{3 4} Certain infections as tuberculosis are important in endemic areas. All these causes were investigated and ruled out in our patient.

Collagen vascular diseases are the second most frequent aetiology, especially in older children and adolescents (ranging from 5% to 22%).³ The systemic form of juvenile idiopathic arthritis is the main entity. Neoplastic processes must be ruled out too.

The longer the fever lasts and the older the patient, the lower the probability of infectious aetiology. This is why further investigations were performed in our patient,⁵ but no cause was found after 4 months of follow-up.

Positron emission tomography (PET) is based on the distribution of deoxyglucose labelled with a positron-emitting radiopharmaceutical. Therefore, it follows the metabolic pathway of glucose, accumulating in cells with higher rates of metabolism. It can detect diseases even before presenting morphological changes.⁶ Complementing this technique with a CT scan and superimposing both images, we obtained a precise anatomical correlation of the metabolic activity in the image (PET–CT).⁷

FUO appears to be an accepted indication for fluorodeoxyglucose (FDG) PET in clinical practice. The non-specificity of FDG is of great value in evaluating patients with FUO because it accumulates in infections, malignancies and inflammatory diseases, which are the three major causes of FUO.

Currently, several studies show that PET–CT is effective in the detection of vasculitis of the great vessels and in the evaluation of the extension of the disease, with great sensitivity and specificity, making it an excellent diagnostic test, especially in patients in the pre-stenotic phase or with small aortic segment involvement,⁸ where reaching the diagnosis may be more difficult using other radiological techniques. Unfortunately, as vasculitis is a very rare disease, paediatricians may not consider performing a PET–CT in the context of FUO when a rheumatology cause is suspected, as it happened in our patient. This is especially important in TAK. The disease occurs in two phases, an acute inflammatory phase (with fever, constitutional symptoms, arthralgia, myalgia and acute-phase reactants) that may be self-limited and may go undiagnosed, but can lead to the occlusive, irreversible phase, characterised by ischaemic manifestations, where the response to an immunosuppressant is relatively poor.^9–11 That is why PET–CT was so useful in this case, as it helped to make an earlier diagnosis in the acute phase of the disease where treatment was more effective.

The results of the study performed in our patient are evaluated in two ways: one visual (based on diffuse and homogeneous uptake in the vascular wall), and on the other hand, the uptake index is evaluated. The uptake indices of the SUVmax value (g/mL) of the vascular wall with respect to the hepatic SUVmax (g/mL) were calculated and the 4-point scale (0–3) described by Meller et al,¹² which assesses the uptake of the wall of a vascular segment with respect to the hepatic uptake: 0, no uptake; 1, uptake less than the liver; 2, uptake similar to the liver; and 3, uptake higher than the liver. PET criteria indicative of vasculitis (positive) are considered a grade 3 for the thoracic aorta and a grade ≥2 for the rest of the vascular segments.

According to the American College of Rheumatology, there are six criteria which are mandatory for the TAK diagnosis.¹³ Four of the six criteria are the consequence of arterial stenosis. Our patient met only two of the six criteria, as she was diagnosed in the prestenotic phase. However, she met the criteria for childhood TAK according to European Alliance of Associations for Reumathology (EULAR)/Paedriatic Reumathology International Trials Organisation (PRINTO)/Paediatric Reumathology European Society (PReS),¹⁴ supporting the higher sensitivity and specificity of these criteria (table 3).

Table 3.

Childhood Takayasu arteritis criteria (EULAR/PRINTO/PReS)

Mandatory

Additional (at least one)

Angiographic abnormalities of the aorta or its main branches and pulmonary arteries showing aneurysm/dilatation

Pulse deficit (lost/decreased/unequal peripheral artery pulses) or claudication (focal muscle pain induced by physical activity). Four limbs blood pressure (BP) discrepancy (discrepancy of four limbs BP >10 mm Hg difference in any limb). Bruits (audible murmurs or palpable thrills over large arteries). Hypertension (systolic/diastolic BP greater than the 95th centile for height). Acute-phase reactant (erythrocyte sedimentation rate >20 mm per first hour or CRP any value above normal.

BP, blood pressure; CRP, C reactive protein.

As described, she also displayed some gut inflammation associated with her disease.¹⁵ PET–CT is currently the best way to start the diagnosis of TAK since it is easy to perform, with few side effects, and provides great information about the state of the disease. The sensibility is around 92% and the specificity is 100% for the diagnosis of this disease. However, angiography is required for the definitive diagnosis.¹⁶ It could also be useful in recurrences and in the assessment of the response to treatment,¹⁷ but the findings should accompany clinical suspicion of activity.¹⁸ In our case, performing a PET–CT made it possible to reach the diagnosis and to initiate appropriate treatment, improving her quality of life and the prognosis of the disease.

Learning points.

• Positron emission tomography (PET)–CT can be extremely useful for the diagnosis of fever of unknown origin when conventional studies are inconclusive.

• PET–CT is able to detect active rheumatological disorders, allowing for early treatment.

• PET–CT seems particularly indicated in the acute phase of Takayasu’s arteritis (TAK), before morphological changes can be detected.

• Early immunosuppressive treatment can dramatically change the prognosis of TAK disease. This is why multiple imaging studies are warranted for its initial diagnosis.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).