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Infectious DiseasesVolume 7 No 2 June 2018

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Professor Charles Feldman MBBCh DSc PhD FRCP FCP (SA) Professor of Pulmonology and Chief PhysicianCharlotte Maxeke Johannesburg Academic Hospital and Faculty of Health Sciences University of the Witwatersrand, Johannesburg

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Editorial board

Professor Charles Feldman (Editor-in-chief)Professor of Pulmonology and Chief PhysicianCharlotte Maxeke Johannesburg Academic Hospital and Faculty of Health SciencesUniversity of the WitwatersrandJohannesburg

Professor Lucille BlumbergDeputy Director at the National Institute for Communicable Diseases, JohannesburgAssociate Professor, University of the Stellenbosch, Western Cape

Dr Jennifer CoetzeeMicrobiologistNational Reference Laboratory, AmpathPretoria

Dr Raymond FriedmanEar, Nose and Throat SurgeonSandton Clinic, Johannesburg

Professor Robin GreenProfessor of Paediatrics Dept of Paediatrics and Child Health University of Pretoria, Pretoria

Professor Shabir MadhiProfessor of VaccinologyUniversity of the Witwatersrand Director, MRC Respiratory and Meningeal Pathogens Research UnitChair in Vaccine Preventable Diseases, DST/NRF SARChI

Professor Bruce SparksDepartment of Family MedicineUniversity of the WitwatersrandJohannesburg

Professor Anton Stoltz Subspecialist Adult Infectious Diseases Division of Adult Infectious Diseases University of Pretoria

Professor Francois VenterDeputy Executive Director, Wits Reproductive Health and HIV Institute (WRHI)Associate Professor in the Department of Medicine, University of the Witwatersrand Head of Infectious Diseases, Charlotte Maxeke Johannesburg Academic Hospital Ex-president of the Southern African HIV Clinicians Society

s usual, this edition of the Journal contains a number of important and interesting topics.

The first article is written by Dr Tomek Piorkowski, who gives a brief overview of bacteriophage therapy, giving a glimpse of what the

future may hold.

The second article, by Marta Nunes and Shabir Madhi, deals with the topic of influenza and influenza vaccination in pregnant women, which indicates that giving the influenza vaccine to mothers during pregnancy protects both the mothers and the young infants against influenza infection.

The third article is by Juno Thomas, and addresses the topical issue of listeriosis, describing the disease and it management. Juno was at the forefront of the recent investigation of the source of the listeriosis outbreak in South Africa.

As always, the editors of the Journal welcome comments, criticisms and suggestions, and particularly suggestions regarding topics that the readers would like to see featured in future editions of the Journal.

Volume 7 No 2 June 2018

Editorial

In this issue:Editorial Prof Charles Feldman 3

A brief review of bacteriophage therapy Dr Tomek Piorkowski 4

Influenza, influenza vaccination and vaccines in pregnant women Dr Marta Nunes, Prof Shabir Madhi 6

Listeriosis: The disease and its management Dr Juno Thomas 9

Disclaimer. The content contained in this publication contains medical or health sciences information and is intended for professional use within the medical field. No suggested test or procedure should be carried out unless, in the reader’s judgement, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verification of diagnoses and drug dosages should be made. Discussions views, and recommendations as to medical procedures, products, choice of drugs, and drug dosages are the views of the authors. The views expressed by the editor or authors in this newsletter do not necessarily reflect those of the sponsors or publishers. The sponsors, publishers and editor will not be liable for any damages or injuries of any kind arising from the use or misuse of information provided in this publication and do not support the use of products for off label indications.

Production Editors: Ann Lake PublicationsAnn Lake & Helen GonçalvesDesign: Jane GouveiaSponsors: SandozEnquiries: lakeann@mweb.co.za

Volume 7 No 2 June 20184

n March 2016, Professor Tom Pattinson lay dying in a San Di-ego hospital.1 He had extremely drug resistant Acinetobacter baumannii sepsis of the abdomen, an infection he apparently picked up while on holiday in Egypt. He had spent the previ-ous months in and out of delirium in an ICU setting as doctors

threw every antibiotic they could at the infection, with only a partial response at best. The last culture results showed com-plete resistance to every antibiotic available. With no further conventional treatment possible, doctors decided on a trial of bacteriophage therapy.

Bacteriophages, also referred to by the abbreviated form ‘phages’, are viruses that invade bacterial cells, either disrupting bacterial metabolism or causing the bacteria to lyse.2 Different strains of Acinetobacter-specific phage viruses were donated to the facility from military, research and commercial centres, which were then mixed into a cocktail and administered intravenously.

The patient responded to the treatment, although new strains of phage had to be added as it became apparent that the Acinetobacter was becoming resistant to the initial phage viruses that were used. But by June 2016, the patient’s sepsis had cleared and there was no detectable trace of Acinetobacter baumannii in his laboratory tests. After months of being bed-ridden in a chronic septic delirious state, the patient still required extensive rehabilitation, but was otherwise healthy and discharged from the hospital two months later.

This intriguing case study seems particularly relevant to the South African context, struggling as we are with epidemics of drug-resistant tuberculosis and a general background of emerging antibiotic resistance. In this article, I will give a brief historical overview of bacteriophage therapy with some comments on its current state.

A brief history of phage therapyThe existence of phages were first suspected in the 1890’s, when English bacteriologist Ernest Hanking described the effect of water from the Ganges river on the cholera bacterium. Drinking the water from the Ganges was a local traditional treatment for cholera, and on study of the water Hanking did confirm that Ganges river water had antibiotic activity against cholera cultures. Hanking noted that whatever the antibiotic was, the antibiotic activity disappeared on boiling of the water but was not affected by fine filtration. Frederick Twort, another English bacteriologist, then published speculation that perhaps the antibiotic agent was a naturally occurring virus, which would explain it’s resistance to filtration and it’s susceptibility

to heat – this was eventually confirmed by the French-Canadian microbiologist Felix D’Herelle working at the Pasteur Institute in Paris; he is considered the ‘official’ discoverer of bacteriophages.

