Overview
Three childhood infection problems, taken in order of when they strike. First, congenital infections acquired before or at birth, grouped under the TORCHeS acronym, where the organism crosses the placenta or is picked up from genital lesions and causes congenital abnormality or fetal death, and where prevention is the main lever. Second, vaccine-preventable disease in New Zealand, where notification data show that pertussis and measles still produce outbreaks despite a full schedule, with whooping cough used as the worked example of a chain of infection and the points at which vaccination breaks it. Third, Otitis media, the commonest bacterial infection of early childhood, whose recurrent and chronic forms cause hearing loss and language delay in 2 to 5 year olds.
Lecture objectives and reading
- To discuss the importance of congenital infections caused by TORCHeS.
- To briefly discuss occurrence of vaccine-preventable diseases in NZ, especially whooping cough.
- To discuss otitis media and its relevance to developmental delay.
Reading: Mims Medical Microbiology 4th edition, Ch. 23, Congenital Infections, pp. 323 to 328. Further reading: Allerberger F, Wagner M 2010. Listeriosis: a resurgent foodborne infection. Clinical Microbiology and Infection 16: 16 to 23.
Congenital infections: the TORCHeS group
TORCHeS infections are transmitted from woman to fetus during pregnancy, or from woman to neonate at birth. They are a significant cause of fetal and neonatal mortality and of childhood morbidity, and the shared endpoint of all of them is congenital abnormality or fetal death.
The acronym, as expanded in the lecture:
- T Toxoplasma gondii
- O Other: VZV, Parvovirus B19, Listeriosis (elsewhere in the lecture the “Other” group is given as Listeria and GBS, that is Group B Streptococcus)
- R Rubella
- C Cytomegalovirus
- He Herpes simplex virus, HIV
- S Syphilis
Organs targeted, and route of transmission where the slides give it:
| Organism | Organs/systems affected | Route |
|---|---|---|
| Toxoplasma gondii | Brain, eyes, liver, spleen | Via placenta |
| Other (Listeria, GBS) | (not specified) | Via placenta or membrane rupture |
| Rubella | Heart, brain, eyes, ears | [route not labelled on the slide] |
| Syphilis | Heart, brain, eyes, ears | Via placenta |
| Herpes simplex virus | Disseminated | Genital lesions |
| Cytomegalovirus | Brain (including hearing), eyes, liver, spleen | [route not labelled on the slide] |
Common signs
- Slow growth
- Congenital heart disease
- Enlarged liver/spleen
- Jaundice
- Micro/hydrocephaly
- Ocular lesions
- Skin rashes
Timing and treatment
Infection earlier in pregnancy gives worse outcomes, up to fetal loss. Treatment should begin as soon as possible to avoid long-term problems.
Preventing congenital infection
Prevention is organism-specific and is the main practical lever:
- Vaccination: rubella. The slide also raises influenza vaccination in pregnancy as a question, “Influenza vaccination safe during pregnancy?”, without answering it.
- Hygiene: toxoplasmosis, whose sources are cat faeces and undercooked meat.
- Caesarean section: herpes simplex virus, avoiding the genital-lesion route.
- Avoid ready-to-eat products: Listeria.
- Screen for vaginal carriage at 35 to 37 weeks and give intravenous antibiotic during labour: Group B Streptococcus.
Listeria monocytogenes
Listeria monocytogenes survives inside phagocytes. The maternal and fetal presentations differ sharply:
- Maternal: usually asymptomatic, or fever and a ‘flu-like illness.
- Fetus/neonate: fever, rash, pneumonia, sepsis, meningitis.
A mother with a trivial or absent illness can transmit an infection that is fulminant in the neonate. The mild maternal picture is not reassurance.
