Coronaviruses as a cause of vascular disease: a comparative medicine approach

29.1.2021, Translation 2.5.2021
Alison E. Stout DVM, Nicole André LVT, Joshua Zimmerberg MD PhD, Susan C. Baker PhD and Gary R. Whittaker PhD
Original article: Coronaviruses as a cause of vascular disease: a comparative medicine approach

Contact the author: e-mail: grw7@cornell.edu. 618 Tower Rd., Ithaca NY 14853 USA.

Abstract

COVID-19 caused by SARS-CoV-2 often manifests as a respiratory disease including cough, dyspnoea, fever and olfactory loss. However, other manifestations of the disease occur in many organ systems, at least in part due to vasculitis and endothelitis. COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) has recently been identified as part of SARS-CoV-2 infection. In feline medicine, feline coronavirus is a common pathogen that can lead to a deadly disease called feline peritonitis (FIP). Like human COVID-19, the clinical manifestations of FIP are due in part to coronavirus-induced vasculitis, which can also lead to fatal multisystemic inflammatory syndrome in cats. Studies investigating how feline coronavirus infection can cause disseminated vasculitis in FIP cats will provide new information that may help people understand COVID-19. We strive for a comparative medicine approach to tackling coronavirus diseases.

The COVID-19 pandemic in 2019-2020 is caused by the recently discovered zoonotic beta-coronavirus classified as SARS-CoV-2. COVID-19 often manifests as a respiratory disease manifested by fever, cough, dyspnoea, olfactory loss, headache, and malaise. More severe disease may include acute respiratory distress syndrome (ARDS); however, the disease also appears to affect other organ systems, including the gastrointestinal, central nervous system (CNS), cardiovascular, renal, hepatic, endocrine, dermatological, hematological, and ophthalmic systems.17 These systemic symptoms are thought to be due to viral endothelial cell infection and endothelitis49 leading to vasculitis.5 COVID-19 can be considered both a respiratory disease and a vascular disease, with widespread viral tropism and high transmissibility contributing to the current public health crisis and the differentiation of SARS-CoV-2 from SARS-CoV, despite the receptor (ACE2) common to both viruses.

After studying the history and pathogenesis of feline coronavirus, we see parallels between COVID-19 and feline infectious peritonitis (FIP) with a wide variety across human and feline coronavirus infections, as originally found in SARS.41 Feline coronavirus (FCoV) in cats is generally considered to be an initial gastrointestinal or rarely respiratory infection that results in FIP, a systemic vascular disease with high morbidity and mortality in some animals.46 This feline disease, originally called chronic fibrinous peritonitis, was first described in 1963. 22; shortly afterwards, the etiological agent (causative agent) was recognized as a coronavirus. This disease, now called feline infectious peritonitis (FIP), occurs worldwide, is almost always fatal, and mainly affects young cats (under 2 years of age).28,38 The etiological agent responsible for most cases of FIP is feline coronavirus (FCoV), alpha coronavirus.25 While FCoV transmission and infection are widespread in domestic cats, systemic disease develops in only a small subset of animals (Figure 1). Common to these various forms of the disease is the identification of virus-induced vasculitis.27 This review highlights the similarities between COVID-19 and FIP and opens up opportunities for cooperation between the medical and veterinary communities in the fight against these devastating diseases.

Figure 1: FIP develops only in a subset of infected cats, despite the widespread spread of FCoV. Similarly, according to current knowledge, many cases of SARS-CoV-2 infection are characterized by a mild or asymptomatic course.

Clinical and pathological profile of feline coronavirus infection: parallels with COVID-19

Like COVID-19 in humans, FIP is involved in many manifestations of the disease in cats (Figure 2), which are described as "variably manifested by multiple organ failure, seizures, generalized effusion, or shock."14 The disease is commonly classified in one of two clinical forms, effusive or "wet" (characterized by accumulation of protein effusion mainly in the peritoneal or pleural cavities) and non-fusive or "dry" (characterized by granulomatous lesions in many organs, including the brain).19 A "mixed form" is also contemplated, in the clinical spectrum of which granulomatous and pyogranulomatous lesions, which occur in the serous part of the liver, kidneys and intestines, are common. The spectrum of pathologies observed in FIP includes serositis, hepatitis, nephritis, uveitis and coriethinitis.38,55 Neuropathological manifestations of FIPV in cats include meningitis, meningoencephalitis, ependymitis, and choroidal plexitis with inflammation ranging from lymphoplasma to pyogranulomatous, and often including vasculitis and perivasculitis. Ophthalmic manifestations, including uveitis and chorioretinitis, are also common. Case reports point to associated heart lesions, including myocarditis and fibrinous epicarditis.12,34 Dermatological lesions that are less commonly observed in FIP include erythema, nodules, and papules.4,8,10 In some cases, early respiratory symptoms have been reported8,54 and in some cats, immunostaining identified the virus in the lung parenchyma.27 Our latest laboratory has confirmed the presence of the virus in the upper respiratory tract by immunostaining.1

Figure 2: Vasculitis caused by FCoV infection can affect many body systems. Since the first descriptions in the 1960s, numerous studies have revealed various forms of the disease.

