Diagnosis and treatment of chronic spontaneous urticaria
Allen P. Kaplan
Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19
Ahmet Kursat Azkur, Mübeccel AkdisDilek Azkur, Milena Sokolowska, Willem van de Veen, Marie-Charlotte Brüggen, Liam O’Mahony, Yadong Gao, Kari Nadeau, Cezmi A. Akdis
As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID-19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to deteriorating clinical conditions such as cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute-phase reactants, and serum biochemistry in COVID-19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals. In the majority of the patients, a 1-week, selflimiting viral respiratory disease typically occurs, which ends with the development of neutralizing antiviral T cell and antibody immunity. The IgM-, IgA-, and IgG-type virus-specific antibodies levels are important measurements to predict population immunity against this disease and whether cross-reactivity with other coronaviruses is taking place. High viral load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID-19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome, and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine-secreting cells with innate and adaptive immune mechanisms both of which contribute to a poor prognosis. Elevated levels of acute-phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome, and novel approaches to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual patients.
Longitudinal hematologic and immunologic variations associated with the progression of COVID-19 patients in China
Ruchong Chen, MD, Ling Sang, MD, Mei Jiang, PhD, Zhaowei Yang, PhD, Nan Jia, PhD, Wanyi Fu, PhD, Jiaxing Xie, MD, Weijie Guan, MD, Wenhua Liang, MD, Zhengyi Ni, MD, Yu Hu, MD, Lei Liu, MD, Hong Shan, MD, Chunliang Lei, MD, Yixiang Peng, MD, Li Wei, MD, Yong Liu, MD, Yahua Hu, MD, Peng Peng, MD, Jianming Wang, MD, Jiyang Liu, MD, Zhong Chen, MD, Gang Li, MD, Zhijian Zheng, MD, Shaoqin Qiu, MD, Jie Luo, MD, Changjiang Ye, MD, Shaoyong Zhu, MD, Jinping Zheng, MD, Nuofu Zhang, MD, Yimin Li, MD, Jianxing He, MD, Jing Li, MD, Shiyue Li, MD, and Nanshan Zhong, MD, on behalf of the Medical Treatment Expert Group for COVID-19
Background: Crucial roles of hematologic and immunologic responses in progression of coronavirus disease 2019 (COVID-19) remain largely unclear. Objective We sought to address the dynamic changes in hematologic and immunologic biomarkers and their associations with severity and outcomes of COVID-19.
Methods: A retrospective study including 548 patients with COVID-19 with clarified outcome (discharged or deceased) from a national cohort in China was performed. Cross-sectional and longitudinal variations were compared and the associations with different severity and outcomes were analyzed.
Results: On admission, the counts of lymphocytes, T-cell subsets, eosinophils, and platelets decreased markedly, especially in severe/critical and fatal patients. Increased neutrophil count and neutrophils-to-lymphocytes ratio were predominant in severe/critical cases or nonsurvivors. During hospitalization, eosinophils, lymphocytes, and platelets showed an increasing trend in survivors, but maintained lower levels or dropped significantly afterwards in nonsurvivors. Nonsurvivors kept a high level or showed an upward trend for neutrophils, IL-6, procalcitonin, D-dimer, amyloid A protein, and C-reactive protein, which were kept stable or showed a downward trend in survivors. Positive correlation between CD8+ T-cell and lymphocytes count was found in survivors but not in nonsurvivors. A multivariate Cox regression model suggested that restored levels of lymphocytes, eosinophils, and platelets could serve as predictors for recovery, whereas progressive increases in neutrophils, basophils, and IL-6 were associated with fatal outcome.
Conclusions: Hematologic and immunologic impairment showed a significantly different profile between survivors and nonsurvivors in patients with COVID-19 with different severity. The longitudinal variations in these biomarkers could serve to predict recovery or fatal outcome.
