Infection of SARS-COV2 as a trigger for IgA-associated vasculitis.

doi:10.21203/rs.3.rs-1983848/v1

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Case Report

Infection of SARS-COV2 as a trigger for IgA-associated vasculitis.

https://doi.org/10.21203/rs.3.rs-1983848/v1

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Background: IgA-associated vasculitis (IgAV), formerly known as Henoch-Schönlein Purpura-(HSP) disease, is the most common systemic vasculitis of developmental age. Approximately in 50% of the patients with HSP the outbreak of the disease, has been reported to be associated with streptococci, adenowirus, parvovirus, mycoplasma, respiratory syncytial virus (RSV), and influenza infection. Emerging reports in both adults and children has described few cases COVID-19 infection associated with HSP.

Case presentation: We present the case of 7-year-old girl, was diagnosed with HSP, fulfilling 3 clinical criteria (palpable purpura and abdominal pain, arthralgia and edema), without renal involvement at which the infection with SARS-COV2 was confirmed by the presence of IgM and IgG antibodies. In the girl, disclosure of the HSP was preceded by a mild infection of the upper respiratory tract, treated symptomatically. During hospitalization we observed high values of inflammation markers, such as leukocytosis, increased neutrophil count and high NLR which are markers associated with IgAV gastrointestinal bleeding, which was also observed in the girl associated with rotavirus diarrhea

Conclusions: The case presented by us and by other authors indicate a possible role of SARS-CoV-2 in the development of HSP, but this requires further research.

Henoch-Schönlein Purpura

IgAV

SARS-CoV-2

children

IgA-associated vasculitis (IgAV), formerly known as Henoch-Schönlein Purpura (HSP)- disease, is the most common systemic vasculitis of developmental age. According to the new nomenclature established during the International Chapel Hill Consensus Conference 2012 (CHCC 2012), it is included in the group of inflammatory diseases of small vessels associated with immune complexes deposits [1]. The prevalence of morbidity in the autumn and winter period suggests a relationship with infectious factors, especially with a history of upper respiratory tract infections [2]. So far, no single trigger has been identified. Cross-response to bacterial and viral antigens is likely to cause the disease. Other possible triggers are drugs (ACEI, antibiotics, NSAIDs), vaccinations (against influenza, hepatitis A and B), toxins (e.g. after insect bites), food allergens and cancer antigens (lung, breast, prostate, esophagus, colon cancer, lymphomas) [2,3,4,4a]. In IgAV, deposits of immune complexes, which consist mainly of immunoglobulin A1 (IgA1) and the complement component C3, and neutrophil infiltrates are found inside the wall of small vessels (mainly capillaries, venules and arterioles). Typically immune complexes affect the skin, gastrointestinal tract and musculoskeletal system. Red blood cells leaking into the skin lead to typical cutaneous hemorrhages, which is a hallmark of IgAV. Clinical manifestations of IgAV may vary in their severity and order of presentation, which can result in delayed or misdiagnosis. Recent consensus criteria for the diagnosis of HSP in childhood require the presence of palpable purpura, with at least one of listed symptoms: abdominal pain, histopathology showing Immunoglobulin A (IgA) deposition, arthritis/arthralgia or renal involvement [1]. Approximately in 50% of the patients with HSP the outbreak of the disease, has been reported to be associated with streptococci, adenowirus, parvovirus, mycoplasma, RSV, and influenza infection [3, 4].

Severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) was first identified in Wuhan, China, in December 2019 and has quickly spread across the globe. [5 ]. In contrast to adults, younger children have a milder clinical course, less time to resolution of symptoms and lower infectivity [6]. However this virus could induce serious complications in conjunction with both acute infection and associated phenomena such as the multisystem inflammatory syndrome in children (MIS-C) have been reported quite rarely [5] Emerging reports in both adults and children has described few cases COVID-19 infection associated with HSP [7, 8, 9]. Gastrointestinal symptoms, abdominal pain and skin symptoms, have been reported as a frequently occurring in COVID-19. Moreover, possible association of IgA vasculitis like effect together with SARS-CoV2 infection has been suggested. Anti-SARS-Cov2 IgA is the first immunoglobulin to be detectable after COVID-19 infection [10.] Moreover an exacerbated IgA- mediated humoral response in COVID-19 patients may predispose to the formation of IgA complexes deposits of in the vascular endothelium and development of IgA vasculitis [7].

