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Resolving patients' complaints
For most physicians, the resolution of patients’ complaints ranks second only to firing an employee on the Least Favorite Tasks List. With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions.
But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.
I have distilled this unpleasant duty down to a simple, three-part strategy:
• Discover which expectations went unmet and why.
• Agree on a solution.
• Learn from the experience, to prevent similar future complaints.
In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.
At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.
Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.
And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.
But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is the one most people – especially physicians – do poorly: Listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.
So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.
As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.
Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.
If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.
I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.
Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.
Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.
Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.
For most physicians, the resolution of patients’ complaints ranks second only to firing an employee on the Least Favorite Tasks List. With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions.
But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.
I have distilled this unpleasant duty down to a simple, three-part strategy:
• Discover which expectations went unmet and why.
• Agree on a solution.
• Learn from the experience, to prevent similar future complaints.
In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.
At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.
Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.
And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.
But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is the one most people – especially physicians – do poorly: Listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.
So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.
As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.
Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.
If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.
I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.
Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.
Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.
Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.
For most physicians, the resolution of patients’ complaints ranks second only to firing an employee on the Least Favorite Tasks List. With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions.
But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.
I have distilled this unpleasant duty down to a simple, three-part strategy:
• Discover which expectations went unmet and why.
• Agree on a solution.
• Learn from the experience, to prevent similar future complaints.
In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.
At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.
Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.
And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.
But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is the one most people – especially physicians – do poorly: Listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.
So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.
As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.
Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.
If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.
I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.
Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.
Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.
Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.
MDS: What Do Hospitalists Need to Know?
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by dysplasia, ineffective hematopoiesis resulting in peripheral blood (PB) cytopenias affecting one or more cell lines, and a variable risk of progression to acute myeloid leukemia (AML). The last 15 years have witnessed significant advances in our understanding of the complex pathogenesis, classification and prognostication, and therapeutic approaches to MDS. As more elderly patients are diagnosed with MDS, encounters with hospitalized MDS patients or patients in whom MDS should be considered in the differential diagnosis are common events for today's hospitalists. In this review, we discuss the epidemiology, diagnosis, pathogenesis, prognostication, and therapies for MDS, with an emphasis on practical aspects that would be useful for hospitalists caring for these patients.
EPIDEMIOLOGY OF MDS
Although MDS is one of the most common hematologic malignancies, MDS remains understudied epidemiologically.[1, 2] Our understanding of the epidemiology improved after the implementation of reporting requirements to cancer registries, especially the Surveillance, Epidemiology, and End Results (SEER) database in 2001.[1, 2, 3] Age‐adjusted incidence of MDS in the United States ranged between 3.3 to 4.6 per 100,000 persons per year in the period between 2001 and 2008.[1, 2, 4] The majority of MDS patients are elderly, and because MDS incidence increases with age, the number of patients diagnosed with MDS is expected to continue to rise with the aging population.[1, 2, 5] MDS is more common in men compared to women, and in Caucasians compared to African Americans.[1, 2] Different estimates put MDS prevalence in the United States somewhere between 60,000 and 170,000 persons.[2, 6]
DIAGNOSIS OF MDS
Many patients with MDS are asymptomatic at diagnosis and only come to medical attention due to abnormal blood counts done routinely or for other reasons. This contributes to MDS being underdiagnosed. When cytopenias are not severe enough to cause symptoms, it is also frequently overlooked in patients with mild anemia or other cytopenias.[7] Together, being asymptomatic and having relatively mild cytopenias are probably the most important factors that lead to under‐recognition of MDS among primary care physicians (PCPs).[7, 8, 9] There is a misconception that anemia is normal in the elderly, and when patients are not symptomatic that a workup is not needed.[6, 7] This is compounded by a lack of awareness of the importance of making a diagnosis in these patients and of currently available therapies for MDS.[7, 8, 9]
Anemia is not a normal consequence of aging and is always a pathologic state with an underlying etiology.[6, 7] Because a significant number of elderly patients with unexplained anemia could have MDS, patients with symptomatic or progressive anemia, especially if associated with other cytopenias, should be considered for further evaluation.[7, 9] Diagnosis is important given the recent availability of effective therapies for MDS that can improve anemia, decrease transfusion needs, improve life quality, and potentially increase survival. MDS is generally an indolent disease with a relative stability of blood counts in comparison to AML, so prior blood counts and the tempo of the process is an important consideration.[9, 10] The National Comprehensive Cancer Network clinical practice guidelines recommend exclusion of nutritional deficiencies (iron, vitamin B12, folate) and other causes of anemia (eg, gastrointestinal bleeding, renal insufficiency, and anemia of inflammation), assessment of reticulocyte count and serum erythropoietin level, and evaluation of a PB smear for evidence of dysplasia as important initial steps.[10, 11] Eventually the diagnosis of MDS requires a bone marrow (BM) evaluation to confirm the diagnosis and exclude other BM failure states by evaluating for BM cellularity, cell maturation, dysplasia (which should be present in at least 10% of any the myeloid lineages), percentage of blasts (<20%), iron stores and sideroblasts, cytogenetics, MDS‐specific fluorescence in situ hybridization (FISH) panels, flow cytometry, and other special testing.[9, 10] Despite extensive testing, MDS can sometimes be very difficult to differentiate from other bone marrow failure states (eg, hypoplastic MDS from aplastic anemia) (Table 1).[10, 11] In the absence of significant morbidity related to MDS, the definitive diagnosis of MDS can be usually made on an outpatient basis. It is important to ensure adequate follow‐up with PCPs postdischarge and/or outpatient hematologist referral for patients with unexplained cytopenias.
|
Idiopathic cytopenia of undetermined significance: no significant dysplasia or MDS‐associated karyotypic aberrations |
Acute myeloid leukemia: BM blasts 20%, presence of core‐binding characteristic cytogenetic aberrations: t(8;21), t(15;17), inv(16) defines AML regardless of BM blast count; AML can be associated with hepatosplenomegaly or myeloid sarcomas |
Chronic myeloid leukemia: presence of Philadelphia chromosome t(9;22) positive, basophilia, and splenomegaly |
Myelofibrosis: significant BM fibrosis, splenomegaly, and leukoerythroblastic picture in PB (teardrop and nucleated RBCs, left‐shifted myeloid cells) |
Chronic myelomonocytic leukemia: significant PB monocytosis |
MDS/MPN overlap syndromes: dysplasia with myeloproliferative characteristics such as splenomegaly, thrombocytosis, or leukocytosis |
Infections: for example, HIV and parvovirus B19 infections |
Myelophthisis: infiltration of BM with other tumors (eg, melanoma) with resultant PB cytopenias |
Nutritional disturbances: B12, folate, and copper deficiency, and zinc and arsenic excess can mimic MDS |
Medications: drugs that interfere with DNA synthesis such as HIV medications, chemotherapeutic agents, cotrimoxazole, methotrexate, azathioprine, and G‐CSF |
Immune disorders: for example, LGL leukemia, lupus, or rheumatoid arthritis |
Other acquired or congenital hematological disorders: for example, paroxysmal nocturnal hemoglobinuria, congenital dyserythropoietic anemia, dyskeratosis congenita |
PATHOGENESIS AND ETIOLOGY OF MDS
Ineffective hematopoiesis due to excessive apoptosis of hematopoietic precursors is a prominent feature of MDS, which explains the apparent paradox of hypercellular BM and PB cytopenias. Although not fully understood, complex epigenetic, genetic, and immunologic mechanisms contribute to the pathogenesis of MDS and account for disease heterogeneity. Aberrant silencing of tumor‐suppressor and DNA repair genes mediated by hypermethylation of their promoters is believed to play an important part in the pathogenesis of MDS.[12] This theory is supported by the unique sensitivity of MDS to drugs that reverse DNA methylation. Genetic abnormalities not only contribute to the pathogenesis of MDS, but are also among the strongest prognostic indicators for MDS patients, and can also affect therapeutic decisions. Clonal karyotypic abnormalities are observed in 50% of patients with MDS using conventional karyotyping.[12, 13] The most common chromosomal aberrations in MDS include deletions of the long arm of chromosome 5 (del5q), monosomy Y, monosomy 7 (del7) or deletion of its long arm (del7q), trisomy 8, del20q, and complex karyotypes (3 chromosomal aberrations).[12, 13] These cytogenetic abnormalities correlate with the prognosis of MDS (eg, poor prognosis with complex karyotypes and chromosome 7 deletions vs better prognosis with isolated del5q).[12, 13]
Recently, FISH assays and genome‐wide screening techniques (eg, single nucleotide polymorphism arrays, array‐based comparative genomic hybridization, whole genome or exome sequencing) have enabled detection of an increasing number of genetic aberrations and recurrent somatic molecular abnormalities in a significant number of MDS patients (eg, abnormalities of ASXL1, IDH1/IDH2, DNMT3, EZH2, TET2, and SF3B1 genes).[12, 14] Most affected genes are involved in the epigenetic regulation of transcription (DNA methylation and demethylation, histone posttranslational modification) or mRNA splicing.[12, 13, 14]
Immunologic aberrations have also been proposed to contribute to pathogenesis of MDS. For example, in early‐stage MDS, an aberrant immune attack on myeloid progenitors resulting in increased apoptosis can contribute to BM failure.[15] This is supported by association of some forms of MDS with autoimmune diseases and observed responses in some patients to immunosuppressive therapies. The relative contribution of pathogenetic mechanisms varies between the different MDS subtypes. For example, haploinsufficiency of cell‐cycle regulatory and ribosomal protein genes located in the commonly deleted region of 5q play an important role in the pathogenesis of MDS with isolated del5q (5q syndrome).[16] Mutations in the RNA spliceosomal machinery gene SF3B have been shown to play a role in the pathogenesis of the MDS subtype refractory anemia with ringed sideroblasts (RARS), with those patients with RARS carrying this mutation having a more favorable prognosis than those with the wild‐type gene.[14] Several excellent recent reviews provide detailed discussion of the complex pathophysiology of MDS.[12, 13, 14, 17]
Approximately 10% of MDS patients have secondary MDS (MDS occurring after chemotherapy or radiation therapy administration for treatment of another malignancy).[2] Aside from advancing age, the causative factors for the other 90% of cases (primary MDS) are unknown in most patients, although environmental and occupational exposures (eg, smoking, painting, insecticides, pesticides, organic solvents), and genetic syndromes (eg, DNA repair defects such as Fanconi's anemia) are implicated in some patients.[2, 10] Recently, an epidemiologic study found an increased MDS risk with obesity.[18]
PROGNOSTICATION OF MDS
MDS is a form of cancer, and most affected patients eventually die from cytopenic complications or leukemic progression. MDS is not a single disease but rather encompasses a group of heterogeneous subtypes with significantly different natural histories and pace of progression. Therefore, accurate risk stratification of MDS is necessary not only to predict survival and risk of leukemic progression, but also to help choose the most appropriate therapeutic option for individual patients. Information about prognosis should also be utilized when making management decisions with patients for other comorbid conditions (eg, major surgery). Two morphologically based classification systems are commonly used for MDS: the French‐American‐British (FAB) system and the World Health Organization (WHO) classification (Table 2), which most recently has supplanted the FAB system as the primary pathologic classification system.[19, 20, 21] Several prognostic models have been developed around the morphologic classifications to better account for relevant clinical and cytogenetic modifiers of this disease. Although some of these models have been validated by different groups, each of these models has limitations. Although the predictions generated by these models are generally accurate for the different prognostic categories to which the patient is assigned, the extent to which the prediction applies to an individual MDS patient can vary significantly. In addition, comorbid conditions affect survival of MDS patients and are not included in the specific scoring systems. For example, congestive heart failure and chronic obstructive lung disease were associated with shortened survival in MDS patients.[18]
MDS WHO Class | PB Findings | BM Findings |
---|---|---|
| ||
Refractory cytopenias with unilineage dysplasia: includes refractory anemia; refractory neutropenia; refractory thrombocytopenia | Unicytopenia or bicytopenia; PB blasts <1% | BM blasts <5%; unilineage dysplasia (10% of cells in any myeloid lineage); <15% of erythroid precursors are ringed sideroblasts |
Refractory anemia with ring sideroblasts | Anemia; PB blasts <1% | BM blasts <5%; erythroid dysplasia only; 15% of erythroid precursors are ringed sideroblasts |
Refractory cytopenia with multilineage dysplasia | Cytopenia(s); PB blasts <1%; no Auer rods; <1 106/L monocytes | BM blasts <5% ; dysplasia (10% of cells in at least 2 myeloid lineages); no Auer rods |
Refractory anemia with excess blasts‐1 | Cytopenia(s); PB blasts <5%; no Auer rods; <1 106/L monocytes | BM blasts 5%9%; unilineage or multilineage dysplasia; no Auer rods |
Refractory anemia with excess blasts‐2 | Cytopenia(s); PB blasts 5%19%; Auer rods; <1 106/L monocytes | BM blasts 10%19%; unilineage or multilineage dysplasia; Auer rods |
Myelodysplastic syndromeunclassified | Cytopenias; PB blasts 1% | BM blasts <5%; unequivocal dysplasia in <10% of cells at least one myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS |
MDS associated with isolated del5q | Anemia; normal to elevated platelet count; PB blasts <1% | BM blasts <5%; normal to elevated megakaryocytes with hypolobated nuclei; isolated del5q karyotypic abnormality; no Auer rods |
The International Prognostic Scoring System (IPSS) is the most widely used prognostic tool for MDS (Table 3).[22] In this model, an aggregate score is calculated based on points assigned to the percentage of blasts in BM, the number of PB cell lines affected by cytopenias, and the karyotype. Based on this point score, the patient is assigned to 1 of 4 categories that portend significantly different outcomes: low, intermediate‐1 (INT‐1), intermediate‐2 (INT‐2), and high risk. The IPSS was developed from a database of mostly untreated MDS patients and does not account for other important prognostic parameters such as transfusion dependence, depth of cytopenias, and extent/severity of lineage dysplasia.[22] The WHO Prognostic Scoring System was proposed to overcome some of these shortcomings.[23, 24] Efforts to continue to improve the prognostic models further led to a large international collaboration that compiled a much larger database and resulted in the development of a revised IPSS (IPSS‐R).[25] New discoveries of novel prognostic epigenetic, genetic, and immunologic determinants will likely result in the ongoing evolution of the current prognostic systems to further improve their discriminatory power.[26]
Calculation of Score Value Based on Prognostic Variables | |||||
---|---|---|---|---|---|
Score Value | |||||
0 | 0.5 | 1.0 | 1.5 | 2.0 | |
| |||||
Prognostic variable | |||||
Bone marrow blasts (%)a | <5 | 510 | 1120 | 2130 | |
Karyotypeb | Good | Intermediate | Poor | ||
Number of peripheral blood cell line affected by cytopeniasc | 0 or 1 | 2 or 3 | |||
Median Survival and Risk of Progression to AML According to the IPSS Risk Category in Absence of Therapy | |||||
Overall Score | Risk Category | Percentage in the IPSS Population | Median Survival (Years) | Median Time From Diagnosis at Which 25% of Patients Progress to AML (Years) | |
0 | Low | 33% | 5.7 | 9.4 | |
0.51.0 | INT‐1 | 38% | 3.5 | 3.3 | |
1.52.0 | INT‐2 | 22% | 1.1 | 1.1 | |
>2.5 | High | 7% | 0.4 | 0.2 |
MANAGEMENT OF MDS
Most patients with MDS were treated historically with supportive measures only. The approval of 3 agents for treatment of MDS including the DNA methyltransferase inhibitors (DNMTi) azacitidine and decitabine, as well as the immunomodulatory agent lenalidomide, in the last decade advanced the care of MDS patients significantly (Table 4). Nonetheless, the use of allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only known curative modality for patients with MDS and should always be considered as a possible therapeutic option.[27] Unfortunately, the majority of patients with MDS are not considered candidates for alloHSCT due to age, comorbidities, and lack of suitable donors.[27] Therefore, most patients with MDS are managed with noncurative treatment and supportive paradigms. Treatment goals generally depend on the risk stratification for the particular individual, age, functional status, comorbidities, and importantly, the patient's individual preference. For medical decision‐making purposes, MDS is traditionally divided into 2 major risk categories: low‐risk (LR) and high‐risk (HR) groups. LR‐MDS includes the IPSS risk categories of low or INT‐1, whereas HR‐MDS is usually defined by the IPSS risk categories of INT‐2 and high. Newer classification tools (eg, IPSS‐R) and better molecular markers are expected to impact such categories as well as treatment recommendations in the future.[26]
|
Azacitidine (5‐azacytidine, Vidaza) and decitabine (5‐aza,2‐deoxycytidine, Dacogen) |
Class |
Hypomethylating agents, azanucleosides |
Mechanism of action |
Epigenetic modulation by inhibition of DNA methyltransferase enzymes and other mechanisms |
Indication |
First line therapy for HR‐MDS, second line therapy for LR‐MDS after failure of other therapies such as ESAs, lenalidomide, or immunosuppressive agents |
Approved regimens for MDS |
Azacitidine: 75 mg/m2/day IV or SC for 7 days Q 4 weeks |
Decitabine: 15 mg/m2 IV infusion over 3 hours, Q 8 hours for 3 days, Q 6 weeks or 20 mg/m2 IV infusion over 1 hour daily for 5 days Q 4 weeks |
Common side effects |
Fatigue |
Development of or worsening cytopenias (neutropenia, thrombocytopenia, and anemia) and their complications (eg, infections, bleeding) |
Gastrointestinal disturbances (nausea, vomiting, or diarrhea) |
Oral ulcers and rarely mucositis |
Injection site reactions (redness, pain) |
Lenalidomide (Revlimid) |
Class |
Immunomodulatory agent |
Mechanism of action |
Modulation of immune responses, gene expression, angiogenesis, cytokines and cell‐cycle regulatory phosphatases, and possibly other mechanisms |
Indication |
First line therapy for LR‐MDS with del5q (also used commonly off label for LR‐MDS without del5q as second line of therapy after ESAs) |
Approved regimens for MDS |
10 mg orally once daily |
Common side effects |
Skin rash, dryness, and pruritus |
Fatigue |
Muscle cramps |
Development of or worsening cytopenias (neutropenia, thrombocytopenia, and anemia) and their complications (eg, infections, bleeding) |
Gastrointestinal disturbances (nausea, vomiting, or diarrhea) |
Despite recent advances, supportive care for all patients with MDS remains a very important aspect of management, either in combination with other therapies or as sole therapy for frail patients who cannot tolerate further interventions. Supportive therapy focuses on maintaining a high quality of life and includes careful blood count monitoring, use of growth factors, use of transfusions and antibiotics as needed, and use of iron chelation therapy in some patients. Some of the common situations in which hospitalists encounter patients with MDS are listed in Table 5.
|
Complications of cytopenias |
Bleeding: local management based on bleeding site, platelet transfusions, and other blood products (eg, red blood cells, fresh frozen plasma) as appropriate, antifibrinolytics |
Infections and neutropenic fevers: Antibiotics, antifungals, use of colony granulocyte‐stimulating factors or granulocyte infusions advised only in cases of uncontrolled severe infections or sepsis |
Severe or symptomatic anemia: red blood transfusions as appropriate based on patient's comorbidities, all disease‐modifying drugs (lenalidomide, azacitidine, decitabine) and ESAs are slow acting and can take weeks to months before improving anemia |
Complications of therapies |
Neutropenic fevers: as above plus holding therapy |
Most other side effects (see Table 4) are well tolerated and are managed symptomatically without requiring hospitalization. If needed hospitalization for side effects: symptomatic management and holding the drug |
Other medical or surgical condition in a patient with MDS |
Therapy as per the underlying medical condition. For therapeutic decisions (eg, decision to undergo major surgery), prognostication tools such as the IPSS and newer models can be used to inform medical decision making in consultation with an experienced hematologist |
MANAGEMENT OF LR‐MDS
In addition to supportive care or enrollment in clinical trials, therapies for LR‐MDS include erythropoiesis‐stimulating agents, lenalidomide, and immunosuppressive therapy.