Vaccine-preventable disease in New Zealand
Notified cases (all ages) for diseases covered by the NZ vaccination schedule from 6 months to 12 years, with paediatric cases in brackets:
| Vaccine-preventable disease | Cases |
|---|---|
| Diphtheria | 2 (children) |
| Polio | 0 |
| Tetanus | 1 (elderly) |
| Haemophilus influenzae type B | 3 (children) |
| Rubella | 0 |
| Mumps | 13 (7 children) |
| Hepatitis B | 34 (new; 1 child) |
| Measles | 10 (280 in 2014) |
| Invasive pneumococcal (Strep. pneumoniae) | 451 (38 children) |
| Pertussis (whooping cough) | 1,168 (493 children) |
The pattern to take from the table: diphtheria, polio, tetanus, Hib and rubella are essentially controlled, while pertussis dominates the notifications by an order of magnitude, invasive pneumococcal disease is the next largest burden, and measles is low in the tabulated year but capable of outbreaks (280 cases in 2014).
Pertussis: burden and epidemiology
Pertussis is caused by Bordetella pertussis.
- The last New Zealand outbreak started in 2017, with about 4,600 people infected and no deaths.
- The previous outbreak started in 2012 and left three dead: two babies under six weeks old, too young for vaccination, and an unimmunised pre-schooler.
- Worldwide, whooping cough affects 48.5 million people a year, with an estimated 195,000 child deaths a year.
New Zealand notification data from 1998 to 2015 show pertussis is epidemic rather than steady, with repeated peaks (around 1999 to 2000, around 2004 to 2005, and a large sustained rise across 2011 to 2013) separated by troughs around 2002 to 2003 and 2007 to 2008. Notifications in infants under 1 year stay low in absolute number throughout but rise with each epidemic, and hospitalisations track the epidemic peaks.
Chart values were read from a low-resolution embedded raster; the peak heights (roughly 600 to 610 notifications at each epidemic peak, under-1s roughly 0 to 50) are approximate.
Pertussis: organism and chain of infection
B. pertussis is a small, aerobic, gram-negative rod. On electron microscopy it is seen as rods lying among the respiratory cilia.
Virulence factors labelled on the bacterial cell:
- Fimbriae (types 2 and 3)
- FHA (filamentous haemagglutinin)
- Pertactin
- BrkA
- Adenylate cyclase toxin
- TCT (tracheal cytotoxin)
- TCF
- Dermonecrotic toxin
- Pertussis toxin (secreted from the cell)
The chain of infection has six links: causative agent (the pathogenic organism), reservoir/source, means of exit (way out of the body), mode of transmission (method of spread), portal of entry (way into the body), and person at risk. Mapped onto pertussis:
| Link | Pertussis |
|---|---|
| Causative agent | Bordetella pertussis |
| Reservoir/source | Unvaccinated humans |
| Means of exit | Droplets (coughing, sneezing) |
| Mode of transmission | Airborne |
| Portal of entry | Inhalation into the respiratory tract |
| Person at risk | The unimmunised child, especially the newborn |
Pertussis: pathogenesis
How the infection develops, in the slide’s six steps:
- Microscopic droplets carrying B. pertussis are inhaled.
- Bacteria hook onto the cells lining the throat, whose hairlike cilia normally sweep away foreign objects.
- Bacteria reproduce and migrate toward the ciliated cells of the lungs.
- Bacteria release a toxin that paralyses the cilia and kills cells.
- Toxin released in the lungs spreads throughout the body.
- Pneumonia may develop if the tiny air sacs deep in the lungs become infected.
The histological correlate: normal respiratory epithelium carries long, dense cilia; after tracheal cytotoxin (TCT) the cilia are lost or sparse and the epithelial cells are damaged and sloughing. Loss of the mucociliary escalator is what leaves the patient unable to clear secretions except by the paroxysmal cough.
Pertussis: clinical progression
Four stages, plotted as symptom intensity against time from initial exposure:
- Incubation period, 1 to 2 weeks. Symptom intensity flat and low.
- Prodromal stage, 1 to 2 weeks. A small step up in intensity.
