## GUIDANCE MATERIAL TO SUPP ORT THE PROPOSED CHANGES

TO THE MEDICAL PROVISIONS CONTAINED IN

ANNEX 1 — PERSONNEL LICENSING

(Details of the proposed changes to the medical Standards and Recommended Practices

contained in Annex 1 – Personnel Licensing can be found in
ICAO State letter AN 5/22-08/33, dated 5 May 2008)

March 2008TABLE OF CONTENTS

Page

1. Content of regulatory medical examinations ................................................................................. 1

2. Treatment of depression..................................................................................................... ............ 9

3. Reporting of medical conditions............................................................................................. ....... 15

4. Human immunodeficiency virus................................................................................................ .... 17

5. Insulin-treated diabetes .................................................................................................... .............. 35

## CONTENT OF REGULATORY MEDICAL EXAMINATIONS

1. Background

Class 1 applicants are required to have an annual me dical assessment from the time they commence flying until they reach 60 years of age, when the frequency b ecomes 6-monthly. The exception to this is for the passenger-carrying single pilot operator, who require s a medical assessment every six months after age 40 years. The medical assessment varies little dur ing a pilot’s career, although after the initial electrocardiogram (ECG) at the first Class 1 examination the frequency for ECGs increases with increasing age, initially as a Recommendation (two-year ly from age 30-50 years) and then as a Standard (annually from age 50 years). ICAO therefore rec ognizes the increase in cardiovascular risk with increasing age, which is an observation in all Contracting States. There are, however, differences between States regarding the rate of increase in risk with increasing age.

In most Western States, the annual cardiovascular mortality for males reaches around 1 per cent per annum at age 70 years, which is about 100 times greater than at age 30. Further, the risk of developing other physical diseases such as cancer, diabetes and epilepsy is very low in young adults, but increases with increasing age. On the other hand, mental h ealth illness and behavioural problems, including those related to drug and alcohol use, do not demonstrate such a steep gradient, and in the general population these categories are usually more frequent than physi cal disease in younger age groups. It therefore seems appropriate to consider the likely prevalence of diffe rent diseases in the pilot population when considering the type of routine periodic examination they should undergo.

The annual Class 1 medical examination is unlikely to reveal any significant physical problem in pilots under age 40 years. Some items of the physical asses sment could therefore be omitted in alternate years without detriment to flight safety. This would permit additional time to be used to focus on mental health aspects, and on preventative aspects of health. It is widely accepted that illness in later life, both physical and mental, can be prevented or delayed by lifestyle interventions and treatment, if necessary, at an early stage, and professional pilots represent a group of motiv ated individuals who have a keen interest in health maintenance. Such a change of emphasis in the younger pilot should encourage health and, therefore, flight safety benefits later on in a pilot’s career.

The proposed ICAO Standards and Recommended Practices (SARPs) for a Class 1 assessment are being adjusted to permit a licensing authority, in alternate years, to omit certain items from the physical examination in applicants under 40 years of age, ther eby enabling a medical examiner to spend more time discussing medical issues, from an educational viewpoint, with an applicant in this age group. However, a licensing authority may wish, for example, to undertake some assessment of the vision every year in order to ascertain those applicants who would benefit from co rrecting lenses, or a change in prescription, since refractive error can change over time in the younger age group.

It is felt that an examination of, for example, th e heart and lungs, and checking the blood pressure and urine in all pilots under 40 years, on an annual basi s, is unnecessary – a two yearly examination should be adequate. This does not preclude the licensing author ity from requiring more frequent checks in those

who are known to have an increased risk. If the content of the physical examination is reduced in alternate years, this releases some time for discussing aspects of health that may, in the longer term (with a timescale greater than that of the validity of the medi cal assessment/certificate) improve the pilot’s health, and as a consequence, improve flight safety.- 6 -

Two aspects are particularly worthy of considerati on. The first concerns the preservation of physical health. The factors for this are well known. Aspects of diet, exercise, smoking, body weight, etc. and their

effect on health are familiar to all medical examin ers and these can be discussed with the individual applicant in light of the particular circumstances of the individual, such as family history of illness, body weight, exercise habits, etc. Licensing authorities are encouraged to provide guidance to designated medical examiners regarding these aspects of health maintenance.

The second aspect concerns mental health and use of psychoactive substances. Guidance on this area is not so readily available, and at the request of ICAO a small group of experts has reviewed the evidence of benefit in discussing certain topics with applicants, by means of asking specific questions. This review has demonstrated from general population studies that some mental illnesses and misuse of psychoactive substances can be prevented by early intervention, before the situation has deteriorated to an extent where the health, or medical fitness for flying of a licen ce holder, has been adversely affected. A separate section on this topic with draft guidance material has been provided below.

Historically, the focus of the periodic medical examin ation has been to detect medical conditions, almost exclusively physical medical conditions, that may pose a threat to flight safety during the forthcoming period of validity of the medical assessment/certifi cate. The medical examiner’s primary role has therefore been to detect significant conditions that may cause incapacitation in the relatively short term.

The role of the medical examiner as educator has not played a formal part in the process, although many examiners take on this task as a natural part of the role of any doctor. Whilst the role of the medical examiner in determining the physical fitness of th e pilot will continue, because of the low level of physical pathology encountered in the lower age group, an opportunity to improve the health of the applicant, as well as improve flight safety, presents itsel f. One view is that this is not the role of the regulatory medical examiner, but in reality the examiner is in an excellent position to provide this service to flight safety and to the applicant (who, experi ence has shown, is unlikely to seek such advice elsewhere).

By reducing the emphasis on the physical examination in those Class 1 applicants less than 40 years of
age, time is made available to focus on the non-physi cal aspects of health, in a non-threatening manner,
and at no additional cost to the applicant.

2. Development of questions for use by medical examiners

As there is evidence that several fatal aviation accident s have been caused by psychiatric disorders or use of psychoactive substances, it is reasonable that as part of the periodic aviation medical examination there should be questions that pertain to these issues. Little guidance has been provided concerning how such aspects could be addressed in the periodic medical ex amination, although experienced medical examiners have often informally and spontaneously included it in assessment of the applicant. Further, the number of non-physical conditions that can affect the health of pilots and which can lead to long term unfitness in those of middle age appears to be increasing. The conditions addressed by the proposed questions that

medical examiners could use have been shown to be amenable to preventive action, before they develop into significant health problems, and before there is an impact on the pilot’s medical status for flying.

There are various questionnaires available for assessi ng mental health and behavioural aspects of an individual’s health, having a variety of lengths and complexity. However, the main purpose of recommending the questions below is intended to be e ducational, with the questions serving to promote discussion between the medical examiner and the pilo t. To encourage dialogue, it is recommended that no- 7 -

written record of the conversation is retained conc erning these questions and that this should be made clear to the pilot at the outset, thus increasing the like lihood of developing a frank exchange. Further, it is to be expected that only rarely will any formal action need to be considered by the medical examiner to protect flight safety in the light of response to these questions.

The questions suggested address those conditions that are most common in the age range of professional pilots and those which are most likely to affect pe rformance on the flight deck. Statistics show that the main psychiatric conditions that meet these criteria are mood disorders and certain anxiety disorders, especially panic episodes. Additionally, in many Cont racting States, excessive alcohol intake and use of illicit drugs in the general population is occurring w ith increasing frequency and pilots are not immune from these social pressures. Questions have been developed to address these issues as well.

In developing the questions, a review of the literature was undertaken by specialists in the field with the aim of choosing simple questions that can be complete d quite quickly. The majority of pilots will answer all questions in the negative, and it is unnecessary to request pilots without any relevant problems to undertake a prolonged screening questionnaire. Those who answer positively, or with uncertainty can be engaged with further dialogue by the medical examin er. The main aim is to encourage the pilot to consider his lifestyle and improve, where necessary, his or her likelihood of maintaining good mental health, including the avoidance of problems linked to the use of psychoactive substances, during his/her career. Occasionally, the medical examiner may find conditions that are amenable to medical support or even treatment, and the goal is to detect these at an early stage, befo re they become significant problems and before they impact on the pilot’s medical fitness and on flight safety.

Not all medical departments will find th e questions relevant to their par ticular pilot population. Therefore, the questions may not represent the best questions for all States, but they offer guidance, a starting point, for States that wish to develop such an approach.

3. Recommended questions concerning mental he alth and use of psychoactive substances

Questions for Depression:

1) During the past three months, have you often been bothered by feeling down, depressed or hopeless?

2) During the past three months, have you often b een bothered by having little interest or pleasure in doing things?

3) During the past three months, have you been bothered by having problems falling asleep, staying asleep, or sleeping too much, that is unrelated to sleep disruption from night flying or transmeridian operations?

4) In the past three months, has there been a ma rked elevation in your mood lasting for more than

one week?- 8 -

Questions for anxiety/panic attack:

1) In the past three months, have you had an epis ode of feeling sudden anxiety, fearfulness, or

uneasiness?

2) In the past three months, did you experience se nsations of shortness of breath, palpitations (racing heart beat) or shaking while at rest without reasonable cause?

3) In the past year have you needed to seek urgent medical advice because of anxiety?

Questions concerning alcohol use:

1) Have you ever felt that you should cut down on your drinking?

2) Have people annoyed you by criticizing your drinking?

3) Have you ever felt guilty about your drinking?

4) Have you ever needed a drink first thing in the morning?

5) How many alcoholic drinks would you have in a typical week?

6) How many alcoholic drinks would you have on a typical day when you are drinking?

Questions concerning drug use:

1) Have you used drugs other than those required for medical reasons?

2) Which non-prescription drugs have you used ? When did you last use this drug(s)?

References for those who wish to consider the literature themselves are as follows:

1) Alcohol Alert NIAAA Apr 2002 http://pubs.niaaa.nih.gov/p ublications/aa56.htm 2) Screening for Alcohol Problems in Primary Care: Fi ellen, Reid, et al, Arch Intern Med Vol. 160 July 2000. 3) Case-finding Instruments for Depression. two ques tions as good as many. Whooley, Avins et al J Gen Intern Med. 1997; 12: 439-445. 4) Using five questions to screen for five common mental disorders in primary care. A.J. MeansChristensen et al; General Hospital Psychiatry 28 (2006) 108-118. 5) Counselling Resource Welcome to the Drug Abuse Screening Test (DAST). http://counsellingresource.com/quizzes/drug-abuse/index.html

. 6) Manual on prevention of problematic use of substances in the aviation workplace,

Document 9654; International Civil Avia tion Organization, Montreal, Canada, 1995

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## TREATMENT OF DEPRESSION

1. Introduction

A new Recommendation and a Note is proposed con cerning licence holders who have depression and are in need of treatment with antidepressants:

6.3.2.2.1 (and 6.4.2.2.1, 6.5.2.2.1) Recommendation .— An applicant with depression, being treated with antidepressant medication, s hould be assessed as unfit unless the medical assessor, having access to the deta ils of the case concerned, c onsiders the applicant’s condition as unlikely to interfere with the safe exercise of the applicant’s licence and rating privileges.

Note 1.— Guidance on assessment of applican ts treated with antidepressant medication is

contained in the Manual of Civil Aviation Medicine (Doc 8984).

2. Background

The use of antidepressant medication in aircrew and ai r traffic controllers (ATC) has traditionally been disqualifying for medical certification due to the underlying medical condition and the potential safety

relevant side-effects of the available medications to treat it (1, 2). In the United States, in accordance with Federal Aviation Administration (FAA) rules, anti depressant usage must have ceased for at least

three months (3) , while in Europe the Joint Aviation Author ities’ policy is that no certification can be considered whilst using psychoactive medication (4,5)

.

