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\title{COVID-19: A series of important recent clinical and laboratory reports
in immunology and pathogenesis of SARS-CoV-2 infection and care of
allergy patients}



\author[1]{Oliver Pfaar}%
\author[2]{Maria Torres}%
\author[3]{Cezmi Akdis}%
\affil[1]{ University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany.}%
\affil[2]{ Regional University Hospital of Malaga-IBIMA-UMA-BIONAND-ARADyAL}%
\affil[3]{University of Zurich}%


\vspace{-1em}



  
  \date{May 18, 2024}


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The ``\emph{coronavirus disease 2019} (COVID-19)'' outbreak was first
reported in December 2019 (China). Since then, this disease has rapidly
spread across the globe and in March 2020 the World Health Organization
(WHO) declared the COVID-19 pandemic.\textsuperscript{1} Since the
outbreak was first announced, our journal has extensively focused on the
clinical features, outcomes, diagnosis, immunology, and pathogenesis of
COVID-19 and its infectious agent severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2). We published our first COVID-19 article on
19 February, focusing for the first time on the clinical characteristics
of 140 cases of human-to-human coronavirus transmission without any
links to the Huanan Wet Market.\textsuperscript{2} Hypertension and
diabetes were mentioned as risk factors and there was no increased
prevalence in allergic patients. This early study reported that the main
symptoms at hospital admission were fever (91.7\%), cough (75.0\%),
fatigue (75.0\%), gastrointestinal symptoms (39.6\%), and dyspnea
(36.7\%). Lymphopenia and eosinopenia were also reported as important
signs and biomarkers for monitoring and severity of the
patients.\textsuperscript{2} The prevalent eosinopenia in COVID-19
patients and the possible anti-viral role of eosinophils were further
discussed in several following publications in\emph{Allergy}
.\textsuperscript{3,4} Our second COVID-19 paper brought attention to
the wide range of clinical manifestations of this disease, from
asymptomatic cases to patients with mild and severe symptoms, with or
without pneumonia as well as with only
diarrhea.\textsuperscript{5}Patients with common allergic diseases did
not develop distinct symptoms and severe courses. Cases with
pre-existing chronic obstructive pulmonary disease or complicated with a
secondary bacterial pneumonia were severe. Another article, timely
appearing in our journal, alerted the scientific community that even in
experienced hands there was a 14.1\% false negative polymerase chain
reaction (PCR) diagnosis in COVID-19 cases and were later diagnosed
positive after repeated tests.\textsuperscript{6} A pediatric article
was also published extensively analyzing 182 cases and it was reported
that children with COVID-19 showed a mild clinical
course.\textsuperscript{7} Patients with pneumonia had a higher
proportion of fever and cough and increased inflammatory biomarkers
compared to those without pneumonia. There were 43 allergic patients in
this series and there was no significant difference between allergic and
non-allergic COVID-19 children in disease incidence, clinical features,
laboratory, and immunological findings. Allergy was not a risk factor
for disease and severity of SARS-CoV-2 infection and did not
significantly influence the disease course of COVID-19 in
children.\textsuperscript{7}

The immunology of COVID-19 was extensively reviewed in two articles from
leading experts with a comprehensive discussion of the tip of the
iceberg in COVID-19 epidemiology, anti-viral response, antibody response
to SARS-CoV-2, acute phase reactants, cytokine storm, and pathogenesis
of tissue injury and severity. \textsuperscript{8,9}

Two studies timely reported the role of possible trained immunity in
countries with a Bacillus Calmette-Gu\selectlanguage{ngerman}érin (BCG) vaccination programme
and a relatively low COVID-19 prevalence and mortality
rate.\textsuperscript{10,11} In an extensive RNA sequencing analyses of
SARS-CoV-2 receptor and their molecular partners revealed that ACE2 and
TMPRSS2 were coexpressed at the epithelial sites of the lung and skin,
whereas CD147 (BSG), cyclophilins (PPIA and PPIB), CD26 (DPP4) and
related molecules were expressed in both, epithelium and in immune
cells.\textsuperscript{12}

