Episode 306: Streptococcus pneumoniae (Pneumococcus)
With this topic, I move outside my comfort zone, because Streptococcus is obviously not a virus. I’m interested, since severe Streptococcal co-infections in patients hospitalized for Influenza, entered the general news over the last days. Moreover, I getting my first “pneumococcal shot” and I was wondering what the status presens is of this vaccine.
Par 1: Bacterial co-infection with Influenza
Mainly based on
Ep 306-1: Klein et al. (2016) The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. Influenza and Other Respiratory Viruses 10(5), 394–403.
Ep 306-2: Jennifer M Rudd Lethal Synergism between Influenza and Streptococcus pneumoniae J Infect Pulm Dis. 2016; 2(2): .
Frequency of bacterial co-infections in patients hospitalized with Influenza (22 studies since 1988)
Very heterogeneous: from 2 to 65 %!
Type of bacteria
Streptoccus pneumoniae and Stafylococcus aureus represent > 50 % of bacterial co-infections. Others (including Strepto pyogenes) each < 10 %
While patients hospitalized with moderate to severe influenza may be coinfected with both viral and bacterial pathogens, many patients will not be coinfected.
Thus, although recognition and treatment of potential bacterial coinfections is important, particularly community-acquired pneumonia in which pathogens are difficult to detect, clinicians should consider treatment of potential underlying viral processes as well.
To avoid overuse of antibiotics routine cultures are advisable in patients hospitalized with influenza particularly those started on antibiotic therapy empirically
Let is go back to the basics:
Par 2 Microbiology
Par 3 Clinical aspects
Mainly based on Ep 306-3 and -4
- Pneumonia = most frequent clinical manifestation
Complications: empyema, pericarditis, and respiratory failure
The case-fatality rate is 5–7%: much higher among older adults or people with underlying medical conditions
- Causes an estimated 150,000 annual hospitalizations;
- Accounts for up to 30% of adult community-acquired pneumonia;
- In 25–30% occurs with bacteremia or meningitis
- Bacteriemia or invasive pneumococcal infection (IPI) = most dangerous clinical manifestation
- Mainly in children below 2 years with high fever (> 39°C), but otherwise “well appearing”
- Also in older adults and immune-compromised subjects, people without spleen (asplenia)
- Bacteremia may be the primary infection, or it may accompany the acute phase of any focal pneumococcal infection. Pneumococcal bacteremia can be complicated by septic shock
- Secondary seeding may cause infections such as septic arthritis, meningitis, and endocarditis.
Without a known site of infection:
- Estimated 4,000 cases each year
- Up to 70% of invasive pneumococcal disease in children< 2 years
From Pneumococcal pneumonia
- 12% to 16% of invasive pneumococcal disease in children aged up to 2 years
Case-fatality (despite treatment)
- 15 to 20% in children (mainly in those who have meningitis, who are immunocompromised, and/or who have had splenectomy and have severe bacteremia) and in adults
- 30 to 40% in older people
Risk of death is highest during the first 3 days.
- Acute otitis media:
More than 1/3 of children in most populations during the first 2 years of life,
and pneumococcal otitis media commonly recurs.
Complications include: Mild hearing loss, vestibular balance dysfunction, tympanic membrane perforation, mastoiditis, petrositis (infection of bone around ear), labyrinthitis
- Paranasal sinusitis with pain and purulent discharge.
- Often triggered by obstruction of orifices by viral infection, pollutants, or allergens
- May become chronic and multi-microbic
- Can lead to menigitis or abcesses (brain, subdural..)
- Meningitis: may be secondary to bacteremia from other foci (notably pneumonia); direct extension from infection of the ear, mastoid process, or paranasal sinuses.
Neurologic sequelae, such as intellectual and behavioral disabilities, seizures, hearing loss, and motor deficits, can happen in as many as 50%
U.S. statistics: Pneumococcal meningitis
- Causes over 50% of all bacterial meningitis cases;
- Is the leading cause of bacterial meningitis in children younger than 5 years old
- Causes an estimated 2,000 cases each year
Case fatality: 8 % amongst children and 22 % amongst adults
- Other rare manifestations
- Endocarditis and septic arthritis: may result from bacteriemia
- Peritonitis: : in patients with liver cirrhosis and ascites
Preferred: Beta-lactam or Macrolide,
If resistant: respiratory fluoroquinolone eg, levofloxacin, moxifloxacin, gemifloxacin,
tetracycline (eg, omadacycline),
or pleuromutilin (eg, lefamulin)
Prophylactic: in case of a-splenic conditions
- Children < 5 years with functional or anatomic aspleny: penicillin V 125 mg orally 2 times a day
- Older children or adolescents after splenectomy: penicillin 250 mg orally 2 X/day for at least 1 year
Par 3 Serotypes
Capsule polysaccharides = critical for evading phagocytosis → determine pathogenicity
> 90 different pneumococcal serotypes
- Most serious infections are caused by a small number of serotypes (3, 4, 6B, 9V, 14, 18C, 19F, and 23F) = included in the 13 valent pneumococcal conjugate vaccine (PCV13)
- 90% of invasive infections in children and 60% in adults.
