key: cord-0846082-i1mu2fmt authors: Garg, Suruchi; Garg, Mandeep; Prabhakar, Nidhi; Malhotra, Pankaj; Agarwal, Ritesh title: Unraveling the mystery of Covid‐19 Cytokine storm: From skin to organ systems. date: 2020-06-19 journal: Dermatol Ther DOI: 10.1111/dth.13859 sha: 99206715e2abf2f2dd65f2fbe31690994e024edd doc_id: 846082 cord_uid: i1mu2fmt COVID‐19 is a global pandemic that emerged from Wuhan, China. Besides pneumonia and acute respiratory distress syndrome, the disease leads to multisystem involvement in the form of myocarditis, arrhythmias, cardiac arrest, gastrointestinal symptoms, hypoxemic brain injury, acute liver and renal function impairment. There are also reports of cutaneous lesions in form of urticarial and maculopapular rashes, chilblain like fingers and toes (covid feet), livedoid vasculopathy and chicken‐pox like or varicelliform vesicles. Clinically, many of these skin lesions are likely secondary to occlusion of small to medium blood vessels due to microthrombi formation or due to viral laden antigen‐antibody immune complexes; and same explanation may hold true for possible hypoxemic injury simultaneously occurring in other vital organs like lungs, heart, brain and kidneys. The histopathology, immunoflorescence and RT‐PCR analysis of skin biopsies can provide useful insights for ascertaining the pathogenesis of this complex viral syndrome. Apparently, it is interplay of disarmed cellular immunity and over‐activated humoral immunity that culminates in end‐organ changes. The morbidity and mortality can be significantly reduced by upgrading the cellular immunity and downgrading the humoral response; along with prevention of hypoxemic and reperfusion injuries by using antivirals, immunomodulators, antioxidants, anti‐platelets and anticoagulants in judicious and phased manner. This article is protected by copyright. All rights reserved. IL10 pointing towards interplay of both TH1 and TH2 type response. Though CD4 and CD8 count is significantly depressed, there is evidence of hyperactivity of these markers (4, (18) (19) (20) 25) . There is evidence of high proportion of HLA-DR (CD4 3·4%) and CD38 (CD8 39·4%), over activation of T cells and increased level of Th17 and increased cytotoxicity of CD8 T cells; which points towards severe immune injury (26) . Positive RT-PCR results have been obtained from samples taken from nasopharyngeal swabs, bronchoalveolar lavage, blood, stool and urine. Secondary bacterial infections were also found in some deceased patients and persistent lymphopenia or deranged cellular immunity was a bad prognostic sign (27). Chest radiographs and the computed tomography have demonstrated hallmark peripheral ground glass opacities (GGOs) and lung consolidations which are typically bilateral and posterior (28). The sensitivity of the CT scan This article is protected by copyright. All rights reserved. has been found to be higher than routine nasopharyngeal swab in appropriate clinical settings, though the specificity is less. The Dutch study has also described venous congestion and venous thrombosis on CT scan surrounding the areas of GGO, which points towards the vascular injury besides the injury on lung parenchyma (28). CT findings can be used to monitor disease severity and progression also. Severely ill patients who require ICU admission tend to show bilateral areas of multiple lobular and sub-segmental consolidation. On the other hand, patients with lesser symptoms who do not need ICU admission, usually have bilateral GGO and subsegmental consolidation on CT. GGO increase in size with disease progression. Consolidation and crazy paving pattern may also be seen. Resolution of the lesions with disappearance of the crazy paving will be seen during recovery. Larger areas of consolidation also suggest disease progression (29). Lung ultrasonography has come up as another useful, cost effective and non-invasive modality in evaluation and monitoring of patients (30). Histopathological correlation of these GGO obtained from post-mortem core biopsies suggest that there is exudation of fluids into the alveoli due to attachment of viral proteins, endocytosis and subsequent injury to the alveolar surface. Consolidation is a sequential feature where there is fibrosis in interstitial spaces following fibroblast stimulation, hyalinisation and matrix formation (29). Previously, the biopsies performed on SARS patients revealed multinucleated syncytial cells with atypical enlarged pneumocytes in the intra-alveolar spaces, showing