General Practice

BACKGROUND

General Practice is the first point of contact for most patients who ask for professional medical advice in the United Kingdom (UK) National Health Service (NHS)¹. Primary care makes up around 90% of all NHS activity and, as a result of increasing populations overtaking the number of newly qualified General Practitioners (GPs), the burden of tasks from patients has increased exponentially. GPs characterise their workload as “unmanageable” or “unsustainable” and 93% have reported that patient care has been subsequently affected.¹ Funding into General Practice from the NHS expenditure has fallen by almost 20% which has halted the expansion of new practices and recruitment of substantial GPs. The growth of new GPs increased by 0.2% only, between 2009-2014, and this has indirectly pressured existing doctors to care for more patients. This is reducing job morale as well as patients’ satisfaction with services. The main causes of increased workload are increased administrative load, high patient expectations and increased risk of litigation.²

Four years ago, there were four doctors at our practice. As time passed, one doctor emigrated, another doctor passed away and the third had retired. This has left two doctors at the practice at this current time. The practice currently employs locum GPs to cover the pressures of daily patient appointments as, according to new studies, there are now on average an astonishing 2,100 registered patients per GP.³ The loss of permanent doctors in this practice may be due to the location of the GP surgery. Barnsley, according to uSwitch in 2015, was ranked 122 out of 138 local areas across the UK based on 26 factors such as household income, life expectancy, hours of sunshine and the cost of essential goods including food bills, fuel costs and energy bills.⁴ Adding to the lack of permanent GPs, recruitment into General Practice as a specialty has been scarce. Studies have shown that medical graduates chose medical careers that they considered as more stimulating and interesting. One study mentions that medical students are attracted to technical or biomedical forms of medical practice, as opposed to a holistic view of medicine such as that of General Practice.⁵

Non-permanent GPs in the practice are keen on taking on flexible working hours, which meant the permanent doctors are left with a majority of the work including all of the on-call tasks. These tasks include dealing with patient requests that come through to the receptionist such as booking appointments, patient referrals, prescribing medication and issuing sick notes. We aim to identify the prevalence of specific tasks and evaluate ways to reduce the tasks performed by the doctor. We intend to analyse the number of prescribed acute medication that can be placed on a repeat or variable repeat prescription.

METHODS

Data was collected from a single NHS England GP Centre. This centre utilizes the Egton Medical Information Systems (EMIS) web platform for recording consultations, tracking investigation results, prescribing medications, and communicating within the practice.⁶ Using EMIS, we collected all the tasks of the on-call doctor for a single month. In this month, there were no school or public holidays. These tasks are sent to the on-call doctor from the receptionist who receives them directly from patients. At this centre, all tasks from 2pm on a particular day form part of the following days’ workload. Therefore, the tasks of each day were recorded from 2pm the previous day until 2pm that day.

We separated tasks by allocating them into 1 of 5 categories: medication request; request for appointment, advice, or test results; request for a referral; request for sick note; and other which included all miscellaneous tasks.

RESULTS

Total task distribution

A total of 969 tasks were performed in the month. The proportion of tasks over 4 weeks was as follows: week 1 had 26.7% (n=259) of the total tasks; week 2 had 25.6% (n=248); week 3 had 25.1% (n=243); and week 4 had 22.5% (n=218).

Figure 1: Total number (n) of tasks per day across each week for the four weeks of the month

Further to this, regarding the proportion of tasks over the days of the week: Monday had 23.1% (n=224) of the total tasks; Tuesday had 19.8% (n=192); Wednesday had 17.0% (n=165); Thursday had 18.0% (n=174); and Friday had 22.1% (n=214). Figures 1 and 2 show the number and percentage of task distribution respectively across the days and weeks for the month.

Figure 2: Percentage (%) of task distribution per day-of-the-week across each week for the four weeks of the month.

Type of task

The tasks for the month were separated unevenly across the five categories: medication tasks were 50.9% (n=493) of the total tasks; requests for appointments, results and advice were 35.9% (n=348) of the total tasks; referrals were 2.4% (n=24) of the total tasks; sick note were 4.6% (n=45) of the total tasks; and other tasks made up the remaining 6.1% (n=59) of the month. Figure 3 shows the distribution of tasks for the month.

Figure 3: Distribution of tasks/requests according to task-type for the month (total tasks n=969).

We recorded the type of tasks completed per week. Figure 4 shows the distribution of tasks according to task-type for weeks 1, 2, 3, and 4, respectively. Of the total 260 tasks recorded for week 1, 55.8% (n=145) were tasks involving medication; followed by 29.2% (n=76) request for appointments, results and advice; referrals made up 4.2% (n=11); sick notes were 7.3% (n=19); and miscellaneous tasks came to 3.5% (n=9).

The second week had a total of 248 tasks. Of these, 51.6% (n=128) were medication tasks; 34.7% (n=86) were requests for appointments, results and advice; referrals made up 2.4% (n=6); sick notes made up 2.8% (n=7); and miscellaneous tasks were 8.5% (n=21).

The third week had a total of 243 tasks. Of these, 44.4% (n=108) were medication tasks; 45.7% (n=111) were requests for appointments, results and advice; referrals made up 1.2% (n=3); sick notes made up 3.3% (n=8); and miscellaneous tasks were 5.3% (n=13).

The fourth week had a total of 218 tasks. Of these, 51.4% (n=112) were medication tasks; 34.4% (n=75) were requests for appointments, results and advice; referrals made up 2.8% (n=6); sick notes made up 5.0% (n=11); and miscellaneous tasks were 6.4% (n=14).

Figure 4: Comparison of distribution of tasks/requests according to task-type for week 1, 2, 3, and 4, respectively.

Medication tasks

Focusing on the medication category, we had a look at whether medication requests sent to the on-call doctor were drug prescriptions that should have been on a repeat/variable repeat prescription rather than on acute. Out of a total 493 medication tasks for the month, 49.1% (n=242) medication requests could have been on repeat prescription rather than being acutely prescribed. A further analysis of this data yielded comparable findings per week. In the first week, there were 145 total medication tasks, about 50.3% (n=73) of drug prescriptions could have been on repeat. In the second week, out of 128 medications, 46.1% (n=59) of medication could have been on a repeat or variable repeat prescription. In the third week, out of 108 medications, 39.8% (n=43) of drug prescriptions could have been on a repeat or variable repeat prescription. In the fourth week, out of 112 medications, 59.8% (n=67) could have been on a variable repeat or repeat prescription. Table 1 represents the total number of medication tasks that could have been on repeat or variable repeat prescription per day. Figure 5 represents the percentage of medication tasks that were on acute prescription but could have been on repeat or variable repeat prescription across each week.

Table 1: Total medication tasks that could have been on repeat or variable repeat prescription, per day across each week for the four weeks of the month.

Figure 5: Percentage (%) of medication tasks that could have been on repeat or variable repeat prescription, across each week for the four weeks of the month.

DISCUSSION

SUMMARY

The total number of tasks did not differ significantly day-to-day: each day per week (Monday-Friday) held about 15-25% of the total weeks’ tasks. The medication requests contributed to the majority of the total tasks (50.9%); followed by requests for appointments, results and advice (35.9%). Upon further analysis of the medication category, 10-25 medication tasks per day could have been avoided by having certain drugs on repeat prescription rather than being acutely prescribed. Taking into account that a GP would typically spend 2 minutes per task, this could save 20-50 minutes per day, which amount to 100-250 minutes per week, and 400-1000 minutes or 6.5-16 hours per month.

The drug prescriptions that we thought should have been on repeat or variable repeat prescription, rather than on acute prescription, included requests for drugs that patients typically take long-term. This included Proton Pump Inhibitors (PPIs) such as Omeprazole, statins such as Simvastatin, and Angiotensin Converting Enzyme Inhibitors (ACEIs) such as Ramipril. These are for chronic conditions such as gastric reflux, hypercholesterolemia, and hypertension, respectively. Other drugs that we considered would be more feasible if put on repeat or variable repeat prescription were those for palliative patients in care homes that require a constant need for laxatives such as Senna or Lactulose, or drugs such as Paracetamol. These are for constipation or pain management, respectively.

The medication requests that could not have been on repeat or variable repeat prior to the request being sent were drugs that were required acutely, such as for short-lived infection, transient pain relief, changing of drug doses, and prescribing of alternative drugs due to a possible manufacturing problem or unavailability from the pharmacy. These are tasks that we deem necessary to be sent to the GP so that drug doses are changed based on clinical judgement, and not merely on a request sent to the receptionist. This upholds a standard of drug-control and patient safety within the practice.

STRENGTHS & LIMITATIONS

This retrospective study provides an in-depth analysis of the on-call doctors’ day-to-day tasks in terms of the nature and number of tasks. This is a study involving a large number of tasks collected from a month in a single GP surgery which has produced significant results. As non-GPs collected all the data, including data in the medication category, this eliminated bias in reporting acute medication that could have been prescribed as repeat or variable repeat medication. Limitations include the sample size being considered as a relatively small number which cannot be representative of all on-call GPs’ tasks in the rest of England. In addition, this study took place in the month of September and the tasks can be distinctly different when looking into other months.

COMPARISON WITH EXISTING LITERATURE

To date, the existing literature that looks at GP tasks from this perspective is limited. Most studies look at the receptionists’ role in handling patient requests or focus on scrutinizing the technology that GPs rely on to issue repeat or variable repeat prescriptions.

Our study included the number of tasks completed in a single month as well the stratification of tasks done within the month. We separated our results week per week to see if there were any differences between them. In 2014, a quantitative analysis of incoming calls into three GP surgeries described basic numbers of calls and type of patient enquiries that came into the practice. They had received a total of 2,780 calls and found that the most dominant type of request was making a doctor’s appointment. The main finding in the study is that it identifies an aspect of non-effective communication in GP receptionists’ encounters with patients. It describes how some receptionists failed to meet the initial requests of the patient by directing the telephone call forward or even closing calls prematurely before understanding the problem. This increased ‘patient burden’ and lead to lower patient satisfaction score when recorded. Effective receptionists understood and summarized the patients’ requests as well as making alternative actions to help the patients enquiry.⁷

Repeat prescriptions are defined as those that are printed by a practice computer from its repeat prescribing program⁸. In the UK, repeat prescriptions account for up to three quarters of all drugs prescribed, and four fifths of drug costs in General Practice.^9,10 Repeat prescriptions are mostly done as a technology-supported practice that requires collaboration between clinical and administrative staff to ensure patient safety.¹¹ Two conflicting opinions exist around repeat prescribing: the first is that the increased automation aids in improving safety; the second is that the process as a whole may be weakened if assumptions built into the technology do not take full account of the nature of healthcare work such as real life demands like time, space, and resource constraints.^11,12 It is important that the GPs at our practice are aware of the risks involved in potentially putting more drugs onto repeat prescription, and consequently monitor this closely.

IMPLICATIONS FOR RESEARCH AND/OR PRACTICE

The findings collected in our study demonstrate the increasingly demanding role of the on-call GP outside of consultation hours. According to recent surveys, the GP occupation has had its lowest job satisfaction since 2001 because of a higher workload which indirectly lowers quality of patient care and increases negative patient experiences.^13,14 This should be taken with paramount importance, as this can cause harm to both patients and GPs. As results have described the huge number of tasks, it is important to find a way to avoid unnecessary tasks telephoned into the GP surgery. The results of our study were presented to all of the staff in the practice and the underlying message was well received. Medications that are prescribed by the doctors are double checked by the Clinical Commissioning Group pharmacist in the practice to ensure that drugs are safely given to patients.

CONCLUSION

As the funding formula has changed in the last decade, the government budget into the NHS primary care has decreased more than in secondary care even with the ever-growing pressures on primary care services.¹³ Some strategies, such as telephone triage, have been introduced at the practice to reduce workload crisis. However recent evidence has shown this is not effective.¹⁵ In 2015, the primary care workforce commission laid out recommendations to restructure primary care services as the current model for primary care was under doubt. The underlying message in the report was that continuity of care was important for the majority of GPs - the GPs understood patients better when they had been under their care for many years.¹⁶ With this, extra tasks can be avoided if GPs know their patients well. At a glance of primary care, from literature and our findings, it seems that General Practice may follow an unsustainable path. The pressures of workload include increasing patient lists, higher public expectations and growing bureaucracy.¹⁷ Our data collection has proven that there are a lot of tasks to be done in a month by an on-call doctor, however the amount of time that could be saved by prescribing repeat or variable repeat rather than acute medication can save significant time. From our positive results in the medication task section, we hope this can inspire further research into other areas of the GP surgery that can help optimize the time of the doctors. Furthermore, we would like to repeat our retrospective study in one year’s time with the suggestion implemented (appropriate acute medications changed to repeat or variable repeat prescriptions) over a longer period of time. With limitations corrected for, we want to re-analyse the number and type of tasks completed to determine whether this has truly optimized the time of the overworked on-call doctor.