Mechanisms of skin autoimmunity: Cellular and soluble immune components of the skin
Johann E. Gudjonsson, MD, PhD, Kenji Kabashima, MD, PhD, and Kilian Eyerich, MD, PhD
Autoimmune diseases are driven by either T cells or antibodies reacting specifically to 1 or more self-antigens. Although a number of self-antigens associated with skin diseases have been identified, the causative antigen(s) remains unknown in the great majority of skin diseases suspected to be autoimmune driven. Model diseases such as pemphigus, dermatitis herpetiformis, and more recently psoriasis have added greatly to our understanding of skin autoimmunity. Depending on the dominant T- or B-cell phenotype, skin autoimmune diseases usually follow 1 of 6 immune response patterns: lichenoid, eczematous, bullous, psoriatic, fibrogenic, or granulomatous. Usually, skin autoimmunity develops as a consequence of several events—an altered microbiome, inherited dysfunctional immunity, antigens activating innate immunity, epigenetic modifications, sex predisposition, and impact of antigens either as neoantigen or through molecular mimicry. This review summarizes currently known antigens of skin autoimmune diseases and discusses mechanisms of skin autoimmunity.
Molecular mechanisms and epidemiology of COVID-19 from an allergist’s perspective
Koa Hosoki, MD, PhD, Abhijit Chakraborty, PhD, and Sanjiv Sur, MD
The global pandemic caused by the newly described severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused worldwide suffering and death of unimaginable magnitude from coronavirus disease 2019 (COVID-19). The virus is transmitted through aerosol droplets, and causes severe acute respiratory syndrome. SARS-CoV-2 uses the receptorbinding domain of its spike protein S1 to attach to the host angiotensin-converting enzyme 2 receptor in lung and airway cells. Binding requires the help of another host protein, transmembrane protease serine S1 member 2. Several factors likely contribute to the efficient transmission of SARS-CoV-2. The receptor-binding domain of SARS-CoV-2 has a 10- to 20- fold higher receptor-binding capacity compared with previous pandemic coronaviruses. In addition, because asymptomatic persons infected with SARS-CoV-2 have high viral loads in their nasal secretions, they can silently and efficiently spread the disease. PCR-based tests have emerged as the criterion standard for the diagnosis of infection. Caution must be exercised in interpreting antibody-based tests because they have not yet been validated, and may give a false sense of security of being ‘‘immune’’ to SARS-CoV-2. We discuss how the development of some symptoms in allergic rhinitis can serve as clues for newonset COVID-19. There are mixed reports that asthma is a risk factor for severe COVID-19, possibly due to differences in asthma endotypes. The rapid spread of COVID-19 has focused the efforts of scientists on repurposing existing Food and Drug Administration–approved drugs that inhibit viral entry, endocytosis, genome assembly, translation, and replication. Numerous clinical trials have been launched to identify effective treatments for COVID-19. Initial data from a placebocontrolled study suggest faster time to recovery in patients on remdesivir; it is now being evaluated in additional controlled studies. As discussed in this review, till effective vaccines and treatments emerge, it is important to understand the scientific rationale of pandemic-mitigation strategies such as wearing facemasks and social distancing, and implement them.
Nucleic acid approaches to antibody-based therapeutics for COVID-19: A perspective
Elizabeth Parzych, PhD and David B. Weiner, PhD
The evolving algorithm of biological selection in severe asthma
Nikolaos G. Papadopoulos, Peter Barnes, Giorgio Walter Canonica, Mina Gaga, Liam Heaney, Andrew Menzies-Gow, Vicky Kritikos, Mark Fitzgerald
New therapeutic options for severe asthma have recently emerged, mostly in the form of monoclonal antibodies (“biologicals”) targeting relevant inflammatory pathways. Currently available agents target different aspects of “Type 2” immunity, and their indications often include overlapping patient groups. We present a round-table discussion that took place during the Annual Meeting of the Respiratory Effectiveness Group (REG), on the reasoning behind the use of different add-on medications for severe asthma, and crucially, on selection strategies. The proposed rational is based on current evidence, including real-life studies, as well as on the appreciation of the relevant complexities. Direct head-to-head comparisons of biologicals are lacking; therefore, algorithms for initial choice and potential switch between agents should be based on understanding the key characteristics of different options and the development of a clear plan with predefined targets and shared decision-making, in a structured way.