We present the case of 7-year-old girl with immunoglobulin A vascullitis and COVID-19. She was diagnosed with HSP, fulfilling 3 clinical criteria (palpable purpura and abdominal pain, arthralgia and joint’s edema), without renal involvement and was admitted to the general pediatric department for further medical evaluation.

A 7-year-old girl, previously healthy, was admitted to the General Pediatric Ward due to the appearance of petechial skin lesions located mainly in the lower limbs, as well as pain and swelling of many joints (Fig. 1A-C). Two weeks before hospitalization, the girl had a mild, fever-free upper respiratory tract infection, treated symptomatically, and the remaining household members were healthy at that time.

On admission, the girl was in good general condition, did not have a fever, physical examination revealed a petechial rash typical of Henoch's Schönlein purpura in the area of the ankles, feet and shins, swelling accompanied by heat and limited mobility in the ankle joints, left knee joint and wrists and fingers, limited mobility in the right knee and right elbow joints, drying of the oral mucosa, palpation tenderness of the abdominal wall around the navel. Laboratory tests ( Table 1) showed increased inflammatory parameters ( CRP, WBC with lymphocytic smear), elevated D-dimers, acetonuria, single episode of proteinuria. Antigen test on admission for SARS-CoV-2 was negative. A chest X-ray and an ultrasound of the abdominal cavity were also performed, in which no significant abnormalities were found. According to the modified by Fessatou S et al. clinical score of IgAV on admission the girl have gain 3 points. This clinical scoring is the sum of points depending on the severity of joint, renal and gastrointestinal symptoms (mild course ≤ 4 points, severe > 4 points) [11].

Table 1

Laboratory parameters values of the index patient during hospitalization
Parameter	Result
Parameter	At the beginning of hospitalization	During the deterioration	At the end of hospitalization
Hemoglobin (g/dl)	14.4	9,2	12.8
Total leukocyte count (cells/µl)	15.63	38	24.84
Differential count (%)/(cells/µl)
Neutrophils	73.6/11,52	82.2/31,26	66.3/16,5
Lymphocytes	16.5/2,58	14.1/5,32	21.3/5,28
Platelets ( cells/µl)	418	477	571
NLR (neutrophils count to lymphocytes count ratio) (1-1,91) [18]	4.46	5.86	3.12
PLR (platelets count to lymphocytes count ratio) ( 95,47-152,32) [18]	162,01	433,66	108.14
MPR (mean platelet volume divided by platelet count ) (0,029-0,037) [18]	0.022	0.018	0.016
IgA (g/l) (0.33-2.35)	2.9
IgM (g/l) (0.36-1.98)	1.89
IgG (g/l) (8.53-14.4)	11.45
C3 (g/l) (0.9-1.8)	1.21
C4 (g/l) (0.1-0.4)	0.23
24 h urinary protein (mg)	1800
Serum Creatinine (mg/dL)	0.45	0.38	0.34
Sodium (mEq/L)	138	133	141
Potassium (mEq/L)	4.42	4.86	4.73
Aspartate aminotransferase (IU/L) (0-40)	27.1	22.2	16.1
Alanine aminotransferase (IU/L) (0-41)	8.6	10.8	21.6
Protein (g/dL) (5.7-8.2)		5.7	7.3
Albumin ( g/dL) (3.8-5.4)		3.49	4.4
Prothrombin time (11-16)	15.4	12.5	15.5
Kaolin-kephalin time (28-40)	31.8	22.7	28.8
Fibrynogen mg/dl (200-400)	449	208	309
INR (0.8-1.2)	1.16	1.7	0.95
C-reactive protein ( mg/L) (0-5)	21.93	55.5	0.99
d-Dimer ug/ml (0-0.5)	9.12	3.92	0.73
Procalcitonin ( ng/mL) (0-0.5 )		2.38	0.08
Rapid SARS-CoV-2 antigen test	Negative
Sars-CoV-2 IgM positive >1.00 index		3.2
Sars-CoV-2 IgG positive >7.1 BAU/ml		132.67

