Myeloma is one of the great success stories of modern haemato-oncology. The survival of patients has greatly improved over the last 20 years, firstly following the introduction of autologous stem cell transplantation (ASCT), and thereafter following the development of two new drug classes, proteasome inhibitors (bortezomib, carfilzomib, ixazomib) and immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide).
For younger transplant-eligible patients, the median survival is currently approximately eight years. In parallel, refinements in diagnostic criteria and prognostic markers have facilitated the application of more risk-stratified approaches. For many patients, myeloma is therefore a chronic disease, albeit a malignancy, and the model of patient care is increasingly one of chronic disease management.
Despite these advances, myeloma remains an incurable malignancy of plasma cells, which accounts for approximately 10 per cent of all haematological malignancies in international registries.
According to the Multiple Myeloma Cancer Factsheet of the National Cancer Registry Ireland (NCRI) (May 2017), the annual incidence of myeloma in Ireland is 7.1 per 100,000 in men and 4.1 per 100,000 in women and a total of 271 new cases are diagnosed here every year. In general, the median age at diagnosis is around 70 years and, in a large Mayo Clinic series, 15 per cent of patients were below the age of 50 years. The NCRI found that the survival rate at five years had improved from 27.5 per cent (1994-1998) to 49.6 per cent (2009-2013) and that the estimated 10-year survival is 30.2 per cent.
A 57-year-old schoolteacher had increasing mid-back discomfort over three months. One weekend, she developed a fever and a cough productive of green sputum, and her partner found her to be confused. She was brought to the GP, who referred her to the local emergency department. On presentation, she was disoriented, febrile to 38.5 degrees and had bilateral crepitations on auscultation. A chest x-ray revealed pneumonia. She was anaemic (Hb 10g/dl), had an elevated creatinine (140umol/l) and was hypercalcaemic (3.1mmol/l). Her total protein was 99g/L (66-87) and albumin 32g/l (35-to-50). She was rehydrated, commenced on intravenous antibiotics and treated for hypercalcaemia.
Serum protein electrophoresis (SPEP) detected an IgG kappa paraprotein of 45g/L and kappa light chains were present in her urine. She was referred to the haematology service with probable myeloma. There was an infiltrate of plasma cells on her bone marrow aspirate and an urgent CT scan of her spine revealed multiple thoracic vertebral compression fractures. Fluorescent in situ hybridisation (FISH) cytogenetic analysis detected the translocation, t(4;14).
She was started on treatment with the combination of oral cyclophosphamide, subcutaneous bortezomib and oral dexamethasone. Following discharge six days later, she went on to attend the day ward on a weekly basis over the next four months. Her paraprotein was 9g/L following completion of this induction therapy. As she had no significant medical history, she had been referred for stem cell collection. These were harvested by leukapheresis and she proceeded to an autologous stem cell transplant. The transplant admission lasted three weeks and was complicated by infection, mucositis and hair loss. At her assessment three months’ post-transplant, the paraprotein has fallen further to 2g/L, consistent with a further deepening of her remission. She was then commenced on maintenance treatment with oral lenalidomide and further follow-up consisted of once-monthly visits for clinical review, laboratory tests, her high-tech prescription for lenalidomide and an intravenous bisphosphonate for bone protection.
Symptomatic myeloma requiring treatment evolves from the pre-malignant condition, monoclonal gammopathy of undetermined significance (MGUS), although this asymptomatic precursor state has often gone undetected prior to the diagnosis of myeloma. MGUS is present in 3 per cent of the population over the age of 50 years and is increasingly common with age. The risk of progression to myeloma has been reported to be approximately 1 per cent per year over the following 25 years.
Although often an incidental finding on screening, the detection of a serum paraprotein understandably leads to concern. It is important to be aware that the risk of progression to myeloma varies widely and can be assessed based on the isotype (IgG, IgA, etc) of the paraprotein, its size and whether the serum-free light chain ratio is normal or not.
If SPEP detects an IgG paraprotein of less than 15g/L and if the serum free light chain kappa:lambda ratio is normal, these criteria identify a group of patients with low-risk disease, constituting almost 40 per cent of all MGUS patients, who only have a 5 per cent risk of progression to myeloma at 20 years. As a result, the MGUS guidelines of the British Committee for Standards in Haematology recommend that such patients be discharged from haematology clinics back to GPs for routine monitoring (https://www.b-s-h.org.uk/guidelines/).
Smouldering multiple myeloma (SMM) is an intermediate state between MGUS and myeloma. It is diagnosed when the plasma cells infiltrate within the bone marrow increases to greater than 10 per cent and/or the paraprotein increases to more than 30g/L in the continuing absence, however, of end-organ damage. The risk of progression to symptomatic myeloma is 10 per cent per year.
