A 16 years old girl was brought to the ER on New-Year’s Eve, with increasing breathlessness over few hours, following 2 days of low-grade fever. She had attended school regularly until the same morning. There was no history of cough, sputum, haemoptysis, rash, seizure, syncope, palpitations or chest pain. No vomiting, aspiration, exposure to fumes; insect bites, unusual food intake or medication was reported. There was no weight loss, diarrhea, dysuria or recent stressors. Not sexually active, she’d recently had a normal period.

Clinical examination showed an averagely built adolescent, breathless but comfortable lying down. Respiratory rate was 36/min, oxygen saturation was 92%. There was no cyanosis, stridor or audible wheeze. Bilaterally radial pulses were imperceptible, femorals were feeble and carotids were well felt. Cardiac monitor showed normal rhythm of 90 beats/min. Arm BP was unrecordable bilaterally. She was warm but not febrile. Moderate pallor and sweating were observed. No urticarial-rashes, angioedema, lymphadenopathy, edema or icterus were noted. Trachea was central; chest expansion and resonant percussion-note were equal on both sides. Cardiac and liver dullness were preserved. Breath sounds were normal. Apex beat and heart sounds were normal. Abdominal and neurological examinations were unremarkable. Capillary blood glucose was 76 mg/dl and blood gases showed mild hypoxemia.

With a provisional diagnosis of warm-shock (anaphylactoid/toxin-mediated/sepsis-related), emergency management was initiated. Oxygen was given by face-mask; crystalloids were administered rapidly (500 ml/h initially); and bladder was catheterized to monitor urine output. Hydrocortisone 200 mg was given straightaway and 100 mg repeated 6 hourly. Empiric treatment for community-acquired sepsis was instituted (third-generation cephalosporins and vancomycin). Anti-histaminic were added. Despite adequate hydration and urine output there was no improvement in BP for 2 h; therefore, ionotropic support was initiated. Breathlessness resolved and oxygen saturation improved within 6 h.

X-ray chest showed mild hilar prominence. Resting ECG was normal.

At 48 h, although improved breathing was sustained, BP in all 4 limbs remained low- around 60/40 mm Hg with feeble radial, femoral and popliteal pulses. Surprisingly, carotids and dorsalis-pedis were well felt bilaterally. She was sitting-up and standing without hemodynamic instability. Weight was 42 kg. Urine output and repeat blood-tests showed no deterioration despite apparent hypotension. Inotropes were therefore tapered off and urinary catheter removed.

Abdominal ultrasound showed liver size 14.5 cm, spleen 11 cm, kidneys 10 cm length, normal texture and no free fluid. Few retroperitoneal lymph-nodes were present. Doppler-study on renal arteries showed normal flow. CECT scan of  chest (Figure 1) showed a large, conglomerate, lobulated and necrotic, mediastinal lymph-node mass, possibly of tubercular etiology; causing compression of the large airways. Abdominal CT scan (Figure 2) showed few enlarged mesenteric lymph nodes, the largest measuring 12 × 6 mm.

On day 4, in the light of feeble peripheral pulses and a previous history of claudication in both calf muscles 2 months earlier; contrast-enhanced helical CT scan of aorta and its branches was performed in angiographic mode (Figure 3). 3D-MIP and VR reconstructions were obtained. Bilateral severe luminal narrowing of sub clavian and axillary arteries and circumscribed infra-renal aortic narrowing for a 49 mm segment were seen. Fundoscopy was normal. ATT and oral prednisolone were continued.

On day 7, she developed symptomatic hypocalcaemia in the form of carpopedal spasms and positive Trousseau’s sign. Severe hypovitaminosis D, hypocalcaemia and hypokalemia along with low urinary potassium and calcium were detected (Table 1). ECG showed a prolonged cQT interval of 510 ms. Symptoms did not recur after replacement therapy and cQT interval normalized in 2 days. Other micronutrient supplements were added in view of deficient iron, folate and B12 (Table 1), along with a high-protein diet. Mantoux and HIV testing were negative.

With a diagnosis of tubercular mediastinal-lymphadenitis and non-specific aorto-arteritis (NSAA), she was referred to a higher centre. There she underwent bronchoscopic lymph-node biopsy and cardiovascular MR imaging and angiography. The lymph-node biopsy showed epithelioid granulomata, caseation and occasional acid-fast bacilli. GeneXpert-test (molecular detection of mycobacteria and rifampicin resistance), was negative. The MR imaging and angiography was suggestive of NSAA with active tuberculosis (Table 2). Salient features were enlarged, necrotic and conglomerate lymph-nodes in right para-tracheal, sub-carinal, hilar and supra-clavicular locations with nodular lesions in right lower-lobe. Angiographic narrowing of infra-renal aorta; occlusion of superior mesenteric artery and both sub-clavians with distal reformation; and diffuse disease of bilateral anterior tibial and left peroneal arteries.

PRESENT CONDITION AND FUTURE PLAN

Decision for angioplasty was deferred since her NSAA was active and widespread. Adequate collaterals had already formed and no vital organ was at immediate risk. Under close follow-up, presently she has completed 8 of the planned 9 months of ATT. She is still on 5 mg prednisolone, which was gradually tapered after 4 months. No other immunosuppressant or anti-platelet agent has been introduced due to steady improvement. Having gained 8 kg weight, she has no limb-claudication, Raynaud’s phenomena, cough, breathlessness, pain chest/abdomen or syncope. There is steroid-induced acne but no significant hyperglycemia or dyslipidemia. All micronutrient deficiencies are corrected. Peripheral pulses remain feeble, although volume has improved. BP in both upper limbs is 70/40 mm Hg. In the lower limbs it is 96/50 mm Hg (right) and 84/44 mm Hg (left). Faint bruits are heard over the left anterior tibial artery and abdominal aorta.

