++
Although the types of infectious diseases caused by Haemophilus
influenzae have changed considerably in recent years as
a result of the widespread implementation of routine childhood immunization
against type b organisms, this organism remains an important pathogen.
There are two major categories of H influenzae:
unencapsulated strains (untypeable, NTHi) and encapsulated strains (typeable).
The unencapsulated strains are responsible chiefly for infections
at mucosal surfaces, including conjunctivitis, otitis media, sinusitis,
and bronchitis. In contrast, one of the six antigenically distinct
encapsulated strains, strain type b, is associated with most invasive
diseases such as septicemia, meningitis, cellulitis, septic arthritis,
epiglottitis, and pneumonia. Prior to the availability of an effective
vaccine, H influenzae type b (Hib) was the most
common cause of pediatric bacterial meningitis in the United States.
++
Humans are the only natural host for H influenzae.
Maintenance of the organism in the human population depends on person-to-person transmission,
which appears to occur by the respiratory tract to hand to respiratory
tract route. This mode of transmission was best documented during
nosocomial outbreaks of NTHi pneumonia in the elderly. Nontypeable strains
colonize the upper respiratory tract of as many as 75% of
healthy adults. Type b H influenzae (Hib) strains
colonize the nasopharynx of children at a rate of 3% to
5%; the effectiveness of the conjugate vaccines is related
(in part) to their ability to diminish the incidence of nasopharyngeal
colonization (see below). Although both nontypeable and type b strains
of H influenzae are easily spread via person-to-person
transmission, only the Hib strains have historically been associated
with invasive disease in children. Nasopharyngeal colonization by
Hib is for the most part asymptomatic, but breakthrough bacteremia with
subsequent development of focal infection was at one time a common
occurrence and a major pediatric public health problem in the United
States.
++
In the prevaccine era, invasive Hib disease characteristically
had a striking age-related incidence, with approximately 85% of
disease occurring in children younger than 5 years. The peak incidence
of the most serious form of invasive disease, meningitis, occurred
between 6 and 12 months of age. Hib epiglottitis was, in contrast,
predominantly a disease of older children, with more than 80% of
the infections occurring in children older than 2 years. In the
prevaccine era, approximately 20,000 instances of invasive Hib disease
occurred annually in the United States, affecting about 1 in 200
children younger than 5 years.1
++
Chronic illnesses associated with increased risk for invasive
Hib disease include sickle cell disease, asplenia, agammaglobulinemia,
trisomy 21, Hodgkin disease, and complement deficiencies. Increased
risk has also been associated with childcare attendance, the presence
of siblings younger than 5 years, household crowding, lower socioeconomic
status, and passive smoke exposure. Breast-feeding confers some protection
against disease. A bimodal seasonal disease pattern has been described,
with one peak of illness in the autumn between September and December, and
a second peak in the spring between March and May.2 Although
invasive Hib infection has historically been uncommon in adults,
apparently due to the gradual development of protective antibodies
over time in the context of asymptomatic nasopharyngeal colonization,
Hib can occasionally cause invasive infection in adult patients. Remarkably,
in a post-Hib vaccine era, Hib meningitis has now become more common
in adult patients than in children. Surveillance data in Canada
and from the Centers for Disease Control and Prevention in the United States
has indicated an increasing incidence of invasive H influenzae disease
in adults.3 It does not appear that the increasing
prevalence is due to emergence of more virulent H influenzae.
A more plausible explanation is that there are more adults with
chronic underlying disease, which predisposes them to invasive H influenzae infection.
++
The epidemiology of invasive Hib disease has changed dramatically
in recent years as a consequence of the widespread administration of
conjugate vaccines. In 1987, the first Hib vaccine (purified capsule
polysaccharide, PRP) was licensed in the United States for administration
to children 18 months of age and older. Over the next few years,
dramatic decreases in the incidence of invasive disease were seen
in older children. However, because Hib meningitis had always been
a more significant problem in children younger than 1 year, the
most significant decline in invasive disease was not observed until
late 1990, when protein-PRP conjugate vaccines were approved for
use in infants, beginning at 2 months of age.