Depression is a common worldwide disorder in the ad ult population, although reported prevalence varies quite widely (6). In the United States the lifetime prevalence of major depressive disorder was found to be 16.2 per cent, which would involve almost 34 million US adults, and for a twelve-month period the figure was 6.6 per cent (7) .Whilst there is no evidence that selectiv e serotonin reuptake inhibitors (SSRI)

medications are more efficacious than older an tidepressant medications, th is new generation of antidepressants is better tolerated by patient s and has an improved side effect profile (8, 9, 10)

.

Many patients require long term treatment with an tidepressants to reduce the risk of recurrence. One systematic review (11) found that continuing antidepressant medication treatment after recovery dramatically reduced the proportion of patients who re lapsed over one to three years, compared with placebo. The average rate of relapse on placebo was 41 per cent, compared with 18 per cent on active

treatment.

There is emerging evidence in the lite rature that suggests that policies which disqualify pilots from flying whilst on antidepressant medications may lead to pilots flying when depressed and untreated, or flying on antidepressant medication but not reporting it to the regulatory authority (12, 13, 14) . An Aerospace Medical Association position paper (12) stated that, according to the Aviation Medicine Advisory Service database of pilots’ telephone inquiries, appr oximately 15 per cent of pilots who had been advised by their physicians to take antidepressant me dications showed an intention to take the medications and continue flying without informing the Federal Aviation Administration.

Canfield et al. (13) reported on post-mortem toxicological evaluations performed on 4 143 pilots. Psychotropic medications were found in 223 pilots but only fourteen of these pilots had reported a- 10 -

psychological condition to the FAA and only one of the fourteen pilots had reported the psychotropic

medication.

In Australia in 1987, the Civil Aviation Safety Au thority (CASA) began allowing aviation personnel who had been depressed to operate once they had been eff ectively treated and had become stable with the use of antidepressant medications. The po licy had become somewhat liberal with the allowance of use of most medication groups including monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants (TCA). There were no reported adverse outcomes rela ted to this policy but in 2003 a more restrictive approach was introduced with increased surve illance and limitation to specific medications (17) . A study published in August 2007 looking at safety outcomes su ch as accidents and incidents in 481 certificate holders over a ten year period found no evidence of a dverse outcomes related to allowing pilots to fly on antidepressant medication provided specific criteria were met (14).

In Canada, pilots on maintenance therapy are allowed to fly “with or as co-pilots” under an aeromedically supervised treatment protocol in wh ich pilots are followed prospectively (18).

The AsMA position paper (12) points out that several factors must be considered in relation to safety should certificate holders be allowed to operate wh ilst using antidepressant medications. Firstly, it is important to establish the diagnosis. SSRIs are used to treat not just depression, but some other aeromedically significant illnesses su ch as obsessive compulsive disorder and panic disorder. Second, patients generally have their adverse reactions to SSRIs early in treatment; these side effects usually diminish as the patient becomes physiologically accus tomed to the medication. Third, the newer SSRIs have fewer side effects than the older antidepr essants because the pharmaceutical industry is designing them to act only on receptors in specific areas of the brain.

Some of these medications are sedating and some are not, thus offering a therapeutic choice in treating depressed patients who show psychomotor agitation or re tardation. Fewer side effects generally result in improved aeromedical safety. However, successful treatment of depression is a dynamic and complex process involving more than just writing a prescription and the SSRIs can have some aeromedically significant side effects and withdrawal effects that are of little importance in ordinary clinical practice (12).

Finally, an important aspect to consider is that a diagnosis of depression often carries with it significant social stigma and in many societies it is common that symptoms of depression are not discussed openly with either colleagues or the medical profession. Aero medical policies that plac e an absolute prohibition on operating after a diagnosis of depression may also make it less likely that an aviator or air traffic

controller will seek treatment or declare th eir illness to the licensing authority.

3. Draft guidance

3.1 The assessment of pilot and ATC applicants with depression

Depressive mood disorders (ICD-10: Depressive epis ode; DSM-IV-TR: Major Depressive Disorder) are common disorders which present with depressed mood, reduced energy, impaired concentration and memory, loss of interest in surr oundings, slowed cerebration, difficulty in making decisions, alteration of appetite and sleep, guilt feelings, and low self esteem . Suicide is common; the incidence varies with cultural background, but may approach 20 per cent per depressive episode.

The illness is usually of insidious onset and persists for many months when not treated adequately. Depression may be accompanied by a number of somatic symptoms. There may be diurnal variation in- 11 -

the symptoms, and many persons with depression may ha ve some good days in be tween. It is not unusual for sufferers to try to modify their symptoms (esp ecially the dysphoria and insomnia) by the use of alcohol and prescribed medications or illicit drugs.

Depression leads to subtle (and sometimes overt) incap acitation, mainly due to the decreased ability to concentrate, as well as to distractibility and indecisi on, which are frequent features of the illness. It is these symptoms, along with the risk of suicide, whic h make a depressed individual unsuitable to work in the aviation environment. Because the symptoms wa x and wane during a depressive episode, there may be days when the individual is relatively well and may appear to be fit to fly. However, impaired concentration and lack of cognitive agility are always more or less present and may interfere with the ability to integrate the multiple sensory inputs required to make decisions in an emergency.

Depression is by nature a recurrent disorder and although single episodes do occur, the history of a depressive episode should alert the medical examiner to ask specific questions to en sure that the applicant does not currently have the illness. Those persons w ho have had one serious depressive episode have approximately a 50 per cent risk of experienci ng a second episode. Because depressive mood disorders are recurring disorders, it is imperative that the “r ecovered” patient be monitored closely for signs of recurrence for a period of time following recovery. Th ere is evidence that recu rrence is most likely to happen during the first two years. An educative appro ach may help the individual recognize the earliest signs and thus facilitate early intervention.

Historically, pilots have not been allowed to retu rn to flying unless they have ceased taking medication for at least some months after having returned to their euthymic state of health. In recent years, the use of SSRIs has become widespread in the general population and there is reason to believe that such treatment may be compatible with flying duties in carefully select ed and monitored cases. This may be in a situation of an initial successful response to treatment of acute depressive episode, or where treatment is aimed at the prevention of recurrences.

It should be noted that even with good responses, th ere may be the potential for impairment of cognition and decision making ability from either an incomplete r esponse to treatment or from safety relevant side effects of medications. From the patient’s perspec tive, the pronouncement of “being well” may refer only to relative improvement in comparison with the untreated state. Applicants theref ore need to be carefully assessed for the presence of any residual symptoms a nd any performance relevant side effects of the

medication.

3.2 The assessment of pilot and air traffic c ontroller applicants treated with antidepressants

States may, on a case-by-case basis certificate applican ts who are prescribed (and are taking) an approved SSRI antidepressant medication for an established di agnosis of depression which is in remission. Conditions necessary for air safety may be imposed on the certificate as appropriate, for example "holder to fly as or with co-pilot", thus limiting operations to multi-crew aircraft. Pilots and ATCs taking other types of anti-depressants will not usuall y be considered for certification.

States’ certification of pilots and ATCs taking medi cations accepted by the Licensing Authority should be conditional on the following:

a) The applicant should be under the care of a medi cal practitioner experienced in the management of depression- 12 -

b) The applicant should:

1) be stable on an established and appropriate dose of medication for at least four weeks before returning to flying/ATC duties and exhibiting:

i) minimal acceptable side-effects ii) no medication interactions or allergic response

2) be subject to regular clinical review by the medical practitioner with progress reports provided to the medical department of the Licensing Authority. The applicant may be

involved in other concurrent tr eatment (e.g. psychotherapy).

3) have an absence of other significant psychiatric co-morbidities

4) require no other psychoactive medications

c) Symptoms of depression being well controlled, without evidence of psychomotor retardation

d) An absence of suicidal ideation or intent

e) No history of psychotic symptoms

f) An absence of features of arousal (e.g. irritability or anger)

g) The presence of a normal sleep pattern

h) Resolution of any significant preci pitating factors of the depression

Ongoing cognitive-behavioural, rational-emotive or si milar therapy is desirable, but not necessarily required for certification.

Pilots or ATCs authorized to fly or perform duties when taking SSRIs or related antidepressant medications must cease exercising the privileges of their licences if their antidepressant medication is altered or if the dose changed. Their supervising me dical practitioner may return them to duty when they

are assessed as stable and wit hout unacceptable side effects.

Pilots and ATCs whose medication is being reduced with a view to cessation should stop exercising the privileges of their licences for the entire period duri ng which they are weaned off medication, plus an additional period of two weeks. Their supervising medi cal practitioner may return them to duty when they are assessed as stable and without unacceptable side effects or evidence of withdrawal syndrome.

The use of objective assessment tools in the monito ring of these certificate holders is encouraged. The Hamilton ratings scale is one such tool and formal neuropsychological testing is another option. Simulator or other functional based testing can al so be utilized to assess performance. States should provide guidance on preferred medications with lower si de effect profiles such as sertraline, citalopram, and escitalopram.

Outcome criteria/data on the cohort re turned to work should be establis hed prospectively and captured for review of the programme.- 13 -

4. References

1. International Civil Aviation Organization. Inte rnational standards and recommended practices. Personnel licensing. Chapter 6. Medical provisions for licensing. Montreal: ICAO; 2005.

2. Manual of Civil Aviation Medicine (Doc 8984-AN/895), Second Edition, 1985. ICAO publication.

3. Federal Aviation Authority Guide for Aviation Me dical Examiners. Accessed 18 December 2005 http://www.faa.gov/about/office_org/headquarters _offices/avs/offices/aam/ame/guide/media/ amd47psych.pdf

4. Joint Aviation Authorities’ Policy. JA R-FCL 3 Appendix 10, paragraph 2.

5. Joint Aviation Authorities (Europe) Manual of Ci vil Aviation Medicine. Accessed 18 December

2005 http://www.jaa.nl/licensing/manual/11%20-%20Psychiatry.pdf

6. Prevalence, Severity, and Unmet Need for Treatme nt of Mental Disorders in the World Health Organization World Mental Health Surveys. The WHO World Mental Health Survey Consortium JAMA. 2004; 291:2581-2590.

7. Ronald C. Kessler; Patricia Berglund; Olga Deml er; Robert Jin; Doreen Koretz; Kathleen R. Merikangas; A. John Rush; Ellen E. Walters; Philip S. Wang The Epidemiology of Major Depressive Disorder: Results From the Nati onal Comorbidity Survey Replication (NCS-R)

JAMA 2003 289: 3095-3105

8. Westenberg HG, Sandner C. Tolerability and safet y of fluvoxamine and other antidepressants. Int J Clin Pract. 2006 Apr;60(4):482-91. http://www.pubmedcentral.nih.gov/articlere nder.fcgi?tool=pubmed &pubmedid=16620364

9. Arroll B, MacGillivray S, Ogston S, et al. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a metaanalysis. Ann Fam Med. 2005;3(5):449– 456.

10. Cipriani A, Geddes JR, Furukawa TA, Barbui, C. Metareview on short-term effectiveness and safety of antidepressants for depression: an ev idence-based approach to inform clinical practice. Can J Psychiatry. 2007 Sep;52(9):553-62

11. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003; 361(9358):653–661.

12. Jones DR, Ireland RR. Aeromedical regulation of aviators using selective serotonin reuptake inhibitors for depressive disorders. Aviat Space Environ Med 2004; 75:461–70.

13. Canfield DV, Salazar GJ, Lewis RJ, Whinnery JE. Pilot medical history and medications found in post mortem specimens from aviati on accidents. Aviat Space Environ Med. 2006 Nov;77(11):1171-3.

14. Ross J, Griffiths K, Dear K, Emonson D, Lambeth L. Antidepressant use and safety in civil aviation: a case-control study of 10 years of Australian data. Aviat Sp ace Environ Med. 2007 Aug;78(8):749-55.

