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Penicillin allergies: facts, fiction and development of a protocol

Penicillins, a member of the beta-lactam family, are the most commonly prescribed antibiotic class in Australia. Beta-lactam agents are used in a sexual health setting for the management of syphilis, uncomplicated gonococcal infections and pelvic inflammatory disease. Patients frequently report allergies to penicillin, which can be protective but also counterproductive if it does not represent a ‘true’ allergy. Features of a reported reaction may be stratified as either high or low risk, which has implications for both re-exposure to penicillins; but also cross-reactivity to other members of the beta-lactam family such as cephalosporins. We reviewed the evidence surrounding penicillin allergies, in the context of developing a local protocol for penicillin-allergic patients at a sexual health clinic.

Case scenario

v5_i1_a20A 27-year-old male is referred to a sexual health clinic by a general practitioner (GP). He presents with a widespread maculopapular rash, fever and malaise for the past four days. Whilst he does not describe any other symptoms, he did notice a painless genital ulcer approximately four weeks ago. The ulcer resolved spontaneously; hence he initially did not seek medical advice. He does not have a stable sexual partner and mentions engaging in several episodes of unprotected sex with both women and men in the previous three months. Secondary syphilis is the suspected diagnosis given the widespread rash and preceding chancre, and testing confirms this with a positive syphilis enzyme-linked immunoassay (EIA) screening test, Treponema pallidum particle agglutination assay (TPPA), and an rapid plasma reagin (RPR) of 1:32. As part of a sexual health screen, he tested positive for rectal gonorrhoea by culture. The treatment regime includes 1.8 g intramuscular benzathine penicillin for syphilis, in addition to 500 mg intramuscular ceftriaxone and 1g oral azithromycin for gonorrhoea, all given as stat doses. Before signing the drug order, the clinician questions about any allergies. The patient mentions having an allergic reaction to penicillin when he was six years old but cannot remember any particular details. What is the plan now?

Introduction

This case presents a challenging scenario for the clinician. In this article, we hope to outline some of the facts surrounding penicillin allergies, dismiss some myths and provide a systematic approach to aid decision-making, especially in the sexual health setting where there are limited treatment options for gonorrhoea and syphilis.

The beta-lactam family of antibiotics are one of the most commonly prescribed antibiotic classes in medicine. The beta-lactam ring forms the structural commonality between different types of penicillins and this is also shared with other drug classes, such as the cephalosporins and carbapenems.

Penicillin allergy is the most commonly reported medication allergy, either by the patient or medical providers. [1] The implications of this ‘label’ can be either protective or counterproductive. For those patients with a severe previous reaction, such as anaphylaxis, this allergy is important and re-exposure can prove disastrous and potentially fatal. However, for other patients with a minor or inconclusive reaction, not administering penicillin may be denying the patient first-line, efficacious treatment. Additionally, there are concerns that treating patients with alternative agents in this context contribute to the development of resistance, which is of public health concern. [2]

Whilst the use of beta-lactam antibiotics crosses many realms of medicine, this article is written in the context of developing a protocol for the management of patients with penicillin allergy in an urban sexual health clinic. It is not designed to provide guidance outside of this setting, nor to replace existing protocols in other clinical units.

Rationale for a protocol

Management of patients with penicillin allergy requiring beta-lactam treatment was reviewed as part of an overall revision of internal treatment guidelines. Sexually transmitted infections pose treatment challenges whereby certain conditions or patient sub-groups (e.g. pregnant women) have no equally efficacious or appropriate alternatives to penicillins. [3] For example, one acceptable alternative to penicillin for syphilis treatment is to administer oral doxycycline, however the potential harm associated with this treatment (permanent dental staining) contraindicates its use in pregnancy. [4]

Development process

Senior clinicians at the sexual health clinic provided the protocol brief in May 2013. This included, but was not limited to: reviewing existing guidelines for the management of penicillin-allergic patients both at a national and international level; reviewing literature about the incidence of penicillin allergy, and cross-reactivity rates in patients with a documented history of penicillin allergy; formulating a protocol, based on existing protocols and evidence which would be applicable for managing patients with a penicillin allergy; designing a flowchart which summarises the protocol in a clear manner, including clear decision making and referral points in addition to an estimation of risk; engaging senior nursing staff and the director to assess the usability and practicality of the protocol; and presenting a draft for consideration to medical and nursing personnel, with subsequent review, endorsement and implementation.

Use of penicillins and cephalosporins for treatment of sexually transmitted infections

Current protocols in the clinic suggest the use of beta-lactam antibiotics as first line treatment for the following conditions, in accordance with national guidelines [5,6]:

Syphilis

IM benzathine penicillin 1.8 g stat single dose for early syphilis (including early latent syphilis), 3 weekly doses for late latent syphilis

Uncomplicated gonococcal infections

IM ceftriaxone 500 mg stat (in conjunction with azithromycin 1 g orally)

Pelvic inflammatory disease (PID)

IM ceftriaxone 500 mg stat (in conjunction with doxycycline 100 mg BD for 14 days and metronidazole 400 mg BD for 14 days)

Mechanism of penicillin allergy and associated reactions

This article focuses on the main concern with penicillin allergy, which is the possibility of anaphylaxis, an IgE-mediated (type I) hypersensitivity reaction. However, the clinician should be aware that delayed type hypersensitivity reactions (type IV) can also occur, causing exanthema or other skin eruptions, such as morbilliform reactions. These are not determined by the beta-lactam ring or side chains of the antibiotics, but rather, the ability for a drug to act independently as a hapten and become antigenic in nature. [7] This antigenicity triggers an immune response through interaction with antigen-presenting cells (APC) and T-cells. [8]

The major determinant of anaphylactic reactions to beta-lactam antibiotics is the beta-lactam ring, which is shared amongst the penicillin class, as this binds to endogenous lysine proteins to form a hapten. [9] However, there is also evidence to suggest that an IgE-mediated reaction can occur with the minor determinants of the molecule, which is the R chain (acyl) side group of individual penicillins (Figure 1). IgE binding results in mast cell activation and histamine release, in addition to the release of inflammatory mediators.

In patients who develop an IgE-mediated reaction, there is subsequent risk of a more severe reaction on re-exposure. IgE-mediated reactions can have effects on the following body systems: dermatologic (urticarial rashes, angioedema, macroglossia), respiratory (asthma, bronchospasm, wheezing, laryngeal swelling), gastrointestinal (abdominal pain, vomiting, diarrhoea, cramping), and cardiovascular (hypotension, vascular collapse, altered consciousness, shock).

Whilst no universal definition exists for anaphylaxis, two commonly accepted definitions in Australia are: (1) the acute onset of illness, with typical skin features (urticarial rash, erythema/flushing, angioedema) plus involvement of one other body system; or (2) the acute onset of hypotension, bronchospasm or upper airway obstruction with or without skin features. [10]

Figure 1.The beta-lactam ring is found in penicillins and several other closely related drug classes. Variants in the R chain are found within each drug class.
Figure 1.The beta-lactam ring is found in penicillins and several other closely
related drug classes. Variants in the R chain are found within each drug class.

Incidence of penicillin allergy and cross reactivity with cephalosporins
Various early studies suggested the incidence of penicillin allergy to be approximately 2% per course, with anaphylaxis estimated in 0.05% of all penicillin courses. [1] However, a large retrospective cohort study in the UK, which looked at 3,375,162 patients prescribed subsequent courses of penicillin, found a much lower incidence of only 0.18%. [11] It must be noted when quoting these figures that the definition of an ‘event’ in this study did not include asthma or eczema; however, when included, the incidence increased from 0.18% to 9% which makes interpretation difficult as we consider asthma a feature of allergy in Australian definitions. [11]

It is difficult to accurately identify if a trend over time exists in patients having a penicillin allergy. Multiple protocols exist internationally about the diagnosis of penicillin allergy and subsequent testing. [12] Furthermore, an element of bias may be present from both the patient and the clinician as the label of an ‘allergy’ can be highly subjective, and a permanent feature on a health record without subsequent confirmation.

Many early studies have quoted 10% cross-reactivity between penicillins and cephalosporins. [13,14] Unfortunately, these original studies assessing cross-reactivity over three decades ago were flawed, poorly designed open studies, lacking control groups, and have consequently overestimated this figure. [15] Furthermore, it is also postulated that the original manufacturing processes of cephalosporins contributed to inflated allergy rates, due to cross-contamination with penicillin compounds. [15] Since manufacturing processes have been refined, there has been a reduced incidence in cross-reactivity. If studies past 1980 are exclusively considered, a patient with a confirmed penicillin allergy (by positive skin test) will react with a cephalosporin in less than 2% of occasions. [15]

There is further evidence to suggest that there is less cross-reactivity with newer cephalosporins (second generation and onwards). A recent review and meta-analyses have found that third generation cephalosporins, such as ceftriaxone, have a cross reactivity rate of only 0.8% in those patients who are confirmed to be penicillin-allergic by skin testing, compared to 2.9% with older cephalosporins such as cephalexin. [16,17] Furthermore, these papers established that the risk of anaphylaxis due to cephalosporin cross-reactivity is quite small, as there was a higher incidence of anaphylactic reactions to cephalosporins with a negative penicillin skin test, compared to positive skin test patients. [16] This demonstrates that anaphylaxis reactions are often unpredictable.