viral cytopathic-like changes. Some cases showed neutrophilic infiltration with suspected superadded bacterial infection; fibrinoid necrosis of vessel wall, fibrin plugs and pulmonary infarcts were also seen in cases beyond 14 days (31). This article is protected by copyright. All rights reserved. Patients with COVID induced ARDS have much higher rates of mortality as compared to those without ARDS. Critically ill COVID patients show reduced fibrinolysis. Fibrin deposition and microvascular thrombi are known to occur in the pulmonary vasculature of severely ill COVID-19 patients and may contribute to the ARDS (32). In the context of cardiac injury, the biochemical parameters were more consistent with myocardial injury. There was focal oedema, fibrosis and myocardial hypertrophy in postmortem examination of heart tissue (26, 29) . Brain tissue showed hypoxemic injuries along with underlying electrolyte imbalance (22) . Liver demonstrated diffuse mononuclear and periportal and centrilobular hepatic necrosis. Infiltration was more towards cholangiocytes (presence of ACE2 receptors) rather than hepatocytes along with sinusoidal dilatation and focal haemorrhages and hepatic necrosis (26, 29) . A Korean scoping study mentioned that elevated liver enzymes and suppression of CD4 and CD8 count was directly correlated with disease severity. Though, it was also mentioned that it could be due to Lopinavir or Ritonavir and that these drugs should be used with caution as these may lead to injury in cholangiocytes (32). Splenic tissue was shown to be atrophic; and there were areas of focal hemorrhagic necrosis, macrophage proliferation and phagocytosis. There was also lymph node atrophy and decrease in number of lymph nodes along with necrosis. Immunohistochemical staining demonstrated that CD4 + T cells and CD8 + T cells were decreased in spleen and lymph nodes (33,34). Though there is extensive damage found in other organs, kidneys were relatively preserved. Acute renal impairment was unlikely as studied in a series of 116 patients and only 3 of 48 urine samples were found to be positive for SARS-Cov-2 who did not have previous renal disease (35). This article is protected by copyright. All rights reserved. The virus attacks these receptors through s-proteins present on its surface and enters the alveolar epithelial cells and enterocytes by the process of endocytosis through receptor binding proteins. The patient starts getting mild fever, cough and abdominal discomfort, though many patients remain completely asymptomatic depending upon viral load and resistance posed by host immunity. Most of the patients with good immunity tide over the infection at this stage. Initial response to the virus is by cell mediated immunity, generated in regional lymph nodes which involve activation of NK cells and helper T cells, also handled by thymus, spleen and liver. The virus also shows vasotropism towards endothelial cells in the blood vessels. The blood vessels are the easy targets due to their close proximity in alveoli and abundant presence of ACE2 receptors on the former (36-38). Endothelium gets upregulated by the expression of selectin and other adhesion molecules released by respiratory epithelium and neighbouring cells. Activated endothelium can also secrete proinflammatory cytokines like IL6, type 1 and 2 IFNs and TNF-α in response to a virus infection (38). There are elevated D-dimer levels detected earlier in course of illness while IL6 levels start rising by 13th day of illness, by this time D-dimer is already 10 times elevated (22) . This article is protected by copyright. All rights reserved. is an important marker in disorders of coagulation; this leads to a possibility that the process of microthrombi formation starts early in alveolar vessels and IL6 is a late response secondary to humoral response. This discrepancy between D-dimer and IL 6 also suggests that early D-dimer elevation may represent a true thrombotic state due to cellular activation triggered by the virus (28). Elevated serum D dimer may also lead to embolic vascular events like stroke (23) . Oudkerk et. al highlighted that the sequential D-dimer levels and CT scans can be utilized in monitoring of patient for possible pulmonary thrombo-embolism and venous clots and delineated when to start the prophylactic anti-coagulant therapy (28). The patients with more severe disease present with rather complex pathogenesis. The cell mediated immunity is knocked off by the viral load in the initial