Cocaine–Levamisole-Associated Vasculopathy Mimicking ANCA-Associated Vasculitis and Presenting With Pulmonary–Renal Syndrome Requiring VV-ECMO Support

Introduction

Levamisole, once used as an anthelmintic, is now found in up to 70–80% of cocaine samples in North America, creating a growing public health burden due to its association with immune dysregulation and vasculopathy [1]. Cocaine–levamisole-associated vasculopathy (CLAV) is characterized by neutropenia, thrombotic events, skin necrosis, and the highly distinctive pattern of dual MPO and PR3 ANCA positivity, which is uncommon in idiopathic ANCA-associated vasculitis (AAV) but is characteristic of drug-induced disease [2–4].

Pulmonary involvement ranges from mild infiltrates to life-threatening diffuse alveolar hemorrhage (DAH), while renal manifestations include pauci-immune necrotizing crescentic glomerulonephritis [2,3]. The dual-organ involvement of pulmonary hemorrhage and crescentic GN is one of the most severe phenotypes of ANCA-related disease and has been associated with high morbidity, relapse risk, and mortality in recent cohort analyses [5].

Extracorporeal membrane oxygenation (ECMO) has only rarely been reported in CLAV-related DAH but can be lifesaving when hypoxemia is refractory to conventional ventilatory strategies [2,6,7]. This case report aims to illustrate the diagnostic reasoning, immunosuppressive sequencing, and objective ECMO criteria guiding escalation of care in a fulminant presentation of CLAV mimicking AAV.

Case Report

A 30-year-old previously healthy woman presented to the emergency department with profound fatigue, progressive shortness of breath, and new-onset hemoptysis. One week earlier, she had been evaluated at an urgent care center for an upper respiratory tract infection and completed a short course of antibiotics. The day before admission, her primary care physician noted abnormal blood work results, prompting referral to the hospital. She denied fever, rash, arthralgia, urinary symptoms, gastrointestinal bleeding, or history of autoimmune disease. Importantly, the physical examination revealed no purpuric or necrotic skin lesions. She reported having heavy menstrual bleeding 4 weeks prior.

On arrival, vital signs showed heart rate 112 bpm, blood pressure 116/74 mmHg, temperature 36.5°C, respiratory rate 20 breaths/min, and oxygen saturation 96% on room air. Physical examination was unremarkable except for pallor. Laboratory evaluation revealed severe anemia (hemoglobin 5.8 g/dL), mild leukopenia (WBC 4.8× 103/μL), thrombocytosis (platelets 422×103/μL), and hypokalemia (2.4 mmol/L). Serum creatinine was 1.5 mg/dL (reported without labeling as AKI due to absence of documented baseline or KDIGO criteria). Urinalysis demonstrated proteinuria, microscopic hematuria, and red blood cell casts.

Imaging with CT pulmonary angiography (Figure 1) showed no evidence of pulmonary embolism but revealed extensive bilateral pan-lobar infiltrates. She received 2 units of packed red blood cells, potassium repletion, and empiric ceftriaxone plus azithromycin for suspected pneumonia (Table 1).

Serologic testing revealed markedly elevated MPO-ANCA and low-level PR3-ANCA positivity. Complement levels were normal, and ANA and anti-GBM antibodies were negative. Urine toxicology was positive for cocaine, which the patient later acknowledged using intermittently.

Renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis with approximately 70% crescents and minimal chronicity. She received intravenous methylprednisolone 1 g daily for 3 days, followed by rituximab as initial induction therapy.

Three days after discharge, she returned with sudden worsening hemoptysis and severe respiratory distress. On arrival, she required high-flow oxygen. Arterial blood gases on FiO2 1.0 showed pH 7.23, PaCO2 58 mmHg, and PaO2 78 mmHg, corresponding to a PaO2/FiO2 ratio <80. Repeat imaging showed interval worsening of bilateral infiltrates. Bronchoscopy confirmed diffuse alveolar hemorrhage based on progressively bloodier lavage aliquots.

Despite paralysis, prone positioning, and maximal ventilatory support, the hypoxemia persisted and respiratory acidosis worsened. Plasmapheresis was initiated. Given refractory hypoxemia, rising PaCO2, and inability to maintain lung-protective ventilation, she was initiated on veno-venous ECMO (VV-ECMO) using objective criteria including PaO2/FiO2 <80 for >6 h, hypercapnic acidosis, and progressive DAH.

