May

Introduction

Nocardia sp. are aerobic, gram-positive microorganisms found mainly in soil and stagnant water. Nocardiosis commonly occur in immunocompromised patients, is often multi-systemic and easily mistaken for tuberculosis when involving the lungs ^{1 2}. We report a complex case of disseminated nocardiosis in a patient already suffering from Myasthenia Gravis (MG) and azathioprine-induced myelosuppression, in which selection of antimicrobials and management planning became complex.

Case Report

A 68-year old lady, known to have generalized MG for 12 years, presented to our centre following a week history of diarrhea and lethargy. She describes having loose stools, up to 8 times per day, chills and rigors, but denied per rectal bleeding or melaena. The patient was, on regular oral prednisolone (50mg a day). She had recently ceased her azathioprine 4 months prior due to severe anaemia, linked to myelosuppression following a bone marrow aspiration test revealing markedly reduced erythropoiesis, normal oesophageo-gastro-dudodenoscopy and colonosocopy, and having normal thiopurine methyltransferase levels prior to azathioprine initiation. The patient had several admissions in that 4 months due to her anaemia, requiring packed cell transfusions, and had recently sustained an interhemispheric subdural bleed two weeks prior following a mechanical fall. At the time, hemoglobin and platelet levels had returned within normal range. Clinical examination was unremarkable and her vitals on arrival included an oxygen saturation of 98% on room air with a normal chest radiography on arrival (Figure 1a). The patient was subsequently treated for infective gastroenteritis, and was started on metronidazole.

Figure 1: Chest radiography on (a) initial presentation and (b) 48-hours into admission, showing newly developed diffuse bilateral consolidation.

Unfortunately, 48 hours into her inpatient stay, the patient developed acute dyspnoea in which her oxygen saturation dropped to 77% under room air and examination revealed diffuse, coarse crepitations bilaterally. A repeat chest radiograph confirmed diffuse consolidation bilaterally (Figure 1b). She was subsequently treated for a hospital-acquired pneumonia, and had her antibiotics swapped to intravenous ceftriaxone. Unfortunately, the patient showed little improvement on the ward, which prompted further investigation. Her blood cultures revealed presence of nocardia farcinica which was resistant to ceftriaxone. In view of being immunosuppressed, a computed tomography (CT) imaging of the brain, thorax, abdomen and pelvis (Figure 2) was performed. Imaging showed extensive bilateral lung consolidation and reticulonodular opacities, predominantly in upper lobes. There was also evidence of sigmoid colon diverticulitis with a rim-enhancing collection adjacent to the posterior aspect of the proximal-to-mid sigmoid colon (2.9 x 2.6 x 2.6 cm).

Figure 2: Computed tomography (CT) imaging of (a) the brain, revealing inter-hemispheric hyperdensity consistent with a subdural haematoma, (b) the thorax, revealing extensive bilateral lung consolidation and reticulonodular opacities, predominantly in upper lobes, and (c) abdomen, showing sigmoid colon diverticulitis with a rim-enhancing collection adjacent to the posterior aspect of the proximal-to-mid sigmoid colon (2.9 x 2.6 x 2.6 cm).

Following consultation with our Infectious Disease team, the patient was treated for likely disseminated nocardiosis using intravenous trimethoprim/sulfamethoxazole as a recommended first line therapy. Unfortunately, following 72 hours of trimethoprim/sulfamethoxazole administration, the patient developed severe pancytopenia (haemoglobin 63 g/L, white cell count 2.0 x 10⁹/L and platelets 33 x 10⁹/L) requiring packed red cell and platelet transfusions, as well as immediate cessation of trimethoprim/sulfamethoxazole. Further decisions on antimicrobial proved difficult as it was noted that other effective alternatives against nocardiosis, including amikacin and fluoroquinolones may potentially exacerbate MG symptoms. Furthermore linezolid, another possible alternative, could potentially exacerbate her thrombocytopenia and worsen the pre-existing subdural haematoma. Thus, a decision was made to commence co-amoxiclav and meropenem concurrently despite neither being first-line therapy. The patient subsequently had an uneventful CT-guided drainage of the sigmoid abscess, with the assistance of our General Surgical colleagues, and was kept on prolonged intravenous antibiotic therapy for 3 months. Following improvement in clinical state, she was allowed discharge from hospital with ongoing oral co-amoxiclav and linezolid with regular bloods tests to monitor for myelosuppression as an outpatient, which has not occurred till this date. With support from clinical and radiological improvement, we aim for 12 months of therapy.

Discussion

Various cases of nocardia sp bacteraemia have been reported, in which immune system dysfunction was primarily due to chronic glucocorticoid therapy ^{1 3 4}. A retrospective review of 40 patients from a Chinese tertiary hospital revealed that half of patient with nocardiosis were on corticosteroids prior to infection onset ⁵. An even larger case series reported up to 94% of pulmonary nocardial infection being linked to use of immunosuppressants ⁶.

Management of nocardiosis can be challenging. Often, imipenem, trimethoprim/sulfamethoxazole, amikacin or a combination of these antibiotics are recommended, with treatment duration being guided by clinical and radiological improvement often extending up to a year ⁷. Bactericidal agents including carbapenems and amikacin are often recommended alongside trimethoprim/sulfamethoxazole in cases of disseminated nocardiosis to ensure greater success in treatment ^{7, 8}. The use of amikacin however should be cautioned in cases of MG, and reports have described management using linezolid as an alternative ^{1, 9}.

In our patient, the risk of worsening pancytopenia as illustrated following trimethoprim/sulfamethoxazole administration led to hesitance in using linezolid. Furthermore, the consequences of thrombocytopenia would have been devastating for the patient due to having residual subdural hematoma. Thus, the choice of antibiotics was limited to that of second-line agents including co-amoxiclav and meropenem on top of surgical drainage of existing abscesses, which has also been shown to be beneficial ^{1 5}. However, it should be noted that the risk of pancytopenia remains to be multifactorial in our patient, ranging from pre-exisitng myelosuppression to ongoing sepsis and initiation of culprit medications

Mortality of nocardiosis infections ranges depending on organ involved, rates being under 40% in cases of pulmonary spread, and up to 100% when disseminated to the central nervous system (CNS) ⁶. Unfortunately, nocardia farcinica, the subtype reported in our case, has been shown to be more resistant to antimicrobials and carries a greater risk of dissemination to the CNS, a point being greatly considered as our centre continues to manage the patient ¹⁰.

Conclusion

Nocardiosis, although not uncommon in immunocompromised individuals, poses a unique challenge in the MG population due to limitations in suitable antibiotics. Our case highlights the importance of a multi-disciplinary approach, involving various specialties including the infectious disease, neurology, general surgical and microbiology to ensure successful management of such complex cases.

Introduction

Calcinosis cutis involves deposition of calcium salts in skin and subcutaneous tissue. It is commonly associated with autoimmune connective tissue diseases and can be a source of pain and disability¹. It can occur in damaged or devitalized tissues in the presence of abnormal or even normal calcium/phosphorus metabolism. These calcifications can lead to contractures, muscle atrophy, skin ulceration and infections². There are four types of calcinosis cutis: idiopathic, dystrophic, metastatic, and iatrogenic. Determining the type of calcinosis is very important for accurate management³.Calcinosis cutis is a condition seen in the middle to elderly aged population and has rarely been described in neonates in the medical literature. We discuss a neonate in the succeeding text who presented to our Emergency department with a leg swelling.

Case Report

A 20 days old full term neonate was brought to our Emergency department with right leg swelling for the past ten days. He was feeding well and was afebrile. On examination there was swelling of right lower leg including the right foot with minimal redness of overlying skin. We did x-rays of the right foot and right leg, which showed a sheath of cutaneous calcification in right foot (Image A and Image B) and anterior-lateral of right leg (Image C and Image D).

Image A

Image B

Image C

Image D

There was no evidence of any bony destruction. White cell count and other inflammatory markers were normal. Upon reviewing the previous records we found that soon after the birth the neonate was admitted with pneumonia and during the hospital admission there was extravasation of calcium gluconate infusion at the dorsum of the right foot which explains the whitish sheath seen in the imaging. Musculoskeletal ultrasound did not reveal any signs of fluid collection or periosteal swelling. The patient was treated conservatively and regular follow up was insignificant and showed complete regression of the swelling three months later.

Discussion

Calcinosis cutis is an uncommon disorder caused by an abnormal deposit of calcium phosphate in the skin in various parts of the body. It is often noted in the subcutaneous tissues of connective tissues diseases primarily systemic lupus erythematosus, scleroderma and juvenile dermatomyositis^4,7. Four main types of calcinosis cutis have been recognized according to etiology: associated with localized or widespread tissue changes or damage (dystrophic calcification), that associated with an abnormal calcium and phosphorus metabolism (metastatic calcification), not associated with any tissue damage or demonstrable metabolic disorder (idiopathic calcification), and Iatrogenic^2-3,6-7.

It is recommended that patients be evaluated for abnormalities of calcium and phosphorus metabolism and that they be assessed for associated systemic conditions, such as collagen vascular diseases, renal insufficiency, and vitamin D poisoning. Determining the exact type of calcinosis cutis is very important for selecting accurate management³. Many agents have been used for treatment of calcinosis but none has been accepted as a standard therapy. Case studies have shown that aggressive treatment of the underling inflammatory condition with intravenous immunoglobulin, anti TNF agents, thalidomide and haematopoietic stem cell transplantation has also led to improvement of the calcinosis^1,3. Moreover, agents such as warfarin, bisphosphonates and diltiazem have been aimed at treating the process of calcinosis with varying success³.Some experts have advocated surgical excision in severe resistant cases⁴.Calcinosis cutis has been rarely reported in neonates. It almost exclusively occurs due to iatrogenic causes⁸. Calcium gluconate has been widely used in the treatment of neonatal hypocalcemia which is a common problem confronted in this age group. When extravasation of calcium gluconate occurs; swelling, erythema, signs of soft tissue necrosis or infection may be seen. Rarely local calcification appears, called calcinosis cutis^9-10.

Plain radiography is gold standard for diagnosis but are initially negative because calcium solutions used therapeutically are radiolucent. X-ray findings usually appear within 1-3 weeks⁹.This is consistent with our case. The pathogenesis of calcinosis cutis caused by extravasation of IV calcium is degeneration and soft tissue necrosis¹¹. If extravasation of calcium gluconate is suspected; the IV line must be removed immediately. Cold packs should be applied for 15 minutes four times a day to treat edema at extravasation sites and limb elevation for 48 hours is suggested¹². Supportive care remains the main element of the treatment and only in case of skin necrosis and secondary infection, debridement and antibiotics should be used⁸.

