The Case of a Janitorial Supervisor With Occupational Asthma Complicated by the Mixed Colonization of the Respiratory Tract by Candida albicans and Alternaria spp.

Patients on immunosuppressant agents, including oral corticosteroids, are susceptible to fungal colonization despite being otherwise immunologically intact. This case report highlights a state-of-the-art biological modifier therapy for the complex care of a patient with refractory occupational asthma, allergic rhinitis, and mixed fungal colonization. A dyspneic 38-year-old male janitor with steroid-dependent occupational asthma refractory to omalizumab therapy was colonized with Candida and Alternaria following a promotion to a managerial position in a moldy office. He was treated with itraconazole and systemic steroids. Pulmonary workup revealed moderate obstructive ventilatory defect, peripheral airway hyperresponsiveness, and eosinophilic airway inﬂammation. Three additional biological modiﬁers (reslizumab, benralizumab, and dupilumab) were administered to this patient. His asthma was ultimately controlled with reslizumab and dupilumab. Fractional exhaled nitric oxide (FeNO) normalized after dupilumab monotherapy, enabling the patient to taper off chronic prednisone therapy. Various occupational exposures are crucial epidemiologic factors related to infection and go hand-in-glove with long-term prednisone treatment towards increasing susceptibility to fungal colonization. Steroid-sparing anti-interleukin-5 (IL-5) agents and dupilumab should be considered as alternative treatment options for patients, such as ours, with eosinophilic, prednisone-dependent asthma refractory to omalizumab therapy.


Introduction
Occupational exposure to cleaning and sterilizing agents is a known cause of occupational asthma. The occupational exposome is vastly greater among professional cleaners compared to that in the domestic setting. Additionally, cleaning workers in the healthcare setting are at an even higher risk of developing respiratory symptoms because the cleaning agents they use are required to have stronger antimicrobial and disinfecting properties. A history of atopy, presence of high serum immunoglobulin E (IgE), poorlycontrolled asthma, and occupational exposures are all characteristics of sensitizer-induced asthma, which is an occupational asthma subtype wherein aerosolized irritants promote eosinophilic inflammation [1][2][3][4]. Cleaning agents have specifically been shown to induce asthma through both sensitizer (immunogenic) and irritant effects. For example, benzalkonium chloride, a common antimicrobial cleaning agent, has been shown to induce IgE and eosinophilic inflammation [5][6]. Janitors are also often exposed to aerosolized dust mite and mold antigens, such as Dermatophagoides pteronyssinus and farinae, as well as Penicillium and Aspergillus spp., which have also been implicated in occupational asthma [7][8][9].
Patients on immunosuppressant agents, which include oral corticosteroids for occupational asthma, are susceptible to fungal colonization despite being otherwise immunologically intact [10]. Patients with eosinophilic, prednisone-dependent asthma have been found to have increased local eosinophil-producing processes, which respond well to anti-interleukin-5 (IL-5) therapy [11]. In 2017, reslizumab was recommended as an add-on therapy for severe eosinophilic asthma by the Global Initiative for Asthma; it has been shown to reduce pulmonary eosinophilia in animal models without inducing immunosuppression [12]. If reslizumab is not available, other anti-IL-5 monoclonal antibodies and other biological modifiers, such as dupilumab (FDA approval granted in 2018), could also be considered as an alternative treatment option for this patient population. This case report highlights a state-of-the-art biological modifier therapy for the complex care of a patient with refractory occupational asthma, allergic rhinitis, and mixed fungal colonization.