Not long afterwards, the first attempts at therapeutic use of bacteriophages began, with D’Herelle and his colleagues creating an orally administered phage mix to treat bacterial dysentery. Other researchers tried the injectable route, using phages to treat Staphylococcus aureus infection through local infiltration of phages. The initial positive results led to the attempted commercialisation of bacteriophage therapy.

Unfortunately, the mixed results of commercial bacteriophage treatments made it a controversial treatment – it did not help that the first enthusiastic pioneers of phage therapy, such as D’Herelle, did not see the need or value of placebo groups in their therapeutic studies. The rapid rise of bacteriophage resistant bacteria also seems to have been a contributing factor to therapeutic failure. With the discovery of penicillin and the start of the era of antibiotics, bacteriophage therapy was quickly abandoned in the very countries that had initially pioneered it. Bacteriophage therapy continued to be developed and used in Eastern Europe, but for much of the Cold War, bacteriophage studies behind the Iron Curtain continued to be plagued by poor trial design, often with no placebo groups or with poorly shared trial data, preventing firm conclusions from being made regarding bacteriophage therapy. Eastern European centres in Poland, Georgia and Russia do however remain important centers of bacteriophage production and research.

There are currently no bacteriophage products approved for use in the US or the EU, highlighting the current lack of a firm evidence base for this treatment modality. It remains a treatment of last resort, when faced with antibiotic resistant organisms.

Mechanism of action of phage therapyBacteriophages are ubiquitous in the environment; soil is a common source of bacteriophages and for Professor Pattinson’s Acinetobacter treatment, bacteriophages were harvested from sewage. Phages are isolated from the source material and then propagated, filtered, concentrated, and then stored.3

Bacteriophages have been given through almost every traditional route: Orally (as both liquid suspensions and tablets), rectally, topically, intravenously, aerosols and as intrapleural injections. The ideal method of administration has yet to be defined. Once administered, bacteriophages attach themselves to specific receptors in the bacterial cell wall, allowing them

A brief review of bacteriophage therapy

Dr Tomek Piorkowski MBChB (Pret)House Call Doctor, www.docthomas.co.za Pretoria East

Volume 7 No 2 June 2018 5

to inject the viral genetic material into bacteria, effectively hijacking the bacteria’s metabolic processes. Phages with a therapeutic effect are divided into lytic and lysogenic bacteriophages. Lytic bacteriophages are presumed to kill bacteria in vivo through replication inside the bacterial cell and initiating a lytic cycle that ends with bacterial cell lysis. Lysogenic bacteriophages insert their genetic material into the bacteria, but the triggering of the lytic cycle may only occur after several bacterial cell replications. In other words, lytic bacteriophages destroy the first generation of bacteria; lysogenic bacteriophages insert a time bomb into the genetic material of the bacteria that only goes off after several cell replications in a difficult to predict manner. Not surprisingly, lytic bacteriophages are considered more potent than lysogenic bacteriophages.

Unfortunately, as bacteriophages have to achieve direct contact with a bacterial cell wall, they are considered to be an ineffective modality in the treatment of intracellular pathogens. This makes it a challenge to treat tuberculosis, for example, as the mycobacterium continues to replicate inside macrophages where it is also inaccessible to bacteriophages.4 Indeed, previous studies using bacteriophages in tuberculosis-infected animals have shown no therapeutic effect.5 This resistance to mycobacterium and intracellular parasites may require the development of novel bacteriophage delivery mechanisms in order to cross the human cell membrane.

Current trends and developments in bacteriophage therapyBacteriophage therapy’s great weakness is a lack of a robust evidence base. Several trials, however, have been done or are currently being done in order to address this.

Clinical safety trials have been done,6 and combined with the longstanding experiences of Eastern European doctors, seem to confirm that phage therapy is likely to be safe.

Currently, the very first multi-centric clinical trial of bacteriophage therapy – the Phagoburn study – is running in Europe, testing the utility of topical bacteriophage cocktails in burn wound patients, specifically in the treatment of E. coli and P. aeruginosa infection of wounds.7

Historically, bacteriophage mixes have consisted of a variety of lytic and other type of bacteriophages. As non-lytic bacteriophages have far weaker potency and are probably one of the reasons of historical failures in bacteriophage treatment, modern bacteriophage therapy is likely to focus on lytic bacteriophages.

Another problem is the historically poor specificity of bacteriophages. Bacteriophages often have a very narrow band of specificity, often only attacking specific strains of a bacterial species. Ideally, bacteriophages should be carefully matched to the bacterial strains they are meant to destroy. This will need to be addressed in the modern era either by careful diagnostic profiling of the bacterium before therapy, or by giving polyvalent cocktails of bacteriophage to attack multiple potential strains at once.

Bacteriophage mixes had historically poor levels of purity, stability and viability of bacteriophages. This will presumably be addressed by advances in pharmaceutical manufacturing techniques, which will include rapid typing and production of bacteriophages in order to match bacteriophages to the specific strain affecting the patient and to be able to rapidly adapt alternative bacteriophage therapies (within days) if phage resistance develops in a patient.

Bacteriophage therapy could open up novel methods of discovering antimicrobial molecules, such as specifically searching for the phage-derived lytic proteins that trigger bacterial lysis.4 Bacteriophage therapy can also possibly be given prophylactically, as attempted by the Russians during the Cold War, leading to possible new vaccine-type modalities.

One challenge that bacteriophage therapy historically could not address is the treatment of organisms that reside intracellularly, such as mycobacteria. One new method to address this problem, specifically with regards to M. tuberculosis and M. avium, is the use of Mycobacterium smegmatis, a species of mycobacteria that does not cause disease, as a delivery vehicle to bring the bacteriophage into the intracellular space so that it can be active against the pathogenic mycobacteria.8 This delivery vehicle may be adapted to target other intracellular bacteria as it is developed.

In summary, bacteriophage therapy has a long and proven track record of treating individual cases but has not been properly tested with randomised controlled trials. The need to investigate this treatment modality will become more urgent as the problem of antibiotic resistance continues to increase. A larger evidence base is still required.

