THE CASE

You're covering the inpatient pediatric service on an early spring day. You suddenly receive a page from the admitting resident: an infant is in respiratory distress with jaundice. Her initial vital signs were a temperature of 36.8 °C, heart rate of 115 bpm, respiratory rate of 60 bpm, blood pressure of 98/53, and a pulse oximetry measurement of 100% on room air.

IMAGE: GETTY IMAGES/BLEND IMAGES/JOSE LUIS PELAEZ INC (BABY)

You proceed with a review of systems and medical history. Except for a diaper rash in the first two months of life, she has not had any other skin problems. The mother has been staying at home to care for the baby, and there have been no visitors or other children in the house.

Her birth history reveals normal prenatal labs and a full-term pregnancy that was complicated by placental abruption. She spent a week in the neonatal intensive care unit for tachypnea requiring oxygen. Her newborn screen was normal. At 10 weeks of age, she was admitted with fever, diarrhea, and lethargy and found to have Salmonella spp (serogroup M) in her blood, urine, and stool that responded well to antibiotics.

She received her four-month shots one week ago. At that visit, her pediatrician was concerned about her slow weight gain, which he was attributing to her previous history of formula intolerance and lower birth weight of 2.61 kilograms (5th to 10th percentile). He prescribed an empiric trial of ranitidine for suspected gastroesophageal reflux, simethicone for gassiness, and fluconazole for her thrush that had failed to respond to nystatin. Developmentally, she can fully lift her head off the bed from a prone position and she turns her head to sound. The parents are African American and have no family history of failure to thrive, liver disorders, or pulmonary disorders.

Your exam reveals an alert baby in mild respiratory distress. Her anterior fontanelle is flat, she has icteric sclerae, normal tympanic membranes, mild rhinorrhea, and no oral thrush. The neck is supple without lymphadenopathy. She has tachypnea, with coarse breath sounds bilaterally, good aeration, mild subcostal retractions, no stridor, and no wheeze. The heart exam is normal. She has a mildly distended abdomen with normal bowel sounds. Her liver is palpable 3 cm below the costal margin and a spleen tip is felt 1 cm below the left costal margin. Her genital and neurological exam is normal. Her skin is only notable for jaundice. Her admission weight is 4.5 kg (<5th percentile), her length is 56 cm (<5th percentile), and her head circumference is 38 cm (<5th percentile).

An underlying disorder?

Table 1: Differential diagnosis for cholestatic jaundice in infancy

Table 2: Differental diagnosis for acute respiratory distress in infancy

The most common infectious etiology causing respiratory symptoms in this age group would be viral, including respiratory syncytial virus (RSV), parainfluenza, influenza, adeno-, rhino-, corona and human metapneumoviruses (MPV). However, these viruses are not commonly associated with hepatic dysfunction. In normal hosts, cytomegalovirus can cause a mild hepatitis and occasionally a pneumonitis. Non-polio enteroviruses (eg, echovirus) will commonly present with gastrointestinal complaints, including cholestasis. Severe cases can also present with pneumonia.

Bacterial pulmonary infections in infancy (beyond the neonatal period) are most commonly caused by Streptococcus pneumoniae, Staphylococcus aureus or group A Streptococcus. Bacteremia is estimated to occur with pneumonia in 8% of radiologically confirmed outpatient cases.¹ The inflammatory response in bacteremia can cause poor tissue perfusion to various organs including the liver. In addition, bacteremia can lead to focal infections. S pneumoniae is the most common etiology of bacteremia in this age group, and can be associated with jaundice in Streptococcus-associated hemolytic uremic syndrome. ²

In our patient with a previous episode of Salmonella infection, it is also possible that the child is in a chronic carrier state with persistent asymptomatic excretion of Salmonella organisms. The risk of this carrier state is increased if the child has concurrent biliary tract disease. Congenital syphilis can also cause a cholestatic picture with or without respiratory compromise ("pneumonia alba"), but these findings are usually only in the neonatal period. Congenital toxoplasmosis can produce hepatosplenomegaly, cholestasis, and pneumonitis.

If the child has either a primary (eg, severe combined immunodeficiency) or secondary (eg, malnutrition, HIV, malignancy) immunodeficiency, she could also be susceptible to respiratory infections such as Pneumocystis jiroveci pneumonia (formerly called Pneumocystis carinii pneumonia but still abbreviated as PCP), Mycobacterium tuberculosis (TB), Cryptococcus neoformans, and Mycobacterium avium intracellulare (MAC). These organisms can disseminate from the lungs to various organs, including the hepatobiliary tree, leading to significant cholestasis.

Other non-infectious conditions should also be considered. Hypothyroidism is one such disease, but the respiratory distress is largely due to a large tongue, which was not present in this patient. Alpha-1 antitrypsin deficiency will usually present with jaundice in the first week of life,³ and does not demonstrate respiratory effects until young adulthood. A sweat test to rule out cystic fibrosis should always be considered when hepatic and pulmonary manifestations are present. Although a pancreatic pseudocyst can develop a fistula into the thorax, this infant does not have any suggestive history of prior pancreatitis episodes. A primary or metastatic oncologic process could also explain her symptoms, and should be screened with proper imaging, serum uric acid, and serum LDH levels. In this age group, the most common cancers would be neuroblastoma, Wilms' tumor, and hepatoblastoma.

Two metabolic disorders to consider include Niemann-Pick disease (type A) and Gaucher disease. Loss of sphingomyelinase activity in Niemann-Pick disease leads to deposition of lipids in multiple organs, causing hepatosplenomegaly, jaundice, and progressive lung disease with frequent infections. Gaucher disease results from glucosylceramide accumulation in organs that can cause infiltrative lung disease and massive hepatosplenomegaly.