haemophilus influenzae type b ( hib ) is responsible for most cases of invasive h. influenzae disease , including meningitis and septicemia , in unvaccinated children . with the decline in the incidence of invasive hib disease as a result of the hib vaccine program ,
nontypeable h. influenzae ( nthi ) has become an important cause of invasive h. influenzae disease in vaccinated children .
nthi is part of the normal flora in the upper respiratory tract of children and commonly causes local respiratory tract diseases , including otitis media , sinusitis , conjunctivitis , and bronchitis [ 2 , 3 ] .
meningitis and septicemia have been reported rarely in children with underlying predisposing conditions , including head trauma , cerebrospinal fluid ( csf ) leakage , and immune compromise , in neonates associated with colonization of the maternal genital tract [ 7 , 8 ] , and more rarely in previously healthy children [ 911 ] . according to a japanese nationwide surveillance system ,
the frequency with which nthi meningitis in children occurs seems to vary , depending on the populations surveyed : 4 ( 0.7% ) of the 535 patients with h. influenzae meningitis were nthi strains ; 2 ( 4.9% ) of the 41 pediatric patients with h. influenzae meningitis were nthi strains .
we report a case of a previously healthy 2-year - old girl who developed meningitis and septicemia caused by nthi biotype  , and wish to emphasize that nthi must be borne in mind as a potential pathogen that can cause invasive disease , even in previously healthy children .
on 7 september 2008 a previously healthy 2-year - old girl was admitted to the hospital with a 12-h history of fever and vomiting . she had no rhinorrhea or cough before her hospital stay .
she had been born at 40  weeks of gestation , and her birth weight was 3062  g. subsequent mental and physical development had been normal .
she had been immunized with various vaccines as appropriate according to the immunization schedule for children ( bcg , diphtheria , tetanus , pertussis , poliomyelitis , measles , rubella , and varicella ) .
she lived with her parents and 3-year - old brother , and attended a nursery school . on admission
, she had a body temperature of 39.2c , heart rate of 122 beats / min , respiratory rate of 40/min , and an instant capillary refill time without cold peripheries .
laboratory data on admission were : white blood cell ( wbc ) count , 13400/l ( neutrophils 91% , monocytes 2% , lymphocytes 7% ) ; serum aspartate aminotransferase ( alt ) , 29 
iu / l ; serum alanine aminotransferase ( ast ) , 17  iu / l ; serum lactate dehydrogenase ( ldh ) , 252 
iu / l ; serum c - reactive protein ( crp ) , 1.5  mg / dl .
she was initially treated with intravenous fluid and antipyretics , with her condition monitored closely . on the second day of admission ,
she had a body temperature of 39.3c , heart rate of 145 beats / min , and respiratory rate of 45/min .
she became disoriented and the glasgow coma scale showed an eye opening ( e ) score of 4 , verbal response ( v ) score of 2 , and best motor response ( m ) score of 5 .
no anterior fontanelle bulging or hemiparesis were observed , and kernig s sign and babinski s sign were negative .
the laboratory data on september 8 were : wbc count , 15300/l ( neutrophils 82% , monocytes 9% , lymphocytes 8% ) ; alt , 30  iu / l ; ast , 16  iu / l ; ldh , 307 
iu / l ; fasting blood glucose , 144  mg / dl ; crp , 15.0  mg / dl ; csf cell count , 3146 cells/l ( polymorphonuclear leucocytes , 78% ) ; csf protein , 51  mg / dl ; csf glucose , 35  mg / dl .
gram staining of the csf revealed the presence of small , gram - negative , pleomorphic rods resembling h. influenzae .
however , a csf test kit designed to detect the capsular antigens of bacteria causing meningitis ( pastrorex meningitis ; bio - rad laboratories , tokyo , japan ) gave a negative result for hib antigen . on the basis of the clinical and laboratory findings , diagnosis of bacterial meningitis was made , and empiric treatment with ceftriaxone sodium hydrate ( ctrx ) ( 120  mg / kg / day , 12-hourly ) and meropenem hydrate ( mepm ) ( 140  mg / kg / day , 8-hourly ) was started . to avoid neurological sequelae , dexamethasone ( 0.60  mg / kg / day , 6-hourly )
the isolates were subsequently identified as h. influenzae by 16s rrna gene sequencing , followed by a basic local alignment search tool ( blast ) search in the laboratory of ubukata kimiko at the kitasato institute for life sciences kitasato university .
on serotyping , no agglutination was observed with antisera against the capsular serotypes a through f , leading to categorization of the strain as nontypeable .