Erythropoiesis‐Stimulating Agents
Anemia in MDS is a multifactorial process that includes ineffective erythropoiesis and suboptimal serum erythropoietin responses.[10, 28, 29] There are no randomized studies to suggest that erythropoiesis‐stimulating agents (ESA) therapy prolongs survival in MDS patients. Nonetheless, ESAs improve anemia significantly in some patients and are widely used.[30, 31] Approximately 20% to 30% of unselected MDS patients and about 40% of LR‐MDS patients achieve clinically meaningful erythroid responses with ESA therapy with a median response duration of 2 years.[30, 31] It is important to correct coexisting nutritional deficiencies (eg, iron or folate deficiency) to optimize responses to ESA.[10] Granulocyte colony‐stimulating factor can be synergistic with ESAs especially in patients with RARS.[10] Patients with LR‐MDS who have low endogenous serum erythropoietin levels (<200500 mU/mL) and lower red blood cell (RBC) transfusion requirements (<2 U per month) are more likely to respond to ESA therapy.[32, 33] Compared to certain solid tumors, ESA therapy in MDS has not been associated with an increased risk of thromboembolic events.[34]
Lenalidomide
5q syndrome is a subtype of MDS characterized by refractory macrocytic anemia, normal or elevated platelet counts, low BM blast percentage, small hypolobated dysplastic megakaryocytes, an isolated interstitial deletion in 5q, and an indolent natural history.[17, 35] Lenalidomide, an oral derivative of thalidomide, induces high response rates in LR‐MDS patients with 5q deletions, including hematologic improvements, RBC transfusion independence (TI) (56%67%, median duration >104 weeks), cytogenetic responses (50%76%), and complete remissions.[35, 36] These findings resulted in approval of lenalidomide (Revlimid; Celgene Corp., Summit, NJ) for patients with IPSS low or INT‐1 MDS with transfusion‐dependent anemia and 5q deletions with or without additional cytogenetic abnormalities. In addition, lenalidomide has some activity against LR‐MDS without 5q deletions (TI, 26%, median duration 41 weeks) and some patients with HR‐MDS and 5q deletions (TI, 25.5%, median duration 26 weeks.[37, 38] Therefore, lenalidomide is a reasonable consideration in some patients with LR‐MDS without 5q deletions with primary or secondary resistance to ESA therapy.[10]
Immunosuppressive Therapy
Some patients with LR‐MDS respond to immunosuppressive therapy with antithymocyte globulin with or without cyclosporine. Characteristics that correlate with higher response rates: LR‐MDS, younger age (<60 years), hypoplastic MDS, normal karyotype, human leukocyte antigen‐DR15 histocompatibility type, and presence of a paroxysmal nocturnal hemoglobinuria clone.[10, 39]
MANAGEMENT OF HR‐MDS
The goal of management for HR‐MDS is to modify the natural history of the disease and to prolong survival. In addition to a supportive care‐only approach or clinical trial referral, 3 standard therapeutic approaches are used for patients with HR‐MDS: alloHSCT, intensive chemotherapy, and DNMTi therapy. The use of intensive AML‐like chemotherapy for HR‐MDS is associated with high toxicity and very limited long‐term success. Despite recent innovations in the field of transplantation, only a minority of MDS patients undergo alloHSCT, as most patients with HR‐MDS are elderly and/or medically infirm. Even for the minority of patients who do undergo alloHSCT, relapse after alloHSCT remains a major challenge.
DNA Methyltransferase Inhibitor Therapy
5‐azacitidine (AZA), (Vidaza; Celgene Corp.) and decitabine (DAC) (Dacogen; Eisai, Inc.) are potent inhibitors of DNA methyltransferases, which are enzymes responsible for cytosine methylation.[38, 40] These so‐called differentiation agents appear to restore normal hematopoiesis for many MDS patients, and the approved regimens of DNMTi in MDS result in overall response rates in about 40% to 60% of patients. Unfortunately, complete remissions (CR) are rare (10%20%) and the duration of responses are also somewhat limited (median CR duration, 10 to 14 months).[41, 42, 43, 44] In randomized clinical trials, both AZA and DAC resulted in significant improvements in blood counts, reduction in transfusion needs, reduced infection rates, decreased risk of progression to AML, and improvements in patient‐reported quality‐of‐life measures.[41, 42, 43, 44] AZA, but not DAC, prolonged survival in HR‐MDS patients in a large randomized trial (median overall survival for the AZA group was 24.5 months compared to 15 months for a group of patients treated with 1 of 3 conventional care regimens).[41, 42, 43, 44] AZA and DAC have not been compared head to head in trials, but most experts recommend AZA for first‐line use in HR‐MDS based on its effect on survival.[10]
AZA and DAC have also been studied as treatments for patients with AML. These agents differ from traditional intensive chemotherapy, as both agents are commonly administered on an outpatient basis, and hematologic responses are generally expected after 4 to 6 cycles of treatment as compared to a single course of intensive cytarabine‐based induction chemotherapy used to treat AML.[45] Additionally, the impact on survival may not require the achievement of a CR based on the finding that MDS patients saw improved survival even in patients whose best responses were hematologic improvements.[46] However, therapy with DNMTi is not curative, and patients are maintained on treatment as long as they are responding and not experiencing major side effects. Still, all patients will eventually lose response to DNMTi.
CONCLUSIONS
MDS is a form of cancer that largely affects elderly patients and leads to a BM failure state and increased risk of leukemic transformation. MDS is underdiagnosed and is frequently overlooked in the differential diagnosis of anemia in the elderly. DNMTi, lenalidomide, and ESA therapy offer effective therapeutic options for many MDS patients, including some considered too old or frail for intensive medical interventions. The use of prognostic models help physicians and patients better understand the common course of patients with MDS and facilitate tailoring of risk‐adapted therapy. It is expected that our improved understanding of the genetic, epigenetic, and immunologic mechanisms that operate in MDS will help develop better classification tools and rationally design effective new therapies.
Acknowledgments
The authors thank Dr. Balazs Zsenits (Medical Director of the Rochester General Hospitalist Group, Rochester General Hospital, Rochester, NY) for his critical review of the article.
Disclosures: Dr. Steven Gore owned stock in Celgene until November 2011, received research support from Celgene and Novartis, and consulted for Celgene. Drs. B. Douglas Smith, Amer Zeidan, and Bishoy Faltas have no relevant disclosures.
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Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by dysplasia, ineffective hematopoiesis resulting in peripheral blood (PB) cytopenias affecting one or more cell lines, and a variable risk of progression to acute myeloid leukemia (AML). The last 15 years have witnessed significant advances in our understanding of the complex pathogenesis, classification and prognostication, and therapeutic approaches to MDS. As more elderly patients are diagnosed with MDS, encounters with hospitalized MDS patients or patients in whom MDS should be considered in the differential diagnosis are common events for today's hospitalists. In this review, we discuss the epidemiology, diagnosis, pathogenesis, prognostication, and therapies for MDS, with an emphasis on practical aspects that would be useful for hospitalists caring for these patients.
EPIDEMIOLOGY OF MDS
Although MDS is one of the most common hematologic malignancies, MDS remains understudied epidemiologically.[1, 2] Our understanding of the epidemiology improved after the implementation of reporting requirements to cancer registries, especially the Surveillance, Epidemiology, and End Results (SEER) database in 2001.[1, 2, 3] Age‐adjusted incidence of MDS in the United States ranged between 3.3 to 4.6 per 100,000 persons per year in the period between 2001 and 2008.[1, 2, 4] The majority of MDS patients are elderly, and because MDS incidence increases with age, the number of patients diagnosed with MDS is expected to continue to rise with the aging population.[1, 2, 5] MDS is more common in men compared to women, and in Caucasians compared to African Americans.[1, 2] Different estimates put MDS prevalence in the United States somewhere between 60,000 and 170,000 persons.[2, 6]
DIAGNOSIS OF MDS
Many patients with MDS are asymptomatic at diagnosis and only come to medical attention due to abnormal blood counts done routinely or for other reasons. This contributes to MDS being underdiagnosed. When cytopenias are not severe enough to cause symptoms, it is also frequently overlooked in patients with mild anemia or other cytopenias.[7] Together, being asymptomatic and having relatively mild cytopenias are probably the most important factors that lead to under‐recognition of MDS among primary care physicians (PCPs).[7, 8, 9] There is a misconception that anemia is normal in the elderly, and when patients are not symptomatic that a workup is not needed.[6, 7] This is compounded by a lack of awareness of the importance of making a diagnosis in these patients and of currently available therapies for MDS.[7, 8, 9]
Anemia is not a normal consequence of aging and is always a pathologic state with an underlying etiology.[6, 7] Because a significant number of elderly patients with unexplained anemia could have MDS, patients with symptomatic or progressive anemia, especially if associated with other cytopenias, should be considered for further evaluation.[7, 9] Diagnosis is important given the recent availability of effective therapies for MDS that can improve anemia, decrease transfusion needs, improve life quality, and potentially increase survival. MDS is generally an indolent disease with a relative stability of blood counts in comparison to AML, so prior blood counts and the tempo of the process is an important consideration.[9, 10] The National Comprehensive Cancer Network clinical practice guidelines recommend exclusion of nutritional deficiencies (iron, vitamin B12, folate) and other causes of anemia (eg, gastrointestinal bleeding, renal insufficiency, and anemia of inflammation), assessment of reticulocyte count and serum erythropoietin level, and evaluation of a PB smear for evidence of dysplasia as important initial steps.[10, 11] Eventually the diagnosis of MDS requires a bone marrow (BM) evaluation to confirm the diagnosis and exclude other BM failure states by evaluating for BM cellularity, cell maturation, dysplasia (which should be present in at least 10% of any the myeloid lineages), percentage of blasts (<20%), iron stores and sideroblasts, cytogenetics, MDS‐specific fluorescence in situ hybridization (FISH) panels, flow cytometry, and other special testing.[9, 10] Despite extensive testing, MDS can sometimes be very difficult to differentiate from other bone marrow failure states (eg, hypoplastic MDS from aplastic anemia) (Table 1).[10, 11] In the absence of significant morbidity related to MDS, the definitive diagnosis of MDS can be usually made on an outpatient basis. It is important to ensure adequate follow‐up with PCPs postdischarge and/or outpatient hematologist referral for patients with unexplained cytopenias.
|
Idiopathic cytopenia of undetermined significance: no significant dysplasia or MDS‐associated karyotypic aberrations |
Acute myeloid leukemia: BM blasts 20%, presence of core‐binding characteristic cytogenetic aberrations: t(8;21), t(15;17), inv(16) defines AML regardless of BM blast count; AML can be associated with hepatosplenomegaly or myeloid sarcomas |
Chronic myeloid leukemia: presence of Philadelphia chromosome t(9;22) positive, basophilia, and splenomegaly |
Myelofibrosis: significant BM fibrosis, splenomegaly, and leukoerythroblastic picture in PB (teardrop and nucleated RBCs, left‐shifted myeloid cells) |
Chronic myelomonocytic leukemia: significant PB monocytosis |
MDS/MPN overlap syndromes: dysplasia with myeloproliferative characteristics such as splenomegaly, thrombocytosis, or leukocytosis |
Infections: for example, HIV and parvovirus B19 infections |
Myelophthisis: infiltration of BM with other tumors (eg, melanoma) with resultant PB cytopenias |
Nutritional disturbances: B12, folate, and copper deficiency, and zinc and arsenic excess can mimic MDS |
Medications: drugs that interfere with DNA synthesis such as HIV medications, chemotherapeutic agents, cotrimoxazole, methotrexate, azathioprine, and G‐CSF |
Immune disorders: for example, LGL leukemia, lupus, or rheumatoid arthritis |
Other acquired or congenital hematological disorders: for example, paroxysmal nocturnal hemoglobinuria, congenital dyserythropoietic anemia, dyskeratosis congenita |
PATHOGENESIS AND ETIOLOGY OF MDS
Ineffective hematopoiesis due to excessive apoptosis of hematopoietic precursors is a prominent feature of MDS, which explains the apparent paradox of hypercellular BM and PB cytopenias. Although not fully understood, complex epigenetic, genetic, and immunologic mechanisms contribute to the pathogenesis of MDS and account for disease heterogeneity. Aberrant silencing of tumor‐suppressor and DNA repair genes mediated by hypermethylation of their promoters is believed to play an important part in the pathogenesis of MDS.[12] This theory is supported by the unique sensitivity of MDS to drugs that reverse DNA methylation. Genetic abnormalities not only contribute to the pathogenesis of MDS, but are also among the strongest prognostic indicators for MDS patients, and can also affect therapeutic decisions. Clonal karyotypic abnormalities are observed in 50% of patients with MDS using conventional karyotyping.[12, 13] The most common chromosomal aberrations in MDS include deletions of the long arm of chromosome 5 (del5q), monosomy Y, monosomy 7 (del7) or deletion of its long arm (del7q), trisomy 8, del20q, and complex karyotypes (3 chromosomal aberrations).[12, 13] These cytogenetic abnormalities correlate with the prognosis of MDS (eg, poor prognosis with complex karyotypes and chromosome 7 deletions vs better prognosis with isolated del5q).[12, 13]
Recently, FISH assays and genome‐wide screening techniques (eg, single nucleotide polymorphism arrays, array‐based comparative genomic hybridization, whole genome or exome sequencing) have enabled detection of an increasing number of genetic aberrations and recurrent somatic molecular abnormalities in a significant number of MDS patients (eg, abnormalities of ASXL1, IDH1/IDH2, DNMT3, EZH2, TET2, and SF3B1 genes).[12, 14] Most affected genes are involved in the epigenetic regulation of transcription (DNA methylation and demethylation, histone posttranslational modification) or mRNA splicing.[12, 13, 14]
Immunologic aberrations have also been proposed to contribute to pathogenesis of MDS. For example, in early‐stage MDS, an aberrant immune attack on myeloid progenitors resulting in increased apoptosis can contribute to BM failure.[15] This is supported by association of some forms of MDS with autoimmune diseases and observed responses in some patients to immunosuppressive therapies. The relative contribution of pathogenetic mechanisms varies between the different MDS subtypes. For example, haploinsufficiency of cell‐cycle regulatory and ribosomal protein genes located in the commonly deleted region of 5q play an important role in the pathogenesis of MDS with isolated del5q (5q syndrome).[16] Mutations in the RNA spliceosomal machinery gene SF3B have been shown to play a role in the pathogenesis of the MDS subtype refractory anemia with ringed sideroblasts (RARS), with those patients with RARS carrying this mutation having a more favorable prognosis than those with the wild‐type gene.[14] Several excellent recent reviews provide detailed discussion of the complex pathophysiology of MDS.[12, 13, 14, 17]
Approximately 10% of MDS patients have secondary MDS (MDS occurring after chemotherapy or radiation therapy administration for treatment of another malignancy).[2] Aside from advancing age, the causative factors for the other 90% of cases (primary MDS) are unknown in most patients, although environmental and occupational exposures (eg, smoking, painting, insecticides, pesticides, organic solvents), and genetic syndromes (eg, DNA repair defects such as Fanconi's anemia) are implicated in some patients.[2, 10] Recently, an epidemiologic study found an increased MDS risk with obesity.[18]
PROGNOSTICATION OF MDS
MDS is a form of cancer, and most affected patients eventually die from cytopenic complications or leukemic progression. MDS is not a single disease but rather encompasses a group of heterogeneous subtypes with significantly different natural histories and pace of progression. Therefore, accurate risk stratification of MDS is necessary not only to predict survival and risk of leukemic progression, but also to help choose the most appropriate therapeutic option for individual patients. Information about prognosis should also be utilized when making management decisions with patients for other comorbid conditions (eg, major surgery). Two morphologically based classification systems are commonly used for MDS: the French‐American‐British (FAB) system and the World Health Organization (WHO) classification (Table 2), which most recently has supplanted the FAB system as the primary pathologic classification system.[19, 20, 21] Several prognostic models have been developed around the morphologic classifications to better account for relevant clinical and cytogenetic modifiers of this disease. Although some of these models have been validated by different groups, each of these models has limitations. Although the predictions generated by these models are generally accurate for the different prognostic categories to which the patient is assigned, the extent to which the prediction applies to an individual MDS patient can vary significantly. In addition, comorbid conditions affect survival of MDS patients and are not included in the specific scoring systems. For example, congestive heart failure and chronic obstructive lung disease were associated with shortened survival in MDS patients.[18]
MDS WHO Class | PB Findings | BM Findings |
---|---|---|
| ||
Refractory cytopenias with unilineage dysplasia: includes refractory anemia; refractory neutropenia; refractory thrombocytopenia | Unicytopenia or bicytopenia; PB blasts <1% | BM blasts <5%; unilineage dysplasia (10% of cells in any myeloid lineage); <15% of erythroid precursors are ringed sideroblasts |
Refractory anemia with ring sideroblasts | Anemia; PB blasts <1% | BM blasts <5%; erythroid dysplasia only; 15% of erythroid precursors are ringed sideroblasts |
Refractory cytopenia with multilineage dysplasia | Cytopenia(s); PB blasts <1%; no Auer rods; <1 106/L monocytes | BM blasts <5% ; dysplasia (10% of cells in at least 2 myeloid lineages); no Auer rods |
Refractory anemia with excess blasts‐1 | Cytopenia(s); PB blasts <5%; no Auer rods; <1 106/L monocytes | BM blasts 5%9%; unilineage or multilineage dysplasia; no Auer rods |
Refractory anemia with excess blasts‐2 | Cytopenia(s); PB blasts 5%19%; Auer rods; <1 106/L monocytes | BM blasts 10%19%; unilineage or multilineage dysplasia; Auer rods |
Myelodysplastic syndromeunclassified | Cytopenias; PB blasts 1% | BM blasts <5%; unequivocal dysplasia in <10% of cells at least one myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS |
MDS associated with isolated del5q | Anemia; normal to elevated platelet count; PB blasts <1% | BM blasts <5%; normal to elevated megakaryocytes with hypolobated nuclei; isolated del5q karyotypic abnormality; no Auer rods |
The International Prognostic Scoring System (IPSS) is the most widely used prognostic tool for MDS (Table 3).[22] In this model, an aggregate score is calculated based on points assigned to the percentage of blasts in BM, the number of PB cell lines affected by cytopenias, and the karyotype. Based on this point score, the patient is assigned to 1 of 4 categories that portend significantly different outcomes: low, intermediate‐1 (INT‐1), intermediate‐2 (INT‐2), and high risk. The IPSS was developed from a database of mostly untreated MDS patients and does not account for other important prognostic parameters such as transfusion dependence, depth of cytopenias, and extent/severity of lineage dysplasia.[22] The WHO Prognostic Scoring System was proposed to overcome some of these shortcomings.[23, 24] Efforts to continue to improve the prognostic models further led to a large international collaboration that compiled a much larger database and resulted in the development of a revised IPSS (IPSS‐R).[25] New discoveries of novel prognostic epigenetic, genetic, and immunologic determinants will likely result in the ongoing evolution of the current prognostic systems to further improve their discriminatory power.[26]
Calculation of Score Value Based on Prognostic Variables | |||||
---|---|---|---|---|---|
Score Value | |||||
0 | 0.5 | 1.0 | 1.5 | 2.0 | |
| |||||
Prognostic variable | |||||
Bone marrow blasts (%)a | <5 | 510 | 1120 | 2130 | |
Karyotypeb | Good | Intermediate | Poor | ||
Number of peripheral blood cell line affected by cytopeniasc | 0 or 1 | 2 or 3 | |||
Median Survival and Risk of Progression to AML According to the IPSS Risk Category in Absence of Therapy | |||||
Overall Score | Risk Category | Percentage in the IPSS Population | Median Survival (Years) | Median Time From Diagnosis at Which 25% of Patients Progress to AML (Years) | |
0 | Low | 33% | 5.7 | 9.4 | |
0.51.0 | INT‐1 | 38% | 3.5 | 3.3 | |
1.52.0 | INT‐2 | 22% | 1.1 | 1.1 | |
>2.5 | High | 7% | 0.4 | 0.2 |
MANAGEMENT OF MDS
Most patients with MDS were treated historically with supportive measures only. The approval of 3 agents for treatment of MDS including the DNA methyltransferase inhibitors (DNMTi) azacitidine and decitabine, as well as the immunomodulatory agent lenalidomide, in the last decade advanced the care of MDS patients significantly (Table 4). Nonetheless, the use of allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only known curative modality for patients with MDS and should always be considered as a possible therapeutic option.[27] Unfortunately, the majority of patients with MDS are not considered candidates for alloHSCT due to age, comorbidities, and lack of suitable donors.[27] Therefore, most patients with MDS are managed with noncurative treatment and supportive paradigms. Treatment goals generally depend on the risk stratification for the particular individual, age, functional status, comorbidities, and importantly, the patient's individual preference. For medical decision‐making purposes, MDS is traditionally divided into 2 major risk categories: low‐risk (LR) and high‐risk (HR) groups. LR‐MDS includes the IPSS risk categories of low or INT‐1, whereas HR‐MDS is usually defined by the IPSS risk categories of INT‐2 and high. Newer classification tools (eg, IPSS‐R) and better molecular markers are expected to impact such categories as well as treatment recommendations in the future.[26]
|
Azacitidine (5‐azacytidine, Vidaza) and decitabine (5‐aza,2‐deoxycytidine, Dacogen) |
Class |
Hypomethylating agents, azanucleosides |
Mechanism of action |
Epigenetic modulation by inhibition of DNA methyltransferase enzymes and other mechanisms |
Indication |
First line therapy for HR‐MDS, second line therapy for LR‐MDS after failure of other therapies such as ESAs, lenalidomide, or immunosuppressive agents |
Approved regimens for MDS |
Azacitidine: 75 mg/m2/day IV or SC for 7 days Q 4 weeks |
Decitabine: 15 mg/m2 IV infusion over 3 hours, Q 8 hours for 3 days, Q 6 weeks or 20 mg/m2 IV infusion over 1 hour daily for 5 days Q 4 weeks |
Common side effects |
Fatigue |
Development of or worsening cytopenias (neutropenia, thrombocytopenia, and anemia) and their complications (eg, infections, bleeding) |
Gastrointestinal disturbances (nausea, vomiting, or diarrhea) |
Oral ulcers and rarely mucositis |
Injection site reactions (redness, pain) |
Lenalidomide (Revlimid) |
Class |
Immunomodulatory agent |
Mechanism of action |
Modulation of immune responses, gene expression, angiogenesis, cytokines and cell‐cycle regulatory phosphatases, and possibly other mechanisms |
Indication |
First line therapy for LR‐MDS with del5q (also used commonly off label for LR‐MDS without del5q as second line of therapy after ESAs) |
Approved regimens for MDS |
10 mg orally once daily |
Common side effects |
Skin rash, dryness, and pruritus |
Fatigue |
Muscle cramps |
Development of or worsening cytopenias (neutropenia, thrombocytopenia, and anemia) and their complications (eg, infections, bleeding) |
Gastrointestinal disturbances (nausea, vomiting, or diarrhea) |
Despite recent advances, supportive care for all patients with MDS remains a very important aspect of management, either in combination with other therapies or as sole therapy for frail patients who cannot tolerate further interventions. Supportive therapy focuses on maintaining a high quality of life and includes careful blood count monitoring, use of growth factors, use of transfusions and antibiotics as needed, and use of iron chelation therapy in some patients. Some of the common situations in which hospitalists encounter patients with MDS are listed in Table 5.
