Pediatric Haemophilus Influenzae Infection 

Updated: Apr 04, 2016
Author: Mobeen H Rathore, MD, CPE, FAAP, FIDSA; Chief Editor: Russell W Steele, MD 

Overview

Background

Although the type of infectious diseases caused by Haemophilus influenzae has changed considerably in recent years because of the widespread and routine immunization of children against type b organisms, H influenzae remains a significant pathogen. The recent vaccine shortage in the United States from December 2007 to September 2009 is a reminder that despite the decline in the incidence of invasive disease, Hib immunization remains critical in the control of the disease.[1]

First isolated in 1892 by Robert Pfeiffer from the sputum of patients with pandemic influenza infection, H influenzae was thought to be the infectious agent responsible for flu. In 1920, the organism was named Haemophilus influenzae (from the Greek haemophilus, meaning "blood-loving") to reflect the fastidious growth requirement of the organism, as well as its apparent association with influenza. In 1933, the discovery of the viral etiology of influenza eventually refuted this erroneous association. Nevertheless, subsequent findings revealed that H influenzae was responsible for a wide spectrum of clinical diseases.

In the 1930s, Margaret Pittman defined 2 major categories of H influenzae: the unencapsulated strains and the encapsulated strains. The unencapsulated strains were chiefly responsible for infections at mucosal surfaces, including otitis media, conjunctivitis, bronchitis, and sinusitis. In contrast, one of the 6 antigenically distinct encapsulated strains, strain type b, was associated with invasive diseases (eg, septicemia, meningitis, cellulitis, septic arthritis, epiglottitis, 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.

Pathophysiology

Pathogenesis

A major virulence factor of H influenzae is its polysaccharide capsule, which plays a central role in molecular pathogenesis and the immune response. Six antigenically and biochemically distinct capsular polysaccharide subtypes (a-f) have been identified (see Laboratory Studies). Although, historically, type b encapsulated strains have been of primary clinical and immunologic importance because of their association with invasive infection, including meningitis, the other encapsulated strains also can cause invasive disease.

The type b capsular polysaccharide is well characterized at the molecular level. It is composed of repeating heteropolymers of ribosyl and ribitol phosphate. Rapid diagnostic latex agglutination tests are available for the identification of this polyribosyl ribitol phosphate (PRP) after its release in infected patients. This polysaccharide structure is unique to type; the other capsular Haemophilus serotypes are composed of hexose rather than pentose sugars.

Another important component of the H influenzae cell wall that contributes to pathogenesis is lipopolysaccharide (LPS). Although chemically different from the LPS of the Enterobacteriaceae, the biological activity of Hib LPS appears to be similar to that of other gram-negative endotoxins. Finally, numerous outer membrane proteins have recently been identified as important components of pathogenesis and immunity. Pili (or fimbriae), fibrils, and a protein called Hia mediate adherence of Hib to cells of the human respiratory tract. The multiple adhesins target specific cells of the airway and provide redundancy for adherence to respiratory tissues. H influenzae encodes 3 distinct immunoglobulin A (IgA) proteases that may be involved as virulence factors by interfering with host mucosal defenses.

Because the entire genome of a laboratory strain of H influenzae has been sequenced, additional insights into its molecular mechanisms of pathogenesis will undoubtedly be gained in the near future.

Age-related susceptibility and immune response

In pioneering experiments in the 1930s, Fothergill and Wright demonstrated that blood obtained from children aged 3 months to 3 years lacked bactericidal activity against type b strains, whereas the blood of neonates, older children, and adults was bactericidal. Eventually, this effect was shown to depend on the presence of a specific antibody against the type b capsule. In 1942, Alexander proposed that the polyribosyl ribitol capsular polysaccharide was intrinsically antiphagocytic and that efficient ingestion by phagocytes was facilitated by opsonization with type-specific antibodies.

Subsequent evidence has demonstrated that antibody to PRP protects individuals against invasive disease. It activates complement, is opsonophagocytic, and protects animals from experimental challenge. Indeed, passive transfer of type b antiserum was shown to be effective in the treatment of Hib disease in the preantibiotic era. Ultimately, the most compelling evidence for the protective properties of anticapsular antibody is the observation that purified PRP vaccines confer protection. Induction of the antibody to the type b capsular polysaccharide is the means by which all Hib vaccines result in protection.

The age-dependent susceptibility to infections is correlated with the age-dependent nature of the immune response to Hib capsular polysaccharide. When infants are at maximal risk of infection (ie, at the nadir of protective transplacental immunity), their serum anti-PRP antibody levels are low or absent. Even after they recover from illness, their antibody levels are low and their immune responses are poor. As a consequence, second or third episodes of invasive Hib disease are described, and a previous episode of invasive infection does not obviate Hib immunization. Infants' failure to make serum anti-PRP antibodies is typical of the natural delay in the development of their immune response to polysaccharide antigens.

