16 March 2023: Articles
A 64-Year-Old Man Hospitalized for COVID-19 Pneumonia and Treated with Tocilizumab Who Developed Chronic Cavitary Pulmonary Aspergillosis
Unusual or unexpected effect of treatment, Adverse events of drug therapy , Educational Purpose (only if useful for a systematic review or synthesis), Rare coexistence of disease or pathologyAdebola Oluwabusayo Adetiloye1BDEF*, Farhana Alladin1EF, Rasha Alaameri1EF, Julio C. Valencia-Manrique1EF, Olurotimi Badero2EF, Armeen Poor3EF
Am J Case Rep 2023; 24:e938359
BACKGROUND: The management of (Coronavirus disease 2019) COVID-19 pneumonia is ever-evolving. Tocilizumab, a monoclonal antibody against interleukin-6 (IL-6) receptor, have known mortality benefit in severe COVID-19 pneumonia, but data are limited regarding safety. Attributable to the immunomodulatory nature of this medication, patients may be at risk for opportunistic infections, including chronic cavitary pulmonary aspergillosis (CPPA), a slowly progressive disease characterized pulmonary infiltrates and often a newly-formed cavity. However, current guidelines do not emphasize post-treatment surveillance of patients for opportunistic infections, including CPPA.
CASE REPORT: We present a particular case of a 64-year-old man treated for COVID-19 pneumonia with Tocilizumab and dexamethasone who developed cavitary pulmonary aspergillosis. He presented to the emergency department with hemoptysis, associated with worsening productive cough, shortness of breath, and weight loss. Computed tomography (CT) of the chest showed areas of focal consolidation and a cavitary lung lesion within the left upper lobe. Sputum culture was positive for Aspergillus niger. The patient received a long course of oral triazole therapy for CPPA, with clinical improvement. CT scan of the chest at 9 months showed that the Itraconazole therapy was effective in resolving the extensive airspace disease and decreasing the size of the upper-lobe cavity and fungal ball.
CONCLUSIONS: This article illustrates the possibility of a serious infection such as CCPA as an adverse effect of Tocilizumab treatment, especially with concurrent immunosuppressive therapy. Furthermore, this case highlights the importance of regular monitoring of patients who have received Tocilizumab therapy to ensure that early signs of opportunistic infections such as CPPA are detected and treated promptly to prevent permanent lung damage.
Keywords: COVID-19, Dexamethasone, pulmonary aspergillosis, Tocilizumab, Itraconazole
Chronic pulmonary aspergillosis (CPA) is an uncommon, slowly destructive pulmonary disease characterized by progressive cavitation (chronic pulmonary cavitary aspergillosis), fibrosis, and pleural thickening . CPA is a severe fungal infection often seen in immunocompetent or mildly immunosuppressed patients with underlying respiratory disorders . A variety of lung conditions have been linked to CPA. Pulmonary tuberculosis, allergic bronchopulmonary aspergillosis (ABPA) and chronic obstructive pulmonary condition (COPD) are predominant risk factors for CPA [3–5]. However, following the outset of the COVID-19 pandemic, CPA is increasingly being recognized as a sequela of COVID-19 pneumonia.
COVID-19 is a novel disease whose pathophysiology, clinical course, and outcomes are still being investigated. The disease was first reported in Wuhan City in Hubei province China in December 2019 and was subsequently named “COVID-19” by the World Health Organization (WHO) on 11 February 2020 . The virus that causes COVID-19 is named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestations of COVID-19 pneumonia vary, ranging from mild flu-like symptoms to severe ARDS at the other end of the spectrum [7,8]. The pathophysiology of COVID-19 is complex, and research is ongoing to better understand how the virus affects multiple organ systems; however, it is widely recognized that dysregulation of T cell homeostasis, cytokine storm, and thrombotic and microangiopathic vasculopathy play important roles [6,9,10].
The management of COVID-19 pneumonia is still evolving. Current data suggest mortality benefits with Tocilizumab, Baricitinib, and dexamethasone, which are drugs that modulate the immune system, especially later in the course of the disease, and a possible clinical advantage using antivirals such as Remdesivir early in the course of infection . Tocilizumab is an anti-IL-6 receptor monoclonal antibody with immunosuppressive action and according to clinical trials, it is predicted to mitigate against the deleterious effect of IL-6 triggered by SARS-CoV-2 infection .
Despite promising benefits, there is lack of robust evidence to confirm its efficacy and safety in patients with COVID-19 pneumonia [13–15]. In addition, there is lack of adequate data to help physicians determine which population benefits more from the drug and which patient population should be excluded [14,15]. Adverse effects of Tocilizumab range from transient decreases in neutrophil count and abnormal liver function tests to life-threatening opportunistic infections such as pulmonary tuberculosis (TB) and invasive fungal infections including chronic pulmonary aspergillosis (CPA) [16,17]. Therefore, the risks and benefits of therapy with Tocilizumab should be carefully weighed prior to initiating treatment in patients with COVID-19. This report is of a 64-year-old man hospitalized for COVID-19 pneumonia treated with Tocilizumab who developed cavitary pulmonary aspergillosis.