In a contemporary medical practice caring for complex patients with utmost efficiency, primary care physicians and specialists are expected to work together to organize a seamless transfer from acute to chronic care. The job of the generalist is to sort out and integrate different recommendations from numerous specialists and apply those strategies in the care of the patient long after the index admission. During such interactions with specialists, primary care physicians often realize the impact of differing viewpoints on the overall patient care well beyond the anticipated time frame, whether acute or chronic. To that end, and to better inform such recommendations, this paper proposes the top 10 things primary care physicians wish every specialist knew when addressing problems on the busy hospital ward.

1. Organ-systems work together, not independently

As we see in examples such as the cardio-renal syndrome, hepato-renal syndrome, or hepato-pulmonary syndrome, as the patient gets sicker, the interaction of organ-systems begins to dominate. Indeed, predicting the outcome in comorbid conditions depends not only on understanding the culprit organ, but rather quantifying a complicated interaction of multiple organ-systems. For example, the ADHERE registry algorithm shows the most important predictor for in-hospital death in heart failure patients is not the cardiac function per se, but rather creatinine clearance and BUN^[1]. In other words, the commonly used comments from a specialist asked to evaluate their system of expertise, ‘such and such organ is fine’, might soon become irrelevant and obsolete in the context of multiple complex systems.

Moreover, recent research revealed that genotype, endotype and phenotype are quite different in COPD and asthma^[2]. Therefore, even though a disease may manifest in a single system, the pathophysiological process from which it arose may have been triggered in different organs.

2. Mortality is not the only outcome measure

Specialists seem to treat all-cause mortality as the most important outcome measure in most cases. Or, they choose strategies based on organ specific survival as an alternative, such as MACE (major adverse cardiac events) or creatinine-doubling time^[3]. Life is far more than just being alive. Subsequently, the quality of life (QOL) measures, which capture patient-centred outcomes, provide insight into the effectiveness of interventions but also their meaningfulness to patients, and such measures are gauging previously uncaptured positive aspects of interventions^[4]. The difficulty of defining well-being remains a challenge for researchers and arises from the differences brought about by cultural and societal elements which are context-bound and unique to each community.

3. ADL is one of the most critical prognostic indicators

New biological markers are numerous around here - new renal injury markers, such as NGAL or KIM, to name a few. But a quick, old-fashioned, bedside assessment can easily reveal impairments in Activities of Daily Living (ADL) at each patient visit; and ADLs by Functional Assessment Measures have been consistently shown as strong outcome predictors in acute and chronic illnesses, especially within elderly populations^[5]. In fact, functional measures were deemed to be as important as other objective measures in some prognoses^[6]; for instance, in the BODE score for COPD survival prediction, the ADL measure carries the same weight as the PFT (Pulmonary Function Test). In the management of elderly patients, hospitalization^[7] and initiation of haemodialysis^[8] significantly influence the worsening of ADLs. In the development of a 1-year mortality index after hospital admissions among elderly patients, ADL was of pivotal importance^[9].

Functional impairment is also a strong indicator for readmission: there is a dose-response correlation of severity of impairment and the risk of readmissions^[10]. Intensifying the in-hospital post-ICU physical and nutritional therapy has been shown to improve many aspects of recovery^[11]. In patients with numerous chronic illnesses, the number of comorbidities strongly correlates with the decline of ADL^[12]. Interventions to maintain pre-hospitalization ADL is important in facilitating recovery from hospitalization, and in one study in-hospital mobility programs helped patients to maintain pre-hospitalization ADL while the usual care group experienced significant decline^[13].

4. Effectiveness, not efficacy, matters most in the real-world

“Doctor, I cannot afford the medicine prescribed to me when I was discharged!” This is oft-repeated in offices of generalist physicians. If a patient cannot afford medication and therefore does not take it, the treatment lacks efficacy. In the inpatient setting, efficacy of intervention determines the outcome since patients are most likely to receive the prescribed intervention. This is not the case in the outpatient setting, and the effectiveness of an intervention depends on many other elements, such as the accuracy of diagnosis, patient compliance to the proven intervention, prescription drug coverage, access to care, and finally, efficacy of the intervention^[14].

5. Mental wellness is essential to physical wellness

Health is not limited to the physical body; it also involves mental wellness. In fact, mental and physical health are inseparable. Naturally, serious illnesses affect mood and cognition: therefore, it is important to acknowledge that mental health issues lie squarely within the spectrum of physical disease management. Generalists can help patients with multiple comorbidities manage depressive symptoms through brief psychological interventions; such symptoms related to cognition and mood are expected consequences of any serious illnesses.

Studies have shown that among elderly patients without dementia at baseline, noncritical hospitalization is associated with the development of cognitive dysfunction^[15]. Among elderly patients, the prevalence of cognitive dysfunction is significantly higher in ADHF (acute decompensated heart failure) admissions^[16] or survivors of severe sepsis^[17]. Depression and depressed mood are prevalent in patients suffering serious illnesses^[18]. New models are emerging to integrate psychotherapy in multiple comorbid patients and have been proven to be effective^[19].

6. Pay heed to illness trajectory

“My grandma has never been the same after her hip surgery. Please fix her!”

Primary care physicians often note a decline in the general function and cognition of their patients after index admissions to the hospital. As noted earlier, acute hospital admissions have a strong independent effect on the severity of disability amongst elderly persons^[20]. The multidimensional frailty score, which incorporates ADL and cognitive function, predicts one-year mortality based on a simple scoring system^[21]. Poor functional status attributes to frailty and has led to poor surgical outcomes in the elderly^[22]. The prevalence of functional impairment steadily increases from 28% in the 2 years prior to death to 56% in the last month of life^[23]. Studies demonstrate that gait speed is an important predictor for survival amongst the elderly^{[24] [25]} as well as grip strength^{[26] [27]}.

Furthermore, elderly patients sustain significant impairments long after the index hospitalization^[28]. Amongst elderly patients discharged from the ICU, more than 50% die within a month^[29]. At one-year follow-up, critical ADL capacity, such as taking medications or shopping, was impaired in more than 70% of ICU survivors who remained ventilated for longer than 48 hours^[30]. Delirium sustains a long-lasting effect even after patients are discharged from the hospital, the longer the duration of delirium, the more sustained is the cognitive impairment^[31].

7. Care for the care-givers

There is increasing evidence that caregivers sustain long lasting effects from patient illnesses. Depressive symptoms increase overall for surviving spouses regardless of hospice use^[32]. The RECOVER study^[33] demonstrated that caregivers suffered from high levels of depressive symptoms up to 1 year after a loved one’s ICU admission. In the era of chronic illnesses, it is essential to be mindful of the contributions made by caregivers in disease management. Tools are widely available for the clinician to assess caregiver burden^[34]. This is important because family-support interventions have been shown to improve the quality of communication and decrease the patient’s length of stay in ICU^[35].

8. ‘Exercise and diet’ trumps ‘medicine and surgery’

The COURAGE trial demonstrated that after 7 years, there is no difference between medical management and percutaneous intervention (PCI) in managing coronary disease^[36]. As time progresses after the initial event, the benefits of surgical intervention become less apparent. Similarly, in the long run, intensive statin therapy has not proven to be of greater clinical significance compared to those receiving moderate levels of statin^[37]. As the saying goes, in the long run, “we are what we eat.” Innumerable studies have shown that diet and physical habits have a lasting effect on the health of individuals^[38]. Bariatric surgery has been demonstrating dramatic and long-lasting effects on diabetes control, while the DiRECT study demonstrated that intensive exercise and diet successfully achieved remission in nearly half of the intervention group, compared to only 4% of controls^[39]. Despite the substantial increase in chronic illnesses that are closely tied to our lifestyle and eating habits, physicians of all specialties are poorly trained to provide nutritional counselling to patients^[40].

9. Whose definition of health matters?

If health is defined, as defined by the WHO, is not simply the lack of illness, but “a state of complete physical, mental and social well-being,” it must incorporate many other elements dictated by societal, cultural, moral and philosophical norms and values. Furthermore, the definition of health and the path to attain it should come from the society and community it reflects, since neither healthcare personnel nor the healthcare industry own health. Therefore, the definition should emerge from community interventions and multidisciplinary groups filled with varied stakeholders, rather than from the ivory tower of healthcare researchers. Therefore, medical decision-making processes are rapidly moving away from the paternalistic approach to consensus-based, collegial decisions. Shared decision-making, informed consent, discussions of different treatment options and acquiring second opinions have become standard practice and reflect the empowerment of patients, and communities, to define their own healthcare. Ultimately, as long as patients are competent, they decide their treatment after consulting with physicians, who advocate for the patients’ goals in care and advise them accordingly.

10. Empower healthcare recipients

In the long-term management of chronic illness, participation of the patient is essential. And transparent communication is pivotal for better participation and shared decision-making^[41]. In the new model of health, healthcare providers must play an active role in advocating for patients and promoting well-being while acknowledging that health is a dynamic concept^[42]; these physicians do not simply “coordinate care.” This shift from the physician-centred to the patient-centred approach, in and of itself, will be empowering for patients.

CONCLUSION

Transition of care is one of the most important steps connecting hospital care to primary care. Those problems currently labelled as miscommunication might be more than just a lack of handoff tools or timely messaging; they rather stem from a difference in priorities and varied interpretations of patients’ problems by these two groups of providers. Many questions remain unanswered when facing the future of collaborative healthcare: what kind of doctors are most suited to address the complex interaction of illnesses involving multiple organs? Who can develop a new framework to capture this dynamic and complex interaction of systems, covering many organs in a single patient? Moreover, the next generation of healthcare providers will need to be trained to bear in mind this fundamental concept of patient management. As the twenty-first century progresses, discoveries within medical science will continue to advance the field further away from the current organ-based specialization to pathophysiology-based specialization. This article advances the discussion on the altering role of generalist physicians and the advice of their specialist colleagues, as together they face more and more changes within the practice of medicine.

Introduction

Oestrogen receptors (ERs) are expressed in a large proportion (approximately 70%¹) of breast cancers (BCs). Oestrogen stimulates the growth of breast epithelial cells (both normal and cancerous) by binding to these receptors. Aromatase inhibitors (AIs) prevent the conversion of androstenedione to oestrogen by the enzyme aromatase in peripheral tissues, which is the predominant source of oestrogen in post-menopausal women. Consequently, they are routinely offered to post-menopausal women with ER-positive early invasive breast cancer as adjuvant therapy². However, decreased residual oestrogen levels are associated with increased bone resorption by osteoclasts. The menopause initiates an accelerated phase of bone loss lasting 4 to 8 years, which is followed by a slower phase which continues indefinitely³. AI-induced bone loss (AIBL) occurs at a higher rate than natural menopausal bone loss⁴. Women are therefore at increased risk of fractures while they are on AI therapy⁵, with an associated higher rate of fractures as demonstrated in the ATAC trial⁶.

Recent data have supported more prolonged use of AIs (10 years instead of 5) to achieve lower BC recurrence rates⁷. This may lead to changes in future clinical practice in that ER-positive BC patients may be on an even longer course of AIs. This is likely to translate into a higher fracture risk in patients on long term treatment, and bone health in these patients should remain an important consideration.

Several guidelines have emerged over the years, as summarised by Hadji et al⁸, to aid the assessment of fracture risk in women receiving BC treatment, and management of AIBL. In the UK, the guidance in use and recommended by the National Institute of Health and Clinical Excellence (NICE) is a UK expert group consensus position statement issued in 2008 (Guidance for the Management of Breast Cancer Treatment-Induced Bone Loss)⁹. This includes two treatment algorithms for the assessment and management of bone loss in early BC: one for women with adjuvant treatment-induced premature menopause and the other for postmenopausal women starting adjuvant AI.

Despite the existence of various guidelines on the management of AIBL in BC patients, few articles have been published on the practical adherence to guidance. We carried out an audit of the management of AIBL in BC patients in a large general practice (with roughly 9000 registered patients) in Bradford (UK). Given the small number of eligible patients in our study, we undertook a review to identify all studies in the English literature assessing practical adherence to guidance on AIBL to establish whether gaps identified in our practice reflects a more widespread issue.