Assessing the type and severity of penicillin allergy

Evidence suggests that history from the patient, especially when vague or not documented, is insufficient for assessing the degree of penicillin allergy. [18] Furthermore, the potential for allergy changes over time, with 80% of individuals with a documented IgE-mediated reaction having no evidence of reactive IgE after 10 years from initial reaction. [19] Most IgE-mediated reactions occur within seconds (IV administration) or up to an hour if administered orally with food. [20] Reactions outside of this timeframe are less likely to be IgE-mediated.

Hence, when taking a history, specific information should be sought to identify the presence of low- or high-risk features of the previous penicillin-related reaction, and consequently stratify the risk of future allergic reactions to a penicillin or cephalosporin.

High-risk features include: reaction occurred within one hour of administration; reaction occurred within the last 10 years; well documented history of features suggestive of anaphylaxis; required hospitalisation; any features suggestive of anaphylaxis as defined previously; and features of type IV hypersensitivity reactions including blistering, mucosal involvement, early onset desquamation (peeling), blood abnormalities such as derangements in liver function, renal function, or eosinophils. [15]

Low-risk features include: reaction occurred more than one hour after administration; reaction occurred more than 10 years ago; history is vague, unclear or poorly documented; localised reaction of mild severity involving one system only (rash not displaying any ‘high-risk features’ or stomach cramping); and a reaction that is not a true allergy; for example, an amoxicillin-Epstein Barr virus reaction. [10,15]

Role of the radioallergosorbent test, skin testing and desensitisation for penicillin allergy

In any patient with features of penicillin allergy, there should be consideration of referral for immunological skin testing and/or desensitisation, which can be performed quickly and is cost effective. The radioallergosorbent test (RAST) is more expensive, takes time to analyse and has poor positive predictive value. Desensitisation is performed in a supervised setting, can take 4-12 hours to complete in an acute setting, and results in a temporary reduction in immunogenic potential towards penicillins or associated medications. [21] Immediately following desensitisation, the first dose of penicillin is usually given. It must be noted that penicillin skin testing should also include testing against related beta-lactams such as cephalosporins, as a positive penicillin skin test cannot accurately predict cross-reactivity. [17]

Recommended drug choice in penicillin allergic patients

Based on the information outlined, and current existing guidelines, the following recommendations have been derived:

  1. Any patient who has high-risk features on history should not receive a beta-lactam agent. [22] An alternative efficacious drug should be prescribed. If there is no efficacious alternative, or a cephalosporin is required, referral to immunology should occur for skin testing and desensitisation if needed.
  2. 2. In those patients who have only low-risk features on history, the following question must be addressed: ‘which antibiotic is required?’ If a penicillin-based compound (i.e., benthazine penicillin) is required, the same precautions should be taken as mentioned above. However, if a cephalosporin such as ceftriaxone is required, the medication may be administered as the risk is less than 1% for third-generation cephalosporins. In this setting, the patient should be advised of the small but possible risk of an allergic reaction. [16]

Routine monitoring

Regardless of what antibiotic is prescribed, routine monitoring is advised as all serious allergic reactions need appropriate medical care. Observation facilities in addition to life support equipment and staff trained in first aid are essential in administering stat doses of antibiotics for the treatment of sexually transmitted infections. Signs and symptoms to look for during the observation period include the following: rash, swelling around the face/tongue/eyes, breathing difficulty, wheeze, vomiting, diarrhoea, abdominal pain, syncope or pre-syncope (low blood pressure), altered consciousness or shock. If any of these features are present or there is concern, refer to the local anaphylaxis and emergency protocols.

Case outcome

Although specific details of the previous allergic reaction could not be recalled by the patient, collateral history from his family suggested an urticarial reaction at the age of seven, with no other systemic features and not requiring hospitalisation. Consequently, the patient was deemed low-risk for a cross-reactivity allergic reaction towards ceftriaxone. He received the original prescribed treatment of 500 mg IM ceftriaxone and 1 g oral azithromycin without any adverse effects, or features of an allergic reaction. To treat his syphilis, he underwent a rapid desensitisation and subsequently received 1.8 g intramuscular benzathine penicillin, with no adverse effects.

Conflicts of interest

None declared.

Correspondence

J Floridis: john.floridis@nt.gov.au

References

[1] Solensky R. Allergy to penicillins. In: UpToDate. [Online].; 2012 [cited 2013 June 1] Available from: http://www.uptodate.com/contents/allergy-to-penicillins?source=search_result&search=allergy+to+penicillins&selectedTitle=1~150.

[2] Solensky R. Penicillin allergy as a public health measure. J Allergy Clin Immun. 2014;133(3):797-8.

[3] Emerson C. Syphilis: A review of the diagnosis and treatment. Open Infect Dis J. 2009;3:143-7.

[4] Australian Medicines Handbook Pty Ltd. Australian Medicines Handbook Rossi S, editor. Adelaide; 2013.

[5] STD Services. Diagnosis and Management of STDs (including HIV infection). 7th ed. Adelaide: Royal Adelaide Hospital; 2013.

[6] Antibiotic Expert Group. Therapeutic Guidelines: Antibiotics. Version 14. Melbourne: Therapeutic Guidelines Limited; 2010.

[7] Adam J, Pichler W, Yerly D. Delayed drug hypersensitivity: models of T-cell stimulation. Brit J Clin Pharmaco. 2011;71(5):701-7.

[8] Friedmann P, Pickard C, Ardern-Jones M, Bircher A. Drug-induced exanthemata: a source of clinical and intellectual confusion. Eur J Dermatol. 2010;20(3):255-9.

[9] Arroliga M, Pien L. Penicillin allergy: Consider trying penicillin again. Clev Clin J Med. 2003;70(4):313-26.

[10] Australasian Society of Clinical Immunology and Allergy. ASCIA. [Online].; 2012 [cited 2013 May 28] Available from: www.allergy.org.au/health-professionals/anaphylaxis-resources/adrenaline-autoinjector-prescription.

[11] Apter A, Kinman J, Bilker W, Herlim M, Margolis D, Lautenbach E, et al. Represcription of penicillin after allergic-like events. J Allergy Clin Immun. 2004;113(4):764-70.

[12] Macy E. The clinical evaluation of penicillin allergy: what is necessary, sufficient and safe given the materials currently available? Clin Exp Allergy. 2011;41(11):1498-1501.

[13] Dash C. Penicillin allergy and the cephalosporins. J Antimicrob Chemoth. 1975;1(3):107-18.

[14] Petz L. Immunologic cross-reactivity between penicillins and cephalosporins: a review. J Infect Dis. 1978;137 Suppl:S74-S79.

[15] Solensky R. Penicillin-allergic patients: Use of cephalosporins, carbapenems and monobactams. In: UpToDate. [Online].; 2013 [cited 2013 June 1] Available from: http://www.uptodate.com/contents/penicillin-allergic-patients-use-of-cephalosporins-carbapenems-and-monobactams?source=search_result&search=penicillin+allergic+patients&selectedTitle=1~150.

[16] Pichichero M. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics. 2005;115(4):1048-57.

[17] Pichichero M, Casey J. Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis. Otolaryngol Head Neck Surg. 2007;136(3):340-7.

[18] Wong B, Keith P, Waserman S. Clinical history as a predictor of penicillin skin test outcome. Ann Allergy Asthma Im. 2006;97(2):169-74.

[19] Blanca M, Torres M, Garcia J. Natural evolution of skin test sensitivity in patients allergic to beta-lactam antibiotics. J Allergy Clin Immun. 1999;103(5 Pt 1):918-24.

[20] Pichler W. Drug allergy: Classification and clinical features. In: UpToDate. [Online].; 2013 [cited 2013 May 28] Available from: http://www.uptodate.com/contents/drug-allergy-classification-and-clinical-features?source=search_result&search=drug+allergy%3A+classification&selectedTitle=1~150.

[21] Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines. Management of persons who have a history of penicillin allergy. 2011 January 28.

[22] Smith W. Adverse drug reactions. Allergy? Side-effect? Intolerance? Aust Fam Physician. 2013;42(1-2):12-6.

Categories
Review Articles Articles

The role of viruses in carcinogenesis

It is accepted that populations in the so-called developed world have gone through an ‘epidemiological transition’ where chronic disease has replaced infection as the primary cause of death. However, there is mounting evidence that infections play a key role in certain chronic diseases such as cancer. Cancers of infectious origin provide the perfect opportunity for harnessing the advances that have been made in the control of communicable diseases to attempt the control of noncommunicable diseases. Worldwide, one in every five malignancies can be attributed to infections: this figure is considered conservative and expected to rise. About two-thirds of these cancers occur in less developed countries. The majority of these malignancies are recognised to be caused by viruses via mechanisms of chronic inflammation, immunosuppression or the expression of oncogenic proteins. An understanding of virally mediated carcinogenesis may provide new targets for the development of specified viral therapy that not only impacts on viral infections but human cancer as well. From a public health perspective, viral carcinogenesis is important because it shows potential for preventative and therapeutic programmes to reduce the burden of cancer, particularly in less developed countries.

