Editor’s note:Ask the Expert is a columnaimed at providing pediatricians information on pressing topics related to COVID-19. Email your questions to[email protected].
Q: A previously healthy 8-year-old male presents to your office with a history of six days of fever and increasing abdominal pain with nausea and diarrhea. Examination shows diffuse abdominal tenderness with some right lower quadrant localization. The respiratory exam is normal. Should you worry about SARS-CoV-2 infection?
A: At the beginning of the COVID-19 pandemic in December 2019, reports from Wuhan, China focused on respiratory symptoms. Patients typically presented after an average incubation period of about five days with fever, dyspnea, cough, pharyngitis and lethargy.
As this novel coronavirus, SARS-CoV-2, spread globally, reports began to describe the multiorgan involvement that characterizes a severe infection, including respiratory (pneumonia and adult respiratory distress syndrome), cardiac (coronary artery abnormalities, myocarditis), intestinal (diarrhea, nausea, vomiting, loss of appetite), hepatic (hepatitis), renal (acute kidney injury), central nervous system (hyposmia or loss of smell, dysgeusia or distortion of taste, impaired consciousness), skin (COVID-19 toes) and hematologic and coagulation abnormalities.
On March 2, 2020, the first pediatric case of confirmed COVID-19 was reported to the Centers for Disease Control and Prevention (CDC).
Preliminary data published by the CDC as of the last week of May noted the cumulative hospitalization rate of laboratory-confirmed COVID-19 was 225 per 100,000 among U.S. adults older than 64 years of age (https://bit.ly/3gHHWYc). The rate is typical of an influenza season for that age group (during the 2019-’20 influenza season, the cumulative hospitalization rate was 180 per 100,000).
The hospitalization rate for children 5-17 years attributable to COVID-19 is 1.9 per 100,000, about 11 times lower than the hospitalization rate for influenza during the 2019-’20 influenza season (25 per 100,000).
At the end of April, the consensus among pediatricians was that COVID-19 infection in children appeared to be surprisingly mild.
During the last week of April, this consensus began to change when pediatricians in the United Kingdom described a syndrome of severe illness consisting of features of Kawasaki disease and toxic shock syndrome characterized by fever, abdominal pain and cardiac involvement. More than 50% of children required admission to the intensive care unit. While the association with COVID-19 infection was not established, most patients had either a positive nasopharyngeal swab for COVID-19 (by polymerase chain reaction), antibody evidence of previous infection by COVID-19 or both. This syndrome first was called pediatric inflammatory multisystem syndrome (PIMS) but now is referred to as multisystem inflammatory syndrome in children (MIS-C).
The CDC defines MIS-C as a severe illness in individuals younger than 21 years of age consisting of fever, laboratory evidence of inflammation with more than one organ involved (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, neurologic) and no alternative plausible diagnosis. Infection based on reverse transcriptase polymerase chain reaction, serology or antigen test or COVID-19 exposure less than four weeks prior to the onset of symptoms is included. A striking characteristic of MIS-C is the degree of inflammation demonstrated in blood tests (discussed below).
As with all new and evolving infectious diseases, the full spectrum of illness will be determined in time, with only the most symptomatic cases being identified initially. Likely, children with less severe MIS-C illness will be recognized, but the less severe end of the spectrum and the risk of progression to more severe illness are not presently understood.
Although more than 50% of children with MIS-C appear to satisfy the criteria of Kawasaki disease, certain findings are unusual, even for incomplete Kawasaki disease. Unlike most patients with Kawasaki disease, coronary artery abnormalities may be found at presentation in children with MIS-C. They also appear to be older (appearing later in the first decade of life), while about 75% of patients with Kawasaki syndrome are younger than 5 years of age. Among patients with MIS-C, the incidence of shock is higher, the inflammatory markers are higher and gastrointestinal (GI) symptoms are more prominent than in patients with Kawasaki disease.