Our study

Methods

We carried out a retrospective study in a general practice in April 2015. Using the clinical electronic system used at the practice (SystemOne), we performed a search for all registered patients documented to currently be on AIs or to have previously been on them at any point, for the treatment of BC, using the search terms “anastrazole”, “Arimidex”, “exemestane”, “Aromasin”, “letrozole” and “Femara”. We excluded male patients (not addressed by current guidelines) and patients who started their treatment with AIs prior to the issuance of the UK guidance in 2008. For each patient we gathered data on the indication of treatment, menopause status, the date of initiation +/- completion of treatment, details of dual energy Xray absorptiometry (DEXA) scan and bone mass density (BMD), blood biochemistry results, documented risk factors for fractures and details of bone protection treatment. We audited our practice against the UK guidance.

Summary of the UK guidance

All post-menopausal patients starting AIs should have a baseline DEXA within 6 months of treatment initiation. Patients are stratified as low, medium and high risk for fractures based on the baseline T-scores. Medium and high risk patients should have vitamin D and calcium supplements, and high risk patients should be started bisphosphonates. A repeat DEXA scan should be performed 2 years later for medium and high risk patients to re-assess BMD and augment bone protection therapy as appropriate. Patients aged 75 years and above with at least one clinical risk factor for fractures should be started on a bisphosphonate regardless of their baseline BMD.

Results

There were 12 female patients who started AIs for BC treatment from 2008 onwards. Treatment was initiated between the years 2008 and 2014 (inclusive). The mean age was 67 years (range 57-81 years) and all 12 were post-menopausal at the time of adjuvant hormonal therapy initiation. Three were initially on tamoxifen and switched to an AI after 2 years of tamoxifen therapy.

Three patients (25%) did not receive an initial DEXA scan and had no subsequent risk fracture management. One of them was 75 years of age at the time of AI initiation and was on long term steroids (i.e. should have been on a bisphosphonate regardless of BMD), but she was not on a bisphosphonate.

Of the remaining 9 (75%) who did have a DEXA scan,

One was at high risk (T-score -2.7), and was appropriately started on a bisphosphonate and calcium and vitamin D supplements.

7 patients were at medium risk of osteoporotic fractures (T-score range -2.0 to -0.1). All were started on calcium and vitamin D supplements.

7 were eligible to have had a repeat DEXA scan at the time of the study but only 4 had a scan. Of these four, one was found to have incurred significant bone loss and was started on a bisphosphonate.

The mean interval between AI initiation and baseline DEXA was 1.9 months (range 0.2-4.4). The mean interval between the initial and repeat DEXA scans was 4.1 years (range 2.5-5.1).

Figure 1 illustrates the proportion of scans requested by different clinical teams involved in the patients’ care.

Figure 1: Who requests DEXA scans?

Literature review

Methods

We performed a search with the following terms on the Ovid Medline and Embase databases: “bone loss”, “osteoporosis”, “osteopenia”, “aromatase inhibitor”, “breast cancer”, “guidelines” and “guidance”. Of the 137 results returned after deduplication, we selected original and review articles assessing management of AIBL against established guidelines. We retrieved further papers by reviewing the references of these articles.

Results

The original articles generated are shown in Table 1. While conference abstracts have not been included here, they have been reviewed for the purpose of our discussion.

Table 1: Original articles publishing the results of audits of bone health management in BC patients on AIs against established guidelines

*ASCO: American Society of Clinical Oncology, ESMO: European Society for Medical Oncology, NCCN: National Comprehensive Cancer Network, ARBI: Arimidex Bone Mass Index and Oral Bisphosphonates

Discussion

The results of our audit show that we are failing to meet our current national standards pertaining to management of AIBL in BC patients. Our literature review confirms that this is a widespread issue and that results from larger studies are in agreement with ours.

25% of our patients never had a baseline BMD measurement. Similar findings have been reported in the literature^11,12,14. However, Roberts et al report much higher rates of DEXA screening pre –AI¹⁰. Reasons for this were felt to be the presence of an institutional treatment algorithm as well as a survivorship programme.

We had a poor rate of repeat DEXA scans. Gibson et al and Spangler et al also noted that the highest rate of DEXA scanning was around the time of AI initiation compared to after initiation of therapy^11,14. For the patients who had a repeat BMD measurement in our study, practice was not in line with recommendations as the interval between the initial and repeat DEXA scans (mean 4.1 years) was much longer than the recommended 2 years. This may be because recommendations made by the breast surgery team were different (intervals of 3 to 5 years being recommended in some cases in clinic letters written to the GP by the breast team).

Gibson et al found that 75% of their patients were on calcium and vitamin D, which deviates from the ASCO guidelines that they audited their results against¹⁴. The ASCO guidelines recommend that all BC patients should be on calcium and vitamin D therapy. In some studies^10.12 not all women diagnosed with osteoporosis were started on bisphosphonates. Although women diagnosed with osteoporosis were started on bisphosphonates in our cohort, the suboptimal uptake of DEXA scans means that we may have missed the diagnosis in a number of patients.

From the articles included in our literature review, several reasons have been suggested as causes for deviation from guidelines when it comes to management of AIBL in BC patients. Lack of awareness of guidelines, especially amongst general practitioners (GPs), has been recognised as a barrier, as well as the expectation that other healthcare professionals should be addressing this aspect of care¹⁰. In our study, DEXA scans were mostly requested by the specialist breast team initiating AIs, or by the GP at the request of the breast team. Based on our experience, it is not clear who the responsibility of bone health management lies with – the breast surgery team, the oncologist or the GP. In a survey of 307 UK-based breast surgeons and oncologists 57% of responders felt that oncologists should be responsible for this¹⁸. In practice, patients may be discharged from specialist clinic follow-ups while they are still on hormonal therapy and GPs would be expected to continue their care. When this happened in our cohort of patients, there was no evidence of clear written communication from specialist teams to the GP regarding outstanding aspects of care that the GP would be expected to follow up.

An analysis of five different guidelines regarding antiresorptive treatment in postmenopausal women with hormone-receptor positive BC showed that little consistency exists among the five guidelines¹⁹. The variety of guidelines and recommendations regarding bone loss in BC patients probably leads to inconsistency in practice. In our study, specialist teams have sometimes recommended an interval of 3 to 5 years between BMD tests, deviating from the national recommendation of 2 years. This can translate into confusion when care is taken over by the community team after the patient is discharged from the specialist team.

Recommendations

We therefore suggest that institutional guidelines on bone health management in BC patients on AIs (as well as other hormonal therapies) should be created to improve awareness amongst clinicians as this has shown to improve rates of DEXA scanning¹⁰. Local guidelines should closely mirror national guidelines to allow delivery of standardised care across the country, but should include clear recommendations as to which local team should be responsible for bone health management, as well as recommendations regarding the creation of a care plan for general practitioners when the patient is discharged from specialist teams.

A UK-based study has shown that a “one stop” nurse-led bone health clinic within the breast care service can be a cost-effective way of ensuring adherence to guidelines²⁰. Patients to be started on an AI are identified by the multidisciplinary team (MDT). They are referred to the clinic which arranges a baseline DEXA and other appropriate investigations. Such a clinic may be a consideration in institutions where resources allow. Studies have also shown that simple interventions such as presentations at MDT meetings and display of posters to increase awareness of guidelines amongst clinicians have led to significant improvement in compliance^16,17.

Lack of patient awareness of the negative effects of AIs has also been highlighted in the literature²¹. Improving patient education can improve patients’ compliance with treatment and decrease the rates of unattended appointments for BMD screening. It can also give more control to patients over management of their bone health, as they may be able to discuss with their clinicians where they notice a gap (e.g. if they have failed to receive an appointment for a DEXA scan). Ligibel et al have noted that women from areas with lower levels of education are less likely to undergo BMD tests¹⁵.Patient education can also help reduce the impact that such health-seeking behaviours have on compliance to bone health management.

Current guidelines make no mention of bone health management in male BC patients on hormonal therapy. Although they constitute a small percentage of BC patients, it would be reasonable to include recommendations of their bone loss management in updated guidelines so that this aspect of their care is not neglected.

Strengths and limitations

Our audit is limited by its small sample size and its retrospective nature which meant that we relied on documentation of variable accuracy. We had no information regarding patients who failed to attend appointments despite their clinicians’ invitations for DEXA scans or biochemistry tests, and no information on compliance to medication. However, the results from recent conference abstracts on UK based studies^22,23 generated from our literature review reflect our results, suggesting that this is indeed a national issue. The literature review presented is the most extensive currently available on the subject, gathering up-to-date evidence on worldwide compliance to guidelines on AIBL.

Conclusion

Although the sample size of our study does not allow us to draw conclusions purely based on our data, the literature review that it has prompted has shown that several years after issuance of various guidelines on the management of BC treatment-induced bone loss, in particular AIBL, important gaps still exist in practice. We have presented a summary of up-to-date evidence in the literature to identify potential reasons for this and possible solutions to the current problems, hoping that this will improve current practice.

However, the current guidelines are now several years old. In the last few years, there has been a lot of research on the role of bisphosphonates in BC. A consensus paper assessing recent evidence has suggested that bisphosphonates should be considered for the prevention of bone loss in patients with a T score of <-2.0 or with at least two clinical risk factors for fracture²⁴. The paper also suggests considering the use of bisphosphonates as adjuvant BC treatment, based on a large meta-analysis including 18 766 patients which demonstrated significant benefits of bisphosphonates in terms of prevention of bone metastases and BC survival in postmenopausal women²⁵. This may well change routine adjuvant treatment of BC in the next few years and must be taken into consideration if and when new guidelines on the management of AIBL are issued, or when writing local guidelines.

Introduction

Currently, depression is the leading cause of disability in the world and is predicted to become the second largest killer after heart disease by the year 2020¹. Eighty percent of individuals with depression report functional impairment while 27% report serious difficulties at work and home life². According to a study conducted in 2011, India has the highest rate of depression (36%) in low income countries with women being affected twice more than men³. Cancer in children occurs randomly and spares no ethnic group, socio-economic class, or geographical region. An estimated 11,630 new cases are expected to occur among children aged 0-14 years in 2012 in the US, out of which 1,310 will die by end of 2013 due to it⁴. Based on Karachi Cancer Registry it is estimated that about 7500 children get cancer every year in Pakistan⁵. The mortality rates for childhood cancers have declined by 68% over the past four decades, from 6.5 per 100,000 in 1969 to 2.1 in 2009⁴. However, the diagnosis of cancer in one’s child marks the beginning of social and psychological devastation for the whole family especially the mother. The length and intensity of treatment can be as distressing as the disease itself, negatively affecting their functionality as parents and in turn the child’s ability to handle the treatment⁶. As a primary care provider mother’s responsibility increases substantially starting a vicious cycle of anxiety and socio-economic uncertainty leading her to depression much more than the father⁷. The available data supports that mothers of children with cancer represent a group prone to high levels of emotional distress, and that the period following their child’s diagnosis and the initiation of treatment may be predominantly stressful and disturbing leading them to depression⁸. Such mothers have difficulty in taking care of themselves, their household and especially their sick children. Many parents continue to suffer from clinical levels of distress, even after five years off treatment of their child⁷. Many studies have shown that chronic depression and distress may lead to decrease in immune functioning and an increased risk of infectious disease in healthy individuals ^9-11. Mothers are generally with the child mainly and hence are most affected from their child’s disease. In this study, we intended to estimate the frequency and severity of depression in mothers having children with cancer.

There is limited evidence from Pakistan regarding depression in mothers of children with cancer. The previous studies conducted had certain limitations such as small sample size, assessment of depression in both parents and that too of children with leukaemia only. This study intends to determine the frequency and severity of depression among mothers of children with cancer.

Methods

A cross sectional survey was conducted in the paediatric oncology clinics at The Aga Khan University Hospital, a teaching hospital in Karachi over a period of six months (September 2011- March 2012). Mothers of children with cancer were enrolled in the study, consecutively according to the inclusion and exclusion criteria. Mothers having children less than 15 years of age with any type of cancer, diagnosed by oncologist (2 months after diagnosis to rule out bias for normal grief period)¹², mothers bringing their sick child for the first time to the teaching hospital or as follow up or for day care oncology procedures were included in the study. Mothers who had existing psychiatric illness (and or already diagnosed as having depression by a doctor) and/or taking medications for it, any recent deaths in family (within six months of interview) or having other co-morbidities (malignancy, myocardial infarction in previous year, neuromuscular disease limiting ambulation or blindness) were excluded.