References available on request.

Key messages

• Bacteriophage therapy has been shown to be effective in isolated cases of antibiotic-resistant sepsis

• Bacteriophages have extremely narrow ranges of specificity and have to be carefully selected to match the known or suspected strain of the bacterium

• Therapeutic bacteriophage products consist of polyvalent virus cocktails that are harmless to the host but cause bacterial cell lysis of the target bacterium

• Due to requiring direct access to the bacterial cell wall, bacteriophages are currently unlikely to be effective in treating intracellular pathogens, such as mycobacterium

• There are no approved bacteriophage products on the market; this will hopefully change as current and future trials begin to assess bacteriophage therapy in an evidence-based manner

Volume 7 No 2 June 20186

Influenza, influenza vaccination and vaccines in pregnant women Dr Marta C. Nunes, Prof. Shabir A. Madhi Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South AfricaDepartment of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa

Influenza virusesnfluenza is a contagious, acute viral illness of the respiratory tract, caused by influenza viruses which circulate worldwide and cause global epidemics and infrequently pandemics from novel mutated strains of the virus. Influenza viruses belong to the orthomyxoviridae family and can be divided into three

types that infect humans, A, B and C as defined by the antigenic-ity of the nucleoproteins and matrix proteins.1 Influenza-A vi-ruses are further divided into subtypes according to the anti-genic properties of the surface glycoproteins hemagglutinin and the neuraminidase. Eighteen antigenically different hemaggluti-nins (H1–18) and eleven different neuraminidases (N1–11) have been identified and their combination designates the virus sub-type. Currently, H1 and H3 subtypes of influenza-A are endemic in humans. The 2009 pandemic influenza A/H1N1 virus caused a global pandemic, but is now established as a seasonal influ-enza virus which co-circulates with other A/H3N2 and influenza-B seasonal viruses. Circulating influenza-B viruses are classified into two groups, Yamagata-like or Victoria-like lineages.2

Influenza-A and -B viruses are responsible for seasonal epidemics and current vaccines are designed to target these viruses. Influenza type C viruses are detected much less frequently and cause mild infections, not presenting significant public health concerns. Influenza types differ in the range of animal hosts that they can infect; humans are the only known reservoir of influenza-B and -C, whereas influenza-A is also found in other animals.3 Given the multiple subtypes, higher mutation rate and diverse hosts, influenza-A poses the greatest pandemic threat. People are susceptible to influenza throughout their lives due to the virus ability to continually mutate by antigenic drift (minor mutations) and antigenic shift (major mutatutions and only affects influenza-A viruses).4

The major targets of the antibody response against influenza virus are the hemagglutinin and neuraminidase glycoproteins, which induce neutralising antibody. Hypervariability of the amino acid sequences encoding these proteins is largely responsible for epidemic and pandemic influenza outbreaks. For this reason, if an antigenic mismatch exists between the vaccine and circulating influenza strains, vaccinated people may not be afforded complete protection.

Burden of influenza illnessInfluenza infection affects all age-groups and causes mild to severe illness. The World Health Organization (WHO) estimates that during normal seasonal epidemics 5%-15% of the population is typically infected by influenza viruses, with 3 to 5 million cases of severe illness and up to 650,000 influenza-

associated deaths per year globally.5,6 The highest burden of severe illness is concentrated in those aged <1 year, the elderly (≥65 years) and pregnant women.7,8 Furthermore, HIV-infected adults are also at greater risk of influenza hospitalisation and death. Influenza infection attack rates and disease severity vary considerably from season to season and across world regions. In tropical areas, influenza occurs throughout the year albeit with peaks; in temperate regions like in South Africa, influenza is highly seasonal and typically occurs during winter months.

In South Africa it has been estimated that on average there are 11,800 seasonal influenza-associated annual deaths. Seasonal influenza-associated mortality rate is 23.0 per 100,000 population annually, which translates to 2.3% of all deaths. The highest mortality rates are detected in the elderly ≥75 years old (386.0 per 100,000), followed by infants <1 year old (87.3 per 100,000).9 Furthermore among individuals >5 years old, an estimated 30% of all influenza-attributable deaths are in HIV-infected individuals.10 Pregnant women are also at higher risk for influenza-associated mortality. Among an estimated 646-1428 seasonal influenza-associated deaths annually in women of childbearing age in South Africa during 1999-2009, approximately 90% occurred in HIV-infected women and the influenza-associated mortality was three-fold higher in pregnant compared with non-pregnant women.11 In addition an estimated 47,000 episodes of influenza-associated severe acute respiratory illness occur annually in South Africa of which 22,481 result in hospitalisation.12 A recent study from South Africa showed that extremes of age [<6 months (adjusted odds ratio (aOR), 37.6), 6–11 months (aOR, 31.9), 12-23 months (aOR, 22.1), 24–59 months (aOR, 7.1), and ≥65 years (aOR, 40.7) compared to those aged 5-24 years], underlying medical conditions (aOR, 4.5), HIV infection (aOR, 4.3), history of working in a mine (aOR, 13.8) and pregnancy (aOR, 12.5) were significantly associated with increased risk of influenza-associated hospitalisation.13 Influenza infections are also responsible for 43%–67% of outpatient visits for influenza-like illness (ILI) during the peak of influenza season in South Africa.14

Influenza vaccinesAlthough influenza vaccines have less than optimal effectiveness against influenza illness, it nevertheless remains the best strategy to prevent influenza illness. Current seasonal influenza vaccines need to be reformulated annually in order to elicit a protective antibody response that recognises viral genetic variants that are predicted to arise through antigenic drift. In South Africa annual vaccination is recommended for individuals at increased risk of complications or healthy individuals wishing to reduce their risk of contracting influenza.15 Since 2010, the

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South African Department of Health (SADoH) has conducted annual influenza vaccination campaigns, with approximately one million doses distributed annually. The National Advisory Group for Immunization (NAGI) in South Africa, recommends the prioritisation of pregnant women, elderly and HIV-infected individuals for influenza vaccination.

