In our cohort, consisting of patients who received nbDMARDs and bDMARDs for various rheumatic diseases, one patient who had a history of household exposure had been diagnosed with COVID-19. In the pandemic period, none of the patients in our cohort have experienced a severe health condition, including the one diagnosed with COVID-19 who recovered with an uncomplicated course.
Similar to the previous coronavirus outbreaks, SARS-CoV-2 infection seems to influence children less prevalently, and the course of the disease appears to be milder as compared with adults [11-14]. Although there is no clear-cut explanation, some relevant speculations have been asserted. Since children are different from adults in several aspects, such as immune defense functions against viruses, they have a distinctive feature of eliminating the viral disease [12]. Differences in expression and function of ACE-2 receptor, playing a crucial role in the invasion capacity of COVID-19, sets precedent relevancy to the issue [12, 14-16].
Another point is that children do not seek medical attention as they overcome the disease, usually without demonstrating any sign or symptom [13, 17]. Correspondingly, more than half of our patients with household contacts were not brought to a hospital as they were asymptomatic. Unfortunately, given its spreading potential, this may hinder the detection and management of the disease and thereby promote the spread of the infection. During the interview, when this point was mentioned, parents stated that they strictly adhered to home-based quarantine rules and social distancing policy. Psychosocial distress, the fear of social stigma, or lack of awareness of the possible consequences of the pandemic may be the other likely reasons keeping them from seeking medical help.
In epidemiological studies, sample size is small due to the rarity of the infection in children, but the data presented is mainly parallel. The most common symptoms are fever and dry cough, as in adults [11, 13, 18, 19]. Gastrointestinal symptoms may also accompany mostly in children [7, 20]. When our patients were asked about the complaints, it was noticed that the musculoskeletal system symptoms were in the foreground. Since similar complaints are met in the course of rheumatic diseases, the hospital attendance rate was low among patients who had complaints such as arthralgia, myalgia, and fever during the pandemic process and without history of contact.
The current epidemiological studies show that children primarily contract the disease through household exposure, but rarely vice versa [19-21]. The incubation period may differ in adults and children, making it challenging to identify the primary source [22]. In our case, the virus was transmitted from father or uncle. The prevalence of the disease in adults seems to be a significant reason for the parents being the index case of the infection in the family. On the other hand, children’s social ecologies and the probability of contact with contamination sources can concretize the difference. They generally grow and develop within a familiar circle nested by their family and relatives. In our cohort, the disease was not detected in other households contacted patients supporting the claim that children are less likely to become infected. On the contrary, several sources suggest children are just as likely as adults to become infected but are less likely to be symptomatic or develop severe symptoms [12, 17, 19]. Further research is required to better understand notable differences observed by age.
In general, as still developing organisms, children may be more susceptible to some infections. Especially those with immunocompromised states are vulnerable to various viral or bacterial agents (such as tuberculosis) and may encounter a more severe disease course [23, 24]. Hence, the screening of the patients, particularly those receiving nbDMARDs and bDMARDs, for such common infections is a part of a routine in pediatric rheumatology practice. Novel coronavirus demonstrating high morbidity and mortality worldwide has raised substantial concern for the patients with immune-related conditions and subspecialties as rheumatology dealing with their management [24, 25]. In our cohort, 14.3% of the patients interrupted their medications during the pandemic period. The conspicuous reason was that patients treated with infusion therapy or who used drugs in subcutaneous form could not provide access to health institutions. Noteworthy was the concern that treatment would increase the risk, as expected. These results underline the importance of patient-doctor communication throughout the patient's entire treatment process. Current evidence suggests not withdrawing the immunosuppressive treatment and no need for additional dose adjustment during the pandemic process unless physician indication or presence of specific symptoms [7, 8, 15, 24-26]. Although current guidelines, yet available online, relevant to the topic are mostly based on adult series, they served as an essential guide to elucidate multiple issues yet not resolved in this field [9, 27, 28]. However, considering the mentioned differences between children and adults, there is a need for evidence focusing primarily on pediatric rheumatology patients and identifying high-risk individuals.