The first, holistic immunological model of COVID-19: Implications for prevention, diagnosis, and public health measures
Paolo Maria Matricardi, Roberto Walter Dal Negro, Roberto Nisini
The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic or mild infection, mainly in children, to multi-organ failure, eventually fatal, mainly in the eldest. We propose here the first model explaining how the outcome of first, crucial 10-15 days after infection, depends on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, mannose-binding lectin). If SARS-CoV-2 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high-affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm), leading to complications often requiring intensive therapy and being, in some patients, fatal. Lowmoderate physical activity can still be recommended. However, extreme physical activity and oral breathing with hyperventilation during the incubation days and early stages of COVID-19 facilitates re-inhalation and early direct penetration of high numbers of own virus particles in the lower airways and the alveoli, without impacting on the airway’s mucosae covered by neutralizing antibodies ("viral auto-inhalation" phenomenon). This allows the virus to bypass the efficient immune barrier of the upper airway mucosa in already infected, young, and otherwise healthy athletes. In conclusion, whether the virus or the adaptive immune response reaches the lungs first is a crucial factor deciding the fate of the patient. This “quantitative and time-/sequence-dependent” model has several implications for prevention, diagnosis, and therapy of COVID-19 at all ages.
Type 2 immunity in the skin and lungs
Cezmi A. Akdis, Peter D. Arkwright, Marie-Charlotte Brüggen, William Busse, Massimo Gadina, Emma Guttman-Yassky, Kenji Kabashima, Yasutaka Mitamura, Laura Vian, Jianni Wu, Oscar Palomares
There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 activate B cells to class-switch to IgE and also play a role in T-cell and eosinophil migration to allergic inflammatory tissues. IL-13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL-4 and IL-13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL-5 acts on activation, recruitment, and survival of eosinophils. IL-9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL-5 and its receptor, and IL-4 receptor alpha. Some patients with severe atopic disease have little evidence of type 2 hyperactivity and do not respond to biologics which target this pathway. Studies in responder and nonresponder patients demonstrate the complexity of these diseases. In addition, primary immune deficiency diseases related to T-cell maturation, regulatory T-cell development, and T-cell signaling, such as Omenn syndrome, severe combined immune deficiencies, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and DOCK8, STAT3, and CARD11 deficiencies, help in our understanding of the importance and redundancy of various type 2 immune components. The present review aims to highlight recent advances in type 2 immunity and discuss the cellular sources, targets, and roles of type 2 mechanisms in asthma and AD.
Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells
Hiroki Kimura, MD, PhD, Dave Francisco, MS, Michelle Conway, BS, Fernando D. Martinez, MD, Donata Vercelli, MD, Francesca Polverino, MD, PhD, Dean Billheimer, PhD, and Monica Kraft, MD
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has dramatically changed our world, country, communities, and families. There is controversy regarding risk factors for severe COVID-19 disease. It has been suggested that asthma and allergy are not highly represented as comorbid conditions associated with COVID-19.
Objective: Our aim was to extend our work in IL-13 biology to determine whether airway epithelial cell expression of 2 key mediators critical for SARS-CoV-2 infection, namely, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), are modulated by IL-13.
Methods: We determined effects of IL-13 treatment on ACE2 and TMPRSS2 expression ex vivo in primary airway epithelial cells from participants with and without type 2 asthma obtained by bronchoscopy. We also examined expression of ACE2 and TMPRSS2 in 2 data sets containing gene expression data from nasal and airway epithelial cells from children and adults with asthma and allergic rhinitis.
Results: IL-13 significantly reduced ACE2 and increased TMPRSS2 expression ex vivo in airway epithelial cells. In 2 independent data sets, ACE2 expression was significantly reduced and TMPRSS2 expression was significantly increased in the nasal and airway epithelial cells in type 2 asthma and allergic rhinitis. ACE2 expression was significantly negatively associated with type 2 cytokines, whereas TMPRSS2 expression was significantly positively associated with type 2 cytokines.
Conclusion: IL-13 modulates ACE2 and TMPRSS2 expression in airway epithelial cells in asthma and atopy. This deserves further study with regard to any effects that asthma and atopy may render in the setting of COVID-19 infection. (J Allergy Clin Immunol 2020;146:80-8.)