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Vol. 21 • No. 3 • March 2021

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Diabetic nephropathy complexities

Are day hospitals the solution for elective procedure Covid backlog?

Scheduling status: Proprietary name and dosage form: Tambocor Tablets. Composition: Each tablet contains flecainide acetate 100 mg. Reg. No.: S/6.2/17. Scheduling status: Proprietary name and dosage form: Tambocor CR 100 Capsules. Composition: Each controlled release capsule contains flecainide acetate 100 mg. Reg. No.: 37/6.2/0199. Scheduling status: Proprietary name and dosage form: Tambocor CR 200 Capsules. Composition: Each controlled release capsule contains flecainide acetate 200 mg. Reg. No.: 37/6.2/0201. Scheduling status: Proprietary name and dosage form: Tambocor Injection. Composition: Each ampoule contains 15 ml of solution of flecainide acetate 10 mg/ml, for intravenous use only. Reg. No.: S/6.2/16. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd,. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No.: 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 15255L. IN4081/21.

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References: 1. Synjardy® approved prescribing information, Boehringer Ingelheim 2020. 2. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME® Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. 3. Hadjadj S, et al. Diabetes Care 2016; 2016 Oct;39(10):1718-28. doi: 10.2337/dc16-0522. 4. Boehringer Ingelheim data on file. Synjardy® is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control - in patients inadequately controlled on their maximally tolerated dose of metformin alone - in patients inadequately controlled with metformin in combination with other glucose-lowering medicine. For full prescribing information refer to the professional information approved by the Regulatory Authority. Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg. Tel: +27 (011) 348-2400. Cpy. Reg. No. 1966/008618/07. BI Ref. No. PC-ZA-101048. Expiry date: March 2023.

SF | CONTENTS

March 2021 | Vol. 21 No. 3 www.medicalacademic.co.za

INSIDE this issue

4 EDITORIAL 6 8 12 NUTRITION 14 CARDIOLOGY

The minefield of saving lives

Burnout, a signal not a sentence Are day hospitals the solution for elective procedure backlog?

Fear of fatness

Efficacy of fixed-dose, triple therapy in essential hypertension

24 NEPHROLOGY 27 31 ALLERGOLOGY

Diabetic nephropathy complexities

An overview of calcium phosphatebinders in CKD

There is something new in the air

NFECTIOUS 36 IDISEASES

The post-antibiotic apocalypse is coming, warns WHO

40 NEUROLOGY

CPD: The neuroscience of ADHD

ADHD is not ‘on ly ’ a beha vioural disorde r, it is a comp lex neuroc ognitiv e disorde r

16 17 GASTRO ENTEROLOGY

Rhythm control for ALL patients with early AFib

Probiotics for ‘belly button’ pain

CPD: Disorders of gut-brain interaction

Disclaimer: Please take note that the products featured in this journal are available in South Africa. Products may be marketed under a different name or might not be registered in your country. For more information, contact your local representative. All content in The Specialist Forum is sourced independently and under no circumstances should articles be considered promotional unless specified with a postscript.

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This article was independently sourced by Specialist Forum.

The minefield of saving lives by Merlita Kennedy and Jared Ishmael, Webber Wentzel

he recent move to charge a medical practitioner with murder rather than culpable homicide for the death of a patient after surgery is alarming, because it could deter innovation and new entrants to the profession. Media reports suggest that South African medical practitioners are increasingly being criminally charged when patients pass away under their care. While this may appease those close to the deceased, what effects will this trend have on South African medical practitioners and medical practice in South Africa? It has been reported by various South African media outlets that the National Prosecuting Authority of South Africa (NPA) has changed the charges against a prominent medical practitioner, aged 73, from culpable homicide to murder following the death of a patient after surgery.1 The NPA has not advanced any reasons for amending the charges. It must be noted that the anaesthetist who worked alongside this medical practitioner was killed in 2020 at the age of 56 and to date, no arrests have been made. 2 Murder is defined as the intentional killing of another human. Culpable homicide is defined as the negligent unlawful killing of another human being3. The charges of culpable homicide and murder, while both relate to the killing of a human being, differ in the way that they address fault or culpability. The former centres on negligence while the latter centres on intention in its various forms. The nature of medical practice is that practitioners often carry out procedures on people whose health is already compromised (which is why they need medical assistance) and this often happens under immensely stressful conditions. That a medical practitioner will produce the desired result cannot be guaranteed, given the number of variables associated with medical practice. Consequently, medical practitioners cannot be compelled to provide the desired result but to diligently apply themselves in a manner similar to that of a reasonable practitioner, regardless of the consequences.

Threat of harsh sanction The threat of harsh sanction, may, in the eyes

of the NPA, deter medical practitioners from deviating from that standard. However, the prospective implications are severe: medical practitioners will be conflicted between performing procedures to assist patients and the threat of criminal sanction if those procedures produce an unintended adverse result. In addition, given the risky nature of medical innovation, practitioners will be reluctant to carry out what may be medically innovative procedures, for fear of criminal sanction. The criminal sanction of medical practitioners for conduct undertaken in the performance of their duties will have a chilling effect on new entrants to medical practice because the profession itself will carry the risk of criminal sanction for procedures performed on every patient in the normal course of the medical practitioner’s career, without time limitations. As a result, colloquially speaking, a medical practitioner could face criminal sanction for 'a hard day’s work'. This must be viewed in the context of South Africa’s low doctorpatient ratio of approximately 40.7 doctors per 100 000 people4 and the poor socio-economic conditions of the majority of South Africans.

Grievances of those who have lost loved ones While the grievances of those who have lost loved ones following medical procedures deserve to be heard and addressed, a balance must be struck between holding medical practitioners accountable and allowing them the freedom to practise and innovate in a profession that is pivotal to human existence and wellbeing.

References 1. https://www.iol.co.za/news/npa-charges-dr-peterbeale-with-murder-fraud-over-10-year-old-patientsdeath-a65a8c36-f795-4946-b55c-8d162849573a 2. https://www.iol.co.za/thepost/news/i-had-nothingto-do-with-hit-on-doctor-77f6de3b-8332-4d5b-89a74424368e5c31 3. James Grant Critical Criminal Law RS 02 of 2018 at page 14. 4. https://www.medicalbrief.co.za/archives/africa-checkputs-together-numbers-doctor-patient-ratios/ SF

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TREVICTA

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A signal, not a sentence Globally, doctors are 2.5 times more likely to commit suicide than the general population, while physician burnout is a leading cause of medical error. The World Health Organization (WHO) states that burnout is ‘a state of vital exhaustion’.

n light of what some are calling a ‘crisis in healthcare’, the WHO now officially recognises burnout as a medical diagnosis. This has resulted in the drafting of a new definition by the WHO that describes burnout as ‘a syndrome conceptualised as resulting from chronic workplace stress that has not been successfully managed’. This is an important departure from the previous definition in that it is recognised as being associated specifically with workplace stress.

What is burnout? Burnout is characterised by feelings of energy depletion or exhaustion, increased mental distance from one’s job, or feelings of negativism or cynicism related to one’s job and reduced professional efficacy. Apart from being the leading cause of medical errors, burnout takes a toll on the mental and physical well-being of the individual affected.

Burnout among South African healthcare professionals Globally, burnout rates among physicians range between 25% and 60%. A South African study by Liebenberg et al found that 81% of

physicians in rural areas report burnout, with 31% reporting high burnout measured by all three of the Maslach Burnout InventoryHuman Services Survey (MBI-HSS) subscales (emotional exhaustion, depersonalisation, and personal accomplishments). Furthermore, 48.5% of nurses reported burnout. Doctors working in the public sector are at greater risk of burnout. Coetzee et al conducted a study among South African anaesthetists working in the public versus the private sector, and found: Table 1: Public vs private sector burnout MBI-HSS subscale measurements

Public sector

Private sector

Emotional exhaustion

45.2%

20.9%

High depersonalisation

50%

26.7%

Low personal accomplishment

46%

37.2%

The 2020 Medscape National Physician Report (United States) indicates that female physicians reported more symptoms of burnout (48% female vs 37% male). A recent study by the Professional Provident Society found that 50% of South African physicians report being depressed due to a

combination of being overworked, working long hours and burnout. Depression is one of the leading causes of suicide.

What causes burnout? Numerous internal and external reasons have been put forward that may contribute to physician burnout: De Hert lists the following internal reasons for burnout among physicians: » High idealistic self-expectations » Perfectionism » Strong need for recognition » Always wanting to please other people » Supressing own needs » Feeling irreplaceable » Overestimation to deal with challenges » View work as the only meaningful activity » Work becomes a substitute for social life. Clark identified five external reasons for burnout among physicians in the United States, which may be applicable to South African physicians as well:

1. Clunky workflow epidemic In the United States, poorly designed electronic health records (EHR) contribute to 50% of

SF | EDITORIAL

March 2021 | Vol. 21 No. 3 www.medicalacademic.co.za

burnout rates. Instead of spending time with patients, doctors report that over half of their workday is spend on EHR tasks. This means that they often have to work longer hours to catch up.

2. Overwhelming amount of new tech The use of technology in the healthcare sector is increasing exponentially. Although the intent is to make managing a practice go smoother, they may in fact actually be causing more stress. Healthcare professionals (HCPs) already have limited time. New technologies demand more time for training, integration, and ensuring proper cybersecurity. Table 2: Five-stage model for the development of burnout Stage

Characteristics

Honeymoon ñ Job satisfaction stage ñ Commitment to job (stage 1) ñ Accepting responsibility ñ Compulsion to prove oneself ñ Substantial energy levels ñ Free-flowing creativity ñ Unbridled optimism ñ High productivity levels Onset of stress (stage 2)

Chronic stress (stage 3)

Burnout (stage 4)

Habitual burnout (stage 5)

ñ Cardiovascular symptoms ñ Anxiety ñ Inability to focus ñ Irritability ñ Reduced sleep quality ñ Lack of social interaction ñ Lower productivity ñ Avoidance of decision-making ñ Change in appetite ñ Fatigue ñ Headache ñ Neglect of personal needs ñ Persistent tiredness/ exhaustion ñ Procrastination ñ Cynical attitude ñ Resentfulness ñ Apathy ñ Decreased sexual desire ñ Denial of problems ñ Feeling threatened/ pressured ñ Obsession with problems ñ Chronic headaches ñ Pessimistic outlook ñ Chronic gastrointestinal problems ñ Physical symptoms ñ Neglect of personal needs ñ Self-doubt ñ Escapist activities ñ Social isolation ñ Behavioural changes ñ Aggressive behaviour ñ Alcohol/drug use ñ Chronic sadness ñ Chronic mental fatigue ñ Chronic physical fatigue ñ Depression

3. Long hours and sleep deprivation As a result of having to work longer hours resulting in less sleep, burnout rates of 57% have been reported among HCPs who work more than 72 hours a week. Sleep deprivation influences mood, attention span and memory.

4. Financial stress Many HPCs start their careers with student debts. In addition, debts accumulate when they try to start their own practice. To meet their financial obligations, they often take on more work. In addition, the threat of a malpractice lawsuit can cause extreme levels of stress.

5. Loss of control In the past, physicians were the primary decision-makers of patient care. Now they have to cede some of their decision-making powers to administrators, medical schemes, technology and lawyers. This can make them feel as though they have lost autonomy. In the United States, almost 25% of burnout are attributed to the loss of autonomy.

Burnout is a signal, not a sentence According to an article in the Harvard Review, burnout is a signal that something is wrong and not a long-term sentence. By understanding the signs and causes, you can recover and build a road map for prevention.

Can burnout be prevented? According to de Hert, a multifactorial prevention approach, and treatment of burnout are required. The approach should focus on the individual’s own personality and attitude, as well as interventions on an organisational level.

On a personal level If symptoms are minor, recommends de Hert, measures such as changing life habits and optimising work–life balance can make a huge difference. These measures focus on three Rs: » Relief from stressors » Recuperation via relaxation and sport » Return to reality in terms of abandoning the ideas of perfection.

Minor symptoms (stage 2 and 3) Personal wellness strategies that have been used successfully in physician burnout programmes include: » Focus on relationships: Understand the importance of spending quality time with family, friends and significant others. This strategy also includes actively developing connections with colleagues, to share and reflect with them on emotional and existential aspects of being a physician » Religious belief and/or spiritual practice: Nurture your spirituality. It has been reported

that up to 34% of people mentioned this aspect to be important and even essential » Work attitudes: This has two components. The first one refers to finding meaning and fulfilment in work, the second one to actively choosing and limiting the type of medical practice such as working part-time, being involved in education and/or research, managing schedule and discontinuing unfulfilling aspects of practice » Self-care: Actively cultivate personal interests and self-awareness in addition to professional and family responsibilities. This also implies actively seeking professional help in case of personal physical and psychological problems or illness. Examples of such practices are, among others, exercise, self-expression activities, adequate nutrition and sleep, regular medical care or professional counselling » Adapt a specific life philosophy: Develop a philosophical approach to life that is based on a positive outlook where you identify your own values and act accordingly with emphasis on the balance between personal and professional life.

Severe symptoms (stage 4 and 5) If the symptoms of burnout are severe, psychotherapeutic interventions are recommended. There may also be a place for antidepressants, preferably combined with psychotherapy.

Organisational level According to de Hert, organisations have to take cognisance of HPC burnout. Create awareness and recognise the problem, he stresses. This can play a crucial role in promoting physicians’ well-being. He recommends that organisations adopt for example the following strategies that will contribute to the wellness of HPCs: » Promoting autonomy » Providing adequate office resources and support staff » Facilitating a collegial work environment » Minimising work-home interference by providing flexible scheduling and childcare adapted to irregular work hours.

Conclusion HPC burnout is a global crisis. Numerous internal and external factors have been proposed as the cause of HPC burnout. Internal factors include long working hours, while external factors include loss of autonomy and financial stress. Various strategies have been put forward on a personal, as well organisational level, to deal with HPC burnout. One of the key pillars is creating awareness and recognising the crisis. References available on request. SF

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March 2021 | Vol. 21 No. 3 www.medicalacademic.co.za

This article was independently sourced by Specialist Forum.

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Are day hospitals the solution for elective procedure backlog? The 2020/21 lockdown due to Covid-19 resulted in thousands of elective surgeries being put on hold, leaving surgeons and hospitals grappling to reduce the backlog. Many elective surgeries are time sensitive and those not falling under the definition of urgent/ emergency surgery, which have been postponed over recent months, by implication have become urgent or qualify as emergency surgery, says Leonie Bredell, relationship manager for the Day Hospital Association of South Africa (DHASA).

any of these surgeries can be performed in a day hospital setting. Experts warn that with South Africa’s winter just around the corner, the country may experience a third or even a fourth wave of Covid-19, increasing the backlog even more. This pandemic has only just started. We are going to get a third wave, even a fourth, Prof Tivani Mashamba, diagnostic researcher at the University of Pretoria, told The Guardian newspaper in January. If the country goes into lockdown again, it means many patients who require elective procedures have now been waiting for more than 12 months to go undergo procedures.

Are day hospitals the solution? In the United States, Europe and Australia, surgeons were encouraged to make use of day hospitals to address backlogs. International trends have shown: » An increase in the number of surgeons working in day hospitals » Momentum in disciplines such as orthopaedics, gynaecology and urology moving more procedures to day hospital environments » A wider variety of procedures per discipline, performed in day hospitals » Medical funders moving away from traditional hospital networks, revoking co-payments for patients choosing

non-designated service provider hospitals and co-payments linked to certain procedures. During lockdown, day hospitals did experience an uptake in interest from surgeons. Day hospitals were able to assist surgeons looking for alternative settings to perform surgical cases for patients that could not be deferred. This was especially prevalent in geographical areas hard hit by the pandemic, with acute hospital resources caring and battling Covid-19 on the frontlines. Urgent and emergency day surgery procedures still went ahead at around 10% of normal daily capacity.

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Why is the South African day hospital industry lagging?

One of the many benefits of day hospitals is that the risk of infection is much lower compared to acute hospitals. According to Bredell the risk of contracting Covid-19 is negligible in day hospitals because

Bibi Goss-Ross, COO and executive director at Advanced Health Ltd, writes that in general, a hospital account consists of the following tariff structures: » Hospital » Theatre » Consumables » Equipment. If you compare a day ward fee in a day hospital with a larger acute hospital, the day hospital fee is lower. Theatre fees are billed per minute in theatre – once again, day hospitals are the cheaper option when compared to larger acute hospitals. Day hospitals, by nature surgically orientated, only offer theatre facilities and ward accommodation and are streamlined, and do not have to make provision for highly

between acute- and day hospitals were significantly greater. Growth in the day hospital industry over recent years has resulted in acute hospitals lowering their price on day procedures to remain competitive in the healthcare market. The question remains – if day hospitals close their doors what would happen to overall hospital costs in the industry? Without a doubt this will increase again, which is exactly why the day hospital industry feels strongly that patients and funders have to support the day hospital concept and doctors should without a doubt secure theatre slots in both acute and day hospital settings. It is vital to the sustainability of the overall healthcare industry that day procedures are performed in the most cost-effective setting with careful consideration of patient suitability to the environment and the risks involved with any surgical procedure. Day hospitals generate income by

the environment in which they operate is more controllable. For example, because of the small size and the lay-out of day hospitals, the quicker patient turnaround times due to the shortstay, and the fact that no long-term ill

specialised units and other medical services found in larger acute hospitals like trauma, intensive care, maternity units etc. making it easier to offer cost effective rates to medical aids and patients. Ten years ago, the difference in pricing

performing same day surgical procedures only. Medical schemes can provide data on day hospital procedure outcomes and the cost-effectiveness of these procedures in comparison to the same service in larger acute hospitals.

