Invasive Disease Due to Type e Haemophilus influenzae

Varman, Meera MD

Infectious Diseases in Clinical Practice:
doi: 10.1097/IPC.0b013e3181695607
Case Reports

Abstract: Invasive disease secondary to Haemophilus influenzae type b (Hib) has decreased dramatically since the introduction of the Hib vaccine. Cases of non-Hib have been reported infrequently. Some are associated with immunodeficiency. We present a case of an infant with bacteremia, meningitis, and septic hip due to H.influenzae type e.

Author Information

Department of Pediatric Infectious Disease, Creighton University, Omaha, NE.

Address correspondence and reprint requests to Meera Varman, MD, Department of Pediatric Infectious Disease, 601 N, 30th St, Suite 2321, Omaha, NE 68131. E-mail:

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Previously healthy 11-month-old white female infant presented with 2-day history of fever up to 103.7°F associated with lethargy, fussiness, rhinorrhea, and nonbilious emesis. The infant was evaluated at the local emergency department and was diagnosedwith viral syndrome. The following day, she continued with fever, nonbilious emesis, poor oral intake, and reduced urine outputand was hospitalized for further evaluation. Parents denied anyseizures, focal neurological deficit, or shortness of breath ordiarrhea.

Medical history revealed she was delivered at term via cesarian section, and her birth weight was 8 lb 9 oz. She had received 2 doses of Haemophilus influenzae vaccine and 2 doses of conjugated pneumococcal vaccine.

She attended a child care center a few weeks before hospitalization. There was no history of exposure to animals, ill contacts, or tuberculosis. She had traveled to Texas in summer for 3daysto visit relatives. Her family history was nonsignificant.

Upon hospitalization, her vital signs were temperature of 98.5°F; heart rate, 132 beats/min; respiratory rate, 28 breaths/min; and blood pressure, 90/51 mm Hg. During her physical examination,she was noted to be lethargic without spontaneous movementsand had minimal response to tactile stimuli. Her anterior fontanel was closed, and her eyes were sunken with reactive and symmetrical pupils and positive Brudzinski sign. Lungs were clear, and cardiovascular examination was normal except for tachycardia. There was no abdominal distension or hepatosplenomegaly, andbowel sounds were heard. Her skin was mottled without any rash. She had cold extremities with poor capillary refill of 5 to 6seconds. Her dehydration was corrected by normal saline bolusesand initiated on intravenous ceftriaxone therapy at a dose of 100 mg/kg per day divided every 12 hours.

Upon admission, her white blood cell (WBC) count was low at 3950 cells/μL; segments, 58%; lymphocytes, 31%; monocytes, 10%; hemoglobin, 11.2 g/dL; hematocrit, 33.1%; and platelets, 38,000/μL. Her C-reactive protein (CRP) was elevated at 20.1 mg/dL; sodium, 138 mEq/L; bicarbonate, 17 mg/dL; and glucose, 61mg/dL. The rest of her electrolytes was all within normal limits. Her cerebrospinal fluid had an elevated WBC count of 383 cells/μL; red blood cells, 17,000 cells/μL; low glucose, <20 mg/dL; and high protein, 131 mg/dL. The CSF Gram stain showed many white blood cells andmany gram-negative rods. Gentamicin was added at a dose of 7.5 mg/kg per day for synergy. The blood and spinal fluid cultures grew β-lactamase-positive H. influenzae non-type b, and the subsequent serotyping at the Centers for Diseases Control (Epidemiological Investigation Laboratory Meningitis and Special Pathogens Branch) identified the isolate as serotype e. The isolate was resistant to ampicillin and susceptible to ceftriaxone. Thus, the therapy was continued with the latter. The enteroviral polymerase chain reaction in the CSF was negative. Her leukopenia improved in24 hours, but she continued to have thrombocytopenia with a platelet count as low as 11,000 requiring platelet transfusion.

On day 4 of hospitalization, she spiked higher temperature with reduced left hip movement and fussiness with diaper change. Ultrasound of the hip revealed left hip effusion which was drained and irrigated by an orthopedic surgeon. The hip joint fluid showed WBCs of more than 100 cells/μL, and the Gram stain and the culture did not yield any organisms since she was pretreated. On day 5 of hospitalization, her CRP was 6.4 mg/dL, and her sedimentation rate was more than 100 mm/h.

Magnetic resonant imaging of the head revealed mild dural enhancement. Her hearing evaluation demonstrated mild deficiency in certain frequencies on the right side. She clinically improved by day 8. She was discharged home on ceftriaxone therapy. One week after discharge from the hospital, her CRP decreased to 2.5 mg/dL, and her erythrocyte sedimentation rate trended down to 77 mm/h.

Upon follow-up at 3 weeks after the onset of illness, she had developed mild truncal and neck weakness, which subsequently resolved in the following weeks. Follow-up hearing evaluation revealed mild improvement in her hearing. She responded well to 3.5 weeks of ceftriaxone, and her inflammatory parameters were within normal limits.