PRP stimulates B cells but does not adequately activate macrophages and appropriate helper T cells. Therefore, it is considered to be a T-cell–independent antigen. Characteristics of T-cell–independent antigens include the following: immune responses to them are limited, particularly in young infants; no booster response occurs with repeated antigenic stimulation; and the antibodies have low affinity to the antigen and mostly consist of immunoglobulin M (IgM). The development of a Hib vaccine that was more immunogenic and protective in young infants required the conversion of PRP from a T-cell–independent antigen to a T-cell–dependent antigen; the principles of carrier-hapten linkage were used to accomplish this.

The role of other host immune responses in limiting Hib disease is poorly understood. PRP-specific IgA antibodies have been described. This finding suggests a possible role for secretory antibodies that can block Hib attachment to the respiratory tract mucosa, but the clinical relevance of this proposed mechanism remains to be demonstrated. Complement also appears to be involved in the host defense against Hib. Both encapsulated and unencapsulated strains of H influenzae activate the classical and alternative complement pathways in vitro. The clinical correlates of this observation are the results suggesting that individuals with C2, C3, and C4b deficiencies are more susceptible to invasive Hib disease.

Antimicrobial resistance

Another clinically important aspect of the molecular microbiology of Hib is the identification of the genes responsible for its antimicrobial resistance. Resistance to ampicillin has become extremely common; 5-50% of isolates in various parts of the world are resistant. The mechanism of resistance typically is due to the presence of a plasmid-encoded enzyme, beta-lactamase. Plasmid-encoded resistance to chloramphenicol, tetracycline, and sulfonamides can exist independently; in some countries, multiple resistance determinants reside on the same plasmid. Chromosomally mediated antibiotic resistance, due to the accumulation of point mutations, most commonly involves amoxicillin. This resistance is low level and can coexist with plasmid-mediated resistance. Trimethoprim resistance most commonly is due to mutations in chromosomal dihydrofolate reductase. Susceptibility testing should be performed with all isolates identified in invasive infections.

Transmission and infection

Humans are the only natural host for H influenzae. Therefore, maintenance of the organism in the human population depends on person-to-person transmission, which efficiently occurs via respiratory droplet spread. Although both nontypeable strains and Hib easily are spread via person-to-person transmission, Hib strains have historically been associated with invasive disease in children. Before effective vaccines were available, nasopharyngeal acquisition of Hib occurred in most children aged 5 years or younger. Although nasopharyngeal Hib colonization may not produce symptoms, breakthrough bacteremia with subsequent focal infection was common at one time, and it was a major public health problem in children in the United States.

The molecular determinants responsible for the nasopharyngeal colonization and subsequent bacteremic invasiveness of Hib remain poorly understood. Invasive disease requires the spread of bacteria from the upper respiratory tract to the bloodstream and, subsequently, to other body sites. The organism must first colonize the respiratory mucosal epithelium, and several bacterial surface proteins appear to play an important role in the attachment process. The organism then invades the nasal mucosa. The exact mode of entry of the organism into the blood vessel is unknown; it may enter via the lymphatics. The size of the bacterial inoculum and the intercurrent presence of a viral respiratory tract infection potentiate the risk of invasive disease.

It has been suggested that H influenzae can invade and enter respiratory epithelial cells by means of transcytosis. Strains that are able to resist lysis by the complement system (ie, those with a capsule) or opsonophagocytosis (due to the lack of a natural antibody) then can replicate in the bloodstream, causing invasive disease. As organisms divide, bacteremia increases steadily over hours. When bacteremia occurs, its magnitude and duration are determined by the dynamics of bacterial proliferation and clearance by anti-PRP antibodies and phagocytes. When the bacterial concentration exceeds 104 organisms per milliliter, metastatic seeding occurs, especially to the meninges via the choroid plexus. Although the meninges are involved in more than half of recognized cases of invasive Hib disease, other potential metastatic sites include the lungs, joint synovium, pleura, peritoneum, and pericardium.

Noninvasive or mucosal infections are much more common than invasive disease, particularly in the postvaccine era. These generally are due to nontypeable strains of H influenzae, and bacteremia seldom is present. Therefore, these infections are presumed to 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 tubes, bronchi, or sinus passages. Disease is more likely if normal clearance mechanisms or immune function is impaired, for example, after viral infection, sinus obstruction, or eustachian tube dysfunction.

Risk factors and epidemiology

Chronic illnesses associated with an increased risk of invasive Hib disease include sickle-cell disease, asplenia, agammaglobulinemia, Hodgkin disease, and complement deficiencies. Risk is also increased in those who attend daycare and in those who have young siblings, a crowded household, a lower socioeconomic status, or exposure to cigarette smoke. Breastfeeding confers some protection against disease.

The epidemiology of invasive Hib disease has changed dramatically in recent years because of the widespread use of conjugate vaccines. In 1987, the first Hib vaccine (purified PRP) was licensed in the United States for use in children aged 18 months and older. Over the next few years, the incidence of invasive disease dramatically decreased in older children. However, because Hib meningitis was a greater problem in infants younger than 1 year, the most significant decline was not observed until late 1990, when protein-PRP conjugate vaccines were approved for use in infants aged 2 months or older. In populations with high rates of vaccination, the incidence of Hib disease has decreased by more than 95%. While the vaccine shortage between 2007-2009 did not result in an overall increased incidence of Hib invasive disease, cases in infants whose vaccinations were deferred were reported.[2] The trends in Hib diseases epidemiology need closemonitoring.

