Internal Medicine

INTRODUCTION

The most recent outbreak of severe acute respiratory syndrome (SARS) has been caused by coronavirus-2 (SARS-CoV-2) – a new single-strand, positive-sense-RNA beta-coronavirus first reported in 2019 in Wuhan, China. The virus has spread to nearly all countries across the world.^1-4

SARS-CoV-2 infection, also known as Coronavirus Disease 2019 (COVID-19), replicates mainly in the upper and lower respiratory tract. The transmission of COVID-19 from symptomatic and asymptomatic patients is usually through respiratory droplets, generated by coughing and sneezing or through contact with contaminated surfaces.^4,5 The disease has an incubation period of approximately 5.2 days.⁶

Most infections are mild and uncomplicated.⁴ After one week of the onset of disease, 5-10% of patients tend to develop pneumonia, needing hospitalisation.^4,6 Some of these patients develop further complications, often leading to death.^4,6 The overall case fatality rate is 1.4%, with a noticeably higher rate after the sixth decade of life.⁴

People aged ≥ 60 years, especially with underlying medical conditions – such as cardiovascular disease, hypertension, diabetes mellitus (DM), chronic respiratory disease, cancer, immunodeficiency, obesity – and those of male-sex, have an increased risk of dying.^4,7-12 Risk of severe adverse outcome is also associated with an increased number of associated co-morbidities.¹⁰

The impact of active cancer, endocrine disorders, autoimmune inflammatory rheumatic diseases etc. on COVID-19 outcomes has been investigated widely.^13-18 Divergent views have emerged regarding the role of renin angiotensin aldosterone system (RAAS) inhibitors, steroids, and immunomodulators in COVID-19 mortality.

The objective of our study was to evaluate the risk posed by epidemiological and demographic variables in our local population. We also sought to analyse the impact of co-morbidities on in-hospital mortality in confirmed COVID-19 patients.

METHODS

Study design:

We conducted a retrospective analysis of demographics characteristics (age and sex) and medical co-morbidities – hypertension, chronic heart failure, ischaemic heart disease, DM, thyroid disorders, asthma, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m2), chronic liver disease, active malignancy, immunosuppression, post-transplant status, chronic inflammatory arthritis and other rheumatic disorders – in all patients with confirmed COVID-19, who were admitted in two peripheral district general hospitals under a single National Health Service (NHS) trust serving primarily the rural population of western England.

Inclusion and Exclusion Criteria:

To determine COVID-19 status, nose and throat-swab specimens were obtained for real-time reverse transcription polymerase chain reactions (rt-PCR) in all adult (≥18 years) patients, attending one of the two district general hospitals (Royal Shrewsbury Hospital, Shrewsbury; and Princess Royal Hospital, Telford) under Shrewsbury & Telford Hospitals NHS Trust (SaTH) in the period from 1^st March to 15^th May 2020.

Patients who tested positive (either by N gene and ORF1ab gene positive / ORF1ab gene positive or N gene positive) and required subsequent in-hospital management were included in the study. Patients who were discharged after initial senior review (usually by a consultant physician), or brought in as a cardiac-respiratory arrest, were excluded. Re-admissions to the hospital beyond 48 hours following hospital discharge due to COVID-19 were excluded from the study. Patients diagnosed solely on radiological or clinical findings without a positive rt-PCR test were not included in our study.

We analysed the data based on the index-admission (including failed-discharge: re-admission within 48 hours following hospital discharge). No follow-up data was collected post-hospital discharge of these patients.

Data collection & analysis:

A list of all confirmed COVID-19 patients over a 76-day period was identified from the trust microbiology database. A search of the electronic patient records was completed by four members of our team. Supplementary data was gleaned from existing hospital paper records. Patient demographics, presenting symptoms, associated co-morbidities, medications, admission and discharge dates, intensive therapy unit (ITU) admissions, renal profile, referral source and outcomes were recorded in the specifically designed electronic datasheet.

Study Outcome:

The impact of epidemiological and demographic characteristics, and pre-existing medical conditions on the mortality of confirmed COVID-19 patients requiring in-hospital treatment was analysed.

RESULTS

A total of 303 confirmed COVID-19 (rt-PCR positive) samples were collected over a 76-day period. Five patients had been tested twice, and this was accounted for. Thirty-five patients were excluded from the study: twenty-four of them discharged after initial senior review without requiring in-hospital treatment, seven brought in with cardio-pulmonary resuscitation (CPR) in progress, three had inadequate data, and one was <18 years old. Of the 263 patients admitted, 70 (26.6%) died in hospital (Figure-1).

Figure-1: Flowchart of sampling and analysis

We stratified the mortality rates among the admitted patients by age (Table-1). A chi-square test of independence revealed that the mortality rate was significantly related to an advanced age (χ² =27.078, p<0.001). The age and sex distributions of admissions and mortality are shown in Figure-2 (a, b, c).

Table-1: Medical admissions and mortality stratified by age

N: number of patients, m: male, f: female.

Figure-2 (a,b,c): Age, Sex, Admission and Mortality pyramids

We considered two age cohorts - below 60 and ≥60 years of age and other relevant demographic parameters (sex and residence in own-home/care-home) to analyse the impact on mortality rates (Table-2). Of the admitted patients, 159 (60.5%) were male, and 104 (39.5%) were female. The mortality rate was strongly associated with advanced age ≥60 years (χ² =17.120, p<0.001) but independent of sex distribution (χ² =1.784, p=0.182). However, it was also affected by the care facility (χ² =18.146, p<0.001) with a higher mortality rate among the group of patients with residence in a long-term care-home.

Table-2: Admission and Mortality stratified by demographic variables

N: Number of patients; Care-home: Long-term care in residential or nursing home.

To identify the strength of the associations, we conducted a univariate logistic regression analysis with mortality as the dependent variable and the demography and presence/absence of the co-morbidities as the independent variable (Table-3). We found that age as a continuous predictor had an odds ratio of 1.058 (p<0.001), which translated to increased odds of dying by 5.8% for every year of advanced age. Using age as a categorical predictor with the other two categories, the odds of death for patients aged below 60 years was found to be 0.195 times the odds of death for the patients aged 60 years or above.

Table-3: Univariate logistic regression analysis of the demographic variables and co-morbidities

^*Cardiovascular: Hypertension, chronic heart failure, ischaemic heart disease, chronic arrhythmias; ^§Respiratory: Asthma, chronic obstructive pulmonary disease, interstitial lung disease, asbestosis; ^$DM & Endocrine: Diabetes Mellitus (DM), thyroid disorders, Addison's; ^£Renal: Chronic Kidney Disease (eGFR < 60 mL/min/1.73 m2), on dialysis, chronic nephritis, renal transplant; ^§§Rheumatic: Rheumatoid arthritis, inflammatory Polyarthritis, chronic vasculitis Syndrome, connective tissue disorders; ^±Liver & hepato-biliary: Fatty liver, non-alcoholic steatohepatitis, liver transplant; ^€Thyroid: Hypothyroidism, hyperthyroidism, post-thyroidectomy; ^€€Long-term oral steroids: Prednisolone, hydrocortisone, dexamethasone; ^$$Immunomodulators: Methotrexate, tacrolimus, sirolimus, mycophenolate, dapsone, sulfasalazine and azathioprine.

Based on the Charlson Comorbidity Index (CCI) score, the severity of co-morbidities was categorised into four cohorts: mild/no co-morbidity (CCI:0), moderate (CCI:1-2), severe (CCI:3-4), and very severe (CCI≥5) [Table-4(4a)].

Table-4: Impact of CCI score and specific medical-conditions on admission and mortality
4a) Admission and mortality stratified by CCI score based cohorts

4b) Admission and mortality stratified by specific medical-conditions

N: Number of patients; DM: Diabetes Mellitus; *RAAS-inhibitors; ^§Non RAAS-inhibitors.

The impact of CCI score-based cohorts on mortality are shown in Figure-3 (a-f). CCI value also predicted significant association with odds ratio 1.255 (p<0.001). If the CCI score was utilised as a categorical predictor with the other two parameters (age and place of primary care), it remained a significant predictor with the odds of death for the patients with CCI-scores between 0-4 turning out to be 44.8% (p=0.005) of the odds of death for the patients with CCI scores ≥5 (Table-3).

Figure-3(a - f): Pie-chart representing impact of CCI score-based cohorts on mortality


a) Overall admitted patients: discharge and mortality; b) CCI score 0: discharge and mortality; c) CCI score 1-2: discharge and mortality; d) CCI score 3-4: discharge and mortality; e) CCI score ≤4: discharge and mortality; f) CCI score ≥5: discharge and mortality.

Interestingly, the eGFR at presentation turned out to be a significant predictor of mortality (OR=0.961, p<0.001). Of the co-morbidities, pre-existing renal disease was found to be an important predictor of mortality with OR=1.996 (p=0.027). Long-term oral steroids were another significant predictor of mortality, with the odds of death for the patients with long-term oral steroids use being 341.2% (p=0.016) of the odds of death for the patients without such medication. Patients with no background medical conditions (OR=0.181, p=0.022) fared better, with significantly lower odds of death compared to patients with at least one known medical condition (Table-3).

We also analysed the mortality of our patients with specific medical condition-based cohorts [Table-4(4b)]. A high mortality of 52.9% [OR (95%CI): 4.053(1.091–15.063), p=0.037] was observed in patients who were on long-term oral steroids. A 33.3% [OR (95%CI):1.510(0.791–2.883), p=0.212] mortality rate was observed among in-patients with known diabetes on pharmacotherapy.

Many of the demographic variables and the co-morbidities were inter-related – the odds of death for a patient coming from their own-home was only 26% (OR=0.263, p<0.001) of the odds for those residing in a long-term care-home (Table-3). To offset the possibility of any confounding effect, we utilised multiple logistic regression analysis with all the important variables taken together (Table-5). Taking consideration of confounding effects, only age, care facility, presence of active malignancy and long-term oral steroids were found to be significant predictors of mortality. Interestingly, the presence of active malignancy was found to have a lower risk of death – this is possibly due to a bias on account of a relatively small number of patients in that subset of our study. Age was the most significant predictor of mortality, followed by a primary area of the care facility and the presence of active malignancy.

Table-5: Multiple logistic regression analysis of the demographic variables and co-morbidities

DM: Diabetes Mellitus

DISCUSSION

COVID-19 has taken 800,000 lives world-wide as reported by the World Health Organisation (WHO) on August 30, 2020. A recent systematic review and meta-analysis have reported the association of COVID-19 with a severe disease course in about 23% of infected patients and has a mortality of about 6%.¹⁹ The mortality rate varies in different geographical areas. In-hospital mortality was significantly higher in the United States of America (USA) (22.23%) and Europe (22.9%) compared to Asia (12.65%) – (p<0.0001).²⁰ However, there was no significant difference when compared to each other (p=0.49).²⁰ Our study showed a 26.6% in-hospital mortality.

The mean age of the patients in our study was 68.74 years (SD:16.89) – 60.5% of them were male and 39.5% female. 70.7% of these patients were aged ≥60 years. Univariate analysis showed that the mortality rate was significantly age-dependent (OR=1.058, p<0.001) – mortality (33.9%) was higher in patients aged ≥60 years, rising sharply ≥80 years to 44.0% (χ² =27.078, p<0.001). Our results were consistent with other studies.²¹

Among the demographic characteristics, mortality-risk was independent of sex distribution (χ² =1.784, p=0.182) in our study. This is in contrast to a meta-analysis, which reported the association between male-sex and COVID-19 mortality (OR =1.81; 95%CI:1.25–2.62).²² Multicentric studies in the United Kingdom (UK) would be warranted to see the trend in the local population.

Long-term care-home residents suffered 50.0% mortality (χ² =18.146, p<0.001). The London School of Economics report on May 14, 2020, estimated that the COVID-19 related deaths of care-home residents contributed to 54% of all excess deaths in England and Wales. Our study findings indicate long-term care-homes as hot-spots requiring shielding and protective measures against COVID-19 – a conclusion corroborating other studies.²³

We aimed to define the predictive-role of co-morbidities on COVID-19 mortality, an aspect that has been probed earlier as well.^7-12 The CCI score remains a reliable method to measure co-morbidity.²⁴ For admission to intensive care, NICE recommended CCI-score ≥ 5 requires critical care advice to help in treatment decision regarding the essential benefit of organ support for seriously unwell COVID-19 patients. We examined the predictive mortality-risk of CCI scores among the admitted patients.

The mortality rate in cohorts with CCI ≤4 and CCI scores ≥5 were 20.3% and 36.2% respectively. The odds of death for CCI ≤4 cohort was less than half (44.8%) compared with CCI scores ≥5 cohort. Based on this finding, we strongly recommend CCI scoring as a clinical risk-stratification tool in COVID-19.

We examined the impact of organ specific co-morbidities on in-hospital mortality in our study as well. Patients with no background medical conditions showed a low mortality rate 6.9% [OR (95%CI): 0.181(0.042–0.782), p=0.022] and had better outcomes with significantly lower odds of death, compared to patients with at least one medical condition on univariate logistic regression analysis (Table-3). The mortality rate was 3.2% in CCI-0 cohort [Table 4(4a)].

The impact of COVID-19 on patients with CKD, glomerulo-nephropathies, on dialysis dependent patients and post renal transplant patients remains unclear. Patients with SARS-CoV-2 infection were frequently found to have renal dysfunction – the latter was associated with greater complications and in-hospital mortality.²⁵ A mortality rate of 3.6%, was reported in patients attending an outpatient haemodialysis centre.²⁶ Another study has concluded 3.07-fold (95%CI:1.43–6.61)mortality among renal failure patients.²⁷ We found, the pre-existing renal disease to be a cause of significant concern with 37.7% mortality [OR(95%CI): 1.996(1.082 – 3.681), p=0.027] with the eGFR at presentation being a significant predictor (OR=0.961, p <0.001) (Table-3).

The use of steroids in COVID-19 continues to be explored.The RECOVERY trial in UK, after evaluation at 28 days, concluded that dexamethasone reduced deaths by one-third in ventilated patients [age-adjusted rate ratio (RR) 0.65; 95% CI: 0.48–0.88; p=0.0003], and by one-fifth in other patients receiving supplemental oxygen with or without non-invasive ventilation (RR 0.80; 95%CI: 0.67 to 0.96; p=0.0021), although no benefit was observed in mild or moderate cases not requiring oxygen support (17.0% vs.13.2%; RR 1.22; 95% CI, 0.93e1.61; p¼0.14). In contrast, a systematic review concluded that the results from retrospective studies are heterogeneous, and it was difficult to assign a definite protective role of corticosteroids in this setting.²⁸ We found long-term oral steroids use to be a significant predictor of mortality – 52.9% [OR(95%CI): 3.412(1.261–9.23), p=0.016] – this was 341.2% of the odds of death for the patients without any long-term oral steroids use (Table-3). The sample size of this cohort was relatively small with 9 deaths out of 17 patients. However, based on our results, it may be safe to suggest that further population-based studies would be required to determine the impact of long-term oral corticosteroid use in COVID-19.

A major proportion of endocrine disorders are of autoimmune aetiology. The impact of thyroid disorders on COVID-19 is yet to be studied widely.^15,16 We found no increased risk of mortality [OR (95%CI): 0.914 (0.285–2.934), p=0.880] in patients with thyroid disorders. However, 33.33% [OR(95%CI): 1.510(0.791–2.883), p=0.212] mortality was seen among the diabetic patients on pharmacotherapy in our study [Table-4(4b)].

Pre-existing hypertension is an accepted risk factor for COVID-19 mortality.^26,27 However, the role RAAS-inhibitors and upregulation of ACE-2 receptors in COVID-19 mortality call for targeted clinical research for further clarification.²⁹ A meta-analysis of four studies showed that patients treated with RAAS-inhibitors had a lower risk of mortality [RR: 0.65(95%CI:0.45–0.94), P=0.20].³⁰ We did not observe any significant mortality-risk difference between RAAS-inhibitors treatment group [OR(95%CI): 0.760(0.365–1.586), p=0.465] and non RAAS-inhibitor treatment groups [OR(95%CI): 0.704(0.253–1.964), p=0.503] [Table-4(4b)]. We recommend the continuation of RAAS-inhibitors during COVID-19 unless there exist other compelling medical reasons for their discontinuation.

A prospective study in the UK concluded that the mortality from COVID-19 in cancer patients appeared to be driven principally by age, gender, and co-morbidities.¹³ The study could not identify evidence suggesting cancer patients on cytotoxic chemotherapy, or other anticancer treatment, were at an increased risk of mortality from COVID-19 compared to the general population.¹³ We also did not detect any increased risk of mortality in patients with active malignancy [OR(95%CI): 0.078(0.008–0.725), p=0.025)] (Table-5).

The impact of various non-specific immunomodulators in COVID-19 outcome remains inconclusive.¹⁴ Our study did not reveal any significant predictive mortality-risk with the use of long-term immunomodulators (methotrexate, tacrolimus, sirolimus, mycophenolate, dapsone, sulfasalazine and azathioprine) on multiple logistic regression analysis. We reached the same conclusion with patients suffering from chronic rheumatic disorders on similar analysis (Table-5).

Our study had some unique characteristics. We analysed all the eligible samples over a consecutive 76-day period at the initial peak of the pandemic. The study was conducted across two district general hospitals, allowing an insight into two differently located rural populations. We conducted univariate and multiple logistic regression analysis of the demographic variables and co-morbidities to examine the predictive-risk of contributing factors in COVID-19 mortality. The association between CCI scores and in-hospital mortality was also analysed in detail. We included demographic characteristics such as age, sex and residence in a long-term care-home while factoring in the associations.

Our study was not without limitations, though. We were unable to study the predictive-risk of obesity, socioeconomic status and ethnicity due to inadequate data. The “White British” group consisted of 80.61% of admitted patients, and no ethnicity was documented in 17.11% of our patients (Table-6, Figure-4).

Table-6: Medical admissions and mortality stratified by ethnicity

N: Number of patients

Figure-4: Bar charts showing Admission and Mortality stratified by Ethnicity

We relied solely on electronic database and hospital records to conduct the study retrospectively. The few subsets of patients such as those on prescribed long-term oral steroids, immunomodulators, thyroid disorders, chronic liver disease, and active malignancy had relatively small sample sizes with possible introduction of bias. We did not categorise diabetic patients into insulin dependent/non-insulin dependent or well/poorly glycaemic control cohorts. We did not aim to split the respiratory group into well or poorly controlled asthma or COPD subsets. Patients on a long-term steroid inhalation treatment were not included in the steroid cohort – a more extensive population-based study may be better suited for such an analysis.

CONCLUSIONS

Patients aged ≥ 60 years, residence in a long-term care-home, pre-existing renal disease, multiple co-morbidities (especially those with CCI ≥ 5), and patients on long-term oral steroids need to be considered as having a high risk of dying from COVID-19, along with other established risk factors such as hypertension, diabetes and chronic respiratory disease. RAAS-inhibitors need not be discontinued due to COVID-19. Further studies are necessary to establish links between long-term oral steroids use, chronic rheumatic disease, non-specific immunomodulators and COVID-19 mortality.

Introduction

Lung carcinoma the most common malignancy worldwide, presents as a metastatic disease in majority of the cases. The most frequent sites of distant metastases are liver, adrenal glands, bones, and brain. Skeletal muscle metastasis is an unusual presentation of lung adenocarcinoma.

Case report

A fifty three year old male patient, labourer by occupation, beedi smoker for twenty five years, admitted to tertiary care hospital with pain and swelling over left arm, cough and expectoration for the past two months, accompanied with significant weight loss. There was no evidence of chest pain or haemoptysis. On local examination there was hard swelling over extensor compartment of left upper limb with mild tenderness, no loss of sensation and mild restriction of range of movements on flexion at elbow. Respiratory and other systemic examination was within normal results. Plain CT of thorax defined multilobulated lesion in right perihilar location in right middle lobe (Figure 1).

Figure 1: CT of Thorax: Well defined multi-lobulated lesion in right perihilar location in right middle lobe measuring 2.9 x 2.4 cm.

USG of left arm showed an irregular heterogenous soft tissue lesion noted within the triceps muscle with few areas of intra-lesional necrosis, MRI of left arm showed lobulated lesion in posteromedial aspect of mid and distal arm, involving triceps muscle, medial aspect of brachialis, encasing brachial artery, veins and median nerve (Figure 2).

Figure 2: MRI of Left arm: Well defined irregular lobulated enhancing T1 hypo intense, T2 and T2 flair hyperintense lesion in the posteromedial aspect of mid and distal arm.

PET scan showed enhancing nodular soft tissue lesion noted in middle lobe of right lung, 2.9 x 2.4 centimetres. Biopsy revealed metastatic adenocarcinoma. For further studies Immunophenotyping was done which showed negative for EGFR and ALK. Patient was treated with palliative RT, Pem-Carbo f/b Pemtrexed maintenance and recently 3# of Gemcitabine. The patient died of metastasis to brain within eight weeks of diagnosis.

Discussion

Lung carcinoma is a leading cause of cancer-related mortality. The most common sites of distant metastasis in lung carcinoma are brain, bones, the liver, and the adrenal gland¹. The most common tumours that cause skeletal muscle metastasis are tumours originating from thyroid, oesophagus, stomach, pancreas, colon, rectum, bladder, breast, ovary, and prostateand skeletal muscle metastasis of lung carcinoma was first reported by Fisher ER². Willis RA reported four skeletal muscle metastases in their autopsy series composed of 500 lung carcinoma patients³. Skeletal muscle metastasis is a rare occurrence for any tumour with a reported incidence lees than one percent^4-5. The most common sites of muscle metastasis are thigh muscles, iliopsoas, and paraspinous muscles⁶.

The mechanism of skeletal muscle metastasis is unclear. Despite its rich vascular blood supply and a large mass in the body, it is resistant to haematogenous metastases. Organs that are frequently metastasized, including liver, lung, and bone have rich capillary networks and blood supply. As a result of the muscle metabolism, substances such as lactic acid, free oxygen radicals, and low pH in the environment constitute an infertile medium for proliferating tumour cells. In addition, mechanical insults due to contractions, high tissue pressure, and widely alternating blood flow are also against the survival of tumour cells⁷.