++
The epidemiology of invasive Hib disease has changed dramatically
in recent years as a consequence of the widespread administration of
conjugate vaccines.
++
In populations with high rates of vaccine coverage, the incidence
of Hib disease has been reduced by more than 95%.1 The
protective efficacy of these vaccines exceeded initial expectations
because of an unanticipated decrease in nasopharyngeal carriage, ultimately
leading to a decreased environmental burden of Hib and a resultant
protection even of unimmunized children, an effect of “herd
immunity.” The conjugate vaccines are so effective in preventing
Hib infection that the finding of invasive disease in a fully immunized
child should prompt further diagnostic evaluation for the possibility
of an underlying immunodeficiency.
++
With the widespread introduction of the type b conjugate vaccines,
there have been concerns that serotype replacement might occur.
Sepsis and meningitis due to serotype a strains, the second most
common cause of invasive disease prior to type b vaccine, have been
recognized with increasing frequency.4 Modern epidemiology
can no longer rely on agglutination of strains with animal-derived antisera
for serotyping because there are both false-positive and false-negative
reactions. The characterization of the strains by polymerase chain
reaction is expensive and time consuming, but is necessary for acquiring
an understanding of the apparent increase in invasive H
influenzae infections.5
++
An important aspect of Hib epidemiology is the risk it poses
to contacts. Although the direct contagiousness of invasive Hib
infection is limited, a significant risk for secondary disease exists
among household contacts of a patient with invasive Hib disease,
particularly in the 30 days following exposure to an index patient.
This is a consequence of spread under conditions of continuous household
exposure. Colonization rates higher than 70% have been noted
following exposure in closed populations, such as within families
or in daycare centers. This becomes the rationale for chemoprophylaxis
following exposure to an invasive case of Hib disease (see below).
++
Another less common but recently recognized route of acquisition
of H influenzae is vertical transmission via the
birth canal. This phenomenon has been manifest in recent years as
a “typical” cause of early onset pneumonia. These
NTHi can cause neonatal bacteremia and meningitis after acquisition from
the genital tract. These strains are genetically distinct from those
colonizing the upper respiratory tract and are occasionally a cause
of neonatal conjunctivitis.6
++
H influenzae is a small gram-negative coccobacillus
that may show considerable microscopic pleomorphism, necessitating
careful and cautious interpretation of Gram stains of clinical specimens
(Fig. 263-1). Biochemical identification
of H influenzae is based on the demonstration that growth
on rich media (blood agar) is dependent on supplements, factors
X and V, as found in chocolate agar. The X factor is a heat-stable,
iron-containing protoporphyrin (hemin) essential for the function
of enzymes of the electron transport chain. The V factor is a heat-labile coenzyme, β-nicotinamide
adenine dinucleotide (NAD). Although both factors are present in erythrocytes,
the V factor must be released from the cell in order to sustain
replication, and hence standard blood agar is an unsatisfactory
media for growth of H influenzae. The V factor
may be exogenously provided or derived from lysed red blood cells;
heated blood agar (chocolate agar) provides both factors. The growth
of H influenzae is fastidious, and the viability
of the organism is lost rapidly, necessitating expeditious handling
of clinical specimens. Following overnight incubation, NTHi form gray
colonies that are 0.5 to 0.8 mm in diameter and rough or granular
in appearance. Encapsulated strains typically produce larger, smooth mucoid
or iridescent colonies.
++
++
The polysaccharide capsule of H influenzae has
a central role in the virulence of invasive H influenzae.
Six antigenically and biochemically distinct capsular polysaccharide
subtypes (a-f) have been identified. Although type b encapsulated
strains have historically been of primary clinical and immunologic
importance (because of the association with invasive infection,
including meningitis), the other encapsulated strains are also capable
of producing invasive disease. Lipopolysaccharide (LPS) is another
important component of the H influenzae cell wall
that contributes to pathogenesis. Although chemically different
from the LPS of the Enterobacteriaceae, the biological activity of
Hib LPS is similar to that of other gram-negative endotoxins. Multiple
adhesins target specific cells of the airway and provide redundancy
for adherence to respiratory tissues. H influenzae encodes
three distinct IgA proteases that may play a role as virulence factors
by interfering with host mucosal defenses.7 Another
clinically important aspect of the molecular microbiology of H
influenzae has been the identification of genes responsible
for antimicrobial resistance.