Allergists, respiratory physicians, pediatricians, and other health care
providers treating patients with allergic diseases are frequently in
contact with patients potentially infected with SARS-CoV-2. Practical
considerations and recommendations given by experts in the field of
allergic diseases can provide useful recommendations for clinical daily
work. Since the beginning of this current pandemic, our journal has
disseminated clinical reports, \textsuperscript{2,3,5,6,13} statements
on the urgent need for accuracy in designing and reporting clinical
trials in COVID-19,\textsuperscript{14} preventive
measures,\textsuperscript{10,11,15} and Position Statements elaborated
by experts in the field in close collaboration with the European Academy
of Allergy and Clinical Immunology (EAACI) and its task force
``\emph{Allergy and Its Impact on Asthma (ARIA)}
''.\textsuperscript{16-28} (keynote information in table 1). A
compendium answering 150 frequently encountered questions regarding
COVID-19 and allergic diseases has been recently published by experts in
their respective area.\textsuperscript{29} In addition, readers can put
further questions regarding this ``\emph{living} '' compendium
electronically to the authors and their answers will be available
through a new category in the journal's
webpage.\textsuperscript{30}Besides, EAACI in collaboration with ARIA,
has provided recommendations on operational plans and practical
procedures for ensuring optimal standards in the daily clinical care of
patients with allergic diseases, whilst ensuring the safety of patients
and healthcare workers.\textsuperscript{23}

Table 1: Examples of recently published recommendations, statements and
Position Papers of the EAACI\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Clinical Topic}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Keynote message(s)}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Title and Reference}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\selectlanguage{ngerman}·~~~~~~Prescribed inhaled (or oral) corticosteroids as controller
medication should be further applied to patients with asthma as
cessation may lead to asthma exacerbations.\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
ARIA-EAACI statement on Asthma and COVID-19.\textsuperscript{16}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Allergic rhinitis\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\selectlanguage{ngerman}·~~~~~~Intranasal corticosteroids (including nasal sprays) can be
further applied in COVID-19 patients at the recommended dosages and a
cessation or interruption is not recommended. ·~~~~Furthermore, a
cessation or interruption of allergen immunotherapy (AIT) for both the
subcutaneous route (SCIT) or sublingual route (SLIT) is not recommended
in asymptomatic patients without suspicion for SARS-CoV-2 infection
and/or contact to SARS-CoV-2 positive individuals or in other conditions
as outlined.\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
corticosteroids in allergic rhinitis in COVID-19 infected patients: An
ARIA-EAACI statement Intranasal corticosteroids in allergic rhinitis in
COVID-19 infected patients: An ARIA-EAACI statement.\textsuperscript{21}
Handling of allergen immunotherapy in the COVID-19 pandemic: An
ARIA-EAACI statement. \textsuperscript{22}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Biological-Treatment\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\selectlanguage{ngerman}·~~~~~~Biologicals should be applied in type 2 inflammations (asthma,
atopic dermatitis, chronic rhinosinusitis with nasal polyps) via
self-application in non-infected patients ·~~~~~~In patient with an
active SARS-CoV-2 infection treatment with biologicals should be paused
and re-initiated after recovery and SARS-CoV-2 negativity of
patients.\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Considerations on biologicals for patients with allergic disease in
times of the COVID-19 pandemic: an EAACI Statement.
\textsuperscript{28}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Children\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\selectlanguage{ngerman}·~~~~~~Less severe courses of COVID-19 in the pediatric population have
been reported. ·~~~~~~Similar to the adult age group, severe forms of
asthma and immunodeficiencies are reported to be risk factors. ·~~~~~~A
sufficient control of symptoms in children with allergies, asthma and
immunodeficiency in accordance with current guidelines is key in the
current pandemic.\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Managing childhood allergies and immunodeficiencies during respiratory
virus epidemics - The 2020 COVID-19 pandemic: A statement from the
EAACI-section on pediatrics.\textsuperscript{25}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Drug allergy\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\selectlanguage{ngerman}·~~~~~~Drugs being used in different phases of COVID-19 disease seem to
cause rare but potentially severe drug hypersensitivity reactions
(DHRs). ·~~~~~~Most of these DHRs affect the skin and are non-immediate.
·~~~~~~The most important differential diagnosis of these DHRs is
COVID-19 related exanthems.\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Diagnosis and management of the drug hypersensitivity reactions in
coronavirus disease drug hypersensitivity.\textsuperscript{27}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Ocular allergy\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\selectlanguage{ngerman}·~~~~~~An international survey revealed that experts in the field
recommend that during the ongoing pandemic therapy strategies in line
with current guidelines should be followed. ·~~~~~~However, particular
caution for the use of corticosteroids and immunomodulators in COVID-19
infected patients is expressed.\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Managing ocular allergy in the time of COVID-19.
\textsuperscript{19}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Organization of an allergy clinic\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\selectlanguage{ngerman}·~~~~~~Recommendations on operational plans and procedures to maintain
high standards in the daily clinical care of allergic patients whilst
ensuring necessary safety in the current COVID-19 pandemic should be
followed. ·~~~~~~Nine different scenarios and topics are
discussed.\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
COVID-19 pandemic: Practical considerations on the organization of an
allergy clinic - an EAACI/ARIA Position Paper.
\textsuperscript{23}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Even though there has been a decrease in both infection rates and
prevalence of COVID-19 in some parts of the world, in some countries the
spread of COVID-19 has not been adequately controlled and the numbers
are still rising. Epidemiologists have warned of possible subsequent
waves until an effective vaccination becomes available. Until then,
recommendations for different aspects of patient care are strictly
needed, which underlines the importance of the COVID-19 series of
publications in this journal. The recommendations provided in these
articles will inform allergists and healthcare providers on the
management and treatment of patients during this pandemic. It should be
noted that these statements are based on current evidence and medical
knowledge and there is a paucity of prospective clinical trials
regarding some of the information provided in these documents. These
clinical statements need to be regularly updated with incoming new
clinical data.

