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Sections Haemophilus Influenzae Infections
Overview
Presentation
- History
- Physical
- Causes
- Complications
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DDx
Workup
Treatment
Medication
Questions & Answers
References

Overview

Practice Essentials

Haemophilus influenzae is a small (1 µm × 0.3 µm), pleomorphic, gram-negative coccobacillus.^{[1, 2, 3, 4]}Some strains of H influenzae possess a polysaccharide capsule, and these strains are serotyped into 6 different types (a-f) based on their biochemically different capsules. The most virulent strain is H influenzae type b (Hib). Some H influenzae strains have no capsule and are termed nonencapsulated H influenzae or nontypeable H influenzae (NTHi). The incidence of invasive Hib diseases has greatly decreased because of widespread use of the Hib conjugate vaccine, whereas NTHi strains have become the most common cause of invasive disease in all age groups in countries with routine Hib vaccination.

Signs and symptoms

Signs and symptoms are as follows:

Hib meningitis: Most serious manifestation of Hib infection; antecedent upper respiratory tract infections are common; Hib meningitis manifestations are indistinguishable from other bacterial meningitis causes
Cellulitis: Most commonly involves the buccal and periorbital regions; usually associated with fever
Epiglottitis ^[5]: Fever, sore throat, dysphagia, drooling, and difficulty breathing
Hib pneumonia: Clinically indistinguishable from other bacterial pneumonias—but usually with insidious onset and a history of fever, cough, and purulent sputum production
Hib pericarditis: Fever, respiratory distress, and tachycardia
Septic arthritis: Joint pain, swelling, and decreased mobility
Occult bacteremia: Fever, anorexia, and lethargy
Underlying medical conditions (especially with invasive Hib disease): Pulmonary disease, immunodeficiency states (eg, HIV infection), alcoholism, pregnancy, and malignancy
Neonatal infections: May have nonspecific manifestations; may include signs/symptoms of bacteremia, sepsis, meningitis, pneumonia, respiratory distress, scalp abscess, conjunctivitis, and vesicular eruption
NTHi infections: Commonly causes various mucosal infections, including otitis media and conjunctivitis

Persons at risk for invasive H influenzae disease include the following:

Children younger than 4 years
Contacts (eg, household and daycare) of someone with Hib disease
Persons with sickle cell disease,
Persons with asplenia
Individuals with HIV infection
Individuals with immunoglobulin deficiencies and complement component deficiencies
Hematopoietic stem cell transplant recipients
Patients undergoing chemotherapy or radiation therapy for malignant neoplasms
American Indians and Alaska Natives

See Clinical Presentation for more detail.

Diagnosis

Laboratory testing

Gram staining of body fluids from various sites of infection
Bacterial culture (blood, other body fluids): The most confirmatory method of establishing the diagnosis; slide agglutination with type-specific antisera is used for serotyping H influenzae
Immunologic studies: Detection of the polyribosyl ribitol phosphate (PRP) polysaccharide capsule via countercurrent immunoelectrophoresis, latex particle agglutination, co-agglutination, and enzyme-linked immunosorbent assay; important adjuncts to culturing for rapid diagnosis
Cerebrospinal fluid (CSF) studies (eg, Gram stain, culture, glucose/protein levels)
Blood cell counts: Assessment for anemia, leukocytosis, thrombocytosis, and/or thrombocytopenia
Acute phase reactants: Characteristic elevated erythrocyte sedimentation rates (ESRs) and C-reactive protein (CRP) levels in patients with septic arthritis

Imaging studies

Computed tomography (CT) scanning of the head

In infants and children with suspected bacterial meningitis, CT scanning is recommended before lumbar puncture in those with the following^[6]:

Immunocompromise
History of selected CNS disease, particularly those with CSF shunts, hydrocephalus, space-occupying lesions, history of trauma, post-neurosurgery
Papilledema
Selected focal neurologic deficits, but not cranial nerve palsy of VI or VII
Delayed diagnostic lumbar puncture

In adults with suspected bacterial meningitis, CT scanning is recommended before lumbar puncture in patients with the following^[6]:

Immunocompromise
History of CNS disease
Newly onset seizure
Papilledema
Altered consciousness
Focal neurologic deficit
Delayed diagnostic lumbar puncture
Chest radiography: For suspected pulmonary disease (eg, pneumonia)
Lateral neck radiography (only if functional airway is guaranteed): To confirm epiglottitis and/or assess cervical spine
Echocardiography: For suspected pericarditis

Procedures

Endotracheal intubation or tracheostomy: To secure airway in patients with epiglottitis
Lumbar puncture: When meningitis is suspected
Bronchoscopy
Aspiration of soft or subcutaneous tissue in the presence of cellulitis
Joint, lung, and sinus aspiration
Transtracheal aspiration
Tympanocentesis
Pericardiocentesis
Laparoscopy and tubal cultures in women: For suspected NTHi
Culdocentesis and peritoneal fluid cultures in women: For suspected NTHi

See Workup for more detail.

Management

Antibiotics and supportive care are the mainstays of treatment for H influenzae infections. Immunization/vaccination is an essential component for prevention of Hib infections.

Pharmacotherapy

Antibiotics (eg, azithromycin, cefotaxime, ceftriaxone, cefuroxime, ampicillin, amoxicillin, amoxicillin and clavulanic acid, chloramphenicol, erythromycin and sulfisoxazole, meropenem, rifampin)
Glucocorticoids (eg, dexamethasone)

Surgery

Subdural and pleural empyema: May require surgical drainage if orbital cellulitis is extensive
Pericarditis: Systemic antibiotics and drainage via early pericardectomy or pericardiostomy rather than multiple pericardiocenteses
Septic arthritis of the hip: Surgical drainage to avoid avascular necrosis of the femoral head; repeated aspirations or surgical drain placement may be needed in other infected joints to reduce pressure

See Treatment and Medication for more detail.

Background

Haemophilus influenzae is a small (1 µm X 0.3 µm), pleomorphic, gram-negative coccobacillus. It is a nonmotile, non–spore-forming, fastidious, facultative anaerobe. Some strains of H influenzae possess a polysaccharide capsule. These strains are serotyped into 6 different types (a-f) based on their biochemically different capsules. Some strains have no capsule and are termed nonencapsulated H influenzae or nontypeable H influenzae (NTHi). The different strains can be identified with slide agglutination for serotyping or polymerase chain reaction (PCR) for capsular typing.

The most virulent strain is H influenzae type b (Hib), with its polyribosyl ribitol phosphate (PRP) capsule. It accounts for more than 95% of H influenzae invasive diseases in children and half of invasive diseases in adults, including bacteremia, meningitis, cellulitis, epiglottitis, septic arthritis, pneumonia, and empyema. Less-common invasive Hib infections include endophthalmitis, urinary tract infection, abscesses, cervical adenitis, glossitis, osteomyelitis, and endocarditis.

The other encapsulated strains H influenzae occasionally cause invasive disease similar to that of Hib. H influenzae type A (Hia) has been known to cause invasive disease (eg, meningitis) clinically indistinguishable from that caused by Hib. In a retrospective study in Canada conducted from 2000-2010, of the 130 H influenzae infections reported, 56% were Hia. Meningitis, bacteremia, and pneumonia were the most common clinical presentations.^[7]

The nonencapsulated, or NTHi, strains cause mucosal infections, including otitis media, conjunctivitis, sinusitis, bronchitis, and pneumonia. Less commonly, these strains cause invasive disease in children but account for half of the invasive infections in adults. The population structure of NTHi demonstrates substantial genetic diversity, as opposed to the clonal nature of Hib.^[8]Furthermore, the outer membrane proteins of NTHi show high strain-to-strain variability, making vaccine development a challenge.^{[7, 9]}

The Hib carriage rate is 2-4% in children aged 2-5 years, the age when children usually become colonized. Hib carriage rates are lowest in adults and infants and highest in preschoolers. Since the advent of conjugate Hib vaccine, the nasopharyngeal carrier rate has decreased (< 1% in vaccinated individuals). Only a small percentage of H influenzae carriers develop invasive disease. The frequency of Hib infections in patients with asplenia, splenectomy, sickle cell disease, malignancies, and congenital or acquired immunodeficiencies is higher than in individuals without these conditions. Unvaccinated infants younger than 12 months with a history of invasive disease have a higher risk for recurrence than vaccinated infants.^[10]

In contrast, NTHi carriage rates can be as high as 70% or more.^[11]

Currently, the incidence of Hib invasive diseases has greatly decreased in the United States because of the wide spread of the Hib conjugate vaccine, whereas NTHi strains have become the most common cause of invasive disease in all age groups.