Calcinosis cutis in neonate can be easily misdiagnosed ascellulitis, arthritis, pyogenic abscess, osteomyelitis and thrombophelibitis⁸.In the present case also initially we were suspecting an infectious etiology. Initial x-rays can be misleadingly normal as it take about ten days to precipitate. The clinical and radiological findings usually disappear over a span of 2-6 months which is compatible with our case too¹³.

Introduction

Anterior knee pain or patellofemoral pain is a common clinical presentation especially in females. It is a challenging clinical problem. The specific cause can be difficult to diagnose as the aetiology remains poorly understood and there are various pathologic entities that can result in pain in the anterior aspect of knee.

Multiple surgical options have been used to treat the condition. Lateral retinacular release is one of these options and has been used to treat anterior knee pain with variable results^1-5. The aim of this study was to assess isolated patella lateral retinaculum release as a treatment for anterior knee pain.

Materials and Methods

We performed a retrospective review of all the patients who underwent isolated arthroscopic lateral patella retinacular release under a single surgeon between July 2007 and July 2010. Exclusion criteria included significant patellar instability and severe mal-alignment on both radiological and clinical assessment and additional procedures including cartilage debridement, meniscal tear repair/excision or patella stabilization.

Data was collected from case notes (demographics, pre-operative and intra-operative findings and any post-operative complications), archived radiographs and postal questionnaires including pre and post procedure Oxford Knee Score (OKS), as well as patient satisfaction. Patient satisfaction questions included a grading of satisfaction of 1(completely dissatisfied) - 10 (completely satisfied) and whether patient would reconsider the procedure if given the choice again.

Independent factors assessed were age, sex, tight lateral retinaculum, osteoarthritic x-ray changes of all compartments, intraoperative findings of grade of arthritis and lateral subluxation and postoperative physiotherapy. The primary outcome assessed was patient reported outcome measures, including the improvement in post procedure OKS and patient satisfaction scores. SPSS Version 20 was used for analysis.

Preoperative and Postoperative OKS – total and components - were compared using Wilcoxon Signed Rank Test. The Mann Whitney U test was used for nominal data and Kruskal-Wallis test was used for continuous data for total OKS. Individual OKS components compared were ability to kneel and ability to climb stairs - more representative of patellofemoral joint.

Results

59 patients were identified with male to female ratio of 1:1.5. The mean age was 58.7 (range 25 to 77). 40 patients (67%) returned completed forms. Four patients had further surgery; three total knee replacement and one subsequent arthroscopic procedure for meniscal tears. These patients were excluded from the study. Four patients had bilateral procedures. Therefore after the exclusions for further surgery and those who failed to return completed forms 36 patients were included, on whom 40 procedures had been performed. Changes of osteoarthritis - graded according to Kellgren and Lawrence system - on the medial and lateral facets of the patella were noted on preoperative Merchant views (Table 1) and the tibiofemoral compartment as well.

Table 1 – Pre-Operative Radiographic grades of Patellofemoral change

All patients had undergone standardized preoperative physiotherapy regimen with no significant benefit. Two had, had intra-articular hyaluronic acid injection with no benefit.

All procedures were performed by a single surgeon (PE) and intraoperative findings of cartilage Outerbridge grade were noted in all compartments. Closed lateral retinacular release was performed with Smiley’s knife from just below lower end up to the upper border of patella.

Mean follow up duration was 20.43 months +/- 10.64. Patients were divided into three groups of follow up durations. 6-12 months had 6, 12-18months had 18 and >18months had 16 cases. The best results were in 12-18 month follow up but no statistically significant difference was found between different groups. There was no significant difference in age and gender distribution amongst different durations of follow up. Also there was no significant difference in age, gender and different durations of follow up between responders and non-responders of the questionnaire. There were no reported postoperative complications.

24(60%) underwent post-operative physiotherapy. The mean OKS improved from 23.05 (range11-40) to 35.30 (range14-48) [p value <0.0001]. Individual components of OKS, particularly ability to climb stairs and ability to kneel, also showed statistically significant improvements (Figure 1, Figure 2).

Fig 1 – OKS – ability to climb stairs

Fig 2 – OKS – ability to kneel

Univariate analysis showed improvement of total OKS and OKS for ability to kneel were significantly associated with higher grade of radiographic lateral patellofemoral joint wear (p value 0.025 and 0.042 respectively) and postoperative physiotherapy (p value 0.018 and 0.003) and improvement in OKS for ability to climb stairs was significantly associated with higher grade cartilage wear, noted intraoperatively, for trochlea (p value 0.042) and patella (p value 0.022).

However the OKS components lost this significance if there was Outerbridge Grade 3 or more wear in tibiofemoral articulation.

The procedure had a high mean satisfaction score of 8.2 (range 4 to 10), and 32 of 36 patients would have the procedure again if needed.

Discussion

Anterior Knee pain or patella pain syndrome is a very common clinical problem faced by orthopaedic surgeons. However the aetiology remains poorly understood. Mori et al⁶identified evidence of degenerative neuropathy in 29 out of 35 histologically examined specimens of resected lateral retinaculum; thus suggesting it may originate in the lateral retinaculum. Lateral Retinacular release would denervate this tissue producing symptomatic relief. Osterneier et al⁷ measured patellofemoral contact pressures and kinematics using fresh-frozen cadaver specimens both before and after lateral release. They concluded that release could decrease pressure on the lateral patella facet in flexion but did not stabilize the patella or medialise patella tracking. This possibly explains our finding of improvement with lateral patellofemoral joint wear.

Arthroscopic lateral release remains a controversial topic because of lack of well-designed randomised studies. Fulkerson and Shea⁸ suggested that knees showing lateral patellar tilt without subluxation were more likely to benefit from a lateral release in the absence of grade III or grade IV changes in the articular cartilage. Korkala et al⁹ showed that a lateral release tended to improve symptoms in patients with grade II to grade IV chondromalacia. Our findings concur that greater the patellofemoral articulation cartilage wear the more significant the improvement.

Lodhi et al¹⁰ performed a prospective study of elderly patients with patellofemoral osteoarthritis and pain which conservative management had failed to improve and concluded that the procedure improves function and provides significant pain relief successfully deferring need for arthroplasty; therefore they recommended the procedure in middle aged to elderly patients with symptomatic patellofemoral osteoarthritis.

Twaddle and Parkinson¹¹ suggested lateral release to be an effective, reliable and durable procedure in ‘carefully selected patients’ through their retrospective study.

Our study has deficiencies regarding single surgeon series and retrospective review. However it reflects some of the findings from previous studies suggesting that it is an effective procedure to improve symptoms associated with cartilage changes in patellofemoral articulation without significant tibiofemoral joint osteoarthritis. Further well designed randomized controlled trials are needed to give a more definitive answer.

Conclusion

Isolated lateral patella retinacular release can be effective for anterior knee pain in carefully selected patients, (without significant instability or mal-alignment, with high patellofemoral but low tibiofemoral wear), who have failed conservative management. It particularly improves patients’ ability to kneel and climb stairs, giving a high satisfaction score. The grade of wear of patellofemoral cartilage is the most significant factor in determining this, with post-operative physiotherapy further augmenting the good results.

INTRODUCTION

The state of pregnancy results in a multitude of cutaneous changes in the female. These are a reflection of the profound alterations in the endocrine, metabolic and immunological profiles that occur during this period.¹ Skin manifestations occur due to the production of a number of proteins and steroid hormones by the fetoplacental unit and also by the maternal pituitary, thyroid and adrenals.² The placenta, a new endocrine organ in the woman, produces progesterone. Dehydroepiandrosterone is produced by the fetal adrenals from pregnenolone and this is aromatized to estriol. At term, the level of progesterone is 7 times, estradiol is 130 times and prolactin level is 19 times of that present at 8 weeks of gestation.³ There occurs an overall preference for the Th2 cytokine profile, which helps in fetal protection from the immune system.⁴ This is due to the high levels of progesterone, which promotes Th2 cytokines like IL-4, IL-5 and IL-10 and has inhibitory effects on TNF alpha production. Oestrogen suppresses IL-2 production. The postpartum period is marked by withdrawal of hormones and consequent elevation of Th1 cytokine levels.⁴

Cutaneous changes develop in more than 90% of all pregnant females.⁵ These include common cutaneous changes that occur in most cases to severe diseases, some of which are seen exclusively in the pregnant and postpartum state. Cutaneous manifestations can be grouped into three broad categories: physiological cutaneous changes related to pregnancy; diseases modified by pregnancy and specific dermatoses of pregnancy.⁶

PHYSIOLOGICAL CHANGES IN PREGNANCY

These changes are so common that they are not considered abnormal. Rather, they provide contributory evidence of a pregnant state. This however, does not mean they are cosmetically acceptable to all patients. The various physiological changes during pregnancy have been summarized in Table 1.

Table 1: Physiological changes in pregnancy

Pigmentation:

Hyperpigmentation is one of the most common and early signs of pregnancy, seen in more than 90% of patients.⁷ High levels of Melanocyte Stimulating Hormone (MSH), oestrogen and progesterone are believed to be responsible for hyperpigmentation. Progesterone augments the oestrogen mediated melanin output, the levels of which correlate with pigmentary changes.⁸

Generalized hyperpigmentation is seen which is more marked in the dark haired skin.⁶ Pigmented areas of the body, namely the genitalia, perineum, areolae and upper medial thighs, demonstrate more pronounced pigmentation. Linea nigra, a hyperpigmented line extending from the pubic symphysis to umbilicus and further up to the xiphisternum, replaces the linea alba.⁹ Chloasma, also termed as mask of pregnancy, is the well marginated brownish pigmentation of the face like melasma. It is seen in 45-75% of pregnant women in western literature but in less than 10% cases in women with pigmented skin.^5,10,11 Pigmentary demarcation lines appear on the limbs with borders of abrupt transition; freckles, naevi and scars tend to darken and enlarge.¹²

The pigmentation gradually fades after delivery, though the resolution of skin colour is usually incomplete. Chloasma tends to persist in 30% cases postpartum.¹³ Sun protection and reassurance is all that is needed. Topical formulations containing hydroquinone and tretinoin are avoided in pregnancy and can be added after delivery.

