MICROBIOLOGY

• Small aerobic Gram-negative coccobacillus [Fig] found mainly in the human respiratory tract.
  • The species is fastidious, growth best achieved using solid media agar plates, preferably chocolate agar, with added X (hemin) and V (nicotinamide adenine dinucleotide) factors at 37 °C in a CO₂-enriched incubator.
  • Standard broth cultures will yield the organism but will not do well without reinoculation regularly into new media.
• H. influenzae is the most notable species, but a notable decline in past decades has been achieved 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 a cause of severe, invasive infection. Emergence due to intrinsic capsular virulence factors of Hia as well as pressure from the success of Hib immunization[8].
    • Predominantly noted in the U.S. and Canada. The incidence in Europe, low.
    • In one series, accounted for ~30% of invasive H. influenzae infection in Manitoba.
  • Type f strain also increasingly recognized as a cause of severe infection, though less common than Hia.
• 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.
  • Recent (2017-2018) increased risk for septic arthritis seen in Atlanta, Georgia, among black MSM[2].
• Pneumonia may occasionally mimic PCP with bilateral interstitial infiltrates.
• Effect of long-term antibiotic therapy in HIV/AIDS to reduce OIs:
  • TMP/SMX may reduce the risk of community-acquired pneumonia.
  • Azithromycin or clarithromycin prophylaxis may reduce infection, but no data to confirm.
• Diagnosis:
  • Culture growth from a sterile site
  • Respiratory disease: predominant growth from purulent specimen (PMNs > squamous epithelial cells)
    • The sensitivity of Gram stain and culture probably ~50% in pts with H. influenzae pneumonia.
    • The use of prior antibiotics will decrease yield.

SITES OF INFECTION

• Respiratory:
  • Community-acquired pneumonia (CAP): H. influenzae responsible for 3-40% of HIV-related bacterial pneumonia.
  • Acute exacerbations of chronic bronchitis (AECB): increased colonization in smokers.
  • Bacterial bronchitis
  • Acute bacterial sinusitis
• Meningitis
• Epiglottitis
• Acute otitis media
• Periorbital cellulitis: mainly children, diminished since the introduction of Hib immunization
• Septic arthritis: rare
• GU: some consider as a 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

OTHER INFORMATION

• With the 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.
• Increased rates of invasive Haemophilus infections described in HIV infection, especially MSM populations.

Basis for recommendation

1. Briere EC, Rubin L, Moro PL, et al. Prevention and control of haemophilus influenzae type b disease: recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep. 2014;63(RR-01):1-14.  [PMID:24572654]

   Comment: Although no new recommendations issued, this guideline compiles all prior as well as background information and impact of the Hib conjugate vaccine. Children with HIV should receive Hib immunization.
   

References

2. Collins LF, Havers FP, Tunali A, et al. Invasive Nontypeable Haemophilus influenzae Infection Among Adults With HIV in Metropolitan Atlanta, Georgia, 2008-2018. JAMA. 2019;322(24):2399-2410.  [PMID:31860046]

   Comment: This surveillance study found that the incidence of invasive nontypeable Haemophilus influenzae infections found a recent increase among people with HIV in Atlanta in the years 2017–2018 compared to the previous 8 years of 2008–2060. Investigators found to have unique but genetically related clonal strains that seem to cause septic arthritis among black men who had sex with men and lived in relatively close geographic proximity.
   

3. Mulu W, Yizengaw E, Alemu M, et al. Pharyngeal colonization and drug resistance profiles of Morraxella catarrrhalis, Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae among HIV infected children attending ART Clinic of Felegehiwot Referral Hospital, Ethiopia. PLoS One. 2018;13(5):e0196722.  [PMID:29746496]

   Comment: If this study from Ethiopia children with HIV were found to be frequently colonized with respiratory pathogens. Haemophilus influenzae were noted and 6% of children but this was significantly lower than the rates of staph aureus at 29%, Moraxella catarrhalis at 12.3% and Streptococcus pneumoniae at 10.3%. The lower rate of Haemophilus influenzae was comparable to some studies from Africa; however, was clearly lower than the 7.2% to 24.4% right-sided and other studies. It is unclear why this study had a lower colonization rate but may be due to the fact that participants under the age of 5 were not included in the study.
   

