Age: 0.53
Sex: M
Vaccine: HIBV
Symptoms: Musculoskeletal stiffness, Neurological examination abnormal, Neutrophil count decreased, Nuclear magnetic resonance imaging brain abnormal, Otitis media
Clinical narrative: This case was reported in a literature article and described the occurrence of Hib meningitis in a 15-month-old male subject who was vaccinated with Hib (manufacturer unspecified). No relevant medical history. His 3-year-old brother had reactive airways disease. Previous and/or concurrent vaccination included DTaP; manufacturer unspecified; unknown given on an unspecified date; PREVNAR (non-gsk); Wyeth Labs; unknown given on an unspecified date; varicella virus vaccine; manufacturer unspecified; unknown given on an unspecified date. Immunizations were up-to-date (3 DTaP and Hib vaccinations, with the last being 9 months ago) except for VARIVAX. On an unspecified date, the subject received an unspecified dose of Hib (administration site and route unknown, batch number not provided). 9 months after vaccination with Hib, the subject experienced fever (102 F), lethargy, decreased oral intake, vomiting and urine output. The physician diagnosed otitis media and referred him to the Emergency Department because of a concern for the level of consciousness. On arrival to the ED, vital signs were as follows: temperature, 36.5 deg.C; heart rate, 133 beats per minute; blood pressure, 81/62 mm Hg; respiratory rate, 24 breaths per minute; and pulse oximetry, 97% on room air. Physical examination revealed a child with a weak cry who did not maintain eye contact with the examiner. Stiffness of his neck was noted with flexion and extension. The right tympanic membrane was erythematous and bulging. Pulses and perfusion were normal. Leukocyte count was 3 x10^9/L white blood cells (0.23 segmented neutrophils and 0.55 bands) with Dohle bodies and vacuolization noted on the smear. Two 20-mL/kg saline boluses were given with no improvement in mental status. A blood culture was obtained before ceftriaxone 100 mg/kg was given intravenously. Soft tissue radiographs and computed tomographic (CT) scans of the neck ruled out retropharyngeal abscess but revealed opacification of both maxillary sinuses. Cloudy cerebrospinal fluid (CSF) was obtained from lumbar puncture. Immediately after the procedure and before laboratory results, vancomycin was given. Cerebrospinal fluid had the following: white blood cell count, 3.45 x10^9/L (0.59 neutrophils); red cell count, 1 x10^9/L; glucose, 0.66612 nmol/L, and protein, 2.98 g/L; CSF was also positive by the Phadebact Haemophilus Co-Agglutination Test. When the Gram stain showed gram-negative rods, meropenem was added. The hospital microbiology laboratory serotyped the organism as type b, which was confirmed by the state laboratory. The patient was admitted to the pediatric intensive care unit (PICU) with a diagnosis of meningitis and sepsis. Mental status improved on day 2. Dexamethasone was started, and antibiotics were switched to ceftriaxone alone when blood and CSF cultures returned positive for Hib sensitive to ampicillin. Evaluation for the immunologic response to Hib and immunodeficiency was initiated on day 3, but results were not available during the hospital stay. The patient was transferred to the floor after results of CT scan of the head were normal on day 4. A lumbar puncture was planned on day 7, but the parents refused the procedure. Day 8 was the last day that fever (Tmax, 38.8 deg. C) was present. Blood and urine cultures were sent; vancomycin was added for a possible central venous line infection. Magnetic resonance imaging on day 9 demonstrated a thin subdural hygroma over the left cerebral convexity that measured approximately 4 mm in thickness but normal brain parenchyma. Abdominal ultrasound as part of immunodeficiency evaluation demonstrated a normal spleen for age. On day 12 of hospitalization, vancomycin was discontinued. The patient was discharged after 13 days of antibiotics with appointments scheduled with neurology and immunology. The pediatrician was to arrange audiologic evaluation and early intervention; further immunologic evaluation was also planned. The patient returned to the ED 48 hours after discharge with focal seizure activity. On the day of admission, the patient was afebrile and was more active than in previous days. Parents described right side shaking that lasted several minutes. After the seizure, he was noted to have decreased movement of the right upper and lower extremities. Vital signs in the ED included the following: temperature, 37.9 deg.c; heart rate, 96 beats per minute; respiratory rate, 28 breaths per minute; pulse oximetry, 99% on room air (no blood pressure was recorded). Physical examination revealed an awake child in no immediate distress. Anterior fontanelle was open and flat; pupils were equally round and reactive. No papilledema was noted, and extraocular eye movements were intact. Neurological examination was significant for flaccid right lower extremity and a weak right upper extremity with normal reflexes and sensation. The remainder of the physical examination was unremarkable. There was improvement of the right hemiparesis during his ED stay. Workup in the ED included CT scan of the brain, which demonstrated a left-sided hygroma without midline shift. He then underwent a lumbar puncture that obtained clear fluid with an opening pressure of 17 cm  H2O. Results