++
Plasmid-mediated ampicillin resistance due to production of β-lactamase
has become extremely common in Hib and NTHi, ranging from 5% to
50% of isolates in various parts of the world. Non-β-lactamase–mediated
ampicillin resistance is increasing in the United States; thus,
susceptibility testing should be performed on all isolates identified
in invasive infections.8
++
The molecular determinants responsible for nasopharyngeal colonization
and subsequent invasiveness of H influenzae remain
poorly understood. Invasive disease requires the spread of bacteria
from the upper respiratory tract to the bloodstream, and subsequently,
to other body sites. All H influenzae examined
to date can adhere to, transcytose, and invade human respiratory
epithelium in in vitro models. In the submucosa, the bacteria can
be found within macrophagelike cells and may be transported to the
systemic circulation via these cells. The size of the bacterial
inoculum and the intercurrent presence of a viral respiratory tract
infection are factors that potentiate the risk of invasive disease.
Those strains able to resist complement-mediated lysis (those with
capsule) or opsonophagocytosis (because of a lack of “natural” antibody)
can then replicate in the bloodstream, causing invasive disease.9 Although
meningitis constitutes more than half of all recognized invasive
Hib disease, other potential metastatic sites include the lungs,
joint synovium, pleura, peritoneum, and pericardium.
++
Noninvasive or mucosal infections are much more frequent than
invasive disease, particularly in the postvaccine era. Nontypeable
strains of H influenzae seldom cause bacteremia
in children beyond the neonatal period. It is therefore presumed
that these infections represent extensions of H influenzae from
the respiratory mucosa to contiguous body sites. Noninvasive infections
include otitis media, sinusitis, bronchitis, and pneumonia. Local
extension of nontypeable H influenzae can occur
via the eustachian tube, bronchi, or through the sinus passages.
Disease is more likely if normal clearance mechanisms or immune
function are impaired, such as after viral infection, sinus obstruction,
or eustachian tube dysfunction.
++
Age-dependent susceptibility to Hib infections correlates with
an age-dependent nature of immune response to Hib surface components. In
a population, an average low incidence of antitype b capsular antibody
correlates with a high incidence of disease. However, this correlation
is skewed by a few individuals having high anti-PRP titers. When
individuals are examined, the bactericidal titer does not correlate
with the anti-PRP titer. At the age of maximal risk for infection
(when the nadir of protective transplacental immunity is reached),
bactericidal antibodies are low or absent. The bactericidal activity
of children and adults against Hib and certain NTHi is directed
against LPS and outer membrane proteins. Even after recovery from an
invasive Hib illness, anticapsular antibody levels in infants remain
low. As a consequence, instances of second or third episodes of invasive
Hib disease are well described; thus, a previous episode of invasive
infection does not obviate the need for Hib immunization. This failure
to make serum anti-PRP antibodies is typical of the natural delay
in immune response of infants to polysaccharide antigens. PRP stimulates
B cells but does not adequately activate macrophages and appropriate
T-helper cells, and therefore it is considered to be a T-cell-independent
antigen. The characteristics of T-cell-independent antigens include
limited immune responses, particularly in young infants; no booster
response occurs with repeated antigenic stimulation, and production
of antibody that is of low affinity and mostly consisting of IgM.
The development of a Hib vaccine that was more immunogenic and protective
for young infants required conversion of PRP from a T-cell-independent
antigen to a T-cell-dependent antigen, using the principles of carrier-hapten
linkage.10
+++
Clinical Manifestations
of Disease Caused by Typable Strains
++
Prior to Hib conjugate vaccines, meningitis was the most common
and serious manifestation of invasive Hib disease. The differential diagnosis
and clinical manifestations of meningitis are detailed in Chapter 231. The sequelae from Hib meningitis
differ from other causes of bacterial meningitis. Approximately 30% of
children will have seizures at some point in the course of Hib meningitis.