In countries outside the United States with established Hib immunization programs, such as England and Wales, NTHi is now the cause of nearly all invasive H influenzae diseases across all age groups.^[7]

In Kamikawa subprefecture of Hokkaido, Japan, the incidence rate of H influenzae infection ranged from 15.1-36.3 per 100,000 population from 2006-2011. The Hib vaccine was introduced in November 2008, but vaccination rates rose to more than 90% only in December 2010, when Hib immunization became national policy. Thus, the rates dropped to 10.4 per 100,000 in 2012 and then to zero after 2013. No Hib meningitis cases have been reported since 2012, demonstrating the value of the vaccine in terms of case reduction.^[12]

However, in many developing countries where Hib vaccination is not routine, invasive Hib disease is still a significant cause of morbidity and mortality.

During the pandemic, there was a reduction in H influenzae cases in both the northern and southern hemispheres along with S pneumoniae and N meningitidis. Specifically, the relative risk of H influenzae invasive disease decreased by 49% from meta-analytic data. Unfortunately, cases from H influenzae, S pneumoniae and N meningitidis were increasing again towards the end of 2021.^[13]

Pathophysiology

The nomenclature (Haemophilus is Greek for "blood loving") acknowledges the fact that H influenzae requires 2 erythrocyte factors for growth: X (hemin) and V (nicotinamide-adenine-dinucleotide). These factors are released following lysis of red blood cells, thereby allowing growth of this fastidious organism on chocolate agar. H influenzae consists of 8 biotypes; biotype 3 (Haemophilus aegyptius) is associated with Brazilian purpuric fever, and biotype 4 is a neonatal, maternal, and genital pathogen. Humans are the only natural hosts. NTHi strains are a common resident of the nasopharyngeal mucosa and, in some instances, of the conjunctivae and genital tract.

Transmission is by direct contact or by inhalation of respiratory tract droplets. Nasopharyngeal colonization of encapsulated H influenzae is uncommon, occurring in 2-5% of children in the prevaccine era and even less after widespread vaccination. The incubation period is not known. A larger bacterial load or the presence of a concomitant viral infection can potentiate the infection. The colonizing bacteria invade the mucosa and enter the bloodstream. The presence of antibodies, complements, and phagocytes determines the clearance of the bacteremia. The antiphagocytic nature of the Hib capsule and the absence of the anticapsular antibody lead to increasing bacterial proliferation. When the bacterial concentration exceeds a critical level, it can disseminate to various sites, including meninges, subcutaneous tissue, joints, pleura, pericardia, and lungs.

Host defenses include the activation of the alternative and classical complement pathways and antibodies to the PRP capsule. The antibody to the Hib capsule plays the primary role in conferring immunity. Newborns have a low risk for infection, likely because of acquired maternal antibodies. When these transplacental antibodies to the PRP antigen wane, infants are at high risk of developing invasive H influenzae disease, and their immune responses are low even after the disease. Therefore, they are at high risk for repeat infections since prior episodes of H influenzae do not confer immunity. By age 5 years, most children have naturally acquired antibodies. The Hib conjugate vaccine induces protection by inducing antibodies against the PRP capsule. The Hib conjugate vaccine does not provide protection against NTHi strains. Since the widespread use of the Hib conjugate vaccine, NTHi has become a more common pathogen.

Although NTHi lacks a polysaccharide capsule, the expression of lipooligosaccharides (LOS) allow it to adhere and evade complement-mediated responses contributing to its virulence. Phase variable expression of genes enables it to adapt to the upper respiratory tract and the blood. The presence of phosphorylcholine (PCho) in the LOS decreases the release of IL-1β thereby dampening inflammation and facilitating colonization. In the blood, PCho expression is reduced as it increases CRP and IgM binding which facilitates complement-mediated killing. This allows survival of NTHi l in human serum.^[14]

The NTHi strains colonize the nasopharynx in up to 80% of individuals. The spread of bacteria by direct extension to the eustachian tubes causes otitis media. Spread to the sinuses leads to sinusitis. Spread down the respiratory tract results in bronchitis and pneumonia. Eustachian tube dysfunction, antecedent viral upper respiratory tract infection (URTI), foreign bodies, and mucosal irritants, including smoking, can promote infection. In patients with underlying chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF), NTHi frequently colonizes the lower respiratory tract and can exacerbate the disease.

NTHi strains form biofilm in vitro and ex vivo and have been implicated in chronic infection such as otitis media, sinusitis, and bronchitis. NTHi biofilm formation was found in patients with CF on the apical surface of airway epithelia with decreased antibiotic susceptibility. Studies into the nature of this biofilm structure and proteins will help develop strategies to fight chronic infections. Persons at risk for invasive H influenzae disease include those with asplenia, sickle cell disease, complement deficiencies, Hodgkin disease, congenital or acquired hypogammaglobulinemia, and T-cell immunodeficiency states (eg, HIV infection).

NTHi infection appears to disturb epithelial integrity and barrier function owing to the destruction of cell-cell contacts, which is believed to be a prominent feature in NTHi infection and has been related to a decrease in both E-cadherin mRNA and protein-levels in lung epithelial cells from patients with chronic bronchitis.^[15]

Children younger than 4 years and contacts (eg, household and daycare) of individuals with Hib disease are at higher risk for infection. More research is needed to determine the risk factors for non–type B H influenzae and NTHi. However, persons with sickle cell disease, individuals with asplenia, individuals with HIV infection, persons with immunoglobulin deficiencies and complement component deficiencies, hematopoietic stem cell transplant recipients, patients undergoing chemotherapy or radiation therapy for malignant neoplasms, and American Indians and Alaska Natives are at higher risk for invasive H influenzae disease.^[16]

United States

Before a vaccine became available in 1988, the annual attack rate of invasive Hib disease was estimated at 64-129 cases per 100,000 children younger than 5 years. By 2000, the number of cases in children younger than 5 years decreased by more than 99%. With the success of the Hib conjugate vaccine, at least half of invasive H influenzae infections are now caused by the nonencapsulated strains, and Hib meningitis has almost disappeared in the United States and Canada.

In 2006, the Active Bacterial Core Surveillance Report for H influenzae infection reported the following prevalences in 10 studied states (with a total study population of 35,599,550 persons):

Hib infection - 0.04 cases per 100,000 general population
Non-Hib infection - 0.36 cases per 100,000 general population
NTHi infection - 0.99 cases per 100,000 general population (NTHi infections accounted for 353 of the 551 H influenzae infection cases reported in this series. ^[17])

The latest Active Bacterial Core Surveillance Report for H influenzae infection in 2015 reported the following prevalence rates in 10 studied states (with a total study population of 43,912,887 persons):

Hib infection: 0.02 cases per 100,000 general population
Non-Hib infection: 0.42 cases per 100,000 general population
NTHi infection: 1.24 case per 100,000 population (NTHi infections accounted for 544 of the 822 H influenzae infection cases reported in this series. ^[18])

Meanwhile, the prevalence of Hia infections has increased in some countries since the advent of the Hib conjugate vaccine. However, in the United States, the number of Hia infections reported has remained constant.^{[19, 20]}

International

Before vaccines became available, invasive Hib disease was a leading infectious illness among children worldwide. Hib vaccine is routine in the Americas, most of Europe, and a few countries in Africa and the Middle East.