The protective effectiveness of these vaccines exceeded initial expectations. This result was attributed to their direct effect on nasopharyngeal carriage, which ultimately decreased the environmental burden of Hib and protected even unimmunized children because of the 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 suggest the possibility of an underlying immunodeficiency and prompt further diagnostic evaluation.

An important epidemiologic aspect of Hib disease is the risk that it poses to contacts of the affected person. Although the direct contagiousness of invasive Hib infection is limited, household contacts have a significant risk of secondary disease, particularly in the 30 days after their exposure to the index patient. This risk is related to droplet spread under conditions of continuous household exposure. Colonization rates of more than 70% have been noted after exposure in closed populations, such as those in families or daycare centers. This is the rationale for chemoprophylaxis after exposure to invasive Hib disease.

Another less common but recently recognized route of exposure is the vertical transmission of H influenzae via the maternal birth canal. In recent years, this phenomenon has been evidenced by an increase in cases of neonatal bacteremia and meningitis caused by nontypeable strains acquired from the mother's genital tract. These strains are genetically distinct from those that colonize the upper respiratory tract.

A bimodal seasonal disease pattern has been described; one peak occurs in autumn between September and December, and a second occurs in spring between March and May. Historically, invasive Hib infection has been uncommon in adults (apparently because of the gradual development of protective antibodies over time in the context of asymptomatic nasopharyngeal colonization), but Hib occasionally can cause invasive infection in adults. Remarkably, in the postvaccine era, Hib meningitis is more common in adults than in children. The effect of routine childhood Hib immunization on the epidemiologic characteristics of adult infections, if any, remains to be seen.

Epidemiology

Frequency

United States

Nontypeable strains colonize the upper respiratory tract in as many as three fourths of healthy adults. Hib strains colonize the nasopharynx of 3-5% of children; the effectiveness of vaccines is related, in part, to their ability to dramatically diminish the prevalence of nasopharyngeal colonization.

In the prevaccine era, invasive Hib disease had a characteristic and striking age-related prevalence; approximately 85% of cases occurred in children younger than 5 years. The peak prevalence of the most serious form of invasive disease, meningitis, occurred in infants aged 6-12 months. 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 approximately 1 child in every 200 younger than 5 years.[3] Certain high-risk groups, including Navajo and Alaskan Native Americans, had an even higher incidence of disease.

International

Hib continues to be a major cause of sepsis and meningitis in the developing world, where resources for widespread immunization programs are not available. In addition, a nonserotypeable H influenzae biogroup III (which is identical to the Haemophilus aegyptius group) has been shown to be the cause of a disease called Brazilian purpuric fever (BPF), which was discovered in children in southern Brazil.

A population-based observational study in England found the incidence of H influenzae meningitis per 100,000 children decreased from 6·72 admissions in 1992 to 0·39 admissions in 1994, after the introduction of routine H influenzae type b vaccination. The study also saw a small rise in admissions in the early 2000s which decreased by 2008 after the introduction of catch-up (2003) and routine (2006) booster programs for young children.[4]

Mortality/Morbidity

Even with prompt diagnosis and supportive care, the mortality rate of Hib meningitis is approximately 5%. Long-term sequelae occur in 15-30% of survivors and include sensorineural hearing loss, language disorders, mental retardation, and developmental disorders. In epiglottis, the mortality rate of 5-10% invariably is related to poor early airway control.

Age

In the prevaccine era, invasive Hib disease had a characteristic and striking age-related prevalence; approximately 85% of the cases occurred in children younger than 5 years. Hib was the most common cause of pediatric bacterial meningitis, which had a peak prevalence in infants aged 6-12 months. More than 80% of cases of Hib epiglottitis occurred in children older than 2 years. Hib was the leading cause of septic arthritis in children younger than 2 years. Currently, epiglottitis occurs primarily in older children (aged 2-7 y). The vast majority of cases of cellulitis occur in children aged 2 years or younger.

 

Presentation

History

The history is targeted to identifying the specific Haemophilus influenzae disease syndromes, which include the following:

  • Meningitis

    • Prior to H influenzae type B (Hib) vaccines, meningitis was the most common and serious manifestation of invasive disease.

    • Disease is insidious in onset, with a preceding nonspecific febrile illness. No specific etiologic clues are present. The signs and symptoms can be nonspecific.

    • Young infants may present with irritability, lethargy, anorexia, or vomiting. Only older children are likely to present with the classic findings of headache, photophobia, and meningismus. Therefore, the absence of meningismus is not a helpful finding for excluding meningitis in a young child.

  • Epiglottitis

    • 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 H influenzae.

    • Epiglottitis primarily occurs in older children (aged 2-7 y), and it usually has an abrupt onset with high fever, dysphagia, drooling, and toxicity.

    • Occasional cases of Hib epiglottitis in older children still occur in children who were never fully immunized.

    • Hib is also an important cause of epiglottitis in adult patients.