- Illness, 10 weeks. Intensity rises steeply to a peak; a branch of the curve continues upward to death.
- Convalescent period, about 1 to 3 months. Intensity falls steadily back down.
The illness stage runs about 10 weeks and convalescence a further 1 to 3 months, so the whole course can occupy the better part of half a year. This is the basis of the name "the hundred day cough".
Breaking the chain: prevention and treatment of pertussis
Three interventions, each aimed at a different link:
- Educating parents and parents-to-be regarding vaccination breaks the chain at “person at risk”.
- Rapid detection and treatment, especially azithromycin, breaks it at “causative agent”.
- Vaccination breaks it at “reservoir/source”.
Composition of the pertussis component of selected vaccines
| Vaccine | Producer | Licensed for | PT (µg) | FHA (µg) | PRN (µg) | FIM (µg) |
|---|---|---|---|---|---|---|
| Infanrix | GlaxoSmithKline | 6 weeks to 7 years | 25 | 25 | 8 | – |
| Boostrix | GlaxoSmithKline | older than 10 years | 8 | 8 | 2.5 | – |
| DAPTACEL | Sanofi Pasteur | 6 weeks to 7 years | 10 | 5 | 3 | 5 |
| ADACEL | Sanofi Pasteur | 11 to 64 years | 2.5 | 5 | 3 | 5 |
PT is pertussis toxin, FHA filamentous haemagglutinin, PRN pertactin, FIM fimbriae. The acellular vaccines are built from the virulence factors listed above. The paediatric formulations (Infanrix, DAPTACEL) carry higher antigen doses than their adolescent/adult counterparts from the same producer (Boostrix, ADACEL). DAPTACEL, which includes fimbrial antigen, is the row highlighted on the slide.
Immunisation timeline and the newborn window
- Newborns are at risk until fully immunised.
- Fully immunised at 5 months.
- Preschool booster at 4 years.
- Adolescent booster at 11 years.
- Immunity then reduces over time, leaving parents and close family unprotected.
Whooping cough is passed on by parents and close family in over 70% of newborn cases. Waning adult immunity feeds back onto the infant who is too young to be protected, which is the argument for cocooning and for adult boosters.
Superscript reference markers on this infographic were too small to read [source citations not recoverable].
Herd immunity
The slides illustrate herd immunity with three population scenarios, colour-coded as not immunised but healthy, immunised and healthy, and not immunised, sick and contagious:
- When no one is immunised, disease spreads through the population: a handful of index cases converts most of the population to cases.
- When some of the population is immunised, disease spreads through some of the population: a moderate number of cases results.
- When most of the population is immunised, spread is constrained: only the original one or two cases occur.
The point is that the individual vaccination decision determines other people’s risk, not only the vaccinee’s.
Otitis media: definitions and pathogenesis
- Otitis externa: inflammation of the outer ear.
- Otitis media: inflammation of the middle ear.
- Infectious causes: viruses, bacteria, or both.
The middle ear structures relevant here are the ear canal, tympanic membrane, ossicles (malleus, incus, stapes), the middle ear space, the inner ear, and the Eustachian tube.
Pathogenesis in three steps, beginning at the Eustachian tube:
- Blockage of the Eustachian tube, from allergy, an anatomical cause, or an upper respiratory tract infection.
- Absorption of air from the now-closed middle ear space.
- Middle ear effusion (MEE), fluid drawn into the resulting space.
Bacteria then multiply in that middle ear fluid, which produces the disease patterns:
- Acute
- Chronic/recurrent
- Suppurative
- Viscous effusion, ‘glue ear’
Otitis media: aetiology, diagnosis and biofilms
Acute otitis media is viral in about 50% of cases and bacterial in about 50%.
Organisms and agents that cause OM:
- URT viruses, for example common cold and influenza viruses.
- Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis.
Current vaccines have little effect on otitis media.