There are several hypotheses proposed for skeletal muscle metastasis in lung carcinoma. The most widely accepted hypothesis is the haematogenous route. In this hypothesis, it is believed that tumour cells are formed through tumour embolism. Some authors suggested that skeletal muscle metastases might originate from abnormal lymph nodes found in the muscle. In a study by Bocchino M et al. 1754 lung carcinoma patients treated between 2007 and 2012 were analyzed and forty six (2.6%) had skeletal muscle metastasis⁸. Despite the variations between different studies in terms of the association between histological subtypes and skeletal muscle metastasis, forty patients in that study (87%) had non small cell lung carcinoma and six had (13%) small cell lung carcinoma. Among non small cell lung carcinoma patients, twenty four (60%) had adenocarcinoma. The most common initial manifestation of skeletal muscle metastasis is a pain. Pain can be accompanied by extremity swelling. The case presented herein also applied with pain and swelling. Diagnostic methods for skeletal muscle metastasis are not specific. Direct films usually show only soft tissue shadows. MRI usually reveals hypointense signal in T1 and hyperintense signal in T2. MRI is preferred to distinguish soft tissue metastasis from an abscess, sarcoma, and other conditions⁹, similarly; our patient had hypointense signal on T1 and the hyperintense signal on T2 series. The optimum treatment and prognosis of skeletal muscle metastasis from lung cancer is unclear. Depending on the clinical characteristics, treatment options include observation, surgery, chemotherapy and radiotherapy.

Conclusion

Lung carcinoma with skeletal muscle metastasis should be considered as a potential differential diagnosis in patients presenting with an intramuscular mass.

Acknowledgements

Authors acknowledge the immense co-operation received by the patient and the help received from the scholars whose articles are cited and included in references of this case report. The authors also acknowledge the authors/editors/publishers of all those articles, journals and books from where the literature for this case report has been reviewed and discussed.

Introduction

Since 2005, there has been an increase of 10% in hospital admissions with acquired brain injury (ABI), with 348,453 United Kingdom (UK) admissions in 2016-17.¹ With improvements to both medical and surgical management, a higher proportion of patients survive to hospital discharge, resulting in more people with complex physical and cognitive disabilities reaching the community.^2,3

Prolonged disorders of consciousness (PDOC) can occur following ABI. This can vary from coma, to vegetative state (VS), and minimally conscious state (MCS). Following acute stabilisation, the treating team must provide the correct diagnosis, prognosis, and management. Ethical and legal issues, such as best interests decision-making (considering patient wishes, advanced decisions, and best possible quality of life), deciding when appropriate to provide end-of-life care, and understanding the legal framework around these issues can further complicate the process.

Whilst there is currently no national registry for patients with PDOC, information taken from patients in nursing homes in the UK give an estimated 4000 – 16000 patients in VS, and up to three times this many in MCS.⁴

Early and ongoing assessment of the patient is vital, as is good communication with those close to the patient, and an understanding of the legal requirements of the treating clinician. These are likely to present even more of a challenge to General Practitioners (GP) in the community who are managing these patients as part of their larger responsibilities.

This review article summarises guidance from the Royal College of Physicians (RCP) and British Medical Association (BMA), in conjunction with our own clinical experience, to improve understanding surrounding the assessment, long term management, and the ethical and legal issues in patients with PDOC, aiming to improve the confidence of clinicians managing these patients.^5,6

Identifying Patients

Consciousness requires a combination of wakefulness and awareness (self and environment). Patients with significant deficits in either of these can be said to have a disorder of consciousness. Various brain injuries can result in disorders of consciousness (see Table 1).

Table 1: Aetiology of acquired brain injury.⁵

This article focuses on acute causes of PDOC rather than those with primary neurodegenerative conditions, as they present separate clinical entities with different issues affecting prognosis and management choices.

Disorders of consciousness, like a sliding scale, vary from coma, to VS, and MCS:

• Coma - unrousable unresponsiveness. Patients cannot be roused, lack a sleep-wake cycle, exhibit no purposeful movement, and do not respond to stimuli.
• VS - wakefulness but not awareness. Patients have a sleep-wake cycle and open their eyes spontaneously, but lack awareness of self or their environment. These patients can exhibit spontaneous and reflexive movements, and external stimuli can produce arousal responses.
• MCS - wakefulness but reduced or inconsistent awareness. Patients have a sleep-wake cycle and demonstrate reproducible but inconsistent awareness of self, and ability to interact with others and their environment.

Diagnosis

As per RCP guidance 2020, patients with impaired consciousness for over 4 weeks are deemed to have PDOC.⁵ It is first important to differentiate possible VS / MCS from other conditions:⁵

• Abnormalities on electroencephalography (EEG) can aid diagnosis of coma. These patients tend to progress to VS or death within weeks, so assessments of consciousness are not appropriate during this period.
• Patients with locked-in syndrome have wakefulness and awareness, but paralysis of the limbs and majority of facial musculature, preventing communication by these means. EEG in locked-in syndrome is usually normal, and patients may be able to communicate using eye movements.
• Patients with brainstem death have loss of all brainstem reflexes and respiratory effort, and organ survival is only temporarily achieved with life support machines.

Once ‘mimic’ conditions are ruled out, making a diagnosis of VS or MCS in patients with a suspected disorder of consciousness follows a 3-step process with input of clinicians trained in the management of PDOC:

1. Establishing a cause

This can be straightforward in some cases, such as those with direct trauma to the brain, or acquired brain infections or inflammation causing structural damage to the brain. In other cases this can be more difficult, and it may not possible to reach an exact diagnosis. The treating clinician must establish that the patient’s current condition is due to a brain injury, and take reasonable steps to determine the cause.

2. Reversible causes should be excluded

This includes reviewing medications to stop sedative medications whenever possible, blood tests to look for infection or metabolic / electrolyte abnormalities, up-to-date imaging to rule out new onset hydrocephalus, or performing an EEG to rule out subclinical seizures needing antiepileptic medication. This step also includes establishing that neurological pathways are intact, so that any assessment of consciousness provides an accurate reflection of the patient’s condition. Briefly, this involves examination and investigations to confirm that sensory, visual, auditory, and motor pathways are intact.

3. Structured assessment

There are several tools available which can confirm the diagnosis of VS or MCS. All of these require a trained assessor and an appropriate environment. These tools provide a structured method of assessing the patient to:

• Observe spontaneous behaviours.
• Observe the patient’s reaction to stimuli from different sensory modalities.
• Document the findings of family / friends / members of the healthcare team following their interactions with the patient.

Tools available include the Wessex Head Injury Matrix (WHIM), the JFK Coma Recovery Scale-Revised (CRS-R), and the Sensory Modality Assessment and Rehabilitation Technique (SMART), amongst others. As per RCP guidance, the CRS-R should be the primary assessment tool, and WHIM or SMART can be used to provide additional information. Furthermore, assessments need to be performed on at least 10 occasions, at several different times of the day, and over the course of a 2-3 week period.^5,7-9

The 2020 RCP guidance also addresses how to manage patients that do not present through the acute hospital pathway.⁵ In these ‘late assessment’ cases, formal assessment is still required to establish their level of consciousness and guide management. These patients should be referred to an experienced PDOC assessor to establish the cause of PDOC, rule out reversible causes, and arrange formal evaluation. This should ideally be achieved by outreach assessments, but if this is not possible, structured interviews should be held with family and care staff to complete the CRS-R. If these measures do not provide a definite diagnosis, admission to a PDOC centre can be considered.^5,8

Vegetative State & Minimally Conscious State

Patients in VS are unable to interact with their surroundings or those around them (no voluntary behaviours / communication / purposeful movements), and show no evidence of awareness of self. The patient may demonstrate reflexive behaviour (such as increased heart rate or startle response to noise), or spontaneous, purposeless movements (such as eye movements, teeth grinding, or limb movements). These behaviours can be misleading, which is why an objective and structured assessment method is vital.

Patients in MCS have some evidence of awareness of self or their environment, on a reproducible but inconsistent basis. Patients demonstrate behaviours such as: following simple commands, verbalisation, and purposeful behaviour MCS which is further classified based on the level of responsiveness:

• MCS-minus - less complex behaviours such as orientation to noxious stimuli, or purposeful eye movements.
• MCS-plus - more complex behaviours such as following instructions or interacting with objects.

Prognosis depends on cause, time since brain injury, and the trajectory of improvement (better prognosis for those who quickly progressed from VS to MCS). Those with traumatic brain injury are more likely to regain awareness and have a longer window for potential recovery. The majority of VS patients that regain consciousness tend do so within 12 months in traumatic cases, and 3 months in non-traumatic cases. The majority of MCS patients that regain consciousness do so within 2 years post injury, although others can emerge at up to 4 years. Whilst these are the expected outcomes, there are, however, rare case reports of patients emerging later than this.

VS / MCS-minus are classed as ‘continuing’ at >4 weeks post brain injury, and ‘chronic’ at >3 months for non-traumatic cases, or >12 months in traumatic cases. MCS-plus is classed as ‘continuing’ at >4 weeks post brain injury, and ‘chronic’ at >9 months for non-traumatic cases, or >18 months in traumatic cases. Chronic VS / MCS can be classed as ‘permanent’ when there has been no further change in trajectory of serial CRS-R for 6 months. In permanent PDOC it is predicted that consciousness is highly improbable to recover. It is important to remember these time frames, and their implications during discussions with family, when making best interests decisions and planning further assessments of consciousness.^5,10,11

With the longer time period for potential emergence, and improved survival rate compared to VS, GPs are more likely to come across these patients in the community. Figure 1 outlines the key time points for assessment of VS and MCS.¹²

Figure 1: Timeline for assessment of VS & MCS.⁵

Emergence

A patient is considered to have ‘emerged’ from PDOC if they are able to consistently demonstrate awareness of self and surroundings. The RCP advise that patients who have emerged are able to do at least one of the following:⁵

• Functional interactive communication (accurate yes/no responses to 6/6 basic questions on 2 consecutive evaluations).
• Functional use of objects (intelligent use of ≥2 objects on 2 consecutive evaluations).
• Consistent discriminatory choice-making (correct identification between 2 pictures, 6/6 times, on 2 consecutive evaluations).

Specialist Involvement

Early specialist input from a neurological rehabilitation team is recommended. The Royal College of Physicians Guideline Development Group advise that those with an ongoing disorder of consciousness at 4 days (Glasgow Coma Scale ≤10/15) should be referred for assessment, and advice regarding neurological disability and prevention of complications.^5,13 At 2 weeks the patient should be referred for specialist neurological evaluation to identify the cause of the disorder of consciousness, assess the primary neurological pathways, and advise on further investigations.

Patients with ongoing disorder of consciousness at 4 weeks should have regular input from a specialist neurological rehabilitation team, led by a consultant in Rehabilitation Medicine. Once stable the patient should ideally be transferred to a specialist neurorehabilitation unit for multidisciplinary care, objective assessment of level of consciousness, formal best interests decision-making, and discharge planning.

Following this initial period, the patient should be placed in a unit away from the acute setting, where they can be monitored until it is evident that they are likely to remain in VS / MCS. These ‘slow-stream’ rehabilitation units, are designed to deliver care to patients with complex neurological disability, and provide appropriate maintenance therapy to manage physical disability. Medical input is usually provided by the GP surgery covering the area, although units should also have access to rehabilitation medicine physicians with experience in managing PDOC.

If it is agreed that a patient has permanent VS / MCS, then longer-term of care can be provided in a nursing home or, if appropriate, in the patient’s own home. A skilled assessor should review the patient yearly, with formal assessment of consciousness until either the patient emerges or dies.

Medicolegal & Ethical Issues

Capacity Assessments

By definition a person in PDOC lacks capacity to make decisions about medical treatment. The Mental Capacity Act 2005 requires this to be formally documented in the medical notes. A Deprivation of Liberty Safeguard should be put in place during hospital admission or nursing / residential home stay, providing that restraint and restrictions are in the patient’s best interests.¹⁴

Identifying Advance Decisions

The team providing care need to identify as early as possible whether the patient has a valid and relevant Advance Decision, Health and Welfare Lasting Power of Attorney, or Court-appointed Welfare Deputy. If one of these is in place, the team need to request to see the relevant documentation to understand what exactly it entails.

Best Interests Meetings

All medical treatment provided must be in the patient’s best interests. In the UK, the treating clinician must by law identify those people close to the patient that can provide insight into the patient’s beliefs / previous expressed wishes / likely wishes, and take part in best interests meetings. If there is nobody to fulfil this role then an Independent Mental Capacity Advocate must be appointed. An initial best interests meeting should be held to discuss the diagnosis, likely prognosis, and to plan treatment. Further meetings should be held at planned regular intervals, for major medical decisions, and following repeat assessments to decide future management, discharge planning, and ceilings of care.

Ceiling of Care Discussions:

Many relatives may not feel comfortable bringing up these topics themselves, so it is advisable to make the discussion part of a routine review as standard for PDOC patients.

In patients with PDOC, cardiopulmonary resuscitation (CPR) has a very low success rate, and will likely result in further brain injury due to hypoxia. For the majority of patients where emergence is not expected, or if it is felt that the patient would not accept their level of quality of life, CPR could be considered to be futile. This is because CPR would not provide a perceivable benefit to the patient, but would carry significant risks of harm (worsening brain injury, injury related to the CPR itself, undignified end of life). Decisions regarding ceiling of care or appropriateness of resuscitation should either follow the instructions set out in existing advanced directives, or be discussed together with the treating multidisciplinary team (MDT). It is highly advisable to involve close family / friends in discussions, but ultimately it is a medical decision.

For similar reasons, it should be considered whether hospital admission for treatment of acute deterioration is in the patient’s best interests. For example in a patient with permanent VS, treating an acute chest infection may improve their lungs, but will not improve the patient as a whole in a way that can be perceived and appreciated by that patient, so may be considered futile. Additionally, it may be considered appropriate to stop medications not aimed at providing comfort, or stop performing observations and investigations. As with all major medical decisions, this should be discussed within the MDT and with those close to the patient. Although patients with PDOC have absent / reduced awareness, care should be taken to maximise patient comfort, and if appropriate consider input from the palliative care team.

Decisions relating to withdrawing clinically assisted nutrition and hydration (CANH) have previously been managed differently than withdrawal of life-sustaining treatment. Until recently, the decision to withdraw CANH could not be made without referring to the Court of Protection (COP). More recent guidance published by the BMA advises that in PDOC this is not always necessary. The treating team should first establish whether there are any valid and relevant advance directives / health and welfare attorney with relevant power, and then follow a best interests decision-making process. If all parties are agreed that withdrawal of CANH is in the patient’s best interests, then a second opinion should be obtained (from an independent, expert PDOC physician); if they also agree, then CANH can be withdrawn. If there is any doubt or disagreement about the decision, then an application to the COP is required. Now in the UK, it is essential to have best interests meetings to decide whether provision or continuation of CANH is of benefit to the patient, rather than deciding whether to withdraw it. If CANH is determined to not be of overall benefit to the patient, then it should not be continued. Prior to the withdrawal of CANH, an appropriate end-of-life care plan should be agreed and be ready to put in place.⁶

Conclusion

Disorders of consciousness can occur following brain injury, and vary from coma to MCS. If the disorder of consciousness continues for 4 weeks, it is described as a PDOC. Diagnosis requires structured assessment by trained clinicians, once the patient is medically optimised and reversible causes are excluded. Ongoing assessment is crucial to monitor recovery, guide prognosis, and establish when the disorder is permanent.

There are many ethical and medicolegal issues involved in managing patients with PDOC, which are mainly centred on the patient’s loss of mental capacity to make decisions. The cost implications of providing care as outlined in these guidelines can be quite significant. This article reflects our experience working within the National Health Service (NHS) within the UK, which provides free healthcare to all at the point of delivery. Therefore the costing is less relevant to the patients, although this does need to be considered when commissioning services. In other private healthcare settings, costs may vary widely based on hospital and wider multidisciplinary team costs, and this may need to be taken into account when commissioning services. Also, we appreciate that in other countries there are likely to be different laws surrounding PDOC, and varying views regarding the ethical decisions discussed.

Currently, these guidelines are based on expert opinion from the Royal College of Physicians Guideline Development Group. In future, management of patients with PDOC could be improved with the establishment of a national registry, further studies into PDOC, and better integration with community services. Furthermore, an improved education about PDOC and the issues surrounding it, as we have aimed to outline in this article, will help physicians understand their responsibilities and provide the best possible patient care.

Background:

In December 2019, the Wuhan province of China was struck by an outbreak of viral pneumonia due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or COVID-19.¹ On the 30^th of January, WHO declared a state of global emergency due to the rapid spread of COVID 19 ² and since then it has developed into an epidemic, contributing to over 247,000 global deaths as of 4^th May 2020. COVID-19 has commonly presented with respiratory symptoms, but some gastrointestinal symptoms have also been described.^{3, 4} Here we describe a rare case of COVID-19 presenting with acute psychosis with initially false negative RT-PCR nasopharyngeal swab upon hospital admission.

Case Review

A 40 year old, previously fit and healthy male, with a six day history of dry cough, breathlessness and nasal congestion, presented to accident and emergency via ambulance. Prior to the respiratory tract symptoms, he had a progressively worsening fever, anosmia and intermittent diarrhoea for four days. His observations included a temperature of 39⁰C, oxygen saturations of 95% on room air and a respiratory rate of 30. His initial laboratory tests are shown in Table 1 and imaging in Figure 1.

Table 1: Table showing the relevant laboratory results of the patient upon admission

Figure 1: (Left) An AP X-ray showing bilateral patchy consolidation. (Right) A cross-sectional CT thorax image showing multifocal, peripheral, bilateral, ground-glass opacities with bilateral consolidation.

Over the course of the next two days, he developed acute confusion. A CT scan of his head was done in the first instance to identify any intracranial cause of confusion, but the scan was unremarkable. His behaviour included severe anxiety, aggression, wandering and agitation. His wife confirmed that he had never behaved like this before and had no history of psychiatric illness. He felt as if he was living in a dream, exhibiting derealisation and depersonalization. Worryingly, he also experienced suicidal ideation which he hoped would bring him back to reality. One of the ways in which he tried to kill himself was by jumping out of the hospital window. Due to verbal and non-verbal de-escalations being ineffective, 5mg of Haloperidol was given, but failed to settle the patient. This was the maximum daily dose of haloperidol in accordance with the British Geriatric Society Guidelines for the management of COVID-19 related confusion⁵. Subsequently, the patient was successfully managed with intubation and ventilation for 24 hours, despite the absence of respiratory failure. After extubating, he recovered back to baseline over 2 days, during which a 2^nd RT-PCR nasopharyngeal swab result returned positive for COVID-19. After recovery, he had insight into the events that took place prior to intubation. Retrospectively, he reported auditory hallucinations of hospital staff talking about him all day and night, and the delusions that the hospital staff were against him, and that he was in a dream which could only be escaped by committing suicide.

Discussion

There are two clinically relevant learning points to convey from this case relating to, firstly, the difficulties encountered in diagnosis and, secondly, the management of acute psychosis in COVID-19 with intubation. The diagnosis of COVID-19 was confounded by the first nasopharyngeal RT-PCR swab being negative. Since his symptoms were typical of COVID-19 and with strongly suggestive radiographic findings, it was deemed appropriate to send a repeat COVID-19 nasopharyngeal RT-PCR swab (which indeed came back positive). This patient thus had COVID-19 pneumonia and the official diagnosis was delayed due to a false negative nasopharyngeal RT-PCR swab upon hospital admission.

Various studies have identified a high false negative rate with the COVID-19 swab.^{6, 7} Ai et al., describes 287 patients (n=1014) who had radiographic findings suggestive of COVID-19 with negative nasopharyngeal swabs.⁸ It is important for clinicians to be aware of the poor sensitivity of the RT-PCR COVID-19 swab so that it can be interpreted appropriately when being used to make clinical decisions. Various studies have estimated the RT-PCR COVID-19 swab sensitivity to be approximately 70-75%.⁹ This is hypothesised to be even lower if clinical staff do not use the correct technique when taking the nasopharyngeal swab. Subsequently, there is a growing clinical need for more sensitive laboratory tests for COVID-19 such as antibody tests.¹⁰

Chest radiographs may be normal in early or mild disease, but can assist diagnosis. Of patients with COVID-19 requiring hospitalisation, only 69% had an abnormal chest radiograph at the initial time of admission. Findings are most extensive about 10-12 days after symptom onset. The most frequent findings are bi-basal, peripheral, consolidative and ground-glass airspace opacities. In contrast to parenchymal abnormalities, pleural effusion is rare.^{11, 12} Indeed, this patient’s chest radiograph shown in Figure 1 (left) was performed after 10 days of symptoms, showing features of COVID-19.

The primary findings on CT have been reported in multiple studies to include ground glass opacification, ‘crazy-paving’ texture, air space consolidation, broncho vascular thickening, adjacent pleural thickening and traction bronchiectasis. The ground glass, or consolidative, opacities are usually bi-basal, peripheral and ill-defined.^13-18 Four stages on CT have been described, as shown in Table 2 below.^{19, 20} This patient’s CT Thorax shown above in Figure 1 (right), was performed after 12 days of symptoms and displays features in keeping with the ‘peak’ stage.

Table 2: Table showing the radiographic staging of COVID-19

It is important to mention that in a retrospective, COVID-19 case-controlled study of 104 patients, 54% of asymptomatic patients had CT radiographic features in keeping with COVID-19.²¹ CT scan changes are estimated to be as high as 97%-98% sensitive and can thus be useful when there is a strong suspicion of COVID-19 despite negative nasopharyngeal swabs.^{8, 9, 22} This can avoid clinicians having a false sense of security when managing potential COVID-19 patients who may otherwise be nursed in open bays, consequently exposing unprotected clinical staff and patients; a common problem that we unfortunately encounter in our clinical practise.

The second interesting learning point in this case is with regards to the clinical reasoning behind why this patient was intubated. Patients with severe COVID-19 symptoms such as hypoxaemia, respiratory distress, shock or an SpO2 of <90% are usually commenced on supplemental oxygen therapy of 5L/min, which should then be titrated to maintain an SpO2 of >94%. Continuous positive airway pressure or non-invasive ventilation can then be trialled, and if ineffective, the patient can be intubated for ventilation.²³ This patient’s SpO2 prior to intubation was 94%. Interestingly in this case, the clinical reasoning behind intubation was not respiratory failure, but instead acute psychosis secondary to COVID-19 which had failed to respond to conservative de-escalation measures, as well as haloperidol.

The intubation of this patient aimed to reduce respiratory effort, cross-infection risk, as well as prevent further suicide attempts. As mentioned in the history above, this patient was non-compliant with isolation regulations as he was severely confused and wandering around clinical areas, thus posing a cross-infection risk to staff and other patients.²⁴ Self-isolation precautions have been heavily implemented in the UK because COVID-19 is an extremely virulent infectious disease.²⁵ The basic reproductive number of COVID-19 has been estimated to be 1.55-5.5,^26,27 making it more infectious than the seasonal influenza, at 1.28.²⁸ This highlights the importance of strictly following isolation protocols, and thus, the rationale behind intubation.

