key: cord-0880418-yayymnmc authors: Colaneri, Marta; De Filippo, Maria; Licari, Amelia; Marseglia, Alessia; Maiocchi, Laura; Ricciardi, Alessandra; Corsico, Angelo; Marseglia, Gianluigi; Mondelli, Mario Umberto; Bruno, Raffaele title: COVID vaccination and asthma exacerbation: might there be a link? date: 2021-09-20 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.09.026 sha: 2f410c5dafbaecab3e0d5e28a9eb91582c720054 doc_id: 880418 cord_uid: yayymnmc Introduction There is an ongoing debate as to the role of acute SARS-CoV-2 infection on asthma exacerbation, and its long-term impact on the lung function of individuals with asthma. In contrast, the potential impact of COVID -19 vaccination on asthma is entirely unexplored. Case Study We are shedding light on this critical topic by examining a challenging case of severe asthma exacerbation that a 28-year-old female patient developed after receiving two doses of mRNA-based vaccine BNT162b2 (Pfizer-BioNTech) at our Hospital, IRCCS Policlinico San Matteo of Pavia, in Northern Italy. The patient is a fourth year resident at the hospital, and like all health care workers at the facility, has been vaccinated since early 2021. She was an occasional smoker with a 10-year history of asthma and seasonal allergic rhinitis. She also tested negative for SARS-CoV-2 on several negative molecular swabs and serology tests. Results After receiving the second vaccine dose, she started experiencing a worsening of respiratory symptoms. Following several episodes, and a severe asthma attack, the patient required treatment with mepolizumab, a biologic drug [interleukin-5 (IL-5)] antagonist monoclonal antibody. Conclusion This single case study is insufficient to draw conclusions about the association between asthma exacerbation and the COVID-19 vaccine. While the cause-effect link between vaccination against SARS-CoV-2 and worsening of asthmatic disease might only be suggested, we consider the present case as a valuable prompt for further investigations. This is particularly true from the perspective of mass vaccination of adolescents and children currently underway across the globe. Whereas SARS-CoV-2 may cause a worsening of asthmatic symptoms, concordantly with what is already recognized with other viral infections (Novak et al, 2020) , no evidence supports the hypothesis that people affected by bronchial asthma are at increased risk of an exacerbation when getting COVID-19 vaccination. Although the cause-effect link is fairly intractable, we intend to highlight this critical topic by examining the following case study. We believe that it may be of considerable relevance, given the high prevalence of bronchial asthma, especially teenagers and school-children (Dharmage SC et al, 2019) , most of whom have yet to be vaccinated. Although the COVID-19 vaccination benefits are unquestionable, we argue that being informed about this potential impact on asthma may be equally valuable for both patients and physicians. Written informed consent for publication of clinical data was obtained from the patient. Once approved by the US Food and Drug Administration and the European Medicines Agency, the first doses of the mRNA-based vaccine BNT162b2 (Pfizer-BioNTech) were administered in Italy on December 27, 2020. In our Hospital, IRCCS Policlinico San Matteo of Pavia, Northern Italy, health care workers (HCWs) were vaccinated since the first days of January 2021. Among them, a 28-year-old caucasian woman, a fourth-year resident of the Infectious Diseases Division, completed the two Pfizer doses in February 2021. Due to the surveillance programs on HCWs, she had undertaken several negative molecular swabs for SARS-CoV-2 detection. Hence, she has not been infected with SARS-CoV-2. She was an occasional smoker with a 10-years history of asthma and seasonal allergic rhinitis. She didn't experience any asthma exacerbation requiring hospitalization and she was currently using an inhaled short-acting bronchodilator (SABA) as needed, generally before exercising, with complete relief. Around 10 hours after the second Pfizer dose, she complained of some "COVID-like symptoms," such as fever (axillary temperature up to 39°C), fatigue, and dry cough. Although occurring with a high frequency, in this particular case, the symptoms entirely receded after a total of 5 days, slightly more than commonly reported by vaccine national surveillance systems (AIFA, 2021). Then, around three weeks following the second Pfizer dose, she started to experience a worsening of respiratory symptoms, as mild dyspnea during physical activity and some expiratory wheezing, mostly at night. Therefore, she started a daily controller therapy, up to a dosage of budesonide at 160 μg + formoterol at 4.5 μg t.i.d. 2 times daily. Notably, at that time, the grasses flowering, which typically triggered allergic asthma and rhinitis, had not yet begun. Nevertheless, her symptoms have not receded but instead have worsened, mainly overnight, with frequent awakenings. Being