Tuberculosis mimicking primary systemic vasculitis: not to be missed!

Abstract

Infections are an important differential diagnosis in patients presenting with features of systemic vasculitis. We report a young lady with constitutional features, leg ulcers, digital gangrene and absent peripheral pulses with cervical adenopathy. Chest imaging revealed multiple necrotic lung lesions and involvement of left subclavian artery at its origin from the aorta, Histopathology from cervical lymph nodes showed multiple caseated lymph nodes, which in the context of a positive Mantoux test led us to diagnose tuberculosis and institute appropriate therapy. This is only the second report of tuberculosis presenting as peripheral gangrene, cutaneous ulcers and absent pulses, and serves to educate rheumatologists regarding the need to consider infections as mimics of vasculitis, especially in the developing countries.

Keywords

Tuberculosis gangrene ulcer pulse loss large vessel vasculitis medium vessel vasculitis

Introduction

Vasculitis refers to inflammation of the blood vessels, which may be primary or secondary to environmental agents.¹ Infections are important mimics of vasculitis in developing countries. Tuberculosis (TB) is an endemic infection in South-East Asian countries, including India.² Hence, it needs to be considered in the differential diagnosis of rare diseases including systemic autoimmune conditions. We report TB presenting with a leg ulcer, digital gangrene and absent peripheral pulses. Such a presentation is very unusual.

Case report

A 33-year-old woman presented with inflammatory polyarthritis predominantly affecting the large joints of both upper and lower limbs, intermittent fever, weight loss and loss of appetite for the previous eight months. She also complained of intermittent claudication in both upper limbs experienced while washing clothes for the previous two months. There was no associated dactylitis, enthesitis, back pain or neck pain. Two months previously, she developed a blackish discolouration of the left hallux and small pustular lesions over the left lateral malleolus and the left heel which grew in size and secondarily ulcerated. One month previously, she also developed ulcers over the base of the left hallux and right fifth toe. She had sought native treatment for the same complaints over a period of eight months without much improvement. There was no history of recurrent epistaxis, chronic sinusitis, neurological symptoms, cough, haemoptysis, chest pain, breathlessness, ocular symptoms or orogenital ulcers. She had no prior history of venous thrombosis. She had an episode of jaundice one year previously, lasting two weeks, which resolved spontaneously. She had had no blood transfusions in the past or sexual contact outside marriage. She had previously experienced one spontaneous first trimester abortion. Examination revealed a malnourished patient (body mass index, 15 kg/m²). Distal pulses in both upper and lower limbs (both radial, ulnar, posterior tibial and dorsalis pedis arteries) were absent. The blood pressure was symmetrical in upper limbs. She had multiple bilateral cervical lymph nodes <1 cm in size, mobile and non-tender. There was a well-defined ulcer over the left lateral malleolus (Figure 1a), another ulcer with a necrotic base over the medial aspect of left heel, and deep ulcers over the base of right hallux and left fifth toe. All the ulcers were secondarily infected. There was dry gangrene of the left hallux (Figure 1b). Oral and nasal cavities were normal. Musculoskeletal examination revealed arthritis in both knees. Examination of other systems revealed no significant abnormality.

Figure 1.

(a) Ulcer over left lateral malleolous (6 × 4 cm) with well-defined margins. Base shows slough and areas of healthy granulation tissue. Exposed tendons can also be seen. (b) Gangrene of left hallux.

Considering systemic vasculitis as the most probable diagnosis, the patient was started on oral steroid therapy along with dressing of ulcers and local antibacterial therapy, pending investigation. Evaluation revealed a microcytic hypochromic anaemia (Hb, 92 g/L; mean corpuscular volume, 76.80 fL; mean corpuscular haemoglobin concentration, 301 g/L) with normal leucocyte and platelet counts. Erythrocyte sedimentation rate (ESR) was elevated (105 mm/h). Renal and liver function tests were within normal limits. The urine showed no proteinuria, cellular sediments or casts. Serology tests for hepatitis B and C and HIV were negative. Rheumatoid factor, anti-cyclic citrullinated peptide antibodies, antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA) by indirect immunofluorescence, anticardiolipin antibodies and anti β2GPI antibodies were undetectable. The pathergy test was negative. A chest radiograph showed inhomogeneous opacities in the middle and lower zones in the right lung fields (Figure 2a). High-resolution computerized tomography (HRCT) of the thorax and abdomen revealed subsegmental consolidation in the apical segment of the right lower lobe (Figure 2b) and lingular segment (with centrilobular nodules and tree-in-bud appearance in the lingula) suggestive of endobronchiolitis, along with multiple small cavitating nodules in both upper lobes and left lower lobe, together with numerous necrotic retroperitoneal and iliac lymph nodes. Sputum examination was negative for acid-fast bacilli (AFB) or other microorganisms. In view of absent peripheral pulses, CT angiogram of the aorta and extremities was performed, which showed focal wall thickening at the origin of the left subclavian artery (Figure 3). Peripheral angiogram of upper limbs showed visualisation of the right brachial artery up to the mid-arm and of the left brachial artery up to the proximal forearm (Figure 4a). Both popliteal arteries were not visualised beyond the proximal third of the leg on either side (Figure 4b). Two-dimensional echocardiography was within normal limits. Blood culture was positive for methicillin-resistant Staphylococcus aureus (MRSA), which was attributed to secondary dissemination from the infected leg ulcers. However, there were no features of systemic sepsis. The bacteraemia resolved after treatment with intravenous vancomycin. A tuberculin test was positive (12 mm induration) in spite of steroid therapy. Lymph nodes were biopsied from the cervical region, revealing caseating epitheloid cell granulomata (Figure 5). Although staining for AFB and fungal elements was negative, considering the endemicity of tuberculosis in our country and a positive tuberculin test, TB was considered the most likely diagnosis. Four-drug anti-tubercular therapy was commenced and steroids were tapered off. After four months, her constitutional symptoms had resolved and the leg ulcers had almost fully healed, which suggested a good response.