Her immunology workup showed a low total complement level of 35 mg/dL with a normal C3 and C4. Her quantitative immunoglobulin and IgG subsets were normal. Her serum antibodies to H. influenzae type b was at a protective level of 2.15 μg/mL.

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Haemophilus influenzae is a gram-negative coccobacillus that causes a multitude of systemic as well as respiratory infections both in adults and children. These organisms are classified as typeable and nontypeable stains based on the presence of different capsular polysaccharides. There are 6 capsular serotypes, namely, A through F, which is identified either by serum agglutination or by polymerase chain reaction. Haemophilus influenzae type b (Hib) is themost virulent organism among all 6 capsular serotypes. It caused approximately 95% of serious H. influenzae systemic infections such as epiglottitis, bacteremia, meningitis, arthritis, and pneumonia among children younger than 5 years during prevaccine era.1

In 1990, the Advisory Committee on Immunization Practices recommended routine protein conjugate Hib vaccine for infants.2 Following this routine Hib vaccination, the incidence of nasopharyngeal colonization as well as the invasive diseases due to this organism has dramatically decreased.3,4 However, other capsulated non-type b serotypes of H. influenzae, such as types a, c, d, e, and f, and nontypeable H. influenzae (NTHi) strains have been reported to cause the invasive diseases such as bacteremia, pneumonia, meningitis, and arthritis.5-8

There are concerns as to whether there is an increase in invasive non-Hib diseases among children, secondary to serotype replacement due to vaccination. Both in the United States and Canada, increases in the rate of invasive disease due to non-Hib serotypes have been reported.5,6 In the United States between 1996 and 2004, there was about 650% increase in invasive H. influenzae disease and an overall case fatality of 12.7% and 20% among the elderly. Although 65% of these cases were in extremes of ages, elderly people were infected in about 45% of cases.5 Overall among all age groups, 770 cases were documented, of which half were due to NTHi strains, 8% due to type e compared with 18% by type f. Between 2000 and 2006, an increasing trend in invasive H. influenzae infections is reported from Canada as well. Of the 122 cases noted among children, about half of them were due to NTHi strains, one-fifth were of type a, and only 4 were of type e.6 Half of the cases were in children older than 10 years.

In 1952 Dawson and Zinnemann9 surveyed 650 children between 0 and 4 years for nasal colonization rate and showed that of32 capsulated H. influenzae organisms, 8 were H. influenzae serotype e (Hie) compared with 6 Hib. In 2002, the nasopharyngeal surveillance of 2112 children in Spain showed 26% colonization rate for H. influenzae, of which 0.5% was Hie, and NTHi strains constituted about 25%.10

Some of the children diagnosed with non-Hib infections have been documented to have underlying immune deficiency or other medical conditions such as CSF leak, lymphoproliferative disorder, leukemia, and so on.11 Of the26 cases of invasive Hie infections reported by Campos etal,7 1 in 10 children and 11 of 16 adults were identified tohave underlying immune deficiency. Our index case had anormal quantitative immunoglobulin and protective Hib antibody titers. Her total complement was low with a normal C3 and C4, which could have been due to consumption during acute infection.

In the literature, 60% of type e Hi isolates were reported to be ampicillin resistant with the presence of β-lactamase which is the case in our patient.7 From 1978,among 40 cases of non-Hib in adults and children reported inthe literature, 7 cases were due to Hie meningitis.Among the reported cases of Hie infections, biotypeIV was predominant.12,13 Biotyping was not done for our isolate.

Invasive non-Hib cases presented mainly as meningitis and bacteremia.14 Not many cases of septic arthritis were documented in the literature. In 1975, when Harlow et al15 described 7 cases of H. influenzae septic arthritis among children in a 12-year period, only one belonged to type e serotype. The joints involved were ankle, knee, and metatarsal joints without septic arthritis of the hip joint.15 In our index case, although clinical and radiological evidence for septic arthritis of the hip were present, no organism was isolated from the joint fluid aspirate due to antibiotic pretreatment. The arthritis and meningitis were probably secondary to bacteremia.

Serotype e has the propensity to evade the immune system mediated by the complement.16 Both in adults and in children, the serotypes a, b, and e transformants of H. influenzae are relatively resistant to the serum opsonic and bactericidal activity compared with serotypes c and d. Type f is relatively susceptible. Due to increasing trend in invasive cases of non-Hib serotypes, research is under way for vaccines. Animal studies of nasal vaccine for NTHi strains incorporating adamantylamide dipeptide adjuvant and recombinant P4 and P6 antigens have shown them to be immunogenic.17

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Although the incidence of invasive disease due to Hib has decreased markedly, the non-Hib serotypes can still cause these diseases not only in immunocompromised host but alsoin immunocompetent children. As some of the children diagnosed with non-Hib infections have been diagnosed with underlying immune deficiency or other medical conditions, itis prudent to evaluate these patients for undiagnosed immunodeficiency. Due to a possibility of serotype replacement after the universal vaccination with Hib conjugate vaccine, it is important to serotype the isolates of invasive non-Hib infections.

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