If these gains continue, MR angiography will be repeated annually. She will remain under long-term follow-up. ECG, echocardiography and fundoscopy will be used to assess masked hypertension.

DISCUSSION

Takayasu arteritis (TA) was named after the Japanese ophthalmologist who first described its fundoscopic findings in 1905 [1]. Over 500 publications were reviewed for this case-report. Of these, a few representative publications between 2000 to 2019 have been cited to keep the discussion contemporary. The latest reference-books in cardiology [1,2] and rheumatology [3] have not unequivocally attributed pathogenesis of TA to TB. Genetic predisposition, inflammatory/autoimmune processes and other factors including infections are implicated in its perpetuation. In fact, TA, tubercular, infective and syphilitic arteritides are listed as distinct entities [1]. Despite this several similarities between tubercular arteritis and TA exist. Both are large-vessel granulomatous arteritis, characterized by comparable involvement of the aorta and its major branches; and are prone to relapses/disease progression. Tuberculous arteritis, usually secondary to the dissemination of Mycobacterium tuberculosis infection from the mediastinum and/or lung to the adjacent aorta; mimics TA clinically [4-6], as seems to be the case in our patient.

Classic TA frequently occurs in Asian countries with high TB burden, strangely affecting young females 9 times more often than males. Similar aortitis is also encountered in people of different ethnicities [1-3]. Both may either be incidentally detected, or may present with vaso-occlusive phenomena in vital circulations and rarely as aneurysm formations [7-9]. Association of TA with latent, past or active tuberculosis is widely published [10-17], mainly as case-reports. Jansson et al. [4] have reviewed 18 cases of co-occurring TA and TB, where all patients were below 25 years, over half had lymph-node TB, all received ATT, 90% received steroids; and 2 cases relapsed needing additional immunosuppressants. Lim et al. [5] studied 267 patients of TA between 1994 to 2014, with and without TB. Cases were diagnosed according to the 1990 American College of Rheumatology criteria [18]. A total 94 (35.2%) patients had past or concomitant TB. Clinical features and angiographic findings in TA were not different in the presence or absence of concomitant TB. Previous similar studies also report no significant difference between TA and TB arteritis, except the absence of proven tuberculosis by available methods. Soto et al. [14] processed 181 aortic tissues for gene-sequences indicating TB. The IS6110 sequence identified the M tuberculosis complex and the HupB established differences between M. tuberculosis and M. bovis. They identified a higher frequency of IS6110 and HupB genes in aortic tissues of TA patients suggesting that arterial damage could occur due to previous infection with M. tuberculosis. One report was found that refuted the presence of M tuberculosis in arterial lesions from 10 patients with Takayasu’s arteritis [19]. Biopsies were assessed by acid-fast and auramine-fluorochrome stains, mycobacterial cultures and direct-amplification test.

Whether TA or NSAA; ESR, CRP and procalcitonin have been used as markers of inflammation during active disease and for detection of relapses with varying reliability. Imaging by Doppler and ultrafast-ultrasound fails to pick up active inflammation. Cardiovascular MR is superior to CT angiography in active disease and during follow-ups for relapses. DSA and FDG-PET scans additionally are able to detect vessel-wall oedema and are marginally superior in active disease [7-9,20]. Additional tests to screen for tuberculosis include X-rays, BCG, histopathology, microbiological processing and molecular-methods.

Improved treatment modalities, are associated with better outcomes in the present century compared to the previous [1-3,7-9]. The course of disease is variable. Remissions and relapses are both reported, therefore there is a need for long-term follow-up. Steroids (mainstay), other immune-suppressants and biologic-response-modulators have all been included in recommended treatment options with comparable results [1-3]. Most data comes from open-labelled trials, observational-studies and individual series. Sample-sizes are generally small and histopathological evidence is difficult to gather from living patients.

The ‘surprise’ as indicated in the title of this report, actually came from an unexpected development. Our patient had hypo-calcemic tetany and cQT prolongation on day 7 of presentation. High-dose steroids probably precipitated the derangement in the background of severe vitamin-D deficiency (Table 1). Growing evidence suggests that vitamin D deficiency might be implicated in the development of active TB. Literature review showed considerable data on the association of hypovitaminosis-D with (a) proneness to tuberculosis from insufficient vitamin-D dependent defensins [21-24] and (b) an indolent course of the disease [25-27]. Interleukin (IL)-15 and IL-32 play roles in the vitamin-D mediated TB defense mechanisms. We also found credible reports of an association of vitamin-D deficiency with tubercular and Takayasu arteritis [28,29].

Had it not been for sudden breathlessness from large airway obstruction and a dramatic ‘shock-like’ presentation; this girl’s condition may have gone unnoticed for longer. Indolent course of disease was evinced by a short and mild febrile illness; insignificant rise in phase reactants (ESR, CRP and procalcitonin); and cutaneous anergy on Mantoux-testing; all in the presence of extensive conglomerate necrotising mediastinal and other lymphadenitis plus pulmonary TB. It may have been due to concurrent severe deficiency of micronutrients, especially vitamin-D3. In South-Asia, despite abundant sunlight, hypovitaminosis-D in females does occur. Traditionally the women are fully-clothed when outdoors, at all times. Perhaps, here lies a simple explanation for the gender-difference in incidence of TA and NSAA.

CONCLUSION

Indolent tubercular granulomatous inflammation of arterial walls, facilitated by lowered anti-tubercular defenses from vitamin D deficiency may actually play a significant role in the genesis of NSAA or TA. This case lends credence to the tubercular etiology of NSAA.