Asian Journal of Research in Dermatological Science 3(4): 1-21, 2020; Article no.AJRDES.61157 Looking Beyond the Cutaneous Manifestations of Covid 19, Part 2: The Pathology and Pathogenesis - A Review A. S. V. Prasad1* 1Asst. Professor (Formerly), Department of Internal Medicine, GITAM Dental Collage, G.I.T.A.M University Campus, Rishikonda, Visakhapatnam, India. Author’s contribution The sole author designed, analysed, interpreted and prepared the manuscript. Article Information Editor(s): (1) Dr. Giuseppe Murdaca, University of Genova, Italy. (2) Dr. Peela Jagannadha Rao, Quest International University Perak, Malaysia. (3) Dr. Jayaweera Arachchige Asela Sampath Jayaweera, Rajarata University of Sri Lanka, Sri Lanka. Reviewers: (1) Monier Sharif, Omar Al-Mukhtar University, Libya. (2) E. S. Shobha, Rajiv Gandhi University of Health Sciences, India. (3) Vera Kornisheva, North-Western State Medical University named after I. I. Mechnikov, Russia. (4) Wafaa Mohamed Ezzat, National Research Centre, Egypt. (5) Adam Reich, University of Rzeszów, Poland. Complete Peer review History: http://www.sdiarticle4.com/review-history/61157 Received 31 August 2020 Review Article Accepted 16 September 2020 Published 29 September 2020 ABSTRACT This is the second part of the article, titled "looking beyond the cutaneous manifestations of Covid 19 Part 1: The Clinical Spectrum – A Review”, which is exclusively relegated to the pathology and pathogenesis aspects. The cutaneous manifestations of Covid 19 are classified into four broad groups, from the pathology and pathogenesis point of view and the histopathology of all the cutaneous lesions are briefly reviewed. The role of vasculitis and endothelitis in the pathogenesis of skin lesions in Covid 19, are discussed. The vasculitis and thrombotic microangiopathy (TMA) are discussed at length as they occupy the centre stage of pathogenesis, in the literature, at present. The various types of vasculitis reported in literature, are classified on the basis of skin lesions seen and the rationality of the various terms used in the context of the pathogenesis are explained. It is stressed that that the central players in the pathogenesis of skin lesions in Covid 19 are, vasculitis, activation of complement pathways and coagulation cascade and the cross- talk between the two at various points in their respective pathways. For the details of the complement activation, activation of coagulative cascade and for the details of the role of innate and adaptive immunity _____________________________________________________________________________________________________ *Corresponding author: E-mail: [email protected]; Prasad; AJRDES, 3(4): 1-21, 2020; Article no.AJRDES.61157 system, the readers may refer to the author’s previous article titled “Local Immunity Concept in the Context of the Novel Corona Viral Infection- A Consideration.” *** (reference of which is provided under the additional information at the end of the article). Some contentious issues concerning the role of the vasculitis and immune complex mediated damage, of the vessel wall in the pathogenesis of cutaneous lesions of Covid 19, are discussed. A non-immune, non-vasculitis, alternative mechanism is suggested by floating a two hit hypothesis. The necessity to apply the rigours of diagnostic criteria of vasculitis is emphasized to get a standard picture of the histopathology and pathogenesis of cutaneous manifestations of Covid 19 by future research. Keywords: Vasculitis; thrombotic microangiopathy; MAC complex; coagulation cascade; complement activation. 1. INTRODUCTION theme of the pathogenesis of the skin lesions in Covid 19, seems to be activation of coagulative No single mechanism, perhaps explains all the cascade pathways (extrensic and contact dermatological manifestations of Covid 19. For pathways) and the complement activation example, the localized acral lesions like, the pathways (alternate pathway, MBL pathway and Covid toes, histologically resembles primary the classical pathway) with a cross talk between chilblain (perniosis) histopathology, and the the two. The two interacting pathways pathology and pathogenesis of exanthematous (coagulative and complement activation) are fully truncal lesions like vesicular and papular types discussed in the article published under th title etc. are no different from that of any other viral “Acute Immune Mediated Lung Injury in COVID disease. The levidoid and necrotic lesions, Which 19: A Review” *(for details at the end of the are seen in critically ill, elderly Covid 19 patients, article) by this author. Hence discussion will be resemble the pathology of the lungs in Covid 19. centred on the cross talk between the two Even the ICD-10 classification of the skin systems. Likewise, the