Failure to thrive

Toddler With Failure to Thrive and Fever, Blistering Rash After Varicella Vaccination

JAIME GRUBERT, MD
Cincinnati Children’s Hospital Medical Center

RANDALL FISHER, MD and KELLY MAPLES, MD
Eastern Virginia Medical School

Dr Grubert was a research assistant at Children’s Hospital of The King’s Daughters in Norfolk, Va, at the time this case was written. She is now a resident in pediatrics at Cincinnati Children’s Hospital Medical Center. Dr Fisher is associate professor of pediatrics at Eastern Virginia Medical School in Norfolk and medical director, division of infectious diseases at Children’s Hospital of The King’s Daughters. Dr Maples is assistant professor of pediatrics and internal medicine at Eastern Virginia Medical School and a member of the division of allergy and immunology at Children’s Hospital of The King’s Daughters.

JOHN W. HARRINGTON, MD—Series Editor: Dr Harrington is associate professor of pediatrics at Eastern Virginia Medical School in Norfolk and director of general academic pediatrics at Children’s Hospital of The King’s Daughters, also in Norfolk.

A 17-month-old boy with intermittent fever, coryza, cough, diarrhea, decreased urine output, and rash of 1 week’s duration is brought to the emergency department. The father reports that the rash began as a single lesion on the forehead then spread to other areas. The lesions appear as little blisters, which later rupture and crust over.

HISTORY

The toddler was born at full-term. Birth weight was 3.4 kg. History included failure to thrive, feeding difficulties, recurrent ear infections, and developmental delay. He is currently not walking independently. One month before presentation, the patient had received routine immunizations, including varicella vaccine, from a missed 12-month well visit. A complete blood cell (CBC) count obtained before immunization at age 15 months revealed a white blood cell (WBC) count of 6100/µL, with 14% lymphocytes.

The parents report no known exposure to varicella. There is no family history of immunodeficiency.

PHYSICAL EXAMINATON

The toddler is irritable and uncooperative. He weighs 7.9 kg. His temperature is 39.3ºC (102.7ºF); heart rate, 204 beats per minute; respiration rate, 36 breaths per minute; and blood pressure, 118/88 mm Hg.

The rash consists of scattered crusted erosions, some grouped in clusters, most pronounced on the forehead, temples, and ears. There are no vesicles or mucosal lesions. Lungs are clear. Abdomen is soft and nontender, with hypoactive bowel sounds. The liver edge is palpable about 2 finger breadths below the right costal margin.

LABORATORY RESULTS

A Tzanck smear from the base of a crusted lesion obtained by dermatology is positive for multinucleated giant cells. Serology results are negative for HIV, hepatitis (A, B, and C), Epstein-Barr virus, cytomegalovirus, and parvovirus B19. Further testing reveals mild microcytic anemia and elevated levels of liver enzymes and lactate dehydrogenase.

RADIOLOGY

A chest x-ray shows findings consistent with interstitial pneumonitis.

Which pediatric emergency(cies) would you rapidly evaluate for?

A. Disseminated varicella.

B. Profound lymphopenia.

C. Severe combined immunodeficiency.

D. Eczema vaccinatum.

(Answer and discussion on next page)

Correct Answer: A, B, and C

Familiarity with the normal absolute lymphocyte counts in infants and toddlers is essential. A WBC count of 6100/µL, with 14% lymphocytes equates to an absolute lymphocyte count of only 854/µL, which is profoundly lymphopenic for a toddler. A normal absolute lymphocyte count in the first month of life is 6100/µL (range, 4000-10,500/µL, at age 1 year is 7000/µL (range, 4000-10,500/µL), and at age 2 years is 6300/µL (range, 3000-9500/µL).1

Practice Pearl 1: Always interpret an absolute lymphocyte count based on child’s age, not the normal values listed with the CBC report. The normal
absolute lymphocyte count varies with age and is much higher in infants and toddlers than in adults and older children.

In the ED, the absolute lymphocyte count was 57/µL. The child was also found to have hypogammaglobuline-mia: IgG, < 150 mg/dL (normal, 762 mg/dL 6 209 mg/dL); IgM, 25 mg/dL (normal, 58 mg/dL 6 23 mg/dL); and IgA, 10 mg/dL (normal, 50 mg/dL 6 24 mg/dL). Lymphoctyte enumeration results and response to mitogens (concanavalin A, pokeweed mitogen, and phytohemagglutinin) were abnormally low. The finding of elevated levels of deoxyribonucleotides and depressed levels of adenine deaminase (ADA)—an enzyme required for the breakdown of nucleic acids—confirmed the diagnosis of ADA-deficient severe combined immunodeficiency (SCID).

Viral cultures grew varicella-zoster virus (VZV), and most of the patient’s symptoms were attributed to disseminated vaccine-strain varicella.

Practice Pearl 2: Infants with failure to thrive of unclear cause warrant an immune evaluation and should not receive live-virus vaccines until after
that time.

SCID describes a phenotype of disorders characterized by the absence of both humoral and cellular immunity. This serious disorder can be successfully treated when the diagnosis is made early. Affected infants often appear healthy at birth; however, after maternal antibody wanes, severe life-threatening infections can develop.

Practice Pearl 3: Until newborn screening for this disorder becomes universal, the message should be clear: SCID is a pediatric emergency. 

(For a discusssion of newborn screening for SCID, visit http://www.pediatricsconsultant360.com/exclusive/newborn-screening-severe-combined-immunodeficiency-scid.)

Currently, 17 gene mutations are known to cause SCID or its variants.2 In the ADA-deficient variant, enzyme deficiency leads to a toxic accumulation of purine metabolites detrimental to progenitor lymphocytes. In our patient, this resulted in unhindered replication of vaccine-strain VZV. Other reports of serious infections caused by live-virus vaccines in children with unidentified SCID have been described.3-6 Early diagnosis and treatment of SCID with hematopoietic stem cell transplantation is essential to prevent death and reestablish normal immune function.7,8

Outcome in this case. Because the patient had disseminated varicella with probable CNS involvement, our regional tertiary referral center declined bone marrow transplantation. He received enzyme replacement therapy with polyethylene glycol-modified adenosine deaminase (PEG-ADA), monthly subcutaneous immunoglobulin, daily oral acyclovir, and prophylactic trimethoprim/sulfamethoxazole—3 times per week for opportunistic infections. Within the first few months of treatment, varicella retinitis developed, despite acyclovir therapy, and resulted in blindness in the left eye. The child continued to struggle with weight gain and required a gastrostomy tube for nutritional support.

Although the patient responded well to PEG-ADA therapy (with increased ADA levels, 0% deoxribonucleotides, an improved lymphocyte count, and normal lymphocyte proliferation), its effects generally wane over time. This is because of neutralizing antibodies against the bovine enzyme.9 Lifelong therapy is also extremely expensive. Gene therapy may eventually be an alternative for this patient.