Diagnosis of myeloma
The diagnosis of symptomatic myeloma requires the presence of an infiltrate of malignant plasma cells (>10 per cent) in the bone marrow (see Figure 1), a monoclonal paraprotein in the serum and/or urine, and either the presence of end-organ damage as evidenced by the so-called CRAB criteria of hypercalcaemia (C), renal insufficiency (R), anaemia (A), and bone (B) lesions, or the presence of one of three biomarkers highly predictive of early progression to such end-organ damage: (1) greater than 60 per cent plasma cells within the bone marrow; (2) a highly skewed ratio of the involved to the uninvolved serum free light chain (>100:1), and; (3) more than one focal lesion greater than 5mm in diameter on MRI.
The commonest symptoms at presentation are fatigue and bone pain. Mid-to-low back pain has often been present for several months before cross-sectional imaging reveals damage, commonly vertebral fractures and co-existing asymptomatic lytic lesions. Occasionally, patients present with pathological fractures (Figure 2).
Be alert to an unexplained gap between the total protein (60-to-80g/L) and the serum albumin (35-to-50g/L) on the ‘liver profile’, as this may indicate the presence of a paraprotein and should prompt consideration of a request for a SPEP.
The following laboratory investigations should be performed in a patient suspected of having myeloma: FBC; renal profile; calcium level; and serum and urine protein electrophoresis. The serum free light chain assay is an expensive confirmatory assay and is usually ordered in the haematology clinic.
Except in rare cases of non-secretory MM, the identification and quantification of a monoclonal protein (M-protein) in the serum or urine is essential to the diagnosis and monitoring of myeloma. SPEP provides a measurement of the three principal immunoglobulins, IgG, IgA and IgM. If a monoclonal band or paraprotein is detected on the gel, immunofixation with antibodies to heavy chains (G, A, M) and light chains (kappa, lambda) is automatically performed to identify the paraprotein, eg, IgG kappa or IgA lambda.
The serum free light chain assay is a test using an antibody specific for free circulating immunoglobulin light chains. This test is reported as the ratio of kappa to lambda light chains. This test has improved our ability to diagnose and monitor light chain myeloma and has removed the need for sequential 24-hour assessments of urinary light chain excretion, a difficult test to perform in an older, frailer population and one that is often incomplete.
A urine collection should still be performed at diagnosis to assess for nephrotic syndrome. The spot protein to creatinine ratio (PCR) may be used as a surrogate for a 24-hour urinary protein in patients with newly-diagnosed myeloma. It is important to be aware that the standard urinalysis reagent strips do not detect light chains. If there is a discrepancy between such a urine dipstick test for protein and a separate test for urinary protein excretion, this raises the possibility of light chain proteinuria.
Until recently, a skeletal survey comprised of plain x-rays of the skull, trunk and limbs was the principal imaging modality used to assess for myeloma-related bone disease. However, this is a relatively insensitive technique and guidelines from the International Myeloma Working Group (IMWG) in 2017 recommended either whole-body, low-dose CT, whole-body MRI or, occasionally, PET/CT as the imaging techniques of choice.
The encouraging improvements in survival rates mask the fact that myeloma, though always a clonal malignancy of plasma cells, is a disease characterised by marked clinical and biological variability. Host factors such as age or frailty, the disease burden and tumour biology all combine to determine overall survival in any given patient. The Revised International Staging System (R-ISS) incorporates serum albumin, beta-2 microglobulin, LDH and FISH cytogenetic results as markers in a robust prognostic tool for newly-diagnosed patients.
FISH is a genetic test consisting of the use of labelled probes on plasma cells from a bone marrow aspirate to assess for the presence of specific known chromosomal abnormalities, principally hyperdiploidy, a good prognostic marker, and translocations involving the immunoglobulin-heavy chain enhancer at 14q, generally conferring a worse prognosis, eg, t(4;14), t(14;16) or t(14;20). FISH results are used to stratify patients in clinical trials and can also usefully inform treatment decisions in routine clinical practice.
There are several phases to treatment: Induction chemotherapy following diagnosis; ASCT for younger, fitter ‘transplant-eligible’ patients; maintenance treatment until disease progression; and treatment at relapse.
Bortezomib is a first-in-class proteasome inhibitor, which has been available for use in Ireland since 2004. The main complications are transient gastrointestinal upset and peripheral neuropathy. This latter complication has been found to be less common when it is administered subcutaneously rather than intravenously and on a once-weekly rather than a twice-weekly schedule.
Immunomodulatory drugs are derived from the parent compound, thalidomide, which tragically led to an epidemic of foreshortened limbs (phocomelia) when it was used as treatment for ‘morning sickness’ in the first trimester of pregnancy in the 1950s in Europe. In 1999, thalidomide was found to be effective in the treatment of relapsed myeloma and prompted the development of the more potent, less-toxic compounds, lenalidomide and pomalidomide. As they are teratogenic, strict prescribing guidelines are in place to avoid inadvertent foetal exposure.