Some preliminary work was carried out in the early period of the pandemic from jeopardous regions to investigate the association between SARS-CoV-2 and immunosuppressive drugs. In a report from Italy on adult patients with chronic arthritis treated with DMARDs, there was no increased risk of respiratory or life-threatening complications among the confirmed and suspected cases [29]. Another report presented from one of the most affected regions in Italy reported that there were no confirmed or suspected cases of COVID-19 in 123 children with rheumatic diseases (the majority of JIA) on bDMARDs treatment [30]. In another report from the same region of Italy, among 530 patients, 54 of whom were children, three confirmed cases with mild symptoms were notified, and it was underlined that the compliance of the social distancing might be reflected in the results [31]. Among the patients in our cohort, 18 were close contacts who have been socially interacted with the confirmed cases of whom 17 were with household members. Of the patients with a history of contact, three developed symptoms, and only one was diagnosed with COVID-19. Because all of the contact patients had not been tested, a definite ratio of the diagnosis was hard to be given, still it was obvious that the infection has not caused any severe symptoms or complications in any patient. The limited resources available indicate that rheumatic diseases, generally heterogeneous and associated with immune dysregulation, and various immunosuppressive drugs used in the treatment do not pose a risk for COVID-19. Our study supported this issue.
Another link between the field of rheumatology and the current pandemic is the shared drugs commonly used in rheumatology and recently included in the management of COVID-19 [25, 32]. Novel researches, presenting a better understanding of the immune mechanisms with cytokine networks in the process of SARS-CoV-2, started to illuminate the etiopathogenetic patterns as well as the treatment [4, 16, 33]. In the light of in vivo and in vitro studies, antiviral effects of some antirheumatic drugs came to the fore in the process [33-36]. In our patients receiving hydroxychloroquine therapy, we neither encountered an exacerbation associated with current autoimmune diseases nor a severe impact of the pandemic. However, in other respects, the alliance caused a shortage of drug supply for rheumatology patients within the early period of the pandemic [37, 38] also for 14 patients of our cohort. Comparative studies with large populations are needed to mention its potency and protective role in the pandemic.
The only case diagnosed with COVID-19 in our cohort has been using leflunomide, which is another nbDMARDs that have been demonstrated to have antiviral capacity, particularly against cytomegalovirus and herpes simplex-1[36, 39]. Nevertheless, leflunomide is not one of the drugs shining in the strategy against COVID-19 [36].
Glucocorticoids and IVIG, which are used in many fields of medicine and are frequently used in rheumatology, are the first remedies for COVID-19, but have failed to take part in routine use [6, 25]. The fact that glucocorticoids may increase virus replication on one hand, and have potent anti-inflammatory effects, on the other hand, led to a contradiction in pandemic and this controversy extends to the management of chronic patients already under glucocorticoid therapy [25, 36]. When we go back over our data, there were no active usages of steroid or IVIG among the contacted patients. More studies related to the follow-up and management of these patients are required.
Biologic DMARDs selectively blocking inflammatory cytokines, such as TNF-α inhibitors, anti-IL6, anti-IL1, and JAK inhibitors, represents a milestone in the treatment of inflammatory rheumatic disorders. Given the similarities of the cytokine storm syndromes, these drugs gained prominence in the era of SARS-CoV-2 [24, 36, 40, 41]. Particularly tocilizumab is a candidate to be indispensable treatment approach in the management of severe disease [25, 42]. In our cohort, an 11-year-old male patient with sJIA under tocilizumab treatment who had a history of contact with a confirmed case remained asymptomatic, and the PCR result was negative. At a large adult cohort from Italy, one of the two cases with COVID-19 was using tocilizumab. In this report, the role of biological agents in acute respiratory distress syndrome was emphasized, and it was pointed out that this patient might lack immune triggers [43]. Even though the experiences from rheumatology patients on tocilizumab therapy have been a guide, it has not yet been possible to consider their place in the risk cluster.
The countries with the inclusion of BCG vaccination in their national vaccination programs were considered to be shown a lower contagion and mortality rate, suggesting that the vaccine may induce trained immunity for SARS-CoV-2 [44]. Since our country is one of the regions where BCG is routinely administered, most of the patients in our cohort (88.4%) were vaccinated. Besides, the patients are regularly screened for tuberculosis before and throughout biological treatment. There is no definitive proof of causality that justifies the protective role of BCG vaccination [45]. Moreover, one should not overlook the differences in demographic, social and genetic structure of the populations while assessing the link to BCG and COVID-19.
Comorbid conditions such as diabetes mellitus and cardiovascular diseases have been associated with an increased risk in the course of SARS-CoV-2 [13]. Although rarely seen in children, we questioned comorbid conditions and drugs in our patients to evaluate our results justly. Close contacts in our cohort had no comorbid conditions in addition to rheumatic diseases. ACE inhibitors were used concurrently with antirheumatic drugs in some of our patients. Select hypothetical claims have been mooted considering the role of ACE-2 enzyme in the etiopathogenesis of SARS-CoV-2. Patients with diabetes mellitus or hypertension using ACE-inhibitors or angiotensin receptor blockers have been found to have an increased risk regarding the severity of COVID-19 [46]. The assertion was not supported as it was based on incomplete experimental evidence, and it was strongly emphasized that patients using these drugs should continue their treatment [47].