Like patients with meningococcal disease, children with Hib bacteremia
can have a petechial rash. They can also have a secondary site of
infection, such as a septic arthritis or facial cellulitis (see
below). Shock is present in approximately 20% of cases.
Anemia is common, the result of a combination of accelerated red
blood cell destruction and diminished erythropoiesis. Complications
of H influenzae type b meningitis include subdural
effusion or empyema, ischemic or hemorrhagic cortical infarction,
cerebritis, ventriculitis, intracerebral abscess, and hydrocephalus.
Intravenous antibiotics and supportive care are the mainstays of
therapy, but the mortality from Hib meningitis remains approximately
5%, even with prompt diagnosis. Long-term sequelae occur
in 15% to 30% of survivors and are manifest as
sensorineural hearing loss, language disorders, mental retardation,
and developmental disorders. A meta-analyses of randomized controlled
clinical trials in children has shown that the incidence of severe hearing
loss due to H influenzae was decreased by the administration
of corticosteroids, an effect that was more evident in children
in high-income countries.11
++
Acute upper airway obstruction caused by Hib infection of the
epiglottis and supraglottic tissues is perhaps the most dramatic
and rapidly progressive form of disease caused by this organism.
In contrast to the peak incidence of meningitis in children younger
than 1 year, epiglottitis occurs primarily in older children (2–7
years of age) and usually has an abrupt onset with high fever, dysphagia, drooling,
and toxicity. Occasional cases of Hib epiglottitis are still observed
in older children who were never fully immunized, and Hib is also
an important cause of epiglottitis in adult patients.
++
Classically, the child with Hib epiglottitis will drool because
of an inability to swallow oropharyngeal secretions. Progressive
respiratory distress develops over a period of hours with tachypnea,
stridor, cyanosis, and retractions. The patient may sit forward
with the chin extended to maintain an open airway (“tripod” position). Few
conditions produce such a striking constellation of symptoms and
findings. A lateral neck radiograph is helpful if the clinical presentation is
subtle, but the study should be performed cautiously and without
undue delays, with a physician experienced in airway management
in attendance (Fig. 263-2). Diagnostic studies should
not delay the need for direct inspection of the epiglottis in the
operating room and insertion of an endotracheal tube (Fig.
263-3). The mortality rate is 5% to 10% and
is invariably related to poor control of the airway early in illness.
++
++
+++
Septic Arthritis/Osteomyelitis
++
In the prevaccine era, Hib was the leading cause of septic arthritis
in children younger than 2 years. Approximately 8% of H
influenzae invasive disease presents as septic arthritis, typically
affecting large joints, particularly knees, ankles, hips, or elbows.
A contiguous osteomyelitis may be present, but isolated osteomyelitis
without an adjacent septic joint is uncommon. Characteristically,
there is a preceding nonspecific illness, followed by pain, swelling,
and erythema of the involved joint. Clinical signs in children with
a septic hip may be less prominent than for other joints, with findings
limited to decreased range of motion of the joint, often with the
leg abducted at the hip and externally rotated. In some cases, pain is
referred from the hip to the lower leg. Septic arthritis of the
hip joint requires surgical drainage; the majority
of cases involving the shoulder also require open drainage. There
is a strong association of septic arthritis with meningitis, necessitating
lumbar puncture in these patients.
++
H influenzae type b cellulitis usually involves the
face, head, or neck. The vast majority of cases occur in the first
2 years of life. Buccal cellulitis, seen almost exclusively in children during
the first year of life, presents as a raised, warm, tender, and
indurated area that progresses to a violaceous hue. The clinical
presentation may mimic erysipelas. Periorbital (preseptal) cellulitis
is similarly seen in young children and often occurs in the setting
of contiguous sinus disease. It must be differentiated by appropriate imaging
from the more serious orbital cellulitis. Hib cellulitis is a bacteremic
disease, and meningitis must be excluded by lumbar puncture.
