Introduction

Tuberculosis (TB) is caused by bacteria of the Mycobacterium tuberculosis complex and predominantly affects the lungs. Symptoms include fever, night sweats, fatigue, cough, and weight loss. In 2017, an estimated 10.0 million people (range 9.0–11.1 million) developed TB disease worldwide (5.8 million men, 3.2 million women and 1.0 million children). Extrapulmonary tuberculosis was present in 14% of TB incident cases [1].

Takayasu arteritis (TA) is a systemic granulomatous inflammation of the large and medium-sized arteries. Arterial thrombosis, occlusion, and aneurysms with end-organ ischemia are common complications [2]. The leading causes of death in TA are heart failure, hemorrhage and pulmonary infection [3]. Young women of child-bearing age seem to be more frequently affected than older women or men of any age group [4]. Annual incidences vary between 1/1,000,000 per year in Europe, 2/1,000,000 per year in Japan, 2.2/1,000,000 per year in Kuwait and 2.6/ 1,000,000 per year in North America. Reported female:male ratios range from 1.2:1 in Israel to 6.9:1 in Mexico [2]. The pathogenesis of TA is poorly understood. Several genetic loci associated with increased susceptibility have been identified, the most robust of which is located within the human leukocyte antigen (HLA) class I region [5]. However, environmental factors are also thought to play a role. TB has been discussed repeatedly as a possible cause or trigger of TA because lesions in the two diseases show histological similarities [6].

This report presents a case in which TA co-occurred with pulmonary and multiorgan TB and analyses previously published cases of co-occurring TA and TB.

Case report

A 20-year-old HIV-negative female from Syria presented with recurrent tenderness of the entire left thorax, present for the last 9 months, increasing dyspnea, subfebrile temperatures, and weight loss of 10 kg over the last 12 months.

The patient had arrived in Germany as a refugee from Syria 6 months before hospital admission and given birth to a healthy boy 1 month later. There were no other events in her past medical history, apart from iron deficiency anemia.

Clinical findings included reduced respiratory sounds at the base of the right lung, cachexia (body weight 48 kg, height 170 cm, body mass index 16.6 kg/m2), a difference of 14 mm Hg between the systolic blood pressures of the left arm (97/61 mmHg) and the right arm (111/73 mmHg), and bruits over the left subclavian artery and the common carotid arteries. The pulse of the left radial artery was weaker than the pulse of the right radial artery.

A chest radiograph and computed tomography (CT) scan of the thorax revealed an extensive pleural effusion on the right side accompanied by atelectasis of the adjacent lung tissue, a minor pleural effusion on the left side, disseminated miliary-like opacities in both lungs and lymphadenopathy of the mediastinum and the hili (Fig. 1). A magnetic resonance tomography (MRT) of the cranium revealed seven small ring-like, contrast medium-absorbing cerebellar lesions of up to 7.3 mm in size, and at least 16 supratentorial lesions of up to 5 mm in size in both cerebral hemispheres, consistent with intracerebral tuberculoma (Fig. 2). The interferon-gamma release assay (QuantiFERON-TB-gold-in-tube) was positive. Because of the high likelihood of pulmonary and extrapulmonary TB with cerebral tuberculoma and intrathoracic lymphadenopathy, antituberculous treatment was started with weight-adjusted daily oral doses of isoniazid/pyridoxine, rifampin, pyrazinamide and ethambutol. After three weeks of culture, the bronchoalveolar lavage (BAL) grew Mycobacterium tuberculosis.

Fig. 1
figure 1

A chest radiograph reveals extensive pleural effusion on the right side accompanied by atelectasis of the adjacent lung tissue, disseminated miliary-like opacities in both lungs and lymphadenopathy of the hili

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Fig. 2
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An MRT scan of the cranium revealed seven small ring-like, contrast medium-absorbing cerebellar lesions of up to 7.3 mm in size (arrow), and at least 16 supratentorial lesions of up to 5 mm in size in both cerebral hemispheres, consistent with intracerebral tuberculoma

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An MRT scan of the thoracic aorta revealed concentric mural thickening of the aortic arch and supra-aortic branches, a long stenosis of the left common carotid artery, a proximal stenosis of the right common carotid artery, and another stenosis of the middle section of the left subclavian artery. The vertebral arteries were normal (Fig. 3). Thickening and stenosis of the tunica intima of the extracranial sections of the carotid arteries and stenosis of the left internal and right external carotid arteries were revealed by duplex ultrasound. A diagnosis of concomitant TA was made. Prednisolone [initially 250 mg once daily (OD)] and oral acetylsalicylic acid (100 mg OD) were added to the treatment regimen, with prednisolone then gradually tapered to 7 mg OD.

