Palpable purpura with foot drop: Common presentations in an uncommon disease.

Churg-Strauss syndrome is a rare disease manifested by hypereosinophilia, vasculitis and tissue infiltration. This report describes the case of a 45-year-old man who presented with a history of fever, difficulty in breathing, reddish lesions over the extremities and inability to walk since two weeks. The cutaneous features prompted us to conduct serial lab investigations which led to an early, potentially life saving diagnosis.

INTRODUCTION

Eosinophilic granulomatosis with polyangitis (EGPA) is one of the rarest but still potentially life threatening systemic necrotizing vasculitis predominantly affecting small vessels.[1] Named CSS for many years, this eponym has now been recognized as EGPA by the 2012 Revised International Chapel Hill Consensus Conference nomenclature of vasculitides.[2] Here we describe a patient who presented with an inability to walk and asymptomatic skin rash. He had been treated for encephalopathy and bronchial asthma in the past. Laboratory investigations helped to reach the final diagnosis of CSS with mononeuritis multiplex, skin, and pulmonary involvement.

CASE REPORT

A 45-year-old male presented with two weeks history of multiple asymptomatic red lesions on his hands and lower limbs, difficulty in breathing, fever, and weakness of both legs with difficulty in walking. No mucosal lesions were present. He had been treated for severe asthma and encephalopathy in the past. There was no history of similar disease in the family. The physical examination revealed multiple palpable purpuric papules and plaques distributed over the dorsum of hands and posterior aspect of the legs [Figure 1] with left foot drop.

Figure 1

Palpable purpura on the leg

Routine investigations revealed a prominent eosinophilia of 29% and erythrocyte sedimentation rate (ESR) of 28 mm/h. Renal function was normal. Immunofluorescence assay for antinuclear antibodies was negative and perinuclear antineutrophil cytoplasmic antibodies (p ANCA) or cytoplasmic ANCA were not detected in his serum. Rheumatoid factor was positive at 233.4 IU/ml. A chest radiograph showed emphysematous lung fields with prominent bronchovascular markings consistent with bronchial asthma but no prominent infiltrates were noted. Motor and sensory nerve conduction studies showed reduced compound muscle action potential amplitudes from both posttibial and left common peroneal nerves indicative of sensory motor peripheral neuropathy.

A skin biopsy of the purpuric lesion revealed leucocytoclastic small vessel vasculitis comprising of inflammatory infiltrate of neutrophils and eosinophils [Figure 2]. There was extravasation of red blood cells and occasional granulomas comprising of palisading histiocytes, eosinophils and lymphocytes in the deep dermis [Figure 3]. Direct immunofluorescence showed blood vessel wall staining with IgM, C3 and fibrinogen [Figure 4]. These findings supported the diagnosis of CSS.

Figure 2

Leucocytoclastic vasculitis in superficial dermis (H and E ×40)

Figure 3

Red granuloma in the deep dermis comprising palisading histiocytes, eosinophils and lymphocytes (H and E ×40)

Figure 4

Direct immunofluorescence: Blood vessel wall staining with IgM, C3 and fibrinogen

The patient received oral corticosteroids (prednisolone) at a dose of 1 mg/kg/day, and the dose was tapered after one month. He also received bronchodilators, antibiotics, and combination of oral methylcobalamin with gabapentin. Skin lesions and his general condition showed improvement following treatment and he is on regular follow-up.

DISCUSSION

It was in 1951 that Jacob Churg and Lotte Strauss first described a syndrome characterized by asthma and a “strikingly uniform clinical picture” with “fever and eosinophilia, and symptoms of cardiac failure, renal damage and peripheral neuropathy resulting from vascular embarrassment in various systems of organs”. They considered the observed tissue alteration to be a distinct histopathologic entity, which they termed “allergic granuloma”.[3] The presence of any four or more of the six classification criteria developed by the American College of Rheumatology (ACR) [Table 1] yielded a sensitivity of 85% and a specificity of 99.7%.[45] Our case fulfilled four of the six ACR criteria.