Figure 1. Picture representing the wide range of clinical aspects
involved in the pathogenesis of COVID-19.

References

1. Coronavirus disease (COVID-2019) situation reports.
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports,
Accessed on 16 Apr 2020.

2. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140
patients infected with SARS-CoV-2 in Wuhan, China. \emph{Allergy.} 2020.

3. Jesenak M, Banovcin P, Diamant Z. COVID-19, chronic inflammatory
respiratory diseases and eosinophils - Observationsfrom reported
clinical case series. \emph{Allergy.} 2020.

4. Zhang M, Guogang X, Fengming D, al. e. The role of peripheral blood
eosinophil counts in COVID-19 patients. Allergy. 2020 (in press).

5. Dong X, Cao YY, Lu XX, et al. Eleven faces of coronavirus disease
2019. \emph{Allergy.} 2020.

6. Zhang JJ, Cao YY, Dong X, et al. Distinct characteristics of COVID-19
patients with initial rRT-PCR-positive and rRT-PCR-negative results for
SARS-CoV-2. \emph{Allergy.} 2020.

7. Du H, Dong X, Zhang JJ, et al. Clinical characteristics of 182
pediatric COVID-19 patients with different severities and allergic
status. \emph{Allergy.} 2020.

8. Sokolowska M, Agache I, Akdis CA. Immune response in Covid-19:
mechanisms, clinical outcome, diagnostics and perspectives -- an EAACI
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9. Azkur AK, Akdis M, Azkur D, et al. Immune response to SARS-CoV-2 and
mechanisms of immunopathological changes in COVID-19.
\emph{Allergy.}2020.

10. Gursel M, Gursel I. Is global BCG vaccination-induced trained
immunity relevant to the progression of SARS-CoV-2
pandemic?\emph{Allergy.} 2020.

11. Ozdemir C, Kucuksezer UC, Tamay ZU. Is BCG vaccination affecting the
spread and severity of COVID-19? \emph{Allergy.} 2020.

12. Radzikowska U, Ding M, Tan G, et al. Distribution of ACE2, CD147,
CD26 and other SARS-CoV-2 associated molecules in tissues and immune
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risk factors. \emph{Allergy.} 2020.

13. Cai Q, Huang D, Ou P, et al. COVID-19 in a designated infectious
diseases hospital outside Hubei Province, China. \emph{Allergy.} 2020.

