COVID-19: Beyond a respiratory illness. A Multi-system Inflammatory Syndrome (MIS)- Amisha Parekh

MULTISYSTEM INFLAMMATION SYNDROME (MIS):

MIS-C: Recently, reports have shown that the majority of the deaths in young people having COVID19 have occurred due to multisystem inflammatory syndrome (MIS-C) [1]. It is a syndrome found in young people below 21 years of age and is presented as fever, severe illness, and the involvement of two or more organ systems, in combination with laboratory evidence of inflammation and laboratory or epidemiologic evidence of SARS-CoV-2 infection [2]. MIS-C typically manifests 3-4 weeks after SAR-COV2 infection, clinical features of which predominantly included shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers [3,4]. The abdominal pain in MIS-C can be so severe that patients could even be presumed to be having appendicitis. Children who develop MIS-C could be even asymptomatic for COVID19, having positive SAR-COV2 antibodies but negative RT-PCR at the time of evaluation [4].

MIS-A: A syndrome similar to MIS-C has also been found in adults above 21 years of age having extra-pulmonary dysfunction who may not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection in these patients. A study found that MIS-A patients had only minimal respiratory symptoms, hypoxemia, or radiographic abnormalities, thereby, distinguishing itself from severe COVID-19 patients [3].

MIS-C and MIS-A might represent post-infectious processes?

30% adults and 45% of the children reported to CDC through July 2020, had negative PCR and positive SARS-CoV-2 antibody test results indicating MIS to be a post-infectious process [3]. However, a study recently contemplated that MIS-C could be a persistent infection as there is an increase in the number of naive T-cells at different locations in the body which would eventually clear the infection in lungs but remain as a persistent infection at other sites [5]. A Lancet study also suggested that there is persistent activation of the innate immune inflammatory response to curb the ongoing infection probably occurring due to the ability of SARS-CoV-2 to block type 1 and type 3 interferon response signalling to the adaptive immune system without disruption of cytokine production [5].

 

GASTROINTESTINAL INVOLVEMENT IN COVID19:

Disturbance in the gut microbiome:

A recent study revealed for the first time that COVID19 patients expressed a disturbance in the gut microbiome. The study found an increase in the number of opportunistic pathogens in the gut of COVID19, one of which was A. viscosus, an opportunistic pathogen of the oral cavity and upper respiratory tract. This study suggested that COVID19 infection could be associated with long-term detrimental effects on the gut microbiome as there was a loss of salutary species in the gut of the patients despite clearance of the virus [6].

Gastrointestinal symptoms and COVID19 severity:

A study found that COVID19 patients persistently presented with gastrointestinal symptoms (GI) like diarrhoea, nausea and vomiting and 28% of these patients with GI symptoms did not have any respiratory symptoms [7]. This study also revealed that the severity of the disease was more in patients having GI symptoms than those without GI symptoms [7].

SARS-COV-2 virus at various locations in the GI tract:

A study performed endoscopy in six subjects revealed that SARS-COV2 virus was detected in three out of six subjects in biopsies taken during endoscopy at various GI locations. In two severely diseased patients, the virus could be detected in oesophagus, stomach, duodenum and rectum proving that this virus is present throughout the GI tract [8,9].

 

DELAYED VIRAL CLEARANCE IN COVID19 PATIENTS HAVING GI SYMPTOMS:

SARS-COV2 virus in stools of COVID19 patients:

Various studies have detected SARS-CoV-2 virus in anal swabs and stool samples in almost 50% of patients with COVID-19 and elevated levels of faecal calprotectin have been found in COVID19 patients with diarrhoea, indicating an inflammatory response in the gut [6].

