Our planet is suffering from SARS CoV-2 since the first couple of days in 2020. World Health Organization (WHO) declared this novel coronavirus outbreak as pandemic on 11st of March 2020, and the first confirmed case in Turkey was reported on the same day. We have encountered this little-known foe relatively later compared to many other countries. Until that time, many treatment and prevention strategies have been already developed by the health care providers of other countries. Therefore, we were able to make stringent isolation decisions like lockdown promptly and able to establish our national treatment guidelines which contains hydroxychloroquine and other current available options. Hence, even it is early to mention it, numbers of confirmed cases and deaths seem to be moderately low in our country.
However, we have a large number of registered pediatric patients with AIDs, and due to their chronic health conditions and/or immunosuppressive treatment of some of them, parents had concerns for their children regarding the current outbreak. As we got hundreds of phone calls. it was necessity for us to perform this study. Since 11st of March 2020, a total of 7 pediatric patients with AIDs were diagnosed as COVID-19 among the patients we follow-up in regular. None of them were receiving biologic treatment, 6 were on colchicine treatment, 5 were symptomatic; 4 were prescribed and followed-up via outpatient clinic and/or phone, 1 was hospitalized for 5 days, 2 were asymptomatic and were not prescribed, and all of 7 recovered completely. To our best knowledge, this is the first report describing frequency, demographic and clinical findings and outcomes of COVID-19 in pediatric patients with AIDs.
Since stringent isolation measures are widely approved and children be infected mostly via exposure to a known adult case, intrafamilial transmissions merit a special approach [11]. In our study, in 6 of 7 patients with positive PCR, source of infection was a family member. Although, COVID-19 may lead to serious conditions such as multiorgan dysfunction and even death, it seems that children are tend to have a milder disease course [6]. In the study of Dong et al [12] which consist the largest number of pediatric patients up to now, 94% of the patients were asymptomatic, mild or moderate. In another report from Wuhan, there were 1391 children who were tested due to contact with confirmed cases, only 12.3% were positive, and only 1, which one had intussusception, died [13]. Similarly, in our study group, none of the patients required intensive care and/or ventilation support, even the hospitalized one, and all of them recovered completely. Some hypothetical ideas were emerged regarding non-severity of the disease in childhood such as; lower exposure to viruses and air pollution due to being isolated at home mostly thanks to shutting down of the schools, lower smoking rates, higher viral co-infections which may lead to limit replication of SARS CoV-2, and possibly different distribution of ACE2 which acts as a receptor for virus entry into human cells [14].
Although, chronic health conditions such as hypertension and diabetes mellitus were found to be risk factors for worse disease course in COVID-19, immunocompromised situations such as rheumatic diseases requiring immunosuppressive treatment were not [15]. In a report of Monti et al [9], 4 of 320 patients with rheumatoid arthritis confirmed with COVID-19 and none of them developed serious pulmonary complications. Although, there is a limited data, there are some suggestions that patients with AIDs may be vulnerable to infections [16,17]. Regarding COVID-19, based on molecular studies, it has been suggested that enhanced innate immune activation may promote a worse disease outcome [5]. However, most of our patients with AIDs are on colchicine treatment, and colchicine is one of the off-label medications used in the treatment of COVID-19, currently [18]. Gandolfini et al [19] have noted clinical improvement in their COVID-19 patient by using colchicine. In our study, among 376 patients on colchicine treatment, only 6 were confirmed COVID-19, and all of them recovered completely. To our knowledge, until today, there is no data available describing COVID-19 among pediatric and/or adult patients with AIDs.
Among our patients who had a contact history with confirmed COVID-19 cases, one with DADA2, was receiving etanercept for 2 months and 3 of her family members were confirmed cases (father, brother and grandmother); other one with CAPS, was receiving canakinumab for 2.5 years and 2 of her family members were confirmed cases (mother and father). Compared to other coronaviruses (SARS-CoV and MERS-CoV) which caused outbreaks in the past 2 decades, SARS CoV-2 has a higher capability to infect individuals [20]. Given the immunosuppressive effects of biologic treatment and highly contagious nature of SARS CoV-2, it was striking that these two patients who were receiving biologic treatment and had close contact histories were completely asymptomatic and PCR tests were negative in both. Consistent with our study, none of the patients who received immunosuppressive treatment developed lung disease, even some were confirmed COVID-19 cases, as reported from a liver transplantation unit in Italy [21]. Similarly, Conticini et al [22] reported that there were 2 patients with confirmed COVID-19 in their rheumatology department, 1 was a 50-year-old woman affected by rheumatoid arthritis, receiving rituximab, and 1 was an 87-year-old woman affected by giant cell arteritis, receiving tocilizumab; both of them discharged and then remained asymptomatic.
Although serious concerns for patients on immunosuppressive treatment seems reasonable at first, there is no insufficient data in the literature for supporting this. Besides, since it is known that main mechanism of lung injury occurs due to a hyperinflammatory situation resembling cytokine storm syndrome, studies investigating the therapeutic effects of biologic agents on COVID-19 were launched [23]. In hospitalized patients with COVID-19, serum IL-6 levels were found to be elevated, and tocilizumab; an anti-IL-6 agent was found to be effective on the treatment of COVID-19 patients with cytokine storm syndrome [24]. Anakinra, an anti-IL-1 agent has a favorable effect on patients with hyperinflammation, as well [25]. It was shown in a report from France that, anakinra had provided clinical improvement in 8 of 9 patients with COVID-19 [26]. Moreover, as it is known that SARS CoV-2 might induce TNF – alpha converting enzyme for penetration into human cells, a trial evaluating the effects of anti-TNF agents on COVID-19 has been registered in China, currently [27]. Therefore, this relative favorable position of children receiving biologic treatment, may be attributed to that they are unlikely to develop hyperinflammatory conditions resembling cytokine storm syndrome, due to their insufficient immune system.
Since a little percentage of cases may be misdiagnosed by PCR test, many centers in our country launched performing chest CT routinely, particularly in symptomatic ones. In our study, chest CT was performed in 6 of 7 patients with confirmed COVID-19. There were 2 patients with CT findings compatible with COVID-19. One of these two had ground-glass opacities, the most common CT finding in COVID-19 patients [3,4]. The other one had consolidation surrounded by the ground-glass opacities (Halo sign). Although, Halo sign is a rare CT sign in adults, Xia et al [8] suggest that it is a typical sign in pediatric patients.
The main limitations of our study were that there were no included otherwise healthy patients who admitted to hospital due to suspicion of COVID-19 as a control group, and we had a short observation period due to that we have encountered the outbreak relatively later compared to many other countries.
In conclusion, further studies including field screenings are required and our finding are insufficient to allow any conclusions. However, our preliminary experience shows that pediatric patients with AIDs, even if they receive biologic treatment may not be at increased risk for either being infected with SARS CoV-2 or having worse disease course. Given that there is no evidence whether colchicine or biologic treatment provides an additional risk for COVID-19, and the disease flares are a great risk for vulnerability to any kind of infections; we rheumatologist, should warn our patients for not withdrawing of their medication unless we advise.