Physiological connective tissue changes:

Gross distension of abdomen with adrenocortical activities are responsible for the red-blue depressed streaks seen on abdomen and breasts in 70-90% pregnancies, called striae distensae.^5,14 These usually develop in the second trimester. Females with pre-existing striae on breasts and thighs are more likely to develop striae gravidarum¹⁵, seen in White women more than Asian and African-American.¹⁴ Preventive therapies are controversial and postpartum treatment options include topical tretinoin, excimer laser or surgery.¹⁰

Soft tissue fibromas of pregnancy are called molluscum fibrosum gravidarum. They appear in the second trimester on the neck, face and beneath the breasts. These disappear after delivery.¹⁶

Physiological vascular changes:

Vascular growth factors released during pregnancy by the pituitary, adrenals and placenta are believed to be causative and this has been demonstrated in vitro as well.¹⁷ Non-pitting oedema of the face, hands and feet is present in around half of all females in the later part of pregnancy.¹³ This is probably due to sodium and fluid retention and pressure of the gravid uterus on the inferior vena cava. Spider naevi or spider angiomas are small raised lesions with a central pulsatile punctum and radiating telangiectatic vessels frequently present over the area drained by the superior vena cava. They are present in 67% of White women and 11% Black women during the second trimester.⁵ Palmar erythema is seen in two-thirds of White and one-third of Black women.⁸ Other vascular changes include varicosities of legs and anus (40%)¹³, cutis marmorata (0.7%)¹⁸ and capillary haemangioma (5%)⁹. These changes revert after the postpartum period.

Physiological glandular changes:

Eccrine gland activity is usually increased but the palms show decreased sweating. Thus, the incidence of miliaria and dishidrotic eczema is increased. There is inconclusive evidence to suggest that apocrine gland activity is decreased during pregnancy.¹⁹ Sebaceous activity increases in the third trimester leading to acne and enlargement of Montgomery’s tubercles.¹⁴ One-third to half of all pregnant women develop these tubercles, which are modified sebaceous glands.^5,8 However, sebum excretion has not been found to decrease in lactating females post-delivery.²⁰

Oral mucosal changes:

Oedema and hyperaemia of the gingivae in pregnancy is attributable to local irritation and nutritional deficiencies and is seen in around 80% women.⁵ Gingivitis not related to poor oral hygiene may occur. Granuloma gravidarum or pregnancy epulis might occur that regresses postpartum.

Hair changes:

Hair changes are seen in 3-12% of pregnant females.²¹ Hirsuitism and hypertrichosis occurs due to oestrogen. This leads to an increase in the percentage of hair in anagen.² Approximately 2-3 months after delivery, loss of telogen hair occurs.²² This is termed as late anagen release as the hair follicles are no longer stimulated to stay in anagen phase by the maternal hormones. The hair recovery occurs in 3-12 months. A small number of females may experience episodic shedding of hair for long periods. This has been proposed to be due to the inability of some hair follicles to revert to asynchronous shedding.²³ Rarely, male pattern baldness may occur in women.²

Nail changes:

Nail growth increases during pregnancy.⁶ Brittleness of the nail plate and distal onycholysis may be seen.¹⁹ Beau’s lines may develop after delivery.¹² Reassurance is all that is needed for these benign nail problems.

DISEASES MODIFIED BY PREGNANCY

Many pre-existing dermatoses may be exacerbated or ameliorated by pregnancy. Certain tumours may also show remission or exacerbation. This is due to the shift in pregnancy to the Th2 state and a return to Th1 state in the postpartum period and also the discontinuation of some drugs due to their teratogenic potential.

Infections:

Depressed cell-mediated immunity makes the pregnant woman susceptible to more severe and frequent infections.²⁴

Candidiasis is quite common and was found to be the commonest cause of white discharge per vagina, being present in 22% pregnant females.⁵ Half of all neonates born to infected mothers are positive for Candida and some may show signs of infection.²⁵ Pityrosporum folliculitis, caused by Pityrosporum ovale, is more common in pregnancy.²⁵

Genital warts are the commonest sexually transmitted disease seen in 4.7% subjects, these increase in size during pregnancy.^9,25 Prophylactic caesarian section to prevent laryngeal papillomas in the neonate is not recommended now.²⁶ Herpes simplex virus infection carries 50% risk of transmission to neonate in the primary episode and 5% risk in recurrent episode, caesarean section might be warranted to prevent such transmission.²⁶ Varicella zoster virus infection has been reported to cause pneumonia in 14% of mothers and death in 3%.²⁷ Bowenoid papulosis, caused by human papilloma virus appears first during pregnancy or may get aggravated.⁶

Pregnancy prepones the clinical manifestations in HIV infected females, possibly due to additive immune suppression. Pneumocystis pneumonia or listeriosis may prove to be fatal.²⁷ Kaposi’s sarcoma may occur in these females.²⁷ 20-30% women present with leprosy for the first time in pregnancy and the postpartum period.²⁸ The disease tends to downgrade towards the lepromatous pole in pregnancy and upgrades during lactation.²⁹ Type 1 lepra reactions are more frequent in the first trimester and after delivery, whereas type 2 lepra reactions peak in third trimester.²⁹ Trichomoniasis is diagnosed in 60% of pregnant women.²⁵

Autoimmune diseases:

Systemic Lupus Erythematosus (SLE) is associated with a better prognosis than previously thought, if the disease is in remission and nephropathy and cardiomyopathy are not present.¹⁰ If the disease is active, half of the patients’ disease will get worse and there might be fatalities.¹⁴ SLE tends to be more severe if it first presents in pregnancy.¹⁴ Babies of such mothers are likely to develop neonatal lupus.

Patients with scleroderma are usually unaffected and some are improved in pregnancy. However, occasional reports of renal crisis, hypertension and pre-eclampsia are reported.³⁰ Course of dermatomyositis is usually unaltered but the disease may worsen in some patients.³¹

Pemphigus tends to be exacerbated or present for the first time in pregnancy.³² The clinical presentation in pregnancy is similar to that of the regular presentation. Differentiation from herpes gestationis is important.

Metabolic diseases:

Effect of pregnancy on porphyria cutanea tarda is not clear, though some females show biochemical and clinical deterioration.³³ Acrodermatitis enteropathica shows clinical worsening.³⁴

Connective tissue diseases:

Pregnancy can lead to bleeding, uterine lacerations and wound dehiscence in patients of Ehlers-Danlos syndrome. Pseudoxanthoma elasticum patients may suffer massive gastrointestinal bleeds.³⁵ Lichen sclerosis et atrophicus of the vulva usually improves in pregnancy and a normal delivery is mostly possible.

Disorders of glands:

Acne can aggravate during pregnancy. Hidradenitis suppurativa and Fox-Fordyce disease become better as a result of decreased apocrine gland activity.²⁷

Keratinization diseases:

The course of psoriasis remains unaltered in 40% females during pregnancy while it improves in a similar percentage of females and worsens in the remaining.³⁶ It is more likely to deteriorate in the postpartum period.³⁷ Psoriatic arthritis has been found to worsen or present for the first time in pregnancy.²

Generalized pustular psoriasis of Von Zambusch may rarely occur. Though most patients have a preceding or family history of psoriasis, some may develop the disease without ever having a preceding episode.³⁸ Peak incidence is seen in the last trimester and the disease tends to recur.³⁸ Multiple, discrete, sterile pustules at the margins of erythematous macules on the umbilicus, medial thigh, axillae, inframammary folds, gluteal creases and sides of neck are seen. These break to form erosions and crusts. Painful, circinate mucosal erosions may form. Prednisolone is used for management.¹² Von Zambusch pustular psoriasis of pregnancy was earlier termed ‘Impetigo Herpetiformis’ but the term is best avoided as it is impossible to differentiate it from the former, both clinically and histologically.⁶ Erythrokeratoderma variabilis is reported to worsen during pregnancy.²⁷

Tumours:

A melanoma that develops during pregnancy carries worse prognosis but if pregnancy occurs after the tumour is resected, the prognosis is unaltered.³⁹ Metastasis in the fetus has been seen and a minimum period of two years following tumour resection is recommended.³² A female with neurofibromatosis may develop neurofibroma for the first time in pregnancy or older neurofibromas may grow in size. Rupture of major vessels may occur.⁶ Pregnancy may worsen mycosis fungoides and eosinophilic granuloma.⁶

Miscellaneous diseases:

Prognosis of atopic dermatitis is unpredictable in pregnancy, with reports of both improvement and worsening.²⁷ Predisposed patients may first develop atopic dermatitis during pregnancy.⁴⁰ Allergic contact dermatitis may improve in pregnancy.¹² Hand eczema may worsen in the puerperal period.⁶ Erythema multiforme may be precipitated by pregnancy.⁶ Autoimmune progesterone dermatitis has been described in pregnancy.¹² This disease is characterized by hypersensitivity to progesterone demonstrated by a positive intradermal skin test and cutaneous lesions resembling urticaria, eczema, erythema multiforme and dermatitis herpetiformis.⁴¹ The disease is associated with fetal mortality and recurs in subsequent pregnancies.¹²

PREGNANCY SPECIFIC DERMATOSES

These are a heterogeneous group of inflammatory skin diseases specific for pregnancy.⁴² Most of these conditions are benign and resolve spontaneously in the postpartum period but a few of these are associated with fetal complications.⁴² Almost all of them present with pruritus and a cutaneous eruption of varying severity.⁵

Classification:

The first attempt to classify these conditions was made by Holmes and Black in 1982-83 who classified them into: a) Pemphigoid Gestationis (PG) or Herpes Gestationis(HG), b) Polymorphic Eruption of Pregnancy (PEP) or Pruritic Urticarial Papules and Plaques of Pregnancy (PUPPP), c) Prurigo of Pregnancy (PP) and d) Pruritic Folliculitis of Pregnancy (PF).^43,44 Shornick was of the view that all patients with PF also had papular dermatitis, so he included PF in the PP group. He included Intrahepatic Cholestasis of Pregnancy (ICP) in his classification for dermatoses where secondary skin lesions due to scratching are produced. He proposed that failure to consider ICP in the classification has led to confusion in terminology of pregnancy specific diseases. Thus, his classification included PG, PEP, PP and ICP.⁴⁵ Ambros-Rudolph et al carried out a retrospective review of 505 pregnant patients over a 10 year period and gave a more rationalised classification system in 2006. They clubbed PP, PF and eczema of pregnancy in one group called Atopic Eruption of Pregnancy (AEP) due to their overlapping features and found this group to be the most common pruritic condition in pregnancy. Thus, they proposed four conditions: a) AEP, b) PEP, c) PG and d) ICP.⁴⁶ The various specific pregnancy dermatoses have been elaborated in Table 2.

Table 2: Comparison of different pregnancy specific dermatoses in relation to clinical characteristics, prognosis, investigations and treatment.

Atopic eruption of Pregnancy (AEP): (Syn: Besnier’s prurigo, prurigo gestationis, Nurse’s early onset prurigo of pregnancy)

It is the most common pregnancy specific dermatoses that includes eczematous or papular lesions in females with personal or family history of atopy and elevated IgE - accounting for nearly half of all patients.⁴⁶ The disease tends to recur in subsequent pregnancies with 75% of all cases occurring before the start of the third trimester.⁴⁷ It carries no risk for the mother or baby however, infant may develop atopy later in life.⁴⁸ Treatment is symptomatic with antihistamines and corticosteroids.