- Patterns are changing, in part because of the widespread use of polyvalent vaccine.
- Serotype 3 = heavily encapsulated → common invasive pneumococcal disease in adults.
- Serotype 19A, which is highly virulent and multidrug-resistant, has emerged as an important cause of respiratory tract infection and invasive disease; it is thus now included in the 13-valent pneumococcal conjugate vaccine.
Par 4 Vaccinations
Ep 306-5: Musher The remarkable history of pneumococcal vaccination Pneumonia (2022) 14:5
Ep 306-6: Moberley_S, Holden_J, Tatham_DP, Andrews_RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD000422.
Previously a purely polysaccharide (unconjugated) vaccine was used. PPSV23 e.g. Pneumovax:
contains serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F, and so covers 90 percent of the types found in invasive pneumococcal infections (IPI)
As can be seen, the effectiveness in adults with chronic illness is non-existing and it is suboptimal in most other instances.
In fact, purely polysaccharide antigens do not engage T cells and the immunological memory is short lived in adults. Moreover, the major problem with PPSV was that it failed to immunize infants and toddlers, who were also at highest risk for pneumococcal disease.
Therefore, progressively more serotype polysaccharides are being conjugated to protein carriers, in order to enhance immune memory.
Composition: according to CDC https://www.cdc.gov/vaccines/vpd/pneumo/hcp/about-vaccine.html
PCV13 (Prevnar13®) includes purified capsular polysaccharide of 13 serotypes of Streptococcus pneumoniae (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 18C, and 23F)
PCV15 (Vaxneuvance®) 15 serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F
PCV20 (Prevnar20) 20 serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F
In all cases:
- individually conjugated to a nontoxic variant of diphtheria toxin known as CRM197.
- 125 µg aluminum phosphate adjuvant
IMMUNOGENICITY of polysaccharide PPSV23 and conjugated PCV13
Ep 308-7: Jackson Immunogenicity and safety of PCV13 versus PPVS23 Vaccine 2013
Comparison of pneumococcal Opsono-phagocytic antibodies (OPA) geometric mean titer (GMTs) 1 month after vaccination with PCV13 and PPSV23 in subjects 60–64 years of age
a n = Number of subjects with a determinate OPA titer to the given serotype.
b GMTs were calculated using all evaluable subjects with available data for the specified blood draw.
c Ratio of GMTs PCV13 to PPSV23 is calculated by back transforming the mean difference between vaccine groups on the logarithmic scale.
d CIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures
PCV13 is more immunogenic after 1 month and it maintains higher titers after 1 year (the latter not shown).
Unfortunately, I could not find an RCT comparing both regimens for protection efficacy
EFFECTIVENESS OF CONJUGATED VACCINES (PCV7/PCV13)
Australia: Ep 306-8: Sanjay Jayasinghe Clinical Infectious Diseases 2017;64(2):175–83
PCV7 immunization of children with high uptake (> 90 % up to 12 mo and > 60 % up to 24 mo of age) resulted in substantial and sustained reductions in incidence of vaccine-type invasive pneumococcal disease (IPD).
Following PCV13 introduction in 2011, with similar coverage but lower uptake of the supplementary dose, only serotype 19A showed reductions in children and adults of similar magnitude to those post-PCV7
These 2 periods combined yielded an overall 47% decline in all-age total IPD.
Clearly in the post PCV7 period, the PCV-13 non PCV7 ( ) increased, but it decreased after PCV13 introduction.
Serotypes lacking in both vaccines ( ) tended to increase throughout
Israel: Ep 306-9: Shalom Ben-Shimol Clinical Infectious Diseases 2022;74(9):1639–49: Invasive Pneumococcal Disease in Israel in Children and Adults in the 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Era
IPD rates in children <5 and 5–17 years declined by 67%, comparing late-PCV13 versus pre-PCV periods
IPD rates in adults declined by 53% in aged 18–44, but no decline in other age groups.
