Even as the COVID-19 pandemic continues to seek out new victims, puzzling new presentations are further confusing the situation. A new study published online in The Lancet Rheumatology in May 2020 reports a case of severe COVID-19 in a child who rapidly developed acute respiratory distress symptoms without prior respiratory symptoms. This case should alert clinicians to consider this diagnosis in children as well.
Earlier trends in the pandemic led many clinicians and researchers to conclude that the virus typically spares young people, including children, several countries have since sent in reports of babies and children who died of COVID-19.
Unusual Presentation Of COVID-19
The current study deals with a child of 14 who presented with fever, abdominal pain, nausea, and vomiting, all present for 3 days. The mother had had mild respiratory symptoms 3 weeks prior to the child’s illness.
On the day of admission, the child had a fever of 38.1 oC, and showed a tense abdomen, particularly guarding in the right side, upper and lower quadrants. Blood tests showed that the lymphocyte counts were down to a tenth of the lower limit of normal. The inflammatory marker C reactive protein (CRP) was very high, at 30 times the normal value. There were a significant number of pus cells (30) in the urine but no bacteria.
The child was suspected of having acute appendicitis and started on antibiotics. Namely, a combination of piperacillin-tazobactam, but nasopharyngeal swabs were also tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by RT-PCR, which turned out to be negative. Imaging by chest X-rays and abdominal ultrasound returned normal results.
SARS-CoV-2 coronavirus, the virus which causes COVID-19. Illustration Credit: Kateryna Kon / Shutterstock
Following admission, the child became progressively more breathless, with a cough, and needed supplemental oxygen. Failing to respond, he was finally put on continuous positive airway pressure (CPAP) ventilation support.
The child still looked sicker, and a rash broke out all over his body. Despite receiving intravenous fluids, he continued to have a persistently rapid heartbeat. At this point, a chest CT was taken and showed the characteristic features of COVID-19 pneumonia, leading to a diagnosis of presumptive COVID-19.
Cytokine Storm Syndrome
The child was thought to have hyperimmune manifestations due to “secondary multi-system inflammatory disease,” also called a “cytokine storm syndrome.” This was based on the clinical features combined with the apparent evidence of severely and acutely raised inflammatory markers, coagulation dysfunction, with the appearance of antiphospholipid antibodies and a severe drop in complement levels to less than a tenth of normal.
The negative PCR for SARS-CoV-2 performed on nasopharyngeal swabs on day 3, 5, and 7, and on stool sample on day 11, ruled out the use of the antiviral remdesivir, leaving only the recombinant IL-1 receptor blocker anakinra. Evidence of cardiac damage and dysfunction led to the initiation of aspirin as an antithrombotic agent. The child’s condition began to improve with this drug, and only coronary dilation remained evident at the time of discharge.
As the patient improved, anakinra was tapered off in 6 days, and the serologic testing showed IgG positive on day 11. The researchers reported that this is the first reported child with cytokine storm syndrome who presented without initial respiratory symptoms.
The researchers note that the diagnosis was presumptive, based on the CT chest, the blood tests for inflammation, and evidence of other biochemical abnormalities. The three negative PCR tests may reflect the onset of an acute inflammatory process after the child developed and recovered from the infection itself since the sensitivity of the test is 60%.
Another reason may possibly be that the virus was actively replicating at another site. The virus is known to replicate in both respiratory and intestinal epithelium, blocking the early immune responses mediated by interferon type I.
The virus is also known to infect macrophages and monocytes, the innate immune cells, without successfully replicating within them. However, in the presence of immune complexes, the virus can infect these cells more efficiently, boosting the release of proinflammatory cytokines like IL-1, IL-6, tumor necrosis factor (TNF). This is called antibody-dependent enhancement (ADE).
ADE depends on the ability of the antibody to act like a bridge holding the virus to the host cell through its two very different sites. The virus-specific recognition site attaches to the virus, while the other end is attached to the antibody-recognition site on the host cell. Thus, the antibody facilitates the binding of the virus to the immune cell and its entry into the cell, which could not have successfully occurred on its own.
ADE results in overactive immune responses as well as more rapid viral replication. These phenomena lead to an increasing number of new infectious viral particles, severe tissue damage, and the exponential recruitment of innate and adaptive immune cells.
Direct and Immune Damage Results in ARDS
This hyperinflammatory situation and organ damage are part of the process that culminates in ARDS. The lungs are damaged not only by the direct cytopathic effect of the viral infection but, perhaps even more, by the unopposed and dysregulated immune response. For instance, children with cytokine storm syndrome following juvenile idiopathic arthritis or other causes, or even as a primary condition, can develop ARDS.
This is another possibility explaining the accelerated course of respiratory and imaging findings in the absence of a positive PCR test. The generation of immune complexes and their deposition in the blood vessels, as well as the IL-1-mediated endothelial activation, could activate the clotting and complement cascades, which eventually lead to thromboembolism.
The Potential for Anakinra Use in Cytokine Storm
The off-label use of anakinra was intended to restrict the action of IL-1 by blocking IL-1 receptor signaling. This receptor mediates the expression of IL-6 and TNF by activating NF-κB-dependent pathways. It was chosen ahead of IL-6 blockers, which are currently being tested in multiple trials because it is upstream of IL-6. Moreover, it causes less neutropenia, potential liver damage, and less elevation of serum lipids, thus reducing the risk of exacerbating these phenomena that are already present because of cytokine storm syndrome.
It is also not associated with a higher risk of secondary infection, unlike that which is seen with the long-term use of IL-6 blockers. Indeed, anakinra reduces the death rate in sepsis patients.
The clinical presentation in this child has not been previously reported, namely, fever and abdominal pain without any respiratory symptoms, but with the rapid onset of ARDS. The researchers comment: “During the ongoing pandemic, COVID-19 must be considered in patients with increased inflammatory variables and abdominal symptoms.”