Introduction

The process of carcinogenesis involves multiple contributing factors. These include environmental, lifestyle, host factors, genetically inherited traits and infectious agents. Infectious agents are important from a public health aspect as they represent a significant and preventable cause of cancer. The infection-attributable cancer burden has been estimated at 1.9 million cases, or 17.8% of the total global cancer burden. [1] The percentage of infection-attributable cancer is higher in developing countries (26.3%) than in developed countries (7.7%), reflecting the higher prevalence of infectious diseases. Of these infection-associated cancers, viruses are the most common causative agents with 12.1% of cancers worldwide attributed to viral infections. [1]

This article aims to outline current knowledge of the role of viruses in mediating cancer, explore the main mechanisms involved and propose exciting preventative and therapeutic approach for virus-associated cancers in the 21st century.

Mechanisms by which viruses mediate cancer

The International Agency for Research on Cancer (IARC) recognises seven viral agents that have been linked with cancer: Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV), Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), Karposi-Sarcoma Herpes Virus (Human Herpes Virus 8), Human T-cell leukemia virus type I (HTLV-1) and Human Immunodeficiency Virus type 1 (HIV). [2] These seven viruses classified as ‘carcinogenic to humans’, and the recently discovered Merkel Cell Virus which has not yet been included by the IARC, are summarised in Table 1.

The induction of cancer development by viruses requires persistent infection of the host.  It is hypothesised that long-term infection initiates cellular changes that predispose to cancer progression. [3]

In addition to persistent infection, the specific actions of these viruses are discussed below and can be broadly grouped into viruses that induce cancer by (i) chronic inflammation (eg. HCV), (ii) immunosuppression (eg. HIV) and by (iii) direct actions of viral oncogenic proteins (eg. EBV, HPV). [3]

(i) Cancer associated with chronic inflammation: Hepatitis B and C Viruses

Once a viral infection is initiated, recovery requires the activation of the innate and adaptive arms of the immune system. Acute inflammation is usually a short process that eliminates the pathogen. However, chronic inflammation may result if acute inflammation continues unresolved and fails to eradicate the pathogen. Chronic inflammation itself may promote carcinogenesis via the release of many factors including nitric oxide, cytokines and chemokines thus mediating DNA damage and effecting cell proliferation and neoangiogenesis. [3]

HBV and HCV infections are examples of chronic infections associated with ongoing inflammation. HBV and HCV are responsible for 54% and 31% of human hepatocellular carcinoma (HCC) cases worldwide. [4,5] These hepatotropic viruses can induce cirrhotic livers from which HCC can arise. This review will focus on HCV.

In those infected with HCV, 80% will develop chronic infection, and in 30 years 10-30% of these chronic HCV infections will develop cirrhosis. The subsequent rate of cirrhotic HCV liver disease developing HCC is 1-3% per year. [6] Since current WHO estimates suggest that 3% of the world’s population, or 150 million people, are HCV infected, this represents a significant virus-associated cancer burden.

HCV is a RNA virus of the hepacivirus family of the genus Flaviviridae. HCV does not integrate itself into the host genome and several viral proteins (core protein and the NS3, NS4B and NS5A) have been suggested as potential oncogenic candidates in-vitro. For example, the HCV NS5A protein has been shown to bind and sequester the cellular p53 protein to the perinuclear membrane, and it may be the be key to HCC development. [7] However, it is thought that HCC primarily occurs due to repeated rounds of hepatocyte destruction and regeneration from chronic inflammation, producing a procarcinogenic cirrhotic microenvironment, [3,8] rather than through the action of viral oncogenes. Cirrhosis appears to be the main risk factor for HCC, but exogenous factors could also play a role, such as chronic alcohol consumption, viral co-infection (such as HIV modulating immunosuppression), diabetes and obesity [4] highlighting the multifactorial triggers for the induction of cancer. [9]

HCV is also a well-established cause of essential mixed cryoglobulinemia, a lymphoproliferative disease that can evolve into B-cell non-Hodgkin lymphoma (NHL). [10] HCV has been suggested to be lymphotropic, but this is not well defined. [11] Again, since HCV has not been demonstrated to encode direct oncogenic proteins, the mechanisms of HCV-induced NHL are likely to be via chronic inflammation.

(ii) Cancer associated with immunosuppression and insertional mutagenesis: HIV

It is estimated that there are approximately 34.2 million individuals worldwide living with HIV infection, two-thirds of these being in sub-Saharan Africa. [12] People with HIV have a substantially higher risk of certain cancers compared with uninfected people of the same age. These cancers are termed AIDS-defining malignancies and include: Kaposi sarcoma, a mesenchymal tumour originating from lymphatic endothelial cells, cervical cancer and NHL. [13] Additionally, other types of cancer, such as Hodgkin’s disease (HD), anal cancer, lung cancer and testicular germ cell tumours appear to be more common among HIV-infected subjects compared to the general population and are termed AIDS-associated cancers. [14]

HIV is an RNA lentivirus of the Retroviridae family. The members of this family all integrate into the host chromosome and thus have the potential to cause direct insertional mutations or activation of cellular oncogenes.  Other members of the Retroviridae family, such as Mouse mammary tumour virus (MMTV) have a well-defined link with tumours in mice, which are likely mediated by insertional activation of cellular genes in breast tissue through hormone responsive elements in the MMTV promoter. [15] Similarly, insertional mutagenesis and the induction of lymphoma has been identified in humans treated with gammaretrovirus [16] and lentivirus vectors used in gene therapy. [17] In contrast, there is little evidence for an HIV oncogenic protein, although studies have suggested that the transactivator protein of viral gene expression, Tat, which has oncogenic potential, is secreted by HIV. It has also been suggested that Tat can re-enter non-infected cells blocking apoptosis and accelerating tumour formation. [18]

The above described AIDS-associated cancers are linked with low CD4+ T-cell counts, and this may lead to co-infections with other oncogenic viruses such as HPV (cervical cancer) and Kaposi’s sarcoma-associated herpesvirus (Kaposi’s sarcoma), or the reactivation of existing infections with opportunistic oncogenic viruses such as EBV (Burkitt’s lymphoma). [18] However, the specific mechanisms by which depressed immunity may increase the risk for cancer are unclear, except for KS and most subtypes of NHL that are strictly associated with a low CD4 count. [19] Supporting the link between cancer and immunosuppression, the pattern of cancers in immunosuppressed organ transplant recipients is similar to people with HIV/AIDS. [20]

Thus, the evidence suggests that HIV can be associated with carcinogenesis through insertional mutagenesis. Moreover, HIV may indirectly cause cancers by inducing a chronic state of immunosuppression, reducing immunosurveillance for neoplastic cells, and increasing the risk of reactivation of latent oncogenic viruses as well as the risk of acquiring new oncogenic viral infections.

(iii) Cancer associated with Oncogenic viruses

Of the identified and accepted carcinogenic viruses, EBV, HHV-8, HTLV-1and HPV are tumour viruses that express viral oncogenic proteins to exert carcinogenesis. HBV also produces the HBx protein that disrupts signal transduction and deregulates cell growth: however, HBV-associated carcinogenesis is believed to be mainly mediated through chronic inflammation as described for HCV. [3] Oncogenic viruses can transform cells by carrying viral oncogenes into a cell or by activating cellular proto-oncogenes. [5] The virally derived oncogenes produce transforming growth factors that deregulate growth control and proliferation, leading to malignant transformation. Specific examples are discussed below, with the oncogenic viruses divided into DNA and RNA tumour viruses.

DNA Tumour Viruses

EBV best illustrates DNA tumour viruses. EBV is a double-stranded DNA virus of the herpesviridae family, and causes infectious mononucleosis. Like all herpesviruses, EBV causes a life-long latent infection, and EBV is the primary cause of B-cell transformation in Burkitt’s lymphoma. [14] This was the first human tumour associated with an infectious agent. Since then, EBV has been implicated in a number of other cancers (see Table 1).

In the case of EBV-lymphoma, expression of the viral oncogene, latent membrane protein-1 (LMP1), transforms cells into lymphoblasts by the disruption of cellular signal transduction. [3] In contrast, in most NPCs, the viral BamHI-A reading frame-1 (BARF1) gene is expressed. BARF1 has been identified as an important oncogene in NPC pathology. [21] Thus, EBV has a number of different oncogene expression profiles associated with different cancers. EBV is extremely widespread in prevalence affecting more than 90% of the world’s population, [22] yet only a small fraction of the infected populations have a cancer attributable to EBV.  Therefore, beside viral factors, host responses also play a role in the neoplastic transformation of EBV-infected cells.