++
Although the vast majority of children with Hib bacteremia present
with a focus of infection, occasionally bacteremia can be the sole
manifestation of disease in the febrile child. These children are
usually younger than 2 years and have temperatures of 39°C (102.2°F)
or higher. In the prevaccine era, Hib was the second leading cause
of occult bacteremia, behind Streptococcus pneumoniae. However,
there is an important distinction between Hib and pneumococcal bacteremia,
whereas most episodes of untreated occult pneumococcal bacteremia resolved
spontaneously without sequelae, 30% to 50% of
children with occult Hib bacteremia will develop focal infections,
including meningitis. Hence, in any child with a positive blood culture
for Hib, the possibility of meningitis must be seriously considered.
++
Hib pneumonia is clinically indistinguishable from other bacterial pneumonias.
It was estimated to cause as many as one third of cases of documented
bacterial pneumonias in the prevaccine era. Radiologically, it can
appear as a segmental, subsegmental, interstitial, or lobar pattern.
There is a strong association with pleural effusion; 50% of
cases have evidence of pleural involvement on initial radiographic
examination. The most useful diagnostic test is the blood culture,
which is positive in almost 90% of cases. Complications
of Hib pneumonia include pericarditis, meningitis, and pleural empyema
often requiring decortication.
++
The classic presentation of H influenzae pericarditis
is that of a toxic child with fever, respiratory distress, and a
clear chest on examination. Associated conditions include pneumonia
and meningitis. Hib pericarditis may become clinically manifest
while a child is receiving antibiotic therapy and should be considered
in the differential diagnosis of the child with persistent fever
while receiving therapy for H influenzae meningitis.
Although the diagnosis may be suggested after careful inspection
of the cardiac silhouette and jugular veins, echocardiography is
the best modality for establishing the diagnosis of pericardial effusion. Pericardiocentesis
is the diagnostic procedure of choice. Early pericardectomy, in conjunction
with antibiotics, is the treatment of choice.
++
In recent years, H influenzae has been increasingly
recognized as a cause of bacteremia and meningitis in the neonatal
period. Neonatal infections are usually caused by nontypeable H influenzae,
which can also be cultured from the maternal genital tract, the
presumed source of the infection. The disease is one of early onset
sepsis, with more than 80% of cases occurring during the
first day of life. Maternal-to-fetal transmission probably occurs
in utero because the infection is associated with prematurity, low
birth weight, and maternal complications such as premature rupture
of membranes and chorioamnionitis.12 Routine therapy
with ampicillin and gentamicin for presumptive neonatal sepsis may
not be effective if an ampicillin-resistant strain of H
influenzae has caused the infection.
+++
Brazilian Purpuric
Fever
++
A nonserotypeable H influenzae, biogroup III (which
has characteristics identical to the Haemophilus aegyptius group),
is the etiology of Brazilian purpuric fever (BPF), first recognized
in children in southern Brazil. Following an antecedent episode
of purulent conjunctivitis, children with BPF become bacteremic
and present with fever, shock, and purpura indistinguishable from
that caused by meningococci. The disease has not been reported in
the United States.
+++
Other Invasive
Infections
++
Hib bacteremic disease has also been rarely associated with seeding
of other body sites. Endophthalmitis, glossitis, uvulitis, thyroiditis, endocarditis,
lung abscess, epididymitis, peritonitis, pericarditis, intraperitoneal
abscesses, hepatobiliary disease, and brain abscesses have been
reported.
+++
Clinical Manifestations Caused
by Nontypeable Strains
++
Nontypeable strains of H influenzae frequently
cause otitis media, sinusitis, conjunctivitis, and bronchitis, the
latter in adults. Conjunctivitis is usually bilateral and purulent,
and is often associated with acute otitis media (“conjunctivitis-otitis” syndrome).
Although these respiratory tract infections are common, they are
rarely life threatening and are not associated with bacteremia.