In the 1990s, the frequency of Hib diseases decreased remarkably, and even developing countries reported only 2-3 cases per 100,000 of the population younger than 5 years.

In Canada, 10 centers reported 485 cases of invasive H influenzae disease in 1985. In 2000, 8 years after Canada implemented their Hib immunization program, their Immunization Monitoring Program, ACTive (IMPACT) reported only 4 cases. A report of invasive Hib disease in Canadian children identified 29 cases from 2001-2003. The number of cases progressively decreased over the 3 years, with 16 cases reported in 2001, 10 in 2002, and only 3 cases in 2003. A total of 15 cases of meningitis were reported. Six cases of pneumonia with bacteremia and 4 cases of epiglottitis were reported. Two Hib-related deaths occurred. Twenty of these children were unvaccinated or incompletely vaccinated, and 11 were younger than 6 months. Eight of the 9 children who had completed the vaccination series were immunocompromised or had other predisposing conditions. The report noted that the number of cases in older children was unchanged from previous years and that protection did not decline with age.

In England and Wales, the Hib vaccine was introduced in 1992, and the number of invasive Hib cases in children and adults dramatically decreased. Some felt that this was because of herd immunity due to interruption of transmission from immunized children to those who were unvaccinated. However, from 1998, the number of Hib cases was noted to be rising, and, in 2002, 134 cases occurred in children aged 4 years or younger. The increase in invasive Hib in England and Wales was also seen in persons aged 15 years and older and reached prevaccine levels. This was associated with reduced antibody concentration in the older age group. This reduction in herd immunity may be due to reduced transmission of Hib organisms from persons who were vaccinated to adults who were unimmunized, providing fewer opportunities for boosting of natural immunity.

In Africa and Asia, Hib vaccination coverage is still suboptimal,^[21]so Hib remains an important disease pathogen. Although measures have been taken to immunize infants and children against Hib in developing countries, the progress has been relatively slow, partly because of financing for the vaccine, sustainable immunization programs, and the need for data on the burden of invasive Hib disease. In Lambok, Indonesia, from 1998-2002, high incidences of vaccine-preventable Hib meningitis and Hib pneumonia were reported in children younger than 2 years. In a district in Malawi, Africa, the incidence of H influenzae meningitis decreased from 20-40 per 100,000 to zero in 2005 after the vaccine was introduced in 2002.

However, a study of invasive disease due to H influenzae in South Africa from 2003-2009 found an increase in the incidence the disease in vaccinated children and concluded that a revision of the Hib conjugate vaccine recommendations should be considered.^[22]

In many developing countries where Hib vaccine is not administered, Hib infection is a major cause of lower respiratory tract infections and is the leading cause of deaths due to bacterial pneumonia in children.^[23]

A prospective multicenter (10 primary healthcare centers) study of pediatric nasopharyngeal carriers of H influenzae was conducted in the Mediterranean coastal region of Spain, and results showed that all were NTHi. Among all the isolates, 20% were resistant to ampicillin (10% of which were beta-lactamase–producing). During winter, carriage rates more than doubled.^[24]

In 12 European countries from 2007-2014, NTHi infections comprised 78% of all H influenzae cases, increasing in those younger than 1 month and those older than 20 years. H influenzae serotype F cases increased in patients older than 60 years. Hib cases decreased in patients aged 1-5 months, 1-4 years, and older than 40 years, highlighting the success of Hib vaccination.^[25]

In 2017, 2 cases of Hia infection were reported in Italy, and both were of the ST23 clone (previously only known to have been present outside Europe), which was concerning.^[26]In the North America Arctic area, which includes Nunavik and Nunavut, Canada, and Alaska, invasive Hia isolates also belonged to the ST23 clonal complex.^[27]

In Hungary, a single-center 14-year retrospective review of adults with invasive H influenzae infection showed an annual incidence of 0.1 cases per 100,000 inhabitants. NTHi strains were the most prevalent (79%), with 14% of all isolates exhibiting ampicillin resistance.^[28]

Mortality/Morbidity

Overall mortality from Hib meningitis is approximately 5%. Morbidity rates from meningitis, however, are high. If subtle neurologic changes are included, as many as 50% of individuals with Hib meningitis have some neurologic sequelae, including partial-to-total sensorineural hearing loss, developmental delay, language delay, behavioral abnormalities, language disorders, impaired vision, developmental disabilities, motor problems, ataxia, seizures, and hydrocephalus. Approximately 6% of individuals with Hib meningitis experience permanent sensorineural hearing loss. Epiglottitis carries a mortality rate of 5-10% (because of acute respiratory tract obstruction), and neonatal H influenzae disease carries a mortality rate of 55%.

A systematic analysis by the Global Burden of Disease Study 2019 revealed that from 1990 to 2019, H influenzae had the largest drop in mortality among children younger than 5 years (76·5% [69·5-81·8]) compared to S pneumoniae, N meningitidis, K pneumoniae and viruses.^[29]

Epidemiology

From the 1980s (prevaccine era) to 2005 (vaccine era), the incidence of vaccine-preventable invasive Hib disease decreased by ≥99.8%, and the associated mortality rate decreased by ≥99.5%.^[30] In parts of the world where the vaccine is not in regular use, morbidity and mortality rates of Hib disease remain high.

Licensing of the Hib conjugate vaccine led to a substantial decline of Hib disease in the United States. In China, Hib immunization resulted to less Hib infection and more frequent reports of NTHi respiratory infections. NTHi has been isolated in 9.1% of 3,984 children with upper respiratory tract infection in China, with the highest carriage rate observed in the 3 to 4 year age group.^[31]

Epidemiologic studies suggest that Hia infection occurs more in indigenous North American populations, with clinical presentation closely resembling that of Hib infection.^[32]

In 2006, the Active Bacterial Core Surveillance Report estimated that, in the United States, 4800 cases (1.6 per 100,000 population) of invasive H influenzae infection occurred, resulting in 700 deaths (0.23 per 100,000 population).^[17]In contrast, the latest Active Bacterial Core Surveillance Report for H influenzae infection in 2015 reported 6,100 (1.9 per 100,000) cases of invasive disease and 1,015 (0.32 per 100,000) deaths.^[18]

Bacteremia and invasive disease associated with NTHi are becoming more prevalent and carry a significant mortality rate.^[17]Increased NTHi cases can also be seen in patients with cancer, consistent with the changing H influenzae epidemiology in the rest of the population after the Hib vaccine was introduced.^[33] Because of Haemophilus influenzae serotype b (Hib) vaccination, non-Hib serotypes have emerged, including the incidence rate of Haemophilus influenzae serotype f (Hif) infection [estimated incidence rate of 0.15/100 000 population per year (range: 0.05-0.40/100 000), and a median case fatality ratio of 14.3 %].^[34]

H influenzae is among the 3 most common bacteria isolated among patients with COVID19 infection, next to Mycoplasma pneumoniae and Pseudomonas aeruginosa. Nevertheless, only 7% of the 2,183 patients included in the review had bacterial co-infection, that is less than that observed in previous influenza pandemics. This finding does not support the routine use of antibiotics in patients with confirmed COVID19 infection. ^[35]

As mentioned, during the pandemic, there was a reduction in H influenzae cases in both the northern and southern hemispheres along with S pneumoniae and N meningitidis. Specifically, the relative risk of H influenzae invasive disease decreased by 49% from meta-analytic data. Unfortunately, cases from H influenzae, S pneumoniae and N meningitidis were increasing again towards the end of 2021.^[13]

Transmission

H influenzae is recovered exclusively from humans, with no other known hosts.^[36]It is a frequent colonizer of the nasopharynx and rarely is found in the genital tract. Infants and toddlers are considered to be reservoirs. Transmission occurs primarily by inhalation of droplets or direct contact with secretions. In neonates, transmission may occur with aspiration of amniotic fluid or contact with genital secretions.^[37]NTHi frequently colonizes the lower respiratory tract of patients with COPD and cystic fibrosis.^[36]

Outbreaks of H influenzae upper respiratory tract infection usually occur in crowded settings. Although H influenzae infections are common in the community, nosocomial outbreaks of upper respiratory tract infection have been reported. In a general hospital in western Japan, about 27 of 78 (34.6%) people developed respiratory symptoms during the 3-week period following admission of the index patient.^[38]All isolates have a similar gel electrophoresis pattern, with beta-lactamase-negative ampicillin-resistant NTHi present in 13 individuals.