14. Bonini S, Maltese G. COVID-19Clinical trials: quality matters more
than quantity. \emph{Allergy.} 2020.

15. Sotgiu G, Gerli AG, Centanni S, et al. Advanced forecasting of
SARS-CoV-2-related deaths in Italy, Germany, Spain, and New York
State.\emph{Allergy.} 2020.

16. Bousquet J, Jutel M, al. ACe. ARIA-EAACI statement on Asthma and
COVID-19. Allergy 2020 (submitted). .

17. Carli G, Cecchi L, Stebbing J, Parronchi P, Farsi A. Is asthma
protective against COVID-19? \emph{Allergy.} 2020.

18. Johnston SL. Asthma and COVID-19: is asthma a risk factor for severe
outcomes? Allergy 2020 (in press).

19. Leonardi A, Fauquert JL, Doan S, et al. Managing ocular allergy in
the time of COVID-19. \emph{Allergy.} 2020.

20. Licari A, Votto M, Brambilla I, et al. Allergy and asthma in
children and adolescents during the COVID outbreak: What we know and how
we could prevent allergy and asthma flares. \emph{Allergy.} 2020.

21. Bousquet J, Akdis C, Jutel M, et al. Intranasal corticosteroids in
allergic rhinitis in COVID-19 infected patients: An ARIA-EAACI
statement. \emph{Allergy.} 2020.

22. Klimek L, Jutel M, Akdis C, et al. Handling of allergen
immunotherapy in the COVID-19 pandemic: An ARIA-EAACI
statement.\emph{Allergy.} 2020.

23. Pfaar O, Klimek L, Jutel M, et al. COVID-19 pandemic: Practical
considerations on the organization of an allergy clinic - an EAACI/ARIA
Position Paper. \emph{Allergy.} 2020.

24. Klimek L, Jutel M, Bousquet J, al. e. Treatment of chronic
rhinosinusitis with nasal polyps (CRSwNP) in the COVID-19 pandemic -- An
EAACI Position Paper. Allergy 2020 (submitted).

25. Brough HA, Kalayci O, Sediva A, et al. Managing childhood allergies
and immunodeficiencies during respiratory virus epidemics - The 2020
COVID-19 pandemic: A statement from the EAACI-section on
pediatrics.\emph{Pediatr Allergy Immunol.} 2020.

26. Untersmayr E, al. e. Immunology of COVID-19: mechanisms, clinical
outcome, diagnostics and perspectives -- a report of the European
Academy of Allergy and Clinical Immunology (EAACI). Allergy. 2020.

27. Gelincik A, Brockow K, Celik GE, et al. Diagnosis and management of
the drug hypersensitivity reactions in Coronavirus disease
19.\emph{Allergy.} 2020.

28. Vultaggio A, Agache I, Akdis CA, et al. Considerations on
Biologicals for Patients with allergic disease in times of the COVID-19
pandemic: an EAACI Statement. \emph{Allergy.} 2020.

29. Riggioni C, Comberiati P, Giovannini M, et al. A compendium
answering 150 questions on COVID-19 and SARS-CoV-2. \emph{Allergy.}2020.

30. Allergy homepage.
https://onlinelibrary.wiley.com/doi/toc/10.1111/(ISSN)1398-9995.COVID-19.
Accessed on 16 Jun 2020.

Disclosure of conflict of interests:

Dr. Pfaar reports grants and/or personal fees from ALK-Abell\selectlanguage{ngerman}ó,
Allergopharma, Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie
GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, Biomay,
Circassia, ASIT Biotech Tools S.A., Laboratorios LETI/LETI Pharma, MEDA
Pharma/MYLAN, Anergis S.A., Mobile Chamber Experts (a GA2LEN Partner),
Indoor Biotechnologies, GSK, Astellas Pharma Global, EUFOREA, ROXALL,
NOVARTIS, SANOFI AVENTIS, Med Update Europe GmbH, and streamedup! GmbH.
Dr. Torres has no conflict of interest in relation to this work. Dr.
Akdis reprots grants from Allergopharma, Idorsia, Swiss National Science
Foundation, Christine Kühne-Center for Allergy Research and Education,
European Commission's Horizon's 2020 Framework Programme, Cure, Novartis
Research Institutes, AstraZeneca, SciBase, GSK, and other from Sanofi
and Regeneron.\selectlanguage{english}
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