The main reason, says Bredell, is because many surgeons and patients are unfamiliar with this so-called ‘new generation’ of day hospitals. Furthermore, surgeons erroneously believe that day hospital facilities are not sufficiently equipped or staffed, have no available capacity and that quality and risk management protocols are lacking. In 2019, DHASA embarked on a project that debunked these misconceptions for the members they represent.

Benefits of day hospitals Lower risk of infection

patients are admitted, infection control is more manageable.

More cost-effective

Table 1: Examples of procedures that can be done at day hospitals Approved General procedures/ breast surgeries procedures

Ophthalmology

Orthopaedic procedures

Cosmetic procedures

Urological Ear, nose, and Gynaecological Gastrointestinal procedures throat procedures procedures

Skin biopsies

Mastectomy Cataract surgery Achilles tendon for release gynaecomastia

Blepharoplasty

Cystoscopy Cochlear and ureteral implant dilation

Cerclage of uterine cervix

Incision and drainage of abscess and/or cyst

Lumpectomy Corneal surgery (fibroadenoma) and transplants

Arthroscopy, arthrotomy and arthrodesis

Breast augmentation

Male genital procedures such as circumcision

Middle ear Dilation and procedures curettage such as tympanoplasty

Simple superficial lymphadenectomy

Intra-ocular injections

Ganglionectomy

Face lift

Removal of ureteral stones

Tonsillectomy Endometrial and/or ablation adenoidectomy

Debridement and removal of lesions (depending on site and size) as well as superficial wound care

Other eye procedures such as removal of foreign body and conjunctival surgery

Tendon and/or ligament repair, muscle debridement, fascia procedure

Labiaplasty

Renal calcultus removal and stent insertion

Repair nasal turbinates, septum, ear fistula

Hysteroscope

General surgical procedures include Laparoscopic appendicectomy

Laser surgery

Minor joint arthroplasty

Liposuction

Scope and pyelogram

Scopes (nasal endoscopy, laryngoscopy

Laparoscopic gynaecological procedures

Umbilical hernia repair

Treatment of glaucoma

Release of trigger finger and repair of bunion or toe deformity

Scar excision, revision surgery or removal of lesions

Treatment of simple closed fractures or dislocations, removal of pins, plates, k-wires (subject to individual case review)

Other procedures such as mastopexy, nose reconstruction or rhinoplasty

Other general surgical procedures include anal dilation, excision lipoma, haemorrhoidectomy, inguinal hernia repair

Simple Sterilisation procedures for nose bleeding and sinus procedures

Anorectal procedures Scopes such as oesophagoscopy, gastroscopy, colonoscopy

SF | EDITORIAL

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According to Bredell, DHASA believes the day hospital industry is part of the solution to reduce the cost of private healthcare. By encouraging industry engagement, collaboration, and active relationships, they have managed to provide patients with access to day procedures at a lower cost, while at the same time safeguarding funder reserves.

Patient benefits Patient benefits include minimum disruption to daily life as procedures are done on the same day, requiring no overnight stay. Studies show that recovery times are faster in for example home environments. As mentioned already, the risk of infection is reduced and tariffs are charged according to medical scale of benefits.

Surgeon benefits Surgeons are assisted by well-trained and experienced nursing staff, who do not work shifts or rotate. This means that doctors always work with teams that they are familiar with. Management teams are flexible and willing to negotiate on treatment co-payments and provide support and assistance with pre-authorisations.

ch sear % e r l a 0 tion e than 7 a n r Inte hat mor edures st roc show rgical p ed in a of su perform tting e be can ospital s h day

What surgeries can be performed at day hospitals? Short-stay elective procedures that do not require critical care can also be performed at these modern, state-of-the-art facilities, says Bredell. Case selection is extremely important and relies on the clinical expertise and judgement of surgeons, in consultation with anaesthetists, as well as the patient, says Bredell.

A number of surgical procedures across various disciplines ranging from orthopaedic to plastic surgery can be performed currently in day hospitals. In fact, international research shows that more than 70% of surgical procedures can be performed in a day hospital setting. Goss-Ross adds that continuous medical and technological advances will create the opportunity for more complex procedures to be performed in day hospitals.

Conclusions Day hospitals offer benefits to patients, surgeons making use of the facilities and healthcare funders, reducing private healthcare costs. Patient and surgeon education about the benefits of day hospitals is lacking. Ross-Goss, however, believes that the day hospital in South Africa will follow international trends, which saw an increase in the utilisation of these state-of-the-art facilities. International studies show that more than 70% of surgeries can be performed in a day hospital setting. Medical technological advances will create the opportunity for more complex procedures to be performed in these settings in future. SF

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Fear of FATNESS FATNESS

March is eatin g disorde r awaren ess month

Eating disorders do not discriminate. They are complex psychiatric disorders that can affect anyone, regardless of age, sex, or race, states Eating Disorders South Africa.

he Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) and the 11th revision of the World Health Organisation’s International Statistical Classification of Diseases and Related Health Problems published in 2019, classify feeding and eating disorders as: 1. Anorexia nervosa 2. Bulimia nervosa 3. Binge eating disorder (BED) 4. Avoidant/restrictive food intake disorder (ARFID).

eating disorders is unknown. However, studies suggest an increase in bulimia and in BED. Increases in anorexia have also been noted – especially in young women. The estimated lifetime prevalence of anorexia is estimated to be 1.4% in women, and 0.2% in men. It is slightly higher for bulimia (1.9% in women and 0.6% in men). The lifetime prevalence for BED is 2.8% in women, and 1% in men. An Australian study found that the three‐month prevalence of ARFID was 0.3%.

Diagnostic features

The long road to recovery and stumbling blocks

People with an eating disorder have a “complex, problematic relationship with food” that are enhanced during difficult times such as we are currently experiencing, write Touyz et al. They caution that during Covid-19, patients with eating disorders should be even more closely monitored.

Prevalence According to Hay, the true prevalence of

The road to recovery is a long one. A 22‐year follow‐up study (n=228) in women with anorexia or bulimia, treated in a specialist centre, found that 66% of patients recover within nine years. Less is known about long‐ term outcomes for BED and other eating disorders, according to Hay. Patients with eating disorders often have concurrent depressed mood, higher body

Table 1: Key diagnostic features of the main feeding and eating disorders Anorexia nervosa

Bulimia nervosa

Binge eating disorder

Avoidant/restrictive food intake disorder

Eating

Severe restriction

Irregular, skipping Irregular but meals common as no extreme well as restriction restriction

Severe restriction of all or selected foods

Weight

Underweight

Normal or above normal

Underweight and/or with nutrition deficiency

Body image

Overvaluation Overvaluation with or without ‘fear of fatness’

Overvaluation but not mandatory

No overvaluation

Binge eating

May occur

Regular without NA compensation

Purging, fasting, driven exercise weight control behaviour(s)

One or more is Regular as present compensatory behaviours

Regular and with compensation

Not regular

None

image concerns, and poor relationships, as well as other co‐morbidities. These factors negatively impact the recovery process and are often associated with poorer outcomes. According to Hay, a major challenge in the management of eating disorders is closing the ‘treatment gap’. Studies show that the majority of people with anorexia, bulimia and BED delay seeking care for a decade or longer. She notes that many factors contribute to this problem. The most important are low levels of health literacy, help‐seeking for weight loss management rather than the eating disorder, stigma, shame, as well as poor affordability and access to evidence‐based psychological therapies.

Treatment The authors of a 2018 consensus document about the nutritional evaluation and management of eating disorders, stress the importance of an individualised and multidisciplinary (registered dietitian, specialist physician/paediatrician, psychiatrist, nurse/s, an exercise therapist, activity/occupational therapist and social worker or family therapist) approach. According to Candela et al, patients with anorexia and bulimia are often malnourished, and have severe nutritional deficiencies. A nutritional approach is recommended, which should include individualised dietary advice, which guarantees an adequate nutritional state and nutritional education. The objective is to facilitate the voluntary adoption of eating behaviours that promote health and allow the long-term modification of eating habits, and the cessation of purgatory and bingeing behaviours, explain the authors. Psychological support (eg trans‐diagnostic cognitive behaviour therapy [Enhanced]) is a first-line treatment. Support must address

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eating behaviour as well as psychiatric comorbidities. Psychotropic drugs are effective and widely used although these drugs are not essential, note Candela et al. Treatment should preferably be managed by an expert in eating disorders and can be undertaken in an outpatient setting. Hospitalisation should be reserved to correct serious somatic or psychiatric complications or as a measure to contain non-treatable situations, according to Candela et al and Hay. In addition to specific psychological therapy, treatment needs to address important nutritional issues.

as an antioxidant. Anorexia is associated with loss of bone mass. Vitamin D supplementation have been shown to improve bone mineral density, according to Díaz-Marsá et al.

Nutritional rehabilitation

According to Díaz-Marsá et al, the pattern of food intake in patients with eating disorders is 'erratic', which can lead to altered neuronal mechanisms in the dorsal striatum and its

The aim of nutritional rehabilitation or refeeding in patients with anorexia is to achieve weight restoration. Gastric feeding and total parenteral nutrition (TPN) may be indicated for refractory cases. TPN is a specialised procedure and should be undertaken only when medically necessary and by an experienced clinician. Patients with refractory anorexia is classified as mild, moderate, severe, or critical, based on whether they are 10%, 20%, 30%, or more, respectively, below ideal body weight. Mehler et al warn that before refeeding is attempted, the possibility of complications should be considered. The most 'catastrophic' of these is refeeding syndrome, which is

connections with the frontal circuits. Decreased brain volume and thinning of the cerebral cortex have also been reported, which imply a deficit in different nutrients, namely electrolytes, vitamins and minerals, among others. Electrolyte abnormalities are caused by purging (self-induced vomiting and incorrect use of laxatives, diuretics, or enemas). In addition, vomiting may cause hypokalaemia (low potassium levels) and/or hypochloraemic alkalosis (low chloride intake or excessive chloride wasting). Laxative abuse can cause hypomagnesaemia (low magnesium levels) and hypophosphataemia (low levels of phosphate). These anomalies may require emergency supplementation to address individual needs, note Díaz-Marsá et al. Hypocalcaemia is common in patients diagnosed with eating disorders, which can lead to poor bone density. Hypophosphataemia is easily detectable and treatable, but extremely serious if not detected in time. As a result of poor nutrition, patients with eating disorders also have low plasma iron levels. In addition to diet, erythrocyte haemolysis in these patients may also contribute to iron deficiency. Food restriction can lead to low plasma thiamine levels, which can cause various neuropsychological symptoms, such as worsening of depressive symptoms. Vitamin B9 or folic acid deficiency has also been reported in patients with eating disorders. This vitamin is essential for human growth, nerve function, and for reducing levels of the amino acid homocysteine. Short-term cobalamin deficiency can produce symptoms of anaemia (fatigue or weakness), or affective symptoms, while long-term deficiency has been associated with brain damage. Vitamin C is necessary for the growth and repair of tissues in all parts of the body and acts

common in significantly malnourished patients during the early phase of nutritional replenishment whether it is by the oral, enteral (ENT), or parenteral (TPN) route. The risk of refeeding syndrome directly correlates with the degree of weight loss, which occur as a result of anorexia. Patients who are more than 30% below their IBW should initially be refed in a hospital setting. Several approaches can be used to minimise the risk of refeeding syndrome. The most important of these is avoidance of overly aggressive refeeding early on. Mehler et al recommend that intake levels should be started at about 600kcal/day–1000kcal/day, and steadily increased by 300kcal–400kcal every three to four days. Supplementing the diet with a liquid supplement in the early stages of refeeding to achieve the prescribed calorie goal is a very effective strategy to achieve large caloric intake and weight gain, note the authors. Some programmes recommend ultimately attaining an intake of 4000kcal/day-5000kcal/ day per day, while others recommend 3000kcal/ day-3600kcal/day. Mehler et al caution that even for normal weight adults, weight gain does not correlate exactly with the total excess calories ingested over basal requirements. Therefore, it may be difficult to precisely define the factors that consistently correlate with the number calories needed to gain one pound. The basal metabolic rate on admission is invariably low, but it begins to increase early on in the nutritional rehabilitation process. In general, starved anorectics are metabolically inefficient, and may require more than the expected 3500kcal/day beyond maintenance caloric needs to restore 0.5kg of body weight. The caloric requirement necessary for weight gain can vary between

Does nutritional supplementation have a role in the treatment of eating disorders?

1800kcal/day and 4500kcal/day. Some simple general rules to follow when considering refeeding are: The total energy expenditure should never exceed twice the basal energy expenditure Caloric intake should rarely exceed 70kcal/kg-80kcal/kg of body weight In the severely anorectic patient, begin a diet at 20kcal/kg to 25 kcal/kg Protein intake should not exceed 1.5gr/ kg-1.7gr/kg grams of body weight (generally in the 1gr/kg to 1.5gr/kg range) If TPN or EPN feedings are used, carbohydrate intake should not exceed 7 mg/kg/min Weight gain should be in the two to 1kg12kg per week range.

3 4

5 6

Table 2: Recommended ideal body weight chart

Height (cm)

Weight (kg)

Height (cm)

Weight (kg)

152

48.1

152

36.5

155

50.8

155

38.5

158

53.5

158

40.8

161

56.2

161

43.1

164

45.3

167

61.7

167

47.6

170

69.8

170

54.4

173

72.6

173

56.7

176

75.2

176

179

61.2

182

80.7

182

63.5

185

83.5

185

65.8

188

86.2

188

192

88.9

192

70.3

Source: https://handbook.bcehs.ca/ clinical-resources/clinical-references-cards/ ideal-body-weight-table/

Conclusions The prevalence of anorexia, bulimia and BED are increasing – especially among young women. Studies show that the majority of patients with bulimia, and about half of those with anorexia will recover. The road to recovery is long (on average nine years). One of the big challenges in the treatment of eating disorders is that patients take ten years or more before seeking help. Most patients can be treated in an outpatient setting. Hospitalisation should be reserved to correct serious somatic or psychiatric complications or as a measure to contain non-treatable situations. Patients with eating disorders have severe nutritional deficits. In patients with anorexia, nutritional rehabilitation using liquid supplements, have shown to be successful. The risk of refeeding syndrome should be assessed before this is attempted. References available on request. SF

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Efficacy of fixeddose, triple therapy in essential hypertension

Hypertension is the leading cause of mortality worldwide, accounting for more than 10 million deaths every year. The majority of deaths occur in low-and middle-income counties. An estimated one billion people in these countries have hypertension, according to the International Society of Hypertension (ISH).1

part from cardiovascular disease (CVD), people with hypertension are also at increased risk of diabetes (15%-20%), lipid disorders (elevated low-density lipoprotein-cholesterol and triglycerides [30%]), overweight/obesity (40%), hyperuricaemia (25%) and metabolic syndrome (40%). Hypertensive patients, who have one or more of these risk factors, have an additional risk of cerebrovascular and renal diseases.1

Essential versus secondary hypertension Hypertension diagnosis is based on: If the average of two or more diastolic blood pressure (BP) measurements on at least two subsequent visits is ≥90mmHg or when the average of multiple systolic BP (SBP) readings on two or more subsequent visits is consistently ≥140mmHg.3 In about 95% of cases, no clear cause can be determined. These patients are classified as having essential, also referred to as primary or idiopathic hypertension. According to the ISH, isolated systolic hypertension (defined as SBP ≥140mmHg and diastolic BP (DBP) <90mmHg) is the most common form of essential hypertension in young individuals, including children, adolescents, and young adults.1,3

In 5% of patients, an identifiable and potentially reversible cause can be identified. This is known as secondary hypertension. Secondary hypertension should be considered in the presence of suggestive symptoms and signs, such as:2 » Severe or resistant hypertension » Age of onset younger than 30 years (especially before puberty) » Malignant or accelerated hypertension » An acute rise in blood pressure (BP) from previously stable readings. Essential hypertension is defined as high BP in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary hypertension or mendelian forms (monogenic) are not present. Essential hypertension is defined as high blood pressure (BP) in which secondary causes are not present. 2,3

Suboptimal BP control According to the ISH, nonadherence to treatment recommended by a physician, is one of the main causes of sub-optimal BP control. These include for example taking medication, following a diet, or implementing lifestyle changes. Nonadherence to treatment is an indicator of poor prognosis in hypertensive patients.1

Some 45.2% of all hypertensive patients do not adhere to treatment. In uncontrolled patients, this number is much higher (83.7%). Studies show that 25% of patients do not buy all the medications prescribed by their physicians, 10% often forget to take the prescribed medication on a daily basis, 30% discontinue initial treatment after six months and 50% after one year.4 There are numerous reasons why patients do not adhere to treatment. These include for example: » Hypertension has no obvious symptoms, which led to the dubbing of the disease as the ‘silent killer’ » Patients do not understand their disease » Patients are often not involved in the treatment decision-making process and therefore do not understand the seriousness of their disease » Others stop treatment because of the side effects associated with some medications such as fatigue, headache, peripheral oedema, cough, allergy, polyuria, erectile and libido dysfunction, and metabolic changes.4 Physicians play an important role in addressing issues of nonadherence. Physician-related factors are very common, when prescribing complex drug regimens, when failing to explain