The treatment included prophylactic antibiotic therapy ( cefuroxime intravenously), parenteral hydration, and vascular sealing medication (cyclonamine, rutoside). Due to the intensification of abdominal pain in the following days after admission and the presence of occult blood in the stool test, the treatment with prednisone at a dose of 1 mg/kg/day was added to the treatment with good results, following the abdominal pain relief. On the 10th day of hospitalization in the evening and night hours, a sudden deterioration of the general condition was observed, with violent vomiting and massive bleeding from the lower gastrointestinal tract (numerous abundant diarrheal stools mixed with fresh blood). The ultrasound examination of the abdominal cavity revealed incidents of intussusception within the small intestine (in the description of the ultrasound of the abdominal cavity: fragmentary visualization of intestinal loops, segmentally swollen up to 7–9 mm in the area of the small intestine, containing significant amounts of loose food contents with accompanying oscillating movement). Descending colon, sigmoid colon and rectum were filled with loose contents - fresh blood and signs of gastrointestinal obstruction in the abdominal examination (in the left abdomen and middle abdomen, several short levels of fluid were visible, however free gas under the diaphragm domes was not visualized). Laboratory tests ( Table 1) revealed an increase in inflammatory parameters (CRP − 55.5 mg/l, procalcitonin − 2.38 ng/ml, WBC-38 000/ul, with a granulocytic smear), a decrease in red cell parameters (HGB 9.2 g/dl, Ht- 26%),, consumption of coagulation parameters (fibrinogen − 208 mg/dl, kaolin-kephalin time-22.7 sec, prothrombin time 12.7 sec). The presence of rotavirus infection was also confirmed by a rapid, immunochromatographic test for the qualitative detection of antigens. The girl presented fever up to 38.5C degrees, vital signs revealed: HR-180 beats/min, O₂ Sat 98%, BP − 90/65 mmHg. The patient was consulted by a surgeon and no indications for rapid surgical intervention were found. Conservative treatment was implemented: intensive parenteral hydration, anti-emetic drugs, cytoprotective drugs. Methylprednisolone pulses of 30 mg/kg for three consecutive days together with, a broad-spectral antibiotic (carbapenem) and an single infusion of fresh-frozen plasma were added for the treatment. In the next several hours, the patient's hemodynamic stabilization was achieved (HR-100-110 beats/min, BP − 100/60 mmHg, O₂ sat 98%) with the improvement of the general condition. Blood morphotic parameters were further monitored, and were stable, the girl passed a few more loose stools with some amount of fresh blood.

Due to the current epidemiological situation in our country and the possible occurrence of a multi-system inflammatory syndrome associated with COVID-19 infection, laboratory diagnostics was extended to test antibodies for the SARS-Cov-2, obtaining a reactive result in both classes of antibodies. Laboratory parameters during hospitalization were shown in Table 1. In the following days of the stay, systemic steroid therapy was continued, no disturbing symptoms were observed. After 17 days of stay, the child was discharged home in good general condition, with normal blood counts, negative inflammatory markers, absent proteinuria, with normal BP parameters, with the recommendation to gradually reduce the doses of systemic steroids. She was advice to stay under the care of gastroenterological and nephrological control in an outpatient setting. After three weeks cardiovascular evaluation was performed with echocardiography to exclude post-COVID-19 complications. Laboratory tests after that time were normal and IgA concentration lowered to 1,9g/l reaching the normal value.

In the present case, we consider the likely importance of SARS-COV2 as a trigger for HSP. IgA vasculitis associated with COVID − 19 infection was documented only in few children before [9, 12–15]. Four human coronaviruses (hCoVs) -229E,HKU1, NL63 and OC43 circulate globally and typically cause mild upper respiratory infection and might be a possible triggers of HSP in children [3]. Moreover in the previous reports hCoV NL63 was implicated as the likely triggering pathogen of acute hemorrhagic edema of infancy (AHEI), a benign type of small-vessel leukocytoclastic vasculitis with perivascular IgA deposition that is seen in one -third of AHEI cases [16]. Moreover a link between COVID-19 and, Kawasaki disease, another chidchood vasculitis was reported [17] In the girl, skin changes were preceded by a mild infection of the upper respiratory tract, treated symptomatically. Negative bacteriological test results and low ASO titer excluded with high probability the infection of Streptococcus pyogenes, which, apart from viruses, is considered one of the main triggers of HSP. On admission, high values of inflammation markers, such as leukocytosis, increased neutrophil count and high NLR were present, which we have previously shown, like other authors, are a significant predictor of systemic involvement in HSP [18]. It has also been suggested that higher NLR and PLR are markers associated with IgAV gastrointestinal bleeding, which was also observed in the girl. Despite the treatment, on the 10th day of hospitalization, there was a sudden deterioration of the child's condition and massive gastrointestinal bleeding associated with anemia and increased inflammatory parameters, associated with rotavirus diarrhea (nosocomial infection). Rotaviruses can be the cause of HSP [ 3 ], but due to the short 1–3 days of incubation period, this may not be the case here.