A similar feature in FIP outbreaks and patients with COVID-19 is extensive vascular involvement.3,5,20 In one of the first reports recognizing vascular involvement in FIP cases, four types of lesions were described: "perivascular edema", "vascular wall degeneration", "endothelial proliferation" and "adventitial and / or perivascular infiltration".20 In 1989, Boudreaux and colleagues described FIP lesions in several cats as "obliterating" vascular walls. Similarly, August concluded in 1984 that "FIP could be more accurately termed feline coronavirus vasculitis."3 As a naturally occurring disease in cats, FIP and FCoV infection provide an opportunity to understand the pathogenesis of SARS-CoV-2, especially with regard to the co-development of vascular manifestations.

Although observations of myocarditis, rhinitis or skin lesions in FIP are rare, they allow comparison with COVID-191,8,12,42. Frostbite-like lesions, a condition colloquially called "COVID-fingers", have been reported in several patients with COVID-19, although the direct association of these manifestations with COVID-19 remains open.30,33 In cats, a similar condition is known as plasma cell subdermatitis and may also be associated with FCoV. Plasma cell pododermatitis manifests as paw inflammation along with the potential for color changes, ulcerations, and cracks.40 In the case of feline subdermatitis, an association with an infectious disease has been suspected.11 In addition to observing similar paw lesions in FCoV-secreting cats, our laboratory has previously identified subdermatitis in cats due to FIP. Although "COVID fingers" and subdermatitis in cats are rare consequences of infection, they further highlight the spectrum of similarities between COVID-19 and FIP.

One of the characteristic symptoms of COVID-19 is anosmia (loss of smell). Also, in most cases of FIP, the onset of anorexia is common.38,53 Although a non-specific clinical symptom that can be attributed to many different causes, anorexia can be attributed to loss of odor perception - an extremely important sensation that drives appetite in cats. While anosmia is difficult to measure in cats, the relationship between olfactory bulb infection and possible spread to the brain by human and feline coronaviruses deserves further evaluation, especially with regard to the neurological manifestations of both diseases.14,29

Immune component of FIP disease

Based on previous observations of complement and immunoglobulin circulation, including immune complexes, FIP is classically characterized as immune-mediated.24,39 In particular, type III hypersensitivity and Arthus-like reactions lead to the development of immune complexes that can build up in the walls of blood vessels, leading to vasculitis. Despite attempts to classify FIP as a type III hypersensitivity reaction, further work by Kipar and colleagues has shown numerous differences.26,27 Type III hypersensitivity has also been studied in patients with COVID-19.43 The importance of FIP as a type IV hypersensitivity reaction with apparent perivascular lesions consisting of T-lymphocytes, granulocytes and a characteristic feature of FIP, macrophage infiltrates, was also evaluated.36 Delayed-type hypersensitivity is observed in cats inoculated intradermally with FCoV, leading to perivascular cellular infiltrates of macrophages, neutrophils and lymphocytes in the absence of immune complexes.52 However, cellular extravasation associated with FIP lesions contributes to endothelial disruption and the inflammatory response that underlies FIP.27 Specifically, antigen (LFA) -1 associated with β2 integrin adhesion molecules and lymphocytes, β1 integrin very late antigen (VLA) -4 and β2 macrophage antigen (Mac-1) have been demonstrated to be increased in peripheral blood leukocytes isolated from cats with FIP.35 Integrins (LFA) -1 and (VLA) -4 play an important role in neutrophil and monocyte migration across the endothelium and are involved in the development of vasculitis in other disease processes,9,47 while (Mac-1) may play an additional role in the development of thrombosis.51 The hypothetical role of endothelitis, which underlies COVID-1949, parallels previous findings on FIP and the resulting acute vasculitis.

