Netherlands

Early CF lung disease is characterized by neutrophil influx. Airway macrophages (Mφ) are also presentin the lumen to scavenge pathogens and clear apoptotic cells. Pulmonary inflammation can cause long-term Mφ paralysis, and Mφ dysfunction has also been described in CF lungs. We hypothesized that Mφdysfunction in early CF lung disease results from an altered expression of scavenging receptors. Weassessed the expression of key scavenging receptors (CD163, CD91, CD36, CD16) and of SIRPα, aninhibitor of phagocytosis, and its ligand CD47.

Broncho-alveolar lavage fluid (BALF) cells were collected from 19 CF infants of the I-BALL cohort(Erasmus MC), at ages 1, 3 or 5, and analyzed using flow cytometry. The neutrophil-to-macrophage(N/Mφ) ratio was calculated. Surface marker expression levels on Mφ were compared between agegroups and N/Mφ ratio quartiles. Findings were validated in 36 CF patients within the 1-5 age range fromthe AREST-CF cohort (Telethon Kids Institute).

Mean BALF N/Mφ ratios showed a positive correlation with age (Spearman ρ= 0.59, p = 0.008). WhileCD16, CD36 and CD91 levels remained consistent, CD163 expression was decreased in 5 year oldscompared to 1 year olds (p = 0.04). Expression of both CD47 and SIRPα trended towards a decreaseacross age groups. In the AREST-CF cohort, reduced Mφ scavenger receptor expression correlated with high BALF N/Mφ ratios rather than age. Expression levels of CD163 (p=0.03), CD47 (p = 0.03) andSIRPα (p = 0.004) were significantly lower in the top BALF N/Mφ ratio quartile.

Our data show that the BALF N/Mφ ratio in CF infants increases with age. Expression of severalscavenger receptors is decreased at the age of 5 in the I-BALL cohort, and in subjects with high N/Mratios in the AREST-CF cohort. We propose that the N/Mφ ratio provides an age-independent indicatorof inflammation severity. Prolonged low SIRPα expression has been linked to poor phagocytosis. Thesedata suggest that in early CF lung disease, Mφ become functionally paralyzed, which may contribute toan increasingly neutrophil-dominated milieu that incites structural damage.

Dutch Lung Congress

Airway macrophages in early CF lung disease show signs of immune paralysis

immune paralysis

macrophages

cystic fibrosis

[![](https://assets.underline.io/uploads/markdown_image/1/image/261902fdf187a88bfa74da226ff77186.png)](https://drive.google.com/file/d/1gUViQJJHCSgM38OhwpDoTdN89evCsZ-7/view?usp=sharing)
[![](https://assets.underline.io/uploads/markdown_image/1/image/1605292c232e6f185c7f87ee38e8502a.png)](https://drive.google.com/file/d/1kPkznVX_6cx-n846z_pUtyVDZql9KImc/view?usp=sharing)


### **Welcome Message**

Welcome to the inaugural **Dutch Lung Congress.**  We have all missed our opportunities to network and interact with our colleagues in the last twelve months or more.  While our desire was to meet face to face once again, when it became evident that this would not be possible until much later in 2021 (or even into 2022) the hard working committee organizing the Dutch Lung Congress found, what we hope will be, an excellent alternative to facilitate our annual meeting.

The Dutch Lung Congress aims to bring together everyone interested in research related to pulmonary diseases in the Netherlands.  We hope this event will provide opportunities for multidisciplinary interactions to enhance our approaches for addressing these challenging diseases.  Each session will include input from patients, clinical and basic and/or translational scientists discussing the latest information around the central themes chosen by the organizing committee.  One advantage of holding our congress as a virtual event this year is that we will have the opportunity to hear from world leading experts from all over the globe.  We hope you enjoy the programme the organizing committee have put together and will engage in dynamic discussions with all the speakers.