Diagnostic features:
- Fever, pain (with diarrhoea/vomiting)
- Appearance of the drum
- Tympanometry
Otoscopic appearances to distinguish:
| Appearance | Drum |
|---|---|
| Normal | Translucent grey, light reflex and malleus visible |
| OM with effusion | Dull, amber or pink, fluid visible behind the drum |
| Acute OM (AOM) | Red, inflamed, bulging |
| Chronic suppurative OM | (illustrated otoscopically on the slide) |
| Tympanostomy tube in place | (illustrated otoscopically on the slide) |
Biofilms in recurrent and chronic OM
Both recurrent OM and chronic OM are attributed to bacteria growing in biofilms. The consequences of the biofilm mode of growth:
- Escape immune surveillance
- Greater antibiotic resistance
- Difficult to eradicate
- Difficult to culture
The biofilm explains the clinical frustration of recurrent OM: a negative culture does not exclude bacterial infection, and antibiotics that would kill planktonic organisms fail against the same species in a biofilm.
Otitis media: complications and treatment
Complications:
- Infection of the mastoid space or bone
- Meningitis (rare)
Consequences: bilateral, chronic or recurrent disease causes hearing loss and delayed language in 2 to 5 year olds. This is the link between an ear infection and developmental delay.
Antibiotic treatment:
- Acute OM: antibiotics not routine; the slide raises withholding for 1 to 3 days.
- Agents when treating: amoxycillin, co-amoxyclav, or co-trimoxazole.
- Glue ear: no antibiotics.
- Chronic or persistent effusion / glue ear: tympanostomy tubes.
Summary concepts
- Certain microorganisms can cross the placenta, causing fetal abnormalities or death, so prophylactic measures are important.
- Outbreaks of some vaccine-preventable infectious diseases still occur, particularly pertussis and measles.
- Childhood rashes are an important diagnostic indicator.
- Vomiting and diarrhoea are generalised symptoms of childhood infection.
- Otitis media can be viral or bacterial in origin, or both, and recurrent infection can lead to developmental delays.
Self-test
- Expand the TORCHeS acronym in full.
- List the common clinical signs shared by TORCHeS infections.
- Distinguish the route of transmission of congenital syphilis from that of neonatal herpes simplex virus.
- Explain why infection earlier in pregnancy carries a worse prognosis, and state what the slides say should be done about timing of treatment.
- List the organs or systems affected by congenital cytomegalovirus, and by congenital rubella.
- Describe the specific preventive measure given for each of: rubella, toxoplasmosis, herpes simplex virus, Listeria, and Group B Streptococcus.
- Distinguish the maternal presentation of listeriosis from the fetal or neonatal presentation, and state the feature of Listeria monocytogenes that the slides highlight.
- A woman at 36 weeks is screened for vaginal carriage of an organism. Name the organism, and describe what is done if the screen is positive.
- From the NZ notification data, list the two vaccine-preventable diseases with the highest case counts and give their numbers.
- Describe the epidemiological pattern of pertussis notifications in NZ between 1998 and 2015.
- State the global annual burden of whooping cough in cases and in child deaths, and describe who died in the 2012 NZ outbreak.
- Describe the morphology and staining of Bordetella pertussis, and list five of its virulence factors.
- Map pertussis onto the six links of the chain of infection.
- Describe, in order, the six steps by which a pertussis infection develops after inhalation.
- Explain how tracheal cytotoxin changes the respiratory epithelium, and why this produces a prolonged cough.
- List the four clinical stages of pertussis with their durations.
- Name the three interventions that break the pertussis chain of infection, and state which link each one targets.
- Compare the pertussis toxin content of Infanrix with that of Boostrix, and explain what the difference reflects.
- Give the pertussis immunisation timeline from birth to adolescence, and explain why newborns still catch the disease despite it.
- Explain how herd immunity constrains spread, using the three population scenarios from the slides.
- Distinguish otitis externa from otitis media.
- Describe the three-step pathogenesis of middle ear effusion.