|
Complications of cytopenias |
Bleeding: local management based on bleeding site, platelet transfusions, and other blood products (eg, red blood cells, fresh frozen plasma) as appropriate, antifibrinolytics |
Infections and neutropenic fevers: Antibiotics, antifungals, use of colony granulocyte‐stimulating factors or granulocyte infusions advised only in cases of uncontrolled severe infections or sepsis |
Severe or symptomatic anemia: red blood transfusions as appropriate based on patient's comorbidities, all disease‐modifying drugs (lenalidomide, azacitidine, decitabine) and ESAs are slow acting and can take weeks to months before improving anemia |
Complications of therapies |
Neutropenic fevers: as above plus holding therapy |
Most other side effects (see Table 4) are well tolerated and are managed symptomatically without requiring hospitalization. If needed hospitalization for side effects: symptomatic management and holding the drug |
Other medical or surgical condition in a patient with MDS |
Therapy as per the underlying medical condition. For therapeutic decisions (eg, decision to undergo major surgery), prognostication tools such as the IPSS and newer models can be used to inform medical decision making in consultation with an experienced hematologist |
MANAGEMENT OF LR‐MDS
In addition to supportive care or enrollment in clinical trials, therapies for LR‐MDS include erythropoiesis‐stimulating agents, lenalidomide, and immunosuppressive therapy.
Erythropoiesis‐Stimulating Agents
Anemia in MDS is a multifactorial process that includes ineffective erythropoiesis and suboptimal serum erythropoietin responses.[10, 28, 29] There are no randomized studies to suggest that erythropoiesis‐stimulating agents (ESA) therapy prolongs survival in MDS patients. Nonetheless, ESAs improve anemia significantly in some patients and are widely used.[30, 31] Approximately 20% to 30% of unselected MDS patients and about 40% of LR‐MDS patients achieve clinically meaningful erythroid responses with ESA therapy with a median response duration of 2 years.[30, 31] It is important to correct coexisting nutritional deficiencies (eg, iron or folate deficiency) to optimize responses to ESA.[10] Granulocyte colony‐stimulating factor can be synergistic with ESAs especially in patients with RARS.[10] Patients with LR‐MDS who have low endogenous serum erythropoietin levels (<200500 mU/mL) and lower red blood cell (RBC) transfusion requirements (<2 U per month) are more likely to respond to ESA therapy.[32, 33] Compared to certain solid tumors, ESA therapy in MDS has not been associated with an increased risk of thromboembolic events.[34]
Lenalidomide
5q syndrome is a subtype of MDS characterized by refractory macrocytic anemia, normal or elevated platelet counts, low BM blast percentage, small hypolobated dysplastic megakaryocytes, an isolated interstitial deletion in 5q, and an indolent natural history.[17, 35] Lenalidomide, an oral derivative of thalidomide, induces high response rates in LR‐MDS patients with 5q deletions, including hematologic improvements, RBC transfusion independence (TI) (56%67%, median duration >104 weeks), cytogenetic responses (50%76%), and complete remissions.[35, 36] These findings resulted in approval of lenalidomide (Revlimid; Celgene Corp., Summit, NJ) for patients with IPSS low or INT‐1 MDS with transfusion‐dependent anemia and 5q deletions with or without additional cytogenetic abnormalities. In addition, lenalidomide has some activity against LR‐MDS without 5q deletions (TI, 26%, median duration 41 weeks) and some patients with HR‐MDS and 5q deletions (TI, 25.5%, median duration 26 weeks.[37, 38] Therefore, lenalidomide is a reasonable consideration in some patients with LR‐MDS without 5q deletions with primary or secondary resistance to ESA therapy.[10]
Immunosuppressive Therapy
Some patients with LR‐MDS respond to immunosuppressive therapy with antithymocyte globulin with or without cyclosporine. Characteristics that correlate with higher response rates: LR‐MDS, younger age (<60 years), hypoplastic MDS, normal karyotype, human leukocyte antigen‐DR15 histocompatibility type, and presence of a paroxysmal nocturnal hemoglobinuria clone.[10, 39]
MANAGEMENT OF HR‐MDS
The goal of management for HR‐MDS is to modify the natural history of the disease and to prolong survival. In addition to a supportive care‐only approach or clinical trial referral, 3 standard therapeutic approaches are used for patients with HR‐MDS: alloHSCT, intensive chemotherapy, and DNMTi therapy. The use of intensive AML‐like chemotherapy for HR‐MDS is associated with high toxicity and very limited long‐term success. Despite recent innovations in the field of transplantation, only a minority of MDS patients undergo alloHSCT, as most patients with HR‐MDS are elderly and/or medically infirm. Even for the minority of patients who do undergo alloHSCT, relapse after alloHSCT remains a major challenge.
DNA Methyltransferase Inhibitor Therapy
5‐azacitidine (AZA), (Vidaza; Celgene Corp.) and decitabine (DAC) (Dacogen; Eisai, Inc.) are potent inhibitors of DNA methyltransferases, which are enzymes responsible for cytosine methylation.[38, 40] These so‐called differentiation agents appear to restore normal hematopoiesis for many MDS patients, and the approved regimens of DNMTi in MDS result in overall response rates in about 40% to 60% of patients. Unfortunately, complete remissions (CR) are rare (10%20%) and the duration of responses are also somewhat limited (median CR duration, 10 to 14 months).[41, 42, 43, 44] In randomized clinical trials, both AZA and DAC resulted in significant improvements in blood counts, reduction in transfusion needs, reduced infection rates, decreased risk of progression to AML, and improvements in patient‐reported quality‐of‐life measures.[41, 42, 43, 44] AZA, but not DAC, prolonged survival in HR‐MDS patients in a large randomized trial (median overall survival for the AZA group was 24.5 months compared to 15 months for a group of patients treated with 1 of 3 conventional care regimens).[41, 42, 43, 44] AZA and DAC have not been compared head to head in trials, but most experts recommend AZA for first‐line use in HR‐MDS based on its effect on survival.[10]
AZA and DAC have also been studied as treatments for patients with AML. These agents differ from traditional intensive chemotherapy, as both agents are commonly administered on an outpatient basis, and hematologic responses are generally expected after 4 to 6 cycles of treatment as compared to a single course of intensive cytarabine‐based induction chemotherapy used to treat AML.[45] Additionally, the impact on survival may not require the achievement of a CR based on the finding that MDS patients saw improved survival even in patients whose best responses were hematologic improvements.[46] However, therapy with DNMTi is not curative, and patients are maintained on treatment as long as they are responding and not experiencing major side effects. Still, all patients will eventually lose response to DNMTi.
CONCLUSIONS
MDS is a form of cancer that largely affects elderly patients and leads to a BM failure state and increased risk of leukemic transformation. MDS is underdiagnosed and is frequently overlooked in the differential diagnosis of anemia in the elderly. DNMTi, lenalidomide, and ESA therapy offer effective therapeutic options for many MDS patients, including some considered too old or frail for intensive medical interventions. The use of prognostic models help physicians and patients better understand the common course of patients with MDS and facilitate tailoring of risk‐adapted therapy. It is expected that our improved understanding of the genetic, epigenetic, and immunologic mechanisms that operate in MDS will help develop better classification tools and rationally design effective new therapies.
Acknowledgments
The authors thank Dr. Balazs Zsenits (Medical Director of the Rochester General Hospitalist Group, Rochester General Hospital, Rochester, NY) for his critical review of the article.
Disclosures: Dr. Steven Gore owned stock in Celgene until November 2011, received research support from Celgene and Novartis, and consulted for Celgene. Drs. B. Douglas Smith, Amer Zeidan, and Bishoy Faltas have no relevant disclosures.
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by dysplasia, ineffective hematopoiesis resulting in peripheral blood (PB) cytopenias affecting one or more cell lines, and a variable risk of progression to acute myeloid leukemia (AML). The last 15 years have witnessed significant advances in our understanding of the complex pathogenesis, classification and prognostication, and therapeutic approaches to MDS. As more elderly patients are diagnosed with MDS, encounters with hospitalized MDS patients or patients in whom MDS should be considered in the differential diagnosis are common events for today's hospitalists. In this review, we discuss the epidemiology, diagnosis, pathogenesis, prognostication, and therapies for MDS, with an emphasis on practical aspects that would be useful for hospitalists caring for these patients.
EPIDEMIOLOGY OF MDS
Although MDS is one of the most common hematologic malignancies, MDS remains understudied epidemiologically.[1, 2] Our understanding of the epidemiology improved after the implementation of reporting requirements to cancer registries, especially the Surveillance, Epidemiology, and End Results (SEER) database in 2001.[1, 2, 3] Age‐adjusted incidence of MDS in the United States ranged between 3.3 to 4.6 per 100,000 persons per year in the period between 2001 and 2008.[1, 2, 4] The majority of MDS patients are elderly, and because MDS incidence increases with age, the number of patients diagnosed with MDS is expected to continue to rise with the aging population.[1, 2, 5] MDS is more common in men compared to women, and in Caucasians compared to African Americans.[1, 2] Different estimates put MDS prevalence in the United States somewhere between 60,000 and 170,000 persons.[2, 6]
DIAGNOSIS OF MDS
Many patients with MDS are asymptomatic at diagnosis and only come to medical attention due to abnormal blood counts done routinely or for other reasons. This contributes to MDS being underdiagnosed. When cytopenias are not severe enough to cause symptoms, it is also frequently overlooked in patients with mild anemia or other cytopenias.[7] Together, being asymptomatic and having relatively mild cytopenias are probably the most important factors that lead to under‐recognition of MDS among primary care physicians (PCPs).[7, 8, 9] There is a misconception that anemia is normal in the elderly, and when patients are not symptomatic that a workup is not needed.[6, 7] This is compounded by a lack of awareness of the importance of making a diagnosis in these patients and of currently available therapies for MDS.[7, 8, 9]
Anemia is not a normal consequence of aging and is always a pathologic state with an underlying etiology.[6, 7] Because a significant number of elderly patients with unexplained anemia could have MDS, patients with symptomatic or progressive anemia, especially if associated with other cytopenias, should be considered for further evaluation.[7, 9] Diagnosis is important given the recent availability of effective therapies for MDS that can improve anemia, decrease transfusion needs, improve life quality, and potentially increase survival. MDS is generally an indolent disease with a relative stability of blood counts in comparison to AML, so prior blood counts and the tempo of the process is an important consideration.[9, 10] The National Comprehensive Cancer Network clinical practice guidelines recommend exclusion of nutritional deficiencies (iron, vitamin B12, folate) and other causes of anemia (eg, gastrointestinal bleeding, renal insufficiency, and anemia of inflammation), assessment of reticulocyte count and serum erythropoietin level, and evaluation of a PB smear for evidence of dysplasia as important initial steps.[10, 11] Eventually the diagnosis of MDS requires a bone marrow (BM) evaluation to confirm the diagnosis and exclude other BM failure states by evaluating for BM cellularity, cell maturation, dysplasia (which should be present in at least 10% of any the myeloid lineages), percentage of blasts (<20%), iron stores and sideroblasts, cytogenetics, MDS‐specific fluorescence in situ hybridization (FISH) panels, flow cytometry, and other special testing.[9, 10] Despite extensive testing, MDS can sometimes be very difficult to differentiate from other bone marrow failure states (eg, hypoplastic MDS from aplastic anemia) (Table 1).[10, 11] In the absence of significant morbidity related to MDS, the definitive diagnosis of MDS can be usually made on an outpatient basis. It is important to ensure adequate follow‐up with PCPs postdischarge and/or outpatient hematologist referral for patients with unexplained cytopenias.