Initially prednisone at a dose of 1 mg, was used due to moderate abdominal pain and occult blood in the stool, then was replaced with intravenous methylprednisolone, which have been applied in accordance with the guidelines [19]. In 2 cases of pediatric IgAV after COVID-19 infection, similarly to ours, massive bleeding from the gastrointestinal tract occurred.

HSP is most often characterized by a mild, self-limiting course and good prognosis, but in some cases, serious complications may develop. Symptoms from the gastrointestinal tract (GT) concern 50–70% of patients; most often there are abdominal pain, nausea, vomiting, latent bleeding. Hematemesis, gastrointestinal bleeding, intussusception, bowel ischemia with secondary necrosis, bowel perforation are less frequent [2, 18] Infection with SARS-COV2 was confirmed in the girl by the presence of IgM and IgG antibodies. It was not possible to determine anti-SARS-COV2 antibodies in the IgA class in the girl. It can be added that the serum IgA concentration (2.99 mg/l) was initially increased and decreased after 3 weeks of treatment. It has been reported that IgA is present in serum of COVID-19 patients, The levels of Ag- specific IgA were markedly increased∼2 weeks after symptom onset and remained continuously elevated for the following 2 weeks. Moreover the relative levels of IgA were markedly higher in severe patients as compared non -severe patients,

IgA is traditionally recognized to play an anti-inflammatory role and prevent tissue damage at mucosal sites [10 ]. However, recent reports also demonstrated that serum IgA is involved in the formation of immune complexes to amplify inflammatory responses by inducing proinflammatory cytokine and chemokine production by various cells including macrophages, dendritic cells, monocytes and Kupfer cells [20]. It is believed, that severe COVID-19 might be at last in part an IgA mediated disease (related to IgA deposition and vasculitis), which helps to explain common organ injuries in COVID-19 (kidney injury, acute pulmonary embolism) [10].

The case presented by us and by other authors [9, 12–15] indicate a possible role of SARS-CoV-2 in the development of HSP, but this requires further research.

IgAV :IgA-associated vasculitis, HSP: Henoch-Schönlein Purpura, RSV: respiratory syncytial virus, COVID-19 : Coronavirus disease 2019, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2 , IgG: immunoglobulin G; IgA : immunoglobulin A; IgM : immunoglobulin M, CHCC 2012: International Chapel Hill Consensus Conference 2012, ACEI : angiotensin- converting enzyme inhibitors, NSAIDs : non –steroidal anti-inflammatory drugs, MIS-C: multisystem inflammatory syndrome in children, HR: heart rate, BP: blood pressure, O₂ sat: oxygen saturation, hCoVs: human coronaviruses, AHEI : acute hemorrhagic edema of infancy, ASO: antystreptolysin, CRP: C-reactive proteins; NLR: neutrophils count to lymphocytes count ratio; PLR: platelets count to lymphocytes count ratio;

Ethics approval and consent to participate

Written informed consent was obtained from the patient's mother described in the case report. The need for local ethics committee approval was waived.

Consent for publication

Written informed consent was obtained from the patient's mother for publication of this Case report. A copy of the written consent is available for review by the Editor of this journal.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed.

Competing interests

All authors declare that they have no competing interests.

Funding

None.

Contributions

All authors contributed to the conception of the work and writing and preparing figures and table. All authors participated in revision and have approved the submitted version.

Acknowledgements

We would like to thank the patient's mother for agreeing to describe her daughter’s case.

B. Consent for publication

Written informed consent was obtained from the patient's mother for publication of this Case report. A copy of the written consent is available for review by the Editor of this journal.

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Infection of SARS-COV2 as a trigger for IgA-associated vasculitis.

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