Various influenza vaccine products have been developed, including inactivated influenza vaccines (IIV; both trivalent and quadrivalent), live attenuated vaccines and a recombinant influenza vaccine. In South Africa at present only trivalent sub-unit IIV is available. Ideally, vaccination should occur before onset of influenza activity in the community and should continue to be offered as long as influenza viruses are circulating. Children 6 months to 8 years of age not previously vaccinated should receive two doses of vaccine one-month apart initiated as soon as possible after vaccine becomes available. The currently licensed IIV for children 6-24 months of age, is half the concentration used in adults.

In general, IIV is most effective in healthy adults, whilst higher dose formulations (not available in South Africa) are recommended for the elderly. Also, in children, an adjuvanted IIV formulation, which is not licenced for use, was shown to be superior to the licensed non-adjuvant IIV. Three Cochrane Systematic Reviews evaluating the effects of influenza vaccines in healthy adults, healthy children and older adults including data from all circulating influenza strains irrespective of match between vaccine and circulating strains have recently been published.16-18 The review on healthy adults estimated a pooled vaccine efficacy against laboratory-confirmed influenza of 59% (95%CI: 53,64, a reduction from 2.3% to 0.9%) and ILI of 16% (95%CI: 5,25, reduction from 21.5% to 18.1%). Meaning that 71 adults would need to be vaccinated to prevent one of them experiencing influenza, and 29 would need to be vaccinated to prevent one ILI case.17 In healthy children aged 2 to 16 years, IIV reduced the risk of influenza from 30% to 11% (vaccine efficacy: 64%, 95%CI: 52,72) and of ILI from 28% to 20% (vaccine efficacy: 28%, 95%CI: 21,35). Five children would need to be vaccinated to prevent one case of influenza, and 12 children would need to be vaccinated to avoid one case of ILI.16 Among adults ≥65 years old the authors demonstrated that individuals receiving influenza vaccine were at lower risk of developing laboratory-confirmed influenza compared to unvaccinated individuals (2.4% vs. 6%) and experience less ILI (3.5% vs. 6%). These results indicate that 30 older adults would need to be vaccinated to prevent one person experiencing influenza, and 42 would need to be vaccinated to prevent one ILI episode.18 Although studies have shown that antibody response and protection elicited by influenza vaccination are lower amongst the elderly, influenza vaccination in this group is still associated with reductions in influenza disease.

In the USA for example, during the 2014-2015 influenza season, the influenza A/H3N2 virus that circulated widely drifted from the vaccine virus, leading to reduced overall vaccine effectiveness (19%) against influenza-A viruses. Given the reduced vaccine effectiveness and high burden of illness, it was estimated that 92 people needed to be vaccinated to prevent a single case of

influenza and 3115 people needed to be vaccinated to prevent a single hospitalisation. Changes in the vaccine composition and improved vaccine effectiveness (47%) against the circulating influenza virus types during the 2015-2016 season, meant that only 29 people needed to be vaccinated to prevent a single case of influenza and 2033 needed to be vaccinated to prevent one influenza-associated hospitalisation.19

Previous studies from South Africa have reported influenza vaccine effectiveness estimates from 2005 to 2015 which ranged between 46% and 87% when there was a good match and ranged between -14% and 38% when the circulating A/H3N2 strain showed marked genetic drift.20-22

Influenza vaccines in pregnant womenThere is currently no influenza vaccine approved by regulators in any country for use in infants <6 months old. Infants can, however, be protected from influenza illness in their first months of life by maternal antibodies transferred via the placenta during pregnancy and possibly through breastmilk post-partum.23-26 Efforts have therefore turned to active maternal vaccination as a means to provide neonates and young infants with passive immunity to influenza. Based on the substantial risk of severe disease in young infants and pregnant women (including the post-partum period), and the safety of influenza vaccine during pregnancy the WHO, and other national public health organisations including the SADoH as suggested by NAGI recommend that pregnant women should be vaccinated at any stage during pregnancy and be given the highest priority for influenza vaccination.27-29

Immunological and physiological changes that occur during pregnancy may affect the immune responses to vaccines and to infection.30 Nevertheless, the immunogenicity of IIV, based on the induction of hemagglutinin antibodies, is generally similar in pregnant and non-pregnant women.31,32 Four randomised controlled trials from South Africa, Mali, Bangladesh and Nepal, have demonstrated the efficacy of seasonal IIV vaccination during pregnancy in preventing laboratory-confirmed influenza in infants <6 months old.23,25,26,33 In a meta-analysis of the four trials we calculated that the pooled efficacy of maternal influenza vaccination in preventing influenza in the infants was 36% (95%CI: 22,48).34 Moreover four observational studies reported on the impact of maternal vaccination on laboratory-confirmed influenza hospitalisations in infants35-38 and the pooled vaccine effectiveness was 72% (95%CI: 39,87).34 An interesting observation from the South African trial was that maternal vaccination was also associated with a 57% (95%CI: 7,81) reduction in all-cause acute lower respiratory tract infection (LRTI) among infants <3 months old. Notably, this observation was independent of identifying influenza virus among the hospitalised cases; suggesting that preventing influenza infection may prevent subsequent LRTI in young infants.39

The duration of passive protection in the infant conferred by vaccination during pregnancy depends on the levels of antibodies achieved by vaccination which are contingent on the efficiency of the transport across the placenta and how quickly

Volume 7 No 2 June 20188

References 18-41 available on request.

Key messages

• Among vaccine-preventable diseases influenza is unique, since to maintain immunity it is necessary for recurrent re-vaccination due to the ongoing antigenic drift of the viruses.

• The impact of seasonal influenza vaccination on the burden of influenza disease can vary considerably from year to year. A number of factors contribute to this variability, including the virus types dominant in the season and the antigenic match between the virus strains included in the vaccines and the circulating virus strains.

• Influenza vaccination programs can reduce the burden of outpatient visits, hospitalizations and deaths due to influenza.