One highlight of our congress will be the Young Investigator Session.  Remember to join us for this exciting session when we will hear from the presenters who submitted the top scoring abstracts.  This promises to be a session full of exciting science that will display the strengths that constitute the future talent in our field.

When we are not listening to these great presentations we can all meet in Gathertown.  Within this interactive platform you will be able to meet colleagues and friends for networking. Enjoy a private chat over a virtual coffee, visit the booths of our sponsors and other parties, chat with the Young Investigator Board members or take some timeout in the relaxation spaces.  While in Gathertown take the opportunity to visit all the diverse posters on display. Chat live with the presenters or leave them a question on the discussion board for them to engage with you.  Make sure you check for any messages each time you enter Gathertown to make the most of your networking opportunities.

We look forward to seeing you during the DLC and the great scientific (and other) discussions we are anticipating during our 2021 meeting.

On behalf of the DLC organizing Committee
<br>**Janette Burgess
<br>Chair, DLC Organizing Committee**
![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)



### Special Session: Publieksmiddag
![](https://assets.underline.io/uploads/markdown_image/1/image/77e768dd500e6205175e5cafba59abdc.png)






![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)
**More about the committee team:**:
[Barbro N. Melgert, PhD] (https://drive.google.com/file/d/1q_IIH3JvTivumCUzzsZGX7BgD41HxQmk/view?usp=sharing)
// [Bas Holverda, PhD] (https://drive.google.com/file/d/1QKXHmTTQjgs4OZVuM8doXU055S-fu_uU/view?usp=sharing)
// [Frits Franssen, PhD] (https://drive.google.com/file/d/1d7HRUJaqGuRFzkPN3SVgkbBfqFkDkWq2/view?usp=sharing)
// [Janette Burgess, PhD] (https://drive.google.com/file/d/1VHFlrEN6uCQGeeW3Lj4I8aTw7HsB0GFr/view?usp=sharing)
// [Michel van den Heuvel, PhD] (https://drive.google.com/file/d/1JeOEP8MHxiK_4lONr8UM2HaxdxpkAmA2/view?usp=sharing)
// [Patrick Bhairosing] (https://drive.google.com/file/d/1xI8ORq-g1bbVcrlRDviZ9NhAwanc4dFl/view?usp=sharing)
// [Gimano Amatngalim, PhD] (https://drive.google.com/file/d/1fyVDDKARLNjRk_JZk8_GyhGMjmp6DWHp/view?usp=sharing)
// [Peter Kunst, PhD] (https://drive.google.com/file/d/1QhtB4nQezpAjbfUAcBnINc-Bm3Shy2Lf/view?usp=sharing)
// [Dr. Michel van den Heuvel, Prof., MD, PhD] (https://drive.google.com/file/d/1JBdNEBXZCEikEZhJ6MoD5DhQfXMz3bP6/view?usp=sharing)
![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)

Please register with DLC to be able to enter the conference on Underline.io. If you have already registered, please login to Underline.io to be able to see full conference content. In case you do not have an Underline account, please create one. Thank you 

Please login to your Underline account

poster

Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mediated decay (NMD) and CFTR protein modulation. Rescue of PTC CFTR protein was assessed by the forskolin-induced swelling of 12 intestinal organoid cultures, homozygous or compound heterozygous for distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function. We anticipate that this novel approach can strongly contribute to the development of CFTR modulating treatments for pwCF that currently have no CFTR modulating treatments available.

Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Background
Fatigue is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis. However, the difference in fatigue perceptions for these patients is unknown and this may be important to better understand what fatigue means to the individual patient. 
Methods 
This cross-sectional quantitative study aims to determine the different perceptions of fatigue as ‘frustrating’, ’exhausting’, ‘pleasant’, ‘frightening’ using the Fatigue Quality List and to assess determinants related to these perceptions of fatigue.
Beside the fatigue quality connotations, demographics, lung function, fatigue severity (Checklist Individual Strength subscale Fatigue), dyspnea (modified-Medical Research Council), fatigue catastrophizing (Fatigue Catastrophizing Scale), anxiety/depression (Hospital Anxiety and Depression Scale) and general health status (EuroQoL 5-dimension 5-level) were assessed.
Results
Mean frequency score of fatigue-related perceptions in patients with IPF was 3.4 points and in patients with sarcoidosis 4.0 points. Severely fatigued patients with IPF reported their fatigue less ‘pleasant’ significantly more often than patients without severe fatigue. Fatigue severity, dyspnea, catastrophizing and general health were significantly correlated with the negative connotations categories of the Fatigue Quality List in patients with IPF. Severely fatigued sarcoidosis patients reported their fatigue perceptions significantly more often as ‘frustrating’, ’exhausting’, ‘frightening’ and less ‘pleasant’ than patients without severe fatigue. Moreover, in patients with sarcoidosis fatigue severity, dyspnea, catastrophizing and depression were significantly associated with all four categories of the Fatigue Quality List that describe the experienced fatigue (p<0.05).
Conclusions
The current findings of experiences of fatigue in patients with IPF or pulmonary sarcoidosis provide insights for professionals treating these patients. Although similarities were found in the several experiences of fatigue across non-severely and severely fatigued patients, differences were also evident and could be mapped for IPF and sarcoidosis.


Perceptions of Fatigue in Patients With Idiopathic Pulmonary Fibrosis or Sarcoidosis

Background
Self-management is considered important in the management of patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis. However, data about the degree of activation for self-management is lacking.
Objectives
To determine the degree of activation for self-management in patients with IPF or sarcoidosis using the patient activation measure (PAM) and to evaluate the association between PAM scores, clinical characteristics and health-related outcomes. 
Study Design and Methods
This cross-sectional prospective study assessed besides the PAM also demographics, lung function, dyspnea (modified-Medical Research Council (mMRC)), fatigue (Checklist Individual Strength-Fatigue (CIS-Fatigue)), anxiety/depression (Hospital Anxiety and Depression Scale (HADS-A/HADS-D)) and generic health status (EuroQol five-dimensional-five-level (EQ-5D-5L)).
Results 
Mean PAM was 55.0 (9.1) points in patients with IPF (n=59), and low levels of patient activation for self-management (PAM ≤55.1 points) were present in 56% of the patients. PAM Scores correlated significantly (p<0.05) with mMRC (ρ =-0.476), HADS-A (ρ =-0.326), HADS-D (ρ =-0.459) and EQ-5D-5L (ρ =0.393). In patients with sarcoidosis (n=59) the mean PAM score was 55.7 (11.0) points, and 46% of the patients reported low PAM levels. Significant correlations were found with mMRC (ρ =-0.356), HADS-A (ρ =-0.394), HADS-D (ρ =-0.478) and EQ-5D-5L (ρ =0.313). 
Conclusion
About half of the outpatients with IPF or sarcoidosis have a low degree of activation for self-management, and these patients generally report more dyspnea, anxiety, depression and a lower health status. Whether patients with a low degree of activation can be successful in self-managing their disease remains to be determined.

Patient Activation for Self Management Idiopathic Pulmonary Fibrosis or Sarcoidosis 

Background
The COVID-19 pandemic has a large worldwide societal impact. Restrictive measures have aimed to restrain the burden on the healthcare systems. However, while early treatment to prevent hospitalization is still urgently needed, the role of primary care in the treatment is limited. Home-based monitoring of oxygen saturation and disease status makes it possible to monitor patients who show early signs of worsening COVID-19 and to identify those patients who further deteriorate and may need to be referred to hospital or can be treated. This strategy may thus be a promising measure to prevent or delay hospital admission.

Objective
To evaluate a home-based platform for monitoring of oxygen saturation and assess its added value in preventing or delaying hospital admission of patients with COVID-19 in primary care.