phase of illness. The histopathological studies demonstrate that there is atrophy of spleen and thymus and widespread periportal and centrilobular destruction in liver along with depression of NK cells and T cells (25, 29) . There is also evidence of depression of circulating hemopoetic stem cells released from bone marrow eventually leading to depression of cell mediating immunity (38). Apparently, the virus gains entry into vessels present in interstitial spaces and starts damaging the endothelial cells leading to the generation of nitric oxide and reactive oxygen species in presence of leukocytes (38); finally there are haemorrhagic exudates in lungs as detected by post-mortem core needle biopsy (27). The injury produced on endothelial cells evokes a cascade of events involved in coagulation process. Body tries to repair it by depositing platelets and red blood cells and releasing various proinflammatory mediators. This in turn, leads to production of microthrombi in the blood vessels. When these virus laden microthrombi get dislodged and circulate in different organs of body; they lead to ischemic This article is protected by copyright. All rights reserved. injuries as seen in heart, liver, brain and skin tissues and occasionally kidneys. (Figure 1 ) The thrombocytopenia in circulation could be attributed either to impaired lung function leading to lesser production from megakaryocytes or due to consumption coagulapathy due to widespread thrombotic process going on in more severe cases, later presenting as disseminated intravascular coagulation (DIC) (38). Now, besides alveolar capillaries, whether the virus is able to gain entry into the small blood vessels of nose and nasopharynx is debatable; the anosmia and dysgeusia experienced in early phase of illness may possibly be justified by endocytosis and injury of tiny feeding blood vessels of olfactory bulb, facial and glossopharyngeal nerves. a. Antiviral drugs like Remdesivir, oseltavir, lopinavir, ritonavir etc (32). VI. Use of antioxidants like vitamin C , vitamin E, glutathione and superoxide dismutase to reduce free radical injuries (53) and to counter possible vasculitic cascade (54). a. Vasodilators like pentoxyphyllin, losartan (55). b. Judicious use of anticoagulants like revaroxaban, low molecular weight heparin -enoxaparin, heparin and aspirin to minimize microthrombi formation (56). These treatment options are summarised in table 1. COVID-19 is one unique pandemic where every section of society has lessons to learn from. Six months have gone by and there is no definitive cure to this deadly pandemic but surely the current scenario has taught us many lessons. Under the circumstances, the best approach will be to indulge in healthy eating habits, respecting the circadian rhythm and building up own immunity against pathogens (57). Following section is purely based on opinion of authors: 1. The present scenario is a wake-up call for us 'humans' to introspect ourselves. It's high time to respect the ecosystem and to refrain from falling prey to nature's punishment of not following the rules of food chain. If we go by the concept of overcrowding in food chain, nature has its own rational ways of creating predators to curb uncontrolled population which unfortunately is happening with humans in the current scenario. 2. The world politics need to understand that proving superiority of one nation over other using power, intimidation and manipulation tactics needs to be introspected and discouraged. On the contrary, world needs to learn empathy and tolerance This article is protected by copyright. All rights reserved. and all possible actions should be taken up to save 'mother earth' from physical, chemical and biological assaults. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. Figure 1 : Flowchart explaining how the SARS-CoV-2 virus attacks the nasopharynx and gains entry into lung, gastrointestinal system and blood vessels due to abundant presence of ACE2 receptors. Cell mediated immunity is disarmed by atrophy and destruction of lymph nodes, thymus, spleen and liver. Blood vessels in lung are easy target due to presence of ACE2 receptors initiating cascade of micro-thrombi formation, immune complex deposition and exaggerated humoral immune response leading to subsequent hypoxemic injury to various vital organs. This article is protected by copyright. All rights reserved. Coronavirus disease 2019 (COVID19): situation report-84. 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