15. Hudson DE Jr. SSRI use in professional aircre w. [abstract]. Aviat Space Environ Med 2002;

73:244–5.

16. Hudson DE Jr. SSRI use in professional aircre w. Panel presentation. Aerospace Medical Association annual meeting. 9 May 2002, Montreal, Canada.- 14 -

17. Civil Aviation Safety Authority (CASA) (2003) . Use of antidepressant medication by depressed pilots and air traffic controllers. Desi gnated Aviation Medical Examiners handbook. Australia: Civil Aviation Safety Authority.

18. Lange M. Maintenance SRI use in professional p ilots: the Canadian experience [Abstract]. Aviat Space Environ Med 2002; 73:244.

19. Ahmet Sen, Ahmet Akin Gülhane Dennis V. Canfie ld Arvind K. Chaturvedi. Selective Serotonin Reuptake Inhibitors:Medical History of Fatally Injured Aviation Accident Pilots DOT/FAA/AM-07/19 Office of Aerospace Medicine

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## REPORTING OF MEDICAL CONDITIONS

In previous editions of Annex 1, it was a Reco mmendation that licence holders should inform the Licensing Authority of pregnancy, decrease in medical fitness for more than 20 days, or the continued use of prescribed medication. However, experience h as shown that Licensing Authorities have interpreted this in different ways and, following discussion w ith States it has been re vised to the following:

1.2.6.1.1 Recommendation

.— States should ensure that licence holders are aware of physical and mental conditions an d treatments that are relevant to flight safety. They should provide guidance concerning those circumstances wh en medically related information should be forwarded to the Licensing Authority

It is clearly important that licence holders are aware of those medical conditions that are relevant to flight safety, so that, when they have developed a medical condition, they know when to seek medical help, and when to cease flying. For example, cardiac disease is an important flight safety risk for all Licensing Authorities, although the degree of risk is likely to vary from State to State, depending on the prevalence

of such disease in different States. States should inform applicants of this potential risk to their medical fitness and to their health and Licensing Authorities may wish to place more or less emphasis on this aspect of fitness for holders of licences issued by thei r State. The same principle applies to certain infections, depending on the prevalence of such in fections in different parts of the world.

States can provide information concerning relevant physical and mental conditions in many ways. Examples include: internet website; information circul ar; medical examiner briefing. The most effective way(s) is likely to differ from State to State. A me dical examiner briefing may be effective and for Class 1 applicants under 40 years of age it is suggested that this could be formally included in the preventative and educative part of the medical assessment, as di scussed in other parts of the proposed amendment to

Annex 1.

For many conditions, modern medical practice has ch anged the length of time re quired in hospital, and some conditions that, in the past, involved a lengthy hospital stay, can now be dealt with very quickly, even as an outpatient. One State lists the following conditions (which are not exhaustive) as requiring advice from a designated medical examiner before a return to operations can be considered:

a) any surgical operation b) any medical investigation with abnormal results c) any regular use of medication d) any loss of consciousness e) kidney stone treatment by lithotripsy f) coronary angiography g) transient ischaemic attack h) abnormal heart rhythms including atrial fibrillation/flutter

In many instances of ill-health, a medical practitioner without any training in aviation medicine may be unable to provide a ppropriate advice to a licence holder rega rding fitness to fly. Any licence holder

should be aware of the action to take in the even t of suffering a common cold, without having to seek advice from a designated medical examiner unless there are complicating factors, but for more serious conditions advice concerning fitness to operate should be readily available from those with specialist knowledge, e.g. a designated medical examiner or the Licensing Authority headquarters. If a “temporarily unfit” assessment is made, the method for regaining fitn ess should be clear and, when fitness is regained, return to operations should not be unduly delayed. If a licence holder is affected by the circumstances- 16 -

such as those listed above, it is considered that they should be aware of the need to seek aviation medicine advice before exercising licence privileges.

— — — — — — — —

## HUMAN IMMUNODEFICIENCY VIRUS (HIV)

SUGGESTED PROTOCOL FOR AS SESSMENT OF HIV DISEASE

1. Following an initial diagnosis of HIV seropositivity

Assess temporarily unfit, pending submission of reports.

a) HIV Specialist Review

• History of infection • Current and previous symptoms • Stability of condition • History of opportunistic infections or associated illnesses • History of CD4+ T cell counts • History of Viral Load measurements • Medication history (including ‘over the counter ’ medications and alternative medicines) • Report concerning side effects of medications • Laboratory testing to include:

– Hepatitis B & C, Cytomegalovirus, toxoplasma, tuberculosis. – Full Blood Count, urea, creatinine and electrolytes, liver function tests, fasting glucose, lipids.

b) Neurology Review – can be undertaken by HIV specialist, or neurologist

Assessment for neurological sequelae. Include assessment of primitive reflexes (because of their association with cognitive decline)

c) Neuropsychological Review

• Baseline neuropsychological assessment. • Tests should include timed psychomotor t asks and memory tasks requiring attention, learning, active monitoring and retrieval of information.

d) Psychiatry Review

Assessment for psychiatric sequelae related to HIV seropositivity and antiretroviral treatment.

e) Cardiology Review (only if indicated)

Cardiological review is recommended if the following exist:

• Lipodystrophy or metabolic syndrome (dys lipidaemia — raised total cholesterol, low high density lipoprotein cholesterol and raised triglycerides or insulin resistance with hyperglycaemia);- 18 -

• Cardiac risk factors are present, including:

– hypertension, evidence of left ventricular hypertrophy, smoking, raised lipids, diabetes, age over 40 years.

2. Aeromedical Certificatory Assessment

On receipt of satisfactory reports, applicants who are asymptomatic, stable, without significant opportunistic infection may be considered for certificati on, if their CD4* count is above the minima stated below. Once diagnosed HIV positive, solo operation as a pilot should not be accepted for Class 1 or Class 2 applicants.

a) Table 1 — Applicants not established on combined antiretroviral therapy (cART)

Age (yr) Minimum CD4+ count

20 – 39 350

40 – 59 400

60 + 500

Applicants over 40 years of age with CD4+ counts below these levels but above 350/mm 3
may be considered for certification on an individual basis.

b) Table 2 Applicants established on co mbined antiretroviral therapy (cART)

CD4 Count > 350 = 0 201

− 350 = +0.62 51

− 200 = +1.46 ≤ 50 = +2.44

BMI ≤ 18 = +0.80 18.1

− 25 = 0 > 25 =

− 0.29

Viral Load < 500 = 0 ≥ 500 = +0.18 CD4 slope (3 month) <

− 25/mm 3 = +0.49

− 25 to +25/mm 3 = 0 > 25/mm 3 = +0.18

Anaemia No = 0 Hb > 14.0g/dl male Hb > 12.0g/dl female Mild = +0.68

Hb 8.01

− 14.0g/dl male

Hb 8.01

− 12.0g/dl female Severe = +1.02

Hb ≤ 8.0g/dl

ART experience prior to

cART Yes = 0 No =

− 0.39

Taking antiretrovirals Yes = 0 No = +1.24 Age Age × 0.027 Infected with HIV Via intravenous drug use = +0.25 Via any other route = 0 Prior diagnosis of AIDS at starting cART No = 0 Yes = +0.19

Score % Risk of clinical progression in following twelve months

<1.5 0.5

1.5 – 2.99 1.4

3.0 – 4.49 6.25

≥ 4.5 >20

Table 2 enables a risk assessment to be unde rtaken. The figures are summated to reach a score that allows a prediction of risk of progression during the next 12 months.- 19 -

Notes :

Acceptable medications include: abacavir, didanosin e, emtricitabine, lamivudine, tenofovir, zidovudine, atazanavir, fosamprenavir, lopinavir/ ritonavir, ne lfinavir, saquinavir, nevirapine and efavirenz

Unacceptable medications include enfuvirtid e, zalcitabine, indinavir and stavudine.

Recently available medication, e.g. tipranavir, darunavi r, raltegravir and maraviroc, may be acceptable on

an individual basis. Particular atte ntion needs to be given to the toxicity and side-effect profile of such

medications.

A “temporary unfit” assessment should be made when in itiating, modifying or discontinuing ART. When stable, recertification after 3 months of monitoring may be permitted providing that there has been an acceptable serological response, no ongoing side-effect s and FBC, LFTs, lipids and fasting glucose are acceptable.

Those commencing or modifying efav irenz treatment require a psychiatric and neurological examination at initial certification or within 6 months after initiating therapy.

Reviews should take account of any over the counter medications and alternative therapies being taken

3. Follow-up

Regular follow-up is required, to include:

• 3 monthly CD4 * and viral load measurements • 6 monthly neurology assessment (by HIV specialis t or neurologist including consideration of the need for psychiatric evaluation) • if taking ART: 6-monthly LFTs, FBC, lipids and fasting glucose. • Annual cognitive function assessment

– Evidence of having passed a Licence Profic iency Check (LPC) or the report from a medical flight test (MFT) with a Flight Inst ructor Examiner (FIE) may be considered in lieu of this where disease stability and th e risk of disease progression is acceptable. Impaired performance will require further ne uropsychological assessment to be compared with baseline testing and any deficits will requi re that the pilot is declared temporarily unfit. Neuropsychological assessment should be undertaken if there are any clinical concerns about cognitive impairment.

Further co-infection testing should be undertaken where clinically indicated and those with new positive tests must be deferred for further assessment.

If an applicant develops new symptoms and/or fails to achieve the nominal levels listed above * he must be declared temporarily unfit and referred to the Licensing Authority.

* CD4+ T cell counts are subject to substantial variability due to both biological and laboratory methodologies and can vary up to 30 per cent on repeated measures in the absence of a change in clin ical status. Therefore it is important to monitor trends over time rather than take a decision on one specific determination. Sudden changes in the count need to be confirmed by a second determination.- 20 -

References :

1. Table 1 is derived from Phillips A. CASCADE Colla boration. Short-term risk of AIDS according

to current CD4 cell count and viral load in antir etroviral drug-naive individuals and those treated in the monotherapy era. AIDS 2004 Jan 2. 18(1):51-8 and from the WHO guidelines on initiating

ART.

2. Table 2 is derived from Mocroft A, Ledergerber B, Zilmer K, Kirk O, Hirschel B, Viard J-P, Reiss P, Francioli P, Lazzarin A, Machala L, Phillips A, Lundgren J; for the EuroSIDA study group and the Swiss HIV Cohort Study Short-term clinical disease progression in HIV-1-positive patients taking combination antiretroviral therapy: the EuroSIDA risk-score. AIDS. 21(14):1867- 1875, September 2007.- 21 -

II. REVISED DRAFT OF CHAPTER ON HIV CONTAINED IN DOC 8984

(Note.

—This is a revised draft of the current chapter on HIV, part of Doc 8984 (Manual of Civil
Aviation Medicine) , that is currently available in draft form on the ICAO public website)

1. Introduction

In the introductory chapters of this manual the b asic principles for the assessment of an applicant’s

medical fitness for aviation duties are outlined. In the general medical provisions of Annex 1 th e SARPs related to Human Immunodeficiency Virus (HIV) are the same for all three classes of medical assessment (medical certification) – commercial pilots, private pilots, and air traffic controllers – and state that:

6.3.2.20.1 Applicants who are seropositive for human immunodeficiency virus (HIV) shall be assessed as unfit unless full investigation provi des no evidence of HIV-associated disease that might give rise to incapacitating symptoms.

Note 1.— Early diagnosis and active management of HIV disease with antiretroviral therapy reduces morbidity and improves prognosis and t hus increases the likelihood of a fit assessment.

The main purpose of the guidance material contained in this section is assist with determining the requirements for a full investigation and risk assessme nt for disease that might lead to incapacitation in HIV-seropositive applicants.

