In a large case-control study, including MIS-C cases and SARS-CoV-2-positive outpatient controls less than 18 years old, metabolic or confirmed or suspected genetic disorders were non associated to a higher risk to develop MIS-C (9).
However, patients with IMD, who frequently experience multiorgan dysfunctions, may be at risk of acute or chronic metabolic decompensation. In these patients an infection may trigger life-threatening episodes.
The expected risk of severe COVID-19 infection is greater in children with disorders of complex molecule degradation, many of which are lysosomal storage diseases (LSD) habitually characterized by progressive multisystem involvement (10).
At the beginning of the pandemic, rare disease specialists were troubled about the impact of SARS-CoV-2 infection in these patients. In a survey, all healthcare providers described 42 patients with COVID-19 infection (11).
In a large cohort of patients with IMD, 6 patients (2.7%) had moderate or severe COVID-19, two (0.9%) patients died for a lethal COVID-19. three patients (one with 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] lyase deficiency, one with long-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD] deficiency, and one with MMA) had an acute metabolic decompensation during the infection and were hospitalized. Standard treatment protocols for metabolic decompensation were managed. However, they did not develop MIS-C. Standard treatment protocols for metabolic decompensation were managed. However, they did not develop MIS-C.
Two children (1.5% of the pediatric patients) (one with LCHAD and the other with biotinidase deficiency) developed MIS-C and recovered with treatment with favipiravir, IVIG, anakinra, anti-inflammatory drugs, antibiotics, anticoagulants (8). The high incidence of MIS-C in this cohort may be casual but needs further studies (8).
In a retrospective observational study conducted in Polland, almost all patients with infection reported mild symptoms, typically described in COVID-19. Only in three children, the worsening of primary disease symptoms was observed (two patients with Niemann Pick type C (NPC) and one NPB (Niemann Pick disease type B)) they showed psychomotor agitation or motor skills worsening, despite the maintenance of symptomatic treatment during SARS-CoV-2 infection.
One pediatric patient with very long-chain acyl-CoA dehydrogenase deficiency (VLADD) was hospitalized because of metabolic decompensation.
One patient with Fabry disease had an ischemic stroke, secondary to thromboembolic complications. Fabry disease, in fact, predisposes to endothelial dysfunction with secondary hemorrhagic or ischemic events (12). Furthermore, the pathogenetic mechanisms that predispose to endothelial damage are attributable to chronic inflammation. These characteristics of the pathology are fertile ground for the onset of vascular events during MIS-C, typically characterized by cytokine storm and thromboembolism (13; 14; 15).
In fact, COVID-19-associated pediatric vasculitis, other than MIS-C, is rare (16). However, a genetic background as in Fabry disease, MELAS or hyperhomocysteinemia (17), can predispose to this fearful complication, and the risk is higher in MIS-C patients.
A study describing the impact of SARS-CoV-2 infection on metabolic outcome in IMD patients, showed that the most frequent clinical signs were fever (52.1%) and fatigue/myalgia (47.8%). None of the patients presented severe or critical disease. However, four patients (two patients diagnosed with propionic acidemia, one patient with methylmalonic acidemia and one patient with 3-hydroxy‐3‐methylglutaryl‐CoA lyase deficiency (HMG‐CoA lyase deficiency)) developed a metabolic decompensation, with clinical and biochemical findings of an acute metabolic attack. The patient with MMA had a severe metabolic acidosis, hyperlactatemia, renal function disorder, during the course of a mild COVID‐19 infection (18). A patient with HMG‐CoA lyase deficiency had metabolic acidosis, hyperlactatemia, hypoglycemia, vomiting and insufficient feeding, during the course of a moderate COVID‐19 infection. In these four patients, a prompt emergency treatment was performed for metabolic decompensation. In organic acidemia, patients including MMA and propionic acidemia, oral treatment was substituted by intravenous carnitine. Parenteral nutrition with a hypercaloric support, lipid and glucose in addition to continuous intravenous insulin infusion was started to raise anabolism. Intravenous bicarbonate replacement was added to control metabolic acidosis, and protein intake was stopped for 24 h. The treatment of the patient with HMG‐CoA lyase deficiency included intravenous carnitine, intravenous bicarbonate and high glucose rated intravenous nutrition (18).
One case report of a 1-year‐old patient with propionic acidemia, had a moderate COVID‐19 infection with only a slight hyperammonemia and no major changes in blood gas analysis and plasma lactate level. COVID-19 caused his first metabolic crisis. However, he recovered without a severe clinical outcome (19).
Considering all categories of IMD, individuals with intoxication-type metabolic disorders and energy metabolism disorders are mainly at risk for metabolic decompensation during an intercurrent infectious disease (18). In intoxication‐type IMD, infectious diseases can trigger catabolism, which leads to endogenous breakdown of proteins and increased deposit of toxic metabolites. In energy metabolism disorders, infectious diseases can trigger catabolism that rises cellular energy request. The lack of response to this energy need leads to an energy deficit and metabolic decompensation.
Lastly, IMD do not appear to worsen COVID-19 course. However, COVID‐19 infection can develop a severe life‐threatening metabolic decompensation in these patients (18).
This case highlights the role of anakinra in a child with a severe form of MMA and MIS-C, with the significant clinical and biochemical improvement and the resolution of MOF, secondary to the cytokine storm of MIS-C and the metabolic imbalance. However, anakinra did not improve the metabolic imbalance, as persistent high levels of methylmalonic acid demonstrate.
Anakinra showed a good safety profile also in a severe metabolic disease. The good safety profile is well demonstrated in the international literature, in patients with systemic juvenile idiopathic arthritis (20) and Kawasaki disease (21). Clinical data support the employ of anakinra as a first-line biologic as early as possible, to abate the cytokine cascade not exclusively in severe and/or complicated MIS-C (14; 15; 22).
At our knowledge, this is the first case described in the literature of MIS-C in a child affected by MMA, treated with anakinra.
With the advent of biologic disease-modifying anti-rheumatic drugs in rheumatic diseases, children are expected to increase the frequency of common infections and the risk of serious and opportunistic infections. In a multicentric study, the “Pharmacovigilance in Juvenile Idiopathic Arthritis patients” (Pharmachild), a significant opportunistic infection rate was documented, especially for herpes simplex, tuberculosis and Candida Albicans (23).
In our child Candida Albicans and Staphylococcus Aureus sepsis occurred and required the withdrawal of anakinra treatment.
Further studies are needed to define the appropriateness and safety of therapy with anakinra in Candida Albicans sepsis, a lethal complication to which the child went through prolonged venous catheterization and the high risk of infections, typical of the underlying metabolic disease.