|
Idiopathic cytopenia of undetermined significance: no significant dysplasia or MDS‐associated karyotypic aberrations |
Acute myeloid leukemia: BM blasts 20%, presence of core‐binding characteristic cytogenetic aberrations: t(8;21), t(15;17), inv(16) defines AML regardless of BM blast count; AML can be associated with hepatosplenomegaly or myeloid sarcomas |
Chronic myeloid leukemia: presence of Philadelphia chromosome t(9;22) positive, basophilia, and splenomegaly |
Myelofibrosis: significant BM fibrosis, splenomegaly, and leukoerythroblastic picture in PB (teardrop and nucleated RBCs, left‐shifted myeloid cells) |
Chronic myelomonocytic leukemia: significant PB monocytosis |
MDS/MPN overlap syndromes: dysplasia with myeloproliferative characteristics such as splenomegaly, thrombocytosis, or leukocytosis |
Infections: for example, HIV and parvovirus B19 infections |
Myelophthisis: infiltration of BM with other tumors (eg, melanoma) with resultant PB cytopenias |
Nutritional disturbances: B12, folate, and copper deficiency, and zinc and arsenic excess can mimic MDS |
Medications: drugs that interfere with DNA synthesis such as HIV medications, chemotherapeutic agents, cotrimoxazole, methotrexate, azathioprine, and G‐CSF |
Immune disorders: for example, LGL leukemia, lupus, or rheumatoid arthritis |
Other acquired or congenital hematological disorders: for example, paroxysmal nocturnal hemoglobinuria, congenital dyserythropoietic anemia, dyskeratosis congenita |
PATHOGENESIS AND ETIOLOGY OF MDS
Ineffective hematopoiesis due to excessive apoptosis of hematopoietic precursors is a prominent feature of MDS, which explains the apparent paradox of hypercellular BM and PB cytopenias. Although not fully understood, complex epigenetic, genetic, and immunologic mechanisms contribute to the pathogenesis of MDS and account for disease heterogeneity. Aberrant silencing of tumor‐suppressor and DNA repair genes mediated by hypermethylation of their promoters is believed to play an important part in the pathogenesis of MDS.[12] This theory is supported by the unique sensitivity of MDS to drugs that reverse DNA methylation. Genetic abnormalities not only contribute to the pathogenesis of MDS, but are also among the strongest prognostic indicators for MDS patients, and can also affect therapeutic decisions. Clonal karyotypic abnormalities are observed in 50% of patients with MDS using conventional karyotyping.[12, 13] The most common chromosomal aberrations in MDS include deletions of the long arm of chromosome 5 (del5q), monosomy Y, monosomy 7 (del7) or deletion of its long arm (del7q), trisomy 8, del20q, and complex karyotypes (3 chromosomal aberrations).[12, 13] These cytogenetic abnormalities correlate with the prognosis of MDS (eg, poor prognosis with complex karyotypes and chromosome 7 deletions vs better prognosis with isolated del5q).[12, 13]
Recently, FISH assays and genome‐wide screening techniques (eg, single nucleotide polymorphism arrays, array‐based comparative genomic hybridization, whole genome or exome sequencing) have enabled detection of an increasing number of genetic aberrations and recurrent somatic molecular abnormalities in a significant number of MDS patients (eg, abnormalities of ASXL1, IDH1/IDH2, DNMT3, EZH2, TET2, and SF3B1 genes).[12, 14] Most affected genes are involved in the epigenetic regulation of transcription (DNA methylation and demethylation, histone posttranslational modification) or mRNA splicing.[12, 13, 14]
Immunologic aberrations have also been proposed to contribute to pathogenesis of MDS. For example, in early‐stage MDS, an aberrant immune attack on myeloid progenitors resulting in increased apoptosis can contribute to BM failure.[15] This is supported by association of some forms of MDS with autoimmune diseases and observed responses in some patients to immunosuppressive therapies. The relative contribution of pathogenetic mechanisms varies between the different MDS subtypes. For example, haploinsufficiency of cell‐cycle regulatory and ribosomal protein genes located in the commonly deleted region of 5q play an important role in the pathogenesis of MDS with isolated del5q (5q syndrome).[16] Mutations in the RNA spliceosomal machinery gene SF3B have been shown to play a role in the pathogenesis of the MDS subtype refractory anemia with ringed sideroblasts (RARS), with those patients with RARS carrying this mutation having a more favorable prognosis than those with the wild‐type gene.[14] Several excellent recent reviews provide detailed discussion of the complex pathophysiology of MDS.[12, 13, 14, 17]
Approximately 10% of MDS patients have secondary MDS (MDS occurring after chemotherapy or radiation therapy administration for treatment of another malignancy).[2] Aside from advancing age, the causative factors for the other 90% of cases (primary MDS) are unknown in most patients, although environmental and occupational exposures (eg, smoking, painting, insecticides, pesticides, organic solvents), and genetic syndromes (eg, DNA repair defects such as Fanconi's anemia) are implicated in some patients.[2, 10] Recently, an epidemiologic study found an increased MDS risk with obesity.[18]
PROGNOSTICATION OF MDS
MDS is a form of cancer, and most affected patients eventually die from cytopenic complications or leukemic progression. MDS is not a single disease but rather encompasses a group of heterogeneous subtypes with significantly different natural histories and pace of progression. Therefore, accurate risk stratification of MDS is necessary not only to predict survival and risk of leukemic progression, but also to help choose the most appropriate therapeutic option for individual patients. Information about prognosis should also be utilized when making management decisions with patients for other comorbid conditions (eg, major surgery). Two morphologically based classification systems are commonly used for MDS: the French‐American‐British (FAB) system and the World Health Organization (WHO) classification (Table 2), which most recently has supplanted the FAB system as the primary pathologic classification system.[19, 20, 21] Several prognostic models have been developed around the morphologic classifications to better account for relevant clinical and cytogenetic modifiers of this disease. Although some of these models have been validated by different groups, each of these models has limitations. Although the predictions generated by these models are generally accurate for the different prognostic categories to which the patient is assigned, the extent to which the prediction applies to an individual MDS patient can vary significantly. In addition, comorbid conditions affect survival of MDS patients and are not included in the specific scoring systems. For example, congestive heart failure and chronic obstructive lung disease were associated with shortened survival in MDS patients.[18]
MDS WHO Class | PB Findings | BM Findings |
---|---|---|
| ||
Refractory cytopenias with unilineage dysplasia: includes refractory anemia; refractory neutropenia; refractory thrombocytopenia | Unicytopenia or bicytopenia; PB blasts <1% | BM blasts <5%; unilineage dysplasia (10% of cells in any myeloid lineage); <15% of erythroid precursors are ringed sideroblasts |
Refractory anemia with ring sideroblasts | Anemia; PB blasts <1% | BM blasts <5%; erythroid dysplasia only; 15% of erythroid precursors are ringed sideroblasts |
Refractory cytopenia with multilineage dysplasia | Cytopenia(s); PB blasts <1%; no Auer rods; <1 106/L monocytes | BM blasts <5% ; dysplasia (10% of cells in at least 2 myeloid lineages); no Auer rods |
Refractory anemia with excess blasts‐1 | Cytopenia(s); PB blasts <5%; no Auer rods; <1 106/L monocytes | BM blasts 5%9%; unilineage or multilineage dysplasia; no Auer rods |
Refractory anemia with excess blasts‐2 | Cytopenia(s); PB blasts 5%19%; Auer rods; <1 106/L monocytes | BM blasts 10%19%; unilineage or multilineage dysplasia; Auer rods |
Myelodysplastic syndromeunclassified | Cytopenias; PB blasts 1% | BM blasts <5%; unequivocal dysplasia in <10% of cells at least one myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS |
MDS associated with isolated del5q | Anemia; normal to elevated platelet count; PB blasts <1% | BM blasts <5%; normal to elevated megakaryocytes with hypolobated nuclei; isolated del5q karyotypic abnormality; no Auer rods |
The International Prognostic Scoring System (IPSS) is the most widely used prognostic tool for MDS (Table 3).[22] In this model, an aggregate score is calculated based on points assigned to the percentage of blasts in BM, the number of PB cell lines affected by cytopenias, and the karyotype. Based on this point score, the patient is assigned to 1 of 4 categories that portend significantly different outcomes: low, intermediate‐1 (INT‐1), intermediate‐2 (INT‐2), and high risk. The IPSS was developed from a database of mostly untreated MDS patients and does not account for other important prognostic parameters such as transfusion dependence, depth of cytopenias, and extent/severity of lineage dysplasia.[22] The WHO Prognostic Scoring System was proposed to overcome some of these shortcomings.[23, 24] Efforts to continue to improve the prognostic models further led to a large international collaboration that compiled a much larger database and resulted in the development of a revised IPSS (IPSS‐R).[25] New discoveries of novel prognostic epigenetic, genetic, and immunologic determinants will likely result in the ongoing evolution of the current prognostic systems to further improve their discriminatory power.[26]
Calculation of Score Value Based on Prognostic Variables | |||||
---|---|---|---|---|---|
Score Value | |||||
0 | 0.5 | 1.0 | 1.5 | 2.0 | |
| |||||
Prognostic variable | |||||
Bone marrow blasts (%)a | <5 | 510 | 1120 | 2130 | |
Karyotypeb | Good | Intermediate | Poor | ||
Number of peripheral blood cell line affected by cytopeniasc | 0 or 1 | 2 or 3 | |||
Median Survival and Risk of Progression to AML According to the IPSS Risk Category in Absence of Therapy | |||||
Overall Score | Risk Category | Percentage in the IPSS Population | Median Survival (Years) | Median Time From Diagnosis at Which 25% of Patients Progress to AML (Years) | |
0 | Low | 33% | 5.7 | 9.4 | |
0.51.0 | INT‐1 | 38% | 3.5 | 3.3 | |
1.52.0 | INT‐2 | 22% | 1.1 | 1.1 | |
>2.5 | High | 7% | 0.4 | 0.2 |
MANAGEMENT OF MDS
Most patients with MDS were treated historically with supportive measures only. The approval of 3 agents for treatment of MDS including the DNA methyltransferase inhibitors (DNMTi) azacitidine and decitabine, as well as the immunomodulatory agent lenalidomide, in the last decade advanced the care of MDS patients significantly (Table 4). Nonetheless, the use of allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only known curative modality for patients with MDS and should always be considered as a possible therapeutic option.[27] Unfortunately, the majority of patients with MDS are not considered candidates for alloHSCT due to age, comorbidities, and lack of suitable donors.[27] Therefore, most patients with MDS are managed with noncurative treatment and supportive paradigms. Treatment goals generally depend on the risk stratification for the particular individual, age, functional status, comorbidities, and importantly, the patient's individual preference. For medical decision‐making purposes, MDS is traditionally divided into 2 major risk categories: low‐risk (LR) and high‐risk (HR) groups. LR‐MDS includes the IPSS risk categories of low or INT‐1, whereas HR‐MDS is usually defined by the IPSS risk categories of INT‐2 and high. Newer classification tools (eg, IPSS‐R) and better molecular markers are expected to impact such categories as well as treatment recommendations in the future.[26]
|
Azacitidine (5‐azacytidine, Vidaza) and decitabine (5‐aza,2‐deoxycytidine, Dacogen) |
Class |
Hypomethylating agents, azanucleosides |
Mechanism of action |
Epigenetic modulation by inhibition of DNA methyltransferase enzymes and other mechanisms |
Indication |
First line therapy for HR‐MDS, second line therapy for LR‐MDS after failure of other therapies such as ESAs, lenalidomide, or immunosuppressive agents |
Approved regimens for MDS |
Azacitidine: 75 mg/m2/day IV or SC for 7 days Q 4 weeks |
Decitabine: 15 mg/m2 IV infusion over 3 hours, Q 8 hours for 3 days, Q 6 weeks or 20 mg/m2 IV infusion over 1 hour daily for 5 days Q 4 weeks |
Common side effects |
Fatigue |
Development of or worsening cytopenias (neutropenia, thrombocytopenia, and anemia) and their complications (eg, infections, bleeding) |
Gastrointestinal disturbances (nausea, vomiting, or diarrhea) |
Oral ulcers and rarely mucositis |
Injection site reactions (redness, pain) |
Lenalidomide (Revlimid) |
Class |
Immunomodulatory agent |
Mechanism of action |
Modulation of immune responses, gene expression, angiogenesis, cytokines and cell‐cycle regulatory phosphatases, and possibly other mechanisms |
Indication |
First line therapy for LR‐MDS with del5q (also used commonly off label for LR‐MDS without del5q as second line of therapy after ESAs) |
Approved regimens for MDS |
10 mg orally once daily |
Common side effects |
Skin rash, dryness, and pruritus |
Fatigue |
Muscle cramps |
Development of or worsening cytopenias (neutropenia, thrombocytopenia, and anemia) and their complications (eg, infections, bleeding) |
Gastrointestinal disturbances (nausea, vomiting, or diarrhea) |
Despite recent advances, supportive care for all patients with MDS remains a very important aspect of management, either in combination with other therapies or as sole therapy for frail patients who cannot tolerate further interventions. Supportive therapy focuses on maintaining a high quality of life and includes careful blood count monitoring, use of growth factors, use of transfusions and antibiotics as needed, and use of iron chelation therapy in some patients. Some of the common situations in which hospitalists encounter patients with MDS are listed in Table 5.
|
Complications of cytopenias |
Bleeding: local management based on bleeding site, platelet transfusions, and other blood products (eg, red blood cells, fresh frozen plasma) as appropriate, antifibrinolytics |
Infections and neutropenic fevers: Antibiotics, antifungals, use of colony granulocyte‐stimulating factors or granulocyte infusions advised only in cases of uncontrolled severe infections or sepsis |
Severe or symptomatic anemia: red blood transfusions as appropriate based on patient's comorbidities, all disease‐modifying drugs (lenalidomide, azacitidine, decitabine) and ESAs are slow acting and can take weeks to months before improving anemia |
Complications of therapies |
Neutropenic fevers: as above plus holding therapy |
Most other side effects (see Table 4) are well tolerated and are managed symptomatically without requiring hospitalization. If needed hospitalization for side effects: symptomatic management and holding the drug |
Other medical or surgical condition in a patient with MDS |
Therapy as per the underlying medical condition. For therapeutic decisions (eg, decision to undergo major surgery), prognostication tools such as the IPSS and newer models can be used to inform medical decision making in consultation with an experienced hematologist |
MANAGEMENT OF LR‐MDS
In addition to supportive care or enrollment in clinical trials, therapies for LR‐MDS include erythropoiesis‐stimulating agents, lenalidomide, and immunosuppressive therapy.
Erythropoiesis‐Stimulating Agents
Anemia in MDS is a multifactorial process that includes ineffective erythropoiesis and suboptimal serum erythropoietin responses.[10, 28, 29] There are no randomized studies to suggest that erythropoiesis‐stimulating agents (ESA) therapy prolongs survival in MDS patients. Nonetheless, ESAs improve anemia significantly in some patients and are widely used.[30, 31] Approximately 20% to 30% of unselected MDS patients and about 40% of LR‐MDS patients achieve clinically meaningful erythroid responses with ESA therapy with a median response duration of 2 years.[30, 31] It is important to correct coexisting nutritional deficiencies (eg, iron or folate deficiency) to optimize responses to ESA.[10] Granulocyte colony‐stimulating factor can be synergistic with ESAs especially in patients with RARS.[10] Patients with LR‐MDS who have low endogenous serum erythropoietin levels (<200500 mU/mL) and lower red blood cell (RBC) transfusion requirements (<2 U per month) are more likely to respond to ESA therapy.[32, 33] Compared to certain solid tumors, ESA therapy in MDS has not been associated with an increased risk of thromboembolic events.[34]
Lenalidomide
5q syndrome is a subtype of MDS characterized by refractory macrocytic anemia, normal or elevated platelet counts, low BM blast percentage, small hypolobated dysplastic megakaryocytes, an isolated interstitial deletion in 5q, and an indolent natural history.[17, 35] Lenalidomide, an oral derivative of thalidomide, induces high response rates in LR‐MDS patients with 5q deletions, including hematologic improvements, RBC transfusion independence (TI) (56%67%, median duration >104 weeks), cytogenetic responses (50%76%), and complete remissions.[35, 36] These findings resulted in approval of lenalidomide (Revlimid; Celgene Corp., Summit, NJ) for patients with IPSS low or INT‐1 MDS with transfusion‐dependent anemia and 5q deletions with or without additional cytogenetic abnormalities. In addition, lenalidomide has some activity against LR‐MDS without 5q deletions (TI, 26%, median duration 41 weeks) and some patients with HR‐MDS and 5q deletions (TI, 25.5%, median duration 26 weeks.[37, 38] Therefore, lenalidomide is a reasonable consideration in some patients with LR‐MDS without 5q deletions with primary or secondary resistance to ESA therapy.[10]
Immunosuppressive Therapy
Some patients with LR‐MDS respond to immunosuppressive therapy with antithymocyte globulin with or without cyclosporine. Characteristics that correlate with higher response rates: LR‐MDS, younger age (<60 years), hypoplastic MDS, normal karyotype, human leukocyte antigen‐DR15 histocompatibility type, and presence of a paroxysmal nocturnal hemoglobinuria clone.[10, 39]
MANAGEMENT OF HR‐MDS
The goal of management for HR‐MDS is to modify the natural history of the disease and to prolong survival. In addition to a supportive care‐only approach or clinical trial referral, 3 standard therapeutic approaches are used for patients with HR‐MDS: alloHSCT, intensive chemotherapy, and DNMTi therapy. The use of intensive AML‐like chemotherapy for HR‐MDS is associated with high toxicity and very limited long‐term success. Despite recent innovations in the field of transplantation, only a minority of MDS patients undergo alloHSCT, as most patients with HR‐MDS are elderly and/or medically infirm. Even for the minority of patients who do undergo alloHSCT, relapse after alloHSCT remains a major challenge.
DNA Methyltransferase Inhibitor Therapy
5‐azacitidine (AZA), (Vidaza; Celgene Corp.) and decitabine (DAC) (Dacogen; Eisai, Inc.) are potent inhibitors of DNA methyltransferases, which are enzymes responsible for cytosine methylation.[38, 40] These so‐called differentiation agents appear to restore normal hematopoiesis for many MDS patients, and the approved regimens of DNMTi in MDS result in overall response rates in about 40% to 60% of patients. Unfortunately, complete remissions (CR) are rare (10%20%) and the duration of responses are also somewhat limited (median CR duration, 10 to 14 months).[41, 42, 43, 44] In randomized clinical trials, both AZA and DAC resulted in significant improvements in blood counts, reduction in transfusion needs, reduced infection rates, decreased risk of progression to AML, and improvements in patient‐reported quality‐of‐life measures.[41, 42, 43, 44] AZA, but not DAC, prolonged survival in HR‐MDS patients in a large randomized trial (median overall survival for the AZA group was 24.5 months compared to 15 months for a group of patients treated with 1 of 3 conventional care regimens).[41, 42, 43, 44] AZA and DAC have not been compared head to head in trials, but most experts recommend AZA for first‐line use in HR‐MDS based on its effect on survival.[10]
AZA and DAC have also been studied as treatments for patients with AML. These agents differ from traditional intensive chemotherapy, as both agents are commonly administered on an outpatient basis, and hematologic responses are generally expected after 4 to 6 cycles of treatment as compared to a single course of intensive cytarabine‐based induction chemotherapy used to treat AML.[45] Additionally, the impact on survival may not require the achievement of a CR based on the finding that MDS patients saw improved survival even in patients whose best responses were hematologic improvements.[46] However, therapy with DNMTi is not curative, and patients are maintained on treatment as long as they are responding and not experiencing major side effects. Still, all patients will eventually lose response to DNMTi.
CONCLUSIONS
MDS is a form of cancer that largely affects elderly patients and leads to a BM failure state and increased risk of leukemic transformation. MDS is underdiagnosed and is frequently overlooked in the differential diagnosis of anemia in the elderly. DNMTi, lenalidomide, and ESA therapy offer effective therapeutic options for many MDS patients, including some considered too old or frail for intensive medical interventions. The use of prognostic models help physicians and patients better understand the common course of patients with MDS and facilitate tailoring of risk‐adapted therapy. It is expected that our improved understanding of the genetic, epigenetic, and immunologic mechanisms that operate in MDS will help develop better classification tools and rationally design effective new therapies.
Acknowledgments
The authors thank Dr. Balazs Zsenits (Medical Director of the Rochester General Hospitalist Group, Rochester General Hospital, Rochester, NY) for his critical review of the article.
Disclosures: Dr. Steven Gore owned stock in Celgene until November 2011, received research support from Celgene and Novartis, and consulted for Celgene. Drs. B. Douglas Smith, Amer Zeidan, and Bishoy Faltas have no relevant disclosures.
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- Myelodysplastic syndromes: increasing disease awareness. Introduction. Am J Med. 2012;125:S1. .
- Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood. 2008;112:45–52. , , , et al.
- Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109:1536–1542. , , , .
- Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004;104:2263–2268. , , , , .
- Myelodysplastic syndromes: increasing disease awareness. Discussion. Am J Med. 2012;125:S33–S34. .
- Why are myelodysplastic syndromes unrecognized and underdiagnosed? A primary care perspective. Am J Med. 2012;125:S15–S17. .
- Clinical presentation, diagnosis, and prognosis of myelodysplastic syndromes. Am J Med. 2012;125:S6–S13. , .
- NCCN Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. J Natl Compr Canc Netw. 2011;9:30–56. , , , et al.
- Dysplasia has A differential diagnosis: distinguishing genuine myelodysplastic syndromes (MDS) from mimics, imitators, copycats and impostors. Curr Hematol Malig Rep. 2012;7:310–320. .
- Interpreting new molecular genetics in myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program. 2012;2012:56–64. , .
- Updates in cytogenetics and molecular markers in MDS. Curr Hematol Malig Rep. 2011;6:126–135. , , , , .
- Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders. Leukemia. 2012;26:2447–2454. , , , .
- Reduced natural killer (NK) function associated with high‐risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood. 2007;109:4816–4824. , , , et al.
- Identification of RPS14 as a 5q− syndrome gene by RNA interference screen. Nature. 2008;451:335–339. , , , et al.
- Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol. 2011;29:504–515. , , .
- Obesity, lifestyle factors, and risk of myelodysplastic syndromes in a large US cohort. Am J Epidemiol. 2009;169:1492–1499. , , , et al.
- Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189–199. , , , et al.
- World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting–Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17:3835–3849. , , , et al.
- WHO classification of MDS. In: World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. , , , et al.
- International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088. , , , et al.
- Time‐dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503–3510. , , , et al.
- Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification‐based Prognostic Scoring System (WPSS). Haematologica. 2011;96:1433–1440. , , , et al.
- Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–2465. , , , et al.
- Prognostication in myelodysplastic syndromes: beyond the International Prognostic Scoring System (IPSS). Am J Med. 2013;126:e25. , , , .
- Myelodysplastic syndromes: who and when in the course of disease to transplant. Hematology Am Soc Hematol Educ Program. 2012;2012:49–55. , .
- “Low‐risk” myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro‐ versus anti‐apoptotic bcl‐2‐related proteins. Br J Haematol. 1998;103:1075–1082. , , , , , .
- Ineffective haemopoiesis and apoptosis in myelodysplastic syndromes. Br J Haematol. 1998;101:220–230. , .
- Hematopoietic growth factors in myelodysplastic syndromes. Semin Oncol. 2011;38:635–647. .
- Patient and physician characteristics associated with erythropoiesis‐stimulating agent use in patients with myelodysplastic syndromes. Haematologica. 2012;97:128–132. , , , et al.
- Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G‐CSF: the GFM experience. Blood. 2008;111:574–582. , , , et al.
- Erythroid response to treatment with G‐CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Br J Haematol. 1997;99:344–351. , , , et al.
- Erythropoiesis‐stimulating agents are not associated with increased risk of thrombosis in patients with myelodysplastic syndromes. Haematologica. 2012;97:15–20. , , , et al.
- Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–1465. , , , et al.
- A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion‐dependent patients with low‐/‐ntermediate‐1‐risk myelodysplastic syndromes with del5q. Blood. 2011;118:3765–3776. , , , et al.
- Phase 2 study of lenalidomide in transfusion‐dependent, low‐risk, and intermediate‐1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111:86–93. , , , et al.
- Efficacy and safety of lenalidomide in intermediate‐2 or high‐risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood. 2009;113:3947–3952. , , , et al.
- Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. 2008;26:2505–2511. , , , , .
- DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin Hematol. 2008;45:23–30. , .
- Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher‐risk myelodysplastic syndromes: a randomised, open‐label, phase III study. Lancet Oncol. 2009;10:223–232. , , , et al.
- Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–2440. , , , et al.
- Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803. , , , et al.
- Low‐dose decitabine versus best supportive care in elderly patients with intermediate‐ or high‐risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29:1987–1996. , , , et al.
- Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24:3895–3903. , , , et al.
- Prognostic factors for response and overall survival in 282 patients with higher‐risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117:403–411. , , , et al.
- Epidemiology of myelodysplastic syndromes. Am J Med. 2012;125:S2–S5. .
- Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010. J Natl Compr Canc Netw. 2011;9:57–63. .
- Myelodysplastic syndromes: increasing disease awareness. Introduction. Am J Med. 2012;125:S1. .
- Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood. 2008;112:45–52. , , , et al.
- Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109:1536–1542. , , , .
- Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004;104:2263–2268. , , , , .
- Myelodysplastic syndromes: increasing disease awareness. Discussion. Am J Med. 2012;125:S33–S34. .
- Why are myelodysplastic syndromes unrecognized and underdiagnosed? A primary care perspective. Am J Med. 2012;125:S15–S17. .
- Clinical presentation, diagnosis, and prognosis of myelodysplastic syndromes. Am J Med. 2012;125:S6–S13. , .
- NCCN Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. J Natl Compr Canc Netw. 2011;9:30–56. , , , et al.
- Dysplasia has A differential diagnosis: distinguishing genuine myelodysplastic syndromes (MDS) from mimics, imitators, copycats and impostors. Curr Hematol Malig Rep. 2012;7:310–320. .
- Interpreting new molecular genetics in myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program. 2012;2012:56–64. , .
- Updates in cytogenetics and molecular markers in MDS. Curr Hematol Malig Rep. 2011;6:126–135. , , , , .
- Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders. Leukemia. 2012;26:2447–2454. , , , .
- Reduced natural killer (NK) function associated with high‐risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood. 2007;109:4816–4824. , , , et al.
- Identification of RPS14 as a 5q− syndrome gene by RNA interference screen. Nature. 2008;451:335–339. , , , et al.
- Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol. 2011;29:504–515. , , .
- Obesity, lifestyle factors, and risk of myelodysplastic syndromes in a large US cohort. Am J Epidemiol. 2009;169:1492–1499. , , , et al.
- Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189–199. , , , et al.
- World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting–Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17:3835–3849. , , , et al.
- WHO classification of MDS. In: World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. , , , et al.
- International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088. , , , et al.
- Time‐dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503–3510. , , , et al.
- Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification‐based Prognostic Scoring System (WPSS). Haematologica. 2011;96:1433–1440. , , , et al.
- Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–2465. , , , et al.
- Prognostication in myelodysplastic syndromes: beyond the International Prognostic Scoring System (IPSS). Am J Med. 2013;126:e25. , , , .
- Myelodysplastic syndromes: who and when in the course of disease to transplant. Hematology Am Soc Hematol Educ Program. 2012;2012:49–55. , .
- “Low‐risk” myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro‐ versus anti‐apoptotic bcl‐2‐related proteins. Br J Haematol. 1998;103:1075–1082. , , , , , .
- Ineffective haemopoiesis and apoptosis in myelodysplastic syndromes. Br J Haematol. 1998;101:220–230. , .
- Hematopoietic growth factors in myelodysplastic syndromes. Semin Oncol. 2011;38:635–647. .
- Patient and physician characteristics associated with erythropoiesis‐stimulating agent use in patients with myelodysplastic syndromes. Haematologica. 2012;97:128–132. , , , et al.
- Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G‐CSF: the GFM experience. Blood. 2008;111:574–582. , , , et al.
- Erythroid response to treatment with G‐CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Br J Haematol. 1997;99:344–351. , , , et al.
- Erythropoiesis‐stimulating agents are not associated with increased risk of thrombosis in patients with myelodysplastic syndromes. Haematologica. 2012;97:15–20. , , , et al.
- Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–1465. , , , et al.
- A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion‐dependent patients with low‐/‐ntermediate‐1‐risk myelodysplastic syndromes with del5q. Blood. 2011;118:3765–3776. , , , et al.
- Phase 2 study of lenalidomide in transfusion‐dependent, low‐risk, and intermediate‐1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111:86–93. , , , et al.
- Efficacy and safety of lenalidomide in intermediate‐2 or high‐risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood. 2009;113:3947–3952. , , , et al.
- Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. 2008;26:2505–2511. , , , , .
- DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin Hematol. 2008;45:23–30. , .
- Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher‐risk myelodysplastic syndromes: a randomised, open‐label, phase III study. Lancet Oncol. 2009;10:223–232. , , , et al.
- Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–2440. , , , et al.
- Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803. , , , et al.
- Low‐dose decitabine versus best supportive care in elderly patients with intermediate‐ or high‐risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29:1987–1996. , , , et al.
- Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24:3895–3903. , , , et al.
- Prognostic factors for response and overall survival in 282 patients with higher‐risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117:403–411. , , , et al.
The chargemaster speaketh
Who knew?
I was almost speechless when the federal government released data that show striking variation across America, and even within individual communities, in what hospitals charge patients. The 100 most frequently billed discharges of 2011 are represented in the data, and the associated DRGs represent close to 7 million discharges.
President Obama promised more transparency in and by government, and this headline from the Washington Post about CMS’s data-sharing move makes it crystal clear for all to see: "One hospital charges $8,000 – another, $38,000." Yes, for the same service. But that is just the tip of the iceberg. The article goes on to note that, according to hospitals’ once-secret "chargemaster" lists, the cost of joint replacements ranged from $5,304 in Ada, Okla., to a whopping $223,373 in Monterey, Calif. And, while a case of uncomplicated pneumonia may cost only $5,093 in Water Valley, Miss., you better hope you are not visiting Philadelphia when you get sick, or you can plan to tack on additional $119,000 to that bill. Surely, it is not the cost of the medications that accounts for this vast difference. National guidelines for treating pneumonia apply to all 50 states, so the care should be comparable. So what accounts for the extremes in hospital charges?
Okay, there’s the cost-of-living factor, and thus the hospitals’ overhead is undoubtedly drastically different in small-town U.S.A. vs. a popular metropolis, but it is shocking that this gap is so huge. While I have always known that there were differences in charges for medical services based on where you go, I never imagined such a stark contrast in the price tag for the same service in the same country – and sometimes even in the same city. As if the medical profession were not already struggling with its reputation eyes of the public. These data really paint of negative picture of the medical community.
So, what is the real significance of the discrepancy in these charges? For many with good insurance, nothing. Insurance companies decide what they are willing to pay for a given billing code and, typically, the rest is written off. Patients are not liable for the difference. Not quite true if you are uninsured.
Though the American Hospital Association states that centers often provide assistance to patients with meager finances, those who are most vulnerable and least able to pay for medical care may end up with the entire bill, frequently a bill that they will never be able to pay. That bill may eventually cause them to file for bankruptcy, which will adversely affect their lives and their children’s lives for many years to come – all because they became sick and assumed that the quality of care and the price for services rendered would be reasonable and comparable across all institutions.
While some may cringe at the revelation of the price discrepancy, I am glad this information came to light. Now consumers will be able to compare hospitals’ pricing as well as their quality measures and make better decisions about which hospital is best for them.
Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a mobile app for iOS. This blog, "Teachable Moments," appears regularly in Hospitalist News.
Who knew?
I was almost speechless when the federal government released data that show striking variation across America, and even within individual communities, in what hospitals charge patients. The 100 most frequently billed discharges of 2011 are represented in the data, and the associated DRGs represent close to 7 million discharges.
President Obama promised more transparency in and by government, and this headline from the Washington Post about CMS’s data-sharing move makes it crystal clear for all to see: "One hospital charges $8,000 – another, $38,000." Yes, for the same service. But that is just the tip of the iceberg. The article goes on to note that, according to hospitals’ once-secret "chargemaster" lists, the cost of joint replacements ranged from $5,304 in Ada, Okla., to a whopping $223,373 in Monterey, Calif. And, while a case of uncomplicated pneumonia may cost only $5,093 in Water Valley, Miss., you better hope you are not visiting Philadelphia when you get sick, or you can plan to tack on additional $119,000 to that bill. Surely, it is not the cost of the medications that accounts for this vast difference. National guidelines for treating pneumonia apply to all 50 states, so the care should be comparable. So what accounts for the extremes in hospital charges?
Okay, there’s the cost-of-living factor, and thus the hospitals’ overhead is undoubtedly drastically different in small-town U.S.A. vs. a popular metropolis, but it is shocking that this gap is so huge. While I have always known that there were differences in charges for medical services based on where you go, I never imagined such a stark contrast in the price tag for the same service in the same country – and sometimes even in the same city. As if the medical profession were not already struggling with its reputation eyes of the public. These data really paint of negative picture of the medical community.
So, what is the real significance of the discrepancy in these charges? For many with good insurance, nothing. Insurance companies decide what they are willing to pay for a given billing code and, typically, the rest is written off. Patients are not liable for the difference. Not quite true if you are uninsured.
Though the American Hospital Association states that centers often provide assistance to patients with meager finances, those who are most vulnerable and least able to pay for medical care may end up with the entire bill, frequently a bill that they will never be able to pay. That bill may eventually cause them to file for bankruptcy, which will adversely affect their lives and their children’s lives for many years to come – all because they became sick and assumed that the quality of care and the price for services rendered would be reasonable and comparable across all institutions.
While some may cringe at the revelation of the price discrepancy, I am glad this information came to light. Now consumers will be able to compare hospitals’ pricing as well as their quality measures and make better decisions about which hospital is best for them.
Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a mobile app for iOS. This blog, "Teachable Moments," appears regularly in Hospitalist News.
Who knew?
I was almost speechless when the federal government released data that show striking variation across America, and even within individual communities, in what hospitals charge patients. The 100 most frequently billed discharges of 2011 are represented in the data, and the associated DRGs represent close to 7 million discharges.
President Obama promised more transparency in and by government, and this headline from the Washington Post about CMS’s data-sharing move makes it crystal clear for all to see: "One hospital charges $8,000 – another, $38,000." Yes, for the same service. But that is just the tip of the iceberg. The article goes on to note that, according to hospitals’ once-secret "chargemaster" lists, the cost of joint replacements ranged from $5,304 in Ada, Okla., to a whopping $223,373 in Monterey, Calif. And, while a case of uncomplicated pneumonia may cost only $5,093 in Water Valley, Miss., you better hope you are not visiting Philadelphia when you get sick, or you can plan to tack on additional $119,000 to that bill. Surely, it is not the cost of the medications that accounts for this vast difference. National guidelines for treating pneumonia apply to all 50 states, so the care should be comparable. So what accounts for the extremes in hospital charges?
Okay, there’s the cost-of-living factor, and thus the hospitals’ overhead is undoubtedly drastically different in small-town U.S.A. vs. a popular metropolis, but it is shocking that this gap is so huge. While I have always known that there were differences in charges for medical services based on where you go, I never imagined such a stark contrast in the price tag for the same service in the same country – and sometimes even in the same city. As if the medical profession were not already struggling with its reputation eyes of the public. These data really paint of negative picture of the medical community.
So, what is the real significance of the discrepancy in these charges? For many with good insurance, nothing. Insurance companies decide what they are willing to pay for a given billing code and, typically, the rest is written off. Patients are not liable for the difference. Not quite true if you are uninsured.
Though the American Hospital Association states that centers often provide assistance to patients with meager finances, those who are most vulnerable and least able to pay for medical care may end up with the entire bill, frequently a bill that they will never be able to pay. That bill may eventually cause them to file for bankruptcy, which will adversely affect their lives and their children’s lives for many years to come – all because they became sick and assumed that the quality of care and the price for services rendered would be reasonable and comparable across all institutions.
While some may cringe at the revelation of the price discrepancy, I am glad this information came to light. Now consumers will be able to compare hospitals’ pricing as well as their quality measures and make better decisions about which hospital is best for them.
Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a mobile app for iOS. This blog, "Teachable Moments," appears regularly in Hospitalist News.
Early surgery for adhesive bowel obstruction can save lives
INDIANAPOLIS – Patients requiring surgery for adhesive small bowel obstruction have markedly lower major morbidity and mortality rates if they’re operated on within 24 hours of hospital admission, according to an analysis of a large national database.
This finding is at odds with the conventional wisdom.
Both the World Society of Emergency Surgery and the Eastern Association for the Surgery of Trauma recommend in published guidelines an initial 3-5 days of nonoperative management to give the obstruction a chance to resolve on its own, Dr. Pedro G. Teixeira noted in presenting the study findings at the annual meeting of the American Surgical Association.
He and his coinvestigators identified 4,163 patients in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for 2005-2010 who underwent emergency laparotomy for adhesive bowel obstruction. Thirty-day mortality was 3% in those operated upon within 24 hours of hospital admission. It rose in stepwise fashion thereafter: 4% mortality with surgery at 24-48 hours, 7% with surgery at 48-72 hours, and 9% a threefold increase – when surgery was delayed beyond 72 hours, according to Dr. Teixeira of the University of Southern California, Los Angeles.
Similarly, the incidence of systemic infectious complications, including pneumonia, urinary tract infections, and sepsis, climbed from 12% with early operation to 17% when surgery occurred at 24-48 hours, 21% at 48-72 hours, and 24% thereafter.
In a multivariate analysis adjusted for baseline comorbidities and other potential confounding variables, surgery delayed for 24 hours or more after admission was associated with a highly significant 58% increased risk of mortality, a 33% increase in surgical site infections, a 36% greater risk of pneumonia, and a 47% increased risk of septic shock, he continued.
Discussant Gregory J. Jurkovich commented that this study challenges current dogma and harkens back to a century-old adage that has since been cast aside, namely, "Never let the sun set on a bowel obstruction."
The trouble is, however, that having a low threshold for surgery within 24 hours would subject a massive number of patients to an unnecessary operation.
An analysis of Nationwide Inpatient Sample data for 2009 by other investigators concluded that bowel obstruction resolved on its own within 3 days in 60% of patients and within 5 days in 80%. Fewer than 20% of the patients who presented with adhesive small bowel obstruction without evidence of ischemia underwent surgery, noted Dr. Jurkovich, director of surgery at Denver Health Medical Center and professor of trauma surgery and vice chairman of the department of surgery at the University of Colorado at Denver.
Dr. Teixeira concurred that bowel obstruction will resolve on its own in most patients. The challenge for surgeons in light of his study findings, he stressed, is to expedite the identification of those patients who will fail the period of nonoperative management. The best tool for that, in his view, is a CT scan of the abdomen and pelvis with water-soluble contrast.
At the University of Southern California, he explained, a patient who presents with adhesive bowel obstruction without evidence of ischemia undergoes the CT scan and is admitted to the surgical observation unit for close monitoring.
"At our institution, failure to demonstrate contrast progression through the colon within 24 hours would be a very strong indication for surgical exploration," according to Dr. Teixeira.
He reported having no financial conflicts.
The study by Dr. Teixeira is intriguing in
that it suggests a return to practice patterns from a prior era.
![]() |
Dr. Chad Whelan |
The study does report increased risk in
complications including mortality with delays in surgery for small bowel
obstructions, even with risk adjustment. However, this is not a controlled
trial which limits our ability to reach definitive conclusions from it. Still,
hospitalists often are the primary physicians for patients admitted for small
bowel obstructions and should be aware of these findings so that they can
ensure that they have early surgical involvement.
Chad Whelan, M.D., is associate chief medical officer for
performance improvement and innovation and an associate professor of medicine
at the University
of Chicago Medical Center.
The study by Dr. Teixeira is intriguing in
that it suggests a return to practice patterns from a prior era.
![]() |
Dr. Chad Whelan |
The study does report increased risk in
complications including mortality with delays in surgery for small bowel
obstructions, even with risk adjustment. However, this is not a controlled
trial which limits our ability to reach definitive conclusions from it. Still,
hospitalists often are the primary physicians for patients admitted for small
bowel obstructions and should be aware of these findings so that they can
ensure that they have early surgical involvement.
Chad Whelan, M.D., is associate chief medical officer for
performance improvement and innovation and an associate professor of medicine
at the University
of Chicago Medical Center.
The study by Dr. Teixeira is intriguing in
that it suggests a return to practice patterns from a prior era.