HHV-8 is a DNA virus of the herpesviridae family, and HHV-8 infection is strongly associated with Kaposi’s sarcoma. The mechanism, however, of HHV-8-induced carcinogenesis is very different to that of the related virus, EBV. HHV-8 infects endothelial cells and encodes a viral G protein-coupled receptor (vGPCR). This vGPCR has dysregulated signalling function and acts as an oncogene, inducing angioproliferative tumours. [23]

HPV is a DNA virus of the papillomavirus family, and there are 30-40 types. Approximately fifteen types of HPV are oncogenic viruses, causing 5.2% of total human cancers. [24] These cancers include those of the ano-genital mucosae (cervix, vagina, vulva, anus and penis), and the mouth and the pharynx. [24,25] The predominant transmission of these HPV infections is sexual. [26] While HPV is an accepted aetiological factor for oral and pharyngeal cancers, the major risk factors are tobacco and alcohol, with the effects of these exposures being multiplicative. [25] Oncogenic HPV can be detected by PCR in virtually all cases of cervical cancer, with specific genotypes HPV16 and 18 identified as the primary causes of cervical cancer. These viral genotypes have also been associated with 86-95% of HPV-associated non-cervical cancers. [26,27] These viruses infect the basal layer of the stratified epithelium and express two important viral oncoproteins, E6 and E7. [23] These proteins destabilise the cellular tumour suppressor genes, p53 and the retinoblastoma protein (RB). [28] This dysregulation of cellular growth directly leads to cell transformation and cancer.

RNA Tumour Viruses

HTLV-I is a retrovirus related to HIV, which is associated with adult T-cell leukaemia. Only 1% of HTLV-I infected individuals will develop leukaemia, and only after a long latency period of 20-30 years. [29] HTLV-I infection rates are elevated in certain Indigenous populations of Central and Northern Australia, as well as the southern islands of Japan, the Caribbean basin and South Africa. [14] Unlike HIV, HTLV-I infections are not associated with immunosuppression, but HTLV-I encodes an oncogenic protein; the viral Tax protein. [30,31] Tax is a transcription factor and is known to bind to a number of cellular genes involved in cell cycle progression and growth regulation, such as NFkB and p53. [32] Via promotion of transcription and cell cycle progression, Tax is proposed to set up a self-stimulating loop that causes continuous proliferation of infected T-cells, and ultimately leukaemia.

The growing cancer burden attributable to viruses

While there are only seven viruses clearly recognised as carcinogenic to humans, this is conservative, with the discovery of new associations between infections, particularly viruses, and cancer anticipated.

MCV is a recently discovered DNA virus that is found to be associated with approximately 80% of Merkel Cell Carcinomas, an aggressive form of skin cancer. [33] MCV is a relatively common virus, yet only leads to cancer in rare circumstances. It is thought that this is because for MCV to become carcinogenic, two rare mutagenic steps must occur:  viral integration and T antigen mutation. Integration of MCV is not a regulated event, unlike for HIV and HTLV-I, and occurs rarely. The integration, probably of only parts of the MCV genome into cells, renders the virus replication-incompetent, but allows parts of the virus, such as the T-antigens, to be maintained in these cells. [34] MCV T antigens can be oncogenic, and target cellular tumour suppressors and cell cycle regulatory proteins. Thus, the whole replicative virus may not be present, but the residual oncogenic T-antigen is, and can promote transformation of the cell leading to cancer.

Cancerous cells themselves are generally not transmissible. In humans, during the two known physiological routes for tumour cell transmission (pregnancy and organ transplantation), the immune system is altered.  Transplacental transmission of lymphoma, acute leukaemia, melanoma and carcinoma have been observed, as well as acute leukaemia cells transmitted to the foetuses in multiple case pregnancies with the subsequent disease development in the newborn. [35] Similarly, in organ transplantation, donor derived tumour cells have been observed, with the immunosuppressive therapy following transplantation potentially facilitating the engraftment and growth of donor derived tumour cells. [35] Fortunately, these transmissible tumours are rare, with the development of donor-derived tumours in solid organ transplant recipients at 0.04%. [15] Additionally there have been rare case reports of human contagious cancers documented via needle stick (colonic adenocarcinoma), [36] and a surgeon contracting a malignant fibrous histiocytoma from a patient following an intraoperative cut to his left palm. [37]

Cancer prevention and public health strategies

In theory, the cancers resulting from viral infections represent an exciting potential for public health intervention strategies and therapeutics to prevent these cancers.  In particular, the high number of cancers attributable to viral infections in developing countries presents a real need and opportunity for public health programs to reduce both infectious disease and cancer burden. [38]

The mode of transmission of the seven IARC-recognised carcinogenic viruses is provided in Table 2. The implementation of public health education, awareness, treatment and prevention programs to reduce the horizontal spread of these viruses and manage these viral infections in patients is a public health priority, but has the additional benefit of reduction in the associated cancer risks.

Public health programs should be prioritised to target vertical transmission of viral infections such as HBV and HIV. The WHO outlined targets and recommendations in 2010 with the prevention of mother to child transmission (PMTCT) strategy, targeting anti-retroviral therapy (ART) in pregnant women and providing guidelines for HIV in relation to infant breastfeeding. [39] Similar guidelines may be applicable to our Indigenous population afflicted by HTLV-I, which has a well described increased mother to child transmission rate associated with breastfeeding. [40] However, breastfeeding recommendations in resource poor settings need careful consideration. [41]

More outstanding, are the successful programs for screening and management of viral infections associated with cancer. For example, the National Cervical Screening Program (NCSP) in Australia has had a huge benefit in reducing the mortality rates from cervical cancer from 3.9/100,000 in 1991 to 1.9/100,000 in 2007, [42], demonstrating that cancer prevention via monitoring oncogenic viral infections is a real possibility. [43] Additionally, such programs as the NSW Cancer Council ‘B positive’ program, implemented in 2008 aims to increase HBV awareness and the treatment and management of chronic HBV infection to reduce the risk of HCC. [44]

Vaccination and treatments to prevent cancer-associated viral infections

Historically, the world has experienced, with polio and smallpox, elimination or virtual elimination of viral diseases through vaccination. There are now vaccines available for both HBV and HPV, two major infectious causes of HCC and cervical cancer, respectively. The HBV surface antigen is the basis for the vaccine against the HBV, which was first available in the 1980s, and is the first vaccine for prevention of a human cancer. [45] Vaccination programmes of children with the HBV vaccine have already proved successful in protecting against chronic carriage and HCC, [46,47] and HBV vaccination has now been introduced into the Australian childhood immunisation schedule. Long-term and full coverage of newborns against HBV has the potential of reducing HCC by approximately 85%. [14]

The two currently marketed vaccines for HPV utilise the L1 coat protein in the form of virus-like particles to prevent persistent infection with HPV16 and HPV18. [48-50] These viral subtypes are estimated to cause 71.8% of all HPV-related cancers, cervical and non-cervical. [25] These vaccines need to be administered prior to exposure to HPV16 and 18, which makes delivery in a public health setting more difficult than an infant setting. In Australia in 2007, the National HPV vaccination Program was made available to teenage women, and is now part of the school age vaccination program. From 2013 will also be made available to 12-13 year old males. [51] However, the current cost is not practical for all groups, especially those in developing countries, [14] and although the HPV vaccination program in developing countries is supported by the WHO, the applicability and benefits of HPV vaccination have been queried and recently suspended in India. [52] The efficacy of these HPV vaccines in preventing infections at sites other then the cervix, vagina and vulva should be assessed. [27] Specifically, research is required on the administration to high-risk groups (e.g. men who have sex with men and HIV positive people) for anal cancer. [24]

Unfortunately, the described RNA viruses associated with cancer, HIV and HCV, are highly genetically variable and therefore prove to be difficult candidates for prophylactic vaccines. For these viruses, anti-viral therapy appears to be more successful. For example, the risk of infection-associated cancers in HIV positive individuals is related to ongoing HIV replication. The use of suppressive highly active antiretroviral therapy (HAART) has dramatically reduced the risk for opportunistic infections and improved overall life expectancy in patients with HIV-infection and AIDS. [53] A significant decrease in the incidence of KS has been observed in patients treated with HAART. [19] Moreover, HAART and preserved CD4 count preferentially reduces the risk of malignancies associated with oncogenic infections. [54] Similarly, patients with HCV who were prescribed the anti-viral agent, interferon, showed regression of their splenic lymphoma. [55]

Recently approved HCV NS3-4A protease inhibitors are proving effective in clearing and curing HCV infection. In the future, this may significantly impact on HCV infection rates and subsequent incidence of HCC.

Exciting Therapeutic Targets

Our understanding of mechanisms of viral initiation of carcinogenesis has provided the opportunity to design innovative, targeted cancer therapies based on the pathways disrupted by the transforming viral genes.