  • Septic arthritis and osteomyelitis: In the prevaccine era, Hib was the leading cause of septic arthritis in children younger than 2 years.

  • Cellulitis

    • Hib cellulitis usually involves the face, head, or neck.

    • Most cases occur in children aged 2 years or younger.

  • Occult bacteremia: In the prevaccine era, Hib was the second leading cause of occult bacteremia after Streptococcus pneumoniae.

  • Pneumonia: Hib pneumonia caused as many as one third of the documented cases of bacterial pneumonia in the prevaccine era.

  • Pericarditis

  • Neonatal disease

    • In recent years, H influenzae has been increasingly recognized as a cause of bacteremia and meningitis in neonates. Neonatal infections are usually caused by nontypeable H influenzae, which can be cultured with samples from the maternal genital tract, the presumed source of the infection.

    • The disease involves early-onset sepsis;[5] more than 80% of cases occur in 1-day-old neonates.

    • 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.

  • Brazilian purpuric fever

    • A nonserotypeable H influenzae biogroup III (identical to the H aegyptius group) organism has been demonstrated to be the cause of a disease called Brazilian purpuric fever (BPF) discovered in children in southern Brazil.

    • After an antecedent episode of purulent conjunctivitis, children with BPF become bacteremic and present with fever, shock, and purpura fulminans.

    • The disease may mimic meningococcemia, but this has not been reported in the United States.

  • Nontypeable H influenzae disease

    • Underlying medical conditions, such as prematurity, cerebrospinal fluid (CSF) leak, congenital heart disease, and immunoglobulin deficiency, may predispose an individual to invasive disease caused by the nontypeable strains of H influenzae.

    • Immunization with conjugate Hib vaccines does not confer protection against the nontypeable strains. Therefore, nontypeable H influenzae remains a major cause of otitis media in children. (Other common causes of acute otitis media in children are S pneumoniae and Moraxella catarrhalis.) Hib is an unusual cause of acute otitis media, particularly in the era of conjugate vaccines.

    • Occasionally, the encapsulated non-Hib strains of H influenzae are implicated as causes of invasive disease.

    • Recent findings from a series of H influenzae type f meningitis cases suggest that these organisms conceivably could emerge as important causes of invasive disease in children in the post-Hib vaccine era, although this trend has not yet become widespread.

Physical

Physical examination findings depend on the clinical syndrome. Because Hib is primarily a bacteremic infection, comprehensive physical examination and complete evaluation are mandatory, with a focus on excluding meningeal, lung, and pericardial involvement.

At physical examination, findings may include the following:

  • Meningitis

    • Approximately 30% of children 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.

    • Patients can also have a secondary site of infection, such as septic arthritis or facial cellulitis.

    • Shock is present in approximately 20% of patients.

    • Anemia is common; it is caused by a combination of accelerated RBC destruction and diminished erythropoiesis.

    • Complications of Hib meningitis include subdural effusion or empyema, ischemic or hemorrhagic cortical infarction, cerebritis, ventriculitis, intracerebral abscess, and hydrocephalus.

  • Epiglottitis

    • Typically, a child with Hib epiglottitis drools because of an inability to swallow the oropharyngeal secretions, and progressive respiratory distress develops over a period of hours, with tachypnea, stridor, cyanosis, and retractions.

    • The patient may sit forward with his or her chin extended, in the so-called tripod position, to maintain an open airway. Few conditions produce such a striking constellation of symptoms and findings.

    • Lateral neck radiography can be helpful if the clinical presentation is subtle (see Imaging Studies), but diagnostic studies should not delay direct inspection of the epiglottis in the operating room and insertion of an endotracheal tube. The mortality rate of 5-10% is invariably related to poor early airway control.

  • Septic arthritis and osteomyelitis

    • These usually affect the large joints, particularly knees, ankles, hips, and elbows.

    • Contiguous osteomyelitis may be present, but isolated osteomyelitis without an adjacent septic joint is uncommon.

    • Characteristically, preceding nonspecific illness is present; this is followed by pain, swelling, and erythema of the involved joint.

    • Clinical signs in children with a septic hip may be less prominent than in those with other affected joints. Findings may be limited to a decreased range of motion in the joint or referred pain from the hip.

    • A strong association exists between septic arthritis and meningitis; lumbar puncture is necessary.

  • Cellulitis

    • Buccal cellulitis occurs almost exclusively in infants aged 1 year or younger. In infants, the onset of illness includes fever and a raised, warm, tender, and indurated area that develops a violaceous hue.

    • The clinical presentation may mimic erysipelas.

    • Periorbital (preseptal) cellulitis occurs in young children, and it often occurs in the context of contiguous sinus disease. It must be differentiated from the more serious orbital (postseptal) cellulitis, which can be a life-threatening complication of invasive Hib disease (or disease caused by other pathogens).

    • Often a complication of disease in the paranasal sinuses, orbital cellulitis can lead to cranial sequelae, including cavernous sinus thrombosis. (Typically, hospital admission for intravenous antibiotics, imaging studies [CT scan, MRI], and consultations with an ophthalmologist and a neurosurgeon is required.)