2. Background

HIV infection is pandemic with cases reported from virtually every country. Untreated the infection usually leads to Acquired Immunodeficiency Synd rome (AIDS) with AIDS-defining opportunistic infections or associated illnesses. A 2007 report fr om UNAIDS/WHO estimated that 33.2 million people are living with HIV. There were 2.5 million new infec tions in 2007 with 1.7 million (68 per cent) of these occurring in sub-Saharan Africa and important increases in Eastern Europe and Central Asia, where there are some indications that infection rates have risen by more than 50 per cent since 2004. In 2006, 2.1 million people died of AIDS defining illnesses. The prevalence of HIV infection in pilots and air

traffic controllers is unknown.

3. Causative agent

In 1984, the human immunodeficiency virus type 1 (HIV-1) was discovered as the primary causative agent. In 1986, a second type of HIV, called HIV-2, was isolated from AIDS patients from West Africa.

Both HIV-1 and HIV-2 have the same modes of transmission and are associated with similar opportunistic infections and AIDS. In persons infect ed with HIV-2, immunodeficiency seems to develop more slowly and to be milder. HIV-2 infection is predominantly found in West Africa and there is less known about managing infection and predicting outcomes, than for HIV-1. Care is required therefore, with interpreting the information pr ovided in this chapter to determine fitness for certification of persons

with HIV-2 infection.- 22 -

The etiological agent is a retrovirus and the CD4+ T- lymphocyte is the primary target for HIV infection. The CD4+ T-lymphocyte coordinates a number of impor tant immunological functions, and a loss of these functions results in progressive impairment of the i mmune response. Studies of the natural history of HIV infection have documented a wide spectrum of disease manifestations, ranging from asymptomatic infection to life-threatening conditions characteri zed by severe immunodeficiency, serious opportunistic infections, and cancers. Other studies have shown a strong association between a decrease of the number of CD4+ T-lymphocytes and an increase of the risk and severity of opportunistic illnesses.

4. Transmission

HIV is transmitted by sexual contact (both homose xual and heterosexual), by blood and blood products, and by infected mothers to infants either intrapartu m, perinatally, or via breast milk. There is no evidence that HIV is transmitted by casual contact or by insects, such as mosquito bites. HIV has been demonstrated in seminal fluid, cervical smears, and vaginal fluid. In these it appears to concentrate where there are increased numbers of lymphocytes and monoc ytes in the fluid, as in genital inflammatory conditions. There are strong associations of HIV tran smission with a history of sexually transmitted diseases (STDs) and of HIV transmission with anal in tercourse. Although the virus can be identified from virtually any body fluid, there is no evidence that tran smission can occur via exposure to tears, sweat, and urine. There is no convincing evidence that saliva can easily transmit HIV infection, although occasional cases have been reported in which the victim was bitten by someone infected with HIV.

5. Course of HIV infection

The typical course of the HIV-infection in untreated patients is presented in Figure 1. After entrance of the virus in the host system, the CD4+ T cells (and to lesser extent cells of monocyte lineage) are the major targets of HIV infection.

In primary HIV infection, virus replication in CD4+ T cells intensifies prior to the initiation of an HIV-specific immune response, leading to a burst of viraemia and to rapid dissemination of virus to other lymphoid organs, brain, and other tissues. At that stage, 3-6 weeks after primary infection, 50-70 per cent of the patients experience an “acute retroviral syndrome” (acute HIV infection). The hallmark of acute infection is a high level HIV ribonucleic acid (RNA) or viral p24 antigen in conjunction with a negative HIV enzyme-linked immunosorbent assay (ELISA) test, negative or evolving Western blot test, and subsequent demonstration of full antibody seroconversion. Seroconversion typically occurs within 21-28 days after exposure (range 7 days to 12 months). The classic presentation of acute retrovi ral syndrome resembles a m ononucleosis-like illness, which is often mistaken for malaria in tropical settings. The most common symptoms include fever, fatigue, myalgia/arthralgia, pharyngitis, lymphadenopath y, rash, anorexia, non-sp ecific gastrointestinal complaints, and sometimes neurological symptoms. Sy mptoms spontaneously resolve in most patients.- 23 -

There is evidence that the persiste nce of the acute retroviral syndrome beyond 14 days, as well as a shorter incubation than 21 days, are predictors of a more rapid progression to AIDS. Significant viraemia persists for several weeks, and subs ides after 9-12 weeks to much lower le vels, while at the same time the level of CD4+ T cells increases after having reached its trough at about 6 weeks after infection (Fig. 1). During the period of peak viraemia, it is believed that HIV-specific immune responses begin to drive down the viral load until a “set point” between viral replication and immune pressure is reached. This occurs within the first 6-12 months following infec tion, and most HIV-researchers assume that the level of this set point is highly prognostic of the patient’s rate of progression to AIDS.

Once the infection has been established, the virus is never cleared completely from the body. A chronic infection develops that persists with varying degrees of virus repli cation. For adults in developed countries, the average time of progression to the clinical signs and symptoms of AIDS is approximately 10 years in the absence of antiretroviral therapy. Progr ession is markedly age-related, with older patients doing much worse than younger patients. Although the patients are asymptomatic during this period, in the majority of untreated cases viral load gra dually increases and CD4+ T cells gradually decrease, patients become symptomatic and clinically ill finally developing severe opportuni stic infections. Some (20 per cent) untreated persons de velop AIDS defining illnesses within 5 years of infection, whereas others (<5 per cent) have sustained long-term (>10 y ears) asymptomatic HIV infection without decline of

CD4+ T cell counts to <500/ μ L. Perhaps 2 per cent of untreated infected persons – often called “long-term non-progressors” – seem to be able to c ontain HIV replication to extremely low levels and

maintain stable CD4+ T cell counts within normal ra nge for lengthy periods (>12 years). The appearance of effective antiretroviral therapy, resulting in nea r-complete suppression of viral replication, has brought long-term delay of progression to AIDS defining illn esses and prevention of related conditions for many HIV-seropositive subjects in the developed world. These drugs also appear to significantly reduce the rate

of sexual and vertical transmission of the virus a nd are of importance in a population such as aircrew, who are highly mobile.

6. Clinical manifestations of HIV infection

The latency period (clinical latency period; Fig. 1) is characterized by large inter-individual variability in duration. Initial symptoms of HIV-related immunosuppression (Stage 2, mild symptom, in the WHO clinical staging classification) include herpes zoster , recurrent UTRIs and seborrhoeic dermatitis. Stage 3 denotes more advances symptoms and includes persistent oral candidiasis, oral hairy leukoplakia, severe weight loss or fever or chronic diarrhoea and sever e bacterial infections or pulmonary tuberculosis.

After a latency period, untreated HIV-positive indivi duals will develop WHO Stage 4 disease or an AIDS defining illnesses, which may be characterized by neuropsychiatric symptoms including dementia, cognitive or other psychological changes associated w ith HIV encephalopathy, opportunistic respiratory and central nervous system (CNS) infections, a nd diseases of the cardiovascular, gastrointestinal, hepatobiliary, kidney and genitourinary, and endocrin e system. The majority of neurological disorders will be HIV-associated dementia complex (HAD). Other neurological involvement includes myelopathies, peripheral neuropathies and myopathies, opportunistic infections, primary central nervous system lymphoma, and cerebrovascular diseases. More over, cognitive and psychiatric symptoms, visual changes, headache, seizures, dizzi ness, involuntary movements, gait disturbances, cranial neuropathies and focal deficits can impair safe functioning of HIV-positive pers onnel engaged in aviation duties.

Conditions included in the 1993 AIDS surveillance case definition are shown in Table 1.

Along with the four-level WHO clinical staging syst em for HIV disease, the Ce nters for Disease Control and Prevention (CDC) in the United States have also devised a classification system for HIV disease- 24 -

progression. This was linked with AIDS case de finition (which was as initially intended for epidemiological use as a surveillance tool) and allo ws only for a unidirectional progression through the categories from asymptomatic (Category A) to having an AIDS indicator condition (Category C). It is recognized now that some people can make a signi ficant recovery from AIDS defining illnesses and so the development of these illnesses is not necessarily an indicator of long-term unfitness for aeromedical certification. The WHO has recently modified the clini cal staging system to recognize that antiretroviral therapy will reverse disease progression and that sub sequent HIV-related events and clinical staging events can be used to guide decision ma king on when to switch to second-line ART.

Table 1.

— AIDS defining illnesses

Candidiasis of oesophagus, bronchi, trachea or lungs Cervical cancer, invasive Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (greater than 1 month duration) Cytomegalovirus disease (other than liver, spleen or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy (Dementia), HIV related Herpes simplex: chronic ulcer(s) (greater than 1 month duration); or bronchitis, pneumonitis or oesophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (greater than 1 month duration) Kaposi’s sarcoma Lymphoma, Burkitt’s (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary) Mycobacterium, other species or unidentifie d species, disseminated or extrapulmonary Pneumocystis carinii pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy Salmonella septicaemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV

7. Assessment of HIV and disease that might give rise to incapacitating symptoms

7.1 Current health

General examination

Besides specific screening for progression of the di sease and CNS involvement (described separately), HIV-positive applicants should be thoroughly screened to exclude any disqualifying condition. HIV and/or antiretroviral medication may also affect heart, respiratory system, liver, and metabolic functions and so the assessment should include haematological, cardiovascular, and pulmonary evaluation, liver and kidney function, and metabolic tests. Opportunistic in fections generally occur with advanced or severe disease and the physician should always pay attenti on to signs and symptoms of Stage 3 or Stage 4 disease, such as oral or oesophageal candida, pneumocystis carinii pneumonia, toxoplasmosis,- 25 -

cytomegaly, progressive multifocal leukoencephalopath y, tuberculosis, and f ungal infections. This especially applies for candida infections, which can be seen early in the course of HIV infection, heralding the onset of clinical immunodeficiency.

The following specific assessments are recommended:

a) Immunological status

Two laboratory tests are routinely used as surrogate markers of HIV disease progression to

determine indications for treatment and to monito r the efficacy of therapy. These are the CD4+ T cell count and plasma HIV RNA (or viral load).

CD4+ T cell count

.— The extent of immune system damage is indicated by the CD4+T cell count, which is a measure for disease status a nd can enhance the assessment of the risk of developing opportunistic infecti ons and other sequelae of HIV infection when used together with

viral load determinations. CD4+ T cell counts ar e subject to substantial variability due to both biological and laboratory methodologies and can va ry up to 30 per cent on repeated measures in the absence of a change in clinical status. Theref ore it is important to monitor trends over time and to repeat a test to confirm a value rather than take a decision on one specific determination. Sudden changes in the count need to be conf irmed by a second determination. The number of CD4+ cells varies diurnally, being higher in th e morning, increasing slightly with smoking and decreasing acutely with stress and with intercurre nt infection. A significant change between two tests (two standard deviations) is defined approx imately as more than a 30 per cent change of the count. For practical use, a decline in CD4+ T cells by 75/year is considered to indicate a higher risk for progression to AIDS, when the reference CD4+ T cell count is <500/ μ L. A CD4+ T cell

count of <200/ μ L is AIDS-defining even in the absen ce of any signs and symptoms of HIV

disease.