Case Presentation
A 38-year-old male, a former smoker with poorly controlled asthma despite being treated with fluticasone/salmeterol or budesonide/formoterol with spacers, and year-long oral prednisone therapy, presented to a community-based outpatient clinic with dyspnea. His past medical history consisted of chronic sinusitis, nasal polyposis status post-sinus surgery, and multiple hospitalizations for phlegmatic dyspnea and pneumonia. Percutaneous skin prick testing was significant for Dermatophagoides farinae and pteronyssinus, and his serum IgE had been found to be 2,000 IU/ml during a previous hospitalization.
He had worked for many years as a janitor in professional healthcare settings, with occupational exposure to fumes from industrial cleaning agents. Recently, the patient had been promoted to a supervisory position and he had moved into a moldy office where he had subsequently developed a chronic cough, dyspnea, and wheezing.
Omalizumab was initiated at 225 mg every two weeks to manage his poorly controlled, steroid-dependent asthma with elevated serum IgE. Over the next year, his response to omalizumab kept fluctuating, requiring steroids at times to control exacerbations. Forced expiratory volume in one second (FEV1) and forced expiratory flow at 25-75% (FEF25-75) still showed only partial or minimal reversal of airway obstruction (Figures 1, 2). He remained chronically dependent on steroids since his symptoms would flare up while tapering. Omalizumab failed to improve the frequency of his asthma exacerbations. One year after initiating treatment at our office, the patient presented with green nasal discharge bilaterally and worsening dyspnea. He was afebrile, and the physical exam revealed constant anterior and posterior rhonchi with wheezing throughout all lung fields. A chest X-ray revealed infiltrates in the right lower lobe (Figure 4). Sputum culture grew Candida albicans and Alternaria spp., which were verified by microscopy with lactophenol cotton blue. Itraconazole and prednisone were initiated as antifungal therapy. The peripheral blood eosinophil percentage increased from 2.4 to 9.6% during this time (reference range: 0-3%), equating to an absolute eosinophil count of 806 cells/μl [4]. Despite improvement in respiratory symptoms, antifungal therapy was discontinued after one month due to itraconazole-induced personality changes. At this time, repeat sputum culture was found to be negative for fungal growth. He had no known history of immunodeficiency ( Table 1). To reduce exposure to mold, the patient switched his office to one without visible mold and installed a high-efficiency particulate air filter to improve air quality and reduce aeroallergens.

FIGURE 4: Radiographic demonstration of pulmonary infiltrates
Left: lateral chest X-ray that shows that the posterior triangle has infiltrates at the level of the lingula. Right: posterior-anterior view chest X-ray did not demonstrate infiltrates  Due to his asthma that was refractory to omalizumab, and persistent signs of eosinophilic inflammation (elevated FeNO and peripheral eosinophilia), three different biological modifiers were tried. Reslizumab was initiated at 30 mg every four weeks after omalizumab was discontinued. Pre-and post-bronchodilator values for FEF25-75 and FEV1 improved with three months on reslizumab (Figures 1, 2). Benralizumab, also administered at 30 mg every four weeks after reslizumab, was discontinued for the following reasons: the inconvenience of receiving injections at a local community hospital; worsening of FEF25-75 and FEV1 (Figures 1, 2). Dupilumab was given at 300 mg every two weeks following the failure of benralizumab, and consequently, FEF25-75 and FEV1 returned to normal (Figures 1, 2).

Discussion
Our patient's persistently elevated FeNO levels reflected eosinophilic airway inflammation, an indicator of occupational asthma [15]. His airway obstruction in the central and peripheral airways was refractory to steroid and omalizumab therapy. Omalizumab has been well-documented to be efficacious in eosinophilic asthma and non-allergic eosinophilic disease through direct anti-IgE mechanisms and indirect effects on the production of pro-eosinophilic cytokines [16]. Since the patient's asthma was refractory to omalizumab therapy, it is likely that continued exposure at work had caused his eosinophilic inflammation to persist through non-IgE mechanisms. Due to the persistent need for steroids to control symptoms, even with omalizumab therapy, our patient was colonized by Candida albicans and Alternaria.
We suspect that mixed fungal colonization arose secondary to immunosuppression from the steroids. Similar cases have been reported in the past with chronic steroid use inducing secondary immunosuppression, leading to invasive fungal pneumonia [17][18]. It must be noted that despite the presence of pulmonary infiltrates at the level of the lingula, the patient did not meet the criteria for invasive fungal infection as outlined by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group