E-type AEP: This group comprises of 67% of AEP patients and includes patients with eczematous features; previously referred to as Eczema of Pregnancy (EP). It was not until 1999 that a high prevalence of atopic eczema was noted in pregnancy.⁴⁹ 80% of pregnant women develop the first episode of atopic dermatitis during pregnancy.⁴⁶ This is attributed to the Th2 cytokine profile in pregnancy and a dominant humoral immunity.⁴ It is more common in primigravida, in single gestation, begins in early pregnancy and affects whole body including face, palms and soles.⁴⁶

P-type AEP: This group includes what was referred to previously as Prurigo of Pregnancy and Pruritic Folliculitis of Pregnancy. Prurigo of Pregnancy (PP) is seen in one out of 300 to 450 pregnancies and occurs predominantly in the second to third trimester.⁵⁰ Excoriated or crusted papules are seen over the extensors of extremities and abdomen and are associated with some eczematization. The eruption lasts up to 3 months after delivery and recurrences in subsequent pregnancies are common.⁵¹ PP is associated with ICP with the differentiating feature being the absence of a primary lesion in the latter.⁵⁰ Personal and family history of atopic dermatitis or raised IgE may be seen in PP.⁵² Serology is normal. There are no specific changes on histopathology and immunofluorescence results are found to be negative.⁵⁰ There appears to be no maternal or fetal risk.⁴⁵

Pruritic Folliculitis of Pregnancy (PF), first described by Zoberman and Farmer, is now believed to be as common as PG or PP, though only a few cases have been reported.⁵⁰ It begins in the latter two trimesters and affects roughly one in 3000 pregnancies.⁵¹ Pruritus is not a defining feature, despite what the name suggests.² Multiple, follicular papules and pustules occur on the shoulders, arms, chest, upper back and abdomen and are acneiform in nature.⁴² The lesions tend to resolve in a couple of months following delivery. Histopathological examination reveals non-specific features with sterile folliculitis and immunofluorescence studies are negative.⁵⁰ No maternal or fetal risk is described except for low birth weight neonates in a single study.⁵² Pathogenesis of PF is unknown with no definite role of androgens or immunologic abnormalities.⁵³ There is no evidence to suggest that it is a hormonally aggravated acne as proposed by some workers.⁵⁴

Polymorphic Eruption of Pregnancy (PEP): (Syn: Pruritic Urticarial Papules and Plaques of Pregnancy or PUPPP, Bourne’s Toxaemic Rash of Pregnancy, Toxic Erythema of Pregnancy, Nurse’s Late Prurigo of Pregnancy)

With a prevalence of a case in every 130-300 pregnancies, this disease is the second most common pregnancy specific dermatoses and was seen in 21.6% pregnancies reviewed by Ambros-Rudolph et al.⁴⁶ They found it began in late pregnancy in 83% cases and 15% in the postpartum period.⁴⁶ The disease occurs predominantly in primigravida and a familial predisposition is present.⁵⁵ Lesions are pleomorphic, usually urticarial but purpuric, vesicular, polycyclic and targetoid lesions may be present. The striae on the abdomen are the first to be involved and there is a characteristic periumbilical sparing.⁵⁶ The lesions seldom occur on the body above the breast and on hands and feet.¹² The lesions resolve with scaling and crusting in six weeks. The disease is more common in excessive weight gain during pregnancy and in multiple gestation.^57,58 Histopathology is non-specific and shows spongiosis, occasional subepidermal split and eosinophilic infiltration. Serology and immunofluorescence is negative.⁵⁰ Treatment is symptomatic, oral steroids are needed in severe cases. There are no associated maternal or fetal complictions,⁵⁹ although infants may later develop atopic dermatitis.²

The pathogenesis is unknown however, the abdominal distension leading to collagen and elastic fibre damage in striae is hypothesized, leading to formation of antigens and triggering inflammatory cascade.⁶⁰ The role of progesterone has been suggested by the increased progesterone receptor immunoreactivity in skin lesions of PEP.⁶¹ The discovery of fetal DNA in skin lesions of women with PEP has furthered the hypothesis that abdominal distension leads to increased permeability of vessels and permit chimeric cell migration in the maternal skin.⁶² Linear IgM dermatosis of pregnancy is an entity characterized by pruritic, red, follicular papules and pustules on the abdomen and proximal extremities seen after 36 weeks gestation and a linear band of IgM deposition on basement membrane zone. It has been characterized as a variant of PEP or PP by different authors.¹²

Pemphigoid Gestationis (PG): (Syn: Herpes Gestationis or HG, Gestational Pemphogoid, Dermatitis Herpetiformis of Pregnancy)

PG is the most clearly characterized pregnancy dermatosis and the one which also affects the fetal skin.⁶³ It is a rare, self-limiting, autoimmune bullous disease with an incidence of 1:1700 to 1:50000 pregnancies.⁶³ Mean onset occurs at 21 weeks gestation, though it occurs in the postpartum period in a fifth of all cases.⁶⁴ Constitutional symptoms, burning and itching herald the onset of the disease. Half of patients develop urticarial lesions on the abdomen, particularly in the periumbilical region, that change rapidly to a generalized bullous eruption usually sparing the face, palms, soles and mucosae. Vesicles may arise in herpetiform or circinate distribution. Face is involved in 10% cases and oral mucosa in 20%.¹² The disease shows spontaneous improvement in late gestation but flares may occur at the time of delivery in 75% of the cases.⁶³ Though the disease may remit after a few weeks after delivery, a protracted course, conversion to bullous pemphigoid or recurrence with menstrual cycle and use of oral contraceptive pills has been reported.⁵⁰ PG tends to recur in subsequent pregnancies in a more severe form and at an early stage with longer stay in postpartum.⁵⁰ Skipped pregnancies have been described.^63,65 The disease is also linked with hydatiform mole and choriocarcinoma.⁶⁶

The classical histopathological finding is the presence of a subepidermal vesicle, spongiosis and an infiltrate consisting of lymphocytes, histiocytes and eosinophils.⁶⁴ An inverted tear drop appearance due to oedema in the dermal papilla is seen in early urticarial lesions.¹⁵ Direct immunofluorescence reveals a linear deposition of C3 along the dermo-epidermal junction in 100% cases and is diagnostic of the disease, while a salt split skin shows an epidermal staining.⁶⁷ Antithyroid antibodies may be present but thyroid dysfunction is not common.⁶³ Systemic corticosteroids are the mainstay of management. About one in ten children born to women with PG develop blisters due to passive transfer of antibodies, this resolves on its own. Severity of the disease has been correlated with the risk of prematurity and small for gestational age babies.⁶⁸

Pathogenesis of PG involves the production of IgG1 antibodies against NC16A domain of carboxyl terminus of Bullous Pemphigoid Antigen 2 (BPAg2), leading to activation of complement, recruitment of eosinophils to the local site and damage of the basement membrane and consequent blistering.² The aberrant expression of MHC class II antigens of paternal haplotype is believed to stimulate an allogenic response to placental basement membrane and this is believed to cross react with the skin in PG.^63,69

Intrahepatic Cholestasis of pregnancy (ICP): (Syn: Obstetric Cholestasis, Pruritus Gravidarum, Icterus Gravidarum, Recurrent Jaundice of Pregnancy, Idiopathic Jaundice of Pregnancy)

Pruritus in pregnancy is fairly common and can be due to various reasons like pregnancy specific dermatoses and other co-existing dermatoses such as scabies, urticaria, atopic dermatitis, drug reactions etc. It was found to be present in more than half of 170 pregnant women in an Indian study.⁷⁰ This must be differentiated from ICP where the skin lesions arise secondary to itching.

ICP was first described by Kehr in 1907.⁶³ ICP being referred to Pruritus Gravidarum (for pruritus without skin changes occurring early in pregnancy and related to atopic diathesis and no cholestasis) and Prurigo Gravidarum (for pruritus associated with PP like skin lesions and associated with cholestasis) lead to much confusion regarding nomenclature.⁶³ The disease has an incidence of 10-150 cases per 10,000 pregnancies⁷¹, being more common in South America and Scandinavia, probably due to dietary factors.⁵⁰ Patients complain of sudden onset pruritus beginning from the palms and soles and later generalizing to the whole body. Skin lesions are secondary to itching and range from excoriations to prurigo nodularis, extensors are more severely involved. Jaundice is seen in 20% cases only.⁷² Clay coloured stools, dark urine and haemorrhage secondary to vitamin K malabsorption can occur. Family history can be elicited in half of the cases and an association with multiple gestation is described.⁷³ Resolution of ICP occurs soon after delivery. Recurrence in subsequent pregnancies is seen in 45-70% cases and routinely with the use of oral contraceptive pills, though no detectable abnormalities are seen in the duration between two pregnancies.⁶³ Histopathology is non-specific and immunofluorescence is negative. Diagnosis is made by increased serum bile acid levels, transaminases are elevated. Prothrombin time may be prolonged. A 2.7 times increased risk of gallstones is reported in primigravida with ICP compared to non-pregnant women.⁷⁴ ICP is associated with significant fetal morbidity including premature births in 20-60% cases, intrapartum fetal distress including meconium aspiration in 20-30% and fetal mortality in 1-2%.⁷¹ Risk is particularly more if serum bile acid levels exceed 40 micromoles per litre.⁷⁵ Meconium may cause umbilical vein compression and induction of labour at 36 weeks gestation has been recommended in severe cases.⁵⁰ The goal of treatment is reduction of serum bile acids. Ursodeoxycholic acid, given in the dose of 15mg/kg orally daily is the only proven therapeutic agent that decreases fetal mortality.^63,76 Cholestyramine reduces vitamin K absorption and increases the risk of haemorrhage. Other agents like S-adenosylmethionine, dexamethasone, silymarin, phenobarbitone, epomediol and activated charcoal are not that effective and do not affect fetal risk.⁶³ Topical emollients and antipruritic agents offer symptomatic relief but antihistamines are not that effective.⁵⁰

The key event in the pathogenesis of ICP is elevation of bile acids. Oestrogens are said to have cholestatic properties by reducing hepatocyte bile acid uptake and also by inhibiting basolateral transport proteins.⁵⁰ Progesterone may additionally saturate the transport capacity of these transport proteins in hepatocyte.⁷¹ Genetic predisposition occurs due to mutation in genes encoding bile transport proteins, with cholestasis developing in pregnancy as their capacity to secrete substance is exceeded.⁶³ Bile acids passing through the placenta produce vasoconstriction of placental veins, fetal cardiomyocyte dysfunction and also abnormal uterine contractility, all leading to fetal hypoxia.⁷¹

CONCLUSION

Pregnancy is associated with a wide variety of cutaneous changes. These may range from common, benign changes termed physiological or more severe, posing significant risk to the mother as well as the baby. Physiological pregnancy changes may be of cosmetic concern to the patient and seldom need anything more than counselling. Pre-existing dermatoses may aggravate during this period, posing a challenge to the treating physician. Women suffering from such diseases need to be warned of complications and risks before trying to conceive. A strict watch for possible complications and appropriate management at an early stage is warranted. Women should also be looked for pregnancy specific dermatoses and their complaints should not be lightly overlooked as non-specific or physiological. Careful history and examination with a judicious use of investigations will help to arrive at a diagnosis and in prompt institution of treatment.