Conclusion

There are two primary learning points to be appreciated from this case report. Firstly, the false negative rate with RT-PCR COVID-19 nasopharyngeal swabs is high, and this identifies a crucial diagnostic role for CT Thorax in ‘swab-negative’, symptomatic patients with suspected COVID-19. Secondly, acute psychosis is an emerging indication for intubation to consider when managing patients with highly virulent respiratory infections, such as COVID -19. The mechanisms behind COVID-19 induced acute psychosis remained yet to be elucidated, but, in this case, COVID-19-induced encephalitis was amongst the differential diagnoses.

Introduction

Convex probe EBUS-TBNA has been a major development in respiratory medicine. In the last decade we have seen numerous articles supporting the high diagnostic accuracy of EBUS-TBNA in the diagnosis of lung cancer, staging of lung cancer, diagnosis of extra-thoracic malignancies & benign conditions (e.g., TB & sarcoidosis)¹. Patients included in this study reflect the real-life referrals that we see as respiratory physicians in our daily practice. This shows that the trend of doing EBUS-TBNAs for non-cancer patients is rising. Lung cancer is a common cause of cancer death worldwide². Various guidelines (including NICE) have found this procedure safe & recommend it for the staging of lung cancer. In the last 10 years, lots of district general hospitals have started this service in UK & it is mainly delivered by respiratory physicians.

This has provided a specialist service for patients in their local area, which has reduced travelling and waiting times.

Setting & Methods

In this district general hospital under discussion, EBUS service was setup in 2018, under supervision of a tertiary care centre. We carried out 82 procedures during the first year of this service. All of these cases were reviewed for this article. Data was recorded on an excel spreadsheet (data included: number of cases, age, gender, lymph node stations sampled, complications, pathology & microbiology results of EBUS TBNA). Minimum of 4 passes were done at each lymph node station. Where EBUS was done for diagnostic purposes, stations to be sampled were at the discretion of the operator. Samples obtained via EBUS-TBNA were flushed into CytoLyt (methanol-water solution). EBUS-TBNAs were carried out in the absence of rapid on-site evaluation (ROSE). Where a cancer was suspected but EBUS-TBNA showed normal findings, samples were obtained via another modalities (e.g., CT biopsy) & FDG PET was carried out as well (if not done already). In cases of isolated mediastinal & hilar lymphadenopathy (IMHL), where EBUS-TBNA did not reveal any pathology, interval surveillance CTs were carried out for monitoring purposes. Where lymphadenopathy did not resolve, surveillance scans were carried out for a year. The outcomes of these surveillance CTs & PET CTs were also reviewed for this study. Diagnosis of reactive lymphadenopathy was made if EBUS-TBNA sample did not reveal any pathology, repeat CT did not show any change (or showed reduction/ resolution of lymphadenopathy) & the clinician did not consider the patient to have another diagnosis. EBUS-TBNA was labelled as false negative, if pathology result was negative, but node was positive on PET (in suspected cancer patients).

Results

Out of these 82 patients who underwent EBUS-TBNA, 55 (about 67%) were male & 27 were female (about 33%) (Figure 1).

The age range of patients at the time of procedure was 28 to 88 years. Majority of the patients were between the age of 52 – 88 years (80% of the cases) (Figure 2).

The 82 EBUS-TBNA procedures were carried out for the following main reasons (Figure 3):
A. 42 procedures for cancer reasons (i.e. 51% of the total procedures)
a. For diagnosis of lung cancer (38 procedures)
b. Diagnosis of suspected extra-thoracic cancer (3 cases)
c. Staging of lung cancer (1 case)
B. 40 procedures for IMHL (i.e. 49%)

The final diagnoses in 38 procedures carried out for “diagnosis of lung cancer” were as follows:
1. 25 patients were diagnosed with lung cancer (12 squamous cell cancers, 7 adenocarcinomas, 4 small cell cancers, 1 undifferentiated lung cancer & 1 neuroendocrine tumour)
2. Final diagnosis in 9 cases was reactive lymphadenopathy (repeat CT showed resolution of lymph nodes in 3 cases, reduction in the size in 1 case & stable nodes in 5 cases)
3. Extra-thoracic malignancies were diagnosed in 2 cases (1 metastatic prostate cancer & 2^nd was metastatic disease from primary parotid gland tumour)
4. We had false negative results in 2 cases (1 patient was diagnosed with small cell lung cancer on CT biopsy & 2^nd with adenocarcinoma on ultrasound biopsy)

It was found in 11 cases, where the clinicians initial suspicion was a possible lung cancer, that the final diagnoses were reactive lymphadenopathy and extra-thoracic malignancies.

Some of these patients had lung nodules as well (along with mediastinal & hilar lymphadenopathy). These nodules either resolved or remained stable. In the case of metastatic prostate cancer, prior MRI showed prostate confined disease & the clinician suspected this size significant lymphadenopathy to be due to a lung primary. In the case of metastatic parotid tumour, the initial diagnosis of parotid cancer was a very long time ago & metastatic disease was not expected.

Final diagnoses in 3 patients who had EBUS-TBNA for “extra-thoracic malignancies” were as follows:
1. Prostate cancer (here pelvic MRI showed locally advanced disease)
2. Colon cancer (known colon cancer)
3. Ovarian cancer (patient had ovarian mass & abdominal/pelvic lymphadenopathy)

As most of the surgical patients go directly to tertiary care centres (from this hospital), we therefore didn’t have many patients for staging purposes during the 1^st year of the service. We only had 1 patient for “staging EBUS-TBNA” during this time. In this case stations 4L, 7 & 12L were sampled. Only station 12L was PET positive & also positive on EBUS-TBNA sample. Station 4L & 7 were PET and EBUS-TBNA negative. There was no size significant nodes seen on staging CT in any other area, only 12L node was PET avid & we were not able to identify any size significant lymphadenopathy at any other station via EBUS as well. Sensitivity in this staging EBUS was 100%.

In these 42 diagnostic & staging procedures (carried out for cancers or suspected cancers), summary of the pathological diagnoses from lymph nodes aspirates is as follows:
1. Squamous cell carcinoma of lung 13 approximately (31%)
2. Adenocarcinoma of lung origin 7 approximately (17%)
3. Small cell lung cancer 4 approximately (9.5%)
4. Neuroendocrine tumour of lung origin 1 approximately (2.3%)
5. Undifferentiated lung cancer 1 approximately (2.3%)
6. Metastatic prostate cancer 2 approximately (4.75%)
7. Metastatic parotid gland cancer 1 approximately (2.3%)
8. Metastatic ovarian cancer 1 approximately (2.3%)
9. Metastatic colon cancer 1 approximately (2.3%)
10. False negative 2 approximately (4.75%)
11. Reactive lymphadenopathy 9 approximately (21.5%)

Out of the 40 procedures for IMHL, we were not able to get an adequate sample in 1 case and this patient underwent repeat EBUS-TBNA. Repeat sample showed granulomas; findings were consistent with the clinical diagnosis of sarcoidosis. Final diagnoses in these 40 cases are as follows:
1. Metastatic adenocarcinoma from pancreaticobiliary origin = 1 (2.5%)
2. Bronchogenic cyst = 1 (2.5%)
3. Insufficient sample = 1 (2.5%)
4. Tuberculosis = 3 (7.5%)
5. Granulomas = 16 (40%)
6. Reactive lymphadenopathy = 18 (45%)

Serious diagnoses were made in 10% cases of IMHL (4 out of 40). One patient had metastatic adenocarcinoma from pancreaticobiliary origin & didn’t have any abdominal symptoms or any abnormalities on CTs in the abdomen. 3 patients were diagnosed & later treated for active tuberculosis. Out of these 3 patients only 1 had features of active disease, but sputum negative. The other 2 patients had only mediastinal lymphadenopathy, no lung infiltrates & no sputum production.

A total of 122 lymph nodes were sampled. Details are as follows (figure 4):

Commonly sampled nodes were station 7 nodes. This is consistent with international literature published on EBUS-TBNA.

There were no complications from the procedures performed. None of our patients experienced significant airway bleeding (requiring admission or blood transfusion), mediastinal infection, pneumothorax, pneumo-mediastinum, haemo-mediastinum or airway lacerations.

Discussion

EBUS TBNA is one of the methods to access the mediastinal & hilar lymph nodes. This is a minimally invasive way to get samples from these nodes. Several invasive, minimally-invasive & non-invasive techniques are available to diagnose & stage lung cancers. Choice depends upon the extent of the disease. About 50% of lung cancer patients have evidence of metastatic disease at the time of presentation ³. Patients with intrathoracic disease undergo several investigations. Now we know that EBUS-TBNA should be considered as the initial investigation for patients with early stage suspected lung cancer ⁴. Research carried out has shown that EBUS-TBNA had a sensitivity of 90% ⁵. A recent national BTS audit on bronchoscopy & EBUS showed national diagnostic sensitivity of 90% for staging EBUS-TBNA. BTS quality standards statement sets target of 88% sensitivity for staging EBUS-TBNA⁶. As far as diagnostic EBUS-TBNA is concerned, we had 2 false negative results out of 41 (4.8%), that gives the sensitivity for diagnostic procedures of 95.2%.

There is significant evidence available that ROSE does not increase the diagnostic yield of even conventional TBNA ⁷. Trisolini et al demonstrated in this randomised controlled trial that ROSE did not give any significant diagnostic advantage & did not affect the percentage of adequate specimens. Articles have also shown that ROSE does not reduce the EBUS-TBNA procedure time ⁸. The use of immunohistochemistry on EBUS-TBNA reduces the rate of unclassified non-small cell lung cancer when compared with cytological diagnosis alone ⁹. EBUS-TBNA samples are sufficient to allow immunohistochemical and molecular analysis. I am happy to say that we were able to get ALK, EGFR & PDL1 testing on the EBUS-TBNA samples (where indicated), at our centre. The presence of a cytopathologist or cytotechnologist during the procedure for ROSE purposes can increase the cost significantly. This increased cost can have a significant impact on starting the service at the level of a district general hospital. Another issue which needs clarification, is the number of passes required before declaring the material is inadequate while using ROSE technique. Studies have shown that significant number of samples inadequate on ROSE were still able to give a diagnosis with the help of immunohistochemical analysis.

Here we have seen that 40 EBUS-TBNA procedures were carried out for IMHL. Unfortunately, in this group, one patient was diagnosed with unexpected malignancy, i.e., metastatic adenocarcinoma of pancreaticobiliary origin. In the remaining cases we had benign diagnoses. In the IMHL group about 45% cases had the diagnosis of reactive lymphadenopathy. Out of the total number of 82, about 33% cases were diagnosed with reactive lymphadenopathy. We made the diagnosis of reactive lymphadenopathy in patients where EBUS samples showed normal lymphocytes; these patients had surveillance CTs & clinical follow up as well. Clinicians’ impression & surveillance scans were also reviewed for the purpose of this diagnosis. In this IMHL group, 40% cases were diagnosed with sarcoidosis. In these cases, in addition to clinicians’ impressions, we reviewed cytology, microbiology & surveillance CT reports. Processing method for specimens impacts on the yield for granulomas. Cell block preparation, as carried out in this hospital, showed higher yield for granulomas ¹⁰.

During the first year of the EBUS service at this centre, there was no suspected or diagnosed lymphoma patient who underwent this procedure. International data suggests, for the diagnosis of lymphoma, EBUS-TBNA aspirates should be sent for cytopathology, immunohistochemistry, flow cytometry, cytogenetics and molecular studies ^11,12,13.

Conclusion

EBUS-TBNA is a safe & minimally invasive procedure. It is a first line investigation for lung cancer staging. EBUS-TBNA has been effective in diagnosing extra-pulmonary malignancies ¹⁴. In the last decade we have also seen that its utility has increased significantly in diagnosing benign conditions like sarcoidosis and TB.

We feel operators’ training is also very important in achieving excellent results. Mastering the complexity of this procedure is time consuming. Standardised training is mandatory to achieve high skill levels¹⁵ and we hope there will be a standardised approach to this in future.

Introduction

Acute upper gastrointestinal bleeding presenting as either hematemesis or melena or both is an important medical emergency. The etiological spectrum of upper gastrointestinal bleeding (UGIB) varies from region to region¹. Various endoscopic therapy for patients with signs of recent haemorrhage in peptic ulcer have changed the outlook of UGIB management. An addition of proton pump therapy to non-variceal UGIB has further reduced hospital stay, recurrent bleeding and need for surgery². Another milestone in the decline of UGIB has been eradication of H pylori. Globally, the prevalence of H. Pylori infection has decreased due to better hygiene, early diagnosis and eradication³. These factors have contributed to the changing trends in UGIB. The patients with UGIB have 50% incidence of H. pylori infection positivity and re-bleeding occurs in 7-16 % of the total cases¹. Once frequent UGIB due to peptic ulcer have now declined all over the globe as demonstrated by various researchers ^4,5,6. Unfortunately, despite advancement in endoscopic and pharmacological treatment, the mortality in UGI bleeding ranges between 3 and 14%⁷. Particularly, patients with UGI bleeding due to the duodenal ulcer are known to be more prone to death as demonstrated by Quan et al⁸. The advanced age and patients admitted in hospital with comorbidity are at an increased risk of re-bleeding and mortality. Re-bleeding and mortality rates are higher among patients with variceal bleeds and invariably 50-60% of patients with cirrhosis have variceal bleeding¹. This warrants a careful approach in the management of UGI bleed. To predict the re-bleeding rates in a given case of UGI bleeding various clinical and endoscopic models have been developed from time to time. Of these – Rockall score, combining clinical (Age, shock, presence of co-morbid diseases) and endoscopic findings have proved quite valuable in the prediction of hospital admission duration and mortality rate⁹. The reason for the feasibility of Rockall score is that it depends mainly on simple clinical data and after an endoscopic procedure the score becomes more practical ⁹. The Rockall score divides patients into 4 subgroups according to their clinical data to estimate death and re-bleeding tendency. While comparing Rockall score, Blatchford scores at first assessment, and the Addenbrooke score it was concluded that Rockall score has an accuracy of 98% in predicting death, and was sensitive in 86.4% of cases in predicting re-bleeding¹⁰. Hence we calculated Rockall score in our study cohort and assessed various prognostic factors including changing trends over the past decades.

Methods

Study design

This retrospective study was conducted from January 2015 to December 2017 at King Abdul Aziz Specialist hospital Taif, a tertiary care centre in the western region of Saudi Arabia. The data was collected from case files and electronic medical records. The data about age, comorbid diseases, presence of shock, endoscopic intervention, hospital stay duration, the requirement for blood transfusion, surgery were collected to measure the outcome of UGI bleeding.

Depending upon hemodynamic status upper GI bleeding patients were managed either in the intensive care unit (ICU) or high dependency unit of the hospital. Blood transfusion had been given to maintain Hb levels above 8gm/dl. Platelets transfusions if the platelet counts were < 70,000 and fresh frozen plasma when INR was deranged in chronic liver disease patients.

The recurrent bleeding was defined by hematemesis, melena, or both, with either shock

(pulse rate>100 beats/min, systolic blood pressure< 100mmHg accompanied by cold sweats, pallor, oliguria) or a decrease in haemoglobin concentration of 2 g/dL over 24 hours.

Re-endoscopy, if needed, was used only to confirm recurrent bleeding.

The timing of UGI endoscopy after admission was recorded in each patient. The details of stigmata of recent haemorrhage (spurting vessels, active bleeding in an ulcer, a visible vessel, or a clot over the ulcer that could not be dislodged upon gentle washing with water delivered through the endoscope channel). Rockall score was calculated in all patients.

Patients with variceal bleeding were primarily managed with octreotide infusion ,antibiotics and endoscopic variceal ligation (EVL) or endoscopic sclerotherapy (EST) depending upon the situation. All patients were followed for rebleeding clinically and by haemoglobin levels during their hospital stay. Patients who remained hemodynamically stable for 72 hours were discharged.

After the fifth day, patients positive for H. pylori on CLO test during endoscopy received triple therapy (Capsule Amoxicillin 1gm twice daily and Tab. Clarithromycin 500 mg twice daily for 2 weeks. Tab. Es omeprazole 20mgdaily twice daily was continued for 4weeks. The patients who were H. pylori-negative received Tab. Esomeprazole 20 mg twice daily for 4 weeks.

Inclusion criteria:

• Patients with confirmed upper GI bleeding (variceal and non-variceal) were enrolled in this study.
• The variceal bleeding due to portal hypertension included both cirrhotic & non-cirrhotic patients.

Exclusion criteria:

• Patients with terminal cancer.
• Patients with upper GI bleeding where endoscopy had not been done due to any reason and Rockall score could not be calculated.
• Patients with persistent shock necessitating emergency surgery, as a life-saving procedure.

Statistical methodology:

Data were statistically described in terms of frequencies (number of cases) and valid percentages for categorical variables. Mean and the standard deviation was used to describe parametric numerical variables while the median and inter-quartile range were used for non-parametric variables. Spearman's rho test was used for testing the correlation between the non-parametric numerical variable (Rockall score) and patients’ age. All statistical calculations were done using computer program IBM SPSS (Statistical Package for the Social Science; IBM Corp, Armonk, NY, USA) release 21 for Microsoft Windows.

Results

A total of 120 participants (76 males,63.3%) with a mean± SD age of 58. 4± 18. 7 years, were included in this study. The Rockall score showed a median (IQR) value of 3 which indicates a low to moderate risk of bleeding recurrence and death.

Majority of the study cohort [n=88(74%)] were Saudi nationals and [32(6.7%)] patients were from other nations. All patients had received an initial resuscitation as per the UGIB protocol of the hospital. Of 120 patients, 30 patients (25%) had undergone endoscopy immediately after admission in the intensive care of the hospital due to hemodynamic instability. Fourteen patients (11.7%) had undergone endoscopy within 6 hours of hospital admission and 63% patients had undergone endoscopy within 24 hours of hospital admission. The details are shown in figure 1.

The Rockall score was calculated for all patients based on their age, presence of shock, comorbidities, diagnosis and major stigmata of recent haemorrhage. The details are shown in table 1.

Table 1: Parameters of Rockall score in the non-variceal bleeds

It was observed that 46(38.3%) patients had undergone endoscopic variceal ligation (EVL) , and 20(16.7%) patients endoscopic sclerotherapy (EST) .

Heater probe had been used in 5.0% and Gold probe in 5.0% of patients with signs of recent haemorrhage (SRH) . Nevertheless, 48(40.0%) patients had no features of SRH therefore they had not received any endotherapy. Instead they had been managed with IV proton pump inhibitors as per the protocol and supportive treatment.

The data on final EGD diagnosis are shown in table 2.

Table 2: The Most Frequent EGD Diagnoses

(CLD: Chronic liver diseases, GI: Gastro intestinal, EGD: oesophagogastroduodenoscopy, PHT: Portal hypertension)

None of the study cohort patients had undergone surgery to control his or her UGI bleeding and there was no mortality due to UGIB recorded during this period.

In order to test the correlation between Rockall score and age, spearman rho correlation test was carried out and data showed a significant (p<0. 001) moderate positive relationship (correlation coefficient=0. 553) between age and Rockall score of included patients. This means a lower tendency for recurrent bleeding and a lower mortality rate among younger patients.

Discussion

The results of our study showed that hematemesis was the most frequent presenting symptom of UGI bleeding. These results are similar to the study by Minakari et al ¹¹, however, majority of the patients in the above-mentioned study had a peptic ulcer as the commonest aetiology. Contrary to their results portal hypertension outnumbered the peptic ulcer disease as shown in Table 2 in this study. UGI endoscopy had been carried out immediately after admission in 25% of the patients due to ongoing bleeding and the majority of patients had UGI endoscopic examination within 24hrs as shown in Fig1.

Figure 1: Timing of Esophagogastroduodenoscopy (EGD) after hospital admission

While assessing the endoscopy timing especially among variceal bleeding Hsu YC et al ¹² concluded that the delayed endoscopy for more than 15 hours , high MELD score, failure of the first endoscopy and hematemesis were independent risk factors for in-hospital mortality in cirrhotic patients with acute variceal haemorrhage. The cirrhotic patients in our study cohort were either Child-Turcotte-Pugh class A or B and none of the patients had hepatic encephalopathy on presentation. After endoscopic therapy, they were managed with standard treatment for variceal bleeding.

The prevalence of H. pylori positivity among UGI bleeding in this study was 60% and all positive patients had been given standard eradication therapy. Data from a different Saudi Arabian centre revealed H. pylori prevalence to the tune of 70% affecting predominantly females in patients with peptic ulcer disease¹³ but authors had not studied it’s prevalence in UGI bleeding.

This study demonstrated rebleeding in 16 (13. 33%) patients who were re-endoscoped and bleeding was controlled by various endotherapies. In this study re-bleeding was found to be more frequent among older patients with comorbidities. Rebleeding was also common among patients with history of NSAID intake and presence of oesophagal varices which is following literature¹⁴. While comparing present results with previous data we observed that previously the commonest cause of UGI bleeding was a duodenal ulcer it is the variceal bleeding due to cirrhosis (HCV) now. We also compared the results of the current study with previous studies across different parts of the globe^14,15,16. Duodenal ulcer previously used to be the most frequent cause and invariably various surgical methods like vagotomy etc were used to control bleeding prior to PPI era. However, with the advent of PPI and H pylori eradication the frequency of UGI bleeding due to peptic ulcer have declined.

We recorded only 120 patients with UGI bleeding over three years at our centre nevertheless, this may not reflect the true incidence in the region as it was the data from a single centre only. But the overall incidence of UGI bleeding has decreased over the past decades all over the globe. The study by Loperfido et al¹⁷ compared the incidence of 587 patients with UGIB between 1983-1985 and 2002-2004 period. The authors observed that UGI bleeding decreased from 112.5 to 89.8 per 100,000/y. The peptic ulcer incidence also decreased to the half between the two studied periods. In the above-mentioned study it was also revealed that frequency of ulcer bleeding decreased by 41.6% in people younger than 70 years. There has been an obvious change in the trend of UGI bleeding in Saudi Arabia over the past 23 years like other regions of the globe. The number of patients with UGI bleeding has decreased and aetiology of UGI bleeding has also shifted from an ulcer to variceal one.