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the benefits and risks of the medication, and when disregarding the financial burden to the patient. Doctor-patient communication is crucial and should always be reinforced.4

One of the most effective strategies to improve adherence is the use of combination antihypertensive therapy. About 70% of hypertensive patients require the combination of at least two antihypertensive agents to reduce BP levels below the recommended goals.5 Combination therapy should be initiated in patients with SBP 20mmHg above the target or DBP 10mmHg above the recommended goal. 5 Combination therapy provides greater antihypertensive power than the use of high doses of monotherapy, adding several mechanisms of action that block various pathways of increased BP, in addition to providing greater protection to target organs

uncontrolled hypertension, and well tolerated, providing support for clinicians in choosing a fixed-dose triple combination over the freecombination of a RAAS inhibitor, a diuretic, and a calcium antagonist.6 Mourad et al conducted a four month, double-blind, randomised, controlled trial to demonstrate the superiority of perindopril/ indapamide/amlodipine single pill, over perindopril/indapamide after one month and to determine further up-titration efficacy and safety in patients with mild-to-moderate hypertension.7 After a one-month run-in period on perindopril/indapamide 5mg/1.25mg, patients with SBP/DBP at least 150/95mmHg and no diabetes or renal insufficiency, received perindopril/indapamide/amlodipine 5mg/1.25mg/5mg single pill or continued on the same treatment. 7 At one, two, and three months, patients with uncontrolled BP (SBP/DBP ≥140/90mmHg) were gradually up-titrated with a higher dose of

than monotherapy, and reduced potential for side effects. 5 Mazza and colleagues compared the efficacy of a fixed-dose triple combination therapy and a free combination of three antihypertensives in patients with uncontrolled hypertension.6 Participants (n=92) with uncontrolled essential hypertension previously treated with a renin-angiotensin-aldosterone system inhibitor, plus hydrochlorothiazide were switched to once-daily fixeddose triple combination therapy with perindopril/indapamide/amlodipine (5mg-10mg/1.25mg-2.5mg/5mg-10mg).6 Patients were age- and sex-matched with a control group of hypertensive patients receiving free combination therapy with three drugs including a RAAS inhibitor, a diuretic, and a calcium channel blocker. Office BP and 24-hour ambulatory BP monitoring (ABPM) were evaluated at baseline and after one and four months.6 The team reported significant reductions in ambulatory 24-hour, day-time, and nighttime SBP, and pulse pressure (PP) were found in the fixed-dose triple combination therapy group relative to reductions seen with free combination therapy, after the first month only of follow-up.6 Target BP values (mean 24-hour ambulatory SBP/DBP <130/80 mmHg) were reached by more recipients of fixed-dosed triple combination therapy group than free combination therapy (64.8% versus 46.9%) at month four of follow-up, despite reductions in 24-hour ABPM values from baseline being similar in both groups at this time point.6 They concluded that a fixed-dose triple combination therapy (perindopril/indapamide/ amlodipine) was effective at reducing SBP and PP in previously treated patients with

the triple therapy up to perindopril/indapamide/ amlodipine 10mg/2.5mg/10mg in both groups. 7 Efficacy was assessed on office supine SBP (main criterion) and DBP, BP control, and response rates. Treatment effect on ABPM and home blood pressure monitoring (HBPM) parameters was also assessed in two subpopulations of 276 and 263 patients, respectively. 7 A total of 454 hypertensive patients were randomised (227 to each group). After a month, superior SBP (-3.1mmHg) and DBP (-2.8 mmHg) reductions were observed with perindopril/indapamide/amlodipine, which were even more pronounced after excluding white-coat effect in the sustained hypertension population (-5.3mmHg/-3.7mmHg). 7 Similar results were observed in terms of BP response (72% versus 53%) and control rates (32% versus 25%). Up-titration was effective at each visit in both treatment arms. 7 Both ABPM and HBPM results confirmed the superiority of the triple therapy at a month on ASBP/ADBP and HSBP/HDBP (-4.5mmHg/2.0mmHg for ABPM, and -4.9mmHg/-3.1mmHg for HBPM. Up-titration steps resulted in further significant decreases in both ABPM and HBPM.7 The team concluded that perindopril/ indapamide/amlodipine in a single pill produces superior reductions in blood pressure compared with dual therapy. Triple therapy up-titration was well tolerated and effective leading to BP control rates of over 80%. Analysis of 24-hour ABPM and HBPM results corroborated these findings.7 In the Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients or PIANIST STUDY, Tóth et al evaluated fixeddose triple combination therapy (perindopril 10mg/indapamide 2.5mg/amlodipine 5mg or 10mg) in difficult-to-treat hypertension.

Combination therapy improves adherence

Box 1: Hypertension definitions, according to SAHS The following BP definitions are recommended by the South African Hypertension Society:9 BP SBP category*

DPB

Normal

<120mmHg

<80mmHg

Optimal

120–129mmHg <80mmHg

High normal

130–139mmHg 80–89mmHg

Grade 1

140–159mmHg 90–99mmHg

Grade 2

160–179mmHg 100–109mmHg

Grade 3

≥180mmHg

≥110mmHg

Isolated systolic

≥140mmHg

<90mmHg

* Individuals with SBP and DBP in two categories should be designated to higher BP based on two or more careful readings obtained on two or more occasions. 9 This was an observational, four-month, openlabel study (n=4731). 8 Patients at high or very high CV risk and suboptimal hypertension control were included. After four months of therapy, office BP (OPB) decreased by 28.3mmHg ± 13.5mmHg/13.8mmHg ± 9.4mmHg to 132.2mmHg ± 8.6/80.0mmHg ± 6.6mmHg. 8 BP targets were reached by 72% of patients and by 81% and 91% of patients previously treated with an angiotensin-converting enzyme inhibitor/hydrochlorothiazide or an angiotensin receptor blocker/ hydrochlorothiazide, respectively. 8 Changes in OBP were 18.7mmHg ± 8.3/9.7mmHg ± 7.2mmHg for grade 1, 30.4mmHg ± 10.1mmHg/14.7mmHg ± 8.6mmHg for grade 2, and 45.4mmHg ± 15.1mmHg/20.7mmHg ± 12.1mmHg for grade 3 patients. In patients who underwent AMBP monitoring, 24-hour mean blood pressure decreased from 147.4mmHg ± 13.8mmHg/82.1mmHg ± 11.9mmHg to 122.6mmHg ± 9.1mmHg/72.8mmHg ± 7.4mmHg.8 Tóth and team concluded that triple combination perindopril/indapamide/amlodipine was effectively and safely administered to a large population of high- and very high-risk hypertensive patients who had not reached target OBP values with previous treatment.8

Conclusion Hypertension is the leading cause of mortality worldwide. LMICs carry the highest burden. Despite the efficacy, safety and costeffectiveness of antihypertensive agents, nonadherence among patients is high, increasing the risk of CVD, morbidity, and mortality. One of the most effective strategies to improve adherence, is the use of fixed-dose combination therapy. References available on request. SF

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Rhythm control for ALL patients with early AFib

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Please note that th i s is a shorte ned ve rs of the a rticle. T ion h article is avail e full a bl our onl ine pla e on Systematic and early initiation of rhythm control therapy should be tform Medica part of the management of all patients with early atrial fibrillation (AFib) l Academ ic. who are at risk of concomitant cardiovascular diseases (CVDs).

his should be done in combination with oral anticoagulation and rate control, as well as the treatment of underlying CVDs. The risk of CV complications is increased during the first year after AFib is diagnosed. This is according to Prof Paulus Kirchhof, director of the department of cardiology at the University Heart and Vascular Center Hamburg (Germany), and professor of CV medicine at the Institute of CV Sciences at the University of Birmingham (United Kingdom). Prof Kirchhof is the lead author of the landmark Early Treatment of AFib for Stroke Prevention Trial (EAST-AFNET 4). He was one of the keynote speakers at the recent virtual Cardiac Arrhythmia Society of Southern Africa 2021 symposium. He provided a brief overview

of the findings of the trial, which was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient.

Take-home messages Early initiation of improved CV outcomes in patient with early AFib and CV conditions without affecting nights spent in hospital As expected, the early rhythm control strategy was associated with more adverse events related to rhythm control therapy but the overall safety of both treatment strategies was comparable These results have the potential to inform the future use of rhythm control therapy, further improving the care of patients with early AFib

Systematic and early initiation of rhythm control therapy should be part of the management in all patients with recently diagnosed AFib and concomitant CV conditions in addition to oral anticoagulation, rate control and therapy of concomitant CV conditions. Whenever you ask yourself if you should initiate anticoagulation therapy in a patient with AFib, you should from now on ask yourself if you need to initiate rhythm control therapy. Prof Kirchhof concluded that the cardiology community needs to relearn the art of prescribing anti-arrhythmic drugs, that has somehow disappeared from medical training curricula. That specialist knowledge needs to be reappreciated and reacquired, he emphasised. SF

Recommended as a treatment option for restoring and maintaining Sinus Rhythm (SR) in patients with Paroxysmal Atrial Fibrillation (PAF) and minimal or no structural heart disease1 European Society of Cardiology (ESC) Guidelines 2020

Signiﬁcantly reduces the number of AF recurrences in paroxysmal AF and the symptoms associated with AF 2

AF = Atrial Fibrillation References: 1. Gerhard Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). European Heart Journal 2020;00:1-126. 2. Aliot E, et al. Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation. Europace 2011;13:161-173. Scheduling status: Proprietary name and dosage form: Tambocor Tablets. Composition: Each tablet contains flecainide acetate 100 mg. Reg. No.: S/6.2/17. Scheduling status: Proprietary name Proprietary name and dosage and dosage form: Tambocor CR 100 Capsules. Composition: Each controlled release capsule contains flecainide acetate 100 mg. Reg. No.: 37/6.2/0199. Scheduling status: form: Tambocor CR 200 Capsules. Composition: Each controlled release capsule contains flecainide acetate 200 mg. Reg. No.: 37/6.2/0201. Scheduling status: Proprietary name and dosage form: Tambocor Injection. Composition: Each ampoule contains 15 ml of solution of flecainide acetate 10 mg/ml, for intravenous use only. Reg. No.: S/6.2/16. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd,. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No.: 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 15255L. IN4081/21.

15255L TAMB HALF PAGE Advert 185X148mm R.indd 1

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Probiotics for ‘belly button’ PAIN PAIN Paediatric functional abdominal pain disorders (FAPDs) are commonly seen in clinical practice. Up to 25% of all children and infants worldwide are affected. There is a relatively high risk of persistence of symptoms (29%) even after 10 years of follow-up or in adulthood. FAPDs negatively impact school performance and social relationships.1,2,4

ome IV defines FAPDs as episodic or continuous abdominal pain that does not occur solely during physiological events such as eating. Rome IV subclassifies FAPDs into a number of clinically distinct entities, namely irritable bowel syndrome (IBS), functional dyspepsia (FD), abdominal migraine and FAPDs not otherwise specified. See box 1 for the diagnostic criteria.1,4 The Rome IV definition states that a diagnosis of FAPD is likely after appropriate medical evaluations have failed to attribute symptoms to another medical condition.1

Presentation of pain According to the American College of Gastroenterology (ACG), children describe pain around the umbilicus (belly button). The pattern of abdominal pain however is difficult to predict. Location and severity may differ. For example, some children experience a sudden onset of pain, while others describe pain that increases slowly in severity. Some are in constant pain, while in others it comes and goes.3 Furthermore, symptoms may differ. Symptoms can range from upper abdominal pain associated with nausea, vomiting and early satiety, to bloating, indigestion, or experiencing abdominal pain with bowel movements.3 The ACG cautions that other possible causes

of FAPD should be investigated (eg acid reflux, lactose intolerance, parasitic infections of the small and large intestines, Helicobacter pylori infection that may cause ulcers in the first portion of the small bowel, celiac disease, food allergies, hepatitis, gall bladder problems, an inflamed pancreas, an intestinal obstruction, appendicitis, and some rare disorders) before a definitive diagnosis is made. 3

Development of functional abdominal pain McClellan and Ahlawat explain that the development of FAPDs is likely multifactorial. There appears to be sensitisation to the range of normal physiological sensations, which result in visceral hyperalgesia. For example, sensations such as bloating or indigestion may produce pain beyond what is typically experienced by non-affected individuals.4 An initial sensitising event (eg an infection, allergy, altered gut microbiome, or motility disorder) occurs first and later progresses to hypersensitivity. Psychosocial factors such as stress or comorbid anxiety and depression are also associated with the development of hypersensitivity.4

Risk factors Age does not seem to play a role in the onset

of FAPDs. Known risk factors include:1 » Sex: Young and adolescent girls are more affected than boys (15.9% versus 11.5%). Notably, this difference was also evident at a pre-pubertal age (10 years) (9.9% girls versus 7.7% boys) » Psychosocial factors: Several studies reported that children and adolescents with FAPDs have a poor mental health status and lower quality of life compared to healthy children. Up to 50% of children with FAPD are reported to have clinically relevant anxiety or depression.1 » Genetic factors: A family history of IBS and other FAPDs has been reported as an epidemiological risk factor. For IBS, a substantial overlap in the incidence of abdominal symptoms between mothers and their children has been described. This overlap might be related to certain genes but might more likely be due to a number of social factors, including attentive parental response to child pain behaviours.1

Management and treatment interventions According to Romano et al, current treatment strategies include:2 » Support and empathy for the family with reassurance that no serious disease is present

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» Medical management that includes dietary fibre, peppermint oil and antidepressants. With this approach, about 30%–40% of children have resolution of their symptoms. Thaphar et al note that the role of gut microbiota in the onset of FAPDs is increasingly being recognised and a number of interventions targeting gut microbiota, including probiotics, the low FODMAP diet, prebiotics, and antibiotics, are increasingly being used for the management of FAPDs.1

How effective are probiotics? Numerous studies have investigated the efficacy of probiotics in the management of FAPDs. Romano et al (2014) investigated the effect of daily supplementation with the probiotic Lactobacillus reuteri (L. reuteri) DSM 17938 in children with FAPDs. Children (n=60) aged between six- and 16-years who fulfilled the Rome criteria were included in this double-blind, randomised, placebo-controlled study. They were randomised to receive either L. reuteri or identical placebo for four weeks. Follow-up was four weeks without supplementation. Frequency and intensity of pain was self-recorded by participants. The team found that children in the L. reuterisupplementation group had significantly lower pain intensity compared with those in the placebo group. The team concluded that supplementation with L. reuteri reduced perceived abdominal pain intensity, which may encourage clinicians to use this probiotic in children with FAPD.2 Weizman et al (2016) also focused on the efficacy of L. reuteri in children (n=101) with FAPD. Children between the ages of six and 15 were randomised to receive either L. reuteri or placebo for four weeks. Follow-up was four weeks and the frequency and intensity of pain was self-reported. The team found that L. reuteri was significantly superior to placebo in relieving frequency (1.9 versus 3.6 episodes/week) and intensity (4.3 versus 7.2 score/week) of abdominal pain following four weeks of supplementation. L. reuteri was also associated with a lower incidence of perceived abdominal distention and bloating.5 Jadrešin et al (2017) looked at the effect of three months supplementation of L. reuteri in children (n=55) with FAPDs. Follow-up was 30days without supplementation. Children between four- and 18-years were randomised to receive L. reuteri daily, or placebo. Symptoms were evaluated using the Wong-Baker FACES rating scale and the Bristol scale for stool shape and consistency. They found that children in the L. reuteri group had significantly more days without pain (median 89.5 versus 51 days). Abdominal pain was less severe in children taking probiotics during the second month and fourth month. Both groups experienced significant reduction in the severity of abdominal pain from first to fourth month, with the reduction more prominent in the intervention group.6

Maragkoudaki et al’s (2017) study randomised children (n=54) with a confirmed diagnosis of FAPD to either L. reuteri or placebo for four

Box 1: Rome IV diagnostic criteria for FAPDs IBS The criteria must be fulfilled for at least two months and include all of the following: » Abdominal pain at least four days per month associated with defaecation and/or a change in the frequency of stool and/or a change in the appearance of stool » Abdominal pain does not resolve with resolution of the constipation (children in whom the pain resolves have functional constipation, not IBS) » After appropriate evaluation, the symptoms cannot be fully explained by another medical condition.

FD The criteria must be fulfilled for at least two months before diagnosis and must include one or more of the following bothersome symptoms at least four days per month: » Postprandial fullness » Early satiation » Epigastric pain or burning not associated with defaecation » After appropriate evaluation, the symptoms cannot be fully explained by another medical condition.

Abdominal migraine The criteria must be fulfilled for at least six months before diagnosis and include all of the following occurring at least twice: » Paroxysmal episodes of intense, acute periumbilical, midline or diffuse abdominal pain lasting one hour or more (should be the most severe and distressing symptom) » Episodes are separated by weeks to months. The pain is incapacitating and interferes with normal activities, stereotypical pattern, and symptoms in the individual patient » The pain is associated with two or more of the following: anorexia, nausea, vomiting, headache, photophobia, or pallor » After appropriate evaluation, the symptoms cannot be fully explained by another medical condition.