Prematurity, cerebrospinal fluid (CSF) leak, congenital heart disease, and
immunoglobulin deficiency may predispose to invasive disease with
nontypeable strains of H influenzae. In the absence
of these predisposing conditions, nontypeable H influenzae systemic
infection should prompt an immunologic investigation. Importantly, immunization
with conjugate Hib vaccines does not confer protection against nontypeable
strains: nontypeable H influenzae remains a major
cause of otitis media in children and appears to be increasing in
prevalence since the introduction of pneumococcal conjugate vaccines.
Encapsulated non-Hib strains of H influenzae are
increasingly identified as causes of invasive disease.13 An
apparent increase in reports of H influenzae types
a and f meningitis suggest that these organisms could conceivably “emerge” as
important causes of invasive disease in children in the post-Hib vaccine
era, although this trend has not yet become widespread.
++
The primary criterion for the diagnosis of H influenzae infection
is isolation of the organism from the infectious focus (blood, CSF,
or any other site of infection, such as joint, pericardial, or empyema
fluid). Patients with epiglottitis usually have positive blood cultures; cultures
from the inflamed epiglottis should be obtained only after the airway
has been secured. Whenever invasive disease is encountered, or meningitis
is suspected on clinical grounds, lumbar puncture should be performed.
Because the organism is fastidious, specimens should be processed
immediately after they are acquired. Gram stain should be performed
on any body fluid possibly infected with H influenzae.
Organisms are seen in about 90% of stained CSF smears in
patients with meningitis, and the Gram stain appearance of CSF has
important implications in the management of pediatric meningitis.
The appearance of gram-positive cocci suggests the possibility of
pneumococcal meningitis, and the possible need for empiric vancomycin
therapy, whereas the appearance of organisms consistent with H
influenzae suggests that antibiotic administration should
consider local resistance patterns. The CSF of a child with Hib
meningitis characteristically has a marked pleocytosis, a low glucose
concentration, and an elevated protein concentration, but these findings
are not specific for the diagnosis of Hib meningitis.
++
The type b capsular polysaccharide (PRP) can be detected in body
fluids (serum, urine, joint fluid, CSF) from children with invasive
disease. The three most commonly used assays are countercurrent
immunoelectrophoresis (CIE), latex particle agglutination (LPA),
and coagglutination (CoA). The tests are most useful when performed
on CSF from children with meningitis who have been pretreated with
antibiotics because cultures may be unrevealing in this setting.
Unfortunately, immunization with the Hib conjugate vaccines often
results in urinary excretion of antigen for days to weeks, and such false-positive
results limit the usefulness of these assays in that fluid. False-positive
reactions are unusual in the CSF.
++
For infections caused by nontypeable strains of H influenzae,
antigen detection and blood cultures are of little diagnostic value
because bacteremia is rare. The diagnosis is usually clinical, although
a microbiological diagnosis can be established for pneumonia/bronchitis
by culture of sputum, for otitis media by diagnostic tympanocentesis,
for sinusitis by culture of sinus aspirate, and for conjunctivitis
by vigorous culture of the eye exudate containing epithelial cells
with adherent bacteria.
++
Because bacteremia is central in invasive H influenzae type
b disease, therapy must anticipate the need for adequate central
nervous system (CNS) penetration and be of sufficient duration to
sterilize the primary and any secondary foci. The emergence of antibiotic
resistance further necessitates that therapy of invasive infections
includes β-lactamase–stable agents. The
antibiotic susceptibility of H influenzae isolated
from the nasopharynx should not be used to guide therapy. Although a
correlation may exist between the specific nasopharyngeal strain
and that present in the middle ear, the correlation cannot be used
to guide therapy. In addition, the nasopharynx may yield nonhemolytic
Haemophilus haemolyticus, which is an avirulent commensal.
++
Because of the emergence of ampicillin-resistant isolates of H
influenzae in the setting of proven or suspected Hib meningitis, cefotaxime
or ceftriaxone are recommended until the antibiotic susceptibility
of the organism is known, or an alternative diagnosis is established.