A pre-coded validated and structured Urdu^{13, 14} and English^{15, 16} version of the questionnaire was used for data collection the questionnaire took about 20 minutes to complete and consisted of two sections. Section A, included mother’s and child’s demographic details and treatment status. Section B, consisted of Hamilton Depression Rating Scale (HAM-D 17) a validated scale (sensitivity 78.1% and specificity 74.6%) for assessing frequency and severity of depression in both hospitalised patients and the general population¹⁵. Scores of < 7 indicate no depression and scores > 7 are labelled as depressed. Mothers who were found to be depressed were further classified into mild (scores 8-13), moderate (scores 14-18), severe (scores 19-22) and very severe depression (scores > 23)¹⁶. Mothers with mild to moderate depression were referred to the family physicians; those with severe, very severe, or suicidal tendencies were urgently referred to a psychiatrist.

Institutional Ethical Committee of the Aga Khan University Hospital approved the study. Confidentiality of participants was maintained and informed written consent was obtained.

Sample sizecalculated by WHO software. The prevalence of maternal depression ranges from 56.5% to 61.5% ^{17, 18} as evident from different international studies. With 95%, confidence interval and bound on error of 10% the sample size came out to be 95. After an addition of 5% for non-responders, the total required sample size was 100 study participants. Data was double entered and analyzed in SPSS version19. The outcome variable was dichotomized as no depression and depression (cut off score7). Analysis was performed by calculating frequencies of categorical variables (maternal age, education, current marital status, employment, co- morbidities, diagnosed depression and treatment in mother, number of children, gender of sick child, cancer type, time since diagnosis of cancer in child, treatment given so far and current treatment status of child and family income). Means and Standard Deviation was reported for current age of the child.

Results

One hundred and sixty mothers were approached out of which 100 mothers consented to participate in the study yielding a response rate of 62.5% (100/160). With regards to the mothers the most common age group was the 30-39 year old category (43%). Fifty-five percent of mothers had a high level of education (those who had completed class 11-12 or engaged in professional education). Nearly all the mothers (98%) were married and were homemakers (95%). Only 5% of mothers were working outside the home. More than half of the participants (57%) had one to three children while 43% had more than three. Monthly financial income for 65% of the participants were more than fifty thousand Pakistani rupees (Table 1).

Table 1: Demographic Characteristics of Mothers (N=100)

* (Not Educated: Those who do not have primary education, Primary 1-5 years of schooling, Secondary: 6 to 10 years of schooling, Intermediate: Who have studied class 11 and 12, Higher: Who have completed or engaged in professional education)

The demographic characteristics of child are detailed in Table2. Seventy-five percent of sick children were male while 25% were females (n=100). Half the children were diagnosed with cancer between the age of three to nine. Fifty percent of children (n=50), had their diagnosis of cancer in the last one to five years. More than half of children (57%) were on treatment during study phase. Different types of cancers occurring in children are shown in Figure1.

Table 2: Demographics and social characteristics of sick child (N=100)

*Mean (SD) (t-test values)

Figure 1: Frequency of various types of cancer in children (N=100)

*Others (BLL, Rhabdomyosarcoma, Glioblastoma, Nephroblastoma)

Seventy eight percent of the mothers were depressed. Sixty-nine percent (n= 54) had mild depression, nearly 25% (n=19) had moderate, while 5% (n= 4) had severe and 1% (n=1) had very severe depression.(Table 3)

Table 3: Frequency and levels of severity of Depression in mothers

Discussion

Depressed patients are frequently encountered in nearly all specialty clinics. However, depression in caregivers accompanying patients is usually overlooked and hence missed, as doctors are mostly focused on the patient’s evaluation, condition, and treatment. When the patient is a child and the diagnosis is cancer, this difficult circumstance has a sudden and long term impact on both the child and the family. Many parents of a child with cancer will have very strong feelings of guilt. As such, parents of cancer survivors may be at risk for impaired physical and mental health. An increasing body of literature supports the conclusion that various levels of parental distress are ongoing, long after treatment is completed ^{19, 20}.

The prevalence of depression in mothers in this study was as high as 78%. Mild depression was seen in 69% of mothers, moderate in 25%, severe in 5% while 1% had very severe depression. This high prevalence of depression in such mothers has not been reported from Pakistan before. The soaring levels of depression however have been consistent with the study conducted in Turkey in 2009 in mothers of children with leukaemia²¹ where 88% (n=65) mothers were depressed. Mild depression was reported in 22.7 % (n=18) and major depression in 61.5% (n=40). Similar results were reported from a study conducted on both parents of children with leukaemia in 2002 in Pakistan where 65% (n=60) of mothers were found to be depressed ¹⁷. Nevertheless, severity of depression in this study was not noted. A Sri Lankan study in 2008, showed moderate to severe depression to be 22.9% and 21.9% in mothers having children with mental and physical disorders respectively²². Another study conducted in Florida in 2008 suggests that an increased symptom of depression in mothers is related to significantly lower ratings in quality of life for their children¹⁸.

The existing data supports the argument that mothers of children with cancer represent a group prone to high levels of emotional distress. The time following their child’sdiagnosis and the commencement of treatment may be particularly stressful and traumatic ²³ with an incidence as high as 40% ^24-26. There could be multi-factorial reasons for this alarmingly high rate of depression seen in Pakistani mothers. One of the causes could be the political instability that Pakistan has been facing for past few years leading to economic volatility. The study conducted in 2002 in Karachi saw 65% of maternal depression¹⁷ which has now risen to 78% in this study. Due to political unrest, everyday strikes, bombasts, these mothers may also have difficulty in reaching hospital on scheduled visits leading to postponement of treatment. Other reason could be economic inflation. The cost of daily living has soared while allocated medical budget was 0.27% of its gross domestic product (GDP) on health in 2011-12, which is insufficient to cater the needs of the population (Economic Survey of Pakistan of 2011-2012).

Lately, there has been a recent trend towards nuclear families in Pakistan rather than living in extended families as before²⁷. This in turn may lead to mother being the soul person in looking after the sick and her healthy children as well as managing house chores and doctor’s appointments leading to more frustration. This study also showed that 57% mothers had three children while 43% had more than three children. This could also be one of the factors for high rate of depression as looking after multiple children is demanding and may lead to decreased coping skills of mothers.

Other possible reason for this high rate of depression could be that mostly educated mothers were visiting the hospital that have access to internet and can search up all details, good or bad, on their child’s disease. This may start a vicious circle of worry for mothers. Other possible reasons for this growing depression could be gender of child (as in this society male child is thought to be the support and bread earner of the family), child’s current treatment status and time since diagnosis of cancer in child.

Strengths and Limitations

To the best of authors’ knowledge, this study has touched upon a topic that was not yet been attended to, in local context. Moreover, in this study adjustment phase of two months, for acute stress and posttraumatic stress disorder was given for diagnosis of depression in mothers. It was done to rule out bias in study. HAM-D also focuses on symptoms in the past 1 week, to minimize the recall bias. The findings in this study offer evidence and importance of the need for developing psychological support for families especially mothers who are caring for a child with cancer, in Pakistan.

This study has several limitations. The study was conducted in a tertiary care private hospital, which mostly caters a specific segment of population. Hence, the results may not be a true representation of the population. All data in this study was self-reported by the participants. Thus, it is anticipated that there may be some bias in their responses and recall. Lastly, since this was a cross-sectional study so temporality is difficult to establish.

Conclusion

In conclusion more than three-fourth of our study participants were depressed.

The outcome is expected to identify depressed mothers so that effective strategies can be developed to enhance their coping skills and medically treat them when required. This in the long term is expected to increase quality of life for both their sick and healthy children as well as mothers themselves.

Future Research and Policy Recommendations

Future studies are recommended in order to confirm our findings. Such studies need to be conducted on a larger scale, at national level, in various hospitals and settings to counteract limitations of our study with appropriate means of measuring depression in mothers. Factors, not explored in this study such as personality styles and coping skills of mothers can be explored as these may be significant aspects leading to depression. Further co-morbidities, such as anxiety and post traumatic stress disorder symptoms related to child’s cancer should also be investigated.

Other associated factors, such as the political and economic situation, which perhaps may also be a leading cause of depression in our part of the world, should also be assessed. Simultaneously, measures should be taken to root such factors out at national levels.

The results of current study show the need of incorporating mothers into a treatment process designed for psychological interventions, not only after the diagnosis of cancer in their child but also during their child’s treatment. Psychosocial services should be recognised as an important constituent of comprehensive cancer care for families of children with cancer.

It is highly advocated that the healthcare professionals who work with the families of children with cancer should evaluate the children and their families concerning the psychological and social aspects of their lives. Arrangements for family counselling for those needing help should be made. Mothers should also be referred to family physicians and social support if available. The mother’s crucial position in the family and the proximal and distal effects of her adaptation to the crisis of cancer in the family should lead to the design of interventions intended at decreasing her distress and at promoting her adaptive coping skills as improving mothers’ problem-solving skills has been associated with reductions depression and anxiety²⁸. Thus, all hospitals, dealing with paediatric cancer cases should have a family counselling and support system.

Overview Of History

Mycobacterium tuberculosis was first isolated on 24^th March 1882 by a German Physician Robert Koch, who received a Nobel Prize for this discovery in 1905 ¹. Tuberculosis is one of the oldest diseases in the history of mankind with evidence of tubercular decay found in some Egyptian mummies from 3000-2400 BC ². The study of tuberculosis was also known as phthisiatry from phthisis, the Greek term for tuberculosis. Hippocrates identified phthisis as the most widespread disease of the time which involved the coughing up of blood, fever and was almost always fatal ³. Avicenna first identified that pulmonary TB was an infectious disease and developed the method of quarantine in order to limit the spread of disease ^{4 & 5}. The disease was given the name of tuberculosis in 1839 by JL Schonlein ⁶.

Burden Of Disease

Tuberculosis (TB) is an infectious disease caused by various strains of mycobacteria; of which the commonest cause is Mycobacterium tuberculosis ⁷. The disease can affect any part of human body but commonly attacks the lungs. One third of the world’s current population has been infected by Mycobacterium tuberculosis and new infections occur at a rate of 1 per second ⁸. About 5-10% of these infections leads to active disease which, if left untreated, kills about 50% of its victims. TB affects approximately 8 million people worldwide and about 2 million people die of this disease annually. In the 19^th century pandemic tuberculosis killed about 1/4^th of the adult population of Europe ⁹. Nevertheless, these figures may be only the tip of the iceberg. Tuberculosis is again on the rise and main cause for the resurgence of TB is immunodeficiency as a result of HIV co-infection or, less commonly, immunosuppressive treatment such as chemotherapy or corticosteroids.

Introduction To Mycobacteria

Mycobacteria are aerobic and non-motile bacteria (with the exception of Mycobacterium marinum which is motile within macrophages) which are characteristically alcohol-acid fast ¹⁰. They are present in the environment widely in water and various food sources. They are usually considered to be Gram-positive bacteria, but they do not generally retain the crystal violet stain and are thus called Gram-positive acid-fast bacteria. These acid-fast bacilli (AFB) are straight or slightly curved rods 0.2-0.6 mm wide and 1-10 mm long. Mycobacteria are classified on the basis of growth & their ability to produce pigment.

On the basis of growth:

• Rapid growing: Mycobacteria that forms colonies clearly visible to naked eye within 7 days on sub-cultures
• Slowly growing: Mycobacteria that do not form colonies clearly visible to naked eye within 7 days on sub-culture

On the basis of pigmentation mycobacteria are divided into 3 groups:

• Photochromogens (Group I): Produce non-pigmented colonies in dark and pigmented colonies when exposed to light and re-incubation e.g., M. kansasii, M. marinum etc
• Scotochromogens (Group II): Produce deep yellow to orange colonies when grown in the presence of either light or darkness e.g., M. scrofulaceum, M. xenopi etc
• Non-chromogens (Group III & IV): Non-pigmented in light and dark or only a pale yellow, buff or tan pigment that does not intensify after exposure to light e.g., M. tuberculosis, M. avium-intra-cellulare, M. ulcerans etc

For Clinical Purposes mycobacteria are divided into 3 main classes:

• Mycobacterium tuberculosis complex: These are the mycobacteria which can cause TB and include M. tuberculosis, M. bovis, M. pinnipedii, M. africanum, M. microti and M. canetti.
• Mycobacterium leprae causes leprosy, also known as Hansen’s disease.
• Non-tuberculous mycobacteria (NTM) or environmental mycobacteria, atypical mycobacteria and mycobacteria other than tuberculosis (MOTT). These include all other mycobacteria which can cause pulmonary disease resembling tuberculosis, lymphadenitis, skin disease or disseminated disease. These include: Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium fortuitum and M. Kansasii which can cause both tuberculosis and leprosy in mammals.