Race

The frequency of Hib disease is especially high in certain ethnic groups, including African Americans, American Indians (eg, Alaskan Eskimos, Navajo, Apache, Yakima, Athabaskan), and Australian Aborigines. Prior to availability of the Hib vaccine, the incidence of invasive disease was 10% higher in American Indians and Alaskan native children than the rest of the US population. The rate of Hib disease among rural Alaskan native children is high (5.4 per 100,000) despite Hib vaccination.^[39]

In Queensland, Australia, the yearly incidence rate in all children younger than 5 years was 7.4 per 100,000, but the indigenous children (Aboriginal and Torres Strait Islander) of the same ages appeared to be more vulnerable, with an annual incidence rate of 10.2 per 100,000.^[40]

Sex

Hib disease has no sexual predilection; however, women are at risk for postpartum sepsis, tuboovarian abscess, and chronic salpingitis caused by NTHi that colonize the genital tract.

Age

In general, Hib infections are rare in patients older than 6 years because of the acquisition of secondary immunity; however, immunocompromised individuals remain susceptible.

Hib meningitis primarily affects children younger than 2 years, with a peak frequency in infants aged 6-9 months. Epiglottitis is most common in children aged 2-7 years but can also occur in adults. Hib pneumonia typically occurs in children aged 4 months to 4 years. Hib causes septic arthritis and cellulitis in children younger than 2 years; before the conjugate vaccine became available, Hib was the leading cause of arthritis in this age group. Hib septic arthritis also occurs in adults. Prior to introduction of the Hib vaccine, Hib was the leading cause of occult bacteremia after Streptococcus pneumoniae in children aged 6-36 months. In the vaccine era, Hib occult bacteremia is rare. H influenzae otitis media can occur at any age but is most common in children aged 6 months to 6 years.

NTHi causes neonatal sepsis through vertical transmission via the female genital tract, maternal sepsis, and, infrequently, other invasive diseases. It also causes otitis media, sinusitis, bronchitis, and pneumonia in all age groups.

In 2006, the Active Bacterial Core Surveillance Report found that NTHi infection was most common among persons younger than one year and those aged 65 years or older, accounting for 6.5 and 4.3 cases per 100,000 general population, respectively.^[17]By 2015, NTHi rates were 4.88 and 2.72 per 100,000 in the same age groups, respectively, although rates were highest in individuals aged 85 years and older, at 11.37 per 100,000.^[18]

Prognosis

The prognosis of meningitis depends on age at presentation, duration of illness prior to antimicrobial therapy, CSF capsular polysaccharide concentration, and the rapidity with which it is cleared from the CSF, blood, and urine. Dexamethasone administered concurrently or shortly before the initial administration of antibiotics decreases the likelihood of hearing loss associated with Hib meningitis.

The prognosis of uncomplicated Hib pneumonia and nonencapsulated H influenzae infections usually is good.

Patient Education

Alert parents and caregivers of the index patient that if any exposure to the index patient has occurred within a childcare setting to seek prompt medical care for any signs or symptoms that may be related to Hib infection.

For excellent patient education resources, visit eMedicineHealth's Cold and Flu Center. Also, see eMedicineHealth's patient education articles Sepsis (Blood Infection); Immunization Schedule, Children; and Flu in Children.

