Blog
About

2
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      SARS-CoV-2 infection complicated by inflammatory syndrome. Could high-dose human immunoglobulin for intravenous use (IVIG) be beneficial?

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Dear Editor, We have read with interest your editorial [1]. Indeed, the pandemic infection coronavirus disease 2019 (COVID-19), caused by the new coronavirus named severe acute respiratory syndrome coronavirus 2-related (SARS-CoV-2), is a major concern worldwide because of its highly contagious nature, the great number of patients requiring intensive care therapy and the high mortality rate. In the absence of vaccine or passive immunotherapy, one of the principal aim in the treatment of these patients is to prevent the potent virus-induced inflammatory stimuli from leading to the acute respiratory distress syndrome (ARDS), that has a severe prognosis. Indeed, following SARS-CoV-2 infection, different clinical pictures may arise. They range from: 1) asymptomatic, or mild fever with a dry cough with or without seasonal flu-like symptoms, to 2) dyspnea ranging from effort to spontaneous respiratory problems requiring hospitalization. This clinical condition can resolve or progress in 17–19.6% of symptomatic patients to 3) ARDS, requiring positive pressure oxygen therapy and often, intensive care therapy. In this phase, disseminated intravascular coagulation [2] and multi-organ failure can also be observed (5%). This rapidly evolving condition is the main cause of death worldwide in infected patients [[3], [4], [5]]. Clinical recovery can occur at any of the above-mentioned stages, but more rarely from stage 3 (3.4%) [[3], [4], [5]]. Stage 3 is preceded by a marked rise of serum ferritin and C-reactive protein (CRP) levels and increased erythrocyte sedimentation rate, and is associated to severe edema due to an alveolar capillary leak-like syndrome (responsible for the ground glass picture seen at chest high resolution CT scan), leading to a marked impairment of gas exchange, requiring assisted ventilation. Overall, these clinical and laboratory pictures suggest a pro-inflammatory cytokines-driven ARDS. Thus, ARDS is induced by a potent virus-mediated inflammation, resembling the inflammation observed in some auto-immune/−inflammatory diseases such 1) juvenile idiopathic arthritis [6]; 2) Kawasaki disease [7], 3) the catastrophic anti-phospholipid syndrome (CAPs) [8] and 4) the systemic capillary leak-like syndrome (SCLLS) [9], the latter two being complications of the antiphospholipids antibodies syndrome (APS) [10]. Before ARDS takes place, only one drug with immunomodulatory properties, namely hydroxy-chloroquine, is currently being used in these patients. Different mechanisms of action have been hypothesized or assessed for it, including down-modulation of natural and adaptive immunity [11], reduction of the intracellular viral replication and uptake [12]. At ARDS stage, the targeting of IL-6 seems to be promising and after successful attempts in stabilizing the alveolar capillary membrane and shortening the intensive care unit stay [[13], [14], [15], [16]], a number of controlled clinical trials are ongoing with anti-IL-6 monoclonal antibody (mAb) (NCT04306705, NCT04317092, and EudraCT Number: 2020–001110-38). It cannot be excluded that small molecules given per os, like the JAK-1 inhibitor, which interfere with IL-6-triggered intracellular signals, may eventually be used instead of mAb to prevent ARDS. 1 Human immunoglobulin for intravenous use (IVIG) can be useful to lower inflammation in SARS-COV-2 infection and preventing ARDS The IVIG preparation consists of highly purified immunoglobulins (Ig), mostly of the IgG class, obtained from between 1,000 and 15,000 healthy donors per batch [17,18]. Therefore, the majority of these molecules are natural antibodies with polyreactive properties, that can recognize and neutralize different pathogenic exogenous antigens (viral or bacterial antigens / toxins and superantigens) [19], as in the case of coronavirus infection, or endogenous antigens (i.e., cytokines, chemokines and metalloproteases), as in the case of CAPs and SCLLS [9,20] or of Kawasaki disease, parvovirus infection or streptococcus-derived superantigens, hypothesized to trigger the vasculitis [21]. The anti-inflammatory / immune-regulatory role of IVIG also relies on their Fc region interaction with the corresponding Fcγ receptors (FcγRs). Since FcγRs are expressed on cells involved in natural (phagocytes) and adaptive (T cells, B cells) immunity, and on cells (antigen presenting-cells) bridging natural and adaptive immunity, the interaction may modulate signaling through FcγRs, ultimately inducing potent anti-inflammatory effects [18,22,23]. IVIG may also influence the number and function of regulatory T cells (Tregs) which help to control inflammation and inhibit T cell activation [24], tumor necrosis factor (TNF)-α production, IL-6 and matrix metalloproteinase 9 activity, primarily responsible for the vascular damage in a mouse model of inflammatory disease [25]. Striking evidence of the anti-inflammatory role of IVIG is the decreased serum levels of inflammatory cytokines following their infusion in patients with Kawasaki disease [26]. The above-mentioned properties are the rationale for suggesting IVIG use in SARS-CoV-2 infection to prevent and counteract the cytokine-mediated interstitial and alveolar wall edema responsible for ARDS. IVIG polyreactivity might also serve to speed virus clearance. Besides being given to patients with (primary or secondary) IgG deficiency as replacement therapy to prevent infections, at the dosage of 0.4 g/kg administered in one day every three-four weeks [17,18], IVIG preparations were also successful in treating inflammatory, immune-mediated diseases or infectious diseases, at a five-fold higher dosage (2 g/kg given in two to 5 days). High dosage is required to ensure an optimal binding of natural antibodies to pathogenic antigens, considering the relatively low antigen-binding affinity of natural antibodies, and to ensure a sufficient saturation of FcγRs on immune cells. To support the concept that IVIG may be successfully used in COVID-19 is the similar etiology or inflammatory pathogenesis between SARS-CoV-2 infection and diseases for which the use of IVIG has been approved by the European Medicines Agency (EMA)(https://www.ema.europa.eu/en/) and the US Food and Drug Administration (FDA) (https://www.fda.gov/), including Kawasaki disease, or for which IVIG are employed off-label with beneficial effects (Table 1 ) [18]. The latter include inflammatory diseases 1) induced by endotoxemia or infectious diseases, especially those observed in subjects with organ(s) function impairment, such as in aggressive viral infections, or in subjects with compromised clinical conditions; or 2) auto-immune/−inflammatory - genetically sustained – rheumatic diseases, such as the aforementioned vasculitides, CAPs and SCLLS, the latter two resembling an inflammatory syndrome likely triggered by endogenous or exogenous antigens in the context of APS [9,10]. SCLLS has also been observed in Kawasaki disease [27]. Last but not least, IVIG were found to be effective in the treatment of patients with SARS [28]. Table 1 Infectious and autoinflammatory diseases considered for the off-label use of human normal immunoglobulin for intravenous (IVIG) [18]. Table 1 Disease Rationale and/or mechanism of action Prophylaxis in haematopoietic stem cell transplantation Ig replacement Infection disease conditions (toxemia, parvovirus 19) Neutralization of pathogenetic exogenous antigen, anti-inflammatory effects Infections in solid organ transplantation, surgery, trauma, burns Ig replacement Idiopathic arthritis (especially the juvenile inflammatory form) Fc-mediated Dermatomyositis and polymyositis Fc-mediated Catastrophic antiphospholipid syndrome Fc-mediated, Fab-mediated Systemic capillary leak-like syndrome Fc-mediated, Fab-mediated Vasculitides (ANCA-associated) Fab-mediated, Fc-mediated, blocking of CDC and ADCC. Skin autoimmune diseases (pemphigo, epidermolysis bullosa, atopic dermatitis, chronic urticaria) mostly Fc-mediated, anti-inflammatory, Myasthenia gravis Fab-mediated Asthma Anti-inflammatory ADCC, antibody-dependent cell-mediated cytotoxicity; ANCA, anti-neutrophil cytoplasmic antibody; CDC, complement-dependent cytotoxicity. To date, there has been only one report (dated March 25) of the successful administration of IVIG in three patients with severe COVID-19 [29], but randomized clinical trials have been started (NCT 04261426). As several months will pass before these ongoing trials are concluded, we believe IVIG meet all the criteria for off-label use in SARS-CoV-2 infection, in view of their immunomodulatory and protective action against superinfections, which can be arise in the ARDS phase [30,31]. In conclusion, SARS-CoV-2 infection can at a certain point turn into a true inflammatory syndrome. Before ARDS develops, we propose that IVIG can be useful in preventing inflammation through different mechanisms of action. IVIG may also serve as immunological support in SARS-CoV-2 infected patients, protecting them from being overwhelmed by superinfections.