- List the four patterns of bacterial otitis media that follow bacterial multiplication in middle ear fluid.
- List the bacterial and viral causes of otitis media, and state the proportion of acute OM that is viral versus bacterial.
- Distinguish the otoscopic appearance of a normal drum, OM with effusion, and acute OM.
- Explain why bacteria in biofilms make recurrent and chronic OM difficult to diagnose and to treat.
- State the complications and the developmental consequence of chronic or recurrent bilateral otitis media.
- Describe the antibiotic approach to acute OM, to glue ear, and to chronic persistent effusion.
- A 3 year old has had repeated ear infections in both ears since infancy. Middle ear swabs have grown nothing, courses of amoxycillin have not helped, and his parents report his speech is behind his peers. Explain the likely mechanism behind each of these three findings and state the management the slides give.
- Pertussis and otitis media are both respiratory-tract infections of childhood, and vaccination performs very differently against them. Explain that difference using the content of this lecture.
Answers
Reveal answers
- T Toxoplasma gondii; O Other, comprising VZV, Parvovirus B19 and Listeriosis (given elsewhere in the lecture as Listeria and Group B Streptococcus); R Rubella; C Cytomegalovirus; He Herpes simplex virus and HIV; S Syphilis.
- Slow growth, congenital heart disease, enlarged liver/spleen, jaundice, micro/hydrocephaly, ocular lesions, skin rashes.
- Syphilis crosses via the placenta. HSV is acquired from genital lesions, that is at delivery rather than transplacentally, which is why caesarean section is the preventive measure for HSV.
- Infection earlier in pregnancy gives worse outcomes, up to fetal loss. Treatment should begin as soon as possible to avoid long-term problems.
- CMV: brain (including hearing), eyes, liver, spleen. Rubella: heart, brain, eyes, ears.
- Rubella, vaccination. Toxoplasmosis, hygiene, avoiding cat faeces and undercooked meat. HSV, caesarean section. Listeria, avoid ready-to-eat products. Group B Streptococcus, screen for vaginal carriage at 35 to 37 weeks and give intravenous antibiotic during labour.
- Maternal listeriosis is usually asymptomatic or causes fever and a ‘flu-like illness. In the fetus or neonate it causes fever, rash, pneumonia, sepsis and meningitis. Listeria monocytogenes survives inside phagocytes.
- Group B Streptococcus, screened for vaginal carriage at 35 to 37 weeks. If positive, intravenous antibiotic is given during labour.
- Pertussis (whooping cough), 1,168 cases of which 493 in children; invasive pneumococcal disease (Strep. pneumoniae), 451 cases of which 38 in children.
- Epidemic rather than steady: repeated peaks around 1999 to 2000, around 2004 to 2005, and a large sustained rise across 2011 to 2013, with troughs around 2002 to 2003 and 2007 to 2008. Notifications in under-1s remain low in absolute number but rise with each epidemic, and hospitalisations track the peaks. Exact heights are approximate as the chart was low resolution.
- Worldwide, 48.5 million people affected yearly with an estimated 195,000 child deaths yearly. The 2012 NZ outbreak left three dead: two babies under six weeks old, too young for vaccination, and an unimmunised pre-schooler.
- A small, aerobic, gram-negative rod. Virulence factors include fimbriae (types 2 and 3), FHA, pertactin, BrkA, adenylate cyclase toxin, TCT, TCF, dermonecrotic toxin and pertussis toxin.
- Causative agent, Bordetella pertussis. Reservoir/source, unvaccinated humans. Means of exit, droplets from coughing or sneezing. Mode of transmission, airborne. Portal of entry, inhalation into the respiratory tract. Person at risk, the unimmunised child, especially the newborn.
- (1) Microscopic droplets carrying B. pertussis are inhaled. (2) Bacteria hook onto the cells lining the throat, whose cilia normally sweep away foreign objects. (3) Bacteria reproduce and migrate toward the ciliated cells of the lungs. (4) Bacteria release a toxin that paralyses the cilia and kills cells. (5) Toxin released in the lungs spreads throughout the body. (6) Pneumonia may develop if the tiny air sacs deep in the lungs become infected.