Introduction:

Candida species is a leading cause of nosocomial infections and the most common fungal infection in intensive care units.  Candida infection ranges from invasive candidal disease to blood stream infections (candidaemia).  The incidence of Candida infection has been rising over the past two decades, particularly with the use of immunosuppressive drugs for cancer and HIV^1,2,3 , and most of these infections occur in ICU settings.⁴  Candida infection is associated with high mortality and morbidity. Studies have shown that mortality attributable to candidaemia ranges from 5 to 71% depending on the study. ^5.6.7Candidaemia is also associated with longer length of hospital stay and higher cost of care.

Early recognition of Candida BSI has been associated with improved outcome. Candida sepsis should be suspected in a patient who fails to improve and has multiple risk factors for invasive and bloodstream Candida infection. A variety of risk factors identified for candidaemia include previous use of antibiotics, sepsis, immunosupression, total parenteral nutrition, central venous line, surgery, malignancy and neutropaenia. Patients admitted to ICU are frequently colonised with Candida species. The role of colonisation in Candida blood stream infection and invasive candidal disease has always been debated. Few studies support the use of presumptive antifungal treatment in ICU based on colonisation and number of sites colonised by Candida. The NEMIS study has raised doubt about this approach of presumptive treatment.  The Infectious Disease Society of America (IDSA) 2009 guidelines identify Candida colonisation as one of the risk factors for invasive candidiasis, but warn about the low positive predictive value of the level of Candida colonisation. ⁸ We conducted a retrospective cohort study in our medical ICU to identify risk factors for Candida blood stream infections including the role of Candida colonisation.

Hospital and Definitions:

This study was conducted at Interfaith Medical Center, Brooklyn, New York.  It is a 280 bed community hospital with 13 medical ICU beds. A case of nosocomial Candida blood stream infection was defined as a growth of Candida Species in a blood culture drawn after 48 hours of admission. Cultures in our hospital are routinely done by the Bactec Method – aerobic and anaerobic cultures. Cultures are usually kept for 5 days at our facility and if yeast growth is identified, then species identification is done. In our ICU it is routine practice to do endotracheal culture and urine culture for all patients who are on mechanical ventilator supports and failing to improve. In patients who are not mechanically ventilated, it is routine practice to send sputum culture and nasal swabs to identify MRSA colonisation.

Study Design:

This study was a retrospective cohort study. We retrospectively reviewed all patients’ charts admitted to our medical ICU from 2000 to 2010 which stayed in the ICU for more than 7 days, irrespective of their diagnosis. Data were collected for demographics – age and sex. Data were also collected for risk factors for candidaemia – co-morbidities (HIV, cancer, COPD, diabetes mellitus, end-stage renal failure (ESRF)), presence or absence of sepsis, current or previous use of antibiotics, presence of central venous lines, steroid use during ICU stay, requirement of vasopressor support and use of total parenteral nutrition (TPN). Culture results for Candida including species identification were obtained for blood, urine and endotracheal aspirates.

Statistical Methods:

Patients were divided in two groups based on presence or absence of Candida BSI. Demographic data and risk factors were analysed using the chi square test to look at the difference between the two groups. Endotracheal aspirates and sputum cultures were combined to create a group with Candida respiratory tract colonisation. Binary logistic regression with forward likelihood ratio method was used to create models. Different models were generated for risk factors. Interactions between antibiotic use, steroid use, vasopressor support and sepsis were analysed in different models. Interactions between urine cultures and endotracheal aspirates/sputum cultures were also analysed by a different model. The model with the lowest Akaike information criterion (AIC) was chosen as the final model. The candidaemia risk score was calculated based on this final model to predict the risk of Candida BSI. Receiver operating curve (ROC) analysis was used to select the best cut-off value for the candidaemia risk score. Candida species in urine and endotracheal aspirates were compared with Candida species in blood culture using the kappa test. Data were analysed using SPSS statistical analysis software version 18.

Study Results:

A total of 1483 patients were included in the study.  56 patients (3.77%) had a blood culture positive for Candida species. Table 1 demonstrates demographic characteristics of the study population.  There were no significant differences in the both groups for age, sex, diabetes mellitus, COPD, HIV, cancer and ESRF. As demonstrated in the table, 82.1% of patients in candidaemia groups recently used or were taking antibiotics as compared to 39.6% of patients in groups with no candidaemia. The P value was significant for this difference.  Similarly, 71.4% of patients in the group with candidaemia had sepsis as compared to 30.6% in the other group with a P value of 0.000. Use of vasopressor (severe septic shock) was different between two groups – 23.2%  and 10.1%, P value of 0.004. Steroid use, central lines and total parenteral nutrition use was higher in the candidaemia group as compared to the group without candidaemia. Similarly the rate of positive Candida cultures in urine and endotracheal aspirates was higher in the candidaemia group as compared to the group without.

Table 2 shows that 57.1% of Candida BSI were caused by C. Albicans, 30.4% by C. Glabrata and 12.5% by C. Parapsilosis. This incidence rate of species is similar to that found in other studies. Table 3 shows the two models with the lowest AIC value. The only difference between these two models was antibiotic use- previous or current use of antibiotics compared to current use of antibiotic in sepsis. Table 4 shows that when multifocal site positivity (urine and endotracheal culture) were used in the model, the AIC value increased significantly. This means that when multifocal sites were used in place of individual sites for the model, good amounts of information were lost and this model did not have good predictive value as compared to the model where individual sites are used for prediction of candidaemia. The model with lowest AIC was chosen as the final model. Binary logistic regression analysis with forward conditional analysis showed that only TPN, central venous line, previous or current antibiotic use, endotracheal aspirate culture positivity for Candida species and urine culture positive for Candida species were included in a statistical significant model. The final model had a P value of 0.000.  Odds ratio with 95% confidence intervals and respective P values for all these risk factors are shown in Table 5.  Age greater than 65 years, sex, sepsis or septic shock, co-morbidities and steroid use were not significant risk factors for candidaemia.

From this model, the candidaemia risk score calculated would be: Candidaemia risk score = 1.184 for previous or current antibiotic use + 0.639 for presence of central venous line + 1.186 for total parenteral nutrition + 0.760 for positive endotracheal culture for Candida + 1.255 for positive urine  culture for Candida.

Table 6 shows the relationship between the Candida strain identified in endotracheal/sputum culture to that in blood culture. Similarly, Table 7 shows the relationship between the Candida strain identified in urine culture and that in blood culture. Strains identified in endotracheal aspirate culture had a very high value for the Kappa test and urine culture had a moderate value for agreement by the Kappa test. Thus, it can be inferred that Candida strain identified in blood culture was very similar to that identified in urine or endotracheal culture.

Table 1: Demographic characteristic of study population

Table 2: Candida strains responsible for Candida blood stream infection

Table 3: Models with lowest two AIC

Table 4: Model with 2 sites positive for Candida

Table 5: Odds ratio with 95% confidence interval for risk factors for candidaemia

Table 6: Endotracheal aspirate culture in candidaemic patients

Table 7: Urine cultures in candidaemic patients

Discussion

Candida is the most common nosocomial fungal infection in the ICU. Candidaemia accounts for approximately 5-8% of nosocomial BSI in the hospitals in the US.^9,10,11 It accounts for approximately 50-75% of the cases of invasive fungal infection in the ICU^12,13 and its rate varies from 0.2-1.73 per 1000 patient days.^9,14,15 In a study done by Theoklis et al., candidaemia was associated with a mean 10.1 day increase in length of stay and a mean $39,331 increase in hospital charges.¹⁶ A study of 1,765 patients in Europe found that Candida colonisation was associated with increased hospital length of stay and increase in cost of care by 8000 EUR.¹⁷ ICU patients are at increased risk of infection because of their underlying illness requiring ICU care, immunosuppressant use, invasive or surgical procedures and nosocomial transfer of infections. A number of risk factors have been identified in different studies. In a matched case-control trial, previous use of antibiotic therapy, Candida isolated at other sites, haemodialysis and presence of a Hickman catheter were associated with increased risk of candidaemia.¹³ Similarly age of more than 65 years, steroid use, leucocytosis and prolonged ICU stays were risk factors for Candida BSI in 130 cases.¹⁸ Surgery, steroids, chemotherapy and neutropaenia with malignancy are the other identified risk factors.¹⁹

Candida BSI has a very high mortality rate. The attributable mortality varies from 5-71% in different studies.^5,12,16,20 Even with treatment, there is high mortality as demonstrated in a study by Oude Lashof et al where out of 180 patients treated for candidaemia, 33% died during treatment and 55% completed treatment without complications.²¹ Risk factors for increased mortality in patients receiving antifungal treatment are delayed Candida antifungal treatment or inadequate dosing.²² Multivariate analysis of 157 patients with Candida BSI, APACHE II score, prior antibiotic treatment and delay in antifungal treatment were independent risk factors for mortality with odds ratio of 1.24, 4.05 and 2.09, respectively.²³ Delayed treatment is also associated with increased fluconazole resistance as compared to early treatment and preventive treatment.²⁴ Inadequate antifungal medication dose and retention of central venous catheters were also associated with increased mortality in a study of 245 Candida BSI, with adjusted odds ratios of 9.22 and 6.21, respectively.^25,26

Candida albicans accounts for 38.8-79.4 % of the cases of Candida BSI. C. Glabrata is responsible for 20-25% of cases of candidaemia and C. tropicalis is responsible for less than 10% of cases of candidaemia in the US.^9,20  ICU patients are frequently colonised with different Candida species. Candida colonisation can be from either endogenous or exogenous sources. Candida colonisation rates vary with the site- tracheal secretion (36%), throat swabs (27%), urine (25%) and stool (11%).²⁷ Candida colonisation increases with the duration of the stay, use of urinary catheters and use of antibiotics. ^28,29,30