In a large study, published in 1995 ,the data on 1246 patients over 14 years Al Karawi et al¹⁸ observed that duodenal ulcer was the most common cause of UGI bleeding followed by varices. The bleeding rates per annum in their study was 89 cases per annum while this study recorded only 40 admissions of active UGI bleeding per annum. Further, the variceal bleeding outnumbered the duodenal ulcer bleeding contrary to their results connoting a changing trend in Saudi Arabia. The data from southern region of Saudi Arabia also showed variceal bleeding to be the commonest cause of UGI bleeding ¹⁹.

In yet another study from Riyadh central hospital, it was revealed that most of the patients with UGI bleeding were having oesophagal varices²⁰. Non cirrhotic portal hypertension (NCPH) was documented in 8 patients in the current study and all were hailing from Egypt which is an endemic region for schistosomiasis and NCPH. The predominant cause of portal hypertension was Chronic liver disease due to chronic HCV in this study. While studying the pattern of liver disease in Saudi Arabia Fashir B et al²⁰ have demonstrated HCV to be the commonest cause of CLD in this part of the globe. This reflects that meticulous screening and treatment of chronic HCV can go a long way in the reduction of UGIB in the region. Having said this it may not be out of place to mention that keeping in view the global epidemic of obesity variceal bleeding due to CLD following NASH may steep up in coming years and become the important cause of UGIB. This highlights a red alert to curb the menace of obesity all over the globe and halt the increasing trend of variceal bleeding in future.

Regarding the trend of gastric ulceration, UGI bleeding has now shifted from H. Pylori infection to the massive use of medications such as NSAIDs or steroids, all over the world¹⁶ especially among older people. We demonstrated drug-induced UGI bleeding in 20(16%) patients in this study as shown in table 2. Further the use of warfarin is estimated to increase as the population ages and atrial fibrillation , other cardiovascular ailments are increasing steadily. In a study by McGowan et al²² Tablet Warfarin was an independent predictor of major bleeding after the percutaneous coronary intervention (PCI) in patients receiving dual antiplatelet therapy.

Another most common diseases in the elderly population is Rheumatoid arthritis (RA) . Rheumatoid arthritis is considered as a comorbid disease in the Rockall score and increases the scale for mortality and hemorrhagic shock. The wide use of NSAIDs in RA patients steeps the incidence of peptic ulcers and its complications including UGIB²³. This risk is significantly elevated when SSRI medications in combination with NSAIDs are prescribed to allay anxiety and depression in these chronic disorders. The physicians prescribing these medications together should exercise caution and discuss this risk of UGIB with patients²⁴.

UGI bleeding due to malignancies were noted in 4 patients in our study cohort which is similar to the data shown in the southern region of Saudi Arabia¹⁹.

In this study, about 12-16% of the patients were diagnosed with either gastric ulcer or hemorrhagic gastritis. The data from Arar, the northern Saudi Arabian city , revealed prevalence of gastric ulcer to be twice as common as duodenal ulcer. The authors of this study observed that the use of NSAIDs, H. Pylori infection and stress were among the most relevant reasons for developing peptic ulcer disease , however authors in their study didn’t study bleeding complications of peptic ulcer disease²⁵.

Conclusion

Based on discussed results, it can be concluded that the frequency of UGI bleeding has declined and peptic ulcer is no longer the most predominant cause of UGI bleeding in Saudi Arabia. Instead, variceal bleeding outnumbers other causes of UGIB. This changing trend now demands that to prevent variceal bleeding we need to focus on the management of chronic HBV, HCV and NASH. Further all medications especially NSAIDs must be cautiously used particularly in elderly people. A step further would be to control hypertension and subsequent atrial fibrillation so that drug-induced UGI bleeding are reduced in future.

Introduction:

According to DSM V, delirium is defined as disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). This disturbance develops over a short period of time and it represents an acute change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.

The focus of the researchers has shifted from treatment to prevention of the syndrome. There is a need to study risk factors for prevention of delirium¹. Data on delirium in the intensive care unit is scarce in the Indian subcontinent².

A multicenter study indicated risk factors significantly contributing to delirium were related to patient characteristics (smoking, daily use of more than 3 units of alcohol, living alone at home), chronic pathology (pre-existing cognitive impairment), acute illness (use of drains, tubes, catheters, use of psychoactive medication, a preceding period of sedation, coma, mechanical ventilation) and the environment (isolation, absence of visit, absence of visible daylight, transfer from another ward, use of physical restraints)¹. Psychoactive medications can provoke a delirious state. Lorazepam has an independent and dose related temporal association with delirium³.

Each additional day spent in delirium is associated with 20% increased risk of prolonged hospitalisation and 10% increased risk of death⁴.

Hence, the present study was done to assess risk factors and precipitating factors of delirium in a medical intensive care unit of a tertiary care hospital.

Materials and methods:

This is an observational study done over a period of 1 year in a tertiary care medical college hospital located in southern part of India. Ethical committee approval for the study was obtained from the institutional ethical committee.

All patients admitted to medical intensive care unit in our tertiary care hospital, were screened for presence of delirium during the first 72 hours of admission using Richmond Agitation Sedation Scale (RASS) and Confusion Assessment Method for ICU (CAM-ICU). Patients with delirium were classified as delirious and the remaining as non-delirious patients. Comatose patients (RASS score -4 or -5) were excluded from the study.

Patients were initially screened with Richmond Agitation Sedation Scale (RASS). It is a 10-point scale, with 4 levels of agitation (+1 to +4) and 5 levels of sedation (-1 to -5). Level zero indicates calm and alert patient. Patients with RASS score of -4 or -5 (deep sedation and unarousable patients) were excluded from the study. Patients with RASS score of +4 to -3 were then screened for presence of delirium using Confusion Assessment Method for ICU (CAM-ICU). CAM–ICU has 4 criteria:

1) Acute onset and fluctuating course of delirium

2) Inattention

3) Disorganized thinking

4) Altered level of consciousness

The diagnosis of delirium requires the presence of criteria 1 and 2 and of either criterion 3 or 4.

Risk factors for developing delirium were assessed in the study population. Risk factors are those proven factors which may also be present before patient’s admission to intensive care unit, and which predispose the patient to develop delirium. Risk factors were compared between delirious and non-delirious patients. Risk factors which were assessed were history of diabetes and hypertension, history of previous stroke, history of previous cognition impairment, history of previous psychiatric illness, history of previous trauma, history of previous episodes of delirium, history of bowel and bladder disturbances prior to admission (such as constipation and urinary retention respectively), history of alcohol abuse (consumption of more than 2 units of alcohol), history of smoking (more than 10 cigarettes per day), history of consumption of substances other than cigarettes and alcohol (such as cannabis, cocaine etc.), history of uncorrected visual or hearing disturbances before admission, history of usage of barbiturates (such as phenobarbital), benzodiazepines (such as alprazolam, chlordiazepoxide, clobazam, clonazepam) & opioids (such as morphine) before admission, history of usage of sedatives (such as haloperidol, midazolam, fentanyl) and pain killers (such as morphine, tramadol) at the time of admission. Metabolic risk factors which were compared between delirious and non-delirious subjects were uraemia, hyponatremia, hyperbilirubinemia, metabolic and respiratory acidosis.

Precipitating factors weredefined as factors that were the likely causes of delirium in delirious patients. Precipitating factors for delirium which were looked into were exposure to toxins (alcohol/drugs), deranged metabolic parameters, infections and central nervous system causes.

SPSS21 software was used to calculate statistics. Independent t-sample test and the Pearson Chi-square test were used to calculate differences between delirious and non-delirious subjects. Odds ratios (OR) was calculated for all factors using univariate binary logistic regression.

Results:

Total number of patients enrolled in the study was 1582, of which 406 were diagnosed with delirium. Percentage of patients developing delirium within first 72 hours of admission was 25.7%. Hypoactive delirium was present in 52% and hyperactive delirium in 48% of patients. Patients who experienced delirium (57.5 + 17 years) were older compared to their non-delirious (53.3 + 18.1 years) counterparts (p value <0.0001). Among delirious subjects, majority were in the age group of 61-70 years (Figure 1).

Figure 1- Age distribution among delirious patients

38.2% of delirious patients and 39.3% of non-delirious patients were females. 61.8% of delirious patients and 60.7% of non-delirious patients were males.

Alcohol consumption [OR = 6.54 (95% CI 3.76-11.4, p = 0.0001)], previous psychiatric illness [OR = 3.73 (95% CI 1.712-8.159, p = 0.033)], previous cognition impairment [OR = 2.739 (95% CI 1.509-4.972, p = 0.001)], sedatives usage at the time of admission [OR = 2.488 (95% CI; 1.452-4.264), p = 0.001)], visual disturbances [OR = 2.227 (95% CI; 1.328-3.733, p = 0.002)], bowel and bladder disturbances [OR = 1.677 (95% CI 1.044-2.693, p = 0.032)] were significant risk factors contributing to delirium after univariate analysis (Table 1). Metabolic acidosis [OR = 1.996 (95% CI 1.469-2.711, p = 0.0001)] and hyperbilirubinemia [OR = 1.448 (95% CI 1.111-1.886, p = 0.006)] were significant metabolic parameters contributing to delirium after univariate analysis (Table 2).

Precipitating factors (Table 3) for delirium are those factors that were considered the most likely causes of delirium among the delirious patients. Precipitating factors for delirium were classified into toxins, deranged metabolic parameters, infections and central nervous system causes, of which metabolic parameters were most common. Among metabolic parameters, uraemia (25.1%), hepatic encephalopathy (22.7%) and hyponatremia (19.5%) contributed to the majority of cases with delirium.

Table 1 – Univariate analysis of risk factors of delirium

Table 2- Univariate analysis of metabolic parameters

Table 3- Precipitating factors of delirium in the present study

Discussion:

Delirium is classified into hyperactive, hypoactive and mixed type. Hyperactive subtype is present if there is definite evidence in the previous 24 hours of at least two out of the following factors - increased quantity of motor activity, loss of control activity, restlessness, wandering. Hypoactive subtype is present if there is definite evidence in the previous 24 hours of at least two of the following factors - decreased amount of activity, decreased speed of actions, reduced awareness of surroundings, decreased amount of speech, decreased speed of speech, listlessness, reduced alertness, withdrawal. Mixed subtype is present if there is evidence of both hyperactive and hypoactive subtypes in the previous 24 hours⁵. Percentage of patients with hypoactive delirium was high in this study (52%). Hypoactive delirium often carries relatively poor prognosis, occurs more commonly in elderly patients and is frequently overlooked or misdiagnosed as having depression or a form of dementia.

In the present study, delirium was more prevalent in the elderly population. Most of the elderly patients will have multiple risk factors making them more vulnerable to delirium. Delirium is often the only sign of an underlying serious medical illness in an elderly patient and particular attention should be given to identify and correct the underlying illness.

History of alcohol consumption of more than 2 units per day, prior to admission of the patient, was the major risk factor contributing to delirium in this study (OR = 6.54). This was similar to other studies done by Bart¹ et al & Ouimet⁶ et al where consumption of more than 3 units of alcohol (OR 3.23) & 2 units of alcohol (OR 2.03) respectively, was a significant risk factor for delirium. Patients with a previous psychiatric illness were at increased risk for delirium in this study (OR – 3.73). However, other studies explaining its importance in contributing to delirium were not available. Previous cognition impairment was a significant risk factor contributing to delirium (OR = 2.73). The study by Bart¹ et al found that previously diagnosed dementia was an important risk factor (OR = 2.41). Positive correlation with dementia was reported by McNicoll et al⁷ (RR 1.4) and Pisani et al⁸ (OR 6.3). Usage of sedatives (OR = 2.48) at the time of admission was a significant risk factor for developing delirium. Bart¹ et al found that use of psychoactive medication may disturb the neurotransmission in the brain provoking a delirious state and use of benzodiazepines is a risk factor for delirium (OR – 3.34). Pandharipande³ et al found that Lorazepam was an independent risk factor for daily transition to delirium (OR – 1.2). Pisani⁸ et al found that use of benzodiazepines was a significant risk factor for developing delirium with odds ratio of 3.4. Uncorrected visual disturbances were a significant risk factor for developing delirium in this study (OR-2.22). Inouye⁹ et al found that vision impairment (adjusted relative risk – 3.5) was an independent baseline risk factor for delirium. Bowel and bladder disturbances were a significant risk factor contributing to delirium in this study (OR – 1.67). Morley¹⁰ opined that constipation is a frequent, often overlooked precipitating factor for delirium. Tony¹¹ et al was of the opinion that a careful history and physical, including a rectal examination with consideration of disimpaction, may be helpful in assessing and managing delirious patients. Waardenburg¹² concluded that significant urinary retention can precipitate or exacerbate delirium, a disorder referred to as cystocerebral syndrome. Liem and Carter¹³ suggested that increased sympathetic tone and catecholamine surge triggered by the tension on the bladder wall may contribute to delirium. Metabolic acidosis and hyperbilirubinemia were significant metabolic parameters contributing to delirium in this study.Similar findings were reported by Aldemir¹⁴ et al.

Among delirious patients, most common precipitating factors for delirium in this study were uraemia (25.1%), hepatic encephalopathy (22.7%) and hyponatremia (19.5%). Alterations of serum electrolytes, renal function predispose to delirium¹⁵. Hyponatremia causes delirium and the mechanism is not well understood^{16, 17}. Blood urea nitrogen/creatinine ratio greater than 18 is an independent risk factor for delirium in general medical patients⁹.Hepatic failure leads to hyperammonemia, which leads to excessive NMDA (N-methyl-D-aspartate) receptor activation, resulting in dysfunction of glutamate-nitric oxide-cGMP pathway and causing impaired cognitive function in hepatic encephalopathy¹⁸.Excess activation of NMDA receptors results in neuronal degeneration and death¹⁹. In hepatic failure, there may be a shift in regional cerebral blood flow and cerebral metabolic rates from cortex to subcortex resulting in delirium²⁰.

Patients who develop delirium during their stay in hospital have higher 6-month mortality rates, longer hospital stay, increased economic burden and a higher incidence of cognitive impairment at hospital discharge²¹. Limitation of this study was long term follow up of patients who developed delirium was not done.

Conclusion:

Delirium is common in intensive care unit patients and hypoactive delirium is more common. Major risk factor contributing to delirium was alcohol consumption before admission. Most common precipitating factors contributing to delirium were deranged metabolic parameters.

Delirium in ICU patients especially hypoactive delirium is easily missed. Hence, all ICUs should implement both RASS and CAM-ICU for early detection of delirium. Future research needs to be directed at development of scoring systems for detection of delirium, which are easy to use and are accurate.

Introduction:

The spectrum of psychiatric illness in Systemic lupus erthyromatosus (SLE) include psychotic, depressive, subtle cognitive and personality disorders of histrionic type. The occurrence of psychiatric manifestations in SLE varies widely from 5 to 83%. It is postulated that there is a direct action of the disease on the central nervous system by autoantibodies namely anti phospholipid and anti-ribosome P auto antibodies or cytokines like interleukin 2, interleukin 6, alpha interferon ¹. During the course of the disease side-effects of glucocorticosteroids and hydroxychloroquine or anxious reaction to chronic and potentially lethal illness is postulated to be another mechanism of psychiatric manifestation of SLE . SLE patients are prone to develop myriad of psychological distress in addition to neuropsychitric manifestations which require a social and psychological support. While some of these manifestations are treated by corticosteroids and psychotropic drugs¹ medications with anticholinergic side-effects, like phenothiazines, tricyclic antidepressants and hydroxyzine which enhance the oral dryness should be avoided in SLE.

Clinical scenario:

A 27-year-old male suddenly developed aggressive behaviour for the first time in his life ,while on his work place. The patient had no insight into his illness and was brought to the local psychiatric hospital by his colleagues where he was admitted as a case of acute mania. He was managed with electroconvulsive therapy (EST) in addition to antipsychotic medication as neuro imaging including CT scan and MRI brain were normal. A few days later , the patient was discharged on anti-psychiatric medicines. However, after six months while on antipsychotic medication, he developed a low grade fever .He was admitted to a local hospital where in addition to base line investigations a lymph node biopsy was done which revealed follicular hyperplasia, without any abnormal cell. Patient’s HBV, HCV, HIV were negative. The patient developed anorexia , significant weight loss and progressive difficulty in getting up from a sitting position .He also developed shortness of breath and presented to King Abdul Aziz specialist hospital in Taif, Saudi Arabia virtually in a bed bound state . He was admitted in the intensive care unit of the hospital .The examination revealed pallor, generalised lymph-adenopathy, palmer rash, alopecia and mouth ulcers. The patient had mild pericardial effusion and Mitral regurgitation (MR)++ on echocardiography. Further evaluation showed significant proteinuria. Serum ANA, dsDNA were positive .Lupus anticoagulant was negative. Keeping in view above symptoms and signs the patient was diagnosed as a case of SLE² (Mouth ulcers, Pericardial effusion ,ANA positive , dsDNA positive ) The patient was managed with pulse dose of methylprednisolone 1g intravenously (IV) daily for 5days, followed by oral prednisone 60 mg once daily, which was tapered on follow up . Patient tolerated the treatment well and improved progressively . He became ambulatory and rejoined his job. The psychiatric medications were stopped.

However, on follow up the patient continued to have proteinuria 1.8 gm/24 hr. He was readmitted and the kidney biopsy revealed class IV lupus nephritis. He was given pulse cyclophosphamide 1gm/m² intravenously and later started on tablet Mycophenolate 1.5gm once daily. The proteinuria improved and he is following our clinic for the last two years now .Patient’s follow up investigations are shown in table 1.

Table: 1 Patients’ hospital investigations and results

Discussion:

The correct diagnosis of central or even peripheral nervous system manifestations in patients with SLE can be challenging because of many SLE-related and non-SLE-related processes present in a patient. The index case proved to have acute mania as the first manifestation of SLE which remained under oblivion till he developed serositis another complication of SLE. While this patient came to clinical attention after one year a case of SLE masquerading schizophrenia for 14 years was reported by Funaunchi et al³. In another report, a 14-year-old boy with a two-year history of cognitive dysfunction and behavioural problems SLE was diagnosed after two years⁴ . It appears that the psychiatric symptoms may occur as the first manifestation of juvenile SLE. It will not be out of place to mention that the psychiatric manifestation can be at times dire which could even result in harm to others in a given society. The case of Folie a trios syndrome, characterized by the transfer of delusional ideas from one person to two other persons culminating in murder has been reported in a patient with SLE⁵ . In a significant retrospective data from China (a cohort of 518) neuropsychiatric manifestations in SLE were observed in 96(19%) of the above study cohort . The seizure disorder accounted for the most prevalent disorder of neuropsychiatric manifestations (NP) of SLE followed by cerebrovascular disease and acute confusional states. In the above study, 96 patients with psychiatric symptoms, acute psychosis was observed in 10(11%)patients. Authors in this study were of the opinion that this percentage could have been higher if subtle cognitive dysfunction were included as well. Authors of the same study further concluded that the antiphospholipid antibodies were significantly associated with NP manifestations, especially cerebrovascular disorders⁶.

The autoantibodies have been found to be biomarkers for future neuropsychiatric events in SLE. A prospective study throughout ten years conducted among 1047 SLE patients demonstrated that individuals who had evidence of lupus anticoagulant (LA) were at an increased future risk of intracranial thrombosis. Further, those with anti-ribosomal P antibodies were at an increased future risk of lupus psychosis⁷. The Lupus anticoagulant in the index case was negative, and anti-ribosomal P antibodies were not available . A study by Sanna et al⁸ have shown that an association exists between anti-NR2 antibodies and depressed mood in addition to decreased short-time memory and learning. Authors in this study concluded that antibodies to NMDA receptors thus might represent as one of the several mechanisms for cerebral dysfunction in patients with SLE.

The CT scan brain of the index case was normal. However, massive bilateral calcification of sub-cortical structures in a patient with SLE with the psychotic disorder has been reported^9. The psychiatric diseases are related to vasculitis and non-inflammatory vasculopathy of the small cerebral blood vessels. Further, a study has shown that ninety per cent of the patients with psychosis, organic brain syndrome or generalised seizures had increased IgG antineuronal activity as compared with only 25 per cent of the patients who presented with hemiparesis or with chorea/hemiballismus. The authors in the above study concluded that the diffuse central nervous system manifestations of SLE are a direct result of the interaction of the antibody with neuronal cell membranes¹⁰.

The management neuropsychiatric manifestation in SLE should include treatment of the disease itself and specific psychotropic treatment. The index case had rapid improvement following Glucocorticosteroid therapy. Intravenous infusions of immunosuppressive agents, such as cyclophosphamide, have been found to be effective in such conditions ¹ . Psychotropic drugs may be used, but it is prudent to mention that SLE-inducing drugs, like chlorpromazine, carbamazepine and lithium carbonate must be avoided. Following treatment with steroids, the index case improved and all his antipsychiatric medications were finally stopped and he resumed his job.

To conclude the index case highlights that even though SLE is more frequent among females of childbearing age but males are no way immune to SLE . While evaluating patients with multiple unexplained somatic complaints and psychiatric symptoms SLE ought to be ruled out. The existence of neuropsychiatric manifestations in SLE constitutes an indisputable clinical reality that every practitioner must be able to recognise and treat.

Background

Necrotising soft tissue infections (NSTI) are severe and rapidly progressive, requiring rapid recognitions and early, often surgically-based, management. Mono-microbial types of NSTI (i.e. Type 2 NSTI), which amounts for 20 to 30% of overall cases, are often linked to invasive Group A Streptococcus or Staphylococcus Aureus infections ¹. Rarely, Group B Streptoccocus (GBS), also known as Streptococcus Agalactiae, are implicated ². We report a unique case of NSTI of the lower limbs due to GBS, with acute pericardial dissemination leading to cardiac tamponade, leading to a diagnostic dilemma due to co-existing cardiogenic and septic shock.

Case Report

A 51-year old gentleman of Chinese ethnicity presented with right foot pain and swelling over 2 weeks, associated with chest pain and shortness of breath during that period. He had a 10-year history of poorly controlled diabetes mellitus with a Hba1c level of 8.8 %, hypertension and dyslipidaemia.

He was hypotensive on arrival, with a blood pressure of 91/60 mmHg and hypoxic, requiring high flow oxygen of 15L/min to maintain saturations at 100%. Otherwise other vitals were stable, pulse rate being 72 beats per minutes, respiratory rate 24 breaths per minute and a temperature of 37.4 degrees Celsius.

Clinical examination revealed a gangrenous lateral two toes extending into the lateral malleolus on the right foot, with evidence of pus discharge and associated warmth and crepitus up to hindfoot level on palpation. There was also evidence of dry gangrene in the fourth toe of the left foot, with presence of a small puncture at dorsum of foot with pus discharge. Similarly, crepitus was felt up to midfoot level on palpation of the left side. Bilateral dorsalis pedis and posterior tibialis pulses were palpable but feeble.