![]() |
Dr. Chad Whelan |
The study does report increased risk in
complications including mortality with delays in surgery for small bowel
obstructions, even with risk adjustment. However, this is not a controlled
trial which limits our ability to reach definitive conclusions from it. Still,
hospitalists often are the primary physicians for patients admitted for small
bowel obstructions and should be aware of these findings so that they can
ensure that they have early surgical involvement.
Chad Whelan, M.D., is associate chief medical officer for
performance improvement and innovation and an associate professor of medicine
at the University
of Chicago Medical Center.
INDIANAPOLIS – Patients requiring surgery for adhesive small bowel obstruction have markedly lower major morbidity and mortality rates if they’re operated on within 24 hours of hospital admission, according to an analysis of a large national database.
This finding is at odds with the conventional wisdom.
Both the World Society of Emergency Surgery and the Eastern Association for the Surgery of Trauma recommend in published guidelines an initial 3-5 days of nonoperative management to give the obstruction a chance to resolve on its own, Dr. Pedro G. Teixeira noted in presenting the study findings at the annual meeting of the American Surgical Association.
He and his coinvestigators identified 4,163 patients in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for 2005-2010 who underwent emergency laparotomy for adhesive bowel obstruction. Thirty-day mortality was 3% in those operated upon within 24 hours of hospital admission. It rose in stepwise fashion thereafter: 4% mortality with surgery at 24-48 hours, 7% with surgery at 48-72 hours, and 9% a threefold increase – when surgery was delayed beyond 72 hours, according to Dr. Teixeira of the University of Southern California, Los Angeles.
Similarly, the incidence of systemic infectious complications, including pneumonia, urinary tract infections, and sepsis, climbed from 12% with early operation to 17% when surgery occurred at 24-48 hours, 21% at 48-72 hours, and 24% thereafter.
In a multivariate analysis adjusted for baseline comorbidities and other potential confounding variables, surgery delayed for 24 hours or more after admission was associated with a highly significant 58% increased risk of mortality, a 33% increase in surgical site infections, a 36% greater risk of pneumonia, and a 47% increased risk of septic shock, he continued.
Discussant Gregory J. Jurkovich commented that this study challenges current dogma and harkens back to a century-old adage that has since been cast aside, namely, "Never let the sun set on a bowel obstruction."
The trouble is, however, that having a low threshold for surgery within 24 hours would subject a massive number of patients to an unnecessary operation.
An analysis of Nationwide Inpatient Sample data for 2009 by other investigators concluded that bowel obstruction resolved on its own within 3 days in 60% of patients and within 5 days in 80%. Fewer than 20% of the patients who presented with adhesive small bowel obstruction without evidence of ischemia underwent surgery, noted Dr. Jurkovich, director of surgery at Denver Health Medical Center and professor of trauma surgery and vice chairman of the department of surgery at the University of Colorado at Denver.
Dr. Teixeira concurred that bowel obstruction will resolve on its own in most patients. The challenge for surgeons in light of his study findings, he stressed, is to expedite the identification of those patients who will fail the period of nonoperative management. The best tool for that, in his view, is a CT scan of the abdomen and pelvis with water-soluble contrast.
At the University of Southern California, he explained, a patient who presents with adhesive bowel obstruction without evidence of ischemia undergoes the CT scan and is admitted to the surgical observation unit for close monitoring.
"At our institution, failure to demonstrate contrast progression through the colon within 24 hours would be a very strong indication for surgical exploration," according to Dr. Teixeira.
He reported having no financial conflicts.
INDIANAPOLIS – Patients requiring surgery for adhesive small bowel obstruction have markedly lower major morbidity and mortality rates if they’re operated on within 24 hours of hospital admission, according to an analysis of a large national database.
This finding is at odds with the conventional wisdom.
Both the World Society of Emergency Surgery and the Eastern Association for the Surgery of Trauma recommend in published guidelines an initial 3-5 days of nonoperative management to give the obstruction a chance to resolve on its own, Dr. Pedro G. Teixeira noted in presenting the study findings at the annual meeting of the American Surgical Association.
He and his coinvestigators identified 4,163 patients in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for 2005-2010 who underwent emergency laparotomy for adhesive bowel obstruction. Thirty-day mortality was 3% in those operated upon within 24 hours of hospital admission. It rose in stepwise fashion thereafter: 4% mortality with surgery at 24-48 hours, 7% with surgery at 48-72 hours, and 9% a threefold increase – when surgery was delayed beyond 72 hours, according to Dr. Teixeira of the University of Southern California, Los Angeles.
Similarly, the incidence of systemic infectious complications, including pneumonia, urinary tract infections, and sepsis, climbed from 12% with early operation to 17% when surgery occurred at 24-48 hours, 21% at 48-72 hours, and 24% thereafter.
In a multivariate analysis adjusted for baseline comorbidities and other potential confounding variables, surgery delayed for 24 hours or more after admission was associated with a highly significant 58% increased risk of mortality, a 33% increase in surgical site infections, a 36% greater risk of pneumonia, and a 47% increased risk of septic shock, he continued.
Discussant Gregory J. Jurkovich commented that this study challenges current dogma and harkens back to a century-old adage that has since been cast aside, namely, "Never let the sun set on a bowel obstruction."
The trouble is, however, that having a low threshold for surgery within 24 hours would subject a massive number of patients to an unnecessary operation.
An analysis of Nationwide Inpatient Sample data for 2009 by other investigators concluded that bowel obstruction resolved on its own within 3 days in 60% of patients and within 5 days in 80%. Fewer than 20% of the patients who presented with adhesive small bowel obstruction without evidence of ischemia underwent surgery, noted Dr. Jurkovich, director of surgery at Denver Health Medical Center and professor of trauma surgery and vice chairman of the department of surgery at the University of Colorado at Denver.
Dr. Teixeira concurred that bowel obstruction will resolve on its own in most patients. The challenge for surgeons in light of his study findings, he stressed, is to expedite the identification of those patients who will fail the period of nonoperative management. The best tool for that, in his view, is a CT scan of the abdomen and pelvis with water-soluble contrast.
At the University of Southern California, he explained, a patient who presents with adhesive bowel obstruction without evidence of ischemia undergoes the CT scan and is admitted to the surgical observation unit for close monitoring.
"At our institution, failure to demonstrate contrast progression through the colon within 24 hours would be a very strong indication for surgical exploration," according to Dr. Teixeira.
He reported having no financial conflicts.
AT THE ASA ANNUAL MEETING
Major Finding: Surgery for adhesive small bowel obstruction had a 30-day mortality rate of 3% if performed within 24 hours of hospital admission, rising stepwise to 9% when the operation was delayed beyond 72 hours.
Data Source: This was a retrospective analysis of 4,163 patients in the American College of Surgeons National Quality Improvement Program database for 2005-2010 who underwent emergency laparotomy for adhesive bowel obstruction.
Disclosures: The presenter reported having no conflicts of interest.
Children with ulcerative colitis benefited from fecal transplants
Seven out of nine children with active ulcerative colitis experienced at least a temporary clinical response within 1 week of a series of fecal transplants – with four of the patients staying in complete remission 1 month later.
The procedures represent the first time fecal transplantation has been used to treat ulcerative colitis, Dr. Sachin Kunde and his colleagues reported online in the Journal of Pediatric Gastroenterology and Nutrition (2013 March 29 [doi: 10.1097/MPG.0b013e318292fa0d]).
"Utilization of fecal material transplantation in ulcerative colitis may not be as simple as its use in recurrent C. difficile infection," wrote Dr. Kunde of the Helen DeVos Children’s Hospital, Grand Rapids, Mich., and his coauthors. Still, they said, this early success in a devastating, hard-to-manage disease should be the launching point for larger trials.
The study group comprised 10 patients who ranged in age from 7 to 20 years. All had mild to moderate, active ulcerative colitis. Disease duration ranged from 1 to 8 years. Participants had stable disease and received medical treatment for at least 2 months before the procedure. Only one patient had used anti–tumor necrosis factor (anti-TNF)-alpha medications.
The intervention consisted of a 5-day series of daily enemas containing fresh stool from a donor. Each of the patients chose an adult donor; most were first-degree relatives. One patient chose a close family friend. The donors took daily over-the-counter stool softeners to produce the required amount – a mean of 90 g/day. This was blended with 250 mL of sterile normal saline, strained, and divided into four 60-mL portions. In each treatment, all four of the portions were infused, each over a 15-minute period.
The patients did not receive any bowel preparation before the procedures. They received the enemas while lying on the left side, and then rotating to the right side and back again to allow the solution to travel into the colon.
Ten patients entered treatment. However, one could not retain the enemas and so was not included in the final analysis. The remaining patients were able to tolerate an enema volume of 75-240 mL (average retention, 165 mL). Retention was not directly related to age, the investigators noted, since the subject who could not retain it was the oldest. Retention times ranged from 3 to 24 hours.
There were no serious adverse events during the study. Patients did report the expected discomfort of left-sided abdominal fullness. One experienced a moderate fever and chills 3 hours after the first two transplants, which spontaneously resolved over 6 hours. For the final three procedures, that patient took prophylactic acetaminophen and diphenhydramine.
Another patient had a low-grade fever after one transplant, which resolved without intervention. There were no cases of sepsis.
One patient experienced a disabling hematochezia 3 weeks after the transplant series. This was judged to be a flare unrelated to the transplant.
In the first week after the transplant series, seven of the nine patients in the analysis (78%) had a clinical response, defined as a decrease of more than 15 points in the Pediatric Ulcerative Colitis Activity Index. Six of the nine (67%) maintained that improvement at 1 month.
Three experienced clinical remission at 1 week, which lasted for 1 month. Two patients had a PUCAI score of 0 from week 3 until the end of the 7-week follow-up period.
The pilot study shows the feasibility of fecal transplants for ulcerative colitis, Dr. Kunde said. But while the technique is similar to that employed in C. difficile treatment, a more prolonged treatment seems necessary to elicit a response in ulcerative colitis.
"In order to better understand how fecal transplants can be used to treat ulcerative colitis, many unanswered questions need to be addressed. We must further investigate standardization of ... preparation, ideal donor selection, ideal route of administration, and optimal duration of scheduling [the transplants] to induce and maintain a clinical response. Most importantly, the effects of fecal material transplant on the colonic microbiome and mucosal inflammation in ulcerative colitis need to be explored."
The Helen Devos Children’s Hospital supported the research. The authors did not disclose any financial relationships.
There has been much excitement about the use
of fecal material to treat recurrent Clostridium difficile infection.
Along the theory that the gut microbiome may be the “final frontier” of many
human diseases, so-called fecal microbiota transplantation (FMT) is of great
interest for other GI disorders.
Given the observation that patients with inflammatory
bowel disease (IBD) have an altered gut microbiome, clinicians and scientists
have wondered whether modifying the gut flora via FMT would provide symptom
improvement or disease control. It is much more complicated than treatment for C.
difficile, since IBD is a much more complex disorder, and as a single
organism or infectious etiology is not known. Clearly, our current
understanding is far from satisfying any of Koch’s postulates
of infectious disease. The observed dysbiosis may instead be a result of the underlying
inflammatory disorder or even a result of some of our treatments for IBD.
Nonetheless, providing FMT to patients with IBD is an interesting concept.
Dr. Kunde and his colleagues had promising results,
but they were careful in their selection of patients, the severity of disease,
and concomitant therapies. Safety appears acceptable, but there were some
short-term adverse events. We should await additional studies with mechanistic
and translational components and, importantly, safety follow-up to guide us
further.
Dr. David T. Rubin is a professor of medicine, the codirector
of the Inflammatory Bowel Disease Center, and the associate section chief for educational
programs at the University of Chicago. He had no relevant disclosures.
There has been much excitement about the use
of fecal material to treat recurrent Clostridium difficile infection.
Along the theory that the gut microbiome may be the “final frontier” of many
human diseases, so-called fecal microbiota transplantation (FMT) is of great
interest for other GI disorders.
Given the observation that patients with inflammatory
bowel disease (IBD) have an altered gut microbiome, clinicians and scientists
have wondered whether modifying the gut flora via FMT would provide symptom
improvement or disease control. It is much more complicated than treatment for C.
difficile, since IBD is a much more complex disorder, and as a single
organism or infectious etiology is not known. Clearly, our current
understanding is far from satisfying any of Koch’s postulates
of infectious disease. The observed dysbiosis may instead be a result of the underlying
inflammatory disorder or even a result of some of our treatments for IBD.
Nonetheless, providing FMT to patients with IBD is an interesting concept.
Dr. Kunde and his colleagues had promising results,
but they were careful in their selection of patients, the severity of disease,
and concomitant therapies. Safety appears acceptable, but there were some
short-term adverse events. We should await additional studies with mechanistic
and translational components and, importantly, safety follow-up to guide us
further.
Dr. David T. Rubin is a professor of medicine, the codirector
of the Inflammatory Bowel Disease Center, and the associate section chief for educational
programs at the University of Chicago. He had no relevant disclosures.
There has been much excitement about the use
of fecal material to treat recurrent Clostridium difficile infection.
Along the theory that the gut microbiome may be the “final frontier” of many
human diseases, so-called fecal microbiota transplantation (FMT) is of great
interest for other GI disorders.
Given the observation that patients with inflammatory
bowel disease (IBD) have an altered gut microbiome, clinicians and scientists
have wondered whether modifying the gut flora via FMT would provide symptom
improvement or disease control. It is much more complicated than treatment for C.
difficile, since IBD is a much more complex disorder, and as a single
organism or infectious etiology is not known. Clearly, our current
understanding is far from satisfying any of Koch’s postulates
of infectious disease. The observed dysbiosis may instead be a result of the underlying
inflammatory disorder or even a result of some of our treatments for IBD.
Nonetheless, providing FMT to patients with IBD is an interesting concept.
Dr. Kunde and his colleagues had promising results,
but they were careful in their selection of patients, the severity of disease,
and concomitant therapies. Safety appears acceptable, but there were some
short-term adverse events. We should await additional studies with mechanistic
and translational components and, importantly, safety follow-up to guide us
further.
Dr. David T. Rubin is a professor of medicine, the codirector
of the Inflammatory Bowel Disease Center, and the associate section chief for educational
programs at the University of Chicago. He had no relevant disclosures.
Seven out of nine children with active ulcerative colitis experienced at least a temporary clinical response within 1 week of a series of fecal transplants – with four of the patients staying in complete remission 1 month later.
The procedures represent the first time fecal transplantation has been used to treat ulcerative colitis, Dr. Sachin Kunde and his colleagues reported online in the Journal of Pediatric Gastroenterology and Nutrition (2013 March 29 [doi: 10.1097/MPG.0b013e318292fa0d]).
"Utilization of fecal material transplantation in ulcerative colitis may not be as simple as its use in recurrent C. difficile infection," wrote Dr. Kunde of the Helen DeVos Children’s Hospital, Grand Rapids, Mich., and his coauthors. Still, they said, this early success in a devastating, hard-to-manage disease should be the launching point for larger trials.
The study group comprised 10 patients who ranged in age from 7 to 20 years. All had mild to moderate, active ulcerative colitis. Disease duration ranged from 1 to 8 years. Participants had stable disease and received medical treatment for at least 2 months before the procedure. Only one patient had used anti–tumor necrosis factor (anti-TNF)-alpha medications.
The intervention consisted of a 5-day series of daily enemas containing fresh stool from a donor. Each of the patients chose an adult donor; most were first-degree relatives. One patient chose a close family friend. The donors took daily over-the-counter stool softeners to produce the required amount – a mean of 90 g/day. This was blended with 250 mL of sterile normal saline, strained, and divided into four 60-mL portions. In each treatment, all four of the portions were infused, each over a 15-minute period.
The patients did not receive any bowel preparation before the procedures. They received the enemas while lying on the left side, and then rotating to the right side and back again to allow the solution to travel into the colon.
Ten patients entered treatment. However, one could not retain the enemas and so was not included in the final analysis. The remaining patients were able to tolerate an enema volume of 75-240 mL (average retention, 165 mL). Retention was not directly related to age, the investigators noted, since the subject who could not retain it was the oldest. Retention times ranged from 3 to 24 hours.
There were no serious adverse events during the study. Patients did report the expected discomfort of left-sided abdominal fullness. One experienced a moderate fever and chills 3 hours after the first two transplants, which spontaneously resolved over 6 hours. For the final three procedures, that patient took prophylactic acetaminophen and diphenhydramine.
Another patient had a low-grade fever after one transplant, which resolved without intervention. There were no cases of sepsis.
One patient experienced a disabling hematochezia 3 weeks after the transplant series. This was judged to be a flare unrelated to the transplant.
In the first week after the transplant series, seven of the nine patients in the analysis (78%) had a clinical response, defined as a decrease of more than 15 points in the Pediatric Ulcerative Colitis Activity Index. Six of the nine (67%) maintained that improvement at 1 month.
Three experienced clinical remission at 1 week, which lasted for 1 month. Two patients had a PUCAI score of 0 from week 3 until the end of the 7-week follow-up period.
The pilot study shows the feasibility of fecal transplants for ulcerative colitis, Dr. Kunde said. But while the technique is similar to that employed in C. difficile treatment, a more prolonged treatment seems necessary to elicit a response in ulcerative colitis.
"In order to better understand how fecal transplants can be used to treat ulcerative colitis, many unanswered questions need to be addressed. We must further investigate standardization of ... preparation, ideal donor selection, ideal route of administration, and optimal duration of scheduling [the transplants] to induce and maintain a clinical response. Most importantly, the effects of fecal material transplant on the colonic microbiome and mucosal inflammation in ulcerative colitis need to be explored."
The Helen Devos Children’s Hospital supported the research. The authors did not disclose any financial relationships.
Seven out of nine children with active ulcerative colitis experienced at least a temporary clinical response within 1 week of a series of fecal transplants – with four of the patients staying in complete remission 1 month later.
The procedures represent the first time fecal transplantation has been used to treat ulcerative colitis, Dr. Sachin Kunde and his colleagues reported online in the Journal of Pediatric Gastroenterology and Nutrition (2013 March 29 [doi: 10.1097/MPG.0b013e318292fa0d]).
"Utilization of fecal material transplantation in ulcerative colitis may not be as simple as its use in recurrent C. difficile infection," wrote Dr. Kunde of the Helen DeVos Children’s Hospital, Grand Rapids, Mich., and his coauthors. Still, they said, this early success in a devastating, hard-to-manage disease should be the launching point for larger trials.
The study group comprised 10 patients who ranged in age from 7 to 20 years. All had mild to moderate, active ulcerative colitis. Disease duration ranged from 1 to 8 years. Participants had stable disease and received medical treatment for at least 2 months before the procedure. Only one patient had used anti–tumor necrosis factor (anti-TNF)-alpha medications.
The intervention consisted of a 5-day series of daily enemas containing fresh stool from a donor. Each of the patients chose an adult donor; most were first-degree relatives. One patient chose a close family friend. The donors took daily over-the-counter stool softeners to produce the required amount – a mean of 90 g/day. This was blended with 250 mL of sterile normal saline, strained, and divided into four 60-mL portions. In each treatment, all four of the portions were infused, each over a 15-minute period.
The patients did not receive any bowel preparation before the procedures. They received the enemas while lying on the left side, and then rotating to the right side and back again to allow the solution to travel into the colon.
