Chronic Spontaneous Urticaria (CSU) is a debilitating condition presenting with wheals, angioedema, or both lasting for 6 weeks or more.1 The international EAACI/GA2 LEN/EDF/WAO urticaria guideline recommends second-generation H1-antihistamines as the first-line therapy. Up-dosing to fourfold as second-line therapy can improve response; however, some cases do not respond to antihistamines. Omalizumab is the only approved biological for patients with CSU who remain symptomatic despite a high dose of H1-antihistamine.1–4

The unpredictability of wheals or angioedema and the overwhelming nature of itching can lead to persistent stress and reduced quality of life. Studies have reported an association between stress, anxiety, depression and CSU.5–7 It is important to assess these factors with validated tools.

Since The World Health Organization declared Coronavirus Disease 2019 (COVID-19) a public health emergency of international concern, a pandemic,8 diverse clinical consequences have come to the scene. This unpredictable, fast-spreading infectious disease has been causing universal awareness, but also anxiety and distress.9 Since prior studies elucidated that mental well-being had been affected during outbreaks, adverse psychosomatic outcomes are expected to increase.10–12 The psychological aspect of COVID-19, in terms of fear, stress, anxiety, and depression has yet to be considered thoroughly, especially in patients with chronic diseases.

After the first COVID-19 case was detected in Turkey on March 9, 2020, several containment measures such as social distancing, travel restrictions, and closure of schools and workplaces were implemented. This “Quarantine Period (QP)” lasted for three months. As the number of cases declined by the end of May 2020, restrictions decreased gradually in an effort to maintain routine daily life. This “Return to Normal Period (RTNP)” lasted for three months till the end of August 2020. Behaviors of patients with chronic diseases have been heavily affected during the pandemic considering their adherence to medications, and attendance to follow-up visits however there are no documented data showing the consequences of restrictions on behaviors of patients having chronic diseases. CSU patients can also be expected to be affected similarly by the pandemic and it is important to know the influence of the pandemic on these patients especially when the close relationship between CSU activation and the psychological status of the patients is considered. Therefore, our aim was to investigate the impact of the COVID-19 pandemic on the course of refractory CSU together with patients’ adherence to omalizumab and treatment adjustments.

This is the first study investigating the impact of the COVID-19 pandemic on refractory CSU patients treated with omalizumab. Our findings revealed that the COVID-19 pandemic can impair the course of refractory CSU and interventions to support ongoing treatments are therefore crucial. Furthermore, it provides an additional contribution to the recommendations of the recent EAACI statement on biological treatment in CSU during the pandemic17 by showing that up to 8 weeks extension in subsequent omalizumab injections can be tolerated in refractory CSU during the pandemic.

CSU patients are shown to have higher levels of stress and disease activity is correlated with emotional stress levels.18,19 In a recent study evaluating the impact of the pandemic on 509 mild/moderate CSU patients, revealed increased urticaria activity and higher stress levels during QP compared to BP and RTNP.20 In this present study, the authors were able to determine the increase in disease activity in refractory CSU patients receiving omalizumab during the pandemic. Since emotional disturbances and stressful life events influence CSU courses, it might be speculated that the COVID-19 pandemic would have detrimental effects on CSU patients.

Fear is one of the characteristic features of infectious diseases.21 With the high infection rate and relatively high mortality, individuals can worry about COVID-19. In this respect, the authors used the FC-19 scale which is a valid tool for assessing fear of COVID-19 and significantly correlated with depression and anxiety.16 Shin et al.22 also stated that the fear/anxiety neurocircuitry has overlap and interacts with the neurocircuitry that orchestrates the stress response. In our study, FC-19 scores were significantly higher during QP compared to RTNP, and FC-19 scores were correlated to DASS-21 scores. Furthermore, among patients who continued omalizumab treatment, those showing an increase in urticaria activity had higher FC-19 scores in QP, indicating the impact of fear on the course of CSU.

Response to a psychosocial stressor is different between genders. Reduced fear conditioning is seen in stressed men whereas stressed women can show enhanced fear learning.23,24 This might be the probable explanation for our female patients displaying higher FC-19 scores while DASS-21 scores weren’t different than men.

The containment measurements such as reducing visits to hospitals and isolation at home implemented to avoid the spread of this highly contagious disease became an obstacle for follow-up and treatment of chronic diseases. Similarly, Kocatürk et al. stated that the weekly number of CU patients treated at UCARE centers decreased by more than 50% during the COVID-19 pandemic.25

A study evaluating the effects of the pandemic on CU patients revealed 44% of omalizumab cessation.26 In our study, 81.7% of the patients continued omalizumab. This relatively higher rate of adherence can be attributed to the regulations in our clinics for the continuation of ongoing omalizumab treatments during the pandemic.