Table 1: Blood Investigations on Admission

Figure 1a & 1b: Radiography of the (1a) left foot and (1b) right foot respectively, demonstrating gas within soft tissue bilaterally.

Figure 2: Chest radiography demonstrating cardiomegaly and globular-shaped heart, with loss of left-sided cardiophrenic and costophrenic angles.

Figure 3: Electrocardiogram demonstrating widespread saddle-shaped ST-elevation, consistent with pericarditis.

Figure 4: Parasternal Long Axis view of bedside echocardiography showing evidence of pericardial effusion and right atrial and ventricular collapse

Figure 5: Purulent pericardial aspirate via pericardiocentesis

Initial blood investigations are highlighted in Table 1. HIV Antibody, Hepatitis B Surface Antigen and Hepatitis C Antibody serology were all negative. Lower limb radiography revealed evidence of gaseous shadows bilaterally (Figure 1). The clinical and radiological findings were consistent with necrotising soft tissue infection of bilateral feet, and the patient was advised for extensive wound debridement and possible amputation of the affected sites during an orthopaedic consult.

However, on closer review of the chest radiography, there was evidence of cardiomegaly with a globular-shaped heart (Figure 2). His electrocardiogram on arrival, revealed diffuse ST-segment elevations on majority of leads, ST-segment depression on lead aVR consistent with pericarditis (Figure 3).

A bedside echocardiogram was performed, revealing a massive pericardial effusion, measuring largest at 2 cm in depth, with evidence of both right atrial and ventricular collapse (Figure 4).

An urgent pericardiocentesis was performed, under echocardiographic guidance, which revealed turbid-looking aspirate (Figure 5). Urgent microscopic analysis revealed 45 Cells per mm³, majority of which were lymphocytes, and gram stain showed moderate amounts of pus cells with occasional gram positive cocci. Pericardial fluid was negative for acid-fast bacilli.

A repeat transthoracic echocardiogram was performed post-pericardial drain insertion, revealing minimal remnant pericardial fluid, with the pericardial drain in-situ, and no evidence of any mass or vegetation. Unfortunately, a transoesophageal echocardiography and Computed Tomography (CT) imaging of the mediastinum (to rule out mediastinitis and pneumonitis) was not performed, as management of the NSTI took precedence.

The patient was started on intravenous antibiotics, both tazobactom-pipericillin and clindamycin. There was a delay in performing limb saving wound debridement as the patient was reluctant for invasive management, but had later consented to the procedure which was performed only on day 3 of admission. Tissue cultures were taken peri-operatively. Unfortunately, the patient deteriorated post-operatively due to extensive blood loss and overwhelming septicaemia and succumbed to his illness 72 hours after. Subsequently, it was revealed that cultures from blood, pericardial aspirate and tissue aspirate were positive for GBS infection.

Discussion

GBS is a common microorganism, often colonising the gastrointestinal and reproductive tract ³. Rarely, GBS colonises the skin and can cause necrotising fasciitis, i.e. necrotising soft tissue infection (NSTI), with only 22 cases having been reported in the past ii. Majority of these patients are either immunocompromised or have other predisposing factors including recent thoracic intervention or trauma ^{4, 5}.

GBS-related infections of cardiac structures are rare, as a whole, with 2 to 3% of cases presenting as native valve endocarditis and far less as pericarditis, mycotic aneurysms and intraventricular abscesses ³. Parikh et al reviewed the types of microorganisms isolated from purulent pericarditis samples and revealed that only 5% were due to streptococcal organism, sans Streptococcus Pneumoniae, possibly less so due to GBS ⁶. Our literature search revealed only one case of GBS-related purulent pericarditis reported although the case was not linked in any way to a NSTI to our knowledge ⁷.

Our case was unique as, at the time of writing, there were no other reports of GBS-related lower limb NSTI in combination with mediastinal involvement. There have been only a handful of cases of necrotising fasciitis reported with mediastinal involvement, the majority of which were supra-diaphragmatic with only one reporting NSTI of the lower limb due to Aspergillus infection ^{8 9}.

The similarity in culture results obtained from blood, tissue aspirate and the pericardial fluid in our patient suggest dissemination of GBS from the NSTI, possibly via a haematogenous route, although bacterial-related pericardial dissemination can also occur via direct spread from infected foci from neighbouring intra-thoracic structures or sub-diaphragmatic ⁴. The possibility of multi-routed spread should remind clinicians that, albeit rare, mediastinal involvement in NSTI is a possible complication of such disease.

Conclusion

This case highlights the rare possibility of cardiac involvement in cases of NSTI, and the possibility of cardiac tamponade causing cardiogenic shock masquerading alongside septic shock. It also highlights the importance of combining clinical findings with ancillary testing, including bedside echocardiography, when faced with challenging cases of sepsis to help look for possible foci of infection.

Physicians pursue the interest that during the hospital stay the best patient care needs to be provided; and achieving that in a short time - as a result the patient is expected to recover from illness and return to normal life.

The ability to prevent possible complications that the patients are exposed to, has always generated ambiguity in the current medical practice, since it is assumed, that the relief of the patients once the treatment is established, should always be the same¹. However, it is the awareness and proper care of comorbidities and the baseline condition of the patients that determine the success rate of the treatment, without requiring additional interventions beyond the ones proposed at the beginning of the treatment ^{2, 3}.

This important factor has generated in practitioners the need to be able to monitor the clinical evolution of the patients. Laboratory tests are an important basis of medical diagnosis, and are frequently used to monitor the clinical progress of the hospitalised patient. The patient clinical state sometimes changes suddenly or continuously; requiring the surveillance of the basic variables such as vital signs. Vital signs monitoring activate a warning signal for the immediate reassessment of the patient and reorient the medical decisions at any moment during the hospitalisation, with the goal of avoiding further deterioration or adequately treating any new disease state that the patient may develop ^{3, 4}.

From that point of view and long time ago the medical community has observed the need to generate a code that could be universal and that could be used as an early warning of the patient worsening. As a result of this situation, in different countries around the world, researchers and clinicians have developed scales, scores, algorithms and others tools to identify early patients in risks to be in critical conditions. Those tools are based on the ability of easy data collection and simple clinical interpretations allowing the clinical personnel to make objective and early assessment of the overall clinical state of the patients ⁴.

These scales or scores are not ideal, since there is no perfect scale, and all have statistical weaknesses either in their sensitivity or specificity. The clinical judgment and the physician experience, added to a score from any of these scales, may guide the path to follow according to the particular scenario to treat the patient illness ⁵.

Selecting the ideal scale to be adopted is one of the controversial topics in which a practitioners and institutions can be involved in. Occasionally other services in the hospital such as clinical laboratory and clinical imaging values play an important role in the process of diagnosis of the disease and are counted in the risk scales making easier to have good standard of care. Scientific studies assess the statistical performance of these scales yield controversial results that sometimes distort or endorse these results ⁵. This is why the decision of the ideal scale is based first on the target population that physicians in charge will care of and select the appropriate scale or score that will be applied, to know the implications of the most representative age group of patients that will be attended and to use scales which data acquisition be a simple and quick task to perform⁶.

Based on that, the Royal College of Physicians of the United Kingdom headed by Bryan Williams and collaborators, and many other researchers worldwide have analysed a significant number of scales on the basis that the scale should use systems (track and trigger warning systems protocol) divided into three types. Single parameter systems, multi-parameter systems, total weighted scoring systems and combined systems ⁶.

The researchers came to the conclusion that the performance of these scales was better than those that conserve the third type of system, since not only the parameters are categorized but also those who develop the scale proposed management to be carried out in an easy, orderly scheme and logical within a framework of independent work or in addition to more robust strategies that involve management schemes within a hospital institutions - the so-called (Rapid Response Systems RRS) ⁷.

For Williams et al, the MEWS changed its name after being accepted by the Royal College of Physicians of the United Kingdom as the NEWS scale with its variables defined as (respiratory rate, oxygen saturation, systolic blood pressure, heart rate, consciousness or new confusion and temperature). This score has been recognized and quickly adopted worldwide. The NEWS has an immediate applicability as a parameter of high sensitivity in the detection of clinical deterioration, despite its known low specificity. Thus inviting the attending physician to approach and reassess the state of the patient. The score makes changes in medical decisions according to the new conditions found during the patient’s assessment⁷.

This kind of scales must be endorsed internationally and be easily replicable by all practitioners who wish to adopt them. This allows other physicians to obtain results when implementing actions, reaching better clinical outcomes similar to clinical studies previously published. In the daily practice and clinical application we find different scenarios to use the scales, where the main problem of its application represent extra costs in lab test or clinical images and the time invested by the practitioners and medical personnel ⁷.

For this reason, the scales for clinical assessment should be easy and flexible to be implemented by any person, ideally for any member of the healthcare team to avoid barriers during the process of data acquisition. From this perspective, the scales that are based on easily collected parameters are the most appropriate, but they are often the scales that suffer the rigors of the biases when they are undervalued or overvalued, just the operability can be affected by personnel knowledge and skill.

The interesting thing about this exercise is to see that the people who have the most continuous contact with the patient, such as the nursing staff, physicians with the practice have the ability to use them in their practice and this would make the scales a valuable resource to perform clinical assessments and achieve the goal proposed.

In this new era where the reincorporation of a patient into daily life in a short time is ideal scenario, the medical and nurse staffs and also service providers seek to alleviate the patient's health breakdown. It is here from the hospital point of view where the proper care not only in the quality of care but also in the prevention of complications plays an important role in the applicability of these early detection scales. This is an invitation to success from its inception and to tend to patients being hospitalized for the minimum time required.

The identification of dark patches on the skin may be the first indication of type 2 diabetes mellitus (DM type 2). DM type 2 is a complex heterogeneous group of metabolic conditions characterised by elevated levels of serum glucose. Causative factors are impairment in both insulin action and insulin secretion. The darkening of the skin is usually evident on the hands and feet, in folds of skin, along the neck, and in the patient’s groin and armpits.¹ The affected skin differs from that which surrounds it, and it feels velvety and also thicker. That skin may have hanging from it the small, soft, skin-coloured growths known as tags, and the area affected may be pruritic. This condition is a nonspecific dermatological disorder termed acanthosis nigricans (AN), which often occurs in patients with high insulin levels. Hud et al. (1992) found that 74% of the obese population exhibits AN.²The association of AN, skin tags, and diabetes mellitus due to insulin resistance – along with obesity in adolescents and young adults – is a well-defined syndrome.^3,4,5

High-insulin levels in the blood may increase the body’s production of skin cells, many of which have increased pigmentation that gives the skin a darkened appearance – dark patches appear on the skin. These are often the outcome of insulin receptors in the skin being triggered, causing mutations of normal tissue that are dark in colour and/or irregular in shape. The condition may be an indication that the blood sugar is persistently high. The term ‘acanthosis nigricans’ was originally proposed by Unna et al. in 1891, but the first descriptions of it were made a year earlier by two researchers working independently of each other: Pollitzer and Janovsk.⁶ Kahn and colleagues tried to clarify the link between AN and insulin resistance in 1976.⁷ Eventually, its presence became established as an indicator of insulin resistance or diabetes mellitus in obese patients.⁸ In 2000, the American Diabetes Association formally accepted AN as such.⁹ It should be borne in mind that AN must not be considered a characteristic feature of DM type 2; it is not a condition that is developed by all those who suffer from the disease.

Figures 1,2,3 - Acanthosis Nigrans

Pathogenesis

Although the pancreas produces insulin in DM type 2, the body cannot make use of it efficiently. The outcome is a build-up of glucose in the bloodstream, which may lead to high levels of blood glucose and insulin. At low concentrations, insulin regulates the metabolism of carbohydrates, lipids, and protein and may promote growth by binding to ‘classic’ insulin receptors. High concentrations of insulin may stimulate keratinocyte and fibroblast proliferation through high-affinity binding to the insulin-like growth factor 1 (IGF-1) receptors.¹⁰ In obese patients elevated IGF-1 levels may contribute to keratinocyte and fibroblast proliferation;¹¹ the binding stimulates the proliferation of keratinocytes and fibroblasts, which leads to AN.

To put this simply, AN is the outcome of a toxic effect of hyperinsulinemia. Excess insulin causes the normal skin cells to reproduce rapidly rate, and it has been demonstrated to cross the dermo-epidermal junction and reach keratinocytes. In those who have dark skin, these new cells have increased melanin. The higher level of melanin results in the creation of a patch of skin that is noticeably darker than the skin surrounding it. The presence of AN is therefore a strong indicator of increased insulin production and, therefore, it is also a predictor for future DM type 2.

When the occurrence of AN is recognised, a prediabetic person has the opportunity to become more alert to their symptoms and to take precautions in the form of diet restrictions and weight loss. This is because overweight people tend to develop resistance to insulin over time. If too much insulin is the cause of AN, it is relatively easy for the patient to counter it by changing to a healthier diet, taking exercise, and controlling their blood sugar. Obesity-associated AN may be a marker for higher insulin needs in obese women with gestational diabetes,¹²andAN has been shown to be a dependable early indicator for metabolic syndrome in paediatric patients.¹³

Autoimmunity?

Unknown autoantibodies other than insulin receptors have been implicated in AN, which may explain the effectiveness of cyclosporine treatment. Kondo and colleagues identified a very rare occurrence – without type B insulin resistance – of generalised AN with Sjögren's syndrome and systemic lupus erythematosus-like features.¹⁴Theirs was the first report of generalised AN involving an area from the mucosa of the larynx to the esophagogastric junction, accompanied by autoimmune disorder (AD) responding to systemic immunosuppressive therapy. AN skin lesions and mucosal papillomatosis were medicated with oral cyclosporine A and were accompanied by lower autoantibody titres. That was an outcome of the development of antibodies to insulin receptors in AD such as systemic lupus erythematosus.¹⁵

Raymond et al. have reported on the association of AN with disordered immunoreactivity.¹⁶ The onset of AN may precede a variety of classic ADs, and different categories of ADs may be present at the same time. If AN is an AD, DM type 2 may also represent a slow and subtle autoimmune process. AN and DM type 2 then become two different expressions of the same disease process, but the former is apparently benign and the latter is ultimately potentially fatal. Autoimmunity is a well-known pathogenic component in DM type 2. The assumption that its pathogenesis encompasses autoimmune aspects is increasingly recognised. That is based on the presence of circulating autoantibodies against β cells, self-reactive T cells, and also on the glucose-lowering efficacy in DM type 2of some immunomodulatory therapies.¹⁷ The autoimmune hypothesis of AN has the potential to modify the direction of DM type 2 research.

The symptoms of ADs are inconstant and this is in divergence to the mechanisms of antigen recognition and effector function that are alike in the response to pathogens. ¹⁸ The symptoms basically depend on the triggering autoantigen and the target tissue. In certain conditions, autoantibodies function as receptor antagonists and in other situations, they function as receptor agonist. Autoantibodies of both types can be made against insulin receptor. When they serve as antagonists as in DM Type 2, the cells of patients are unable to take up glucose, the consequence is hyperglycaemia whereas in patients with agonistic antibodies, cells deplete blood glucose resulting in hypoglycaemia.¹⁸ One wonders whether AN may be an early by-product of such an autoimmune process.

Vitiligo which is the result of depigmentation of the skin is in fact an opposite disorder to AN. Vitiligo is recognised as an AD.¹⁹Thyroid disorders, particularly Hashimoto thyroiditis and Graves’ disease, other endocrinopathies, such as Addison disease, diabetes mellitus, alopecia areata, pernicious anaemia, inflammatory bowel disease, psoriasis, and autoimmune poly-glandular syndrome are all associated with vitiligo. ²⁰ Kakourou et al identify that Hashimoto's thyroiditis is 2.5 times more frequent among children and adolescents with vitiligo than in a healthy age- and sex-matched population and it usually follows the onset of vitiligo. ²¹

As in the case of other ADs, vitiligo susceptibility may involve both target organ-specific genes and immune response genes. ²² The autoimmune theory suggests alteration in humoral and cellular immunity in the destruction of melanocytes of vitiligo. ²³. Vitiligo lesions have an infiltrate of inflammatory cells, particularly cytotoxic and helper T-cells and macrophages;histological evidences further back up an autoimmune aetiology. ²⁴ Like AN, Vitiligo is thus gene linked; immunity derangements may be providing the matrix and genes are the craftsmen in both conditions.

Vitiligo occurs more commonly in DM Type 1. A few recent studies have revealed its increased incidence in DM Type 2. ²⁵ These may be isolated case studies, but offer new insight into the pathogenesis of DM Type 2. There is a logical thread running between the autoimmune assertion of AN and its depigmentation counterpart (vitiligo) which is recognised as an AD. If AN is proven as an AD, the AD hypothesis of DM Type 2 becomes more binding. The autoimmune process of AN warrants further consideration and further study is needed to confirm or falsify the hypothesis of an autoimmune spectrum disorder between AN, vitiligo and DM Type 2.

Even though the common assumption that bacteria flora occupying human body outnumber the body cells has been proven wrong, their revised ratio of 1:1 is still astounding.²⁶ The exact role of the resident microbial colony in human body is unclear. There are less ADs observed among the hunters’ tribal population of Tanzania whose faecal matter contain more varieties of microbes than people in developed countries. ^27,28 This is an observation that need further verification. It is possible that the occupied microbial army may be maintaining the harmony among the human body cells from attacking each other and serving as moderators. Now that anti-autoimmune activity in molecules produced by parasites have been confirmed in haematology lab, these findings may have clinical significance. The aetiology of ADs is multifactorial. Genetic, environmental, hormonal, psychological stress and immunological factors are all considered important in their development. I content that the clue to the mechanism of development of certain ADs and ways of counteracting them may be embedded in the bacterial colony and their interaction with human cells.

International studies

A pilot study by Bhagyanathan and colleagues demonstrated that children with AN have a high incidence of insulin resistance.²⁹ They posit that the detection of insulin resistance in children may present an opportunity to prevent the onset of microvascular changes before the development of DM type 2. Once DM type 2 by hyperglycemia is diagnosed it may be too late for that. Insulin resistance is one of the mechanisms involved in the pathogenesis of DM type 2; therefore, early recognition of insulin resistance is paramount in the prevention or delay of the onset of diabetes. Their study was of 62% of children who had AN alongside high insulin resistance. In children with AN and a high BMI, the incidence of insulin resistance was about 80%. This is evidence that the easily detectable symptoms are of value in the screening of children who are at high risk of developing DM type 2. Bhagyanathan et al. conclude that AN has potential as a screening method because those who have high insulin resistance as well as AN are at high of future DM type 2.

An earlier US study, by Brickman and colleagues, had yielded somewhat similar results.³⁰ This involved 618 youths from different ethnic groups at nine paediatric practices. They were aged from 7 to 17 years. A survey was made of their demographics and their family history with regard to DM type 2, and their weight and height were also measured. AN was scored and digital photographs of their necks were taken. AN was identified in 19%, 23%, and 4% of the African American, Hispanic, and Caucasian youth respectively. It was also found in 62% of those studied who had a BMI greater than the 98th percentile. Using multiple logistic regression, the researchers found that the level of BMI, the presence of maternal gestational diabetes, female gender, and not being Caucasian, were all independently associated with AN. AN was common among the overweight young people and was associated with risk factors for glucose homeostasis abnormality. Brickman et al. concluded that identification of AN offers an opportunity to advise families about the causes and consequences of the condition. ³⁰ That has the potential to motivate those with responsibility for the young people to encourage and effect healthy lifestyle changes that decrease the risk of the development of DM type 2 and cardiovascular disease.

In their research in India, Vijayan et al. determined that BMI, waist circumference and AN are three physical markers for the recognition of insulin resistance in children.³¹ They conducted a cross-sectional school-based study in a semi-rural environment in the state of Kerala, which has become known as the diabetic capital of the country. Their study encompassed 283 children between the ages of 10 to 17. The prevalence of insulin resistance was 35%; this estimate was arrived at by using a homeostasis model assessment of insulin resistance (HOMA-IR). Of the children studied, 30% had a waist circumference above the 75th percentile and 18.7% had a BMI above 85th percentile. AN was diagnosed in 39.6% of the population studied. A significantly high prevalence of insulin resistance was observed among the children with a waist circumference exceeding the 75th percentile, a BMI above the 85th percentile, or a diagnosis of AN. The most sensitive physical marker of insulin resistance was AN (90%) and the most specific was BMI (91%). By combining these parameters their sensitivity may be increased to 94% and their negative predictive value to 96%. Vijayan et al. conclude that these easily recognisable physical markers are an efficient warning of insulin resistance among children.

Acanthosis nigricans in different conditions

AN is not a disease, but a symptom of disease. A high prevalence has been observed recently, and there are a number of varieties. These include benign, obesity associated, syndromic, malignant, acral, unilateral, medication-induced, and mixed AN.^32,33 It has been established that AN may occur in a number of conditions, and a brief discussion of these is appropriate for this paper. Different types of AN are listed in Table 1. It often appears gradually in the prediabetic state, but abruptly in malignancy.

AN may be triggered by a plethora of medications, such as birth control pills, human growth hormones, thyroid medications, and even some bodybuilding supplements. All these medications may cause changes in insulin levels. Medications used to ease the side effects of chemotherapy have also been linked to AN. In most cases, the condition clears up when the medications are discontinued. In rare cases, AN may be caused by gastric cancer (especially gastric adenocarcinoma) or an adrenal gland disorder such as Addison’s disease. Hypothyroidism, Cushing’s disease, and polycystic ovarian disease are also common causes of AN. ^34,35

When AN is present without any identifiable cause in middle-aged and older patients with extensive skin findings, internal malignancy needs to be ruled out. AN has been reported in association with many kinds of cancer, by far the most common being an adenocarcinoma of gastrointestinal origin. In these patients it is a rapid-growing dermatological pigmentation disorder. The skin changes are typically more extensive and severe than those seen in benign AN. Findings may include thickening, unusual roughness and dryness, and/or potentially severe itching (pruritus) and irritation of the skin regions affected. Pigmentary changes may be more pronounced than those observed in benign AN and they are not restricted to areas of hyperkeratosis. Malignant AN is frequently associated with the mucous membranes and with distinctive abnormalities of the oral (mouth) region. For example, reports indicate that the lips and the back and sides of the tongue may have an unusually ‘shaggy’ appearance, sometimes with elevated, wart-like, non-pigmented tissue growths (papillomatous elevations). Malignant AN is also commonly characterised by wart-like thickening around the eyes, unusual ridging or brittleness of the nails, thickening of the skin on the palms of the hands, hair loss, and sometimes other symptoms. Investigators have reported that the development of malignant AN may occur as much as five years before the onset of other symptoms, although the time span before malignancy is typically of shorter duration.