Both antibiotics have bactericidal activity against Hib, including β-lactamase-producing
strains, and both penetrate well into infected CSF. Ceftriaxone
is approved for once-daily therapy of meningitis at a dose of 100
mg/kg/d and can be administered by daily intramuscular
injections if intravenous access is difficult, or used to complete
a course of outpatient therapy in the patient who is clinically
stable. Empiric therapy with ampicillin alone is not justified because
approximately 50% of Hib isolates in the United States
are resistant, although it is effective for isolates that are documented
to be susceptible. Other extended-generation cephalosporins with
indications for meningitis include ceftazidime and cefepime, but
because of their overly broad spectrum they are not desirable choices
for therapy of documented Hib meningitis. Vancomycin should be included
empirically (until culture results are available) for all cases
of pediatric meningitis in those areas of the United States where
levels of S pneumoniae resistance to penicillin are high and when
S pneumoniae cannot be excluded.
++
Meropenem is an acceptable alternative to third-generation cephalosporins
with a well-established track record of efficacy for pediatric meningitis,
including meningitis caused by Hib. However, meropenem does not
appear to have activity for strains of S pneumoniae with high-level
resistance to penicillins, and therefore should not be used as single-agent
therapy when pneumococcal meningitis is suspected.
++
Cefuroxime has good activity against H influenzae and
Staphylococcal aureus, and is a reasonable choice for empiric therapy
of some infections when H influenzae is in the
differential diagnosis, such as pneumonia, cellulitis, or bone and
joint infections. However, caution must be taken with this agent
if the diagnosis of meningitis has not been excluded because cefuroxime
is associated with delayed sterilization of the CSF.14
++
Although chloramphenicol became the drug of choice for Hib infections
shortly after the appearance of ampicillin-resistant strains in
the 1970s, with the emergence of the third-generation cephalosporins, chloramphenicol
is now rarely used because of the need to monitor serum levels to
prevent toxicity. In addition, chloramphenicol-resistant strains
are becoming increasingly prevalent in some parts of the world,
so local resistance patterns must be considered. However, ampicillin
in combination with chloramphenicol remains a reasonable option
for treatment of invasive Hib disease in the United States. Although
adequate blood levels of chloramphenicol can be achieved with oral administration,
it is usually advisable to initiate therapy intravenously. Oral chloramphenicol
has been used successfully to complete the course of antibiotic
therapy in invasive Hib disease, but the current lack of availability
of formulations of oral chloramphenicol in the United States limits the
usefulness of this option. Serum levels should be monitored and
maintained between 10 and 20 mg/L in all patients receiving chloramphenicol.
Although chloramphenicol has dose-related and reversible bone marrow toxicity,
this is usually evident only in the neonate, the child with liver
disease, or after prolonged treatment. Idiosyncratic aplastic anemia
in young children is very rare.
++
The duration of antibiotic therapy is determined by the site
of infection and the clinical response. Children with uncomplicated
Hib meningitis can be treated for 7 to 10 days. Children with cellulitis
can be changed to oral therapy after several days of parenteral
therapy, provided they have had a satisfactory clinical response
and do not have meningitis. Patients with septic arthritis should
receive at least 14 to 21 days of therapy, in conjunction with appropriate
surgical care. Children with pericarditis, empyema, or osteomyelitis
may require longer courses of intravenous antibiotic treatment (3–6
weeks) followed by a course of oral therapy. Children with occult
Hib bacteremia should be treated initially with parenteral antibiotics,
given the risk for focal infection.
++
Supportive therapy is also vital in the management of children
with invasive Hib disease. The recommended dose of dexamethasone
is 0.6 mg/kg/d divided every 6 hours for 4 days,
with the first dose given just before or with the first antibiotic
dose. Management of the child with meningitis requires anticipation
of complications such as shock, SIADH, subdural empyema, and secondary foci
of infection. Prolonged fever during treatment of Hib meningitis
is common and does not imply failure of the antibiotic regimen,
but should prompt consideration of additional foci of infection
(pericarditis, subdural effusion, etc). Children treated with dexamethasone have
a shorter duration of fever acutely, but are still at risk to develop
secondary fevers late in the course of illness.
