Leukocytoclastic vasculitis (also known as hypersensitivity vasculitis or allergic vasculitis) is a small vessel inflammatory disease.1,2 Cutaneous lesions are the major feature of the disease, but involvement of other organ systems may be present.1,2 The etiologies are multiple, including drugs, chemicals, other underlying diseases, malignancies, and infections. Various rheumatologic syndromes, including vasculitis, are well recognized as a potential consequence of infection by human immunodeficiency virus (HIV).3-5 Furthermore, peripheral nerve damage is even now a common neurological complication of HIV infection, whereas it is less frequent as side effect of new antiretroviral drugs; its prevalence is relatively low in asymptomatic HIV infection.6,7
We present the case of a woman with leukocytoclastic vasculitis and dysesthesias in the legs that suggest a concomitant sensory neuropathy as the unusual presenting features of an underlying HIV infection.
A 42-year-old woman came to our observation, in the beginning of autumn, complaining of severe dysesthesias and paresthesias to the feet and lower limbs, associated with prickly and severe itching and burning with scratch lesions.
Her clinical history was negative. She is a shop owner and remained a widow approximately 8 years before; she has never been pregnant nor assumed alcohol, medication, hard drugs, or oral contraceptives.
Dysesthesias began 1 year before in winter, with a partial remittance during spring and summer but with reappraisal in the summer during a short holiday spent in the mountains when a sudden fall in temperature occurred. At the beginning of autumn, when temperature decreased, dysesthesias with a prickling sensation reappeared along with some erythematous nodular crops in the region of the feet, which resembled urticarial lesions. Symptoms were not controlled either with acetaminophen or with antihistaminics.
After a consultation with a dermatologist and a rheumatologist, a diagnosis of a relapsing fixed erythema, as a probable display of a system vasculitis, was given. Treatment with low doses of prednisolone was started, without any response.
At that time, laboratory findings showed the following: white blood cell count, 4200/μL; neutrophils, 51.9%; C-reactive protein level, 7 mg/L; immunoglobulin (Ig) G, 2.14 g/L (reference range, 0.7-1.6 g/L); and total IgE, 16 kU/L. Liver and thyroid function tests, clotting parameters, antistreptolysin titer, rheumatoid factor, serum complement fraction, folate, and vitamin B12 were normal. Investigation for main alimentary allergens, anti-thyroperoxidase and anti-thyroglobulin, cancer markers, hepatitis B surface antibody, hepatitis B surface antigen, hepatitis C virus, and hepatitis C virus RNA, VDRL and fluorescent treponemal antibody absorption test, angiotensin-converting enzyme, cryoglobulins, anti-DNA antibodies, lupus anticoagulant, antimitochondrial antibodies, antismooth muscle antibodies, anti-Sm, anti-ribonucleoprotein, Topo/anti-Scl70, anti-Jo1, antihistones, anti-Ro/SSA, anti-La/SSB, and antiphospholipid antibodies were negative. Only antinuclear antibody testing (by IIF on Hep2-cells; titer, 1:160 with speckled pattern) and antineutrophil cytoplasmic antibody (ANCA) screening were positive, but antimyeloperoxidase and antiproteinase 3 were negative.
Electrocardiogram, chest radiograph, abdominal ultrasound, arterial and venous echo-color doppler of lower limbs, and brain computed tomography were normal.
During the last 8 to 10 days before admittance to alleviate dysesthesias, she habitually soaked her feet and lower limbs in cold water or she walked outdoor barefoot despite the temperature being near to 0°C, causing freezing lesions on her legs and feet.
She never complained of fever, there was neither weight loss nor loss of appetite.
On admission, temperature, pulse rate, and pressure were 36.7°C, 86/min regular, and 125/75 mm Hg, respectively. Cardiovascular and respiratory examinations were normal. The liver was palpable at 3 cm below the right costal margin, without tenderness. There were neither clubbing nor superficial lymphadenopathies. Carotid, brachial, radial, femoral, popliteal, and pedial pulses were symmetrically normal.