clinical and diseases classifies "vasculitis limited to skin" epidemiological spectrum of the various under "L", category and "necrotizing cutaneous manifestations of Covid 19 are vasculopathies "corresponding to systemic discussed by this author in the article, titled vasculitis, with musculoskeletal system and “Looking Beyond the Cutaneous Manifestations connective tissue conditions under "M" category of Covid 19- Part 1: The Clinical Spectrum” ** (ICD10 data.com). It shows that the local as well (details athe end of the article.) To avoid as systemic versions of the same disease are repetition the article proceeds directly with the considered as distinct entities. By the same pathology and pathogenesis of the cutaneous anolgy, localised lesion like Covid toes, is a manifestations in the present article. The distinct entity and levidoid and necrotic skin interested readers may refer to the part 1 of this lesions, which are associated with simultaneous series, for the detailed description of these systemic involvement affecting the lungs and aspects of the skin lesions of Covid 19**(vide kidney etc, have separate and distinct infra, under additional article information). pathologies. The levidoid / necrotic lesions can Unfortunately, unanimity is lacking among the be viewed as the forerunners of a coagulopathy authors as to the pathology and pathogenesis of in the fatal cases of Covid 19 disease involving the cutaneous lesions of Covid 19.The final word multiple viscera .There is no unanimity of the on the pathology and pathogenesis of these opinion, as to whether the pathology of the lesions as a whole, is yet to be said. So, no cutaneous lesions is due to direct infection by the readymade answers to the issues under SARS CoV 2 or due to the dysregulated host consideration may be expected as the article immune response. The inflammatory injury of the intends to review the reported views in n the intima of the small sized blood vessels literature in this regard and makes an attempt to (vasculitis) perhaps explains the pathology of rationalize them. Covid toes with the subsequent activation of the coagulation cascade accounting for the 2. DISCUSSION microvascular thrombosis that characterizes the levidoid/necrotic lesions and the concurrent From the point of view of pathology and severe lung pathology as well – the two shot pathogenesis, the cutaneous lesions are concept of pathogenesis of cutaneous classified by this author into 4 broad groups manifestations seen in Covid 19. The central (Table 1). 2 Prasad; AJRDES, 3(4): 1-21, 2020; Article no.AJRDES.61157 2.1 Diagnostic Value and Limitations of Primary or idiopathic perniosis result of Histopathological (HP) Studies of vasospasm of the superficial vasculature and Cutaneous Lesions in Covid 19 secondary inflammatory reaction [1]. It is usually associated with cold temperatures and The cutaneous lesions are diagnosed clinically, vasospasm [2]. Secondary perniosis are basing on their morphological presentation associated with systemic inflammatory Histopathological (HP) study is confirmatory to conditions. Histopathology of Covid toes shows clinical diagnosis, where a known pattern dermal edema and a lymphocytic perivascular associated with a disease is known. The Covid and perieccrine inflammatory infiltrate. 19 pandemic is, of recent origin and the Occasional necrotic keratinocytes and focal cutaneous lesions have come under scrutiny only areas of basal vacuolization may be seen in the from the end of April, 2020. There is no epidermis. No microvascular thrombi are standardized histopathology data available seen.Very recently Kolivras et al. [3] reported the before the pandemic .The percentage of skin first histopathology of a chilblain like lesion lesions seen, in Covid 19 patients are as such showing a superficial infiltrate and deep few, out of which only a handful of studies by lichenoid, perivascular and perieccrine infiltrates researchers focussed on biopsy and HP studies. of lymphocytes without any thrombi. Among1099 confirmed cases in Wuhan, only 0.2% presented with cutaneous symptoms. So a 2.3 Similarity with Histopathology of review of the histological details of various skin Primary Perniosis lesions of Covid 19 is limited to few authentic studies. The recently reported lesions such as, The salient features of periniosis are-“Dense dengue-like lesions, Kawasaki disease -like superficial and deep lymphocytic infiltrate, lesions as well as paediatric Multisystem Subepidermal oedema may be marked. The Inflammatory Disease are severely handicapped characteristic feature is lymphocytic perivascular by lack of HP studies. As such it is not surprising infiltrate within the dermis and sometimes if the reviewers draw a blank in this regard. On extending to