Are Diagnosticians Chasing COVID-Linked Zebras?

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The emergence of multiple inflammatory syndrome in children (MIS-C) in association with COVID-19 may be complicating the investigation and diagnosis of more common viral and bacterial infections, potentially delaying treatment and prolonging hospital stays.

Two recent articles published online in Hospital Pediatrics provide evidence of this phenomenon. The articles outline case studies of children who underwent extensive investigation for MIS-C when in fact they had less severe and more common infections. MIS-C is a severe but rare syndrome that involves systemic hyperinflammation with fever and multisystem organ dysfunction similar to that of Kawasaki disease (KD).

Dr Matthew Molloy

In one of the articles, Matthew Molloy, MD, MPH, of the Division of Pediatric Hospital Medicine at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, and colleagues aptly ask: "What are we missing in our search for MIS-C?"

E coli, Not SARS-CoV-2

That question arose from a case involving a 3-year-old boy who had a 6-day history of fever and fatigue. Three days earlier, he had tested negative for strep antigen and COVID-19. He had a persistent, high fever, reduced appetite, and reduced urine output and was taken to the emergency department. On physical examination, there was no rash, skin peeling, redness of the eye or oral mucosa, congestion, rhinorrhea, cough, shortness of breath, chest pain, abdominal pain, nausea, vomiting, or diarrhea.

Urinalysis results and exam findings were suspicious for pyelonephritis. Other findings from an extensive laboratory workup raised the alarm that the boy was suffering from MIS-C as opposed to incomplete KD. After admission to hospital medicine, the cardiology, rheumatology, and infectious disease teams were called in to consult.

Repeat labs were planned for the following day before initiating therapy. On day 2, the child's urine culture was positive for gram-negative rods, later identified as Escherichia coli. The boy was started on ceftriaxone. Left renal scarring was apparent on ultrasound. The patient's condition resolved after 36 hours, and he was discharged home with antibiotics.

"Diagnosis Derailed"

Calling this a case of "diagnosis derailed," the authors noted that in the pre-COVID era, this child's signs and symptoms would likely have triggered a more targeted and less costly evaluation for more common infectious and noninfectious causes, including pyelonephritis, absent any physical exam findings consistent with KD.

"However, the patient presented in the midst of the COVID-19 pandemic with growing awareness of a new clinical entity," Molloy and colleagues write. "Anchored to the patient's persistent fever, the medical team initiated an extensive, costly, and ultimately unnecessary workup to avoid missing the diagnosis of MIS-C; a not yet well-described diagnosis with potentially severe morbidity."

Confirmation bias and diagnostic momentum likely contributed to the early focus on MIS-C rather than more common alternatives, the authors acknowledge. The addition of mildly abnormal laboratory data not typically obtained in the evaluation of fever led the team astray. "The diagnosis and definitive treatment may have been made earlier had the focus on concern for MIS-C not been present," Molloy told Medscape Medical News.

Keeping Value in Care

The authors recognized that their initial approach to evaluating for MIS-C provided low-value care. "In our desire to not 'miss' MIS-C, we were performing costly evaluations that at times produced mildly abnormal, non-specific results," they write. That triggered a cascade of specialty consultations, follow-up testing, and an unwarranted diagnostic preoccupation with MIS-C.

Determining the extra price tag for the child's workup would be complex and difficult because there is a difference in the cost to the hospital and the cost to the family, Molloy said. "However, there are potential cost savings that would be related to making a correct diagnosis in a timely manner in terms of preventing downstream effects from delayed diagnoses."

Even as clinicians struggle with the challenging SARS-CoV-2 learning curve, Molloy and associates urge them to continue to strive for high-value care, with an unwavering focus on using only necessary resources, a stewardship the pandemic has shown to be critical.

"The COVID-19 pandemic has been an incredibly stressful time for physicians and for families," Molloy said. "COVID-19 and related conditions like MIS-C are new, and we are learning more and more about them every week. These diagnoses are understandably on the minds of physicians and families when children present with fever." Notwithstanding, the boy's case underscores the need for clinicians to consider alternate diagnoses and the value of the care provided.

Impact of Bias

Molloy's group brings home the cognitive biases practitioners often suffer from, including anchoring and confirmation bias and diagnostic momentum, according to J. Howard Smart, MD, chief of pediatrics at Sharp Mary Birch Hospital for Women and Newborns in San Diego, California, and an assistant clinical professor of pediatrics at University of California, San Diego.

Dr J. Howard Smart

"But it is one thing to recognize these in retrospect and quite another to consider whether they may be happening to you yourself in real time," he told Medscape Medical News. "It is almost as if we need to have a 'time out,' where we stop and ask ourselves whether there is something else that could be explaining our patient's presentation, something that would be more common and more likely to be occurring."

