Giant cell arteritis manifested by chronic dry cough

Abstract

A 77-year-old man visited the hospital with a chronic cough persisting for 2.5 months accompanied with night sweats, weight loss (3.5 kg) and elevated C-reactive protein level. Chest CT of the lung field was normal, but aortic wall thickening accompanied by a contrast effect was noted. Positron emission tomography–CT (PET–CT) showed that the aorta and subclavian artery were inflamed, suggesting large-vessel vasculitis. Ultrasonography showed thickening of the superficial temporal artery wall (macaroni sign). Biopsy revealed lymphocytic infiltration in the tunica media and foreign-body giant cell reaction with the elastic lamina, resulting in a diagnosis of giant cell arteritis (GCA). The cough was considered a symptom of GCA as it resolved following prednisolone administration. Cough may rarely be an initial GCA symptom. However, for chronic cough accompanied with elevated inflammatory findings but with a normal lung field, imaging studies such as PET–CT are useful for the differential diagnosis.

Background

Chronic cough is defined as a cough that persists for more than 8 weeks.¹ In Europe and America, cough-variant asthma, gastro-oesophageal reflux disease (GERD), and upper airway cough syndrome are common diseases that cause adult chronic cough despite normal chest X-ray and chest auscultation findings.²

If the cause of chronic cough is unclear, chest X-ray is recommended. Smoking cessation and ACE inhibitor therapy discontinuation are also generally advised. Researchers suggest the introduction of an empirical treatment that assumes the presence of upper airway cough syndrome, cough-variant asthma and GERD even without abnormal chest X-ray results.³

If the empirical treatment does not succeed or the patient has bloody sputum, night sweats and weight loss, chest CT and sputum tests should be performed to rule out lung cancer and tuberculosis.

Giant cell arteritis (GCA) may present respiratory symptoms that can cause chronic cough.⁴

Chronic cough in GCA does not show any abnormality in X-ray and CT, and GCA is difficult to diagnose using management algorithms such as the CHEST guidelines.

Hence, GCA should be considered as a differential diagnosis in the case of chronic cough before the development of serious complications such as vision loss. In this case report, we describe a case of GCA, with chronic cough as the primary symptom.

Case presentation

A 77-year-old man with dry cough that persisted for 2.5 months prior to consultation was admitted to our hospital. Initially, his primary care doctor prescribed garenoxacin, but the effect was poor.

One month before admission, he experienced night sweats, and his body weight decreased by approximately 3.5 kg. He consulted his primary care doctor again, and his medication was changed to clarithromycin and dextromethorphan; however, the cough did not improve. He also experienced a mild dull headache in the left head region, prompting him to seek consultation in a neurosurgery clinic. He underwent head CT, which revealed no abnormalities. Tulobuterol tape and mometasone furoate inhalation were prescribed 2 weeks before admission. The cough still did not improve. Hence, he was referred to our hospital. He did not experience fever throughout the hospital course.

The cough was dry, and no respiratory distress or chest pain was noted on exertion. Neither abnormalities in visual acuity or hearing nor signs of the jaw or upper limb claudication were noted. However, claudication of the lower limb was observed. He had ceased cigarette smoking when he was 60 years old.

On consultation, his vital signs were as follows: body temperature, 36.9°C; blood pressure, 145/77 mm Hg; pulse, 88 beats/min and oxygen saturation (room air), 98%. Cord-like structures were palpated in the bilateral temporal arteries, and the beat was reduced on the right side. Chest auscultation sounds were normal. No vascular murmurs were heard in the cervical or supraclavicular regions. Furthermore, no abnormalities were detected in the oral cavity, auricle or eye region.

On blood testing, his haemoglobin level was 111 g/L (normal range, 120–176), indicating mild anaemia, and his platelet count was high (391×10⁹/L; normal range, 130–369). In addition, his alkaline phosphatase level (327 U/L; normal range, 106–322), C-reactive protein (CRP) level (7.18 mg/dL; normal range, 0–0.14) and erythrocyte sedimentation rate (ESR; 84 mm/hour; normal range, 0–15) were elevated. Serine proteinase 3-anti-neutrophil cytoplasmic antibody and myeloperoxidase-anti-neutrophil cytoplasmic antibody were both <1.0 U/mL, which were negative, and his ferritin level was elevated to 358.9 ng/mL (normal range, 4.2–136.7). Moreover, the syphilis reaction (rapid plasma reagin and Treponema pallidum hemagglutination test) and investigations for hepatitis B, hepatitis C and HIV were negative, and the antinuclear antibody titre was less than 1:40, which was negative.