Table 1. Different types of acanthosis nigricans

Genetic links

It is worth noting that certain types of AN may be genetically linked.³⁶ The interaction of genes and the environment is not clearly understood and the different variables of DM type 2 are not established. It is a heterogenous disorder and there is a general consensus that diabetic comorbidities may be the outcome of genetic and environmental susceptibilities.^{37,38,39,40,41} Such factors may have an influence independently or in combination with one another that brings about hyperglycaemic conditions.It would be interesting to explore the possibility of a link between the diabetic genes and the AN gene. DM type 2 may be potentiated by poor quality of insulin or decreased production of insulin, and the distinction between those manifestations is not well recognised. The controversy concerning the relative roles of insulin deficiency and insulin resistance in DM type 2 continues to be unresolved.⁴² Despite the early demonstration that obese people have elevated plasma insulin concentrations, many studies over the years have failed to control satisfactorily for the influence of obesity.⁴³ Another difficulty with the interpretation of plasma insulin concentrations is that sustained hyperglycaemia may have detrimental effects on insulin secretion.⁴⁴ Diabetes mellitus affects every cell of the body, and therefore it affects the beta cells of the pancreas in turn. The spiralling effect of hyperglycaemia adds to the malfunctioning of beta cells, and that results in impaired quantity and quality of insulin. Only a subset of diabetic patients shows AN, and other groups of obese diabetic patients do not develop AN. AN is linked with higher insulin production and obesity, whereas AN may not be present in diabetes with a reduced quantity of insulin. The presence of AN may serve as one of the biological markers to determine subtypes of DM type 2.

The incidence of AN varies in different races, which is evidence that AN may have a genetic contribution – indeed, it has been regarded by some as being strongly influenced by genetic factors. It is thought to be autosomal in nature. AN is common among African-Americans, Hispanics, and American Indians, but it is rare among white people.^45,46 A study from the USA reports the prevalence of AN as 3% among Caucasians, 19% in Hispanics, and 28% in American Indians. ⁴⁷ More recently, studies from Sri Lanka and south India show the prevalence of AN as high as 17.4% and 16.1% respectively in the adult population in general.^48,49

Type 2 diabetes mellitus and schizophrenia

DM type 2 is relatively common among people who have mental health issues. Increased risk for cardiovascular disease and other serious illnesses related to insulin resistance – for example, certain epithelial cell carcinomas, AN, and polycystic ovary syndrome – are long-term concerns associated with the cluster of metabolic abnormalities stemming from insulin resistance. These are often referred to as the metabolic syndrome.⁵⁰ Impaired action of insulin in patients with schizophrenia was reported over fifty-five years ago and later confirmed in Australia.⁵¹ The prevalence of DM type 2 in patients with schizophrenia was found to be higher than it was in the general population, even before antipsychotic medication was in widespread use.

The mechanisms underlying the relationship between schizophrenia and diabetes remain unexplained. The present author has argued in favour of the autoimmune hypothesis of a subset of schizophrenia.^52,53 The proposal is that if AN is an AD, it may be co-existing with DM type 2, or the DM type 2 itself may even be an extension of the same autoimmune process. In other words, there may be a continuum of pathological process between AN and DM type 2. It follows that schizophrenia sufferers may have a predisposition to develop DM type 2; schizophrenia may even be considered as a clinical surrogate of DM type 2.

When AN occurs in a schizophrenic patient, they sometimes develop a delusional misinterpretation of the condition, such as that it is a result of skin cancer or even a manifestation of an external agency. Such situations may result in severe anxiety. Schizophrenia is frequently associated with poor lifestyle choices on the part of the patient, such as a diet high in fat, reduced levels of physical activity, and high rates of smoking-all of these may contribute to the development of a metabolic syndrome and insulin resistance.^54,55 It is worth considering investigation into the early warning signs for DM type 2 – including the AN – before commencing a patient on antipsychotic drugs that lead to a metabolic syndrome.

It is now well recognised that patients treated with clozapine or olanzapine are more often classified as having DM type 2 or impaired glucose tolerance in comparison with patients treated with other second-generation antipsychotics. Clozapine increases the risk of diabetes if there is a history of pre-existing diabetes or a family history of diabetes. According to a US study, the risk is higher if the patient is African-American or of Hispanic origin. Such patients may need close blood sugar monitoring during the initiation of clozapine treatment. I contend that if a patient already has AN, weight-increasing antipsychotics should be avoided. Even though aripiprazole is the most metabolic-sparing agent among the second-generation antipsychotics, Manu et al. report a case of AN in a patient treated with it. That patient did have a family history of DM type 2, which adds to the interest of the case.⁵⁶

Diagnosis and treatment

There is no specific treatment for AN. Treatment is directed towards the specific symptoms that are apparent in each individual. It should be borne in mind that such treatment may require the coordinated efforts of a team of medical professionals. Correcting the underlying disease improves the skin symptoms. Steps that may be taken, depending on what the disease is, include correcting hyperinsulinemia through diet and medication, encouraging the loss of weight in those with obesity-associated AN, removing or treating a tumour, and discontinuing a medication that causes AN. The control of obesity contributes significantly to reversing the whole process, essentially by reducing both insulin resistance and compensatory hyperinsulinemia. However, the pigmentary changes may persist. In drug-induced AN, offending medicines should be stopped. In hereditary AN, lesions tend to enlarge gradually before stabilising and/or regressing on their own.

For those with AN, the recommended treatment may include the use of certain synthetic, vitamin A-like compounds (retinoids). For individuals with malignant AN, disease management requires treatment by oncologists. Reports indicate that AN has improved with therapy used to treat underlying malignancies and has reappeared with tumour recurrences. Other treatment for this disorder is symptomatic and supportive. The treatments considered are used primarily to improve appearance, and include topical retinoids, dermabrasion, and laser therapy. The final outcome of AN varies depending on the cause of the condition. Benign conditions, either on their own or through lifestyle changes and/or treatment, have good outcomes. The prognosis for patients with malignant AN is often poor as the associated cancer is often advanced.

AN may be diagnosed on the basis of thorough clinical evaluation, identification of characteristic physical findings, a complete patient history including medication history, a thorough family history, and various specialised tests.⁵⁷ The age at detection will vary, depending upon the form of AN present and on other factors. For example, benign forms of AN often become evident during childhood or puberty. It is less common for benign AN to be apparent at birth or to develop in adulthood. The latter cases most typically involve AN in association with obesity.

In individuals with skin changes that suggest AN, diagnostic assessment may include various laboratory tests. Examples are the glucose tolerance test and the glycated haemoglobin (HbA1c) test. Additional laboratory studies or other specialised tests may also be utilised in diagnosis in order to help detect or rule out certain other underlying disorders – including a number of endocrine and autoimmune conditions – that may be associated with AN. In addition, in some instances, particularly where the patient presents with signs suggestive of malignant AN, testing may include biopsy and microscopic evaluation of small samples of skin tissue affected.

The onset of malignant AN usually occurs after the patient reaches 40 years of age. Various factors may be indicative of malignant AN in association with an underlying cancer. These include symptom onset in adulthood that is not associated with the use of particular medications, obesity, a positive family history, and certain underlying disorders known to be associated with AN. It is rare for malignant AN to develop during childhood. In such instances, warning signs may include skin changes that progress rapidly and also involvement of the mucous membranes.⁵⁸

AN may be metaphorically linked to the dark pigmentation that appears on the skin of the ripe Sharon fruit. Sharon fruit is the trade name for a variety of persimmon that is grown in Israel. In the fruit the dark patches on the ripe and sugary fruits are the result of condensed tannins. Insulin-resistant AN may be referred to as the Sharon fruit sign in order to emphasise the diagnostic value of the condition. It has been suggested that the official terminology for AN is inappropriate for a significant warning of an increasingly common disease for which early diagnosis is imperative. Because the complex name may have a negative impact on its identification by both clinicians and patients, a less formal term is in use among some of those who are concerned with patient care. It must be borne in mind that AN, otherwise Sharon fruit sign, manifests only in those with the insulin-resistant condition and should not be considered a characteristic feature of DM Type 2. Identification of the Sharon fruit sign may be helpful in the early diagnosis of DM type 2.

Discussion

Diabetes puts an enormous burden on patients, their families, and the health-care system. Detection of the disease at an early state using physical markers and instituting preventive measures will reduce the economic strain on society to a great extent. According to the latest global data from the World Health Organization (2016), an estimated 422 million adults are living with DM type 2 and diabetes prevalence is increasing rapidly.⁵⁹ In 2013 the International Diabetes Federation estimated that 381 million people were living with diabetes.⁶⁰ That number is anticipated to almost double by 2030.⁶¹ About 3.8 million people in the UK have DM type 2, and the charity Diabetes UK has made predictions that it may become as high as 6.2 million by 2035/36.

Most often a diagnosis of DM type 2 is made only when such symptoms as loss of weight, polydipsia, and polyurea have become manifest. By that time the damage to the body may have already come about. Complications arising from diabetes cover the entire area of medical science, so early detection is crucial. Intervention at the prediabetic stage helps to arrest the progress of this condition. AN may herald DM type 2, endocrinopathies, and malignancies. This cutaneous disorder is easily detectable and highly useful in the early detection of the disorders associated with it. Early screening for AN in preadolescent and adolescent people would provide a relatively simple, inexpensive, and non-invasive tool for identifying those young people who have hyperinsulinemia and could benefit from early intervention. That would prevent the development of DM type 2. Young people tend to be reluctant to undergo traditional screening measures and definitive diagnostic tests as they find them invasive and unpleasant.

A sedentary life style and unhealthy dietary habits – as well as the side effects of antipsychotics – make chronically ill psychotic patients more vulnerable to DM type 2 than the general population. Long-standing detained patients in particular are restricted in their mobility and may become more prone to obesity and insulin resistance. It is not clear whether the pathogenesis of psychosis itself has a diabetogenic effect. It is evident that because of the high incidence of DM type 2 among mental health service users, psychiatrists need to become more alert in the diagnosis, management, and prevention of the complications of DM type 2.

A 23 y/o male was brought to our Emergency Department after having a seizure. He was alert and his vital signs were stable. He is known to have epilepsy and is on regular anti-epileptic medication for three years. He is being followed up at a neighborhood medical center at his native village . On physical examination numerous brown papules were seen over his nose and both cheeks in a butterfly pattern which correspond to facial angiofibromas (Figure 1). Ash Leaf Hypomelanotic macules were seen over his extremities (Figure 2). Few hyperpigmented café au lait macules were observed over his trunk (Figure 3). A big fibroma was also seen over his scalp (Figure 4). Areas of thick leathery texture of orange peel known as Shagreen patches were observed on back (Figure 5).

Figure 1: Facial angiofibromas

Figure 2: Ash Leaf spot

Figure 3: Cafe au lait macule

Figure 4: Scalp fibroma

Figure 5: Shagreen patch

A Brain CT scan revealed multiple subependymal giant cell astrocytomas. Laboratory investigations were normal.

This patient was clinically diagnosed as Tuberous Sclerosis Complex having a myriad of skin lesions.¹

Tuberous sclerosis complex is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia.² Seizures are commonly encountered in Emergency Room however, conspicuous lesions as described above must alert the physician to guide the patient for a multidisciplinary approach.³

Introduction

Isolated splenic tuberculosis is extremely rare, particularly in the immunocompetent persons. Splenic tuberculosis, however, can be part of military tuberculosis in immunocompromised patients. Tuberculosis spleen invariably presents in the form of an abscess. The risk factors for splenic abscess described in the literature are sickle cell disease, hemoglobinopathies, splenic trauma endocarditis or tuberculosis elsewhere in an immunocompetent patient. Although rare cases of splenic tuberculosis in immunocompetent patients have been described in the past. With re-emergence of tuberculosis due to AIDS and use of immunosuppressive medications around the globe, it is very important to bear this rare clinical condition while evaluating pyrexia of unknown origin in a given case.

Case 1

A 54-year-old male vet nary doctor by profession presented with the history of off and on fever of 8 weeks duration. The fever was low grade, intermittent and was associated with weight loss of 4 kilograms. There was no evening rise of temp and no sweating. The patient denied any history of a cough, urinary symptoms or diarrhoea. There was no history of travel or contact with sick people. He had been type II diabetic for last 12 years controlled on oral hypoglycemic agents and had no history of acute or chronic complications. There was no history of tuberculosis in the past or in close contacts . He was non-alcoholic and denied any high-risk behaviour. The clinical examination revealed an average built person who was conscious oriented and had stable vitals. There was no jaundice or lymphadenopathy. Abdominal examination revealed moderate splenomegaly. The liver was not palpable and there was no ascites. Respiratory and cardiovascular systems were normal. During the hospitalisation temp. recorded ranged from 38⁰ C to 39⁰C with no night sweats during his hospital stay. Patient’s evaluation showed haemoglobin levels of 10.5g/dl Leukocyte and platelet counts were normal. ESR was 88mm for the first hour. The tests on kidney and liver functions were normal. An ultrasound abdomen showed the presence of two heterogenic space occupying lesions measuring 3×4cms suggestive of splenic abscesses. An echocardiogram was done to rule out any features of subacute bacterial endocarditis. All the valves of his heart were normal and no feature of endocarditis was noted. The patient had normal ejection fraction and the pericardial cavity was normal too. Blood cultures and urine cultures were found to be sterile. A 24-hour collection of urine showed no evidence of albuminuria and funduscopic examination ruled out retinopathy. Keeping in view splenic abscesses CT guided fine needle aspiration was done and acid-fast bacillus were demonstrated by Zeal-Neilson s stain and the patient was put on antitubercular treatment. The culture of the aspirate a few weeks later turned out to be positive for Mycobacterium tuberculosis. His HIV serology was negative .The patient continued standard four-drug regimen for two months followed by two drug regimen for another seven months. Patients fever settled after two weeks of treatment and followed our clinic till completion of his treatment.

CASE 2

A 24-year-old female student presented with the history of off and on fever of 5 weeks duration. The fever was low grade intermittent and not associated with sweating She also complained of loss of appetite and weight loss of 3 kilogrammes over a period of 2months She denied any history of a cough, urinary symptoms. The patient had no history of contact with sick persons or travel. She had no co morbid illness. On examination she was conscious oriented and had mild pallor, no lymphadenopathy or jaundice was noted. Her respiratory and cardiovascular system was normal. Abdominal examination showed splenomegaly 5cms below the costal margin. Her laboratory data showed haemoglobin levels of 9.8gm/dl WBC count of 4200 and platelets were 1.5×103. ESR was 90mm in the first hour. Blood culture, widal tests and Brucella serology were negative. Tests on liver and kidney functions were normal. An ultrasound abdomen showed the presence of three small space occupying lesions in the spleen.Each was measuring 2×2 cms. Portal vein diameter and spleno-portal axis were normal. CT scan abdomen confirmed splenic abscesses and no abdominal lymphadenopathy was noted. CT guided fine needle aspiration was done which turned out to be positive for AFB and cultures a few weeks later confirmed Mycobacterium tuberculosis. Her transthoracic echocardiography showed normal values and didn’t show any features of vegetations. Her HIV serology was negative. The patient was started on conventional four drugs antitubercular regimen for two months followed by two drug regimen for another seven months. Her fever settled and she had marked improvement in her appetite and her weight increased.

DISCUSSION:

Splenic abscesses presenting as fever of unknown origin is well known. Most of the cases of TB spleen present as fever, vague ache in left hypochondrium or weight loss. Although the frequency of splenic tuberculosis is more common in immunosuppressed patients but splenic abscess due to tuberculosis has been described in immune competent patients as well^1. Due to the advent of AIDS epidemic prevalence of tuberculosis has increased globally and more cases are now getting reported. Another scenario leading to increased frequency of this previously rare entity is the widespread use of immunosuppressed therapies for chronic disorders like Rheumatoid arthritis, Crohn's disease Psoriasis etc. The index cases were neither HIV positive nor where on any immunosuppressant medication but developed splenic lesions, reflecting some other hitherto unknown predisposing factor for such lesions. The splenic abscess does occur in the setting of infective endocarditis as infective emboli get lodged in the spleen. Splenic abscess following endocarditis in an 80 year old male presenting with abdominal pain during the course of treatment was reported by Pereira et al² and in another series³ of 3 patients with bacterial endocarditis, splenic abscess was diagnosed based on CT abdomen with evidence of endocarditis on Echocardiography. In the same series two of the patients underwent splenectomy before valve repair while as splenectomy was performed after the valve repair in the other patient .The echocardiogram in index cases, however, were normal without any evidence of endocarditis. After the diagnosis and initiation of ATT, the index cases became afebrile and splenectomy was thus averted . While one of the cases had well controlled diabetes mellitus but the other patient was euglycemic and had no other known risk factor for splenic tuberculosis as is described in the literature. What lead to splenic tuberculosis in the second case remained unidentified? .There is a well known linkage between diabetes mellitus and TB and as per WHO a bidirectional screening has been recommended. Sri Lankan data⁴ on 112 patients with TB found that 8 patients with TB already were already known cases of diabetes mellitus and in their study further screening unravelled TB in another 17 patients. It is thought that metabolic adaptation is critical during the pathogenesis of mycobacterium tuberculosis^5,6..

In time management of tubercular abscess is very crucial as without treatment patients can have complicated clinical course.Splenic abscess can rarely rupture or lead to fistulous communication with adjacent organs. A gastrosplenic fistula has been reported by Lee et al⁷ in a 61-year-old male presenting with abdominal discomfort and cough. The authors demonstrated a fistulous tract between the spleen and the stomach on endoscopic examination. The fistulous track healed in their case after completion of anti-tubercular treatment. It is quite possible that delay in diagnosis may be a factor that leads to such complications. The index cases, however, had favourable outcome without any complications and successfully completed anti-tubercular treatment.

The other side of the coin is that complications are even known during the antitubercular treatment as a result of reaction to antitubercular treatment. Spontaneous rupture during treatment leading to splenectomy was reported by et Yea et al⁸ .Splenic tubercular abscess are known to be associated with miliary tuberculosis or with haematological diseases where leucopenia and thrombocytopenia are profound⁹.The index cases had normal platelet count and leucocytic count highlighting that there was neither bone marrow suppression nor hypersplenism. The patients with ITP on treatment are also prone to develop Tuberculosis of spleen and conversely, patients with TB spleen can per se develop thrombocytopenia.

The management of splenic abscess used to be splenectomy in the past but with the advent of FNAC splenectomy is avoided . Here a word of caution is that various other lesions in spleen can mimick splenic TB hence it is very important to confirm the disease especially in endemic areas where TB is prevalent. Kunnathuparambil et al¹⁰ described melioidosis in a 47 year old male who was treated as case of splenic tuberculosis based on splenic lesions on imaging and fever. The diagnosis of splenic tuberculosis in past was mainly reached after histological examination of surgical specimens but now fine needle aspiration has become the procedure of choice. Spleen being highly vascular organ bleeding is the most feared complication of any intervention but fine needle aspiration has been found to be technically safe and in a retrospective data no significant complication was observed¹¹ .With the advent of non-invasive biomarkers diagnosis of tuberculosis has advanced further and a step further is Quantiferon Gold test which has come up another non-invasive modality in the diagnosis of TB. In various studies¹², the sensitivity of this test to the tune of 75% has been demonstrated.

While treating an HIV patient the clinician requires high alert in patients presenting with pain abdomen as the splenic abscess is one of the differentials and it is recommended that initial ultrasound must be carried out to diagnose this condition¹³. In modern era ,Splenectomy may be offered only to resistant cases otherwise ATT is considered to be the therapy of choice.

To conclude tuberculosis of spleen must be kept in mind while evaluating fever of unknown origin in any patient on immunosuppressant treatment or having HIV and even in immunocompetent patients as well. The Fine needle aspiration is a safe diagnostic modality and treatment with antitubercular medication is rarely unsuccessful.

Introduction

Chest pain accounts for 1% of all GP consultations, but in only 8%-18% of cases is it an indicator of underlying ischemic heart disease.¹ Given the potential diagnostic uncertainty associated with chest pain at initial presentation, specialist evaluation of patients in a Rapid Access Chest Pain Clinic (RACPC) is of value and represents an important process in the evaluation of symptoms. These clinics were established with the aim of providing rapid outpatient assessment of patients with suspected cardiac disease in order to permit earlier provision of appropriate treatment and investigations where required.

Stable chest pain typically presents as angina, a triad of dull central chest pain, brought on with exertion and relieved by rest or GTN spray. The aetiology is usually stable atherosclerotic plaque disease which is associated with low mortality and can be treated with oral anti-anginals, as demonstrated by meta-analyses and the landmark COURAGE study. ^{2, 3}

NICE Clinical Guideline 95 (NICE CG95) suggests that choice of initial investigation for stable chest pain should be guided by a patient’s pre-test probability of having CAD. Calculations of the pre-test probability take into consideration a patient’s age, gender, cardiac risk factors and symptoms. Patients are defined as high risk of cardiac disease if they have diabetes, smoke or have hyperlipidaemia (total cholesterol >6.47mmol/litre). Patients with none of the above are considered low risk. Symptoms are defined as “typical angina” if the pain is: 1) constricting discomfort in the front of the chest or in the neck, shoulders, jaw or arms; 2) is precipitated by physical exertion and 3) is relieved by rest or GTN spray within approximately five minutes. Pain is defined as “atypical angina” if only two of the above criteria are met and defined as “non-anginal” if one or none of the above criteria are met.

NICE pre-test probabilities of CAD (Table 1), are based on a version of Diamond and Forrester’s pre-test probabilities published in 1979, modified using data from Duke’s cohort study, published in 1993.^{4, 5, 6} Recent studies suggest that these NICE pre-test probabilities may overestimate the prevalence of CAD in a primary care population and may risk over investigating patients.^{7, 8} In addition to having financial implications, this may cause patients undue anxiety and unnecessarily put them at risk of complications.

Table 1: NICE Clinical Guideline 95 pre-test probabilities table.

Each cell represents the percentage risk of each group of patients having CAD, based on their typicality of symptoms, gender, age and cardiac risk factors (lo, low and hi, high)⁴

ESC guidelines utilise an updated, validated model of the Diamond-Forrester model by Genders et al. to create pre test probabilities of CAD (Table 2), based on patient’s age, gender and typicality of symptoms. ^{9, 10}

Table 2: ESC guidelines clinical pre-test probabilities in patients with stable chest pain symptoms 

Each cell represents likelihood of each group of patients having CAD, based on typicality of symptoms, age and gender.⁹

We hypothesised that strict adherence to NICE guidelines results in over-estimation of the pre-test probability of CAD and therefore over-investigation of patients presenting with stable chest pain. ESC guidelines may offer more accurate pre-test probabilities of CAD and allow a more targeted and cost-effective use of investigations.