• Influenza vaccination during pregnancy protects both the mothers and the young infants against influenza infection.

the acquired antibodies wane. The effect of antibody decay was evident from the highest vaccine efficacy observed during the first 8 weeks of life in the South African trial (86% in infants <8 weeks old vs. 49% in infants <6 months old) and the first 4 months of life in Mali (68% in infants <4 months old vs. 33% in infants <6 months old).25,40

In South Africa a small trial in HIV-infected pregnant women showed that before vaccination and one month post-vaccination, HIV-infected compared to HIV-uninfected pregnant women, had lower levels of influenza-specific antibodies.41 Although the transplacental antibody transfer was similar in the HIV-infected and HIV-uninfected cohorts for two of the three vaccine strains, due to the lower antibody levels post-vaccination among the HIV-infected women, their newborns had lower antibodies at birth than those born to HIV-uninfected women.41 This study did not find a protective effect of maternal vaccination in HIV-exposed infants and a similar influenza attack rate was detected in infants born to mothers who received IIV (5%) and those born to unvaccinated mothers (6.8%).23

When assessing the effect of influenza vaccination during pregnancy on the mothers themselves the clinical trials found that women who received influenza vaccine were at lower risk of developing influenza illness and the vaccine efficacy against laboratory-confirmed influenza ranged from 31% in Nepal to 70% in Mali. The trial among HIV-infected women in South Africa also found a 57% (95%CI: 0.2,82) vaccine efficacy within that cohort. In pregnant women to avoid missed opportunities for vaccination and since the transplacental transfer of antibodies is a cumulative process, providers should offer vaccination when vaccine is available at any time during pregnancy, not only to protect the mothers as early as possible during the influenza season, but also to increase the level of antibodies transferred to their fetus.

References1. Zhang, J. and R.A. Lamb, Characterization of the membrane

association of the influenza virus matrix protein in living cells. Virology, 1996. 225(2): p. 255-66.

2. Tan, Y., et al., Differing epidemiological dynamics of influenza B virus lineages in Guangzhou, southern China, 2009-2010. J Virol, 2013. 87(22): p. 12447-56.

3. Zambon, M.C., Epidemiology and pathogenesis of influenza. J Antimicrob Chemother, 1999. 44 Suppl B: p. 3-9.

4. Smith, D.J., et al., Mapping the antigenic and genetic evolution of influenza virus. Science, 2004. 305(5682): p. 371-6.

5. Lafond, K.E., et al., Global Role and Burden of Influenza in Pediatric Respiratory Hospitalizations, 1982-2012: A Systematic Analysis. PLoS Med, 2016. 13(3): p. e1001977.

6. who, http://www.who.int/mediacentre/factsheets/fs211/en/.

7. Zhou, H., et al., Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. Clin Infect Dis, 2012. 54(10): p. 1427-36.

8. Dawood, F.S., et al., Burden of seasonal influenza hospitalization in children, United States, 2003 to 2008. J Pediatr, 2010. 157(5): p. 808-14.

9. Cohen, C., et al., In- and Out-of-hospital Mortality Associated with Seasonal and Pandemic Influenza and Respiratory Syncytial Virus in South Africa, 2009-2013. Clin Infect Dis, 2018. 66(1): p. 95-103.

10. Tempia, S., et al., Deaths associated with respiratory syncytial and influenza viruses among persons >/=5 years of age in HIV-prevalent area, South Africa, 1998-2009(1). Emerg Infect Dis, 2015. 21(4): p. 600-8.

11. Tempia, S., et al., Mortality Associated With Seasonal and Pandemic Influenza Among Pregnant and Nonpregnant Women of Childbearing Age in a High-HIV-Prevalence Setting-South Africa, 1999-2009. Clin Infect Dis, 2015. 61(7): p. 1063-70.

12. Murray, J., et al., Determining the Provincial and National Burden of Influenza-Associated Severe Acute Respiratory Illness in South Africa Using a Rapid Assessment Methodology. PLoS One, 2015. 10(7): p. e0132078.

13. Tempia, S., et al., Risk Factors for Influenza-Associated Severe Acute Respiratory Illness Hospitalization in South Africa, 2012-2015. Open Forum Infect Dis, 2017. 4(1): p. ofw262.

14. McAnerney, J.M., et al., Twenty-five years of outpatient influenza surveillance in South Africa, 1984-2008. J Infect Dis, 2012. 206 Suppl 1: p. S153-8.

15. Green, R.J., et al., Influenza guideline for South Africa--update 2008. S Afr Med J, 2008. 98(3 Pt 2): p. 224-30.

16. Jefferson, T., et al., Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev, 2018. 2: p. CD004879.

17. Demicheli, V., et al., Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev, 2018. 2: p. CD001269.

Volume 7 No 2 June 2018 9

Listeriosis: The disease and its management

Dr Juno ThomasHead: Centre for Enteric Diseases National Institute for Communicable DiseasesNational Health Laboratory Service Johannesburg

isteria monocytogenes causes listeriosis in humans, a severe albeit rare foodborne disease. This organism is an important foodborne pathogen of public health con-cern for two principal reasons: It causes severe disease (>90% of cases require hospitalisation) with a high mor-

tality rate (20-30%), and can cause outbreaks which may be large, prolonged and challenging to solve.1

In 2017 and early 2018, South Africa experienced the world’s largest listeriosis outbreak with >1 000 cases and at least 200 deaths. Ready-to-eat processed meat products manufactured at a single production facility were identified as the source of the outbreak, and following a recall of the implicated food products the number of outbreak-related cases declined sharply.2

MicrobiologyL. monocytogenes is a Gram-positive bacterium widely found in the natural environment (water, soil, vegetation) as well as the intestinal tract of many mammals. Colonisation or transient carriage of L. monocytogenes occurs in approximately 1-10% of heathy adults.3

The bacterium is able to grow and survive at a wide pH range, at high salt concentrations, and most importantly at refrigeration temperatures. This makes it able to survive and persist in the food processing environment, survive food processing hurdles and proliferate in food products – including foods that are refrigerated. 4

PathogenesisThe main route of transmission occurs through the consumption of contaminated food. Vertical transmission from a pregnant woman to her fetus also occurs.5,6

Disease occurs as a result of the failure of cell-mediated immunity to control proliferation of Listeria in the liver, which leads to bacteraemia and invasion of other organs (notably, the central nervous system and placenta).