Although rare, MIS-C cases appear to occur about one month after a peak in COVID-19 infections, suggesting an immune-mediated process rather than a consequence of viral involvement. It is important to remember that in most settings, children represent less than 1% of COVID-19 positive patients, and most symptomatic children experience only mild illness. The risk of MIS-C following COVID-19 infection is not known but is likely to be extremely low, based on current understanding.
SARS-CoV-2 infection of the intestine appears to occur more commonly than initially recognized. While initial reports emphasized respiratory symptoms in both children and adults, GI symptoms appear to be common even in the absence of respiratory involvement. Bowel abnormalities may be due to direct infection of intestinal epithelial cells by SARS-CoV-2 or uncontrolled clotting that results in bowel ischemia.
COVID-19 is associated with a prothrombotic state in some patients with increases in fibrinogen, fibrin degradation products, fibrinogen and D-dimer. Although the incidence of thrombosis is not known, an increased incidence of thromboembolic disease occurs in some patients with severe disease.
The cellular receptor for SARS-CoV-2 is the protein angiotensin converting enzyme 2 (ACE2). ACE2 receptors are present in the colon and hepatocytes and other GI organs. In some GI organs, ACE2 receptors appear to be present in greater amounts than in lung tissue. It is not known if infection of cells of the gastrointestinal epithelium may serve as a portal of entry for the virus. GI symptoms may appear before respiratory symptoms or respiratory involvement may not occur.
Patients with fever and new gastrointestinal tract symptoms, even in the absence of respiratory tract symptoms, should be considered as possible COVID-19 patients, especially if there is a history of viral exposure.
Differential diagnosis
In the case presented here, several possibilities should be considered in the differential diagnosis. Appendicitis is less common in early childhood but becomes the most common reason for abdominal surgery in children by approximately 10 years of age.
Other less common causes of acute abdominal pain in this age group should be considered such as inflammatory bowel disease. However, during the pandemic, six days of fever in addition to nausea, diarrhea and abdominal pain in an adolescent indicate a need to address the possibility of SARS-CoV-2 infection. A possible association between COVID-19 and an increased risk of appendicitis has been considered.
For this 8-year-old child, blood should be obtained to evaluate the presence of systemic inflammation. Recommended tests include complete blood count with differential (lymphopenia), C-reactive protein (often markedly elevated to >200), ferritin, lactate dehydrogenase, fibrinogen, troponin, BNP (B-type natriuretic peptide is a hormone that increases with heart failure).
Bacterial infections such as bacteremia or pyelonephritis may present with similar symptoms, so a blood culture may be indicated. If the markers of inflammation are elevated and the child appears ill, prompt admission to a hospital should be arranged where pediatric intensive care and specialists in infectious diseases and cardiology are available. If the child has only mild symptoms and the test results are normal or only mildly elevated, a reasonable approach would be to repeat the blood tests regularly with frequent visits to assess the direction of illness.
Knowledge evolving
The full spectrum of COVID-19 infection in pediatric patients remains poorly understood. In general terms, infection appears to range from asymptomatic infection with an absence of signs or symptoms to mild illness with fever, fatigue, myalgia and cough to moderate disease with pneumonia to severe disease with dyspnea, cyanosis and hypoxia to critical illness with respiratory failure, shock and multiorgan dysfunction. GI symptoms may be present at any symptomatic stage.
The ability to anticipate which patient may progress from one stage to another is limited, and some patients have deteriorated rapidly. In time, a better understanding of the distinction between the acute infectious phase of COVID-19 and the immune-mediated phase that characterizes MIS-C will facilitate improved management.
At the present time, pediatricians should remember that complications from COVID-19 infection appear to be milder among children than adults. Relatively fewer children than adults require hospitalization, and even fewer require intensive care. Although severe outcomes including MIS-C have occurred in children, based on current understanding, such complications appear to be very rare.
Dr. Meissner is professor of pediatrics at Floating Hospital for Children, Tufts Medical Center. He also is an ex officio member of the AAP Committee on Infectious Diseases and associate editor of the AAP Visual Red Book.