a physician herself, the patient independently started three short-term cycles of oral steroid therapy, with prednisone 50 mg/day for five days, subsequently tapering off for a further five days, and doubled the antihistaminic dosage up to a daily dosage of 10 mg b.i.d of ebastine before agreeing to a specialistic evaluation. After one month, in April 2021, because her asthma had failed to come back under control, she was referred to the Operational Unit of Allergology of our Hospital. On physical exam, she just had rhinitis symptoms, with copious clear nasal discharge and continual drip, red eyes, as a result of allergic conjunctivitis and sneezing. The lungs were clear to auscultation with some mild bilateral basal wheeze. Peripheral oxygen saturation (SpO2) was 100% in room air. Her routine blood tests were performed while taking steroid therapy for the third and last selfprescribed cycle, and thus, they did not show any eosinophilia, with a total leukocyte count of 9300 and a negative C-reactive protein. Moreover, the total IgE level was 800 kU/L, and the IgEpositive response was significant for grasses and other types of pollens, cat allergens, and crustaceans. The fractional exhaled nitric oxide (FeNO) After that visit, she has been recommended a multi-drug regimen, which comprised budesonide at 320 μg + formoterol at 9 μg b.i.d. combination, tiotropium bromide 2.5 μg, and montelukast at 10 mg/day. Due to the prolonged steroids consumption, the physician had attempted to boost the other drugs' dosage while trying to entirely spare prednisone. However, some days later, the patient experienced another acute exacerbation of asthma, with wheezing and dyspnea, requiring intravenous steroid treatment (a bolus of methylprednisolone 1 mg/kg). Therefore, she resumed using oral steroids with benefit. At the time she also performed a molecular swab for SARS-CoV-2 detection and an anti-N serology test, which resulted negative. Subsequently, chest radiography and computerized tomography (HRCT) were performed, both of which resulted in normal. To exclude any other comorbidity favoring asthma exacerbation, the patient also underwent a nasal endoscopy which only showed mild turbinate congestion. However, this condition quickly improved with the daily application of a nasal corticosteroid and antihistamine spray. Common infectious causes were also excluded, given the negative serology for antibodies anti-Chlamydia pneumoniae and anti-Mycoplasma pneumoniae, the negative SARS-CoV-2 anti-N protein IgG, and the complete absence of symptoms as fever, productive cough, or other organspecific recalls. Autoimmune disorders were also sought and discarded. In addition, an echocardiogram and electrocardiogram were also obtained to rule out any other cardiological causes of breathlessness. Furthermore, the patient never had contact with potential allergic triggers, such as crustaceans or cats, that could have caused the asthmatic crises. Significantly, the typical allergic symptoms, i.e., rhinitis and conjunctivitis, diminished and then completely vanished throughout treatment, whereas the bronchial hyperreactivity was irrespectively unchanged. Although she was not dyspnoic during her daily routine, and she could continue working normally, without any other unusual symptomatology, the patient was no further physically active and had frequent nocturnal awakenings. All this, while compliantly performing the prescribed treatment, which included the addition of steroids. However, in June 2021, during the umpteenth scaling of steroid therapy, the patient suffered a more severe asthma attack, which prompted emergency department admission. She was frankly dyspnoic with SpO2 < 90% and was instantly handled with oxygen administration (5 Liters/min), inhaled therapy with bronchodilators, and simultaneous intravenous treatment with 1 g of hydrocortisone. At this stage, it was decided to refer the patient to the Pneumology Unit of our Hospital, where it was decided to start treatment quickly with an humanized, monoclonal antibody against interleukin-5. Specifically, Mepolizumab was started three days later although eosinophilia with more than 300 eosinophil/microliter, the first of Mepolizumab eligibility criteria as per NICE guidance (Bermejo I et al, 2018) , was not fulfilled. The timeline of events is described in figure 1 . SARS-CoV-2 is an acute viral infection, which might be expected to flare up a chronic pulmonary disease, such as asthma (Yang JM et al, 2020) , thus not diverging from other viral respiratory infections, including other types of coronavirus (Edwards MR et al, 2012) . As a result, moderateto-severe asthma has been listed as a risk factor for COVID-19 morbidity and mortality. However, the rate of asthma disease is reported as relatively low among the COVID-19 cases, especially in the observational case series from China, Europe, and South America (Skevaki C et al, 2020) . By contrast, a higher prevalence of asthma among patients hospitalized with