Fig. 3
figure 3

An MRT scan of the thoracic aorta revealed concentric mural thickening of the aortic arch and supra-aortic branches, stenosis of the middle section of the left subclavian artery (A), a long stenosis of the left common carotid artery (B) and a proximal stenosis of the right common carotid artery (C). The vertebral arteries were normal

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The patient showed clinical and radiological signs of remission within the first year of follow-up with complete resolution of cerebellar and supratentorial lesions after 12 months of antituberculous therapy. No neurological symptoms were observed at first presentation or within the follow-up period. A follow-up duplex ultrasound showed no progression of carotid or subclavian arteritis. The bruits over the left subclavian artery and common carotid arteries persisted. In the twelfth month of follow-up, an MRT scan of the affected blood vessels showed vessel wall thickening and contrast medium enhancement along the thoracic aorta, consistent with radiological signs of active TA [7]. Immunosuppressive therapy was supplemented with a weekly dose of methotrexate (initially 15 mg subcutaneous administration [sc.], then 20 mg sc.) which, after an initial phase of remission, did not prevent a further relapse 6 months later, when an MRT scan showed the previous radiological signs of active vasculitis in the affected vessels and the descending aorta in particular. We decided to terminate methotrexate therapy and opt for anti-interleukin-6 agents, starting a weekly dose of tocilizumab (162 mg sc.). Seven weeks into the adjusted immunosuppressive therapy regimen the patient was in a good general state. A follow-up MRT scan is planned in a few months.

Search strategy

A systematic search of the literature on the electronic databases Pubmed and Scopus was conducted using the search terms “Takayasu’s arteritis AND tuberculosis” and “large vessel vasculitis AND tuberculosis” in October 2018. Criteria for inclusion in this study were reports in English or German language of patients with a diagnosis of TA (meeting the American College of Rheumatology [ACR] 1990 or EULAR/PRINTO/PRES classification criteria [8, 9]) and TB (previous active TB diagnosis and treatment or clinical evidence of active TB supported by tuberculin sensitivity testing/interferon-gamma release assay/acid-fast staining/culture/radiological imaging). The search yielded 78 case reports, 17 of which (describing 18 cases) met the inclusion criteria. The current case was also included for analysis.

Literature review and analysis

Most reports (15; 83.3%) were published in or after the year 2000. The mean age of patients presenting with co-occurrence of TA and TB was 16.8 (range 9–24), the female:male ratio was 3.8:1. The main presenting symptoms were fever (52.6%), weight loss, claudication of extremities (each 31.6%), cough, dyspnea and headaches (each 26.3%). One patient presented with a cervical mass, one with a reticulated rash, one because of a syncope episode and one with convulsion. Two patients had previously been treated for pulmonary TB (1 and 2 years earlier, respectively) and one had a previous diagnosis of papulonecrotic tuberculid before the first evidence of TA was found. In all other cases (16; 84.2%) diagnoses of active TB and TA were made simultaneously at presentation or a few weeks apart (Table 1). In two of these cases the patients had been treated for TB several years earlier. Another case report described a history of hypertension, possibly an early symptom of TA, in a young woman years before a concomitant diagnosis of TA and TB was made. The most frequently observed angiographic lesion types according to the angiographic classification of TA lesions proposed in 1994 [10] were type V (6; 31.6%) followed by types IV and I (4; each 21.1%) (Table 1). In five cases (26.3%) TA was associated with heart failure. TB limited to the lungs was only described in four cases (21.1%). Extrapulmonary TB (EPTB) was reported in 14 cases (73.7%), in three of which evidence of both pulmonary TB and EPTB was found. There was one case of intestinal TB, one case of renal TB and one case of papulonecrotic tuberculid. In one case tuberculous arteritis was suspected but could not be confirmed. Eleven reports (57.9%), including our case, described evidence of TB lymphadenitis (Table 1). In seven of these cases biopsies were performed. In three cases, biopsy showed caseating tubercles suggestive of TB lymphadenitis. In 4 cases, bacteriological confirmation by culture and/or Ziehl–Neelson staining was successfully performed from biopsy tissue of two cervical, one supraclavicular and one hilar lymph node [11,12,13,14].

Table 1 Co-occurrence of TA and TB: Cases from the literature review
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Corticosteroids were used in 17 cases (89.5%). In one case, concomitant Crohn’s disease led to the use of sulfasalazine and azathioprine without corticosteroids. All patients but one received both antituberculous and immunosuppressive therapy. Pantel et al. described an improvement in symptoms of TA and a return of pulses solely upon administration of antituberculous therapy [12]. Two reports described TA relapses upon corticosteroid tapering during/after antituberculous therapy, necessitating the administration of methotrexate and, in one case, subsequently rituximab. Methotrexate was used in five cases (26.3%), cyclophosphamide in two cases, azathioprine in one case (Table 1). The time of follow-up varied drastically from a few weeks to four years. Remission from active TA was described in all patients. TA manifestations in one patient led to nephrectomy and one received a splenorenal bypass. No patient died in hospital or during follow-up.