Presence of the virus in faeces even after clearance from the respiratory system:

A study found that there were 53.4% patients that tested positive for the virus in the stool and more than 20% of infected patients had a positive virus in faeces even after clearance of virus from the respiratory tract [9]. Similarly, a study found that eight out of ten pediatric COVID19 patients persistently tested positive on rectal swabs even after nasopharyngeal tests became negative and SARS-CoV-2 RNA was detected in the stool of these children 20 days after negative conversion of viral RNA in respiratory specimens [10]. A Lancet study has even suggested the possibility of extended duration of viral shedding in faeces, for nearly 5 weeks after the patients’ respiratory samples tested negative for SARS-CoV-2 RNA [11]. Thus, it may be necessary to conduct stool tests before the patient is discharged or before the patient is declared as recovered.

Variation in the inflammatory response in patients with only digestive symptoms:

A study found that the levels of some inflammatory cytokines such as IL-2, IL-4, and IL-10 in patients with only digestive symptoms were slightly higher compared to those with respiratory symptoms and there was also a delay in achieving the peak values during the course of the disease [12]. This study demonstrated a significant correlation between IL-2 and TNF level in patients having only digestive symptoms compared with the patients having only respiratory symptoms and suggested that respiratory and digestive symptoms may correspond to two different T-cell differentiation patterns [12].

 

LIVER INVOLVEMENT IN COVID19:

Abnormal liver function and COVID19: Various studies have shown that SARS-CoV-2 infection can lead to liver injury [13]. Liver injury associated with COVID-19 infection has also been revealed through autopsy and biopsy. Severe COVID-19 patients have been found to have higher levels of aspartate aminotransferase, alanine aminotransferase, and total bilirubin (TBL) compared to others. Recently a study found that COVID19 infection can cause acute hepatitis and this severe liver damage could be expressed even before the typical symptoms of COVID-19 which could result in misdiagnosis in the early stages. A study also suggested that the hepatobiliary system was vulnerable to damage not only in severe COVID19 patients but even if the patients had relatively mild symptoms [13].

 

DERMATOLOGIC SYMPTOMS OF COVID19:

Lesions associated with asymptomatic or mild COVID19: Chilblain-like acral eruptions and purpuric and erythema multiforme-like lesions [14].

Lesions associated with a severe form of COVID19: Acro-ischemic lesion and maculopapular rash [14].

 

OPHTHALMOLOGIC SYMPTOMS OF COVID19:

SARS‐CoV‐2 has been found in tears and conjunctival secretions of COVID19 patients with conjunctivitis [15]. A study found that 31.6% of COVID19 patients had ocular manifestations like conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions [16].

 

ANOSMIA (LOSS OF SENSE OF SMELL) AND COVID19:

Recent evidence suggests that anosmia is experienced by most of the COVID19 patients and has also been found in many patients who are asymptomatic except for the loss of sense of smell [17].

 

CONCLUSION:

During the course of this pandemic, COVID19 has presented itself with numerous atypical symptoms involving multiple systems which could help in identifying the asymptomatic individuals. A careful observation of these symptoms and timely check can help curb further spread by the asymptomatic individuals as well as prevent severity by early diagnosis. Antibody tests and lab tests that would help in identifying SARS-COV2 virus and associated inflammatory states could be performed to curb MIS associated fatality and confirming stool test negativity for weeks after the nasopharyngeal swab tests have turned negative before declaring the patient as recovered could help in preventing further spread of the infection.

 

REFERENCES:

[1] Bixler D, Miller AD, Mattison CP, et al. SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(37):1324-1329. Published 2020 Sep 18. doi:10.15585/mmwr.mm6937e4.

[2] Ebina-Shibuya R, Namkoong H, Shibuya Y, Horita N. Multisystem Inflammatory Syndrome in Children (MIS-C) with COVID-19: Insights from simultaneous familial Kawasaki Disease cases. Int J Infect Dis. 2020;97:371-373. doi:10.1016/j.ijid.2020.06.014.

[3] Morris SB, Schwartz NG, Patel P, et al. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection - United Kingdom and United States, March-August 2020. MMWR Morb Mortal Wkly Rep. 2020;69(40):1450-1456. Published 2020 Oct 9. doi:10.15585/mmwr.mm6940e1.