Modern induction chemotherapy usually consists of a ‘triplet regimen’ incorporating a proteasome inhibitor, usually bortezomib, or an immunomodulatory drug, usually thalidomide or lenalidomide, in combination with corticosteroids and cyclophosphamide. The woman in the case report described in this article received cyclophosphamide, bortezomib and dexamethasone (CyBorD). Alternatives would include lenalidomide, bortezomib and dexamethasone (RVD) or bortezomib, thalidomide and dexamethasone (VTD). Most patients will respond to any of these regimens. A notable change over the last decade has been the use of lower doses of dexamethasone, usually now given in weekly pulses rather than in longer four-day blocks.
As the median age at diagnosis of myeloma is around 70 years, many newly-diagnosed patients are frail and have multiple coexisting illnesses. Dose-reduced triplet regimens or orally-administered doublets, such as lenalidomide and dexamethasone, are likely to be better tolerated in this population. In the absence of transplantation, longer courses of less intensive treatment are often an effective, less toxic approach.
ASCT remains the standard-of-care for the treatment of younger, fitter patients. In a large MRC UK randomised controlled trial, those in the transplant arm survived, on average, one year longer. The upper age limit is based upon biological rather than chronological age although, for practical purposes, it is approximately 70 years. The transplant admission lasts for three weeks and the main complications are myelosuppression and mucositis.
At St James’s Hospital, Dublin, 557 patients underwent ASCT for myeloma between 1999 and 2016, 503 ‘up-front’ shortly after diagnosis and 54 as a second transplant, usually several years later (see Figure 3). The population consisted of 306 (60.8 per cent) men and 197 (39.2 per cent) women. The median ages at transplant were: 53 (35-to-67) years (I), 57 (31-to-69) years (II) and 59 (29-to-70) years (III), respectively.
During this period, novel drug classes have included proteasome inhibitors (bortezomib, carfilzomib (Named Patient Programme (NPP)) (2016-2017)), immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide) and, more recently, monoclonal antibodies (daratumumab (NPP) (2016-2017)). These developments have led to consistently improving five-year overall survival rates in younger transplant-eligible patients in these three consecutive six-year cohorts, as follows: 62 per cent (I), 67 per cent (II) and 80 per cent (III), respectively (see Figure 4).
Maintenance treatment consists of the continued use of a therapy until disease progression. Two large, randomised, controlled trials evaluated the efficacy of maintenance low-dose lenalidomide in the post-transplant setting. A recent meta-analysis reported improved overall survival at seven years of follow-up in those patients who received maintenance.
There have been two main advances in the treatment of myeloma in the last three years. The first has been the development of several antibodies targeting proteins on the plasma cell surface. Daratumumab is a humanised IgG1κ monoclonal antibody against CD38, which has shown promising single-agent activity in relapsed and refractory myeloma. It is available for use in Ireland from April 2018. Other novel antibodies include isatuximab, also targeting CD38, and elotuzumab, targeting the protein SLAMF7.
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new approach to the treatment of haematological malignancies, including myeloma.
This technique involves the collection of peripheral blood lymphocytes from patients by apheresis. These are then genetically engineered in vitro to target cell surface proteins expressed by a given cancer cell and re-infused back into the patient following immunosuppressive treatment.
The most promising results so far in myeloma have been based on CAR-T cells targeting the B-cell maturation antigen (BCMA), a protein whose expression is largely restricted to plasma cells. High response rates have been reported in heavily pre-treated patients who had become refractory to all other treatment options. These are, however, early days and although highly promising, challenges include toxicity, cost and patient selection. Clinicians are working with the pharmaceutical industry to bring CAR-T cell clinical trials to Ireland over the coming year.
In summary, the last 20 years have seen a complete transformation of the field of myeloma therapies, which has resulted in deeper remissions and greatly improved survival rates (see Figure 5). Although currently incurable, the range of available therapies and the prospect of CAR-T cell approaches raise the possibility that we may achieve cures in some patients in the coming years.
Sickle cell disease (SCD) is an autosomal recessive haemoglobinopathy that we now encounter with increasing frequency in clinical practice in Ireland. The clinical hallmark is a triad of painful vaso-occlusion, micro-infarct end organ damage and a haemolytic anaemia. The disease is characterised by a point mutation in the beta globin gene leading to the substitution of valine for glutamic acid in the beta haemoglobin chain. This seemingly simple amino acid substitution causes a life-threatening and complex multi-organ disease with multiple pathophysiological pathways. Mortality has been high in SCD especially in the early childhood years.