Spread Of Tuberculosis

Today we know that TB is an airborne and highly infectious disease. A person becomes infected when he or she inhales Mycobacterium tuberculosis suspended in air as micro-droplets. Patients suffering from pulmonary TB who have detectable Mycobacterium tuberculosis in their sputum are known as smear positive cases of pulmonary TB. The bacterial load in sputum can be as high as 10,000,000 bacilli/mL. When such smear positive patients of pulmonary TB cough, sneeze or expectorate they produce micro-droplets of phlegm containing Mycobacterium tuberculosis (MTB). The size of these micro-droplets varies from 0.5 to 5mm in diameter. These micro-droplets can remain suspended in air up to 8 hours or even more (depending upon droplet size and environmental conditions including air flow). A single sneeze can produce up to 40,000 of these droplets ¹¹. MTB cannot invade the mucous membranes of the respiratory tree and must reach the alveoli where it replicates. The size of the MTB-containing micro-droplet must be <1mm to be carried to the end of the bronchial tree otherwise it will be deposited on the walls of bronchial tree and cleared away by mucociliary action. Current knowledge asserts that even less than 10 bacteria may cause pulmonary infection ^{12 & 13}. A sputum smear positive patient of TB, if left untreated, can cause infection in 10-15 new people each year.

Definition of TB contacts: People exposed to someone with infectious TB, generally including family members, roommates or housemates, close friends, coworkers, classmates, and others. They are a high priority group for latent-TB infection (LTBI) treatment as they are at high risk of being infected with TB.

Definition of close TB contacts: A person who had prolonged, frequent, or intense contact (i.e. >8 hours/day) with a person with sputum positive TB while he or she was infectious. They are more likely to become infected with TB than the contacts those who see the patient less often.

Pathogenesis

Once in the distal end of bronchial tree, MTB is engulfed by a macrophage in order to start replication within this host cell. Depending upon genetic factors, these macrophages can provide a variable environment for the replication of MTB. If this primary infection starts with a single mycobacteria and the initial host response is incapable of halting this process, within weeks or months there will be millions of tubercle bacilli within the body. MTB spreads in sequence from this primary site to the hilar-mediastinal lymph node initially. When seen on the X-ray, this primary focus of pulmonary infection is called a Gohn focus. It is generally located in the upper lobe or the apical segment of the lower lobe ⁷. The Gohn focus plus enlarged hilar-mediastinal node is called a Gohn complex. Tubercle bacilli enter the thoracic duct from the hilar-mediastinal lymph nodes, then by passing via the subclavian vein and right atrium, gain access to pulmonary and systemic circulation. As a result MTB can access, and subsequently infect, any organ of the body. Immunocompetent hosts can normally generate an effective immune response within 3-8 weeks, which tackles the primary Gohn focus and can cause involution of the lesions throughout the body. This immune response is a delayed type hypersensitivity reaction to the cell wall protein of bacilli and this is also responsible for positive tuberculin skin test, which appears 4-12 weeks after infection. The primary immune response is not however sufficient to sterilize the tissues and MTB can remain dormant in these foci. Latent foci may persist in the lungs or other organs of the body and are capable of producing disease reactivation which may be pulmonary or extra-pulmonary. In some cases where the initial host response is not capable of causing involution of the primary disease (such as infancy or an immunocompromised state) the infection proliferates and spreads, causing so-called “progressive primary disease”.

Mycobacterium bovis is a mycobacterium that causes tuberculosis in cattle but which can also infect humans. It can be transmitted from cattle to human by ingestion of infected milk and very rarely by inhalation of animal aerosol micro-droplets and by eating infected raw meat. The process of pasteurisation kills M. bovis and other bacteria in milk, meaning that infections in human are rare ¹⁴.

When To Suspect Tuberculosis

Primary Tuberculosis: Tuberculosis caused by infection with tubercle bacilli and characterized by the formation of a primary complex in the lungs consisting of a small peripheral pulmonary focus and hilar or para-tracheal lymph node involvement; it may cavitate and heal with scarring or progress. It is mainly seen in children but 10% cases of adults suffering from pulmonary TB have primary infection.

Reactivation Tuberculosis: Also known as chronic TB, post-primary disease, recrudescent TB, endogenous reinfection, and adult type progressive TB. It represents 90% of adult cases (in a non-HIV population), and is due to reactivation of dormant AFBs which are seeded at the time of the primary infection. The apical and posterior segments of the upper lobe and superior segment of the lower lobe of the lung are frequently involved.

Clinical Features: Symptoms and signs vary greatly as do radiological signs. A literature review showed that common signs and symptoms seen in TB infection were ^{15, 16, 17, 18}:

• Cough, which can be either productive or non-productive; it is often initially a dry cough which can later become productive.
• Fever which seen in usually 70% of cases; generally it is low grade but could be as high as 390C, lasting for 14 to 21 days and in 98% cases is resolved completely by 10 weeks.
• Night sweats which is usually seen in 50% of cases
• Weight loss
• Pleural effusion: 50% of the patients with pleuritic chest pain had pleural effusion
• Chest pain: mainly pleuritic with some patients describing retrosternal and inter-scapular dull pain occasionally worsened by swallowing. This pain is believed to be due to enlarged bronchial/ mediastinal lymph nodes
• Dyspnoea can be present in 33% of cases
• Haemoptysis can be seen in 25%of cases
• Fatigue
• Arthralgia
• Pharyngitis

Common radiological findings were as follows:

• Hilar lymphadenopathy: can be seen as early as 1 week after the skin conversion and in almost all of cases within 2 months. It can be associated with right middle lobe collapse
• Pleural effusion: typically within the first 3-4 months but can be seen as late as one year
• Pulmonary infiltrates mainly in the upper zones and peri-hilar areas

How To Investigate ¹⁹

HIV testing should be done in all patients presenting with clinical features of tuberculosis

Active Pulmonary TB

• CXR: Perform an X-ray chest PA view. If the appearance is suggestive of active tuberculosis perform further investigations
• Sputum smear & culture for AFB: send at least 3 sputums for AFB smear and culture including at least one early morning sample. This ideally should be before starting treatment or within 7 days of starting treatment.
• If clinical features and CXR are suggestive of active TB, do not wait for culture and sensitivity results, start the patient on the 4 drug initial treatment. This can be modified according to culture results later on.

Active Non-Respiratory TB

A tissue sample should be taken from the suspected non-respiratory site and sent for histological analysis, AFB smear and culture analysis. Common examples of non-respiratory tuberculosis are tuberculous lymphadenopathy, tuberculous meningitis and disseminated tuberculosis.

Physicians should think about CNS tuberculosis such as TB meningitis if a patient with risk factors (i.e., immigrants from endemic areas, positive history of close contact etc) presents with signs and symptoms such as headache, low grade fever, photophobia and/ or focal neurological signs. Lumbar puncture (LP) after a CT brain to rule out any contra-indication for LP may yield the diagnosis in these scenarios. An MRI brain is also very sensitive for picking up tuberculomas in such cases.

Latent TB

Offer Mantoux testing to the household contacts and close contacts of the person with active TB (aged 5 and older). If the Mantoux is positive or if results are unreliable, as can be the case with BCG-vaccinated persons consider interferon gamma testing (T-spot TB Test). If Mantoux is inconclusive, the patient should be referred to a TB specialist. A similar approach should be used for new entrant TB screening.

QuantiFERON-TB Gold (QFT-G) Test & QuantiFERON-TB Gold in Tube (QFT-GIT) Test

Both of these tests have replaced the QuantiFERON-TB (QFT) Test. It is an interferon gamma release assay (IGRA) and measures a component of cell-mediated immune reactivity to mycobacterium tuberculosis. In QFT-G test a blood sample is mixed with antigens (2 Mycobacterium TB protein) and a control. Mixtures are incubated for 16 to 24 hours and then the amount of interferon gamma is measured. If the patient is infected with mycobacterium TB, white blood cells will release interferon gamma when they come in contact with TB antigens. Clinical features, chest X-ray and sputum/ tissue smear and culture for AFB are needed to differentiate between active and latent TB.

Its advantages over tuberculous skin testing are:

• This test requires a single patient visit to draw a sample
• Results are available within 24 hours
• Results are not dependent on reader
• It is not affected by prior BCG vaccination

Its limitations/ disadvantages include:

• The blood sample must be processed within 12 hours of collection (while white cells are still viable)
• There is limited data for use of QFT-G in immune-compromised patients, children under 17 years of age and persons recently exposed to MTB
• False positive results may occur with Mycobacterium szulgai, kansasii and marinum infection

QFT-GIT is a modification of QFT-G test. It consists of 3 blood collection tubes containing: 1) no antigen, 2) TB antigen, 3) mitogen. These tubes must be transferred to an incubator within 16 hours of blood collection. Interferon gamma detection is then carried out via ELISA. Its specificity varies from 96-99% and sensitivity is as high as 92% in individuals with active disease.

T-Spot TB Test

It is a type of ELISPOT assay, developed by the researchers at the University of Oxford in England. It counts the number of effector T-cells in the blood that produce gamma interferon so gives an overall measurement of antigen load on immune system. As it does not depend upon production of antibody or recoverable pathogen, it can be used to detect latent TB and it is much faster. In one study it was found that its sensitivity is 97.2% ²⁰.

Treatment Of Tuberculosis (Caused By Mycobacterium Tuberculosis)

Active TB will kill 2 of every 3 people affected, if left untreated. Disseminated TB is 100% fatal if untreated. For the treatment of TB, drugs are used in combination and never singly. Patients require regular supervision of their therapy during treatment to monitor compliance and side effects of medications. Treatment of atypical mycobacterial infections should be under the care of specialized units as this needs special care and drug regimens are complicated. Drugs for treatment of TB are divided into 3 categories:

1^st Line Drugs: 1^stline anti-TB drugs are very effective against TB. There are 5 first line drugs. All have 3 letter and 1 letter standard abbreviations.

• Rifampicin is RMP or R
• Isoniazid is INH or H
• Ethambutol is EMB or E
• Pyrazinamide is PZA or Z
• Streptomycin is STM or S

Using a single drug usually results in treatment failure and drug resistant strains ²¹. The frequency of Mycobacterium tuberculosis developing spontaneous mutations conferring resistance to an individual drug is well known: 1 in 10⁷for EMB, 1 in 10⁸ for STM & INH, 1 in 10¹⁰ for RMP ²². A patient with extensive pulmonary TB usually has 10¹²bacteria in his body and hence will have about 10⁵ EMB-resistant bacteria, 10⁴ STM-resistant bacteria, 10⁴ INH resistant bacteria and 10² RMP resistant bacteria. Drug-resistant tuberculosis occurs when drug-resistant bacilli outgrow drug-susceptible bacilli. Mutations can produce bacilli resistant to any of the anti-tuberculosis drugs, although they occur more frequently for some drugs than others. The average mutation rate in M. tuberculosis for resistance to isoniazid is 2.56 x 10^-8mutations per bacterium per generation; for rifampicin, 2.25 x 10^-10; for ethambutol, 1.0 x 10^-7; and for streptomycin, 2.95 x 10^-8. The mutation rate for resistance to more than one drug is calculated by multiplying the rates for the individual drugs. For example, the mutation rate for resistance to both isoniazid and rifampicin is approximately 2.56 x 10^-8 times 2.25 x 10^-10, or 5.76 x 10^-18. The expected ratio of resistant bacilli to susceptible bacilli in an unselected population of M. tuberculosis is about 1:10⁶ each for isoniazid and streptomycin and 1:10⁸ for rifampicin. Mutants resistant to both isoniazid and rifampicin should occur less than once in a population of 10¹⁴ bacilli. Pulmonary cavities contain about 10⁷ to 10⁹ bacilli; thus, they are likely to contain a small number of bacilli resistant to each of the anti-tuberculosis drugs but unlikely to contain bacilli resistant to two drugs simultaneously ²³.

There are different regimens available for the treatment of TB. The initial 2 months of treatment (usually rifampicin based) is called Initial Phase or Intensive Phase Treatment which later leads to Continuation Phase Treatment. Initial intensive phase treatment is designed to kill actively growing bacteria. Drugs are listed using their single letter abbreviation and a prefix denotes the number of months a treatment has to be given and a subscript denotes intermittent dosage. For example; 2RHEZ/4RH₃ = 2 months of initial phase treatment with Rifampicin, Isoniazid, Ethambutol, Pyrazinamide and 4 months continuation phase treatment with Rifampicin and Isoniazid given 3 times per week. If there is no subscript, it means the drugs are given daily.