Methodology

Clinic records of all patients who attended the RACPC at Tunbridge Wells Hospital between July 2005 and December 2012 were reviewed. This service is run by a cardiology specialist. Patient demographics, cardiac risk factors and information regarding the nature of patient symptoms were collected prospectively and completed at the time of the patient’s RACPC appointment. Results of cardiac investigations were collected from paper and computerised records, and included diagnoses of significant CAD made following invasive coronary angiogram. These results were compared with patients’ pre-test probabilities of CAD calculated using both NICE and the ESC’s calculation methods. Outcome and readmissions were obtained from electronic records from the Maidstone and Tunbridge Wells NHS Trust computer records retrospectively.

Results

Study population

A total of 1968 records were reviewed. 59% (n = 1162) of patients were male and 41% (n = 806) were female. Their mean age was 60 years. At initial assessment, 69.8% patients (n=1373) had non-anginal chest pain, 19.5% (n=383) had atypical angina and 10.8% (n=212) had typical angina, based on the NICE guideline definitions of chest pain.

97.2% (n= 1912) patients underwent further investigation; 15% (n=256) of these were subsequently diagnosed as having significant CAD, accounting for their symptoms. The 2.8% (n=56) of patients who did not undergo investigation either chose not to, were unable to, were lost to follow up, or were diagnosed as having a non-cardiac cause of their symptoms at the initial RACPC appointment.

NICE CG95 pre test probabilities compared against cohort data

Table 3: NICE guidelines 95 pre test probabilities compared against cohort data

Each cell represents the proportion (%) of cohort patients from each group who were diagnosed with CAD. We have colour-coded cells to represent the NICE estimated pre-test probability of CAD in each group. Red cells represent 61-90+% probability, pink cells represents 30-60% probability, blue cells represent 10-29% probability and white cells represents <10% probability of CAD according to NICE Guidelines. “ – “ marks a cell where pre-test probabilities of CAD could not be calculated for cohort patients.

Table 4: A comparison of NICE pre-test probabilities and cohort patient data.

The risk of CAD as predicted by NICE guidelines 95 on the left compared with the actual number of cohort patients in each category and the proportion of those patients diagnosed with significant CAD.

The average discrepancy between the pre-test probability and actual incidence of CAD in cohort patients was 28% (range 20% - 88%). In 48% of cells in the NICE CG95 pre-test probability table (Table 1) the pre-test probability of CAD was overestimated by 30% or more (Table 3). A marked discrepancy between pre-test probability and actual incidence of CAD was found between “high risk” and “very low risk” patients. On average, high risk patients had an overestimated pre-test probability of 34.3 – 40.9% per cell compared with low risk patients whose pre-test probability was only overestimated by 6.5% (Table 3).

The cells highlighted in dark red in table 3 represent high risk patients whose pre-test probability was of 61-90+%, according to NICE CG95. In our cohort, only 31.2% (n=214, 95% CI 27.6-34.5) of high risk patients in this category were diagnosed with CAD. On average, actual incidence of CAD compared with pre-test probability was overestimated by 34.4% – 40.9% in each cell.

The pink cells in table 3 represent medium risk patients with a pre-test probability of CAD of 30-60%, according to NICE CG95. In our cohort, only 4.4% (n=24, 95% CI 3.0 – 6.5) of medium risk patients had a positive angiogram (Table 4). The average overestimate of actual incidence against pre-test probability was 35.9%.

The cells highlighted in blue in table 3 represent low risk patients with a pre-test probability of CAD of 10-29%, according to NICE CG95. In our cohort, only 2.5% (n=7, 95% CI 1.2 – 5.0) of low risk patients were diagnosed with CAD (Table 4). On average, the pre-test probability of CAD exceeded the found incidence of CAD by 18.6% (Table 3).

The white cells in table 3 represent very low risk patients with pre-test probability of CAD <10% according to NICE CG95. In our cohort, only 0.28% (n= 1, 95% CI 0.1 – 1.6) of patients were diagnosed with CAD. Average overestimation in this group was 6.5% in each cell.

ESC guidelines pre test probabilities compared against cohort data

Table 5: A comparison of ESC pre-test probabilities with cohort patient data.

Each cell shows the proportion (%) of cohort patients from each group diagnosed with CAD. Each cell is colour coded to correspond with the ESC estimated pre-test probability. Dark red cells represent >85% probability, pale pink cells represent 66-85% probability, pale blue cells represent 15-65% probability and white cells represent <15% probability.

Table 6: A comparison of ESC pre-test probabilities and cohort patient data

The risk of CAD as predicted by ESC guidelines on the left compared with the actual number of cohort patients in each category and the proportion of those patients diagnosed with significant CAD.

The average discrepancy between pre-test probability of CAD, according to the ESC’s risk stratification table, and actual incidence of CAD in cohort patients was 20.7%. In 28% of cells, the pre-test probability of CAD exceeded the found incidence of CAD by 30% or more (Table 5).

The cells highlighted in dark red in table 5 represent very high risk patients with a pre-test probability of CAD greater than 85%, according to ESC guidelines (Table 5). 73.4% (n= 58, 95% CI 63.7 – 82.7) of cohort patients in this high-risk category were diagnosed with CAD (Table 6). On average, incidence of CAD in each cell has been overestimated by 13% in this category.

The cells highlighted in pale pink in table 5 represent high risk patients, with a pre-test probability of CAD of 66-85%, according to ESC guidelines. 58.5% (n=103, 95% CI 51.1 – 65.5) of cohort patients in this high-medium risk category were diagnosed with CAD (Table 6). On average, the pre-test probability of CAD exceeded the found incidence of CAD in each cell by 17.7% (Table 5).

The cells highlighted in pale blue in table 5 represent medium risk patients with a pre-test probability of CAD of 15-65%, according to ESC guidelines. 6.4% (n=93, CI 5.3 –7.8) of cohort patients in this risk category were diagnosed with CAD (Table 6). On average, the pre-test probability of CAD exceeded the found incidence of CAD by 24.1%in each cell (Table 5).

The cells highlighted in white in table 5 represent patients whose pre-test probability of CAD was less than 15% according to ESC guidelines. Only 0.76% (n=2, 95% CI 0.2 –2.7) of cohort patients in this risk category were diagnosed with CAD (Table 6). On average, pre-test probability of CAD exceeded found incidence of CAD in each cell by 6.2% (Table 5).

Discussion

Only 15% of a total of 1968 patients referred to RACPC were diagnosed with significant CAD. The majority (70%) of referred patients had “non-anginal” chest pain and low pre-test probabilities of CAD, reflecting the importance ascribed by General Practitioners of ruling out ischemic heart disease as the underlying cause for chest pain, even in low risk patients. This may not be surprising given the large media attention to heart disease and sustained campaigns for early warning signs of heart attack in the British media. It is therefore of great public interest for cardiac disease to be identified.

NICE CG95 pre test probabilities compared against cohort data

Comparing cohort data to the pre-test probabilities of CAD outlined in NICE CG95, NICE have overestimated the number of patients likely to have CAD in the majority of groups. Strict adherence to NICE CG95 therefore carries the risk of over-investigating patients. NICE recommend CT calcium scoring as the first line investigation for patients with a low (10-29%) pre-test probability of CAD. 284 patients fall into this category and only 7 patients were shown to have CAD. This means that 40.5 patients need to be treated in order to identify 1 positive patient (NNT= 40.5).

In patients with a medium (30-60%) pre-test probability of CAD, NICE recommends functional imaging as the first line diagnostic investigation. In our cohort 544 patients would undergo functional imaging, but only 24 of these patients would be diagnosed with CAD, NNT=22.7.

Finally, in patient groups with a high (61-90%) pre-test probability of CAD, NICE recommends invasive coronary angiography as the first line diagnostic investigation. In our cohort of 1968 patients, 691 patients had a high pre-test probability of CAD, and 214 had significant coronary artery disease on angiography, NNT= 3.2.

Although invasive coronary angiography is considered the gold standard investigation for diagnosing CAD, and permits simultaneous therapeutic intervention, the procedure is not without risk, particularly in elderly patients and those with renal impairment.¹¹ Furthermore, invasive angiography is expensive and is costed by the East Kent Hospitals University NHS Foundation Trust at £1166.02 per procedure (private correspondence).

NICE CG95 offers no guidance on managing patients who have a <10% pre-test probability of CAD. 347 of our cohort patients fell into this very low risk category and only 1 was diagnosed with CAD. Therefore, NICE CG95, if strictly adhered to, would have missed one diagnosis of CAD in our patient cohort.

ESC pre test probabilities compared against cohort data

ESC guidelines tend to offer more conservative estimates of pre-test probability of CAD compared with NICE guidelines. Using the ESC’s risk stratification table, almost all patients, except those with over 85% pre-test probability and those with less than 15% pre test probability, would be investigated for chest pain. This is due to their claim that non-invasive, image-based diagnostic methods for CAD have typical sensitivities and specificities of around 85%, so that roughly 15% of these investigations could be yielding false results. Hence, due to these inaccuracies, in patients with pre-test probabilities of CAD below 15% or above 85%, ESC state that performing no test at all could provide fewer incorrect diagnoses.⁹

In our patient cohort, 79 patients had very high (>85%) pre-test probability of CAD, but only 58 patients (73%) were diagnosed with CAD. For this patient risk group, ESC guidelines suggest that further investigation may not be necessary and that a diagnosis of CAD may be assumed. Thus, applying ESC guidelines to our cohort could result in 21 patients being incorrectly diagnosed with stable angina, and more serious causes of chest pain, for example pulmonary emboli or gastric ulceration, may be missed. However, in practice, it is likely that many patients in this very high pre-test probability category would have undergone angiography, because patients who have "severe symptoms" or who are clinically thought to have "high risk coronary anatomy" should be offered an invasive angiography with or without pressure wire studies. The vagueness of the guidelines allows interventionists to interpret this in the clinical context.

In ESC guidelines, invasive coronary angiography is not specifically recommended as a first line investigation for stable angina, regardless of the pre-test probability of CAD. In patients with a high (66-85%) pre-test probability of CAD, ESC guidelines recommend non-invasive functional imaging first line. Of the 176 patients who fell into this category, only 102 (58.0%) patients were ultimately diagnosed with CAD.

In patients with medium (15-65%) pre-test probability of CAD, ESC guidelines advise exercise ECG testing (or non-invasive imaging for ischemia if local expertise is available) as first line diagnostic investigations. Of the 1451 patients which fell into this category, only 93 were diagnosed with CAD, NNT= 15.6. Fortunately, exercise ECG testing would not expose the patient to potentially harmful radiation or medication, but their poor diagnostic power may result in the need for further investigations, despite a negative result.

In patients with low risk of CAD (<15%) ESC guidelines suggest making an assumption that the patient does not have CAD and advocates conducting no further investigations. In our cohort, 263 patients fell into this low risk category, two (0.8%) of which were diagnosed with CAD.

The ESC guidelines appear to have higher specificity than the NICE guidelines, and only two patients would have been missed had ESC guidelines been adhered to, compared to one patient missed if NICE guidance was used. Thus, although highly sensitive, ESC guidelines when applied to our cohort have lower sensitivity than NICE guidelines.

Comparison of number of investigations

Following ESC guidance for our cohort of patients would have resulted in fewer diagnostic invasive angiograms being performed than if NICE guidance had been followed. ESC guidance only recommends invasive angiography if first line, non-invasive investigations generate positive results. Overall, however, ESC guidance would result in a greater number of overall investigations being performed.

In total, NICE advises that all 691 of our high risk cohort patients should undergo invasive angiography as a first line investigation. 544 with medium risk should undergo functional testing first and 24 of these patients (assuming an angiogram would follow a positive result) would go on to have invasive angiography. 284 low risk patients should undergo CT calcium scoring first, of which 7 would go on to have functional imaging and angiography if the above logic is followed. This generates a total of 1557 investigations; 722 angiograms, 551 functional imaging investigations and 284 cardiac CT scans.

In comparison, using ESC guidance, 176 of our high risk patients would have functional imaging investigations, 103 patients with positive results would then undergo invasive angiography. 1451 patients would receive exercise ECGs, of which 93 with positive results would undergo functional imaging and invasive angiography. This generates a total of 1916 investigations; 196 angiograms, 269 functional imaging investigations and 1451 exercise ECGs.

If we assume that stress echocardiograms are used as “functional imaging” we can estimate costs for our cohort when applying each set of guidelines. Costs for each investigation are supplied by East Kent Hospitals University NHS Foundation Trust and are as follows: Outpatient elective coronary angiograms are costed at £1,166.02; stress echocardiograms are costed at £132.30; exercise ECGs at £40.26 and CTs of one area at £102.47 (private correspondence). If we were to apply NICE guidelines to our cohort, £841,866.44 would be spent on angiograms, £72,897.30 would be spent on stress echocardiograms and £29,101.48 on CT scans. This is a total of £943,865.22 on investigations.

If we were to apply ESC guidelines to our cohort, £228,539.92 would be spent on coronary angiograms, £35,588.7 would be spent on stress echocardiography and £58,417.26 would be spent on exercise ECGs. A total of £322,545.88 would be spent on investigations. Overall, this is £621,319.34 cheaper than applying NICE guidelines.

Limitations of study

This study is based on data from a single site and may not be nationally representative. The final diagnosis was made clinically by an experienced interventional cardiologist, which introduces subjectivity and the risk of interpreter bias. Not all patients underwent the gold standard of invasive coronary angiography to demonstrate the presence of CAD. However, all patients were seen and fully assessed by a cardiologist and 97% underwent investigations if deemed necessary.This study has all the limitations of a registry study. In addition, costs for investigations may vary throughout the country, and indeed the world, with varying expertise available.

Conclusion

In conclusion, strict adherence to NICE CG95 over-estimates the pre-test probability of CAD in our local population group. This is consistent with previous studies conducted in South London where there is a larger Afro-Caribbean population, as well as with studies conducted in the North of England.^8,9 Adherence to ESC guidelines in place of NICE guidelines may enable a more targeted and cost-effective use of investigations. Strict application of the ESC guidelines to the study cohort would have resulted in investigations costing an estimated £322,545.88, compared to £943,865.22 if NICE guidelines were applied. However, conducting fewer investigations carries greater risk of misdiagnosis, and using ESC guidelines in isolation introduces the possibility of assuming CAD in patients without conducting investigations to confirm this.

It is advisable that local cardiology departments audit their stable chest pain guidelines to ensure that the interpretation of pre-test probabilities is in keeping with the local population. Unfortunately there is no ideal policy and local protocols should reflect the local population.

Introduction

Tuberculosis is an important and major infectious disease worldwide, especially in developing countries with an estimated global case fatality rate of 13% in 2007. The World Health Organization estimated that there were 13.7 million prevalent cases of TB infection worldwide, with each year bringing about 9.27 million new cases, 44% of which are new smear-positive cases¹. Musculoskeletal tuberculosis is rare, chest wall tuberculosis is rarer and involvement of costochondral junction is among the rarest forms of tuberculosis. Tubercular costochondritis usually presents with insidious onset non-specific pain and swelling, resulting in delay in the diagnosis. Diagnosis is usually made by typical radiological findings and microbiological and histological evidence of tuberculosis. Treatment consists of antitubercular therapy with or without surgery.

Case report

30 year male, smoker, from low socio economic status presented with history of low grade fever, malaise and anorexia which began gradually two months back. For about one month he had pain in right side of chest just adjacent to lower part of sternum. The pain had started insidiously, gradually worsened with time, and was dull and aching in character. Pain was localized to the right lower parasternal area, occasionally radiating to the back. The pain was aggravated by physical activity and deep inspiration and was relieved to some extent by ordinary anti- inflammatory medications. There was significant history of pulmonary tuberculosis in the patient’s sister 1 year ago. There was no history of cough, haemoptysis, fever with chills or history of tuberculosis in the past.

On general physical examination, the patient was weak and febrile. On local examination, there was a bulge in the right lower parasternal area, corresponding to the right 9th costochondral junction. On palpation, there was severe tenderness in the same area. There was no peripheral lymphadenopathy and abdomen was soft and non-tender with no organomegaly. Chest examination was unremarkable. The rest of the examination was normal.

In terms of investigations, the chest radiograph, ECG, haemogram, kidney function tests and liver function tests were normal. ESR was high (34), Mantoux test was positive(15mm). Sputum for AFB was negative. Axial CT chest demonstrates expansion of the left 9th costal cartilage with soft tissue thickening on both the inner and outer aspect of the cartilage (Fig.1). FNAC (Fine Needle Aspiration Cytology) of the costochondral junction revealed Mycobacterium tuberculosis and on culture and histopathology of aspirated material revealed tubercular granuloma (Fig.2). A final diagnosis of tubercular costochondritis was made and the patient was treated with anti tubercular drugs for 9 months. Patient's symptoms improved after 2 weeks of treatment and swelling and tenderness subsided. Post treatment axial CT demonstrated complete resolution of soft tissue abnormality previously seen around the costal cartilage (Fig.3).

Figure 1: CT chest showing evidence of costochondritis.

Figure 2: Typical tubercular granuloma with central caseous necrosis on histopathology.

Figure 3: Post ATT CT showing complete resolution of costochondritis.

Discussion

Tuberculosis is very common infectious disease in developing countries like India, resulting in significant morbidity and mortality. Musculoskeletal tuberculosis is relatively uncommon and accounts for 1 to 2% of all the tuberculosis patients^2,3 and accounts for about 10% of all extrapulmonary TB infections⁴. Tuberculosis of the chest wall constitutes 1 to 5% of all cases of musculoskeletal TB^5,6. TB abscesses of the chest wall are usually seen at the margins of the sternum and along the rib shafts, and can also involve the costochondral junctions, costovertebral joints and the vertebrae⁷. In one study⁸, on the basis of the part of the rib involved, the roentgenographic findings for patients with rib tuberculosis was divided into four categories: Costovertebral (35%), Costochondral (13%),Shaft (61%), and Multiple cystic bone. TB of the thoracic wall is usually caused by reactivation of some latent foci of primary tuberculosis formed during hematogenous or lymphatic dissemination but direct extension from contiguous mediastinal lymph nodes can also occur⁹. In developing countries such as ours, tuberculosis is endemic and all the rare forms of the disease have been described, but in developed countries, resurgence of tuberculosis due to HIV may be responsible for atypical presentations .

Thoracic wall tuberculosis mostly presents insidiously with pain and swelling, but the diagnosis of chest wall TB is often delayed due to lack of specific symptoms and signs and gradual course¹⁰. Approximately less than 50% of chest wall TB patients may have active pulmonary TB^11,12. Imaging techniques like X-Rays and CT scan play an important role in diagnosis and follow up of these patients. According to a study done by Vijay YB et al¹³, radiological signs may not be present initially at the time of presentation with symptoms, abscesses or sinuses may be present much before the imaging modalities detect them. Computed tomography (CT) scan is more valuable for localization and detection of bone destruction and soft tissue abnormalities. Atasoy et al demonstrated the role of Magnetic Resonance Imaging (MRI) for early detection of marrow and soft tissue involvement in sternal tuberculosis due to high contrast resolution of MRI¹⁴.Diagnosis is usually confirmed by finding acid fast bacilli (AFB) and positive AFB cultures of bone (positive in up to 75% of cases), and caseous necrosis and granuloma on histopathology¹¹.

Complications of thoracic wall tuberculosis include secondary infection, fistula formation, spontaneous fractures of the sternum, compression or erosion of the large blood vessels, compression of the trachea and migration of tuberculosis abscess into the mediastinum, pleural cavity or subcutaneous tissues as discharging sinus. Chest wall TB needs to be differentiated from benign and malignant tumors [chondroma, osteochondroma, fibrous dysplasia, lipoid granuloma, chondrosarcoma, myeloma multiplex]¹¹, metastatic carcinoma, lymphoma or other kinds of infection^15,16.

The treatment of choice of chest wall TB is still not clear. Whether antitubercular therapy alone or surgical debridement (or excision based on lesion extension) combined with antitubercular therapy should be done needs further studies. But the general rule is if there are any complications, surgery is the treatment of choice followed by antitubercular therapy. We conclude that the diagnosis of thoracic wall tuberculosis is a challenge for physicians and is suspected by gradual onset clinical features and confirmed by microbiology, histopathology and radiography findings. Early diagnosis and treatment are important to prevent complications caused by bone and joint destruction.

Case Summary

Three and half year old male child presented to PICU, Narayana health BANGALORE, with a short history of fever of 8 days with headache  and  cough for 2 days. At admission the child was febrile, dull looking, haemodynamically stable with no meningeal signs or focal neurological deficit. He was admitted and evaluated for the cause of fever. Same day child developed generalized seizures along with fever, hence a possibility of meningitis or electrolyte imbalance (hyponatremia) kept as child had initial serum sodium of 128meq/l. The cause of hyponatremia was looked into and child managed with antiepileptic drugs and 3% normal saline infusion. The initial sepsis screen was in-conclusive and CSF analysis showed 3 lymphocytes with low glucose and elevated protein levels, hence partially treated meningitis was considered (as h/o admission to a hospital for 3 days prior to admission in our hospital). The antimeningitic dose of IV antibiotics were given.  On day 3 of admission child developed meningeal signs with worsening sensorium, hence  neuro imaging was done (MRI brain) which showed multiple well defined ring enhancing lesion at bilateral central and cerebrallar hemisphere, thalamus, pons with mild perilesional edema. This radiological picture suggested a possibility of nerucysticercosis, however the clinical picture did not match with the same, hence pediatric neurology opinion was taken and simultaneous workup for tuberculosis were started. Child was also started on IV steroid. A strong possibility of CNS toxoplasmosis was kept by neurologist based on radiological picture. The workup for TB was inconclusive (negative mantoux, normal ESR, negative gastric aspirate for AFB) however child was empirically started on category II ATT in view of deteriorating clinical state. Repeat CSF evaluation showed increasing cell counts and similar biochemical picture as before, the sample was also send for Gene-Xpert (DNA amplification study). On day 6 of admission child developed lethargy and drowsiness hence antiedema measures were initiated. Same day he developed tonic posturing with unequal pupil, hypertension and bradycardia indicating raised Intracranial pressure (ICP), for which he was intubated and ventilated and urgent repeat CT head was done which showed increase in ventricular size and hydrocephalus. Immediately EVD was put by neurosurgeons after which there was gradual improvement in child’s condition and he was extubated within 48 hours. The reports showed negative HIV and toxoplasma serology and positive CSF gene study for AFB confirming the diagnosis of CNS tuberculosis, hence ATT and antiedema measures were continued and the EVD was later converted into VP shunt. Child by 2^nd week of illness became afebrile with improved sensorium and function.