For example, recent studies reveal that the cellular survivin oncoprotein is activated by MCV large T antigen protein via targeting the cellular Rb (p53) protein, and that survivin inhibitors can delay MCV-induced tumour progression in animal models. [56] Clinical trials are now in progress to determine whether these survivin inhibitors have any therapeutic benefits. Additionally, MCV is a target for cell-mediated immune responses, and so important research efforts are being focused on immunologic therapies that may benefit MCC patients. [56] These findings provide a proof of principle for specifically treating virus-associated cancers by targeting the mechanisms by which they induce oncogenesis. In the case of MCV, a promising rational drug target has been uncovered within only four years of the initial discovery of MCV as a causative cancer agent. Similarly, other new treatments for cancer might be rapidly developed should we identify new viral associations with malignancies.

Conclusion

Viruses are an important aetiological cause of human cancers, especially in the developing world where they lead to a significant burden of disease.  Although viruses make an important contribution to human cancer development, it is often difficult to prove the association of viral infections with cancer, due to latency in tumour development and the multifaceted interaction with the host.  It is reasonable to think that the calculations of cancers attributable to viruses are underestimates and that cancers other than the ones described may also be associated with viral infections. The viruses in this review exemplify the best-established human tumour viruses, but there are many other potential candidates.  Undoubtedly, as our knowledge of carcinogenesis and viruses expand, further cancer-associated viruses will be discovered. From a public health point of view, infectious diseases are often preventable or treatable; therefore, cancers associated with infections are, or may become, preventable.  Prevention may be in the form of vaccination, novel therapies to target the immune system or oncogenic proteins, or education and public health interventions.

Conflict of interest

None declared.

Correspondence

V Boon: boon0035@flinders.edu.au

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Categories
Review Articles Articles

Treatment of persistent diabetic macular oedema – intravitreal bevacizumab versus laser photocoagulation: A critical appraisal of BOLT Study for an evidence based medicine clinical practice guideline

Laser photocoagulation has remained the standard of treatment for diabetic macular oedema (DME) for the past three decades. However, it has been shown to be unbeneficial in chronic diffuse DME. Intravitreal bevacizumab (ivB) has been proposed as an alternate and effective treatment of DME. This review evaluates the evidence behind comparing bevacizumab to laser photocoagulation in treating persisting DME. A structured systematic search of literature, with critical appraisal of retrieved trials, was performed. Four randomised controlled trials (RCTs) supported beneficial effects of ivB over laser photocoagulation. Only one RCT, the BOLT study, compared laser to ivB effect in persistent DME. The results from the study showed significant improvement in mean best corrected visual acuity (BCVA) and greater reduction in mean central macular thickness (CMT) in the ivB group, with no significant difference in safety outcome measures.

Introduction

Diabetic macular oedema is a frequent manifestation of diabetic retinopathy and is one of the leading causes of blindness and visual acuity loss worldwide. [1] The presence of DME varies directly in proportion with the duration and stage of diabetic retinopathy, with a prevalence of three percent in mild non-proliferating retinopathy, 38% in moderate-to-severe non-proliferating retinopathy and 71% with proliferative retinopathy. [2]

Diabetic macular oedema (DME) is a consequence of micro-vascular changes in the retina that lead to fluid/plasma constituent accumulation in the intra-retinal layers of the macula thereby increasing macular thickness. Clinically significant macular oedema (CSME) is present when there is thickening within or close to the central macula with hard exudates within 500μm of the centre of the macula and with retinal thickening of at least one disc area in size. [3,4] As measured in optical coherence tomography, central macular thickness (CMT) corresponds approximately to retinal thickness at the foveal region and can quantitatively reflect the amount of CSME a patient has. [5] Two different types of DME exist: focal DME (due to fluid accumulation from leaking micro-aneurysms) and diffuse DME (due to capillary incompetence and inner-retinal barrier breakdown).

Diabetic macular oedema pathogenesis is multi-factorial; influenced by diabetes duration, insulin dependence, HbA1C levels and hypertension. [6] Macular laser photocoagulation has remained the standard treatment for both focal and diffuse DME, based on the recommendations of the Early Treatment Diabetic Retinopathy Study (ETDRS) since 1985. This study showed the risk of CSME decreases by approximately 50% (from 24% to 12%) at three years with the use of macular laser photocoagulation. However, the improvement in visual acuity is modest, observed in less than three percent of patients. [3]

Recent research indicates that macular laser therapy is not always beneficial and has limited results, especially for chronic diffuse DME, [3,7] with visual acuity improving in only 14.5% of patients. [8] Following laser treatment, scars may develop and reduce the likelihood of vision improvement [3] hence alternate treatments for DME such as intravitreal triamcinolone (ivT), have been investigated. Intravitreal triamcinolone (ivT) works via a number of mechanisms including reducing vascular permeability and down regulating VEGF (vascular endothelial growth factor). Anti-VEGF therapies have been the focus of recent research, and those modalities have been shown to potently suppress angiogenesis and to decrease vascular permeability in ocular disease such as DME, leading to improvement in visual acuity. [9] The results of treating DME with anti-VEGFs are controversial and are in need of larger prospective RCTs. [10]

Currently used anti-VEGFs include bevacizumab, ranibizumab and pegatanib. Ranibizumab has been shown to be superior in treating DME, both in safety and efficacy, compared to laser therapy, in several studies that include RESTORE, RESOLVE, RISE and RIDE studies. [11-13] It has been recently approved by the Food and Drug Administration (FDA) for treating DME in the United States of America. [14] Bevacizumab (Avastin®) is a full length monoclonal antibody against VEGF, binding to all subtypes of VEGF. [10] In addition to treating metastatic colon cancer, bevacizumab is also used extensively off-label for many ocular conditions that include age related macular degeneration (AMD), DME, retinopathy of prematurity and macular oedema secondary to retinal vein occlusion. [15] Documented adverse effects of ivB include transiently elevated intraocular pressure (IOP) and endopthalmitis. [16] Systemic effects associated with ivB injection include rise in blood pressure, thrombo-embolic events, myocardial infarction (MI), transient ischemic attack and stroke. [16,17] Other significant adverse events of bevacizumab when given systemically include delayed wound healing, impaired female fertility, gastrointestinal perforations, haemorrhage, proteinuria, congestive heart failure and hypersensitivity reactions. [17] Although not currently approved, a 1.25-2.5mg infusion of ivB is used for treating DME without significant ocular/systemic toxicity. [15]

The DRCR.net study (2007) has shown that ivB can reduce DME. [18] In addition, several studies, which have been carried out on diabetic retinopathy patients with CSME evaluating the efficacy of ivB ± ivT versus laser, demonstrated better visual outcomes with BCVA. [6,19- 21] Meta-analysis of those studies indicated ivB to be an effective short-term treatment for DME, with efficacy waning after six weeks. [6] This review evaluates the evidence behind the effect of ivB, compared to laser, in treating persisting DME despite standard treatment.

Clinical question

Our clinical question for this focused evidence based medicine article has been constructed to address the four elements of the problem, the intervention, the comparison and the outcomes as recommended by Strauss et al. (2005) [22]. “In diabetic patients with persistent clinically significant macular oedema (CSME) is intravitreal Bevacizumab (Avastin®) injection better than focal/grid laser photocoagulation in preserving the best-corrected visual acuity (BCVA)?”

Methodology

Comprehensive electronic searches in the British Medical Journal, Medical Journal of Australia, Cochrane Central Register of Controlled Trials, MEDLINE and PUBMED were performed for relevant literature, using the search terms diabetic retinopathy, CSME, CMT, bevacizumab and laser photocoagulation. Additional information from the online search engine, Google, was also incorporated. Reference lists of studies were then hand-searched for relevant studies/trials.

Selection

Results were restricted to systematic reviews, meta-analysis and randomised clinical trials (RCTs). Overall six RCTs were identified, which evaluated the efficacy of ivB compared to lasers in treating DME. [18- 21,23,24] There was also one meta-analysis comparing ivB to non-drug control treatment (lasers or sham) in DME. [7] One study was published showing pilot study results of the main trial, so the final version was selected for consideration to avoid duplication of results. [20,23] One study was excluded because it excluded focal DME patients. [19] The DRCR study (2007) was excluded because it was not designed to evaluate if treatment with ivB was beneficial in DME patients. [18] A meta-analysis by Goyal et al. was also excluded because it evaluated bevacizumab with sham treatment and not laser therapy. [7]

Thus, three relevant RCTs were narrowed down for analysis (Table 1) in this evidence based medicine review. [20,21,24] However, only the BOLT study (2012) evaluated the above treatment modalities in persistent CSME. The other two RCTs evaluated the treatment efficacies in patients with no prior laser therapies for CSME/diabetic retinopathy. Hence, only the BOLT study (2012) has been critically appraised in this report. The study characteristics of the other relevant RCTs evaluating ivB versus lasers are represented in Table 1, and where possible will be included in the discussion.

Outcomes

The primary outcomes of interest are changes in BCVA and CMT, when treated with ivB or lasers for DME, whilst the secondary outcomes are any associated adverse events. All three studies were prospective RCTs with NHMRC level-II evidence. Table 1 summarises the overall characteristics of the studies.