Viral load .— The rate of progression of HIV disease is predicted by the magnitude of active HIV replication, which is reflected by the viral load . Measurement of the viral load through the use of quantitative plasma HIV RNA assays permits as sessment of the relative risk of disease progression and time to death. However, plasma HIV RNA levels obtained within the first six months of HIV infection do not accurately predic t disease progression. In contrast, plasma HIV RNA levels stabilize after approximately six to nine months of initial HIV infection and the viral set point is considered predictive of s ubsequent disease progression. Immunizations and

intercurrent infections can lead to transien t elevations of plasma HIV RNA levels. Values obtained within 4 weeks of such episodes may not accurately reflect the actual plasma HIV RNA level. Two specimens should be obtained within on e to two weeks of each other and analyzed by the same quantitative method (e ither Branched DNA=bDNA, or Reverse Transcriptase Polymerase Chain Reaction=RT-PCR). Plasma HI V RNA assays are also used as the best measure of the activity of antiretroviral therapy. A viral load of <5000 copies/ml is considered low and provides evidence for non-progression of the disease. The minimal change in viral load considered to be statistically significant (2 st andard deviations) is a threefold or a 0.5 log 10 copies/ml change. For practical use, an increase by >20,000 copies/year is considered to indicate a higher risk of progression to AIDS.

b) Assessing co-infection

Hepatitis B and C are frequent co-infections in HIV-infected individuals. They can cause progressive liver disease especially in those recei ving anti-retroviral therapy. The progression of HIV infection appears to be slowed in people co -infected with Hepatitis G virus. Other sexually- 26 -

transmitted diseases such as syphilis should also be considered. Tuberculosis is the most common HIV associated opportunistic infection in deve loping countries, compared to pneumocystis pneumonia in industrialised countries. Cytomegalovi rus is the most frequent cause of retinitis in

advanced HIV infection. Other associated co-inf ections include Epstein-Barr virus, toxoplasma gondii (associated with multiple CNS lesions) and JC virus (named after the initials of the patient in whom it was first discovered) that cause progressive multifocal leukoencephalopathy, and cryptococcal meningitis, particularly in tropical countries.

c) Neurological assessment

The spread of HIV-1 into the CNS is known to occur early in the cour se of the infection. However, except for early HIV-associated mening itis (as part of an acute HIV seroconversion illness), the majority of nervous system complications of HIV in the CNS take years to appear. HIV-related neurological disorders may arise from infection, neoplasm, systemic metabolic derangement, antiretroviral therapy, or di rect HIV effects on the nervous system.

Several large-scale studies have shown that HIV- associated cognitive dysfunction is antedated by immunological (CD4+ T cell) decline. This findi ng is important when considering aeromedical

fitness.

During neurological examination, specific attenti on should be paid to extra-pyramidal signs, and ocular disorders such as dissociated nystagmu s, gaze-evoked nystagmus, impaired saccadic function, and smooth pursuit. Testing of primitive reflexes (glabellar, snout, Rossolimo, digital signs) should be part of the examination because they are associated with cognitive decline in HIV patients without overt neurological disease.

Most studies demonstrate that the risk of new-onset seizures in asymptomatic individuals is low. In the majority of cases, seizures in HIV-positiv e individuals are caused by disorders that generally occur in late stages of HIV-infec tion, such as encephalopathy, neoplasm, or opportunistic infections.

d) Cognitive function testing

HIV associated dementia (HAD), also known as AIDS dementia complex and HIV encephalopathy is a late complication of HIV disea se that occurs in those with very low CD4+ cell counts. Fortunately, HAD is very responsive to anti-retroviral therapy and has become uncommon in the developed world. In the developi ng world, more studies are required to enable

conclusions to be made on HAD. Since the in troduction of Highly Active Anti-Retroviral Therapy (HAART) in 1996 the incidence of HAD h as declined significantly by about 50 per cent compared to the early 1990s. Studies conducted in the pre-HAART era found that HAD was associated with increasing age, a diagnosis of AIDS and injection drug use. The majority of cases have presented with advanced immunosuppression w ith CD4+ counts <200. However more cases are presenting at higher CD4+ counts since the advent of HAART.

The clinical presentation in adults includes promin ent psychomotor slowing, deficits in learning, attention/working memory, speeded information pr ocessing, mental flexibility, and motor control. Neuropsychological testing can demonstrate deficits in these areas. Typically, HAD progresses slowly over several months, rather than being sudd en in onset, and those affected or their families describe a slowing of thought with loss of interest in activities previously enjoyed and a tendency to forget details. Less commonly, psychotic beha viour may be quite florid. Diagnosis of HAD can be made clinically, but MRI imaging or CT scanning should be considered to exclude- 27 -

opportunistic lesions. The scans may be normal in the presence of HAD but generally cerebral atrophy is present.

e) Mild neurocognitive impairment

It is difficult to come to a clear conclusion on the absolute risk a nd significance of mild neurocognitive impairment in asymptomatic HI V infected individuals. Whilst some studies comparing cognitive function in asymptomatic HIV positive persons and HIV negative persons find no difference others have detected a highe r frequency of cross-sectional neuropsychological test abnormalities than in seronegative controls. However, few have shown that these cognitive impairments are progressive, or predictive of la ter development of dementia. The clinical significance of new cognitive symptoms or test impairment in asymptomatic HIV infection is uncertain because the reported neuropsychological abnormalities do not necessarily affect every day function, may not progress, and in so me individuals may improve on retesting.

Where abnormalities have been detected they re late to timed psychomo tor tasks and memory tasks, which require attention, learning and active monitoring or retrieval of information. These may be assessed using trail making, digit sy mbol substitution, grooved pegboard and computerized reaction time tests. The development of sensitive a nd reliable neuropsychological test batteries now means that evolving neurocognitive impairment may be detected at a relatively early stage in individuals at risk of HIV dementia.

Under ideal circumstances every patient should receive baseline neuropsychological assessment when first diagnosed with HIV but there is no perf ect approach. Tests vary in their sensitivity and specificity, as well as the degree to which they are affected by other general factors such as age, education and cultural backgroun d, premorbid neurological disease, and alcohol and drug use, fatigue and constitutional sympto ms, and mood. This is a reason for assessing cognitive ability domains utilizing more than one test of each domain.

Overall neuropsychological assessment may be e nhanced by the results of functional assessment such as the Proficiency Checks that commercial pilo ts undertake in a flight simulator. This may be particularly useful where cognitive function tes ting has detected mild impairments of uncertain significance or instead of cognitive function testi ng in asymptomatic individuals who are at low risk of disease progression (see Risk of Progression).

f) Simulator checks

In general, simulator checks test two main abiliti es, which are: learned skills, e.g. controlling an aircraft after engine failure, flying an instrume nt approach with engine(s) failed, and decision making, e.g. choosing an appropriate course of action given more than one alternative, determining the cause of a malfunction from a given set of data. Most, if not all, of the identified types of neurocognitive deterioration can be identified by a well-designed simulator check. Controlling a twin-engine aircraft after an engine failure, following take-off and when flying an approach and go-around is a demanding psychomotor task and should be part of any routine simulator test. Memory tasks are also necess ary as a routine, but can be emphasized by the

airline medical officer in discussion with the trai ning captain. Tasks such as recall of six digits when changing frequencies can be required of the affected pilot, delegation to the second pilot should not be permitted, and conditio nal clearances (“after waypoint X, descend to flight level 120” can test longer term memory.- 28 -

It is vital to involve the operator’s training department when assessing a pilot who is returning to line flying after the diagnosis of HIV infecti on. Good communications should be established and

the airline’s medical adviser shoul d ensure that he or she is very familiar with the simulator environment and with the tasks required of pilots in routine checks. It is only if the medical adviser is knowledgeable of simulator tests, and mutual trust is established between the medical adviser and training department that the most benefit can be obtained from simulator checks. Any performance that is regarded as below averag e for that individual pilot should be seen as a cause for concern, and should require further assessment.

g) Psychiatric assessment

Although it is assumed to be uncommon that psychiatric symptoms are the first manifestations of CNS involvement, the psychiatric examination should address the potentially serious complications of infection with HIV. There is evidence that the averag e HIV infected person experiences at least transient difficulties following notification of HIV seropositivity. A study (in the pre-HAART era) among HIV-infected US milita ry personnel in 1993 showed that 17 per cent of the subjects had experienced serious suicidal ideation or behaviours since notification of seropositivity. Ten percent had a major mood diso rder and 5 per cent a psychoactive substance disorder. The knowledge of being seropositive per se may be a reason for (temporary) disqualification. The examiner should focus on si gns of depression, other mood disorders and use of psychoactive substance. A si milar study of military personnel does not appear to have been undertaken since the introduction of HAART, but there is evidence of a lower prevalence of mood disorders amongst those attending HIV outpatient clinics compared to the pre-HAART era.

Psychiatric symptoms may also be associated with medication, e.g. Efavirenz and assessment should be made after commencing this treatment a nd before considering a return to certification. Consideration should be given to psychiatric assessm ent, particularly at the first assessment after seroconversion, with subsequent review associated with clinical indication and the introduction of efavirenz in any HAART regimen.

h) Cardiological assessment

Lipodystrophy and a metabolic syndrome may arise as an interaction between HIV disease and/or immune recovery and antiretroviral medication. Th is may manifest as dyslipidaemia with raised total cholesterol, low HDL cholesterol and rai sed triglycerides or insulin resistance with hyperglycaemia. Cardiology review may be require d in the presence of these or other significant cardiac risk factors, e.g. hypertension, smoking, raised lipids, diabetes, age and evidence of left ventricular hypertrophy. Some antiretroviral medici nes are more likely to cause these side effects and expert consultation with a view to changing ART regimen is indicated.

i) Medication

The clinical effectiveness and tolerability of antiretroviral therapy has improved markedly over the last few years. Most regimens are patie nt-friendly with low pill burden and few dietary restrictions. Since 1996, there have been dramatic falls in the incidence of new AIDS cases and AIDS associated deaths in the developed world. Many (highly active) antiretroviral therapy regimens (HAART or ART) result in near-complete suppression of HIV-1 replication. For HIV-2 the picture is not quite so clear, as it is far less prevalent and there is limited clinical experience. Both the nucleoside reverse transcriptase inhibito rs (NRTI) and protease inhibitors (PI) classes of

ARV medicines are active but neither efaviren z nor nevirapine as, non-nucleoside reverse transcriptase inhibitors (NNRTI) are active against HIV-2.- 29 -

HAART does not cure HIV infection so once star ted life-long therapy is always necessary. Although complete eradication of the infection ca nnot be achieved, sustained inhibition of viral replication results in partial a nd often substantial reconstitution of the immune system in most patients, greatly reducing the risk of clinical disease progression.

Combination ART usually starts with 2 NRTI toge ther with a NNRTI as the first-line therapy. The PI class is usually reserved for second-line therapy. Some drugs are so similar or have synergistic toxic effects and so should not be combined. Expert opinion should always be sought. Adequate viral suppression for most patients on ther apy is defined as a reduction in viral load to

undetectable levels. There are cases in which adequate viral suppression may not be achieved despite appreciable increases in CD4 cell count. Increases in CD4 cell count in people with good virological control show an average increase of approximately 100 cells/mm 3 per year for subsequent few years until a threshold is reached , which in many patients may be within the normal range. However, successful outcomes have not been observed across all patients.

Problems encountered with HAART are drug resistan t virus, poor patient adherence, drug-drug interactions when treating co-infections like tuberc ulosis, and drug toxicity. In the beginning of the HAART era it was hoped that all HIV-seropositive persons would benefit from antiretroviral therapy. Nowadays, clinicians have consider able reservations about treating asymptomatic immunocompetent cases, because of the risk of ad verse drug effects, the challenge of long-term adherence and development of virus resistance.

In asymptomatic patients with HIV, decisions on when to start treatment are based on an assessment of the risk of disease progression over the medium term if treatment is not started (e.g. using data from the CASCADE collaboration – see section on “Risk of Progression”) versus the potential risks of starting treatment earlier (toxicity and resistance), and in any case always before the CD4+ lymphocyte count has fallen to below 200 cells/mm 3

.