EpidemiologySince L. monocytogenes is ubiquitous in the environment, it is likely that accidental contamination of food occurs fairly frequently, and that consumption of contaminated food is quite common.

Although most listeriosis cases are sporadic (i.e. not outbreak-related), outbreaks are increasingly recognised worldwide. Reported outbreaks have been associated most commonly with

unpasteurised dairy products (milk and soft cheeses), ready-to-eat processed meat/poultry products, and ready-to-eat seafood (such as smoked fish or mussels) but outbreaks have also been linked to contaminated fresh produce (fruits, vegetables and sprouts).

Changes in the way food is produced, distributed and stored have contributed to the increased risk of L. monocytogenes contaminating food and causing outbreaks.

Listeriosis in South AfricaIn the 1920s, Dr Harvey Pirie, a bacteriologist working at the South African Institute for Medical Research, described a bacterial infection among wild rodents in the Orange Free State. The organism was similar to one found by Dr EG Murray in Cambridge which caused disease in rabbits; together, Pirie and Murray proposed the name Listeria monocytogenes.7

The first human case of listeriosis in South Africa was reported in 1955.8 Prior to the 2017-2018 outbreak, clusters of cases which likely represented outbreaks were described in 1977-1978 (14 cases in Johannesburg) and 2015 (3 cases in Western Cape Province).9,10 The 1977-1978 cluster was not linked to any food products, since it was only in 1981 that L. monocytogenes was definitively proven to be transmitted by contaminated food. The 2015 cluster was identified retrospectively, and the cluster could not be linked to any food products.

Up until 2017, listeriosis had historically been a rare foodborne disease in South Africa with <100 cases diagnosed annually. An unusual increase in cases of neonatal listeriosis was noted at two academic public hospitals in Gauteng Province during July and August 2017, prompting further investigation. It soon became evident that an unprecedented and rapidly increasing number of cases were being diagnosed, and whole genome sequencing of L. monocytogenes isolates from patients showed that a single strain (sequence type 6, or ST6) was responsible for >90% of the cases countrywide. Through intensive epidemiological, laboratory and traceback investigations, the source of the outbreak was confirmed as ready-to-eat processed meat products (polony and other delicatessen-style cold meat products) manufactured at the Enterprise Foods's Polokwane production facility. Ready-to-eat processed meat/poultry products have been responsible for numerous listeriosis outbreaks worldwide, and are well-known to be at high risk for causing disease if contaminated.

Since 15 December 2017, listeriosis is a category 1 Notifiable Medical Condition and as such requires immediate reporting by

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the most rapid means available upon diagnosis, followed by a written or electronic notification to the Department of Health within 24 hours of diagnosis by healthcare providers, private health laboratories or public health laboratories.

Clinical manifestationsL. monocytogenes causes invasive disease mainly in certain well-defined risk groups, most of which have impaired cell-mediated immunity due to pregnancy, extremes of age, cancer, underlying chronic disease or medication (Table 1).1,11

Healthy persons infected with L. monocytogenes do not typically develop any symptoms. Should they develop disease, the most common form is a self-limiting febrile gastroenteritis. Rarely, otherwise healthy persons can develop invasive disease.

Listeriosis can be divided into five clinical manifestation categories, with varying incubation periods and clinical presentations, as summarised in Table 2.11-15

1. Febrile gastroenteritisHealthy persons can develop a self-limited febrile gastroenteritis, particularly after consumption of a large inoculum of L. monocytogenes in contaminated food. Illness typically occurs

Table 1. Risk factors for listeriosisPregnancy Chronic liver diseaseNeonates (≤28 days) Chronic renal diseaseCancer (haematolog-ical and solid organ) Diabetes mellitus

HIV Alcoholism

Autoimmune disease Immunosuppressive therapy (cytotoxic medications, corticosteroids)

Transplant recipients (solid organ and bone marrow)

Adults ≥65 years

Table 2. Clinical manifestations and laboratory investigations for listeriosisClinical manifestation category

Incubation period Clinical features Laboratory investigations

Febrile gastroenteritis

Median 24 hours (range 6 hours – 10 days)

• Fever and non-bloody diarrhoea; may be accompanied by arthroymalgia, headache, or vomiting. Typically of 1-3 days’ duration and self-limiting.

• Affects both healthy persons and those in high risk groups

• Stool culture with specific request for L. monocytogenes culture. This is NOT routinely indicated, unless there is exposure to a known contaminated food source, or a cluster of cases with suspected exposure to a common contaminated food source.

• Blood culture*

Pregnancy-associated

Median 21 days (range 7 – 67 days)

Can manifest as maternal listeriosis, fetal listeriosis or neonatal listeriosis

• Maternal listeriosis: Blood cultures are suggested for febrile gastroenteritis or nonspecific febrile flu-like illness in pregnant women in an outbreak setting*.

• Blood, CSF, amniotic fluid or placental tissue cultures as indicated for suspected neonatal/fetal listeriosis*

BacteraemiaMedian 5 days (range 1 – 29 days)

Fever; may be accompanied by diarrhoea, flu-like symptoms, decompensated comorbidity, sepsis

• Blood culture*

Central nervous system

Median 10 days (range 1 – 16 days)

Protean manifestations, including: Meningitis, meningoencephalitis, rhombencephalitis, cerebral abscesses

• Blood culture*• CSF culture*

Other Variable, depending on site of infection

A wide range of infections are described.

• Blood culture*• Culture of other sample sites

depending on presentation (e.g. pus, tissue, synovial fluid)*

*In cases where cultures remain negative for L. monocytogenes but there is a high index of suspicion for listeriosis, consider PCR testing.

Volume 7 No 2 June 2018 11

24 hours after ingestion and usually lasts 2 days. Common symptoms include fever, watery diarrhoea, nausea, headache and arthralgia. Hospitalisation following gastroenteritis due to listeriosis is more common amongst children or the elderly, in whom blood cultures may be positive.