Clinical Presentation

Khattak ZE, Anjum F. Haemophilus Influenzae. StatPearls. Treasure Island (FL): StatPearls [Internet]; April 27, 2023. [Full Text].
Contreras A, Posada R. Haemophilus influenzae Infections. Pediatr Rev. July 2023. 44 (7):422-424. [Full Text].
Oliver SE, Rubis AB, Soeters HM, et al. Secondary Cases of Invasive Disease Caused by Encapsulated and Nontypeable Haemophilus influenzae — 10 U.S. Jurisdictions, 2011–2018. MMWR. April 14, 2023. 72(15):386-390. [Full Text].
Bertran M, D'Aeth JC, Hani E, Amin-Chowdhury Z, Fry NK, Ramsay ME, et al. Trends in invasive Haemophilus influenzae serotype a disease in England from 2008-09 to 2021-22: a prospective national surveillance study. Lancet Infect Dis. 2023 Jun 22. [QxMD MEDLINE Link]. [Full Text].
Guerra AM, Waseem M. Epiglottitis. 2022 Jan. [QxMD MEDLINE Link]. [Full Text].
Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004 Nov 1. 39 (9):1267-84. [QxMD MEDLINE Link].
Collins S, Vickers A, Ladhani SN, Flynn S, Platt S, Ramsay ME, et al. Clinical and Molecular Epidemiology of Childhood Invasive Nontypeable Haemophilus influenzae Disease in England and Wales. Pediatr Infect Dis J. 2016 Mar. 35 (3):e76-84. [QxMD MEDLINE Link].
LaCross NC, Marrs CF, Gilsdorf JR. Population structure in nontypeable Haemophilus influenzae. Infect Genet Evol. 2013 Mar. 14:125-36. [QxMD MEDLINE Link].
Moxon ER. Bacterial variation, virulence and vaccines. Microbiology. 2009 Apr. 155 (Pt 4):997-1003. [QxMD MEDLINE Link].
Ward JI, Kenneth MZ. Haemophilus influenzae. Feigin RD, Cherry JD, Fletcher J, eds. Textbook of Pediatric Infectious Diseases. 4th ed. Philadelphia, Pa: WB Saunders and Co; 1998. 1464-1482.
Gilsdorf JR. What the pediatrician should know about non-typeable Haemophilus influenzae. J Infect. 2015 Jun. 71 Suppl 1:S10-4. [QxMD MEDLINE Link].
Sakata H, Adachi Y, Morozumi M, Ubukata K. Invasive Haemophilus influenzae infections in children in Kamikawa subprefecture, Hokkaido, Japan, 2006-2015: The effectiveness of H. influenzae type b vaccine. J Infect Chemother. 2017 Jul. 23 (7):459-462. [QxMD MEDLINE Link].
Shaw D, Abad R, Amin-Chowdhury Z, et. al. Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS Consortium. Lancet Digit Health. 2023 Sep. 5 (9):e582-e593. [QxMD MEDLINE Link].
Langereis JD, de Jonge MI. Unraveling Haemophilus influenzae virulence mechanisms enable discovery of new targets for antimicrobials and vaccines. Curr Opin Infect Dis. 2020 Jun. 33 (3):231-237. [QxMD MEDLINE Link].
Kaufhold I, Osbahr S, Shima K, Marwitz S, Rohmann K, Drömann D, et al. Nontypeable Haemophilus influenzae (NTHi) directly interfere with the regulation of E-cadherin in lung epithelial cells. Microbes Infect. 2017 Aug 10. [QxMD MEDLINE Link].
National Center for Immunization and Respiratory Diseases, Division of Bacterial Diseases. Haemophilus influenzae Disease (Including Hib). Centers for Disease Control and Prevention. Available at https://www.cdc.gov/hi-disease/clinicians.html. July 25, 2016; Accessed: September 26, 2017.
Watt JP, Wolfson LJ, O'Brien KL, Henkle E, Deloria-Knoll M, McCall N, et al. Burden of disease caused by Haemophilus influenzae type b in children younger than 5 years: global estimates. Lancet. 2009 Sep 12. 374(9693):903-11. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network Haemophilus influenzae, 2015. Available at https://www.cdc.gov/abcs/reports-findings/survreports/hib15.pdf. Accessed: September 11, 2017.
Jacups SP. The continuing role of Haemophilus influenzae type b carriage surveillance as a mechanism for early detection of invasive disease activity. Hum Vaccin. 2011 Dec 1. 7(12):[QxMD MEDLINE Link].
Active Bacterial Core Surveillance Report, Emerging Infections Program Network Haemophilus Influenzae, 2006. Available at http://www.cdc.gov/ncidod/dbmd/abcs/survreports.hib.pdf.
Mahapatra T. Vaccine coverage estimation using Global Positioning System and Google Earth: A commentary. Ann Trop Med Public Health. June 22, 2017. 10:295-6. [Full Text].
Jin Z, Romero-Steiner S, Carlone GM, et al. Haemophilus influenzae type a infection and its prevention. Infect Immun. 2007 Jun. 75(6):2650-4. [QxMD MEDLINE Link].
MacNeil JR, Cohn AC, Farley M, Mair R, Baumbach J, Bennett N, et al. Current epidemiology and trends in invasive Haemophilus influenzae disease--United States, 1989-2008. Clin Infect Dis. 2011 Dec. 53(12):1230-6. [QxMD MEDLINE Link].
Ortiz-Romero MDM, Espejo-García MP, Alfayate-Miguelez S, Ruiz-López FJ, Zapata-Hernandez D, Gonzalez-Pacanowska AJ, et al. Epidemiology of Nasopharyngeal Carriage by Haemophilus influenzae in Healthy Children: A Study in the Mediterranean Coast Region. Pediatr Infect Dis J. 2017 Oct. 36 (10):919-923. [QxMD MEDLINE Link].
Whittaker R, Economopoulou A, Dias JG, Bancroft E, Ramliden M, Celentano LP, et al. Epidemiology of Invasive Haemophilus influenzae Disease, Europe, 2007-2014. Emerg Infect Dis. 2017 Mar. 23 (3):396-404. [QxMD MEDLINE Link].
Giufrè M, Cardines R, Brigante G, Orecchioni F, Cerquetti M. Emergence of Invasive Haemophilus influenzae Type A Disease in Italy. Clin Infect Dis. 2017 Jun 1. 64 (11):1626-1628. [QxMD MEDLINE Link].
Tsang RS, Proulx JF, Hayden K, Shuel M, Lefebvre B, Boisvert AA, et al. Characteristics of invasive Haemophilus influenzae serotype a (Hia) from Nunavik, Canada and comparison with Hia strains in other North American Arctic regions. Int J Infect Dis. 2017 Apr. 57:104-107. [QxMD MEDLINE Link].
Szabo BG, Lenart KS, Tirczka T, Ostorhazi E. Clinical and microbiological characteristics of adult invasive Haemophilus influenzae infections: results of a 14-year single-center experience from Hungary. Infection. 2018 Dec. 46 (6):855-860. [QxMD MEDLINE Link].
GBD 2019 Meningitis Antimicrobial Resistance Collaborators. Global, regional, and national burden of meningitis and its aetiologies, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2023 Aug. 22 (8):685-711. [QxMD MEDLINE Link].
von Gottberg A, Cohen C, Whitelaw A, Chhagan M, Flannery B, Cohen AL, et al. Invasive disease due to Haemophilus influenzae serotype b ten years after routine vaccination, South Africa, 2003-2009. Vaccine. 2011 Nov 26. [QxMD MEDLINE Link].
Dong Q, Shi W, Cheng X, Chen C, Meng Q, Yao K, et al. Widespread of non-typeable Haemophilus influenzae with high genetic diversity after two decades use of Hib vaccine in China. J Clin Lab Anal. 2020 Apr. 34 (4):e23145. [QxMD MEDLINE Link].
Tsang RSW, Ulanova M. The changing epidemiology of invasive Haemophilus influenzae disease: Emergence and global presence of serotype a strains that may require a new vaccine for control. Vaccine. 2017 Jul 24. 35 (33):4270-4275. [QxMD MEDLINE Link].
Singh V, Nanjappa S, Pabbathi S, Greene JN. Invasive Haemophilus influenzae Infection in Patients With Cancer. Cancer Control. 2017 Jan. 24 (1):66-71. [QxMD MEDLINE Link].
Reilly AS, McElligott M, Mac Dermott Casement C, Drew RJ. Haemophilus influenzae type f in the post-Haemophilus influenzae type b vaccination era: a systematic review. J Med Microbiol. 2022 Oct. 71 (10):[QxMD MEDLINE Link].
Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect. 2020 Aug. 81 (2):266-275. [QxMD MEDLINE Link].
Murphy TF. Haemophilus influenzae. Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Elsevier Health Sciences; 1-2:
Butler DF, Myers AL. Changing Epidemiology of Haemophilus influenzae in Children. Infect Dis Clin North Am. 2018 Mar. 32 (1):119-128. [QxMD MEDLINE Link].
