P-ANCA vasculitis with diffuse alveolar haemorrhage preceded by a spider bite

Abstract

We report a patient with antineutrophilic cytoplasmic antibody (ANCA) vasculitis that was preceded by witnessed black widow spider bites. The patient initially presented with a diffuse painful skin rash that developed after a few hours post bite. He was treated initially with topical ointment for the suspected bite. However, subsequently a few days later the patient returned to the hospital with similar, but more progressive rash with haemoptysis and acute hypoxic respiratory failure requiring supplemental oxygen. Immunology work up showed elevated titre of peri-nuclear ANCA. Bronchoscopy revealed diffuse alveolar haemorrhage. The patient was treated successfully with methylprednisolone and rituximab.

Background

The antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) represent a diagnostic challenge due to its rarity and complexity of clinical presentation. The pathogenesis of vasculitis is multifactorial, including genetic and environmental factors.

Here we report a 71-year-old man with P-ANCA vasculitis that was triggered by a black widow spider bite. This case provides a possible correlation between microscopic polyangiitis (MPA) and spider bites. Moreover, this case demonstrates a diagnostic challenge as the patient was seen first with an isolated skin rash around the spider bite, which can be typical. However subsequently he developed a more extensive rash with diffuse alveolar haemorrhage (DAH) and was discovered to have vasculitis. To the best of our knowledge and our literature review, there are very few reported spider bites possible triggers of systemic vasculitis.

Case presentation

A 71-year-old Caucasian man presented to the hospital with a diffuse painful skin rash, migratory arthralgias and haemoptysis. Two weeks prior to presentation, the patient had recently relocated to Fresno, California. While unpacking, he observed three spiders crawling on his body with subsequent raised bumps presumably from being bitten. A few hours later, he noticed an itchy skin rash on his lower extremities, which prompted a visit to a local urgent care clinic. He was prescribed a topical ointment which resulted in partial improvement. Two days later, his rash became painful, pruritic and widespread. In addition to the rash the patient noticed haemoptysis and shortness of breath prompting admission to the hospital. Previous medical, surgical and family history were not relevant. On admission, patient was hypoxic to 88% saturation, but rest of the vitals were unremarkable. Dermatological examination was significant for petechiae, ecchymosis, papules and macules located on bilateral lower extremities, groin, buttocks, lower abdomen and bilateral upper extremities (figure 1A, B). Chest examination was remarkable for bilateral basilar chest crackles. Otherwise, physical examination was unrevealing.

Figure 1.

Photograph of actual presenting rash. (A) Diffuse palpable abdominal rash. (B) Diffuse lower extremity ecchymosis.

Investigations

Primary laboratory investigations included a complete blood count which revealed normocytic anaemia with haemoglobin of 0.102 g/L, normal white blood cells and platelets. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were 83 mm/hour and 34.5 mg/L, respectively. Renal and liver function were unremarkable.

Serological tests were submitted as follows: ANCA screen was positive for p-ANCA titre at 1:80 with undetectable level of serine proteinase 3 or myeloperoxidase antibodies. Human immune deficiency virus antibody and antigen, rapid plasma reagent, herpes simplex virus 1 and 2 typing were negative. Rheumatoid factor, anticyclic citrullinated peptide, antinuclear antibodies, double-stranded DNA, anti-Sjögren’s-syndrome-related antibody A (SSA) and B (SSB), anti-ribonucleoproteins antibodies, antitopoisomerase (also known as anti-Scl-70) and cryoglobulins were negative. Coccidioidomycosis IgM/IgG were negative, as well as a hepatitis panel was unremarkable.

Skin biopsy demonstrated leukocytoclastic vasculitis with deep dermatosis, negative for IgA staining. CT of the chest with and without contrast showed consolidation at the right lung base with associated interlobular septal thickening and scattered ground glass opacities in the more superior right lower lobe with small layering right-sided low-attenuation pleural effusion (figure 2A, B). Bronchoscopy showed DAH. Pertinent tests were as follows: Streptococcus pneumoniae urinary antigen, legionella urinary antigen, mycoplasma tests were unremarkable. Pneumocystis pneumonia polymerase chain from bronchoalveolar lavage sample was also negative. Screening with QuantiFERON-Tuberculosis gold was negative.