2. Pregnancy-associated listeriosisMaternal immunosuppression during pregnancy promotes bacteraemia, with seeding to the placenta. In the placenta, bacteria proliferate and are protected from further immune attack, and subsequently infect the fetus. • Disease in pregnant women

Most infections are asymptomatic, and of those cases who do develop clinical disease, most present as a mild febrile illness. This is typically non-specific, presenting as a febrile flu-like illness (fever, backache, headache, myalgia, sore throat) or sometimes febrile gastroenteritis (fever, vomiting/diarrhoea).

• Fetal disease Infection is typically severe and results in miscarriage or stillbirth in 25-35% of cases.

• Neonatal listeriosisDisease is classified as early onset (day 1-6 of life) and late onset (day 7-28) depending on time of symptom onset after birth. Clinical features include sepsis, respiratory distress or pneumonia, and meningitis. Granulomatosis infantiseptica is a form of neonatal disease characterised by disseminated abscesses and granulomas in multiple organs. Mortality rate is high (up to 30%) and 40% of surviving neonates suffer severe neurological and developmental sequelae.

3. BacteraemiaThis is the most frequent manifestation of listeriosis in immunocompromised persons, adults and the elderly. The bacteraemia has no obvious focus, and usually presents as

a nonspecific febrile illness; fever may be accompanied by diarrhoea, flu-like symptoms, or decompensated comorbidity. There may be a history of antecedent diarrhoea.

4. Central nervous system diseaseDisease most typically manifests as meningoencephalitis or meningitis, which present similarly to acute bacterial meningitis/meningoencephalitis. There may be a history of antecedent diarrhoea. Involvement of the brainstem (brainstem encephalitis) is associated with cranial nerve involvement or cerebellar signs (ataxia, tremor), or the development of hemiparesis. Brain abscesses can also occur.

5. Focal infectionsThese are uncommon. A wide range of focal infections have been described, including mycotic aneurysms (mostly of the abdominal aorta), septic arthritis (including prosthetic joint infections), endocarditis, endophthalmitis, and osteomyelitis.

DiagnosisListeriosis is diagnosed by a positive culture from a clinical sample, or by positive polymerase chain reaction (PCR) testing. L. monocytogenes is not fastidious and can be readily cultured from clinical specimens such as blood, cerebrospinal fluid (CSF), amniotic fluid, placenta, and others. Where there is a high clinical index of suspicion for listeriosis but specimens (including CSF, blood and placenta) are culture negative, a PCR-based test may be of value. Detection of L. monocytogenes in stool samples is challenging and not routinely performed.6 Recommended microbiological investigations for the diagnosis of listeriosis are shown in Table 2.

There is no serological test to determine exposure/infection due to L. monocytogenes in asymptomatic persons.

Table 3. Antibiotic treatment for invasive infection due to Listeria monocytogenes

AdultsNeonates and children

Age category Ampicillin (IVI) Gentamicin (IVI)*

Recommended treatment

Ampicillin 3g IVI 6-hourly with or without gentamicin* 3mg/kg/day IVI in three divided doses

Neonates < 7 days and <2000g

100mg/kg/day in 2 divided doses 2.5mg/kg/dose every

12 hoursNeonates < 7 days and >2000g

150mg/kg/day in 3 divided doses

Neonates 8-31 days and <2000g

150mg/kg/day in 4 divided doses

2.5mg/kg/dose every 8-12 hours

Neonates 8-31 days and >2000g

200mg/kg/day in 4 divided doses

2.5mg/kg/dose every 12 hours

Infants >31 days and children

300mg/kg/day in 4-6 divided disease with a maximum of 12g/day

Gentamicin 7.5mg/kg per day in 3 divided doses

Age category Co-trimoxazole (ivi)Treatment in the presence of confirmed penicillin allergy

Co-trimoxazole** 20mg trimethoprim/kg/day in divided doses 6 hourly for 21 days

Neonates <31 days Co-trimoxazole 8-12mg trimethoprim /kg/day in divided doses 6 hourly

Infants >31 days and children

Co-trimoxazole 8-12mg trimethoprim /kg/day in divided doses 6 hourly

*Consider adding gentamicin. Note that gentamicin is contraindicated in pregnancy**Cotrimoxazole should be used with caution in pregnancy

Volume 7 No 2 June 201812

ManagementAmpicillin is considered the drug of choice for treating listeriosis. Consider adding gentamicin, as available evidence suggests that it may be of benefit. For patients with β-lactam allergy, cotrimoxazole is the preferred second-line agent. Table 3 details the antibiotic treatment guidance.11,16-19

There is no evidence for the optimal duration of therapy for listeriosis; recommended duration of therapy advised in most international guidelines is shown in Table 4.17,19

PreventionThere are two primary strategies for preventing listeriosis: Reducing contamination of food products, and providing risk reduction guidance to high-risk individuals. Such guidance includes advice on food hygiene and avoidance of at-risk food. The World Health Organization’s five keys to safer food20 (Figure 1) is a useful resource for generic food hygiene advice. Additionally, the WHO advises that pregnant women protect themselves against L. monocytogenes infection by:21

• Avoiding high risk foods, which are not cooked prior to eating. This includes smoked and lightly preserved fish or seafood, unpasteurised milk and its products (e.g. soft cheeses), pâté, and prepared salads from stores.

• Cooking meat and poultry products, including raw, processed (e.g. ham, viennas, polony and cold meats) and leftovers thoroughly.

• Avoiding perishable foods that are past their ‘consume before’ dates.

References1. Denny J, McLauchlin J. Human Listeria monocytogenes

infections in Europe – an opportunity for improved European surveillance. Euro Surveill. 2008;13(13):pii=8082

2. NICD listeriosis outbreak situation report of 07 May 2018. Available at http://www.nicd.ac.za/wp-content/uploads/2018/05/Listeriosis-outbreak-situation-report-draft-_07May2018_fordistribution.pdf

3. Hernandez-Milian A, Payeras-Cifre A. What is new in listeriosis? BioMed Res Int. 2014;2014:358051

4. de Noordhout CM, Devleesschauwer B, Angulo F, Verbeke G et al. The global burden of listeriosis: a systematic review

and meta-analysis. Lancet Infect Dis. 2014;14(11): 1073-825. Schlech WF, Lavigne PM, Bortolussi RA, Allen AC, Haldane

EV, Wort AJ, Hightower AW, Johnson SE, King SH, Nicholls ES, Broome CV. Epidemic listeriosis--evidence for transmission by food. N Engl J Med. 1983 Jan 27;308(4):203-6.