The patient continued to complain of severe dysesthesias in the feet and the lower limbs, where the skin seemed erythematous with evident lesions related to the repeated exposure to cold. The toes were purplish. A central nervous system (CNS) examination was normal, and in particular, bone-tendinous reflexes and tactile, thermic, and pallesthetic sensitiveness were normal.
New laboratory findings showed the following: total proteins, 83 g/L; γ-globulins, 19 g/L; β2-microglubulin, 211 nM; and angiotensin-converting enzyme, 42 IU/mL (reference range, 8-52 IU/mL). The lymphocyte subpopulation analysis found the following: total CD3 of 940/μL (74% [reference range, 58%-72%]), with a reduction of CD4 of 305/μL (24% [reference range, 34%-48%), a relative increase of CD8 of 610/μL (48% [reference range,15%-27%]), and decreased CD4/CD8 ratio of 0.50 (reference range, 1.60-2.80). Cultures of blood, stool, and urine were negative. The microscopic analysis of a blood smear was normal.
A nailfold capillaroscopy found mild and aspecific abnormalities.
A skin biopsy of the lateral side of left leg was performed and revealed hyperkeratosis of the epidermis with sclerosis, lymphomonocytic and granulocytic infiltration, and endothelial hyperplasia of arterioles, consistent with leukocytoclastic vasculitis (Fig. 1); the immunofluorescence analysis was negative.
To check for a sensory neuropathy related to the underlying vasculitis, an electrophysiological study of the lower limbs was done, showing normal sensory-motor nerve conduction; this finding reinforced the hypothesis of a pure sensory small fiber neuropathy. Unfortunately, a histological demonstration could not be drawn because the patient refused another skin biopsy.
We evaluated the possibility that the vasculitis could be related to an infectious disease; thus, a complete analysis was started, in particular, herpes simplex 1 antibody IgG index of greater than 16.1, herpes simplex 2 antibody IgG of 0.50, and herpes simplex 1-2 antibody IgM index of 0.30; mononucleosis IgG antibodies of greater than 120 UA/mL and IgM antibodies are negative; Epstein-Barr virus IgG antibody index of 7.7 and IgM index of 0.20; mycoplasma IgG antibody index of 0.80 and IgM index of 0.40 (intervals of reference for all viruses: <0.9, negative; 0.9-1.1, doubt; >1.1, positive). The skin test for tuberculosis was negative.
The patient denied any possibility for HIV infection risk; however, she accepted to undergo HIV 1 to 2 enzyme immunoassay test that resulted positive and was then confirmed by Western blot. The HIV-RNA quantitative was 160 × 103 copies/mL. Antiretroviral therapy with tenofovir, emtricitabine, and lopinavir/r was started; the clinical picture quickly improved, and dysesthesias disappeared in a few weeks. Six months later, the patient was completely asymptomatic, and the cutaneous lesions had completely disappeared.
Searching for sources of HIV infection, it was revealed that the patient's partner was known to be HIV positive for 2 years, but the patient was unaware of this.
Leukocytoclastic vasculitis is a clinical and pathological entity affecting the small vessels, shared by multiple diseases including Henoch-Schönlein purpura, hypocomplementemic urticarial vasculitis, cryoglobulinemic vasculitis, and serum sickness.1,2 Infections (ie, Mycoplasma pneumoniae, Mycobacterium tuberculosis, Salmonella, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, herpes simplex virus, and HIV),3-5 drugs, malignancies, and collagen vascular diseases have been implicated as triggering factors.8 Cutaneous lesions are the major feature of the disease, but visceral involvement may be also observed.1,9 Multisystem organ involvement may occur in up to 50% of patients, most commonly in the small vessels of kidneys, gastrointestinal tract, joints, muscles, lungs, and peripheral nerves.1,6,9
The main pathogenic mechanism is the immune complex deposition, typically involving IgG and IgM, along the postcapillary venules, activation of complement cascade and leukocytotactic factors. Neutrophils migrate and release lysosomal enzymes, causing local destruction of the vessel wall, with accumulation of neutrophils, and immune complex debris. Destruction of the vessel wall allows for fluid leakage and extravasation of red blood cells, along with inflammation.1,9
Prognosis is related to both the site and the extent of involvement; thus, early diagnosis and therapeutic intervention are essential.