Usual anti-TB regimens are:

• 2RHEZ/4RH3 (in less endemic areas)
• 2RHEZ/4RH (mostly practised, especially in non-endemic areas including UK); standard recommended regimen 24
• 2RHEZ/7RH (in most endemic areas)
• 2RHEZ/10RHE (in cases of disseminated, bone and CNS tuberculosis)

2^nd Line Drugs 25 & 26: These are less effective than 1st line drugs, have more toxic side effects and are usually not available in most of the developing countries of the world. There are 6 classes of 2ndline anti-TB drugs:

• Aminoglycosides: e.g., Amikacin (AMK) & Kanamycin (KM)
• Polypeptides: e.g., Capreomycin, Viomycin
• Fluoroquinolones: e.g., Ofloxacin, Ciprofloxacin (CIP), Levofloxacin, Moxifloxacin (MXF)
• Thioamides: e.g., Ethionamide, Prothionamide
• Cycloserine:
• p-Aminosalicylic acid: (PAS or P)

3^rd Line Drugs: These are drugs which may be useful, but are not on the WHO list of second line drugs. These are not as effective. 3^rdline drugs include:

• Rifabutin (this is an effective drug but is very expensive for developing countries, so it not included in WHO list). Occasionally this can be used for patients who are intolerant to or have bacterial resistance to Rifampicin.
• Macrolides: Clarithromycin (CLR), Azithromycin
• Linezolid: (LZD) not of proven efficacy
• Thioacetazone (T)
• Thioridazine
• Arginine
• Vitamin D
• R207910: efficacy not proven

Indications of Steroids in the treatment of TB

Steroids should be used along with anti-TB drugs in following situations:

• CNS TB (proven benefit)
• TB pericarditis (proven benefit)
• TB involving eye (definitely beneficial)
• TB pleuritis (beneficial – 20-40mg tapered over 4-8 weeks)
• Extremely advanced TB (beneficial)
• TB in children (may be beneficial)
• Miliary TB (beneficial)
• Genitourinary TB (beneficial)
• Laryngeal TB (may be beneficial – scanty evidence)
• TB peritonitis (may be beneficial – scanty evidence)

Important Definitions / Terms ^{25, 27, 28, 29}

New Case: A patient diagnosed as having TB who has never had anti-TB treatment before or had taken anti-TB treatment for less than 4 weeks.

Sputum Smear Positive Case of Pulmonary TB: A patient who has 2 out of 3 consecutive sputum samples positive for AFB.

Sputum Smear Negative Case of Pulmonary TB: A patient clinically and radiologically suspected to have pulmonary TB but with 3 consecutive sputum samples which are negative for AFB and is also culture negative for AFB.

Culture Positive Case of Pulmonary TB: A patient with 3 consecutive sputum smear samples which are negative for AFB but with at least 1 specimen positive for AFB in culture.

Short Course Therapy for TB: The short course therapy for treatment of TB includes 2RHEZ/4RH and also known as standard regimen. If PZA is not included in the regimen for treating TB, the course should be extended from 6 months to 9 months. If rifampicin is not included in treatment regimen then the length of course should be 18 months in total.

Treatment Failure: A TB patient is said to have treatment failure if they remain smear or culture positive while on treatment at the 5^th month or if they were initially smear positive, became negative but then reverted to positive at the end of 5months of treatment. Another scenario is that of a patient who was initially smear negative but then becomes smear positive after 2 months of treatment. Important things to note are:

• Never add a single drug to a failing anti-TB regimen
• Most cases are due to non-compliance
• There is a high chance of Mycobacterium developing resistance to anti-TB drugs

Relapse of TB: A patient is said to have a relapse of TB if they were treated and declared cured but is again smear or culture positive; with the same organism. If the patient gets an infection with a new MTB then they are deemed to be a new case. Because genetic analysis of the infecting MTB is required to determine if re-infection is with the same organism or a new one, it is difficult to accurately diagnose TB relapse.

TB Default Case: A TB patient who completed 1 month of anti-TB treatment, stopped the treatment, and then returns for TB treatment over 2 months after treatment was first initiated. If the patient returns within 2 months of initial treatment, then his/ her initial regimen should be continued.

Re-treatment Regimen: A patient should be a given re-treatment regimen when they relapse or are a TB default case. In highly endemic areas for TB, most authorities prefer an initial intensive phase with 5 drugs for 3 months (2 months RHEZS and 1 month RHEZ).

Chronic Case of TB: A patient is said to be a chronic case of TB, who remains sputum smear positive after 1 re-treatment course. Such patients invariably have drug resistant TB.

Extra-pulmonary TB: TB involving organs other than lungs is called extra-pulmonary TB. For the purpose of treatment and understanding, TB of the central nervous system is excluded from this classification.

Pulmonary TB: Tuberculosis involving lungs is called pulmonary TB.

Respiratory TB: TB involving lungs, pleural cavity, mediastinal lymph nodes or larynx.

CNS Tuberculosis: TB can involve the meninges, brain & spinal cord. It is called TB-meningitis, cerebritis & myelitis respectively. Standard treatment is for 12 months and steroids are mandatory. INH & PZA have 100% penetration into CSF.

Miliary Tuberculosis: This a complication of 1–3% of all TB cases. Tuberculosis involving 2 or more organs/ systems of the body is called disseminated TB or miliary TB. It is also called tuberculosis cutis acuta generalisata and tuberculosis cutis disseminate. It is a form of tuberculosis that is characterized by the wide dissemination and by the tiny size of the TB lesions (1–5 mm). Its name comes from a distinctive pattern seen on a chest X-ray of many tiny spots distributed throughout the lung fields with the appearance similar to millet seeds—thus the term "miliary" tuberculosis. Miliary TB may infect any number of organs, including the lungs, liver, and spleen.

MDR-TB: Multi-drug Resistant TB (MDR-TB) is defined as TB caused by mycobacterium tuberculosis resistant to isoniazid and rifampicin. The diagnosis and appropriate treatment of MDR-TB is still a major challenge.

XDR-TB: Extensively-drug Resistant TB (XDR-TB) is defined as TB caused by mycobacterium tuberculosis resistant to isoniazid, rifampicin, quinolones and any 1 of 3 injectables: kanamycin, capreomycin or amikacin.

Treatment Categories of TB Patients:

There are four treatment categories of TB patients for details see table 1.

Table 1

Directly Observed Treatment Short-course (DOTS):

In this programme a trained person observes the patient swallowing tablets for preferably the whole course of treatment or at least the initial 2 months of treatment. Daily or thrice weekly dosages are recommended but twice weekly dosages are not recommended because of the risk of omitting (by mistake or by chance) one dose. This would result in once weekly dose and it is not acceptable. WHO recommends the DOTS strategy in an attempt to control tuberculosis. There are 5 main points of action:

• Government commitment to control TB
• Diagnosis based on sputum smear microscopy tests done on patients who actively report TB symptoms
• Direct observation short course chemotherapy treatment
• Definite supply of drugs
• Standardized reporting and recording of cases and treatment outcomes

DOTS-Plus:

WHO extended the DOTS programme in 1998 to include treatment of MDR-TB and this is called DOTS-Plus. It requires the capacity for drug susceptibility testing and provision of 2^nd line anti-TB drugs with facilities for identification and drug sensitivities.

Latent TB Infection (LTBI):

A patient is said to have LTBI when he is infected with MTB but does not have any symptoms and signs suggestive of active TB and has a normal chest X-ray. Such patients are non-infectious but 10% of these persons go on to develop active TB in their life at a later stage. They have positive tuberculin skin test and positive Interferon Gamma Release Assay (IGRA) tests (e.g. T-SPOT.TB test, QuantiFERON-TB Gold &QuantiFERON-TB Gold-in tube tests). There are different regimens for treatment of LTBI, commonly used are the following:

• 9H; 9 months INH (gold standard – only practised in USA)
• 6H; 6 months INH
• 3RH; 3 months INH + RMP (recommended in UK)

Common Causes Of Rising Burden Of Tuberculosis

• The following are a few causes of rising burden of TB globally:
• Non-compliance with medication
• Presence of drug resistant strains of mycobacteria
• Faulty regimens
• Un-diagnosed cases
• Under-diagnosed cases
• Lack of newer, more effective anti TB medication.

Role Of Pcr In The Diagnosis Of Tuberculosis

There have been a number of studies regarding the role of PCR in the diagnosis of TB. They show that it has a high sensitivity and specificity but gold standard is still tissue smear and culture for AFB. In certain scenarios PCR of different tissue samples (pulmonary or extra-pulmonary) urine, CSF, sputum and blood can be useful and can also tell us about mycobacterial rifampicin resistance.

Role Of Physicians In Prevention & Control Of Tuberculosis In Relation To Airtravel ³⁰

• Inform all patients with infectious TB that they must not travel by air on a flight exceeding 8 hours until they have completed at least 2 weeks of adequate therapy.
• Inform all patients with MDR-TB and XDR-TB that they must not travel by air until they are culture-negative.
• Advise patients with TB who undertake unavoidable air travel of less than 8 hours’ duration to wear a surgical mask or to otherwise keep the nose and mouth covered when speaking or coughing during the flight. This recommendation should be applied on a case-by-case basis and only with the agreement of the airline(s) involved and the public health authorities at departure and arrival.
• Inform relevant health authorities of the intention of a patient with infectious TB to travel against medical advice.
• Inform relevant health authorities when a patient with infectious TB has a recent history of air travel (travel within 3 months).

Side Effects Of Medications Used For Treatment Of Tuberculosis ^{31, 32, 33, 34}

Patients who are on treatment for TB should be monitored regularly for any signs of medication toxicity. This may include blood tests in addition to clinical examination. Common side effects of the routinely used 4 anti-TB medications (INH, rifampicin, Ethambutol & PZA) are as follows:

Hepatotoxicity: INH, PZA and rifampicin are known to cause liver toxicity. Ethambutol is a safer medication in patients with known liver problems. INH is contraindicated in patients with active hepatitis and end stage liver diseases. 20% patients can have an asymptomatic rise in AST concentration in the first 3 months of therapy. Symptoms of liver toxicity include anorexia, nausea, vomiting, dark urine, jaundice, fever, persistent fatigue, abdominal pain especially in the right upper quadrant. Routine base line LFTs are recommended prior to starting treatment. After that they should be repeated at least once a month and more frequently in those who are at risk of developing hepatotoxicity. Patients at increased risk of hepatotoxicity include:

• HIV positive
• Pregnant or post-partum (3 months after delivery)
• History of or at risk of chronic liver disease (daily use of alcohol, IV drug users, hepatitis, liver cirrhosis)
• Patients taking any other medication which have potential hepatotoxic side effects
• The risk of hepatotoxicity increases with age (> 35 years old)

Suspect drug induced liver injury if there is AST/ ALT rise > 3 times base line with symptoms or > 5 times in the absence of symptoms, or disproportionate rise in ALP and total bilirubin. In such a situation:

• Stop hepatotoxic anti-TB medications (INH, rifampicin and PZA) immediately
• Admit the patient to hospital
• Carry out serological tests for Hepatitis A, B,  and C (particularly in those who are at risk for hepatitis)
• Look for other causes (hepatotoxic medications, high alcohol consumption)
• In acutely ill smear or culture positive patients start liver friendly medications i.e. Ethambutol Quinolones, and Streptomycin, until the cause for hepatotoxicity is identified.
• Re-challenge: Once LFTs are normal (or < two times the upper normal limit) start with Ethambutol and add INH 1^st. If LFTs do not rise after 1 week add Rifampicin. Next add PZA if there is no rise in LFTs after 1 week of adding Rifampicin. If at any point LFTs increase or symptoms recur, stop the last added drug – as this is the culprit drug.

Gastro-intestinal (GI) upset: GI upset is quiet common with anti-TB medications and usually occur in the first few weeks of therapy. Symptoms usually are nausea, vomiting, anorexia, abdominal pain. In such a case recommend good hydration, change the timing of medication (advise to take with a light snack and at bed time) and also check LFTs for possible hepatitis. Aluminium salt containing antacids can reduce bioavailability of INH, so avoid them 1 hour before and 2 hours after INH administration.