Discussion

Our patient presented with unspecific symptoms that had been present for almost 1 year. Unspecific symptoms were described in most of the reviewed reports. The patient fulfilled the criteria for multiorgan TB and the ACR 1990 criteria for Takayasu arteritis with type IIa angiographic lesions [8]. Angiographic lesions were heterogeneous in the reviewed cases, the most frequently observed lesions were also described as the three most common lesion types in a study of Indian and Japanese patients (types I, IV and V) [10].

Immunosuppressive treatment is required to prevent irreversible vessel damage in TA patients. Corticosteroid monotherapy led to remission in eleven reviewed cases of co-occurring TA and TB (57.9%), compared to a remission rate of up to 60% in cases of TA alone [2]. However, relapses frequently occur when a dose reduction is attempted, as observed in our case and two of the reviewed cases [18, 19]. Other treatment options for TA include methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus hydrate, leflunomide, anti-TNF agents and tocilizumab [4]. A possible exacerbation of TB during treatment of TA with immunosuppressive agents has to be taken into consideration as anti-TNF agents are well known for their potential to reactivate latent TB [28]. When methotrexate failed to prevent TA relapses, rituximab was successfully used in one case [19] and tocilizumab was used in our case.

Eleven retrospective studies analyzed by Lim et al. have observed much higher frequencies of TB (history of TB, positive tuberculin skin test or active TB) in cases of TA compared to the general population in the respective countries or control groups [29]. A retrospective study by Lupi-Herrera et al. showed that 21% of TA patients had TB lymphadenitis at presentation or in their histories while only 1% had pulmonary TB [30]. However, no further details of microbiological TB confirmation were provided. In a study of 267 Korean patients with TA, 47 had a diagnosis of TB, with a high prevalence of TB lymphadenitis (12/47, 25.5%)—well above the national Korean rate of 4.4% [29]. In six patients, lymph node biopsy showed caseous granulomas. However, TB was confirmed by polymerase chain reaction (PCR) in one patient only, while the remaining cases were not microbiologically analyzed. Like TA, TB lymphadenitis seems to be more common in young female patients. It presents most commonly as cervical lymphadenitis but various other locations have been described [31]. Of the 57.9% of cases involving TB lymphadenitis in the reviewed reports, hilar (4; 36.4%) and cervical (3; 27.3%) lymphadenitis were the most frequently described locations (Table 1). Microbiological confirmation of TB lymphadenitis was obtained in four (21.1%) of the reviewed cases.

In rare cases TB can mimic the presentation of large vessel vasculitis [32, 33]. In one of the reviewed cases TA lesions could not be differentiated from possible tuberculous arteritis due to anatomical proximity of pulmonary TB lesions to the aortic arch, presenting a possible dissemination route [17]. As both TA and tuberculous arteritis share radiological features, imaging methods do not represent a reliable diagnostic tool for differentiation. In uncertain cases clinical management decisions are challenging as erroneous administration of immunosuppressive therapy could adversely affect the course of TB [17].

An autopsy study in Mexico detected the IS6110 and HubB gene sequences of Mycobacterium tuberculosis in 70% of aortic tissue samples from TA patients, compared to 82% in patients with tuberculosis and 32% in patients with atherosclerosis [6]. However, the DNA extraction in this study was performed from paraffin-embedded tissue. In fresh arterial samples obtained from 10 TA patients without clinical evidence of active tuberculosis, microscopy, mycobacterial culture, and PCR were all negative for M. tuberculosis complex [34].

While there is no conclusive evidence that mycobacteria play a direct role in the pathogenesis of TA, an immunological cross-reaction between mycobacterial and arterial antigens may be possible. Patients with TA tend to display a heightened humoral immune response to Mycobacterium tuberculosis antigens, in particular to the 65 kDa heat shock protein [35], which may suggest that, due to the sequence homology between the phylogenetically conserved human and mycobacterial heat shock proteins, a TB infection can cause an autoimmune response directed against the arterial adventitia [35].

This review comprises only a small number of cases spanning a large time period and a wide variety of cultures, both factors which may limit their comparability. Most patients presented with active TB and TA. We found a surprisingly high frequency of TB lymphadenitis.

In the majority of cases antituberculous and immunosuppressive therapy were given to manage both conditions, preventing fatal outcomes within the documented periods of follow-up. However, in our and two other cases, TA had to be treated with additional immunosuppressive therapy after the end of antituberculous therapy, indicating that successful completion of antituberculous therapy does not affect the course of TA.