Modern treatment approaches including new-born screening, pneumococcal prophylaxis, transcranial Doppler ultrasound and the introduction of early disease-modifying treatment has seen mortality decrease, the mean age at death increase, and fewer children dying from infection. Aggressive management strategies in childhood yield a sickle-related survival rate of 94 per cent at 18 years and 99 per cent at 16 years. This improvement in childhood mortality has not yet been seen in the adult population who have a median life expectancy in the US of 42 years for males and 48 years for females.
Most patients with SCD will experience vaso-occlusive events at some point in their life and these episodes account for over 90 per cent of all emergency hospital admissions. They can lead to acute organ failure or chronic organ damage affecting all systems. Diagnosis is now typically achieved in the neonatal period due to the introduction of a screening process where haemoglobin electrophoresis is performed on cord blood at delivery. This allows for the early detection of the condition, initiation of parental education and commencement of supportive therapy including antibiotic prophylaxis, pneumococcal vaccination and folic acid supplementation. The morbidity of SCD is highly variable, but can be devastating. Early introduction of disease-modifying treatment is essential to prevent or ameliorate the consequences of this disease.
Pain is a commonly seen presentation in children with SCD. The first episode of pain typically affects the small bones of the hands and is referred to as dactylitis. This affects approximately 50 per cent of children with SCD by two years of age. As these children get older the long bones become affected and by adolescence pain is typically associated with the ribs and vertebrae. This pain can be severe and debilitating.
Many other acute complications of SCD have life-threatening consequences. Acute chest syndrome is the most common cause of hospitalisation for patients with SCD, with a peak incidence in early childhood, and is responsible for approximately 25 per cent of sickle-related deaths. The neurological system can also be affected with the occurrence of stroke. Prior to the findings of the STOP study, 10 per cent of children with SCD had a stroke before the end of the second decade of life. Now children are screened with transcranial Doppler ultrasound, which has reduced the stroke risk rate to approximately 1 per cent. Acute splenic sequestration is a life-threatening complication that occurs in up to 30 per cent of patients with SCD up to six years of age. It is characterised by rapid enlarging of the spleen followed by circulatory collapse. All organs of the body are at risk of severely debilitating and life-threatening chronic complications. Some of the more commonly encountered complications include avascular necrosis (AVN), pulmonary hypertension and retinopathy. Avascular necrosis occurs with an incidence of 2.5 per 100 patient years and has even been described in children as young as five years old. It often requires treatment with joint replacement.
The primary defect in the pathogenesis of SCD is that the resulting haemoglobin is less soluble when exposed to deoxygenated conditions and forms polymers within the red blood cell (RBC). These polymers aggregate causing the RBC to enlarge and deform. This provides it with the characteristic sickle shape. Upon re-oxygenation the RBC cell typically resumes its normal biconcave form, however after numerous episodes of sickling, the cells become irreversibly sickled. These sickle shape cells also are more easily dehydrated when deoxygenated and as a result acquire abnormal intracellular signalling pathways, which activate RBC adhesion molecules on the RBC membrane. These adhesion molecules are involved in the adhesion of RBCs, endothelial cells, neutrophils, monocytes and platelets, inducing the activation of multiple pro-inflammatory pathways. The resulting abnormal RBC has a shorter life span and has increased adhesive interactions. The clinical implication is that the RBC haemolyses and there is a slowing of blood flow in the microcirculation leading to painful vaso-occlusion and micro infarct end organ damage.
The management of SCD is multidisciplinary and is comprised of strategies to treat acute sickle cell crisis and long-term disease modifying approaches to prevent complications. This long-term approach is divided into supportive measures, disease modifying treatment and curative options.
Hydroxyurea was approved by the US Food and Drug Administration (FDA) in 1998 and the European Medicines Agency in 2007 for the management of patients with SCD although its use in children is still considered to be off-label by the FDA. It has proven successful in the prevention of complications in SCD and reduces mortality. In spite of our two decades of experience of hydroxyurea we still do not have a full understanding of its mechanism of action. Primarily it affects cell division by inhibiting the enzyme ribonucleotide reductase and thus depletes the cell of deoxyribonucleotide triphosphates (dNTPs). This leads to arrest of cell division or cell death.
Hydroxyurea also works by increasing foetal haemoglobin (HbF) production at the expense of normal adult haemoglobin (HbA). It does this by interfering with beta globin gene expression at the beta globin locus. HbF is the predominant haemoglobin in foetal life and early infancy and binds to oxygen with higher affinity than normal adult haemoglobin. This allows adequate oxygen transfer to the foetus during gas exchange in the intervillous space between mother and baby where there is mixing of both oxygenated and deoxygenated maternal blood. By six months of age it becomes almost entirely replaced by adult haemoglobin. Hydroxyurea reverses this natural post-natal switch from HbF to HbA and this results in reduced polymerisation, sickling, adhesion and haemolysis. The microcirculation blood flow improves and vaso-occlusive events are reduced. Hydroxyurea’s ability to increase nitric oxide further improves blood flow in the microcirculation. Nitric oxide is a potent vasodilator that becomes depleted in haemolysis. Free haemoglobin released by haemolysed RBCs scavenges nitric oxide and depletes it. By reducing haemolysis and inhibiting the scavenging effect of free haemoglobin, the vasodilatory effect of nitric oxide is preserved.