In 2004 the Panel on Clinical Practices for Treatment of HIV Infection (convened by the Department of Health and Human Services, USA) published revised indications for antiretroviral therapy, which are shown in table 2. Similar cut-off values are used in guidelines in other industrialized countries. WHO recommendations, adopted by many low and middle-income countries are slightly more conservative and th e debate about early treatment with HAART vs. deferring until lower CD4+ counts are reached goes on.

When assessing aeromedical certification of persons on HAART, consideration must be given to aeromedically relevant adverse effects and clinic ians treating aviation pe rsonnel should be asked to carefully design treatment regimens to minimise these. Drugs that are likely to interfere with flight safety should be avoided e.g. indinavi r, which causes nephrolithiasis (with radiolucent stones), and with others specialist assessment ma y be required before deciding on certification, e.g. efavirenz, which may cause psychiatric symptoms.- 30 -

Table 2.— Indications for antiretroviral therapy
(Panel on Clinical Practices for Treatment of HIV Infection, 2004, USA)

1 Antiretroviral therapy is recommended for all patients with history of an
AIDS-defining illness or severe symptoms of HIV infection regardless of

CD4+ T cell count.

2 Antiretroviral therapy is also recommended for asymptomatic patients with

< 200 CD4+ T cells/ μ L.

3 Asymptomatic patients with CD 4+ T cell counts of 201-350 cell/ μ L should

be offered treatment.

4 For asymptomatic patients with CD4+ T cell of >350/ μ L and plasma HIV
RNA >100.000 copies/mL most experien ced clinicians defer therapy but
some clinicians may consider initiating treatment.

5 Therapy should be deferred for patient s with CD4+ T cell counts of >350

cells/ μ L and plasma HIV RNA < 100.000 copies/mL.

Only drugs that are licensed by national author ities will be acceptable. During the initiation of therapy and when adjustments are made to the regimen used, applicants should be assessed as temporarily unfit. Further assessment should then be made for side effects that are likely to be disabling after treatment is stable for a period of months, before any decision on certification is

made. Adverse effects of HAART include GI intolerability, drug hypersensitivity, Stevens-Johnston syndrome, cytochrome P450 inte ractions, CNS effects, myopathy, neuropathy, bone marrow depression, nausea, diarrhoea, fatigue , headache, hepatitis, hepatic steatosis, lactic acidosis, pancreatitis, dilated cardi omyopathy, renal colic, nephrolit hiasis, haematuria, abdominal pain, metabolic syndrome and lipodystrophy. There is considerable variability in the occurrence of adverse effects between drugs and between i ndividuals. Noteworthy is the occurrence of a lipodystrophy syndrome, characterized by a “buffalo hump” fat distribution, in 50 per cent of the cases. This syndrome is associated with aeromedic al risk factors, such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, and Ty pe 2 diabetes mellitus. Possible cognitive effects of HAART, relevant for flight safety, may be assessed with validated neuropsychological test batteries or a functional evaluation, e.g. simulato r check. A 1997 study showed no impairment of cognitive processes in patients treated with the NRTIs didanosine, or zi dovudine (monotherapy). Regular follow up is required to monitor treatment efficacy, ARV adherence, toxic side effects or evidence of drug resistance.

j) Other issues

Magnetic Resonance Imaging (MRI) can detect white matter abnormalities, high signal abnormalities in gray matter structures, and/or cerebral atrophy of HIV encephalopathy. However, such changes are relatively non-specifi c and the differentiation of different causes for

the abnormalities is difficult with conventiona l MRI. Significant improvements may come as functional imaging methods, such as perfusion im aging, magnetic resonance spectroscopy (MRS) and brain mapping with functional MRI become more widespread in clinical practice.- 31 -

Cerebrospinal Fluid (CSF) - Abnormalities of the CSF in HIV-associated dementia are generally non-specific, with mild elevations in protein and pleocytosis. It appears that HIV RNA levels in CSF correlate with the presence of cognitive impairment, although the precise relationship of HIV-1 RNA values in CSF and the risk of development or progression of neurological disease has not yet been determined. Even in patient s with neurological disease, CSF RNA levels are relatively low. The false-negative rate of C SF RNA values is high, and minor neurological dysfunction is often not associated with high CSF HIV RNA levels. CNS syphilis screening should be routinely performed with any CSF sample.

7.2 Risk of progression

In HIV-seropositive persons, the average latency peri od to developing AIDS is 10 years and without any therapy, survival of about 12 years. Treatment significantly extends survival and near normal life expectancy may even be possible with relatively non-t oxic and highly effective combination ART. During the latency period most HIV infected persons are asymptomatic and those engaged in aviation duties

would be able to continue their careers for several years (if the HIV diagnosis is made early on after infection) until therapy is started and for many years once HAART has been successfully commenced. However, some patients may present relatively late in the course of their infection and there is inter-individual variability in the rate of progression to symptomatic disease and then AIDS as well as in the occurrence of adverse effects of HAART. As symptomatic HIV-related disease including (subtle) cognitive impairment, AIDS-defining illnesses and sever al adverse effects of HAART are incompatible with aviation duties, prediction and early detectio n of cognitive involveme nt and/or AIDS-related symptoms and long-term monitoring for the adverse eff ects of treatment are essential for the aeromedical assessment of a HIV-seropositive appli cant. In the absence of HIV-related symptoms (including cognitive decline), aeromedical considerations could be aide d by risk assessment methods that use CD4+ T cell counts, viral load, and age.

Several large study groups have publishe d data that can be used in the assessment of the risk of disease progression for those who are treatment naïve and those who commenced therapy.

The Concerted Action on SeroConversion to AIDS a nd Death in Europe collaboration (CASCADE) have produced a Poisson regression model based on data of 5126 person-years of 3226 asymptomatic seropositive subjects who either had no treatment or monotherapy, to predict the 6-month risk of developing AIDS. This can be modified to give a 12-month risk (see Table 3).

For the assessment of individual cases, adverse trends in CD4+ and viral load levels and the applicant’s age should be taken into account.

For those who have already commenced HAART data from EuroSIDA or the Antiretroviral Therapy (ART) Cohort Collaboration can provide a basis for assessing the risk of disease progression. The former reports on the risk of clinical progression (diagnos is of a new AIDS defining illnesses or death). The scoring system is shown in Table 4. The ART Cohor t Collaboration found that 6 months after starting ART, the current CD4 count and viral load, but not the baseline values, are strongly associated with subsequent disease progression. The data presented by the collaboration is limited by its broad categories (although recent updates on their original publicatio n have improved this). The CDC category A and B (both asymptomatic individuals and those who have had symptoms of conditions attributed to or complicated by HIV infection) are included in one group and the age ranges divided into 4 groups. Their most recent study reports that the annual risk of developing a new AIDS defining illnesses during the first year after commencing HAART is around 1 per cent pe r annum for those whose 6 month CD4+ count is >=350, viral load is <500 and where HIV transmission was not by intravenous drug use, the person meets- 32 -

the criteria for CDC category A or B and aged 16-29yr and gradually decreases over the subsequent four years. A calculator can be found on their web site athttp://www.art-cohortcollaboration.org/6mhiv_form.html

Table 3.— Risk of developing AIDS in those who have had no treatment or monotherapy

Rate = exp{-3.55 + [-0.21 √ (CD4 cell count)] + 0.71 (log viral load) + 0.024(Age)}

12-month percentage risk of developing AIDS = [1 – exp(-1Rate)] x 100%

exp = exponential function

CD4 cell count = count x 10 6 cells/l
log = logarithm
viral load = copies/ml
Age = age in years

Example : A 25 year old pilot with CD4+ cell count of 450 and viral load of 5000 will have a 12-month risk of developing AIDS of 0.84 per cent.

Rate = exp {-3.55 + [-0.21 x √ 450] + [0.71 x log5000]+ [0.024 x 25]} = 0.008

12-month percentage risk of developing AIDS = [1 – exp(-1 x 0.008 )] x 100% = 0.84%

A pilot aged 50yr with the same serological measurements would have a 12-month risk of developing AIDS of 1.52 per cent.

Derived from Phillips A. CASCADE Collaboration . Short-term risk of AIDS according

to current CD4 cell count and viral load in antiretroviral drug-naive individuals and those treated in the monotherapy era. AIDS 2004 Jan 2. 18(1):51-8.

Table 4.— Risk of Clinical Progression in those being treated with combination Anti-Retroviral Therapy (cART) CD4 Count (/mm 3 ) >350 = 0 201

− 350 = +0.62 51

− 200 = +1.46 ≤ 50 = +2.44 Body Mass Index ≤ 18 = +0.80 18.1

− 25 = 0 >25 =

− 0.29

Viral Load (copies/ml) <500 = 0 ≥ 500 = +0.18

CD4 slope (3 month) <

− 25/mm 3 = +0.49

− 25 to +25/mm 3 = 0 >25/mm 3 = +0.18

Anaemia No = 0 Hb >14.0g/dl male Hb >12.0g/dl female Mild = +0.68

Hb 8.01

− 14.0g/dl male

Hb 8.01

− 12.0g/dl female Severe = +1.02

Hb ≤ 8.0g/dl

Retroviral treatment prior to cART Yes = 0 No =

− 0.39- 33 -

Currently taking

antiretrovirals Yes = 0 No = +1.24

Age Age × 0.024

Total Score % Risk of Clinical Progression in following 12 months (95% CI)

<1.5 0.50

1.5

− 2.99 1.40

3.0

− 4.49 6.25

≥ 4.5 ≥ 20.00

Example : 30yr old who has had no previous anti-retroviral therapy prior to cART, whose current CD4 count is 400, viral load 50, BMI 22 and no anaemia. Their CD4 slope increased by 15/mm 3 in the last three months and they are currently taking cART. Total score is 0.38 and therefore their risk of progression for next 12 months is 0.66 per cent.

(Data from Mocroft A, Ledergerber B, Zilmer K, Kirk O, Hirschel B, Viard J-P, Reiss P, Francioli P, Lazzarin A, Machala L, Phillips A, Lundgren J; for the EuroSI DA study group and the Swiss HIV Cohort Study Short-term clinical disease progression in HIV-1-positive pati ents taking combination antiretroviral therapy: the

EuroSIDA risk-score. AIDS. 21(14):1867-1875, September 2007)

Both these studies indicate that the lowest risk of progression in the most favourable groups is about 0.7 to 1.0 per cent per annum (but not significantl y less than 1 per cent) after commencing HAART. The populations used in these studies are predominantly Western European, Israeli and Australian and so caution may be required when applying the data to pilots from out with these regions. In addition the socioeconomic groups of pilots and air traffic controllers may differ from the study populations.

It is recommended that CD4+ T cell count and viral load levels should be determined every three to four months and that clinical condition, including gene ral, neurological and, if indicated, psychiatric examinations should be assessed every six months. A neuropsychological evaluation may be considered every twelve months. Regular assessment of cockpit pe rformance may be considered in lieu of this or to enhance assessment in asymptomatic, stable applic ants with very low risk of progression. Further co-infection testing will be required where clinically indicated and those with new positive tests may require specialist evaluation prior to further certificatory assessment.

Clearly not every individual with HIV infection will be fit for certification. However, some applicants may be fit and remain so for a prolonged period and it is to assist in the identification of such individuals that the information in this chapter is written. The assessment of HIV-positive applicants requires specialist expertise and careful consideration of all the points mentioned in this chapter and applicants

need to be advised at the outset that continued certification will require ongoing medical scrutiny and prolonged follow-up.

8. Asymptomatic HIV positive cases and travel vaccination

Vaccinations can temporarily increase the viral lo ad for approximately four weeks. As a rule, immune-compromised people should not receive vaccin es based on live-attenuated organisms, such as measles and yellow fever. However, risk is not in creased in true asymptomatic and immuno-competent cases, confirmed by a sufficient CD4+ T cell level (> 350/ μ L) and these cases will have a normal response of the immunological system to these vaccinations.