The role of Candida colonisation in Candida BSI is frequently debated.  Some studies have suggested that Candida colonisation of one or more anatomical sites are associated with increased risk of candidaemia.^31,32,33,34 Typically, 84-94% of the patients developed candidaemia within a mean time of 5- 8 days after colonisation according to two studies.^35,36  In another study, only 25.5% of colonised patients developed candidaemia.³⁷ Similarity between strain identified in blood culture and that identified at various colonising sites was observed in one study.³⁸  Candida colonisation by exogenously acquired species has also been implicated as a cause of candidaemia.³⁹ In one study, 18-40% of cases of candidaemia were associated with clustering defined as “isolation of 2 or more strain with genotype that had more than 90% genetic relatedness in the same hospital within 90 days.” ⁴⁰ Similar correlations for clusters are also noted for C. tropicalis candiduria⁴¹ and for C. Parapsilopsis.⁴² In a prospective study of 29 surgical ICU patients colonised with Candida, the APACHE II score, length of previous antibiotic therapy and intensity of Candida colonisation was associated with a significant risk of candidaemia.  The Candida colonisation index calculated by non-blood body sites colonised by Candida over the total number of distinct sites tested for patients, was associated with a 100% positive and negative predictive value of candidaemia.²⁹ Other studies do not support Candida colonisation as a risk factor for candidaemia. In a case-control study of trauma patients, only total parenteral nutrition was associated with an increased risk of candidaemia. Candida colonisation, steroid use, use of central venous catheters, APACHE II score, mechanical ventilation for more than 3 days, number and duration of antibiotics, haemodialysis, gastrointestinal perforation and number of units of blood transfused in first 24 hours of surgery. were not significant risk factors for candidaemia.⁴³ NEMIS study found that in a surgical ICU, prior surgery, acute renal failure, total parenteral nutrition and triple lumen catheters were associated with increased risk of candidaemia; the relative risk for each risk factor being 7.3, 4.2, 3.6 and 5.4, respectively. Candida colonisation in urine, stool or both were not associated with increased risk of candidaemia.¹⁵

The effect of Candida colonisation of the respiratory tract on candidaemia and on mortality and morbidity is unclear. In a retrospective study of 639 patients, Candida respiratory tract colonisation was associated with increased hospital mortality (relative risk of 1.63) and increased length of stay (median increase of 21 days).³⁰ In a study of 803 patients by Azoulay et al., respiratory tract colonisation was associated with prolonged ICU and hospital stays. These colonised patients were at increased risk of ventilator-associated Pseudomonas pneumonia, with an odds ratio of 2.22.⁴⁴ However, in a postmortem study of 25 non-neutropaenic mechanically ventilated patients, 40% of the patients were colonised with Candida, but only 8% had Candida pneumonia.^45,46  Jordi et al. found that out of 37 patients, definite or possible colonisation was found in 89% of patients and only 5% of cases were defined as Candida BSI.⁴⁷.The effect of candiduria is also ill defined. Candida colonisation in urine has been implicated as a risk factor in certain studies. In a study done by Bross J et al., central lines, bladder catheters, 2 or more antibiotics, azotaemia, transfer from another hospital, diarrhoea and candiduria were significant risk factors for candidaemia. Candiduria had an odds ratio of 27 for development of candidaemia.⁴⁸ Similar findings about candiduria were noted by Alvarez-Lerma et al.⁴⁹

IDSA recommends starting empirical antifungal treatment for high risk neutropaenic patients who fail to improve on antibiotics after 4 days. Recommendation to start empirical antifungal therapy in low-risk neutropaenic patients and non-neutropaenic patients are not made by IDSA because of low risk of candidaemia.⁸ However, early detection of Candida BSI is vital because of increased mortality associated with delayed antifungal treatment and failure to remove central venous lines. Early detection of Candida BSI in a colonised patient can be facilitated by using a score based on the risk factors.^50,51Similarly, b-D glucan assays can be used in patient colonised with Candida, to determine Candida BSI and need for antifungal treatment.⁵² Combined used of such risk factor identification systems and b-D glucan assays will help to detect candidaemia in earlier stages and will decrease mortality. Our study suggests that total parenteral nutrition, previous or current antibiotic use, central lines, candiduria and respiratory tract colonisation are risk factors for Candida BSI. With the help of our candidaemia risk score system, a score of more than 2 is associated with a higher risk of Candida BSI. This risk factor scoring system along with b-D glucan assays can be used to detect Candida BSI in earlier stages.

Conclusion:

Our study suggests that urine or respiratory tract colonisation is associated with an increased risk of Candida BSI, along with total parenteral nutrition, central venous lines and previous or current antibiotic use. We identified a scoring system which can be used along with a b-D glucan assay to detect candidaemia earlier.

INTRODUCTION:

The prevalence of current use of alcohol in India ranged from 7% in western states of Gujarat (officially under prohibition) to 75% in the North eastern state of Arunachal Pradesh ^1.The prevalence of hazardous use of alcohol was 14.2% in rural south India². Thus, alcohol abuse has a major public, family and health related problems withimpairment of social, legal, inter personal and occupational functioning in thoseindividuals who have been addicted to alcoholism. 

A wide variety of biochemical and haematological parameters are affected by regular excessive alcohol consumption. The blood tests traditionally used most commonly as markers of recent drinking are the liver enzymes, gamma glutamyltranserase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and the mean volume of the red blood cells (mean corpuscular volume (MCV). But they were not sensitive or specific enough for use as single tests³. 

Elevated Gamma glutamyltransferase levels are an early indicator of liver disease; chronic heavy drinkers, especially those who also take certain other drugs, often have increased GGT levels. However, GGT is not a very sensitive marker, showing up in only 30–50 percent of excessive drinkers in the general population. It is not a specific marker of chronic heavy alcohol use, because other digestive diseases, such as pancreatitis and prostate disease, also can raise GGT levels ⁴. 

AST and ALTare enzymes that help metabolize amino acids, the building blocks of proteins. They are an even less sensitive measure of alcoholism than GGT; indeed, they are more useful as an indication of liver disease than as a direct link to alcohol consumption. Nevertheless, research finds that when otherwise healthy people drink large amounts of alcohol, AST and ALT levels in the blood increase. Of the two enzymes, ALT is the more specific measure of alcohol-induced liver injury because it is found predominantly in the liver, whereas AST is found in several organs, including the liver, heart, muscle, kidney, and brain. Very high levels of these enzymes (e.g., 500 units per liter) may indicate alcoholic liver disease. Clinicians often use a patient’s ratio of AST to ALT to confirm an impression of heavy alcohol consumption. However, because these markers are not as accurate in patients who are under age 30 or over age 70, they are less useful than some of the other more comprehensive markers⁵. 

AST /ALT ratio of more than1.5 strongly suggests and ratio >2.0 is almost indicative of alcohol induced damaged to liver ⁶.It has been suggested that an AST/ ALT ratio greater than 2 is highly suggestive or indicative of alcoholic etiology of liver disease. But extreme elevations of this ratio, with AST level greater than five times the normal should suggest non-alcoholic cause of hepatocellular necrosis ⁷. 

Sialic acid, which is a derivative of acetyl neuraminic acid, attached to non-reducing residues of carbohydrate chain of glycoproteins and glycolipids is found to be elevated in alcohol abuse ⁸. 

In this study we compared sensitivity, specificity and diagnostic efficiency of serum Sialic acid with other traditional markers like AST (Aspartate amino transaminase), ALT (Alanine amino transaminase), GGT (Gamma Glutamyl Transferase), as a marker of alcohol abuse. 

MATERIALS AND METHODS: 

This was a case-control study which was conducted on 100 male subjects aged 20-60 years, 50 cases and 50 controls. Cases comprised of patients diagnosed to have Alcohol Dependant Syndrome (ADS) who were admitted in Psychiatry-ADS ward, at Mahathma Gandhi Memorial Hospital,Warangal. Study was approved by the Institutional ethical committee. Amount, duration and the type of alcohol in the form of Rum, Whisky, Brandy, Vodka, Gin, Arrack, etc consumed was enquired, those subjects who consumed more than half bottles of these spirits daily (or intermittently with abstinence of 2-3 days), for more than 5 years were chosen for this study. Dependence of their alcoholism was enquired in the form of CAGE questionnaire ⁹.

C : Cut down drinking,
A : Annoyed others by drinking,
G : Guilty feeling of drinking.
E : Eye-opener

Those who satisfied two or more questions were taken as cases ¹⁰ and their blood samples were collected for the study after their informed consent. Controls were selected from healthy subjects came for master health check up at MGMH health clinic, with no history ofalcoholism.

Exclusion criteria:

Patients with history of Diabetes mellitus, Cardiac disease, Viral/Bacterial Hepatitis, Alcoholic hepatitis, tumors, meningitis and history of current use of hepatotoxic and nephrotoxic drugs were excluded from the study. 

4ml of blood was collected from each subject from median cubital vein by venipuncture, serum was separated and the different parameters were analyzed. Estimation of serum Sialic acid was done by modified thiobarbturic acid assay of warren¹¹ (Lorentz and Krass) by colorimetric method.  Estimations of Aspartate transaminase ^{12, 13, 14} Alanine transaminase ^{13, 15, 16} Gamma glutamyl transferase ^{17, 18} were done by IFCC recommended methods on Dimension Clinical chemistry system (auto analyzer).

Statistical analysis: Student t test (two tailed, independent) has been used to find the significance of study parameters between controls and cases. Receiving Operating Characteristics (ROC) tool (SPSS 17 version) has been used to find the diagnostic performance of study parameters. 

RESULTS: 

It was observed that all the study parameters were significantly increased (p value < 0.001) in subjects with alcohol abuse when compared to the controls as shown in the Table 1. The ROC analyses of the different parameters were shown in Fig 1 and Table 2. GGT was having highest Diagnostic efficacy followed by AST and SA as a marker of alcohol abuse. 

Figure 1: ROC Curve analysis of different parameters

Table1: Comparison of study parameters between controls and cases

Table 2: ROC Analysis of different study parameters

DISSCUSSION:                                                                                            

Alcoholism is a serious health issue with major socio-economic consequences. Significant morbidity is related to chronic heavy alcohol use and alcoholics seek advice only when a complication of drinking sets in. The diagnosis is often based on patients self-reporting of alcohol consumption, which is unreliable and requires high degree of clinical suspicion. 