Clinical manifestations of HIV infection are various and represent a diagnostic challenge.
Skin conditions related to HIV infection may display in very different ways.10 We can observe infective (herpes virus simplex and zoster, papillomavirus, cytomegalovirus, poxvirus, Staphylococcus aureus, Bartonella species, Treponema pallidum, and Candida species) and noninfective manifestations (seborrheic dermatitis, psoriasis, eosinophilic folliculitis, atopic dermatitis, and leukocytoclastic vasculitis) or neoplastic disorders (Kaposi sarcoma, lymphoreticular malignancies of both B and T cells). Numerous infective diseases (viral, bacterial, and fungal) can affect skin of HIV patients, and because of immunosuppression, they may show a more aggressive behavior than the immunocompetent subjects.
Human immunodeficiency virus infection can be associated with the appearance of various rheumatic syndromes traditionally related to an inappropriate hyperactivation of the immune system. The prevalence of rheumatic syndromes is reported to range from 11% to 70% in different studies.3
The rheumatologic manifestations associated with HIV are reported in Table 1.
The frequency of vasculitis in seropositive HIV patients is low, in the order of 1%.3,8 Systemic necrotizing vasculitis, leukocytoclastic vasculitis, cryoglobulinemia, and CNS vasculitis have been reported.1,4,5 The organs that are usually involved include the following: skin, peripheral nerve, skeletal muscle, and the CNS; in addition, the lung, gastrointestinal tract, oropharynx, and kidney can also be affected, although less commonly.3-5
The link between immune dysfunction and infection in the development of autoimmune diseases in HIV-infected patients is intriguing and still not completely known. Although an abnormal immune activation triggered by the exposure to an infectious agent is one of the suggested mechanisms, various theories have been proposed to explain the virus-associated vasculitis.3,8 The virus may attack the vascular and perivascular tissue directly; alternatively, cellular or humoral immune mechanisms involved in the pathophysiology of the disease may lead to the "in situ" formation or to the deposition of circulating immune complexes in the vascular wall, thus resulting in inflammation (ie, vasculitis). The demonstration of vascular deposits of HIV antigens, immunoglobulins, and complement components seems to support such a pathway in the setting of an abnormal immunologic reactivity to a variety of xenoantigens including HIV and other opportunistic infectious agents and drugs used for the treatment.3,5,8
The diagnosis of HIV-related vasculitis lies with serology and histological findings by light microscopy and immunohistochemistry and in situ hybridization. There are cases of vasculitis in HIV-positive patients in which a causative agent is not found, despite a careful investigation. In this case, vasculitis should be regarded as the result of direct infection by HIV.3,5,8
Tests for circulating ANCA directed toward antimyeloperoxidase or antiproteinase 3 are of considerable value in the diagnosis of ANCA-associated vasculitis including Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, idiopathic necrotizing and membranous glomerulonephritis, and related overlapping forms of vasculitis.11 In the case reported here, a positive screening for p-ANCA by indirect immunofluorescence was not confirmed by an enzyme-linked immunoassay using myeloperoxidases and proteinase-3 as antigens, which thus lowered its clinical significance that ANCA may be found in HIV infection.12 Indeed, it has been observed that HIV may induce ANCA in 20% to 83% of cases probably by means of a polyclonal B cell activation, especially in cases with hypergammaglobulinemia.12,13 Similarly, the "borderline" positivity for antinuclear antibody in the absence of any other sign or symptom suggesting a connective tissue disease has also been interpreted as a nonspecific immune reactivity in the context of the viral infection.