Critical appraisal

The BOLT Study (2010) is a twelve month report of a two year long single centre, two arm, randomised, controlled, masked clinical trial from the United Kingdom (UK). As such, it qualifies for NHMRC [25] level-II quality of evidence. It is the only RCT that compared the efficacy of ivB with laser in patients with persistent CSME (both diffuse and focal DME) who had undergone at least one laser therapy for CSME previously. Comparison of study characteristics of the three RCTs chosen are presented in Table 2.

Major strengths of the BOLT Study compared to Soheilian et al. and Faghihi et al. studies include the duration of study and increased frequency of review of patients in ivB groups. The BOLT Study was a two year study, whereas the other two studies’ duration was limited to less than a year (Table 1). Because of its lengthy duration, it was possible to evaluate the safety outcome profile of ivB in the BOLT Study, unlike in the other two studies.

Research has indicated that the effects of ivB could last between two to six weeks, [6] and the effects of lasers could last until three to six months. [3] In BOLT, the ivB group was assessed every six weeks, and re-treatment provided with ivB as required, while the laser group were followed up every four months ensuring the preservation of efficacy profile and its reflection in the results. Whereas, in Sohelian et al., [20] follow up visits were scheduled every twelve weeks after the first visit, and in Faghihi et al., [21] follow up was at six and sixteen weeks. Therefore, there may have been a bias against the efficacy profile of ivB, given the insufficiency in the nature of follow up/treatment. Apart from the follow up and therapy modalities, the groups were treated equally in BOLT, preserving the analysis against treatment bias.

Weaknesses of the BOLT Study [24] include limited number of patients: 80 eyes in total, with 42 patients allocated to ivB and 38 patients to laser therapy. Of them, in the ivB group, six patients discontinued intervention; only 37 patients were included in the analysis at 24 months and five were excluded as the data was not available. Similarly, of the 38 patients allocated to the laser group, 13 patients discontinued the intervention; 28 patients were analysed overall where ten were excluded from analysis. However, the BOLT Study performed intention to treat analysis minimizing dropout effects. Given these, we feel the BOLT Study fulfills the criteria for a valid RCT with significant strengths.

Magnitude and precision of treatment effect from BOLT Study

Best corrected visual acuity outcomes

Significant difference existed between mean ETDRS BCVA at 24 months in the ivB group (64.4±13.3) compared to the laser group (54.8±12.6) with p=0.005 (Any p-value <0.05 indicates statistical significance between the groups under comparison). Furthermore, the study reports of the ivB group gaining a median of 9 ETDRS letters whereas the laser group gaining a median of 2.5 letters (p=0.005). Since there was a significant difference between the duration of CSME between the two groups, the authors of the study performed analysis after adjusting for this variable. They also adjusted for the baseline BCVA and for patients who had cataract surgery during the study. The mean BCVA still remained significantly higher in the ivB group compared to laser.

Marked difference has also been shown in the proportion of people who gained or lost vision between the two treatment groups. Approximately, 49% of patients in the ivB group gained more than or equal to ten ETDRS letters compared to seven percent of patients in laser group (p-value = 0.01). Similarly, none of the patients in the ivB group, compared to 86% in the laser group (p=0.002), lost fewer than 15 ETDRS letters. In addition, the study also implied that BCVA and CMT can be maintained long term with reduced injection frequency of six to twelve months. However, the authors also suggest that increasing the frequency of injections to every four weeks (rather than the six week frequency opted in the study) may provide better visual acuity gains as reported in RISE and RIDE studies. [13]

Central macular thickness outcomes

The mean change in the CMT over the 24 month period was -146±171μm in ivB group compared to -118±112μm in the laser group (p=0.62), showing statistically no significant difference in ivB/laser effectively reducing the CMT. This differed from the twelve month report of the same study that indicated improvement in CMT in the ivB group compared to the laser group.

Retinopathy

Results of the BOLT Study indicated a trend of reducing retinopathy severity level in the ivB group, while the laser group showed stabilised grading. However, the Mann-Whitney test indicated no significant difference between the groups (p=0.13). [24]

We summarised the results of the author’s analysis of the step-wise changes in retinopathy grading levels, for further analysis, into three categories: deteriorating, stable and improving (Table 3). As shown in the table, we calculated the p-values using the chi-square test between both groups for each category.

We attempted to further quantify the magnitude of ivB treatment compared to lasers on the retinopathy severity level by calculating the number needed to treat (NNT) using the data in Table 3. The results showed an absolute risk reduction of nine percent with an NNT of 10.9 (95% CI indicating harm in 21.6 harm to benefit in 3.6 patients treated). Since the confidence interval indicates an uncertainty between benefit and harm, this trial does not give sufficient information to inform clinical decision making regarding change in retinopathy severity levels with ivB treatment.

Safety outcome measures

As mentioned, one of the strengths of the BOLT Study is evaluating the safety profile of ivB given its two year duration. The study analysed the safety outcomes of macular perfusion and retinal nerve fibre layer (RNFL) thickness in detail. The results indicated no significant difference in the mean greatest linear diameter of foveal avascular zone between the laser and the ivB group, from baseline or in the worsening of severity grades. Similarly, no significant changes in median RNFL thickness have been reported between ivB and laser groups.

At 24 months, the number of observed adverse events, ocular and systemic, in the study was low. We have analysed the odds ratio (Table 4) as per the published results in the study. Statistically significant higher chances of having eye pain and irritation (eighteen times greater risk) during or after intervention, sustaining sub-conjunctiva haemorrhage and of having a red eye (eighteen times greater risk) was found in the ivB group compared to lasers. As can be further inferred from the table, no significant differences in sustaining other non-ocular adverse events, ocular serious adverse events or non-ocular serious adverse events including stroke/MI/other thrombo-embolic events were found between both the groups.

Clinical applicability of results

The BOLT Study participants were from Moorfields Eye Hospital (UK) and had comparable demographics and healthcare standards to Australia. In the study, both patient (BCVA, retinopathy severity level changes, adverse events) and disease-oriented outcomes (CMT) were considered, making the study both theoretically and practically relevant, informing both clinicians and researchers of the outcomes. Given this, clinical applicability of the results to the Australian population appears reasonable. All other personnel involved in the study (outcome assessors) and imaging technology are available as well, making the treatment feasible in our setting.

In Australia, the overall diabetic retinopathy prevalence is 24.5%, [6] the statistics associated with it rise every year due to the progressing obesity/diabetes epidemic. Bevacizumab is currently approved under the pharmaceutical benefits scheme for metastatic colon cancer.

It is being successfully used ‘off-label’ for the treatment of ocular conditions including age related macular degeneration and diabetic macular oedema. It costs about 1/40th the cost of ranibizumab, another anti-VEGF drug that has current approval for AMD treatment in Australia and FDA approval for DME treatment in America. [26] Since recent studies indicate no superior effect of ranibizumab versus bevacizumab in safety and efficacy profile in preserving visual acuity, [27,28] and since recent NICE guidelines also recommend not using ranibizumab for diabetic macular oedema due to high costs involved with the administration of that drug, [29] bevacizumab must be further considered and evaluated for cost effectiveness in routine usage in clinical practice.

Given the benefits with ivB, that is, improved BCVA, no significant adverse events and no risk of permanent laser scarring of the retina, and the aforementioned discussion, using ivB in treatment for persisting DME appears to be evidence based, and relatively safe practice.

Conclusion

The BOLT Study assessed the safety and efficacy of ivB in persistent DME despite previous laser therapy. The power of the study was 0.8 enabling it to detect BCVA differences between two groups. In line with many other previous studies evaluating ivB’s efficacy, the results indicate significant improvement in the mean ETDRS BCVA, and no significant differences in severe systemic/ocular adverse events compared to the laser group. This study supports the use of ivB in patients with CSME, with adequate precision. However the magnitude of the effect on changes in the severity of diabetic retinopathy, in CMT changes and other adverse events, needs to be evaluated further through large prospective RCTs.

Conflict of interest

None declared.

Correspondence

pavani.kurra@gmail.com

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Doctors’ health and wellbeing: Where do we stand?

Doctors continue to record significant rates of burn out, stress-related illness, substance abuse and suicide, despite greater awareness of these issues in the profession. [1,2] Whilst improved support services have been a positive move, there are underlying systemic issues that must be addressed within the profession.