Hydroxyurea is not helpful in the acute management of a crisis as it takes weeks to months to become effective. There is no specific marker in clinical use to determine if the treatment will be of any benefit to the patient and in clinical practice it is offered to any patient who may achieve benefit. Many reproducible studies demonstrate that hydroxyurea reduces mortality with long-term use and reduces long-term complications in both adults and children. The 2011 Baby HUG trial showed that infants treated with hydroxyurea had improved splenic function, reduced pain episodes, reduced chest syndromes, reduced dactylitis and reduced need for transfusion. The treatment is largely very well tolerated and the predominant side effect is cytopaenias. As a result, these patients require regular full blood counts.
Blood transfusion therapy in SCD is of benefit in both the acute management of vaso-occlusive events and in the chronic management to prevent micro-infarct end organ damage. Most patients with SCD will undergo numerous transfusions in their lifetime putting them at risk for transfusion-associated complications. A simple top-up red RBC transfusion dilutes the volume of sickle cells containing haemoglobin S and replaces them with normal RBCs containing haemoglobin A. The resulting normal RBCs have a longer lifespan than their sickled counterparts. There is feedback to the kidneys to reduce erythropoietin production and the production of new sickle cells is slowed. The transfused blood increases the oxygen saturation of the circulation, increasing oxygen delivery to the tissues. This principle of increasing oxygenation is used in the pre-operative setting where a top-up RBC transfusion to a haemoglobin value of 10g/dL is associated with a reduced incidence of post-operative vaso-occlusive events.
In the long-term management of SCD, reducing the haemoglobin S percentage to below 30 per cent leads to a reduction in vaso-occlusive pain and acute chest syndromes. Many patients with SCD are commenced on chronic transfusion programmes scheduled at patient specific intervals guided by the patient’s clinical findings, haemoglobin level and haemoglobin S percentage. Regular transfusions are required for secondary prevention of stroke, acute chest syndrome, painful events and priapism. The SIT trial randomly assigned children with SCD and silent cerebral infarcts to monthly transfusions versus observation for three years and found that there were significant improvements in the quality-of-life of patients receiving regular transfusions. There were also reduced rates of pain, acute chest syndrome and symptomatic avascular necrosis.
In July 2017 the US FDA-approved L-glutamine oral powder for patients five years and older to reduce the complications of SCD. This was the first drug licensed for the management of SCD since hydroxyurea in 1998. Many studies have demonstrated that RBCs that are sickled have increased susceptibility to oxidative stress. Oxidative stress is measured by changes in nicotinamide adenine dinucleotide (NAD) homeostasis and is defined as the NAD redox potential. NAD redox potential is 20-30 per cent lower in sickle RBCs, but NAD is found in higher levels in sickle cells than in controls. This suggests that in the event of oxidative stress there is increased uptake of NAD by the sickle RBC. Sickle RBCs absorb glutamine, a precursor of NAD at increased rates compared to non-sickle cells. A hypothesis was formed that with increased glutamine supplementation, increased transport and utilisation of glutamine in sickled RBCs will lead to increased NAD and NADH levels thus providing increased defence against oxidative stress. The benefits of administering both L-glutamine and hydroxyurea together appear to be greater than either agent alone.
It is known that activation of the inflammatory system plays an important role in the pathogenesis of SCD. Cytokines are released and they quickly activate white blood cells. These activated white and red blood cells then bind to the endothelial cells via several selectins and integrins expressed by endothelial cells. Adhesion of inflammatory and red blood cells to the endothelium is primarily initiated by P selectin. Both animal and human studies have identified that deficiency of P selectin in those with SCD leads to defective adhesion of white blood cells to endothelial walls. This ultimately protects from vaso-occlusion. There are numerous potential treatments targeting P selectin in various stages of investigation.