Clinical histories and questionnaires are the commonest initial means of detection of alcohol abuse. They are cheap, easily administered but are subjective. If the history remains uncertain and there is suspicion of alcohol abuse, biological markers provide objectivity. A combination of markers remains essential in detection. Liver is the prime target organ for alcohol-induced disease. Liver enzymes are also important indicators of liver dysfunction, possibly as markers of alcohol dependence. Commonly used markers are GGT, AST and ALT. Laboratory markers help clinicians to raise the issue of excessive drinking as the possible cause of health problem, unfortunately because of lack of sensitive and specific methods, the detection of problem dinking in clinical settings has remained difficult. Therefore, findings of increased serum SA concentrations in alcoholics have raised the possibility of developing new tools for such purpose.

In the present study on analyzing the results it was found that an increased concentration of Serum Sialic acid and other traditional biochemical markers GGT, AST, ALT was observed in cases compared to that of controls. Over all GGT had a good sensitivity and specificity. The other traditional markers used in alcohol abuse varied considerably in their specificities and sensitivities. The increase in serum Sialic acid concentration in alcohol abusers in our present study is in accordance with the studies conducted by other investigators ^{8, 19, 20, 21}.The diagnostic accuracy of SA was in accordance with the study by Antilla P et al ¹⁹ .The increase in serum GGT, ALT and AST concentration in alcohol abusers were in accordance with the studies conducted by other investigators ^{19, 22}.

CONCLUSION:

In our study, Sialic Acid proved to be a good test with sensitivity of 80% and specificity of 93.33% with a diagnostic accuracy of 86.66% showing that SA can be used as a biochemical marker in alcohol abuse where secondary effects of liver disease hamper the use of traditional markers.

Limitations of the study are as follows: This study was done in small group of people only; a larger study consisting of alcohol abusers with and without specific liver disease should be conducted to confirm the role of SA as a new marker for alcohol abuse where the traditional markers will be altered by the different liver diseases.

CASE PRESENTATION

A 67 year old Caucasian male presented to our institution with a one day history of uncontrollable movements. The patient was being evaluated by a psychiatrist, neurologist and a neuro-opthalmologist for a three month history of severe anxiety, gait instability and palinopsia, respectively. The patient had progressively worsened over the prior two weeks and at the time of presentation reported visual hallucinations with increased confusion. His involuntary movements escalated to the point where it appeared that he was having seizures.

His medical history was significant for gouty arthritis, hypertension, and major depression. His surgical history was notable for an open reduction and internal fixation of his left hip 6 years prior. There was no history of any blood or blood product transfusion. He was an insurance executive and did not have significant occupational exposures. His social and family history was unremarkable. His medications upon arrival included captopril, atenolol, bupropion, lamotrigine, clonazepam, folic acid, and ibuprofen.

On admission he was arousable, well nourished, afebrile, haemodynamically stable but disorientated. His cardiopulmonary, abdominal and integumentary examinations were unremarkable. Neurological examination was significant for bilateral symmetric hyperreflexia, diffuse cogwheel rigidity without a resting or postural tremor, and multi-focal dysrhythmic generalised myoclonus. No neck tenderness or nuchal rigidity was noted. A CT of the head without contrast in the causality department was negative for haemorrhage or any acute intracranial pathology.

His initial assessment showed confusion, hallucinations, myoclonus with medication induced delirium. Lewy body dementia, occipital lobe epilepsy, peduncular hallucinosis and prion disease were all considered in the differential diagnosis. On admission, laboratory data including a CBC, CMP, serum ammonia level, cardiac enzymes, urinalysis, and coagulation profile were unremarkable. A toxicology screen for illicit drugs and heavy metals was negative. The initial lumbar spinal fluid (CSF) analysis was only notable for mild proteinorachia of 57 mg/dL. Gram stain, India-ink stain, acid-fast bacilli (AFB), bacterial & fungal cultures, as well as PCR for viral nucleic acid (herpes, Varicella-Zoster, Epstein-Barr virus, arboviruses, and cytomegalovirus virus) were all negative. MRI with contrast was remarkable only for periventricular ischemic changes consistent with small vessel disease. The patient’s bupropion and lamotrigine were discontinued upon admission, and his clonazepam was increased with resolution of the myoclonus after 24 hours.

The admission EEG showed diffuse slowing with no epileptiform discharges or triphasic waves. Due to progressive neurologic deterioration, he was followed with serial electroencephalograms. On hospital day 5, he became unresponsive and the subsequent EEG revealed non-convulsive status epilepticus (NCSE). Temporary resolution of his seizures was achieved with lorazepam and pentobarbital infusions. After 3 days of almost complete suppression, the pentobarbital was discontinued without NCSE recurrence. On hospital day 15 the EEG again displayed NCSE. A ketamine drip was added to his drug regimen with only brief improvement. Pentobarbital had been restarted and progressively titrated up to the maximal dose without achieving burst suppression. Despite being on the maximal dose of pentobarbital, ketamine, valproic acid, levetiracetam, and topiramate he continued to display NCSE (Figure 1A).

At this point (hospital day 16), therapeutic hypothermia was initiated and continued for 48 hours. The patient’s core body temperature was maintained between 32-33 °C followed by slow rewarming to normothermia over the following 48 hours. Near complete suppression of epileptiform activity was observed on the EEG (Figure 1B). Ketamine and pentobarbital were successfully weaned off during the following days and phenobarbital was introduced without recurrence of NCSE.

Figure 1A.  Electroencephalogram from hospital day 15. Refractory non-convulsive status epilepticus while on ketamine, levetiracetam, valproic acid, topiramate and pentobarbital.

DISCUSSION

Creutzfeldt-Jakob disease is the archetype of prion mediated neurodegenerative disorders. There are 4 types of CJD; sporadic, familial, iatrogenic and variant⁴. The sporadic type accounts for 85 per cent of all cases of CJD⁴. The diagnosis of CJD and transmissible spongiform encephalopathy (TSE) can be elusive. The World Health Organisation’s diagnostic criteria for CJD require at least one of the following: (1) Neuropathological confirmation,  (2) confirmation of protease-resistant prion protein (PrP) via immunohistochemistry or Western blot,  or (3) presence of scrapie-associated fibrils⁴. However, newer and less invasive means for diagnosis have been explored in recent literature. CSF analysis for protein 14-3-3, tau protein, S100B protein and neuron-specific enolase have demonstrated sensitivities of 93 per cent, 89 per cent, 87 per cent and 78 per cent, respectively⁵. In addition, the use of MRI fluid-attenuated inversion recovery (FLAIR) and diffusion weighted imaging (DWI) techniques have yielded sensitivities of 91-92 per cent and specificities of 94 -95 per cent respectively, especially when utilised early in the disease state⁶. In our case, the initial MRI was unremarkable and only the repeated MRI, performed three weeks after admission, revealed basal ganglia signal intensities consistent with CJD.

One of the most studied and well characterised tools used to support the diagnosis of CJD is the EEG. The typical pattern observed in the early stages of CJD is frontal intermittent rhythmic delta activities (FIRDA). As the disease progresses, characteristic periodic sharp wave complexes (PSWC) can be observed, usually 8 to 12 weeks after the onset of symptoms⁷. However, the reported sensitivity of EEG is relatively low, ranging from 22 to 73 per cent, and is largely dependent of the subtype of CJD⁸. In our case, the patient presented with NCSE, which is an uncommon presentation of an uncommon disease. In a retrospective review of 1,384 patients with probable or definite CJD, only 0.007 per cent or 10 patients presented with NCSE². Our patient did not demonstrate EEG findings consistent with CJD until late in his hospital course. Hence, CJD must be considered as a diagnosis in a patient who presents with refractory non-convulsive status epilepticus without overlooking the more common causes⁹.

The last important observation is the potential utility of therapeutic hypothermia in patients with refractory NCSE. Therapeutic hypothermia has long been known to suppress epileptiform discharge^10,11. However, the safety and efficacy have not been broadly studied in human subjects. Corry and colleagues conducted a small study examining the effects of therapeutic hypothermia on 4 patients with refractory status epilepticus. The results were promising in that therapeutic hypothermia was successful in aborting seizure activity in all 4 patients and effectively suppressed seizure activity in 2 of the 4 patients after re-warming¹². We were able to observe similar result in achieving temporary resolution of NCSE with therapeutic hypothermia in combination with antiepileptic medication in our patient. 

Introduction

Patients with morbid obesity suffer a wide range of symptoms that relate to their oesophagus and stomach. It is rather paradoxical that patients who are overweight suffer the symptoms of difficulty in swallowing, pain during eating or pain after eating because the symptoms of eating difficulty do not translate into weight reduction. There are a range of underlying causes that include gastro-oesophageal reflux disease, dysmotility in the oesophagus, peptic ulceration and the nature and pattern of dietary intake.  The pathophysiology of gastro-oesophageal reflux disease and of dysphagia will be considered. The detrimental effects of the treatments of balloons, gastric bands and gastric bypass will be described and options for management discussed.  The serious complications of adenocarcinoma and its premalignant precursor, Barrett’s oesophagus will be reviewed.

Gastro-oesophageal reflux disease (GORD)

GORD is highly prevalent in obese people with increasing BMI a risk factor for developing the disease. The relation between GORD and obesity has been studied for decades and there have been conflicting results. A person with BMI of ³30 kg/m²   is 3 times more likely to suffer from heartburn and acid regurgitation ¹.

Though the mechanism of this is poorly understood, a number of epidemiological studies have proven this association. Since recently, more evidence has emerged in favour of a positive association ². In 2000, Lagergren et al, based on a population based interview study on 820 Swedish, concluded that GOR symptoms occurred independent of BMI ³. His claim was supported by two previous studies, one of which used oesophageal pH measure and other assessed the impact of weight loss on symptom relief ^{4, 5}. A contrary view has emerged since this, with large number of western studies showing a positive association ^{1, 2, 6-12}. This, however, has not been the case with Asian and Afro-Caribbean population. In a large population study with various ethnicities, a strongly positive association was found between BMI and GOR symptoms in white population. This was not the case in Asian and black population ¹³, a view re-iterated by another study from Iran ¹⁴. The overall incidence of GORD is high in western world between 10% and 20%, compared to 5% in Asia ⁶.

The mechanism of GORD in obesity is very poorly understood. Various theories have been postulated and the evidence for each is discussed below, including the theory that the patho-physiology of reflux in the morbidly obesity could differ from others and might require a different therapeutic approach ⁹

Increased intra-abdominal pressure as a cause of reflux

Increasing intra-abdominal pressure has been hypothesised to be the cause for reflux symptoms. Increasing BMI has been shown to increase intra-gastric pressure and pressure study in a prospective cohort has shown 10% increase in intra-gastric pressure with rise in each unit of BMI ¹⁵. A pH and manometry study in general population with GORD showed a higher pressure gradients across the Oesophago-gastric junction than that in controls both before and during transient lower oesophageal sphincter relaxation. This phenomenon is thought to be caused by increased intra-gastric pressure, supporting the above theory ¹⁶.