Investigations

Contrast-enhanced CT revealed wall thickening accompanied by a contrast effect in the bilateral subclavian arteries and aorta extending from the thoracic aorta to the bilateral common iliac arteries (figure 1). On positron emission tomography–CT (PET–CT), uptake was detected at sites corresponding to the regions with thickened walls, and it was especially marked in the bilateral subclavian arteries (figure 2). Therefore, the great vessels were inflamed. Contrast-enhanced CT and PET–CT revealed no abnormalities in the lung field or pulmonary vessels.

Figure 1.

Contrast-enhanced CT findings. Wall thickening (arrow head) was noted in the early arterial phase (A), and the regions with thickened walls were enhanced in the delayed phase (B).

Figure 2.

Positron emission tomography–CT findings. Uptake was evident in the regions of the descending aorta with wall thickening. Uptake was noted in an extensive region of the aorta, extending from the thoracic aorta to the common iliac artery, and it was more evident in the bilateral subclavian arteries.

Temporal-artery ultrasonography revealed circumferential thickening of the wall of the bilateral superficial temporal arteries and narrowing of the inner lumen (macaroni sign) (figure 3). On biopsy of the superficial temporal artery, the intimal thickening was severe, lymphocytes and neutrophils infiltrated in the tunica media and giant cells were present. Elastic van Gieson staining confirmed a foreign-body giant cell reaction with the elastic lamina, which was consistent with the findings of GCA (figure 4).

Figure 3.

Ultrasonography findings of the temporal artery. The wall of the superficial temporal artery thickened circumferentially, and the inner lumen was narrowed (macaroni sign).

Figure 4.

Pathological findings (biopsy of the superficial temporal artery). (H&E staining) Intimal thickening was severe, with lymphocytic infiltration in the tunica media. Foreign-body giant cell reaction was also noted (arrow head) (EVG: Verhoeff-Van Gieson staining). The elastic lamina was ruptured.

Differential diagnosis

Based on the inflammatory findings of the great vessels on contrast-enhanced CT and PET–CT, GCA, aortitis, infectious aortitis, syphilis, Behçet’s disease and systemic lupus erythematosus were included in the differential assessment.

Considering that the blood culture and the serological reaction for syphilis were both negative, we ruled out infection-associated large-vessel vasculitis. Additionally, Behçet’s disease was excluded because the patient had no previous history of stomatitis. Given that the antinuclear antibody was negative, systemic lupus erythematosus (SLE) was also excluded. Furthermore, aortitis was considered unlikely because the patient was elderly.

The patient’s age (≥50 years old) and the occurrence of newly developed headache, beat reduction of the temporal artery, and ESR elevation conformed to the American College of Rheumatology classification criteria. Therefore, together with the results of biopsy of the temporal artery, the patient was ultimately diagnosed with GCA.⁵

Treatment

A rheumatologist was consulted, and the patient was administered 30 mg prednisolone at 0.5 mg/kg/day because he was elderly and had no fever and eye ischaemia.

Outcome and follow-up

One week after administration of prednisolone, the CRP level became negative and the cough and dull headache were resolved. Four weeks after administration, claudication of the lower limb was resolved and we started tapering the prednisolone dose. The cough and claudication of the lower limb were judged as being due to GCA.

Discussion

This report presents a rare case of chronic cough with aortic inflammation that was caused by GCA. The clinical course of this case presented the following clinical questions:

1. Does GCA cause chronic cough? What is the mechanism?

2. When should GCA be suspected in patients with chronic cough?

3. How should we diagnose chronic cough caused by GCA?

Does GCA cause chronic cough? What is the mechanism?

Chronic cough may present as the primary symptom of GCA.⁴ GCA is a disease that occurs through the pathological development of granulomatous vasculitis accompanied with giant cells in the aorta and its main branch arteries.

When GCA is localised to the cranial area, such as to the temporal artery, it is designated as cranial GCA (C-GCA), whereas cases that are not localised to the cranial area, with arteritis present outside the cranial area, are referred to as large-vessel GCA (LV-GCA).⁶

The affected blood vessels are different between LV-GCA and C-GCA; thus, differences in the frequency of symptoms are also expected.