One of promise is crizanlizumab. It is a humanised monoclonal antibody that binds selectively to P selectin. A phase 2 multicentre randomised controlled trial known as SUSTAIN was reported in the New England Journal of Medicine (NEJM) in 2016. In this trial high-dose treatment was associated with reduced frequency of sickle cell pain events compared to placebo. The annual sickle cell-related pain event rate was reduced by 32.1 per cent in patients already treated with hydroxyurea and by 50 per cent in those who were not already receiving hydroxyurea. The treatment was well-tolerated and there is much promise for this therapy as it undergoes further investigation
Haematopoietic stem cell transplant
Haematopoietic stem cell transplant (HSCT) is recognised as a potentially curative treatment for SCD. The current gold standard is myeloablative HLA matched sibling donors due to the reduced risk of both graft versus host disease and graft rejection. There have also been approaches using less myeloablative conditioning regimens. There are trials ongoing exploring the use of unrelated donors and despite the successes of this technique in the treatment of malignant blood disorders, results in SCD patients have largely had unsatisfactory results. The major difficulty in employing HSCT as a curative treatment for patients with SCD remains patient selection. This is attributed to disease heterogeneity, challenges in identifying patients at high risk of developing advanced disease, patient eligibility due to advanced multi-organ disease and concerns relating to transplant-related mortality. In clinical practice the experience of HSCT and SCD has yielded a five-year survival rate of 90-97 per cent, a transplant-related mortality rate of 7-10 per cent and an SCD-free survival rate of 80-90 per cent. The role of early transplantation in children to reduce SCD mortality has not been fully explored, but remains an area of ongoing investigation. HLA-haploidentical transplant is an appealing treatment due to the expansion of the donor. A ‘half matched’ related donor, usually the mother or father is used. An optimal conditioning regimen has not yet been identified, but it remains an area of advancing research.
Less than 18 per cent of eligible patients have a HLA-matched sibling donor for transplant. As a result, gene therapy is an increasingly exciting area of research in SCD and it may provide a long-term, potentially curative, treatment. Successful, sustained gene therapy has been reported previously in mouse models by lentiviral transfer of an anti-sickling beta-globin variant. In 2017 the NEJM published the outcome of a 13-year-old boy who was enrolled in a clinical trial to receive gene therapy using a LentiGlobin BB305 vector. This lentiviral vector is currently being used in seven patients with SCD and 22 patients with beta thalassaemia. It has a stable safety profile and has no evidence of insertional oncogenesis at 30 months. In this boy the transduced cells engrafted and normal cell counts followed across all lineages by day 88 post-transplant. The investigators did not report any vector-related side effects and the child remains well.
The complications of SCD are devastating to patients and until now progress has been slow in the achievement of cure. Thankfully, due to the recent advances in our knowledge of SCD pathogenesis we have, however, reached an exciting time. We have more potential treatment targets than ever and it is likely that considering the numerous pathological mechanisms involved, optimal therapy will require a multi-targeted treatment approach. Dynamic international collaboration and availability of funding is essential to support the ongoing research required to treat this highly complex disease.
References on request
Using the cardiology solution’s electronic vetting, the team has been able to triage echos, reducing the number by 8.9 per cent in 2016 as a result of eliminating inappropriate requests and ensuring 80 per cent of requests from the hospital’s acute ward are carried out on the same day as ordered.
The adoption by SUH of McKesson Cardiology in 2013 provided an opportunity to streamline processes and improve workflow. Replacing a manual, paper-based process, echo orders are automatically received into McKesson Cardiology
from the HSE’s national NIMIS radiology system, and then fed directly through to the echocardiogram machines. All the echo images and measurements are then stored within the cardiology database, enabling the cardiac physiologists to undertake reports on the system.
Ms Anita Flynn, Senior Cardiac Physiologist, explains: “The process not only streamlined echo referrals but also provided doctors with access to the electronic reports at the touch of a button. For doctors previously used to time-consuming creation of paper orders and storing printed reports within patient charts, the entire process became far more efficient and effective.”
Achieving BSE accreditation
With the upgrade to their cardiology solution in 2015, SUH took a step further — leveraging the improved reporting and embedded BSE range measurements to support its bid for BSE accreditation to demonstrate the quality of services being delivered. Mr Anthony Ryan, Chief 2 Cardiac Physiologist, SUH, noted that BSE departmental accreditation “is a recognised benchmark of quality.
It indicates to patients, resource allocators and health professionals that an echo department meets quality standards.”
The department has leveraged the new software to achieve improvements at every step of the pathway, from initial echo orders through to reporting. A key aspect of the new workflow is the use of electronic vetting, which has enabled SUH to triage echo requests to both ensure urgent cases are prioritised and minimize unnecessary activity.
Using secure login, cardiac doctors and advanced nurse practitioners can order echos via NIMIS, which are now actively graded by the echo team. “If we don’t feel the doctor has included enough relevant information, we send the order back with a request for more clinical information,” Ms Flynn confirms.
“They have 10 working days to provide that information, at which point we will either approve the request or deny because it is not compliant with BSE guidelines.”
As a result of this vetting process, SUH reduced its echo workload by 8.9 per cent in 2016 by weeding-out inappropriate requests. At the same time, the triage process has ensured the hospital’s acute assessment patients are prioritised, with 80 per cent of echo requests received from the acute ward undertaken on the same day as ordered.