Ten patients entered treatment. However, one could not retain the enemas and so was not included in the final analysis. The remaining patients were able to tolerate an enema volume of 75-240 mL (average retention, 165 mL). Retention was not directly related to age, the investigators noted, since the subject who could not retain it was the oldest. Retention times ranged from 3 to 24 hours.
There were no serious adverse events during the study. Patients did report the expected discomfort of left-sided abdominal fullness. One experienced a moderate fever and chills 3 hours after the first two transplants, which spontaneously resolved over 6 hours. For the final three procedures, that patient took prophylactic acetaminophen and diphenhydramine.
Another patient had a low-grade fever after one transplant, which resolved without intervention. There were no cases of sepsis.
One patient experienced a disabling hematochezia 3 weeks after the transplant series. This was judged to be a flare unrelated to the transplant.
In the first week after the transplant series, seven of the nine patients in the analysis (78%) had a clinical response, defined as a decrease of more than 15 points in the Pediatric Ulcerative Colitis Activity Index. Six of the nine (67%) maintained that improvement at 1 month.
Three experienced clinical remission at 1 week, which lasted for 1 month. Two patients had a PUCAI score of 0 from week 3 until the end of the 7-week follow-up period.
The pilot study shows the feasibility of fecal transplants for ulcerative colitis, Dr. Kunde said. But while the technique is similar to that employed in C. difficile treatment, a more prolonged treatment seems necessary to elicit a response in ulcerative colitis.
"In order to better understand how fecal transplants can be used to treat ulcerative colitis, many unanswered questions need to be addressed. We must further investigate standardization of ... preparation, ideal donor selection, ideal route of administration, and optimal duration of scheduling [the transplants] to induce and maintain a clinical response. Most importantly, the effects of fecal material transplant on the colonic microbiome and mucosal inflammation in ulcerative colitis need to be explored."
The Helen Devos Children’s Hospital supported the research. The authors did not disclose any financial relationships.
FROM PEDIATRIC GASTROENTEROLOGY AND NUTRITION
Major finding: Fecal transplants effected clinical improvement in 78% of children with ulcerative colitis.
Data source: Nine children were enrolled in a small prospective study.
Disclosures: The Helen Devos Children’s Hospital supported the research. The authors did not disclose any financial relationships.
Are Electronic Health Records Hindering Patient Care?
SHM board member Eric Siegal, MD, SFHM, wasn't surprised by the findings in a new report in the Journal of General Internal Medicine that found medical interns spent just 12% of their time in direct patient care and a whopping 40% of their time using computers.
"There certainly are advantages to electronic health records (EHRs), but one of the clear consequences is that it's impossible to function in the hospital without spending a lot of time in front of a computer screen. EHRs have turned physicians into secretaries," says Dr. Siegal, medical director of critical-care medicine at Aurora St. Luke's Medical Center in Milwaukee. "Work that we used to hand off to a unit clerk or to somebody else to do has now dropped into our laps."
Dr. Siegal and two of the authors of "In the Wake of the 2003 and 2011 Duty Hours Regulations, How do Internal Medicine Interns Spend Their Time?" agree that the growing EHR presence means that hospitalists and other internists spend a significant amount of time on data input and management, potentially at the cost of other activities. The observational study, which tracked general medicine inpatient ward rotations at Johns Hopkins School of Medicine and the University of Maryland, both in Baltimore, found that interns spent 64% of their time in indirect patient care, 15% in educational activities, and 9% in miscellaneous activities.
"We've created the perfect system to give us these results," says John Hopkins hospitalist and senior author Leonard Feldman, MD, FACP, FAAP, SFHM. "We need to place a value judgment as a medical community on whether these results are what we want our training programs to look like."
Dr. Feldman says EHRs need to be more efficient than current iterations, which focus more on data collection.
"I have been remarkably unimpressed with how many EMRs organize data and how surprisingly difficult it is for us to efficiently glean and prioritize information that we need to make decisions," Dr. Siegal adds.
Study lead author Lauren Block, MD, also of Johns Hopkins, says increased efficiency with EHRs is just one pathway to more direct patient care. Another is focusing on improving how physicians interact with the patients. She says teaching medical interns how to make the most of the time they have with patients—including digital interactions—is the next step toward improving the patient experience.
"It's not just the quantity of time, it's the quality of time," Dr. Block says. "Medical education has to find a way to address that and make sure that all the various modes of communication we use with patients are done well, and done in a manner that's safe, respects patients’ privacy, and meets patient needs."
Visit our website for more information on time hospitalists spend on EHR.
SHM board member Eric Siegal, MD, SFHM, wasn't surprised by the findings in a new report in the Journal of General Internal Medicine that found medical interns spent just 12% of their time in direct patient care and a whopping 40% of their time using computers.
"There certainly are advantages to electronic health records (EHRs), but one of the clear consequences is that it's impossible to function in the hospital without spending a lot of time in front of a computer screen. EHRs have turned physicians into secretaries," says Dr. Siegal, medical director of critical-care medicine at Aurora St. Luke's Medical Center in Milwaukee. "Work that we used to hand off to a unit clerk or to somebody else to do has now dropped into our laps."
Dr. Siegal and two of the authors of "In the Wake of the 2003 and 2011 Duty Hours Regulations, How do Internal Medicine Interns Spend Their Time?" agree that the growing EHR presence means that hospitalists and other internists spend a significant amount of time on data input and management, potentially at the cost of other activities. The observational study, which tracked general medicine inpatient ward rotations at Johns Hopkins School of Medicine and the University of Maryland, both in Baltimore, found that interns spent 64% of their time in indirect patient care, 15% in educational activities, and 9% in miscellaneous activities.
"We've created the perfect system to give us these results," says John Hopkins hospitalist and senior author Leonard Feldman, MD, FACP, FAAP, SFHM. "We need to place a value judgment as a medical community on whether these results are what we want our training programs to look like."
Dr. Feldman says EHRs need to be more efficient than current iterations, which focus more on data collection.
"I have been remarkably unimpressed with how many EMRs organize data and how surprisingly difficult it is for us to efficiently glean and prioritize information that we need to make decisions," Dr. Siegal adds.
Study lead author Lauren Block, MD, also of Johns Hopkins, says increased efficiency with EHRs is just one pathway to more direct patient care. Another is focusing on improving how physicians interact with the patients. She says teaching medical interns how to make the most of the time they have with patients—including digital interactions—is the next step toward improving the patient experience.
"It's not just the quantity of time, it's the quality of time," Dr. Block says. "Medical education has to find a way to address that and make sure that all the various modes of communication we use with patients are done well, and done in a manner that's safe, respects patients’ privacy, and meets patient needs."
Visit our website for more information on time hospitalists spend on EHR.
SHM board member Eric Siegal, MD, SFHM, wasn't surprised by the findings in a new report in the Journal of General Internal Medicine that found medical interns spent just 12% of their time in direct patient care and a whopping 40% of their time using computers.
"There certainly are advantages to electronic health records (EHRs), but one of the clear consequences is that it's impossible to function in the hospital without spending a lot of time in front of a computer screen. EHRs have turned physicians into secretaries," says Dr. Siegal, medical director of critical-care medicine at Aurora St. Luke's Medical Center in Milwaukee. "Work that we used to hand off to a unit clerk or to somebody else to do has now dropped into our laps."
Dr. Siegal and two of the authors of "In the Wake of the 2003 and 2011 Duty Hours Regulations, How do Internal Medicine Interns Spend Their Time?" agree that the growing EHR presence means that hospitalists and other internists spend a significant amount of time on data input and management, potentially at the cost of other activities. The observational study, which tracked general medicine inpatient ward rotations at Johns Hopkins School of Medicine and the University of Maryland, both in Baltimore, found that interns spent 64% of their time in indirect patient care, 15% in educational activities, and 9% in miscellaneous activities.
"We've created the perfect system to give us these results," says John Hopkins hospitalist and senior author Leonard Feldman, MD, FACP, FAAP, SFHM. "We need to place a value judgment as a medical community on whether these results are what we want our training programs to look like."
Dr. Feldman says EHRs need to be more efficient than current iterations, which focus more on data collection.
"I have been remarkably unimpressed with how many EMRs organize data and how surprisingly difficult it is for us to efficiently glean and prioritize information that we need to make decisions," Dr. Siegal adds.
Study lead author Lauren Block, MD, also of Johns Hopkins, says increased efficiency with EHRs is just one pathway to more direct patient care. Another is focusing on improving how physicians interact with the patients. She says teaching medical interns how to make the most of the time they have with patients—including digital interactions—is the next step toward improving the patient experience.
"It's not just the quantity of time, it's the quality of time," Dr. Block says. "Medical education has to find a way to address that and make sure that all the various modes of communication we use with patients are done well, and done in a manner that's safe, respects patients’ privacy, and meets patient needs."
Visit our website for more information on time hospitalists spend on EHR.
ED Physicians, Hospitalists Can Collaborate More to Optimize Patient Care
Hospitalists and ED physicians belong to two of the largest U.S. medical specialties and increasingly they are the only physicians seen by some hospitalized patients. Comanagement between the specialties is increasing in some hospitals, and in others, they might be the only physicians in the building after hours. They share similar workspaces, schedules, and responsibility for decisions about the most expensive care in medicine.
And yet there is not enough collaboration between the two specialties beyond brief phone encounters at handoff, says hospitalist Alpesh Amin, MD, MPA, MACP, SFHM, executive director of the hospitalist program at the University of California at Irvine. Dr. Amin coauthored a recent review highlighting opportunities for closer HM-ED collaboration with Charles Pollack Jr., MD, MA, FACEP, FAAEM, FAHA, who chairs the emergency department at Pennsylvania Hospital in Philadelphia.
A good place to start is for the two groups to simply sit down together regularly to discuss matters of common interest, perhaps monthly or quarterly, Dr. Amin says.
"Talk about clinical pathway development for common hospital diagnoses and how to improve admission processes," he adds. "There may be a role for the hospitalist in the emergency department when the patient gets handed off for hospital admission."
Collaboration also can improve patient flow and reduce ED diversion, shorten boarding times in the ED, and enhance quality and patient safety, Dr. Amin adds. "It's about how to optimize patient care for the benefit of the patient and the hospital," he says.
Visit our website for more information on hospitalists in the ED.
Hospitalists and ED physicians belong to two of the largest U.S. medical specialties and increasingly they are the only physicians seen by some hospitalized patients. Comanagement between the specialties is increasing in some hospitals, and in others, they might be the only physicians in the building after hours. They share similar workspaces, schedules, and responsibility for decisions about the most expensive care in medicine.
And yet there is not enough collaboration between the two specialties beyond brief phone encounters at handoff, says hospitalist Alpesh Amin, MD, MPA, MACP, SFHM, executive director of the hospitalist program at the University of California at Irvine. Dr. Amin coauthored a recent review highlighting opportunities for closer HM-ED collaboration with Charles Pollack Jr., MD, MA, FACEP, FAAEM, FAHA, who chairs the emergency department at Pennsylvania Hospital in Philadelphia.
A good place to start is for the two groups to simply sit down together regularly to discuss matters of common interest, perhaps monthly or quarterly, Dr. Amin says.
"Talk about clinical pathway development for common hospital diagnoses and how to improve admission processes," he adds. "There may be a role for the hospitalist in the emergency department when the patient gets handed off for hospital admission."
Collaboration also can improve patient flow and reduce ED diversion, shorten boarding times in the ED, and enhance quality and patient safety, Dr. Amin adds. "It's about how to optimize patient care for the benefit of the patient and the hospital," he says.
Visit our website for more information on hospitalists in the ED.
Hospitalists and ED physicians belong to two of the largest U.S. medical specialties and increasingly they are the only physicians seen by some hospitalized patients. Comanagement between the specialties is increasing in some hospitals, and in others, they might be the only physicians in the building after hours. They share similar workspaces, schedules, and responsibility for decisions about the most expensive care in medicine.
And yet there is not enough collaboration between the two specialties beyond brief phone encounters at handoff, says hospitalist Alpesh Amin, MD, MPA, MACP, SFHM, executive director of the hospitalist program at the University of California at Irvine. Dr. Amin coauthored a recent review highlighting opportunities for closer HM-ED collaboration with Charles Pollack Jr., MD, MA, FACEP, FAAEM, FAHA, who chairs the emergency department at Pennsylvania Hospital in Philadelphia.
A good place to start is for the two groups to simply sit down together regularly to discuss matters of common interest, perhaps monthly or quarterly, Dr. Amin says.
"Talk about clinical pathway development for common hospital diagnoses and how to improve admission processes," he adds. "There may be a role for the hospitalist in the emergency department when the patient gets handed off for hospital admission."
Collaboration also can improve patient flow and reduce ED diversion, shorten boarding times in the ED, and enhance quality and patient safety, Dr. Amin adds. "It's about how to optimize patient care for the benefit of the patient and the hospital," he says.
Visit our website for more information on hospitalists in the ED.
CDC: Test for hepatitis C in all baby boomers
The Centers for Disease Control and Prevention is urging hepatitis C testing for all Americans born between 1945 and 1965, as new data indicate that the baby boomers account for the largest proportion of cases yet are largely ignorant of their status.
"The take-home message from today’s report is that you may not remember everything that happened in the ’60s and ’70s, but your liver does," said CDC Director Thomas Frieden in a briefing with reporters.
"The bottom line here is, if you were born between those years, get tested," he said. "And if you’re positive, get follow-up testing."
Besides targeting consumers, the CDC also issued updated testing recommendations for physicians.
The guidelines, published May 7 in Morbidity and Mortality Weekly Report (MMWR), update the CDC’s 2003 testing recommendations.
The agency issued the update "because of changes in the availability of certain commercial HCV [hepatitis C virus] antibody tests, evidence that many persons who are identified as reactive by an HCV antibody test might not subsequently be evaluated to determine if they have current HCV infection, and significant advances in the development of antiviral agents with improved efficacy against HCV," according to the report.
The CDC first proposed such broad testing a year ago. New surveillance data published in MMWR give credence to the idea that baby boomers seem to be at particular risk.
Researchers from the CDC and the New York City Department of Health and Mental Hygiene analyzed hepatitis C testing data from 2005 to 2011 from eight U.S. sites: Colorado, Connecticut, Minnesota, New Mexico, New York City, New York State, Oregon, and San Francisco. Health officials at all of the sites received CDC funding for conducting enhanced surveillance.
The analysis found that 63% of the 217,755 people with newly reported positive HCV were born in the years 1945-1965. Of the total who tested positive, 107,209 (49%) had a positive antibody test, and 110,546 (51%) had a positive follow-up RNA test. That means about half of those who have an initial positive test are not following up with a confirmatory RNA test.
That is discouraging, said Dr. Frieden. "Right now, there are better hepatitis C treatments available than ever, and there are more treatments coming in the coming year," he said. "So, confirming that someone is infected is more important than ever."
The CDC estimates 100,000-120,000 deaths could be prevented with proper testing and follow-up care.
About 3 million people are currently infected; half will end up with cirrhosis, and at least a third will die from complications. Eighty percent of people with hepatitis C are chronically infected.
The CDC is updating its 2003 guidance for physicians on hepatitis C testing by urging that a positive HCV antibody test be followed up with RNA testing.
The findings in the MMWR study "give us an idea of the gap between those who are and are not receiving the test, and show us that we have a substantial challenge in front of us," said Dr. John Ward, director of the division of viral hepatitis in the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.
Baby boomers are likely to have been infected in their teens or 20s through transfusions or risky behaviors such as injection drug use. The CDC says risk factors for hepatitis C infection also include:
• Receiving clotting factor concentrates made before 1987, when more advanced methods for manufacturing those products were developed.
• Having a solid organ transplant before July 1992, when better testing became available.
• Chronic hemodialysis.
• Known exposure to HCV, such as needlesticks involving HCV-positive blood.
• HIV infection.
• Being born to an HCV-positive mother.
The CDC is exploring ways to make testing more available and to reach out to patients, Dr. Ward said. The agency has funded 25-30 demonstration projects, he added. Among the projects being tested: routine screening in the emergency department, and built-in reminders for physicians to test patients born in the target years.
Dr. Frieden urged immediate adoption of those reminders. "For health care providers, it’s very important to put in automatic systems to make sure that if someone has a positive antibody test, they go on to have follow-up testing and then get into care," he said.
The CDC issued its testing recommendations to coincide with Hepatitis Awareness Month and Hepatitis Testing Day, which is May 19.
On Twitter @aliciaault
The Centers for Disease Control and Prevention is urging hepatitis C testing for all Americans born between 1945 and 1965, as new data indicate that the baby boomers account for the largest proportion of cases yet are largely ignorant of their status.
"The take-home message from today’s report is that you may not remember everything that happened in the ’60s and ’70s, but your liver does," said CDC Director Thomas Frieden in a briefing with reporters.
"The bottom line here is, if you were born between those years, get tested," he said. "And if you’re positive, get follow-up testing."
Besides targeting consumers, the CDC also issued updated testing recommendations for physicians.
The guidelines, published May 7 in Morbidity and Mortality Weekly Report (MMWR), update the CDC’s 2003 testing recommendations.
The agency issued the update "because of changes in the availability of certain commercial HCV [hepatitis C virus] antibody tests, evidence that many persons who are identified as reactive by an HCV antibody test might not subsequently be evaluated to determine if they have current HCV infection, and significant advances in the development of antiviral agents with improved efficacy against HCV," according to the report.
The CDC first proposed such broad testing a year ago. New surveillance data published in MMWR give credence to the idea that baby boomers seem to be at particular risk.
Researchers from the CDC and the New York City Department of Health and Mental Hygiene analyzed hepatitis C testing data from 2005 to 2011 from eight U.S. sites: Colorado, Connecticut, Minnesota, New Mexico, New York City, New York State, Oregon, and San Francisco. Health officials at all of the sites received CDC funding for conducting enhanced surveillance.
The analysis found that 63% of the 217,755 people with newly reported positive HCV were born in the years 1945-1965. Of the total who tested positive, 107,209 (49%) had a positive antibody test, and 110,546 (51%) had a positive follow-up RNA test. That means about half of those who have an initial positive test are not following up with a confirmatory RNA test.
That is discouraging, said Dr. Frieden. "Right now, there are better hepatitis C treatments available than ever, and there are more treatments coming in the coming year," he said. "So, confirming that someone is infected is more important than ever."
The CDC estimates 100,000-120,000 deaths could be prevented with proper testing and follow-up care.
About 3 million people are currently infected; half will end up with cirrhosis, and at least a third will die from complications. Eighty percent of people with hepatitis C are chronically infected.
The CDC is updating its 2003 guidance for physicians on hepatitis C testing by urging that a positive HCV antibody test be followed up with RNA testing.
The findings in the MMWR study "give us an idea of the gap between those who are and are not receiving the test, and show us that we have a substantial challenge in front of us," said Dr. John Ward, director of the division of viral hepatitis in the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.
Baby boomers are likely to have been infected in their teens or 20s through transfusions or risky behaviors such as injection drug use. The CDC says risk factors for hepatitis C infection also include:
• Receiving clotting factor concentrates made before 1987, when more advanced methods for manufacturing those products were developed.
• Having a solid organ transplant before July 1992, when better testing became available.
• Chronic hemodialysis.
• Known exposure to HCV, such as needlesticks involving HCV-positive blood.
• HIV infection.
• Being born to an HCV-positive mother.