FAPD not otherwise specified The criterial must be fulfilled for at least two months before diagnosis and at least four times per month and include all of the following. » Episodic or continuous abdominal pain that does not occur solely during physiological events (for example, eating and menses) » Insufficient criteria for IBS, FD, or abdominal migraine » After appropriate evaluation, the abdominal pain cannot be fully explained by another medical condition.

weeks. They found that both L. reuteri and the placebo significantly reduced the frequency and intensity of abdominal pain episodes at four and eight weeks compared to baseline. However, L. reuteri decreased the use of pain-relieving drugs at four weeks and school absences at four and eight weeks, unlike placebo. They concluded that while both L. reuteri and the placebo were effective in alleviating pain in children with FAPD, only L. reuteri improved the child's and family's normal activities.7 Trivić et al (2021) reviewed evidence for the use of strain-specific probiotic in children with FAPDs. The review included nine randomised controlled trials (a total of 702 children, 506 with functional abdominal pain, four- to 18-years). Lactobacillus rhamnosus GG and Lactobacillus reuteri DSM 17938 were the only two probiotic strains investigated. Significant reduction in pain intensity and increase in number of days without pain were found in children taking L. reuteri. They concluded that L. reuteri was proven to decrease the pain intensity in children with FAPDs.8

Conclusion FAPDs negatively impact children’s quality of life. The onset of FAPDs is multifactorial. Girls are at higher risk of developing FAPDs. Other risk factors include psychosocial factors and a genetic predisposition. The role of gut microbiota in the onset of FAPDs is increasingly being recognised. Numerous studies have found that probiotics decrease frequency and intensity of pain in children with FAPDs.

References 1. Thapar N, Benninga MA, Crowell MD et al. Paediatric functional abdominal pain disorders. Nature Reviews Disease Primers, 2020. 2. Romano C, Ferrau V, Cavataio F et al. Lactobacillus reuteri in children with functional abdominal pain (FAP). J Paediatr Child Health, 2014. 3. American College of Gastroenterology. Functional abdominal pain in children https://gi.org/topics/ functional-abdominal-pain-in-children/ 4. McClellan N and Ahlwat R. Functional Abdominal Pain In Children. StratPearls (Internet), 2020. https://www.ncbi.nlm.nih.gov/books/NBK537298/. 5. Weizman Z, Abu-Abed J, Binsztok M et al. Lactobacillus reuteri DSM 17938 for the Management of Functional Abdominal Pain in Childhood: A Randomized, DoubleBlind, Placebo-Controlled Trial. J Pediatr, 2016. 6. Jadrešin O, Hojsak I, Mišak Z et al. Lactobacillus reuteri DSM 17938 in the Treatment of Functional Abdominal Pain in Children: RCT Study. JPGN, 2017. 7. Maragkoudaki M, Chouliaras G, Orel R et al. Lactobacillus reuteri DSM 17938 and a placebo both significantly reduced symptoms in children with functional abdominal pain. Acta Paediatrica, 2017. 8. Trivić I, Niseteo T, Jadrešin O et al. Use of probiotics in the treatment of functional abdominal pain in children-systematic review and meta-analysis. Eur J Pediatr, 2021. SF

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The way we respond to life’s stressors have strong implications for our psychological and physiological well-being. In terms of the latter, gastrointestinal (GI) function is particularly affected by stress.5

M3661 Exp: 03/2023

Disorders of gutbrain interaction

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ommon GI symptoms due to stress include heartburn, indigestion, nausea, vomiting, diarrhoea, constipation and associated lower abdominal pain.5

What is stress? According to the American Psychiatric Association, stress can be defined as “a sense of being overwhelmed, worried, pressured, exhausted, and lethargic”. Stress influences people of all ages, gender, ethnicity, and socioeconomic groups. 3,4,6 Studies show that 20%-90% of the general population is exposed to one or more extreme stressful event in their life. We are currently experiencing one of the most stressful periods in human history. Since the outbreak of Covid-19, the prevalence of stress has increased globally

These were the five biggests stressors for South Africans in 2020.

59% indicated that corruption was a major stressor

in the general population. Uncertainty, fear, and social isolation due to strict lockdown regulations, are some of the top stressors.1,2

What worries the world now? Global polling firm, Ipsos recently published the findings of their What Worries the World survey, which tracks public opinion on the most important social and political stressors across 27 countries. They found that:2 » 47% of respondents indicated that Covid-19 is one of the biggest issues facing their countries » 38% are stressed about unemployment » 29% said poverty and social inequality stress them the most » 27% expressed concerns about financial and political corruption » 26% were worried about crime and violence. In South Africa, the picture looks a bit different.

59% of respondents were stressed about unemployment

58% replied they were stressed about crime and violence

29% said poverty and social inequality were their biggest source of stress 24% were stressed about Covid-19.

But it is not always the ‘big’ issues that cause the most stress. Work-related stress has increased exponentially over the last century because of industrialisation and globalisation, according to the International Labour Organization. In Europe for example, between 50% and 60% of all lost working days were stress-related.9 A study by the American Institute of Stress found that 25% of workers viewed their jobs as the number one stressor in their lives, 80% felt stressed on the job, nearly 50% indicate that they needed help in learning how to manage stress, and 25% felt like “screaming or shouting” because of job stress.10 Apart from work-related stress, stress can also be triggered by everyday events such as a fight with a loved one or an exam. These are examples of external factors. It can also be caused by internal factors such as negative emotions and feelings (pain or sadness).5 A sudden or short-term, acute stressor provokes a fight or flight response – the brain’s way to ensure survival. When the stressor passes, negative feedback is triggered to terminate the stress response and to bring the body back to a state of steady internal, physical, and chemical conditions (homeostasis).8 However, some individuals do not achieve homeostasis, which may lead to the onset of psychiatric disorders (eg depression, anxiety, post-traumatic stress disorder [PTSD] or acute stress disorders), which in turn negatively affect physiological health (eg changes in GI functioning, brain activity, pain modulation, and the cardiovascular system).1,6,8

The gut-brain axis As mentioned already, GI function is particularly sensitive to stress. Early as well as late life stress have been linked to the onset, as well as the severity of symptoms in several chronic disorders of the digestive system. Patients with irritable bowel syndrome (IBS) and functional dyspepsia (FD) - two of the most common functional gastrointestinal diseases (FGIDs) – are particularly affected.5,6 The GI tract and central nervous system (CNS) constantly communicate with each other. This bidirectional relationship is influenced by a number of complex pathways including the immune system, the hypothalamic-pituitary axis (HPA), and gut microbiota. 5,6 Stress can result in overactivity or underactivity along the HPA and the autonomic nervous system, as well as the metabolic, and immune systems, resulting in alteration in braingut interactions, ultimately affecting different physiological functions of the GI tract.8 The prefrontal cortex, the limbic system (eg the hippocampus and the amygdala) and the hypothalamus are the main brain areas involved in the stress response. The amygdala is involved in the stress effect on the GI tract. The amygdala

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receives information from the gut, through the parabrachial nucleus and the dorsal vagal complex, and can modulate the sympatho-vagal balance, a marker of brain-gut interactions.7

Impact of stress on the gut Stress has been shown to cause slowing of gastric emptying, increase in distal colonic motility, and acceleration of intestinal transit. In IBS and FD, persistent alterations of autonomic responsiveness likely play a role in altered bowel habits and alteration in gastric emptying, respectively.6

Irritable bowel syndrome IBS affects 11% of the global adult population. IBS is characterised by abdominal pain, experienced on average at least once per week, and pain that is associated with two or more of the following characteristics: » Defecation » Changes in the frequency of stool » A change in the form of the stool. These characteristics should be present for at least three months, with symptom onset at least six months before diagnosis.11,13 The prevalence of IBS – especially IBSconstipation - is higher in women (60%-75%) than men. It has been postulated that the role of sex hormones in the stress response, colonic motility, epithelial barrier function, immune activation, and several regulatory mechanisms of the gut-brain axis, may account for this gender difference.11 Patients with IBS have a high prevalence (40%-80%) of at least one comorbid psychiatric condition (eg anxiety and depression). A 2013 study also showed that IBS patients experience an increase in stress prior to progression from an IBS non-patient to an IBS patient.11 The study found that stress caused by for example the end of a relationship, a divorce, or a family member leaving home, were frequently reported 38 weeks prior to the onset of IBS symptoms.11

Functional dyspepsia FD affects between 27%-40% of the general population. FD is characterised by the presence of permanent or periodic symptoms such as upper abdominal pain, nausea, a feeling of burning in the stomach area, fullness in the stomach and early satiety. Symptoms appear at least six months before diagnosis, last at least three months in the absence of an organic disease that explains the appearance of these symptoms.12,13 Numerous studies have investigated stress as a risk factor for the development of FD, but most studies focused on ‘big’ events rather than everyday stress. Deding et al’s study focused on the effects of everyday stress and whether it plays a role in the onset or FD, or whether it affects the severity of symptoms.12 Of the 23 698 participants, 2547 fulfilled the

Rome IV criteria for FD or IBS. The team found that FD patients had significantly higher median stress scores compared to controls and felt more stressed and more susceptible to stress.12 During the 33 months of follow-up, FD patients, who experienced the highest levels of self-perceived everyday life stress, visited their healthcare professionals more and filled more prescriptions compared to the other groups.12 The group with the second lowest stress level had an increased risk of FD of 1.16. The group with the third and second highest stress levels had an increased risk of 1.2 and the group with the highest stress level had an increased risk of 1.3.12 The proportions of FD patients in the stress level groups ranged from 11.6% to 24.9%. The researchers concluded that while stress play a role in the onset of IBS, in FD, stress affects symptom severity. Healthcare professionals should be aware of stress signals in patients with FD symptoms, noted the researchers.12

Treatment of stressrelated GI disorders Effective management of FGIDs requires a biopsychosocial approach, say the experts. The biopsychosocial approach focuses on the complex mix of environmental (eg influence of the patient’s family, the individual’s own psychological states and traits) and physiological factors.13,14 Healthcare professionals must consider and address all these factors to effectively manage FGIDs. The treatment plan should be guided by the nature of symptoms, severity, the presence of psychosocial comorbidities and their impact on the patient. The effectiveness of treatment largely depends on the patient–provider relationship.13,14 An effective patient–provider relationship improves patient and provider satisfaction, adherence to treatment, symptom reduction, and improved clinical outcomes.13 Stress modification, psychotherapy and hypnosis appear helpful for IBS and FD symptoms. Tricyclic antidepressants also appear effective for IBS and other functional bowel symptoms, even in low doses. Recent evidence indicates the medication may work by reducing the brain’s response to intestinal pain during stress. 5 Sedatives such as the benzodiazepine can reduce the effect of stress on the gut. Studies have shown that under stressful conditions, chlordiazepoxide blunted the colonic motor response to mental stress in IBS patients. This effect may explain the benefits of combined sedative-anti-spasmodic medications for IBS.5

Conclusion Stress has been shown to play a major role in FGIDs - especially in patients with IBS and FD. Short- and long-term exposure to stress can

trigger IBS and exacerbates symptom severity in FD. Healthcare professionals should take cognisance of the psychological ‘make-up’ of patients and incorporate strategies that addresses stress.

References 1. Fanai M and Khan MAB. Acute Stress Disorder. StratPearls (Internet), 2021. 2. Ispos. What worries the world today? https://www.ipsos. com/sites/default/files/ct/news/documents/ 2020-12/www-summary-december-2020.pdf 3. America Psyhological Association. What’s the difference between stress and anxiety? Knowing the difference can ensure you get the help you need. https://www.apa.org/ topics/stress/anxiety-difference 4. Shahsavari MA, Abadi EAM, Kalkhoran MH et al. Stress: Facts and Theories through Literature Review. International Journal of Medical Reviews, 2015. 5. Mertz H. Stress and the Gut. http://www.med.unc.edu/ ibs/files/2017/10/Stress-and-the-Gut.pdf 6. Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut, 2000. 7. Bonaz B, Pellissier S, Sinniger V et al. The Irritable Bowel Syndrome: How Stress Can Affect the Amygdala Activity and the Brain-Gut Axis. IntechOpen, 2012. 8. Qin H-Y, Cheng C-W, Tang X-D et al. Impact of psychological stress on irritable bowel syndrome. World J Gastroenterol, 2014. 9. International Labour Organization. Workplace Stress. https://www.ilo.org/wcmsp5/groups/public/---ed_ protect/---protrav/---safework/documents/publication/ wcms_466547.pdf 10. The American Institute of Stress. Workplace Stress. https://www.stress.org/workplace-stress 11. Carco C, Young W, Gearry RB et al. Increasing Evidence That Irritable Bowel Syndrome and Functional Gastrointestinal Disorders Have a Microbial Pathogenesis. Front Cell Infect Microbiol, 2020. 12. Deding U, Torp-Pedersen C, Boggild H et al. Perceived stress as a risk factor for dyspepsia: a register-based cohort study. European Journal of Gastroenterology & Hepatology, 2017. 13. Ivashkin VT, Poluektova EA, Glazunov AB et al. Pathogenetic approach to the treatment of functional disorders of the gastrointestinal tract and their intersection: results of the Russian observation retrospective program COMFORT. BMC Gastroenterology, 2020. 14. Black CJ, Drossman DA, Talley NJ et al. Functional gastrointestinal disorders: advances in understanding and management. The Lancet, 2020. SF

To com plete this mo nth’s C PD questio nnaire, please go www.m edicalac to ademic.c o.za and na vigate t o t he C PD s of the w ection ebsite.

WHEN ANXIETY AND STRESS CREEP IN, IBS SYMPTOMS 1 FLARE UP STRESS IS A SIGNIFICANT CONTRIBUTOR TO BRAIN-GUT AXIS DYSREGULATION IN IBS 1, 2, 3 Stress activates the HPA axis & the ANS which affects; 6 visceral sensitivity, gastrointestinal motility, and the gut microbiota. 1 This leads to the following IBS symptoms: 1 Abdominal pain* 7

recurring at least 1 day a week in the last 3 months

Bloating 7, 13 Changes in bowel habits* 7 Diarrhoea* and distension 7

Eating triggers symptoms 8 Feeling of incomplete evacuation 8 Gas or flatulence 7, 9 Having passing mucous in the stool 8

LIFE EVENTS THAT CAN LEAD TO STRESS: 4, 5 • • • • •

work problems at home financial problems marital separation death of a family member FOR STRESS-RELATED IBS

Librax® is the ONLY 2-in-1 antispasmodic & anxiolytic treatment for IBS 10 ACTIONS NORMALISES THE DYSREGULATION OF THE BRAIN GUT AXIS 11, 12

ACTIVE INGREDIENTS

CHLORDIAZEPOXIDE & CLIDINIUM BROMIDE

PRODUCT * Consider diagnosis of IBS 13 IBS = Irritable Bowel Syndrome; ANS = Autonomic Nervous System; HPA = Hypothalamic-Pituitary-Adrenal References: 1. Konturek PC, Brzozowski T, Konturek SJ. Stress and the Gut: Pathophysiology, Clinical Consequences, Diagnostic Approach and Treatment Options. Journal of Physiology & Pharmacology. 2011;62(6):591-599. 2. Prins A. The brain-gut interaction: the conversation and the implications. S Afr J Clin Nutr. 2011;24(3):S8-S14. 3. Kinsinger SW. Cognitive-behavioral therapy for patients with irritable bowel syndrome: current insights. Psychol Res Behav Manag. 2017;10:231-237. 4. Khatri M. WebMD. IBS Triggers and How to Avoid Them. Last reviewed 25 March 2018. Available at: https://www.webmd.com/ibs/ibs-triggers-prevention-strategies?print=true Last accessed 08 November 2020. 5. Qin H-Y, Cheng C-W, Tang X-D, Bian Z-X. Impact of psychological stress on irritable bowel syndrome. World J Gastroenterol. 2014;20(39):14126-14131. 6. Greenword-Van Meerveld B, Johnson AC. Mechanisms of Stress-induced Visceral Pain. J Neurogastroenterol Motil 2018;24:7-18. 7. Lacy B, Patel N. Rome Criteria and a Diagnostic Approach to Irritable Bowel Syndrome. J Clin Med. 2017;6(99) http://dx.doi.org/10.3390/jcm6110099 Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704116/ Last Accessed 08 November 2020. 8. National Institute for Health and Care Excellence (NICE). Irritable bowel syndrome in adults: diagnosis and management. Clinical guideline. Published: 23 February 2008. Available at https://www.nice.org.uk/guidance/cg61/resources/irritable-bowelsyndrome-in-adults-diagnosis-and-management-975562917829 Last accessed 08 November 2020. 9. Quigley E, Fried M, Gwee KA, Khalif I, Hungin P , Lindberg G, et al. Irritable bowel syndrome: a global perspective. World Gastroenterology Organization Global Guideline. Updated September 2015. Available at http://www.worldgastroenterology.org/UserFiles/file/guidelines/irritable bowel syndrome english 2015.pdf Last accessed 8 November 2020. 10. IMS Data October 2020. 11. Thakur AK, Shakya A, Husain GM, Emerald M, Kumar V. Gut Microbiota and Mental Health: Current and Future Perspectives. J Pharmacol Clin Toxicol 2014;2(1):1016. 12. CHLORDIAZEPOXIDE HYDROCHLORIDE AND CLIDINIUM BROMIDE- chlordiazepoxide hydrochloride and clidinium bromide capsule . Available at: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=98a991b9-2af3-4055-a16e-f784c7dbbb8a&type=display [Accessed 08 November 2020]. 13. Ford AC, Moayyedi P, Chey WD, et al ACG Task Force on Management of Irritable Bowel Syndrome. American College of Gastroenterology monograph on management of irritable bowel syndrome. Am J Gastroenterol 2018;113(Suppl 2):1-18. S5 Librax® (Tablets), B994 (Act 101/1965). Each tablet contains 5 mg chlordiazepoxide & 2,5 mg of clidinium bromide. For full prescribing information refer to the Professional Information approved by the Medicines Regulatory Authority. Mylan (Pty) Ltd. Reg. No.: 1949/035112/07. 4 Brewery Street, Isando, Kempton Park, 1600. Tel: (011) 451 1300 Fax: (011) 451 1400. www.mylansa.co.za M3648 Exp: 02/2023