on biotyping , the organism failed to produce indole and to decarboxylate ornithine , but was able to hydrolyze urea , leading to its categorization as biotype . h. influenzae biotype  could be distinguished from h. aegyptius by its fermentation of xylose or by its growth on tryptic soy agar containing x and v factors .
all of the csf , blood , and throat swab cultures yielded beta - lactamase - negative nthi biotype . the minimum inhibitory concentrations ( mic ) of several antibiotics for the organism are listed in table  1.table  1minimum inhibitory concentration of several antibiotics for nontypeable haemophilus influenzae biotype  isolated from the cerebrospinal fluidantibioticmic ( g / ml)ampicillin0.25cefditoren<0.03cefcapene<0.03cefotaxime<0.03panipenem1telithromycin8clarithromycin<0.03meropenem<0.03ceftriaxone<0.03chloramphenicol1levofloxacin<0.5 minimum inhibitory concentration of several antibiotics for nontypeable haemophilus influenzae biotype  isolated from the cerebrospinal fluid a repeat csf culture on september 9 was also positive . blood culture was not repeated . on september 12 ,
, ctrx was stopped when the serum crp had remained within the normal range for 7  days . on september 28 ,
because of the unusual finding of nthi meningitis , further investigations were performed on the child .
the results revealed normal levels of immunoglobulin g ( igg ) , igg subtypes , iga , igm , cd4 , cd8 , and of the blood complement components .
cranial and paranasal sinus computed tomography and magnetic resonance imaging of the head were normal .
dexa dexamethasone , ctrx ceftriaxone , mepm meropenem , wbc white blood cell , crp c - reactive protein clinical course of a 2-year - old girl with nontypeable haemophilus influenzae meningitis .
dexa dexamethasone , ctrx ceftriaxone , mepm meropenem , wbc white blood cell , crp c - reactive protein
we report a rare case of meningitis and septicemia caused by nthi biotype . this case demonstrates that nthi should be borne in mind as a potential pathogen that can cause meningitis and septicemia , even in previously healthy children .
almost all cases of h. influenzae meningitis in unvaccinated children are caused by hib or biotype  strains .
in contrast with hib , nthi is primarily recognized as a commensal organism in the upper respiratory tract . however , nthi biotype  seems to have the potential to cause invasive disease such as meningitis [ 4 , 9 , 10 ] and septicemia [ 7 , 9 ] .
therefore , children presenting with invasive nthi disease should be promptly subjected to further evaluation and diagnostic imaging for identifying predisposing factors such as head trauma , csf leakage , and immune compromise . concerning the possible route of transmission of nthi biotype 
, it seems likely that the meningitis and septicemia in our patient were caused by the strain isolated from her throat culture , because all strains isolated from the csf , blood , and throat belonged to identical biotypes and the mic distributions were almost identical .
a subgroup of nthi strains is spontaneous capsule - deficient progeny of hib strains called b strains .
the b strains might be generated by loss of their capsulation ability through homologous recombination .
the frequency of b strains in hib is 0.10.3% [ 14 , 18 , 19 ] .
the b strains can not be ruled out for our patient s strain , because the slide agglutination test against the capsular serotypes are not able to differentiate between nthi and b strains . since the 1980s , when hib conjugate vaccines were introduced in many foreign countries , the incidence of hib meningitis has decreased dramatically . as a consequence , nthi has become relatively more important as a pathogen for meningitis . in december 2008 , hib conjugate vaccine was introduced in japan . since the introduction of hib conjugate vaccine , investigation of capsular serotypes is necessary in all cases of h. influenzae meningitis , because hib vaccine does not protect against meningitis due to nontypeable strains .
we conclude that nthi biotype  must be borne in mind as a potential pathogen that can cause meningitis and septicemia , even in previously healthy children .
 nontypeable haemophilus influenzae ( nthi ) commonly colonizes the upper respiratory tract of children and causes otitis media , sinusitis , and bronchitis . 
 invasive nthi diseases such as meningitis and septicemia have rarely been reported , especially in children with underlying predisposing conditions such as head trauma and immune compromise . 
 however , we report a previously healthy 2-year - old girl who developed meningitis and septicemia caused by nthi biotype . she was treated with dexamethasone , meropenem , and ceftriaxone , and recovered uneventfully . 
 we wish to emphasize that nthi should be borne in mind as a potential pathogen that can cause meningitis and septicemia , even in previously healthy children . 
Introduction
Case report
Discussion