Fig 1 & 2: MRI showing multiple ring enhancing lesions

Discussion

Tuberculosis remains a leading cause of morbidity and mortality in the developing world. CNS involvement is thought to occur in 2-5% of patients with tuberculosis and up to 15% of those with AIDS related tuberculosis ^1,2. Although CNS involvement by tuberculosis is seen in all age groups, there is a predilection for younger patients, with 60-70% of cases occurring in patients younger than 20 years of age ^2. Haematogeneous spread from the lungs or gastrointestinal tract is most common, leading to small subpial or subependymal infective foci. These are termed Rich foci and form a reservoir from which intracranial manifestations may arise ^3,4. Tuberculomas often present with symptoms and signs of focal neurological deficit without evidence of systemic disease. The radiologic features are also nonspecific and differential diagnosis includes malignant lesions, sarcoidosis, pyogenic abscess, toxoplasmosis and cysticercosis.^5,6

Regarding treatment, the Center for Disease Control and Prevention recommends 12 months of treatment for CNS TB when the MT strain is sensitive to all drugs.⁷ However numerous variables can affect the response of the disease to therapy and it has been suggested that treatment duration should be tailored to the radiological response.⁸ After 12 months of treatment more than two-thirds of the patients still have contrast enhancing lesions. Although it is not clear if this represents an active lesion or just inflammation, continuing treatment is probably prudent. Total resolution of the tuberculoma is observed when scans demonstrate no enhancing lesions or only an area of calcification.⁸

In the case described above child had tubercular mengitis, multiple tuberculous, hydrocephalus and raised ICP. Although clinical presentations were suggestive of same, however the radiological picture and initial CSF finding raised suspicion is diagnosis. As tuberculoma and NCC shows many common clinical features, there are few distinguishing features such as the cysticercosis is smaller, less perilesional edema, multiple numbers and less of midline shift as compared to tuberculoma. However in our patient the multiple tuberculi gave a suspicion of NCC. It was only gene expert which confirmed our diagnosis.

Hence clinical cases like Tuberculoma, the radiological findings of which can usually be distinguished from other common illness like Neurocysticercosis or Toxoplasmosis, sometimes pose challenge in terms of radiological diagnosis suggesting the need for detailed evaluation to reach the diagnosis and guide treatment.

Introduction

Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that affects approximately 400,000 people in the United States and 2.5 million worldwide.¹ There are rare variants of this disease that can profoundly delay diagnosis and treatment. Examples of such variants include: Tumefactive MS, Acute Disseminated Encephalomyelitis, Neuromyelitis Optica, Marburg’s MS and Balo Concentric Sclerosis.² These variants have a uniquely aggressive presentation and do not exhibit classic MS features.² Classic MS features include relapsing and remitting sensory and motor impairments, optic neuritis and pain. These aggressive variants are more likely to present with symptoms similar to neoplasm such as motor impairments and seizures. When dealing with these aggressive MS variants diagnostic options include Magnetic Resonance Imaging (MRI), Single Photon Emission Computed Tomography (SPECT) scan, MR spectroscopy and Cerebrospinal Fluid (CSF) analysis.³

Invasive tests such as brain biopsy are not warranted unless absolutely necessary. In MS, a biopsy must not be completed in order to confirm a diagnosis. However, to confirm a diagnosis of cancer a biopsy is required.

We present a rare case of Tumefactive MS that exhibited a clinical picture identical to brain metastasis. This was diagnosed with surveillance MRI and CSF analysis in the absence of a brain biopsy.

Case presentation

A 48-year-old African American female was brought in by emergency medical services after falling with a brief loss of consciousness. Associated symptoms included dull chest pain, diaphoresis and shortness of breath. While in the emergency department she also developed nausea, vomiting and dizziness. The patient reported no similar previous episodes and denied precipitating events. There was nothing else to note on review of systems. The past medical history included hypertension with no previous surgeries and family history included breast cancer of the mother diagnosed at age 47. The patient denied tobacco, alcohol and intravenous drug use. She noted an allergy to iodine.

On physical examination the patient was afebrile, normotensive and tachycardic with an oxygen saturation of 89% on room air. She was alert and oriented but pale and diaphoretic with mild left sided chest pain. Cardiac examination revealed a normal rhythm tachycardia and no murmurs were heard. Her neurological examination showed a normal mental status, normal cognition/comprehension and that Cranial Nerves II-XII were intact.

Laboratory findings included haemoglobin of 9.8 g/dL, 30.8% haematocrit and potassium of 3.3 mmol/L. Electrolytes were otherwise normal. Cardiac workup showed a normal ECG and slightly elevated cardiac enzymes of 0.319 ng/mL.

Given the patients tachycardia and desaturation, a stat Ventilation-perfusion (V/Q) scan was completed (patient had an iodine allergy). The V/Q scan revealed a perfusion defect suggesting pulmonary embolism (PE) as the cause of symptoms. Subsequently the patient was placed on appropriate anticoagulation.

Head CT (computed tomography) showed a left centrum semiovale round hypodense lesion measuring 1.4 cm, a left basal ganglia round hypodense lesion measuring 1.0 cm and a left occipital lobe round hypodense lesion measuring approximately 1.0 cm (Figure 1). No midline shift was seen. MRI showed multiple hypointense T1/hyperintense T2 nonenhancing lesions, mainly within the left cerebrum (Figure 2 A-F). The three largest lesions within the left posterior centrum semiovale (2A), left globus pallidus (2B) and left posterior corona radiata adjacent to the occipital horn (2C) measured 1.5 cm, 1.0 cm and 1.0 cm respectively. Perilesional vasogenic oedema was seen in all except the basal ganglia lesion. There were bilateral cerebral scattered foci of hyperintense FLAIR/T2 signals (D-F). The imaging suggested a differential diagnosis which included metastasis, infection or primary CNS malignancy.

Further work up in search for possible malignancy was completed. Skin map revealed no concerning nevi. Mammogram showed no tumor. CT of the abdomen and pelvis revealed a 2.6 cm indeterminate hypodense lesion in the left lobe of the liver (Figure 3A) along with an enlarged fibroid uterus (17x 7 x 14 cm). Liver biopsy was considered but a repeat MRI and ultrasound showed the lesion to be cystic, so this was deferred following surgical oncology recommendations (Figure 3B). For the hypertrophic uterus found on imaging, gynecology felt no further workup was necessary as they attributed the findings to a fibroid uterus.

Tumor markers CA 27-29, CA 19-9, CA 125 and AFP were all sent and came back negative. Initial lumbar puncture with CSF analysis was not completed secondary to possible complications that could be incurred while on necessary PE anticoagulation.

Due to a non-focal neurological examination, she was discharged on Levetiracetam 500 mg for seizure prophylaxis and Dexamethasone 4 mg for perilesional oedema. Over subsequent months the patient did well without headaches, vision changes or seizure like activity. On subsequent visits to the clinic, she had no evidence of focal neurological deficits except for mild bilateral symmetric hyperreflexia. Given that the metastatic work up remained negative, we considered obtaining a baseline Positron emission tomography (PET) scan to ensure we were not missing any possible metastasis.

She subsequently went back to work full-time and reported no symptoms. Repeat MRI of the head (Figure 4 A-C) showed predominantly T1 hypointense and T2 hyperintense (A-B) lesions with significant decrease in size from MRI done three months ago. These lesions demonstrated no enhancement to incomplete ring enhancement, with diminished vasogenic oedema (A). These findings suggested an inflammatory demyelinating process so a lumbar puncture was obtained after anticoagulation was held. CSF analysis was done using Isoelectric Focusing (IEF) and immunoblotting methodology. This revealed a normal myelin basic protein but with eight oligoclonal bands restricted to the CSF. These findings solidified the suspicion of Tumefactive MS.

Figure 1. Head CT without contrast: left centrum semiovale round hypodense lesions measures 1.4 cm with perilesional vasogenic edema

Figure 2. MRI of brain showing axial T1-weighted (A-C) hypodense lesions of the left centrum semiovale(A), left basal ganglia(B) and left occipital lobe(C). Axial T2-weighted (D-F) views show multiple hyperdense lesions corresponding to the same locations. Perilesional vasogenic edema is seen.

Figure 3A. Thorax CT without contrast. 2.6 cm left lobe liver lesion.

Figure 3B. MRI of abdomen showing coronal T2-weighted half-Fourier acquisition single-shot turbo spin-echo (HASTE) hyperdense lesion. A mildly enlarged liver measuring 18.7 cm in craniocaudal span. Simple 2.8 x2.4 cm cyct in the medial segment of left lobe.

Figure 4. MRI of brain (3 month after initial scans) showing axial T-2 weighted (A-B) hyperdense lesions of the left centrum semiovale(A) and left basal ganglia(B). There is irregular peripheral enhancement. Considerable decrease in size is seen from previous MRI (Figure 2). Left posterior centrum semiovale, left globus pallidus and left occipital lobe lesion measure 1.3 cm, <1 cm and <1 cm respectively. Vasogenic edema is diminished in comparison to previous study.

Discussion

Tumefactive MS lesions are defined as solitary demyelinating plaques greater than 2 cm.⁵ Lesions are difficult to distinguish between primary or metastatic given similarity of imaging features.⁵ Imaging features suggestive of Tumefactive MS include incomplete ring enhancement, absence of mass effect and absence of cortical involvement.^{6 7} Kim describes that CT hypoattenuation of magnetic resonance enhancing lesions was found to be highly specific for distinguishing Tumefactive MS lesions from CNS cancer pathology.⁶ It has been shown that SPECT using I-IMP is useful for diagnosing CNS malignancy.³ This is because there would be increased uptake in comparison to the MS lesions - implying increased metabolic activity.³ However this study has its limitations in diagnosis. In a few isolated cases I-IMP was found in greater quantities in MS tumor-like lesions.³

The imaging studies for this patient established a concern for metastasis, infection or primary malignancy. Extensive cancer workup was completed as previously discussed. Since all tumor markers were negative a baseline PET scan was considered however, was not done secondary to insurance denial. Due to the asymptomatic presentation of her disease, a primary differential diagnosis of brain metastasis and anticoagulation therapy for PE, a CSF analysis was not considered until much later. We were able to use surveillance MRI and CSF analysis to see some resolution of these lesions and confirm the diagnosis. Brain biopsy was never warranted but in unique symptomatic cases it may have been.⁶

The cornerstone of diagnosing MS is the demonstration of lesions in both time and space - termed the McDonald Criteria.⁸ The revised criteria allow a diagnosis of MS, “possible MS” or “not MS”.⁸ This is what made the diagnosis of our patient difficult, as no clinical symptoms or attacks were evident. It was demonstrated that over the course of three months the lesions seen on MRI evolved. From the size of 1.5 cm, 1.0 cm and 1.0 cm they became 1.3 cm, <1.0 cm and <1.0 cm respectively (Figure 2, Figure 4). This was likely the effects of steroids that the patient was on due to her vasogenic oedema. Here an evolution in time and space is demonstrated which excluded brain metastasis and infection. This brings into discussion the diagnostic value of surveillance MRI, which in our case was helpful and appropriate as the patient did not have clinical symptoms.

Conclusion

The diagnosis of Tumefactive MS can be extremely difficult and time consuming. As seen in our case, it can mimic other conditions. Our patient was able to be diagnosed with MRI surveillance and CSF analysis. The definitive diagnostic test for MS is a brain biopsy but this is not preferred due to the invasiveness of the procedure. With the advent of newer diagnostic tests such as SPECT, MR Spectroscopy, surveillance MRI and CSF analysis, diagnosis can be attained and treated presumptively.

CASE

A 79 year old lady presented to the accident and emergency department with severe abdominal pain. On admission she was hypotensive and hypothermic. Blood tests demonstrated raised inflammatory markers and white count, but were otherwise unremarkable. A CT scan revealed no abnormalities. She was treated with intravenous fluids and empirical antibiotics.

She had multiple co-morbidities, including ischaemic heart disease, hypertension and chronic kidney disease.

Figure 1 – Upper Oesophagus

Figure 2 – Distal Oesophagus

Figure 3 - Gastro-eosophageal Junction

Figure 4 – Stomach (in retroflexion)

Figure 5 - Duodenum

Three days into her admission she had a single episode of hematemesis and a gastroscopy was arranged. Endoscopic features were as per figures 1- 5. Histology taken at the time showed necrotic tissue with evidence of candidiasis. Her treatment was optimised with a two-week course of fluconazole with the dose adjusted for her renal function and parenteral nutrition, with good clinical response. She was discharged after a two week hospital admission. A repeat gastroscopy 10 weeks later showed complete resolution of endoscopic features with no evidence of perforation or stricture formation.

DISCUSSION

The images seen at endoscopy demonstrate a region of oesophageal ulceration progressing to a diffuse, circumferential, black discoloration of the distal esophageal mucosa, with an abrupt transition to normal mucosa at the gastro-esophageal junction (Figs. 1-3). These endoscopic features, in the absence of a history of ingestion of caustic substances, are diagnostic of Acute Oesophageal Necrosis (AON), also known as ‘Black Oesophagus’. Whilst histology confirming necrosis is not necessary to make the diagnosis, it is confirmatory.

AON was first described in 1990 by Goldberg et al, since which over one hundred cases have been reported in the literature¹. Population studies have suggested the incidence of this condition to be between 0.08% and 0.2%, although interestingly one post-mortem series of 1000 patients failed to reveal any cases^2-4. There is a male preponderance, with an incidence four times greater than that for women and a peak incidence during the sixth decade of life^{5, 6.}

The aetiology of this condition is not entirely clear; however case reports to date suggest that this is almost exclusively observed in those who are systemically unwell, usually in the context of multi-organ dysfunction^5-7. It has been postulated that necrosis most commonly occurs as a consequence of hypo-perfusion caused by a low flow state in those with underlying vascular disease. This is likely to account for the predilection for the distal third of the esophagus, which is relatively less vascular⁵. Individual cases have occurred in association with bacterial, viral and fungal infections, whilst malnutrition, malignancy and immune-compromise appear to be important factors^{3, 5, 6}.

The most common indication for the gastroscopy that makes the diagnosis of AON is hematemesis and melena, accounting for over 75% of cases⁶. It is therefore likely that AON is significantly under reported as endoscopy is often precluded in those who are clinically unstable. Further it is not clear whether hematemesis is a universal symptom of this condition; it is conceivable that AON may go undiagnosed in those in whom this is not a feature.

Whilst AON has no specific treatment, its presence is indicative of significant systemic compromise and predicts a poor prognosis. This diagnosis should alert physicians that close monitoring and aggressive treatment is required to optimise patient outcomes. There is no clear role for the use of anti-acid therapy, however this is commonly used in management due to patient symptoms, which usually includes hematemesis. Similarly, candidiasis may occur in conjunction with AON, whilst it is not thought to be causative, treatment is considered prudent given the poor prognosis associated with this condition.

For those that recover from their acute systemic insult the prognosis appears to be good. The long-term sequale of this condition includes oesophageal stenosis due to structuring. Evaluation with a repeat gastroscopy if therefore indicated if dysphagia develops.

CONCLUSION

The clinical course of AEN is variable, with an associated mortality of 32%⁵. The severity of the underlying clinical condition appears to be the most important factor in determining prognosis. There is no specific treatment for AON. The current body of experience suggests aggressive management of abnormal physiology optimises outcomes^{5, 6}. Antibiotics, antifungals and nutritional support should be considered on an individual basis.

Introduction

As syphilis is a notable clinical and pathological imitator, its diagnosis remains challenging. Physicians should be vigilant to suspect syphilis in cases of non-specific signs, such as lymphadenopathies, even in patients with no apparent risk for sexually transmitted infections or a history of primary syphilis.

Case Report

We report the case of a seventy-year old woman with a medical history of arterial hypertension. She had neither smoked cigarettes nor drunk alcohol and she had no significant medical family history. The patient presented with a history of swelling in the left axilla of one year duration. The swelling gradually increased in size and was painless. There was a history of occasional low-grade fever and weight loss, but no cough or night sweats.

On initial examination, the patient was thin with generalised lymphadenopathy: she had an axillary adenopathy that measured 4 cm in diameter in the right axilla and one measuring 3 cm in the left axilla. She also had two cervical lymph nodes that were less significant, and one enlarged right inguinal lymph node of about 3 cm in diameter. The existing lymph nodes were painless, mobile, mildly tender and smooth. Otherwise, breasts, limbs and other regions were essentially normal. No skin rash or suspect lesions were noticed. All her family members were well, with no contributory medical history, and none of them had similar symptoms.

A complete blood count revealed a white blood cell count of 5300/l (neutrophils 40%, eosinophils 19%, lymphocytes 30%, monocytes 10%), and a C-reactive protein of 14 mg/l. The remaining results of her full blood count, electrolytes, liver enzymes, lactate dehydrogenase and urine analysis were within normal limits. Calcium and phosphate levels were normal in both blood and urine analyses. Both human immunodeficiency virus screening and the serological tests for hepatitis B and C were negative. Mantoux test did not show any indurations. Smear and culture of the sputum were negative. Her chest x-ray and abdominal ultrasound were normal.

A CT scan of the patient’s neck and chest showed a marked anterior mediastinal mass of about 50 mm diameter with multiple calcifications. Several small lymph nodes were also noticed in the cervical and axillary areas. An axillary lymph node biopsy was performed. Histopathological examination of the biopsy specimen revealed a granulomatous lesion with epithelioid and multinucleated giant cells (Fig.1) associated with calcifications and central areas of caseous necrosis (Fig.2), which were highly suggestive of tuberculosis.

Fig 1: Epithelioid granuloma with giant cell

Fig 2: Eosinophilic granuloma with acellular caseous necrosis

According to these clinical and pathological findings, the most common granulomatous diseases are mycobacterial diseases such as tuberculosis, hence why the diagnosis of tuberculous lymphadenitis was highly suspected, and the patient was given anti-TB drugs. However, other differential diagnoses were considered, including bacterial infections like syphilis or actinomycosis, protozoal infections such as toxoplasmosis, and miscellaneous diseases such as sarcoidosis, Crohn's disease and Wegener's granulomatosis. To distinguish disease processes and make a definitive diagnosis, further investigations, such as special stains, culture methods and serologic tests, were indicated.

Additional histological stains, including Ziehl-Nielsen, were performed and returned negative, excluding the diagnosis of tuberculosis. In the meantime, the serological tests showed a positive venereal disease research laboratory test (VDRL: 1/8) and Treponema Pallidum haemagglutination assay (TPHA: 1/350). As a result, the diagnosis of secondary syphilis was confirmed and tuberculosis treatment was ceased.

The patient received intramuscular injections of 2.4 million units of benzathine penicillin every three weeks. Additional clinical and laboratory examinations were performed for both the patient and her family. She did not present with any manifestations of cardiovascular or neurological syphilis. Her husband’s VDRL and TPHA tests were negative. After a nine-month follow-up, the patient had no clinical or laboratory evidence of syphilis.

Discussion

Syphilis is predominantly a sexually-transmitted disease with both local and systemic manifestations. The causative organism is the spirochete Treponema Pallidum (TP) which was first demonstrated on the 17^th of May 1905 ¹.

Syphilis has many non-specific signs and symptoms that may be overlooked by the physician, because in some cases it may simply be indistinguishable from other more common diseases. In fact, syphilis can share clinical manifestations with other treponemal and non-treponemal diseases, and it may be asymptomatic in some stages. Unfortunately, undiagnosed and untreated syphilis may lead to life-threatening complications such as hepatitis, stroke and neurological damage ². Therefore its clinical diagnosis must be supported by laboratory tests.

Several older methods can be used to confirm syphilis diagnosis such as direct identification of TP by dark-field microscopy or direct fluorescent antibody tests, but such tests are not practical in a routine clinical setting and these methods can only be performed on lesion exudate or tissue ³.

As a consequence, the diagnosis in most patients is based on serological tests. Guidelines from the United States of America (USA) and Europe recommend a combination of two tests: the first one is a non treponemal (cardiolipin, reaginic) test, essentially Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR); and the second is a treponemal test, essentially TP haemagglutination assay (TPHA), TP particle agglutination, or the fluorescent treponemal antibody absorption (FTA-abs) test ^3,4.

In our patient, the most significant clinical finding was lymphadenopathy. This case presented diagnostic difficulties because of its clinical and histopathological resemblance to other pathological conditions. In fact, the presence of generalised lymphadenopathy and the finding of granulomatous lesions with epithelioid cells in the biopsy were highly suggestive of tuberculosis. As a matter of fact, tuberculosis tops the list of aetiological causes of granulomatous infections⁵. Worldwide it is considered the leading cause of contagious disease leading to approximately 1.4 million deaths per year ⁶. Its prevalence is still extremely high in certain populations especially in low-and middle-income countries such as Tunisia where the disease is endemic.

Tuberculosis is caused by Mycobacterium tuberculosis (M. tuberculosis) and M. bovis, an acid and alcohol fast organism ^7,8. Histopathology is characterized by the presence of epitheloid granuloma with Langerhans giant cells and central caseous necrosis ⁷.

Lymphadenitis is the most common extra-pulmonary manifestation of tuberculosis but its diagnosis is difficult, often requiring biopsy. In such granulomatous disease, and in cases of persisting doubts, it is necessary to identify the specific etiological agent by further investigations such as special stains, culture methods and molecular techniques like polymerase chain reaction (PCR) and serological tests, as in the case of syphilis.

In the case of tuberculosis infection, demonstration of the mycobacteria can be done with Ziehl-Neelsen staining or by immunofluorescence using auramine-rhodamine. Mycobacterial culture and detection of mycobacterial DNA using PCR are also used ^7,9. Since the growth of mycobacterium in culture requires a long time, additional histological stain with Ziehl-Nielsen was performed, but returned negative in the case of our patient. As a consequence, the diagnosis of tuberculosis was excluded and syphilis was considered as a definitive diagnosis.

Conclusion

Granulomatous lesions can be seen in numerous diseases. A definitive diagnosis cannot be made on the basis of the history and physical examination alone, confirmatory testing should be performed in order to identify the specific etiologic agent correctly. Diagnosis of the disease in the initial stages would be beneficial not only to allow the patients to receive early treatment, but also to prevent the spread of the disease to others.