Physician distress results from a complex interplay of several factors that include a challenging work environment, specific physician characteristics and other contextual factors such as stigma (Figure 1). [3] Specific physician characteristics that may make us prone to stress-related illness include the motivated and driven personality types that many of us possess; these are useful in meeting heavy workloads, but can be detrimental in times of distress. When combined with a great sense of professional obligation to patients, an “admirable but unhealthy tradition of self-sacrifice” can ensue. [4]

Stigma is also a contributing factor, with many doctors concerned about how they will be perceived by others. Common stigmatised attitudes include the fear of being considered weak, concern about registration status and career impact, and the need to appear healthy to patients. [1] These individuals are less likely to seek help for their illness or to take time off, which can be compounded by the pressure of ‘letting the team down’ when they do. Attitudes such as this develop early on as a medical student, and are often reinforced later in professional practice by colleagues and supervisors. [5,6]

These factors contribute to a culture within medicine of the frequent neglect of preventive health issues. [7] Commonly, there is a reliance on informal care from colleagues (‘corridor consultations’), and many doctors may self-diagnose and self-treat. [8] While this might suffice for minor illnesses, during times of serious distress or mental illness, this approach may lead to late or suboptimal treatment and a poor prognosis or to relapse. [6]

In the past, little effort has been made to promote prevention, wellbeing and appropriate self-care, particularly in the early stages of the profession such as during medical school. Current undergraduate medical curricula focus almost exclusively on the acquisition of clinical knowledge, with a clear deficit in the development of self-care skills and an understanding of the personal challenges of the profession. [5] This is increasingly evident in new graduates, with 38% of Australian junior doctors recently reporting that they were unprepared for life as a doctor and 17% who would not choose medicine as a career again, if given the choice. [8]

With a suicide rate up to two and a half times greater than the general population, a culture of self-care and wellbeing in the profession needs to be nurtured to ensure a more resilient medical workforce. [1,5]

So where do we stand?

The doctors’ wellbeing movement has had strong leadership through individual doctors and small groups such as Doctors’ Health Services. [7] In South Australia, ‘Doctors’ Health SA’ has developed into a fully independent, profession-controlled organisation that acts as a focal point for doctors’ health and provides clinical services in the central business district for doctors and medical students. The program offers comprehensive after-hours check-ups and easier access to a state-wide network of general practitioners and health professionals associated with the program. Similar programs are in development in other states. [8]

Medical student groups have also played important roles in health promotion and advocacy for student welfare needs. The Australian Medical Students’ Association has focussed heavily on medical student health and wellbeing in recent years, developing policy and resources to support student wellbeing. [9] Student-run wellbeing events are also now common place at most medical schools around Australia. It is essential that medical educators also play a role in promoting student wellbeing; Monash University has been a leader in this area, with the incorporation of a ‘Health Enhancement Program’ into its core medical curriculum, which aims to teach students about the relevance of mental and physical health in medicine. Further examples of initiatives aimed at students are listed in Table 1. [5]

Table 1. Summary of interventions to improve medical student wellbeing and health seeking behavior.

Intervention / Setting Aims Intervention Evaluation Results
Health Enhancement Program

(Monash University School of Medicine)

Australia

Evidence level: III-1* [15]

Foster behaviours, skills, attitudes and knowledge of self-care strategies for managing stress and maintaining healthy lifestyle, and understanding of the mind-body relationship. Eight lectures on mental and physical health, mind-body medicine, behaviour change strategies, mindfulness therapies, and the ESSENCE lifestyle program, supported by six two-hour tutorials. Depression, anxiety and hostility scales of the Symptom Checklist-90-R incorporating the Global Severity Index (GSI) and WHO Quality of Life (WHOQOL) questionnaire to measure effects on wellbeing. Improved student well-being was noted for depression and hostility subscales but not the anxiety subscale.

 

Mental Health in Medicine Seminar

(Flinders University Medical Students Society)

Australia

Evidence level: III-3*

Foster behaviours, skills, attitudes and knowledge of self-care strategies or managing stress and maintaining healthy lifestyle, and understanding of the mind-body relationship. Half-day didactic seminar discussing epidemiology, stigmatising attitudes, causes, risk factors, signs and symptoms of depression, stress management, and support avenues as a student and physician. Pre/post intervention survey to assess changes in mental health literacy (knowledge/attitudes towards depression and helpseeking behaviour). Based on International Depression Literacy Survey. Results pending at time of publication.
Student Well-Being Program (SWBP)

(West Virginia Uni. School of Medicine)

United States

Evidence level: III-3* [16]

Prevention and treatment of medical student impairment Voluntary lunch hour lectures (six lectures over six month period) for first and second year students addressing various aspects of wellbeing. Post-intervention questionairre distributed to 94 students assessing erceptions of depression, academic difficulties, substance abuse, health-seeking behaviour. Participants who had one or more symptoms of impairment were more likely to feel a need for counselling and to seek help
Physician Life-style Management Elective

(Wright State Uni. School of Medicine)

United States

Evidence level: III-3* [17]

Enhance the quality of medical student life-planning as a future physician and prevent physician disability. Voluntary two week elective (lectures) for first year students focusing on physician health, practice management, relationships, and physician disability. Ratings of each didactic session were collected from seventeen first year medical students. Students rated sessions on the residency experience highest followed by assertiveness training, then by emotional health management.
Wellness Elective

(Case Western Reserve University School of Medicine)

United States

Evidence level: III-3* [19]

Provide students with information on wellness, stress reduction, and coping strategies.

 

Series of six, weekly lectures from medical and allied health professionals on wellness, coping strategies and stress reduction. Evaluated via essay review and a questionnaire administered after the elective concluded. Participants reported that the elective helped them realise the importance of personal wellbeing, self-care, and provided a variety of coping strategies.
Self-care intervention

(Indiana University School of Medicine)

United States

Evidence level: III-3* [18]

Promote positive health habits and emotional adjustment during students’ first semester via selfawareness and self-care interventions. Lecture, written information, and group discussions on emotional adjustments, sleep hygiene, substance use and recognition/ management of depression and anxiety. Survey assessing patterns of sleep, alcohol consumption, depression, exercise, caffeine use, satisfaction with teaching, social life, physical health, emotional health, finances, time management. Promising effects on patterns of alcohol consumption, exercise and socialisation.

Influenced some sleep and exercise behaviours, but not overall emotional or academic adjustment.

*National Health and Medical Research Council levels of evidence. I: Systematic review of randomised controlled trials. II: One properly designed randomised controlled trial. III-1: One well designed pseudo-randomised controlled trial. III-2: Non-randomised trials, case–control and cohort studies. III-3: Studies with historical controls, single-arm studies, or interrupted time series. IV: Case-series evidence

Sadly, the doctors’ health agenda is still lacking within our hospitals, particularly for junior medical staff. Hospitals remain challenging places to work for interns and residents, with variable levels of support from the institutions. Administrative or support staff such as medical education officers may be asked to consider doctors’ health issues, but usually as an add-on to their daily roles, rather than as a core component of it. This has led to a sporadic approach towards junior doctor health, with the level of support dependent on individual clinical training staff. The Queen Elizabeth Hospital (SA) has a unique support program for interns, which incorporates five wellbeing sessions throughout the year as part of the weekly education schedule; however, this remains the exception rather than the rule.

For doctors’ health to move forward, it needs to become a mainstream workforce issue within medical education, training and practice. Leadership across each of these areas is important so that we can begin to implement systemic initiatives to facilitate resilience in doctors. One key area of focus should be greater mentoring and peer support, particularly within hospitals. [10,11] Whilst junior medical staff currently work fewer hours than in the past, this has also resulted in less ‘living in’, and reduced opportunities for peer support. Doctors’ common spaces, once typical places for medical staff to debrief with colleagues, are also the first areas to be expended within hospitals looking for more administrative space.

Health promotion also needs to occur across the learning and professional continuum of medical practice. It is essential that medical students and junior doctors are targeted, as this seems to be the time when an acceptance of self-treatment and stigmatised attitudes become entrenched.[6] With a greater awareness of these issues amongst the next generation of doctors, we can gradually shift the culture within the profession. Whilst this is difficult and many of us are set in our ways, it is incumbent upon all of us to have a vision of a medical profession that is strong, vibrant and resilient.

Tips for those who are struggling
Don’t be afraid to tell someone; struggling in medicine is more common than you think.
Don’t rely on alcohol or other drugs to cope. This can have a brief mood-lifting effect but can later cause feelings of depression or anxiety.
Try to eat a healthy diet and stay active.
Keep connected with other people, including a support network outside of medicine.
Seek help early from a friend, teacher, doctor, or counsellor. All states and territories now have specific health services for doctors and medical students.

Conflict of interest

None declared.

Correspondence

M Nguyen: minh.nguyen@flinders.edu.au

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Eye protection in the operating theatre: Why prescription glasses don’t cut it

Introduction
Needle-stick injury represents a serious occupational hazard for medical professionals, and much time is spent on educating students and practitioners on its prevention. Acquiring a blood-borne viral infection such as Human Immunodeficiency Virus (HIV), Hepatitis B or C from a patient is a rare yet devastating event. While most often associated with ‘sharps’ injuries, viral transmission is possible across any mucocutaneous membrane – including the eye. Infection via the transconjunctival route is a particularly relevant occupational hazard for operating room personnel, where bodily fluids are commonly encountered. Published cases of HIV seroconversion after ocular blood splash reinforce the importance of eye protection. [1]

Surgical operations carry an inherent risk of blood splash injury – masks with visors are provided in operating theatres for this reason. However, many surgeons and operating personnel rely solely upon prescription glasses for eye protection, despite spectacles being shown to offer an ineffective safeguard against blood splash injury. [2]

Incidence of blood splash injury
The incidence of blood splash is understandably more prevalent in some surgical specialties, such as orthopaedics, where power tools and other instruments increase the likelihood of blood spray. [3] Within these specialties, the risk is acknowledged and the use of more comprehensive eye protection is usually routine.