Miyahara R, Suzuki M, Morimoto K, Chang B, Yoshida S, Yoshinaga S, et al. Nosocomial Outbreak of Upper Respiratory Tract Infection With β-Lactamase-Negative Ampicillin-Resistant Nontypeable Haemophilus influenzae. Infect Control Hosp Epidemiol. 2018 Jun. 39 (6):652-659. [QxMD MEDLINE Link].
Haemophilus Influenzae serotype b (Hib) disease. Available at http://www.cdc.gov/ncidod/dbmb/diseaseinfo/haeminfluserob_t.htm. Accessed: Feb 15, 2008.
Cleland G, Leung C, Wan Sai Cheong J, Francis J, Heney C, Nourse C. Paediatric invasive Haemophilus influenzae in Queensland, Australia, 2002-2011: Young Indigenous children remain at highest risk. J Paediatr Child Health. 2017 Sep 4. [QxMD MEDLINE Link].
Gorga SM, Gilsdorf JR, Mychaliska KP. Haemophilus influenzae Serotype f Epiglottitis: A Case Report and Review. Hosp Pediatr. 2017 Jan. 7 (1):54-56. [QxMD MEDLINE Link].
Forstner C, Rohde G, Rupp J, Schuette H, Ott SR, Hagel S, et al. Community-acquired Haemophilus influenzae pneumonia--New insights from the CAPNETZ study. J Infect. 2016 May. 72 (5):554-63. [QxMD MEDLINE Link].
Walker WT, Jackson CL, Allan RN, Collins SA, Kelso MJ, Rineh A, et al. Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to Haemophilus influenzae biofilm formation. Eur Respir J. 2017 Sep. 50 (3):[QxMD MEDLINE Link].
Shoemark A. Haemophilus influenzae; biofilms in primary ciliary dyskinesia: a moving story. Eur Respir J. 2017 Sep. 50 (3):[QxMD MEDLINE Link].
Sriram KB, Cox AJ, Clancy RL, Slack MPE, Cripps AW. Nontypeable Haemophilus influenzae and chronic obstructive pulmonary disease: a review for clinicians. Crit Rev Microbiol. 2017 May 25. 1-18. [QxMD MEDLINE Link].
Tan WS, Peh HY, Liao W, Pang CH, Chan TK, Lau SH, et al. Cigarette Smoke-Induced Lung Disease Predisposes to More Severe Infection with Nontypeable Haemophilus influenzae: Protective Effects of Andrographolide. J Nat Prod. 2016 May 27. 79 (5):1308-15. [QxMD MEDLINE Link].
Harris TM, Rumaseb A, Beissbarth J, Barzi F, Leach AJ, Smith-Vaughan HC. Culture of non-typeable Haemophilus influenzae from the nasopharynx: Not all media are equal. J Microbiol Methods. 2017 Jun. 137:3-5. [QxMD MEDLINE Link].
Roush SW, Murphy TV. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA. 2007 Nov 14. 298(18):2155-63. [QxMD MEDLINE Link].
Price EP, Harris TM, Spargo J, Nosworthy E, Beissbarth J, Chang AB, et al. Simultaneous identification of Haemophilus influenzae and Haemophilus haemolyticus using real-time PCR. Future Microbiol. 2017 Jun. 12:585-593. [QxMD MEDLINE Link].
Bjarnason A, Lindh M, Westin J, Andersson LM, Baldursson O, Kristinsson KG, et al. Utility of oropharyngeal real-time PCR for S. pneumoniae and H. influenzae for diagnosis of pneumonia in adults. Eur J Clin Microbiol Infect Dis. 2017 Mar. 36 (3):529-536. [QxMD MEDLINE Link].
Dunne EM, Mantanitobua S, Singh SP, Reyburn R, Tuivaga E, Rafai E, et al. Real-time qPCR improves meningitis pathogen detection in invasive bacterial-vaccine preventable disease surveillance in Fiji. Sci Rep. 2016 Dec 23. 6:39784. [QxMD MEDLINE Link].
Farahani H, Ghaznavi-Rad E, Mondanizadeh M, MirabSamiee S, Khansarinejad B. Specific detection of common pathogens of acute bacterial meningitis using an internally controlled tetraplex-PCR assay. Mol Cell Probes. 2016 Aug. 30 (4):261-265. [QxMD MEDLINE Link].
Khumalo J, Nicol M, Hardie D, Muloiwa R, Mteshana P, Bamford C. Diagnostic accuracy of two multiplex real-time polymerase chain reaction assays for the diagnosis of meningitis in children in a resource-limited setting. PLoS One. 2017. 12 (3):e0173948. [QxMD MEDLINE Link].
Carnalla-Barajas MN, Soto-Noguerón A, Martínez-Medina L, et. al. Diagnosis of bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae using a multiplex real-time PCR technique. Braz J Microbiol. 2022 Dec. 53 (4):1951-1958. [QxMD MEDLINE Link].
Abdeldaim GM, Strålin K, Korsgaard J, Blomberg J, Welinder-Olsson C, Herrmann B. Multiplex quantitative PCR for detection of lower respiratory tract infection and meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. BMC Microbiol. 2010 Dec 3. 10:310. [QxMD MEDLINE Link].
Gadsby NJ, Russell CD, McHugh MP, Mark H, Conway Morris A, Laurenson IF, et al. Comprehensive Molecular Testing for Respiratory Pathogens in Community-Acquired Pneumonia. Clin Infect Dis. 2016 Apr 1. 62 (7):817-823. [QxMD MEDLINE Link].
Søgaard KK, Hinic V, Goldenberger D, Gensch A, Schweitzer M, Bättig V, et al. Evaluation of the clinical relevance of the Biofire(©) FilmArray pneumonia panel among hospitalized patients. Infection. 2023 Aug 12. [QxMD MEDLINE Link].
Soysal A, Toprak DG, Türkoğlu S, Bakir M. Evaluation of the line probe assay for the rapid detection of bacterial meningitis pathogens in cerebrospinal fluid samples from children. BMC Microbiol. 2017 Jan 11. 17 (1):14. [QxMD MEDLINE Link].
Roisin S, Huang TD, de Mendonça R, Nonhoff C, Bogaerts P, Hites M, et al. Prospective evaluation of a high multiplexing real-time polymerase chain reaction array for the rapid identification and characterization of bacteria causative of nosocomial pneumonia from clinical specimens: a proof-of-concept study. Eur J Clin Microbiol Infect Dis. 2018 Jan. 37 (1):109-116. [QxMD MEDLINE Link].
Higgins O, Clancy E, Forrest MS, Piepenburg O, Cormican M, Boo TW, et al. Duplex recombinase polymerase amplification assays incorporating competitive internal controls for bacterial meningitis detection. Anal Biochem. 2018 Apr 1. 546:10-16. [QxMD MEDLINE Link].
Bruin JP, Kostrzewa M, van der Ende A, Badoux P, Jansen R, Boers SA, et al. Identification of Haemophilus influenzae and Haemophilus haemolyticus by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Eur J Clin Microbiol Infect Dis. 2014 Feb. 33 (2):279-84. [QxMD MEDLINE Link].
Zhu B, Xiao D, Zhang H, Zhang Y, Gao Y, Xu L, et al. MALDI-TOF MS distinctly differentiates nontypable Haemophilus influenzae from Haemophilus haemolyticus. PLoS One. 2013. 8 (2):e56139. [QxMD MEDLINE Link].
Månsson V, Gilsdorf JR, Kahlmeter G, Kilian M, Kroll JS, Riesbeck K, et al. Capsule Typing of Haemophilus influenzae by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Emerg Infect Dis. 2018 Mar. 24 (3):443-452. [QxMD MEDLINE Link].
Takeuchi N, Segawa S, Ishiwada N, Ohkusu M, Tsuchida S, Satoh M, et al. Capsular serotyping of Haemophilus influenzae by using matrix-associated laser desorption ionization-time of flight mass spectrometry. J Infect Chemother. 2018 Jul. 24 (7):510-514. [QxMD MEDLINE Link].
Topaz N, Boxrud D, Retchless AC, Nichols M, Chang HY, Hu F, et al. BMScan: using whole genome similarity to rapidly and accurately identify bacterial meningitis causing species. BMC Infect Dis. 2018 Aug 15. 18 (1):405. [QxMD MEDLINE Link].
Singleton R, Hammitt L, Hennessy T, et al. The Alaska Haemophilus influenzae type b experience: lessons in controlling a vaccine-preventable disease. Pediatrics. 2006 Aug. 118(2):e421-9. [QxMD MEDLINE Link].
Kiedrowska M, Kuch A, Żabicka D, Waśko I, Ronkiewicz P, Wasiak K, et al. Beta-lactam resistance among Haemophilus influenzae isolates in Poland. J Glob Antimicrob Resist. 2017 Aug 14. [QxMD MEDLINE Link].
Li JP, Hua CZ, Sun LY, Wang HJ, Chen ZM, Shang SQ. Epidemiological Features and Antibiotic Resistance Patterns of Haemophilus influenzae Originating from Respiratory Tract and Vaginal Specimens in Pediatric Patients. J Pediatr Adolesc Gynecol. 2017 Jun 16. [QxMD MEDLINE Link].