Study design
The COVID-19 Primary care Platform for Early treatment and Recovery (COPPER) study includes adult patients who consult their general practitioner for COVID-19 symptoms. Patients who are not immediately referred to a hospital are monitored at home for 28 days by measuring pulse oxygen saturation 3 times daily in rest and after the 1-minute sit-to-stand exercise. In addition, patients answer questions on symptoms and signs that may indicate worsening of disease once per day. The results of the daily measurements are monitored by a medical call center who alert the general practitioner when necessary.

Results
Although not enough data have been collected to show hospitalization effects, the platform showed to be an effective way of monitoring disease progression. Measurements that might indicate the need for clinical intervention, like low pulse oxygen saturation and chest pain, triggered warnings to the remote caretakers who could contact and reassess patients accordingly.

Conclusion
A distant monitoring platform appears to be a useful tool for monitoring of patients with pulmonary diseases. In the context of the COVID-19 pandemic it may lower the burden placed on healthcare workers during a straining time such as this one.

Home-based monitoring and early treatment of COVID-19 to reduce hospital admissions and improve outcomes: the COPPER studies.

Background: Airway neuroplasticity occurs in asthma and contributes to airway hyperresponsiveness (AHR). Corticosteroids, an established asthma therapy, are known to reduce airway inflammation and improve lung function. However, their effect on airway neuroplasticity has not been described yet.

Aim: To investigate the effects of corticosteroids on airway neuroplasticity.

Methods: BALB/cByJ (Jax-strain) mice were sensitized and challenged to ovalbumin (OVA) for 4 weeks. Budesonide was administered before every OVA challenge. 24 hours after the last challenge, lungs were collected for immunohistochemistry.
To elucidate the direct effect of corticosteroids on airway cholinergic neurons, we exposed human pluripotent stem cells (hPSCs)-derived airway cholinergic neurons to dexamethasone for 5 days. 

Results: In the murine asthma model, budesonide inhibited the OVA induced expression of the neuronal marker β-III-tubulin (p<0.05). The anti-inflammatory effect of budesonide was shown by its ability to supress eosinophil infiltration into the airway (p<0.05). The eosinophil count correlated with β-III-tubulin expression irrespective of treatment arm (p<0.0001). hPSCs-derived airway cholinergic neurons that were exposed to dexamethasone showed significant reductions in choline acetyltransferase (ChAT) and β-III-tubulin double-positive staining.

Conclusions: Corticosteroids inhibit airway neuroplasticity in a murine chronic asthma model and prevent hPSCs-derived airway cholinergic neuronal differentiation. Therefore, both indirect (anti-inflammatory effects) and direct inhibition of neuronal marker expression may contribute to the effects.


Corticosteroid effects on airway neuroplasticity in experimental models of asthma

Research question
Will an intervention with the IPCRG Desktop Helper (number 10) with or without a supporting e-learning module reduce medication-comorbidity clashes (MCC) in patients with COPD? 

Background 
Over 85% of patients with COPD have one or more comorbidities. Depending on a patient’s specific comorbidity, medications for the treatment of COPD may be contra-indicated, due to drug-disease interactions. The Desktop Helper (number 10) of the International Primary Care Respiratory Group (IPCRG) is a tool for GPs to identify potential contra-indicated medications. The Desktop Helper will be built in the Electronic Medical Records system (EMR) of the GP practice to facilitate case findings of patients with COPD, multimorbidities and contra-indicated medications due to the comorbidities. 

Methods 
A four-arm pragmatic cluster randomized controlled trial will be conducted in GP practices in the Netherlands. The control condition (arm 1: usual care) will be compared with three intervention arms (arm 2: the Desktop Helper, arm 3: e-learning, and arm 4: the Desktop Helper and the e-learning). In total 36 GP practices will be recruited, 9 in each arm. 
The Desktop Helper includes 11 clinical rules to enable the identification of patients with COPD, multimorbidities and contra-indicated medications due to the comorbidities and to provide clinical decision support using VIPlive. The e-learning provides more information regarding COPD and comorbidities, the relevant MCC and gives advice regarding the case-finding. 
At baseline and at 26 weeks, a data-extraction of comorbidities and prescribed medications will be obtained from the EMR of participating GP practices. 