Omalizumab can only be injected in hospitals via prescription in Turkey. During QP, TMoH facilitated access to prescribed medication for those who had valid prescription consent reports. By the courtesy of access to prescribed medication, 20% of our patients continued their injections at different centers other than their initial healthcare center, and 2.4% of the patients had home therapy. At this point, the authors should emphasize the importance of specific attention to tailored interventions in medications for chronic diseases during special periods such as outbreaks in order to maintain effective follow-up and treatment. A recent study by Öztürk et al. stated that 59% of the adult/pediatric allergists in Turkey used telemedicine for the management of urticaria/angioedema patients.27

The recent EAACI statement on the usage of biologicals during COVID-19 advised not to change therapy in non-infected individuals based on expert opinion.17 Nevertheless, successful omalizumab treatment adjustments have been shown in patients with refractory CSU before the pandemic.28–30 In our study, the authors for the first time showed that dose interval adjustments can be tolerated in refractory CSU patients during the pandemic, but cessation can worsen the course of the disease. Patients those prolonged omalizumab intervals had higher UAS7BP scores. Therefore, interval prolongation can be recommended for patients with good urticaria control in order to reduce hospital visits during the pandemic.

On the other hand, 78.9% of patients who ceased omalizumab had increased urticaria activity. Since our patients were refractory CSU patients, loss of disease control when omalizumab was halted was expected.

COVID-19 has been a risk for all human beings and the presence of comorbidities such as diabetes mellitus, hypertension, cardiovascular disease, and chronic respiratory disease were identified as risk factors for severe COVID-19. In our study, patients having these comorbidities had higher UAS7, DASS-21t, and FC-19s, but weren’t statistically significant. Nevertheless, 47.1% of them had an increase in urticaria activity during QP and this is statistically significant when compared to patients without comorbidities. It can be speculated that knowing to have comorbidities that are associated with severe COVID-19 infection resulted in the loss of disease control, which might be another indicator of the association of fear and stress with urticaria activity.

There were two limitations in this study. The first is the small sample size of patients with prolonged intervals of omalizumab which may have affected the accuracy of statistical results. The authors recommended our patients not change therapy according to the EAACI statement.17 Patients in Group 2 prolonged the intervals independent of our suggestions.

As the second limitation, the authors could not evaluate the mental health of our patients with the same tools prior to the study.

The authors found that both the fear and stress induced by COVID-19 and cessation of omalizumab yielded an increase in urticaria activity. Therefore, patients on omalizumab should continue their treatment either with the same dose intervals or prolonged intervals and tailored interventions such as telemedicine and home therapy should be considered for patients with chronic diseases during periods of outbreaks in order to maintain effective follow-up and reduce unnecessary visits to hospitals.

None declared.

Müge Olgaç: Has made substantial contributions to conception and design, acquisition of data, analysis, and interpretation of data; has been involved in drafting the manuscript, revising it critically for important intellectual content.

Osman Ozan Yeğit: Has made substantial contributions to or acquisition of data, analysis and interpretation of data; has been involved in drafting the manuscript, revising it critically for important intellectual content.

Sengul Beyaz: Has made substantial contributions to the acquisition of data, analysis and interpretation of data; has been involved in drafting the manuscript.

Özdemir Can Tüzer: Has made substantial contributions to the acquisition of data, analysis and interpretation of data; has been involved in drafting the manuscript.

Deniz Eyice Karabacak: Has made substantial contributions to conception and design, acquisition of data, and has been involved in drafting the manuscript.

Nida Oztop: Has made substantial contributions to the acquisition of data, analysis and interpretation of data; has been involved in drafting the manuscript.

Pelin Karadağ: Has made substantial contributions to the acquisition of data, and interpretation of data; has been involved in drafting the manuscript.

Raif Coşkun: Has made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; has been involved in drafting the manuscript.

Semra Demir: Has made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; has been involved in drafting the manuscript and revising it critically for important intellectual content.

Bahauddin Colakoglu: Has made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; has been involved in drafting the manuscript or revising it critically for important intellectual content.

Suna Buyukozturk: Has made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; has been involved in revising the manuscript critically for important intellectual content.

Aslı Gelincik: Has made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; has been involved in revising the manuscript critically for important intellectual content.

None declared.