Maddi S, Kolsum U, Jackson S, Barraclough R, Maschera B, Simpson KD, et al. Ampicillin resistance in Haemophilus influenzae from COPD patients in the UK. Int J Chron Obstruct Pulmon Dis. 2017. 12:1507-1518. [QxMD MEDLINE Link].
Tsang RSW, Shuel M, Whyte K, Hoang L, Tyrrell G, Horsman G, et al. Antibiotic susceptibility and molecular analysis of invasive Haemophilus influenzae in Canada, 2007 to 2014. J Antimicrob Chemother. 2017 May 1. 72 (5):1314-1319. [QxMD MEDLINE Link].
Tribuddharat C, Srifuengfung S. Multiple drug resistance in Haemophilus influenzae isolated from patients in Bangkok, Thailand. J Glob Antimicrob Resist. 2017 Jun. 9:121-123. [QxMD MEDLINE Link].
Deguchi T, Ito S, Hatazaki K, Horie K, Yasuda M, Nakane K, et al. Antimicrobial susceptibility of Haemophilus influenzae strains isolated from the urethra of men with acute urethritis and/or epididymitis. J Infect Chemother. 2017 Jun 12. [QxMD MEDLINE Link].
Wajima T, Seyama S, Nakamura Y, Kashima C, Nakaminami H, Ushio M, et al. Prevalence of macrolide-non-susceptible isolates among β-lactamase-negative ampicillin-resistant Haemophilus influenzae in a tertiary care hospital in Japan. J Glob Antimicrob Resist. 2016 Sep. 6:22-26. [QxMD MEDLINE Link].
Yamada S, Seyama S, Wajima T, Yuzawa Y, Saito M, Tanaka E, et al. β-Lactamase-non-producing ampicillin-resistant Haemophilus influenzae is acquiring multidrug resistance. J Infect Public Health. 2020 Apr. 13 (4):497-501. [QxMD MEDLINE Link].
Su PY, Huang AH, Lai CH, Lin HF, Lin TM, Ho CH. Extensively drug-resistant Haemophilus influenzae - emergence, epidemiology, risk factors, and regimen. BMC Microbiol. 2020 Apr 28. 20 (1):102. [QxMD MEDLINE Link].
Kuo SC, Chen PC, Shiau YR, Wang HY, Lai JF 1st, Huang W, et al. Levofloxacin-resistant haemophilus influenzae, Taiwan, 2004-2010. Emerg Infect Dis. 2014 Aug. 20 (8):1386-90. [QxMD MEDLINE Link].
Chang CM, Shih HI, Wu CJ, Lauderdale TL, Lee NY, Lee CC, et al. Fluoroquinolone resistance in Haemophilus influenzae from nursing home residents in Taiwan: correlation of MICs and mutations in QRDRs. J Appl Microbiol. 2020 Jun. 128 (6):1624-1633. [QxMD MEDLINE Link].
Torumkuney D, Smayevsky J, Relloso MS, Sucari A, Pennini M, Brilla E, et al. Results from the Survey of Antibiotic Resistance (SOAR) 2015-17 in Latin America (Argentina, Chile and Costa Rica): data based on CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. J Antimicrob Chemother. 2020 Apr 1. 75 (Suppl 1):i43-i59. [QxMD MEDLINE Link].
Torumkuney D, Bratus E, Yuvko O, Pertseva T, Morrissey I. Results from the Survey of Antibiotic Resistance (SOAR) 2016-17 in Ukraine: data based on CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. J Antimicrob Chemother. 2020 Apr 1. 75 (Suppl 1):i100-i111. [QxMD MEDLINE Link].
Torumkuney D, Hammami A, Mezghani Maalej S, Ayed NB, Revathi G, Zerouali K, et al. Results from the Survey of Antibiotic Resistance (SOAR) 2015-18 in Tunisia, Kenya and Morocco: data based on CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. J Antimicrob Chemother. 2020 Apr 1. 75 (Suppl 1):i2-i18. [QxMD MEDLINE Link].
Jean SS, Lee WS, Ko WC, Hsueh PR. In vitro susceptibility of ceftaroline against clinically important Gram-positive cocci, Haemophilus species and Klebsiella pneumoniae in Taiwan: Results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) in 2012-2018. J Microbiol Immunol Infect. 2020 May 11. [QxMD MEDLINE Link].
Sader HS, Carvalhaes CG, Duncan LR, Shortridge D. Antimicrobial Activity of Ceftolozane-Tazobactam and Comparators against Clinical Isolates of Haemophilus influenzae from the United States and Europe. Antimicrob Agents Chemother. 2020 Apr 21. 64 (5):[QxMD MEDLINE Link].
World Health Organization. WHO publishes list of bacteria for which new antibiotics are urgently needed. World Health Organization. Available at https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed. February 27, 2017; Accessed: August 28, 2023.
Van PH, Binh PT, Minh NH, Morrissey I, Torumkuney D. Results from the Survey of Antibiotic Resistance (SOAR) 2009-11 in Vietnam. J Antimicrob Chemother. 2016 May. 71 Suppl 1:i93-102. [QxMD MEDLINE Link].
Torumkuney D, Gur D, Soyletir G, Gurler N, Aktas Z, Sener B, et al. Results from the Survey of Antibiotic Resistance (SOAR) 2002-09 in Turkey. J Antimicrob Chemother. 2016 May. 71 Suppl 1:i85-91. [QxMD MEDLINE Link].
Jamsheer A, Rafay AM, Daoud Z, Morrissey I, Torumkuney D. Results from the Survey of Antibiotic Resistance (SOAR) 2011-13 in the Gulf States. J Antimicrob Chemother. 2016 May. 71 Suppl 1:i45-61. [QxMD MEDLINE Link]. [Full Text].
Hu F, Zhu D, Wang F, Morrissey I, Wang J, Torumkuney D. Results from the Survey of Antibiotic Resistance (SOAR) 2009-11 and 2013-14 in China. J Antimicrob Chemother. 2016 May. 71 Suppl 1:i33-43. [QxMD MEDLINE Link].
Torumkuney D, Chaiwarith R, Reechaipichitkul W, Malatham K, Chareonphaibul V, Rodrigues C, et al. Results from the Survey of Antibiotic Resistance (SOAR) 2012-14 in Thailand, India, South Korea and Singapore. J Antimicrob Chemother. 2016 May. 71 Suppl 1:i3-19. [QxMD MEDLINE Link].
Kacou-Ndouba A, Revathi G, Mwathi P, Seck A, Diop A, Kabedi-Bajani MJ, et al. Results from the Survey of Antibiotic Resistance (SOAR) 2011-14 in the Democratic Republic of Congo, Ivory Coast, Republic of Senegal and Kenya. J Antimicrob Chemother. 2016 May. 71 Suppl 1:i21-31. [QxMD MEDLINE Link].
Zafar A, Hasan R, Nizamuddin S, Mahmood N, Mukhtar S, Ali F, et al. Antibiotic susceptibility in Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus pyogenes in Pakistan: a review of results from the Survey of Antibiotic Resistance (SOAR) 2002-15. J Antimicrob Chemother. 2016 May. 71 Suppl 1:i103-9. [QxMD MEDLINE Link].
Satola SW, Collins JT, Napier R, et al. Capsule gene analysis of invasive Haemophilus influenzae: accuracy of serotyping and prevalence of IS1016 among nontypeable isolates. J Clin Microbiol. 2007 Oct. 45(10):3230-8. [QxMD MEDLINE Link].
Scarborough M, Gordon SB, Whitty CJ, et al. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med. 2007 Dec 13. 357(24):2441-50. [QxMD MEDLINE Link].
van de Beek D, de Gans J, McIntyre P, et al. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2007. (1):CD004405. [QxMD MEDLINE Link].
Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2015 Sep 12. CD004405. [QxMD MEDLINE Link].
Gudina EK, Tesfaye M, Adane A, Lemma K, Shibiru T, Wieser A, et al. Adjunctive dexamethasone therapy in unconfirmed bacterial meningitis in resource limited settings: is it a risk worth taking?. BMC Neurol. 2016 Aug 26. 16 (1):153. [QxMD MEDLINE Link].
Ogunlesi TA, Odigwe CC, Oladapo OT. Adjuvant corticosteroids for reducing death in neonatal bacterial meningitis. Cochrane Database Syst Rev. 2015 Nov 11. CD010435. [QxMD MEDLINE Link].
McIntyre PB, Berkey CS, King SM, et al. Dexamethasone as adjunctive therapy in bacterial meningitis. A meta- analysis of randomized clinical trials since 1988. JAMA. 1997 Sep 17. 278(11):925-31. [QxMD MEDLINE Link].
[Guideline] Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004 Nov 1. 39(9):1267-84. [QxMD MEDLINE Link].
Peltola H, Roine I, Fernández J, Zavala I, Ayala SG, Mata AG, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2007 Nov 15. 45 (10):1277-86. [QxMD MEDLINE Link].
