Underlying Immunologic Disorder or MIS-C? A Complex Condition Puzzles Physicians

By Harry Lesmana, MD

A 14-month-old was admitted to Cleveland Clinic’s Pediatric Intensive Care Unit after several days of high fever and upper respiratory symptoms, like cough and congestion. She was later noted to have markedly elevated inflammatory indications.

In the midst of a COVID-19 surge, the child was identified as possibly having multisystem inflammatory syndrome in children, or MIS-C, a rare complication associated with COVID-19. The patient had never tested positive; although, she did have a known exposure to the virus.

Medical history of tetralogy of Fallot, ruling out Kawasaki disease

Notably, the patient was born with tetralogy of Fallot (Tof), a rare congenital heart disease. The condition was screened for in utero with a chromosome analysis leading up to a prenatal diagnosis. Once born, she underwent cardiac surgery at Cleveland Clinic and was followed by the pediatric cardiac surgery service prior to this presentation.

After a series of genetic testing, including screening for DiGeorge syndrome, or 22q11 deletion syndrome, the most common cause of ToF from a genetic standpoint—the cause of ToF was ruled sporadic with no clear link to congenital heart disease.

We were initially suspicious of atypical Kawasaki disease, known for systemic inflammation, specifically affecting the heart. But the child was evaluated by one of our pediatric cardiologists, who reported a normal baseline heart, ruling out any cardiac conditions.

Treating the condition as MIS-C

In the absence of another diagnosis, we proceeded to treat her condition as MIS-C with a steroid and intravenous immune globulin, a standard regimen for pediatric patients with COVID-19. The fever and generalized inflammation persisted.

Now on the rheumatology service, they started her on anakinra, an interleukin-1 inhibitor used to block inflammation. It worked well in the short term, and the patient returned home — only to be readmitted a few months later with the same symptoms: persistent fever, elevated inflammatory markers (notably, skin rashes) — and still no clear etiology.

The rheumatology team considered juvenile idiopathic arthritis (JIA), although she didn’t meet the exact classical criteria. JIA is often characterized by joint swelling and inflammation. The skin rashes were biopsied and to no avail — it was just inflammation and the underlying cause remained a mystery.

New symptoms emerge

When she later began to experience difficulty breathing and grunting at night, the team began pulmonary evaluations. A CT scan of the chest revealed inflammation in the lung and multiple enlarged lymph nodes. This time, in addition to the persistent fever, there was also evidence of multisystem inflammation, including that of her liver and hematology systems.

We were understandably perplexed and began to consider a new diagnosis: hemophagocytic lymphohistiocytosis syndrome, a severe systemic inflammatory syndrome.

Rheumatology, still the primary service, involved the hematology/oncology service to rule out possible underlying cancer in the patient. The enlarged lymph nodes could have meant lymphoma was responsible for triggering the fever and cutaneous skin rashes.

Pulmonology was also involved because of the child’s breathing difficulties. To be sure there was no infection in the lung, the child underwent a bronchoscopy. While under sedation, they also biopsied the lymph node, ruling out lymphoma.

A plan developed through multidisciplinary discussion

At this point, the degree of inflammation was suggestive of an underlying problem with her immune system. Notably, her kidney function was fine, but the inflammation in her skin, lungs, hematopoietic system (anemia with thrombocytopenia) was incredibly concerning.

Her care teams presented all the clinical information, including the workup and potential treatment options, in a multidisciplinary conference. At this point, it was still unclear if this was a pure rheumatologic condition versus underlying HLH.

If it was HLH, we would need to be prepared to discuss the possibility of a bone marrow transplantation. Of course, this option is not without risk and, in the absence of a clear diagnosis, we definitely did not want to subject the patient to an unnecessary treatment.

She had extremely high levels of CXCL9 in her blood — 700 times higher than normal levels. This is emblematic of HLH and suggests a dysregulation in the pathway.

After much discussion, we decided the best course of treatment would be to start the patient on emapalumab, a medication used in the setting of hyperinflammatory syndromes. The patient had several infusions, and so far she is doing great. All of her symptoms have resolved.

Results from a whole-genome sequencing were negative, ruling out an underlying genetic condition.

An unusual immune response to COVID-19?

Most healthy adults and children with normal immune systems and no comorbidities are not likely to develop severe infection. But some people do develop an exaggerated immune response or inflammatory response to COVID-19.

In this case, we believe that the patient’s underlying immune system disorder may have been uncovered through an abnormal response to COVID-19.