Florida Study Uncovers Correlation Between Pediatric COVID-19 And Immunoglobulin A Vasculitis

Pediatric COVID-19: Researchers from Nicklaus Children’s Hospital-Florida, USA have uncovered a correlation between Immunoglobulin A (IgA) vasculitis and children with COVID-19.


 
Immunoglobulin A (IgA) vasculitis, formerly called Henoch-Schönlein purpura or HSP, is a disease that causes the antibody immunoglobulin A to collect in small blood vessels, which then become inflamed and leak blood. Nearly all individuals with IgA vasculitis develop a red or purple rash link.
 
IgA vasculitis is an autoimmune disorder. This is when the body's immune system attacks the body's own cells and organs. Typically, with IgA vasculitis, this immune response may be caused by an upper respiratory tract infection.
 
IgA vasculitis is the most common form of vasculitis in children. The diagnosis is made clinically and patients will present with a rash, together with gastrointestinal, musculoskeletal, and renal system involvement. Progress in the classification of the systemic vasculitides has facilitated better understanding of the pathogenesis underlying these inflammatory conditions.
 
It was reported that over the past year, several cases of IgA vasculitis have been reported in both children and adults in association with SARS-CoV2 infection, raising the question of whether there is any causal or even a synergistic association.
 
The study team conducted a systematic review following the guidelines of Meta-analysis of Observational Studies in Epidemiology. A literature search was conducted using MEDLINE, SciELO and Google Scholar using the search terms “COVID-19” or “SARS-CoV-2" in combination with “IgA vasculitis”, or “Henoch-Schonlein Purpura”.
 
The study team considered articles to be eligible for inclusion if they reported a case report or series of cases of IgA vasculitis associated with proven COVID-19 infection. The team excluded cases from further review if the case reported was a patient older than 18 years. WHO causality assessment categories were used to standardize case causality.
 
Upon reviewing the complete article and applying an exclusion criteria, 12 articles describing 12 cases of COVID-19 associated IgA vasculitis in children were included.
 
The study findings showed that in 83% of the cases the diagnosis of COVID-19 was made on presentation of IgA vasculitis symptoms or on presentation to seek medical care. In 17% of cases the SARS Cov-2 test was positive before IgA vasculitis symptoms presentation. The mean age of the patients was 7.3 years of age (SD ±4.8). Male to female ratio was 3:1. Out of the 12 patients, 6 presented 2/4 criteria for IgA vasculitis and 6 presented 3/4 criteria. None presented 4/4 criteria.
 
During the pandemic, several autoimmune phenomena have been described to co-occur with or following COVID-19. The exact role of COVID-19 in the development of these IgA-related diseases is still being explored.
 
The study findings of the review of case series and case reports with standardized causality assessment identified 12 cases of IgA vasculitis associated with and/or in the context of COVID-19 infection in children.
 
The study findings were published on a preprint server and are currently being peer reviewed. //www.researchsquare.com/article/rs-1043944/v2">https://www.researchsquare.com/article/rs-1043944/v2
 
The SARS-CoV-2 variants of concern (VOC) have impacted children and younger adults more adversely due to the different virulence of the VOCs. COVID-19-related cutaneous complications like urticaria, erythema multiforme, chilblain-like lesions in children, and acute hemorrhagic edema in infants of ages between four and five months have been reported.
 
In addition, numerous COVID-19-related symptoms of IgA vasculitis have also been observed especially in children.
 
The Pediatric COVID-19 study reviewed research articles to assess a possible association between COVID-19 infection and IgA vasculitis manifestation in children.
 
The study only included articles published between 1 January 2020 and 30 August 2021 that reported a case of IgA vasculitis associated with COVID-19 or a series of cases with the association. IgA vasculitis cases were selected based on mandatory criteria including palpable purpura without the presence of thrombocytopenia and supportive criteria inclusive of at least one or more manifestations out of acute-onset diffuse abdominal pain, proteinuria, haematuria, or acute-onset arthralgia, arthritis, presence of predominant IgA deposits in proliferative glomerulonephritis, or leukocytoclastic vasculitis.
 
All cases of COVID-19 infection were identified based on SARS-CoV-2 ribonucleic acid (RNA) detection in a sample using a SARS-CoV-2 specific antigen test or a diagnostic molecular amplification test.
 
The study team collected data from each article eligible for the study, including age, gender, comorbidities, symptoms, and the sequential correlation of SARS-CoV-2 detection and IgA vasculitis manifestations.
 
The causality criteria recommended by the causality assessment system of the World Health Organization-Uppsala Monitoring Center (WHO-UMC) was applied to the selected reports to assess the possible causal association of COVID-19 and IgA vasculitis.
 
In the study, the causality assessment system was used to assess any causal link between the two diseases into one to six different levels of certainty, ranging from certain, probable/likely, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable.
 
The study findings indicated that in the 12 eligible reports selected, patients had a mean age of 7.3 years.
 
The 12 pediatric patients in each report consisted of three females and nine males. Three had a Mediterranean origin, two were Caucasian, one was Asian, three were Hispanic, one was Black, and two had an unspecified origin. Eight of the 12 patients were reported as healthy, one had unspecified health status, and three had a positive medical history of Hirschsprung disease, atopic dermatitis, and suprasellar germinoma characterized by secondary panhypopituitarism.
 
As per the inclusion criteria, all 12 patients had symptoms of palpable purpura.
 
Interestingly, seven patients had gastrointestinal (GI) symptoms, including two patients who presented hematochezia while abdominal pain was the most common GI manifestation. Oligoarthritis was observed in seven patients, of which five cases presented with ankle pain involvement and one case with one knee involved. Also, three patients had hematuria, while hypertension was not present in any patients. A total of six out of the 12 patients met two of the indicators of IgA vasculitis, six patients met three criteria, and none of the patients met all of the four criteria.   
  
Importantly, an elevated level of c-reactive protein (CRP) was observed in six patients, while an insignificant number of patients had inflammatory markers like ferritin and D-dimer.
 
Also, it was found that out of the 12 patients, four presented elevated IgA levels. One had normal IgA levels, while the IgA levels of seven patients were not measured.
 
It should be noted that in 83% of the cases, SARS-CoV-2 was detected after the presentation of IgA vasculitis symptoms or after the patient sought medical attention.
 
Only in two or 17% of the total patients, a COVID-19-positive diagnosis was observed before the presentation of IgA vasculitis.
 
It was found that one of these patients was tested COVID-19-positive two days before the appearance of IgA vasculitis symptoms, while the other patient was detected COVID-19-positive 37 days prior to symptom onset.
 
The research findings showed that the 12 identified cases provided sufficient evidence of association of IgA vasculitis with the presence of SARS-CoV-2 infection in children. A prevalence of COVID-19-related IgA vasculitis was noted, particularly in early childhood.
 
Also, it was noted that the increase in association of COVID-19 and IgA vasculitis was observed thrice as many times in males than in females, while non-COVID-19-associated IgA vasculitis was detected five times more in males than females.
 
The study team said that the inflammatory responses of COVID-19 are very similar to the manifestations of autoimmunity. Although the exact role of SARS-CoV-2 in the manifestation of IgA vasculitis is still unknown, further research to investigate the specific association can help manage the two conditions more efficiently.
 
The study team added, “In spite of criteria being met for IgA vasculitis in the context of COVID-19 in these cases, we need to be aware that these findings, including such GI symptoms, hematuria, proteinuria and even arthritis can be present during a viral illness regardless of IgA vasculitis. Moreover, there is evidence that since COVID-19 causes direct damage to capillaries, it can manifest with leucocytoclastic vasculitis.
 
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