    • The clinical triad of chemosis, proptosis, and ophthalmoplegia should prompt consideration of the diagnosis of postseptal cellulitis.

    • Hib cellulitis is a bacteremic disease, and meningitis must be excluded by means of lumbar puncture.

  • Occult bacteremia

    • Although most children with Hib bacteremia have 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 or higher.

    • An important distinction between Hib and pneumococcal bacteremia is that most episodes of untreated occult pneumococcal bacteremia resolve spontaneously without sequelae, whereas 30-50% of children with occult Hib bacteremia have focal infections, including meningitis. Hence, in any child with blood culture results positive for Hib, the possibility of meningitis must be seriously considered.

  • Pneumonia

    • Hib pneumonia is clinically indistinguishable from other bacterial pneumonias. It has a strong association with pleural effusion; therefore, radiography may be helpful (see Imaging Studies).

    • The best diagnostic test is blood culture, which has positive findings in almost 90% of patients.

    • Complications of Hib pneumonia include pleural empyema, pericarditis, and meningitis.

  • Pericarditis

    • The classic presentation of H influenzae pericarditis is that of a toxic-appearing child with fever, respiratory distress, and a clear chest on examination.

    • Associated conditions include pneumonia and meningitis.

    • Hib pericarditis may become clinically apparent when a child receives antibiotic therapy. It should be considered in the differential diagnosis in a child who has a persistent fever while receiving therapy for Hib meningitis.

    • Although the diagnosis may be suggested after careful inspection of the cardiac silhouette and neck veins, echocardiography is the best test for establishing the diagnosis of pericardial effusion.

    • Pericardiocentesis is the diagnostic procedure of choice.

  • Other invasive infections

    • Hib bacteremic disease is rarely associated with seeding of other body sites.

    • Endophthalmitis, glossitis, uvulitis, thyroiditis, endocarditis, lung abscess, epididymitis, peritonitis, intraperitoneal abscesses, hepatobiliary disease, and brain abscesses have been reported.

  • Nontypeable H influenzae disease

    • Nontypeable strains of H influenzae frequently cause otitis media, sinusitis, conjunctivitis, and bronchitis. Conjunctivitis is usually bilateral and purulent and often occurs in association with acute otitis media (ie, conjunctivitis-otitis syndrome).

    • Although these respiratory tract infections are common, they are rarely life threatening. In general, they are not associated with bacteremia.

    • The finding of nontypeable H influenzae systemic infection should prompt immunologic investigation, even if the obvious risk factors are absent.

  • CNS involvement: The CNS is a major target organ in invasive H influenzae disease.

  • Cardiovascular involvement

    • Children with invasive Hib disease often have septic shock.

    • Cardiovascular instability may manifest as blood pressure instability.

    • Myocardial dysfunction may occur, and pericarditis is a known and important complication.

  • Respiratory involvement

    • Invasive Hib disease may cause pneumonia or upper airway obstruction secondary to epiglottitis.

    • Clinicians skilled at airway management should be available to coordinate the treatment of these children.

  • Fluid and electrolyte disturbances: When meningitis is present, children may have disturbances in fluid and electrolyte homeostasis due to shock and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • Culture

    • This is the most important laboratory study in the context of suspected Haemophilus influenzae disease.

    • In children, the organism causing these infections is blood borne: hence, blood culturing is important in all cases.

    • H influenzae can be cultured from samples of CSF, synovial fluid, pleural and pericardial fluid, and leading-edge aspirates of cellulitis.

  • Antigen detection

    • Numerous methods are available for identifying the H influenzae type b (Hib) PRP capsular polysaccharide antigen in clinical specimens.

    • Suitable specimens for study may be obtained from urine and CSF. These are particularly helpful in the patient who has been pretreated with antimicrobial therapy.

    • Antigen detection has little use in clinical practice, except in the situation mentioned above; most clinical laboratories do not offer this test.

  • Biochemical identification

    • Biochemical identification of H influenzae is based on the demonstration that growth in rich media (blood agar) is dependent on supplements, namely, factors X and V. Factor X is a heat-stable iron-containing protoporphyrin (hemin) that is essential for the function of enzymes in the electron-transport chain in aerobic metabolism. Factor V is the heat-labile coenzyme nicotinamide adenine dinucleotide (NAD).

    • Although both factors are present in erythrocytes, factor V must be released from the cell to sustain its growth; hence, standard blood agar is an unsatisfactory media for the growth of H influenzae. The lysis of RBC releases factor V, providing an exogenous source such as that in chocolate agar.

    • The metabolic requirement of factors X and V for growth remains the major basis for the laboratory identification of H influenzae. The growth requirements of H influenzae are fastidious, and the organism rapidly loses viability; therefore, clinical specimens must be handled expeditiously.

    • After overnight incubation, gray colonies appear; these have a diameter of 0.5-0.8 mm and are rough or granular. Encapsulated strains typically produce larger mucoid or glistening colonies.

Imaging Studies

See the list below:

  • Chest or lateral neck radiography, brain CT echocardiography, and technetium bone scanning may be appropriate.

  • Imaging studies depend on the clinical syndrome.