Conclusion 
This study provides the GP practices a supporting tool for the prescription of medication to patients with COPD and comorbidities. Hopefully, it will contribute to a reduction of MCC and therefore an improvement of healthcare for these specific patients. 

Declaration of interest  
This study is funded by Boehringer Ingelheim the Netherlands.  
Clinical trial registration number: NTC04539457 


Managing appropriate prescribing in primary care COPD patients with comorbidities: Evaluation of an IPCRG Desktop Helper in a pragmatic cluster randomized controlled trial

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which impaired healing to recurrent micro-injury is thought to lead to fibrosis. Recent findings hint to a role for B cells and autoimmunity in IPF pathogenesis. Increased expression of the signaling molecule Bruton’s tyrosine kinase (BTK) and an enhanced response to B cell receptor (BCR) stimulation was shown to be an over-arching observation in circulating B cells from patients with a systemic autoimmune disease. Recently, we showed that circulating B cells from a fraction of IPF patients, compared to healthy controls, also expressed increased levels of BTK. However, given the involvement of BTK in many different signaling pathways, it remains unclear if BCR signaling is altered in IPF. Here, we showed that the response to BCR stimulation was enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-Ig-induced phosphorylation of BTK and its substrate phospholipase Cy2 in naïve but not in memory B cells. In IPF naïve B cells, enhanced BCR signaling correlated with surface expression of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor). This was in contrast to healthy controls, where BCR signaling correlated with expression of the B cell activating factor (BAFF) receptor. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, and commonly used in IPF treatment, induced substantial changes in BCR signaling. These findings support the involvement of B cells and autoimmunity in IPF pathogenesis and suggest that targeting BCR signaling has potential value as treatment option.

Aberrant B cell receptor signaling in naïve B cells from patients with idiopathic pulmonary fibrosis

Background: Hyaluronic acid (HA) is a key component of the extracellular matrix. HA and its metabolism are suggested to be altered in the lungs of patients with COPD. The present study explored systemic HA, and its metabolic regulators, in patients with COPD and smoking (SC) and non-smoking controls (NSC). Furthermore, associations of HA with acute exacerbations (AECOPD), airway-related hospitalizations, systemic inflammation and cardiovascular risk were studied.
Methods: HA was measured by ELISA in plasma of 192 patients with clinically stable COPD (GOLD II-IV), 84 SC (≥10 pack years) and 107 NSC (<10 pack years) enrolled in the ICE-Age study (Ciro, Horn, the Netherlands). mRNA expression of the enzymatic regulators HA-synthase 3 (HAS-3) and hyaluronidase 2 (HYAL-2) was assessed in PBMCs of a subset of subjects.
Results: Plasma HA was reduced in patients with COPD compared to NSC (p=0.033), but was comparable after adjusting for age and sex. Expression of HAS-3 did not differ between groups, but was substantially less detectable in more patients with COPD (56%) than SC (33.3%) and NSC (10%), p<0.001. Expression of HYAL-2 was enhanced in patients with COPD compared to SC (p=0.019) and NSC (p<0.001), also in the age- and sex- adjusted model (p<0.001). Plasma HA was not associated with AECOPD, airway related hospitalizations in the past year, or any of the inflammatory markers (WBCs, fibrinogen, IL-6, IL-8, TNF-α and CRP) in patients with COPD. Arterial pulse wave velocity explained some of the variance, i.e. <10%, in plasma HA (p=0.006). 
Conclusion: Overall, these results indicate that expression of HYAL-2, but not plasma HA nor HAS-3, is enhanced in patients with COPD compared to (non)smoking controls. Furthermore, HA was not associated with clinical outcomes, yet, cardiovascular risk might play a role in its systemic regulation in stable COPD. Case-control studies are indicated to establish the causality of our findings.