— — — — — — — —

## INSULIN-TREATED DIABETES

GUIDANCE FOR CERTIFICATION OF AIRCREW WITH

INSULIN TREATED DIABETES MELLITUS

This guidance should be used in conjunction with the Manual of Civil Aviation Medicine (Doc 8984, Chapter 4) and Annex 1 (below) — Risk Analysis and Literature Review.

1. Introduction

Several Contracting States permit a pplicants having insulin treated diab etes to exercise the privileges of their licence. The purpose of this guid ance material is to provide a protocol that will enable other States to consider such applicants under the flexibility Standard in Annex 1 — Personnel Licensing

, paragraph 1.2.4.8. The key areas of concern in certi ficating aircrew with insulin treated diabetes mellitus are hypoglycaemia and the enhanced risks of micro and macrovascular disease. In the paragraphs that follow, the focus will be on the risks of hypoglycaemi a, but the protocol at the end of the section will

include an assessment of cardiovascular risk.

2. Hypoglycaemia

Achieving and sustaining near normal glycaemia is a central target in the management of patients with both Type 1 and Type 2 diabetes mellitus whose micr ovascular complications ar e then reduced 1, 2. However, the clinical consequence of improving gl ycaemic control is an increase in the frequency of hypoglycaemia 2, 3 which is a concern in the risk assessment of diabetic aircrew. The relative risk of severe hypoglycaemia (requiring the assistance of anothe r) is greater for intensively treated (to achieve lower HbA1C levels) patients with Type 1 diabetes (about 27 per cent per year according to the Disease Control and Complications Trial [DCCT]) 3 than for t hose with Type 2 (2 per cent per year according to the UK Prospective Diabetes Study [UKPDS]) 2 despite similar glycaemic control.

Several factors may explain why patients with Type 2 diabetes are less prone to severe hypoglycaemia. Normally, as plasma glucose concentrations fall, there is a hierarchy of defense responses. The first is an increase in the release of counter-regulatory horm ones as plasma glucose falls to approximately 3.8 mmol/L which is designed to prevent glucose c oncentrations from falling further. The second is an awareness of warning symptoms, predominantly autonomic (sweating, hunger, anxiety, tachycardia, etc.), which begin as plasma concentration decreases to a pproximately 3.4 mmol/L. In patients well educated in diabetic management, such symptoms will prompt preventative steps, i.e. ingestion of carbohydrate, which will prevent neuroglycopaenia, whic h commences at approximately 3.0 mmol/L.

In people who have had Type 1 diabetes for over fi ve years, counter-regulatory hormone responses to hypoglycaemia are generally impaired. Initially, most patients lose their glucagon response to hypoglycaemia, thereby becoming dependent on catecholamine responses to prevent or reverse hypoglycaemia. Sometimes even that response become s impaired and the risk of severe hypoglycaemia increases several fold. Additionally, episodes of mild hypoglycaemia, even if symptomless, can further impair glucose counter regulation and may reduce ß-adrenergic sensitivity leading to a situation of “hypoglycaemic unawareness”. In this situation, patients may not recognize impending hypoglycaemia until it is too late to institute preventative measures (Ger ich J F) 4. The situation is somewhat different in Type 2 diabetes; firstly, although glucagon respons es are commonly impaired, catecholamine responses are usually normal or increased. Secondly, the patient s are insulin resistant and thirdly, they have persistent ß-cell function. The ability to modulate in sulin secretion can act as a buffer, since endogenous insulin secretion will decrease as plasma glucose falls. Th is opportunity is not available in Type 1 patients- 36 -

whose insulin availability is pre-determined by th e amount already injected. Fourthly, most Type 2 patients are not on intensive insulin regimes so they are less at risk of hypoglycaemic unawareness as a result of insulin induced hypoglycaemia.

This differing rate of hypoglycaemia has been confirmed recently by Heller et. al. (5) who found no differences in the rate of severe hypoglycaemia in T ype 2 diabetic patients trea ted with sulfonylureas or insulin for less than 2 years (0.1 and 0.2 episodes pe r subject – year) and this frequency was far less than that encountered in Type 1 diabetes (< 5 years 1.1; > 15 years 3.2 episodes per subject – year).

From a number of studies including Akram et. al. (6) , the risk factors for severe hypoglycaemia include previous hypoglycaemia, long duration of diabetes and impaired hypoglycaemic awareness.

3. Protocol

From the literature review, the risk of hypoglycaemia in Type 1 diabetes is outside that which would be acceptable in terms of the “1 per cent rule”. States using different risk criteria should make their own

assessment of risk.

For aircrew with Type 2 diabetes, whether taking insu lin or not, individuals should be at low risk of hypoglycaemia. What follows is a cautious protocol that may assist States to determine fitness in applicants who present with Type 2 diabetes. It pr ovides guidance and may be adjusted by individual States to suit their own requirements.

4. Initial assessment

• Stimulated C-peptide levels * > 25 per cent of normal;

• No previous hypoglycaemic episodes requiring the intervention of another person;

• Stable blood glucose control: satisfactory HbA1C ~ 7 – 8 per cent;

• Adequate self-monitoring with a memory chip glucose meter;

• No evidence of hypoglycaemic unawareness;

• Good diabetes education and understanding;

• Positive attitude to monitoring and self-care.

An annual assessment may include:

• Review of adequate self-monitoring with a glucose meter;

• Review of blood glucose control with satisfactory, stable HbA1C;

• Report from the treating physician to confirm no complications of diabetes, including renal and visual complications;

* C-peptide is an indicator of beta cell activity. Most Type 1 diabetics are C-peptide negative.- 37 -

• Annual cardiovascular assessment such as a sy mptom limited exercise ECG and clinical review by a cardiologist.

Follow-up should be agreed jointly between the treating physician and the medical assessor.

This approach could be extended to encompass pilots and air traffic control officers with Type 2 diabetes on sulphonylureas as well as those on insulin. This would avoid any period of unfitness on sulphonylureas with the resultant potential degradation in training.

5. References

1. The Diabetes Control and Complications Trial Re search Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993; 329: 977-86.

2. UK Prospective Diabetes Study (UKPDS) Gr oup. Intensive blood-glucose control with sulphonylureas or insulin compared with conven tional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-53.

3. The DCCT Research Group. Hypoglycaemia in the diabetes control and complications trial. Diabetes 1997; 46: 271-86.

4. Gerich J F. Hypoglycaemia and counter re gulation in type 2 diabetes. Lancet 2000; 356:

1946-47.

5. Heller S. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50(6): 1140-7.

6. Akram K, Pedersen-Bjergaard U, Carstensen B et al. Frequency and risk factors of severe hypoglycaemia in insulin-treated Type 2 diabetes: a cross-sectional survey. Diabetic Medicine 2006; 23: 750-6.- 39 -

ANNEX 1

INSULIN TREATED DIABETIC AIRCREW

1. Risk analysis and literature review

Any risk assessment requires a review of the litera ture looking at the prevalence of hypoglycaemia in insulin treated diabetes mellitus and the applicati on of clinical judgement as to whether one can extrapolate population data to individual cases. It is proposed to discuss the rate of hypoglycaemia firstly in Type 1 diabetes and secondly review the differing rates in Type 2.

It is very difficult to assess the frequency of hy poglycaemia in insulin treated diabetic populations because of the wide variation of severity and outcome. For example, the common occurrence of asymptomatic biochemical hypoglycaemia that is onl y evident if blood glucose is measured frequently and the failure to recognize or record many mild episodes including those occurring during sleep. However, a critical review of the medical literature on the subject provides some data on which to base a risk assessment. Since the publicati on of the Diabetes Control and Complication Trial {DCCT} (1993) in Type 1 diabetes which showed that tight diabetic co ntrol could assist in the prevention of complications, diabetic physicians have striven to improve overall control. However, this study showed an approximate three-fold increase in prevalence of severe hypoglyc aemia in the intensively treated group compared to that of the conventionally treated (0.54 v 0.17 episodes/patient/year). An analysis of the cumulative incidence of successive episodes indicated that intens ive treatment was also associated with an increased risk of multiple episodes within the same patient (e.g . 22 per cent experienced five or more episodes of severe hypoglycaemia within five years of follow-up v 4 per cent in the conventional group). Several sub-groups defined by baseline characteristics, in cluding males, adolescents and subjects with no C-peptide or with a prior history of hypoglycaemia had a particularly high risk of severe hypoglycaemia in both treatment groups. Ward and colleagues (1990) found in an out-patient study of 158 patients in Auckland that almost all, 98 per cent, had experien ced hypoglycaemic episodes and for 30 per cent these were a major problem. These symptoms of hypoglycaemia, which represent a combination of neuroglycopaenia and autonomic neural stimulation, would be likely to degrade pilot performance. In theory this may be modulated by good hypoglycae mic awareness and adequate early correction. The adverse effects of hypoglycaemia on cognitive function, in Type 1 diabetes, have been studied by Holmes (1983, 1986), Pramming (1986) and Herold (1985). C ox and colleagues (1993) studied this problem in a driving simulator and found that the degradation in performance was not reliably recognized by subjects, none of whom had lost hypoglycaemic awareness. In practice, therefore, it would be unacceptable for a pilot to experience a hypoglycaemic episode in flig ht where a lack of hypocglycaemic awareness would present a risk to the safety of the flight.

The risk of severe hypoglycaemia with intensive insu lin therapy was further explored in a study by Bott and colleagues (1997) in 636 insulin dependent diab etics. The incidences of severe hypoglycaemia between participants in the study varied between 0. 05 and 0.27 cases per patient per year. In particular, the authors sought to find a relationship between a level of haemoglobin A1 wh ich could predict severe hypoglycaemia but there was no linear or exponential relationship.

More recently Egger and colleagues (1997) performed a meta-analysis of 14 trials which contributed to 16 comparisons of 1028 patients with Type 1 diabetes allocated to intensive in sulin treatment and 1039

allocated to conventional treatment. The authors found a substantial risk of adverse effects associated

with intensive insulin treatment which included an excess of severe hypoglycaemia confirming that the- 40 -

findings noted in the DCCT (1991) were not excepti onal, but commented that multiple daily injection schemes may be safer than treatment with insulin pumps.

Having accepted that there is evidence in the literature that intensive insulin regimens increase the rate of hypoglycaemia, it is logical to postulate how one might predict the frequency of such hypoglycaemic episodes and perhaps prevent them.

Cox and colleagues (1994) studied 78 insulin de pendent subjects with diabetes mellitus from two different sites performing self-monitoring of blood glucose. Over the following six-month period these subjects recorded their severe hypoglycaemic episodes (stupor or unconsciousness). There was no difference in the number of severe hypoglycaemic ep isodes between the subjects in good versus poor metabolic control. The higher frequency of severe hy poglycaemia during the subsequent six months of follow-up was predicted by frequent and extreme lo w self-monitoring blood glucose readings and the variability in the day-to-day readings of the blood gl ucose. Regression analysis indicated that 44 per cent of the variance in severe hypoglycaemic episodes could be accounted for by initial measures of blood glucose variance and the extent of low blood gluco se readings. Individuals who had lower haemoglobin A1 levels were not at a higher risk of severe hyp oglycaemic episodes and thus blood glucose variability and low blood glucose readings were good predictors of severe hypoglycaemia.

Casparie (1985) found that one of the causes of hypoglycaemia in a study of 32 severe hypoglycaemic episodes in 26 patients (a patient per year incidence of 8 per cent) was often a lack of alertness or carelessness in calculating the insu lin dose. The author felt that by teaching patients to respond more adequately to changing circumstances in daily life a nd to react to warning signs by appropriate action would also reduce the incidence of hypoglycaemia. The difficulty in predicting hypoglycaemic episodes in an individual patient was highlighted by Gol dgewitch and colleagues (1983) when they found that emotional factors were often given as a cause of hypo glycaemia but in 11 per cent of cases there were no obvious reasons for the hypoglycaemic attacks in spite of the appropriate management of their diabetic

control.

