MICROBIOLOGY

  • Small aerobic Gram-negative coccobacillus found mainly in human respiratory tract.
  • H. influenzae is the most notable species, but decline in past decades due to active childhood immunization (Hib).
    • Historically, encapsulated, type b (Hib) strain accounts for most bacteremic pneumonia and invasive disease, whereas non-encapsulated strains mostly cause otitis media, sinusitis, AECB and pneumonia.
      • H. influenzae serotype a (Hia) increasingly noted as cause of severe, invasive infection. Emergence due to intrinsic capsular virulence factors of Hia was well as pressure from success of Hib immunization [17].
        • Predominantly note in US and Canada. Incidence in Europe, low.
        • In one series, accounted for ~30% of invasive H. influenzae infection in Manitoba.
      • Type f strain also increasingly recognized as cause of severe infection, though less common than Hia.
    • Sensitivity of Gram stain and culture probably ~50% in pts with H. influenzae pneumonia. Use of prior abx will decrease yield.
  • Non-typeable H. influenzae strains more common now than type b.
  • Other Haemophilus strains (H. aphrophilus, now called Aggregatibacter aphrophilus) occasional cause of infection in HIV.

CLINICAL

  • Up to 80% may be carriers of non-typeable H. influenzae.
    • Colonization of type b strains (which had accounted for most invasive disease) reduced considerably in children now < 1% w/ introduction of conjugate vaccine. Strains type a and type f increasingly identified as causing severe H. influenzae infection.
    • Most infections (about two-thirds) caused by non-typeable strains.
  • HIV appears to be a risk factor for developing invasive disease due to H. influenzae type b, especially bacteremic pneumonia. However, H. influenzae type b remains rare, so immunization unwarranted in adults, including HIV+ pts.
  • Pneumonia may occasionally mimic PCP with bilateral interstitial infiltrates.
  • TMP/SMX may reduce risk of community-acquired pneumonia.
  • Azithromycin or clarithromycin prophylaxis may reduce infection, but no data to confirm.

SITES OF INFECTION

  • Respiratory:
  • Meningitis
  • Epiglottitis
  • Acute otitis media
  • Periorbital cellulitis: mainly children, diminished since introduction of immunization
  • Septic arthritis: rare
  • GU: some consider as potential pathogen in men with urethritis.
  • Conjunctivitis: H. influenzae biogroup aegyptius may cause severe conjunctivitis (aka Brazilian purpuric fever) mostly in children. Described in S. America, but may occur elsewhere.

TREATMENT

Respiratory Infections (mild-moderate)

Severe Infections (pneumonia, meningitis, epiglottitis)

  • Life-threatening illnesses: treat with parenteral therapy.
  • Meningitis (only): dexamethasone 0.6 mg/kg/d IV ÷ 4 doses for children >2 mos w/ H. influenzae type B (Hib) meningitis; decreases risk of deafness/neurological sequelae.

Prevention

  • Children: Hib vaccines available in many forms--all interchangeable for primary or booster needs. See Hib vaccine module for details. HIV+ children are viewed as being at high risk of infection, and should not skip booster doses in case of vaccine shortages. Booster doses can be made up with any product.
  • Adults: Hib vaccine not recommended in U.S. routinely for adults, because most serious non-pediatric Haemophilus infections are due to non-encapsulated strains or Hia or Hif not covered by vaccine.
    • UK does recommend single dose of Hib vaccine with rationale that pneumonia incidence is higher in HIV infected, little data to back practice.
    • If other risk factors (e.g., asplenia, bone marrow transplant) present, consider immunization.
Guidance for Haemophilus influenzae type b (Hib) vaccination in high-risk groups [1]

High-risk group*

Hib vaccine guidance

Patients aged < 12 mos

Follow routine Hib vaccination recommendations

Patients aged 12–59 mos

If unimmunized or received 0 or 1 dose before age 12 mos: 2 doses, 8 wks apart
If received ≥2 doses before age 12 mos: 1 dose 8 wks after last dose
If completed a primary series and received a booster dose at age ≥12 mos: no additional doses

Patients aged < 60 months undergoing chemotherapy or radiation therapy†

If routine Hib doses administered ≥14 days before starting therapy: revaccination not required
If dose administered within 14 days of starting therapy or given during therapy:
repeat doses starting at least 3 mos following therapy completion