Figure 2.

(a) Chest X-ray showing inhomogeneous opacities in middle and lower zones of the right lung field. (b) CT of thorax showing subsegmental consolidation in apical segment of right lower lobe and lingular segment with centrilobular nodules and tree-in-bud appearance in lingula suggestive of endobronchiolitis.

Figure 3.

CT aortic angiogram showing a focal area of wall thickening at the origin of the left subclavian artery (arrow).

Figure 4.

(a) Upper limb CT angiogram with volume rendered reconstruction showed occlusion of left brachial artery just proximal to its bifurcation, with no flow in radial and ulnar arteries. Right brachial artery is visualized only up to the mid-arm. (b) Lower limb CT angiogram showed severe narrowing of proximal anterior tibial and peroneal arteries and posterior tibial arteries on both sides with no flow in their middle and distal thirds with distal reformation.

Figure 5.

Lymph node biopsy showing extensive caseous necrosis (haematoxylin and eosin staining [H&E] ×100). Inset shows epithelioid cells and lymphocytes rimming the caseous necrosis (H&E staining × 400).

Review of literature and discussion

Our initial diagnosis was Takayasu’s Arteritis (TA)³ because of the age of onset, absent pulses, claudication, constitutional symptoms and angiography showing involvement of subclavian artery near its origin. However, gangrene is an extremely unusual manifestation of TA.⁴ It was also distinctly odd to have nodular cavitating pulmonary lesions in TA, although these could have resulted from systemic bacteraemia due to MRSA. Polyarteritis nodosa (PAN)⁵ was considered in view of the history of jaundice, weight loss, digital gangrene and cutaneous ulcer. Features of claudication, absent pulses with angiography suggestive of large vessel involvement and necrotic lung nodules (suggesting small vessel involvement), however, precluded the diagnosis of PAN. A third possibility was ANCA-associated vasculitis (AAV),⁶ which can present with cavitating lung nodules and weight loss. Gangrene and ulcers may also rarely be seen and large vessel involvement has been described in case series.⁷ However, it was odd that there was no upper respiratory tract, renal or peripheral nervous system involvement. ANCA in serum were also undetectable.

Behcets’ disease (BD)⁸ is a systemic vasculitis which can involve small, medium and large vessels. It can present with cutaneous ulcers. There are reports of BD presenting with gangrene.⁹ However, the absence of oral or genital ulcers along with a negative pathergy test rendered a diagnosis of BD unlikely. Antiphospholipid syndrome¹⁰ may have similar presentation with gangrene, non-healing ulcers, arthritis and history of abortion. However, constitutional symptoms, necrotising lung lesions, lymphadenopathy and negative serology for anti-phospholipid antibodies ruled this out. Infective endocarditis¹¹ was considered in view of necrotising pneumonia and blood culture showing MRSA, but echocardiography did not show vegetations or structural abnormalities as predisposing factors. Moreover, the modified Duke criteria¹² were not fulfilled. There was no evidence of any underlying malignancy which could have caused these symptoms in spite of extensive evaluation. Syphilitic aortitis was another consideration, but the lack of extramarital sexual contact and the absence of genital ulcers ruled against this diagnosis.¹³ Aortitis is usually seen in tertiary syphilis, by which time the systemic features have usually resolved, which was not the case in our patient. Hence, a Venereal Disease Research Laboratory (VDRL) test for syphilis was not performed. These differential diagnoses are discussed in Table 1.

Table 1.

Discussion of differential diagnoses considered in our patient.