++
In children with epiglottitis, the first priority is airway management.
Endotracheal intubation is optimally performed in the operating
room by an experienced anesthesiologist. If it can be done safely,
cultures of the epiglottis may be obtained at this time, and blood
cultures should be obtained once the airway is secure. Intravenous
antibiotics should be provided as soon as possible.
++
For patients with joint infections, subdural empyema, pericarditis,
or pleural empyema, surgical consultation is required. Infected
joint fluid should be aspirated from the child with septic arthritis,
particularly with septic arthritis of the hip joint, to reduce pressure
and to prevent avascular necrosis of the femoral head. Most orthopedic
surgeons prefer open drainage of the hip.
++
Numerous orally administered antimicrobials are available to
treat respiratory tract infections caused by nontypeable H
influenzae. Generally, therapy in this setting is empiric, without
specific culture confirmation of H influenzae as
the etiology. Despite the increasing prevalence of β-lactamase–producing
organisms, both among Hib strains and nontypeable H influenzae,
amoxicillin remains the drug of choice for empiric therapy of acute
otitis media and sinusitis because of its low cost and safety. Agents
with activity against β-lactamase-producing organisms
should be used if amoxicillin therapy fails. Consideration must
be given to performance of diagnostic tympanocentesis in such patients,
particularly to exclude the possibility of high-level, penicillin-resistant
isolates of S pneumoniae. Among the available alternative antimicrobials
are amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, erythromycin-sulfisoxazole,
newer macrolides such as clarithromycin and azithromycin, and second- and
third-generation oral cephalosporins, such as cefuroxime axetil,
cefixime, cefpodoxime, cefdinir, cefprozil, and loracarbef.
++
Two modalities are available to prevent Hib disease: chemoprophylaxis
to prevent secondary disease and active immunization to prevent
endemic disease. The widespread success of immunization has rendered
chemoprophylaxis largely of historical interest only.
++
Many studies have documented the increased risk of invasive disease
among household contacts in the month following onset of disease
in the index case. The attack rate is a function of age, approaching
4% in children younger than 2 years. Rifampin is the most
effective antibiotic for eradicating Hib from the nasopharynx, primarily
because of its exquisite ability to penetrate respiratory secretions.
Children younger than 12 years should receive 20 mg/kg
once daily for 4 days, and adults should receive 600 mg once daily
for 4 days. The quinolones may also be effective, although they
are not approved for this use in children. Prophylaxis should be
instituted as soon as possible because the risk of secondary disease
is greatest during the few days after disease onset in the index
patient. Prophylaxis is recommended only if it can be given within
2 weeks of disease onset. Because therapeutic antibiotics do not
consistently eradicate Hib from the nasopharynx, rifampin should
also be given to the index patient prior to hospital discharge.
Although there have been daycare-associated outbreaks of invasive
Hib disease, the use of rifampin chemoprophylaxis in childcare settings
remains controversial, primarily because the risk of secondary disease
in this setting is not well defined. Coordination with the local
health department and consultation with an expert is warranted.
Fortunately, most childcare attendees are now immunized and therefore
at low risk of secondary disease.
++
The first vaccine used in an effort to prevent Hib invasive disease
was a purified type b capsular polysaccharide vaccine, introduced
in the United States in 1985. Postlicensure, the majority of studies
suggested that protection afforded by this vaccine was, at best,
marginal. By 1988, this vaccine was replaced by the more immunogenic
conjugate vaccines. These vaccines covalently linked PRP (the process of “conjugation”)
to an immunogenic carrier protein, in the process creating a semisynthetic
carrier-hapten. With these vaccines, much higher levels of antibodies
are induced, particularly in infants and young children; booster responses
are seen with subsequent injections; and the antibody is predominantly
IgG. Four Hib-conjugate vaccines have undergone extensive evaluation
in humans and have been licensed for use in infants beginning at
2 months of age. All four Hib-conjugate vaccines evoke protective
immunity. Recommendations for Hib vaccination are detailed in Chapter 244.