Patients aged ≥15 mos undergoing elective splenectomy

If unimmunized:§ 1 dose prior to procedure¶

Asplenic patients aged >59 mos and adults

If unimmunized:§ 1 dose

HIV-infected children aged ≥60 mos

If unimmunized:§ 1 dose

HIV-infected adults

Hib vaccination is not recommended

Recipients of hematopoietic stem cell transplant, all ages

Regardless of Hib vaccination history: 3 doses (at least 4 wks apart) beginning 6–12 mos after transplant

*Persons with functional or anatomic asplenia, HIV infection, immunoglobulin deficiency including immunoglobulin G2 subclass deficiency, or early component complement deficiency, recipients of a hematopoietic stem cell transplant, and those receiving chemotherapy or radiation therapy for malignant neoplasms.

†Some experts suggest conducting serologic testing for these patients (Source: Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2013;[Epub ahead of print] doi: 10.1093/cid/cit684).

§Patients who have not received a primary series and booster dose or at least 1 dose of Hib vaccine after 14 months are considered unimmunized.

¶ Some experts suggest vaccination at least 14 days before the procedure (Sources: CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2011;60[No. RR-2]; CDC. Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993;42 [No. RR-4]; Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2013;[Epub ahead of print] doi: 10.1093/cid/cit684.) Some experts suggest administering a dose prior to elective splenectomy regardless of prior vaccination history (Source: American Academy of Pediatrics. Haemophilus influenzaeinfections. In: Pickering L, Baker C, Kimberlin D, Long S, eds. Red book: 2012 report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2012:345–52).

  • Chemoprophylaxis: for contacts of patient with invasive Hib disease.
    • Contact defined as spending >4h/d for at least 5/7 days preceding hospitalization of index case.
    • Unimmunized contacts (adults and children < 48 mos): administer rifampin prophylaxis 20 mg/kg/d (600 mg max) x 4d to eradicate carrier state and reduce secondary cases.
    • Chemoprophylaxis not recommended if all household contacts < 48 mos have completed immunization series.
    • Rifampin only effective if taken within 7d of index case hospitalization.

Selected Drug Comments

Drug

Recommendation

Amoxicillin

Production of beta-lactamases in >30-40% of H. influenzae isolates means that amoxicillin or ampicillin should not be used empirically for serious infections.

Amoxicillin/clavulanate

More effective microbiologically than amoxicillin, with ~100% susceptibility, as the addition of beta-lactamase inhibitor means that this drug treats all isolates.

Azithromycin

Generally reliable for pedestrian respiratory tract infections, though some isolates are resistant and resistance may be more common in those patients on azithromycin for MAC prophylaxis.

Ceftriaxone

Drug for serious infections.

Cefuroxime axetil

Reliable, first-line choice that will treat beta-lactamase producers.

Doxycycline

Drug not commonly used to treat H. influenzae, although resistance rates in U.S. < 2-3%.

Moxifloxacin

Excellent activity with among the lowest MICs of the widely used FQ class.

Trimethoprim/sulfamethoxazole

Most isolates susceptible, though resistance rates rising, and may be more common in those on TMP/SMX prophylaxis.

Telithromycin

Only member of the ketolide drug class related to macrolides, available in oral formulation; now only FDA-approved for pneumonia (CAP) due to concerns for potential hepatotoxicity. H. influenzae coverage similar to azithromycin. Rarely used.

Ciprofloxacin

Member of fluoroquinolone class usually with excellent activity against Haemophilus species; however, not used empirically for lower respiratory tract infection due to poor activity against the pneumococcus.

OTHER INFORMATION

  • With introduction of infant immunization program w/ Hib vaccine, childhood meningitis, epiglottitis, bacteremia and arthritis now all uncommon.
  • Incidence of pneumonia in HIV patients on ART likely less than older literature suggests in HIV populations.

Basis for recommendation

  1. Briere EC et al: Prevention and control of haemophilus influenzae type b disease: recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep 63:1, 2014  [PMID:24572654]

    Comment: Although no new recommendations issued, this guideline compiles all prior as well as background information and impact of Hib conjugate vaccine.

References

  1. Arya BK et al: Impact of Haemophilus influenzae Type b Conjugate Vaccines (HibCV) on Nasopharyngeal Carriage in HIV Infected Children and Their Parents from West Bengal, India. Pediatr Infect Dis J Jun 7  [PMID:27276182]

    Comment: Small study suggesting that Hib use in HIV-infected children dropped baseline colonization almost 10x. No outcomes in this study.