Laparoscopic and endoscopic procedures may particularly be viewed as low-risk, despite the rates of positive blood splash evident on post-operative examination of eye protection in one prospective study approaching 50%. [4] These results imply that even minimally invasive procedures need to be treated with a high level of vigilance.

The prevalence of blood splash during general surgical operations is highlighted by a study that followed one surgeon over a 12 month period and recorded all bodily fluids evident on protective eyewear following each procedure. [5] Overall, 45% of surgeries performed resulted in blood splash and an even higher incidence (79%) was found in vascular procedures. In addition, half of the laparoscopic cases were associated with blood recorded on the protective eyewear postoperatively.

A similar prospective trial undertaken in Australia found that protective eye shields tested positive for blood in 44% of operations, yet the surgeon was only aware of the incident in 18% of these cases. [6] Much blood spray during surgery does not occur at a visually perceivable level, with this study demonstrating that the incidence of blood splash during a procedure may be considerably higher than is realised.

Despite the predominance of blood splash occurring within the operating theatre, the risks of these injuries are not limited to surgeons and theatre staff – even minor surgery carries a considerable risk of blood splash. A review of 500 simple skin lesion excisions in a procedural dermatology unit revealed positive blood splash on facemask or visor in 66% of cases, which highlights the need for protective eyewear in all surgical settings. [7]

Risk of blood splash injury
Although a rare occurrence, even a basic procedure such as venepuncture can result in ocular blood splash injury. Several cases of confirmed HCV transmission via the conjunctival route have been reported. [8-10]

Although the rates of blood-borne infectious disease are reasonably low within Australia, and likewise the rates of conversion from a blood splash injury are low at around 2%, [9] the consequences of contracting HIV, HBV or HCV from a seropositive patient are potentially serious and require strict adherence to post exposure prophylaxis protocols. [11] Exposure to bodily fluids, particularly blood, is an unavoidable occupational risk for most health care professionals, but personal risk can be minimised by using appropriate universal precautions.

For those operating theatre personnel who wear prescription glasses, there exists a common belief that no additional eye protection is necessary. The 2007 Waikato Eye Protection Study [2] surveyed 71 practicing surgeons, of which 45.1% required prescription glasses while operating. Of the respondents, 84.5% had experienced prior periorbital blood splash during their operating careers, and 2.8% had gone on to contract an illness from such an event. While nearly 80% of the participants routinely used eye protection, amongst those who wore prescription glasses, 68% used them as sole eye protection.

A 2009 in vitro study examining the effectiveness of various forms of eye protection in orthopaedic surgery [12] employed a simulation model, with a mannequin head placed in a typical position in the operating field, with femoral osteotomy performed on a cadaveric thigh. The resulting blood splash on six different types of protective eyewear was measured, and found that prescription glasses offered no benefit over control (no protection). While none of the eye protection methods tested offered complete protection, significantly lower rates of conjunctival contamination were recorded for recommended eyewear, including facemask and eyeshield, hard plastic glasses and disposable plastic glasses.

Prevention and management of blood splash injury
Given that blood splash is an occupational hazard, the onus is on the hospital and clinical administration to ensure that there are adequate supplies of protective eye equipment available. Disposable surgical masks with full-face visors have been shown to offer the highest level of protection from blood splash injury [12] and ought to be readily accessible for all staff involved in procedures or settings where contact with bodily fluids is possible. The use of masks and visors should be standard practice for all theatre staff, including assistants, scrub nurses and observers, regardless of the use of prescription spectacles.

Should an incident occur, a procedure similar to that used for needle-stick injury may be followed to minimise the risk of infection. The eye should first be rinsed thoroughly to remove as much of the fluid as possible and serology should be ordered promptly to obtain a baseline for future comparisons. An HIV screen and acute hepatitis panel (HAV IgM, HB core IgM, HBsAg, HCV and HB surface antibody for immunised individuals) are indicated. Post-exposure prophylaxis (PEP) should be initiated as soon as practicable unless the patient is known to be HIV, HBV and HCV negative. [13]

Conclusion
Universal precautions are recommended in all instances where there is the potential for exposure to patient bodily fluids, with an emphasis on appropriate eye protection. Prescription glasses are unsuitable for use as the sole source of eye protection from blood splash injury. In light of the fact that a blood splash injury can occur without knowledge of the event, regular blood tests for health care workers involved in regular procedural activity may allow for early detection and intervention of workplace acquired infection.

Conflict of interest
None declared.

Correspondence
S Campbell: shaun.p.campbell@gmail.com

References
[1] Eberle J, Habermann J, Gurtler LG. HIV-1 infection transmitted by serum droplets into the eye: a case report. AIDS. 2000;14(2):206–7.
[2] Chong SJ, Smith C, Bialostocki A, McEwan CN. Do modern spectacles endanger surgeons? The Waikato Eye Protection Study. Ann Surg. 2007;245(3):495-501
[3] Alani A, Modi C, Almedghio S, Mackie I. The risks of splash injury when using power tools during orthopaedic surgery: a prospective study. Acta Orthop Belg. 2008;74(5):678-82.
[4] Wines MP, Lamb A, Argyropoulos AN, Caviezel A, Gannicliffe C, Tolley D. Blood splash injury: an underestimated risk in endourology. J Endourol. 2008;22(6):1183-7.
[5] Davies CG, Khan MN, Ghauri AS, Ranaboldo CJ. Blood and body fluid splashes during surgery – the need for eye protection and masks. Ann R Coll Surg Engl. 2007;89(8):770-2.
[6] Marasco S, Woods S. The risk of eye splash injuries in surgery. Aust N Z J Surg. 1998;68(11):785-7.
[7] Holzmann RD, Liang M, Nadiminti H, McCarthy J, Gharia M, Jones J et al. Blood exposure risk during procedural dermatology. J Am Acad Dermatol. 2008;58(5):817-25.
[8] Sartori M, La Terra G, Aglietta M, Manzin A, Navino C, Verzetti G. Transmission of hepatitis C via blood splash into conjunctiva. Scand J Infect Dis 1993;25:270-1.
[9] Hosoglu S, Celen MK, Akalin S, Geyik MF, Soyoral Y, Kara IH. Transmission of hepatitis C by blood splash into conjunctiva in a nurse. American Journal of Infection Control 2003;31(8):502-504.
[10] Rosen HR. Acquisition of hepatitis C by a conjunctival splash. Am J Infect Control 1997;25:242-7.
[11] NSW Health Policy Directive, AIDS/Infectious Diseases Branch. HIV, Hepatitis B and Hepatitis C – Management of Health Care Workers Potentially Exposed. 2010;Circular No 2003/39. File No 98/1833.
[12] Mansour AA, Even JL, Phillips S, Halpern JL. Eye protection in orthopaedic surgery. An in vitro study of various forms of eye protection and their effectiveness. J Bone Joint Surg Am. 2009 May;91(5):1050-4.
[13] Klein SM, Foltin J, Gomella LG. Emergency Medicine on Call. New York: McGraw-Hill; 2003. p. 288.

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Markets and medicine: Financing the Australian healthcare system

Introduction

In early 2010 the Commission on the Education of Health Professionals for the 21st Century (the Commission) convened to outline a strategy for advancing healthcare towards a system that provides “universal coverage of the high quality comprehensive services that are essential to advance opportunity for health equity within and between countries.” [1] The strategy focuses on the education of health professionals to empower their capacity as agents of social transformation. [1] This paper endeavours to encourage medical students to think critically and ethically about the consequences of different modes of health finance on the equity of the Australian healthcare system. In doing so, it contributes to this project of health professionalism in the 21st century.

Health finance may seem of little relevance to aspiring or practicing health professionals. However, it is an important determinant of how and to whom medical services are delivered and a critical aspect of Australia’s response to the increasing resource demands of the healthcare system. Rising costs are attributable to a variety of trends including innovative but expensive technology, an ageing population, and increasing prevalence of lifestyle associated disease. Policy makers continue to debate the most effective funding methods to achieve effective use of resources, quality services and equity within the healthcare system…

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Why medical school is depressing and what we should be doing about it

Introduction

In recent years, there has been quite some attention given to supporting the health and well-being of doctors but less to that of medical students, particularly their mental health and well-being. [1-3] Up to 90% of medical students will need medical care whilst in medical school, and while many of these health needs may be routine, medical students are more susceptible than age-matched peers for serious mental illnesses such as depression, anxiety, substance misuse and burnout. [4,5] Preliminary data from a study last year showed that Australian medical students reported higher rates of depression, while another study estimated that one quarter of students suffered from symptoms of mental illness. [6] There is also some evidence that difficulties during medical school may manifest later in one’s medical career. [7] With up to a third of hospital physicians at one point experiencing psychiatric morbidity, identifying and supporting these individuals is essential as these doctors are more likely to deliver sub-optimal patient care, misuse substances and leave the profession early. [8] This article will discuss how medical school can and does have a profound effect on our mental well-being, putting us at risk of depression, burnout and other mental illnesses…