Rash: All anti-TB medications can cause a skin rash. Management is based on severity:

• Mild rash or itching: administer anti-histamines 30 minutes prior to anti-TB medications and continue with the therapy. If no improvement, add prednisolone 40mg/day and gradually taper down when the rash clears.
• Petechial rash: Red pinpoint sized dots under the skin due to leakage from capillaries – suspect rifampicin hypersensitivity. Monitor LFTs and full blood count. If platelet count is below normal (base line), stop rifampicin and do not restart it.
• Erythematous rash with fever: and/ or mucous membrane involvement; stop all anti-TB medications immediately and hospitalize the patient. Rule out anaphylaxis (angio-oedema, swollen tongue, throat, stridor, wheezing, flushed face, hypotension) and Stevens-Johnson Syndrome (systemic shedding of mucous membranes and fever). If situation does not permit to stop TB medication then try 3 new drugs i.e. aminoglycoside and 2 oral agents from second line. Once the rash has settled, can re-introduce first line TB medications one by one every 2-3 days, 1^st rifampicin, then INH, then PZA and then Ethambutol. While re-introduction, monitor the signs and symptoms of rash, if rash recurs at any point remove the last agent added.

Peripheral neuropathy: signs and symptoms include numbness and tingling in feet and hands, increased sensitivity to touch and stabbing pain. INH can cause peripheral neuropathy. It is more common in malnourished people, diabetes, HIV, renal failure, alcoholism, pregnancy and in breast feeding women. Prevention is the key; prophylaxis is with Pyridoxine (vitamin B6) 10mg/ 100mg INH (normally 25 – 50mg) per week is used in high risk patients.

Optic neuritis: the main agent responsible for this is Ethambutol. It is dose related and gets more intense if treatment is continued. Signs and symptoms are difficulty in reading road signs, decreased red-green colour discrimination, blurring or vision, and colour blindness. These can be unilateral or bilateral. Ethambutol is not recommended in children <5 years of age as visual changes are difficult to monitor. Visual acuity and colour blindness tests are recommended at baseline and also on a monthly basis. Fluctuations of 1 or 2 lines on the Snellen chart  is considerable and Ethambutol must be stopped. More than 10% visual loss is considered significant.

Fatigue: INH can cause fatigue and in such situations patients should take the medication at bedtime. If it continues, check LFTs to look for hepatotoxicity.

Flu-like symptoms/joint aches and pains: These are usually seen with Rifampicin and treatment is symptomatic.

Drug-induced lupus: It is seen with INH and blood tests should be done to differentiate it from SLE. It can be managed with steroids while the patient is taking INH.

Introduction

Grapefruit (Citrus paradise) is thought to have originated as a cross between the Jamaican sweet orange (Citrus sinensis) and the Indonesian pomelo (Citrus maxima) fruit. It was first bred in Barbados and brought to Florida in 1820s. Subsequently, different mutant and hybrid varieties were developed. Although the white and pink varieties were being popularly consumed, the ruby red variety has become very popular and commercially successful.

The taste is a mixture of the sweetness and tanginess of an orange and the sourness of a citrus fruit. It is a rich source of vitamins C and potassium. It is found to have antioxidant properties due to the presence of lycopene¹and an ability to inhibit atherosclerosis due to the presence of pectin^2,3. The seed extract is thought to have antimicrobial and antifungal properties.

With good publicity, marketing and coverage by health magazines, grapefruit juice has gained widespread use and in most Western Europe and America it is one of the common fruit juices consumed at breakfast. In the United Kingdom, in terms of fruit juice sales, it ranks second among citrus fruits and the fourth overall.⁴

Pharmacokinetic effects

The interaction of grapefruit juice with medication was first reported by Bailey et al in 1991 after their accidental discovery of up to four fold increase in the blood levels of filodipine when taken with grapefruit juice⁵. Further studies have identified similar interactions with more than 85 drugs⁶. The half life of the effects of grapefruit juice is estimated to be around 12 hours⁷, but these effects may last from 4 hours to 24 hours⁸. The effects are more pronounced with regular consumption of grapefruit juice prior to ingestion of the drug and there can be a cumulative increase in drug concentrations with continued grapefruit juice intake^7,9.

As little as 200-250ml may be sufficient to induce its effects^7,10. Some of the interactions involve medication that have narrow therapeutic window and can therefore cause potent adverse effects such as torsade de pointes, rhabdomyolysis, myelotoxicity, respiratory depression gastrointestinal bleeding, nephrotoxicity and sudden cardiac death.⁶ There is a lack of awareness among both doctors and patients about its effects and interaction with various medications.

Mechanism of action

These pharmacokinetic interactions with grapefruit juice are more observable in drugs with high first pass metabolism and in those with an innate low oral bioavailability. The oral bioavailability of affected drugs is increased but their half life usually remains unaltered^11,12. Grapefruit juice is associated with the inhibition of Cytochrome P450 enzyme system, particularly the CYP3A4 enzyme⁷. The CYP3A4 enzyme is present both in the liver and intestinal mucosa. Once the drug is taken up by the mucosa, the susceptible drug may be metabolised by the CYP3A4 or pumped back into the intestine lumen by P-glycoprotein. The observed effects of grapefruit juice are thought to be mainly due to the inhibition of intestinal CYP3A4 activity, which leads to decreased first pass metabolism and hence increased bioavailability. This inhibitory action is fairly quick and may be due to the rapid degradation of the enzyme or any decrease in its production from the mRNA. The production of mRNA itself from DNA is not thought to be affected¹³. The susceptibility varies between individuals depending upon their genetic expression of CYP3A4, the effects being more prominent in those with high small intestinal CYP3A4 content^{7, 14}.

The effect of grapefruit juice on the P-glycoprotein is unclear. The activation of P-glycoprotein pumps the drug back into the intestinal lumen which should reduce bioavailability and similarly the inhibition of P-glycoprotein increases the bioavailability. Some studies suggest that the inhibition of P-glycoprotein is the mechanism responsible for the increased bioavailability of certain drugs like cyclosporine^15,16.

The active ingredients responsible for interactions of grapefruit juice with medication are not clearly identified. The compounds exerting this action are thought to be either the flavanoids such as naringin and naringinen^17,18,19,20 or the furanocoumarins such as bergamottin and its derivatives^21,22,23,24, but there is no clear consensus.

Drug interactions

Table 1 below lists some of the commonly used drugs whose bioavailability is affected by grapefruit juice. Although the best known interactions have been mentioned in the table, there are many other drugs like carvedilol, estrogens, itraconazole, losartan and methyl prednisolone whose bioavailibility is increased by grapefruit juice and the adverse effects are not yet clear.

Table 1: Potential risk of drug interactions with grapefruit juice^{6, 7,13,25,26,27}

Implications on clinical practice

Clinicians should make themselves aware and educate their patients of these potential interactions, keeping in mind the individual variations in susceptibility. This may be particularly important for medications that have a very narrow therapeutic window, medication that have an innate low oral bioavailability and a high first pass metabolism mainly via CYP3A4.

A patient may develop exceptional beneficial effects or equally, significant adverse effects should he start consuming grapefruit juice mid- treatment. Conversely, a drop in efficacy of a drug is also possible, should a patient using grapefruit juice on a regular basis, stops it suddenly.

To achieve steady concentration of the medication and avoid such potential effects, it may be best to advise patients to avoid consuming grapefruit juice if there is a potential of interaction. The half life of the effect of grapefruit juice appears to be around 12 hours and therefore, it is advisable to discontinue grapefruit juice 72 hours prior to starting any drug with potential interactions. ^8,9

Due to the prolonged effect of CYP3A4 inhibition which may last up to 24 hours, it is not possible to avoid these interactions by separating the times of drug and grapefruit juice consumption.^8,9

There is more research needed to clarify the mechanism of action and to determine the active ingredients. The identification of the active ingredient can allow oral administration of drugs that undergo CYP3A4 mediated high first pass metabolism because of which currently, they can only be given systemically.

In light of the possible increase in bioavailability of specific drugs, although it might be possible for patients to use this to their advantage in reducing the dose of their medication under medical supervision, it is perhaps too early to recommend the use of grapefruit juice as an adjunctive or augmentation strategy.

General Information 

1. Vertigo is the hallucination of movement of the environment around the patient, or of the patient with respect to the environment ¹. It is not a fear of heights.
2. Vertigo is not necessarily the same as dizziness
3. Dizziness is a non-specific term which can be categorised into four different subtypes according to symptoms described by the patients:
   
   1. Vertigo
   2. Presyncope: the sense of impending faint, caused by a reduced total cerebral perfusion
   3. Light-headedness: often described as giddiness or wooziness ²
   4. Disequilibrium: a feeling of unsteadiness or imbalance when standing ²

Classification Vertigo may be classified as:

1. Central - due to a brainstem or cerebellar disorder
2. Peripheral - due to disorders of the inner ear or the Vestibulocochlear (VIII^th) cranial nerve

Incidence/Prevalence: Most patients who complain about dizziness do not have true vertigo:

1.    5 community based studies into dizziness indicated that around 30% of patients were found to have vertigo,     rising to 56.4% in an older population ³
2.   A postal questionnaire study which examined 2064 patients, aged 18-65, 7% described true vertigo in the       previous year ³
3.   A full time GP can therefore expect between 10-20 patients with vertigo in one year ³
4.   93% of primary care patients with vertigo have either benign paroxysmal positional vertigo (BPPV), acute         vestibular neuronitis, or Ménière's disease ⁴. These conditions are highlighted in Table 2 

Causes A wide range of conditions can cause vertigo, and identifying whether deafness or CNS signs are present, can help narrow the differential diagnosis, as shown in Table 1. 

 Symptoms 

1. Vertigo may be due to central lesions or peripheral lesions. Vertigo may also be psychogenic or occur in conditions which limit neck movement, such as vertigo caused by cervical spondylosis, or following a “whiplash” flexion-extension injury.
2. It is essential to determine whether the patient has a peripheral or central cause of vertigo ¹.
3. Information obtained from the history that can be used to make this distinction includes ¹: 
   
   1. The timing and duration of the vertigo
   2. Provoking or exacerbating factors
   3. Associated symptoms such as
      
      1. Pain
      2. Nausea
      3. Neurological symptoms
      4. Hearing loss
4. Central vertigo:
   
   1. The vertigo usually develops gradually
   2. Except in: an acute central vertigo is probably vascular in origin, e.g. CVA
   3. Central lesions usually cause neurological signs in addition to the vertigo
   4. Auditory features tend to be uncommon.
   5. Causes severe imbalance
   6. Nystagmus is purely vertical, horizontal, or torsional and is not inhibited by fixation of eyes onto an object
5. The duration of vertigo episodes and associated auditory symptoms will help to narrow the differential diagnosis ⁵. This is illustrated for various pathologies that cause vertigo, in Table 2
   

   Table 2 Timing of symptoms
   Pathology	Duration Of Episode	Associated Auditory Symptoms	Peripheral or Central Origin
   Benign Paroxysmal Positional Vertigo	Seconds	No	Peripheral
   Vestibular Neuronitis	Days	No	Peripheral
   Ménière's Disease	Hours	Yes	Peripheral
   Perilymphatic Fistula	Seconds	Yes	Peripheral
   Transient Ischemic Attack	Seconds / Hours	No	Central
   Vertiginous Migraine	Hours	No	Central
   Labyrinthitis	Days	Yes	Peripheral
   Stroke	Days	No	Central
   Acoustic Neuroma	Months	Yes	Peripheral
   Cerebellar Tumour	Months	No	Central
   Multiple Sclerosis	Months	No	Central

   It is important to differentiate vertigo from non-rotatory dizziness (presyncope, disequilibrium, light-headedness). Patients can be asked whether they “felt light headed or felt as if the world was spinning around” during a dizzy spell ³.

6. Important points in the history:
   
   1. Onset - specific provoking events such as flying or trauma
   2. Duration:
      
      1. Seconds - Benign positional vertigo
      2. Hours - Ménière's Disease
      3. Weeks - Labyrinthitis, Post-head trauma, Vestibular neuronitis
      4. Years - may be psychogenic
   3. Associated auditory symptoms - rare in primary CNS lesion
   4. Other associated symptoms
      
      1. Nausea and vomiting in a vestibular cause
      2. Neurological symptoms such as visual disturbance, dysarthria in a central lesion

Physical/signs 

1. Examination of ear drums (Otoscopy/ Pneumatic otoscopy) for:
   
   1. Vesicles (Ramsay Hunt syndrome)
   2. Cholesteatoma
2. Tuning fork tests for hearing loss – Rinne/Weber tests
3. Cranial nerve examination. Cranial nerves should be examined for signs of :
   
   1. Nerve palsies
   2. Sensorineural hearing loss
   3. Nystagmus ³ 
4. Hennebert's sign ¹
   
   1. Vertigo or nystagmus caused by pushing on the tragus and external auditory meatus of the affected side
   2. Indicates the presence of a perilymphatic fistula.
5. Gait tests:
   
   1. Romberg's sign (not particularly useful in the diagnosis of vertigo ¹)
   2. Heel-to- toe walking test
   3. Unterberger's stepping test ¹ (The patient is asked to walk on the spot with their eyes closed – if the patient rotates to one side they have labyrinth lesion on that side
6. Dix-Hallpike manoeuvre ¹
   
   1. The most helpful test to perform on patients with vertigo¹
   2. If rotational nystagmus occurs then the test is considered positive for BPPV. During a positive test, the fast phase of the rotatory nystagmus is toward the affected ear, which is the ear closest to the ground.
7. Head impulse test/head thrust test
   
   1. Useful in recognizing acute vestibulopathy ⁶
8. Caloric tests
   
   1. Cold or warm water or air is irrigated into the external auditory canal
   2. Not commonly used

Investigations/Testing to consider:

1. Special auditory tests
   
   1. Audiometry helps establish the diagnosis of Ménière's disease
2. The history is most important and may give a quite good indication of the cause of vertigo. General medical causes such as anaemia, hypotension and hypoglycaemia may present with dizziness, and therefore should be investigated.
3. If features of CNS causes is suspected from the history or examination:
   
   1. CT/MRI Brain imaging as appropriate

Treatment 

1. Treatment should ideally aim at the cause of the vertigo ⁷:
   
   1. Medical management – as described below.
   2. Vestibular rehabilitation exercises – e.g. Cawthorne-Cooksey exercises ⁵.
      