Figure 2.

(A, B) CT chest without contrast cross-section and coronal view: demonstrating pulmonary pathology on presentation.

Differential diagnosis

The differential diagnosis of the initial skin lesion included more common diagnosis such as allergic reaction or local inflammatory reaction due to spider bite verses bacterial and fungal skin infections, atypical viral exanthem and cutaneous vasculitis. Sweet syndrome was also considered in the setting of deep dermatosis on skin biopsy. It was not until later when the patient developed haemoptysis, that ANCA vasculitis was considered at the top of the differentials list. Loxoscelism, which is a myriad of reactions to spider bite that ranges from local skin rash to systemic manifestations, was also entertained.

Treatment

The patient was initially treated with topical ointment for the skin rash, which did not subside the rash. Once the patient returned to the hospital with haemoptysis and was noted to have DAH he was started on methylprednisolone 1000 mg for 3 days and rituximab 375 mg/m² once. There was an immediate response to the dermatological symptoms, and the haemoptysis ceased 3 days later. Patient was discharged on oral prednisone taper. Rituximab was switched to mycophenolate daily per patient request as a maintenance therapy and with subsequent follow-up with rheumatology clinic.

Follow-up and outcome

Patient was seen at 1 week, 4 weeks and 8 weeks intervals after hospital discharge. He was asymptomatic for 1 week after discharge, then subsequently developed worsening shortness of breath with tachypnea. Patient was found to have pulmonary embolism placed warfarin eventually switched to apixaban. Otherwise, all skin rash, arthralgia and haemoptysis had totally resolved. Inflammatory markers including ESR and CRP returned to normal limits. The culprit pulmonary embolism was diagnosed using chest angiographic CT. Antiphospholipid syndrome (APLS) antibodies panel was ordered, which showed elevated anticardiolipin IgM antibody, elevated lupus anticoagulant and elevated β-2-glycoportein IgM antibody. However, IgG for the all previously mentioned antibodies were negative. APLS work up was repeated 12 weeks later and all the antibodies came back negative except from an elevated β-2-glycoprotein IgM. Given that the diagnosis of APLS was not confirmed, hence warfarin was switched to apixaban. Patient had not been placed on deep venous thrombosis prophylaxis during hospitalisation due to haemoptysis and unfortunately developed a pulmonary embolism.

Discussion

AAV is defined as necrotising vasculitis affecting primarily the small vessels, capillaries, venules and arterioles, which commonly present with focal necrotising glomerulonephritis and inflammation of pulmonary capillaries leading to haemoptysis.¹

AAV includes granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis), MPA and eosinophilic GPA (EGPA; also known as Churg-Strauss syndrome). Despite their rarity and unknown underlying aetiologies, there has been an abundant amount of research occurring in AAV.

AAV affects both genders equally with the average age of diagnosis occurring in the fifth decade; however, younger children and elder adults can be affected as well. Most patients (93%–98%) are of Caucasian and Hispanic background. The annual incidence of AAV in the USA is 3.3/100 000, with a prevalence 42/100 000 remarkably higher than previous reports.²

As with most autoimmune diseases, the aetiology and pathogenesis of AAV are undoubtedly multifactorial, with contributions from genetic factors, environmental exposures such as infections/toxins, characteristics of the innate and adaptive immune system, and the intensity and duration of the injury.³

ANCAs are both diagnostic and pathogenic that direct against proteins contained in the lysosomal compartments of neutrophils and monocytes. Recent studies suggest that these antibodies play a role in the pathogenesis of AAV via the activation of neutrophils, cytokine release and the generation of superoxide radicals.⁴

Several hypotheses have been proposed for the nature and origin of the autoantigens that can induce a pathogenic ANCA response. These include exposure to exogenous antigens such as infectious pathogens/drugs. Endogenous autoantigens such as antisense peptides and peptides derived from alternatively spliced transcripts have also been considered as a pathogenic pathway.