Differential diagnosis	Features present in our case	Points against the diagnosis in this case
Large vessel vasculitis: Takayasu’s arteritis	Age at disease onset <40 years Claudication of extremities Arteriography showing large vessel occlusion High ESR Constitutional symptoms (weight loss)	Gangrene and ulcers can be seen but are rare Nodular cavitary lung lesions Lack of hypertension
Medium vessel vasculitis: Polyarteritis nodosa	Weight loss >4 kg Peripheral gangrene Cutaneous ulcers Arthritis	Large vessel involvement Pulse deficit Nodular cavitary lung lesions Lack of hypertension Lymphadenopathy
ANCA-associated vasculitis	Nodular cavitary lung lesions Weight loss Arthritis Peripheral gangrene Cutaneous ulcers	Serology for ANCA negative No upper respiratory tract involvement Lack of renal involvement Lack of peripheral neuropathy Large vessel involvement with pulse loss Lymphadenopathy
Behcet’s disease	Small, medium and large vessel involvement Pyoderma gangrenosum-like lesions Lung nodules Peripheral gangrene Cutaneous ulcers	More common in young men Absence of oral or genital ulcers Pathergy test was negative Lymphadenopathy
Antiphospholipid antibody syndrome	Peripheral gangrene Cutaneous ulcers History of pregnancy loss	Weight loss Vessel wall thickening Lymphadenopathy Cavitary lung lesions APLA negative
Infective endocarditis	Nodular cavitary pneumonia Blood culture showing MRSA Peripheral gangrene	Normal cardiac examination Echocardiogram showed no structural anomalies or vegetations Did not fulfil modified Duke criteria for infective endocarditis¹²
Malignancy	Weight loss Peripheral gangrene Lymphadenopathy	Young age Insidious onset of arthritis
Syphilis	Aortitis	Absence of sexual promiscuity or genital ulcers Absence of ascending aorta involvement, aortic regurgitation and aortic aneurysms
Tuberculosis	Weight loss Positive tuberculin test despite high dose steroid therapy Lymphadenopathy Lymph node biopsy showed caseation surrounded by epithelioid cells	–

ANCA, anti-neutrophil cytoplasmic antibodies; APLA, anti-phospholipid antibodies; ESR, erythrocyte sedimentation rate; MRSA, methicillin-resistant Staphylococcus aureus; PAN, polyarteritis nodosa.

TB was considered as a possibility in view of constitutional symptoms, weight loss, necrotising lymphadenopathy and a positive tuberculin test despite high dose steroid therapy. Lymph node biopsy revealed caseating necrosis with surrounding epitheloid cells. Though staining for AFB was negative, a diagnosis of TB causing large vessel vasculitis was made. It has been suggested that TA may be linked to infection with Mycobacterium tuberculosis, but a strong argument against this has been the inability to demonstrate mycobacterial nucleic acid elements in aortic biopsies from patients with TA.¹⁴ Adhering to Occam’s razor, our aim was to explain all the clinical features with a plausible single diagnosis of TB. The good response to anti-tubercular therapy supports this contention. A search of the databases Scopus and Medline using the keywords ‘Tuberculosis’ and ‘Gangrene’ obtained 93 results in which six presentations of TB and limb or digital gangrene were found (Table 2).^15–20 Among these, only one patient had a triad of gangrene, cutaneous ulcer and pulse deficit.

Table 2.

Cases reported in literature with TB and limb gangrene.

Case no./ Country of origin	Reference no.	Age (years)/ Sex	Distribution of gangrene	Pulse deficit	Ulcers	Lymph nodes enlarged	Vascular imaging
1/China	15	28/F	Left 1st, 2nd and 3rd toes	Left posterior tibial and dorsalis pedis arteries	Left toe	Left cervical	Left posterior tibial and peroneal arteries showed stenosis with luminal irregularity on ultrasound
2/Switzerland	16	66/M	Both feet	None	None	None	Not available
3/Nigeria	17	2/F	Right 2nd, 4th and 5th fingers and left 1st, 2nd, 3rd and 4th toes	Not mentioned	None	Peripheral lymphadenopathy (not specified)	Not available
4/Taiwan	18	74/M	Both hands and feet	None	None	None	Not available
5/Pakistan	19	17/F	Left 1st, 2nd and 3rd toes	Left posterior tibial and dorsalis pedis	None	None	Not available
6/India	20	8/M	Right foot	None	Left sole	Left inguinal	Normal arterial Doppler study
7/India	This case	33/F	Left great toe	Bilateral radial, ulnar, posterior tibial and dorsalis pedis	Left lateral malleolus, left heel, left 5th toe, right 1st toe	Bilateral cervical	CT angiography showed focal wall thickening at origin of left subclavian; non-visualisation of distal arteries in upper and lower limbs

CT, computed tomography; F, female; M, male.

Conclusion

TB may mimic a wide variety of systemic diseases, including systemic vasculitis. Immunosuppressive therapy in this situation may well be counter-productive.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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