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Diabetic nephropathy complexities

Hypertension is common among patients with diabetes. Hypertension increases their risk of chronic kidney disease (CKD) onset and progression, as well as cardiovascular (CV) morbidity and mortality.1,2

ore than 50% of patients with diabetes have hypertension, of whom 50% will develop some degree of renal impairment over time. A meta-analysis of 102 studies showed that patients with diabetes have a two-fold increase risk for CKD, coronary heart disease, major stroke, and mortality.1,3 In patients with diabetes, hypertension is defined as a systolic BP (SBP) ≥130mmHg or a diastolic BP (DBP) ≥80mmHg. The 2020 American Diabetes Association guideline recommends a BP target of <130/80mmHg for patients at high or very high CV risk (with atherosclerotic cardiovascular disease or 10year atherosclerotic CVD risk ≥15%), if it can be safely attained, while for those at lower risk for CVD (10-year atherosclerotic CVD risk <15%) a target of <140/90 mmHg is recommended.1,2,4

Diabetic nephropathy Kidney damage caused by diabetes – diabetic nephropathy – is the main cause of CKD and the leading cause of end stage renal disease (ESRD) in this patient population. 2,5 Although the mechanism of hypertension

in diabetic nephropathy is complex and incompletely understood, it has been postulated that it may be the result of excess sodium retention, activation of the sympathetic nervous and renin-angiotensin-aldosterone systems (RAAS), endothelial cell dysfunction, and increased oxidative stress. 2 The RAAS system plays a pivotal role in the regulation of BP. Apart from hypertension, the RAAS system is implicated in the pathogenesis and progression of numerous CV and renal pathologies, including structural cardiac remodelling, myocardial infarction, heart failure and CKD.6 Guidelines state that CKD can be attributed to diabetes in the presence of macroalbuminuria (>300mg/24 hr) or the presence of microalbuminuria (30mg300mg/24 hr) in the context of diabetic retinopathy or a history of diabetes exceeding 10 years. 2

Inhibition of RAAS system The inhibition of the RAAS system is the cornerstone of preventing diabetic neuropathy. The 2020 International Society of Hypertension

guideline recommends RAAS-inhibitors as first-line treatment in patients with diabetes and hypertension, because they reduce albuminuria in addition to BP. Calcium channel blockers (CCBs) and diuretics (loop-diuretics if estimated glomerular filtration rate <30 ml/ min/1.73m2) can be added, state the authors of the guideline.6,7 Angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEIs) are the two major RAAS inhibitors. ARBs have been in clinical use since 1995. The efficacy and safety of ARBs as a potent antihypertensive agent have been shown in numerous studies.6,8 ARBs have been shown to be more effective than other traditional agents in reducing the onset of clinical proteinuria in individuals with both Type 1 Diabetes (T1DM) and Type 2 Diabetes (T2DM) as well as incipient nephropathy.13 The aim of the Program for Irbesartan Mortality and Morbidity Evaluation was to determine whether ARBs are effective in both preventing the development of clinical proteinuria and delaying the progression of nephropathy in T2DM. It consists of two large

135/87

122/78

Numbers that Matter 117/74

125/82 128/86

142/97

9/10 SA hypertension patients have inadequately controlled hypertension 1

Renoprotective effects of irbesartan go beyond its effect on BP 2

References: 1. Berry KM, Parker W, Mchiza ZJ, et al. Quantifying unmet need for hypertension care in South Africa through a care cascade: evidence from the SANHANES, 20112012. BMJ Glob Health 2017;2:e000348. 2. Ravera M, et al. Prevention and treatment of diabetic nephropathy: the program for irbesartan mortality and morbidity evaluation. J Am Soc Nephrol 2005;16:S48–S52. S3 IRBEWIN® 150; 300 (tablets) respectively. Each tablet contains 150 mg; 300 mg of irbesartan respectively. Reg. No’s.: IRBEWIN® 150; 300: A40/7.1.3/0288; 0289 respectively. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority. Zentiva South Africa (Pty) Ltd, a sanofi company. Reg. no.: 1931/002901/07. Sanofi House, 2 Bond Street, Grand Central Ext. 1, Midrand, 1685. Tel: (011) 256 3700. Fax: (011) 256 3707. www.zentiva.com. MAT-ZA-2000439 - 1.0 - 08/2020

log on to www.sanofihealthconnect.co.za to join the Sanofi Hypertension Academy

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trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Irbesartan in Patients with T2DM and Microalbuminuria (IRMA), which evaluated the renal and CV effects of irbesartan on hypertensive patients with diabetes.13 Irbesartan is one of the oldest ARBs and most effective antihypertensives. It was patented in 1990 and was approved by the American Food and Drug Administration in 1997. In primary hypertension, irbesartan has been shown to lower BP blood over 24 hours. In many countries, including South Arica, irbesartan is approved for the treatment of nephropathy in patients with hypertension and T2DM. In the latter indication, 300mg once daily is the recommended maintenance dosage.12 According to Croom et al irbesartan is as effective as enalapril, atenolol and amlodipine in patients with mild-to-moderate hypertension, and more effective than valsartan in terms of absolute reduction in BP and response rates. 9 Irbesartan produced a greater reduction in DBP at trough than once-daily losartan. The reduction in SBP achieved with irbesartan was similar or greater than that with losartan and similar to that seen with olmesartan. 9 The combination of irbesartan with hydrochlorothiazide produced additive effects on BP reduction. Irbesartan also induced regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy. The team concluded that irbesartan is a valuable agent in the management of patients with these indications. 9

Slowing progression to diabetic nephropathy The IRMA trial showed that fewer patients, treated with 150mg/day and 300mg/day irbesartan compared to placebo, progressed to macroalbuminuria. Hazard ratios of 0.30 was recorded in the 300mg/day group and 0.61 in the 150mg/day group. 8 The IDNT trail found that patients in the irbesartan arm had a 37% lower risk of doubling the serum creatinine versus the amlodipine arm, and 33% lower than the placebo group. Development of ESRD was nominally lower with irbesartan compared with amlodipine. 8 Lewis et al investigated whether irbesartan or amlodipine, a CCB, or placebo can slow the progression of nephropathy in patients with T2DM independently of its capacity to lower the BP. They found that irbesartan was associated with a 23% lower risk of ESRD compared to amlodipine and placebo. Serum creatinine concentration increased slower in the irbesartan group compared to the amlodipine (21%) and placebo (24%) groups.

The authors concluded that irbesartan is effective in protecting against the progression of nephropathy due to T2DM and that protection was independent of the reduction in BP.10 Ros-Ruiz et al evaluated the effects of ultrahigh doses (600mg/per day) of irbesartan on proteinuria and renal function in patients with T2DM. Follow-up was three years. The team found that SBP and DBP decreased significantly at the end of follow-up. Serum creatinine increased by only 0.17mg/dl and proteinuria markedly decreased (59.2%). Some 25% of patients had normal albuminuria at the end of the follow-up period. Lipid profiles significantly improved. They concluded that treatment with ultra-high doses of irbesartan was highly effective and safe in reducing proteinuria and slowing progression to ESRD.11

has been shown to slow down progression to ESRD.

References 1. Ciobanu DM, Kilfiger H, Apan B et al. Resistant hypertension in type 2 diabetes: prevalence and patients characteristics. Clujul Med, 2015. 2. Van Buuren PN and Toto R. Hypertension in Diabetic Nephropathy: Epidemiology, Mechanisms and Management. Adv Chronic Kidney Dis, 2012. 3. Armario P, Blanch P, Castellanos P et al. Resistant hypertension in Diabetes. Journal of Endocrinology and Diabetes, 2020. 4. American Diabetes Association (2020). Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care, 2020. 5. Giorgini F, Vora J, Fenici P et al. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovascular Diabetology, 2020. 6. Forni V, Wuerzner G, Pruijm M et al. Long-term use and tolerability of irbesartan for control of

t abou s i on ensi alent in t r e Hyp as prev betes e ia twic s with d neral nt e ge patie ed to th ion par com populat

hypertension. Integrated Blood Pressure Control, 2011. 7. Unger T, Borgia C, Charchar F et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension, 2020. 8. Leoncini G, Viazzi F, de Cosmo S et al. Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations. Journal of Nephrology, 2020. 9. Croom KF, Curran MP, Goa KL et al. Irbesartan: a review of its use in hypertension and in the management of diabetic nephropathy. NEJM, 2004. 10. Lewis EJ, Hunsicker LG, Clarke WR et al.

Benefits of early initiation of irbesartan Palmer et al compared the effectiveness of early initiation at microalbuminuria, versus late initiation at overt nephropathy, of irbesartan 300mg/daily in patients with T2DM and renal disease. These strategies were compared with control, which consisted of antihypertensive therapy with standard medications (excluding ACE inhibitors, ARBs, dihydropyridine and CCBs). According to the authors, early irbesartan treatment improves life expectancy and reduces treatment costs in hypertensive patients with T2DM and microalbuminuria. Later initiation of irbesartan in overt nephropathy is also superior to standard care. Irbesartan should be started earlier and continued long term, concluded the authors.13

Conclusions Hypertension is common in patients with diabetes, increasing their risk of CVDs and renal dysfunction. Inhibition of the RAAS system has been shown to reduce these patients’ risk of progressing to CKD. ARBs are recommended as first-line therapy for patients at risk of CKD. Treatment of irbesartan

Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. NEJM, 2001. 11. Ros-Ruiz SR, Lara PA, Fernandes JC et al. High doses of irbesartan offer long-term kidney protection in cases of established diabetic nephropathy. Nefrologia, 2012. 12. Seedat YK, Rayner BL and Veriava Y. South African hypertension practice guideline 2014 Hypertension guideline working group: Cardiovasc J Afr, 2014. 13. Palmer AJ, Annemans L, Roze S et al. Costeffectiveness of early irbesartan treatment versus control (standard antihypertensive medications excluding ACE inhibitors, other angiotensin-2 receptor antagonists, and dihydropyridine calcium channel blockers) or late irbesartan treatment in patients with type 2 diabetes, hypertension, and renal disease. Diabetes Care, 2004. SF

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An overview of calcium phosphatebinders in CKD CKD

More than 9% of the global population were diagnosed with all-stage chronic kidney disease (CKD) in 2017. The global mortality rate from CKD increased by 41.5% between 1990 and 2017.1

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bout 1.2 million deaths were directly related to CKD, while an additional 1.4 million cardiovascular disease (CVD) deaths were attributed to impaired kidney function.1 This is according to the authors of the Global Burden of Disease Study (GBDS) (1990-2017), published last year. The authors noted that the prevalence of CKD in sub-Saharan Africa was much higher than expected.1 The above-mentioned numbers show that more people were living with CKD in 2017 than those with diabetes, osteoarthritis, chronic obstructive pulmonary disease, asthma, or depressive disorders. In addition, CKD resulted in more deaths than tuberculosis or HIV, and equalled the number of deaths due to road injuries.1 CKD was ranked the 12th leading cause of mortality in 2017, up from 17th place in 1990. According to the authors, prevention of CKD lags behind other non-communicable diseases.1

What causes CKD? Impaired fasting plasma glucose (57.6%), hypertension (43.2%), high body-mass index (26.6%) and a diet high in sodium (9.5%) were identified as the main risk factors for CKD.1 Three diseases were identified as the main causes of CKD:1 » Diabetes (30%) » Glomerulonephritis » Hypertension

CKD as a risk factor CKD is categorised as stages 1–2, stage 3, stage 4, and stage 5, end-stage kidney disease (ESKD) on maintenance dialysis, and kidney transplantation (see Table 1). According to the report patients with stage 1 to 5 CKD are at risk for CVD, stroke, peripheral vascular disease, and gout.1

Hyperphosphatemia: Prediction of CVD and mortality Hyperphosphatemia, abnormally high serum

phosphate levels, which results from increased phosphate intake, decreased phosphate excretion, or a disorder that shifts intracellular phosphate to extracellular space, is commonly seen in patients with CKD. In patients with ESRD, the prevalence of hyperphosphatemia varies from 50% to 74%. 2,3 The condition is characterised by elevated parathyroid hormone (PTH) levels and is an independent predictor of CVD and mortality in patients with advanced CKD. Hyperphosphatemia is present long before the need for dialysis arises. 9 Hyperphosphatemia, in general, can be caused by:2 » Renal failure: The most common cause of hyperphosphatemia. An eGFR <30ml/ min significantly reduces the filtration of inorganic phosphate, increasing its serum level » High intake of phosphate: Due to excessive use of phosphate-containing laxatives or enemas, and vitamin D intoxication. Vitamin D increases intestinal phosphate absorption » Hypoparathyroidism, acromegaly, and thyrotoxicosis: Enhance renal phosphate reabsorption resulting in hyperphosphatemia » Genetic causes: Several genetic deficiencies can lead to hypoparathyroidism, pseudohypoparathyroidism, and decreased FGF-23 activity. Apart from hyperphosphatemia, CKD can also lead to a number of other chronic disturbances of calcium-phosphate homeostasis, collectively known as CKD mineral and bone disorder (CKD-MBD).4 These metabolic abnormalities lead to arterial intimal and medial calcification, which are associated with CV events. Abnormal bone turnover, architecture and mineralisation result in reduced bone quality and density, with increased risk of fracture.4

Reducing the phosphate load The latest Kidney Disease Outcomes Quality Initiative (KDOQI) guideline (2017) recommends

Table 1: CKD staging definitions in the GBDS and correspondence with Kidney Disease Outcomes Quality Initiative (KDOQI) categories Stage

Definition

KDIGO category

CKD stages 1 and 2

Estimated glomerular filtration rate (eGFR) ≥60 mL/min per 1·73 m2 and ACR ≥30 mg/g (not including kidney transplant recipients)

G1–G2, A2–A3 (not including kidney transplant recipients)

Prevalence

CKD stage 3

eGFR 30–59 mL/min per 1·73 m2 (not G3a–G3b, A1–A3 (not including including kidney transplant recipients) kidney transplant recipients)

3.9%

CKD stage 4

eGFR 15–29 mL/min per 1·73 m2 (not G4, A1–A3 (not including including kidney transplant recipients) kidney transplant recipients)

0.16%

CKD stage 5

eGFR <15 mL/min per 1·73 m2 (not including kidney transplant recipients or patients treated by dialysis)

G5, A1–A3 (not including kidney transplant recipients or patients treated by dialysis)

0.07%

ESKD

Kidney transplant recipients and patients treated by dialysis

Not applicable (classified according to G category, with use of a D or T modifier)

that in patients with stage G3a–G5, serum phosphate should be maintained in the normal range (1.12mmol/L to 1.45 mmol/L).6 In patients with CKD G5D (signifies kidney failure treated by dialysis), the guideline recommends lowering elevated phosphate levels toward the normal range.6 Gastrointestinal phosphate binders are one of the most widely prescribed medications used in CKD (eGFR stages 3-5). These agents lower serum phosphate by reducing intestinal absorption of dietary phosphate, without negatively impacting nutritional status. 3,5,6 The Current Management Of Secondary Hyperparathyroidism: A multicentre Observational Study showed a 22% reduction in all-cause mortality and a 29% reduction in CV mortality in patients treated with phosphate binders. The Dialysis Outcomes and Practice Patterns Study results, showed a 25% reduction in mortality in patients prescribed phosphate binders.7

Types of phosphate binders There are three main types of phosphate binders available:3 Calcium-containing binders

Aluminium-containing binders

Noncalcium-based binders such as sevelamer, lanthanum and sucroferric oxyhydroxide). Calcium and aluminium-containing binders have been used for many years and are relatively cheap compared to noncalciumcontaining binders. 3 According to the KDOQI guideline, it is logical to initiate phosphate binder therapy when: Serum phosphorus levels are elevated, even though the patient is compliant with a dietary phosphate restriction The serum phosphorus levels can be controlled by a dietary phosphate restriction only, but such dietary intervention hinders the intake of other critical nutrients PTH blood levels remain elevated after dietary phosphate restriction, even if the serum phosphorus levels are not elevated.