    • In epiglottis, lateral neck radiography can be helpful if the clinical presentation is subtle, but the study should be performed cautiously, without undue delays, and a physician experienced in airway management should be present.

    • Approximately 50% of patients with pneumonia have evidence of pleural involvement at initial radiographic examination. Pneumonia can have a segmental, subsegmental, interstitial, or lobar pattern.

Procedures

See the list below:

  • Procedures depend on the clinical circumstances. Necessary procedures may include the following:

    • Lumbar puncture

    • Arthrocentesis

    • Pericardiocentesis

    • Endotracheal intubation or tracheostomy

    • Subdural tap

    • Leading-edge aspirate

Histologic Findings

See the list below:

  • H influenzae is a small gram-negative coccobacillus that may have considerable microscopic pleomorphism, which necessitates the careful and cautious interpretation of Gram stains of clinical specimens .

 

Treatment

Medical Care

Medical care depends on the disease syndrome. Children with invasive Haemophilus influenzae disease require careful attention and, often, intensive care. Medical care depends on the organ system or problems involved, as follows:

  • CNS: Lumbar puncture should be considered in a child with invasive H influenzae type b (Hib) disease. Complications, including subdural effusion, ventriculitis, infarction, abscess, sensorineural deafness, and developmental delay, must be considered.

  • Neonatal disease: Routine therapy with ampicillin and gentamicin for presumptive neonatal sepsis may not be effective if an ampicillin-resistant strain of Hib is the cause of the infection.

  • Meningitis: Prompt use of intravenous antibiotics and good supportive care are the mainstays of therapy.

  • Fluid and electrolyte disturbances: Seizures may be due to hyponatremia as a result of syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The fluid status must be closely monitored in children with Hib meningitis, and the use of fluids, particularly hypo-osmolar fluids, on an ad-lib basis is contraindicated.

Surgical Care

Consultation with a surgeon may be required in some children with invasive Hib disease. Procedures that may be necessary include the following:

  • Tracheotomy - For Hib epiglottitis when the airway cannot be managed with endotracheal intubation

  • Arthrocentesis or bone debridement - For osteomyelitis or septic arthritis, particularly involving the hip

  • Neurosurgery - For subdural empyema complicating meningitis or intracranial complications of orbital cellulitis[6]

  • Surgical drainage - For septic arthritis of the hip joint

  • Open drainage - For most cases of septic arthritis of the shoulder

  • Early pericardectomy - For pericarditis; the treatment of choice, used in conjunction with antibiotics

Consultations

Depending on the manifestations of invasive H influenzae disease, consultants required may include neurologists, neurosurgeons, orthopedic surgeons, anesthesiologists, critical care physicians, and infectious diseases physicians. An audiologist should evaluate all children after they receive treatment for H influenzae meningitis.

 

Medication

Antibiotic agents

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Aggressive parenteral antibiotic therapy is required for severe forms of Haemophilus influenzae disease, particularly those caused by the type b strain. More mild forms of disease (ie, sinopulmonary infections caused by nontypeable strains of Haemophilus organisms) may be treated with various oral antibiotics. Only therapies for invasive H influenzae infection are reviewed here.

Third-generation cephalosporins have become the cornerstone of therapy for invasive H influenzae infections, including meningitis, because of their potent bacteriocidal activity and penetration into the subarachnoid space.

Semisynthetic penicillins, particularly ampicillin, may be useful in H influenzae meningitis if the isolate is beta-lactamase negative.

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum gram-negative activity, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

Cefotaxime (Claforan)

Arrests bacterial cell wall synthesis, which in turn inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms.

Cefepime (Maxipime)

So-called fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage. Excellent penetration into CNS; indicated for treatment of adult and pediatric meningitis.

Meropenem (Merrem)

Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. Effective against most gram-positive and gram-negative bacteria. Has slightly increased activity against gram-negative species and slightly decreased activity against staphylococci and streptococci compared with imipenem. In contrast to imipenem, indicated for treatment of bacterial meningitis, including pediatric meningitis.

Chloramphenicol (Chloromycetin)

Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.

Ampicillin (Marcillin, Omnipen, Polycillin, Principen)

Agent with cell wall activity that interferes with transpeptidation step of peptidoglycan biosynthesis. Has bactericidal activity against susceptible organisms. Resistance of H influenzae to ampicillin occurs in 10-40% of patients. Use in combination with chloramphenicol.

Glucocorticoids

Class Summary

Glucocorticosteroids elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli. Use of adjunctive glucocorticosteroid therapy has been demonstrated to decrease the risk of sensorineural deafness in children with H influenzae meningitis.

Dexamethasone (Decadron)

For various allergic and inflammatory diseases. Decreases inflammation by suppressing migration of PMNs and reducing capillary permeability. For maximum benefit, corticosteroids should be initiated as soon as possible in treatment of H influenzae meningitis, ideally prior to the first dose of antibiotics.

