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Differential diagnosis of neonatal sepsis

Differential diagnosis of neonatal sepsis
Diagnosis Distinguishing features Diagnostic tests
Other systemic neonatal infections
Viral infections:
  • HSV
Mucocutaneous vesicles, CSF pleocytosis, elevated CSF protein, thrombocytopenia, hepatitis HSV PCR; viral culture
  • Enteroviruses
Fulminant systemic disease, myocarditis, hepatitis, encephalitis EV PCR
  • Parechovirus
Encephalitis/meningitis, rash on palms and soles HPeV PCR (available through CDC)
  • CMV
Thrombocytopenia, periventricular intracranial calcifications, microcephaly, sensorineural hearing loss, chorioretinitis CMV PCR; viral culture
  • Influenza
Respiratory symptoms, rhinorrhea, gastrointestinal symptoms Influenza PCR, rapid molecular assay, or antigen detection test
  • RSV
Respiratory symptoms, rhinorrhea, cough, apnea, pneumonia RSV PCR or antigen detection test
  • SARS-CoV-2
Respiratory symptoms, cough, tachypnea, gastrointestinal symptoms SARS-CoV-2 PCR or antigen detection test
Spirochetal infections:
  • Syphilis
Skeletal abnormalities (osteochondritis and periostitis), pseudoparalysis, persistent rhinitis, maculopapular rash (particularly on palms and soles or in diaper area) RPR or VDRL
Parasitic infections:
  • Congenital malaria
Anemia, splenomegaly, jaundice Detection of parasitemia on blood smear
  • Toxoplasmosis
Intracranial calcifications (diffuse), hydrocephalus, chorioretinitis, mononuclear CSF pleocytosis, elevated CSF protein Toxoplasma gondii serology
Fungal infection:
  • Candidiasis
Persistent hyperglycemia, thrombocytopenia, multiorgan failure Isolation of Candida in blood, urine, or CSF culture
Noninfectious causes of temperature instability in neonates
Altered environmental temperature Transient; no other systemic symptoms; resolves with simple nonpharmacologic measures
Dehydration Clinical history of poor feeding or fluid losses (eg, vomiting and/or diarrhea)
Neonatal abstinence syndrome History of maternal drug use; sweating, sneezing, nasal stuffiness, and yawning Positive drug screening tests
CNS insult (eg, anoxia or hemorrhage) History of perinatal asphyxia; focal neurologic findings or seizures Abnormal neuroimaging studies
Hypothyroidism Hypotonia, lethargy, hypothermia, large fontanels Abnormal T4 or TSH level on newborn screen
Congenital adrenal hyperplasia Ambiguous genitalia (females), adrenal insufficiency and salt-wasting (hyponatremia, hyperkalemia, dehydration) Abnormal 17a-hydroxyprogesterone level on newborn screen
Noninfectious causes of respiratory and cardiocirculatory symptoms in neonates
Transient tachypnea of the newborn Onset of symptoms within two hours after delivery; symptoms usually resolve within 24 hours CXR findings include increased lung volumes, mild cardiomegaly, prominent vascular markings, fluid in the interlobar fissures, and pleural effusions
Respiratory distress syndrome Most common in preterm infants; rare in term infants; onset of symptoms within first few hours after delivery, progressively worsens over first 48 hours of life CXR findings include low lung volume and diffuse reticulogranular ground glass appearance with air bronchograms
Meconium aspiration History of meconium-stained amniotic fluid; respiratory distress occurs immediately after birth Initial CXR may show streaky, linear densities; as the disease progresses, the lungs may appear hyperinflated with diffuse patchy densities
Pneumothorax Asymmetric chest rise, decreased breath sounds on affected side; hypotension (in cases of tension pneumothorax) CXR will usually detect symptomatic pneumothoraces
Congenital anomalies (including tracheal-esophageal fistula, choanal atresia, and diaphragmatic hernia) Often occur with other congenital anomalies including VACTERL and CHARGE associations; choanal atresia is characterized by noisy labored breathing while feeding CDH is often diagnosed by routine antenatal ultrasound screening; postnatal CXR shows herniation of abdominal contents into hemithorax; TEF is diagnosed with upper gastrointestinal series and/or bronchoscopy
Neonatal abstinence syndrome History of maternal drug use; sweating, sneezing, nasal stuffiness, and yawning Positive drug screening tests
Cardiac arrhythmias (eg, supraventricular tachycardia) Abrupt onset and termination of rapid heart rate Abnormal ECG
Congenital heart disease Infants with ductal-dependent lesions may initially lack symptoms then develop cyanosis and rapid clinical deterioration as the PDA closes in the first few days of life Abnormal pulse oximetry screen; abnormal echocardiography
Noninfectious causes of neurologic symptoms in neonates
Hypoglycemia Common in infants who are large for gestational age and/or infants of diabetic mothers Abnormal blood glucose level
Hypercalcemia Increased neuromuscular irritability and seizures; associated with prematurity, maternal diabetes, and perinatal asphyxia Abnormal serum calcium level
Hypermagnesemia Generalized hypotonia, respiratory depression and apnea; typically results from maternal treatment with magnesium sulfate Abnormal serum magnesium level
CNS insult (eg, anoxia or hemorrhage) History of perinatal asphyxia; focal neurologic findings or seizures Abnormal neuroimaging studies
Congenital CNS malformations (eg, hydrocephalus) Abnormal head circumference Abnormal neuroimaging studies
Neonatal abstinence syndrome History of maternal drug use; sweating, sneezing, nasal stuffiness, and yawning Positive drug screening tests
Inborn errors of metabolism Otherwise unexplained acid-base disorders, hyperammonemia, hypoglycemia, hematologic abnormalities, liver dysfunction, and renal disease Positive newborn screen for inborn errors of metabolism
Pyridoxine deficiency Refractory seizures Abnormal plasma pyridoxal-5-phophate level
CSF: cerebral spinal fluid; HSV: herpes simplex virus; PCR: polymerase chain reaction; EV: enterovirus; HPeV: human parechovirus; CMV: cytomegalovirus; RSV: respiratory syncytial virus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; RPR: rapid plasma reagin; VDRL: venereal disease research laboratory; CNS: central nervous system; T4: thyroxine; TSH: thyrotropin; CXR: chest radiograph; VACTERL: malformations of the vertebrae, anus, cardiac structures, trachea, esophagus, renal system, and limbs; CHARGE: coloboma of the iris or choroid, heart defect, atresia of the choanae, retarded growth and development, genitourinary abnormalities, and ear defects; CDH: congenital diaphragmatic hernia; TEF: tracheoesophageal fistula; ECG: electrocardiogram; PDA: patent ductus arteriosus.
Adapted from: Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious diseases of the fetus and newborn infant, 7th ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010.
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