Calcium-based binders Calcium-based binders include calcium carbonate and calcium acetate and have historically been the first choice, because they also address hypocalcemia, often seen with hyperphosphataemia. 3,8 As mentioned, calcium-containing binders are relatively inexpensive and patients tend to have calcium serum levels in the lower or even below the normal range. 3,8

A SUPPLEMENT WITH PHOSPHATE BINDING POTENTIAL B-CAL ® SA’s No. 1 Prescribed Calcium Range 1

500 mg

Additional benefits

Individuals that may benefit

Calcium

A calcium supplement that provides phosphate binding potential for individuals with kidney impairment2

- Calcium carbonate acts as a phosphate binder in patients with kidney disease.3 Taken with meals or snacks the calcium carbonate binds to the phosphate from the meal and excretes it though the digestive tract before it travels to the blood,2 therefore bypassing the kidneys and alleviating hyperphosphatemia 2

Dosage form

- In addition, calcium carbonate raises serum calcium levels and therefore may assist patients with hypocalcemia.3

Chewable tablets

Dosage and directions for use Suitable for Vegetarians

Chew 1-2 tablets daily with a meal

This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare provider. References: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT NOV 2020. 2. National Institute of Diabetes and Digestive and Kidney disease. Chronic Kidney Disease- Mineral and Bone. [Internet]. 2016. Available from: http://www. niddk.nih.gov/health-information/health-topics/kidney-disease/chronic-kidney-disease-mineral-and-bone-disorder/Pages/facts.asp. 3. Slatopolsky E, Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis, 1986 JUL 17;315(3):157-61. Proprietary name (and dosage form): B-CAL® Tablets. Composition: Each tablet contains: 500 mg Calcium. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information available on request from iNova Pharmaceuticals. IN1377/21

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March 2021 | Vol. 21 No. 3 www.medicalacademic.co.za

Because of its efficacy in lowering phosphates, the KDOQI guideline recommends that calcium-based phosphate binders may be used as initial binder therapy.6 In CKD patients with kidney failure (stage 5), the guideline recommends both calcium-based phosphate binders and other noncalciumbased binding agents as primary therapy.6 In dialysis patients who remain hyperphosphatemic (serum phosphorus >1.78mmol/L) despite the use of either of calcium-based phosphate binders or other noncalcium-containing phosphate-binding agents, a combination of both should be used.6 It is recommended that total elemental calcium intake, including dietary calcium, calcium supplementation, and calcium-based phosphate binders, be kept in the range of 800mg/d to 1000mg/d for patients with CKD G3-G4 to maintain a neutral calcium balance.6

Does calcium increase vascular calcification? Over the past few decades debates have been raging about the link between dietary calcium intake, calcium supplementation and vascular calcification. As a result, many nephrologists are uncertain whether to still use calciumcontaining binders, according to O’Neill. 9 O’Neill argues that hyperphosphatemia and calcium balance might ‘appear’ to contribute to vascular calcification, but the latter is actually determined primarily by factors in the microenvironment of the vessel wall that both inhibit and promote it, not by spontaneous precipitation of calcium phosphate. 9 More importantly, he says, longitudinal

studies have not shown any correlation between progression of vascular calcification and calcium phosphate in patients with renal failure.9 Pana et al (2020) conducted a meta-analysis to determine whether there is a link between calcium intake, calcium supplementation, CVD, and mortality in the British population. Their findings show that calcium supplement users had a lower incidence of myocardial infarction (MI) and peripheral vascular disease compared to those who did not use calcium supplements.10 Outcomes of different dosages were compared with calcium intake of 770mg/day. This is what they found for each of the dosages:10

viewarticle/23205 3. Chan S, Au K, Francis RS et al. Phosphate binders in patients with chronic kidney disease. Aust Prescr, 2017. 4. Sekercioglu N, Thabane L, Martinez JPD et al. Comparative Effectiveness of Phosphate Binders in Patients with Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis. PLoS One, 2016. 5. Scialla JJ, Kendrick J, Uribarri J et al. State-ofthe-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective. American Journal of Kidney Disease, 2020. 6. Ketteler M, Block GA, Evenepoel P et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what’s changed and why it

Conclusion According to Genovesi and Gallieni, one cannot assume that all oral calcium medications are the same, and timing of the oral dose (with or without food) might influence intestinal calcium absorption. They recommend a maximum dose of 1000mg elemental calcium, which they describe as a more prudent, opinionbased recommendation in CKD patients, especially if they already show signs of extraskeletal calcification or if they present CV comorbidities.11

matters. Kidney Int, 2017). 7. Hruska KA, Mathew S, Lund R et al. Hyperphosphatemia of chronic kidney disease. ISN, 2008. https://www.kidney-international.org/action/ showPdf?pii=S0085-2538%2815%2953280-8 8. Ketteler M. Phosphate Metabolism in CKD Stages 3–5: Dietary and Pharmacological Control. International Journal of Nephrology, 2011. 9. O’Neill WC. The fallacy of the calciumphosphorus product. Kidney International, 2007. https://www.kidney-international.org/article/ S0085-2538(15)52740-3/fulltext 10. Pana TA, Dehghani M, Baradaran HR et al. Calcium intake, calcium supplementation and cardiovascular

References

disease and mortality in the British population:

1. Bikbov B, Purcell C, Levey AS et al. Global, regional,

EPIC-norfolk prospective cohort study and meta-

and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global

analysis. European Journal of Epidemiology, 2020. 11. Genovesi S and Gallieni M. Cardiovascular

Burden of Disease Study 2017. The Lancet, 2020. 2. Goyal R. Hyperphosphatemia. StratPearls (internet), 2021.https://www.statpearls.com/ArticleLibrary/

complications of calcium supplementation in chronic kidney disease: are there arrhythmic risks? Expert opinion on drug safety, 2014. SF

Table 2: Calcium intake and mortality Intake

Findings

771mg/day–926mg/day

ñ Associated with lower all-cause mortality, decreased CV mortality and rate of incident stroke ñ Amongst men, higher daily calcium intake (≥771 mg/day) was associated with 26%–40% lower risk of CV mortality ñ No statistically significant associations between calcium intake and CV mortality amongst women ñ In men, associated with a 14%–24% decreased risk of incident stroke ñ No statistically significant relationship between calcium intake and the risk of stroke in women ñ Associated with a 27%–30% lower risk of all-cause mortality in women having ever used hormone replacement therapy (HRT) at baseline

1074mg/day-1254mg/day

ñ Associated with lower all-cause mortality, no associations with all-cause or CV mortality, an a decreased rate of incident stroke ñ In men, associated with a 14%–24% decreased risk of incident stroke ñ No statistically significant relationship between calcium intake and the risk of stroke in women ñ Associated with a 27%–30% lower risk of all-cause mortality in women having ever used HRT at baseline

1074mg/day-1254mg/day

ñ Associated with lower all-cause mortality, decreased CV mortality and rate of incident stroke ñ Associated with 14–24% decreased risk of incident stroke ñ In men, associated with 14–24% decreased risk of incident stroke ñ No statistically significant relationship between calcium intake and the risk of stroke in women ñ Associated with a 27%–30% lower risk of all-cause mortality in women having ever used HRT at baseline

≥1255mg/day

ñ No associations with all-cause mortality ñ No associations between calcium intake and incident CVD, incident aortic stenosis, incident cardiac failure, incident MI or incident peripheral vascular disease ñ 75% decrease in the risk of incident aortic stenosis in participants without hypertension or diabetes

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This article was independently sourced by Specialist Forum.

There's something new in the AIR AIR Before considering the role of a new agent to treat and improve care of allergic rhinitis (AR), it seems wise to follow the immunological journey from exposure to an antigen to the final overwhelming inflammatory cascade it creates. But first, let’s consider why some of us become allergic. New thoughts on the origin of allergy: Foetal origins A TH2-like cytokine profile maintains the pregnant state. In fact, atopic compared to nonatopic mothers are more likely to have several children. The newborn destined to become atopic has low levels of interferon gamma and this continues to occur over the first two years of life. The cause of this defect remains to be discovered. In addition, the foetus is capable of mounting allergen–specific responses from 23 weeks of gestation. Why we all do not become atopic is probably due to deletion of allergen–reactive T-cells from the host by anergy or apoptosis as a consequence of high-dose antigen exposure in the gut and the development of oral tolerance.

The gastrointestinal flora at birth An important part of postnatal regulation of immunoglobulin E (IgE) reactivity seen at birth, may be the acquisition of the appropriate commensal gut flora (also known as the microbiome). There is evidence for this in both mouse and man. Studies comparing the gut commensal flora of neonates from Sweden (with its high prevalence of allergic disease) to those from Estonia (low prevalence of disease) found less intensive colonisation with lactobacilli in Swedish children and more frequent clostridia. In addition or alternatively, there may be impaired recognition and response to bacterial products derived from the microbiome in children who develop atopic disease. The gut flora is required for successful oral tolerance as gramnegative products such as lipopolysaccharides stimulate tissue macrophages to produce anti-TH2 cytokines, IL-1 and TNF-alpha.

The ‘hygiene hypothesis’ Since atopic children have lower circulating levels of interferon gamma, greater exposure to bacteria or their products during early life may increase interferon gamma. Factors that have damped down this mechanism include: » Improvements in public health and hygiene » Changes in infant diets » Early use of antibiotics » Elective caesarean section » Reduced exposure to bacteria with smaller family sizes (less siblings). Several studies have demonstrated an inverse relationship between atopy, seasonal AR (and asthma) and size of family. A possible explanation for this phenomenon may be the TH1/TH2 paradigm. In children living in small families where infections are less common, TH2 cells may develop instead of TH1 cells. As a consequence, IgE responses are produced. In children of large families, where infections are common, the immune system may be TH1

By Prof Robin J Green, Department of Paediatrics and Child Health, University of Pretoria

cell orientated. Atopy is also less common in individuals who grow up in a farming environment and here exposure to a less sterile environment is the postulated explanation.

Allergens and IgE For antigens/allergens to trigger an immunological event they are required to be presented to T lymphocytes. In the airway such antigen-presenting cells (APC) are known as dendritic cells. Dendritic cells are formed from blood monocytes and move to the epithelium of the airway under the influence of chemokines. The antigen-containing dendritic cells then move into regional lymph nodes where interaction with T cells occurs. Within the APC, peptide components of the antigen combine with HLA Class II molecules and are expressed on the surface of the cell. It is this complex which T cells recognise and bind to via the T cell receptor. This bonding is further augmented by cellular adhesion molecules of the immunoglobulin super-family class. (Figure 1).

Figure 1: Antigen presentation to T-cells and resultant activation of mast cells

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CD4+ cells collaborate with neighbouring B cells to produce IgE through the process of immunoglobulin class switching. This process requires not only physical contact between T and B cells (cognate interaction) but also simulation of B cells by cytokines, especially interleukin (IL)-4 but also IL-5, IL-6 and IL-13. Recently it has been shown that CD4+ T cells in fact comprise two groups of cells, the so-called TH1 and TH2 populations. These two sets of T helper cells secrete different cytokines. The TH2 population produces the cytokines which augment IgE production, while TH1 cells suppress IgE production by B lymphocytes. Clearly, atopic individuals have a TH2 subset, and exciting possibilities may exist in this regard for prevention of atopy.

Cells in allergy The mast cell is the primary cell active in allergy induced inflammation. Mast cell granules contain and subsequently release mediators such as histamine, prostaglandin D2, leukotrienes C 4 and D 4, thromboxane A 2, and platelet activating factor. Mast cells also appear to be an important source of the cytokines which stimulate IgE synthesis viz IL‑4, IL-5 and IL-6. Eosinophils also play a pivotal role in allergic inflammation, probably controlling the late phase of these conditions. Their presence in the airway epithelium is a result of a complex interaction of adhesion molecules, chemokines, cytokines and other pro-inflammatory mediators. The nett result of eosinophil activation is the release of a number of products which produce disease. Of all the products of the eosinophil, the granule proteins are most well-known. The T lymphocyte (especially TH2) also plays an important role in allergy, from the induction of IgE production to the elaboration of controlling cytokines.

Cytokines and chemokines The various cells, which orchestrate allergy, communicate with one another through a group of molecules that allow this cell-tocell communication and thereby facilitate immune and inflammatory responses. Initially thought to be produced only by the cells of the specific immune and haematological systems, they are now known to be produced by many cells. Chemokines are cytokines with potent chemotactic function, attracting cells to the site of inflammation. Cytokines include the lymphokines, monokines, interleukins, interferons and haemopoietic growth factors, and are low molecular weight proteins with a short half-life. IL-5, together with IL-3 and granulocyte

Table 1: AR: Major symptoms and responsible mediators Pathological event Symptoms elicited

Mediator(s) responsible

Pruritus

Tickling, palatal ‘clicking’

Histamine (H1), prostaglandins

Mucosal oedema

Nasal obstruction

Histamine (H1), eicosanoids, kinins, prostaglandins

Sneezing

Sneezing or feeling of the need to sneeze

Histamine (H1), eicosanoids

Mucus secretion

Runny nose, postnasal drip

Histamine (H1 ± H2), eicosanoids, muscarinic discharge

Late-phase allergic reactions

Congestion, nasal hyperirritability

Inflammatory factors, eicosanoids, chemotactic factors

macrophage colony stimulating factor (GMGSF), enhance eosinophil activity. Other cytokines such as IL-2, IL-8, and RANTES have recently been shown to be eosinophil chemoattractants. Other cytokines, implicated in IgE synthesis, include IL-4, IL-5 and IL-6, whereas interferon γ (IFNγ), IL-8, and IL-12 are inhibitory. A number of different cytokines are therefore involved in allergy, the important specific cytokines being IL-5 (with IL-3 and GM-CSF) in eosinophil activation, and IL-4 in IgE regulation in atopic disease. Clearly other cytokines are implicated and, while targeting single mediators may be of value, an understanding of the cell/s of origin, and control of cytokine synthesis in allergic disease will be essential for future therapeutic intervention.

Pathogenesis of allergic rhinitis Within the nasal mucosa a process occurs with allergen exposure, with a range of inflammatory cells present. Mast cells are found, bearing specific IgE directed against allergens. Contact by allergen leads to degranulation and the release of inflammatory mediators. Basophils also migrate into nasal mucosa and nasal secretions and are activated in similar fashion to mast cells. Eosinophils also play a crucial role, with release of a large number of inflammatory mediators. In rhinitis, as in asthma, pathophysiological responses can be divided into early/immediate and late-phase responses. The early-phase occurs immediately after degranulation of both mast cells and basophils, with many of the responses attributable to histamine, which acts through its H1 receptor. The late-phase occurs four to 24 hours after mast cell degranulation, and eosinophils are probably most important. Chronic, ongoing nasal hyperreactivity during allergen exposure is the result of accumulation of neutrophils in the nasal mucosa as part of the late-phase allergic reaction. The late-phase response manifests mainly as nasal obstruction, and probably results from cellular infiltration.

Inflammation of the nasal mucosa is a function of epithelial cell damage, mucous production and cellular infiltration. The sources of nasal secretions (mucous) are vascular exudation, submucosal gland secretion and secretion from goblet cells (Table 1).

Phases of allergy Following exposure to an allergen or physical trigger factor, allergic pathology, and consequent symptoms progress in an orderly fashion through a number of phases. Within minutes of exposure, the earlyphase begins. In the upper airway this is mainly a function of mast cell activity. The early-phase may last some hours and may resolve spontaneously. The early-phase is usually followed some hours later by the late-phase, in which eosinophils and other cells produce the classic inflammation described before. Chronic rhinitis with unresolved inflammation is the usual scenario in an untreated or partially-treated patient.

Clinical significance Rhinitis is defined as inflammation of the lining of the nose with the occurrence of nasal congestion, itching, sneezing and/or watery or mucoid rhinorrhoea. There are many different stimuli, usually inflammatory, due to allergens, infections, chemicals, medications, or irritants. However, occasionally rhinitis is non-inflammatory, resulting from cold air, spicy foods, or strong odours. Atopy is of paramount importance in allergic rhinitis, with both genetic and acquired components. The triggers are usually inhalant allergens. Aero-allergens are usually derived from natural organic sources such as house dust mite, pollens, mould spores, insect emanations and animals. Particle size is usually 2-60μm diameter, and allergens are usually proteins of MW 10 000-40 000 daltons. Clearly the most important message from our understanding of the pathophysiology of allergic diseases such as AR is that this is an inflammatory disease, and only by treating

NEW S3

•

for Allergic Rhinitis 1

•

Immediate and sustained relief 2

•

Works within 10 - 15 minutes 2

Multi-Tasking RAPID Relief References: 1. Ryaltris® Professional Information. May 2020. 2. Patel P, Salaptek AM, Tantry SK. Effect of olopatadine-mometasone combination nasal spray on seasonal rhinitis symptoms in an environmental exposure chamber study. American College of Allergy, Asthma & Immunology. 2019;122:630-638. S3 RYALTRIS® (Nasal spray). Reg. no. 53/21.5.1/0457. Each spray delivers 600 µg olopatadine (as olopatadine hydrochloride) and 25 µg mometasone furoate (as mometasone furoate monohydrate). Contains the preservative benzalkonium chloride 0.02 % w/w. Sugar free. For full prescribing information refer to the professional information approved by the South African Health Products Regulatory Authority. Date of publication: 5 May 2020. HCR: Glenmark Pharmaceuticals South Africa (Pty) Ltd. First Floor, Block A, 34 Monte Carlo Crescent, Kyalami Park, Midrand, 1684. P.O. Box 5537, Halfway House, 1685. Tel: +27 (0) 11 564 3900. F: +27 (0) 11 564 3939. www.glenmarkpharma.co.za. ZAR/09/2020/03

Glenmark, touching the lives of patients for over three decades.