The CDC is exploring ways to make testing more available and to reach out to patients, Dr. Ward said. The agency has funded 25-30 demonstration projects, he added. Among the projects being tested: routine screening in the emergency department, and built-in reminders for physicians to test patients born in the target years.
Dr. Frieden urged immediate adoption of those reminders. "For health care providers, it’s very important to put in automatic systems to make sure that if someone has a positive antibody test, they go on to have follow-up testing and then get into care," he said.
The CDC issued its testing recommendations to coincide with Hepatitis Awareness Month and Hepatitis Testing Day, which is May 19.
On Twitter @aliciaault
The Centers for Disease Control and Prevention is urging hepatitis C testing for all Americans born between 1945 and 1965, as new data indicate that the baby boomers account for the largest proportion of cases yet are largely ignorant of their status.
"The take-home message from today’s report is that you may not remember everything that happened in the ’60s and ’70s, but your liver does," said CDC Director Thomas Frieden in a briefing with reporters.
"The bottom line here is, if you were born between those years, get tested," he said. "And if you’re positive, get follow-up testing."
Besides targeting consumers, the CDC also issued updated testing recommendations for physicians.
The guidelines, published May 7 in Morbidity and Mortality Weekly Report (MMWR), update the CDC’s 2003 testing recommendations.
The agency issued the update "because of changes in the availability of certain commercial HCV [hepatitis C virus] antibody tests, evidence that many persons who are identified as reactive by an HCV antibody test might not subsequently be evaluated to determine if they have current HCV infection, and significant advances in the development of antiviral agents with improved efficacy against HCV," according to the report.
The CDC first proposed such broad testing a year ago. New surveillance data published in MMWR give credence to the idea that baby boomers seem to be at particular risk.
Researchers from the CDC and the New York City Department of Health and Mental Hygiene analyzed hepatitis C testing data from 2005 to 2011 from eight U.S. sites: Colorado, Connecticut, Minnesota, New Mexico, New York City, New York State, Oregon, and San Francisco. Health officials at all of the sites received CDC funding for conducting enhanced surveillance.
The analysis found that 63% of the 217,755 people with newly reported positive HCV were born in the years 1945-1965. Of the total who tested positive, 107,209 (49%) had a positive antibody test, and 110,546 (51%) had a positive follow-up RNA test. That means about half of those who have an initial positive test are not following up with a confirmatory RNA test.
That is discouraging, said Dr. Frieden. "Right now, there are better hepatitis C treatments available than ever, and there are more treatments coming in the coming year," he said. "So, confirming that someone is infected is more important than ever."
The CDC estimates 100,000-120,000 deaths could be prevented with proper testing and follow-up care.
About 3 million people are currently infected; half will end up with cirrhosis, and at least a third will die from complications. Eighty percent of people with hepatitis C are chronically infected.
The CDC is updating its 2003 guidance for physicians on hepatitis C testing by urging that a positive HCV antibody test be followed up with RNA testing.
The findings in the MMWR study "give us an idea of the gap between those who are and are not receiving the test, and show us that we have a substantial challenge in front of us," said Dr. John Ward, director of the division of viral hepatitis in the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.
Baby boomers are likely to have been infected in their teens or 20s through transfusions or risky behaviors such as injection drug use. The CDC says risk factors for hepatitis C infection also include:
• Receiving clotting factor concentrates made before 1987, when more advanced methods for manufacturing those products were developed.
• Having a solid organ transplant before July 1992, when better testing became available.
• Chronic hemodialysis.
• Known exposure to HCV, such as needlesticks involving HCV-positive blood.
• HIV infection.
• Being born to an HCV-positive mother.
The CDC is exploring ways to make testing more available and to reach out to patients, Dr. Ward said. The agency has funded 25-30 demonstration projects, he added. Among the projects being tested: routine screening in the emergency department, and built-in reminders for physicians to test patients born in the target years.
Dr. Frieden urged immediate adoption of those reminders. "For health care providers, it’s very important to put in automatic systems to make sure that if someone has a positive antibody test, they go on to have follow-up testing and then get into care," he said.
The CDC issued its testing recommendations to coincide with Hepatitis Awareness Month and Hepatitis Testing Day, which is May 19.
On Twitter @aliciaault
Use of 'liberation therapy' may make MS worse
SAN DIEGO -- Percutaneous transluminal venous angioplasty – also known as "liberation therapy" -- doesn't help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.
The technique "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.
The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.
The idea is to use balloon angioplasty and stents to widen veins in the chest and neck that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.
The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.
"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.
Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.
There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.
PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.
"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.
The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.
Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.
The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.
The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.
The possibility of a causal relationship between MS and CCSVI gave patients with that chronic, debilitating, relapsing disease a glimmer of hope. Anecdotal reports of dramatic improvement with "liberation therapy" for treatment of MS raised expectations even further and created a demand for CCSVI interventions. Still, many vascular and neurological specialists remained skeptical of this approach, citing the lack of high-level evidence to support it. Some were even accused (mostly by patients) of withholding an effective treatment, while advocates of intervention tended to minimize the risks and cost involved. In spite of the controversy surrounding MS and CCSVI, there should be agreement that the "gold standard" for determining treatment efficacy is the randomized controlled clinical trial, and liberation therapy must be held to that standard. While not definitive, the small trial summarized here is a step in the right direction.
Dr. Robert Eugene Zierler, MD, is at the University of Washington, Seattle.
The possibility of a causal relationship between MS and CCSVI gave patients with that chronic, debilitating, relapsing disease a glimmer of hope. Anecdotal reports of dramatic improvement with "liberation therapy" for treatment of MS raised expectations even further and created a demand for CCSVI interventions. Still, many vascular and neurological specialists remained skeptical of this approach, citing the lack of high-level evidence to support it. Some were even accused (mostly by patients) of withholding an effective treatment, while advocates of intervention tended to minimize the risks and cost involved. In spite of the controversy surrounding MS and CCSVI, there should be agreement that the "gold standard" for determining treatment efficacy is the randomized controlled clinical trial, and liberation therapy must be held to that standard. While not definitive, the small trial summarized here is a step in the right direction.
Dr. Robert Eugene Zierler, MD, is at the University of Washington, Seattle.
The possibility of a causal relationship between MS and CCSVI gave patients with that chronic, debilitating, relapsing disease a glimmer of hope. Anecdotal reports of dramatic improvement with "liberation therapy" for treatment of MS raised expectations even further and created a demand for CCSVI interventions. Still, many vascular and neurological specialists remained skeptical of this approach, citing the lack of high-level evidence to support it. Some were even accused (mostly by patients) of withholding an effective treatment, while advocates of intervention tended to minimize the risks and cost involved. In spite of the controversy surrounding MS and CCSVI, there should be agreement that the "gold standard" for determining treatment efficacy is the randomized controlled clinical trial, and liberation therapy must be held to that standard. While not definitive, the small trial summarized here is a step in the right direction.
Dr. Robert Eugene Zierler, MD, is at the University of Washington, Seattle.
SAN DIEGO -- Percutaneous transluminal venous angioplasty – also known as "liberation therapy" -- doesn't help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.
The technique "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.
The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.
The idea is to use balloon angioplasty and stents to widen veins in the chest and neck that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.
The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.
"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.
Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.
There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.
PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.
"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.
The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.
Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.
The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.
The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.
SAN DIEGO -- Percutaneous transluminal venous angioplasty – also known as "liberation therapy" -- doesn't help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.
The technique "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.
The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.
The idea is to use balloon angioplasty and stents to widen veins in the chest and neck that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.
The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.
"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.
Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.
There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.
PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.
"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.
The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.
Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.
The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.
The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.
Ultrasound expedites pediatric emergency evaluations
LAKE BUENA VISTA, FLA. – Ultrasound expedites clinical decision making and often dictates the next step to pursue when managing children in the emergency department.
"It makes sense to use ultrasound for pediatric patients, but there’s been a delay in picking up this idea. Only now is (the use of bedside ultrasonography) becoming more prevalent in pediatric emergency medicine, Dr. Stephanie J. Doniger said at a meeting sponsored by the American College of Emergency Physicians and the American Academy of Pediatrics.
"Among the advantages is that we really never have to perform sedation, and the absolutely most important thing, we don’t need to use ionizing radiation," said Dr. Doniger, director of emergency ultrasound at Children’s Hospital and Research Center, Oakland, Calif.
Still, she said, there are no clear guidelines for ultrasonography’s use in pediatric emergencies. No one body oversees the quality in training or in outcomes. In 2009, ACEP updated its guidelines on bedside ultrasound in the emergency department. The group gave a nod to pediatric use, calling ultrasonography "an ideal diagnostic tool for children ... As in adult patients, emergency ultrasound in children can be life saving, time saving, [can] increase procedural efficiency, and [can] maximize patient safety."
The document says ultrasound is particularly useful in performing the FAST exam, and for bladder evaluations prior to instilling a catheter in infants. Dr. Doniger noted a number of other applications as well.
Ultrasonography is valuable for assessing dehydration by providing a look at the inferior vena cava. "We’re looking here for collapsibility during inspiration. Collapsibility of more than 50% correlates with dehydration."
Appendicitis is tough to image, radiographs are unreliable, and "CTs aren’t great, but we do them if we have to." But ultrasound provides a very good look into what lies beneath, and is one more way to reduce a child’s cumulative radiation dose.
A 2008 study found that a 5-minute bedside ultrasound had a sensitivity of 65% and a specificity of 90% for appendicitis. The positive predictive value was 84%, and the negative predictive value, 76%.
"That might not sound great, but it is a good result to rule in disease. If you have a high suspicion of appendicitis, then use it; if a low suspicion, then don’t."
When looking for an infected appendix, start at the point of maximal tenderness and move to the right while the child is in an oblique position. "It helps if you prop up the hip with some towels," Dr. Doniger said. "The bowel will move away and you’ll have a better view when you compress."
Look for a noncompressible tubular structure with a diameter greater than 6 mm.
The probe can also help find intussusception – a condition that x-rays identify 40%-90% of the time. The ultrasound image of intussusception is target- or doughnut-shaped – a figure formed when the bowel retracts back into itself. A study found that even beginning sonographers can identify this classic sign. Their exams had a sensitivity of 85%, a specificity of 97%, a positive predictive value of 85%, and a negative predictive value of 97%.
Even something that seems innocuous on the surface – like a splinter – will give up its secrets under the ultrasound probe. Foreign bodies may or may not show up on an x-ray, but they are obviously hypoechoic on ultrasound, she said.
Dr. Doniger presented the case of a 13-year-old who thought he got a splinter under his fingernail, but wasn’t sure. He came to the emergency department after his finger became stiff and a little painful. Ultrasound identified the culprit as splinter of wood that was more than 1 inch long.
Guiding the needle during an evaluation for painful hips for effusion is another great use for ultrasound, she said. A 2009 study determined that, compared with ultrasound alone; sonography-guided arthrocentesis for symptomatic hips had 90% sensitivity and 100% specificity, with a 100% positive predictive value and a 92% negative predictive value.
Ultrasound also provides valuable assistance in identifying the landmarks for successful needle placement when performing a spinal tap. A 2007 study equally randomized 46 children to finding the landmarks by palpation or with ultrasound. There were six failed attempts in the palpation group and one in the ultrasound group. Ultrasound was particularly helpful in obese children; four of seven palpation placements failed, compared with no failures in the ultrasound group.
None of the authors declared any financial relationships. The study was funded by the Lynn Sage Cancer Research Foundation, the Avon Foundation, and a private contribution.
LAKE BUENA VISTA, FLA. – Ultrasound expedites clinical decision making and often dictates the next step to pursue when managing children in the emergency department.
"It makes sense to use ultrasound for pediatric patients, but there’s been a delay in picking up this idea. Only now is (the use of bedside ultrasonography) becoming more prevalent in pediatric emergency medicine, Dr. Stephanie J. Doniger said at a meeting sponsored by the American College of Emergency Physicians and the American Academy of Pediatrics.
"Among the advantages is that we really never have to perform sedation, and the absolutely most important thing, we don’t need to use ionizing radiation," said Dr. Doniger, director of emergency ultrasound at Children’s Hospital and Research Center, Oakland, Calif.
Still, she said, there are no clear guidelines for ultrasonography’s use in pediatric emergencies. No one body oversees the quality in training or in outcomes. In 2009, ACEP updated its guidelines on bedside ultrasound in the emergency department. The group gave a nod to pediatric use, calling ultrasonography "an ideal diagnostic tool for children ... As in adult patients, emergency ultrasound in children can be life saving, time saving, [can] increase procedural efficiency, and [can] maximize patient safety."
The document says ultrasound is particularly useful in performing the FAST exam, and for bladder evaluations prior to instilling a catheter in infants. Dr. Doniger noted a number of other applications as well.
Ultrasonography is valuable for assessing dehydration by providing a look at the inferior vena cava. "We’re looking here for collapsibility during inspiration. Collapsibility of more than 50% correlates with dehydration."
Appendicitis is tough to image, radiographs are unreliable, and "CTs aren’t great, but we do them if we have to." But ultrasound provides a very good look into what lies beneath, and is one more way to reduce a child’s cumulative radiation dose.
A 2008 study found that a 5-minute bedside ultrasound had a sensitivity of 65% and a specificity of 90% for appendicitis. The positive predictive value was 84%, and the negative predictive value, 76%.
"That might not sound great, but it is a good result to rule in disease. If you have a high suspicion of appendicitis, then use it; if a low suspicion, then don’t."
When looking for an infected appendix, start at the point of maximal tenderness and move to the right while the child is in an oblique position. "It helps if you prop up the hip with some towels," Dr. Doniger said. "The bowel will move away and you’ll have a better view when you compress."
Look for a noncompressible tubular structure with a diameter greater than 6 mm.
The probe can also help find intussusception – a condition that x-rays identify 40%-90% of the time. The ultrasound image of intussusception is target- or doughnut-shaped – a figure formed when the bowel retracts back into itself. A study found that even beginning sonographers can identify this classic sign. Their exams had a sensitivity of 85%, a specificity of 97%, a positive predictive value of 85%, and a negative predictive value of 97%.
Even something that seems innocuous on the surface – like a splinter – will give up its secrets under the ultrasound probe. Foreign bodies may or may not show up on an x-ray, but they are obviously hypoechoic on ultrasound, she said.
Dr. Doniger presented the case of a 13-year-old who thought he got a splinter under his fingernail, but wasn’t sure. He came to the emergency department after his finger became stiff and a little painful. Ultrasound identified the culprit as splinter of wood that was more than 1 inch long.
Guiding the needle during an evaluation for painful hips for effusion is another great use for ultrasound, she said. A 2009 study determined that, compared with ultrasound alone; sonography-guided arthrocentesis for symptomatic hips had 90% sensitivity and 100% specificity, with a 100% positive predictive value and a 92% negative predictive value.
Ultrasound also provides valuable assistance in identifying the landmarks for successful needle placement when performing a spinal tap. A 2007 study equally randomized 46 children to finding the landmarks by palpation or with ultrasound. There were six failed attempts in the palpation group and one in the ultrasound group. Ultrasound was particularly helpful in obese children; four of seven palpation placements failed, compared with no failures in the ultrasound group.
None of the authors declared any financial relationships. The study was funded by the Lynn Sage Cancer Research Foundation, the Avon Foundation, and a private contribution.
LAKE BUENA VISTA, FLA. – Ultrasound expedites clinical decision making and often dictates the next step to pursue when managing children in the emergency department.
"It makes sense to use ultrasound for pediatric patients, but there’s been a delay in picking up this idea. Only now is (the use of bedside ultrasonography) becoming more prevalent in pediatric emergency medicine, Dr. Stephanie J. Doniger said at a meeting sponsored by the American College of Emergency Physicians and the American Academy of Pediatrics.
"Among the advantages is that we really never have to perform sedation, and the absolutely most important thing, we don’t need to use ionizing radiation," said Dr. Doniger, director of emergency ultrasound at Children’s Hospital and Research Center, Oakland, Calif.
Still, she said, there are no clear guidelines for ultrasonography’s use in pediatric emergencies. No one body oversees the quality in training or in outcomes. In 2009, ACEP updated its guidelines on bedside ultrasound in the emergency department. The group gave a nod to pediatric use, calling ultrasonography "an ideal diagnostic tool for children ... As in adult patients, emergency ultrasound in children can be life saving, time saving, [can] increase procedural efficiency, and [can] maximize patient safety."
The document says ultrasound is particularly useful in performing the FAST exam, and for bladder evaluations prior to instilling a catheter in infants. Dr. Doniger noted a number of other applications as well.
Ultrasonography is valuable for assessing dehydration by providing a look at the inferior vena cava. "We’re looking here for collapsibility during inspiration. Collapsibility of more than 50% correlates with dehydration."
Appendicitis is tough to image, radiographs are unreliable, and "CTs aren’t great, but we do them if we have to." But ultrasound provides a very good look into what lies beneath, and is one more way to reduce a child’s cumulative radiation dose.
A 2008 study found that a 5-minute bedside ultrasound had a sensitivity of 65% and a specificity of 90% for appendicitis. The positive predictive value was 84%, and the negative predictive value, 76%.
"That might not sound great, but it is a good result to rule in disease. If you have a high suspicion of appendicitis, then use it; if a low suspicion, then don’t."
When looking for an infected appendix, start at the point of maximal tenderness and move to the right while the child is in an oblique position. "It helps if you prop up the hip with some towels," Dr. Doniger said. "The bowel will move away and you’ll have a better view when you compress."
Look for a noncompressible tubular structure with a diameter greater than 6 mm.
The probe can also help find intussusception – a condition that x-rays identify 40%-90% of the time. The ultrasound image of intussusception is target- or doughnut-shaped – a figure formed when the bowel retracts back into itself. A study found that even beginning sonographers can identify this classic sign. Their exams had a sensitivity of 85%, a specificity of 97%, a positive predictive value of 85%, and a negative predictive value of 97%.
Even something that seems innocuous on the surface – like a splinter – will give up its secrets under the ultrasound probe. Foreign bodies may or may not show up on an x-ray, but they are obviously hypoechoic on ultrasound, she said.
Dr. Doniger presented the case of a 13-year-old who thought he got a splinter under his fingernail, but wasn’t sure. He came to the emergency department after his finger became stiff and a little painful. Ultrasound identified the culprit as splinter of wood that was more than 1 inch long.
Guiding the needle during an evaluation for painful hips for effusion is another great use for ultrasound, she said. A 2009 study determined that, compared with ultrasound alone; sonography-guided arthrocentesis for symptomatic hips had 90% sensitivity and 100% specificity, with a 100% positive predictive value and a 92% negative predictive value.
Ultrasound also provides valuable assistance in identifying the landmarks for successful needle placement when performing a spinal tap. A 2007 study equally randomized 46 children to finding the landmarks by palpation or with ultrasound. There were six failed attempts in the palpation group and one in the ultrasound group. Ultrasound was particularly helpful in obese children; four of seven palpation placements failed, compared with no failures in the ultrasound group.
None of the authors declared any financial relationships. The study was funded by the Lynn Sage Cancer Research Foundation, the Avon Foundation, and a private contribution.
EXPERT ANALYSIS AT THE ADVANCED PEDIATRIC EMERGENCY MEDICINE ASSEMBLY