  2. Deza G et al: Isolation of Haemophilus influenzae and Haemophilus parainfluenzae in urethral exudates from men with acute urethritis: a descriptive study of 52 cases. Sex Transm Infect 92:29, 2016  [PMID:26139207]

    Comment: Haemophilus spp considered pathogen in 6.8% of those presenting to an STD clinic in Spain.

  3. Navin TR et al: Risk factors for community-acquired pneumonia among persons infected with human immunodeficiency virus. J Infect Dis 181:158, 2000  [PMID:10608762]

    Comment: Large study of 1200 HIV+ pts with community-acquired pneumonia and PCP. Multivariate logistic regression showed that pts less likely than controls to have used TMP-SMX prophylaxis (OR, 0.22; 95% CI, 0.12-0.41) and more likely to have been hospitalized previously with pneumonia (OR, 6.25; CI, 3.40-11.5). Authors suggest that these findings reconfirm efficacy of TMP-SMX in preventing community-acquired pneumonia.

  4. MacLennan CA et al: Immunization of HIV-infected adults in the UK with Haemophilus influenzae b/meningococcal C glycoconjugate and pneumococcal polysaccharide vaccines. J Acquir Immune Defic Syndr May 7  [PMID:27163175]

    Comment: Study of 211 HIV-infected (and 73 uninfected) immunized with Hib/MenCTT found similar responses in both populations. UK Guidelines suggest a single dose of Hib compared to no such recommendation in the US. No good data on outcome back UK recs but incidence of pneumonia is higher in HIV-infected.

  5. Molyneux E et al: 5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double-blind randomised equivalence study. Lancet 377:1837, 2011  [PMID:21620467]

    Comment: Short duration of treatment (5d) appears to be as effective as 10d in this study from Malawi that includes HIV (+) children. H. influenzae was the second most common cause of infection.

  6. Cordero E et al: Haemophilus influenzae pneumonia in human immunodeficiency virus-infected patients. The Grupo Andaluz para el Estudio de las Enfermedades Infecciosas. Clin Infect Dis 30:461, 2000  [PMID:10722428]

    Comment: One of few HIV-specific reports regarding H. influenzae comes from Spain. In this study, most pts were severely immunosuppressed; 73% had a CD4 <100. Subacute clinical presentation observed in 27% and was associated with higher degree of immunosuppression. Authors conclude that this pathogen mainly afflicts those with advanced HIV, and note a surprising attributable mortality of ~11%.

  7. Doern GV, Brown SD: Antimicrobial susceptibility among community-acquired respiratory tract pathogens in the USA: data from PROTEKT US 2000-01. J Infect 48:56, 2004  [PMID:14667792]

    Comment: Published national survey of respiratory isolates showed that overall rate of beta-lactamase production among 2706 isolates of H. influenzae examined in this study was 28.3%. 24 isolates (0.9%) found to be ampicillin-resistant despite failing to produce beta-lactamase. Among beta-lactams tested cefotaxime was most active (MIC90 0.12 mg/L) irrespective of beta-lactamase production. In contrast, cefprozil had relatively poor activity against beta-lactamase-positive isolates with a MIC90 of >8 mg/L. Telithromycin (MIC90 4 mg/L) more potent than clarithromycin, and as potent as azithromycin vs. H. influenzae, irrespective of beta-lactamase status. Gatifloxacin and moxifloxacin were most potent FQ with MIC90 values of 0.03 mg/L.

  8. Bartlett JG: Pneumonia in the patient with HIV infection. Infect Dis Clin North Am 12:807, 1998  [PMID:9779391]

    Comment: Rate of bacteremic Haemophilus pneumonia >100-fold greater in HIV+ pts than general population. Author suggests that H. influenzae infection in HIV+ pts does not require anything other than customary treatment for community-acquired pneumonia.

  9. Watanabe H et al: Clinical and microbiological characteristics of community-acquired pneumonia among human immunodeficiency virus-infected patients in northern Thailand. J Infect Chemother 14:105, 2008  [PMID:18622672]

    Comment: Report from Thailand among 191 HIV-infected patients with CAP. Among sputum isolates, H. influenzae was most commonly detected (38), followed by P. marneffei (10), S. pneumoniae (10), R. equi (9), and S. aureus (9).