          Related collections

          Most cited references 31

          • Record: found
          • Abstract: found
          • Article: not found

          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Clinical Characteristics of Coronavirus Disease 2019 in China

            Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found

              Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

                Bookmark

                Author and article information

                Contributors
                Journal
                Autoimmun Rev
                Autoimmun Rev
                Autoimmunity Reviews
                Elsevier B.V.
                1568-9972
                1873-0183
                1 May 2020
                1 May 2020
                Affiliations
                [a ]Department of Biomedical Science and Human Oncology (DIMO), Systemic Rheumatic and Autoimmune Diseases Unit , University of Bari Medical School , Italy
                [b ]Department of Biomedical Sciences and Human Oncology (DIMO), Unit of Internal Medicine, University of Bari Medical School, Italy
                Author notes
                [* ]Corresponding author at: Department of Biomedical Science and Human Oncology (DIMO), Systemic Rheumatic and Autoimmune Diseases Unit, University of Bari Medical School, Piazza G. Cesare 11, I-70124 Bari, Italy. federico.perosa@ 123456uniba.it
                Article
                S1568-9972(20)30121-X 102559
                10.1016/j.autrev.2020.102559
                7252087
                32361195
                © 2020 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                Categories
                Article

                Immunology

                il-6, sars-cov-2, ivig, autoinflammatory syndrome, caps, capillary leak-like syndrome

                Comments

                Comment on this article