Serotypes include in PCV13 (VT13) rates significantly declined in all ages, ranging between 94% in children <5 years and 60% in adults ≥85 years.
Non-vaccine type (NVT- rates significantly increased in <5-, 50–64-, and ≥65-year age groups.
South-Africa: Ep 306-10: Cohen Lancet Glob Health 2017;5: e359–69
- Effective for preventing vaccine-type pneumococcal infections in young children not infected with HIV, including those who are malnourished or who have been exposed to HIV.
- Children with HIV the point estimate for PCV13 vaccine effectiveness was high, nut NS (sample size?)
First results on PCV20: Ep 306-11: Klein Vaccine 39 (2021) 5428–5435
PCV20 induces similar opsono-phagocytic Ab (OPA) as PCV13 to PCV13 serotypes and clearly higher titers ton PCV20 non-PCV13 serotypes.
FUTURE: 24-valent PCV?
Ep 306-12: Chichili Vaccine 40 (2022) 4190–4198
ASP3772 serotypes =
- 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F (shared with PCV13 and PPSV23, except 6A)
- plus 2, 8, 9N 10A, 11A, 12F, 15B, 17F, 22F, and 33F (shared only with PPSV23)
- plus 20B.
- Robust OPA (opsonophagocytic antibodies) responses for all serotypes were observed across all ASP3772 dose groups in both age cohorts.
- Older adults (aged 65–85 years) who received ASP3772 had significantly higher immune responses to several PCV13 serotypes and all non-PCV13 serotypes than participants who received PCV13.
- OPA responses to the ASP3772 5-µg dose were significantly higher for several serotypes in naïve participants than in older adults with prior exposure to PCV13 who were administered PPSV23 in this study.
Clearly superior to PCV13 for non-PCV13 serotypes, but less of a difference with the pure polysaccharide vaccine (PPSV23). However, this is the short-time effect (after 30 days). It is expected that responses induced by conjugated vaccine will last longer.
ACTUAL RECOMMENDATIONS IN BELGIUM
Based on advice Superior Health Council (High Council for Health) Belgium: only available in Dutch and French
https://www.health.belgium.be/sites/default/files/uploads/fields/fpshealth_theme_file/hgr_9519_advies_vaccinatie_pneumokokken_kinderen_.pdf (Ep 306-14)
https://www.health.belgium.be/sites/default/files/uploads/fields/fpshealth_theme_file/css_9519_avis_vaccination_pneumocoque_enfants_.pdf (Ep 306-15)
- General scheme: 3 doses: Week 8, Week 16 and Month 12
- Pre-mature infants: 4 doses Weeks 8, 12, 16 + Month 12
https://www.health.belgium.be/nl/advies-9674-vaccinatie-tegen-pneumokokken-volwassenen (Ep 306-16)
https://www.health.belgium.be/fr/avis-9674-vaccination-antipneumococcique-adultes (Ep 306-17)
- Adults 18-85 yrs with increased risk
o Preference PCV20
o Alternative: PCV15 followed by PPSV23 after 8 weeks
Revaccination: PPSV23 each 5 years
- Healthy adults > 65 years: Preference PCV20 or PCV15 followed by PPSV23 after 1 year
- Adults over 85: still not clear if vaccination can reduce morbidity and mortality in this age group.
Prevalence in Belgium
In 2021 PCV13, PCV15, PCV20, PPSV23 covered resp. 34,4 %, 40,3 %, 66.6 % and 72.1 % of the circulating serotypes
Clearly, even with the broadest vaccine available there are still serotypes that are not covered.
In the past, it has been shown that in a vaccinated population the not-covered serotypes tend to rise:
Streptococcus pneumoniae important etiology of pneumonia and septic bacteriemia (with various secondary manifestations such as meningitis) mainly in young children, elderly and immunocompromised subjects (a-splenia and other conditions). Also important cause in (recurrent) otitis media and chronic sinusitis.
Antibiotic treatment and prophylaxis possible, but increasing resistance.
Traditional 23-valent polysaccharide vaccine is rather weak. Replaced by conjugated vaccine with increasing number of serotypes (PCV13, PCV15, PCV20, PCV24).
Encouraging results with conjugated vaccines, nut “moving target”: rise of serotypes not included in vaccine.
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