We present the case of 64-year-old Hispanic man with medical history of hypertension who was hospitalized for severe COVID pneumonia (SARS-CoV-2 PCR-positive), that required treatment with Tocilizumab intravenously (8 mg/kg once) and 10 days of dexamethasone therapy (6 mg daily). He was admitted for 7 days and discharged after improvements in symptoms. On the day of discharge, his oxygen saturation was 95% on room air.
Three months later, he presented to the emergency department (ED) with worsening productive cough, shortness of breath, and weight loss in the preceding 1 month and hemoptysis of 2 days duration. There was no reported history of cigarette or illicit drug use, or previous treatment for a chronic lung condition. He immigrated to the United States more than 20 years ago from Mexico. He denied recent travel history or sick contacts. At the time of arrival to the ED, he was afebrile but tachypneic with oxygen saturation of 96% on room air. Physical examination revealed coarse crackles on auscultation of the upper-left lung field.
Laboratory results were significant for leukocytosis with left shift (white cell count 11.26 K/ul with neutrophilia of 78%), elevated D-dimer 628 ng/ml, and negative COVID-19 PCR test. Arterial blood gas, serum lactate, and basic metabolic panel were within normal limits. Chest X-ray (CXR) showed patchy airspace of opacification with possible cavitary lesion within the left upper lobe (Figure 1). CXR obtained 3 months earlier during COVID pneumonia showed moderate to severe bilateral ground-glass opacification (right greater than left) suggestive of atypical pneumonia. Chest CT angiogram was negative for pulmonary embolus but showed significant areas of focal consolidation with a cavitary lung lesion within the left upper lobe of the lung (Figure 2). The mass within the cavity moved to the ventral wall of the cavity when the patient was placed in prone position (Figure 3).
The patient was started on intravenous Ceftriaxone and Azithromycin for community-acquired pneumonia and placed in an airborne isolation room pending work-up for pulmonary tuberculosis. Initial laboratories work-up included negative acid-fast bacilli stain and culture, HIV screen, Cryptococcal antigen, Coccidioides IgM, Histoplasma antigen, Blastomyces antibodies, and sputum bacterial culture. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated with values of 104 mm/h and 67.5 mg/dl, respectfully. Antinuclear antibody (ANA) and other markers of autoimmune disease such as antineutrophil cytoplasmic antibody (ANCA), and rheumatoid factor (RF) were within normal limits. Glycated hemoglobin value was 5.6% and screening for viral and autoimmune hepatitis was negative.
After 7 days of admission, sputum fungal culture grew
Tocilizumab is monoclonal antibody with immunosuppressive action predicted to mitigate against the deleterious effect of IL-6 caused by SARS-CoV-2 infection, but risk of opportunistic infections and questionable efficacy are valid concerns [13,14,17]. Studies have indicated cytokine storm with release of several inflammatory mediators such as interleukin-1 (IL-1), IL-6, IL-8, IL-12, tumor necrosis factor alpha (TNFα) and beta (TGF β) among others as key pathogenetic mechanisms for severe COVID-19 pneumonia, including ARDS and death [6,18,19]. IL-6, a cytokine mainly produced by macrophages and T lymphocytes in response to pathogens, has been shown to be particularly important in COVID-19 pathogenesis and hence is a therapeutic target . There are several monoclonal antibodies that modulate the IL-6 pathway. These include anti-IL-6 drugs that can target the cytokine (Clazakizumab, Olokizumab, Sirukumab) or its cognate receptor (Tocilizumab, sarilumab), or inhibit IL-6 signaling by blocking the soluble IL-6 receptor system .
Several of these agents, especially Tocilizumab and Sarilumab, have been evaluated in randomized studies for efficacy and benefits, with conflicting reports. A study of 452 patients with COVID-19 that randomly assigned participants to 2 groups of Tocilizumab or placebo treatment showed no significantly better outcomes with Tocilizumab . In another randomized study of hospitalized patients with severe COVID-19 pneumonia, Tocilizumab therapy did not lead to significantly better clinical outcomes . These reports contrasts with another study of critically ill patients with COVID-19 which showed improved outcomes, including survival, with Tocilizumab . Current guidelines recommend using Tocilizumab in combination with dexamethasone in certain hospitalized patients who exhibit rapid respiratory decompensation due to COVID-19. These are recently hospitalized patients who have been admitted to the intensive care unit (ICU) within the prior 24 hours requiring invasive mechanical ventilation, noninvasive ventilation, or high-flow nasal cannula (HFNC) oxygen. The guidelines also include recently hospitalized patients not admitted to the ICU who have rapidly increasing oxygen needs requiring noninvasive ventilation or HFNC oxygen with significantly increased markers of inflammation (CRP ≥75 mg/L) .