One of the most important additions to the cardiology solution was the inclusion of the BSE range checking, making redundant the cardiac physiologists’ previous use of wall charts or phone apps to verify measurement range. The system flags any measurements outside the BSE range, which helps to highlight abnormalities.
The system also helps with reporting, with predefined sentences built in. Ms Flynn adds: “Rather than typing out entire sentences regarding a particular echo pathology, using the drop-down boxes we can very quickly and efficiently create the report, with no spelling mistakes.”
In addition, in-built teaching files help trainee echo staff to gain confidence on the system quickly.
The SUH cardiac physiologist team also has access to the reporting database from all its PCs, freeing- up more machines for echo reporting, which ensures there are no backlogs. Ms Flynn confirms: “We didn’t want any reports outstanding for more than two or three days.
Utilising the integration between our cardiology solution and Cognos, we have been able to identify any problems in turnaround times, flagging individuals who were not reporting within 24 hours for inpatient, urgent and routine reports, in line with BSE targets.”
Understanding patient demographics
Approximately 10,000 people die each year from cardiovascular disease (CVD), including coronary heart disease, stroke and other circulatory diseases. CVD is the most common cause of death in Ireland, accounting for 36 per cent of all deaths, according to the HSE. Over one-fifth — 22 per cent — of premature deaths (under age 65) are from CVD. SUH, however, operates in the North-West, an area with a higherthan- average elderly population.
Within the cardiology solution, SUH is able to record a depth of patient information, including not only age, but also body surface area, height and weight, providing more accurate quantitative measurements about BMI, patient mobility and age demographics.
The team is able to demonstrate the number of geriatric and paediatric cardiac echos undertaken on both a monthly and yearly basis — revealing that over 42 per cent of patients were aged 65 years or over and 24 per cent aged over 80 in 2016. “Providing this information to management is key to ensuring we have the right resources of both staff and equipment, such as echo couches for elderly or obese patients,” says Mr Ryan.
Palpitations are a very common presenting complaint to front-line medical services (primary care and emergency departments (EDs)).
They are often a problematic symptom for several reasons:
Palpitations often cause great anxiety and distress for the patient, which can put a lot of pressure on the consulted medic.
Most palpitations are benign, but a small minority can represent a life-threatening condition. Efforts to identify the latter can sometimes overshadow investigations and referrals.
The patient is commonly asymptomatic when they present to their GP, so evaluation for pathology must be undertaken in the absence of signs.
Investigations are often normal and can give false reassurance.
In this article, I will offer five tips on how to approach these patients — how to get the most out of the history, the electrocardiography (ECG) and other investigations and, perhaps most importantly, how to risk stratify your patients.
Tip 1: What to ask in the history
Inevitably, the patient with palpitations will be asymptomatic when they consult their GP/front-line medic. Therefore, the history is crucial in formulating a differential diagnosis.
First, find out what the patient means by ‘palpitations’ (if they use that word) — make sure they don’t actually mean chest pain.
Get a clear but detailed description of the patient’s palpitations.
Ventricular ectopic beats are often described as ‘missed beats’, ‘skipped beats’ or ‘jumps’.
Supraventricular tachycardias usually have a sudden onset, with an elevated heart rate and an abrupt offset. Atrioventricular nodal re-entrant tachycardia (AVNRT), atrioventricular re-entrant tachycardia (AVRT), atrial tachycardia and atrial flutters usually have a regular pulse whereas atrial fibrillation (AF) is irregular.
Ventricular tachycardia usually starts abruptly (sometimes the patient may describe some ‘missed beats’ beforehand), gives an elevated heart rate and often is poorly tolerated by the patient.
It is essential to ascertain (by direct questioning if necessary) whether there are any other symptoms associated with the palpitations.
This is very important in order to risk-stratify the patient.
Symptoms such as chest pain, syncope and pre-syncope are red flags and should prompt the medic to look for structural heart disease and to make an urgent onward referral.
Tip 2: The value of clinical examination and basic investigations
The purpose of the clinical examination in a patient who presents with palpitations is to assess for structural heart disease. A patient with palpitations in the presence of structural heart disease is automatically high-risk and almost always requires an onward referral to a cardiologist (see Tip 5).
When examining the patient, look out for murmurs (aortic stenosis), overload or respiratory crepitations suggesting left ventricular dysfunction and, of course, arterial hypertension (a cause of ventricular ectopy).
The value of basic, cheap and available investigations in formulating a differential diagnosis is perhaps under-appreciated.
A lot can be taken from a basic blood panel, for example. Is the patient anaemic, causing a high output state and sinus tachycardia?
Does the patient have sinus tachycardia or even AF from thyrotoxicosis? What is the potassium? Is this actually renal failure?