[4] Ahmed, Mubbasheer & Advani, Shailesh & Moreira, Axel & Zoretic, Sarah & Martinez, John & Chorath, Kevin & Acosta, Sebastian & Naqvi, Rija & Burmeister-Morton, Finn & Burmeister, Fiona & Tarriela, Aina & Petershack, Matthew & Evans, Mary & Hoang, Ansel & Rajasekaran, Karthik & Ahuja, Sunil & Moreira, Alvaro. (2020). Multisystem inflammatory syndrome in children: A systematic review. E ClinicalMedicine. 26. 100527. 10.1016/j.eclinm.2020.100527.

[5] Schwartz M. MIS-C: post-infectious syndrome or persistent infection? [published online ahead of print, 2020 Oct 5]. Lancet Infect Dis. 2020;S1473-3099(20)30786-6. doi:10.1016/S1473-3099(20)30786-6.

[6] Zuo, Tao & Zhang, Fen & Lui, Grace & Yeoh, Yun Kit & Li, Amy & Zhan, Hui & Wan, Yating & Chung, Arthur & Cheung, Chun & Chen, Nan & Lai, Christopher & Chen, Zigui & Tso, Eugene & Fung, Kitty & Chan, Veronica & Ling, Lowell & Joynt, Gavin & Hui, David & Chan, Francis & Ng, Siew. (2020). Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology. 159. 10.1053/j.gastro.2020.05.048.

[7] Jin X, Lian J, Hu J, et al Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut 2020;69:1002-1009.

[8] Lin L, Jiang X, Zhang Z, et al Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infectionGut 2020;69:997-1001.

[9] Ng SC, Tilg HCOVID-19 and the gastrointestinal tract: more than meets the eyeGut 2020;69:973-974.
Yang L, Tu L. Implications of gastrointestinal manifestations of COVID-19. Lancet Gastroenterol Hepatol. 2020;5(7):629-630. doi:10.1016/S2468-1253(20)30132-1.

[10] Wu Y, Guo C, Tang L, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020;5(5):434-435. doi:10.1016/S2468-1253(20)30083-2.

[11]Duan, Caihan & Zhang, Shengyan & Wang, Jian & Qian, Wei & Han, Chaoqun & Hou, Xiaohua. (2020). Immuno-inflammatory Characters in Low Severity COVID-19 Patients with Digestive Symptoms. 10.21203/rs.3.rs-23267/v1.

[12] Wong SH, Lui RN, Sung JJ. Covid-19 and the digestive system. J Gastroenterol Hepatol. 2020 May;35(5):744-748. doi: 10.1111/jgh.15047. Epub 2020 Apr 19. PMID: 32215956.

[13] Wollina, U, Karadağ, AS, Rowland‐Payne, C, Chiriac, A, Lotti, T. Cutaneous signs in COVID‐19 patients: A review. Dermatologic Therapy. 2020; 33:e13549. https://doi.org/10.1111/dth.13549.

[14] Xia, J, Tong, J, Liu, M, Shen, Y, Guo, D. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS‐CoV‐2 infection. J Med Virol. 2020; 92: 589– 594. https://doi.org/10.1002/jmv.25725.

[15] Wu P, Duan F, Luo C, et al. Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol. 2020;138(5):575-578. doi:10.1001/jamaophthalmol.2020.1291.

[16] Joffily L, Ungierowicz A, David AG, et al. The close relationship between sudden loss of smell and COVID-19. Braz J Otorhinolaryngol. 2020;86(5):632-638. doi:10.1016/j.bjorl.2020.05.002.

 

AUTHOR:

Amisha Parekh is currently an intern in the YMT Dental College and Hospital under Maharashtra University of Health Sciences. Her interests include both clinical dentistry and research. Being an innovator, she has designed and received the copyright for "dental high-speed handpiece fitted with overhead high vacuum evacuator to control aerosol splatter" – copyrighted

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