Cyclophosphamide was started after stabilization on ECMO. Her respiratory status gradually improved, and she was decannulated successfully. Renal function normalized to a creatinine of 0.8 mg/dL.

At 18-month follow-up, the patient remained in remission. Proteinuria had resolved (Table 2), pulmonary symptoms were minimal, and follow-up CT imaging (Figure 2) showed only mild residual ground-glass opacities. MPO-ANCA levels remained elevated, although she exhibited no clinical evidence of relapse.

Discussion

PULMONARY–RENAL SYNDROME SEVERITY AND PROGNOSIS:

The coexistence of DAH and crescentic GN is at the most severe end of the pulmonary–renal spectrum in ANCA-associated disease. Recent cohort analyses have demonstrated that this dual-organ involvement significantly increases the risk of mortality, relapse, and long-term organ dysfunction [5]. The abrupt deterioration observed in this patient underscores the importance of early recognition and immediate immunosuppressive therapy. Furthermore, ongoing cocaine exposure is associated with recurrent disease flares, reinforcing the necessity of cessation counseling as part of management.

RATIONALE FOR ECMO IN CLAV-ASSOCIATED DAH:

Although ECMO is rarely required in AAV or CLAV, its use can be lifesaving when hypoxemia becomes refractory to conventional ventilation. DAH produces shunt physiology, limiting oxygen exchange and creating severe hypoxemia that does not improve with escalating ventilatory support. High airway pressures can worsen hemorrhage, further compromising gas exchange. Veno-venous ECMO allows for lung-protective ventilation while maintaining oxygenation and carbon dioxide removal, providing critical time for immunosuppressive therapy to reverse the underlying inflammatory insult. In this case, ECMO initiation followed objective criteria, including PaO2/FiO2 <80, severe hypercapnia with respiratory acidosis, and failure of maximal ventilatory strategies. Published case reports support the use of ECMO as a salvage therapy in fulminant DAH secondary to CLAV or AAV [6,7].

DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC REASONING:

A systematic evaluation was performed to distinguish CLAV from other causes of pulmonary–renal syndrome. Anti-GBM disease was excluded by negative serologies, and infection-associated DAH was ruled out through negative cultures and imaging findings. Antiphospholipid syndrome was excluded based on serology, and cardiac etiologies of hemoptysis were ruled out through imaging. The absence of immune complex deposition on biopsy, the presence of dual ANCA positivity, and the confirmed cocaine exposure collectively supported CLAV as the most plausible diagnosis. Toxicology screening was essential because many patients do not initially disclose cocaine use.

THERAPEUTIC CONSIDERATIONS:

Management of CLAV involves a combination of drug cessation counseling, immunosuppression, and supportive care. High-dose corticosteroids remain the cornerstone of initial therapy, while either rituximab or cyclophosphamide can be used for induction. Plasmapheresis may be considered in cases of life-threatening DAH or rapidly progressive renal injury, although evidence is variable. It is important to note that persistent ANCA positivity alone does not necessarily predict relapse once cocaine exposure has ceased.

CLINICAL IMPLICATIONS AND LESSONS LEARNED:

This case highlights 5 important lessons for clinical practice. (1) Dual MPO/PR3 ANCA positivity should immediately raise suspicion for drug-induced vasculopathy rather than primary AAV. (2) A detailed exposure history and toxicology screening are essential components of diagnostic evaluation. (3) CLAV can progress rapidly and require the full spectrum of immunosuppressive therapies used in severe AAV. (4) When DAH results in life-threatening hypoxemia refractory to maximal ventilation, VV-ECMO can be a lifesaving adjunct that allows time for definitive therapy. (5) Long-term organ function can normalize, and relapse is uncommon when cocaine cessation is achieved and immunosuppression is administered promptly.

Conclusions

Cocaine–levamisole-associated vasculopathy can present as a fulminant pulmonary–renal syndrome closely mimicking primary ANCA-associated vasculitis. Dual ANCA positivity should prompt consideration of a drug-induced etiology. Early diagnosis, cessation of cocaine use, aggressive immunosuppression, and the use of VV-ECMO when indicated can be lifesaving. With timely intervention, the long-term prognosis can be favorable even in cases complicated by severe diffuse alveolar hemorrhage and crescentic glomerulonephritis.