of analysis were as follows: white blood cells, 0.064x 10^9/L (0.11 neutrophils and 0.77 lymphocytes); red blood cells, 0.017 x10^9/L; glucose, 3.94121 mmol/L; and protein, 1.14 g/L. Gram stain demonstrated rare white blood cell count and no organisms. Bacterial antigen panel was negative as was the final culture. White blood cell count was 24.7 x10^9/L with 0.81 neutrophils, 0.11 lymphocytes, 0.06 monocytes, and 0.02 basophils. Electrolytes and liver function profile were normal. Urine toxicology was negative. Neurology and infectious disease consultations were obtained. Ceftriaxone was given intramuscularly per recommendation of the infectious disease specialist because intravenous access was not obtained immediately. Shortly after the lumbar puncture was completed, the patient had generalized tonic-clonic seizure characterized by lip smacking for which he received 1 mg of lorazepam and 15 mg/kg of fosphenytoin intravenously with resolution. During transport to the PICU, he had recurrence of seizure activity. On transfer to the PICU bed, he became apneic and bradycardic. At that time, his pupils were fixed and dilated. Cardiopulmonary resuscitation was initiated, and his trachea emergently intubated. Mannitol was given along with additional doses of lorazepam and resuscitation medications. Hypertonic saline was infused for presumed cerebral edema. The pediatric neurosurgeon performed a ventricular tap that produced 7 mL of purulent CSF. A ventricular catheter was then placed and yielded 40 mL of CSF, but resuscitation was unsuccessful. The subject died from Hib meningitis. An autopsy was performed and showed brain edema, leptomeningitis, pachymeningitis and subdural empyema. Autopsy demonstrated severe acute and chronic diffuse leptomeningitis described as multilayer exudates with neutrophils, lymphocytes, and proliferating capillaries. There was subdural empyema with organizing pachymeningitis of the left frontal region and diffuse brain edema with acute neuronal injury. No evidence of herniation was noted at autopsy. Immunologic workup from the first hospitalization included quantitative immunoglobulins with an IgG of 4.91 g/L (range, 6.81Y16.48 g/L) and IgA of 0.36 g/L (range, 0.40Y2.50 g/L) both at the lower end of normal for age. No significant tetanus antitoxoid antibodies at 0.08 IU/mL (reference, 0.16 IU/mL) or Hib antibodies at 0.13 mg/L (reference, 0.15 mg/L) were detected. Diphtheria antitoxoid antibodies were present at 0.20 IU/mL (reference, 0.10 IU/mL). Varicella IgG was also negative at 0.81 mg/L (reference, 0.90 mg/L) with vaccination occurring approximately 3 weeks before assessment. There were only 2 increased pneumococcal antibody IgG serotypes despite the receipt of his fourth PREVNAR 4 months before presentation. In vitro mitogen and antigen stimulation studies, which were planned by the Immunologist on an outpatient basis, were never completed. The bandemia and low absolute polymorphonuclear count in our patient were indicative of a sepsis syndrome not septic shock. Because the subject was afebrile, the site of the effusion was small, and the patient was clinically improving, a diagnostic paracentesis was not deemed necessary. Magnetic resonance images were planned as outpatient follow-up for the subject. Our case presented was of a child who not only had unvaccinated contacts but, in addition, had no immune response to the Hib vaccine. We cannot definitely state that the child was immunodeficient because additional testing was needed, but the finding of chronic sinusitis on his initial CT on presentation was consistent. Overall, however, despite the need for some upcoming booster vaccinations, we do think that his profile was suspicious for an immune deficiency considering the fact that he lacked protective responses to a number of previous vaccinations. A defect of his humoral immune system was most likely noting that an X-linked Bruton agammaglobulinemia would be unlikely given a normal number of B cells. It would be presumptuous to diagnose the subject with a specific immune deficiency without additional testing. In vitro mitogen and antigen stimulation studies were also planned with his next laboratory assessment. Additional information would be important as one appreciates that select dysfunctions of cellular, humoral, and even innate immunity would allow one to narrow the diagnosis. The poor outcome may be related to the patient's immunologic deficiency, which, perhaps, did not completely eradicate the organism despite an adequate course of antibiotics, allowing ongoing inflammation and release of cytokines that may have irritated the patient's brain, although this cannot be documented because of the absence of a repeat lumbar puncture during the first course of treatment and the negative CSF chemistries obtained on the second ED visit. This was a subject who did not maintain protective responses to select vaccines (including strong immunogens, like tetanus) that he received according to the recommended vaccination schedule. He was a child who needed boosters; therefore, omission of the booster dose of Hib for him probably did increase his susceptibility to the organism. The sudden demise of our patient with seizures, apnea, bradycardia, and fixed pupils was most consistent with a neurologic cause despite the absence of herniation on autopsy. The author considered the events were related to vaccination with Hib.