Pulmonary aspergillosis in two patients with psoriasis treated with ixekizumab

Dear Editor,

Ixekizumab, a monoclonal antibody to IL-17, is widely used to treat moderate to severe psoriasis in China. Injection site reactions, allergies and infections are the most common adverse events reported with ixekizumab use.¹ Moreover, inhibition of IL-17 may increase the risk of fungal infections; whereas most of the current reports are on cutaneous and mucosal candida infections, including oral and esophageal candida infections, few deep-seated fungal infections have been reported.² In this paper, we report two psoriasis patients with pulmonary aspergillus infection secondary to treatment with ixekizumab, warning us to be vigilant about the risk of pulmonary fungal infection when using IL-17 monoclonal antibodies.

Case 1: A 78-year-old man was diagnosed with severe psoriasis for 2 years. Admission in April 2023 revealed normal serum IgE level and neutrophil count with a negative Mycobacterium. tuberculosis interferon-γ release assay (IGRA) and a negative purified protein derivative (PPD) test. He had emphysema. Chest X-ray showed increased translucency in both lung fields, sparse lung texture and blunting of the left costophrenic angle [Figure 1a]. Ixekizumab was initiated in April 2023 at a loading dose of 160 mg at week 0, followed by 80 mg every 2 weeks until week 12, He achieved complete skin clearance (PASI 100) by week 12 and subsequently received 80 mg every 4 weeks as maintenance therapy.

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Figure 1: (a) Chest X-ray shows: Increased translucency in both lung fields, sparse lung texture, blunting of the left costophrenic angle (red arrow) (Case 1), (b) No abnormality detected (Case 2).

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In March 2024, the patient presented with cough, wheezing and white mucoid sputum without fever or chest pain. Aspergillus fumigatus-specific immunoglobulin E (IgE) and IGRA were negative. A CT scan of the chest showed pulmonary abnormalities as depicted in Figure 2a. Fibre-optic bronchoscopy revealed purulent inflammation in the trachea and bilateral bronchi.

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Figure 2: (a) CT scan of the chest shows: Bilateral emphysema, and focal fibrous proliferation and calcified foci in the upper lobes of both lungs and the lower lobe of the left lung (red arrow), small nodules and calcified foci in both lungs, minimal tracheal secretion and bilateral pleural thickening (Case 1). (b) Bilateral pulmonary infective lesions, bronchitis and focal emphysema (red arrows) (Case 2).

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A multiplex PCR–capillary electrophoresis fragment-length assay on bronchoalveolar lavage fluid (BALF) suggested Aspergillus fumigatus; microorganisms in BALF were identified on sabouraud dextrose agar (SDA) culture medium exhibiting colonies with a blue-green colour [Figure 3a]. Additionally, typical morphology of Aspergillus fumigatus was observed on light microscopy [Figures 3b and c]. A diagnosis of pulmonary aspergillosis was therefore confirmed.

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Figure 3: (a) Sabouraud dextrose agar fungal culture of bronchoalveolar lavage fluid shows blue-green colonies with a villous surface and loose texture. (b) Light micrograph of Aspergillus from bronchoalveolar lavage fluid (400x) shows flask-shaped vesicles with a single-layered structure, along with smooth conidiophores and round, smooth conidia (red arrows). (c) Light micrograph of Aspergillus from bronchoalveolar lavage fluid (100x) shows overall hyphal networks and scattered conidial heads (red arrow).

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Ixekizumab injections were discontinued and capsule itraconazole (200 mg per dose) was administered every 12 hours for 3 months. The patient showed clinical improvement in respiratory symptoms.

Case 2: A 46-year-old woman was diagnosed with psoriasis of more than one year duration. She exhibited a tendency to develop erythroderma. She was admitted to the hospital in November 2022, serum IgE was normal; Mycobacterium tuberculosis IGRA and PPD test were negative. Chest X-ray showed no obvious abnormalities [Figure 1b]. She was started on ixekizumab in November 2022 with the first dose of 160 mg, followed by 80 mg every two weeks until February 2023, followed by maintenance therapy with 80 mg injections per month, with which she achieved substantial clearance of skin lesions (PASI 90).

In July 2023, the patient presented with cough, shortness of breath, wheeze and low-grade fever. Wet rales were auscultated bilaterally. Serum IgE, neutrophil and eosinophil counts were normal. Mycobacterium tuberculosis IGRA, PPD test, 1,3-beta-D-glucan test (G test), galactomannan assay (GM assay) and bacterial culture of BALF were negative. SDA fungal culture and BALF next-generation sequencing suggested Aspergillus niger infection. CT scan of the chest showed pulmonary abnormalities as indicated in Figure 2b. The diagnosis of pulmonary aspergillosis was made.

Ixekizumab injections were discontinued and tablet voriconazole (200 mg per dose) was administered twice daily for 3 months. Concurrently, capsule acitretin (10 mg twice daily) was administered and topical halometasone cream was applied twice daily, with which psoriasis lesions were controlled. The patient showed clinical improvement in respiratory symptoms.

IL-17 signalling is central to the pathogenesis of psoriasis and agents that target this pathway are effective in moderate-to-severe disease. IL-17A also contributes to regulation of the airway microbiome and to mucosal antifungal defence. During fungal infection, damaged epithelial cells release pro-inflammatory cytokines that drive Th17 responses; IL-17 then induces chemokines, promoting neutrophil recruitment and antimicrobial peptides to contain infection.³

Pulmonary aspergillosis, caused predominantly by Aspergillus fumigatus, is the most frequent mould infection of the lungs, spanning a spectrum from invasive pulmonary aspergillosis (IPA) to chronic pulmonary aspergillosis (CPA). Its expression is determined by the interplay between the pathogen, underlying structural lung disease and host immunity.⁴

Case 1 evolved on a background of emphysema with cavitary change—a structural niche that favours a chronic, cavity-linked trajectory. The causative organism was Aspergillus fumigatus, in keeping with its recognised association with cavitary disease. Case 2 involved prolonged IL-17 inhibition and bilateral inflammatory foci with A. niger. Although A. niger is generally less virulent than A. fumigatus, the timing of IL-17 blockade points to dampened mucosal antifungal defences, explaining the more inflammatory, non-cavitary presentation. These two cases illustrate that opportunistic deep fungal infection can occur during IL-17 inhibitor therapy for psoriasis.

A. fumigatus is more virulent, secreting gliotoxin to inhibit macrophage phagocytosis, so the disease course was mainly characterised by chronic cavitation-like destruction.⁵ A. niger is relatively less virulent, but produces ochratoxin which resulted in patchy exudation with bronchial inflammation on the image.^6,7 This suggests that low virulence aspergillus can be pathogenic in the context of IL-17 blockade. This mechanism-specific immunodeficiency is further highlighted by the reported 3.6% incidence of lower respiratory tract infection in rheumatoid arthritis patients following dual IL-17A/TNF inhibition.⁸

In our view, IL-17 monoclonal antibody-associated pulmonary aspergillosis is not inherently rare but rather underrecognised. This under-recognition likely stems from the insidious onset of symptoms and the lack of systematic screening in at-risk population. Given this, we recommend baseline high-resolution CT scan for all patients receiving IL-17 inhibitors, regardless of immune status. Focus on structural immunodeficiency and maintaining a ‘low-threshold imaging + high-resolution BALF’ strategy throughout the course of treatment could transform insidious deep fungal infections into preventable and controllable adverse events.