The interaction between vascular pathogenesis and hemodynamics has long been known in FIP.53 In addition to peripheral pyogranulomatous lesions, phlebitis, endothelial edema with inflammatory infiltrates of tunica media, thrombophlebitis and thrombosis were observed in cats experimentally infected with FCoV, classical FIP.53 Additionally, thrombocytopenia, anemia, jaundice, decreased clotting factors VII-XII, increased antithrombin III, and prolonged activated partial thromboplastin time, prothrombin time, and thrombin time are observed after experimental infection.7,53 Thus, the end result for some cats with FIP is the development of disseminated intravascular coagulation.7,53 This is in contrast to the course in human patients with JIS, who are often anticoagulated at some point in their hospital stay, and the rare development of DIC in humans is associated with a worse course in COVID-19.48 The fibrin product D-dimer, a DIC marker, has been studied rarely in cats with FIP, but has been increased in two cases - as expected, observations in patients with COVID-19 have shown this.

The development of FIP in a subset of cats, although most FCoV-infected cats undergo only a subclinical phase, is thought to be the result of an initial immune response.37 Strong cell-mediated immunity (CMI) together with humoral immunity is thought to lead to a subclinical course of the disease, while a lack of CMI leads to an effusive form of the disease and partial CMI leads to a dry form of the disease.37 Similarly, with respect to the immune response, multisystem inflammatory syndrome in children (MIS-C), which may be a manifestation of SARS-CoV-2, has recently been described.16which may develop due to a delayed response to interferon or due to an aberrant IgG response promoting disease progression.44 In addition to MIS-C, multisystem inflammatory syndrome in adults (MIS-A) has been described as a result of SARS-CoV-2 exposure.32

Antibody-dependent exacerbation of infection

In the case of SARS-CoV-2, there were concerns about antibody-dependent enhancement (ADE) infection,13 largely based on experience with other human viruses, such as respiratory syncytial virus, influenza and dengue; despite the need for caution, formal evidence linking ADE to COVID-19 clinical outcomes remains insufficient.2 In cats, it is noteworthy that the involvement of ADE in FCoV infection and the development of FIP with antibodies that would provide means for FCoV to gain macrophage entry has long been considered.21 So far, despite several trials, a viable FCoV / FIP vaccine is still not available.45,50 In contrast to these FIP vaccine studies, preliminary immunization results for COVID-19, for example with stabilized spike immunogens, documented neutralizing, not potentiating, antibody responses.23

Perspectives

COVID-19 is a complex and challenging disease in humans, and similarly, FIP is a complex disease in cats with many factors contributing to the outcome of the disease. By analogy with the persisting question in metastatic tumor research, "seed and soil", the availability of immunological, pathological and physiological samples and data on these similarly fatal inflammatory syndromes from two different coronaviruses in their own host species allow testing of structure / function hypotheses in venous vasculitis . In addition, due to the lack of enthusiasm for clinical biopsy of human patients with fulminant COVID-19 and the great difficulty in achieving good preservation of pathological specimens, it will take a very long time to learn more about the presence or absence of coronavirus in human patients at baseline and during their progression. inflammatory phase of COVID-19.

As a naturally occurring disease with many parallels with COVID-19, we think that FIP may help in future COVID-19 research. Both baseline vasculopathy in both FIP and COVID-19 underline the need to think of these diseases as multisystemic rather than organ-specific diseases. Although often considered a key enteric mode of transmission for FCoV, it is clear that the oropharyngus is a robust portal to host entry. Another factor to consider is that SARS-CoV-2 infects cats.15,18 Although not currently considered a serious disease in cats, it is not a robust animal model for COVID-19, The increased rate of SARS-CoV-2 infection in cats and possible FCoV co-infections raise, in addition to the possibility of viral recombination, concerns about the overlap of pathology and clinical manifestations of human and feline coronaviruses with surprisingly similar vascular disease profiles. However, the fact that SARS-CoV-2 naturally infects cats may offer a model for preclinical evaluation of SARS-CoV-2 vaccines. We believe that further studies are needed to investigate how coronaviruses can cause vascular disease in order to eliminate these devastating diseases, and FIP provides a platform for joint clinical trials bridging feline and human medicine.

Financing

AES is supported by the NIH Comparative Medicine Training Program T32OD011000. GRW is funded by NIH grants R01AI135270 and R21AI135373, SCB is funded by NIH grant R01 AI085089. FIP research in the author's laboratories is funded in part by the Winn Feline Foundation and the Cornell Feline Health Center.

Thanks

We thank Andrew Miller, Robert Goggs, Natalie Zatz and Beth Licitra for critical reading of the manuscript and helpful discussion.

Conflict of interests

The authors are not aware of any conflict of interest.

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