Table 1

American College of Rheumatology 1990 criteria for classification of Churg–Strauss syndrome

Eosinophilic granulomatosis with polyangitis is a rare disease, with an annual incidence of 0.5–4.2 cases/106.[1] It usually occurs between 14 and 79 years of age, with a mean age of 48 years;[6] pediatric cases have also been reported.[7]

The actual cause of the disease remains a mystery. Immunogenetic factors may confer susceptibility to EGPA. The human leukocyte antigen (HLA)-DRB1 * 04 and *07 alleles and the related HLA-DRB4 gene are associated with an increased risk of developing EGPA.[89] Like most forms of vasculitides, the occurrence of EGPA is likely to require a combination of inherited risk determinants and environmental triggering factors, including antigens and/or infections, which by themselves are insufficient to cause complications.[10]

The formation of antineutrophil cytoplasmic autoantibody (ANCA) may be favored by a genetic predisposition, such as a genetically determined, severe α1-antitrypsin deficiency (which also inhibits proteinase – 3), or genetic heterogeneity of the ANCA antigen itself.[11] ANCA mediates the activation and adherence of neutrophil and eosinophil polymorphonuclear cells to the endothelium, and the release of toxic components, thus damaging the endothelium and initiating the vasculitic process.[4]

Our patient was ANCA negative. ANCA positivity is seen only in ~38% of EGPA and compared to ANCA-negative patients, they more frequently suffer from peripheral neuropathy, renal involvement, and purpura, whereas, endomyocardial involvement and lung infiltrates prevailed in the ANCA-negative subsets.[1] Other biologic abnormalities such as positive rheumatoid factor, increased ESR and immune complexes are considered to be nonspecific.[4]

Three phases have been described in the natural history of the disease although they do not always occur successively. It is traditionally described to evolve through a prodromic, allergic phase characterized by asthma and rhinosinusitis, followed by a second phase with the onset of blood and tissue eosinophilia. The third stage is defined by the emergence of systemic vasculitis. Spontaneous or treatment-induced remission of the disease can occur at this stage, but recurrence is frequent.[12]

Asthma is found in 95–100% of patients and may precede the systemic disease manifestations by many years. It generally arises in adulthood, and its severity varies; unlike in classical bronchial asthma, in EGPA, it does not show the typical seasonal exacerbations.[1314]

The vasculitic phase is heralded by constitutional symptoms and often by an apparently paradoxical improvement of asthma. Neurologic involvement is seen in over 60% of the patients with EGPA.[4] Peripheral neuropathy is characterized by axonal damage on electrophysiological studies and frequently affects the peroneal, tibial, ulnar, and median nerves; the most common pattern is mononeuritis multiplex, often complicated by asymmetric foot or wrist drop, but it may also evolve as a symmetric or asymmetric polyneuropathy; sensory deficits and neuropathic pain are also frequent.[1516]

Skin involvement is seen in 81.3% of patients, palpable purpura of the lower extremities as seen in our patient is the most frequent manifestation.[17] Subcutaneous nodules of the limbs and scalp are seen in about 30% of the patients.[1218] Skin infarction, livedo reticularis, erythematous and bullous lesions, macular erythema, and urticaria may also be seen. The cutaneous involvement generally parallels the systemic course of the disease.[4]

Management of EGPA involves the use of systemic steroids at high doses initially. The objective is to induce clinical remission as quickly as possible, and then to sustain it as long as possible. In cases that fail to respond to steroids, or those with life threatening complications, immunosuppressants like cyclophosphamide may be added. Biologic agents such as the anti-interleukin-5 mepolizumab and possibly rituximab are promising treatment options.[1920]

Our patient presented with EGPA in the vasculitic phase of the disease. He was initially labelled as bronchial asthma and treated with oral steroids for prolonged duration, following which he developed sepsis and encephalopathy. Accurately recognising EGPA is thus imperative as there is significant treatment related morbidity. Though he responded to high dose corticosteroids, a significant fraction of patients in the vasculitic phase remain unresponsive, underlining the importance of early diagnosis in managenent.