MIMs - Handbook of General Medicine 2019

TREATMENT APPROACHES 43

A recent review states that ACEIs reduce the risk of aldosterone antagonist is warranted, but the combina- Treatment approaches
progression to macro-albuminuria in normotensive pa- tions ACEI plus ARB or either plus renin antagonist result
tients with micro-albuminuria and type 1 diabetes mel- in increased side effects and inferiority to single RAAS
litus. ACEIs and ARBs reduce the risk of progression to blockade. Most guidelines still recommend ACEIs as first
macro-albuminuria in normotensive patients with micro- line with ARBs if ACEIs are poorly tolerated.
albuminuria and TIIDM. ACEIs and ARBs, however, do
not consistently reduce the serum creatinine levels.15 REFERENCES
Renoprotection is a key outcome of RAAS blockade
with either ACEIs or ARBs. 1. Hypertension in adults: Diagnosis and management, NICE Clinical
Guideline [CG127] Published date: August 2011 Last updated: No-
A Swedish registry analysis of patients post MI be- vember 2016
tween 2006 and 2012 revealed that RAAS antagonist
treatment did not prevent new-onset atrial fibrillation, 2. ACCF/AHA 2013. Guideline for the management of heart failure;
however, the risk of all-cause mortality in patients with Circulation. 2013;128:1810-1852.
or without heart failure was significantly reduced.16
3. Turgeon RD, et al. Higher versus lower doses of ACE inhibitors, an-
Diabetic retinopathy: A meta-analyses including 21 giotensin-2 receptor blockers and beta-blockers in heart failure with
randomised clinical trials with 13 823 participants repor- reduced ejection fraction: Systematic review and meta-analysis.
ted that RAAS inhibitors were associated with reduced February 28, 2019; https://doi.org/10.1371/journal.pone.0212907
risk of progression (absolute risk difference −3%, 95% CI
−5 to −1; pooled RR 0·87, 95% CI 0·80–0·95; p=0·002) and 4. ATMOSPHERE study; April 2016. N Eng J Med. 2016; 374:1521-1532
increased possibility of regression of diabetic retinopa- DOI: 10.1056/NEJMoa1514859.
thy (8%, 1–16; RR 1·39, 95% CI 1·19–1·61; p=0·00002). A
network meta-analysis demonstrated that the antihy- 5. Liu H, et al. Aliskiren for heart failure: A systematic review and meta-
pertensive medicines with the lowest risk of diabetic analysis of randomized controlled trials. Oncotarget. 2017;8(50):
retinopathy progression were ACEIs, followed by ARBs, 88189-88198.
β-blockers, calcium-channel blockers, and placebo
in rank order. ACEIs were the medicines with the high- 6. Straus M and Hall A. Prog Cardiovasc Dis. 2016 Mar-Apr;58(5):473-82.
est association for regression of diabetic retinopathy. It doi: 0.1016/j.pcad.2015.11.004. Epub 2015 Nov 14.
therefore seems as if ACE inhibitors might be better than
ARBs for treating diabetic retinopathy.17 7. Bangalore, et al. BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.
d2234 (Published 26 April 2011): BMJ 2011;342:d2234.
Despite the sited evidence and years of research
and randomised clinical trials, a recent Cochrane re- 8. ESC Guidelines for the management of acute myocardial infarc-
view states “All-cause death is similar for first-line RAS tion in patients presenting with ST-segment elevation. European
inhibitors and first-line CCBs, thiazides and beta block- Heart Journal. 2017;39,119-177.
ers. There are, however, differences for some morbidity
outcomes. First-line thiazides caused less HF and stroke 9. Marre M, Leye A. Diabetes Vasc Dis Res. 2007;4:163-73doi:10.3132/
than first-line RAS inhibitors. First-line CCBs increased HF dvdr.2007.037.
but decreased stroke compared to first-line RAS inhi-
bitors. The magnitude of the increase in HF exceeded 10. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 dia-
the decrease in stroke. Low-quality evidence suggests betes mellitus. Part 1. A meta-analysis of randomised clinical trials.
that first-line RAS inhibitors reduced stroke and total CV Diabetes Metab. 2004;30:487-496
events compared to first-line beta-blockers. The small
differences in effect on blood pressure between the dif- 11. Dagenais GR, et al. Angiotensin-converting-enzyme inhibitors in
ferent classes of drugs did not correlate with the differ- stable vascular disease without left ventricular systolic dysfunc-
ences in the morbidity outcomes”.18 This is perhaps not tion or heart failure: A combined analysis of three trials. Lancet.
surprising as in patients with no comorbidities the big- 2006;368:581-8
gest risk factor is the blood pressure per se and RAAS
blockers differentiate when the comorbid disease, i.e. 12. Dahlöf B, et al. Prevention of cardiovascular events with an antihy-
underlying RAAS dependent pathology, is increased. pertensive regimen of amlodipine adding perindopril as required
versus atenolol adding bendroflumethiazide as required, in the
Conclusion Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lower-
ing Arm (ASCOT-BPLA): A multicentre randomised controlled trial.
The development of RAAS blockers over more than Lancet. 2005;366:895-906
three decades transformed the way clinicians treat pa-
tients suffering from diabetes, heart failure and ischae- 13. Izzo JL, Zion AS. Value of angiotensin receptor blocker therapy in
mic stroke, and those high-risk patients with multiple diabetes. J Clin Hypertens (Greenwich). 2011;13:290-295
metabolic and cardiovascular comorbidities. It further
seems as if there is little difference in most of the out- 14. Barnett AH, et al. Angiotensin-receptor blockade versus convert-
comes between the two drug classes, i.e. ACEIs and ing-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J
ARBs, with the bulk of the evidence only in some cases Med. 2004;351:1952-61]
(such as diabetic retinopathy) swinging to favour ACEIs.
Combination RAAS blockade is indicated in hyper- 15. Corbo JM, et al. ACE inhibitors or ARBs to prevent CKD in patients
tension and heart failure when the combination with an with microalbuminuria. Am Fam Phys. 2016; 94 (8) (ww.aafp.org/afp)

16. Batra G, et al. ACEIs and ARBs are associated with improved out-
comes but do not prevent new-onset AF after MI. J Am Heart Assoc.
2017; 6: e005165 DOI: 10.1161/JAHA.116.005165]

17. Wang B, et al. Effects of RAS inhibitors on diabetic retinopathy: A
systematic review and meta-analysis. Lancet. 2015; 3 (4): 263-274,
2015DOI:https://doi.org/10.1016/S2213-8587(14)70256-6]\]

18. Chen YJ, et al. First-line drugs inhibiting the renin angiotensin sys-
tem versus other first-line antihypertensive drug classes for hyper-
tension. Cochrane Data base of Systematic Reviews 2018, Issue 11.
Art.No.: CD008170. DOI: 10.1002/14651858.CD008170.pub3. www.
cochranelibrary.com].

HANDBOOK OF GENERAL MEDICINE VOL 1

44 TREATMENT APPROACHES

Hyperthyroidism: causes and treatment

EF Delport roid follicular cells, which then function independently
and are not regulated by thyroid-stimulating hormone.
MBChB, MMed (Int) Solitary toxic adenomas are autonomously functioning
nodules, usually found in younger patients.
Cert Endo & Metab SA (Phys), MSc (Clin Epi),
Endocrinologist, Pretoria East Hospital, Pretoria Thyroiditis, caused by inflammation of the thyroid, can
present with transient hyperthyroidism due to the release
Hyperthyroidism results from excessive synthesis and secre- of preformed thyroid hormone from the colloid space.
tion of thyroid hormone by thyroid tissue.1 It occurs in 2.2%
of the population, with a female-to-male ratio of 5:1.2 Other causes are outlined in Table 1.1,2, 4 It is important
that the correct cause of hyperthyroidism is identified,
Thyrotoxicosis refers to any cause of excessive thyroid because appropriate therapy depends on the under-
hormone. This could be due to overproduction within lying pathology.
the thyroid or originating outside the gland. It also oc-
curs with intentional or accidental ingestion of excess CLINICAL PRESENTATION
thyroid hormone (factitial hyperthyroidism).
A patient with hyperthyroidism exhibits symptoms of en-
AETIOLOGY hanced metabolic activity.1,4 The presentation depends
on the severity of thyrotoxicosis, duration of illness and age
The most common cause of hyperthyroidism is Graves’ of the patient. Signs or symptoms are listed in Table 2.1-5
disease, an auto-immune disease accounting for 50-
80% of cases.3 Antibodies active against the thyroid- The patient may complain about increased sweating,
stimulating hormone (TSH) receptor stimulate synthesis intolerance to heat, tremors, palpitations and weight loss
and secretion of excessive thyroid hormone. despite increased appetite. The patient’s skin is usually
warm to the touch, and thinning of the hair may be pre-
Toxic multinodular goitre accounts for 5% of hyper- sent. Stare and lid lag may be present in all patients with
thyroidism cases. This is the result of hyperplasia of thy- hyperthyroidism, because of sympathetic overactivity.

Table 1. Causes of hyperthyroidism

Antibody-mediated stimulation of thyroid tissue
• Diffuse toxic goitre (Graves' disease)

Autonomously functioning thyroid tissue
• Toxic multinodular goitre
• Toxic adenoma
• Rare forms: struma ovarii, metastatic thyroid carcinoma

Due to TSH-receptor stimulation
• TSH-mediated – TSH-secreting pituitary adenoma
• Β-hCG mediated – choriocarcinoma, hydatiform mole, testicular germ-cell tumours

Iatrogenic
• Iodine, amiodarone
• Radiation

Inflammatory conditions
• Acute or subacute thyroiditis
• Silent thyroiditis

Table 2. Clinical presentation of hyperthyroidism Signs Proximal muscle weakness
• Tremor
Symptoms • Brisk deep tendon reflexes
• Hyperactivity, agitation, nervousness • Resting tachycardia or atrial fibrillation
• Fatigue and weakness • Systolic hypertension and wide pulse pressure
• Insomnia • Systolic flow murmur
• Palpitations • Warm, moist skin
• Excessive sweating • Onycholysis
• Heat intolerance • Thyroid acropathy
• Hair loss • Thinning of the hair/alopecia
• Weight loss with normal appetite • Lid lag, lid retraction
• Diarrhoea •
• Urinary frequency and nocturia
• Amenorrhoea and infertility in women
• Reduced libido and erectile dysfunction in men

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 45

The skeletal and cardiovascular systems are the major thalmometer) and lid width, evaluating extra-ocular Treatment approaches
organs affected by untreated hyperthyroidism. A de- muscle function, and assessing corneal and optic-nerve
crease in bone-mineral density, leading to osteoporosis involvement.7 Patients with clinically significant findings
and an increased fracture risk can occur.6 Patients with should be referred to an ophthalmologist.
hyperthyroidism have an increased cardiac output,
with an increase in heart rate, widening of the pulse DIAGNOSTIC APPROACH
pressure and a decrease in peripheral vascular resist-
ance. Systolic hypertension occurs commonly. Further Diagnostic work-up should be done in all patients pre-
cardiovascular complications include rhythm distur- senting with features of hyperthyroidism.2 Evaluation
bances and congestive cardiac failure.7 should also be considered in patients with an increased
risk of hyperthyroidism, including patients with a strong
In Graves’ disease, the thyroid may be diffusely en- family history of thyroid disorders, long-standing goitre or
larged and smooth. Signs of thyrotoxic eye disease and other underlying auto-immune disorders.2,5
thyroid dermopathy, with skin-thickening over the an-
terior aspect of the tibia, may be present. In a patient Thyroid function tests (TFT) are done to confirm the
with a toxic nodular goitre, one or more discrete nod- diagnosis. Measurement of TSH is the initial test, and a
ules may be palpable. The classic features may not be suppressed level is indicative of hyperthyroidism. Free
present in all patients, especially the elderly, who often thyroxine (fT4) and triiodothyronine (fT3) levels are
present with mainly fatigue and weight loss (apathetic above the normal reference range in thyrotoxicosis, but
thyrotoxicosis). may be normal in subclinical hyperthyroidism.

Graves’ ophthalmopathy is an auto-immune phe- Once the diagnosis has been confirmed, the under-
nomenon triggering fibroblast growth and the accu- lying cause should be determined, to plan appropriate
mulation of hydrophilic glycosaminoglycans retro-or- therapy. The presence of specific antibodies, such as
bitally.3,8 This causes inflammation and swelling of the TSH receptor antibodies, is indicative of Graves’ dis-
extra-ocular muscles, as well as of the retro-orbital con- ease. Radio-active iodine uptake scintigraphy is use-
nective and adipose tissue.2,8 Graves’ ophthalmopathy ful to differentiate between different causes (see Ta-
is usually bilateral, but it can be asymmetric or unilat- ble 5).2,4,5 Other non-specific laboratory findings include
eral. Cigarette-smoking is a confirmed risk factor for its normocytic, normochromic anaemia, granulocytosis,
development.9 The clinical features are summarised in lymphocytosis, hypercalcaemia and abnormal eleva-
Table 3.4,8,9 tion of transaminase and alkaline phosphatase.2,4,5

Different scoring systems have been developed for TREATMENT
classification of eye changes in Graves’ disease (see
Table 4).1,2,7,8 The severity of disease should also be as- The treatment of hyperthyroidism consists of relieving
sessed by measuring exophthalmos (using an exoph- symptoms, as well as correcting the excess hormone
synthesis, by using antithyroid drugs, radio-active treat-
ment or surgery.1-5,10,11 In a randomised prospective trial

Table 3. Clinical features of Graves’ opthalmoplegia

Symptoms Signs Lid lag and lid retraction
• Irritation of the eyes • Proptosis
• Dryness • Periorbital oedema
• Excessive tearing • Conjunctival injection and oedema (chemosis)
• Eye or retro-orbital discomfort or pain • Exposure keratitis and corneal ulceration
• Blurring of vision • Extra-ocular dysfunction, with decreased range of motion
• Photophobia • of eyes
• Diplopia Decreased visual acuity
• Loss of colour vision • Swelling of the optic disk
• Occasional loss of vision •

Table 4. Assessment of severity 4b. Clinical activity score

4a. NO SPECS mnemonic Components
• Spontaneous retrobulbar pain
Class Mnemonic • Pain with eye movement
0. N – No symptoms or signs • Redness of the eyelids
1. O – Only signs, no symptoms (lid retraction, stare, • Redness of the conjunctiva
lid lag) • Swelling of the eyelids
2. S – Soft tissue involvement • Swelling of the caruncle
3. P – Proptosis • Conjunctival oedema (chemosis)
4. E – Extra-ocular muscle involvement
5. C – Corneal involvement 1 point is assigned for the presence of each symptom or sign –
6. S – Sight loss (optic nerve involvement) Score of 0 to 2 – inactive Graves’ ophthalmopathy
Score of 3 or more – active Graves’ ophthalmopathy.
NO – absence or mild degree of involvement
SPECS – more serious degrees of involvement

HANDBOOK OF GENERAL MEDICINE VOL 1

46 TREATMENT APPROACHES

comparing these three therapies, each was equally Graves’ disease or used to achieve a euthyroid state
effective in normalising thyroid-hormone concentra- prior to radio-active treatment or surgery.
tions within six weeks.10 The risk of relapse was the high-
est when using antithyroid drugs (40%), followed by Carbimazole is prescribed at an initial dose of 20-60 mg/
radio-iodine treatment (21%), and lowest when surgery day, varying according to the severity of hyperthyroidism.2
was performed (5%). It is taken in two to three divided doses until thyroid activity
returns to normal, then gradually decreased to maintain
Symptomatic relief the normal thyroid state. The maintenance dosage var-
Beta-adrenergic blockers are very effective in control- ies from patient to patient in the range of 5-15 mg/day.
ling the sympatomimetic symptoms. A beta-blocker Table 6 lists the side effects of thionamides.2,11
should be initiated as soon as the diagnosis of hyper-
thyroidism is made, and continued with antithyroid The goal of treatment is to attain an euthyroid state,
drugs until the patient no longer has evidence of hyper- and an improvement of symptoms is seen within three
thyroidism.5 The dose should be adjusted to keep the to four weeks of treatment.5,10 Assess the patient’s thy-
resting heart rate between 70-90 beats per minute.2 Pro- roid functions every four to six weeks until stabilised on
pranolol can be prescribed at a dosage of 20-40 mg maintenance therapy. Remission rates of 40-70% are
every six to eight hours. Longer-acting atenolol could achieved within one to two years of therapy.
also be used, at 25-50 mg twice daily. Calcium-channel
blockers (diltiazem) can be prescribed to patients who Iodinated contrast agents and iodine:
cannot tolerate beta-blockers.
Ipodate (Oragrafin), an iodinated radiographic agent,
Antithyroid drugs is a potent inhibitor of peripheral conversion of T4 to T3.
Iodine elixirs, such as saturated solution of potassium io-
Thionamides dine or Lugol’s solution, also block T4 conversion to T3
and inhibit thyroid-hormone release from the gland.
The thionamides – propylthiouracil (PTU), metimazole These are used in combination with thionamide therapy
and carbimazole – are the primary drugs used for treat- to rapidly relieve severe thyrotoxicosis, to accelerate
ing Grave’s disease.2,4,11 Carbimazole, which is meta- recovery after radio-active treatment, or to prepare a
bolised to metimazole, is available in South Africa. These patient for surgery.4 Iodine elixirs can be used for very
drugs accumulate in the thyroid tissue, where they in- mild hyperthyroidism.2
hibit the synthesis of T4 and T3, leading to a gradual
reduction in thyroid-hormone levels over two to eight Other medications
weeks.2,5 PTU also blocks the peripheral conversion of
T4 to the more metabolically active T3. Thionamides Glucocorticosteroids inhibit peripheral T4 to T3 conver-
are prescribed as primary treatment for patients with sion and in Graves’ disease, reduce thyroid hormone
secretion.2 Results for their efficacy are anecdotal.4

Lithium blocks thyroid-hormone release, but has lim-
ited use due to toxicity.2

Cholestyramin, when used in combination with thion-
amides, lowers serum T4 and T3 more rapidly than thion-
amide treatment alone.2

Table 5. Scintigrahic appearance of common causes of hyperthyroidism

Diagnosis Scintigraphic appearance
Graves’ disease
Toxic multinodular goitre Diffuse, increased, homogenous uptake in enlarged gland

Toxic adenoma Heterogeneous, multiple nodular areas of increased uptake, interspersed with areas of
suppressed uptake
Thyroiditis
Solitary focus of increased uptake (hot nodule), low or absent uptake in surrounding
tissues

Minimal to absent uptake

Drug-induced hyperthyroidism Minimal to absent uptake

Table 6. Side effects of thionamide drugs11

Minor Skin reactions (rash, urticaria) Major Polyarthrits
• Arthralgias • ANCA-positive vasculitis
• Gastro-intestinal effects (nausea) • Agranulocytosis
• Abnormal sense of taste or smell • Thrombocytopaenia
• Sialadenitis • Aplastic anaemia
• Fever • Immuno-allergic hepatitis
• • Cholestasis
• Hypoprothrombinaemia
• Hypoglycaemia
• Pancreatitis
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ZAR-ELT-00028 07/19

48 TREATMENT APPROACHES

Carnitine is a peripheral antagonist of thyroid hormone Surgery
action and relieves hyperthyroid symptoms.2 It may also Surgical thyroidectomy is not often used as primary
prevent bone demineralisation caused by the disease. treatment for hyperthyroidism, because of efficacy of
antithyroid medications and radio-active iodine. It is in-
Radio-iodine dicated in selected cases, as summarised in Table 7.2,4,5.

Radio-active iodine therapy is currently the preferred The surgery reserves some of the thyroid tissue, but
therapy in the United States, for the treatment of hypothyroidism occurs in about 25% of patients. Major
Graves’ hyperthyroidism.2,12 It is also used for toxic multi- complications include hypoparathyroidism and laryn-
nodular goitre or toxic adenoma. Radio-iodine is given geal nerve damage during surgery.
orally, in capsule or liquid form, as a single dose, to ab-
late a hyperactive thyroid gland.2 It takes 6-12 weeks Treatment for Graves' ophthalmopathy
for thyrotoxicosis to normalise after therapy. If used after Specific treatment for Graves' ophthalmopathy de-
treatment with thionamides, discontinue the antithyroid pends on the severity and stage of the disease. Man-
drugs three to seven days before radio-iodine therapy, agement is summarised in Table 8.8,9
because the effectiveness of radio-iodine may be de-
creased when given concurrently. Treatment of Graves’ dermopathy
Topical glucocorticosteroids, under an occlusive wrap,
Radio-active iodine therapy is a safe option, with no may limit its progression. The use of intradermal gluco-
widespread side effects. Approximately 80% of patients corticosteroids or surgical resection has shown limited
are cured after a single dose of iodine, but these pa- success.2,4
tients need life-long thyroid monitoring, because of
the risk of developing post-ablative hypothyroidism.2,6,10 SUBCLINICAL HYPERTHYROIDISM
Radio-active iodine has been associated with wors-
ening of Graves’ ophthalmopathy, but administering Subclinical hyperthyroidism is characterised by a combi-
prednisone 40-80 mg daily for three months decreases nation of a low serum TSH concentration, with a normal
this risk. Radio-active iodine is contra-indicated during serum T3 and T4 level.13 The prevalence of subclinical
pregnancy or breastfeeding, and it is recommended hyperthyroidism varies between 0.7-12.4%.14 This vari-
to wait six months after treatment before conceiving.2,5
Radiation thyroiditis, with neck pain and a transient ex-
acerbation of thyrotoxicosis, occurs rarely.

Table 7. Indications for surgical thyroidectomy

• Patients with obstructive symptoms or a very large goitre
• Pregnant women allergic to antithyroid drugs
• Other patients with major adverse reactions to antithyroid drugs or poor compliance, but who refuse radio-active

ablation

• Patients with active ophthalmopathy, who desire definite treatment for hyperthyroidism
• Co-existing malignant or suspicious thyroid nodules
• Severe hyperthyroidism in children

Table 8. Treatment for Graves' ophthalmopathy

Reducing factors associated with progression of disease
• Smoking cessation
• Controlling of thyroid dysfunction

Local measures
• Corneal protection from exposure and desiccation with moisturising drops and ointment, as well as taping eyelids
closed during sleep
• Botulism toxin to reduce upper lid retraction
• Dark lenses should be worn for photosensitivity
• Prisms to correct symptomatic dyplopia

High-dose systemic glucocorticoids can be used to reduce orbital inflammation
• Sight-threatening optic neuropathy: 1 g methylprednisolone given intravenously for 3 days, followed by surgery if no
response.
• Mild to severe active ophthalmology: oral glucocorticosteroids 40 mg daily and the dosage tapered over 4 to 6
months

Orbital radiotherapy may be used as an addition to glucocorticotheroid therapy when eye motility is impaired

Surgery Optic decompression surgery for sight-threatening dysthyroid optic neuropathy if no response to high-dose
• glucocorticoids.
Eye-lid surgery may be required for corneal protection.
• If vision is threatened due to corneal-exposure keratitis associated with severe exophthalmos and lid retraction, orbital
• decompression is indicated.
Eye-muscle surgery to correct extra-ocular muscle dysfunction may be required to correct misalignment.
•

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 49

ability depends mostly on the sensitivity of assays used in The diagnosis of a thyroid storm is a clinical diagnosis. Treatment approaches
various studies, the difference in definitions used for diag- Patients usually present with severely exaggerated
nosis, as well as the frequency of assessment of thyroid symptoms, typically seen with thyrotoxicosis. Patients
function in different screening programmes.15 The causes appear very agitated and often confused, and present
of subclinical hyperthyroidism are the same as for overt with palpitations, tachycardia, hyperpyrexia and gas-
hyperthyroidism, but the most common cause is exog- tro-intestinal symptoms.17
enous thyroid hormone replacement therapy.
Treatment is aimed at the suppression of synthesis and
Patients are usually asymptomatic, but many may release of thyroid hormones, symptomatic control of the
present with subtle symptoms or signs of thyrotoxicosis. hyper-metabolic state and full supportive management
The skeleton and cardiovascular system are, however, in an intensive-care unit.
adversely affected. Subclinical hyperthyroidism is asso-
ciated with low bone-mineral density, especially at the FOLLOW-UP
femoral neck and radius. Whether these changes in-
crease fracture rate is still a topic of debate.13 Patients The prognosis for a patient with hyperthyroidism is good
with subclinical hyperthyroidism have a higher risk of atri- with appropriate therapy. For the first two years, closely
al fibrillation; they have increased left ventricular mass, monitor the patient during any treatment at three-month-
increased ventricular contractility, and decreased ex- ly intervals. Thereafter, annual monitoring is recommend-
ercise tolerance. ed, even if the patient is asymptomatic. Patient educa-
tion regarding the risk of relapse, as well as possible late
The natural history of subclinical hyperthyroidism is onset hypothyroidism, is of the utmost importance.
unclear, and the progression to overt hyperthyroidism
seems to be related to the degree of hyperthyroidism, References
and the underlying disorder.
1. Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, et al, editors. Har-
Management of subclinical hyperthyroidism is sum- rison’s Principles of Internal Medicine. New York: McGraw Hill; 2005.
marised in Table 9.
2. Ross SD. Treatment of Graves’ hyperthyroidism. Available at www.
THYROID STORM uptodateonline.com. Accessed March 2012.

A thyroid storm is a rare, but life-threatening complica- 3. Weetman AP. Graves’ disease. N Engl J Med. 2000;343:1236-48.
tion of severe thyrotoxicosis. It usually develops in pa- 4. Goldman L, Ausiello D, Arend WP, et al, editors. Cecil Medicine.
tients with underlying, poorly treated Graves’ disease,
and is often precipitated by a physiological stressful 23rd Ed. Philadelphia: Saunders Elsevier; 2007.
event, such as trauma, infection, surgery or discontinua- 5. American Academy of Clinical Endocrinologists. American Asso-
tion of antithyroid drugs.16 A thyroid storm is a medical
emergency and requires early recognition and aggres- ciation of Clinical Endocrinologists medical guidelines for clinical
sive treatment. practice for the evaluation and treatment of hyperthyroidism and
hypothyroidism. Endocr Pract. 2002;8:457-69.
6. Motomura K, Brent GA. Mechanism of thyroid hormone action: Im-
plications for the clinical manifestations of thyrotoxicosis. Endocrinol
Metab Clin North Am. 1998;27:1-23.
7. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system.
N Engl J Med. 2001;377(7):501-508.

Table 9. Management of subclinical hyperthyroidism14

A. Patients receiving T4 therapy

Treatment is for hyperthyroidism and TSH Adjust T4 dose to maintain TSH concentration within the normal reference range
levels below normal

Patient is on suppressive T4 treatment: Subclinical hyperthyroidism is unavoidable
• To reduce goitre growth Treat with lowest dose of T4 possible to still meet desired goal, as benefits of
• To prevent recurrence of thyroid suppressive therapy outweigh risks
cancer

B. Patients with endogenous subclinical hyperthyroidism and at high risk of skeletal or cardiac complications:
• Age >65
• Other risk factors for arrhythmias
• Postmenopausal women with or at risk of osteoporosis

If serum TSH <0.1mU/ml Treat underlying cause of hyperthyroidism

If serum TSH 0.1-0.5mU/ml Treat underlying cause of hyperthyroidism if:
• There is underlying cardiovascular disease or if bone-mineral density is low
or
• If radionuclide scan shows areas of increased uptake

If none of the above
• Observe patient, review TFT 6-monthly

Patients with endogenous subclinical hyperthyroidism and at low risk of complications:
• Young individuals
• Premenopausal women

If serum TSH <0.1mU/ml Treat underlying cause of hyperthyroidism if patient has symptoms of hyperthyroidism
or if radionuclide scan shows areas of increased uptake

If serum TSH 0.1-0.5mU/ml Observation alone, review TFT 6-monthly

TSH – thyroid-stimulating hormone; TFT – thyroid function test; T4 – thyroxine.

HANDBOOK OF GENERAL MEDICINE VOL 1

50 TREATMENT APPROACHES

8. Bartalena L, Tanda ML. Graves’ Ophthalmopathy. N Engl J Med.
2009; 360(10):994-1101.

9. Bartalena L, Badeshi L, Dickinson AJ, et al. Consensus statement of
the European Group on Graves’ Orbitopathy (EUGOGO) on man-
agement of Graves’ orbitopathy. Thyroid. 2008;18:333-346.

10. Nedrebo BG, Holm PA, Uhlving S, et al. Predictors of outcome and
comparison of different drug regimens for the prevention of relapse
in patients with Graves’ disease. Eur J Endocrinol. 2002;147:583-9.

11. Cooper DS. Antithyroid drugs. N Engl J Med. 2005;352 (9):905-914.
12. Wartofsky L, Glinoer D, Solomon B, et al. Differences and similari-

ties in the diagnosis and treatment of Graves’ disease in Europe,
Japan, and the United States. Thyroid. 1991;1:129-35.
13. Toft AD. Subclinical hyperthyroidism. N Engl J Med. 2001;345(7):512-
516.
14. Ross SD. Subclinical hyperthyroidism. Available at www.uptodate-
online.com. Accessed March 2012.
15. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease. Scien-
tific review and guidelines for diagnosis and management. JAMA.
2004;291(2):228 -238.
16. Nayak B, Burnman K. Thyroid toxicosis and thyroid storm. Endocrinol
Metab Clin North Am. 2006;35:663-686.
17. Ross SD. Thyroid storm. Available at www.uptodateonline.com. Ac-
cessed March 2012.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 51

Hypothyroidism: risk factors and treatment Treatment approaches

EF Delport Iodine deficiency is still a common cause for hypo-
thyroidism worldwide, but fortunately iodination of ta-
MBChB, MMed (Int), Cert Endo & Metab SA (Phys), MSc (Clin Epi) ble salt has lessened the incidence of this form of hypo-
thyroidism.10
Endocrinologist, Pretoria East Hospital, Pretoria
Other common causes of hypothyroidism include thy-
Hypothyroidism results from a deficiency of thyroid hor- roid ablation, surgical thyroidectomy, or radiotherapy
mones or, more rarely, from their impaired activity at for head and neck malignancy. Hypothyroidism may
tissue level. A defect anywhere in the hypothalamic- be drug-induced, or transient due to thyroiditis. Causes
pituitary-thyroid axis can lead to hypothyroidism, but in of hypothyroidism are outlined in Table 1.1,9
the majority of cases it is a primary process in which the
thyroid gland produces insufficient amounts of thyroid Central hypothyroidism (secondary or tertiary) ac-
hormone.1 Decreased thyroid-hormone secretion due counts for less than 5% of hypothyroidism cases.11 It is
to inadequate secretion of either thyroid-stimulating caused by pituitary disease (i.e. pituitary adenomas,
hormone (TSH) from the pituitary gland or thyrotropin- previous pituitary surgery or Sheehan’s syndrome) or hy-
releasing hormone (TRH) from the hypothalamus (sec- pothalamic disorders.
ondary or tertiary hypothyroidism), occurs less often.
Congenital hypothyroidism is rare and occurs in 1 of
The first step in the development of primary hypo- 4 000 live births.9 Because infants are asymptomatic at
thyroidism is a decrease in thyroid secretion of thyroxine birth, neonatal screening programmes are used to pre-
(T4), followed by a slight decrease in free thyroxine (fT4), vent later complications.
which still remains within the normal reference range.
This causes serum TSH to increase, causing subclinical Table 1. Causes of hypothyroidism1,9
hypothyroidism. Progression of thyroid disease leads to
further decline in secretion of T4 and development of Primary hypothyroidism
overt hypothyroidism. Hypothyroidism is a commonly Auto-immune thyroiditis
encountered condition in primary care, and although it
has serious consequences, is easily treatable. • Hashimoto thyroiditis
• Spontaneous atrophic hypothyroidism
PREVALENCE Iodine deficiency
• Regional
Hypothyroidism is a common disorder worldwide. In the Infiltrative disease
United States National Health and Nutrition Examina- • Sarcoidosis
tion Survey, 4.6% of the population had hypothyroidism • Haemochromatosis
(0.3% overt hypothyroidism and 4.3% subclinical hypo- • Amyloidosis
thyroidism).2,3 In a United Kingdom survey, done in • Riedel’s thyroiditis
1995, primary hypothyroidism affected 3.5/1 000 women Congenital
and 0.6/1 000 men per year.4 The prevalence of hypo- • Thyroid agenesis, dysgenesis
thyroidism is higher in females than in males,2,3,4 and also • Defects in hormonal synthesis
higher in whites than in African Americans.2,3 Iatrogenic
• Thyroidectomy
Hypothyroidism occurs more in older age groups.2,4,5 • Radio-iodine therapy
The Framingham study found hypothyroidism (TSH >10 • Drugs (amiodarone, lithium, thionamides,
mIU/L) in 5.9% of women and 2.4% of men older than
60 years.5 The presentation of hypothyroidism in the el- interferon-α)
derly is often subtle and atypical presentations are quite Transient thyroiditis
common. An elevated serum TSH level is a sensitive Secondary/tertiary hypothyroidism
marker of thyroid deficiency in the elderly and often the TSH deficiency
only way to detect it.6 TRH deficiency

AETIOLOGY CLINICAL PRESENTATION

In developed countries, the most common cause of Hypothyroidism causes a generalised decrease in
hypothyroidism is auto-immune thyroiditis (Hashimoto’s metabolism.12 All metabolically active cells require
thyroiditis).1,7 The thyroid gland is gradually destroyed by thyroid hormone, causing multisystemic effects. Symp-
a variety of cell- and antibody-mediated immune pro- toms of hypothyroidism occur gradually and are non-
cesses. The thyroid gland may be diffusely enlarged due specific. They may vary from asymptomatic to, rarely,
to lymphocytic infiltration and fibrosis, but is often not a severe impairment of consciousness, termed myxo-
palpable. Antibodies against thyroid peroxidase and/or edema coma. In the elderly, the clinical features may
thyroglobulin may be present in affected individuals.8,9 be atypical, and the diagnosis is easily missed. Many of
the features of hypothyroidism may occur due to accu-

HANDBOOK OF GENERAL MEDICINE VOL 1

52 TREATMENT APPROACHES

mulation of glycosaminoglycans in the tissue interstitial Central hypothyroidism is diagnosed when there is a
space.13 subnormal fT4 level, with an inappropriately low serum
TSH. In patients where central hypothyroidism is sus-
Classic symptoms of hypothyroidism include fatigue, pected, biochemical evaluation for other pituitary hor-
mild forgetfulness, intolerance to cold, weight gain and mone deficiencies, as well as neuro-radiological studies,
constipation. Patients often complain about dry skin, should be performed.11,15
brittle nails and hair, hair loss and puffiness of the face.
Women may report menstrual irregularities. A hoarse During acute illness, thyroid functions may be difficult
voice, slow speech and enlargement of the tongue, to interpret. Central reduction of TSH release occurs
deafness and carpal tunnel syndrome occur less often. and can mask underlying hypothyroidism. Serum T4 also
Clinical features are summarised in Table 2.12,13 decreases with prolonged illness. During the recovery
phase, patients may have a transiently raised TSH, with
Goitre may be present on examination, and the thy- T4 concentration still reduced, leading to false-positive
roid gland is classically diffusely enlarged with a firm findings for hypothyroidism.9
consistency. Thyroid nodules may be associated with
hypothyroidism, but are not always encountered. Pa- The cause of hypothyroidism is often revealed by a
tients with atrophic auto-immune hypothyroidism have good history and clinical examination. Serum thyroid
no goitre. Pain and tenderness over the thyroid area is peroxidase auto antibodies (TPO-ab) are not routinely
likely because of underlying thyroiditis. measured, as most patients will have chronic auto­
immune hypothyroidism, where TPO-ab are detectable
DIAGNOSTIC APPROACH in more than 90% of patients.16

The diagnosis of primary hypothyroidism is confirmed Measurement of radio-active iodine-uptake scintigra-
with thyroid-function tests. Measurement of serum TSH phy is almost never required in the diagnostic evalua-
is the first-line diagnostic test for identification of hypo- tion of hypothyroidism.
thyroidism.9,14 Serum TSH has a sensitivity of 89-95% and
specificity of 90-96% to detect overt thyroid dysfunc- MANAGEMENT
tion. If the TSH value is above the reference interval,
the diagnosis must be confirmed with measurement of Thyroxine (T4) replacement
serum-free thyroxine (fT4).15 Serum fT4 is low in primary
hypothyroidism. Serum triiodothyronine (T3) concen- In most patients, treatment for hypothyroidism requires
tration is often normal, even in severe hypothyroidism lifelong thyroid-hormone replacement therapy. The aim
due to preferential synthesis and secretion of T3, and of hypothyroidism treatment is to ameliorate symptoms
increased peripheral T4 to T3 conversion when T4 falls. and to restore and maintain TSH within the reference
Measurement of T3 is therefore not helpful in the diag- range. The treatment of choice for hypothyroidism is
nosis of hypothyroidism. synthetic thyroxine. Most patients with hypothyroidism

Table 2. Clinical features of hypothyroidism Nervous system
• Fatigue
General features • Poor concentration, decreased memory
• Lethargy • Dizziness
• Weight gain despite poor appetite • Depression
• Cold sensitivity • Muscle cramps
• Decreased sweating • Carpal tunnel syndrome
• Water retention • Delayed relaxation of tendon reflexes
• Non-pitting oedema • Rare: cerebellar ataxia, myotonia
• Hoarse voice, thickening of the tongue
• Goitre may be present Gastro-intestinal tract
• Constipation due to decreased peristalses
Skin/hair/nail changes • Abdominal distension
• Dry, itchy skin • Ascitis is rare
• Yellow skin
• Vitiligo
• Hair dry and coarse, later hair loss
• Brittle nails
• Thinning of outer third of eyebrows

Cardiovascular Reproductive

• Impaired ventricular contraction Female:

• Bradycardia • Menstrual irregularities

• Increased peripheral resistance, diastolic hypertension • Anovulation and infertility

• ECG: low voltage of QRS complex Male:

• Decreased libido

• Erectile dysfunction

Pulmonary Other Hypercholesterolaemia
• Shortness of breath • Mild anaemia
• Hypoventilation • Impaired renal function
•

HANDBOOK OF GENERAL MEDICINE VOL 1

the HOUSE of Thyroid

ELTROXIN

New Formulation
Levothyroxine sodium

25 µg, 50 µg, 75 µg, 100 µg, 200 µg

Flexible and Convenient

SUGAR FREE
FORMULATION

LACTOSE FREE BREAKLINE FOR
FORMULATION UNIFORM DOSING
GLUTEN FREE FOR 25 MCG WIDE RANGE
FORMULATION 1 ELTROXIN New SCIENTIFICALLY OF STRENGTHS
Formulation DESIGNED
PACKAGING 25 µg
25µg 30s 50 µg
75 µg
100 µg
200 µg

A wider range of patient suitability & convenience,
at no extra cost2

The reformulation involves a change to microcrystalline cellulose as excipient
as opposed to the current lactose based product.3

Patients should be informed to consult their doctors to oversee and monitor the conversion
from the old formulation (ELTROXIN) to the new formulation (ELTROXIN New Formulation).

When switching to the new formulation, thyroid function blood tests
(e.g. thyroid stimulating hormone [TSH] levels) should be obtained 4 to 8 weeks after
switching to the new formulation, to ensure that the dosage is appropriate
to avoid the consequences of under- or over-treatment.4,5

Reference: 1. Aspen Pharmacare Limited, Data on file. Gluten Free. 2. Medikredit pricing data June 2019
3. Aspen data on file ELTROXIN 100 µg batch formulation. 4. Medicines and Healthcare products Regulatory Agency (MHRA). Levothyroxine Tablet
Products: A Review of Clinical & Quality Considerations. 07 January 2013. 5. DAVE JA, KLISIEWICZ A, BAYAT Z, MOHAMED NA, STEVENS Z, et al. 2015.

SEMDSA/ACE-SA Guideline for the Management of Hypothyroidism in Adults. S Afr Fam Pract; 57(6):4-11.

S3 ELTROXIN New Formulation 25 µg. Reg. No.: 47/21.3/0614. S3 ELTROXIN New Formulation 50 µg. Reg. No.: 47/21.3/0615.
S3 ELTROXIN New Formulation 75 µg. Reg. No.: 47/21.3/0616. S3 ELTROXIN New Formulation 100 µg. Reg. No.: 47/21.3/0618.

S3 ELTROXIN New Formulation 200 µg. Reg. No.: 47/21.3/0624. Each tablet contains 25 µg, 50 µg, 75 µg, 100 µg, or 200 µg
of levothyroxine sodium respectively. For full prescribing information refer to the professional information approved by
the medicines regulatory authority (09/2016).

S3 TERTROXIN 20 µg (tablet). Reg. No.: G 3082 (Act 101/1965). Each tablet contains contains 20 µg liothyronine sodium.
For full prescribing information refer to the professional information approved by the medicines regulatory authority (12/1974).
S3 NEOMERCAZOLE tablets 5 mg Reg. No.:G3021 (Act 101/1965). Each tablet contains 5 mg Carbimazole. For full prescribing information refer to the

professional information approved by the medicines regulatory authority (11/2011).
Trademarks are owned by or licensed to the Aspen Group of companies. © 2019 Aspen Group of companies or its licensor.

All rights reserved. Pharmacare Ltd. Co. Reg. No. 1898/000252/06. Healthcare Park, Woodlands Drive, Woodmead, 2191.
ZAR-ELT-00019 07/19

54 TREATMENT APPROACHES

require thyroid-hormone replacement at a dosage of In patients with pituitary insufficiency, fT4 levels are
1.6 μg/kg body mass/day, but the range of dosages measured to determine whether patients remain euthy-
is wide, and may vary from 50 to 200 μg per day to roid. The goal is to maintain fT4 levels in the mid to upper
achieve euthyroid status.17 Recommended starting dos- range of normal to ensure adequate replacement.
age of T4 replacement is listed in Table 3.18
SUBCLINICAL HYPOTHYROIDISM
The thyroid hormone thyroxine is usually given once
daily and should be taken on an empty stomach, ide- Subclinical hypothyroidism is defined as a biochemical
ally an hour before breakfast. The half-life of T4 is seven abnormality, characterised by a mildly elevated TSH
days and it is easily converted to the active form of T3 level, with normal thyroxine and triiodothyronine levels
within tissues. Certain drugs interfere with the gastro- and no or very mild, non-specific clinical symptoms.
intestinal absorption of T4, and should not be taken
simultaneously. These include bile-acid sequestrants, The prevalence of subclinical hypothyroidism ranges
calcium carbonate, ferrous sulphate and proton pump from 1-10% of the adult population, and is more preva-
inhibitors. lent in the elderly, in females and in Caucasians.

There are several formulations of T4 available, and The prevalence is also higher in populations with high
although there might be subtle differences in bioavail- iodine intake.21
ability between these formulations, it is currently recom-
mended to stay with the same preparation, if possible.17,19 Subclinical hypothyroidism has a high rate of progres-
sion to overt hypothyroidism, 2.6% per year if TPO anti-
Clinical improvement is often fairly rapid with the intro- bodies are absent, and 4.3% if they are present. The risk
duction of thyroxine, but full recovery from severe hypo- of progression is also higher in women and those with
thyroidism may take several months. high baseline levels of TSH. Some patients do experi-
ence normalisation of thyroid function and many pa-
Adverse effects of T4 are rare if the correct dose is tients have stable subclinical hypothyroidism without
given. Overt treatment may result in cardiovascular deterioration in thyroid function.22
complications, especially atrial fibrillation, as well as ac-
celerated bone loss and subsequent osteoporosis. Considerable debate exists about whether to treat
patients with subclinical hypothyroidism and no definite
Triiodothyronine (T3) replacement indications for treatment have been established. It is not
clear if the benefits of treating subclinical hypothyroidism
The indication for T3 replacement is controversial. Nor- outweigh the risks and potential complications.21
mal T3 levels could be achieved with levothyroxine
treatment alone in patients after total thyroidectomy. Current consensus guidelines recommend treatment
A meta-analysis evaluating 11 trials of combination T4 for subclinical hypothyroidism in patients with:21,23
and T3 replacement therapy did not show clinical ben- • Positive test for antibodies against thyroperoxidase
efit in symptoms (depression, fatigue or quality of life), or • Serum TSH levels greater than 10 mU/L
in physiological markers, such as lipid profile.20 • Severe symptoms
• High total or LDL cholesterol levels
There are concerns that T3 treatment can cause oste- • Goitre
oporosis and arrhythmias. Due to evidence for the ben- • Pregnancy
efit of levothyroxine plus triiodothyronine currently avail- • Female infertility with ovulatory dysfunction
able, T4 alone should remain the treatment of choice
for replacement therapy in hypothyroidism. SCREENING FOR HYPOTHYROIDISM

Monitoring of replacement therapy There is currently no proven benefit for screening all
people for hypothyroidism. Currently the American
In patients with primary hypothyroidism, measurement Thyroid Association recommends measurement of thy-
of serum TSH is the cornerstone of monitoring T4 replace- roid functions in all adults older than 35 years, and then
ment. After starting levothyroxine, the level of thyroid- every five years thereafter,24 noting that more frequent
stimulating hormone commonly takes six to eight weeks screening may be appropriate in high-risk or sympto-
to normalise.17 TSH should be measured at six weeks matic individuals.
and dose adjustments made accordingly. The patient
should then be re-evaluated with TSH measurement six- The United Kingdom guidelines do not recommend
weekly. T4 dose should be adjusted to maintain the lev- screening in the healthy asymptomatic population, but
el of thyroid-stimulating hormone within the reference testing women at menopause or patients with non-spe-
range.9 Thereafter, annual TSH measurement is sufficient cific symptoms is justified. It also recommends annual
for someone receiving a stable dose of levothyroxine. screening for people at high risk of developing hypo-
thyroidism (see Table 4).25

Table 3. Thyroxine replacement starting dose18

• Young patient Start T4 at 75 μg/ day.
• No CV risk factors Increase slowly if indicated by continued elevation of TSH level.

• Older patients(>60 years) Initiated therapy at low dosage, usual starting dosage 12,5- 25 μg/day.
• Patient at risk for CV disease Increase 25 to 50 μg 4-6 weekly until TSH level normal.
• Patient with IHD

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 55

Table 4. Risk factors for thyroid disease • Previous radio-iodine treatment Treatment approaches
Personal history of thyroid disease • Previous subtotal thyroidectomy
Medical disorders
Diagnosis of auto-immune disease • Past history of neck irradiation
Drug therapy • Patients with Down’s syndrome or Turner’s syndrome

• Patients with type 1 diabetes
• Patients with auto-immune Addison’s disease

• Lithium
• Amiodarone

HYPOTHYROIDISM IN PREGNANCY 5. Sawin CT, Castelli WP, Hershman JM, et al. The aging thyroid.
Thyroid deficiency in the Framingham Study. Arch Intern Med
Maternal hypothyroidism in pregnancy is associated 1985;145(8):1386-1388.
with adverse pregnancy and foetal outcomes7,26 and
inadequate thyroxine replacement in early pregnancy 6. Laurberg P, Andersen S, Bülow Pedersen I, Carlé A. Hypothyroidism
can cause mild reductions in a child’s intellectual abil- in the elderly: Pathophysiology, diagnosis and treatment. Drugs Ag-
ity. Women need more thyroid hormone during preg- ing. 2005; 22(1):23- 38.
nancy and should be advised to increase thyroxine dos-
age by around 30% as soon as they are pregnant. The 7. American Association of Clinical Endocrinologists Thyroid Task Force.
thyroxine dosage should be reduced to pre-pregnancy American Association of Clinical Endocrinologists medical guide-
levels within four weeks of delivery.27 lines for clinical practice for the evaluation and treatment of hyper-
thyroidism and hypothyroidism. Endocr Pract. 2002;8(6):457-469.
MYXOEDEMA COMA
8. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J
Myxoedema coma is a rare, but potentially fatal dis- Med. 1996; 335(2):99-107.
order which may occur in patients with longstand-
ing untreated hypothyroidism. It is characterised by 9. Roberts CGP, Ladenson PW. Hypothyroidism. Seminar. Lancet.
progressive mental deterioration, electrolyte abnor- 2004; 363(9411): 793-803.
malities and organ dysfunction.28 Multiple factors can
precipitate myxoedema coma, most commonly infec- 10. Zimmerman MB, Jooste PL, Pandav CS. Iodine-deficiency disorders.
tions, particularly pneumonia and urosepsis, and cer- Lancet. 2008;372:1251-1262.
tain medications. The patient with myxoedema coma
should be admitted to the intensive care unit, and re- 11. Lania A, Persani L, Beck, Peccoz P. Central hypothyroidism. Pituitary.
ceive treatment with levothyroxine. Mechanical venti- 2008;11:181-186.
lation may be necessary, and hypovolaemia and elec-
trolyte abnormalities must be corrected. Because of the 12. Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, et al,
possibility of secondary hypothyroidism and associated editors. Harrison’s principles of internal medicine.16th Ed. New York:
hypopituitarism, hydrocortisone should be administered McGraw Hill; 2005.
until adrenal insufficiency has been ruled out.
13. Surks MI. Clinical manifestations of hyperthyroidism. Available at
CONCLUSION www.uptodateonline.com. Accessed March 2012

Hypothyroidism is a common disorder and often over- 14. Vaidya B, Pearce SHS. Management of hypothyroidism in adults.
looked. It is easily treated with good prognosis. Most pa- Clinical review. BMJ. 2008; 337:284-289.
tients with hypothyroidism can be managed successfully
in primary care. Most patients require lifelong thyroxine 15. Ross SD. Diagnosis of and screening for hypothyroidism. Available at
replacement therapy. Referral should be considered if www.uptodateonline.com. Accessed March 2012
the patient does not respond to adequate treatment, if
there is underlying comorbidity or complications, and if 16. De los Santos ET, Starich GH, Mazzaferri EL. Sensitivity, specificity,
the patient is pregnant. and cost-effectiveness of the sensitive thyrotropin assay in the diag-
nosis of thyroid disease in ambulatory patients. Arch Intern Med.
References 1989;149:526-532.

1. Ross SD. Disorders that cause hypothyroidism. Available at www. 17. Ross SD. Treatment of hypothyroidism. Available at www.uptodate-
uptodateonline.com. Accessed March 2012. online.com. Accessed March 2012

2. Hallowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4 and 18. Roos A, Linn-Rasker SP, van Domburg RT. The starting dose of levo-
thyroid antibodies in the United States population (1988 to 1994): thyroxine in primary hypothyroidism treatment. Arch Intern Med.
National Health and Nutrition Examination Survey (NHANES III). J Clin 2005;165:1714-1720.
Endocrinol Metab. 2002; 87(2):489-499.
19. Dong BJ, Hauck WW, Gambertoglio JG, Gee L, White JR, et al. Bio-
3. Aoki Y, Belin RM, Clickner R, et al. Serum TSH and total T4 in the Unit- equivalence of generic and brand-name levothyroxine products in
ed States population and their association with participant charac- the treatment of hypothyroidism. JAMA.1997;277:1205-1213.
teristics: National Health and Nutrition Examination Survey (NHANES
1999-2002). Thyroid. 2007;17(12): 1211-23. 20. Grozinsky-Glasberg S, Fraser A, Nahshoni E, et al. Thyroxine-triiodo-
thyronine combination therapy versus thyroxine monotherapy for
4. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of clinical hypothyroidism: Meta-analysis of randomized controlled tri-
thyroid disorders in the community: A twenty-year follow-up of the als. J Clin Endocrinol Metab. 2006; 91(7):2592-2599.
Whickham survey. Clin Endocrinol.1995;43:55-68.
21. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: Scien-
tific review and guidelines for diagnosis and management. JAMA.
2004;291(2):228-238.

22. Biondi B, Cooper DS. The clinical significance of subclinical thyroid
dysfunction. Endocr Rev. 2008; 29(1):76-131.

23. Ross SD. Subclinical hypothyroidism. Available at www.uptodate-
online.com. Accessed March 2012

24. US Preventive Services Task Force. Screening for thyroid disease: Rec-
ommendation statement. Ann Intern Med. 2004 Jan;140(2):125-7.

25. UK Guidelines for the use of thyroid function tests. Association of
Clinical Biochemistry, British Thyroid Association, British Thyroid Foun-
dation. Available at www.british-thyroid-association.org/ TFT_guide-
line_final_version_July_2006.pdf July 2006. Accessed April 2012.

26. Fitzpatrick DL, Russell MA. Diagnosis and management of thyroid
disease in pregnancy. Obstet Gynecol Clin N Am. 2010;37:173-193.

27. Ross SD. Hypothyroidism during pregnancy: Clinical manifestations,
diagnosis and treatment. Available at www.uptodateonline.com.
Accessed April 2012.

28. Wartofsky L. Myxoedema coma. Endocrinol Metab Clin North Am.
2006;35(4):687-698.

HANDBOOK OF GENERAL MEDICINE VOL 1

56 TREATMENT APPROACHES

Recent advances in type 2 diabetes: newer
drugs providing cardiovascular protection

P Joshi However, long-term follow-up yielded some reduc-
tions in cardiovascular disease and mortality in the UKP-
PhD FRCP FRSMed FICA MACE DS, and reduction in cardiovascular disease in the VADT
Emeritus ad hominem Professor of Medicine, Medunsa; study (see Table 1).
Director of Diabetes Care & Clinical Trials Centre,
Brooklyn, Pretoria Longer-acting basal insulins

Epidemiological studies continue to show an increas- The ORIGIN Study (Outcome Reduction with Initial Glar-
ing prevalence of type 2 diabetes (T2D) nationally, re- gine Intervention) was a large randomised control study
gionally and globally.1 Hitherto, medications available (RCT) with over 12 600 subjects. It recruited patients with
for its treatment have shown that tight glycaemic con- new or recent diabetes, impaired fasting glucose (IFG)
trol bears a significant impact on reducing the micro- or impaired glucose tolerance (IGT) and additional
vascular complications of the disease. However, these cardiov­ ascular-risk factors. One of its aims was to de-
benefits have not been revealed in the development of termine if insulin glargine-mediated normoglycaemia
macrovascular disease even when stringent glycaemic can reduce cardiovascular morbidity and/or mortality
control was achieved.4 It is well known that the major in high-risk cardiovascular disease with IFG, IGT, or early
causes of morbidity and mortality ensue from macro- T2D in patients aged ≥50 years with dysglycaemia and
vascular disease. In some instances, drugs aiming to at high cardiovascular risk.
achieve better glycaemic control even resulted in an
increased risk of cardiovascular disease – for example, The study conclusions were that when used to target
rosiglitazone was very effective in attaining glycaemic normal fasting glucose levels for more than six years,
control, but resulted in increased cardiovascular com- insulin glargine had a neutral effect on cardiovascular
plications. This is our modern-day challenge. Over two- outcomes.5
thirds of patients die from cardiovascular disease, and
stroke rates are unacceptably high, being two to four The DEVOTE (Efficacy and Safety of Degludec versus
times higher, compared to the general population.2 Glargine in Type 2 Diabetes) was another long-term,
multinational study that looked at cardiovascular safety
In 2008 the US FDA and the EMA mandated that spon- during treatment with insulin degludec, compared with
sors of new glucose-lowering therapies should demon- insulin glargine U-100, in people with T2D who are at high
strate that therapy would not result in an unacceptable risk of cardiovascular diseases. Participants were aged
increase in cardiovascular risk.3 Hence, newer agents 50 years or above, had T2D, and either heart disease or
have been tested in a number of cardiovascular out- a high risk of heart disease. Subjects were randomly di-
comes trials (CVOT). vided into two groups and received either insulin deglu-
dec or insulin glargine (in addition to their usual diabetes
These newer agents include the following classes of care). This study demonstrated that degludec was non-
drugs: DPP-4 inhibitors, GLP-1 receptor agonists, and inferior to insulin glargine U100 with regard to the primary
SGLT2 Inhibitors. The introduction of these drugs has in- endpoint which was defined as the outcome of the first
fluenced national and international guidelines for the occurrence of cardiovascular death, non-fatal myo-
current treatment of type 2 diabetes. cardial infarction or non-fatal stroke, with no statistically
significant difference between the two treatments.6
The impact of intensive therapy in diabetes in major
clinical trials, such as the DCCT/EDIC in T1D, and the T2D Dipeptidyl peptidase-4 inhibitors
studies, including the UKPDS, ACCORD, ADVANCE and
VADT, have all uniformly shown benefits for microvas- The next class of oral hypoglycaemic agents studied in
cular disease, but not for macrovascular disease (see RCTs were the dipeptidyl peptidase-4 inhibitors (DPP-4
Table 1).4 inhibitors). Figure 1 shows the mechanism of action of
this group of drugs.
Table 1. Impact of intensive therapy in diabetes4
Following ingestion of food, incretin hormone GLP-1
HANDBOOK OF GENERAL MEDICINE VOL 1 is released in the bloodstream which stimulates a glu-
cose-dependent release of insulin from the pancreatic
beta cell; it also suppresses glucose-dependent gluca-
gon release from the pancreatic alpha cell. The action
of GLP-1 in the system lasts some three to five minutes
before it is inactivated by the DPP-4 enzyme. Thus,
DPP-4 inhibitors allow for an increase in systemic GLP-1
levels; the incretin effect.



58 TREATMENT APPROACHES

DPP-4 enzyme ence between treatments for secondary endpoint,
inactivates GLP-1 there was an increased risk of hospitalisation for heart
failure with the use of saxagliptin.7
DPP-4
X inhibitors TECOS
block the Stimulates (Trial evaluating cardiovascular outcomes with sita­
DPP-4 insulin gliptin)
Food enzyme
Small secretion Sitagliptin did not affect rates of 3-point MACE
GLP-1 Suppresses (death from any cause, cardiovascular death, or non-
intestine glucagon cardiovascular death), compared to placebo. Also,
secretion there was no increase in rates of hospitalisation for
heart failure.8
Drucker DJ. Diabetes Care. 2007;30:1335-1343.
EXAMINE
Figure 1. Mechanism of action of DPP-4 inhibitors (Examination of cardiovascular outcomes with aloglip-
tin versus standard of care)
Randomised control studies
A number of DPP-4 inhibitors have been studied in ran- Alogliptin showed similar rates of the primary compos-
domised control studies, notably saxagliptin (SAVOR ite endpoint of cardiovascular death, non-fatal myo-
TIMI-53), sitagliptin (TECOS), alogliptin (EXAMINE) and cardial infarction or non-fatal ischaemic stroke, com-
linag­ liptin (CARMELINA). pared to placebo. There was an increased tendency
towards heart failure, as compared to placebo, but this
Table 2 summarises abstracts of these studies: was not statistically significant.9

SAVOR-TIMI 53 CARMELINA
(Cardiovascular and renal microvascular outcome
(Saxagliptin assessment of vascular outcomes recorded study with linagliptin in patients with type 2 diabetes
in patients with diabetes mellitus-thrombolysis in myo- mellitus)
cardial infarction)
Linagliptin showed similar rates of the primary com-
Primary endpoint: Saxagliptin neither reduced nor posite endpoint of cardiovascular death, non-fatal MI,
increased risk of primary endpoint of cardiovascular
death, non-fatal MI or non-fatal ischaemic stroke, when
compared to placebo. Although there was no differ-

Table 2. Summarised abstracts of DPP-4 inhibitor studies

Tecos Savor-TIMI Examine Carmelina

Medication Sitagliptin8 Saxagliptin7 Alogliptin9 Linagliptin10

# of patients 14 671 16 492 5 380 8 300

History DM2, established CVD DM2, established CVD or DM2, recent acute DM2, high risk for CV

multiple risk factors coronary syndrome event events, BMI <45

Study design Multi-centre, randomised, Multi-centre, randomised, Multi-centre, randomised, Multi-centre, randomised,

double-blind, open label double-blind, placebo- double-blind double-blind, parallel

controlled assignment

Primary outcome 4-point MACE: CV death, 3-point MACE: CV death, 3-point MACE: CV death, 4-point MACE: CV death,
non-fatal MI, non-fatal non-fatal MI, non-
stroke, hospitalisation for fatal ischaemic stroke. non-fatal acute MI, non- non-fatal MI, non-fatal
unstable angina. Non- Superiority and non-
inferiority and superiority inferiority design fatal stroke. Non-inferiority stroke, hospitalisation for
design
design unstable angina

Results Primary outcome: Primary outcome: Primary outcome: Ongoing

sitagliptin 11.4%, placebo saxagliptin 7.3%, placebo alogliptin 11.3%, placebo

11.6%, hazard ratio: 0.98 7.2%, hazard ratio: 1.0 11.8%, hazard ratio: 0.96

(95% Cl: 0.88 to 1.09), (95% Cl: 0.89-1.12), (95%Cl: <1.16), p = 0.32.

p <0.001. Secondary p = 0.99. Secondary Post hoc analysis:

outcome: heart failure outcome, heart failure alogliptin 3.1%, placebo

hospitalisation, sitagliptin hospitalisation: saxagliptin 2.9%, hazard ratio: 1.07

2.8%, placebo 2.8%, 3.5%, placebo 2.8%, (95% Cl: 0.79-1.46),

hazard ratio: 1.00 (95% Cl: hazard ratio: 1.27 (95% Cl: p = 0.66

0.83-1.20), p = 0.98 1.07-1.51), p = 0.007

Additional AT 4 months, HbA1c 0.4 Glycaemic control was NT-pro-BNP concentrations
benefits/risks percentage points lower lower in saxagliptin group decreased significantly
in sitagliptin group vs compared to placebo and similar in the 2 groups.
placebo group; sitagliptin Post-hoc analysis for
group less likely to start hospitalisation for heart
long-term insulin therapy failure

Vellanki P, Davis G. Cardiovascular Outcomes of DPP-4 Inhibitors. Endocrineweb. 2016;7:3

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 59

or non-fatal ischaemic stroke, compared to placebo. supSpGrLeTs2s tinhheiabcittoiorns of Treatment approaches
There was no tendency towards heart failure.10 Glucose SGLT2

The US FDA has included black-box warnings relating inShGibLTit2or Iunrcirneaarsye Luorsitnien
to heart failure for both saxagliptin and alogliptin. SGLT2 glucose
excretion
DPP-4 inhibitors and glycaemic control
Rreedaubcseogrpluticoonse
The influence of DPP-4 inhibitors on the levels of HbA1c
as monotherapy or in combination with other oral anti- Adapted from Wright EM, et al. Physiol Rev. 2011;91:733-794
diabetic drugs, has been evaluated in multiple trials.
The results of these important trials were reviewed.11 Sit- Figure 2. Mechanism of action of SGLT2 inhibitors
agliptin showed an average reduction in HbA1c levels
of 0.67% after 52 weeks of treatment. Treatment with EMPA-REG Outcome
saxagliptin showed an average decrease in HbA1c lev-
els of 0.43-1.17%. Treatment with vildagliptin showed an The purpose of the EMPA-REG Outcome trial (the Em-
average decrease in HbA1c levels of 1.4% after 24 weeks pagliflozin Cardiovascular Outcome Event Trial in Type 2
as monotherapy in a subgroup of patients with no prior Diabetes Mellitus Patients – Removing Excess Glucose)
oral treatment. A meta-analysis included information was to evaluate the cardiovascular effect of empagli-
regarding treatment of type 2 diabetes with sitagliptin flozin, as compared with placebo, in addition to stand-
and vildagliptin for ≥12 weeks, compared with placebo ard of care, in patients with type 2 diabetes at high risk
and other oral antidiabetic drugs.12 This showed a re- of cardiovascular events.
duction of 0.74% in HbA1c levels. In studies with combi-
nation therapy of DPP-4 inhibitors and metformin in one The conclusions of the EMPA-REG Outcome trial were
pill, the results have been synergistic, probably because as follows:
metformin has an upregulating effect on the level of • Empagliflozin had a statistically significant 14% lower
glucagon-like peptide 1 (GLP-1), enhancing the incre-
tin effect of the DPP-4 inhibitors. Another possibility for rate of MACE than placebo. This benefit was primar-
the improved results in the combined drug is improved ily driven by a 38% relative risk reduction in cardio-
compliance when taking one oral drug instead of two. vascular death (HR, 0.62; 95% CI, 0.49-0.77; P <.001),
with no differences in the risk of MI or stroke, com-
DPP-4 Inhibitors are all considered largely weight- pared with placebo (see Figure 3).
neutral, and since their effects are glucose-dependent, • The cardiovascular death rate was reduced by 38%
hypoglycaemia is rare (unless the drug is combined with (see Figure 4) and the all-cause death rate by 32%
a sulphonylurea/insulin). • There was a statistically significant 35% reduction in
heart failure (see Figure 5). These improvements are
SGLT2 inhibitors seen very early after therapy, within weeks to months
(see curve separations in Figures 3-5).
SGLT2 (sodium-glucose cotransporter-2) inhibitors are a • Higher rates of genital infection were seen in patients
class of medicines that are FDA-approved for use with on empagliflozin, compared to placebo
diet and exercise to lower blood sugar in adults with • No increased risk of euglycaemic diabetic ketoaci-
type 2 diabetes. Drugs in this class include empagliflozin, dosis (DKA) was seen with the use of empagliflozin in
canagliflozin, and dapagliflozin (see Table 3). Figure 2 this trial
illustrates their mechanism of action • Weight loss. Glucosuria, produced by SGLT2 inhibitors,
causes calorie loss and a decrease in body weight. In
Table 3. SGLT2 inhibitors the EMPA-REG OUTCOME study, empagliflozin-treat-
ed subjects lost ∼2 kg
Generic Trade name Trial • Hypoglycaemia was rarely found.
Empagliflozin Jardiance
EMPA-REG
Canagliflozin Invokana Outcome

Dapagliflozin Forxiga CANVAS,
CANVAS-R
Ertugliflozin Steglatro
DECLARE-
Sofagliflozin* TIMI 58

VERTIS CV

SCORED

*Dual SGLT1and SGLT2 inhibitor

Ninety percent of glucose filtered through the glomeru- Zinman B, et al. N Eng J of Med. 2015
lus is normally reabsorbed by the S1 segment of the proxi-
mal tubule by the SGLT2 receptors. Inhibition of the SGLT2 Figure 3. EMPA-REG Primary Outcome (3-Point MACE):
receptors blocks this reabsorption with resultant glycosuria. CV death, nonfatal MI and nonfatal stroke
This glucose loss leads to a drop in blood-glucose levels, en-
ergy (and weight) loss, and a reduction in blood pressure. HANDBOOK OF GENERAL MEDICINE VOL 1

60 TREATMENT APPROACHES

Table 4. GLP1 agonists

Generic Trade name Trial
Lixisenatide Adlyxin™ ELIXA
Liraglutide Victoza LEADER
Semaglutide Ozempic SUSTAIN-6
Exenatide Bydureon/Byetta EXSCEL
Dulaglutide Trulicity REWIND
Albiglutide Tanzeum HARMONY

Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. Semaglutide PO PIONEER 6
N Engl J Med. 2015
Mechanism of action
Figure 4. EMPA-REG and CV death All the drugs in this class work in the same way (see Figure 6).
The additional direct subcutaneous injection of GLP-1 RA
Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. further augments the action of GLP-1 in the body, thereby
N Engl J Med. 2015 enhancing its physiological effects. The drug stimulates
glucose-dependent insulin secretion from the beta cell of
Figure 5. EMPA-REG outcome and hospitalisation for the pancreas; it suppresses glucose-dependent glucagon
heart failure secretion by inhibiting the alpha cells of the pancreas, re-
ducing hepatic glucose production; it has an effect on
CANVAS programme the gastro-intestinal tract, producing a feeling of fullness;
The population studied had a high risk of cardiovascular and has a direct effect on the CNS, enhancing satiety. It
events receiving standard of care; 81% of patients had thus suppresses appetite and facilitates weight loss.
prior cardiovascular disease or chronic kidney disease.
Food rSGeteoLscpPfroo-e1onteidsnse Brain Stimulates Insulin
A potentially greater benefit was seen in those with Decreases insulin
established cardiovascular disease and subgroups with appetite secretion
an eGFR <60 ml/min/1.73 m2. Canagliflozin significantly re-
duced risk of primary composite cardiovascular outcome inStemsatilnl e GLP-1 XPancreas Glucagon
by 13% vs placebo, and all-cause death (15%) and risk of Slows Suppresses
cardiovascular death (22%). The sodium-glucose cotrans- gastric glucagon
porter 2 (SGLT2) inhibitor canagliflozin reduced cardio- secretion
vascular events by 14% and cut the rate of renal decline emptying
by 40%, but also doubled the risk for lower-limb amputa-
tion, new Cardiovascular-Outcomes trial data indicate.13 Meier JJ. Nat Rev Endocrinol.2012;8:728-742. Stomach

DECLARE TIMI 58 Figure 6. Mechanism of action of GLP-1 RAs
This trial evaluated dapagliflozin and cardiovascular
outcomes in type 2 diabetes. In patients with type 2 diabetes Randomised controlled studies (see Table 5)
who had or were at risk for atherosclerotic cardiovascular
disease, treatment with dapagliflozin did not result in a higher Lixisenatide (ELIXA Study) is a short-acting GLP-1 RA re-
or lower rate of MACE than placebo, but did result in a lower quiring twice-daily injections. When tested for Primary
rate of cardiovascular death (4.9% vs. 5.8%; hazard ratio, MACE in a RCT, (ELIXA), it showed no statistical differ-
0.83; 95% CI, 0.73 to 0.95; P=0.005) or hospitalisation for heart ence from standard therapy of care (see Figure 7).15
failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88), a finding that
reflects a lower rate of hospitalisation for heart failure.14 Figure 7. Lixisenatide vs. placebo primary outcomes

Glucagon-like peptide-1 receptor agonists LEADER (Liraglutide and Cardiovascular Outcomes in Type 2
Diabetes).16 The results of liraglutide for both the Primary MACE
Table 4 lists the glucagon-like peptide-1 receptor ago- outcomes (13% reduction) and death from cardiovascular
nists (GLP1-1RA) studies that have been conducted. causes (22% reduction) were both statically significant and
Only those of relevance to the current article will be showed superiority over standard care (see Figure 8).
discussed. Semaglutide studies have been conducted
in South Africa (SA), but this drug has not yet been regis-
tered for use. Lixisenatide is not registered in SA.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 61

EXSCEL: Effects of once-weekly exenatide on cardio- Treatment approaches
vascular outcomes in type 2 diabetes.18 For primary
cardiovascular outcomes, all-cause mortality, death
from cardiovascular causes and hospitalisation for heart
failure (see Figure 10).

Figure 8. Liraglutide primary outcomes and death from Key therapy considerations:
cardiovascular causes
a Summary
SUSTAIN 6 (Semaglutide and Cardiovascular Outcomes
in Patients with Type 2 Diabetes).17 The results for sema- The current standard of therapy for type 2 diabetes
glutide for the Primary MACE outcomes (26% reduction) recommends initiation of therapy with metformin at
are statistically significant (see Figure 9). Weight loss was the time of diagnosis.
also greater in this trial, as compared to the LEADER trial. • If glycaemic targets are not reached (HbA1c <7%),
Further trials in the future are being planned for this drug.
a second drug is commenced. It is usually a sulph-
Figure 9. Semaglutide primary outcome onylurea (a modified-release gliclazide is recom­
mended).
• If hypoglycaemia is a problem, or treatment of the
elderly is considered, a DPP-4 Inhibitor is a good
choice, because of low hypoglycaemia risks.
• If weight is a problem, or the patient has established
cardiovascular disease, consideration should be
given to SGLT2 Inhibitors (tablets) or GLP-1 RA (sub-
cutaneous injection). SGLT2 inhibitors should not be
initiated if the eGFR is <60 ml/min/1.73 m2.
• Cost considerations are also important in the selec-
tion of drugs.
• In type 2 diabetes patients with established athero-
sclerotic cardiovascular disease, the ADA/EASD
Guidelines recommend the choice of empagliflo-
zin as the SGLT2 inhibitor of choice, or liraglutide
as the GLP-1 RA of choice because of their docu-
mented, beneficial cardiovascular effects.19

Table 5. Trials with GLP-1 therapeutics

ELIXA LEADER SUSTAIN-6 EXSCEL
Liraglutide Semaglutide Exenatide
Medication Lixisenatide 9 340 2 735 14 000
T2D, high-risk CVD T2D, high-risk CVD T2D, with prior CV events
# Patients 6 068 and/or with or w/o known
Multi-centre, double- Multi-centre, double- CV risks
History T2D, acute coronary blind, placebo-con- blind, placebo-con- Phase 3/4 multi-centre,
event within 180 days trolled; non-inferiority, trolled; non-inferiority, randomised, double-
prior to randomisation superiority superiority blind, placebo-con-
3-point MACE: CV death, 3-point MACE: CV death, trolled, parallel-group
Study design Multi-centre, randomised, non-fatal MI, non-fatal non-fatal MI, non-fatal 3-point MACE: CV death,
double-blind, placebo- stroke stroke non-fatal MI, non-fatal
controlled; non-inferiority, stroke
superiority Liraglutide group: 13.0% Semaglutide group: 6.6%
Placebo group: 14.9% Placebo group: 8.9% Ongoing
Primary outcome 4-point MACE: CV death, HR 0.87; 95% Cl 0.78-0.97 HR 0.74: 95% Cl, 0.58 to
non-fatal MI, non-fatal P <0.001 for non-inferiority 0.95
stroke, hospitalisation for P = 0.01 for superiority P <0.001 for non-inferiority
unstable angina (coro- Reduction in all-cause Increased risk of retino­
nary revascularisation) mortality in Rx group pathy in semaglutide
(8.2% vs. 9.6% in placebo group
Results Lixisenatide group: 13.4% group; HR 0.85; 95% Cl
Placebo group: 13.2% 0.74-0.97; P = 0.02
HR 1.02; 95% Cl 0.89-1.17
P <0.001 for non-inferiority
P = 0.81 for superiority

Additional
benefits/risks

World of Example. Ponywatches.com

HANDBOOK OF GENERAL MEDICINE VOL 1

62 TREATMENT APPROACHES

Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017; 377:1228-1239

Figure 10. Exenatide ER vs. placebo outcomes

REFERENCES 13. Neal B, Perkovic V, Mahaffrey KW, et al. Canagliflozin and cardio-
vascular and renal events in type 2 diabetes. N Engl J Med. 2017;
1. IDF Atlas 2018. Diabetes Res Clin Pract. 2018 Apr;138:271-281. doi: 377:644-657
10.1016/j. diabres.2018.02.023. Epub 2018 Feb 26.
14. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular
2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357
infarction and death from cardiovascular causes. N Engl J Med.
2007; 356:2457-2471 15. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with
type 2 diabetes and acute coronary syndrome. N Engl J Med.
3. Food and Drug Administration Center for Drug Evaluation and Re- 2015;373:2247-2257
search. Guidance for industry diabetes mellitus – evaluating cardio-
vascular risk in new antidiabetic therapies to treat type 2 diabetes. 16. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and
CDER. 2008. http://www.fda.gov/downloads/Drugs/GuidanceCom- cardiovascular outcomes in type 2 diabetes. N Engl J Med.
plianceRegulatoryInformation/Guidances/ucm071627.pdf 2016;375:311-322

4. Bergenstal RM, et al. Type 2 diabetes: Assessing the relative risks 17. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular
and benefits of glucose-lowering medications Am J Med. 2010 outcomes in patients with type 2 diabetes. N Engl J Med. 2016;
Apr;123(4):374.e9-18. doi:10.1016/j. amjmed.2009.07.017. 375:1834-1844

5. Gerstein HC, Bosch J, Dagenais GR, et al. ORIGIN Trial Investigators. 18. Holman R, Bethel MA, Mentz RJ, et al. Effects of once-weekly ex-
Basal insulin and cardiovascular and other outcomes in dysglyce- enatide on cardiovascular outcomes in type 2 diabetes. N Engl J
mia. N Engl J Med. 2012;367;319-328 Med. 2017;377:1228-1239

6. Marso SP, McGuire DK, Zinman B, et al for DEVOTE Study Group. 19. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyper-
Efficacy and safety of degludec versus glargine in type 2 diabe- glycemia in Type 2 Diabetes, 2018. A consensus report by the
tes. N Engl J Med. 2017 Aug 24;377(8):723-732. doi: 10.1056/NEJ- American Diabetes Association (ADA) and the European Associa-
Moa1615692. Epub 2017 Jun 12. tion for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;
41(12):2669-2701. https://doi.org/10.2337/dci18-0033
7. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardio-
vascular outcomes in patients with type 2 diabetes mellitus. N Engl
J Med. 2013;369:1317–26

8. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin
on cardiovascular outcomes in type 2 diabetes. N Engl J Med.
2015;373:232-42

9. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute cor-
onary syndrome in patients with type 2 diabetes. N Engl J Med.
2013;369:1327-35

10. Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design,
and baseline characteristics of the CArdiovascular safety and Re-
nal Microvascular outcomE study with LINAgliptin (CARMELINA®):
A randomized, double-blind, placebo-controlled clinical trial in
patients with type 2 diabetes and high cardio-renal risk. Cardio-
vascular Diabetology, 2018;17:39.

11. Davidson JA. Advances in therapy for type 2 diabetes: GLP-1 re-
ceptor agonists and DPP-4 inhibitors. Cleve Clin J Med. 2009;76(Sup-
pl. 5):S28-S38 [PubMed].

12. Amori RE, Lau J, Pittas AG, et al. Efficacy and safety of incretin ther-
apy in type 2 diabetes: Systematic review and meta-analysis. JAMA
2007;298:194-206 [PubMed].

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TREATMENT APPROACHES 63

Bronchospasm: diagnosis and treatment Treatment approaches

M Mukansi Impact on society

MBChB, MMed (Wits), FCP(SA) Cert Pulmonology (SA) FCCP The morbidity and mortality of the disease have a signi-
MBL(Unisa) ficantly high direct (hospitalisation and therapy) and
Division of Pulmonology, Department of Internal Medicine, indirect (loss of productivity) economic cost to society
Helen Joseph Hospital and Faculty of Health Sciences, and the healthcare system.2,6 Most of the deaths are
University of the Witwatersrand, Johannesburg preventable, being due to sub-optimal treatment and
delay in obtaining help in the final attack.
Bronchospasm is the spasmodic contraction of the
bronchial smooth muscle. Other factors contributing to Pathophysiology
airway narrowing with airway resistance and broncho­
spasm are mucosal oedema, excessive mucus produc- There is a complex interaction between inflammatory
tion and plugging and desquamation of bronchial epi- and resident airway cells. Mast cells, eosinophils, lym-
thelium (see Figure 1).1 Bronchospasm may be a clinical phocytes and their associated products appear promi-
feature of underlying hyperactivity, e.g. asthma, or with­ nent in the airways. Inflammatory events and associated
out underlying disease. The airway calibre of asthmatics alterations in airway smooth muscle function result in
is small, and any further decrease in diameter will have bronchospasm, and structural changes are noted, in
a major effect on airway diameter. This exaggerated particular within the epithelium and sub-epithelium. Fi-
response follows exposure to mechanical or chemical broblasts and smooth muscle bronchial hyper-respon-
irritants or toxins. It presents with cough, wheezing and/ siveness are a manifestation of exaggerated reversible
or dyspnoea.1, 2 airway obstruction due to smooth muscle contraction.1,9
Structural cells, in particular the epithelium, fibroblasts,
Figure 1. Multiple mechanisms of airflow obstruction1 smooth muscle and endothelium, may contribute to
inflammation and/or airway remodelling through the
Prevalence of the disease elaboration of mediators and cytokines. A variety of
genetic, environmental and infective factors appears
The prototype cause of bronchospasm is asthma. A to modulate whether susceptible individuals progress
world health survey conducted between 2002 and to overt asthma. Targeting key components of airway
2003 found that >10% to 15% of South Africans aged inflammation and remodelling is the subject of develop-
18 to 45 years experienced asthma symptoms over a ment in new asthma therapy.1,9
12-month period. South Africa is ranked fourth in the
world for asthma-related mortality in the five- to 34-year Variable airflow limitation and airway hyper-respon-
age group, despite being ranked 25th in the world for siveness represent an exaggerated contractile response
asthma prevalence. Many of the deaths would be pre- of the airway to a variety of stimuli. Intrinsic abnormalities
ventable if suboptimal therapy and delay in presenta- in airway smooth muscle function, airway remodelling
tion could be corrected.3 While high-income countries in response to injury or inflammation, and interactions
have seen a plateau in asthma, developing countries between epithelial and mesenchymal cells appear to
are witnessing an increase.2,6 modulate and add to the effects of airway inflamma-
tion in creating the clinical presentation of asthma.1
Whether the individual is atopic or not, inflammation
in asthma generally involves the same cells that play
a prominent role in allergic responses in the nasal pas-
sages and skin. Initial allergen exposure is followed by
the elaboration of specific IgE antibodies. IgE is a mol-
ecule with a crucial role in the pathogenesis of bron-
chial hyper-reactivity (BHR).8 Regulation of specific IgE
production appears related to overexpression of Th2-
type T-cell response relative to the Th1. Th2 lymphocytes
and their mediators (IL-4, IL-5, IL-13) also contribute to
the development of bronchial hyper-reactivity.8 This is
likely to be a combination of genetic and environmen-
tal influences.

After allergen-specific IgE antibodies are synthesised
and secreted by plasma cells, they bind to high-affinity
receptors on mast cells. When an allergen is subsequent-
ly inhaled and comes into contact with mucosal mast
cells, it cross-links allergen-specific IgE antibodies on the
mast-cell surface, and rapid degranulation and media-

HANDBOOK OF GENERAL MEDICINE VOL 1

64 TREATMENT APPROACHES

tor release follow in a calcium-dependent process. The show significant reversibility (FEV1 >12% and 200 ml im-
mediators include histamines, prostaglandin D2, and provement), while COPD has no significant reversibility
cysteinyl leukotrienes (LTC4, D4 and E4) and contrac- unless it forms part of the ACO (asthma COPD over-
tual airway smooth muscles (ASM) directly, and may lap) entity. In patients who do not meet the criteria of
also stimulate reflex neural pathways.11 This early-phase asthma, COPD, or ACO, or who are unresponsive to
response coincides with an influx of inflammatory cells, bronchodilators and anti-inflammatory therapy, a care-
including the innate immune cells, such as monocytes, ful examination of the flow-volume loop is warranted.
dendritic cells and neutrophils. The mediators released This evaluation will assist in determining the location of
by cells associated with adaptive immunity (T-lympho- the airway obstruction in the extrathoracic or intratho-
cytes, eosinophils and basophils) also cause ASM con- racic area and whether the airway obstruction is dy-
traction that is largely reversible by b-2 agonists.13 While namic or fixed, as illustrated in Figure 2.7
earlier studies failed to show consistent efficacy of bio-
logical agents related to the Th2 cytokines (IL-4, IL-5 and
IL-13), recent studies have shown improved lung func-
tion and reduced exacerbation rates.

Diagnostic issues A. Normal.
B. Variable extrathoracic upper airway obstruction, e.g. paroxysmal
When evaluating bronchospasm, it may be useful to re-
call the adage, “all that wheezes is not asthma (COPD), vocal cord motion.
all that wheezes is an obstruction.” While asthma and C. Variable intrathoracic upper airway lesions, e.g. distal tracheomalcia
COPD are the most common causes of wheezing, a va- D. Fixed upper airway obstruction, e.g. laryngeal tumour (extrathorac-
riety of other conditions can produce airflow obstruc-
tion and thereby expiratory and/or inspiratory wheezes. ic) vs tracheal stenosis (intrathoracic).
When bronchospasm and associated symptoms persist E. Lower airway obstruction.
despite optimal therapy (including inhaler technique),
one must consider the mimickers tabulated in Table 1.4 Figure 2. Schematic flow-volume loop configuration in a
spectrum of airway lesions7
A careful history and physical examination will narrow
the causes of bronchospasm (wheezes) and direct the In addition to visual inspection, the ratio of forced in-
work-up. These clues include, but are not limited to, the spiratory flow (FIF) at 50 to forced expiratory flow (FEF) at
location of a wheeze. Is it anterior to the neck, anterior to 50 when lower than 1, may suggest variable extra-tho-
the chest or posterior to the chest? Is the wheeze focal racic obstruction, as compared to normal where FIF50 is
or diffuse? Are there any extrapulmonary findings, such usually higher than FEF50.
as tonsillar hypertrophy, thyroid goitre, or lymphadeno-
pathy in the neck area, or inflammation of the cartilage The results of the flow-volume loop guide the next
of the nose or ears suggesting relapsing polychondritis? steps in the evaluation. When central airway obstruc-
Are stigmata of rheumatoid arthritis present, suggesting tion is suspected, imaging studies are warranted, e.g.
crico-arytenoid arthritis with airway obstruction?

Pulmonary function testing

The initial evaluation of stable, ambulatory patients is
a spirometry pre- and postbronchodilator. Asthmatics

Table 1. Causes of wheezing other than asthma, based on the anatomic site of obstruction

Extra-thoracic upper airway obstruction Intra-thoracic upper airway obstruction Lower airway obstruction
Postnasal drip syndrome Tracheal stenosis Asthma
Paroxysmal vocal cord motion Foreign body aspiration Pulmonary oedema
Hypertrophied tonsils Benign airway tumours Pulmonary embolism
Supraglottitis Malignancies Bronchiolitis
Laryngeal oedema Intrathoracic goitre Carcinoid syndrome
Laryngostenosis Tracheobronchomegaly Parasitic infections (Loeffler’s syndrome)
Post-extubation granuloma Tracheomalacia Bronchiectasis
Retropharyngeal abscess Cardiac asthma
Benign airway tumour Reactive airway dysfunction syndrome
Anaphylaxis Post-viral infection
Malignancy Drug-induced obstruction
Obesity Toxic gas inhalation
Bilateral vocal cord paralysis
Crico-arytenoid arthritis
Granulomatosis with polyangiitis

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TREATMENT APPROACHES 65

chest CT-scan. On the other hand, when the spirometry • Respiratory therapy Treatment approaches
suggests extra-thoracic obstruction, a laryngoscopy or Clearance of secretions is a significant challenge in
bronchoscopy may be indicated.7
obstructive lung disease. Adequate hydration and
Bronchoprovocation challenge test humidification of inspired gases reduce drying of the
Despite suggestive clinical circumstances, when asth- airways and improve mobilisation of secretions.
ma and RADS have not been excluded, normal spirom- • Treat infections
etry warrants a challenge test. A negative methacho- Administer appropriate treatment for respiratory in-
line challenge test in a patient not on anti-inflammatory fection. Avoid surgery if the infection is not eradicat-
medications, provides strong evidence against asth- ed, particularly if elective. Targeted antibiotic thera-
ma or RADS. Paradoxical vocal cord motion devel- py is recommended more than empiric therapy.
ops flattening of the inspiratory curve in response to a • Premedication for surgery11
pharmacological challenge test, and direct laryngos- Prescribe pre-anaesthetic medication to reduce
copy will assist in confirming the diagnosis.2,5,7 anxiety and relieve the discomfort of procedures.
Benzodiazepines are effective. While narcotics may
Chest radiograph provide pre-operative analgesia, they should be ti-
A chest radiograph is called for in new-onset or refrac- trated carefully in patients with carbon dioxide (CO2)
tory bronchospasms. All patients with a combination of retention. While narcotics may cause histamine re-
bronchospasm, acute respiratory distress and poor re- lease, there is little evidence that premedication
sponse to inhaled bronchodilator therapy, should also be causes clinically significant bronchoconstriction.
x-rayed. A chest radiograph is also warranted in patients • Anaesthesia10
with a focal wheeze, and with recurrent or persistent Suggest consideration of regional anaesthesia in
wheezing that is not clearly asthma- or COPD-related.15 asthmatics/COPD to minimise bronchoconstriction.
Induction with agents such as propofol, may reduce
Chest computerised tomography scan the chance of wheezing, especially when compared
A chest computerised tomography (CT) scan can be to other agents. Anaesthetic agents may block
ordered, based on chest radiograph and pulmonary para­sympathetic irritant pathways, relax bronchial
function tests to identify vascular structures, mediastinal smooth muscles and augment b-2 adrenergic re-
masses or lymphadenopathy, which can extrinsically sponses, e.g. ketamine. Inhalational agents depress
compress the trachea, among others. A high-resolution airway reflexes and cause bronchodilation. They are
CT-scan, looking at the smaller airways and lung paren- recommended for maintenance of general anaes-
chyma, can assist in the diagnosis of bronchiectasis and thesia in patients with bronchospasm.
constrictive bronchiolitis. Lastly, a dynamic (end-inspir- • Mechanical ventilation of bronchospasm11
atory and expiratory) CT-scan can be used to detect Controlled ventilation using slow rates and prolonged
tracheomalacia and airway collapsibility.15 expiratory time will minimise air-trapping. Monitor
chest movements, inspiratory pressures and expira-
Direct visualisation tory date. End-tidal carbon dioxide is invaluable.
Direct visualisation often complements the aetiology of
wheezing suspected on the basis of pulmonary function Pharmacological therapy2,4,13
testing and imaging. Furthermore, at the time of visu-
alisation, a biopsy can be obtained of, e.g. intraluminal We shall now discuss the pharmacological therapy of
masses, such as tumour, amyloid, and papilloma. Laryn- bronchospasm.
goscopy is a logical step in cases of suspected extra- • ß-2 agonists
thoracic obstruction, while a bronchoscopy is ideal in ß-2 agonists include salbutamol, albuterol and terb-
the case of intrathoracic obstruction.2,5
utaline. Epinephrine is indicated for allergic cases.
Treatment2,4 • Anticholinergics
Ipratropium bromide causes bronchodilation and
The goals of therapy are to reverse bronchospasm,
dampen inflammation, clear secretions, treat the trig- enhances the action of ß-2 adrenergic agents. Other
ger and reduce the frequency and severity of exacer- anticholinergics include glycopyrrolate and tiotro-
bations. pium.
• Corticosteroids
Supportive therapy Glucocorticoids are useful in bronchospasm. Possi-
• Avoid triggers ble mechanisms include dampening inflammation,
Avoid or minimise exposure to environmental al- histamine release and inhibition of arachidonic acid
metabolism. Steroids may also increase the sensitivity
lergens and irritants, e.g. cold air, endotracheal of the airways to ß-2 agonists.
tubes and latex. Ideally, elective surgery should be • Magnesium sulphate
delayed. Agents that precipitate GERD should be According to a Cochrane review, inhaled magne-
avoided. sium sulphate nebulised and combined with a ß-2
agonist, such as albuterol, may relieve bronchos-
pasms.12 It can also be administered intravenously,
leading to improved pulmonary function.

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66 TREATMENT APPROACHES

• Theophylline
In the majority of cases, ß-2 agonists are the preferred

bronchodilator because of fewer side effects and a
comparable effect. In adults, their role may be lim-
ited to a small proportion (10%) of patients with ster-
oid-resistant asthma.

When to refer2,4,14

Referral of the patient to a specialist is required if he/she
presents with the following conditions.
• Diagnostic uncertainty
• If, after four to six hours, the bronchospasm is not re-

sponding to reliever medications.
• When the bronchospasm is associated with cardio-

vascular collapse or has serious concomitant cardi-
ac complications.
• If the bronchospasm is caused by a pulmonary em-
bolism.
• When the bronchospasm is associated with other co-
morbidities.
• Bronchospasm associated with impending respira-
tory failure/respiratory arrest.
• Airflow obstruction associated with mental confusion.
• Any patient with severe airflow obstruction who de-
teriorates despite adequate therapy.
• Inadequacy of support and home conditions.
• Cause and severity of prior exacerbations, e.g. ICU
admission and/or intubation.

References

1. Doeing DC, Solway J. Airway smooth muscle in the pathophysiology
and treatment of asthma. J Appl Physiol. 2013;114(7):834-843.

2. Global Initiative for Asthma. Global strategy for asthma manage-
ment and prevention. 2018. Available from: www.ginasthma.org.
Accessed December 18, 2018.

3. Zar HJ, Lalloo UG. Acute asthma treatment guidelines: Reducing mor-
bidity and mortality in South Africa. S Afr Med J. 2013;103(3):159-160.

4. Lalloo UG, Ainslie AG, Abdool-Gaffar AS. Guidelines for the man-
agement of acute asthma in adults: 2013 update. S Afr Med J.
2013;103(3):189-198.

5. Gherasim A, Dao A, Bernstein JA. Confounders of severe asthma:
diagnoses to consider when asthma symptoms persist despite opti-
mal therapy. World Allergy Organ J. 2018;11(1):29.

6. Masekela R, Gray CL, Green RJ, et al. The increasing burden of
asthma in South African children: a call to action. S Afr Med J.
2018;108(7):537-539.

7. Aboussouan LS, Stoller JK. Flow-volume loops. In: UpToDate, Post TW
(Ed), UpToDate, Waltham, MA. Accessed on January 25, 2019.

8. Robinson DS. The role of the T cell in asthma. J Allergy Clin Immunol.
2010;126:1081.

9. Antosova M, Strapkova A, Plevkova J. Bronchial hyper-reactivity:
pathogenesis and treatment options. Open J Mol Integrative Physi-
ol. 2011;01;43-56.

10. Benca J. Bronchospasm. In: Atlee JL, ed. Complications in anaesthe-
sia. Second edition. Philadelphia: Saunders Elsevier;2006:189-192.

11. Riccio MM, Proud D. Evidence that enhanced nasal reactivity to
bradykinin in patients with symptomatic allergy is mediated by neu-
ral reflexes. J Allergy Clin Immunol.1996;97:1252.

12. Rowe BH, Bretzlaff J, Bourdon C, et al. Magnesium sulfate for treat-
ing exacerbations of acute asthma in the emergency department.
Cochrane Database of Systematic Reviews. 2000; Issue 1. Art. No.:
CD001490. DOI: 10.1002/14651858.CD001490.

13. Peebles RS Jr, Permutt S, Togio SA. Rapid reversibility of the allergen-
induced pulmonary late phase reaction by an intravenous beta2-
agonist. J Appl Physiol. (1985) 1998;84:1500.

14. Price D, Bjermer L, Bergin DA. Asthma referrals: A key component
of asthma management that needs to be addressed. J Asthma Al-
lergy. 2017;10:209-223.

15. Ash SY, Diaz SJ. The role of imaging in assessment of severe asthma.
Curr Opin Pulm Med. 2017;23 (1):92-109.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 67

Chronic cough: therapeutic approach Treatment approaches

AD Black sensation of airway irritation and the urge to cough. Ac-
tivation of spinal motor nerves to the larynx, intercostal
MBBCh, FCP, Cert Pulmonology, FCCP muscles and the diaphragm completes the reflex arc
and produces coughing. In some cases, coughing can
Head of Pulmonology, Helen Joseph Hospital, be suppressed voluntarily, and a cough can also be ini-
Department of Medicine, University of the Witwatersrand, tiated voluntarily.6
Johannesburg
Persons with chronic cough may have a heightened
Cough is the most common reason for persons visiting cough reflex secondary to a hyper-responsive neuronal
primary healthcare facilities in South Africa.1 Cough is pathway. This cough reflex results not only in a reduction
classified according to the duration of symptoms to al- of the stimulus required to evoke a cough, but also in a
low for the narrowing of aetiological possibilities. Chron- substantial increase in the number of coughs to a given
ic cough is defined as a cough of more than eight stimulus. Cough reflex hypersensitivity may be transient
weeks’ duration. and reversible, but may be permanent in a subgroup
of patients complaining of long, severe coughing spells.
In a recent epidemiological meta-analysis, the global In patients with cough hypersensitivity syndrome, usually
prevalence of chronic cough was estimated to be 9,6% middle-aged women, an empiric treatment approach
amongst adults, with a lower incidence of 2.3% in stud- may improve symptoms, but rarely stops the cough
ies from Africa.2 This prevalence is probably an underes- completely. The importance of cough reflex hyper-
timate, considering that a cross-sectional study across sensitivity in patients has been recognised and work is
Gauteng and the North West province found 18% of being done to develop pharmacological therapies,
persons over 55 years of age reported having had a specifically targeting receptors within the cough-reflex
cough lasting for at least three months in the past year.3 neural pathway.7

Chronic cough is associated with an increased prob- Therapeutic approach
ability of doctor’s visits and sick-leave days and a lower
quality of life. It affects not only patients, but their fami- Initial clinical evaluation should consist of a detailed
lies as well. Patients with chronic cough often complain history to identify and look for obvious aetiological fac-
of a prolonged paroxysm of coughing which causes so- tors and red flags that may require further appropriate
cial embarrassment and may result in syncope, urinary investigations. Common specific aetiological factors
incontinence and rib fractures. Not only are the symp- include smoking, COPD, ACE inhibitor use, tuberculosis,
toms disturbing, but patient expectations are often not bronchiectasis, lung cancer and interstitial lung disease.
met by their healthcare providers. In a survey of 1 120
people with a chronic cough, a diagnosis was given in Smoking: Smokers should be encouraged to stop
only 53% of cases, and 70% of the patients felt that their smoking, and their symptoms should resolve within six
doctor had not dealt with their cough successfully.4 weeks of smoking cessation. All smokers with a pack-
year history of >20 years should have spirometry to as-
Chronic cough can be treated effectively in the ma- sess for airflow obstruction and smokers >45 years of age
jority of patients, using stepwise empirical therapy with- with a new or changed cough or voice changes need a
out the need for extensive investigations.5 It is essential chest x-ray and assessment for pulmonary malignancy.
for the healthcare provider to explain the rationale for
this approach, i.e. the fact that improvement takes time, Occupational history, as well as pollution exposure,
and that in some patients, treatment success would be should be explored and depending on the exposure,
a decrease in frequency and duration of cough sever- may require further investigations to exclude occupa-
ity, rather than the absence of cough. tionally-related lung disease.

Pathophysiology ACE inhibitor: A drug history, particularly for ACE inhibi-
tor use, is essential. ACE inhibitor-induced cough usually
Cough is a normal defensive reflex that protects the occurs in the first few weeks of treatment, but may hap-
airways from inhaled foreign bodies, excessive mucous pen later. The cough usually disappears within a few
and noxious irritants. The reflex arc is initiated by the weeks of discontinuing the ACE inhibitor. All patients
stimulation of sensory vagal afferent nerves. There are with chronic cough should stop ACE inhibitors even if
two main subtypes of sensory vagal afferent nerves. The it is not thought to be the main cause of the cough,
first is found throughout the airways and is activated in as ACE inhibitors increase cough-reflex hypersensitivity.
response to irritant chemicals, heat, acidity and inflam- ACE II inhibitors are a suitable substitute.
matory mediators. The second responds to osmolarity,
acidity and mechanical stimuli and is found in the proxi- Infection: A history of recent infections is essential;
mal airways. Stimulation of these airway nerves transmits most post-viral infection-related coughs resolve within
signals to the brainstem that carries information to corti- eight weeks. However, Bordetella pertussis infection may
cal and sub-cortical areas of the brain, resulting in the
HANDBOOK OF GENERAL MEDICINE VOL 1

68 TREATMENT APPROACHES

lead to a persistence of cough beyond eight weeks. targeting the most likely cause. Remember that more
This cough syndrome is characterised by paro­xysms of than one process may be present and failure of, or only
coughing, post-tussive vomiting and whooping. Labo- partial response to, an adequate trial of empiric thera-
ratory diagnosis is via PCR of pharyngeal swabs. Myco- py requires sequential empiric treatment for the remain-
bacterium tuberculosis must be excluded, particularly if ing major aetiologies (see Figure 1).
there is a history of fevers, night sweats and weight loss.
Testing of sputum with GeneXpert ultra has a high sensi- Eosinophilic airways
tivity and specificity and provides information regarding
rifampicin sensitivity. Asthma/cough-variant asthma: A history of episodic
wheezing and dyspnoea supports a diagnosis of asth-
Physical examination should pay particular attention ma, but patients may present with a chronic cough as
to the ENT examination and must include examination the only feature.
of the ears, as well as respiratory and cardiovascular
systems. Variable airflow obstruction, as evidenced by peak
flow variability >20% or reversibility of FEV1 >12% post-
All patients with a chronic cough must have a PA and short-acting beta agonist, will clinch the diagnosis. Un-
lateral chest x-ray. Consider testing for HIV infection in fortunately, these tests have a very low negative predic-
all patients as HIV infection will increase the potential tive value, and an empiric trial of inhaled corticosteroids
differential diagnosis. (ICSs) is advocated even in the absence of a negative
airway reversibility test. An improvement in cough se-
Red flags that require further investigation when pre- verity after a six-week trial of moderate-dose, inhaled
sent are listed in Table 1. corticosteroids (beclomethasone or equivalent 400
micrograms twice daily) is highly suggestive of cough-
Table 1. Red flags in chronic cough variant asthma. In patients with cough-variant asthma,
the cough returns on cessation of inhaled cortico-
On history steroids and up to a third of patients goes on to develop
Dyspnoea classic asthma. In patients who respond, management
Significant sputum production is with long-term, inhaled corticosteroids weaned to the
Haemoptysis lowest dose that controls the cough. Currently, there
Fever is no proven role for bronchodilator therapy in cough-
Weight loss variant asthma.8
Voice changes
Dysphagia Non-asthmatic eosinophilic bronchitis: The condition
Recurrent respiratory tract infections is characterised by eosinophilic airway inflammation
On examination with no variable airway inflammation. Non-asthmatic
Any abnormal cardiac or respiratory system findings eosinophilic bronchitis responds to inhaled cortico-
On investigation steroids. In cough-variant asthma, wean the dose of in-
Abnormal spirometry haled corticosteroids to stop the cough, or in the case
Abnormal chest x-ray of recurrence of cough, maintain it at the lowest dose
that controls the cough.
In the majority of non-smokers who are not taking
an ACE inhibitor, and who have no red flags, one or a For both eosinophilic airway conditions, inhaled
combination of four aetiologies will explain the chronic corticosteroids are effective in reducing both cough se-
cough. verity and cough reflex hypersensitivity.

The four dominant aetiologies can be divided into Non-eosinophilic airways
two groups:
• Eosinophilic airways (asthma/cough-variant asthma Upper airway cough syndrome. Patients with a post-
nasal drip of any aetiology, such as allergic, perennial,
and non-asthmatic eosinophilic bronchitis [NAEB] non-allergic and vasomotor rhinitis, rhinosinusitis or na-
and sopharyngitis, can present with a chronic cough as the
• Non-eosinophilic airways (gastro-oesophageal reflux only symptom. On history, one should enquire about na-
disease [GORD] and upper airway cough syndrome sal symptoms, a sensation of fluid dripping into the back
[UACS]).7 of the throat and frequent throat-clearing. Not all pa-
Other recently identified causes of chronic cough in- tients with a post-nasal drip develop a chronic cough,
clude obstructive sleep apnoea and cardiac arrhyth- and a tickling sensation in the throat may suggest in-
mias. More work is needed to establish their importance creased awareness of stimuli and possible cough-reflex
and frequency as a cause of chronic cough, but the hypersensitivity. Clinical examination may be normal or
resolution of cough has been shown when these condi- reveal a cobblestone appearance of the pharynx. It
tions are treated.7 is important to assess the external auditory meatus as
History and examination should try to identify which of foreign bodies may place pressure on Arnold’s nerve
the four aetiologies is the most likely in the individual pa- and stimulate the cough reflex.9 Radiological imaging
tient. Once established, start an empiric trial of therapy of the sinuses does not assist in the initial diagnosis and is
unnecessary. Empiric treatment consists of a two-week
HANDBOOK OF GENERAL MEDICINE VOL 1 trial of nasal corticosteroids and an older-generation
antihistamine, such as loratadine 10 mg orally at night.

TREATMENT APPROACHES 69

Initial assessment: Treatment approaches
history, examination,
spirometry, chest x-ray

Investigate and treat Red flags or cause Unexplained with no red flags. 2-week empiric trial for
accordingly identified Non-smoker. No ACE UACS inhaled nasal
steroids, and old-

generation antihistamine

• No response: stop empiric 6-week empiric trial for
treatment and proceed to CVA and NAEB. Moderate-
next step
dose ICS
• Partial response: continue and
proceed to next step 2-month empiric trial for
GORD
• Full response: no need to
proceed to next step and High-dose PPI
wean treatment to lowest dose
that controls symptoms

UACS – upper airway cough syndrome, CVA – cough-variant asthma, NAEB – non-asthmatic Failure of adequate
eosinophilic bronchitis, ICS – inhaled corticosteroids, GORD – gastro-oesophageal reflux disease response: referral for further

Figure 1. Sequential empiric management of chronic cough investigation therapies

Gastro-oesophageal reflux disease quential empiric therapy, explain the following points
clearly to the patient:
Both symptomatic and asymptomatic gastro-oesopha-
geal reflux disease (GORD) may present with a chron- The treatment is empiric and targets the leading caus-
ic cough, and as with post-nasal drip, not all persons es of chronic cough.
with GORD develop a chronic cough, suggesting that
cough-reflex hypersensitivity may play a role in chronic More than one cause of chronic cough may be pre-
cough in this group of patients. Patients with GORD and sent in a patient.
warning signs such as dysphagia and haematemesis
should be referred for an upper gastro-intestinal tract The final “diagnosis” is assumed based on the re-
work-up. In patients with no warning signs, a two-month sponse to empiric therapy.
trial of proton pump inhibitor (PPI) therapy, e.g. omepra-
zole 40 mg twice daily or equivalent, is appropriate. The The process is long, and the response is not instanta-
PPI should be discontinued if no improvement in cough neous.
severity is seen after two months.
The cough may not disappear, but a decrease in se-
Patients with upper airway cough syndrome and verity and an improvement in the quality of life can be
GORD-related chronic cough are likely to have hyper- achieved in the majority of cases.
responsive cough reflexes. As the current empiric ther-
apy only decreases aggravating factors and does not A change in the nature of the cough and the devel-
reduce cough reflex hypersensitivity, some of these pa- opment of any warning signs should prompt an early
tients may not achieve adequate symptom relief. re-evaluation.

When treating a patient with chronic cough with se- Patients who do not respond adequately to a com-
plete trial of sequential empiric therapy should be
referred for further, more intensive investigations to
exclude rarer triggers of chronic cough and multi-disci-
plinary management of hyper-responsive cough reflex,
if required.

HANDBOOK OF GENERAL MEDICINE VOL 1

70 TREATMENT APPROACHES

Chronic cough is a common symptom with significant
morbidity for both sufferers and their families. Sympto-
matic control of chronic cough can be achieved in
the majority of individuals with a normal chest x-ray,
where smoking, ACE inhibitor use, and red flags have
been excluded by following a subsequent trial of em-
piric therapy targeting the main aetiological conditions
of chronic cough. A small group of patients who do not
respond will require referral for further investigation and
treatment directed at a hyper-responsive cough reflex.

References

1. Mash B, Fairall L, Adejayan O, et al. A morbidity survey of South
African primary care. PLoS One. 2012;7(3):e32358. Doi:10.1371/jour-
nal.pone.0032358.

2. Song W, Chang Y, Faruqi S, et al. The global epidemiology of chron-
ic cough in adults: A systemic review and meta-analysis. Eur Respir
J. 2015;45(5):1479-81.

3. Nkosi V, Wichmann J, Voyi K. Chronic respiratory disease among
the elderly in South Africa: An association with proximity to mine
dumps? Environ Health. 2015;14:33. Doi: 10.1186/s12940-015-0018-7.

4. Chamberlin S, Garrod R, Douiri A, et al. The impact of chronic
cough: A cross-sectional European survey. Lung. 2015;193(3):401-8.

5. Yu L, Xu X, Hang J, et al. Efficacy of sequential three-step empirical
therapy for chronic cough. Respirology. 2017;11(6):225-232.

6. Satia I, Badri H, Al-Sheklly B, et al. Towards understanding and man-
aging chronic cough. Clin Med. 2016;16(6):s92-7.

7. Perotin J, Launois C, Dewolf M, et al. Managing patients with
chronic cough: Challenges and solutions. Ther Clin Risk Manag.
2018;14:1041-50.

8. Pandya A, Lee K, Birring S. Cough Medicine. 2016;44(4):213-16.
9. De Blasio F, Virchow J, Polverino M, et al. Cough management: A

practical approach. Cough. 2011;7(1):7. Doi: 10.1186/1745-9974-7-7.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 71

Chronic obstructive pulmonary disease Treatment approaches

A Peter Neutrophils, alveolar macrophages and lymphocytes
are the predominant inflammatory cell types in response
MBBCh (Wits), DA(SA), FCP(SA) Cert Pulm. to noxious particle inhalation. In patients with an asth-
ma overlap or who are responsive to inhaled cortico-
Specialist Physician and Subspecialist Pulmonologist; steroids, there is an increased eosinophilic count.5 This
Full-time Principal Specialist, Department of Medicine, COPD phenotype responds to steroids, which inhibit eo-
Chris Hani Baragwanath Academic Hospital, Johannesburg sinophilic inflammation.

Chronic obstructive pulmonary disease (COPD) is esti- Diagnostic issues
mated to be the third most common cause of death
by 2020.1 COPD is defined as a “common, preventable A triad of symptoms, risk factors and spirometry enables
and treatable disease that is characterised by persistent a diagnosis of COPD. Dyspnoea, chronic cough and
respiratory symptoms and airflow limitation that is due to sputum production are the key symptoms. Look for risk
airway and/or alveolar abnormalities usually caused by factors, such as smoking, previous tuberculosis, and oc-
significant exposure to noxious particles or gases”.1 cupational or domestic biomass fuel exposure. A forced
expiratory volume in one second (FEV1) to a forced vital
The prevalence and burden of COPD are related to capacity (FVC) ratio of less than 0.7 predicted for age,
the interplay between host factors together with the sex, weight and ethnicity that does not normalise after
noxious particles and gases that are inhaled. The most bronchodilation, favours COPD in the context of symp-
common noxious gas-particle mixture inhaled is to- toms and risk factors.1
bacco smoke, the primary cause of COPD. However,
approximately 20% of smokers develop COPD and thus Characteristics of the individual symptoms are as follows:
host factors and an individual’s genetic response to • The onset of dyspnoea is gradual, persistent and
noxious stimuli play a role in disease development.1
worse with exercise.
Taking into consideration that occupational and do- • The cough may be productive and intermittent in up
mestic exposure to toxic particles in host-susceptible non-
smokers can also cause COPD (about 25-45% of COPD to 30% of patients with associated wheezing.
patients are non-smokers), as well as the increased risk The former definition of cough-productive sputum for
of COPD amongst immunocompromised patients, the three or more consecutive months over two years for
burden of this disease is much higher than previously chronic bronchitis is difficult to use. The reasons are that
thought, especially in developing countries. Recurrent patients often swallow sputum, underlying bronchiecta-
childhood infections, previous pulmonary tuberculosis, sis may be present, and flare-ups of COPD may produce
chronic asthma, poor intra-uterine growth and malnutri- an increase in sputum volume.1 COPD patients who
tion have been identified as increasing the risk for COPD.2 do not fit the chronic bronchitis profile will, therefore,
In a South African study published in 2003, tuberculosis go undiagnosed either because they do not produce
was found to be a stronger predictor of COPD than to- enough sputum or they produce too much sputum and
bacco smoke, and together with other non-smoking risk are consequently diagnosed as having bronchiectasis.
factors, 50% of COPD patients were non-smokers.3 Wheezing may be heard and be associated with
chest tightness, such as asthma. The periodicity of symp-
Impact on society toms with recovery, the absence of occupational or do-
mestic noxious particle inhalation and smoking history,
COPD patients often have comorbid illnesses and pre- together with either a history of childhood symptoms
sent with repeated exacerbations of their pulmonary dis- or sudden onset of symptoms later in life, help to distin-
ease. Multiple hospital visits with decreased lung function guish asthma from COPD. Wheezing is not diagnostic of
and intensive care place a huge burden on medical and COPD, neither is it diagnostic of asthma.1
social resources. In a 2006 large cohort study, the three- The literature is currently debating the asthma COPD
year mortality rate was 47% post hospital admission, and overlap (ACO); is this one disease entity or two dis-
the average cost per admission was 6 725 Euros.4 eases? Asthmatics who smoke can develop COPD,
patients with COPD can develop late-onset asthma.
Pathophysiology of COPD Late-onset, asthma-like symptoms in a non-smoker who
may fit the patient profile of COPD may be difficult to
The inhalation of noxious particles together with the ge- diagnose as having either asthma or COPD. To aid re-
netic response of the host results in lung inflammation. sponsiveness to inhaled corticosteroids in a patient with
The resultant damage and fibrosis caused by the imbal- COPD or the development of asthma in a patient with
ance between oxidative stress and protease-antipro- COPD. A blood eosinophil count of >2% in studies have
tease imbalance result in fibrosis and damage to the shown steroid responsiveness.6 Inhaled corticosteroids
parenchyma and small airways. Ultimately, obstruction are then used in the control of COPD as a single entity
results from the loss of alveolar attachment and support or in a case of asthma-COPD overlap.
in the small airways – airways collapse prematurely on
expiration before alveolar gas-emptying (see Figure 1). 1 HANDBOOK OF GENERAL MEDICINE VOL 1

72 TREATMENT APPROACHES

Cigarette smoke, biomass fuel fumes and inhaled irritants

Epithelial cells Alveolar macrophages

TNF-a, IL-1b, IL-6, GM-CSF and TNF-a, CXCL1, CXCL8, CCL2 (monocyte chemo-
IL-8 and TGF-b attractant protein 1), leukotriene (LT)B4

Neutrophils, lymphocytes, eosinophils are attracted
into the lung by chemokine mediators

Alveolar destruction, mucous hypersecretion –
airflow obstruction (neutrophils). Hyperactivity
asthma-like symptoms (eosinophils).
Increased neutrophil infiltration and alveolar
destruction (lymphocytes)

Figure 1. Pathophysiology of COPD5: interplay of cytokines released by alveolar epithelial cells and macrophages
causing the pathophysiology of COPD

Differential diagnosis of COPD non-smoker is about 25 ml. In smokers, the average loss
can approximate 40 ml per year. Initially, there is a gain
You may find symptoms of COPD in other chronic ill- of about 50 ml in the FEV1 for the first year after smok-
nesses, which need to be investigated. See Table 1, ing cessation. Thereafter, FEV1 loss approximates that
adapted from the Global Initiative for Chronic Obstruc- of a non-smoker.8 Smokers manage to quit at a rate
tive Lung Diseases Guideline.1 of about 1% per annum, but if medical advice is given
about the benefits of quitting, an increase to about 3%
Differential diagnosis of a COPD exacerbation of smokers who quit can be reached.8
A patient with established COPD may have an exacerba-
tion in which symptoms of cough, sputum production and Pulmonary rehabilitation takes the form of any exer-
dyspnoea suddenly increase. Any or all symptoms may cise that uses the major muscle groups for 20 minutes
get worse. An exacerbation is defined as the worsening for two to three sessions per week. The common types
of symptoms that requires a change in medication and/or of exercise would be brisk walking or static cycling. The
admission to hospital. The American Thoracic Society (ATS) intensity of the activity need not be very high in order for
and the European Respiratory Society (ERS) classify exac- the patient to notice the health benefits.8
erbations as level I if there are mild or moderate symptoms
that can be treated at home and respond to short-acting Annual influenza vaccination
beta agonists or antimuscarinic agents. Level II exacerba-
tion is a hospitalisation that responds to antibiotics and Viral infections cause acute exacerbation of COPD in
corticosteroids with the short-acting agents. Level III is res- about a third of patients and make the bronchial epithe-
piratory failure.1,7 The most common cause for an exacer- lium susceptible to bacterial co-infection. Vaccination has
bation is a bacterial or viral infection and sometimes they a protective effect by limiting the risk of exacerbation by
are combined, as a bacterial infection is superimposed on up to four-fold, compared to non-vaccinated patients.9
a viral infection. The differential diagnosis for an exacerba-
tion is biventricular cardiac failure, pulmonary embolism, Pneumococcal vaccination
pneumonia and acute coronary syndrome.1 Since pa-
tients with COPD often have comorbidities, these alterna- Since Streptococcus pneumoniae is the most common
tive diagnoses should be considered. causal organism in pneumonia, pneumococcal vacci-
nation prevents and decreases the severity of infection
Management in COPD patients.10 Patients under the age of 65 with the
same degree of FEV1 reduction, had a five times lower
Non-pharmacological treatment incidence of streptococcal pneumonia if vaccinated
Smoking cessation is the most critical intervention in the with the 23 valent pneumococcal polysaccharide
management of COPD. The average loss of the forced vaccine (PPV23).11 After the age of 65, adults should be
expiratory volume in one second (FEV1) per year in the vaccinated with a pneumococcal conjugate vaccine
(PCV13) as this is effective in preventing pneumonia
HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 73

Table 1. Differential diagnosis of COPD Treatment approaches

Disease Suggestive features
COPD
Mid-life onset, persistent symptoms, history of noxious particle exposure (smoking,
Asthma biomass fuel exposure – domestic or occupational)

Cardiac failure Early life onset, daily variability of symptoms, worse at night and early-morning, history of
allergy, eczema, rhinitis, childhood asthma, family history of asthma
Bronchiectasis
Chest x-ray shows enlarged heart, signs of pulmonary oedema, restrictive lung function
Tuberculosis rather than obstruction
Obliterative bronchiolitis
Large volumes of often purulent sputa, history of lung infection, dilated bronchi and ring
Panbronchiolitis shadows on HRCT* and chest x-ray

* – high-resolution computed tomography All ages, chest x-ray, infiltrates, microbiological evidence, high prevalence of TB

Younger age, non-smoker, may have rheumatoid arthritis or fume exposure, hypodense
areas on expiratory HRCT

Mainly males of Asian ancestry, non-smokers.
Rhinitis often present, HRCT shows centrilobular nodular opacities with hyperinflation.

with an efficacy of 45% and in reducing pneumococcal Consider inhaled corticosteroids (ICS) if the eosinophil

bacteraemia by 75%. PCV13 must be given at least a count is >300 cells/µL or >2% in the differential blood count.

year after the PPV23.12 Short-acting beta-agonists (SABAs) last four to six

hours and should be used on an as-needed basis or for

Pharmacological treatment in stable COPD the patient in category A with few symptoms. Examples

Long-acting beta-agonist agents (LABAs) and long- of SABAs include albuterol or salbutamol and fenoterol.

acting antimuscarinic agents (LAMAs) are the drugs Long-acting beta-agonists (LABAs) with a 12-hour

of choice in COPD. The newer agents have a 24-hour duration are formoterol and salmeterol. Those with a 24-

duration of action and are given once a day, which hour duration include indacaterol and olodaterol.
makes patient compliance easier. The Global Initiative A long-acting antimuscarinic agent (LAMA) with a 12-
for Obstructive Lung Disease (GOLD) categorises COPD
patients according to the level of FEV1 and, secondly, hour duration is aclidinium bromide. LAMAs with a 24-
according to the exacerbation frequency in conjunc- hour duration are tiotropium, umeclidinium and glyco-
tion with the degree of effort-tolerance impairment. pyrronium bromide.
Treatment choices are suggested according to the
degree of impairment. The spirometry measurement of Methylxanthine use is controversial due to its toxicity
FEV1 is also used to quantify the degree of impairment, profile and modest bronchodilator ability.
but it may not be widely available in general practice.
The combination of a LAMA and LABA in one inhaler
The British Medical Research Council has a modified shows greater efficacy than each agent on its own and
is the reason for combination therapy.

dyspnoea scale with a five-point scoring system from 0-4 LAMA/LABA combinations are:
(mMRC), summarised as follows.1 • 12 hours: formoterol and glycopyrronium
• mMRC 0 – dyspnoea with strenuous exercise • 12-24 hours: indacaterol and glycopyrronium
• mMRC 1 – dyspnoea hurrying up hills, inclines • 24 hours:
• mMRC 2 – dyspnoea walking at own pace on level
- Vilanterol and umeclidinium
ground - Olodaterol and tiotropium
• mMRC 3 – dyspnoea after a few minutes or 100 metres ICS and LABA combinations are:
• Formoterol and beclomethasone
on level ground • Formoterol and budesonide
• mMRC 4 – dyspnoea on dressing, washing – unable

to leave the house

The exacerbation frequencies

used are:

• One or less episode in the previ- >2 exacerbations C LAMA D LAMA: LAMA+LABA:
ous year and not requiring hospi- >1 hospital admission
tal admission – describes classes LABA+ICS1

A and B. 0-1 exacerbation A BAny bronchodilator LAMA / LABA
• Two or more exacerbations or (no admission)

at least one hospital admission –

describes classes C and D. mMRC 0-1 mMRC >2
This is summarised into ABCD

compartments in conjunction with

a mMRC score on the X-axis and an Figure 2. Suggested therapy guided by the ABCD categorisation of patients,
exacerbation rate on the Y-axis.1 as in the GOLD 2019 guidelines1

HANDBOOK OF GENERAL MEDICINE VOL 1

74 TREATMENT APPROACHES

• Formoterol and mometasone or polycythaemia with a haematocrit >55% with PaO2
• Salmeterol and fluticasone of 55-60 mmHg.1
• Vilanterol and fluticasone furoate
Follow-up management entails assessing inhaler tech-
An ICS is combined with a LAMA and LABA as triple nique, smoking cessation, vaccination, and symptom
therapy, facilitating the use of three drugs into a once- management to determine whether the patient has
or twice-daily use. Two triple combination inhalers are greater dyspnoea or exacerbations of COPD. Therapy
available, i.e. is then modified accordingly, as outlined in Table 2.
• Fluticasone, umeclidinium and vilanterol – once daily
• Beclomethasone, formoterol and glycopyrronium – Consider adding ICS when eosinophil count >300
cells/µL or >100 cells/µL and >2 moderate exacerba-
twice daily tions or one hospitalisation.1
The sole use of inhaled corticosteroids is not recom-
mended in COPD.1 Comorbidities in COPD

Phosphodiesterase 4 inhibitors COPD has an increased incidence of the following co-
morbidities that impact on health and survival.1
Roflumilast reduces inflammation without any bron- • Lung: Lung cancer is the most common cause of
chodilatation. It is used in conjunction with inhaled
corticosteroids as a once-daily oral dose. It reduces ex- death in COPD, and its incidence is increased two
acerbations in severe COPD patients. There are, how- to four times with linear increases in proportion to the
ever, significant side effects, e.g. nausea, diarrhoea, severity of the FEV1.15 There is an increased rate of
abdominal pain, insomnia and headache, to name but bronchiectasis among COPD patients.
a few.1 • Cardiovascular disease: COPD is associated with an
increased rate of ischaemic heart disease, atrial fibril-
Mucolytics lation, hypertension, systolic and diastolic failure.
• Osteoporosis, diabetes, depression and anxiety and
The use of mucolytics is controversial. There is a small peripheral vascular disease are all diseases encoun-
quality of life benefit from pooled data that showed that tered more frequently in COPD patients. Gastro-
one exacerbation is prevented every three years.13 Se- oesophageal reflux disease (GORD) results in more
lected COPD populations that produce large amounts acute exacerbations of COPD.
of sputum may benefit from the use of mucolytics.1
Acute exacerbations and management
Antibiotics
Bacterial and viral infections, particularly the rhinovirus
The long-term use of azithromycin or erythromycin re- (the common cold) and noxious particle inhalation can
duces the exacerbation rate of COPD; however bac- precipitate an exacerbation.1 Consequently, increased
terial resistance may develop. Corrected QT-interval mucus production and narrowing of the airways as a result
(cQT), interval ECG-monitoring and audiometry testing of inflammation, result in air-trapping and increased dysp-
for ototoxicity are required. The subpopulation group of noea.1 Why some patients are prone to exacerbations is
COPD patients who may benefit the most from mac- not known. However, the most significant predictor of an
rolides are those older than 65 who suffer frequent ex- exacerbation is previous exacerbations, even though ex-
acerbation with moderate to severe COPD. The recom- acerbations also increase with the severity of COPD.16
mended dosing is three times a week.14 There are no
studies to demonstrate therapy for a longer duration While the majority of exacerbations can be treat-
than one year.1 ed at home with antibiotics, steroids and short-acting
bronchodilators (level I exacerbation), those with the
Domiciliary oxygen following clinical signs and symptoms require hospital
admission (level II and III).1
Oxygen requirement assessment is needed when the
patient has a room oxygen saturation of <88% or <PaO2 Hospital admission criteria:
55 mmHg in two readings over three weeks.1 Alternative- • Poor response to antibiotics, steroids and SABAs
ly, domiciliary oxygen should be considered if there are • Sudden, severe symptoms which may be accompa-
signs of right ventricular failure, pulmonary hypertension
nied by confusion and drowsiness

Dyspnoea Exacerbations

1. LAMA or LABA 1. LAMA or LABA

2. LAMA + LABA 2. LAMA + LABA or

3. Change to different drugs keeping 3. LABA + ICS (eosinophils >300)

the LAMA LABA combination 4. LABA + LAMA + ICS

4. Investigate other causes for dyspnoea 5. Roflumilast

5. Consider LAMA + LABA+ ICS 6. Azithromycin

Consider de-escalating ICS if pneumonia or no response to ICS

Table 2. A stepwise approach to continuing symptoms

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 75

• High respiratory rate with decreased oxygen satura- 5. Barnes PJ. Inflammatory mechanisms in patients with chronic ob- Treatment approaches
tion structive pulmonary disease. J Allergy Clin Immunol [Internet].
2016;138(1):16-27. Available from: http://dx.doi.org/10.1016/j.
• Development of new physical signs, such as pedal jaci.2016.05.011
oedema and cyanosis
6. Barnes PJ, Foop M. Asthma-COPD overlap. Chest. 2016;149(1):2015-6.
• Poor social circumstances that may delay travel to a 7. Halpin DMG, Maldon M. [Full text] Impact and prevention of severe
hospital or home support
exacerbations of COPD. A review of COPD. Int J Chronic Obstr Pulm
• The presence of comorbidities, such as heart failure Dis. 2017;12:2891-2908.
or arrhythmia. 8. McDonald M. Chronic obstructive pulmonary disease 8:
Purulent sputum suggests a superadded bacterial in- non-pharmacological management of COPD. Thorax [In-
ternet]. 2003;58(5):453-7. Available from: http://dw2zn6fm9z.
fection and should be treated with an antibiotic. Green search.serialssolutions.com/?url_ver=Z39.88-2004&rft_val_
or yellow sputum in a multicentre study was culture-pos- fmt=info:ofi/fmt:kev:mtx:journal&rfr_id=info:sid/Ovid:med4&rft.
itive in 58.9% and 45.5% of samples respectively, when genre=article&rft_id=info:doi/&rft_id=info:pmid/12728173&rft.
compared to clear sputum which yielded growth in issn=0040-6376&rft.volume=58&rft.issue=5&rft.spage=453&r
18% of cases.17 In this study, the most common bacte- 9. Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U, et al. Acute
rial isolate was Haemophilus influenzae. It was twice as respiratory illness in patients with COPD and the effectiveness of
common as Streptococcus pneumoniae or Moraxella influenza vaccination.* Chest [Internet]. 2004;125(6):2011-20. Avail-
catarrhalis. able from: http://dx.doi.org/10.1378/chest.125.6.2011
10. Gadsby NJ, Russell CD, Mchugh MP, Mark H, et al. Comprehensive
The acute care bundle of a non-life-threatening exac- molecular testing for respiratory pathogens in community-acquired
erbation consists of determining the presence of respir- pneumonia. Clin Infect Dis. 2016;62(7)):817-23.
atory failure, i.e. 11. Alfageme I, Vazquez R, Reyes N, Mun J. Clinical efficacy of anti-
• Respiratory rate (RR) above 30 breaths per minute pneumococcal vaccination in patients with COPD. Thorax. 2006.
2006;61:189-95.
(b/min) 12. Van Werkhoven CH, Van Deursen AMM, Sanders EAM, et al. Poly-
• Accessory muscle use, with improvement on sup- saccharide conjugate vaccine against pneumococcal pneumo-
nia in adults. NEJM. 2015;372;12:1114-25.
plemental oxygenation by venturi mask of 24-30% O2 13. Poole P, Chong J CC. Mucolytic agents for chronic bronchitis or
and no change in mental status with a PaCO2 of 50- chronic obstructive pulmonary disease. Cochrane. 2015.
60 mmHg.1 14. Herath SC, Normansell R, Maisey S. Preventative antibiotic therapy
for people with COPD. Cochrane. 2018.
The Gold guidelines suggest the following therapy:1 15. Hopkins RJ, Duan FF, Chiles C, et al. Lung cancer risk in COPD.
• If the sputum is purulent, antibiotics are indicated 2017;14(3):392-402.
16. Hurst JR, Vestbo J, Antonio A, et al. Abstract. Susceptibility to ex-
and a five- to seven-day course is given with a five- acerbation in chronic obstructive pulmonary disease. NEJM.
day course of 40 mg of prednisone daily. 2010;362;12:1128-38.
• Combined SABA and SAMA nebulisation is given, 17. Miravitlles M, Kruesmann F, Haverstock D, Perroncel R. Bronchitis ex-
and the frequency is increased. acerbations: A pooled analysis. Eur Respir J. 2012;39(6):1354-60.
• Do a chest-x ray to exclude a pneumothorax, car-
diac failure and pneumonia. HANDBOOK OF GENERAL MEDICINE VOL 1
• Life-threatening respiratory failure requires mechani-
cal ventilation with RR >30 b/min, accessory muscle
use with change in mental state, a pH <7.25, PaCO2
>60 mmHg and hypoxaemia still present on FiO2 of
60%. If no contra-indication exists, consider non-in-
vasive mechanical ventilation before invasive venti-
lation since there is a better gas exchange and the
work of breathing can be supported.

Progression of COPD

Continued cigarette-smoking is the most significant fac-
tor in the progression of COPD. Exacerbations result in
further lung damage and cause further exacerbations.
Smoking cessation, prevention of exacerbations and
treatment of oesophageal reflux, if present, will limit ex-
acerbations and the progression of the disease.8,1

References

1. Alvar A, et al. Global Initiative for chronic obstructive lung disease
[Internet]. 2018. Available from: http://www.who.int/respiratory/
copd/GOLD_WR_06.pdf

2. Sundeep S, Barnes P. Chronic obstructive pulmonary disease in
non-smokers. Lancet. 2009;374(9691):733-45.

3. Ehrlich RI, White N, Norman R, et al. Predictors of chronic bronchitis in
South African adults. Int J Tuberc Lung Dis. 2004;8(June 2003):369-76.

4. Blasi F, Cesana G, Conti S, et al. The clinical and economic impact
of exacerbations of chronic obstructive pulmonary disease: A co-
hort of hospitalised patients. Plos/one. 2014;9(6):1-8.

76 TREATMENT APPROACHES

Sinusitis and allergic rhinitis – understanding
the disease process improves the outcomes

DB Vermaak nusitis patients as bacterial and prescribing antibiotics
in every case becomes questionable.
MBChB/LMCC/MMed (L.et.O) Stellenbosch
An untreated allergic rhinitis patient can easily be mis-
ENT Surgeon in Private Practice, Cape Town taken for a sinusitis case, and it is here where listening to
the patient’s specific complaints enables the clinician to
Restoration of the respiratory function is the aim of both distinguish between an allergic, viral or bacterial cause
conservative and surgical therapies. Understanding the of sinusitis. If unchecked, the inflammatory response of
role of the mucosa and mucociliary clearance system allergic rhinitis can quickly progress to a secondary bac-
becomes the aim of understanding sinusitis as a disease terial infection.
process. Therefore, the role of respiratory mucosa is the
focus of this article. Part of the inflammatory response is an infiltration of
neutrophils in the sinus mucosa. These cells contain a
Sinusitis has a different meaning for different people. greenish-coloured enzyme, and in large numbers, they
The sinusitis diagnosis can mean anything from a head- can turn the mucus the same colour. Mucus colour may
ache to a postnasal drip. The biggest mistake doctors also change according to the dust or pollens in the en-
make is accepting at face value the patient’s diagnosis vironment. The discolouration of the phlegm alone does
and prescribing yet again an antibiotic. not constitute a bacterial infection.

JS Josephson wrote in 1994: “Sinusitis is not an entity Managing the sinus inflammation and finding the true
in itself, but must be considered as an inflammatory cause of the inflammation is important. Restoring natural
disease involving the osteomeatal complex, the nasal mucous-membrane hydration and ciliary function should
cavity, the nasopharynx and the upper and lower res- be the ultimate goal. Understanding the mucociliary trans-
piratory tracts”.1 It is this inflammatory cascade that pri- port system and what influences its homeostasis, enables
marily needs a doctor’s attention when treating sinusitis. the physician to treat the disease process more effectively.

All bacterial sinusitis will cause sinus inflammation, but The intervention should aid the restoration of this sys-
not all sinus inflammation is bacterial. This inflammatory tem, and understanding the role of inflammation and
process is more often than not viral, but can also be dehydration on the clearance mechanism becomes
allergy-driven, due to nasal obstruction, or bacterial. paramount. There are over 30 million documented cas-
Therefore the correct diagnosis of the cause of nasal es of sinusitis worldwide and this is the most common
inflammation becomes more important in the treat- reason for prescribing antibiotics.2
ment and management of sinusitis. Diagnosing all si-

1. Antibiotic use in South Africa, Centre for Disease Dynamics, Economics & Policy. 2. Antimicrobial Stewardship: The South African
Perspective. Precious Matsoso Director General; National Department of Health; South Africa 13th November 2015. Source: IMS Health

Figure 1. Trend of antibiotic use in South Africa

HANDBOOK OF GENERAL MEDICINE VOL 1

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78 TREATMENT APPROACHES

Antibiotic resistance is a global health threat, with an- Osteomeatal opening shown with arrows
timicrobial-resistant infections currently claiming 700 000
lives annually. By 2050, antimicrobial resistance could
result in a loss of 10 million lives a year – more than those
lost to cancer.

South Africa’s consumption of antibiotics has increased
by 175% over the last decade (see Figure 1). Prescribing
doctors are the reason for these alarming statistics, and
they need to make a paradigm shift in their prescription
habits, particularly when it relates to the management
of sinusitis.3

The EPOS (European Position Paper) guidelines of
when to suspect bacterial infection are well illustrated
in Figure 2.

Increased symptoms after 5 days Figure 3. Schematic pattern of mucus flow –
cadaver coronal cut
Symptoms persistent symptoms
after 10 days Figure 4. Schematic pattern of mucus flow –
CT-scan coronal cut
Colds
A growing volume of research highlights the signifi-
0 5 10 15 12 cant role played by the mucociliary transport system in
Days Weeks the body. This system is an important defence mecha-
nism which allows the human body to maintain “ ho-
AdAadapptteed fdromfrFookmkensFeot akl. EkPeOSnGsuidWeliJne,s.eRhtinaol Sl.upEpPl. 2O005S;18g:1u. idelines. 2005;18:1 19 meostasis” by protecting it against invading particles,
including bacteria. This system includes two major func-
Figure 2. The EPOS (European Position Paper) guidelines tional mechanisms, namely the ciliary transport and
on when to suspect a bacterial infection mucus-secretion systems, each of which is usually com-
plementary and co-operative.5
The tendency to overprescribe antibiotics at the
slightest suggestion of inflammatory sinusitis has contrib- Sharpey, in 1835, was the first to describe ciliary ac-
uted to the worsening of resistance that has become a tion. The importance of a healthy sinus mucosa was,
global problem. There is a direct correlation between however, only realised when Hilding investigated scar
the volume of antibiotics prescribed and the level of formation and mucociliary clearance in postcanine si-
resistance that emerges in society. The studies of Felm- nus surgery. Messerklinger described the sinonasal mu-
ingham et al and Cars et al illustrate this principle well. cociliary clearance pathway, and it was then that the
goal of medical and surgical treatment was established;
The EPOS guidelines regarding the use of systemic de- restoration of natural sinus physiology, i.e. mucociliary
congestants are also clear – they have no value when clearance.6 The common pathophysiological sequela is
managing sinusitis; their use dehydrates the nasal mu- ineffective sinonasal mucociliary clearance leading to
cosa, rendering the cilia ineffective and creating the stasis and subsequent bacterial infection and/or persis-
ideal environment for the formation of a bacterial bio- tent inflammation.
film and thus secondary bacterial infection.4

Physiology

Histologically, sinuses are lined with pseudostratified
columnar ciliated epithelium. They are arranged in col-
umns containing mucus-secreting goblet cells and pro-
ject cilia. These cilia are bathed in a sol and gel layer of
which the viscosity is partly determined by ion channels.
Consequently, ensuring the balance of ion and water
transport becomes important.

Inflammatory mediators not only paralyse the cilia,
but they also alter the amount and nature of the mu-
cus being formed. The mucus becomes more viscous,
the sol phase becomes extremely thin, and the gel layer
becomes thicker, encroaching on the cilia and aggra-
vating their immobility. Normal secretory draining be-
comes impaired.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 79

The ciliated cells in each sinus beat in a specific direc- syndrome. The ciliary function is also decreased in the Treatment approaches
tion, resulting in a pattern of mucus flow (see Figures 3 presence of low pH, cold air, hypoxia, dehydration, di-
and 4). Since many of the sinuses develop in an outward rect or indirect exposure to cigarette smoke, chemical
and inferior fashion, the ciliated mucosa often move toxins, bacterial toxins, viral infection, and drugs (e.g.
material against gravity to the sinus’ exit. This means anticholinergic medications and antihistamines).
that mucus produced just adjacent to a sinus ostium, if
it is on the afferent side, will travel around the entire sinus The efficiency of this defence mechanism is critical in
cavity, often against gravity, before exiting the ostia. reducing the incidence of respiratory infection. It relies
on the co-ordination and beats frequency of the cilia,
This is one reason for why the creation of accessory and the viscosity of the mucus (which in turn is heavily
ostia at sites outside the physiological ostium will not influenced by the level of humidity) to which the mu-
significantly improve sinus drainage. It sometimes caus- cosa is exposed.8
es mucus draining from the natural ostia to re-enter the
sinus via the newly created opening and cycle through Mucus-secretion system
the sinus again. Researchers described a phenomenon
of stagnation which occurs when two ciliated surfaces The mucous blanket is composed of two layers. The sol
come into contact (particularly applicable at the os- layer exists as a thin, periciliary fluid that allows the cilia
teomeatal complex). This disrupts clearance and can to be mobile between strokes. The upper, or gel, layer
result in sinusitis. Clearance of the disease is accom- is a thick sheet of mucus that supplies an insertion point
plished when the mucociliary mucus clearance mech- for the tips of the cilia. The microvilli have a role in pro-
anism has been restored.7 ducing the sol layer, and the goblet cells and submu-
cosal glands make the gel layer. The mucous blanket is
Ciliary transport primarily composed of mucoglycoproteins which pro-
tect against low humidity and cold weather, in addi-
Cilia are complex structures and play a significant role tion to capturing foreign substances and trapping bac-
in maintaining a healthy sinus environment by clearing teria. The mucous blanket contains other components,
pathogens, allergens, debris and toxins. Ciliary dysfunc- such as immunoglobulin A with its secretory piece,
tion and the cause thereof should be managed in all which inhibits the adherence of bacteria to the epithe-
sinusitis patients. The inflammatory markers in sinonasal lial surface. Immunoglobulin G and interferon, as well as
mucosa are the most common cause of disruption in other inflammatory cells, are present in sinonasal secre-
mobility (see Figure 5). tions, and provide an antiviral role. The mucous blanket
also contains lysozyme and lactoferrin, which are capa-
ble of disrupting some bacteria (see Figure 6).9

Dust particles

Mucus Gel layer Cilia
Sol layer

Goblet cell Bronchial wall
Mucus gland epithelium

Figure 5. Electron microscopy of ciliated Figure 6. Diagram depicting the sol and gel layers of
pseudostratified columnar epithelium the mucous membrane

A defective ciliary function may result from the loss of
ciliated epithelial cells; enhanced airflow; viral, bacte-
rial and inflammatory mediators; scars; and Kartagener

Table 1. Symptom comparison to distinguish between different causes of sinusitis

Symptom Bacterial Allergies Colds (viral)
Facial pain or pressure Yes Sometimes Sometimes
Duration of illness More than 10-14 days Varies Less than 10 days
Nasal discharge Thick, yellow-green Clear, thin, watery Thick, whiteish
Fever Sometimes No Sometimes
Headache Sometimes Sometimes Sometimes
Pain in upper teeth Sometimes No No
Bad breath Sometimes No No
Coughing Sometimes Sometimes Yes
Nasal congestion Yes Sometimes Yes
Sneezing No Sometimes Yes

HANDBOOK OF GENERAL MEDICINE VOL 1

80 NS MonotherapyTRinEATAMEcNuT AtPePRROAhCiHnESosinusitis:
individual symptom score

Rx (2-15 Days)

Change in mean AM/PM symptoms Congestion Rhinorrhea Sinus Facial pain
Headache
0

-0.2

-0.4

-0.6 -0.73 -0.77 -0.71 -0.67
-0.8 -0.91 -0.8 -0.81 -0.82 -0.78

-0.8 -0.89 *

-1 -1.08 *†

-1.2 *† Placebo (n=247)
Amoxicillin 0.5 g TID (n=249)
*P≤0.007 vs placebo. NS 200 µg BID (n=234)
†P≤0.040 vs amoxicillin 0.5 g TID.
32
Adapted from Meltzer et al. J Allergy Clin Immunol. 2005;116:1289.

Figure 7. Nasal steroid monotherapy in acute rhinosinusitis: symptom score

DIAGNOSIS Topical nasal decongestants
Congestion is not only a subjective problem for the
If we accept the concept of sinusitis primarily being an patient, it also adds to the obstruction around the os-
inflammatory disease, it reasons that part of our treat- teomeatal complex. This, in turn, limits sinus drainage
ment should be to identify the cause of the inflamma- and leads to mucus retention and stasis, making sec-
tion. Viral, allergic and bacterial sinusitis can easily ondary bacterial infection all the more likely. Taken over
present with the same symptoms. Table 1 attempts to a short period, topical sympathomimetic drugs aid in
distinguish between the specific signs and symptoms of the reduction of nasal congestion and should be used
the different causes of sinus inflammation. as an adjuvant in any patient being treated for sinusitis.1

Management Saline douche
Due to the irritation of the nasal/sinus mucosa, the gob-
Intranasal steroid let cells in the ciliated pseudostratified columnar epi-
thelium produce copious amounts of secretions. As has
Management of the inflammatory process in sinusitis is been shown, the sol and gel layers of the epithelial lining
the cornerstone of treatment. The use of intranasal ster- are altered, with the gel layer encroaching on the cilia
oids is strongly advocated. Their mode of action is to with an ever-thinning sol layer, thus further impeding the
make the nasal mucosa an inhospitable site for mast cilia function and secondary stages. Saline douche not
cells. They block the synthesis of both leukotrienes and only clears the excess secretions, but also helps to re-
prostaglandins, and prevent the influx of neutrophils. store the cilia motility.12
The inflammatory cascade is thus altered.
Mucolytics
The use of intranasal steroids remains the gold stand- Mucolytic drugs are designed to help loosen and clear
ard of treatment in perineal allergic rhinitis. By limiting the mucus. They break down the disulfate binding of the
the influx of inflammatory markers, nasal congestion nasal/sinus secretions and therefore liquefy the secretions.
and rhinorrhoea become controlled. Subsequent sec- This helps to restore the sol layer of the epithelial cilia.11
ondary bacterial infections are limited.
Antibiotics
Studies have shown that high-dosage, 200 ug BD, The routine use of antibiotics in the treatment of sinusitis
nasal steroids are superior to amoxicillin in the patient’s should be discouraged. Using antibiotics as monothera-
recovery period and symptom score (see Figure 7). py should be condemned. Evidence-based treatment of
Treatment with a monotherapy nasal steroid10 markedly
improved symptoms of congestion, rhinorrhoea, sinus
headache and facial pain.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 81

sinusitis is advocated. Cultured specimens should be ob- 9. Baroody FM, et al. Mucociliary transport in chronic rhinosinusitis. Clin Treatment approaches
tained and antibiotic sensitivity evaluated before start- Allergy Immunol. 2007;20:103-19
ing treatment. If empiric treatment with an antibiotic is
initiated, guidance for the choice of antibiotic should be 10. Meltzer NS, et al. Monotherapy in acute rhinosinusitis. J Allergy Clin
in keeping with the patient’s community and the latest Immunol. 2005;116:1289
resistance levels as obtained by the laboratory. Keep in
mind that almost 90% of all acute bacterial sinus infec- 11. Nasal decongestion for the common cold. Cochrane Database
tions are caused by Streptococcus pneumoniae, Hae- Syst Rev. 2009;(2):CD001953.
mophilus influenzae and Moraxella cattarhalis.13
12. Rabago D, Zgierska A. Saline nasal irrigation for upper respiratory
The treatment guidelines for sinusitis are summarised conditions. American Fam Physician. 2009;80(10):1117-1119, 1121-
in Table 2. 1122

13. Felmingham W, et al. Incidence in Europe of resistance against AB.
J Antimicrob Chemother. 2002;50(suppl S1):25.

Table 2. Summary of treatment guidelines

Treatment Action
Intranasal cortisone Reduces inflammation
*Alone
* With antibiotic Reduce congestion and im-
Topical decongestants prove drainage
Removes secretions, improves
Saline lavage mucosal function
Liquefy phlegm
Mucolytics Controls bacterial infection
Antibiotic

Conclusion

The most appropriate therapeutic approach for the
prophylaxis and primary management of sinusitis is the
maintenance of an efficient mucociliary transport sys-
tem, in order to:
• Hydrate the airways
• Increase the airway surface liquid depth
• Enhance ciliary beat frequency

Sinusitis is a common disease that affects millions of
people annually. It is a disease that affects quality of life
and is often neglected in its diagnosis, and more impor-
tantly, in its treatment. Broadening the thinking around
the pathophysiology and understanding the role of
inflammation in the presenting symptoms, can make
treatment more effective.

The routine use of antibiotics should be discouraged,
and initial treatment of acute sinusitis should focus on
the adjuvant management and treatment protocols.

References

1. Josephson JS (ed). Sinusitis. Clinical Symposia Vol 46. 1994;CIBA:46
2. Thomas M. Antimicrobial therapy guide. J Allergy Clin Immunol.

2010;132:1298
3. Van Boeckel TP, et al. Global antibiotic consumption 2000 to 2010:

An analysis of national pharmaceutical sales data. Lancet Infect
Dis. 2014;14:742-50.
4. Fokkens WJ, et al, EPOS 2012: European position paper on rhinosi-
nusitis and nasal polyps 2012. A summary for otorhinolaryngologists.
5. Antunes MB, et al. Epithelium, cilia, and mucous: Their impor-
tance in chronic rhinosinusitis. Immunol Allergy Clin North Am. 2009
Nov;29(4):631-43
6. Cohen NA. Sinonasal mucociliary clearance in health and dis-
ease. Annals of Otology, Rhinology & Laryngology. 2006;115(9_sup-
pl),20-26.
7. Van Cauwagenberge P, et al. Anatomy and physiology of the nose
and the paranasal sinuses. Immunol Allergy Clin North Am. 2004
Feb;24(1):1-17
8. Cohen NA. Sinonasal mucociliary clearance in health and disease.
Ann Otol Laryngol Suppl. 2006 Sep;196:20-6

HANDBOOK OF GENERAL MEDICINE VOL 1

82 TREATMENT APPROACHES

Vestibular assessments: an update

LT Benigson lationship between vestibular disorders and cognitive
impairment, particularly in the elderly population, with
BA (Speech & Hearing Therapy) WITS MRI studies showing hippocampus atrophies correlating
with a decline in spatial memory tasks.8
Clinical Audiologist, Johannesburg
Diagnosis
LM Hofmeyr
Vertigo and dizziness are not unique entities. They cover
MBChB(UP), MMED ENT(UP) a number of multisensory and sensorimotor syndromes
of various aetiologies and pathogeneses. Vestibular dis-
Ear, Nose and Throat Surgeon, Pretoria orders can be complex and difficult to diagnose, as they
can have multiple causes that often cannot be isolated
At present, there do not appear to be any published to a single source. It is not uncommon for the patient with
data in South Africa recording the statistics of vestibular dizziness to see up to four physicians for their complaint
disorders. However, global statistics report that dizziness and to have visited the hospital emergency department
and vertigo are two of the most common symptoms for at least once.9 Diagnosing vestibular disorders can be fur-
which medical attention is sought amongst working- ther challenging because of discrepancies in the use of
age adults.1 Data from large-scale studies, particularly terminology, such as dizziness, vertigo and disequilibrium,
in the United States, estimate the prevalence of dizzi- all of which can result from a peripheral or central vestibu-
ness and vertigo to be 35.4%.2 Dizziness was found to be lar disorder. Accurate descriptions and reporting of symp-
the primary complaint in 2.5% of all primary care visits, toms are essential in establishing an accurate diagnosis.10
equalling eight million visits per year.3 • Dizziness is a sensation of light-headedness, faintness,

The prevalence of vestibular disorders is higher in the or unsteadiness.
female population and in the elderly. Compared to • Vertigo has a rotational, spinning component, and
men, women are three times more likely to present with
vestibular disorders. This may be due to female hormo- is the perception of movement, either of the self or
nal variations and metabolic disorders. surrounding objects.
• Disequilibrium means unsteadiness, imbalance, or
Studies in the elderly population have reported a loss of equilibrium that is often accompanied by spa-
significant increase in dizziness and vertigo.4 In one tial disorientation.
such study, 80% of Americans over the age of 80 years When a vestibular disorder is suspected, a referral
reported having experienced dizziness. However, these to an audiologist for diagnostic testing is warranted to
symptoms may be due to non-vestibular causes, such establish the site of the lesion. The assessment includes
as blood pressure or medication side effects. It has a battery of tests, including videonystagmography
been found that elderly individuals presenting with ves- (VNG), video head impulse testing (vHIT), cervical and
tibular-related dizziness and vertigo typically suffer from ocular vestibular evoked myogenic potentials (cVEMP/
disorders such as Parkinson’s disease and multisystem oVEMP), electrocochleography (ECochG), comput-
atrophies. In addition, elderly individuals may present erised dynamic posturography (CDP), dynamic visual
with degenerative cerebellar diseases, such as those acuity and gaze stabilisation testing (DVA/GST), and ro-
associated with malignancy (i.e. paraneoplastic syn- tatory chair testing.
drome), drug intoxication, hereditary ataxias, alcohol-
ism and metabolic disorders. Videonystagmography

The most common causes of dizziness and vertigo Videonystagmography (VNG) is a complete diagnostic
seen in the general population include benign paroxys- system for recording, analysing, and reporting eye
mal positional vertigo (BPPV), Ménière’s disease, ves- movements using video-imaging technology, in which
tibular migraine, bilateral vestibulopathy, vestibular hi-tech video goggles with infrared cameras are used.
neuritis, central forms of vestibular vertigo in primarily VNG includes a series of tests used to determine wheth-
vascular and inflammatory disease (multiple sclerosis er a vestibular disease may be causing a balance or
plaques) and functional dizziness.5 dizziness problem. VNG can help to differentiate be-
tween a central and a peripheral vestibular lesion, and,
Impact on quality of life if peripheral, it can decipher between unilateral and
bilateral vestibular loss. VNG addresses the functionality
The psychological impact of the fear of falling should of each ear (see Figures 1 and 2). The following tests are
not be underestimated. There are a number of peer- incorporated in VNG:
reviewed studies documenting the psychological dis-
tress of vestibular disorders on the individual, particu-
larly the presence of anxiety disorders, panic disorders
with or without agoraphobia and major depression. The
comorbid psychological effects are known to result in
functional impairments, limiting the individual’s activi-
ties of daily living.6,7 Furthermore, there is a known re-

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 83

Test of oculomotor function Treatment approaches

Figure 1. VNG testing using the ICS Charter 20011 Tracking: The tracking test measures the ability of sub-
jects to match eye movement to visual target move-
Figure 2. Vestibular testing includes data playback, ment. It is the ability to smooth pursuit, which is con-
reporting, and data-sharing11 trolled by the vestibulo-cerebellum.14
Tests for gaze and spontaneous nystagmus
Assessments of gaze and spontaneous nystagmus are Saccade test: This test assesses the patient’s ability to
enhanced with the use of VNG, which allows for the make fast changes in eye positions, thereby providing
measurement of nystagmus intensity and direction. central information. It assesses the latency, accuracy
Measurements of intensity and direction may be taken and velocity of the saccade. It is also useful in identify-
without fixation (i.e. in complete darkness) (see Fig- ing degenerative disorders of the central nervous sys-
ure 3). The description of the nystagmus provides vital tem.14
differential diagnosis information regarding peripheral
vs central disorders. It is important to consider these Optokinetic test: The optokinetic system is responsible
measurements because some level of spontaneous nys- for the stabilisation of the visual field. VNG tests the op-
tagmus may be seen in healthy individuals.12 tokinetic tracking of targets by passing a light rapidly in
front of a patient from one direction to the other. Asym-
metries are noted and are signs of central nervous sys-
tem dysfunction.14

Skew deviation

The purpose of this test is to identify vertical ocular mis-
alignment, thereby providing diagnostic information to
assist with identifying central disorders, primarily of brain-
stem origin.

Bi-thermal caloric testing

This test assesses the integrity of the superior vestibular
nerve and the lateral semi-circular canal (see Figure 4).
It remains useful in determining the side of the lesion in
cases of Ménière’s disease. The caloric tests stimulate
the vestibular system in the ear by creating a tempera-
ture difference relative to body temperature. Methods
used to create a temperature change include heated
or cooled air (or water) introduced to the ear canal. The
examiner looks for the presence, strength, and direc-
tion of any nystagmus that exists during and following
the introduction of each stimulus. This technique allows
for the evaluation of each labyrinth independently by
comparing the strength of nystagmus that results from
stimulating both the left and right sides.14

Figure 3. Left beating spontaneous nystagmus with Figure 4. Bi-thermal air caloric testing using
vision denied, increased from 4o/sec with fixation to Micromedical Air FX15
13o/sec without fixation13
Induced nystagmus
In the following tests, no nystagmus is expected in the
presence of normal vestibular functioning, or persons
presenting with a symmetrical vestibular loss (such as
bilateral vestibular loss).  In persons with a dynamic im-
balance between the ears (such as due to unilateral
vestibular neuritis or vestibular schwannoma), nystag-

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84 TREATMENT APPROACHES

mus is often seen (usually beating towards the “better” Figure 5. vHIT testing using ICS Impulse11
ear which decays over about 30 seconds).16 
Figure 6. Abnormal vHIT recording in right posterior
Hyperventilation testing: This test requires the patient semi-circular canal18
to take deep, rapid breaths for 30-60 seconds. The ex- Vestibular evoked myogenic potentials
aminer observes any nystagmus during this state of hy- (cVEMP/oVEMP)
perventilation and then observes any changes in the VEMP testing is conducted through the use of surface
presence or intensity of nystagmus after hyperventila- electrodes to evaluate whether the otolithic organs
tion concludes.14 and associated vestibular nerves are intact and func-
tioning normally.19
Vibration testing: This involves placing a handheld vi-
brating instrument on the left and right mastoid bone cVEMP: Myogenic potentials responding to loud
and on the left and right posterior sternocleidomas- click stimuli are recorded at the ipsilateral SCM muscle
toid muscle (SCM) and then observing changes in the (cVEMP). The purpose of the cervical VEMP is to deter-
presence or intensity of nystagmus. The results may be mine if the saccule, as well the inferior vestibular nerve
abnormal in patients with superior semi-circular canal and central connections, are intact and working.19 (See
dehiscence or unilateral vestibular hypofunction.14 Figure 7.)

Head-shaking nystagmus (HSN): HSN is a jerk nystag­ Figure 7. Abnormal right-sided cVEMP tracing20
mus that may follow a prolonged sinusoidal head os- oVEMP: Myogenic potentials responding to loud click
cillation. The patient is positioned upright and instru-
mented so that fixation is removed, but horizontal and stimuli are recorded at the contralateral inferior extra-
vertical eye movements can be observed. The test can-
not be done without a method of eliminating fixation.17

Static and dynamic position testing: Static position
testing is used to observe the vestibular system response
to a change in head/body position, as compared to
the neutral head/body position. The measurements are
taken with or without fixation. The examiner considers
the presence or absence of nystagmus and/or changes
in nystagmus, as well as the patient’s subjective report
of symptom changes.14

Dynamic position tests (e.g. Dix-Hallpike and side-
lying) look for transient nystagmus provoked by head
movements. They are the most commonly used tests
used to confirm a diagnosis of benign paroxysmal posi-
tional vertigo (BPPV).14

Video head impulse test

The video head impulse test (vHIT) assesses the integrity of
all six semi-circular canals objectively and independently
by comparing the eye-velocity response of the VOR in
relation to the head-velocity stimulus in the appropriate
plane of movement (see Figure 5). vHIT shows the pres-
ence of both overt and covert saccades should an ab-
normality be present. It uses an infrared video recording
of eye movements in response to short, brisk head turns
or impulses in the plane of the semi-circular canal.

This allows for objective measurement of eye move-
ments, rather than subjective clinician observations.
The patient is instructed to maintain visual contact on a
stationary target during head impulses. Eye movements
are analysed to determine whether the eyes moved
in the same direction as the head during impulses and
then made a corrective refixation back to the target
(abnormal) (see Figure 6) or if eyes moved in the op-
posite direction of the head during impulses and main-
tained fixation on the target (normal).

Results may demonstrate a problem with semi-circu-
lar canal function on the same side to which the head
was turned prior to the corrective refixation response.
This procedure is non-invasive, relatively short, and uti-
lises stimuli in the physiological range of everyday head
movement.14

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 85

ocular muscle (oVEMP). The purpose of the ocular VEMP ing as the severity of a vestibular deficit increases. The Treatment approaches
is to assess the integrity of the utricle and the superior assessment of a patient’s ability to perform visual tasks
vestibular nerve and its central connections.19 requiring image stabilisation is considered complemen-
tary to physiological tests of the VOR system.23
Electrocochleography

Electrocochleography (ECochG) is a method for re-
cording the electrical potentials of the cochlea. EC-
ochG involves measurement of the stimulus-related
cochlear potentials (SP) – as opposed to the resting po-
tentials, and often includes measurements of the whole
nerve or compound action potential (AP) of the audi-
tory nerve (see Figure 8). The most popular applications
for ECochG include the:
• Diagnosis/assessment/monitoring of Ménière’s dis-

ease/endolymphatic hydrops and the assessment/
monitoring of treatment strategies for these disorders
• Enhancement of wave I of the ABR in the presence
of hearing loss or when less than optimal recording
conditions were used to obtain wave I.
• Measurement and monitoring of cochlear and audi-
tory nerve function during surgery involving the audi-
tory periphery.21

Figure 8. Normal ECochG in the right ear vs abnormal Figure 9. Natus NeuroCom® EquiTest® featuring
ECochG in the left ear22 computerised dynamic posturography24

Computerised dynamic posturography Dynamic visual acuity (DVA)/gaze stabilisation
testing (GST)
Computerised dynamic posturography (CDP) tests pos- DVA quantifies the difference between static and dy-
tural stability or the ability to maintain upright posture namic visual acuity with comparable performance to
in different environmental conditions (see Figure 9). the right and left. It provides an indication of physio-
Maintenance of postural stability depends on vestibu- logical function. Functionally impaired DVA impacts on
lar, visual and somatosensory input. This test investigates the ability to accurately perceive objects during func-
relationships among these three sensory systems and tion and activities of daily living. This may be measured
records the balance and posture adjustments made in the horizontal, vertical and roll plane.25
when different challenges are presented. Effective im-
age stabilisation during head movement is a key factor GST quantifies the head-movement velocities over
in performing activities of daily living. This process can which the patient is able to identify visual targets ac-
be severely impacted by vestibular deficits with the abil- curately. It quantifies the point just before retinal slip
ity to stabilise gaze and maintain visual acuity decreas- or the velocity at which the VOR exercises should be
performed. It proves an indication of functional com-
pensations. Functionally, gaze stability defines the
speeds and activities individuals can perform and still
see clearly.26

Rotatory chair
Rotatory chair tests are usually obtained in addition to
VNG-testing to enhance accuracy in cases such as bi-
lateral canal paresis, special population testing, vestib-
ulo-toxicity, and evaluation of vestibular compensation.
Rotatory-chair-testing can be helpful in detecting bilat-
eral and uncompensated unilateral vestibular disorders
(see Figure 10). Testing involves whole body rotation,
with the patient seated and restrained in a motorised
rotatory chair. Eye movements are recorded in dark-
ness, while the patient is wearing goggles, as in VNG.
The patient’s head is properly secured so that the chair
and head movements correspond. A rotatory chair test

HANDBOOK OF GENERAL MEDICINE VOL 1

86 TREATMENT APPROACHES

battery may include sinusoidal harmonic acceleration 12. Levo H, Aalto H, Petteri Hirvonen T. Nystagmus measured with
tests, visual-vestibular interaction tests (i.e. visual-VOR video-oculography: Methodical aspects and normative data.
and visual-vestibular fixation), and step velocity tests.27 ORL: Journal for Oto-Rhino-Laryngology and its Related Specialties
2004:66:101-104.
Figure 10. System 2000 comprehensive rotational chair
testing28 13. Vestibular neuritis part II. Available at https://hearinghealthmatters.
org/dizzinessdepot/2017/vestibular-neuritis-part-ii/. Accessed Janu-
Conclusion ary 2019.

In recent years, new technology has become avail- 14. Balance system disorders. Available at https://www.asha.org/PRP-
able to assess the patient with dizziness and vertigo. It SpecificTopic.aspx?folderid= 8589942134&section=Assessment. Ac-
is important to understand that all the methods used to cessed January 2019.
evaluate the dizzy patient should be interpreted as part
of a test battery with reference to each other. By no 15. Caloric irrigator. Available at http://www.micromedical.com/pro-
means does it replace a comprehensive case history ducts/caloric-irrigators/air-fx-caloric-irrigator. Accessed January
and clinical examination. 2019.

REFERENCES 16. Katsarkas A, Smith H, Galiana H. Head-shaking nystagmus (HSN):
The theoretical explanation and the experimental proof. Acta Oto-
1. Grill E, Müller M, Brandt T, Jahn K. Vertigo and dizziness: Challenges laryngol. 2000:120:177-181.
for epidemiological research. OA Epidemiology. 2013:1(2).
17. Head Shaking Nystagmus. Available at https://www.dizziness-and-
2. Agrawal Y, Carey JP, Della Santina CC, Schubert MC, Minor LB. Dis- balance.com/research/hsn/Head%20Shaking%20Nystagmus.htm.
orders of balance and vestibular function in US adults: Data from Accessed January 2019.
the National Health and Nutrition Examination Survey, 2001–2004.
Archives of Internal Medicine. 2009:169(10):938-944. 18. Boorazanes M, Crumley-Welsh, Young B. A streamlined approach
to assessing patients with peripheral vestibular disorders. Audiology
3. Sloane PD. Dizziness in primary care. Results from the national am- Today. 2015;27(5):40-48.
bulatory medical care survey. J Family Practice. 1989;29:33-38
19. Vestibular Evoked Myogenic Potentials (VEMP): How do I get start-
4. Vertigo: Evaluation and treatment in the elderly. Available at ed? Available at https://www.audiologyonline.com/articles/vestib-
www2.kumc.edu/otolaryngology/otology/VertEldTalk.htm. Ac- ular-evoked-myogenic-potentials-vemp-16713 . Accessed January
cessed January 2019. 2019.

5. Brandt T, Dieterich M and Strupp M. Vertigo and dizziness. Common 20. Vestibular evoked myogenic potential (VEMP) testing – cervical
complaints. London: Springer Verlag; 2013:1-51 (SCM). Available at https://www.dizziness-and-balance.com/test-
ing/vemp.html. Accessed January 2019.
6. Sinclair AJ, Morley JE, Vellas B. Pathy’s principles and practice of
geriatric medicine. John Wiley & Sons. 2012. 21. Clinical electrocochleography. Available at https://www.audi-
ologyonline.com/articles/clinical-electrocochleography-overview-
7. Mira E. Improving the quality of life in patients with vestibular dis- theories-techniques-1275-1275. Accessed January 2019.
orders: The role of medical treatments and physical rehabilitation.
International Journal of Clinical Practice. 2007;1:109-114. 22. Electrocochleography. Available at http://www.keywordhouse.
com/ ZWxlY3Ryb2NvY2hsZW9ncmFwaHk/. Accessed January 2019.
8. Smith PF, Horii A, Russel N, Bilkey DK, Zheng Y, Liu P, et al. Does ves-
tibular damage cause cognitive dysfunction in humans? Journal of 23. Gaerlan MG, Alpert PT, Cross C, Louis M, Kowalski S. The role of visu-
Vestibular Research 2005;15:1-9. al, vestibular, and somatosensory systems in postural balance. UNLV
Theses, Dissertations, Professional Papers, and Capstones. 2010: 357.
9. Diagnosis and management of balance/vestibular disorders: A
team-based approach. Available at https://www.asha.org/Arti- 24. NeuroCom EquiTest® Family. Available at https://newborncare.na-
cles/Diagnosis-and-Management-of-Balance-Vestibular-Disorder/. tus.com/products-services/neurocom-equitest-family#accordion-
Accessed January 2019 first-item. Accessed January 2019.

10. Causes of dizziness. Available at https://vestibular.org/about-ves- 25. Riska KM and Hall CD. Reliability and normative data for the dy-
tibular-disorders/causes-dizziness. Accessed January 2019 namic visual acuity test for vestibular screening. Otology & Neurol-
ogy. 2016-37.
11. Products and services. Available at https://otometrics.natus.com/
products-services/balance. Accessed January 2019. 26. Lee C and Honaker JA. Development of a new gaze stabilisation
test. Journal of Vestibular Research. 2013;23(2):77-84.
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27. Rotary chair testing. Available at https://www.dizziness-andbal-
ance.com/testing /ENG/rchair.html. Accessed January 2019.

28. System 2000. Available at http://www.micromedical.com/pro-
ducts/rotational-chairs/system-2000-comprehensive-rotational-
chair. Accessed January 2019.

TREATMENT APPROACHES 87

Functional/ulcer-negative dyspepsia: a review Treatment approaches
of the consensus statements of leaders
and workers in the field

JAM Garisch The Rome criteria for functional dyspepsia

MBChB F.C.P. (S.A.) AGAF This modern approach to functional dyspepsia origi-
nated in Rome 30 years ago when Aldo Torsoli, Profes-
Clinical Gastro-enterologist and Interventional Endoscopist, sor of Gastro-Enterology at the University of Rome, en-
St Georges Hospital, Port Elizabeth gaged working teams of selected international experts
to answer difficult clinical questions that could not be
Some 40% of adults experience symptoms of dyspepsia answered by scientific evidence at the time. These re-
every year, but it is estimated that only 10% seek medi- sultant consensus guidelines were presented at the In-
cal care. Of these patients, most are eventually diag- ternational Gastro-Enterology Meeting held in Rome
nosed as having functional or non-ulcer dyspepsia.1 in 1988 and became known as the Rome criteria for
the diagnosis of functional gastro-intestinal disorders.
All branches of clinical practice may experience uncer- The criteria are revised regularly. The current update is
tainty regarding the diagnosis and management of func- known as Rome IV Criteria and the diagnostic criteria
tional gastro-intestinal disorders (FGIDs). Although FGIDs for FD are stated in Table 1.3
have been described for centuries, the understanding
of these disorders, also described as disorders of the gut- The diagnostic criteria for functional dyspepsia, ac-
brain interaction, only emerged over the past decades.2 cording to Rome IV, include one of the following
• Bothersome postprandial fullness
Drossman, in an overview of the history of FGID, high- • Bothersome early satiation
lights how, throughout history, the bowels and intestinal • Bothersome epigastric pain
activity have had meanings that go beyond their ac- • Bothersome epigastric burning and
tual function. They were considered private and shroud- • No evidence of structural upper gastro-intestinal dis-
ed in mystery. Their dysfunction is linked to embarrass-
ment, emotion and shame, and is often expressed as: “I ease that is likely to explain the symptoms.
find this hard to swallow”, “I cannot stomach that any Rome IV furthermore distinguishes between two dis-
longer”, and “I feel butterflies in my stomach”. tinct clinical entities:
• Postprandial distress syndrome defined as compris-
Brain and gut, more than any other organ systems, ing early satiety and/or postprandial fullness at least
are interwoven; each has a nervous system that is linked three times per week.
and derived from the same origin, the embryonic neural • Epigastric pain syndrome defined as bothersome
crest. epig­ astric pain (i.e. severe enough to impact on usu-
al activities) at least one day per week.
This brain-gut connection also explains why stress and The Rome criteria represent a categorisation of func-
psychological factors are so closely linked to gut func- tional dyspepsia that is scientifically determined and
tion and dysfunction, i.e. gastro-intestinal symptoms, ill- guides treatment based on evidence of well-designed
ness and disease. clinical investigations.
It is important to note the existence of the so-called
The possibility that passions or emotions could lead to PDS-EPS syndrome mentioned in the Rome IV Classifica-
the development of medical disease was first proposed tion which represents an overlap of symptoms of both
by the Greek physician Claudius Galen and has been PDS and EPS.
upheld by medical writers into the 21st century.
EPIDEMIOLOGY
DEFINITION
Epidemiological studies have confirmed that EPS (ulcer-
The latest definition for FGIDs reflects the current scien- like dyspepsia) and PDS (dysmotility-like dyspepsia) are
tific knowledge and is non-stigmatising in terms of func- distinct syndromes. A pivotal population-based study –
tional versus organic bases of the disease. The agreed- the Kalixanda study, named after the northern Swed-
upon definition for FGID is as follows: ish towns of Kalix and Haparanda where the research
was conducted – obtained random samples from these
Functional GI disorders are disorders of gut-brain inter- towns where subjects were invited to complete validat-
action. They form a group of disorders classified by GI ed questionnaires and undergo an unsedated endo-
symptoms related to any combination of the following: scopy (EGD) to exclude oesophagitis, peptic ulcer and
motility disturbance, visceral hypersensitivity, altered cancer. Of 1 000 representative community subjects
mucosal and immune function, altered gut microbiota, from Kalix and Haparanda who underwent EGD, 4%
and altered central nervous system (CNS) processing.2
HANDBOOK OF GENERAL MEDICINE VOL 1
Functional dyspepsia (FD) is one of the gastro-intesti-
nal disorders which, according to the Rome III Classifica-
tion, chiefly consists of four symptoms, namely bother-
some postprandial fullness, early satiety, epigastralgia
and epigastric burning.

88 TREATMENT APPROACHES

Table 1. Rome IV criteria or functional dyspepsia3

B1. Functional dyspepsia*
Diagnostic criteria
1. One or more of the following:
a. Bothersome postprandial fullness
b. Bothersome early satiation
c. Bothersome epigastric pain
d. Bothersome epigastric burning
AND
2. No evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms

B1a. Postprandial distress syndrome
Diagnostic criteria

Must include one or both of the following at least three days per week:
1. Bothersome postprandial fullness (i.e. severe enough to impact on usual activities)
2. Bothersome early satiation (i.e. severe enough to prevent finishing a regular-size meal)

No evidence of organic, systemic, or metabolic disease that is likely to explain the symptoms on routine investigations (including
at upper endoscopy)
Supportive remarks

• Postprandial epigastric pain or burning, epigastric bloating, excessive belching, and nausea can also be present
• Vomiting warrants consideration of another disorder
• Heartburn is not a dyspeptic symptom but may often coexist
• Symptoms that are relieved by evacuation of faeces or gas should generally not be considered as part of dyspepsia
Other individual digestive symptoms or groups of symptoms, e.g. from gastro-oesophageal reflux disease and the irritable bowel
syndrome may co-exist with PDS

B1b. Epigastric pain syndrome
Diagnostic criteria

Must include at least one of the following symptoms at least one day a week:
1. Bothersome epigastric pain (ie severe enough to impact on usual activities)

AND/OR

2. Bothersome epigastric burning (ie severe enough to impact on usual activities)
No evidence of organic, systemic, or metabolic disease that is likely to explain the symptoms on routine investigations (including
at upper endoscopy)
Supportive remarks

1. Pain may be induced by ingestion of a meal, relieved by ingestion of a meal, or may occur while fasting

2. Postprandial epigastric bloating, belching, and nausea can also be present
3. Persistent vomiting likely suggests another disorder
4. Heartburn is not a dyspeptic symptom, but may often co-exist
5. The pain does not fulfil biliary pain criteria
6. Symptoms that are relieved by evacuation of faeces or gas generally should not be considered as part of dyspepsia
Other digestive symptoms (such as from gastro-oesophageal reflux disease and irritable bowel syndrome) may co-exist with EPS

had organic disease that explained their dyspepsia, The clinical syndrome of FD, presenting either as PDS
while 16% had FD, of whom 5% had EPS and 12% PDS.5,6 or EPS, is considered to be the result of disrupted gastro-
duodenal neuropathophysiology.
Other population-based studies from Europe and the
United States have confirmed that PDS is more preva- The symptom complex is considered to originate from
lent than EPS. the gastroduodenal region, and is classified according
to the Rome criteria as disorders of brain-gut interaction
Risk factors for PDS and EPS remain to be fully char- without structural alteration.
acterised.
The main physiological mechanisms responsible for
pathoPHYSIOLOGICAL INSIGHTS6,7 the symptom complex are:
• Impaired accommodation associated with early satiety
Functional dyspepsia is a symptom complex charac- • Hypersensitivity associated with symptoms of pain
terised by postprandial upper abdominal discomfort or
pain, early satiety, nausea, vomiting, abdominal disten- and belching
sion, bloating and anorexia in the absence of organic • Delayed gastric emptying of solids characterised by
disease.
severe and clinically relevant postprandial fullness
HANDBOOK OF GENERAL MEDICINE VOL 1 and vomiting.

TREATMENT APPROACHES 89

The causes of FD are progressively better understood Treatment approaches
to be multifactorial and include biological, psycho-
logical, physiological and environmental factors. Other
than the pathophysiological mechanisms of gastro-in-
testinal motor abnormalities and altered visceral sensa-
tion linked to FD, psychosocial factors have also been
identified as an important mechanism that triggers the
syndrome.5 Research has indicated that infections and
food may play a causative role.

The mechanisms contributing to FD are reviewed in
Table 2.6

Table 2. Mechanisms contributing to functional Sibyl Health, Slideplayer.com. 2019
dyspepsia
Figure 1. Pathophysiologic mechanisms in functional
Biologic Genes dyspepsia
Psychologic Cytokines
Physiologic Duodenal eosinophilia It is important to note that evidence shows that in
Environment an important minority, treatment and eradication of
Anxiety/depression H. pylori, has led to long-term symptom resolution even
Brain pain modulating circuits a year after completing eradication therapy.

Duodenal sensitivity The role of duodenal inflammation
Gastric accommodation/emptying Current research suggests that the duodenum con-
Acid tents, which include the microbiome, pathogens and
allergy, may be triggers of FD. The systemic responses
Infections of increased circulating lymphocytes and elevated pro-
Diet inflammatory cytokines and subtle inflammation in the
duodenum may accompany the onset and persistence
Brain-gut disturbances of symptoms. Thus an inflammatory phenotype is char-
acterised by innate inflammation, whilst an eosinophil
Psychological distress is associated with FD, with a strong infiltrate in the duodenum is mainly associated with pa-
link to anxiety. The pathophysiological mechanism of tients with postprandial distress syndrome.8
how anxiety and gut symptoms interact, is still not fully
understood. What is recognised is that anxiety may in These findings suggest that functional does not neces-
some cases precede gut symptoms (a brain-gut link), sarily mean the absence of pathology; rather that sub-
while in others the gut symptoms may precede and in- tle inflammatory pathological changes may exist – the
crease anxiety (suggesting a gut-brain link).6 implication being that this understanding may influence
therapeutic options.
Research continues as to the underlying causes of the
gut-brain central neurotransmitter systems involved in Thus, all three major pathophysiological mechanisms
FD, but recent preliminary PET data have identified a are important.
higher presence of cerebral cannabinoid-1 receptors
in FD, implicating sustained endo-cannabinoid system The biopsychosocial conceptual
dysfunction, which may represent a new central thera- model of FGID4
peutic target. This biopsychosocial conceptualisation of the patho-
genesis and clinical expression of FGID has been repor-
Gastro-intestinal motor abnormalities, altered visceral ted in the Special Issue of Gastroenterology of May
sensation, and psychosocial factors have all been identi- 2016, and shows the relationships between psychoso-
fied as major pathophysiological mechanisms. This per- cial (i.e. personality traits, susceptibility to life stressors,
spective has now replaced the earlier view that the con- psychological state and coping skills) and physiological
dition was the result of a sole motor or sensory disorder factors, functional GI symptoms and clinical outcome
of the stomach. Future therapeutic strategies should be (see Figure 2).
aimed at reducing nociception, as well as enhancing
the accommodation response (see Figure 1). Management of dyspepsia10,11
Functional dyspepsia is a diagnosis of exclusion; there-
The role of Helicobacter pylori infection fore, physicians should focus on excluding serious or
specifically treatable diseases, without spending too
The role of H. pylori in functional dyspepsia is still unclear. much time investigating symptoms.1
Although there is an increased incidence of H. pylori in-
fection in the general population and in patients with HANDBOOK OF GENERAL MEDICINE VOL 1
functional dyspepsia, the significance is due to the
minimal response to treatment of H. pylori in FD. What
is clear from the literature is that H. pylori infection is not
associated with impaired gastric emptying nor reduced
gastric accommodation to meals.

90 TREATMENT APPROACHES

Early life Psychosocial factors
• Genetics • Life stress
• Culture • Personality traits
• Environment • Psychological state
• Coping/cognitions
- Trauma • Social support
- Infection
- Parental behaviours

Brain Gut FGID
CNS ENS • Presentation
• Symptoms
Physiology • Severity
• Motility • Behaviours
• Sensation
• Immune Outcome
• Dysfunction/inflammation • Healthcare use
• Altered microflora • Daily function
• Food/diet • Quality of life
• Healthcare costs

Drossman DA. Modified from Rome III. Functional gastrointestinal disorders: History, pathophysiology, clinical features and Rome IV.
Gastroenterology. 2016 May;6:150:1262-1279

Figure 2. Biopsychosocial conceptual model of FGID

Stanghellini et al summarise the symptoms and sub- Dyspepsia is defined as one or more of the following
groups attributed to FD, which represents one of the symptoms: postprandial fullness, early satiation, epigas-
main subgroups of FGID, as follows: tric pain or burning sensation. Approximately 25 per-
cent of patients with dyspepsia are found to have an
Symptoms: Functional dyspepsia is characterised by underlying organic disease on diagnostic evaluation.
one or more of the following: postprandial fullness, early However, approximately 75 percent of patients have
satiation, epigastric pain, and epigastric burning, which functional (idiopathic or non-ulcer) dyspepsia
are unexplained after a routine clinical evaluation
Table 3. Alarm features in the patient with dyspepsia
Three subcategories are identified:
• Postprandial distress syndrome that is characterised Symptoms and signs
Unintentional weight loss
by meal-induced dyspeptic symptoms Progressive dysphagia
• Epigastric pain syndrome that does not occur exclu- Odynophagia
Unexplained iron deficiency anaemia
sively postprandially Persistent vomiting
• Overlap of the two subgroups.9 Palpable mass or lymphadenopathy
Family history of upper gastro-intestinal cancer
Recent research indicated that FD does not neces-
sarily mean an absence of pathology, that duodenal Indications for upper GI endoscopy
eosinophilia is now an accepted association and that
H. pylori infection is considered to be causally linked 1. Dyspepsia in patients aged 60 or over:
to dyspepsia. Although only a minority will respond to a. Patients >60 years of age with dyspepsia should
eradication, the approach to and extent of the diag- undergo an upper endoscopy to exclude upper
nostic evaluation of a patient with dyspepsia is there- gastro-intestinal neoplasia (conditional recom-
fore based on the presence or absence of alarm fea- mendations, very low quality evidence).
tures, the age of the patient, and the prevalence of H. b. Most patients with a normal upper endoscopy
pylori infection. and routine laboratory tests have functional dys-
pepsia.
The following recommendations for the management c. However, additional evaluation may be required
of adults with FD by George Longstreth et al, as well as a based on symptoms (e.g. abdominal imaging
joint dyspepsia guideline from the American College of with an ultrasound or computed tomography
Gastroenterology (ACG) and the Canadian Association scan in patients with concurrent jaundice or pain
of Gastroenterology (CAG), are summarised below:10,11 suggestive of a biliary/pancreatic source)

A detailed history, physical examination, and labora-
tory studies are necessary to determine the underlying
aetiology and identify alarm features that may warrant
additional evaluation, i.e. the Red Flag approach (see
Table 3).

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 91

2. Dyspepsia in patients aged under 60: 6. Talley NJ. Functional dyspepsia: New insights into pathogenesis Treatment approaches
a. The indication for upper endoscopy is the pres- and therapy. Korean J Intern Med. 2016;31(3):444-456. Doi:10.3904/
ence of alarm features to exclude upper GI neo- kjim.2016.091 https://www.ncvi.nim.nih.gov/pubmed/27048251.
plasia:
i. Clinically significant weight loss (>50 percent 7. Thurshim M. Pathophysiology of functional dyspepsia. Gut. 2002
usual body weight over six to 12 months) Jul;51 Suppl 1:i63-6.
ii. Overt gastro-intestinal bleeding.
iii. >1 alarm feature 8. Walker MM, Talley NJ. The role of duodenal inflammation in func-
iv. Rapidly progressive alarm features tional dyspepsia. J Clin Gastroenterol. 2017 Jan;51(1):12-18.

General principles 9. Stanghellini V, et al. Gastroduodenal disorders. Gastroenterology.
2016:150(6):1380-1392.
1. H. pylori: Patients should have a non-invasive test for
H. pylori. FD patients that are H. pylori-positive should 10. Moayyedi P, Lacy BE, et al. ACG & CAG clinical guidelines: Man-
be prescribed therapy to treat the infection. agement of dyspepsia. American Journal of Gastroenterology.
2017 Jul;112 (7):988-1013. DOI: 10.1038/ajg.2017.154.
2. Proton pump inhibitors: Patients should have em-
pirical PPI therapy if they are H. pylori-negative or 11. Longstreth GF, Lacy BE. Approach to the adult with functional dys-
who remain symptomatic after H. pylori eradication pepsia. UpToDate. Oct 2018.
therapy. In patients with epigastric pain syndrome,
acid-suppression therapy is a first-line therapy and HANDBOOK OF GENERAL MEDICINE VOL 1
an H2 blocker should be considered when the pro-
ton pump inhibitor fails.

3. Prokinetics: Those patients not responding to PPI or
H. pylori eradication therapy should be offered pro-
kinetic therapy. In postprandial distress syndrome, a
prokinetic is preferred (in South Africa, we are cur-
rently limited to metoclopramide and domperidone).

4. Tricyclic antidepressants: Non-responders to PPI or
H. pylori eradication therapy should be offered tri-
cyclic antidepressant (TCA) therapy. In postprandial
distress syndrome, second-line therapy after proki-
netics includes administration of a tricyclic antide-
pressant in low doses, but not a selective serotonin
reuptake inhibitor (SSRI).

5. Psychological therapy: FD patients not responding
to drug therapy should be offered psychological
therapies.

Patients with continued symptoms of dyspepsia de-
spite a trial of a tricyclic antidepressant and prokinetic
should undergo endoscopic evaluation with an upper
endoscopy and biopsies, if not previously performed.
Further evaluation for an alternate diagnosis should be
performed selectively, based on the patient’s symp-
toms. Patients with continued symptoms of dyspepsia
for three months with symptom onset at least six months
before diagnosis and no evidence of structural disease
to explain the symptoms, should be diagnosed and
treated as having functional dyspepsia.11

The diagnosis and management of patients with func-
tional dyspepsia poses a clinical challenge.

REFERENCES

1. Loyd RA, McClellan DA. Update on the evaluation and man-
agement of functional dyspepsia. Am Fam Physician. 2011 Mar
1;83(5):547-552.

2. Drossman DA. Functional gastrointestinal disorders: History, patho-
physiology, clinical features, and Rome IV. Gastroenterology.
2016;150:1262-1279

3. Drossman DA, Hasler, WL. Rome IV – functional GI orders: disorders
of gut-brain interaction. Gastroenterology. 2016 May;150(6):1257-
61. doi: 10.1053/j.gastro.2016.03.035.

4. Drossman DA. Biopsychosocial overview of functional GI disorders.
Gastroenterology. Volume 150. 2016 May;1272-1278

5. Aro P, et al. Peptic ulcer disease in a general adult population. The
Kalixanda Study: A random population-based study. Am J Epide-
miol. 2006;163:1025-1034.

92 TREATMENT APPROACHES

Gastro-intestinal infections

SM Sithole Drugs of choice for oral therapy are ciprofloxacin, lev-
ofloxacin, co-trimoxazole (trimethoprim/sulphamethoxa-
MBCHB, FC Path(SA)Micro zole), amoxycillin and for intravenous (IV) therapy, cef-
triaxone (children) and cefotaxime. Antibiotic therapy is
Consultant Clinical Microbiologist, Johannesburg recommended for three to 10 days. In immunocompro-
mised patients, antibiotic therapy should be initially given
Gastro-enteritis is one of the commonest infectious for longer courses, such as 14 days or weeks to months.
disease syndromes reported worldwide. The vast
majority of acute gastro-intestinal illnesses do not involve The prevalence of antibiotic resistance in NTS is in-
a recognisable inflammatory process. Acute and creasing worldwide. Antibiotic choice should be made
chronic inflammatory enteritides are caused by specific according to the local antibiotic susceptibility pattern.
infectious agents. The acute inflammatory enteritides
include several distal small bowel and colonic infections, Optimal treatment for chronic carriage (shedding
such as salmonellosis, shigellosis, campylobacteriosis, for Salmonella in stool for more than one year, as
giardiasis and amoebiasis, as well as the syndromes of documented by an initial positive culture obtained at
antibiotic-associated pseudomembranous enterocolitis least one month after resolution of acute illness and
(Clostridium difficile). These acute syndromes will be repeat positive cultures) is not well studied.
discussed in this chapter.
Treatment with fluoroquinolones for four to six weeks is
Bacterial pathogens recommended.

Non-typhoidal Salmonella infection Shigella infection

Salmonella Enteritidis and Salmonella Typhimurium are Bacillary dysentery due to Shigella species is a major
the most frequently isolated serotypes causing gastro- cause of morbidity and mortality. Shigellosis has a
enteritis. Non-typhoidal Salmonella (NTS) is associated worldwide incidence of about 165 million cases annually
with animal reservoirs, especially poultry and eggs, and and 1 million associated deaths. Shigella occurs in
is implicated in foodborne infections and outbreaks. overcrowded situations, such as institutions. Transmission
is via faecal-oral spread and by contaminated food
Salmonellae adhere to and invade the gastro- and water sources.
intestinal (GI) tract and submucosal lymphoid system.
The ability of salmonellae to survive within macrophages Shigella gastro-enteritis is generally self-limiting. It is
contributes to the dissemination of the micro-organism characterised by high fever, abdominal cramps and
from the submucosa to the circulation and reticulo- dysentery (small volume, bloody and mucoid). Definite
endothelial system. diagnosis requires stool culture.

The host immune response determines whether the Treatment
infection is subclinical or more aggressive.
Fluid and electrolyte replacement is important. Intesti-
Key features include nausea, vomiting, diarrhoea nal antimotility drugs should be avoided.
and cramping. Symptoms occur within eight to 72 hours
after ingesting contaminated food or water. Diarrhoea Antibiotics have been shown to decrease the duration
resolves in four to 10 days and is self-limiting. Invasive of fever and diarrhoea by approximately two days and,
disease occurs in less than 5% of cases. It is characterised therefore, shorten the duration of shedding and reduce
by bacteraemia and extra-intestinal manifestations person-to-person spread.
which include endocarditis, mycotic aneurysm and
osteomyelitis. Diagnosis is by means of culture of the Antibiotics are recommended for:
organism from stool. • Severely ill patients with diarrhoea, requiring hospitali-

Treatment sation
Fluid and electrolyte replacement is the cornerstone of • Elderly patients
therapy. • Malnourished patients
• Food-handlers, healthcare workers and individuals in
Antibiotic therapy should be considered in the follow-
ing patients: day-care centres (children and care-givers)
• Infants under two years of age. Choice of antibiotic depends on the local resistance
• Adults over 50 years of age (with atherosclerosis) pattern of Shigella spp.
• Immunocompromised patients, owing to, e.g. organ Oral antibiotic drugs of choice are ciprofloxacin, levo-
floxacin and azithromycin.
transplant, AIDS, cancer, lymphoproliferative disease Resistance to co-trimoxazole is sufficiently high that it
and sickle-cell disease precludes its empiric use for shigellosis.
• Severe disease (high fever, more than nine or 10 In children under 18 years of age, parenteral anti-
stools per day) biotic therapy is indicated in suspected or proven Shi-
gella infection if:
HANDBOOK OF GENERAL MEDICINE VOL 1 • There is underlying immune deficiency