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Figure 2: Inflammation is the central issue in AR

Symptoms Signs Inflammation

Complications

previous diagnoses are post-nasal drip, sinusitis, and catarrh. Clinical features of hay fever are allergic facies characterised by pallor, allergic shiners, mouth breathing and a nasal crease (Figure 3). The eardrums can be dull and retracted, the nasal mucosa pale (or hyperaemic) and swollen with mucous, and the throat may have a granular pharyngitis with post-nasal drip. This pharyngitis is characterised by hyperaemic mucosa with raised blebs of shiny mucosa.

Confirmation of the presence of atopy inflammation can any successful attempt be made to prevent morbidity (Figure 2). Anti-inflammatory treatment will prevent inflammation to environmental factors and reduce both early and late reactions, whereas antihistamine therapy will alleviate early symptoms but have less effect on inflammation. The evidence presented suggests that in

Tests available to investigate the presence of atopy are: Í Total IgE This is often used as a screening test, but its use is limited because: » Normal reference values are not available for all populations, it has poor sensitivity and specificity

South Africa we face an allergy explosion or epidemic. The effects of our man-made environment are responsible for much of this.

» Non-allergic conditions (eg parasitic infestations) can produce elevations. (The same limitations apply to the absolute eosinophil count). Í Phadiatop® This is the most reliable in vitro test for screening of patients for sensitivity to inhaled allergens. The sensitivity in South African children is 100% and specificity is 90%. It does not detect and is therefore not influenced by parasitic IgE. Disadvantages are: » Only a positive or negative result is obtained, without identification of the specific aero-allergens » Cost!

History and examination A thorough history is the cornerstone of assessment, particularly in young children some other tests are not possible. Children with AR can be either ‘runners’ or ‘blockers’. Presenting symptoms of hay fever are: Blockers: Blocked nose, post-nasal drip, always clearing throat, rings under eyes (allergic shiners), always rubs nose (allergic salute), snores, restless sleeper, tired and irritable during the day, learning problems, sore throat, halitosis, mouth breathing, sore stomach (mucous gastritis), occasional diarrhoea. Runners: Runny nose, sneezing, itchy and red eyes, frequent colds. Associated features are frequent tonsillitis, history of tympanostomy, tonsillectomy, adenoidectomy, or sinus operations. Frequent

Identification of the specific allergen Tests available to investigate allergy are either in vitro (RAST®) or in vivo SPT (skin prick test).

Í Radio-allergo-sorbent test (RAST ®) The RAST®, which tests for allergen-specific IgE, can be used either for single individual allergens or for mixes of similar related allergens. In practice, patients may react to groups of allergens, to cross-reacting allergens, or only to individual allergens within a specific group. For this reason, mixed-allergen tests have been developed. Four hundred and sixty individual allergen and 66 mixed-allergen RASTs are available. A thorough history will guide one to careful selection of the correct tests to perform. Í Skin prick test The skin prick test (SPT) is regarded as the gold standard for the diagnosis of allergy. It has many advantages over the in vitro tests: » Reliability, particularly for aero-allergens » Easy to perform in the doctor’s consulting rooms » Rapid results (within 10-15 minutes) » Low cost.

Evaluation of the patient’s environment When taking an allergy history, specific questions about the environment should include: Í Cigarette smoking (active or passive) Í Animal contact (especially cats) in the home, neighbour, school etc Í Feathers in the patient’s bed (pillows or duvet) Í Abundant fluffy toys Í Proximity of home to water (in drier regions of South Africa, living near water may be associated with higher house-dust mite (HDM) counts, and consequent greater sensitivity).

Rhinitis management As stated previously, market research recently conducted in the metropolitan areas of South Africa on a sample of two thousand respondents has indicated that only 49% of

Figure 4. Combining two treatments to maximise the treatment of all phases of allergic rhinitis inflammation

Figure 3: A typical allergic face

Antihistamine

Intranasal steroid

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March 2021 | Vol. 21 No. 3 www.medicalacademic.co.za

Figure 5. Limitations of current allergic rhinitis treatment

Overlapping cases of SAR and PR

Ocular symptoms are poorly controlled

Pathophysio logical gaps

Combination of two in separate device causes nonhomogenous distribution of drug and increased runoff

Patients are administering two or more separate treatments for AR Patients are inadequately controlled by monotherapy

Sleep disorders decrease productivity at work

Limitations of current AR treatment

allergic (chronic) rhinitis sufferers consulted a medical practitioner. Of the remainder, 12% consulted a pharmacist, 24% self-medicated, and 15% did not treat their condition at all. The remedies used to treat allergic rhinitis were many, varied and differed between the different race groups. The research showed the need for education on the use of the more sophisticated and appropriate medications. From the market research conducted, it was clear that 50% of AR sufferers did not seek medical advice, but an appropriate educational programme could see better-educated pharmacists being directed or ‘governed’ by the guidelines of the SA Allergic Rhinitis Working Group and referring those sufferers who do not respond to over-the-counter treatments to a medical practitioner. Pharmaceutical companies should ensure that products are correctly marketed for the correct indication, and that some sort of consumer education is undertaken to assist doctors and pharmacists.

late-phase by eosinophils, it makes perfect sense to combine treatments to both phases in one therapy (Figure 4). This two-pronged approach should lend value to ensuring nasal symptoms, complications, and interventions, are minimised on a duplicate process. So, to the current problem with allergic rhinitis treatment is that we have had all these treatments and interventions for years and yet AR is still badly managed. There are many reasons for the poor outcomes for AR treatment (Figure 5). We are left with SA patients with AR who continue to suffer. Now it is time to stand up and demand

New therapy But now for a new therapy that makes AR care easier to achieve, combining the two major impacts of two therapies (Figure 4). Recalling that the early-phase of an allergic response is driven by histamine and the

Table 2. Multiple action olopatadine Olopatadine supresses the migration of THP-1 monocytes induced by SN100A12 protein Olopatadine inhibits anti-IgE stimulated conjunctival mast cell upregulation of ICAM-1 expression on conjunctival epithelial cells Type 1 allergy-induced endolymphatic hydrops and the suppressive effect of H1-receptor antagonist (olopatadine hydrochloride) Mast cell stabilisation and anti-histamine effects of olopatadine ophthalmic solution: A review of pre-clinical and clinical research.

Figure 6. Introduction to RYALTRIS ®

Introduction to RYALTRIS® RYALTRIS is a nasal spray formulation consisting of olopatadine hydrochloride and mometasone furoate. Each spray delivers: 600μg olopatadine (as olopatadine hydrochloride) and 25μg mometasone furoate (as mometasone furoate monohydrate) ®

RYALTRIS®

600μg olopatadine

25μg mometasone furoate

Single device nasal spray formulation Olopatadine is a histamine H1 receptor antagonist. Mometasone furoate is a corticosteroid with anti-inflammatory properties.

better care. And we have. A new care combining the two principal ingredients for AR care. They are a safe and effective topical corticosteroid and an effective multiple action molecule that has antihistamine effects that will take care of break-through symptoms. This product is RYALTRIS® (Figure 6). The antihistamine in RYALTRIS® is a multiple action molecule, olopatadine, with additional actions that suppport AR care (Table 2). There is no doubt that many sufferers of AR need a combination therapy for many reasons (Table 3). Table 3. The need for combination allergic rhinitis treatment Need for combination treatment ñ Evidence suggests that combination of an antihistamine and corticosteroid nasal spray might be more effective in reducing AR symptoms and have additional benefits than monotherapy alone ñ Intranasal formulations of antihistamines and corticosteroid are efficacious monotherapies, which have different onset of action. Antihistamines provide immediate (15-30 minutes) but short-term symptom relief lasting up to 12 hours, and corticosteroids provide sustained symptom relief with a longer onset of action (3-36 hours) ñ Furthermore, combined [fixed dose combination (FDC)] treatment in single device may reduce medical and pharmacy costs (depending on local pricing) compared to using multiple monotherapies ñ Single device use also improves the patient compliance and adherence to the treatment ñ Single medication device offers homogenous uniform distribution as well as no runoff posteriorly and anteriorly It offers broader disease coverage and faster symptom control ñ Intranasal antihistamines are more effective at reducing symptoms of itching, rhinorrhoea and sneezing compared to oral antihistamines, but are less effective at reducing concurrent ocular symptoms. INCS are particularly useful for improving ocular symptoms

Conclusion We have always known that AR nasal inflammation and its associated symptoms and complications have two major sources, release of histamine from mast cells and basic proteins released from eosinophils. The degree to which individual patients suffer symptoms, although it is partly due to lack of medication adherence, is often from failing to target both inflammatory processes. RYALTRIS® is a new combination product that has been shown in clinical trials, to add value to control of AR. References available on request. SF

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The post-antibiotic apocalypse is coming, warns WHO

By isolating, naming, and concentrating the antibacterial substance secreted by a penicillium mould, Dr Alexander Fleming discovered the first modern antibiotic in 1928. Subsequently, numerous antibiotics have been developed that are used to cure infections caused by bacteria.

ome 17 years after his discovery, he warned that “microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out…. In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted”. Unfortunately, Dr Fleming’s words proved to be prophetic. The World Health Organization (WHO) warns that antibiotic resistance (ABR) is rising to dangerously high levels in all parts of the world. New resistance mechanisms are emerging and spreading globally, threatening our ability

to treat common infectious diseases, states the WHO. A growing list of infections – such as pneumonia, tuberculosis, blood poisoning, gonorrhoea, and foodborne diseases – are becoming harder, and sometimes impossible, to treat as antibiotics become less effective. Without urgent action, we are heading for a post-antibiotic era, in which common infections and minor injuries can once again kill, warns the WHO.

Key drivers of antibiotic resistance It is estimated that 700 000 people die annually as a result of ABR, and this figure is set to rise to 10 million by 2050 if no action is taken, according to Farley et al.

An analysis of global antibiotic consumption from 2000–2015 showed a 65% increase in antibiotic use, largely in low- and middleincome countries including South Africa. More than 80% of antibiotics are used in the primary care setting. Suboptimal use of antibiotics is a key driver of ABR. ARB is evident in a patient for one month following an antibiotic course and can last for up to 12 months. It is therefore crucial to prescribe the fewest number of antibiotic courses for the shortest possible period of time. A South African retrospective medical record review by Gasson et al (2018) showed that only 45% of antibiotic prescriptions (654) adhered to guideline recommendations. Studies show

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poor guideline compliance for respiratory problems, urinary tract infections, tonsillitis, and acute diarrhoea. Variables associated with poor compliance to prescribing included seniority of the clinician, prescriber workload, patient age, and area-level socioeconomic status. Studies show that prescribing empiric therapy via guidelines was associated with a 35% relative risk reduction in mortality, and de-escalation in therapy was associated with a 56% relative risk reduction in mortality. Using antibiotics incorrectly and inappropriately by not following guidelines can contribute to the development of resistance, as well as poor clinical outcomes including patient morbidity, warn Gasson et al. Farley et al (2017) conducted a survey among South African clinicians (n=264) to determine their knowledge of, attudes to, and perceptions of ABR. They found that 97.1% of primary care

this too declined by 2%. According to the authors, it is concerning that the class of all other antibacterials comprising daptomycin, fusidic acid, linezolid, and tigecycline, grew at a rate of 16%. This increase may be due to inappropriate use as first-line therapies, lack of awareness of appropriate prescribing, or simply a desire to use newer more expensive therapies driven by availability or marketing by the pharmaceutical industry, as well as possible increases in resistance. In the public sector, a compound annual growth rate of 11% was reported overall. Substantial increases were observed in four classes: All other antibacterials (6876%), injectable fluoroquinolones (287%), injectable cephalosporins (169%), and broad spectrum penicillins oral (167%). Nearly 80% of the public market share was derived from trimethoprim combinations (37%), medium/narrow-spectrum penicillin (22%), and

national and health establishment level governance structures » Improve the appropriate use of diagnostics to identify pathogens and guide treatment » Optimise surveillance and early detection of antimicrobial resistances to enable reporting » Enhance infection prevention and control of the spread of resistant microbes to patients in healthcare settings, wide-reaching vaccination programmes and improvements in water and sanitation » Promote appropriate use of antimicrobials in human and animal health through antimicrobial stewardship.

prescribers believe that antibiotics are overused in South Africa, while 95.8% believe that ABR is a significant problem and 66.5% feel pressurised by patients to prescribe antibiotics. Knowledge scores among prescribers were suboptimal (median 5/7). Knowledge scores were highest in younger respondents compared to older prescribers. A possible reason for this, postulate Farley et al, is that older prescribers having lower knowledge scores could be lack of teaching on ABR at the time of their undergraduate medical training compared with more recent graduates. A novel finding is that knowledge scores are associated with prescribing behaviours. Higher knowledge scores were associated with using narrow-spectrum antibiotics, understanding the potential harm antibiotics can cause, trying alternative strategies such as explaining to patients the disease features that should prompt follow-up, and explaining duration of symptoms.

broad-spectrum penicillin oral (20%).

1.95 days. The risk of death was the same in both the intervention and control groups (11%). With AMS interventions, the length of stay was reduced by 1.12 days. Both enablement and restriction were independently associated with increased antibiotic policy compliance. Campion and Scully specifically reviewed the literature evaluating optimisation and deescalation of antibiotics in the intensive care unit (ICU). Beneficial strategies identified for the ICU include employing empiric guidelines for antibiotic use, collecting appropriate specimens and using molecular diagnostics, optimizing antibiotic dosing, and reducing the total therapy duration. Empiric antibiotic therapy in sepsis should be directed at the suspected location of infection and known risk factors, such as immunosuppression and prior antibiotic exposure, not solely on providing grampositive, gram-negative, Pseudomonas, and methicillin-resistant Staphylococcus aureus (MRSA) coverage. Prior IV antibiotic use, poor functional status, and comorbid conditions may increase the risks of multidrug-resistant organisms. Dual gram-negative coverage (the use of two agents with different mechanisms of action) for empiric coverage of infection, particularly in patients at risk for resistant organisms or reduced susceptibility, may be a useful strategy in critically ill patients, particularly when the susceptibility pattern for antipseudomonal beta-lactam antibiotics is <90%. A betalactam plus aminoglycoside may provide better empiric coverage over beta-lactam alone or beta-lactam plus fluoroquinolone. Locally, Brink et al reported that a pharmacist-driven intervention resulted in a significant reduction in antibiotic use

Antimicrobial prescribing in South Africa In 2012, the South African Antibiotic Stewardship Programme, a multidisciplinary group of experts across human and animal health, public and private health sectors, was formed to implement antimicrobial stewardship (AMS) programmes in hospitals and primary care. Data published by Schellack et al (2017) showed a compound annual growth rate of -2% over three years within the private sector antibiotic market. The majority of the classes showed a decrease, with a 20% reduction in the medium/ narrow-spectrum penicillin class. The dominant class with a market share of 35% remained the broad-spectrum penicillin oral class, however,

piric m e ibing idelines r c s u Pre via g d with y p a ther ssociate risk a was relative ality t a 35% n in mor ctio redu AMS programmes cornerstone of improved antibiotic use AMS is defined as ‘a coherent set of actions which promote using antimicrobials in ways that ensure sustainable access to effective therapy for all who need them’. Robust AMS programmes are widely considered the cornerstone of improved antibiotic use to combat resistance. Surveillance and infection prevention and control are also critical. Global efforts aimed at actively addressing the problem of the growing number of resistant organisms, are underway. These efforts are spearheaded by the WHO, the American Centres for Disease Control and Prevention, the European Centre for Disease Prevention and Control and multiple professional organisations. As mentioned already, the South African AMS Programme was launched in 2014. The objective of the programme is to: » Strengthen, coordinate, and institutionalise interdisciplinary efforts through

How effective are AMS programmes? Davey et al reported on a Cochrane Review of 221 studies of antibiotic prescribing practices for hospital inpatients, bundling interventions into restriction and enablement. The duration of antibiotic treatment decreased significantly by

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from 101.38 DDD/100 patient–days to 83.04 DDD/100 patient–days. Boyles et al reported a decrease in antibiotic consumption from 592.0DDD/1000 patient days to 475.8DDD/1000 patient days, and cost savings of R373 620 – a reduction of 35%. A follow up study by the same authors reported sustained reduction in antibiotic consumption (1046 DDD/1000 patient days to 868 DDD/1000 patient days over a two-year period), amounting to a cost savings of R3.2m over four years.

A recently published study, which included South African doctors, found that there was a lack of consensus among prescribers about what constitutes inappropriate use. Inappropriate use is generally considered as prescribing antibiotics in the absence of

judgements about appropriateness are morally and contextually framed. They also strongly recommend that stewardship interventions should directly target behaviour change. According to Farley et al, their finding that knowledge scores are associated with positive prescribing behaviours suggests that improved education and training is likely to be an important intervention to address ABR in primary care prescribers. Many prescribers (87.5%) wished to have more education on the appropriate use of antibiotics and would value clearer guidelines to improve their antibiotic prescribing in hard copy (80.2%), on smart phone apps (79.7%) or on interactive internet platforms (74.7%). Intervention strategies should focus on prescribers in the over-55 age group, and efforts should focus on patient education and patient-prescriber relationships to try to minimise the pressure placed on prescribers to

bacterial infection. But according to the authors, doctors frame antibiotic use not just in clinical, but also in moral and contextual terms. They recommend drawing up more specific definitions because

prescribe when not necessary. Interventions can include developing communication aids for prescriber/patient interactions, as 90.4% of prescribers requested education resource aids for discussions on

How can antimicrobial stewardship be improved in South Africa?

Who is responsible for antimicrobial stewardship? Roleplayers in the Example actions AMS programme ñ Prescriber

ñ Making accurate diagnoses ñ Following local antimicrobial guidelines ñ Regularly reviewing the need for therapy

ñ Nurse

ñ Taking cultures at appropriate times ñ Ensuring patients understand how to take antimicrobials on discharge

ñ Microbiologist

Boyles TH, Whitelaw A, Bamford C et al. Antibiotic stewardship ward rounds and a dedicated prescription chart reduce antibiotic consumption and pharmacy costs without affecting inpatient mortality or re-admission rates. PloS One, 2013. Boyles TH, Naicker V, Rawoot N et al. Sustained reduction in antibiotic consumption in a South African public sector hospital: four-year outcomes

ñ Following microbiological confirmation of infection, the clinical microbiologist is able to advise on appropriate antimicrobial therapy based on antimicrobial susceptibility results

Chetty S, Reddy M, Ramsamy Y et al. Antimicrobial

ñ Monitoring the choice of antibiotic, duration, indication for use

ñ Analysis of the consumption and total costs of the antibiotics used ñ Taking antimicrobial courses as recommended by the prescriber ñ Not storing or using leftover antimicrobials ñ Antimicrobial ñ Developing guidelines for antimicrobial use stewardship team ñ Supporting audit and feedback for prescribers ñ Educating prescribers ñ Hospital governance

References

from the Groote Schuur hospital antibiotic

ñ Reconciliation with biomarkers and patient clinical picture and diagnosis ñ Patient

d icate d n i e rs ribe eed mor c s e n Pr hey on the t t a th tion use a c u ed iate r p o appr tibiotics of an

ñ Has a diagnostic, consultative, and advisory role, which extends into AMS activities

ñ Able to make informed decisions about empirical antimicrobial therapy based on pathogen surveillance and AMR trends/patterns at a given institution over a period of time ñ Pharmacist

ABR with patients. This would assist with issues of confusion when explaining the difference between viral and bacterial infections that have arisen in similar studies. The majority (96.2%) of prescribers requested data on local resistance patterns, which opens up an opportunity to improve prescribing by introducing systems to supply up-to-date data on these.

ñ Ensuring sufficient sustainable and dedicated funding for antimicrobial stewardship teams ñ Monitoring antimicrobial use and resistance

stewardship programme. S Afr Med J, 2017. stewardship in South Africa: a scoping review of the published literature. JAC-Antimicrobial Resistance, 2019. Farley E, Steward A, Davies MA et al. Antibiotic use and resistance: Knowledge, attitudes and perceptions among primary care prescribers in South Africa. SAMJ, 2017. Dyar OJ, Hutter B, Schouten J et al. What is antimicrobial stewardship? CMI, 2017. Gasson J, Blockman M and Willems B. Antibiotic prescribing practice and adherence to guidelines in primary care in the Cape Town Metro district, South Africa. S Afr Med J, 2018. Manderson L. Prescribing, care and resistance: antibiotic use in urban South Africa. Humanities and Social Sciences Communications, 2020. Schellack N, Benjamin D and Brink A. A situational

ñ Investing in a Clinical Decision Support System

analysis of current antimicrobial governance,

ñ Enabling formulary restrictions

regulation, and utilization in South Africa. Journal of

ñ Pharmaceutical company

ñ Limiting advertising of antimicrobials, especially broad spectrum

ñ National policy maker

ñ Prioritising and funding antimicrobial stewardship activities

ñ Helping ensure there is a continuous supply of antimicrobials ñ Supporting the use of quality metrics and pay for performance

Infectious Diseases, 2017. Tarrant C, Krockow EM, Nakkawita WMID et al. Moral and Contextual Dimensions of Inappropriate” Antibiotic Prescribing in Secondary Care: A ThreeCountry Interview Study. Front Sociol, 2020. SF

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Photo credit: Shutterstock.com

This article was independently sourced by Specialist Forum.

The neuroscience of ADHD ADHD

A 2020 review found that the prevalence of attention-deficit/hyperactivity disorder (ADHD) is higher (7.47%) in children and adolescents in Africa compared to the global average (5.3%).1,2

his was the first review and metaanalysis of ADHD prevalence in children and adolescents in Africa, according to the authors. Similar to international trends, they found that the prevalence was greater in boys (10.60%) than in girls (5.28%).1

Definition and types of ADHD ADHD is the most common neurodevelopmental disorder in children and adolescents. According to the Diagnostic Statistical Manual fifth revision (DSM-5), ADHD is characterised by impaired levels of inattention, disorganisation, and/or hyperactivity-impulsivity.1 Inattention and disorganisation involve failure to stay on task, seeming not to listen, and losing things at levels that are not consistent with age or developmental level.1 Hyperactivity-impulsivity entails overactivity, fidgeting, inability to stay seated, intruding into other people’s activities, and inability

to wait. Symptoms are excessive for age or developmental level.1

Types of ADHD The DSM-5 differentiates between the following types of ADHD:1 » ADHD-I (predominantly inattentive): Characterised by maladaptive levels of inattention, but not hyperactivity–impulsivity » ADHD-HI (predominantly hyperactive– impulsive type): Characterised by maladaptive levels of hyperactivity– impulsivity, but not inattention » ADHD-C: Characterised by significant symptoms of both inattention and hyperactivity–impulsivity. Whilst international studies show a predominance of ADHD-I, followed by ADHD-C and ADHD-HI, the authors of the African systemic review found that ADHD-I was most common subtype of ADHD in Africa, followed by ADHD-HI and ADHD-C. ADHD-I subtype is the most prevalent subtype in

both males and females, while evidence suggest that all three subtypes are prevalent among males.1 Table 1: Prevalence of ADHD subtypes according to gender1 Subtype

Boys

Girls

ADHD-I

4.05%

2.21%

ADHD-C

3.62%

1.5%

ADHD-HI

3.61%

1.52%

Not ‘only’ a behaviour disorder Numerous studies have shown that ADHD is not ‘only’ a behavioural disorder, write Boshomane et al. In essence, ADHD is a complex cognitive disorder, which involves impairment of executive functions (EFs), also called executive or cognitive control. 2,4 One definition of EFs is: ‘A product of the co-ordinated operation of various processes to accomplish a particular goal in a flexible manner’. EFs are vital to manage intellectual resources. Together with metacognition, they play a key role in how we consciously regulate

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To com plete this mo nth’s C PD questio nnaire, please go www.m edicalac to ademic.c o.za and na vigate t o t he C PD s of the w ection ebsite. our thoughts and behaviours. They are also associated with academic performance.3,7 There are three core EFs:4 Inhibition (interference self-control) Working memory (holding information in mind and mentally working with it or said differently, working with information no longer perceptually present) Cognitive flexibility (also called setshifting, mental flexibility or mental setshifting are closely linked to creativity). Neuropsychological studies found that children and adolescents with ADHD exhibited significant deficits in EF domains compared to those without ADHD. Boshomane et al explain that these deficits influence response inhibition, working memory, set-shifting and planning. 2 A recent study shows that 93% of children with ADHD struggled with self-restraint, 73% with emotion regulation, 60% with selfmotivation (especially boys), 57% with time management and 41% with problem-solving.5 Another recent study reports a link between

agreeableness in adolescents (12- to 16-years) with ADHD, and higher scores on neuroticism. The researchers point out that their study included more cases of ADHD-I, which may explain these results since inattentive symptoms appear to be more specifically related to conscientiousness and neuroticism.6 They also observed links between ADHD and some of the personality traits closely related to self-regulation abilities that are impacted in ADHD. For example, high impulsivity and disrupted goal-directed behaviour may be related to lower conscientiousness and agreeableness, and higher neuroticism, which would probably explain some of the breakdowns in the self-regulation abilities of children and adolescents with ADHD.6

lower scores of conscientiousness and

of the parietal and temporal lobes.11

What causes executive dysfunction? Neuroimaging studies show that the prefrontal cortex (PFC) is a key determinant of executive functioning. The PFC consists of the orbitomedial and the dorsolateral prefrontal regions and is connected to many other parts of the brain, notably the limbic and cortical regions

The orbitomedial cortex is involved in sensory processing (taste and olfaction), regulation of the internal environment, control of drives, and emotional behaviour. The dorsolateral cortex is involved in cognitive functions.11 To function properly, the PFC requires optimal levels of two catecholamine neurotransmitters – norepinephrine (NE) and dopamine (DA). Too little (as when we are drowsy or fatigued) or too much (as when we are stressed) markedly impairs PFC regulation of behaviour and thought.8 When functioning is not impaired, the PFC allows us to concentrate and sustain our attention, especially under ‘boring conditions’ such as long delays between stimuli (eg a teacher who talks slowly).8 It helps us to focus on material that is important but not inherently salient (eg studying for a test, reading homework) and to inhibit internal and external distractions, to divide and shift our attention as appropriate with task demands (so-called multi-tasking), to plan and organise for the future as well as to regulate our behaviour and inhibit inappropriate responses.8 Genetic and imaging studies suggest that

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many patients with ADHD have inadequate transmission of NE or DA or both, as well as a smaller PFC and reduced functional activity. Other studies report more disorganised white matter tracks emanating from the PFC in patients with ADHD, which have been associated with weaker prefrontal connectivity.8 Other brain regions connected to the PFC such as the caudate and cerebellum, have also been reported to be smaller in some studies of children with ADHD. There is also evidence of slower prefrontal maturation in some patients with ADHD. 8

f acy o ts c ffi e The timulan HD hos psyc cing AD en be du in re ms has us ero pto sym in num n ls show ical tria clin Are stimulants effective in improving executive functioning? The efficacy of psychostimulants in reducing ADHD symptoms has been shown in numerous clinical trials of both children and adults with ADHD. As mentioned already, the PFC requires optimal levels of norepinephrine (NE) and dopamine (DA). ADHD treatments work by enhancing NE and DA functions, thus improving PFC functioning and activity. 8 NE stimulation of alpha-2A receptors enhances PFC function by strengthening appropriate network connections (increasing signals), and DA stimulation of D1 receptors, which exerts its beneficial effects by weakening inappropriate connections (decreasing noise). 8 Psychostimulants are currently the firstline treatment for ADHD in both children and adults. Methylphenidate (MPH) is the most widely prescribed and exerts its therapeutic effect by blocking the function of the NE and DA transporters. As a result, the bioavailability of NE and DA is improved, correcting deficits. 9 Numerous studies have shown that MPH improves reaction time, task-switching, focused attention, word-matching, and go/no-go tasks in children with ADHD. Low-dose MPH has also been shown to improve sustained attention, signal detection, and attentional setshifting. In addition, it has been shown that MPH improves working memory capacity. 9,10

Considerations when prescribing ADHD medication According to the authors of the 2019 the National Institute for Health and Care Excellence guideline,

the following must be taken into consideration when prescribing ADHD medication:12 Í When prescribing stimulants for ADHD, think about modified-release once-daily preparations for the following reasons: » Convenience » Improving adherence » Reducing stigma (because there is no need to take medication at school or in the workplace) » Reducing problems of storing and administering controlled drugs at school » The risk of stimulant misuse and diversion with immediate-release preparations » Their pharmacokinetic profiles. Í Immediate-release preparations may be suitable if more flexible dosing regimens are needed, or during initial titration to determine correct dosing levels Í When prescribing stimulants for ADHD, be aware that effect size, duration of effect and adverse effects vary from person to person Í Think about using immediate- and modifiedrelease preparations of stimulants to optimise effect Í Be cautious about prescribing stimulants for ADHD if there is a risk of diversion for cognitive enhancement or appetite suppression Í Do not offer immediate-release stimulants or modified-release stimulants that can be easily injected or insufflate if there is a risk of stimulant misuse or diversion Í Prescribers should be familiar with the requirements of controlled drug legislation governing the prescription and supply of stimulants.

Guideline recommendations The 2019 American Paediatric Association (APA) guidelines recommend:13 Recommendations Children aged 4- to 6-years MPH may be considered if behavioural interventions do not provide significant improvement and there is moderate-tosevere continued disturbance in the child’s functioning. In areas in which evidence-based behavioural treatments are not available, the clinician needs to weigh the risks of starting medication before the age of six-years against the harm of delaying treatment. Children aged 6- to 12-years Prescribe approved medications for ADHD, along with parent training in behaviour management (PTBM) and/or behavioural classroom intervention (preferably both PTBM and behavioural classroom interventions).

Conclusion High prevalence of ADHD in children and adolescents is seen in Africa, indicating that ADHD is a serious public health that should be focused on. Early pharmacologic intervention with comprehensive, holistic psychosocial approach in addressing psychological, behavioural, and occupational or educational needs will be the mainstay of ADHD management.

References 1. Ayano G, Yohannes K and Abraha M. Epidemiology of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in Africa: A systematic review and meta-analysis. Ann Gen Psychiatry, 2020. 2. Boshomane TT, Pillay BJ, Meyer A et al. Attentiondeficit/hyperactivity disorder and behavioural planning deficiencies in South African primary school children. South African Journal of Psychiatry, 2020. 3. Viana-Saenz L, Sastre-Riba S, Urracca-Martinez M et al. Measurement of Executive Functioning and High Intellectual Ability in Childhood: A Comparative Meta-Analysis. Sustainability, 2020. 4. Diamond A. Executive Functions. Annu Rev Psychol, 2014. 5. El Wafa HEA, Ghobashy SAEL and Hamza AM. A comparative study of executive functions among children with attention deficit and hyperactivity disorder and those with learning disabilities. Middle East Current Psychiatry, 2020. 6. Kriegel V, Amador-Campos JA and Guardia-Olmos J. Executive functions, Personality traits and ADHD symptoms in adolescents: A mediation analysis. PLoS One, 2020. 7. Elliot R. Executive functions and their disorders: Imaging in clinical neuroscience . British Medical Bulletin, 2003. 8. Arnsten AFT. The Emerging Neurobiology of Attention Deficit Hyperactivity Disorder: The Key Role of the Prefrontal Association Cortex. J Pediatr, 2009. 9. Urban KR and Gao W-J. Psychostimulants As Cognitive Enhancers in Adolescents: More Risk than Reward? Front Public Health, 2017. 10. Metha MA, Owen AM, Sahakian BJ et al. Methylphenidate Enhances Working Memory by Modulating Discrete Frontal and Parietal Lobe Regions in the Human Brain. The Journal of Neuroscience, 2000. 11. Fuster JM. Prefrontal Cortex. International Encyclopedia of the Social & Behavioral Sciences, 2001. 12. NICE. Attention deficit hyperactivity disorder: diagnosis and management, 2019. https://www. guidelines.co.uk/mental-health/nice-adhdguideline/454106.article. 13. Wolraich ML, Hagan JF, Allan C et al. AAP

Children aged 12- to 18-years

subcommittee on children and adolescents with

Prescribed approved medications for ADHD with the adolescent’s assent. The clinician is encouraged to prescribe evidence-based training interventions and/or behavioural interventions as treatment of ADHD, if available.

attention-deficit/hyperactive disorder. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics, 2019. SF

TURN THEIR WORLD RIGHT SIDE UP “These children are frustrated and bored at school. It’s not that they cannot concentrate, it’s that they concentrate on every little thing that happens around them. They have a perception that their teachers don’t like them.”1,2

Unlocking potential

References: 1. Knowles T. The kids behind the label: understanding ADHD. Middle Matters, National Association of Elementary School Principals. June 2009. [cited 2020 June 01]; Available from: https://www.naesp.org/sites/default/files/resources/2/Middle_Matters/2009/MM2009v17n5a3.pdf. 2. Renata Schoeman, All of these things are important to me. 2017 Goldilocks and The Bear Foundation. S6 CONTRAMYL XR 18 mg (Extended Release Tablets). Reg. No. 49/1.2/1137. Each extended release tablet contains 18 mg methylphenidate hydrochloride. Contains sugar (sucrose). S6 CONTRAMYL XR 27 mg (Extended Release Tablets). Reg. No. 49/1.2/1138. Each extended release tablet contains 27 mg methylphenidate hydrochloride. Contains sugar (sucrose). S6 CONTRAMYL XR 36 mg (Extended Release Tablets). Reg. No. 49/1.2/1139. Each extended release tablet contains 36 mg methylphenidate hydrochloride. Contains sugar (sucrose). S6 CONTRAMYL XR 54 mg (Extended Release Tablets). Reg. No. 49/1.2/1140. Each extended release tablet contains 54 mg methylphenidate hydrochloride. Contains sugar (sucrose). For full prescribing information, refer to the Professional Information approved by the Regulatory Authority.

Mylan (Pty) Ltd. Reg. No.: 1949/035112/07. 4 Brewery Street, Isando, Kempton Park, 1600. Tel: (011) 451 1300. Fax: (011) 451 1400. www.mylansa.co.za M3126 Exp 04/2022

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