Vaccines

Class Summary

Active immunization increases resistance to infection. Vaccines consist of microorganisms or cellular components, which act as antigens. Administration of the vaccine stimulates production of antibodies with specific protective properties. For a complete overview of current vaccine recommendations, see the Advisory Committee on Immunization Practices (ACIP) guidelines from the Centers for Disease Control and Prevention (CDC).[7]

Haemophilus influenza type B vaccine (ActHIB, Hiberix, Liquid PedvaxHIB)

Used for routine immunization of children against invasive diseases caused by H influenzae type b by decreasing nasopharyngeal colonization. CDC's ACIP recommends that all children receive one of the conjugate vaccines licensed for infant use beginning routinely at age 2 mo. Administer a 2- or 3-dose Hib vaccine primary series and 1 booster dose (dose 3rd or 4th dose depending on vaccine used in primary series) at age 12 through 15 months to complete a full Hib vaccine series. For unimmunized infants and toddlers, the catch-up immunization schedule (up to age 5 y) may require 1-3 doses depending on when initiated.

Meningococcal C and Y/Haemophilus influenza type B vaccine (MenHibrix)

New combination vaccine indicated for active immunization against both Neisseria meningitides serogroups C and Y and Haemophilus influenzae type b. Administered as a 4-dose series. The first dose may be given as early as 6 week of age and fourth dose may be given as late as 18 months.

Chemoprophylaxis

Class Summary

Chemoprophylaxis is used to prevent secondary disease. With widespread success of immunization, chemoprophylaxis now is of mostly historical interest.

Rifampin (Rimactane, Rifadin)

Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which in turn blocks RNA transcription.

 

Follow-up

Further Outpatient Care

Long-term neurodevelopmental evaluation, in particular audiologic assessment for possible deafness, is important in outpatient follow-up care of children with H influenzae meningitis.

Further Inpatient Care

Inpatient care should concentrate on the disease syndrome associated with invasive Haemophilus influenzae type b (Hib) disease.

As already noted, airway management, careful management of fluid and electrolyte problems (in particular, syndrome of inappropriate secretion of antidiuretic hormone [SIADH]), and use of seizure precautions may be appropriate with invasive infections, depending on the extent of disease.

Deterrence/Prevention

Chemoprophylaxis

Chemoprophylaxis is 1 of 2 modalities for the prevention of secondary Hib disease.

Many reports have documented the increased risk of invasive disease among household contacts in the month after the onset of disease in the index patient. The 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.

Quinolones may also be effective, although they have not been studied sufficiently, and they are not approved for use in children.

Prophylaxis should be initiated as soon as possible, because the risk of secondary disease is greatest during the few days after disease onset in the index patient. Also, prophylaxis is recommended only if it can be administered within 2 weeks of disease onset.

Because therapeutic antibiotics do not consistently eradicate Hib from the nasopharynx, rifampin should be given to the index patient before discharge from the hospital.

The use of rifampin chemoprophylaxis in daycare 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 are warranted. Fortunately, most daycare attendees now are immunized and, therefore, are at low risk of secondary disease.

Active immunization

Active immunization is another modality for the prevention of Hib disease (ie, endemic disease). Polysaccharide vaccines once were used in active immunization.

The first vaccine used in an effort to prevent Hib invasive disease was a purified type b capsular polysaccharide vaccine that was introduced in the United States in 1985. However, the polyribosyl ribitol phosphate (PRP) vaccine was not consistently immunogenic or protective when administered to children younger than 2 years. Infants rarely responded to PRP vaccine, but both the proportion of responders and resultant antibody levels improved dramatically in those aged 1-2 years. Hence, the vaccine was initially licensed for use in children aged 18-24 months or older.

Although the vaccine could not protect infants and young children at greatest risk, it was licensed for use in older children to reduce at least a proportion of disease. After licensure, findings from most studies suggested that protection afforded by this vaccine was, at best, marginal. By 1988, this vaccine was replaced by the more immunogenic conjugate vaccines.

Conjugate vaccines

Conjugate vaccines are now used in active immunization.[8] These vaccines were developed in an effort to enhance immune responses to the PRP antigen. These vaccines consisted of a covalently linked PRP (in the process of conjugation) to an immunogenic carrier protein; a semisynthetic carrier-hapten was created. The predominant antibody is immunoglobulin G (IgG).

Findings from numerous studies in animals and children demonstrate that the HiB conjugate vaccines have immunologic properties characteristic of T-cell–dependent antigens. With these vaccines, much higher levels of antibodies are induced, particularly in infants and young children; booster responses occur with subsequent injections.

Four Hib conjugate vaccines have undergone extensive evaluation in humans, and they have been licensed for use in infants aged 2 months or older (see below).

A covalent linkage between the PRP molecule and a carrier protein is common to all of the Hib conjugate vaccines but is the only similarity because the vaccines differ in composition, structure, and resultant immune responses.

PRP-D vaccine

PRP-D vaccine is the first HiB conjugate vaccine licensed for use in older children, is the least immunogenic vaccine in infants. In efficacy trials, it protected infants and children in Finland but failed to protect young infants in Alaska. In both trials, only approximately one half of the infants had levels of antibody that were considered protective. PRP-D is licensed in the United States only for use in children aged 12 months or older.