Ter Braak and colleagues (2000) carried out a retros pective study of 195 consecutive cases with Type 1 diabetes to ascertain frequency of sever e hypoglycaemia and found this to be 150 episodes per 100 patient years and occurred in 40.5 per cent of the study popula tion. The clinical characteristics which predisposed to hypoglycaemic coma were the presence of neuropathy , coincident treatment with beta blocking agents

and the use of alcohol. These three observations were controlled to adjust for duration of diabetes, which is also a significant predictor of hypoglycaemia.

The data on mild hypoglycaemia are more variable and it is difficult to obtain accurate estimates. However, Pramming (1991) studied the frequency of the symptomatic hypoglycaemic episodes in 411 randomly selected Type 1 diabetic outpatients. From questionnaire analysis the retrospective frequencies of mild and severe hypoglycaemia were 1.6 and 0. 029 episodes per patient per week. From the patient diaries prospective frequencies of mild and sever e hypoglycaemic episodes were 1.8 and 0.027 episodes per patient per week. Interestingly, symptomatic hy poglycaemia was more frequent on working days than during weekends (1.8:1) and more frequent in the mo rning than during the afternoon, evening and night (4.5: 2.2: 1.4:1). Importantly, the symptoms of hypoglycaemia were somewhat non-specific, heterogeneous, and weakened with increasing duration of diabetes. These data are congruent with other data in the literature suggesting that hypoglycaemic unawareness increases with duration of diabetes and, of course, the duration of diabetes is also a predictor of hypoglycaemia.

The basic pathology in Type I diabetes is islet cell failure and that of Type 2 diabetes is of insulin resistance. It is, therefore, inappropriate to transpose hypoglycaemic frequency data from Type 1 individuals to Type 2.- 41 -

MacLeod and colleagues (1992) studied the frequency of severe hypoglycaemia in 600 randomly selected patients with insulin treated diabetes attending a large diabetic outpatient clinic . 175 (29.2 per cent) of the 600 patients reported a total 964 episodes of sever e hypoglycaemia in the preceding year giving an overall frequency of the group of 1.6 episodes per patient per year. Interestingly, the frequency of severe hypoglycaemia in Type 1 diabetics was almost double th at of Type 2 diabetics being treated with insulin (1.7 v 0.73 episodes per patient per year).

This differing rate of hypoglycaemia has been conf irmed recently by Heller et al (2007) who found no differences in the rate of severe hypoglycaemia in T ype 2 diabetic patients trea ted with sulfonylureas or insulin for less than 2 years (0.1 and 0.2 episodes per subject – year) and this frequency is far less than that encountered in Type 1 diabetes (< 5 years 1.1; > 15 years 3.2 episodes per subject – year).

This finding of a lower average rate of hypogly caemia in Type 2 diabetes was noted by Wright and colleagues (2002) in the United Kingdom Prospective Di abetic Study (UK PDS 57) who found the rate of severe hypoglycaemia in Type 2 diabetics treated with insulin alone was 3.2 per cent per annum and 1.6 per cent per annum in those who were treated w ith clorpropramide or glycazide with or without insulin. Cryer (2002) in a review of the literature also suggested that the risk of serious hypoglycaemia is much less in Type 2 diabetes, even in patient s treated intensively as judged by HbA1c levels.

2. Estimation of incapacitation risk

Using the data from this literature review, the rate of severe hypoglycaemia, i.e. hypoglycaemia requiring the help of another in Type 2 diabetes treated with insulin, is of the order of 3 per cent per annum. These data, however, do come from hosp ital populations and the pilot group are highly selected, well motivated and meticulous in managing their diabetes. By selecti ng those with Type 2 diabetes who have a low risk of hypoglycaemia the figure may be less. Using this extrapolation one may estimate the rate to be between 1 and 2 per cent per annum.

4. Risk of subtle impairment of performance

Data to estimate this prevalence are rather difficult to obtain and frequently not robust but from the study of Pramming (1991) one may postulate using the wo rk of McLeod (1992) that the rate of mild hypoglycaemia may be 50 per cent less in Type 2 diab etics than Type 1, giving a figure of approximately 0.85 episodes/patient/week. This may be due in part to the preservation of the glucose counter regulation mechanism which may protect against pr ogression to severe hypoglycaemia.

5. Selection criteria

On the basis of the literature review it would be appropriate in the first instance to look at Type 2 diabetes which would appear to have a lower prevalence of hypoglycaemia. For Class 1 professional pilots the certification category should be limited to a multicre w operation. What follows are the selection criteria used by one Contracting State.

• No hypoglycaemic episodes requiring the intervention of another party during the previous five years. In Type 2 diabetes it is reasona ble to reduce this period to six months

• Stability of blood glucose control in the year prior to certification as measured by glycosylated haemoglobin which should be less than twice the upper limit of normal for the laboratory assay. 90 per cent of blood glucose levels should be greater than 5.5 mmol/L. The individual should have good diabetic educa tion and be well motivated to achieve good- 42 -

control. There should be no evidence of hypoglycaemic unawareness and the individual should fall into the “low risk group of hypo glycaemia” shown in Table 1. In addition they should be regularly monitored by their diabetic specialist to exclude any complications. Specifically, with the increased incidence of cor onary heart disease in Type 2 diabetics, there

should be a cardiovascular assessment to include , for example, an annual exercise ECG to mitigate against the cardiovascular risk.

Table 1


# Hypoglycaemia Risk Among

Insulin users

• Stimulated C-Peptide levels > 25% of normal • No previous hypoglycaemic reactions requiring the intervention of another

person. • Stable blood glucose control as measured by: (a) Glycated Hb (Patient /upper lab normal ratio <2.0. (b) 90% of blood glucose measurements >5.5 mmol.L. • Adequate self monitoring with a memory chip glucose meter. • Good diabetes education and understanding. • No evidence of hypoglycaemia unawareness • Positive attitude to monitoring and self care.

C-peptide is an indicator of beta cell activity Most Type 1 diabetics are C-peptide negative 

### Low Risk

6. Risk benefit analysis

The benefit to aviation of introducing this protocol w ould be to maintain individuals in the flight deck environment who have a wealth of experience as the majority of Type 2 diabetics present with oral hypoglycaemic failure between 40 and 50 years. Indi viduals in this age group have excellent flying experience and arguably may be safer than those more junior individuals without such. By selecting Type 2 diabetics who are already professional pilots and returning them to the flight deck with a

multicrew limitation the risk is further reduced due to the incapacitation training that commercial pilots are required to undertake when operating on two-pilot flig ht decks. This risk can be further mitigated by a stipulation that the pilot must inform their colleagues on the flight deck of the nature of their multicrew

endorsement and instruct them in actions should mild or severe hypoglycaemic events occur. In any long haul operation there is ample time to check blood sugar levels at regular intervals and the availability of carbohydrate is not a problem. In a short haul opera tion it is unlikely that the blood sugar will change dramatically over a one to two hour period but at the midpoint of the flight monitoring should be carried out. Using these interventions this approach h as potential benefit to the aviation industry.- 43 -

7. Monitoring procedures

It is essential that individuals who are accepted for th is approach use a glucometer which is regularly calibrated and has a memory chip. The individual must carry a supply of 10 g portions of readily absorbable carbohydrate to cover the duration of the flight. Prior to the flight the blood glucose must be greater than 6.0 mmol/L. During the flight the blood glucose should be monitored every 30-60 minutes, and if the blood glucose falls below 6.0 mmol/L then a 10 g carbohydrate portion should be ingested. If, for operational reasons, the inflight blood glucose measu rement cannot be done then 10 g of carbohydrate should be ingested. The frequency of monitoring on flights/duty periods over two hours may be reduced depending on individual circumstances, in consulta tion with the diabetologist and aviation medicine specialist.

Blood glucose should be measured a pproximately 30-45 minutes prior to landing and if the blood glucose has fallen below 6.0 mmol/L, 10 g of carbohydrate should be consumed. With modern diabetic management involving prandial bolus injections of insu lin, it is reasonable on long haul flights to have the diabetic pilot inject at appropriate times. In flight s over 8 hours it is likely that the aircraft will carry “heavy crew” and thus this should not present a signifi cant problem. If, despite this approach, the blood glucose exceeds 15 mmol/L then the individual should arrange for medical advice in order that corrective therapeutic measures may occur.

8. End points for terminating

This approach balances risk and be nefit, but should event rates exceed those experienced in the literature and stated above, consideration shoul d be given to discontinuing it. Any significant hypoglycaemia, i.e. requiring the help of another, which has caused any po tential impact on flight safety would again result in close scrutiny with a view to terminating this approach.

The approach is highly specific and an estimate of the numbers likely to be included is difficult. However, in the UK approximately 1-2 professional pilots/20,000 per annum show oral hypoglycaemic failure and it is likely that similar numbers may occur w ithin the jurisdiction of other Authorities. This is similar to the rate experienced by another Contrac ting State which permits pilots on insulin to fly.

9. Acknowledgements

Dr. Hugh O’Neill, Transport Canada Dr. Warren Silberman, FAA.

10. References

Berger M, Mühlhauser I. Implementation of Intens ified insulin therapy: a European perspective. Diabetic Medicine 1995; 12: 201 – 8.

Björk E, Palmer M, Schwarcz E et al. Incidence of severe hypoglycaemia in an unselected population of patients with insulin-treated diabetes mellitus, with sp ecial reference to autonomic neuropathy. Diabetes Nutrition and Metabolism 1990; 4:

303 – 9.

Bott S, Bott U, Berger M et al. Intensified in sulin therapy and the risk of severe hypoglycaemia. Diabetologia 1997; 40: 926 –32.- 44 -

Casparie AE, Elving LD. Severe hypoglycaemia in di abetic patients: Frequency, causes, prevention. Diabetes Care 1985; 8: 141 – 5.

Cox DL, Kovatchev BP, Julian DM et al. Frequenc y of severe hypoglycaemia in insulin-dependent diabetes mellitus can be predicted from self-monito ring blood glucose data. Journal of Clinical Endocrinology and Metabolism 1994; 79(6):

1659 – 1662.

Cryer PE, Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type 2 diabetes. Diabetologia 2002; 45: 937– 48.

Egger M, Davy Smith G, Stettler C et al. Risk of adverse effects of intensified treatment in insulindependent Diabetes Mellitus. Di abetic Medicine 1997; 14:

919 - 28.

Gold AE, MacLeod KM, Frier BM. Frequency of sever e hypoglycaemia in patients with type 1 diabetes with impaired awareness of hypoglycaemia . Diabetes Care 1994; 17(7): 697 – 703.

Goldgewitch C, Slama G, Papoz L et al. Hypogl ycaemic reactions in 172 type 1 (Insulin-dependent) diabetic patients. Diabetologia 1983; 24: 95 – 9.

Heller S. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50(6): 1140-7(8).

Herold K C, Polonsky K S, Cohen R M et al. Variab le deterioration in cortical function during insulininduced hypoglycaemia. Diabetes 1985;34:677-8S.

Holmes C S, Hayford J T, Gonsalez J L et al. A survey of cognitive functio ning at different glucose levels in diabetic persons. Diagetes Care 1983; 6(2):180-5.

Holmes C S, Koepke K M, Thompson R G. Simple versus complex impairments at three blood glucose levels. Psychoneuroendoc rinology 1986; 11:353-7.

Jörgens V, Grü β er M, Bott U et al. Effective and safe transl ation of intensified insu lin therapy to general internal medicine departments. Diabetologia 1993; 36:

99 – 105.

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