Alterations in plasma hyaluronic acid in patients with clinically stable COPD versus (non)smoking controls: a cross-sectional analysis

Introduction
The concept “the right care at the right place” in Severe Asthma (SA) demands regional collaboration with centralization of expertise and decentralization of care. Our Centre of Excellence for SA in South-West Netherlands (Franciscus Gasthuis & Vlietland hospital) has taken the initiative to design a blueprint to optimize regional care for SA patients together with their regional partners (11 hospitals so far and GP-network).

Project approach
The project team consisted of 3 pulmonologists and 1 respiratory nurse from the center of excellence (core team), 3 pulmonologists from referral centers, 1 GP specialized in asthma and 1 patient. First, 15 interviews were conducted with different stakeholders: health care professionals, pharmacists, insurer, patient association and patients to gather different perspectives and best practices in SA care. Then the outcomes were discussed in work sessions. 

Main findings and outcomes
The project team identified four area’s for optimal regional care that require agreement: SA diagnostics, referral processes, infrastructure for regional multidisciplinary consultation (MDC) and regional follow up on treatment. Designing a regional SA care pathway from GP to regional MDC may further improve the quality of care and the value of the regional MDC. The impact of this intervention will be monitored. Process parameters were formulated:
• % of SA patients treated with biologicals discussed in MDC, 
• % of SA patients with individual treatment plan, 
• % of treatment centers with pulmonologist specialized in severe asthma care
• % of SA patient included in the existing RAPSODI* register.

Next steps
The progress of this project will be evaluated monthly by the core team with updates shared in the MDC. The MDC meets every week to discuss patient cases with 3-4 hospital partners in each meeting. A baseline measurement will be conducted for the selected set of parameters and will be structurally discussed every 6 months in the regional MDC to monitor the impact of the interventions.

Conclusions
This blueprint can be used as practical guidance for implementation and further improvement of regional SA care, in particular the role of the regional MDC.

* Registry of Adult Patients with Severe asthma for Optimal DIsease management

This project was realized with the support of AstraZeneca. It is part of the wider PRECISION
project, which has been set up internationally with the aim of improving the quality of care for patients with severe asthma.


Roadmap to improve regional care for severe asthma patients in the Netherlands

Introduction: Sarcoidosis is a multisystemic disorder, characterized by the formation of non-caseating granulomas. the mTORC1 signaling pathway is suggested to play a role in granuloma formation. Recent studies demonstrated conflicting data on mTORC1 expression in patiens with sarcoidosis with either 33% or 100% of patients demonstrating mTORC1 activation within the granulomas. Therefore the aim of our study was to reevaluate the percentage of mTORC1 activation in sarcoidosis patients in a Dutch cohort. We also included Dutch patients with other granulomatous disorders of the lung to investigate whether mTORC1 activation can also be found in these diseases. 
Material and methods: This is a retrospective analysis of 74 patients with sarcoidosis and 39 patients with other pulmonary granulomatous disorders such as HP and vasculitiis. The activation of the mTORC1 signaling pathway was evaluated by immunohistochemical staining of its downstream effector p-S6 in tissue sections. 
Results: Active mTORC1 signaling was detected in 32 (43%) of the sarcoidosis patients and in 12 (31%) of the patients with other granulomatous disorders, demonstrating that this pathway is not specific for granuloma formation in sarcoidosis (p=0.628). 
Conclusion: Activation of mTORC1 can be found in a subgroup of patients with sarcoidoiss, as well as in patients with other granulomatous pulmonary disorders such as HP or vasculitis.

Airway macrophages in early CF lung disease show signs of immune paralysis

Next from Dutch Lung Congress

Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Similar lecture

Reliability of a home spirometer for monitoring children with cystic fibrosis during the COVID-19 pandemic.