COVID-19 was reported by studies from the USA, UK, Ireland, Korea, and Australia (De Boer G et al, 2021) . Hence, it remains unclear whether asthma might constitute a risk factor for a severe COVID-19 course. There is also a theoretical risk that SARS-CoV-2 could be a trigger for asthma exacerbations. So far, there are no data to support or refute this to date. Likewise, a decrease in asthma exacerbations during the COVID-19 lockdown measures has been recently reported in patients with asthma [9] but this data might also be attributable to social distancing and reduced environmental exposures. Some researchers found that asthmatic patients had reduced angiotensin-converting enzyme 2 (ACE2) levels, which has been identified as a SARS-CoV-2 cellular receptor (Kimura H et al, 2020) . If this finding would even suggest a potential protective role of the asthmatic phenotype on SARS-CoV-2 infection and, consequently, COVID-19 severity (Jackson DJ et al, 2020) , other authors hinted a higher expression of transmembrane protease serine 2 (TMPRSS2) among asthmatic individuals, which might facilitate SARS-CoV-2 cell entry by its role in the spike protein cleavage (Radzikowska U et al, 2020) . Moreover, mast cells potentially have an antiviral role (Marshall JS et al, 2019) , and eosinopenia has been pointed out as a marker of severe COVID-19 (Rosenberg et al, 2021) , as opposed to eosinophilia, which is known to be an allergic asthma hallmark. As we can see, there would require more thorough, multi-center investigations to truly establish the complex relationship between However, what is currently even more obscure, is the SARS-CoV-2 impact on the asthmatic disease after the acute phase of the viral infection. In brief, the long-term consequences of COVID-19, if any, on asthmatic individuals. As SARS-CoV-2 is a respiratory virus, lung injury can be expected. Concordantly, there is evidence of an impaired lung function following COVID-19, which belongs to a cluster of recently recognized tissue damage referred to as long COVID. ( Torres-Castro R et al, 2020; Zhao Y miao et al, 2020) . A study also discovered defective pulmonary gas-exchange function among COVID-19 discharged patients compared to healthy individuals (Li H Zhao X et al, 2021) . However, to the best of our knowledge, only Eggert et al. recently attempted to tackle this ongoing debate, showing that no difference in time to resolution of lower respiratory symptoms occurred between asthmatics and non-asthmatics after a 3-months follow-up (Eggert lE et al, 2021) . Nevertheless, this single retrospective study is definitely insufficient to fulfill all the current doubts and uncertainties on the topic. Furthermore, while relatively few data are available on the long-term impact of SARS-CoV-2 infection on asthma, the COVID-19 vaccination effect on this condition is entirely unexplored. Many studies have shown that mRNA vaccines are likely to induce IFN-I production (Cagigi A et al, 2021) while it is known that asthmatics' bronchial epithelium produces less IFN-I in response to a viral infection (Edwards MR et al, 2017) . However, some authors also described a hyperactive IFN-I production during asthma exacerbations, precisely associated with viral infection (Berhauer A et al, 2017) . Hence, we believe it is relevant to consider the impact of the COVID vaccination on asthma, especially in the run-up to mass vaccination of adolescents and children being currently scheduled. All the authors report no conflict of interest Written informed consent for publication of clinical data was obtained from the patient. Rapporto sulla Sorveglianza dei vaccini COVID-19 IFN-α/IFN-λ responses to respiratory viruses in paediatric asthma Mepolizumab for Treating Severe Eosinophilic Asthma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal Immune responses induced by mrna vaccination in mice, monkeys and humans. Vaccines The microbiology of asthma Viral infections in allergy and immunology: How allergic inflammation influences viral infections and illness Asthma exacerbation prevalence during the COVID-19 lockdown in a moderate-severe asthma cohort Epidemiology of asthma in children and adults Asthma phenotypes, associated comorbidities, and long-term symptoms in COVID-19 Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2 Damaged lung gas exchange function of discharged COVID-19 patients detected by hyperpolarized 129Xe MRI Mast cell responses to viruses and pathogen products Viruses and asthma: the role of common respiratory viruses in asthma and its potential meaning for SARS-CoV-2 Asthma-associated risk for COVID-19 development Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors Eosinophils and COVID-19: diagnosis, prognosis, and vaccination strategies Respiratory function in patients post-infection by COVID-19: a systematic review and metaanalysis Allergic disorders and susceptibility to and severity of COVID-19: A nationwide cohort study Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery