Antipyretics (APs) are widely consumed drugs. In 2013, the National Institute for Health and Care Excellence advised that paracetamol and ibuprofen can be prescribed for febrile children in distress.1 In a national cross-sectional study in France, more than 80% of health care professionals resorted to AP to manage fever in children. Paracetamol was the first-choice AP among 88% of health care professionals while ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), was preferred by 11%.2 Diclofenac sodium and mefenamic acid have also been advocated as APs for children.3 4 What makes use of APs truly ubiquitous is their non-prescription, over-the-counter availability. Widespread consumption often entails an increased chance of adverse drug reaction (ADR). Paracetamol and NSAIDs are two of the most common drugs to cause an allergic or pseudo-allergic reaction, secondary to general anaesthetic agents and beta-lactam antibiotics.5 Prevalence of NSAID hypersensitivity ranges from 0.1% to 0.3%.6 Hypersensitivity reactions to ibuprofen occur at 0.01%.7 The epidemiology of paracetamol hypersensitivity is unclear. This is understandable since prescription data for over-the-counter drugs are difficult to obtain. Nevertheless between 1982 and 1991, the Spanish Drug Monitoring System estimated the incidence of ADR to paracetamol to be less than 1 per 100 000 inhabitants below the age of 15 years. Among the reported ADRs, 30% were related to skin eruption, urticaria, or itchiness.8 The real incidence might have been higher, had unreported cases been included. This is a review of the pathogenesis, diagnosis, and management of hypersensitivity to APs.

Hypersensitivity reactions to APs are idiosyncratic responses of the body towards drugs given at a therapeutic dose. Around two thirds of patients with NSAID or paracetamol hypersensitivity are single reactors, while one third are cross-reactors.9 Reaction may either be to the active ingredient or to excipients. Hypersensitivity to APs can manifest as an immune-mediated reaction that stems from an immunoglobulin (Ig) E–mediated (immediate) reaction or a non–IgE-mediated (delayed) reaction. Unlike other drugs, hypersensitivity to APs can also be non–immune-mediated.

Type I hypersensitivity to APs, or an IgE-mediated reaction, is selective in nature. It presents with single NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) or hypersensitivity to NSAIDs with structural similarity but tolerance to NSAIDs from different classes. Ibuprofen and paracetamol are two common causes of SNIUAA.10 Severity ranges from localised urticaria, mucosal swelling, and angioedema to anaphylaxis. Susceptible patients become sensitised to an AP on first exposure, with the production of drug-specific IgE. Specific IgE molecules become attached to high-affinity IgE receptors on mast cells or basophils. Re-exposure to the same AP or cross-reacting drugs leads to cross-linking of adjacent IgE receptors and subsequent degranulation of vasoactive inflammatory mediators like histamine and tryptase.11 Patients with SNIUAA against ibuprofen produce IgE against specific antigen determinants of the drug. Hence they may react to arylpropionic acids with similar chemical structure but tolerate NSAIDs from other groups, such as acetic acids.7 Similarly, patients with selective hypersensitivity to paracetamol confirmed by IgE tests or oral challenge can tolerate other NSAIDs.12

According to the revised Gell and Coombs classification, maculopapular eruption (MPE) is a type IV-c, T-cell–mediated delayed hypersensitivity reaction.13 It is said to be the most common delayed drug rash due to an AP. Implicated drugs include ibuprofen, diclofenac, and paracetamol.14 Such MPE manifests as a morbilliform or scarlatiniform rash that starts on the trunk with subsequent spread to the limbs. Onset of MPE ranges from within 7 to 14 days of first consumption of the drug, but may take only 2 to 3 days in patients with prior sensitisation. The reaction of MPE involves skin-homing T lymphocytes, drug-specific cells that express cutaneous lymphocyte antigen. Around two thirds of the T-cells are CD4+, while one third are CD8+. Having resided in the dermo-epidermal junction, these cells release perforin and granzyme B, two mediators of keratinocyte apoptosis, via their ability to induce pore formation in the cell membrane.15 Histological changes include intracellular, intercellular and dermal papilla oedema, dislodgment of epidermal basal cells, hydropic degeneration, spongiosis of the lower epidermis, and dyskeratosis and necrosis of keratinocytes. Inflammatory infiltration by T-cells is seen at the dermo-epidermal junction and eosinophils in the perivascular region.16

Fixed drug eruption (FDE) is a peculiar type of T-cell–mediated delayed drug hypersensitivity. It starts with solitary, well-circumscribed macules that erupt anywhere on the skin or mucosa, usually over the lips, palms, soles, groins, or glans penis. With time, the lesions evolve into plaques that recur at the same site on re-exposures to the same drug. The interval between drug intake and FDE is around 30 minutes to 8 hours. The eruption resolves spontaneously after cessation of the culprit, leaving hyperpigmentation at the affected site. Pathologically, migration and residence of drug-specific effector-memory CD8+ T-cells in the epidermal side of the dermo-epidermal junction of the affected area account for the recurrence of eruption at the same site. Upon drug re-exposure, quiescent CD8+ cells become activated and secrete interferon-γ and cytotoxic granules into the local microenvironment.17 Paracetamol is one of the most common causes of FDE, as are mefenamic acid, ibuprofen, and aspirin.18

Drug reaction with eosinophilia and systemic symptoms (DRESS) is classified as a type IV-b delayed hypersensitivity reaction with eosinophil involvement. It is characterised by fever, exfoliative dermatitis, lymphadenopathy, haematological abnormalities (hypereosinophilia, atypical lymphocytes), and organ dysfunction. The interval between drug consumption and onset of symptoms is quite prolonged, ranging from 3 weeks to 3 months. The pathophysiology of DRESS involves viral reactivation (eg human herpes type 6) and T-cell activation, two determining factors with a mutual causal relationship.19 FOXP3+ (forkhead box P3) regulatory T-cells are activated early in the course of DRESS, but are subsequently deactivated and become deficient, culminating in the emergence of autoimmune diseases commonly seen in the aftermath of DRESS. Ibuprofen and paracetamol have rarely been associated with DRESS.20 21

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a type IV-c delayed hypersensitivity reaction to infections or drugs including APs. The interval between intake of the culprit drug and SJS/TEN is shorter than that of DRESS, ranging from 1 to 21 days.22 Skin lesions in SJS/TEN are typically target-like with central necrosis, bullae formation, or purpuric lesions. In SJS, less than 10% of the body surface area is involved, whereas in TEN, more than 30% is involved. Gentle rubbing of ‘normal’ skin causes separation of the epidermis (Nikolsky sign). Mucosal and eye inflammation is present in 90% and 60% of cases, respectively. Severe cases culminate in corneal scarring, respiratory distress syndrome, pneumonia, and respiratory failure.23 A caveat in the diagnosis is that the prodromal phase of SJS/TEN may be mistaken as symptoms of a febrile illness, with consequent administration of APs. In the event that SJS/TEN occur secondary to other causes, subsequent appearance of skin and mucosal lesions may impart the wrong impression of AP as the causative agent. In SJS/TEN, CD4 T-cells accumulate in the dermis while CD8 T-cells predominate in the epidermis. T-cell infiltration causes massive apoptosis of the keratinocytes via the toxic action of perforin, granzyme, and Fas/Fas ligand interaction.24 Of note, SJS/TEN due to NSAIDs is exceedingly rare. The incidence for ibuprofen was 0.013 per 1 000 000 as opposed to 0.032 per 1 000 000 for oxicams.25 Compared with controls, the relative risk of paracetamol and ibuprofen for SJS/TEN in children ranges from 5 to 11.26 It is also noteworthy that APs are often prescribed together with antibiotics to treat infection, with the latter two factors (antibiotics and infection) potentially related to SJS/TEN.27

Acute generalised exanthematous pustulosis (AGEP) is a rare type IV-d drug hypersensitivity with sterile subcorneal pustule formation. Onset of pustules occurs around 1 day after drug intake. Most patients present with fever. Non-follicular small pustules with an erythematous base start on the face or intertriginous area and subsequently become generalised. The pustules, which are itchy or burning, persist for 4 to 30 days before desquamation.28 Histological characteristics include papillary oedema, perivascular infiltration by neutrophils, and drug-specific T-cells and epidermal keratinocyte necrosis. Interleukin-8, a neutrophil chemoattractant, is expressed by drug-specific T-cells. Presence of human leukocyte antigens (HLAs)-DR within the inflammatory infiltrate suggests the role of a major histocompatibility complex in causing this peculiar type of drug eruption.29 Among NSAIDs, only the oxicams are significantly associated with AGEP, with a multivariate odds ratio of 8.4. Paracetamol is not considered at an increased risk of causing AGEP.30

Of note, NSAIDs can cause an allergic inflammatory response in different organs. Cases of NSAID-induced hepatitis, pneumonitis, nephritis, and aseptic meningitis have been reported.6

Three types of non-immune drug hypersensitivity to NSAIDs have been described: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous disease (NECD), and NSAID-induced urticaria/angioedema (NIUA). In NERD, patients usually have asthma, rhinosinusitis, and/or nasal polyps. Aspirin or other NSAIDs may precipitate nasal congestion, rhinorrhoea, bronchial obstruction, or dyspnoea within 30 to 180 minutes of ingestion. Urticaria, angioedema, and flushing of the upper thorax may occur. Patients with NECD usually have underlying chronic spontaneous urticaria. Aspirin or NSAIDs may cause flare-up of urticaria and angioedema in 12% to 30% of patients with chronic spontaneous urticaria. On the other hand, NIUA occurs primarily in patients without underlying disease. Immediate reactions that occur less than 15 minutes following consumption and late reactions that occur after several hours have been described.10

Non-immune hypersensitivity to NSAIDs is the result of cyclooxygenase (COX) inhibition, a pharmacological property common to all NSAIDs that accounts for their propensity to cause cross-reactivity. Three COXs—COX-1, COX-2, and COX-3—have been identified, and NSAIDs like ibuprofen inhibit all three COXs. On the contrary, paracetamol is a weak inhibitor of COX-1 and COX-2, especially at a low dose, and preferentially inhibits COX-3.31 In susceptible patients, inhibition of COX leads to overproduction of pro-inflammatory cysteinyl leukotrienes by mast cells and eosinophils but depletion of the homeostatic and anti-inflammatory prostaglandin E₂ (PGE₂).31 Imbalance of leukotrienes and prostaglandins culminates in inflammation in the skin, nasal cavities, sinuses, and airway mucosa.32 Accumulation of leukotrienes in the skin results in urticaria and angioedema characterised by dermal oedema, and lymphatic dilation involving perivascular or interstitial cellular infiltration.33

Recent genetic studies have further elucidated the pathogenesis of NSAID hypersensitivity due to COX inhibition, explaining why it only occurs in some patients. Candidate genes are responsible for various enzymes, receptors, or mediators involved in dysregulation of arachidonic acid metabolism, initiation of immune response, dysfunction of epithelial cells, biochemical signalling, effector function in inflammatory cells, and aspirin metabolism.34 Studies revealed that HLAs are associated with NSAID hypersensitivity, for instance, subjects with HLA DPB1*0301 are at a higher risk of developing NERD.35 Aside from genes, methylation profiles of DNA have been associated with NERD, underscoring the role of epigenetics.36

Discussion of hypersensitivity to APs is incomplete without mentioning the role of excipients that act as vehicles of drugs. It was thought that an excipient, being ostensibly inert, should not cause ADR. Recent reports of excipient hypersensitivity, however, have cast doubt on that.37 Common paracetamol preparations come in the form of tablets, syrup, and suppositories. As with other drugs, excipients in paracetamol contain preservatives, colouring, sugar, and ethanol. Parabens and benzoates, two potential allergens, are preservatives widely used in various paracetamol preparations.

Different excipients are added to produce different formulations. For instance, one type of paracetamol syrup contains propylene glycol, methyl hydroxybenzoate, propyl hydroxybenzoate, xanthan gum, sorbitol solution 70%, sucrose, mango flavouring, and purified water.38 There are currently more than 90 registered manufacturers of generic paracetamol in Hong Kong, producing a stunning inventory of more than 900 paracetamol-containing formulations in the drug registry of the Department of Health.39 Patients hypersensitive to the excipient of one product (eg paracetamol tablet) may tolerate another form (eg paracetamol syrup) or the same form of another brand. Unfortunately, pharmaceutical companies may not disclose excipient components of a drug in their entirety. This makes thorough comparison between different products difficult.

Prudent management of hypersensitivity to APs starts with an attempt to confirm or exclude the diagnosis. As APs are usually prescribed for fever on an as-required basis, clinicians should concentrate on actual consumption rather than prescription. Reactions that appear within 1 to 2 hours of AP consumption constitute immediate hypersensitivity, while reactions that appear several hours or beyond are considered delayed hypersensitivity. Although symptoms usually subside within 24 to 48 hours, some may persist for up to 1 to 2 weeks.40

The number of previous exposures to an AP should be noted. The same drug tolerated on many occasions is unlikely to be the culprit. An AP tolerated only once before may trigger an IgE-mediated reaction the second time it is given to a susceptible patient. An AP given for the first time can still trigger a reaction via T-cell activation or COX inhibition. Previous exposure may not be apparent in case of poor recall or if the AP is given in the context of polypharmacy. With details of the past and present drug treatment, clinicians should estimate the probability of AP hypersensitivity before attaching the label. A validated scoring system can help classify patients as definite, probable, possible, or doubtful cases of ADR.41 The next step is to differentiate between single-reactors and cross-reactors by thorough history taking and collation of data from various sources, including written and electronic drug records.

Care is needed for proper drug identification, as APs may have many trade names. Clinicians can refer to the Drug Database of the Department of Health for a comprehensive list of registered drugs from different pharmaceutical companies.39 Over-the-counter drugs should be carefully studied in history taking. Patients should be encouraged to submit any remaining drugs to hand for identification. Clinicians should try to differentiate between hypersensitivity to the active ingredients versus excipients. Patients who react to different preparations of the same drug are likely hypersensitive to the active ingredient, while those who react only to some preparations may be suffering from hypersensitivity to excipient(s).

A clinical history is valuable in predicting hypersensitivity to APs: 17% of children with such hypersensitivity have a positive family history. Such children are more than 5 times likely to have NSAID hypersensitivity compared with controls.9 Emergence of an ADR within an hour of administration and a history of hypersensitivity to multiple NSAIDs are two other stronger predictors of challenge-proven NSAID hypersensitivity.42

Clinicians should then differentiate between various clinical manifestations. Urticarial rash and angioedema are found in type I hypersensitivity and reactions due to COX inhibition; whereas MPE is erythematous, non-itchy, and flat lesions that blanche on pressure (Fig 1). Isolated discoid lesions recurring at the same site are indicative of FDE (Fig 2). Presence of ‘red-flag signs’ signifies more sinister diseases. Mucosal inflammation and ulcerations associating with unremitting fever, intense skin pain, and Nikolsky sign should raise concern about possible development of SJS/TEN. Widespread MPE associating with persistent fever, peripheral eosinophilia, liver impairment but absence of mucosal inflammation is suggestive of DRESS. In NERD, patients typically have underlying chronic rhinosinusitis, nasal polyps, and asthma complicated by NSAID intolerance. Patients with NECD may have chronic spontaneous urticaria.10

Differential diagnoses of hypersensitivity to APs include hypersensitivity to concomitant drugs and diseases with skin or mucosal manifestations, eg viral infections, chronic urticaria, or Kawasaki disease. On the other hand, SJS is related to infection such as mycoplasma in 25% of affected children.27 As mentioned, AP may be given for fever control after the onset of other symptoms. The febrile illness that requires AP can also cause skin or mucosal symptoms. One should also consider the possibility that the AP is a co-factor of other allergens. A co-factor may not cause allergy per se, but may lower the threshold for allergic reaction to another allergen. Common co-factors include exercise, infection, menstruation, stress, alcohol, angiotensin-converting enzyme inhibitors, and NSAID. Possible mechanisms of co-factors include tight junction dysregulation, increased gastrointestinal absorption of allergens, and COX inhibition. The prevalence of co-factor–dependent anaphylaxis related to NSAID ranges from 1.2% to 4.7%.43

Aside from diagnosis of allergy to an aeroallergen in patients with NERD, the skin prick test for AP is probably useful only in the context of IgE-mediated SNIUAA. A negative skin prick test, however, does not exclude hypersensitivity to APs as many reactions are non–IgE-mediated. Moreover, with the passage of time, even individuals with IgE-mediated hypersensitivity may lose skin test positivity. An intradermal test and atopic patch test may be helpful in diagnosing NSAID-induced delayed hypersensitivity. These tests are generally specific but not sensitive for diagnosis. Lack of standardisation and a scarcity of available commercial reagents limit their utility. Except for diagnosis of IgE-mediated hypersensitivity to APs, skin tests seem to have little diagnostic value.10

A drug provocation test (DPT), which works independently of the underlying mechanism, remains the gold standard for diagnosis of hypersensitivity to APs and establishment of cross-reactivity. As usual formulations are used, DPT is more feasible than skin tests for AP. In a Turkish paediatric study, only five (14%) of 36 children with a history of single NSAID hypersensitivity reacted positively to a DPT using the culprit drug. For 18 children with an alleged history of multiple NSAID hypersensitivity, DPT was positive in eight (44%). Among patients with NSAID hypersensitivity, 50% also reacted to paracetamol.9 Conversely, only 25% of patients with paracetamol hypersensitivity develop cross-intolerance to NSAID.12 The negative predictive value of DPT in children reaches 100% for NSAIDs, so patients who pass a DPT can be safely given the NSAID in future.45 A DPT is generally not recommended during pregnancy, intercurrent illness, or in patients with co-morbidities such as cardiac, hepatic or renal disease, or uncontrolled asthma. Contra-indications to DPT include a history of SJS/TEN, DRESS, AGEP, systemic vasculitis, drug-induced autoimmune diseases, and severe anaphylaxis.46

A typical protocol for DPT starts with 1/50 to 1/20 of a single maximum dose of an AP, followed by four to five incremental doses given at regular intervals (eg 60 minutes) until the single maximum dose is reached.9 Patients who pass a DPT on day 1 can be given a 2-day course on day 2 to ensure full tolerance to the test drug. In case symptoms or signs of ADR appear, DPT should be aborted and anti-allergic treatment immediately given. The threshold cumulative dose can then be determined. For paracetamol, this ranges from 75 mg to 325 mg.47 The same procedure can be repeated at least 1 week later, using another AP from a structurally unrelated class to determine cross-reactivity.48 For instance, patients who fail a DPT for ibuprofen, an arylpropionic acid, can undergo a subsequent DPT for diclofenac, an acetic acid. A DPT should be carried out in the hospital setting with resuscitation facilities available and supervised by clinicians experienced in managing drug hypersensitivity and anaphylactic reaction.

Most in-vitro tests to date have not been validated or standardised. Aside from research purposes they are not routinely recommended for clinical use.

Demonstration of specific IgE (sIgE) against a NSAID in the serum theoretically aids diagnosis of SNIUAA. Serum sIgE against paracetamol has been demonstrated by some researchers.49 Compared with skin prick test, however, serum sIgE against NSAID is less useful. Sensitivity and specificity of sIgE are not known.14

Detection of CD63 signifies activation of basophils and forms the basis of the basophil activation test. As a diagnostic tool for NIUA, basophil activation test is relatively sensitive but not specific.50

As drug-specific T-lymphocytes are frequently involved in NSAID hypersensitivity, a lymphocyte transformation test (LTT) has been advocated as a diagnostic tool. The test is based on measurement of ³H-thymidine uptake by dividing T-cells. The NSAIDs considered suitable for LTT include diclofenac, mefenamic acid, and paracetamol. Sensitivity of the LTT ranges from 60% to 70% with specificity of approximately 85%. A positive LTT is useful for diagnosis, but a negative test does not exclude hypersensitivity. Involvement of a stringent protocol and need for expert interpretation means that LTT can be performed only by specialised laboratories.51

The offending AP should be stopped and antihistamine given. In case of anaphylactic reaction, emergent treatment and resuscitation should be performed. Oxygen, intramuscular adrenaline, and antihistamine should be given. A severe cutaneous adverse reaction should be managed in the intensive care unit. Standard treatment includes intravenous fluids, corticosteroid, intravenous Ig, and other immunosuppressants.23

Management of suspected AP hypersensitivity starts with thorough discussion with patients or caretakers of the pros and cons of the AP as opposed to avoidance. The aims of investigation include confirmation of hypersensitivity and cross-reactivity, differentiation between hypersensitivity to the active ingredient versus excipients, and trial of safe alternatives. Detailed review of drug history is of paramount importance. Above all, DPT is pivotal to achieving the aims of investigation. A combination of drug history and DPT culminates in six alternative approaches to deal with hypersensitivity to APs (Fig 3).

Patients allergic to excipients in one AP may tolerate a different brand or different formulation of the same drug (approach 1). Detailed comparison of constituents may reveal the excipient in question. In case of doubt, DPT can be performed on the alternative brand or formulation to confirm tolerance. In case the patient reacts to different formulations and brands of the same AP, a trial of AP with unrelated structure can be considered (approach 5). A common example is to try ibuprofen in patients with paracetamol hypersensitivity. As mentioned before, three quarters of patients with paracetamol hypersensitivity tolerate NSAIDs. Patients hypersensitive to ibuprofen, an arylpropionic acid, can consider DPT using paracetamol or an acetic acid such as diclofenac.

Patients with cross-intolerance to paracetamol and NSAIDs pose a management dilemma. Avoidance of all APs seems logical (approach 2), especially if the feverish patient is not ‘distressed’. Nonetheless whether a patient is in distress or not is a matter of subjective judgement. For cultural reasons, it is exceedingly difficult to persuade Hong Kong parents not to give APs to a child with a high fever. In case fever control is deemed desirable by either parents or physicians, viable solutions should be sought. Desensitisation (approach 3) is another viable option. A standard desensitisation protocol has been established for aspirin.52 Desensitisation is applicable to patients having NERD or NIUA.10 It is contra-indicated in patients with a history of severe, life-threatening drug reactions such as SJS/TENS or DRESS. Nonetheless desensitisation should only be carried out in medical facilities with resuscitation equipment and expertise in drug allergy. Alternative theoretical choices (approach 4) include subthreshold or low-dose paracetamol,47 53 COX-2 inhibitors,54 pre-medication with antihistamines with or without leukotriene receptor antagonist,55 co-administration of a PGE₂ analogue,56 and traditional Chinese medicine.57 Future studies are needed to define the safety and efficacy of these unconventional treatments.

Patients with a mild or doubtful reaction to an AP can consider a DPT, the gold standard to diagnose or exclude hypersensitivity to the culprit drug. Patients who react to the culprit AP during DPT can either try a structurally unrelated AP (approach 5) or try a different brand/formulation (approach 1). Finally, patients who pass the DPT can be given the culprit drug in future (approach 6), as the test has a very high negative predictive value.10

It is arguable that APs may not be indicated in the first place and should be avoided in patients with hypersensitivity. Although APs should not be prescribed simply for the sake of ‘temperature control’, the need to mitigate patient discomfort should not be disregarded.58 Patients with illnesses such as heart failure, head injury, or sepsis present special problems. Their limited reserve to withstand the hypermetabolic state associated with febrile episodes puts them at particular risk.59 For these patients, APs seem beneficial. In case they have hypersensitivity to APs, viable options should be sought. Attempts to predict such hypersensitivity are daunting. Disappointingly, prediction of severe cutaneous adverse reactions to APs is virtually impossible. However, the presence of a positive family history, reaction within 1 hour of consumption, and history of multiple NSAID hypersensitivities may sound an alarm for the increased risk of genuine immediate hypersensitivity to APs. Clinicians need to strike a balance between ‘hypersensitivity phobia’ for the sake of drug safety and liberal use of APs to uphold patients’ rights. Knowledge of the pathogenesis of AP hypersensitivity and meticulous diagnostics are key to judicious management.

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43. Wölbing F, Fischer J, Köberle M, Kaesler S, Biedermann T. About the role and underlying mechanisms of cofactors in anaphylaxis. Allergy 2013;68:1085-92. Crossref

44. Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy 2014;69:420-37. Crossref

45. Misirlioglu ED, Toyran M, Capanoglu M, Kaya A, Civelek E, Kocabas CN. Negative predictive value of drug provocation tests in children. Pediatr Allergy Immunol 2014;25:685-90. Crossref

46. Aberer W, Bircher A, Romano A, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003;58:854-63. Crossref

47. Ho MH, Tung JY, Lee TL, Tsoi NS, Lau YL. Anaphylaxis to paracetamol. J Paediatr Child Health 2008;44:746-7.

48. Zambonino MA, Torres MJ, Muñoz C, et al. Drug provocation tests in the diagnosis of hypersensitivity reactions to non-steroidal anti-inflammatory drugs in children. Pediatr Allergy Immunol 2013;24:151-9. Crossref

49. de Paramo BJ, Gancedo SQ, Cuevas M, Camo IP, Martin JA, Cosmes EL. Paracetamol (acetaminophen) hypersensitivity. Ann Allergy Asthma Immunol 2000;85(6 Pt 1):508-11. Crossref

50. Ariza A, Fernandez TD, Doña I, et al. Basophil activation after nonsteroidal anti-inflammatory drugs stimulation in patients with immediate hypersensitivity reactions to these drugs. Cytometry A 2014;85:400-7. Crossref

51. Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy 2004;59:809-20. Crossref

52. Macy E, Bernstein JA, Castells MC, et al. Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper. Ann Allergy Asthma Immunol 2007;98:172-4. Crossref

53. Kidon MI, Kang LW, Chin CW, et al. Early presentation with angioedema and urticaria in cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs among young, Asian, atopic children. Pediatrics 2005;116:e675-80. Crossref

54. Corzo JL, Zambonino MA, Muñoz C, et al. Tolerance to COX-2 inhibitors in children with hypersensitivity to nonsteroidal anti-inflammatory drugs. Br J Dermatol 2014;170:725-9. Crossref

55. Nosbaum A, Braire-Bourrel M, Dubost R, et al. Prevention of nonsteroidal inflammatory drug-induced urticaria and/or angioedema. Ann Allergy Asthma Immunol 2013;110:263-6. Crossref

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57. Liew WK, Loh W, Chiang WC, Goh A, Chay OM, Iancovici Kidon M. Pilot study of the use of Yin Qiao San in children with conventional antipyretic hypersensitivity. Asia Pac Allergy 2015;5:222-9. Crossref

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Our previous review paper described and discussed disorders of the prepuce.1 In this paper, we focus on common inguinoscrotal pathologies in children. Inguinal hernia/hydrocoele, undescended testis, acute scrotum, and varicocoele will be discussed. These have a broad disease spectrum, but may have similar clinical presentation and may be discovered by parents, during routine paediatric assessment or incidentally in the clinic. Despite advances in medical technology, proper history taking, physical examination, and understanding of these conditions remain crucial for management and specialist referral.

These two conditions account for most of the pathologies in the inguinoscrotal region in children. For paediatric inguinal hernia, the cumulative incidence was reported to be 6.62% in boys up to 15 years old in a nationwide study in Taiwan: one in 15 boys would develop inguinal hernia before the age of 15 years.2

Both inguinal hernia and hydrocoele occur because of non-closure of the processus vaginalis (patent processus vaginalis). The processus vaginalis forms an extension of the peritoneum during the time of testicular descent into the scrotum in the fetus. It normally undergoes fusion or closure when testicular descent is complete. Failure to close may result in either inguinal hernia or hydrocoele, depending on the size of the defect. If it remains patent or unfused in girls, it becomes the canal of Nuck and may also result in inguinal hernia (Fig 1).

The incidence of inguinal hernia is highest in children under 1 year of age and thereafter decreases.2 In premature babies, the incidence is even higher with babies born less than 32 weeks of gestation having a reported incidence of 9.34%.3

Right-sided hernias are more common (ratios of right, left, and bilateral hernia are approximately 59%, 29%, and 12%, respectively).4 Boys are affected around 10 times more often than girls2; 99% of inguinal hernias in children are of the indirect type.4

Hydrocoele is an abnormal collection of fluid along the processus vaginalis, and can be communicating or non-communicating. In communicating hydrocoele, there is a patent processus vaginalis. Non-communicating hydrocoele includes scrotal hydrocoele and hydrocoele of cord, and here the processus vaginalis is obliterated with the collection of fluid in the tunica vaginalis. Hydrocoele can present in infants or older children and its management differs. For hydrocoele that presents before 1 year of age, there is a 62.7% to 89% chance of spontaneous complete resolution or significant improvement,5 6 7 with the mean time of resolution being about 6 months. Thus, it is worth allowing a period of time to observe a hydrocoele provided other conditions like inguinal hernia or testicular pathology have been excluded.

Parents usually notice the inguinoscrotal pathology in their child during bathing or changing nappies. A painless bulge over the inguinal region or even down to the scrotum may be seen in boys, or a bulge over the vulva in girls with inguinal hernia. The bulge will increase in size when the child cries and decrease when lying down. A proper clinical examination may not be easy in the clinic setting for children and the hernia may not be apparent. A well-taken clinical history is very important in making the correct diagnosis. An ‘intermittent inguinal swelling’ may indicate an inguinal hernia. A static painless scrotal swelling may indicate a scrotal/encysted hydrocoele.

For children who cooperate, the upper and lower extent of the inguinoscrotal mass should be carefully examined. The upper extent of an inguinal hernia should start at the internal ring, that is, the midpoint between the pubic tubercle and anterior superior iliac spine. For scrotal/encysted hydrocoele, clinicians should be able to get above the lesions. A transillumination test is a very helpful in adults but is not reliable in infants/small children. Because of the thin bowel wall the transillumination test can also be positive in infants/small children with inguinal hernia.

Pain and inconsolable crying in a child with a tender irreducible inguinal bulge may indicate an incarcerated inguinal hernia. A younger child is more likely to be affected. The mean age of hernia incarceration was shown to be 1.5 years in a previous study.4 The incidence of incarceration is 3 times higher in premature babies with inguinal hernia.

Very often, parents may not be able to describe the clinical features properly and no pathology can be demonstrated during a clinic visit. We suggest that parents take a clinical photo using mobile phones at home, which can be shown to the doctor during the subsequent clinic visit.

Diagnosis of an inguinal hernia depends largely on clinical history and physical examination. Different imaging techniques can sometimes be helpful in making the diagnosis. Contrast herniography is only of historical interest because of its invasiveness. Ultrasonography (USG) of the inguinal canal to detect occult inguinal hernia has been described and its use varies in different countries. Studies show that the preoperative USG can decrease the future risk of developing metachronous inguinal hernia.8 A positive finding on USG strongly correlates with positive operative findings.9 10 Nonetheless as the accuracy of USG is largely operator-dependent, we feel that while a positive USG finding is strongly suggestive of a clinical hernia, a negative finding should be interpreted with care. Diagnosis of inguinal hernia will very much depend on clinical examination. Of note, USG of the inguinal canal is not a routine procedure when making a diagnosis of inguinal hernia. It may serve as an adjunct when there is doubt about incarcerated hernia versus hydrocoele of cord or concern about underlying testicular pathology for hydrocoele.

Once the diagnosis of inguinal hernia is made, operation is indicated regardless of age due to the risk of incarceration, with a reported rate of approximately 4.19% to 8.2%.2 11 As young children and infants have a higher risk of incarceration, it may be wise to arrange earlier operation. Surgery, however, should still be arranged as early as possible in an otherwise healthy child.

For the management of premature babies with inguinal hernia, there are many factors that should be taken into consideration such as postoperative apnoea, respiratory distress, co-morbidities (eg chronic lung disease in premature babies), and risk of incarceration. There is always debate about the optimal timing of hernia repair in premature babies, that is, surgery just before discharge from neonatal intensive care unit or when the child is older. Although a long waiting time is associated with higher risk of incarceration in infants and premature babies, and emergency repair in patients with incarceration is associated with a higher likelihood of testicular atrophy,12 13 14 surgery is less technically demanding in older babies. Fewer perioperative morbidities are also observed when performing surgery later. Early inguinal hernia repair is associated with prolonged hospital stay and prolonged intubation.15 A study from Hong Kong reported one (1.3%) incarceration in 79 premature patients with a mean body weight at operation of 4360 g.16 This incarceration rate is relatively lower when compared with other studies—9% to 21% by Lautz et al13 from the United States, and 5.2% to 10.1% by Zamakhshary et al12 from Canada. It is likely to be due to the shorter travelling time between a patient’s home and hospital in Hong Kong. Based on our experience, it is reasonable in Hong Kong to wait for surgery until premature babies have achieved a reasonable body weight. Parents should be taught how to observe the symptoms and signs of incarceration before discharge. If the patient lives unreasonably far from the hospital and parents are not able to observe the symptoms and signs of incarceration, earlier surgery should be offered. From our perspective, we would offer repair when the patient’s body weight reaches 2.5 kg, provided there are no other indications for earlier or delayed repair.

As mentioned earlier, there is a high chance of spontaneous resolution of infantile hydrocoele during the first year of life. Patients should therefore be observed and monitored in the first 1 to 2 years of life.5 6 Parents should also be taught about the symptoms and signs of inguinal hernia during this observation period as an inguinal hernia may present as a communicating hydrocoele on first sight. Patients with persistent hydrocoele, giant or symptomatic hydrocoele, hydrocoele associated with inguinal hernia or other conditions (eg presence of ventriculoperitoneal shunt), or who require peritoneal dialysis should be offered surgery.

Open high ligation of patent processus vaginalis was the mainstay of treatment for both inguinal hernia and hydrocoele in children until the advent of laparoscopic surgery. Different laparoscopic techniques are largely categorised into intracorporeal or extracorporeal ligation of the patent processus vaginalis.17 18 19 Benefits of laparoscopic surgery include the possible visualisation of the contralateral deep ring and better cosmetic outcome. Yet it may incur a higher set-up cost or longer operating time.

Two recent systematic reviews/meta-analyses showed very similar results when comparing open and laparoscopic inguinal hernia repair in children.17 20 Both studies showed no significant difference in recurrence rate. Esposito et al17 reported a 1.4% recurrence rate following laparoscopic repair and 1.6% following open repair. For operating time, they noted a significantly shorter time for laparoscopic repair of bilateral hernia when compared with an open approach. There was no difference for unilateral hernia repair. Feng et al20 reported that a laparoscopic extraperitoneal method had a much shorter operating time in both unilateral and bilateral hernia repair. Lower pain scores were also reported in two randomised controlled trials for laparoscopic repair.21 22

Feng et al20 further showed more testicular complications in open repair. Another retrospective review showed similar results.23 Of note, a higher recurrence rate of up to 3.4% for laparoscopic repair was observed in the early era of laparoscopic surgery.18 There is no consensus, however, on whether a laparoscopic or open approach is superior.

In contrast to laparoscopic inguinal hernia repair, laparoscopic repair of hydrocoele has not received the same popularity, with open high ligation still being the mainstay of treatment. Indeed, only a handful of studies can be found in the literature. One reason may be the belief that the deep ring is already closed. A recent study noted that 97% of patients with a clinically non-communicating hydrocoele had a patent processus vaginalis during laparoscopy.24 Among the small number of reports, Saka et al19 showed no significant difference in terms of outcome between open and laparoscopic repair of hydrocoele.

Metachronous contralateral inguinal hernia (MCH)—presence of contralateral inguinal hernia—may present in some patients after successful repair of inguinal hernia. An initial presentation with left-sided hernia,25 26 27 and prematurity are risk factors for MCH.

Before the era of laparoscopy, USG of the groin or routine contralateral exploration were suggested by some surgeons to reduce the risk of MCH and the need for second operation/anaesthesia. Miltenburg et al28 reviewed the use of laparoscopic evaluation and concluded that it could successfully decrease the incidence of MCH.

Today, routine examination during laparoscopic hernia repair has shown the rate of contralateral patent contralateral processus vaginalis (CPPV) to be 30% to 39.7%.25 29 Yet, a meta-analysis revealed that only 6% of all patients returned with MCH after unilateral inguinal hernia repair.26 Thus, the presence of CPPV does not necessarily equate to subsequent clinical inguinal hernia. Kokorowski et al29 concluded that patent processus vaginalis might be over-treated. Repair of the patent processus vaginalis will definitely decrease the risk of MCH, the costs, and the risk of future hernia incarceration. On the other hand, it also carries an operative risk of vas injury, haematoma, and infection of the contralateral side. In view of the uncertainties about the overall balance of risks and benefits of routine prophylactic repair of CPPV, parents should be counselled on the benefits of avoiding potential future development of clinical hernia and the risks of the procedure.

Cryptorchidism has an estimated incidence of 22.8 per 10 000 live births.30 It remains an important condition because of its potential sequelae of subfertility, testicular malignancy, and accompanying inguinal hernia.

Testicular descent is a complex process. Male differentiation starts at around 7 to 8 weeks of gestation under the influence of the SRY gene. Testicular descent involves two phases, the transabdominal phase and the inguinoscrotal phase. The gonad descends from the area near the urogenital ridge to the level of the deep ring in the transabdominal phase. This phase ends at around 15 weeks of gestation. The inguinoscrotal phase is a more complex process in which the peritoneal membrane bulges out and elongates to form the processus vaginalis through which the testes then descend. This phase usually starts at around 25 weeks and ends at 35 weeks of gestation. After descent, the testes will anchor to the connective tissue within the scrotum.

Both phases of testicular descent are controlled by hormones. Any derangement in the pathway can result in cryptorchidism. Conditions known to be associated with cryptorchidism include prematurity, Klinefelter syndrome, and abdominal wall defects like omphalocoele. There is no single cause that can be identified to account for all the scenarios of cryptorchidism.

Cryptorchidism is mostly diagnosed by history and proper clinical examination (Fig 2). As most newborns will undergo a clinical examination before discharge from hospital, the position of the testes should be ascertained. During clinical examination, the infant should be placed supine with legs abducted in a relaxed and warm environment. A cold environment may induce a cremasteric reflex that may move the testes up. Bimanual examination (two-handed technique) should be performed. The doctor’s left hand should be placed at the deep ring and gently sweep along the inguinal canal down to the scrotum. The right hand should try to detect the testes at the scrotum or the lowest possible position. Size, mobility, and consistency of the testes should be assessed. If there are no palpable testes, a potential location of ectopic testes should be sought such as the femoral canal or perineum. The suprapubic region should be examined as well. Both sides should be examined carefully with the same technique. Other concurrent urological anomalies (eg hypospadias) or problems other than undescended testes (eg disorder of sexual differentiation) should be checked. These may warrant further in-depth investigations or indicate a need for urgent karyotyping in the newborn period.

A retractile testis should be distinguished from genuine undescended testis. The clinician should be able to bring the retractile testis down to the scrotum and the testis should stay in the scrotum for a while. It may retract with the cremasteric reflex. Patients with retractile testes should have normal testicular volume and fertility. If there is doubt about the diagnosis, regular assessment or scrotal orchidopexy can be offered.

Ascending testis is a condition in which the testis was previously within the scrotum but later ascends. Presence is usually associated with a history of retractile testis. The postulation is that the spermatic cord does not elongate with age. These patients usually present late. A history of previously noted testicular position should be sought. It has been shown that ascending testis shares a similar histopathology to congenital undescended testis.31 Orchidopexy is also recommended.

Surgical approach for the undescended testis differs depending on the location of the testis. The most important factor is whether or not the testis is palpable. Clinicians, however, may not be able to locate the testis during a clinical examination if the child struggles. If the testis is impalpable, conditions such as intra-abdominal testis, atrophic testis, and ectopic testis should also be considered. Ultrasonography can be used to detect the location and size of the testis.32 Nijs et al33 noted a high sensitivity of USG scan for inguinal testis but very low sensitivity for intra-abdominal testis. They suggested laparoscopic exploration when the testis cannot be detected on physical examination and USG.33 34

Use of gadolinium-enhanced magnetic resonance angiogram was described in 1998 as another investigation for undescended testes with high sensitivity and specificity.35 In another study published in 2000 that compared magnetic resonance imaging (MRI) with laparoscopy in non-palpable testes, the false-positive rate of MRI was 32% and true-positive rate for laparoscopy was 100%.36 As MRI is also limited by its costs, availability and potential need for general anaesthesia in a small child, many clinicians prefer laparoscopy as the method of choice for impalpable testis. Nonetheless there may still be a role for MRI in patients with suspected persistent Müllerian structures or a disorder of sexual differentiation.37

Nowadays, early operation on undescended testis is advocated to reduce the risk of malignancy and potentially preserve fertility. Early referral to a surgical specialist may be more important than investigations. The guideline from American Urological Association (AUA) published in 2014 advised that health care providers should not perform USG or other imaging modalities in the evaluation of boys with cryptorchidism prior to referral, as these studies rarely assist in decision making by the general practitioner.38

As testicular descent will continue after birth, watchful waiting should be the initial management of undescended testes. However, it is advised that all patients with undescended testis discovered at birth be re-examined at 6 months of age and referral made to a specialist if the condition persists.38

A study performed in 1974, which compared the histology of those with undescended testes before and after 2 years of age,39 showed loss of spermatogonia in patients with undescended testis after 2 years of age. Another study also showed that the uncorrected position of undescended testes was associated with ongoing germ cell damage and later fertility problems and risk of malignancy.40 Thus, orchidopexy is advised before 18 months of age.

The surgical plan for undescended testes will be dictated by the position and size of the testis. For palpable testis in the inguinal canal, inguinal orchidopexy should be performed. If no palpable testis can be identified during clinical examination, adjunct imaging studies in an attempt to locate the testis can be ordered before surgery. Laparoscopy, however, remains the gold standard in diagnosing clinically impalpable testis. In most cases the testis is located along the line of normal testicular descent, intra-abdominally or just at the deep ring of the inguinal canal. Rarely, the testis can also be atrophic, ectopic, or even absent. Three approaches have been described for intra-abdominal testes: primary orchidopexy, one-stage Fowler-Stephens orchidopexy, or two-stage Fowler-Stephens orchidopexy. Short testicular vessels are postulated to be the reason why the testis cannot be brought to the scrotum. The Fowler-Stephens procedure involves the division of testicular vessels and repositioning of the testis to the scrotum, either immediately during the procedure (one-stage) or 6 months later (two-stage). The vascular supply will depend on the cremasteric vessels and collateral vessels to the vas after this procedure. Testicular atrophy and ascent (incidence of both approximately 8%) are potential complications of this procedure.41

On the subject of alternative therapy, the AUA guideline advises against using hormone therapy to induce testicular descent as evidence shows low response rates and a lack of evidence for long-term efficacy.38

Patients should be counselled about the increased risk of testicular malignancy and subfertility.40 A histological study of the undescended testes in human fetuses, neonates, and infants showed that the absolute number of germ cells was decreased.42 Mengel et al39 noted a significant decrease in the content of spermatogonia and a lack of tubular growth at the beginning of the third year of life. Lee and Coughlin40 compared paternity rates, the semen and hormone profiles of patients with previously unilateral undescended testes, bilateral undescended testes and normal control subjects; the paternity rates of these three groups of subjects were 89.7%, 65.3% and 93.2%, respectively. Historical studies have indicated improved fertility in patients who had orchidopexy at an earlier age.43

Undescended testis is a known risk factor for testicular germ cell tumour. In a meta-analysis, Dieckmann and Pichlmeier44 showed a relative risk of 4.8 compared with the normal population. The age at which orchidopexy is performed is also important. Pettersson et al45 compared the risk of testicular malignancy between patients who received early or late orchidopexy and showed the relative risk of testicular cancer among those who underwent orchidopexy before reaching 13 years of age was 2.23 (95% confidence interval [CI], 1.58-3.06); for those treated at 13 years of age or older, the relative risk was 5.40 (95% CI, 3.20-8.53). It is postulated that the higher surrounding temperature in undescended testis could arrest germ cell maturation and become carcinoma in situ.46

Although different disease conditions can present clinically with acute scrotum, testicular torsion should be the top differential diagnosis for all patients, as this condition needs precise clinical appreciation and urgent management. The time from presentation to operation is critical and will determine if the affected testis can be salvaged. A high index of suspicion with immediate referral is crucial.

A nationwide epidemiological study in Korea showed the incidence of testicular torsion was 2.9 per 100 000 person-years of males younger than 25 years, and with a bimodal age distribution with peak incidence in infancy and adolescents.47 The salvage rates differ, ranging from 75.7% to 29%.48 49 The diagnosis of torsion depends mostly on clinical evaluation. Diffuse testicular tenderness, hydrocoele, high-lying testis with transverse lie, and absent cremasteric reflex are clinical signs of torsion. Scrotal exploration should be the management of choice in clinically suspect cases. As exploration may be negative, many clinicians have tried adjunctive methods such as the TWIST (Testicular Workup for Ischemia and Suspected Torsion) clinical scoring system,49 Doppler USG, nuclear scintigraphy, MRI, or evaluation of testicular oxygen saturation with near-infrared spectroscopy.50 For Doppler USG, accuracy depends on the skill of the radiologist. Normal intra-testicular perfusion does not exclude the possibility of torsion and there remains a false-negative rate in this modality.51 52 As a missed diagnosis of testicular torsion is one of the most common medicolegal claims in adolescent patients in the United States,53 we must stress again the prime importance of clinical evaluation and decision. Nuclear scintigraphy and MRI are not popular for the same reason. Near-infrared spectroscopy is a novel technology that measures testicular oxygen saturation but its accuracy has not been fully validated in a large population. Scrotal exploration involves open examination of the affected testes and a decision on whether to keep or remove the affected testes and also fix the contralateral side. A bell-clapper anomaly may be appreciated during examination of the testes (Fig 3).

Even after successful testicular salvage, testicular atrophy has been reported in almost 50% of patients. Those patients who presented with pain for more than 1 day were more likely to develop testicular atrophy. No testes survived in a patient who presented with pain for more than 3 days.54

Other causes of acute scrotum include torsion of the testicular appendage (hydatid of Morgagni), epididymo-orchitis, idiopathic scrotal oedema, incarcerated hernia, or Henoch-Schönlein purpura. Torsion of the testicular appendage presents in a very similar manner to torsion of the testes (Fig 4). The patient also complains of intense scrotal pain. A firm-to-hard pea-sized lesion may be palpable at the head of the epididymis. The classic ‘blue dot sign’ may also be appreciated. If testicular torsion can confidently be excluded, treatment can be by observation or simple excision of the testicular appendage. Epididymo-orchitis is a form of urinary tract infection. In small children or early adolescence, it may be a presentation of congenital anatomical urinary tract anomalies.55

Overall we advise general practitioners to seek urgent referral to a specialist without any delay if a patient presents with acute scrotum. Operative exploration should not be delayed by investigations whenever there is a suspicion of testicular torsion.

Varicocoele is an abnormal venous dilatation and/or tortuosity of the pampiniform plexus in the cord. It may present as ‘bags of worms’ clinically and is identified in 15% of healthy men and up to 35% of men with primary infertility.56 It appears in adolescent boys, with 7.8% in boys aged 11 to 14 years and 14.1% aged 15 to 19 years.57

Patients may not have any symptoms and can present late with subfertility. Increased temperature around the testis is believed to affect spermatogenesis and endocrine function of the testis.

The World Health Organization stated that varicocoele was clearly associated with impaired testicular function and infertility.58 They investigated 34 subfertility centres with 9034 men and identified varicocoele in 25.4% of men with abnormal semen compared with 11.7% of men with normal semen.

Comparison of semen analysis in young men (17-19 years old) with and without varicocoele revealed significant differences in total and progressive sperm motility and vitality, which were lower in boys with varicocoele, and number of normal sperm forms.59 It was concluded that spermatogenesis could be affected even at this young age.

Clinical (palpable) varicocoele is detected and graded based on physical examination: a grade 1 varicocoele is one that is only palpable during the Valsalva manoeuvre; a grade 2 varicocoele is easily palpable with or without Valsalva but is not visible; grade 3 refers to a large varicocoele that is easily palpable and detected on visual inspection of the scrotum. Size of both testes should be examined and measured with an orchidometer. Size discrepancy or testicular atrophy may indicate the need for further surgical management. Apart from examination of the genitalia, abdominal examination is also needed. Any abdominal mass/tumour that causes compression or obstruction of the renal veins or gonadal vessels can present with varicocoele. Ultrasonography of the abdomen and scrotum may be needed if an abdominal mass is suspected. Semen analysis may not be practical or necessary in these child or adolescent patients.

Catch-up growth of the testis after varicocoele operation has been demonstrated.60 61 Nonetheless the same has also been demonstrated in varicocoele patients managed conservatively.62 Guidelines or recommendations have been suggested by different professional bodies including the AUA, American Society for Reproductive Medicine, European Association of Urology, and European Society of Paediatric Urology (ESPU). These guidelines are mainly directed to adult patients and there is no consensus on the indications for surgery. A systematic review tried to collaborate the opinions from all the four professional bodies.63 Some agreed indications include varicocoele with reduced ipsilateral testicular volume, bilateral varicocoeles, and varicocoele with pathological semen quality. Symptomatic varicocoele was suggested as an indication by ESPU but not the other three associations.

Different open surgical methods have been described: subinguinal, inguinal (Palomo), and microsurgical subinguinal approach. All involve ligation of testicular vessels, with or without the testicular artery. Laparoscopic high ligation of the vessels has become popular in this era. Lymphatic or artery-sparing techniques are preferred by some as they decrease the postoperative hydrocoele rate.64 65 Radiological embolisation of the testicular vein is another option.

Recurrence rates vary for different surgical procedures but are reported to be ranging from 0% to 35%. The rate of recurrence following various surgical methods have been quoted as: laparoscopic (1.2%), non-magnified inguinal (1.3%), open retroperitoneal (9.3%), microsurgical subinguinal (0.9%-2.5%), retrograde sclerotherapy (3.6%-8.6%), and antegrade sclerotherapy (9%).66

Inguinoscrotal pathologies encompass a large disease spectrum in children. They may have very similar clinical presentations. Careful history taking and accurate clinical examination are crucial in achieving a correct diagnosis resulting in proper and timely management. There are some points to note:

• A properly performed clinical examination is important in establishing the diagnosis of hydrocoele, inguinal hernia, and undescended testes.
• Clinically evident paediatric inguinal hernia should be offered surgical repair when the patient’s general condition permits general anaesthesia, no matter the age.
• Infantile hydrocoele should be managed with an expectant approach. Parents should be taught to observe for associated inguinal hernia.
• Undescended testis is associated with clinical problems of subfertility, increased risk of testicular torsion, and increased risk of testicular malignancy. Early orchidopexy (<18 months of age) should be advised.
• Testicular torsion is a surgical emergency. Urgent referral to a specialist should be made. Insistent investigations (USG) may confuse the clinical diagnosis and delay surgical management.
• Varicocoele is associated with testicular atrophy and subfertility. Intra-abdominal mass should be excluded. Catch-up growth of the affected testis has been noted in some studies after operation.

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13. Lautz TB, Raval MV, Reynolds M. Does timing matter? A national perspective on the risk of incarceration in premature neonates with inguinal hernia. J Pediatr 2011;158:573-7. Crossref

14. Pini Prato A, Rossi V, Mosconi M, et al. Inguinal hernia in neonates and ex-preterm: complications, timing and need for routine contralateral exploration. Pediatr Surg Int 2015;31:131-6. Crossref

15. Lee SL, Gleason JM, Sydorak RM. A critical review of premature infants with inguinal hernias: optimal timing of repair, incarceration risk, and postoperative apnea. J Pediatr Surg 2011;46:217-20. Crossref

16. Chan IH, Lau CT, Chung PH, et al. Laparoscopic inguinal hernia repair in premature neonates: is it safe? Pediatr Surg Int 2013;29:327-30. Crossref

17. Esposito C, St Peter SD, Escolino M, et al. Laparoscopic versus open inguinal hernia repair in pediatric patients: a systematic review. J Laparoendosc Adv Surg Tech A 2014;24:811-8. Crossref

18. Schier F, Montupet P, Esposito C. Laparoscopic inguinal herniorrhaphy in children: a three-center experience with 933 repairs. J Pediatr Surg 2002;37:395-7. Crossref

19. Saka R, Okuyama H, Sasaki T, Nose S, Yoneyama C, Tsukada R. Laparoscopic treatment of pediatric hydrocele and the evaluation of the internal inguinal ring. J Laparoendosc Adv Surg Tech A 2014;24:664-8. Crossref

20. Feng S, Zhao L, Liao Z, Chen X. Open versus laparoscopic inguinal herniotomy in children: a systematic review and meta-analysis focusing on postoperative complications. Surg Laparosc Endosc Percutan Tech 2015;25:275-80. Crossref

21. Chan KL, Hui WC, Tam PK. Prospective randomized single-center, single-blind comparison of laparoscopic vs open repair of pediatric inguinal hernia. Surg Endosc 2005;19:927-32. Crossref

22. Celebi S, Uysal AI, Inal FY, Yildiz A. A single-blinded, randomized comparison of laparoscopic versus open bilateral hernia repair in boys. J Laparoendosc Adv Surg Tech A 2014;24:117-21. Crossref

23. Steven M, Carson P, Bell S, Ward R, McHoney M. Simple purse string laparoscopic versus open hernia repair. J Laparoendosc Adv Surg Tech A 2016;26:144-7. Crossref

24. Wang Z, Xu L, Chen Z, Yao C, Su Z. Modified single-port minilaparoscopic extraperitoneal repair for pediatric hydrocele: a single-center experience with 279 surgeries. World J Urol 2014;32:1613-8. Crossref

25. Toufique Ehsan M, Ng AT, Chung PH, Chan KL, Wong KK, Tam PK. Laparoscopic hernioplasties in children: the implication on contralateral groin exploration for unilateral inguinal hernias. Pediatr Surg Int 2009;25:759-62. Crossref

26. Wenk K, Sick B, Sasse T, Moehrlen U, Meuli M, Vuille-dit-Bille RN. Incidence of metachronous contralateral inguinal hernias in children following unilateral repair—A meta-analysis of prospective studies. J Pediatr Surg 2015;50:2147-54. Crossref

27. Hoshino M, Sugito K, Kawashima H, et al. Prediction of contralateral inguinal hernias in children: a prospective study of 357 unilateral inguinal hernias. Hernia 2014;18:333-7. Crossref

28. Miltenburg DM, Nuchtern JG, Jaksic T, Kozinetiz C, Brandt ML. Laparoscopic evaluation of the pediatric inguinal hernia—a meta-analysis. J Pediatr Surg 1998;33:874-9. Crossref

29. Kokorowski PJ, Wang HH, Routh JC, Hubert KC, Nelson CP. Evaluation of the contralateral inguinal ring in clinically unilateral inguinal hernia: a systematic review and meta-analysis. Hernia 2014;18:311-24. Crossref

30. Agopian AJ, Langlois PH, Ramakrishnan A, Canfield MA. Epidemiologic features of male genital malformations and subtypes in Texas. Am J Med Genet A 2014;164A:943-9. Crossref

31. Rusnack SL, Wu HY, Huff DS, et al. The ascending testis and the testis undescended since birth share the same histopathology. J Urol 2002;168:2590-1. Crossref

32. Kullendorff CM, Hederström E, Forsberg L. Preoperative ultrasonography of the undescended testis. Scand J Urol Nephrol 1985;19:13-5. Crossref

33. Nijs SM, Eijsbouts SW, Madern GC, Leyman PM, Lequin MH, Hazebroek FW. Nonpalpable testes: is there a relationship between ultrasonographic and operative findings? Pediatr Radiol 2007;37:374-9. Crossref

34. Shoukry M, Pojak K, Choudhry MS. Cryptorchidism and the value of ultrasonography. Ann R Coll Surg Engl 2015;97:56-8. Crossref

35. Lam WW, Tam PK, Ai VH, et al. Gadolinium-infusion magnetic resonance angiogram: a new, noninvasive, and accurate method of preoperative localization of impalpable undescended testes. J Pediatr Surg 1998;33:123-6. Crossref

36. Siemer S, Humke U, Uder M, Hildebrandt U, Karadiakos N, Ziegler M. Diagnosis of nonpalpable testes in childhood: comparison of magnetic resonance imaging and laparoscopy in a prospective study. Eur J Pediatr Surg 2000;10:114-8. Crossref

37. Tasian GE, Copp HL, Baskin LS. Diagnostic imaging in cryptorchidism: utility, indications, and effectiveness. J Pediatr Surg 2011;46:2406-13. Crossref

38. Kolon TF, Herndon CD, Baker LA, et al. Evaluation and treatment of cryptorchidism: AUA guideline. J Urol 2014;192:337-45. Crossref

39. Mengel W, Hienz HA, Sippe WG 2nd, Hecker WC. Studies on cryptorchidism: a comparison of histological findings in the germinative epithelium before and after the second year of life. J Pediatr Surg 1974;9:445-50. Crossref

40. Lee PA, Coughlin MT. Fertility after bilateral cryptorchidism. Evaluation by paternity, hormone, and semen data. Horm Res 2001;55:28-32.

41. Alagaratnam S, Nathaniel C, Cuckow P, et al. Testicular outcome following laparoscopic second stage Fowler-Stephens orchidopexy. J Pediatr Urol 2014;10:186-92. Crossref

42. Cortes D, Thorup JM, Beck BL. Quantitative histology of germ cells in the undescended testes of human fetuses, neonates and infants. J Urol 1995;154:1188-92. Crossref

43. Hanerhoff BL, Welliver C. Does early orchidopexy improve fertility? Transl Androl Urol 2014;3:370-6.

44. Dieckmann KP, Pichlmeier U. Clinical epidemiology of testicular germ cell tumors. World J Urol 2004;22:2-14. Crossref

45. Pettersson A, Richiardi L, Nordenskjold A, Kaijser M, Akre O. Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med 2007;356:1835-41. Crossref

46. Hutson JM, Li R, Southwell BR, Petersen BL, Thorup J, Cortes D. Germ cell development in the postnatal testis: the key to prevent malignancy in cryptorchidism? Front Endocrinol (Lausanne) 2013;3:176. Crossref

47. Lee SM, Huh JS, Baek M, et al. A nationwide epidemiological study of testicular torsion in Korea. J Korean Med Sci 2014;29:1684-7. Crossref

48. Yu Y, Zhang F, An Q, Wang L, Li C, Xu Z. Scrotal exploration for testicular torsion and testicular appendage torsion: emergency and reality. Iran J Pediatr 2015;25:e248. Crossref

49. Sheth KR, Keays M, Grimsby GM, et al. Diagnosing testicular torsion before urological consultation and imaging: validation of the TWIST score. J Urol 2016;195:1870-6. Crossref

50. Burgu B, Aydogdu O, Huang R, Soygur T, Yaman O, Baker L. Pilot feasibility study of transscrotal near infrared spectroscopy in the evaluation of adult acute scrotum. J Urol 2013;190:124-9. Crossref

51. Kalfa N, Veyrac C, Lopez M, et al. Multicenter assessment of ultrasound of the spermatic cord in children with acute scrotum. J Urol 2007;177:297-301. Crossref

52. Lam WW, Yap TL, Jacobsen AS, Teo HJ. Colour Doppler ultrasonography replacing surgical exploration for acute scrotum: myth or reality? Pediatr Radiol 2005;35:597-600. Crossref

53. Selbst SM, Friedman MJ, Singh SB. Epidemiology and etiology of malpractice lawsuits involving children in US emergency departments and urgent care centers. Pediatr Emerg Care 2005;21:165-9.

54. Lian BS, Ong CC, Chiang LW, Rai R, Nah SA. Factors predicting testicular atrophy after testicular salvage following torsion. Eur J Pediatr Surg 2016;26:17-21. Crossref

55. Redshaw JD, Tran TL, Wallis MC, deVries CR. Epididymitis: a 21-year retrospective review of presentations to an outpatient urology clinic. J Urol 2014;192:1203-7. Crossref

56. Alsaikhan B, Alrabeeah K, Delouya G, Zini A. Epidemiology of varicocele. Asian J Androl 2016;18:179-81. Crossref

57. Akbay E, Cayan S, Doruk E, Duce MN, Bozlu M. The prevalence of varicocele and varicocele-related testicular atrophy in Turkish children and adolescents. BJU Int 2000;86:490-3. Crossref

58. World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril 1992;57:1289-93. Crossref

59. Paduch DA, Niedzielski J. Semen analysis in young men with varicocele: preliminary study. J Urol 1996;156(2 Pt 2):788-90. Crossref

60. Paduch DA, Niedzielski J. Repair versus observation in adolescent varicocele: a prospective study. J Urol 1997;158(3 Pt 2):1128-32. Crossref

61. Kass EJ, Belman AB. Reversal of testicular growth failure by varicocele ligation. J Urol 1987;137:475-6.

62. Preston MA, Carnat T, Flood T, Gaboury I, Leonard MP. Conservative management of adolescent varicoceles: a retrospective review. Urology 2008;72:77-80. Crossref

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Genetically modified (GM) foods have had their DNA changed by genetic engineering to enhance resistance to pathogens and herbicides and/or to provide better nutritional value. New GM crops are now also being developed for the production of recombinant medicines and industrial products.1 2 3 The first GM food in the form of the Flavr Savr late-ripening tomato was marketed unsuccessfully about two decades ago.4 The research that produced the Flavr Savr tomato was a scientific success but it was a commercial failure. This demonstrated the difficulty of bringing GM products to market; how objections with little or no scientific evidence can influence public opinion and ultimately determine commercial success or failure.4

2015 marked the 25th anniversary of the commercialisation of GM crops. In the last two decades the area of biotech crops planted globally has increased at an astonishing rate. A cumulative two billion hectares, equivalent to twice the land size of China or the US, were successfully cultivated globally between 1996 and 2015.5 Most of the growth has focused on crops in high demand including potato, canola, maize, cotton, soybean, rice, and squash. Foods derived from GM plants are now widely consumed especially in the US but also in other countries, and GM soybean protein is extensively used in processed foods throughout the industrialised world.

When a new gene is introduced into a plant’s genome, a new protein may result that could become an antigen when eaten if it is foreign to a person’s normal diet. In 2000, Grace Booth in the US developed anaphylaxis after eating corn tacos. Earlier that year it was discovered that some taco shells contained a pesticidal protein, Cry9C, derived from Bacillus thuringiensis. Cry9C was introduced into GM corn to kill several predatory insects and was only ever approved for animal feeding. It entered the human food chain because of cross-pollination when the GM crop was planted too close to normal crops. As other causes of Booth’s anaphylaxis could not be determined, Cry9C protein was presumed to be the culprit. The US Centers for Disease Control and Prevention never proved any direct link between Cry9C and development of allergies, but the episode perpetuated the spectre in the minds of the public and media that GM foods cause new allergies.6

Opponents of GM technology have suggested that GM foods contribute to the huge increase in food allergies in the US, especially in children.7 8 This ignores the fact that there are no GM versions of the many foods that commonly cause food allergies, namely eggs, dairy, shellfish, tree nuts, and peanut so the increasing prevalence of these most common food allergies cannot be attributed directly to GM technology.

Despite this logic, critics of the GM food revolution have made a substantial impact to the extent that some nations have rejected much-needed food aid to alleviate famine.9 In the developing world many millions of people are chronically undernourished and do not have access to sufficient food. Such GM food technology may be able to help solve some of these global challenges.

The World Health Organization stated that it is not possible to make generalisations about the safety of GM foods and this should be assessed on a case-by-case basis.10 Notwithstanding this statement, GM foods that are available for public consumption have passed detailed risk assessments, including tests for allergenicity. Foods derived from GM technology have been consumed by millions of people across the world without any consistent reports of ill effects. Furthermore, many conventional foods have been produced over centuries through genetic transfer achieved through artificial breeding. Technology has always played a central role in natural food production.11

A recent scientific advisory board of the National Academies of Sciences, Engineering, and Medicine found “no substantiated evidence of a difference in risk to human health between commercially available GM crops and conventionally bred crops”.12 The advisory board also discovered no persuasive evidence that GM crops had caused any adverse health effects.

Two major concerns about the safety of GM foods are whether they are allergenic or toxic. Allergenicity may have arisen in several ways. Genetic engineering may have resulted in a new protein, or a known allergen was introduced, or the inherent ability of a GM crop to cause allergies was enhanced.

Two widely reported cases of allergenicity in experiments on GM foods fuelled speculation that they may be responsible in part for the worldwide increase in allergies. The first, in 1966, involved transfer of a Brazil-nut protein into a soybean to enhance the soya bean’s nutritional value. An allergenic protein was also transferred and caused an allergic reaction in human volunteers.13 This food was never approved for the market. The second, in 2005, involved experiments on mice in which a bean engineered to resist pea weevil triggered an immune reaction in the lungs of the animals.14 These examples are often cited to support claims that GM technology is dangerous and unpredictable. An alternative interpretation is that safety testing was effective in both cases before either product was released onto the market.

Critics of GM food have also claimed that the rise in the number of soybean-allergic subjects in the UK was linked to the development of GM soybean destined for the US market but there was very little exposure to GM soybeans in the UK.15 More likely the rise in prevalence of soybean allergy in the UK was caused by the greater recent consumption of non-GM soybean.15

There is a complex interplay between a person’s immune system and a potential allergen. Proteins become allergens when they can bind immunoglobulin E. However, even proteins that can bind immunoglobulin E will only cause allergies if the person has a corresponding sensitivity. The more readily GM foods become available, the more people may be exposed to new proteins. Although there is potential for new sensitivities to develop, this is not a foregone conclusion. In addition, GM foods do not always contain a new protein, for example, when some genes are suppressed or a protein is removed. There is research, for example, into the identification and removal of an allergenic protein from soybean using recombinant DNA technology16 and similar work is ongoing for peanut.17

Although this review concerns the allergenic potential of GM foods, it should be highlighted that toxicity of a new gene product is another major concern. This can occur because the transgene encodes a toxin; or transgenesis may cause an unintended effect such as silencing of suppressor genes; or there is overexpression of inherent toxins of the host. Although the level of risk for a single product is readily evaluated by standard toxicological tests, complex admixtures of chemicals as in GM foods are more difficult to analyse. Despite these difficulties, there is very little documented peer-reviewed literature to show that GM crops are potentially toxic.18 One paper reported in 1999 that rats fed with GM potatoes expressing the gene for the lectin Galanthus nivalis agglutinin developed gut mucosal damage,19 but the data were subsequently discredited by the Royal Society.20 21

Definitive testing of new products for safety is complex and it is difficult to predict with complete certainty the potential for any protein to be a food allergen. Robust regulatory measures that include the use of validated scientific protocols for assessments should minimise the risk. Of note, GM crops are tightly regulated by the European Food Safety Authority, US Food and Drug Administration, the US Environmental Protection Agency, and the Animal and Plant Health Inspection Service under the US Department of Agriculture. Consequently, GM plants undergo extensive and detailed safety testing prior to commercialisation, but there is no international consensus on laboratory testing methods on GM foods.

The Codex Alimentarius Commission has adopted guidelines in an attempt to standardise pre-market risk assessment.22 A number of other guidelines have also been published to evaluate allergenic potential.23 24 25 For instance, there are some common features that many allergens share so new GM proteins can be checked against these characteristics on extensive databases. It should be possible, at least theoretically, to determine if a new GM protein is likely to be an allergen by comparing its amino acid sequence and structure with that of known allergens. For this bioinformatic strategy to be useful, there probably has to be a minimum cut-off of 35% homology over an 80-amino-acid window.26 Other approaches include examining whether the serum of allergic individuals reacts with GM foods; and the use of animal models to screen GM foods for allergenicity. The use of animal models is controversial and some scientists believe that although they provide mechanistic information, their use to predict food allergies has not been validated.26 Testing strategies are constantly evolving and each test when used alone has drawbacks. Nevertheless when used in combination, the current analytical tools offer a powerful screen for allergenic potential.

Safety assessment schemes generally follow the principles of substantial equivalence; if a new food is found to be substantially equivalent to an existing food, the new food is considered to be as safe as its conventional counterpart.24 27 28 29 30 31 Safety assessments for GM foods consider seven domains, namely composition; dietary intake; nutritional data; toxicology; allergenic properties; and characteristics of the donor and host organisms.30 31 32 To establish substantial equivalence, extensive comparative studies in both the GM and conventional food have to be conducted. If differences are discovered, further detailed analyses have to be performed. Studies of this type establish to a high degree of certainty that the level of safety of the new GM food is likely to be equivalent to that of non-GM foods. Such testing is not generally required for conventional foods, so there is a marked divergence in the regulatory control of these two different food groups.

Other measures have been used to improve the safety of GM crops in addition to the testing described above. They include measures to separate planting of GM crops from conventional crops.33 At the very least, planting of GM and unmodified crops is separated by a buffer zone with size proportional to the distance pollen can travel. This precaution, however, can only be relative because how far pollens are carried by bees or other pollinators cannot be estimated with any certainty. Other techniques for containment are expensive but have included growing the crops in greenhouses, or in areas where no weed or food crops are grown. Genetic containment has also been tried. This involved the use of technology to limit transfer of pollens or to interfere with fertility and seed formation.33

Post-launch monitoring of consumers for evidence of previously unidentified allergenicity may be critical. Finally, mandatory labelling of GM ingredients has been enforced by legislation in some countries for the sake of transparency. Such ingredient listing and information facilitate tracing and recall if required.

China has a fifth of the world’s population but only about 7% of its arable land. Food security is a national priority. In February 2016, state-owned ChemChina announced its bid to buy the pesticide- and seed-producing giant Syngenta, one of the biggest acquisitions in China’s history. Technology and especially GM crops are viewed by China to be central to a sustainable future. Nonetheless there are major public health concerns about food safety in China including the side-effects and toxicity of GM foods.

China issued its first licence to a GM crop in 1997, namely cotton, that is now widely used. Papaya that are GM was approved 6 years ago but China has since restricted the import of most GM foods34 and regulations demand their mandatory labelling.35 The Ministry of Agriculture has issued a list of GM foods that can be sold in China if clearly labelled and these include: soy products (soybean seeds, soybeans, soybean powder, soybean oil, and soybean meal); corn products (seed corn, corn, corn oil, and corn powder); rape products (planting seed of rape, rapeseed, rapeseed oil, and rapeseed meal); cotton seed; and tomato products (tomato seed, fresh tomatoes, and tomato paste).36 It is generally accepted that China’s slow adoption of GM rice and GM corn has had more to do with negative public pressures than scientific concerns. The formal policy address affirmed that the country will speed up innovative application of agricultural biotechnology breeding to develop new biological varieties that have important value for fostering a large and strong modern seed industry.37 38

Hong Kong has no commercial production of GM crops or livestock. Food products on shop shelves that contain GM food ingredients have been approved for human use by the authorities in their country of origin.

The Hong Kong SAR Government conducted a public consultation followed by an external regulatory impact assessment. This was completed in 2003, after which the Government issued guidelines for voluntary labelling of GM foods so consumers could make an informed choice. It is highly doubtful that a voluntary scheme for food labelling will provide the kind of reassurance the public demands. The Government also decided that it would be appropriate to consider introducing premarket safety assessments to ensure the safety of GM foods.39

Allergies to non-GM foods are common—for example, peanut, shrimp, fish, and soft fruits—as seen in the oral allergy syndrome, so foods produced by both conventional breeding and GM technology have the potential to be allergenic. There are no persuasive data that GM foods pose risks that are anywhere comparable with those encountered daily from consumption of naturally occurring food allergens that are not banned. The recent introduction of kiwifruit has resulted in the appearance of new allergies, but they have not been removed from the market place. Instead food labelling is used to help the consumer avoid exposure if required. There is a continuing need to develop improved validated tools to predict allergenic potential of new GM proteins. Only then can scientific evidence be separated from the realms of fevered speculation. Greater public engagement, post-launch monitoring, and mandatory labelling of GM foods will also go a long way to reassure the community about their safety.

1. Sticken M. Plant genetic engineering to improve biomass characteristics for biofuels. Curr Opin Biotechnol 2006;17:315-9. Crossref

2. Conrad U. Polymers from plants to develop biodegradable plastics. Trends Plant Sci 2005;10:511-2. Crossref

3. Ma JK, Drake PM, Christou P. The production of recombinant pharmaceutical proteins in plants. Nat Rev Genet 2003;4:794-805. Crossref

4. Bruening G, Lyons JM. The case of the FLAVR SAVR tomato. Calif Agric 2000;54:6-7. Crossref

5. International Service for the Acquisition of Agri-Biotech Applications. Brief 51-2015: Executive summary. Available from: http://isaaa.org/resources/publications/briefs/51/executivesummary/default.asp. Accessed 15 Dec 2016.

6. Xu C. Nothing to sneeze at: allergenicity of GMOs. Available from: http://sitn.hms.harvard.edu/flash/2015/allergies-and-gmos/. Accessed 15 Dec 2016.

7. Smith JM. Seeds of deception: exposing industry and government lies about the safety of the genetically engineered food you’re eating. Fairfield, IA: Yes! Books; 2003.

8. Smith JM. Genetic roulette: the documented health risks of genetically engineered foods. Fairfield, Iowa: Yes! Books; 2007.

9. Michael MT. Africa bites the bullet on genetically modified food aid. Available from: http://www.worldpress.org/Africa/737.cfm. Accessed 15 Dec 2016.

10. World Health Organization. Food safety. Available from: http://www.who.int/foodsafety/areas_work/food-technology/faq-genetically-modified-food/en/. Accessed 15 Dec 2016.

11. Bradford KJ, Van Deynze A, Gutterson N, Parrott W, Strauss SH. Regulating transgenic crops sensibly: lessons from plant breeding, biotechnology and genomics. Nat Biotechnol 2005;23:439-44. Crossref

12. National Academies of Sciences, Engineering, and Medicine. Genetically engineered crops: experiences and prospects. Washington, DC: The National Academies Press; 2016.

13. Nordlee JA, Taylor SL, Townsend JA, Thomas LA, Bush RK. Identification of a Brazil-nut allergen in transgenic soybeans. N Engl J Med 1996;334:688-92. Crossref

14. Prescott VE, Campbell PM, Moore A, et al. Transgenic expression of bean alpha-amylase inhibitor in peas results in altered structure and immunogenicity. J Agric Food Chem 2005;53:9023-30. Crossref

15. Herman EM. Genetically modified soybeans and food allergies. J Exp Bot 2003;54:1317-9. Crossref

16. Herman EM. Soybean allergenicity and suppression of the immunodominant allergen. Crop Sci 2005;45:462-7. Crossref

17. Plundrich NJ, White BL, Dean LL, Davis JP, Foegeding EA, Lila MA. Stability and immunogenicity of hypoallergenic peanut protein–polyphenol complexes during in vitro pepsin digestion. Food Funct 2015;6:2145-54. Crossref

18. Hollingworth RM, Bjeldanes LF, Bolger M, et al. The safety of genetically modified foods produced through biotechnology. Toxicol Sci 2003;71:2-8. Crossref

19. Ewen SW, Pusztai A. Effect of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on rat small intestine. Lancet 1999;354:1353-4. Crossref

20. Burke D. GM food and crops: what went wrong in the UK? Many of the public’s concerns have little to do with science. EMBO Rep 2004;5:432-6. Crossref

21. Key S, Ma JK, Drake PM. Genetically modified plants and human health. J R Soc Med 2008;101:290-8. Crossref

22. Codex Alimentarius Commission. Appendix III, Guideline for the conduct of food safety assessment of foods derived from recombinant-DNA plants and Appendix IV, Annex on the assessment of possible allergenicity; 2003. Alinorm 03/34: Joint FAO/WHO Food Standard Programme, Codex Alimentarius Commission, Twenty-Fifth Session, Rome, Italy; 2003 Jun 30 to Jul 5: 47-60.

23. WHO/FAO. Strategies for assessing the safety of foods produced by biotechnology. Report of the Joint WHO/FAO Consultation. Geneva: FAO/WHO; 1991.

24. Policy statement: Foods derived from new plant varieties. US Food and Drug Administration: 1992 (57 FR 22984).

25. Organization for Economic Co-operation and Development (OECD). Food safety evaluation. Paris: OECD Documents; 1996.

26. Goodman RE, Vieths S, Sampson HA, et al. Allergenicity assessment of genetically modified crops—what makes sense. Nat Biotechnol 2008;26:73-81. Crossref

27. Kuiper HA, Kleter GA, Noteburn HP, Kok EJ. Assessment of the food safety issues related to genetically modified foods. Plant J 2001;27:503-28. Crossref

28. Maryanski JH. US Food and Drug Administration policy for foods developed by biotechnology. In Engel KH, Takeoka GR, Teranishi R, editors. Genetically modified foods: safety aspects. Washington, DC: American Chemical Society; 1995: 12-22. Crossref

29. Organization for Economic and Cooperation Development (OECD). Safety evaluation of foods derived by modern biotechnology: Concepts and principles. Paris: OECD; 1993.

30. Food and Agriculture Organization of the United Nations and World Health Organization. Safety aspects of genetically modified foods of plant origin. Report of a joint FAO/WHO expert consultation on foods derived from biotechnology. Geneva: WHO; 2000.

31. Food and Agriculture Organization of the United Nations and World Health Organization. Safety assessments of foods derived from genetically modified microorganisms. Report of a joint FAO/WHO expert consultation on foods derived from biotechnology. Geneva: WHO; 2001.

32. Food and Agriculture Organization of the United Nations and World Health Organization. Evaluation of allergenicity of genetically modified foods. Report of a joint FAO/WHO expert consultation on allergenicity of foods derived from biotechnology. Food and Agriculture Organization of the United Nations and World Health Organization. Rome, Italy: FAO; 2001.

33. Mascia PN, Flavell RB. Safe and acceptable strategies for producing foreign molecules in plants. Curr Opin Plant Biol 2004;7:189-95. Crossref

34. State Council of the People’s Republic of China. 農業轉基因生物安全管理條例 [Regulations on administration of agricultural genetically modified organisms safety]. Promulgated by State Council 2001 May 23, revised 2011 Jan 8. Available from: http://www.fas.usda.gov/gainfiles/200106/110681034.pdf. Accessed Apr 2017.

35. Ministry of Health of the People’s Republic of China. 新資源食品管理辦法 [Administrative measures for novel food]. Promulgated by MOH 2007 Jul 2, effective 2007 Dec 1, repealed 2013 May 31.

36. Ministry of Agriculture of the People’s Republic of China. Which genetically modified agricultural plants are permitted to import to be used as raw materials? Are they permitted to cultivate domestically? [in Chinese]. 2013 Apr 27. Available from: http://www.moa.gov.cn/ztzl/zjyqwgz/zswd/201304/t20130427_3446861.htm. Accessed Apr 2017.

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39. Centre for Food Safety, Hong Kong SAR Government. Genetically modified food: Situation in Hong Kong. Available from: http://www.cfs.gov.hk/english/programme/programme_gmf/programme_gmf_gi_info6.html. Accessed 15 Dec 2016.

Extracorporeal membrane oxygenation (ECMO) provides temporary extracorporeal support of the respiratory and/or cardiac system for patients who fail to respond to conventional therapies, buying time for recovery from the underlying condition, and for specific treatment to take effect. The concept and technology of ECMO originated from cardiopulmonary bypass that was first used in 1953.1 The first case of successful ECMO support in an adult patient was published by Hill et al in 1972.2 3 Currently, ECMO use is not confined to the operating theatre, but has been extended to the intensive care unit and during inter-hospital transfer.

According to the Extracorporeal Life Support Organization (ELSO) Registry report, 86 287 patients received extracorporeal life support (ECLS) globally (up to January 2017).4 The majority of patients were neonates (44.8%), while 24.1% were children and 31.1% were adults. The types of ECLS included respiratory support (58.4%), cardiac support (31.9%), and extracorporeal cardiopulmonary resuscitation (9.7%).4

There are two main types of ECMO configuration: venovenous (VV) and veno-arterial (VA)—VV-ECMO provides solely lung support, while VA-ECMO provides both heart and lung support. Depending on the clinical indications and disease progress, the ECMO circuit can be interchanged between VV and VA, from VV to high-flow VV or from VV to veno-arterial-venous ECMO.

The ECMO circuit consists of an access cannula that drains deoxygenated venous blood from the patient, a pump, an artificial lung (oxygenator) that provides oxygenation and carbon dioxide (CO₂) removal, a heat exchanger, and a return cannula that returns oxygenated blood via a central vein (ie VV-ECMO) or major artery (ie VA-ECMO).

The technique VV-ECMO provides only lung support (Fig 1a). The circuit is connected in series with the right heart and the lungs with the access cannula commonly inserted at the femoral vein. Deoxygenated blood is drained from the venous circulation by a motor pump. The deoxygenated blood then passes through an oxygenator where oxygen diffuses across the oxygenator membrane into the blood. The oxygenated blood then returns to the right heart via a return cannula, placed at the femoral vein or the right internal jugular vein.

The maximal blood flow that can be achieved in an ECMO system is determined by elements of the Hagen-Poiseuille equation, of which the key factor is the cannula size. In situations where maximal blood flow is unable to meet the metabolic demand of the patient, such as sepsis with high cardiac output or large body size, an additional access cannula is inserted.

Patients with acute severe respiratory failure sometimes develop refractory shock due to severe sepsis and/or myocardial ischaemia. In this case, veno-arterial-venous ECMO can provide both respiratory and circulatory support (Fig 1b). This is achieved by the insertion of an additional return cannula into a major artery in the existing VV-ECMO system, such that a proportion of the oxygenated blood is diverted to the arterial circulation to support organ perfusion.

In the native lungs, gaseous exchange occurs by diffusion at the blood gas interface in the alveoli. In the ECMO oxygenator, the same principle applies. The efficiency of gaseous exchange depends on the driving force of the gas and the diffusion efficiency. The driving force of a gas is related to the partial pressure difference across the blood gas interface for the individual gas. The efficiency of diffusion depends on the area for diffusion, distance over which gas has to pass, and the diffusion coefficient for the individual gas. The amount of oxygen delivered by VV-ECMO is influenced by the oxygenator membrane surface area, membrane thickness, haemoglobin level, and ECMO blood flow.

The venous partial pressure of oxygen (PaO₂) at the blood interface of the oxygenator is around 5.3 kPa, while dry 100% oxygen (O₂) runs through the gas interface equivalent to a partial pressure of 101 kPa. This provides a partial pressure gradient for oxygen to diffuse across the semipermeable membrane of the oxygenator from the gas interface to the blood interface.5 An example is shown in the Box.

In reality, the maximal oxygen transfer capability is also determined by the gas exchange surface area and the amount of disruption to laminar flow as blood passes through the oxygenator.

The O₂ consumption (VO₂) is approximately 250 mL/min in a VV-ECMO adult patient.6 Thus from the above example, the DO₂/VO₂ ratio is greater than 2:1 and within the safe range to prevent anaerobic metabolism (DO₂ = oxygen delivery). If the ECMO blood flow is 4 L/min and the cardiac output is 5 L/min, 1 L of blood that returns to the right heart theoretically passes through the pulmonary circulation and the native sick lungs achieving limited gaseous exchange. Therefore, the final O₂ saturation will not be 100% due to this admixture.

Active sepsis results in both increased VO₂ and increased cardiac output. In most situations, the native sick lungs can still partially serve the function of gaseous exchange and contribute to DO₂. Nonetheless when DO₂/VO₂ ratio falls below 2:1, anaerobic respiration occurs with consequent accumulation of lactate.

Similar to O₂, CO₂ can pass through the oxygenator membrane from the blood to the gas interface by diffusion; CO₂ has a higher diffusion coefficient than O₂ because of its greater blood solubility. As a result, CO₂ transfer is 6 times faster than O₂ for the same membrane thickness and pressure gradient. Unlike O₂, CO₂ transfer is independent of blood flow. The most important limiting factor for CO₂ transfer is the relative concentration of CO₂ on either side of the membrane. The partial pressure of CO₂ in the blood interface is about 6 kPa, but there is negligible CO₂ in the gas interface of the membrane. It is possible to remove 250 mL/min of CO₂ with an ECMO blood flow of <1 L/min by flushing the membrane lung with fresh gas flow (Sweep gas) to maintain the high CO₂ gradient across the membrane.

Mechanical ventilation is the mainstay treatment for respiratory failure in patients with severe acute respiratory distress syndrome (ARDS). The use of positive pressure ventilation, however, can induce lung injury by over-distension of the alveoli or from cyclical collapsing and re-opening of the alveoli. Moreover, ventilation-induced lung injury can trigger a systemic inflammatory response and result in multi-organ failure.7

A lung protective ventilation strategy is proven to reduce ventilator-associated lung injury and mortality in ARDS patients.7 Yet in clinical practice, it is often difficult to adhere to these ventilator parameters without causing significant hypercarbia and respiratory acidosis. Of note, ECMO can overcome this challenge as it provides an additional source of blood oxygenation and CO₂ removal through the extracorporeal circuit and oxygenator, and allows lung rest. Table 18 lists the common indications for and contra-indications to VV-ECMO.

Careful patient selection for VV-ECMO is crucial to achieve a favourable outcome, balancing the perceived benefit of improving oxygenation with the risk of complications during ECMO initiation and maintenance. Alternatives to ECMO including prone ventilation and inhaled nitric oxide are also considered in this risk-benefit assessment. Indeed, VV-ECMO for severe ARDS is currently established as a sound rescue therapy rather than a standard of care. The landmark VV-ECMO trial (CESAR: Conventional ventilatory support versus Extracorporeal membrane oxygenation for Severe Adult Respiratory failure) was the first to report improved survival in patients with severe ARDS transferred to an ECMO referral centre compared with those who received conventional treatment.9 This—together with good outcomes from Australasian,10 French,11 and Italian12 experiences in patients with H1N1-associated ARDS—has contributed to the heightened interest in VV-ECMO and its increased use during and after the H1N1 pandemic.

The results of the CESAR trial could be interpreted as a recommendation for transfer to an ECMO-capable centre, where the improved outcomes may have been from the total care at the ECMO centre, and not from ECMO therapy alone.9 Nonetheless no randomised controlled trial has proven that VV-ECMO should be the standard of care for severe ARDS in non-influenza patients. The ongoing ECMO for severe ARDS (EOLIA) trial is a multicentre, international, randomised controlled trial evaluating early ECMO (within 3-6 hours) after the diagnosis of very severe ARDS (PaO₂/FiO₂ <80 mm Hg, where FiO₂ = fraction of inspired oxygen) in patients not responding favourably to optimal ventilation. A positive outcome from this trial may further support the use of VV-ECMO for respiratory failure, and prompt a review of our territory-wide referral network for coordinated transfers to improve patient care.13

An ELSO Centre of Excellence recently reported the long-term outcome for patients with respiratory failure or sepsis treated with ECMO from 1995 to 2013 with 64% survival to discharge and better long-term survival for patients treated for infection.14 This suggests that the reversibility of the disease process is an important consideration when selecting appropriate patients for ECMO.

Different ECMO centres have proposed their own selection criteria for ECMO treatment.15 16 A pretreatment predicting a mortality of higher than 80% is widely accepted as a cut-off for screening a potential ECMO candidate. In addition, ELSO suggests that this 80% mortality risk broadly corresponds to a PaO₂/FiO₂ of <100 mm Hg on FiO₂ >90% and/or Murray score of 3-4 despite optimal care for ≥6 hours.8 In addition, the longer the duration of mechanical ventilation before initiation of ECMO, the worse the outcome.17 It was also reported that ECMO patients had a better survival rate when they were managed in an experienced quaternary referral ECMO centre.9

In 1988, Murray et al18 proposed an extended definition of ARDS, taking into account various pathophysiological features of the clinical syndrome. The Murray scoring system includes four components for stratification of the severity of ARDS. Each component is scored from 0 to 4 according to severity (Table 218). The final mean score is obtained by dividing the collective score by four, which is the number of components used. A score of 0 indicates no lung injury, 1-2.5 indicates mild-to-moderate lung injury, and >2.5 indicates the presence of ARDS.

As an ECLS system, there are three key components of an ECMO circuit—blood pump, oxygenator, and cannula.

The function of the blood pump is to provide the required blood flow to the patient. This can be achieved by means of mechanical (roller pump) or centrifugal force (centrifugal pump). With advances in technology, a centrifugal pump has replaced the roller pump in ECMO as it is more durable, lighter, and results in less haemolysis, and less platelet and complement activation. A centrifugal pump is preload sensitive and afterload dependent. ‘Preload sensitive’ means the blood flow is sensitive to volume at the pump inlet. In the presence of inadequate blood drainage such as in hypovolaemia, the flow reduces automatically. ‘Afterload dependent’ means the blood flow is also sensitive to resistance at the pump outlet. Flow reduction occurs when post-pump resistance increases. Examples include the presence of thrombus in the oxygenator, kinking of the return cannula, and excessive systemic vascular resistance or mean arterial pressure.

The oxygenator was traditionally made of silicone membrane because of their high biocompatibility. It was later replaced by microporous polypropylene hollow fibres with an advantage of lower pressure drop, need for lower priming volume, and better gas exchange efficiency. Direct contact between the gas interface and blood through the microporous fibres, however, results in plasma leakage, which is a serious complication. The newest-generation oxygenator contains multiple hollow fibres that are coated with polymethylpentene and avoids direct contact between the gas interface and blood. Gas transfer is by diffusion. This new oxygenator is more efficient (with lower volume), more effective in gas exchange, causes less platelet and plasma protein loss, and has a thrombo-resistant coating.19

An ideal ECMO cannula provides the desired flow with minimal pressure drop, and minimal damage to blood cells or activation of inflammatory response. According to the Hagen-Poiseuille equation, a cannula with the shortest length and the largest diameter offers the greatest flow. Blood in contact with the inner layer of a cannula activates the coagulation and complement cascades, the kallikrein-kinin system, and other inflammatory cells. Currently available cannulas have a special surface coating to minimise the risk of thrombus formation. An example of such coating is a heparin-coated surface although there remains a risk of developing heparin-induced thrombocytopenia. Newer technology employs a hydrophilic layer with negatively charged groups to repel negatively charged inflammatory proteins and platelets.20

Role prioritisation and good communication are the keys for successful ECMO initiation and setup. Informed consent should be obtained from the patient’s family. The patient should be well-sedated, and coagulopathy (if any) should be corrected before cannulation.

The cannulation procedure is usually performed at the bedside under aseptic conditions. The Seldinger technique is employed with serial dilatation under ultrasound or fluoroscopic guidance. For VV-ECMO, one common approach is a two-cannula technique with either femoral-jugular or femoral-femoral cannulation. Some centres use a single cannula technique and insert a dual lumen catheter (Avalon Laboratories, Rancho Dominguez [CA], United States) into the right internal jugular vein. If a femoral-jugular approach for the two-cannula technique is used, the patient should be placed in the Trendelenburg position. The left internal jugular vein is a less preferred site due to its smaller size and higher risk of vascular injury at the internal jugular-brachiocephalic vein junction. Ultrasound is commonly used during the cannulation procedure to locate the vessel, assess vessel size, and to confirm correct guidewire placement and final position of the cannula. Systemic anticoagulation should be started immediately after cannulation provided there is no absolute contra-indication.

Patients with severe ARDS often have both hypoxaemia and hypercarbia that make the setting of ventilator parameters difficult. Inappropriate setting of mechanical ventilation can lead to further lung damage including excessive transpulmonary pressure (barotrauma), excessive lung volume inside the alveoli (volutrauma), and shearing stress during repetitive opening and closing of the alveoli (atelectrauma).21 Several large randomised controlled trials have proven that a low tidal volume strategy (≤6 mL/kg of ideal body weight) achieves better outcomes than a traditional ventilatory strategy (10-12 mL/kg of ideal body weight ).7 22 23 In addition, maintaining a plateau pressure of <30 cm H₂O minimises the risk of barotrauma. It is hard to achieve these targets in a sick lung using mechanical ventilation alone.

The use of ECMO overcomes the problem as CO₂ removal and blood oxygenation take place in an extracorporeal system. This permits complete lung rest with the application of low tidal volume and plateau pressure (ie lung protective ventilation strategy).24 One of the ventilation strategies recommended by ELSO guidelines is as follows8: pressure-controlled ventilation at positive end-expiratory pressure (PEEP) 15 cm H₂O and pressure control above PEEP at 10 cm H₂O, rate 5/min, inspiratory-to-expiratory time ratio 2:1, and FiO₂ 50%.

The optimal ventilator strategy for patients on VV-ECMO, especially the level of PEEP, is still controversial. Randomised controlled trials show that in patients where a higher PEEP (14-15 cm H₂O) was used, there were fewer mechanical ventilator days and number of organ failure compared with patients using a lower PEEP (9-10 cm H₂O). There was, however, no mortality benefit. A criticism of the randomised controlled trials is that they recruited a large proportion of patients in whom PEEP was inappropriate and who consequently did not respond to its application.25 26 27 More importantly, all these studies were performed in non-ECMO settings.

A conservative fluid strategy is commonly adopted in patients on VV-ECMO for ARDS and may be associated with lower mortality, better lung function, and shorter duration of mechanical ventilation.28 Nonetheless, volume deficit can lead to ECMO blood flow reduction as the centrifugal pump is preload sensitive. Line shaking can occur if volume depletion has become significant with pump flow reduction.

Previous studies showed that 70% of ECMO patients who developed acute kidney injury had a poorer outcome.29 30 31 Continuous renal replacement therapy (CRRT) is commonly used in ECMO patients for renal support and fluid management. There are various methods for delivering CRRT in ECMO patients: by inserting a new venous cannula for CRRT independent of the ECMO circuit, integrating the haemofiltration filter into the ECMO circuit, or by connecting a CRRT machine to the ECMO circuit (Fig 2). To minimise the risk of air embolism, the CRRT circuit should be connected after the ECMO motor pump.32 33 This combination enables a longer filter life and more accurate fluid management.34

There are special concerns regarding the choice of sedative agents in ECMO patients. The ECMO circuit tubing absorbs lipophilic drugs. As such, lipophilic sedative agents such as propofol, midazolam, and fentanyl are rapidly removed from the systemic circulation and larger doses are required to achieve the target effect.35 36 Medications that are formulated as lipid suspensions, such as propofol, can also corrode the oxygenator membrane, especially when there is a high infusion rate.37 These agents should be avoided.

Haemorrhagic and thromboembolic events are common and are the main causes of morbidity and mortality in ECMO patients. Anticoagulation is necessary during ECMO because of the high thrombogenicity associated with blood contact with a non-biological surface.38 Close monitoring is nonetheless essential to avoid overanticoagulation. Activated clotting time is frequently used as a point-of-care monitoring of heparin in ECMO patients,39 while activated partial thromboplastin time is a conventional method for testing the intrinsic and common coagulation pathways. Unfractionated heparin is widely used as the anticoagulant for ECMO patients although potential complications including bleeding, heparin-induced thrombocytopenia, and tachyphylaxis, may arise.40 Bivalirudin, a direct thrombin inhibitor, has been tested in ECMO patients as an alternative to heparin41 and been shown to cause less bleeding, be more cost-effective, and results in the need for fewer allogenic transfusions.42

Extracorporeal membrane oxygenation is a complex and high-risk procedure. Medical crises occur rarely but can be life-threatening (Table 3).4 Making the correct decision hinges on a rapid understanding the situation and the primary cause of the complication.

As the native lung improves, the demand on the extracorporeal system decreases. In general, ECMO weaning can be considered if the patient has substantial signs of native lung recovery, and can tolerate low ECMO support (ie ECMO blood flow <2.0 L/min and lower sweep gas FiO₂ to keep peripheral oxygen saturation >95%).8 Decreasing the ECMO blood flow to <2.0 L/min, however, risks thrombus formation. As an alternative, a weaning trial can be done by either switching off the sweep gas flow or decreasing the FiO₂ to 0.21. The setting of the mechanical ventilator is adjusted accordingly. Decannulation can be considered if the patient is stable for >1 hour following the adjustment.43

The ECMO cannulae are removed after heparin infusion has been stopped for more than 60 minutes, and there is no major coagulopathy. Cannulae that were inserted by a cutdown procedure should be removed in the operating theatre as vessel repair is necessary. Those that were inserted percutaneously can be removed at the bedside.

Venovenous ECMO is considered one of the rescue treatments in patients who fail to respond to conventional therapies. With the accumulation of experience and advances in technology, the application of VV-ECMO has been extended from viral or bacterial pneumonia to other causes of respiratory failure. The number of adult patients receiving this therapy substantially increased following the CESAR trial. One key principle of patient selection is the underlying disease reversibility. The VV-ECMO procedure should be regarded as temporary lung support that serves as a bridge to disease recovery or transplantation. Individual ECMO centres may develop their own inclusion and exclusion criteria based on availability of expertise, resources, and supporting services. Of note, ECMO is not risk free. Understanding the equipment physiology, configuration, and potential complications is essential for its safe application. Meticulous monitoring combined with appropriate patient management is crucial to the success of VV-ECMO in ARDS patients.

1. Gibbon JH Jr, Hill JD. Part I. The development of the first successful heart-lung machine. Ann Thorac Surg 1982;34:337-41. Crossref

2. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med 1972;286:629-34. Crossref

3. Hill JD, De Leval MR, Fallat RJ, et al. Acute respiratory insufficiency. Treatment with prolonged extracorporeal oxygenation. J Thorac Cardiovasc Surg 1972;64:551-62.

4. Extracorporeal Life Support Organization. ECLS registry report, international summary 2017. Available from: https://www.elso.org/Registry/Statistics/InternationalSummary.aspx. Accessed Jan 2017.

5. Chauhan S, Subin S. Extracorporeal membrane oxygenation, an anesthesiologist’s perspective: Physiology and principles. Part 1. Ann Card Anaesth 2011;14:218-29. Crossref

6. Holzgraefe B, Broomé M, Kalzén H, Konrad D, Palmér K, Frenckner B. Extracorporeal membrane oxygenation for pandemic H1N1 2009 respiratory failure. Minerva Anestesiol 2010;76:1043-51.

7. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-8. Crossref

8. ELSO adult respiratory failure supplement to the ELSO general guidelines. Version 1.3. Ann Arbor, MI: Extracorporeal Life Support Organization; 2013.

9. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374:1351-63. Crossref

10. Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators, Davies A, Jones D, et al. Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome. JAMA 2009;302:1888-95. Crossref

11. Pham T, Combes A, Rozé H, et al. Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)–induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis. Am J Respir Crit Care Med 2013;187:276-85. Crossref

12. Patroniti N, Zangrillo A, Pappalardo F, et al. The Italian ECMO network experience during the 2009 influenza A(H1N1) pandemic: preparation for severe respiratory emergency outbreaks. Intensive Care Med 2011;37:1447-57. Crossref

13. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome (EOLIA). Available from: https://clinicaltrials.gov/ct2/show/NCT01470703. Accessed Dec 2016.

14. von Bahr V, Hultman J, Eksborg S, Frenckner B, Kalzén H. Long-term survival in adults treated with extracorporeal membrane oxygenation for respiratory failure and sepsis. Crit Care Med 2017;45:164-70. Crossref

15. Lewandowski K. Extracorporeal membrane oxygenation for severe acute respiratory failure. Crit Care 2000;4:156-68. Crossref

16. Vasilyev S, Schaap RN, Mortensen JD. Hospital survival rates of patients with acute respiratory failure in modern respiratory intensive care units. An international, multicenter, prospective survey. Chest 1995;107:1083-8. Crossref

17. Pranikoff T, Hirschl RB, Steimle CN, Anderson HL 3rd, Bartlett RH. Mortality is directly related to the duration of mechanical ventilation before the initiation of extracorporeal life support for severe respiratory failure. Crit Care Med 1997;25:28-32. Crossref

18. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988;138:720-3. Crossref

19. Formica F, Avalli L, Martino A, et al. Extracorporeal membrane oxygenation with a poly-methylpentene oxygenator (Quadrox D). The experience of a single Italian centre in adult patients with refractory cardiogenic shock. ASAIO J 2008;54:89-94. Crossref

20. Kohler K, Valchanov K, Nias G, Vuylsteke A. ECMO cannula review. Perfusion 2013;28:114-24. Crossref

21. Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med 2006;32:24-33. Crossref

22. Hickling KG, Walsh J, Henderson S, Jackson R. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study. Crit Care Med 1994;22:1568-78. Crossref

23. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347-54. Crossref

24. Ng GW, Leung AK, Sin KC, et al. Three-year experience of using venovenous extracorporeal membrane oxygenation for patients with severe respiratory failure. Hong Kong Med J 2014;20:407-12.

25. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:637-45. Crossref

26. Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:646-55. Crossref

27. Gattinoni L, Caironi P. Refining ventilatory treatment for acute lung injury and acute respiratory distress syndrome. JAMA 2008;299:691-3. Crossref

28. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564-75. Crossref

29. Lin CY, Chen YC, Tsai FC, et al. RIFLE classification is predictive of short-term prognosis in critically ill patients with acute renal failure supported by extracorporeal membrane oxygenation. Nephrol Dial Transplant 2006;21:2867-73. Crossref

30. Smith AH, Hardison DC, Worden CR, Fleming GM, Taylor MB. Acute renal failure during extracorporeal support in the pediatric cardiac patient. ASAIO J 2009;55:412-6. Crossref

31. Yan X, Jia S, Meng X, et al. Acute kidney injury in adult postcardiotomy patients with extracorporeal membrane oxygenation: evaluation of the RIFLE classification and the Acute Kidney Injury Network criteria. Eur J Cardiothorac Surg 2010;37:334-8.

32. Chen H, Yu RG, Yin NN, Zhou JX. Combination of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically ill patients: a systematic review. Crit Care 2014;18:675. Crossref

33. Santiago MJ, Sánchez A, López-Herce J, et al. The use of continuous renal replacement therapy in series with extracorporeal membrane oxygenation. Kidney Int 2009;76:1289-92. Crossref

34. Symons JM, McMahon MW, Karamlou T, Parrish AR, McMullan DM. Continuous renal replacement therapy with an automated monitor is superior to a free-flow system during extracorporeal life support. Pediatr Crit Care Med 2013;14:404-8. Crossref

35. Harthan AA, Buckley KW, Heger ML, Fortuna RS, Mays K. Medication adsorption into contemporary extracorporeal membrane oxygenator circuits. J Pediatr Pharmacol Ther 2014;19:288-95.

36. Lemaitre F, Hasni N, Leprince P, et al. Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood. Crit Care 2015;19:40. Crossref

37. Nader-Djalal N, Khadra WZ, Spaulding W, Panos AL. Does propofol alter the gas exchange in membrane oxygenators? Ann Thorac Surg 1998;66:298-9. Crossref

38. Oliver WC. Anticoagulation and coagulation management for ECMO. Semin Cardiothorac Vasc Anesth 2009;13:154-75. Crossref

39. ELSO anticoagulation guidelines 2014. Ann Arbor, MI: Extracorporeal Life Support Organization; 2014.

40. Pollak U, Yacobobich J, Tamary H, Dagan O, Manor-Shulman O. Heparin-induced thrombocytopenia and extracorporeal membrane oxygenation: a case report and review of the literature. J Extra Corpor Technol 2011;43:5-12.

41. Sanfilippo F, Asmussen S, Maybauer DM, et al. Bivalirudin for alternative anticoagulation in extracorporeal membrane oxygenation: a systematic review. J Intensive Care Med 2016 Jun 29. Epub ahead of print. Crossref

42. Ranucci M, Ballotta A, Kandil H, et al. Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation. Crit Care 2011;15:R275. Crossref

43. ELSO general guidelines for all ECLS cases. Version 1.3. Ann Arbor, MI: Extracorporeal Life Support Organization; 2013.

Total hip arthroplasty (THA) is an effective means of relieving pain and improving functional outcome1 2 3 in a variety of hip pathologies. In Hong Kong, the most common reasons for THA are osteonecrosis, osteoarthritis, and post-traumatic arthritis of the hip.4 Although surgical techniques and implant quality of THA have evolved over the last two decades, approximately 27% patients complain of pain at the first 6-month follow-up after THA.5 6 The pain may worsen with time: up to 4% of patients develop severe chronic pain and require revision surgery.5 Therefore, it is important for clinicians to comprehensively assess patients undergoing THA to determine the pathology of a painful hip and offer prompt treatment.

In this article, we analyse the causes of hip pain following THA, the systematic approach to evaluation and the appropriate diagnostic investigations. Several patients with similar complaints of painful hip but different pathologies will be presented.

Traditionally, the causes of hip pain following THA are classified as intrinsic or extrinsic. Intrinsic causes include pathologies arising from the hip region, and can be further classified as intra-capsular or extra-capsular. Intra-capsular causes relate to components of the implant and include infection, loosening, instability, and implant failure. Extra-capsular causes include pathologies from the surrounding soft tissue such as iliopsoas tendon and trochanteric bursa, as well as heterotrophic ossification. Extrinsic causes include pathologies arising outside the hip region. A very common example is lumbar spine pathology such as lumbar stenosis, disc herniation, or spondylosis. Common intrinsic and extrinsic causes are summarised in the Table.

A comprehensive history can undoubtedly provide most of the important clues to diagnosis. Pain should be explored from different aspects including temporal onset, its nature, location, exacerbating factors, and severity. Whether the patient has a pain-free period following THA is important. If there has been an initial pain-free period followed by later onset of hip pain, events that occurred before the onset of pain should be carefully explored. For example, if the patient has recently fallen or sustained a trauma to the hip then pain may be due to a periprosthetic fracture. A recent dental procedure or infection elsewhere could lead to haematogenous spread of bacteria and subsequent prosthetic joint infection. Other causes of pain that appears after a pain-free period include aseptic loosening, instability, osteolysis, and soft tissue irritation. The nature of pain when it is persistent should then be clarified. If it is similar to that which was present before surgery, then the initial indications for THA should be reviewed. If they were misdiagnosed, then there may be untreated hip pathology. Persistent infection of the joint could also be a cause.

Different types of pain can indicate different pathologies. Mechanical pain may reflect aseptic loosening, stress fracture, or instability of implants. Constant, nocturnal, and rest pain may be a sign of infection or, rarely, malignancy. Burning pain at the right hip, associated with numbness or radiation from the back could be referred pain of lumbar spine pathology. Sharp pain occurs following periprosthetic fracture or soft tissue irritation. Deep and dull pain may indicate intrinsic causes such as infection or osteolysis.

Exacerbating factors should be sought when assessing hip pain. Pain that increases with initiation of movement or during weight bearing, and is relieved by rest could indicate loosening of components. Pain that begins after a certain level of exacerbation or activity suggests vascular or neurogenic claudication. Pain aggravated by climbing stairs or rising from a seated position may be due to iliopsoas tendinitis.

The location of pain may provide a clue as to the location of the pathology or defective components. Groin pain may indicate a failing acetabulum component. Other intrinsic causes of groin pain include iliopsoas impingement or tendinitis. Extrinsic causes include local neurological or vascular pathology, inguinal hernia, spinal pathology or radiculopathy or, rarely, malignancy. Thigh pain may suggest involvement of the femoral component and relate to stem loosening, subsidence and instability, modulus mismatch, or impingement on bone cortex. Nerve injury, for example to the lateral femoral cutaneous nerve, may present as thigh pain. Buttock and leg pain could be secondary to spinal stenosis or radiculopathy.

Perioperative details such as the model and size of implant used, urinary catheterisation, wound, and other systemic infections during the recovery period could be important.

In addition to details about the pain and surgical history, a routine general medical history should not be ignored. In patients with a history of immunosuppression, inflammatory arthritis, obesity or diabetes, there may be a higher rate of prosthetic joint infection. Patients who are depressed or overemotional may be more prone to chronic pain or complex regional pain syndrome. Those prescribed long-term immunosuppressants, biologics, or steroids are at high risk of infection and hence adjustment of these drugs before operation is necessary.

A complete physical examination of the hip should include the painful as well as the contralateral side, the spine and knees as well as a neurological examination of the lower limbs—all critical to making the right diagnosis. The conventional approach to hip examination is to ‘look, feel, and move’. For inspection, we examine the surgical incision that will indicate the approach of the previous THA and quality of postoperative wound healing. Hyperplasia of the surgical scar may indicate previous wound infection. Signs of infection such as erythema, pain, swelling, and increased warmth should be noted if present. The presence of sinus tracts indeed is pathognomonic for prosthetic joint infection. Muscle wasting may be due to deconditioning or nerve injury. Gait analysis is also important as it may reflect abductor insufficiency if the patient walks with a Trendelenburg gait. Short limb gait may indicate leg length discrepancy. When assessing leg length, patients should be asked if they have noted any progressive change in leg length discrepancy, as it may suggest subsidence of the femoral stem. For palpation, sites of local tenderness should be sought as these may pinpoint the exact location of hip pathology. Any swelling at the groin must be carefully examined. Characteristics such as nature, margin, tenderness, fluctuance, compressibility, emptiability, pulsatility, and positive Tinel’s signs should be noted. A reducible mass in the groin with or without cough impulse could be an inguinal, femoral, or obturator hernia. A pulsatile mass could be a true or pseudo-aneurysm. A vague, deeply seated tender swelling could be an ‘aseptic lymphocyte-dominated vasculitis-associated lesion’ if a metal-on-metal bearing or a modular metal-on-metal head-neck articulation has been used. During assessment of patient movement, the range and any tenderness triggered by a specific movement or manoeuvre should be noted. Reproducible pain upon extreme range of movement may indicate instability or impingement by implants. Pain elicited during active movement may indicate instability or loosening while that which appears during passive movement could be due to infection. Any pain triggered by active or resisted hip flexion may be due to acetabulum component loosening, iliopsoas tendinitis, or impingement.

Serological, microbiological, and cytological investigations are important in the assessment of patients with painful THA. Common serum inflammatory markers that could indicate prosthetic joint infection are white blood cell count (WBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Spangehl et al7 reported the sensitivity and specificity of WBC of >11.0 x 10⁹ /L as 0.2 and 0.96, that of ESR as 0.82 and 0.85, and that of CRP as 0.96 and 0.92, respectively. It has been suggested that interpretation of ESR and CRP together improves sensitivity and specificity. In the presence of abnormal serum parameters and/or clinical suspicion of infected THA, aspiration should be performed to obtain synovial fluid for microbiological and cytological examination.8 Gram smear and bacterial culture are routinely requested, while fungal and tuberculosis culture are ordered selectively if indicated. Nonetheless, the sensitivity of Gram staining is low, ranging from 10% to 67%.9 10 Hip aspirate culture is reported to have a variable sensitivity of 50% to 86%.11 12 13 To increase the yield of bacterial culture, all aspirated specimens should be processed immediately.14 Font-Vizcarra et al15 advocated transport of aspirated synovial fluid in a blood culture bottle to achieve higher sensitivity and specificity. Cell count with neutrophil differential also provides an important clue for prosthetic joint infection. Different cut-off values of cell count and neutrophil percentage have been suggested. An international consensus on periprosthetic joint infection in 2013 proposed 3000 cells/µL and neutrophil differential of >80% as being indicative of active infection.16 Parvizi et al17 suggested use of leukocyte esterase reagent strips as a rapid, inexpensive, highly sensitive and specific test to detect periprosthetic joint infection.

Plain radiographs are always the first-line investigation for a painful hip following THA. The anteroposterior view of the pelvis, and the anteroposterior and lateral views of the affected hip, including the tip of the stem area, are standard. These often provide clues about pre-existing hip disease, fixation method of the prosthesis, and design features of the prosthesis and articulations—all of which are important in determining the cause of hip pain. For example, cementless femoral stems, especially extensively porous-coated long stems, could cause mid-thigh pain due to modulus mismatch and stress shielding. Osteolysis is not uncommonly present in metal-on-polyethylene articulation. Details of the procedure should also be evaluated. The abduction angle, horizontal and vertical positions, and version for the socket, as well as the coronal alignment, grades of cement mantle for cemented stem and canal filling for cementless stem are important and should be reviewed. Malalignment of the socket and/or stem can result in instability and increase the risk of early loosening, polyethylene wear, and dislocation. Quality of the cement mantle can be assessed by the Barrack classification that grades according to the percentage of radiolucency present in the medullary canal.18 A poor grade of cementation may lead to loosening and early failure of the implant. To assess loosening of a cemented femoral stem, Harris criteria described three categories: definite, probable and possible, depending on the size of radiolucent zone at the cement-bone interface, subsidence, and presence of fractured cement mantle or stem.19 DeLee and Charnley20 divided the cement-bone area around the cemented socket into three types—radiolucent lines at the lateral one third as type I, involvement at the middle one third as type II, and complete involvement of the cement-bone interface as type III. If one zone is involved, the rate of loosening of the cup is 7%. The risk significantly increases to 71% and 94% in type II and III, respectively.21 For cementless stems, as described by Engh’s classification,22 presence of spot welding and parallel demarcation lines indicates stable bone ingrowth and fibrous fixation, respectively. Subsidence, calcar hypertrophy, and pedestal at the tip of the stem are signs of unstable stem fixation. For cementless cups, signs of loosening include change in abduction angle of >8°, migration of ≥3 mm, implant failure, halo around screws, and shredding of porous coating.23 Endosteal scalloping and periosteal reaction are classic signs of infection. Presence of osteolysis on plain radiographs may indicate particle disease.

Computed tomography (CT) can be useful in evaluating the complications of THA, provided proper parameter modifications are adopted to reduce artefact from the prosthesis.24 25 Accurate measurement of the acetabulum cup version can be achieved with CT because of the ability to measure in multiple orthogonal planes.26 27 28 29 Other potential uses of CT include preoperative assessment of bone loss for acetabulum and femur, evaluation of bone density for stress shielding, and detection of osteolysis, liner wear, and metallosis. Magnetic resonance imaging (MRI) is excellent for evaluation of the periprosthetic soft tissue and hence detection of THA complications. Nonetheless, its use, as with CT, is limited by the occurrence of artefact from the prosthesis. To improve the diagnostic value of MRI in the evaluation of THA complications, metal artefact reduction sequence (MARS)–MRI has been developed and achieves better visualisation of the periprosthetic soft tissue structure that is obscured by signal void in conventional MRI sequences.30 31 The imaging, MARS-MRI, has a high sensitivity to detect particle diseases that can result in proliferative synovitis, pseudotumours, loosening, and osteolysis.32 33 34 Involvement of superficial and deep soft tissue surrounding the prosthesis can also be assessed by MRI.

A nuclear medicine scan such as technetium-99 is often advocated when there is no obvious diagnosis despite extensive investigations. It has a high sensitivity to detect a wide variety of complications including infection, loosening, instability, and stress fractures. Nonetheless, the specificity is rather low and increased uptake can occur for 2 years in uncomplicated THA.35 If a technetium-99 scan is positive, indium-111 white cell scan may be used to differentiate between an infective or non-infective pathology.36

To differentiate between the intrinsic or extrinsic source of pain, a local anaesthetic agent such as marcaine 0.5% can be injected with an 18-Gauge spinal needle under fluoroscopic guidance to the tender spots. Immediate pain relief following injection will confirm the exact site of pathology. Crawford et al37 reported sensitivity of up to 96% for this technique that offered a rapid, reliable diagnostic test with low morbidity.

A 66-year-old woman prescribed a long-term steroid for systemic lupus erythematous underwent Austin-Moore arthroplasty in 1978 for avascular necrosis of bilateral femoral heads. She underwent multiple revision surgeries on both hips due to infective loosening. The latest operation in 2011 was revision of the loosened right acetabulum cup due to infection. The femoral stem was retained at that time as it was well fixed. She enjoyed a pain-free period and could walk with a stick. Serial radiographs showed no loosening of components. She complained of right hip pain during follow-up in 2014, however, and radiographs of the right hip showed endosteal scalloping over the THA (Fig 1a, 1b). Blood tests revealed an elevated ESR and CRP. Hip aspiration was performed and 2 mL of turbid synovial fluid was aspirated. Bacterial culture was negative but cell count was 33 400 cells/µL. The provisional diagnosis was an infected right THA and a two-stage revision was proposed. While waiting for revision, she was admitted for worsening right hip pain for 2 weeks. Radiographs showed a radiolucent line across all Gruen zones and lucent lines were present at zones I and II around the acetabulum cup. Periosteal reaction and endosteal scalloping were also noted. Serum inflammatory markers were all elevated. Extended trochanteric osteotomy, removal of implant, and placement of antibiotic-loaded cement spacer was performed (Fig 1c). Multiple specimens were taken for culture. Erysipelothrix rhusiopathiae was cultured from the anterior capsule granulation tissue. Postoperatively she was given intravenous ampicillin for 4 weeks and switched to oral ampicillin for a further 8 weeks. Levels of ESR and CRP returned to normal. Repeated right hip aspiration, after antibiotics had been stopped for 2 weeks, were negative on bacterial culture. Cell count was 325 cells/µL with neutrophils of 27%. Second-stage revision with cementless acetabulum cup and extensive porous-coated long stem prosthesis was performed and was uneventful (Fig 1d). After 3 months, she had no hip pain and could walk with a stick for more than 30 minutes. Radiographs showed no interval change in alignment nor loosening.

A 65-year-old woman had a medical history of tuberculosis of the right hip with auto-fusion, followed by conversion to THA in 1995. She underwent acetabulum cup revision in 2004 due to aseptic loosening. The procedure was uneventful and she was asymptomatic afterwards. Twelve years later she complained of right hip pain for 2 weeks with no history of trauma. She had been febrile for several days with chills and rigor. She denied any respiratory, abdominal, or urinary symptoms. She walked with a limping gait after onset of pain. Examination upon admission revealed a high fever with stable vital signs. Palpation of her right groin revealed a vague, tender swelling that was neither compressible, reducible, nor pulsatile. Active and passive range of movement of the right hip was significantly limited by pain. Pain was aggravated by internal rotation of the affected hip. Neurovascular status appeared intact. Radiographs of the right hip showed no loosening or migration of THA components. No periosteal reaction or endosteal scalloping was noted. Serum WBC, ESR, and CRP were all elevated (WBC, 14 x 10⁹ /L; ESR, 104 mm/h; CRP, 9.26 mg/L). In view of her febrile state and tender groin swelling, CT right hip with contrast was arranged. No abnormal increase in periprosthetic hypodensities was noted and loosening was unlikely but a rim-enhancing lesion of 3.3 x 6.8 x 11 cm in size at the right iliopsoas was noted and psoas abscess was diagnosed. Then CT-guided drainage was performed by radiologists and 30 mL of blood-stained purulent fluid was aspirated. The aspirate was sent immediately for bacterial culture and revealed Parabacteroides merdae sensitive to rifampicin. She was treated with antibiotics according to the sensitivity tests. Colonoscopy was arranged as the cultured bacteria is usually of gastrointestinal origin. After aspiration of the psoas abscess and administration of antibiotics, she improved clinically. Hip pain resolved, fever subsided, and she was able to walk unaided without pain. Blood tests showed reducing ESR and CRP. Serial CT abdomen and pelvis showed regression of psoas abscess (Fig 2). Despite her clinical improvement and reassuring radiological and serological tests, it remained uncertain whether the right THA was infected. Hip aspiration posed a risk of introducing the bacteria into the hip joint because of the close proximity of the psoas abscess, causing ‘iatrogenic’ prosthetic joint infection. She is being closely monitored and surgical drainage can be offered if she deteriorates in future.

A 75-year-old woman underwent dynamic hip screw for fixation in 1991 due to intertrochanteric fracture of the right proximal femur. In 1992 she underwent cementless THA for the cut-through dynamic hip screw. Unfortunately during follow-up she was noted to have subsidence of the femoral stem with impingement at the lateral cortex. Infection was excluded and revision THA was offered but refused by the patient who could walk with a stick for 30 minutes and had no hip pain. In 2010, she was diagnosed with carcinoma of the transverse colon and right hemicolectomy was performed. Intra-operative specimens showed clear margins and there was no evidence of local or distant metastasis. She defaulted from surgical follow-up, however. In 2014, 22 years after the THA, she complained of insidious onset of right groin and thigh pain for several months. She experienced nocturnal pain at the right hip and an intermittent low-grade fever. Unexplained weight loss over 1 month was noted. She could only walk with a stick for 5 minutes since the onset of thigh pain. Examination showed shortening of the right lower limb by 2 cm and tenderness at the right femur shaft. Serum WBC was slightly elevated (12.5 x 10⁹ /L), and both ESR and CRP were markedly increased (ESR, 111 mm/h; CRP, 13.3 mg/L). Serum tumour marker levels were normal and carcinoembryonic antigen level was static. Radiographs showed extensive osteolytic lesions at the anterior and posterior aspects of the acetabulum cup. Migration of the cup position was noted (Fig 3). In view of the history of malignancy of the transverse colon and abnormal radiographs of the right hip, CT pelvis and right hip with contrast was performed and revealed a large soft tissue mass in the right pelvis with extensive bony erosion of the acetabulum, ilium, ischium, and superior pubic ramus with loosening of the implant (Fig 4). The diagnosis was bone metastasis to the pelvis with erosion. Exploration was performed and a large friable soft tissue mass with extensive destruction of the acetabulum was noted. Intra-operative specimens were revealed on frozen section to be metastatic adenocarcinoma. In view of the massive bone loss over the acetabular side, her advanced age and underlying medical condition, excision arthroplasty was performed in the same operation. Further histopathological tests of intra-operative specimens confirmed metastatic adenocarcinoma that was likely of colorectal origin. All other specimens for microbiological culture, including tuberculosis culture, were negative. She was referred to oncologists and underwent radiotherapy for local control of disease. Her right groin and thigh pain was much relieved after operation. She tolerated sitting well and could ambulate in a wheelchair. The patient was referred to a hospice and finally succumbed 4 months later due to a chest infection.

A 50-year-old woman with osteoarthritis of the left hip secondary to untreated developmental hip dysplasia underwent total hip replacement in the private sector in January 2012. She gained satisfactory pain relief at her left hip until March 2012 when she presented with increased left hip pain that was aggravated by active flexion, stair walking, getting out of bed, and getting on public transport. Examination showed her left lower limb to be lengthened by 1 cm. No local tender spot at the left hip was noted. Active range of flexion was 0° to 110°. Severe pain was noted during active flexion of hip. Blood tests were all unremarkable. Ultrasound-guided aspiration of the left hip showed no growth. Computed tomography of the left hip showed protrusion of the anterior rim of the acetabular cup (Fig 5). After excluding infection, a working diagnosis of iliopsoas tendon impingement due to severe pain triggered by active hip flexion was proposed. Ultrasound-guided injection of local anaesthetic to the left iliopsoas tendon insertion to the lesser trochanter was performed to relieve the pain although it returned 1 week later. Arthroscopic release of the left iliopsoas tendon was performed and was uneventful. Upon follow-up at 6 weeks after operation, her left hip pain was much improved and no pain was noted on walking upstairs or active flexion of left hip.

Any pain that appears after THA should not be overlooked. Making an accurate diagnosis of the pain requires a detailed history, thorough clinical examination, and appropriate investigations. Large-scale reviews in the literature report instability, mechanical loosening, and infection as the three main causes of implant failure necessitating revision surgery38 39 and all should be considered during evaluation. Patients who have undergone THA but have postoperative hip pain should be reviewed by the operating surgeon for further management after an initial assessment. The ultimate goal is to unearth the underlying cause and offer timely treatment, hence preventing unnecessary revision surgery and facilitating the patient’s return to normal activity.

We would like to thank Dr HC Cheng, Chief of Service of the Department of Orthopaedics and Traumatology, United Christian Hospital, Hong Kong for providing an illustrative case of iliopsoas tendon impingement after total hip replacement in this article.

All authors have disclosed no conflicts of interest.

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