In a study of 66 patients with GCA in Japan, many symptoms were considered as signs of C-GCA, generally referred to as temporal arteritis, and none of the patients showed respiratory manifestation at onset.⁷

Meanwhile, respiratory symptoms are considered as signs of LV-GCA. In a retrospective study of the initial symptom of GCA in 260 patients, cough was the initial symptom in 21 patients (8%).⁴ Cough is non-productive in many cases and is relatively rare in GCA.^{8 9}

The mechanism of cough in GCA has remained poorly understood. Nonetheless, vasculitis of large-sized and medium-sized pulmonary vessels and ill-defined granulomas in the alveolar epithelium and bronchial wall have been identified in the biopsy of patients with polymyalgia rheumatica and GCA. Thus, cough may be induced by the stimulation of cough receptors in the bronchus due to aortic inflammation.^{10 11}

These changes are difficult to detect as lung lesions in the CT, and imaging tests often show no abnormalities in the lung fields.

When should GCA be suspected in patients with chronic cough?

Diagnosing GCA as a differential disease of chronic cough is challenging. In the present case, the patient also received antibiotics following repeated consultations, and more than 2 months had passed before he was referred to our hospital.

We found 11 case reports of patients diagnosed with GCA with cough as the main problem (table 1).^12–22 In many cases, more than 2 months had passed before the patients were finally diagnosed with GCA, implying that reaching GCA diagnosis is time-consuming.

Table 1.

Case reports of patients diagnosed with giant cell arteritis with cough as the main problem

No	Patient	Cough	Duration of cough	Other symptoms	Inflammatory marker	Chest imaging findings	TA biopsy	Treatment	Response of symptom(s)
112	57, M	Dry	3 months	Muscle aches, fever, weight loss and headache	ESR, 115 mm/hour	Unremarkable (CT)	Positive	Prednisone 60 mg	Improved immediately
213	70, F	Dry	3 months	Fever and weight loss	ESR, 110 mm/hour	Unremarkable (CT)	Positive	Prednisone 1 mg/kg	Improved in 1 week
314	74, M	Dry	2 months	Fever, weight loss, scalp tenderness and jaw claudication	ESR, 125 mm/hour CRP, 24 mg/dL	–	Positive	Prednisone 60 mg	Improved
415	75, F	Dry	1 month	Fever, weight loss chest pain, deafness, temporal headache and muscle aches	ESR, 58 mm/hour	Multiple nodules (chest CT)	Positive	Prednisone 60 mg	Improved
516	69, M	Dry	2 months	Occipital headache, neck and shoulder pain and fever	ESR, 102 mm/hour	–	Positive	Prednisone 60 mg	Improved in 3 days
617	74, M	Dry	2 months	Fever, weight loss and frontal headache	ESR, 75 mm/hour CRP, 19 mg/dL	Nodule, bronchiectasis, fibrosis,(CT)	Positive	Prednisone 60 mg	Gradually improved
718	60, F	Dry	4 weeks	Weight loss	CRP, 34 mg/dL ESR, 62 mm/hour	Spiculated nodule (CT) Uptake in the aorta (PET–CT)	Positive	Glucocorticoid (no dose mentioned)	Improved
819	54, F	Dry	10 weeks	Fever and shortness of breath	ESR, 120 mm/hour CRP, 18 mg/dL	Unremarkable (CT) Uptake in the aorta (PET–CT)	Positive	Prednisone 60 mg	Improved in 1 week
920	62, M	Dry	3 months	Fever, weight loss, headacheand myalgia	ESR, 96 mm/hour	Unremarkable (CT)	Positive	Prednisone 60 mg	Improved immediately
1021	79, F	Dry	>2 months	Weight loss, toothache and vision loss	ESR 115 mm/hour	Unremarkable (chest X-ray)	Positive	High-dose prednisone, then prednisone 60 mg	–
1122	87, F	Dry	1 month	Fever	ESR 87 mm/hour	Uremarkable (CT)	Positive	Prednisone 40 mg	Improved in a few days

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; F, female; M, male; TA, temporal artery.

GCA diagnosis is time-consuming if cough is the main problem, but it may be complicated by visual loss and ischaemic disease; hence, early diagnosis is important.

In a retrospective review of the medical records of 88 patients with GCA, dry cough was noted in 12 patients (13%), and the CRP level was high compared with that in patients without dry cough (15.38 vs 9.4 mg/dL, p=0.0131), which is characteristic of the disease.²³

As shown in table 1, all patients also had increased inflammation findings.

Thus, when dry cough is noted in elderly patients with high inflammatory reaction, possible GCA should be considered.

How should we diagnose chronic cough caused by GCA?

Generally, temporal-artery biopsy is performed to diagnose GCA in patients with chronic cough.