Ajdukiewicz KM, Cartwright KE, Scarborough M, Mwambene JB, Goodson P, Molyneux ME, et al. Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial. Lancet Infect Dis. 2011 Apr. 11 (4):293-300. [QxMD MEDLINE Link].
Peltola H, Leib SL. Performance of adjunctive therapy in bacterial meningitis depends on circumstances. Pediatr Infect Dis J. 2013 Dec. 32 (12):1381-2. [QxMD MEDLINE Link].
Syrogiannopoulos GA, Lourida AN, Theodoridou MC, et al. Dexamethasone therapy for bacterial meningitis in children: 2- versus 4-day regimen. J Infect Dis. 1994 Apr. 169(4):853-8. [QxMD MEDLINE Link].
Lee S, Yen MT. Management of preseptal and orbital cellulitis. Saudi J Ophthalmol. 2011 Jan. 25 (1):21-9. [QxMD MEDLINE Link].
Orbital Cellulitis. American Academy of Ophthalmology. Available at https://www.aao.org/focalpointssnippetdetail.aspx?id=1b0ef397-e539-4c0d-8608-55bb5c621c94. Accessed: September 27, 2017.
Lawrence R. Guidelines for the management of ADULTS with suspected epiglottitis. Nottingham University Hospitals NHS Trust. Available at https://www.nuh.nhs.uk/handlers/downloads.ashx?id=62734. December 14, 2015; Accessed: September 27, 2017.
Epiglottitis and Supraglottitis. Gloucestershire Hospitals NHS Foundation Trust. Available at http://www.gloshospitals.nhs.uk/en/Trust-Staff/Antibiotic-Guidelines/ENT-Guidelines/Epiglottitis/. April 23, 2014; Accessed: September 27, 2017.
Castellazzi L, Mantero M, Esposito S. Update on the Management of Pediatric Acute Osteomyelitis and Septic Arthritis. Int J Mol Sci. 2016 Jun 1. 17 (6):[QxMD MEDLINE Link].
Peltola H, Pääkkönen M, Kallio P, Kallio MJ, Osteomyelitis-Septic Arthritis (OM-SA) Study Group. Prospective, randomized trial of 10 days versus 30 days of antimicrobial treatment, including a short-term course of parenteral therapy, for childhood septic arthritis. Clin Infect Dis. 2009 May 1. 48 (9):1201-10. [QxMD MEDLINE Link].
Bradley JS. What is the appropriate treatment course for bacterial arthritis in children?. Clin Infect Dis. 2009 May 1. 48 (9):1211-2. [QxMD MEDLINE Link].
Swamy S, Sharma, R. Duration of Treatment of Gram-Negative Bacteremia: Are Shorter Courses of Antimicrobial Therapy Feasible?. Infectious Diseases in Clinical Practice. May 2016. 24:155–160.
Park SH, Milstone AM, Diener-West M, Nussenblatt V, Cosgrove SE, Tamma PD. Short versus prolonged courses of antibiotic therapy for children with uncomplicated Gram-negative bacteraemia. J Antimicrob Chemother. 2014 Mar. 69 (3):779-85. [QxMD MEDLINE Link].
Nelson AN, Justo JA, Bookstaver PB, Kohn J, Albrecht H, Al-Hasan MN. Optimal duration of antimicrobial therapy for uncomplicated Gram-negative bloodstream infections. Infection. 2017 May 6. [QxMD MEDLINE Link].
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, et. al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017 Mar. 45 (3):486-552. [QxMD MEDLINE Link].
Lieberthal AS, Carroll AE, Chonmaitree T, Ganiats TG, Hoberman A, Jackson MA, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013 Mar. 131 (3):e964-99. [QxMD MEDLINE Link].
Chow AW, Benninger MS, Brook I, Brozek JL, Goldstein EJ, Hicks LA, et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis. 2012 Apr. 54 (8):e72-e112. [QxMD MEDLINE Link].
Swingler G, Fransman D, Hussey G. Conjugate vaccines for preventing Haemophilus influenzae type B infections. Cochrane Database Syst Rev. 2007 Apr 18. CD001729. [QxMD MEDLINE Link].
Salam RA, Das JK, Dojo Soeandy C, Lassi ZS, Bhutta ZA. Impact of Haemophilus influenzae type B (Hib) and viral influenza vaccinations in pregnancy for improving maternal, neonatal and infant health outcomes. Cochrane Database Syst Rev. 2015 Jun 9. CD009982. [QxMD MEDLINE Link].
Peltola H, Roine I, Fernandez J, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2007 Nov 15. 45(10):1277-86. [QxMD MEDLINE Link].
Charania NA, Moghadas SM. Modelling the effects of booster dose vaccination schedules and recommendations for public health immunization programs: the case of Haemophilus influenzae serotype b. BMC Public Health. 2017 Sep 13. 17 (1):705. [QxMD MEDLINE Link].
Bridges CB, Coyne-Beasley T, on behalf of the Advisory Committee on Immunization Practices. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older - United States, 2014. Ann Intern Med. 2014;160(3):190-7. Available at http://annals.org/article.aspx?articleid=1819123.
Lowry F. ACIP issues 2014 immunization schedule for adults. Medscape Medical News. February 3, 2014. Available at http://www.medscape.com/viewarticle/820145. Accessed: February 10, 2014.
Robinson CL, Romero JR, Kempe A, Pellegrini C, Advisory Committee on Immunization Practices (ACIP) Child/Adolescent Immunization Work Group. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2017. MMWR Morb Mortal Wkly Rep. 2017 Feb 10. 66 (5):134-135. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention (Source: National Center for Immunization and Respiratory Diseases). Hib Vaccine Recommendations. https://www.cdc.gov/vaccines/vpd/hib/hcp/recommendations.html. Last Reviewed: April 13, 2021; Accessed: August 28, 2023.
Centers for Disease Control and Prevention. Haemophilus influenzae. Centers for Disease Control and Prevention, The Pink Book. Available at https://www.cdc.gov/vaccines/pubs/pinkbook/hib.html. Page last reviewed: August 18, 2021; Accessed: August 28, 2023.
Prymula R, Peeters P, Chrobok V, Kriz P, Novakova E, Kaliskova E, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet. 2006 Mar 4. 367 (9512):740-8. [QxMD MEDLINE Link].
Palmu AA, Jokinen J, Nieminen H, Rinta-Kokko H, Ruokokoski E, Puumalainen T, et al. Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3-4 trial. Lancet Infect Dis. 2014 Mar. 14 (3):205-12. [QxMD MEDLINE Link].
Karppinen S, Toivonen L, Schuez-Havupalo L, Teros-Jaakkola T, Waris M, Auranen K, et al. Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against all respiratory tract infections in children under two years of age. Vaccine. 2019 May 16. 37 (22):2935-2941. [QxMD MEDLINE Link].
Leroux-Roels G, Van Damme P, Haazen W, Shakib S, Caubet M, Aris E, et al. Phase I, randomized, observer-blind, placebo-controlled studies to evaluate the safety, reactogenicity and immunogenicity of an investigational non-typeable Haemophilus influenzae (NTHi) protein vaccine in adults. Vaccine. 2016 Jun 8. 34 (27):3156-63. [QxMD MEDLINE Link].
Teo E, Lockhart K, Purchuri SN, Pushparajah J, Cripps AW, van Driel ML. Haemophilus influenzae oral vaccination for preventing acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2017 Jun 19. 6:CD010010. [QxMD MEDLINE Link].
Szenborn L, Osipova IV, Czajka H, Kharit SM, Jackowska T, François N, et al. Immunogenicity, safety and reactogenicity of the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in 2-17-year-old children with asplenia or splenic dysfunction: A phase 3 study. Vaccine. 2017 Sep 25. 35 (40):5331-5338. [QxMD MEDLINE Link].
Van Damme P, Leroux-Roels G, Vandermeulen C, De Ryck I, Tasciotti A, Dozot M, et al. Safety and immunogenicity of non-typeable Haemophilus influenzae-Moraxella catarrhalis vaccine. Vaccine. 2019 May 21. 37 (23):3113-3122. [QxMD MEDLINE Link].
Gkentzi D, Collins S, Ramsay ME, Slack MP, Ladhani S. Revised recommendations for the prevention of secondary Haemophilus influenzae type b (Hib) disease. J Infect. 2013 Nov. 67 (5):486-9. [QxMD MEDLINE Link].