  10. Melvin AJ, Mohan KM: Response to immunization with measles, tetanus, and Haemophilus influenzae type b vaccines in children who have human immunodeficiency virus type 1 infection and are treated with highly active antiretroviral therapy. Pediatrics 111:e641, 2003  [PMID:12777579]

    Comment: Small study examining vaccine responses in HIV infected children before and after HAART. Authors conclude that repeat immunizations can improve titers in those with previously undetectable responses when performed after institution of HAART.

  11. von Gottberg A et al: Impact of conjugate Haemophilus influenzae type b (Hib) vaccine introduction in South Africa. Bull World Health Organ 84:811, 2006  [PMID:17128361]

    Comment: South African experience describes reduction in both Hib and non-typeable H. influenzae disease in HIV+ populations.

  12. Muñoz P et al: Haemophilus species bacteremia in adults. The importance of the human immunodeficiency virus epidemic. Arch Intern Med 157:1869, 1997  [PMID:9290547]

    Comment: Spanish study emphasizing that Haemophilus bacteremia is no longer a disease in children. 116 pts had bacteremia (0.26 cases per 1000 admissions) with HIV the most common underlying condition [29%]. The HIV+ pts mainly presented with bilateral pneumonia. In this cohort that included HIV-negative adults, ABx resistance was reported: 11% to chloramphenicol, 48% to ampicillin, 78% to erythromycin, 76% to TMP-SMX, 15% to rifampin, and 57% to clarithromycin.

  13. De Sousa dos Santos S et al: Haemophilus influenzae type b immunization in adults infected with the human immunodeficiency virus. AIDS Res Hum Retroviruses 20:493, 2004  [PMID:15186523]

    Comment: Though not routinely recommended, Hib immunization did appear safe without significant alterations in VL or CD4. Antibody responses were judged suboptimal.
    Rating: Important

  14. Cowgill KD et al: Effectiveness of Haemophilus influenzae type b Conjugate vaccine introduction into routine childhood immunization in Kenya. JAMA 296:671, 2006  [PMID:16896110]

    Comment: Though not routinely used in Africa, introduction of Hib immunization appeared to reduce incidence of infection in children <5 by 12%, despite considerable HIV infection in this population.

  15. Farley MM et al: Invasive Haemophilus influenzae disease in adults. A prospective, population-based surveillance. CDC Meningitis Surveillance Group. Ann Intern Med 116:806, 1992  [PMID:1314530]

    Comment: U.S. study finding ~25% of H. influenzae bacteremia occurred in adults. 194 cases of invasive H. influenzae occurred (annual incidence 5.6 cases/100,000 population), of which 47 (24%) were in adults ≥18 (annual incidence 1.7 cases/100,000 adults). Adults with invasive H. influenzae ranged from 18 to 96 yrs; 79% were women. Bacteremic pneumonia accounted for 70% of adult cases. Other sources for invasive H. influenzae in adults were obstetric infections, epiglottitis, and tracheobronchitis; 1 pt had meningitis. Underlying conditions noted in 92% of pts with chronic bronchitis; HIV was most common but, cancer and pregnancy also reported. Interestingly, half of the bacteremic cases were due to H. influenzae type b, which causes a much smaller minority of non-bacteremic Haemophilus infections.

  16. Ulanova M, Tsang RS: Haemophilus influenzae serotype a as a cause of serious invasive infections. Lancet Infect Dis 14:70, 2014  [PMID:24268829]

    Comment: Authors identify factors contributing to the emergence of H. influenzae serotype a (Hia) infection primarily driven by the success of the Hib since the 1990s. Laboratory surveillance has primarily identified US and Canada as where most clinical infections have been described. For reasons that are unclear, incidence of invasive Hia infection is lower in Europe. Much as had been the case for Hib, invasive Hia strikes children mostly ages 6 months to 2 years. In Manitoba, Hia caused ~30% of invasive H. influenzae infection.

  17. Verghese A et al: Bacterial bronchitis and bronchiectasis in human immunodeficiency virus infection. Arch Intern Med 154:2086, 1994  [PMID:8092913]

    Comment: Series from pre-HAART era in pts with advanced HIV suggesting that these pts are at risk of recurrent bacterial bronchitis. Most common pathogens in 18 episodes of bacterial bronchitis were H. influenzae and Streptococcus pneumoniae (5 episodes each) and Pseudomonas aeruginosa (4 episodes). Moreover, they believe repeated bacterial bronchitis may lead to bronchiectasis, which may be more common in HIV infection than generally appreciated.

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Last updated: December 4, 2016