What are the differential diagnoses for a 4-month-old child with increased fussiness, fever, and a bulging fontanelle, especially after recent vaccination and a change to hypoallergenic (hypoallergenic) formula?

Differential Diagnoses for 4-Month-Old with Fever, Fussiness, and Bulging Fontanelle

Bacterial meningitis must be ruled out immediately despite the temporal association with vaccination, though recent evidence suggests bulging fontanelle has very low sensitivity (10%) and specificity (0.3%) for bacterial meningitis in febrile infants. 1

Most Critical Differential: Bacterial Meningitis

Immediate lumbar puncture is indicated because:

• Bacterial meningitis can present without classic meningeal signs in infants—1.5% of cases beyond neonatal period lack nuchal rigidity, Kernig's/Brudzinski's signs, or bulging fontanelle throughout hospitalization 2
• The bulging fontanelle developed acutely (over hours), which is concerning for elevated intracranial pressure 1
• Fever with altered behavior (increased fussiness) warrants CSF examination regardless of meningeal signs 2

However, context matters: Only 1 of 304 febrile infants (0.3%) with bulging fontanelle had bacterial meningitis in a large cohort, and none of the well-appearing infants had bacterial meningitis 1

Post-Vaccination Considerations

Normal post-vaccination fever patterns 3:

• Fever typically begins 6-12 hours after vaccination and resolves within 24-48 hours
• This child's fever started "day prior" to vaccination (unclear timeline), making vaccine-related fever less likely
• Key red flag: Fever beginning ≥24 hours after vaccination should NOT be assumed vaccine-related and requires full evaluation 3

Post-vaccination reactions that mimic serious illness 4:

• Temperature ≥40.5°C (≥105°F) within 48 hours is a precaution, not contraindication
• Hypotonic-hyporesponsive episodes can occur but don't cause permanent sequelae
• Febrile seizures occur 8-14 days post-MMR (not relevant at 4 months) 4

Emerging Viral Etiologies

COVID-19 infection presents with fever and bulging fontanelle in well-appearing infants 5, 6:

• Multiple case reports describe 3-4 month-olds with fever, bulging fontanelle, and COVID-19
• All had benign courses with symptom resolution within 2 days
• CSF examination showed no pleocytosis, negative cultures 5
• Consider COVID-19 testing in well-appearing infants with fever and bulging fontanelle 6

Other viral causes 7:

• Human herpesvirus 6 (HHV-6) can cause transient benign intracranial hypertension mimicking meningitis
• Presents with fever, bulging fontanelle, markedly elevated CSF opening pressure but normal cell count
• Resolves within 24 hours 7

Formula Change Consideration

Hypoallergenic formula intolerance is unlikely to cause:

• Fever (formula reactions are typically non-febrile)
• Bulging fontanelle (no mechanism for increased intracranial pressure)
• This is probably a temporal coincidence rather than causative

Clinical Decision Algorithm

Assess appearance immediately:

1. Ill-appearing infant (lethargy, poor perfusion, respiratory distress):

   • Obtain vascular/intraosseous access immediately 4
   • Administer parenteral antibiotics BEFORE lumbar puncture if unstable 8
   • Do not delay antibiotics for diagnostic testing 8

2. Well-appearing infant (alert, feeding, normal activity):

   • Perform lumbar puncture with opening pressure measurement 1, 7
   • Obtain COVID-19 testing 6
   • Consider neuroimaging if focal neurologic signs present 5
   • Blood cultures and complete blood count 8

Specific examination findings to document:

• Anterior fontanelle size (measure by Popich-Smith method) 5
• Level of consciousness and activity compared to baseline 5
• Presence/absence of neck stiffness (though unreliable in infants) 4, 2
• Pupillary responses and posturing 4
• Petechiae or purpura (suggests meningococcemia) 8

Common Pitfalls to Avoid

• Do not assume bulging fontanelle equals meningitis: 37.8% had CSF pleocytosis but only 0.3% had bacterial meningitis 1
• Do not attribute all symptoms to vaccination: Fever persisting >24 hours or beginning >24 hours post-vaccination requires full sepsis evaluation 3
• Do not delay antibiotics in ill-appearing infants: Administer empiric antibiotics immediately if meningitis suspected, even before lumbar puncture 8
• Do not dismiss well-appearing infants: Bacterial meningitis can occur without meningeal signs, though rare 2

Most likely diagnosis in well-appearing infant: Viral illness (possibly COVID-19) with transient intracranial hypertension 5, 6, but bacterial meningitis must be excluded with lumbar puncture given the acute presentation and fever pattern inconsistent with simple post-vaccination reaction 3, 1.