Adenovirus triggered secondary CAD in toddler

It's the first pediatric case of CAD triggered by human adenovirus, researchers say

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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For a toddler in Brazil, cold agglutinin disease (CAD) occurred secondary to an infection with an adenovirus, a common virus that can cause symptoms similar to a cold or the flu, a case study reports.

According to the researchers, this represents “the first pediatric case of cold agglutinin syndrome (CAS) triggered by human adenovirus.”

The report, “Human adenovirus associated with severe cold agglutinin syndrome: a rare complication in Pediatrics,” was published in Revista Paulista de Pediatria.

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Youngest case of primary CAD reported

CAD is an autoimmune disease characterized by self-reactive antibodies called cold agglutinins that bind to red blood cells at cold temperatures. This causes the cells to agglutinate, or clump, together, marking them for destruction, called hemolysis.

Red blood cells help carry oxygen around the body, so hemolysis can lead to symptoms such as fatigue, pale skin, and an irregular heartbeat.

The disease is called primary when it arises for an unknown reason, or secondary when it occurs as the result of an underlying condition, such as cancer or infections.

Infectious causes most often involve the Epstein-Barr virus (EBV), which results in infectious mononucleosis, or “mono,” and Mycoplasma pneumoniae, a bacterium involved in respiratory infections.

Now, a team of researchers in Brazil described the rare case of a 2.5-year-old girl who developed CAD secondary to an infection with a human adenovirus. Adenoviruses, which are common in young children, can cause mild-to-severe infection, and most frequently affect the respiratory system.

Girl’s symptoms upon arrival at the ER

The girl was taken to the emergency room because she showed fever (40 C or 104 F), a runny nose, reduced appetite and fluid intake, and sleepiness for four days. Physical examination revealed signs of dehydration, but her body temperature was within normal levels.

Blood testing revealed a normal level of hemoglobin, the protein that carries oxygen in red blood cells. White blood cells and platelets, tiny components of blood that help with clotting, also were found in normal range.

A chest X-ray was clear, but a nasal swab, collected to look for bacteria or viruses that cause respiratory infection, came back positive for human adenovirus.

She received fluids directly into the bloodstream to treat her dehydration and was kept in the hospital for closer monitoring.

Three days after being admitted to the hospital, the girl started experiencing vomiting and diarrhea, and her urine turned dark in color. Her hemoglobin level had dropped from 11.6 to 2.6 grams per deciliter, and the protein appeared in urine, which could be contributing to the dark urine.

She showed other signs of hemolysis, such as higher-than-normal levels of lactate dehydrogenase (LDH) and bilirubin, and lower-than-normal levels of haptoglobin.

The number of reticulocytes, or immature red blood cells, also was low, suggesting that not enough red blood cells were being produced. This may be due to cold agglutinin-induced death of red blood cell precursors within the bone marrow, infection-related suppression of bone marrow response, and/or a delayed bone marrow response, the team noted.

Coombs test was positive

A Coombs test, which looks for cold agglutinins bound to red blood cells (direct) or floating freely in blood (indirect), came back positive, strongly suggesting CAD.

When the doctors looked at a blood sample under a microscope, they saw clumps of red blood cells that resembled stacks of coins, called Rouleaux formation.

Further, comprehensive testing found no signs of another autoimmune disease, a cancer, or an infection caused by other viruses, bacteria, or fungi, further confirming a CAD diagnosis due to adenovirus infection.

The girl was given a blood transfusion, folic acid, vitamin B12 supplements, and enough fluids to stay hydrated. She also was kept warm to maintain body temperature.

After these treatments, she began to improve and her hemoglobin level started to stabilize at 10 g/dL. After spending 14 days in the hospital, she was sent home.

“As a preventive measure, the patient was recommended to avoid cold exposure,” the researchers wrote.

About 1.5 months after admission, her hemoglobin and LDH levels, as well as reticulocyte count, had normalized. She showed no signs of cold agglutinins and associated red blood cell agglutination three months after infection.

No hemolysis after one year

One year later, the girl remained clinically well without signs of hemolysis, despite other episodes of respiratory infection caused by an adenovirus.

“To the best of our knowledge, this case is the first description of a child that had no known underlying malignancy or infectious disease typically associated with [secondary CAD],” the researchers wrote.

In children, secondary CAD “is usually abrupt, short in duration, and self-limited,” the team wrote, adding that “the prognosis is generally good.”

Given that adenovirus has been linked more recently to serious complications such as liver inflammation and subsequent liver failure, “pediatric physicians and [blood disease specialists] should be aware of unusual evolution, signs, and symptoms of this infection that warrant more urgent medical attention,” the researchers wrote.