      1. These exercises aim to help the patient return to normal activity more quickly.
      2. Moving the eyes from side to side and up and down while in bed or sitting down - then moving the head, first with your eyes open and then closed
      3. Other forms use gaze and gait stabilising exercises. Most exercises involve head movement

2. For most patients the main priority is effective control of the symptoms.
   
   1. For acute attacks, treatments include ^5,8: -
      
      1. Betahistine hydrochloride 8-16mg upto TDS
      2. Cinnarizine, 15-30 mg TDS or
      3. Prochlorperazine should be reserved for rapid relieve of acute symptoms only ^8,12 - tablets 5-10 mg or buccal 3mg TDS or injection 12.5 mg IM or 25mg PR suppository - if vomiting
   2. Preventive measures for recurrent attacks include:
      
      1. Restrict salt and fluid intake - stop smoking and restrict excess coffee or alcohol ^9,10
      2. Betahistine hydrochloride 16mg regularly TDS seems most effective in Ménière's
      3. Cinnarizine 15-30 mg TDS
   3. Points to consider
      
      1. Warn patients when drugs may sedate ¹⁰.
      2. Prochlorperazine is less sedating than some other recommended antihistamines, but may cause a dystonic reaction (particularly in children and young women) ¹¹.
      3. Benzodiazepines are not recommended ⁹.
   4. Recurrent vertigo
      
      1. The most important first step in the management of recurrent vertigo is to distinguish vertigo from 'dizziness'.
      2.  In attacks of vertigo there is a sense of mobile disequilibrium ("the room spinning") which, if severe, results in uncontrolled staggering in one direction which may be only prevented by grabbing a solid object ¹⁰.
   5. Epley's manoeuvre

         a.     Aims to remove debris from the semicircular canals and deposit it in the utricle where hair cells are not                     stimulated ¹¹      b.     Contraindications include ¹⁰:                                         i.     Severe carotid stenosis                                         ii.     Unstable heart disease                                         iii.    Severe neck disease (cervical spondylosis with myelopathy)                                         iv.    Advanced rheumatoid arthritis Consultation and referral:
   

   1. Refer to secondary care if ¹⁰ :
      
      1. Recurrent separate episodes
      2. Neurological symptoms e.g. dysphasia, paraesthesiae or weakness
      3. Associated sensorineural deafness
      4. If there is an inadequate visualisation of the entire tympanic membrane or an abnormality (e.g. cholesteatoma)
      5. Atypical nystagmus e.g. non-horizontal, persisting for weeks, changing in direction or differing in each eye
      6. Positive fistula sign: pressure on the tragus reproducing symptoms (suggests endolymphatic fistula
   2. If the patient has hearing problems in addition to vertigo then referral should be made to an ENT specialist. Other cases should be referred to a neurologist ¹⁰.
   3. While awaiting referral:
      
      1. Consider symptomatic drug treatment  for no longer than 1 week because prolonged use may delay vestibular compensation
      2. It is important that the person stops symptomatic treatment 48 hours before seeing a specialist, as it will interfere with diagnostic tests such as the Dix-Hallpike manoeuvre.
      3. If the person's symptoms deteriorate, seek specialist advice.

   When to consider hospitalization
   

   1. Admit the patient to hospital if they have severe nausea and vomiting, and are unable to tolerate oral fluids ⁹.
   2. Admit or urgently refer the person to a neurologist if they have:
      
      1. Very sudden onset of vertigo (within seconds) that persists.
      2. Acute vertigo associated with neurological symptoms or signs (e.g. new type of headache - especially occipital, gait disturbance, truncal ataxia, numbness, dysarthria, weakness) which may suggest CVA, TIA, or multiple sclerosis ⁹.
   3. Admit or refer the person as an emergency to an ENT specialist if they have acute deafness without other typical features of Ménière’s disease (tinnitus and a sensation of fullness in the ear). Sudden onset unilateral deafness would suggest acute ischaemia of the labyrinth or brainstem, but can also occur with infection or inflammation.
      
      1. Emergency treatment may restore hearing. The person should be seen within 12 hours of the onset of symptoms ⁹
   4. The urgency of referral depends on the severity of symptoms (e.g. requirement for intravenous fluids because of excessive vomiting) and the suspected diagnosis ⁹.

    Patient InformationThe Ménière's Society www.menieres.org.ukwww.patient.co.uk/doctor/Vertigo.htm

    

Chlamydia Screening In General Practice
Sexually transmitted infections are reaching epidemic proportions in Britain and Chlamydia is the commonest sexually transmitted bacterial infections.
 
Prevalence
Chlamydia is thought to be prevalent in 5-10% of 20-24 years old. About 75% of women and 50% of men are asymptomatic. The National Chlamydia Screening Programme currently finds about 8% of young people tested to be positive ¹ but this may represent selective testing of higher risk individual.
 
National Chlamydia Screening Programme (NCSP)
This was initiated in 2003.The aims & objectives were early detection and treatment of asymptomatic infection, to reduce the onward transmission and to prevent the development of sequelae by screening all sexually active under the age of 25 years annually or with each change of sexual partner.
 
The positive rate for this group in 2008 was 8.7% ¹.
 
An ideal setting to provide screening is General Practice. The nationally agreed target is for 25% of 15-25 years olds-males and females to be screened by 2009/2010 and 35% by 2010/2011.
 
Pathogenesis
Chlamydia is an intracellular bacteria and causes disease by chronic inflammation which is exacerbated by re-infection. It infects the female & male genital tract and is primarily sexually acquired. It can be carried in the throat, thus oral sex can transmit the bacteria.
 
Symptoms
Over 70% of women and 50% of men are asymptomatic.
 
Women may experience:
•  post coital or inter- menstrual bleeding
•  pelvic pain
•  dysuria
•  increased vaginal discharge
•  P.I.D with infertility (10-40% incidence)
 
Men may experience:                      
•   urethral discharge
•   dysuria
•   epididymo- orchitis
•   urinary frequency
 
Symptoms in both men and women:
•   rectal discharge
•   rectal bleed following rectal infection
•   pharyngeal infection - rare.
 
History
Early diagnosis and treatment will reduce the risk of long term complications. A detailed history of following should be taken-
1) History of discharge-Enquire about:
•   colour & consistency of the discharge
•   odour
•   is it aggravated by sexual intercourse
•   any associated itching
•   when was it first noticed
•   any past history of the discharge
•   was it diagnosed and treated earlier
•   any association of the discharge with menstrual cycle
2) Sexual history:
•   date of last sexual intercourse
•   were condoms used
•   and if so were they used consistently
•   regular partner or not
•   any other partners in the last six months
•   has she or her partner had sex with some one else of the same sex
•   any history of sex with a partner from a different country
•   any drug abuse in either the woman or her partner
3) Contraception and cytology:
•    which contraception does she use
•    any recent change of contraception 
•    whether she is up to date with cervical cytology
•    whether all previous screens have been normal
4) Menstrual history:
•    date of LMP
•    are periods regular or have they altered recently
•    any bleeding in between periods or after intercourse
5) History of sexually transmitted infection:
•    any past history of STI
•    was it treated
•    was the partner also treated
•    did they have a test of cure
6) Others symptoms:
•   ower abdominal pain
•   dysparunia
•   dysuria
•   any soreness or warts.
7) History of treatment:
•   any medication been prescribed.
•   any usage of over the counter medications
 
Examination
Examination of the female patient is usually normal but may show some muco -purulent discharge with contact bleeding. If pelvic inflammation is present there will be tenderness on uterine and adnexal bimanual palpation. The patient may sometimes be unwell with temperature. In suspected rectal chlamydia, Proctoscopy may be normal or may show changes of bloody/muco-purulent discharge or ulceration of mucosa.In men with epididymo-orchitis there may be epididymal and testicular tenderness with or with out systemic features.
 
Investigations
•  The older less sensitive (EIAs) Enzyme immunoassays are replaced by Nucleic acid amplification tests (NAATs) .They are based on polymerase chain reaction technology.
•  In some areas a combined NATT is in use for diagnosis of both Chlamydia & gonorrhoea. NATTs are not licensed for rectal or pharyngeal sampling.
•  Men should have a first void urine sample tested. In symptomatic women an endocervical swab is the sample of choice. If the patient does not require a per speculum examination a blind vulvovaginal swab could be an appropriate sample. These are almost as accurate and have become the basis for self test kits, now available widely.
•  A first catch urine (FCU) sample may be taken for women (having not passed urine for at least one hour before) but this is less sensitive in women than in men²
•  Sexually transmitted infection screen should include serological testing for HIV and syphilis. Current guidelines for HIV testing can be found at www.bashh.org.
 
Prevention
No opportunity should be lost to discuss safe sex with young people at the time of new patient check up and when prescribing contraception. It is a good practice to screen Chlamydia with informed consent when performing cervical screening in sexually active women under 25 and those over 25 with two or more partners in the last year or a change of partner in the past year.
 
Management
•  It is appropriate to treat Chlamydia in a general practice setting. Treatment is with either macrolides or tetracyclines.
•  Oral Azithromycin (Zithromax) 1gm stat should be the first choice as it avoids compliance issues. Patients must be advised to avoid sex for 7 days after the treatment. An alternative is oral Doxycycline (Vibramycin) 100 mg twice daily for 7 days or oral Erythromycin (Erymax) 500 mg twice daily for 14 days.
•  Interaction with oral contraceptive pill should be discussed. In pregnant women or those at risk of pregnancy, Azithromycin is still an option.
•  Retesting to verify cure is not advocated, partly because of the high cure rate and partly the test using NAA may remain positive for up to five weeks causing confusion.
•  All at risk partners in the last six months for females and asymptomatic males or four weeks for symptomatic males should be informed. They should be invited and treated even if the test is negative ³.The discussion and treatment can take place by the GP if the patient is registered with the practice or by referral to local genitourinary clinic.
 
Locally Enhanced Service
Each primary care trust has a Chlamydia screening officer. This year the target from the Department of Health is to screen 25% of patients aged 16 to 25 years registered at the practice who are sexually active.
 
Fee Structure
On agreeing a service plan with the PCT the general practice can receive: ( this may vary from one PCT to another PCT)
•  £4.50 per test received in the laboratory for coverage of ≤ 10% of the practice population aged 15-24 years.
•  £5.00 per test received in the laboratory for coverage of 10% to ≤20% of the practice population aged 15-24 years.
•  £6.50 per test received in the laboratory for coverage of 20% to ≤25% of the practice population aged 15-24 years.
•  £8.00 per test received in the laboratory for coverage of over 25% of the practice population aged 15-24 years.
 
How To Achieve Targets
•  Do a computer search of all the target patients.
•  Have a practice meeting
•  Involve the whole team: practice nurses, health care assistants and receptionists
•  Delegate, delegate and delegate! Practice nurses or health care assistants can screen at risk groups
• “new patient health check” is an ideal opportunity to offer screening. Involve the receptionist to hand out leaflets, forms and urine pots
• Make sure the reception area is suitable for handing out these items otherwise use a side room to ensure privacy
• Decide who would be dealing with positive results, treatment and partner notification
• To earn the money for extra effort you and your staff has made, make sure you use the appropriate read codeand ask the practice manager to send the claims monthly
• Remember only patients tested with in the practice premises are included when calculating the percentage screened 

• Make sure you reward your staff appropriately with the money otherwise their enthusiasm may soon vanish