Lower oesophageal sphincter dysfunction as a cause

Kuper et al showed a dysfunction of LOS and altered oesophageal motility even in asymptomatic patients with morbid obesity using pH and manometry study (BMI >40 kg/m²) ¹⁷and Wu et al showed an abnormal post-prandial LOS with prolonged transient lower oesophageal relaxation ^{18, 19}.These findings were re-iterated by ayazi et al, showing obese patients to be more than twice as likely to have a mechanically defective LOS ²⁰.   However, another study back in 1987 had shown a similar LOS pressure in normal weight and obese patients, though the gastro-oesophageal pressure gradient to LOS pressure ratio was high in obese ²¹.

Diet

The amount or composition of dietary intake and its relation to GORD has been studied. There is some evidence that volume, fat content and a high-caloric diet increases the oesophageal acid exposure time, giving rise to symptoms ^22-24. This would suggest an improvement of symptoms with reduction of these in the diet. More studies have shown an improvement in reflux symptoms with improved diet ^25-29. But, there is no convincing evidence to implicate the role of diet in reflux symptoms of obese patients.

Hiatus hernia

The incidence of hiatus hernia is over 50% in morbid obesity ³⁰. Hiatus has been shown to be predicted by intra-gastric pressure, gastro-oesophageal presssure gradient and BMI. BMI has in turn been shown to predict the former two. This confirms a positive association between BMI and presence of hiatus hernia ³¹. High BMI is more likely to have oesophago-gastric junction disruption, leading to hiatal hernia and an augmented gastro-oesophageal pressure gradient, providing a perfect scenario for reflux to occur ³². The incidence of defective LES was twice as much in obese patients with hiatus hernia, compared to obese without it ²⁰. Hiatus hernia thus plays a role in the obese patients and the subsequent development of GORD ³³.

Poor mobility and mental state

There is no evidence to support the theory of reflux symptoms secondary to poor mobility and depression in the morbidly obese patients.

Treatment of GORD in obesity

Medical therapy

Medical therapy with a PPI remains the first line of treatment of GORD symptoms in obesity as in patients with a normal BMI. No guidelines are available for dose adjustments in the obese patients ³⁴. They continue to receive the standard therapy, adjusted to the severity of disease and symptoms.

Endoluminal therapy

Endoluminal therapy was introduced recently as treatment alternative for GORD and has shown promising results. This looked a safe option for use in obese patients. However, published results have shown high rate of post-operative PPI requirement in the obese patients ³⁵. Further evidence has to emerge before this option can be recommended for use in the obese patients.

Balloon

Intra-gastric balloon therapy has been an established temporary procedure for weight loss. GORD symptoms in obese tends to improve with weight loss, but as studies have shown, a balloon insertion tended to worsen symptoms ^{36, 37}. Balloon is hence not considered an option for treatment of obesity with patients with reflux symptoms.

Gastric band

Gastric banding provides a sufficient anti-reflux barrier in most of the obese patients with GORD. Abnormal manometric findings like increased LES (lower oesophageal sphincter) residual pressure and peristaltic wave duration are frequently encountered after banding. The clinical significances of these manometric abnormalities are not clear ³⁸. The oesophageal stasis caused by the band could explain the reflux in patients during longer follow up. Though, the reflux from the distal stomach is prevented by the gastric band, formation of a proximal pouch predisposes to stasis and reflux. This is more common in patients with preoperatively defective oesophageal motility. The studies suggesting a good GORD symptom control following banding had shorter follow up, explaining the results ^{39, 40}. Hence it could be concluded that gastric banding may aggravate GORD symptoms and cause oesophageal dilatation, especially in patients with pre-operative motility defects. Routine pre-operative testing should be done and alternative bariatric surgical procedures such as Roux-en-Y gastric bypass considered in these patients   ^41-43.

Sleeve Gastrectomy (Vertical gastric banding)

Gastrectomy reduces weight, but not gastro-oesophageal acid reflux. Although this procedure has been shown to have anti-reflux properties ⁴⁴, it has fallen to disrepute in terms of relieving the reflux symptoms, especially with the superior results of RYGB ^45-48. A number of these cases requiring revision, due to reflux symptoms, have been reported ^49-51.

Gastric Bypass Vs Anti-reflux surgery

Though laparoscopic fundoplication is the standard operation for GORD, gastric bypass has been shown to improve the reflux symptoms in the morbidly obese, apart from reducing their weight and obesity related co-morbid conditions such as diabetes mellitus, hypertension etc. Patterson et al. showed an equivalent symptomatic improvement and objective DeMeester score improvement with Laparoscopic Nissen fundoplication and laparoscopic gastric bypass. The LES (lower oesophageal sphincter) pressure was also noted to improve, following bypass ⁵². This was in light of an earlier report of 31% recurrence rate of reflux symptoms following laparoscopic Nissen’s in obese patients ⁵³. Hence, morbidly obese patients with GORD should be offered laparoscopic gastric bypass as a surgical option ^{27, 30, 54-59}.

The improvement in GORD symptoms after gastric bypass is related to the way that the operation staples off the distal 90% or more of the stomach body and antrum, removing any possibility that acid generated in this part of the stomach can reach the oesophagus.  The parietal cell mass within the small gastric pouch that is left attached to the oesophagus, the complete elimination of duodeno-gastric reflux owing to a long Roux limb, and decrease in intra-abdominal pressure with weight loss all contribute to an almost total reflux control in all patients. The overall complications secondary to this procedure were lower than in laparoscopic fundoplication ⁵⁴. It is also the procedure of choice for previous other weight-loss surgery, when reflux symptoms develop ^49-51. Thus, a bariatric team prior to surgical intervention should review obese patients with GORD symptoms.

Dysphagia in obesity

Dysphagia in obesity is often related to the interventions used to treat obesity, though it can be primary in nature.

Various modalities of interventions available in obesity have been discussed above. Intra-gastric balloon therapy can be complicated by its displacement into the distal stomach, precipitating dysphagia and outlet obstruction. Gastric bands can be overfilled, causing this problem, and a slipped band or a band eroding through the stomach wall can also lead to dysphagia ^60-64. There has been no report of gastric bypass resulting in dysphagia, in the literature.

It is our understanding that patients with obesity may present with primary oesophageal dysmotility. Although there is little published literature on this issue, it is our hypothesis that fatty infiltration of the oesophageal wall and myenteric plexus may result in a poor amplitude peristaltic contraction.

Other oesophageal conditions associated with obesity

Barrett’s Oesophagus

This is characterised by the replacement of the normal squamous epithelium of the lower oesophagus by a specialised metaplastic columnar epithelium. Barrett’s oesophagus is a known risk factor for oesophageal adenocarcinoma, with a 30 to 125 times increased risk compared to general population ⁶⁵. Risk factors leading to Barrett’s have been poorly understood, though GORD is widely believed to be the main risk factor ^66-68. Since several studies have found an association between obesity and GORD ^{1, 2, 6-12}, and obesity as a risk factor for Barrett's have gained momentum in the recent year. Abdominal obesity or waist circumference has been shown to be more associated with Barrett’s than BMI ⁶⁹.

A recent systematic review showed a statistically significant relation between increasing BMI and Barrett’s ⁷⁰. However, two older systematic reviews had found a rather week relation between these two, showing a need for further well designed studies ^{71, 72}. To mention a few studies, Jacobson et al showed a positive relation between BMI and Barrett’s in women, independent of GORD, though the waist circumference was not found to have any association ⁷³and Stein at al., found a positive relation between BMI and Barrett’s in war veterans ⁷⁴. Abdominal obesity or circumference appears to be more influential in the incidence of Barrett’s oesophagus in another study ⁷⁵. There is however, little evidence to suggest an increased progression of Barrett’s to neoplasia in obesity ⁶⁹

Obesity is a modifiable risk factor and if proven to be a risk for Barrett’s and subsequent neoplasia, resources can be directed at modifying this, as there is evidence to suggest the regression Barrett’s with weight loss ⁶⁹. Barrett’s have been shown to regress with weight loss following gastric bypass and hence this has been recommended as bariatric procedure of choice in the morbidly obese with Barrett’s ^76-79. A precise endoscopic evaluation before bariatric surgery with continuing postsurgical surveillance in patients with known Barrett's oesophagitis, and early evaluation in patients who develop new symptoms of GERD after bariatric surgery is suggested ^{80, 81}

Adenocarcinoma of oesophagus

The incidence of oesophageal adenocarcinoma has increased about 400% during the past three decades, the most rapid rate of increase of any cancer in the United States ^82-84. The association between high BMI and oesophageal adenocarcinoma is strong and well established, though the mechanism of this is still unclear. The risk is higher with increasing BMI, especially in men ^85-94. Obesity has also been shown to play a role in adenocarcinomas with a family history ⁹⁵. The incidence of adenocarcinoma of the cardia of stomach has not been so strongly related to BMI ^{96, 97}. Squamous cell carcinoma of oesophagus has not shown any association to obesity either ^{85, 93, 94, 98, 99}. Few studies have negated the association of obesity with oesophageal adenocarcinoma, but many were due to the fact that they included oesophageal and proximal stomach together ⁹⁶. The majority of these cancers arise from a background of premalignant Barrett’s oesophagus, though less than 10% of the patients with oesophageal adenocarcinoma were known to have Barrett’s oesophagus previously. Presently there is no evidence that strongly supports any specific strategy to screen a subgroup of the population at risk for Barrett’s oesophagus and adenocarcinoma of the oesophagus ¹⁰⁰.

A number of studies have also looked at the mechanism or pathway of this metaplasia-dysplasia-adenocarcinoma sequence.  Visceral adiposity rather than BMI is thought to have a greater role in chronic inflammation and subsequent neoplasia. It has a clear association with Barrett’s as above. Increasing abdominal girth increases the risk of adenocarcinoma and it has been shown for Barrett’s ⁹⁸. Visceral fat is hypothesised as a major producer of interleukin-6, adinopectin, leptin and other adipokines that may be associated with the development of various gastro-intestinal cancers ^101-103. More specifically, insulin-like growth factor has been implicated in the pathogenesis of adenocarcinoma in the obese ¹⁰⁴. Oesophago-gastric tumours after bariatric surgery, has been reported, though rare. This condition, when occurs, requires the close collaboration of the bariatric team to achieve a successful oncological result, due to the altered anatomy like the blood supply to the gastric pouch and excluded stomach ¹⁰⁵.

Conclusion

Obesity is associated with oesophageal disease, benign and malignant, and both the effects of obesity and the effects of it’s treatment can aggravate oesophageal symptoms. The management of reflux and of dysphagia in obese patients requires a broad understanding of these issues.