4. Park DE, Baggett HC, Howie SRC, et al. Colonization Density of the Upper Respiratory Tract as a Predictor of Pneumonia-Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. Clin Infect Dis. 2017;64(suppl_3):S328-S336.  [PMID:28575367]

   Comment: This analysis from the PERCH study helps provide evidence behind the biologically plausible but never well confirmed thought that higher rates of bacterial colonization and density correlate with increased risks of pneumonia.
   

5. Arya BK, Bhattacharya SD, Sutcliffe C, 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. 2016.  [PMID:27276182]

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

6. Deza G, Martin-Ezquerra G, Gómez J, 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. 2016;92(1):29-31.  [PMID:26139207]

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

7. MacLennan CA, Richter A, Hodson J, et al. Brief Report: Immunization of HIV-Infected Adults in the UK With Haemophilus influenzae b/Meningococcal C Glycoconjugate and Pneumococcal Polysaccharide Vaccines. J Acquir Immune Defic Syndr. 2016;73(3):287-293.  [PMID:27163175]

   Comment: A 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 the UK recs but the incidence of pneumonia is higher in HIV-infected.
   

8. Ulanova M, Tsang RSW. Haemophilus influenzae serotype a as a cause of serious invasive infections. Lancet Infect Dis. 2014;14(1):70-82.  [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 the US and Canada as where most clinical infections have been described. For reasons that are unclear, the 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.
   

9. Molyneux E, Nizami SQ, Saha S, et al. 5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double-blind randomised equivalence study. Lancet. 2011;377(9780):1837-45.  [PMID:21620467]

   Comment: The 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.
   

10. Centers for Disease Control and Prevention (CDC). Pediatric bacterial meningitis surveillance - African region, 2002--2008. MMWR Morb Mortal Wkly Rep. 2009;58(18):493-7.  [PMID:19444153]

    Comment: The report notes the significant ongoing burden of >700,000 suspected cases of meningitis. Among these, 69,208 suspected cases were evaluated by laboratory data: 4,674 (7%) samples were culture-positive for bacterial infections under surveillance. 2,192 (47%) were positive for S. pneumoniae, 1,575 (34%) for Haemophilus influenzae, and 907 (19%) for N. meningitidis. The majority of the remaining culture results were negative.
    

11. Roca A, Bassat Q, Morais L, et al. Surveillance of acute bacterial meningitis among children admitted to a district hospital in rural Mozambique. Clin Infect Dis. 2009;48 Suppl 2:S172-80.  [PMID:19191613]

    Comment: Pediatric series (children < 15 yrs) found H. influenza type b the leading cause (14/43 cases, 33%) followed by pneumococci (21%). Authors emphasize that acute bacterial meningitis is a not uncommon cause of illness and hospitalization in sub-Saharan Africa and that the leading pathogens are vaccine-preventable.
    

12. Sigaúque B, Roca A, Sanz S, et al. Acute bacterial meningitis among children, in Manhiça, a rural area in Southern Mozambique. Acta Trop. 2008;105(1):21-7.  [PMID:17959132]

    Comment: Pneumococcus and Haemophilus influenzae remain the top two causes of bacterial meningitis in children. The Haemophilus fatality rate was 45%.
    

13. Akumu AO, English M, Scott JA, et al. Economic evaluation of delivering Haemophilus influenzae type b vaccine in routine immunization services in Kenya. Bull World Health Organ. 2007;85(7):511-8.  [PMID:17768499]

    Comment: Routine Hib immunization has been performed in Kenya since 2001. This WHO report found it to be highly cost-effective. Rates of invasive H. influenzae infection declined by more than 80%.
    