6. Allerberger F, Wagner M. Listeriosis: a resurgent foodborne disease. Clin Microbiol Infect. 2010;16:16-23

7. Frean J, Blumberg L, McCarthy K, Thomas J. Plague and listeriosis: current outbreaks, and an historical South African connection. S Afr J Infect Dis. 2018;33(1):3-4

8. Gant J, McKenzie D. Meningitis due to Listeria monocytogenes: case report. S Afr Med J. 1956;May 12:455-7

9. Jacobs MR, Stein H, Buqwane A, Dubb A, Segal F, Rabinowitz L, Ellis U, Freiman I, Witcomb M, Vallabh V. Epidemic Listeriosis. S Afr Med J. 1978;54(10):389-92

10. Smith AM, Naicker P, Bamford C, Shuping L, McCarthy KM, Sooka A, Smouse SL, Tau N, Keddy KH. Genome Sequences for a Cluster of Human Isolates of Listeria monocytogenes Identified in South Africa in 2015. Genome Announc. 2016 Apr 7;4(2). pii: e00200-16. doi: 10.1128/genomeA.00200-16.

Table 4. Recommended duration of therapy for listeriosisIndication Duration of therapy Additional comments

Febrile gastroenteritis Treatment not requiredConsider oral ampicillin/cotrimoxazole therapy for 5 – 7 days for high-risk group individuals known to have ingested a food implicated in an outbreak

BacteraemiaAmpicillin IVI for 21 days Gentamicin can be added to ampicillin for up to 7 daysMeningitis and

meningoencephalitis

Symptomatic disease in pregnancy

Ampicillin IVI (or high dose oral amoxicillin) for at least 14 days or until delivery

Gentamicin can be added to ampicillin for 3-5 days

Neonatal listeriosis Ampicillin IVI for 21 days Gentamicin can be added to ampicillin for up to 7 daysFocal infections Ampicillin IVI for 21 days Gentamicin can be added to ampicillin for up to 7 days

Key messages

• Although rare, listeriosis is a severe disease with high mortality.

• Invasive disease presentations include bacteraemia and meningitis/meningoencephalitis

• Clinicians should have a high index of suspicion for disease in pregnant women, neonates, the elderly, people with HIV, those living with underlying cancer or chronic diseases or diabetes, and those on immunosuppressant medication

• Ampicillin is the antibiotic of choice for treatment; adding gentamicin may be of benefit

• Healthcare professionals are encouraged to educate high risk persons (especially pregnant women) about listeriosis risk reduction measures

References 11-21 available on request.

Volume 7 No 2 June 2018 13

70°C

5°C

60°C

70°C

Danger zone!

Five keys to safer food

WHO/SDE/PHE/FOS/01.1Distribution: General

Original: English

Des

ign

: Mar

ilyn

Lan

gfe

ld. I

llust

rati

on

: Jan

et P

etit

pie

rre

Knowledge = PreventionFood SafetyWorld Health Organization

Cook thoroughly

✔ Cook food thoroughly, especially meat, poultry, eggs and seafood

✔ Bring foods like soups and stews to boiling to make sure that they have reached

70°C. For meat and poultry, make sure that juices are clear, not pink. Ideally,

use a thermometer

✔ Reheat cooked food thoroughly

Keep food at safe temperatures

✔ Do not leave cooked food at room temperature for more than 2 hours

✔ Refrigerate promptly all cooked and perishable food (preferably below 5°C)

✔ Keep cooked food piping hot (more than 60°C) prior to serving

✔ Do not store food too long even in the refrigerator

✔ Do not thaw frozen food at room temperature

Use safe water and raw materials

✔ Use safe water or treat it to make it safe

✔ Select fresh and wholesome foods

✔ Choose foods processed for safety, such as pasteurized milk

✔ Wash fruits and vegetables, especially if eaten raw

✔ Do not use food beyond its expiry date

Keep clean

✔ Wash your hands before handling food and often during food preparation

✔ Wash your hands after going to the toilet

✔ Wash and sanitize all surfaces and equipment used for food preparation

✔ Protect kitchen areas and food from insects, pests and other animals

Separate raw and cooked

✔ Separate raw meat, poultry and seafood from other foods

✔ Use separate equipment and utensils such as knives and cutting boards for

handling raw foods

✔ Store food in containers to avoid contact between raw and prepared foods

Why?

While most microorganisms do not cause

disease, dangerous microorganisms are

widely found in soil, water, animals

and people. These microorganisms are

carried on hands, wiping cloths and

utensils, especially cutting boards and

the slightest contact can transfer them

to food and cause foodborne diseases.

Why?

Microorganisms can multiply very

quickly if food is stored at room

temperature. By holding at tempera-

tures below 5°C or above 60°C, the

growth of microorganisms is slowed

down or stopped. Some dangerous

microorganisms still grow below 5°C.

Why?

Proper cooking kills almost all dangerous

microorganisms. Studies have shown that

cooking food to a temperature of 70°C can

help ensure it is safe for consumption.

Foods that require special attention

include minced meats, rolled roasts, large

joints of meat and whole poultry.

Why?

Raw materials, including water and ice,

may be contaminated with dangerous

microorganisms and chemicals. Toxic

chemicals may be formed in damaged

and mouldy foods. Care in selection of

raw materials and simple measures

such as washing and peeling may

reduce the risk.

Why?

Raw food, especially meat, poultry and

seafood, and their juices, can contain

dangerous microorganisms which may

be transferred onto other foods during

food preparation and storage.

Figure 1. Five keys to safer food (sourced from www.who.int)

Volume 7 No 2 June 201814

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