We can also extrapolate these hypotheses and add to the ‘two hit’ model of pathogenesis. The presence of an ANCA acts as a primer for the development of full-blown vasculitis after the exposure to triggering factor. This model is supported by observations of infectious episodes before or at diagnosis of AAV and by in vitro studies that have shown that ANCAs are capable of activating neutrophils and monocytes primed with inflammatory cytokines.⁵

Vasculitis associated with insect bites have been documented post bacterial infections causes such as Q fever, Lyme disease and rocky mountain fever or due to delayed hypersensitivity reactions thought secondary to the venom component. Insects sting-induced DAH have been reported in literature and were attributed to anaphylaxis or previous sensitisation.^5–8

Spider bites are generally not dangerous because the amount of venom injected is low and the toxins lack mammal specificity. However, brown spiders (Loxosceles species; brown recluse) and widow spiders (Latrodectus species; black widow) may induce systemic reactions including vasculitis.⁹

The association between ANCA vasculitis and brown spider bite has been reported rarely in literature. To the best of our knowledge, this is the first case of AAV preceded by a black widow spider bite. We hypothesise based on the ‘Two Hit’ hypothesis that the patient was genetically predisposed to vasculitis and that the second trigger may have occurred in setting of methicillin resistant Staphylococcus aureus colonisation of the black widow spider as demonstrated by Stageman et al.¹ There has been a direct association between Wegner’s vasculitis and S. aureus.¹ where they stated that up to 70% of those diagnosed with Wegner’s granulomatosis are chronic carriers of this bacterium¹⁰ In addition, ANCA-positive vasculitis have been reported following S. aureus endocarditis even in non-bacteremic patients.¹¹

An alternative hypothesis is the possibility of molecular mimicry between proteins in the venom and the neutrophilic enzymes which have been shown to play a pivotal role in pathogenesis of vasculitis. The black widow spider venom enzymatic components include elastase which has been noted to be elevated in serum and bronchoalveolar lavage samples collected from patients with active vasculitis and centrally involves ANCA-induced neutrophilic lung injury¹² However, the proteolytic activity of black widow spider venom is not robust as other arthropods such as the brown recluse.¹³

We have also considered the tissue damage and inflammation from the venomous bite might expose neutrophils antigen to the immune system which could amplify the neutrophil-induced damage. This report expands the list of life-threatening complications of spider bites and the list of vasculitis triggers.^{12 14}

The question arises on the identification of the spider that may have triggered the vasculitis. The patient is from the Central Valley of California which is primary agrarian area and black widows are well known to cohabitants. The patient had been insistent that it was spider bite which was iterated by his wife. He described the insect as a black spider with ‘red tie’. We did show multiple pictures of spiders that are known to be in the central valley area and he repetitively chose the insect that was identified as the black widow spider.

ANCA vasculitis is an uncommon presentation in the context of spider bite. Although localised skin rash is not very specific, extensive progressive skin rash should alert the physicians to the possibility of a vasculitis diagnosis. We would like to highlight the possibility of spider bite being recognised as a trigger of ANCA vasculitis in the appropriate clinical setting to obviate a futile search for other underlying diseases. However, further case reports and laboratory research are required to support this assumption in addition to studying the molecular structure of black widow venom that can clarify this association.

Learning points.

• Consider antineutrophilic cytoplasmic antibody vasculitis in the differential diagnosis of diffuse skin rash preceded by black widow spiders’ bites, especially in the rural areas.

• Spider bites-associated skin rash might indicate a need for skin biopsy and further immunology work up.

• Increasing awareness of potential life-threatening complication such as diffuse alveolar haemorrhage in setting of spider bite and diffuse systemic rash.

• Patient education about the systemic manifestation of vasculitis before discharge with strict follow-up for those with skin manifestation only.