14. von Gottberg A, de Gouveia L, Madhi SA, et al. Impact of conjugate Haemophilus influenzae type b (Hib) vaccine introduction in South Africa. Bull World Health Organ. 2006;84(10):811-8.  [PMID:17128361]

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

15. Cowgill KD, Ndiritu M, Nyiro J, et al. Effectiveness of Haemophilus influenzae type b Conjugate vaccine introduction into routine childhood immunization in Kenya. JAMA. 2006;296(6):671-8.  [PMID:16896110]

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

16. De Sousa dos Santos S, Lopes MH, Simonsen V, et al. Haemophilus influenzae type b immunization in adults infected with the human immunodeficiency virus. AIDS Res Hum Retroviruses. 2004;20(5):493-6.  [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
    

17. Doern GV, Brown SD. Antimicrobial susceptibility among community-acquired respiratory tract pathogens in the USA: data from PROTEKT US 2000-01. J Infect. 2004;48(1):56-65.  [PMID:14667792]

    Comment: A published national survey of respiratory isolates showed that the 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 an 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 the most potent FQ with MIC90 values of 0.03 mg/L.
    

18. 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. 2003;111(6 Pt 1):e641-4.  [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.
    

19. Cordero E, Pachón J, Rivero A, et al. Haemophilus influenzae pneumonia in human immunodeficiency virus-infected patients. The Grupo Andaluz para el Estudio de las Enfermedades Infecciosas. Clin Infect Dis. 2000;30(3):461-5.  [PMID:10722428]

    Comment: One of the 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 a higher degree of immunosuppression. Authors conclude that this pathogen mainly afflicts those with advanced HIV, and note surprising attributable mortality of ~11%.
    

20. Madhi SA, Petersen K, Madhi A, et al. Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired lower respiratory tract infections in human immunodeficiency virus type 1-infected children. Clin Infect Dis. 2000;31(1):170-6.  [PMID:10913417]

    Comment: South African report suggesting that HIV+children have a relative risk (RR) ratio of 22.1 compared to HIV-negative children for H. influenzae type b.
    

21. Navin TR, Rimland D, Lennox JL, et al. Risk factors for community-acquired pneumonia among persons infected with human immunodeficiency virus. J Infect Dis. 2000;181(1):158-64.  [PMID:10608762]

    Comment: A large study of 1200 HIV+ pts with community-acquired pneumonia and PCP. Multivariate logistic regression showed that patients 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). The authors suggest that these findings reconfirm the efficacy of TMP-SMX in preventing community-acquired pneumonia.
    

22. Bartlett JG. Pneumonia in the patient with HIV infection. Infect Dis Clin North Am. 1998;12(3):807-20, xi.  [PMID:9779391]

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

23. Muñoz P, Miranda ME, Llancaqueo A, et al. Haemophilus species bacteremia in adults. The importance of the human immunodeficiency virus epidemic. Arch Intern Med. 1997;157(16):1869-73.  [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.
    

24. Verghese A, al-Samman M, Nabhan D, et al. Bacterial bronchitis and bronchiectasis in human immunodeficiency virus infection. Arch Intern Med. 1994;154(18):2086-91.  [PMID:8092913]

    Comment: Series from the pre-HAART era in patients with advanced HIV suggesting that these pts are at risk of recurrent bacterial bronchitis. The 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.
    

25. Farley MM, Stephens DS, Brachman PS, et al. Invasive Haemophilus influenzae disease in adults. A prospective, population-based surveillance. CDC Meningitis Surveillance Group. Ann Intern Med. 1992;116(10):806-12.  [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 of 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.
    

Media

H influenzae

Trantracheal aspirate showing some Gram negative rods, but also Gram negative diplococci that were found in culture to be H. influenzae.

Source: CDC, Dr. Michael Miller