- Normal epithelium has long dense cilia; after TCT the cilia are lost or sparse and the epithelial cells are damaged and sloughing. With the mucociliary escalator destroyed, secretions cannot be cleared except by forceful paroxysmal coughing, and the illness stage lasts about 10 weeks.
- Incubation period 1 to 2 weeks; prodromal stage 1 to 2 weeks; illness 10 weeks; convalescent period about 1 to 3 months.
- Educating parents and parents-to-be about vaccination targets “person at risk”. Rapid detection and treatment, especially azithromycin, targets “causative agent”. Vaccination targets “reservoir/source”.
- Infanrix contains 25 µg pertussis toxin, Boostrix 8 µg. Infanrix is licensed from 6 weeks to 7 years and Boostrix for those older than 10 years, so the paediatric primary formulation carries the higher antigen dose and the adolescent/adult booster a reduced one.
- Newborns are at risk until fully immunised; fully immunised at 5 months; preschool booster at 4 years; adolescent booster at 11 years. Immunity then reduces over time, so parents and close family become susceptible and pass whooping cough to the newborn in over 70% of newborn cases, during the window before 5 months when the infant is not yet protected.
- When no one is immunised, a few index cases convert most of the population to cases. When some are immunised, disease spreads through part of the population and a moderate number of cases results. When most are immunised, spread is constrained and only the original one or two cases occur. So the immunised majority protects the unimmunised individuals within it.
- Otitis externa is inflammation of the outer ear; otitis media is inflammation of the middle ear.
- (1) Blockage of the Eustachian tube by allergy, an anatomical cause, or a URT infection. (2) Absorption of air from the closed middle ear space. (3) Middle ear effusion (MEE).
- Acute; chronic/recurrent; suppurative; viscous effusion or ‘glue ear’.
- Bacteria: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis. Viruses: URT viruses such as common cold and influenza. Acute OM is about 50% viral and about 50% bacterial.
- Normal, translucent grey with visible light reflex and malleus. OM with effusion, dull amber or pink drum with fluid behind it. Acute OM, red, inflamed and bulging.
- Biofilm bacteria escape immune surveillance, have greater antibiotic resistance, are difficult to eradicate and are difficult to culture. So cultures may be negative despite ongoing bacterial infection, and antibiotic courses fail.
- Complications: infection of the mastoid space or bone, and meningitis (rare). Consequence of bilateral chronic or recurrent disease: hearing loss and delayed language in 2 to 5 year olds.
- Acute OM, antibiotics are not routine and withholding for 1 to 3 days is raised; if treating, amoxycillin, co-amoxyclav or co-trimoxazole. Glue ear, no antibiotics. Chronic or persistent effusion or glue ear, tympanostomy tubes.
- Negative cultures and antibiotic failure both point to bacteria growing in a biofilm, which is difficult to culture, escapes immune surveillance and shows greater antibiotic resistance. The speech delay is the recognised consequence of bilateral chronic or recurrent otitis media, namely hearing loss with delayed language in 2 to 5 year olds. Management for chronic or persistent effusion or glue ear is tympanostomy tubes, not further antibiotics.
- Pertussis has a single causative organism with defined virulence factors (PT, FHA, pertactin, fimbriae) that can be made into an acellular vaccine, so vaccination breaks the chain at the reservoir and at the person at risk, and outbreaks persist mainly because immunity wanes in adults and newborns are unprotected until 5 months. Otitis media has multiple causes, roughly half viral and half bacterial, spread across S. pneumoniae, H. influenzae and M. catarrhalis, and the slides state that current vaccines have little effect on it; its chronic forms are also driven by biofilms rather than by acute transmissible infection. So a targeted vaccine works against pertussis but not against the OM syndrome as a whole.