Emphasis was placed on the need to avoid Tocilizumab in patients with immunosuppression, alanine aminotransferase levels greater than 5 times the upper limit of normal, high risk for gastrointestinal perforation and uncontrolled serious bacterial, and fungal infections . There are also recommendations for pretreatment screening for tuberculosis and prophylactic treatment with Ivermectin for patients who are from Strongyloidiasis-endemic areas . However, current guidelines do not focus on identification of patients at risk of fungal infections such as those residing in endemic areas, patients with preexisting lung conditions or post-treatment monitoring of patients for screening, and early detection of fungal infection. In addition, there are no prospective biomarkers for identifying patients at risk of developing fungal infections including aspergillosis with Tocilizumab treatment. Unfortunately, there have been reports of patients developing aspergillosis with anti-IL-6 therapy, ranging from simple aspergilloma to invasive aspergillosis [25–27]. Increased infection risk may be compounded by the concomitant use of glucocorticoids with Tocilizumab [28,29]. Aspergillus species are soil fungi usually found on decaying vegetation. There are more than 300species of Aspergillus, but only a few are associated with human disease, most commonly
CCPA is a slowly progressive disease with pulmonary infiltrates and often a newly-formed cavity, usually with thick walls, frequently containing a fungal ball (complex aspergilloma) with or without concomitant pleural thickening, as opposed to simple aspergilloma, which develops in preexisting lung cavities . CCPA usually develops in states of mild systemic immunosuppression, such as diabetes mellitus connective tissue disorders, malnutrition, alcoholism, liver cirrhosis, and long-term low-dose corticosteroid treatment [33,34]. Inthe present case, we postulate that immunosuppression in the setting of Tocilizumab therapy with concomitant use of dexamethasone and superimposed structural lung damage from COVID-19 pneumonia led to the development of a new cavitary lesion later diagnosed as CCPA considering the positive sputum culture for
Although frequently negative, a positive sputum culture result is extremely helpful in suggesting the diagnosis of CCPA in the setting of compatible signs and symptoms, radiological findings, serological tests such as the galactomannan antigen assay, and exclusion of alternative diagnoses [32,33]. Chronic fibrosing pulmonary aspergillosis (CFPA) is often the result of untreated CCPA, which is characterized by extensive fibrosis with fibrotic destruction of the lung, leading to a major loss of lung function and impaired quality of life . Studies of therapeutic response to antifungals have shown that treatment outcome is influenced by early initiation of therapy. CPA generally requires long-term antifungal treatment and surgery may be considered on a case-by-case basis .
Oral triazole therapy (itraconazole, voriconazole, Posaconazole) for CCPA is currently considered the standard of care, with tolerable adverse effects . In a study of 49 patients with various forms of CPA, oral Itraconazole proved to be an effective alternative to Amphotericin and may be useful in inoperable cases as well as prevention of hemoptysis . Duration of treatment with antifungals must be decided based on the merits of each case, taking into consideration resolution of symptoms, medication tolerability, cost of treatment, and radiographic resolution . However, a minimum of 4 to 6 months of oral triazole therapy is suggested, as responders would have done so by 6 months. However, to achieve key goals of treatment, which include prevention of hemoptysis and further fibrosis, longer treatment duration may be necessary [32,37]. Life-threatening hemoptysis may be prevented by bronchial arteriography with embolization [32,34].
Because of the potentially devastating lung sequel of CCPA and variable response to treatment in extensive disease, adequate attention needs to be placed on prevention and early diagnosis. More research is needed to predict patients for whom the potential benefits of Tocilizumab treatment outweigh risk of life-threatening complication, including aspergillosis. Additionally, we need to develop effective screening tools to help recognize predisposing host conditions for fungal infections or biomarkers for preclinical infection before initiating anti-IL-6 therapy, including the role of antifungal prophylaxis. We also recommend post-IL-6 treatment surveillance (signs and symptoms, early testing, imaging) to detect early stages of fungal infection with the goal of prompt therapy to prevent invasive disease, disseminated infection, and post-infection lung fibrosis.
Current guidelines recommend Tocilizumab in patients with rapid respiratory decompensation due to COVID-19. However, there is no emphasis on identifying patients at risk for fungal infections, including those living in endemic areas or with previous lung conditions. Risk of infection may be increased by the concomitant use of corticosteroids. We postulate that immunosuppression with these medications in the setting of structural lung damage from COVID-19 pneumonia led to the development of chronic pulmonary aspergillosis in our patient. Consequently, post-treatment surveillance of patients with COVID-19 pneumonia treated with Tocilizumab and corticosteroids is critical for early detection and treatment of opportunistic infections.
FiguresFigure 1.. Chest X-ray on Day 1 of admission showing bilateral patchy opacities and possible cavitary lesions in left upper lobe. Figure 2.. Chest CT scan showing thick walled cavitary lesion in the left upper lobe with soft-tissue density within the cavity and areas of focal consolidation. Figure 3.. CT scan of the chest showed the mass within the cavity moved to the ventral wall of the cavity in the prone position. Figure 4.. Chest X-ray at 7 months of Itraconazole therapy showing marked decrease in left upper-lobe opacities. Figure 5.. CT scan of the chest at 9 months of Itraconazole treatment showing resolution of previously extensive airspace disease with decrease in the size of the upper-lobe cavity and fungal ball.
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