Several studies have indicated that approximately 30% to 50% of patients with acquired immunodeficiency virus complains of symptoms that would suggest for a peripheral neuropathy.14 Severe neuropathic pain represents one of the most frequent kinds of pain observed in these patients.6 A distal painful sensorimotor polyneuropathy is the most common type of HIV-associated peripheral neuropathy, heavily impairing their quality of life.6,9,14
The prevalence of sensory neuropathy is relatively low during asymptomatic HIV infection, but its frequency is inversely correlated with CD4+ lymphocyte count.6 Peripheral neuropathies may involve different populations of nerve fibers. Most patients have large fiber neuropathies with typical symptoms characterized by numbness, tingling, weakness, loss of deep tendon reflexes, and abnormal electrophysiological analysis. However, some patients presenting severe pain have a less pronounced picture with a paucity of findings on clinical examination and normal electrophysiology. Many of these patients have small fiber neuropathies. The discrepancy between intolerable subjective sensory complaints and the lack of objective signs sometimes leads to an erroneous diagnosis of psychogenic pain.
In the pathophysiology of the small fiber sensory neuropathy associated with HIV infection, more than one mechanism likely exists, as it is supported by various observations6,7,14,15:
* HIV may act directly by infecting dorsal root ganglion neurons,
* these neurons may also be injured by locally infiltrating activated macrophages that secrete neurotoxic cytokines or other metabolites,
* a direct relationship between the HIV-RNA load and the severity of neuropathic pain,
* an association with other viral infections,
* other cofactors, including nutritional and vitamin deficiencies, may be involved, and
* antiretroviral (eg, didanosine, stavudine, zalcitabine, and rarely lamivudine) toxic neuropathy has been recognized in up to 60% of patients and likely results from mitochondrial dysfunction.
However, the pathophysiology of sensory polyneuropathy is not completely understood, and the most commonly accepted pathogenic mechanism involves neuronal damage secondary to immune activation, similar to what is observed in HIV-associated dementia.6,7,15 Furthermore, an oxidative and inflammatory pathway in acquired immunodeficiency virus-related vasculopathy has also been suggested.16
The pathological changes associated with sensitive neuropathy consist of axonal degeneration of sensory fibers and prominent loss of unmyelinated fibers.7,17 The axonal damage follows the "dying back" pattern of degeneration,18,19 a phenomenon that occurs in other systemic polyneuropathies such as diabetic and alcoholic neuropathies, and it is probably involved also in degenerative diseases affecting the CNS, like Alzheimer and Parkinson diseases and motoneuron disease.
In HIV-infected patients, the reduction of intraepidermal nerve fiber density in the distal leg is associated with sensory neuropathy and increased neuropathic pain, lower CD4 counts, and higher plasma HIV-RNA levels.20
Classically, in patients with full-blown HIV infection, examination reveals diminished deep tendon reflexes, reduced vibratory and position senses, and distal weakness together with electrophysiological abnormalities, such as slowed motor and sensory conduction velocities, reduced motor and sensory action potential amplitudes, and denervation.
In this case, treatment options for neuropathic pain includes a correct antiviral therapy, associated, if ineffective, with anticonvulsants, antidepressants, anti-inflammatory drugs, lidocaine, mexilitene, opioids, topical agents, nerve blocks, nerve stimulators, physical therapy, acupuncture, relaxation, and meditation techniques. An array of over-the-counter remedies have also been tried. The first choice drugs are tricyclic antidepressants and anticonvulsants.21
In our case, the symptoms quickly disappeared after the starting of antiviral therapy, which were not controlled with tachipirine, antihistaminics, and/or corticosteroid assumption.
Present case draws attention to the possibility of an HIV infection underlying a leukocytoclastic vasculitis associated with severe sensory symptoms as a presenting picture. Although rare, this eventuality must be kept in mind when dealing with a leukocytoclastic vasculitis of undetermined origin after a careful analysis.