As shown in table 1, many patients were previously diagnosed by temporal-artery biopsy.

On the other hand, in a retrospective study investigating the initial symptom of GCA in 260 patients, cough was noted in 21 patients, and temporal-artery biopsy was performed in 12 patients (57%).⁴

Temporal-artery biopsy is not always positive in cases of GCA with cough as the main problem. This difference may be caused by the variations in the range of the affected blood vessels.

Previously, in LV-GCA without cranial vasculitis, temporal-artery biopsy was negative, without manifestation of headache.^{24 25}

In other words, in the case of an atypical sign such as chronic cough, LV-GCA should be considered as a differential diagnosis even if the patient has no headache and temporal-artery ultrasound or biopsy is negative.

Chest imaging is important for LV-GCA diagnosis. As previously mentioned, abnormal findings in the lung field are often undetected by CT in many cases, as revealed in table 1. We should thus focus on the great vessels and not the lung field.

Aortic aneurysm and aortic dissection were detected as complications of aortic inflammation.^26–28 Concentric mural thickening in GCA may be identified by CT angiography (CTA) even if the condition has not developed into a major morphological abnormality such as aneurysm formation. In a prospective study on the feasibility of using CTA to diagnose GCA, aortic inflammation was detected in 45%–65% of the patients.^27–29 The sensitivity of CTA is not high, but it is convenient and can be performed at many medical institutions.

Some guidelines recommend CTA or magnetic resonance angiography to identify inflammatory blood vessels and determine their distribution in patients with GCA.³⁰

Meanwhile, ¹⁸F-fluorodeoxyglucose (FDG)–PET can detect inflammation in GCA at the early stage.³¹ Therefore, FDG–PET is more sensitive than CTA. In a recent meta-analysis of patients with GCA, FDG–PET showed high sensitivity (90% (CI 79% to 93%)) and specificity (98% (CI 94% to 99%)) in detecting inflammation of the great vessels.³²

In a patient with GCA who only developed cough, large-vessel vasculitis was suspected according to the promoted incorporation into the aorta on PET–CT.¹⁹ In another report in which GCA was suspected according to similar findings and diagnosis made after temporal-artery biopsy, no typical signs of GCA were observed.³³

PET–CT may be a valuable diagnostic modality for patients with GCA manifesting atypical symptoms such as cough and those who are negative on temporal-artery biopsy.

To diagnose GCA, we should confirm the occurrence of concentric mural thickening through CTA combined with PET. Clarifying the presence or absence of uptake by PET–CT may be useful, as in the case of our patient.³⁴

PET–CT is also useful for differentiation of chronic cough in addition to GCA.

CT images are acquired in many cases of chronic cough accompanied with inflammation. In cases of bronchial tuberculosis, relapsing polychondritis (RP), GCA and intravascular lymphoma (IVL) without abnormal lung field findings detected on CT imaging, PET–CT has been reported to be useful for final diagnosis.^35–38

When no abnormality is present in the lung field on CT in patients with chronic cough accompanied with inflammation, PET–CT should be included in the examination options.

In conclusion, we report a case of chronic cough accompanied with inflammatory reactions such as the elevated CRP level. Large-vessel vasculitis was suspected on PET–CT. Through temporal-artery biopsy, the patient was diagnosed with GCA. GCA may rapidly impair the patient’s quality of life due to ischaemic symptoms such as claudication and visual disturbance. Hence, early diagnosis is important. Therefore, when chronic cough is accompanied with inflammation, imaging tests are important for GCA confirmation.

Patient’s perspective.

• I could not sleep due to my cough, and I was very sick. I did not know the exact name of the disease when I visited various medical institutions, and antibiotics did not work. There were also concerns about tuberculosis and cancer. However, an accurate diagnosis was given at the hospital, and the prescribed treatment began. After that, the symptoms disappeared. I am fine without complications so far. I am grateful for my doctor.

Learning points.

• Chronic cough can become the primary symptom of giant cell arteritis (GCA).

• We should consider GCA as a differential diagnosis in patients with cough accompanied with headache, visual impairment, claudication or inflammation.

• For chronic cough with inflammation, we should perform imaging tests.

• When no abnormality is detected in the lung field, we should examine the patient by CT angiography and/or positron emission tomography–CT (PET–CT).

• If PET–CT reveals ¹⁸F-fluorodeoxyglucose uptake in the wall of large vessels, ultrasound and temporal-artery biopsy should be considered for GCA diagnosis.