HbOC vaccine

HBOC vaccine isthe first HiB conjugate vaccine licensed for use in infants, does not induce a significant antibody response with the first dose, which is administered to infants aged 2 months. After a second dose is administered in those aged 4 months, some, but not all, have protective levels of antibody. With a third dose, given to infants aged 6 months, essentially all have a high level of antibody. The protective effect of the vaccine was proven in a trial involving the Northern California Kaiser Health Plan. Follow-up findings in Northern California and throughout the United States have confirmed its protective effect. Doses are recommended for infants aged 2 months, 4 months, and 6 months, with a booster dose for those aged 12-15 months.

PRP-OMPvaccine

The PRP-OMP vaccine appears to be the most immunogenic HiB conjugate vaccine in young infants. In contrast to the other vaccines, a first dose of PRP-OMP induces a good antibody response in most 2-month-old infants. Further doses in 4-month-old and 6-month-old infants increase the proportion of those who respond, but these do not lead to marked booster responses. Therefore, the use of only 2 doses is recommended: one in infants aged 2 months and one in those aged 4 months; a booster dose is administered at age 12-15 months.

PRP-Tvaccine

Older PRP-T vaccines were similar to HbOC. The first dose given to 2-month-old infants causes little response, if any. Not all infants who receive a second dose when aged 4 months have protective levels of antibody, but after 3 doses, nearly all infants have high antibody levels. This vaccine is recommended for use in infants aged 2 months, 4 months, and 6 months; a booster dose is administered to those aged 12-15 months.

The PRP-T formulation approved most recently (Hiberix) was initially indicated only for use in children aged 15 months to 4 years.[9]  In January 2016, the indication for Hiberix was expanded to include use as a 4-dose series at ages 2, 4, and 6 mo (primary series), and a booster dose between ages 15 mo and 4 y. The effectiveness of this Hib vaccine was based on immune responses in children using serologic endpoints that predict protection from invasive disease due to Hib. Specific levels of antibodies to polyribosyl-ribitol-phosphate (anti-PRP) were measured that have been shown to correlate with protection against invasive disease due to H influenzae type B.[10]

Combination vaccines

The proliferation of newly licensed vaccines in the United States, with a shift away from the use of oral polio vaccine (OPV) to the use of inactivated polio vaccine (IPV), has resulted in the need to administer multiple injections at well-baby visits. In an effort to minimize the number of injections, strategies to mix vaccines in a single syringe have evolved.

Once such vaccine contains diphtheria-tetanus-pertussis (DTP) and HbOC (Tetramune). This product was licensed in 1995 for use as the primary series. However, the increased reactogenicity of whole-cell pertussis vaccine compared with that of the newer acellular pertussis vaccines has limited the usefulness of this product.

One combination vaccine consists of PRP-T and the Connaught diphtheria-tetanus-acellular pertussis (DTaP) vaccine (TriHIBit), which is licensed for administration as the fourth dose in the primary series. Unfortunately, current data are insufficient to support licensure of the DTaP-Hib combination vaccines for use in the primary series for infants. Clinical trials of some mixed Hib conjugate and acellular pertussis revealed a decrease in the anti-PRP antibody titer in some children, rendering problematic the licensure of such combination products for use in the primary series.

Another Hib combination vaccine, PRP-OMP and hepatitis B (Comvax) vaccine, does not appear to have this same degree of interference with anti-PRP responses, and this product is licensed for use in the primary series.

The combination of Dtap-Hib-IPV (Pentacel) is the latest combination vaccine to be approved in the United States. This vaccine is recommended at age 2 months, 4 months, and 6 months, with a booster at age 12-15 months.

A Hib conjugate and meningococcal CY conjugate combination vaccine, MenHibrix, was approved by the FDA in June 2012 for use in infants aged 6 weeks to 18 months for active immunity against meningitis. It is given as a 4-dose series usually at well-baby checkups.

Combination vaccines require cautious evaluation, particularly in high-risk populations. In a high-risk Alaskan Native American population, change from the PRP-OMP vaccine to the DTP-HbOC vaccine resulted in a resurgence of invasive HiB disease, and children immunized with DTP-HbOC had demonstrable nasopharyngeal colonization with HiB. This finding indicated the existence of a reservoir of the organism in an immunized population.

The incidence of invasive Hib disease has declined dramatically in recent years; however, the experience in high-risk Native Americans is a reminder that Hib, though largely forgotten, is not yet eradicated. Diligence must be maintained to ensure that widespread immunization continues to prevent the reemergence of this serious pediatric infection.

The recent shortage of Hib conjugate vaccines in the United States resulted in an increased number of cases of invasive Hib disease and death in some children who were unimmunized or underimmunized against Hib. This recent experience clearly indicates that continued immunization against Hib diseases is necessary to keep the disease in check and keep children protected.[2]

Prognosis

Even with prompt diagnosis and supportive care, the mortality rate with Hib meningitis is approximately 5%. Long-term sequelae occur in 15-30% of survivors and include sensorineural hearing loss, language disorders, mental retardation, and developmental disorders. In epiglottis, the mortality rate of 5-10% is invariably related to poor early airway control.

Patient Education

For patient education resources, see the Cold and Flu Center, as well as Flu in Children.