According to Smart, who was not involved in Molloy's study, the team's premature diagnostic focus on MIS-C was almost the inverse of what typically happens with KD. "It is usually the case that Kawasaki disease does not enter the differential diagnosis until late in the course of the fever, typically on day 5 or later, when it may have been better to think of it earlier," he said.

In the second article, Andrea Dean, MD, of the Department of Pediatrics at Baylor College of Medicine and Texas Children's Hospital, in Houston, Texas, and colleagues outline the cases of five patients aged 8 to 17 years who were hospitalized in May 2020 for suspected MIS-C. They exhibited inflammatory and other concerning indicators but were eventually discharged with a diagnosis of murine typhus.

This flea-borne infection, most commonly reported in the United States in the southeastern Gulf Coast region, Hawaii, and California, is often associated with a triad of fever, rash, and headache.

Cases have been rising in South Texas, and Dean and colleagues postulate that school closures and social distancing may have increased exposure as a result of children spending more time outdoors or with pets. "Alternatively, parental concern for SARS-CoV-2 infection could mean children with symptoms are presenting to care and being referred or admitted to the hospital more frequently due to provider concern for MIS-C," they write.

Cardiac Involvement

The most concerning of the five cases in terms of possible MIS-C, Dean told Medscape Medical News, was that of a 12-year-old boy who had had fever for 6 days in association with headache, eczematous rash, dry lips, and conjunctivitis. Laboratory tests showed a mildly elevated C-reactive protein level, hyponatremia, and thrombocytopenia, as well as sterile pyuria and mildly elevated prothrombin time. He was treated empirically with doxycycline, and his fever resolved over the next 24 hours.

An echocardiogram at initial evaluation, however, revealed mild dilation of the left anterior descending and right coronary arteries, which led to the administration of intravenous immunoglobulin and aspirin for atypical KD, in contrast to MIS-C. The authors postulate that mild cardiac involvement in disorders other than MIS-C and KD may be underrecognized.

The lesson from these cases, Dean and associates conclude, is that hospitalists must maintain a wide differential diagnosis when assessing a child with prolonged fever and evidence of systemic inflammation. The CDC stipulates that a diagnosis of MIS-C requires the absence of a plausible alternative diagnosis.

In addition to common viral, bacterial, and noninfectious disorders, a range of regional endemic rickettsial and parasitic infections must be considered as alternative diagnoses to MIS-C. "Many of these diseases cannot be reliably differentiated from MIS-C on presentation, and as community exposure to SARS-CoV-2 grows, hospitalists should be prepared to admit febrile children with evidence of systemic inflammation for brief observation periods to evaluate for MIS-C," Dean's group writes. In this context, however, empiric treatment for common or even uncommon infectious diseases may avoid overdiagnosis and overtreatment of MIS-C as well as improve patient outcomes.

"We do have specific MIS-C guidelines at our institution," Dean said, "but like all institutions, we are dealing with the broad definition of MIS-C according to the World Health Organization and the CDC, which is really the take-away from this paper."

More Difficult Differentiation

Both groups of authors point out that as SARS-CoV-2 spreads throughout a community, a higher percentage of the population will have positive results on antibody testing, and such results will become less useful for differentiating between MIS-C and other conditions.

Dr Kara Gross Margolis

Despite these series' cautionary lessons, other experts point to the critical importance of including MIS-C early on in the interest of efficient diagnosis and therapy. "In the cases cited, other pathologies were evaluated for and treated accordingly," said Kara Gross Margolis, MD, AGAF, an associate professor of pediatrics in the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at Morgan Stanley Children's Hospital in New York City. "These papers stress the need for a balance that is important, and all potential diagnoses need to be considered, but MIS-C, due to its potential severe consequences, also needs to be on our differential now."

In her view, as this new high-morbidity entity becomes more widespread during the pandemic, it will be increasingly important to keep this condition on the diagnostic radar.

Interestingly, in a converse example of diagnostic clouding, Gross Margolis's group reported last year on a pediatric case series in which the presence of gastrointestinal symptoms in children with COVID-19–related MIS-C muddied the diagnosis by confusing this potentially severe syndrome with more common and less toxic gastrointestinal infections.

According to San Diego's Smart, although the two reports don't offer evidence for a particular diagnostic practice, they can inform the decision-making process. "It may be that we will have enough evidence shortly to say what the best practice is regarding diagnostic evaluation of possible MIS-C cases," he said. "Until then, we must remember that common things occur commonly, even during a global pandemic."

Neither of the two reports received any specific funding. The authors have disclosed no relevant financial relationships.

Hosp Pediatr. Published online January 2021. Molloy et al, Abstract; Dean et al, Abstract

Diana Swift is a medical journalist based in Toronto.

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