Tip 3: Interpretation of the resting ECG
Even in the absence of ‘active palpitations’, the resting ECG can be very useful in the hunt for pathology.
Again, you are looking for features that suggest underlying structural heart disease.
On the resting ECG, look out for:
Left bundle branch block.
ST or T wave segment change suggestive of ischaemia.
Q waves of an old myocardial infarction (MI).
Left ventricular hypertrophy (LVH) by voltage with strain pattern.
Delta wave of Wolff-Parkinson-White (WPW) syndrome.
Heart block (first-, second- or third-degree).
Abnormal QT interval.
On this page, I have collated some ECGs of ‘lesser-spotted’ conditions associated with palpitations.
Figure 1 shows complete heart block.
On this ECG, we can see the following salient features of complete or third-degree heart block:
1. More P waves ($) than QRS (*).
2. Regular P waves (not associated with a QRS complex).
3. Regular QRS complexes (usually at a slower rate than the P waves).
4. Dissociation between the atria and ventricles.
In this example, the QRS complexes are wide (>120ms), indicating that the escape rhythm is coming from low in the conduction system. This is a high-risk situation.
Figure 2 shows ventricular pre-excitation, which when occurs in association with palpitations, gives the WPW syndrome.
The features of WPW evident on this ECG are:
1. Short PR interval (__).
This is caused by accelerated conduction between the atria and the ventricle as the action potential can bypass the AV node and get to the ventricle early via the accessory pathway.
2. Delta wave ($).
A delta wave is the slurred upstroke of the QRS seen across the precordium and in the limb leads here.
It is formed by the fusion of myocardial activation via the AV node (gives a normal, rapid upstroke to the QRS) and myocardial activation via the accessory, or bypass tract (giving a very broad and abnormal QRS).
Figure 3 shows the long QT syndrome.
Here, the QT interval is extremely long (measures 640ms).
Normal intervals are <430ms for men and for <450ms women.
The correct way to measure the QT interval is using the Tangent Method, where one measures from the start of the QRS to the end of the T wave, as determined by a tangent line from the end of the T wave to the isoelectric baseline.
Tip 4: Getting the most out of ambulatory monitoring
The aim of any period of ambulatory monitoring is to get a symptom-rhythm correlation, that is, to record the heart’s rhythm when the patient is having their symptoms of palpitations. This should give the rhythm diagnosis of the patient’s complaint, or indeed, demonstrate a normal sinus rhythm and rate, prompting a search for a non-cardiac cause.
In order to maximise the chance of obtaining a symptom-rhythm correlate, the duration of the monitoring period must match the symptom frequency.
Daily symptoms should be captured on a 24-hour Holter monitor, whereas if the patient reports infrequent monthly symptoms, an alternative form of monitoring should be sought.
In most cardiac departments, a variety of monitors are available. These usually include 24-hour, 48-hour, 72-hour, and seven-day monitors and patient-activated monitors, which can stay on for several weeks.
The newest generation of implantable loop recorders are extremely low-profile, with a battery life of up to three years (for example, the Reveal LINQ device by Medtronic, see Figure 4).
These devices are designed to be inserted in a procedure room within a few minutes and do not require any sutures.
They are most useful in patients with very infrequent symptoms. All have home monitoring capability and both automatic and patient-activated recording.
A very useful recent development in the field of ambulatory monitoring has been that of hand-held smartphone monitors. The AliveCor by Kardia attaches to the back of a smartphone. The two metal thumb pads (see Figure 5) record and display a single-lead ECG. Recordings and events can then be saved for review later by a physician.
Tip 5: How to risk-stratify
Perhaps the most important aspect in the approach to the patient with palpitations is risk stratification. Here, you identify the patient who is in danger or who needs urgent onward referral from the majority of patients who can be reassured.
Figure 6 shows a ‘traffic light’ approach to the risk stratification.
Red-flag symptoms signalling urgent referral include syncope or pre-syncope in association with palpitations and symptoms during exercise.
The patient with known or suspected high-risk structural heart disease (severe aortic stenosis, previous MI, congenital abnormality) who presents with palpitations should always be referred onwards in an urgent manner, as they are at risk of ventricular tachycardia.
The same goes for patients who have a family history of inherited cardiac disease (hypertrophic or dilated cardiomyopathy, Long QT syndrome, etc) or of sudden cardiac death.
A 12-lead ECG showing a broad, complex tachycardia mandates emergency transfer to hospital, as does complete (third-degree) heart block.
Second-degree heart block on ECG should also be urgently referred to the ED, as the risk of progression to complete heart block in high here.
Green — low risk.
Referral not usually required
Amber — medium risk.
Should be referred
Red — high risk.
Urgent/same-day referral to hospital
References available on request
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