ATLANTA – In the opinion of John M. Kelso, MD, assessment of immunization status in older adults should be a routine part of all visits.

“Don’t assume that your patients are getting their vaccines someplace else,” he said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “We should be taking advantage of the fact that these patients are in our offices.”

Inactivated influenza vaccine (IIV3)

For adults aged 65 and older, the high-dose, trivalent version of the flu vaccine (60 micrograms of hemagglutinin per strain, or IIV3-HD) may be preferable to the standard dose of 15 micrograms of hemagglutinin per strain (IIV3-SD). A study of nearly 32,000 patients found that IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza, compared with IIV3-SD (N Engl J Med. 2014;371:635-45). The relative efficacy of high dose vs. standard dose was 24.2%. “That means that one-quarter of all breakthrough influenza illnesses could be prevented if IIV3HD were used instead of IIV3-SD,” Dr. Kelso said.

Another approach is to use an adjuvanted influenza vaccine, which contains the standard 15 micrograms of influenza antigen but the adjuvant is MF59, a squalene-based oil-in-water emulsion. One small study of 282 patients aged 65 and older showed the adjuvanted vaccine to be more effective than the unadjuvanted vaccine (Vaccine. 2013;51:1622-8).

The Centers for Disease Control and Prevention does not express a preference for the high-dose or adjuvanted vaccine, but rather stresses the importance of influenza vaccination with whatever age-appropriate IIV formulation is available at the time of the patient’s visit.

The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23)

All adults who turn 65 years of age should receive the PCV13, followed 1 year later by the PPSV23. For those who already received the PPSV23 after age 65 years of age, they should receive the PCV13 at least 1 year later. “The real bulk of hospitalizations and fatalities from invasive pneumococcal disease are happening to people over 65 year of age,” said Dr. Kelso, who is also a clinical professor of pediatrics and internal medicine at the University of California, San Diego “So there’s a real need here for vaccination.”

Tdap

This should be administered to all adolescents and adults regardless of interval since their last tetanus-diphtheria vaccine. “This includes those age 65 years of age and older in whom the vaccine has been found to be equally safe and immunogenic,” Dr. Kelso said. “This is important not only to prevent pertussis in older adults, but also to prevent them from spreading the disease to infants where it can be fatal.”

Zoster vaccine

One in three adults will develop zoster during their lifetime, he said, and one million episodes occur in the United States each year. Common complications include postherpetic neuralgia and eye involvement that can result in loss of vision. The CDC recommends routine vaccination of all immunocompetent persons over age 60 with one dose of zoster vaccine. “Persons who report a previous episode of zoster can be vaccinated but it is not indicated to treat acute zoster, to prevent persons with acute zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia,” Dr. Kelso said.

He reported having no relevant financial disclosures.

[email protected]

ATLANTA – In the opinion of John M. Kelso, MD, assessment of immunization status in older adults should be a routine part of all visits.

“Don’t assume that your patients are getting their vaccines someplace else,” he said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “We should be taking advantage of the fact that these patients are in our offices.”

Inactivated influenza vaccine (IIV3)

For adults aged 65 and older, the high-dose, trivalent version of the flu vaccine (60 micrograms of hemagglutinin per strain, or IIV3-HD) may be preferable to the standard dose of 15 micrograms of hemagglutinin per strain (IIV3-SD). A study of nearly 32,000 patients found that IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza, compared with IIV3-SD (N Engl J Med. 2014;371:635-45). The relative efficacy of high dose vs. standard dose was 24.2%. “That means that one-quarter of all breakthrough influenza illnesses could be prevented if IIV3HD were used instead of IIV3-SD,” Dr. Kelso said.

Another approach is to use an adjuvanted influenza vaccine, which contains the standard 15 micrograms of influenza antigen but the adjuvant is MF59, a squalene-based oil-in-water emulsion. One small study of 282 patients aged 65 and older showed the adjuvanted vaccine to be more effective than the unadjuvanted vaccine (Vaccine. 2013;51:1622-8).

The Centers for Disease Control and Prevention does not express a preference for the high-dose or adjuvanted vaccine, but rather stresses the importance of influenza vaccination with whatever age-appropriate IIV formulation is available at the time of the patient’s visit.

The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23)

All adults who turn 65 years of age should receive the PCV13, followed 1 year later by the PPSV23. For those who already received the PPSV23 after age 65 years of age, they should receive the PCV13 at least 1 year later. “The real bulk of hospitalizations and fatalities from invasive pneumococcal disease are happening to people over 65 year of age,” said Dr. Kelso, who is also a clinical professor of pediatrics and internal medicine at the University of California, San Diego “So there’s a real need here for vaccination.”

Tdap

This should be administered to all adolescents and adults regardless of interval since their last tetanus-diphtheria vaccine. “This includes those age 65 years of age and older in whom the vaccine has been found to be equally safe and immunogenic,” Dr. Kelso said. “This is important not only to prevent pertussis in older adults, but also to prevent them from spreading the disease to infants where it can be fatal.”

Zoster vaccine

One in three adults will develop zoster during their lifetime, he said, and one million episodes occur in the United States each year. Common complications include postherpetic neuralgia and eye involvement that can result in loss of vision. The CDC recommends routine vaccination of all immunocompetent persons over age 60 with one dose of zoster vaccine. “Persons who report a previous episode of zoster can be vaccinated but it is not indicated to treat acute zoster, to prevent persons with acute zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia,” Dr. Kelso said.

He reported having no relevant financial disclosures.

[email protected]

ATLANTA – In the opinion of John M. Kelso, MD, assessment of immunization status in older adults should be a routine part of all visits.

“Don’t assume that your patients are getting their vaccines someplace else,” he said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “We should be taking advantage of the fact that these patients are in our offices.”

Inactivated influenza vaccine (IIV3)

For adults aged 65 and older, the high-dose, trivalent version of the flu vaccine (60 micrograms of hemagglutinin per strain, or IIV3-HD) may be preferable to the standard dose of 15 micrograms of hemagglutinin per strain (IIV3-SD). A study of nearly 32,000 patients found that IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza, compared with IIV3-SD (N Engl J Med. 2014;371:635-45). The relative efficacy of high dose vs. standard dose was 24.2%. “That means that one-quarter of all breakthrough influenza illnesses could be prevented if IIV3HD were used instead of IIV3-SD,” Dr. Kelso said.

Another approach is to use an adjuvanted influenza vaccine, which contains the standard 15 micrograms of influenza antigen but the adjuvant is MF59, a squalene-based oil-in-water emulsion. One small study of 282 patients aged 65 and older showed the adjuvanted vaccine to be more effective than the unadjuvanted vaccine (Vaccine. 2013;51:1622-8).

The Centers for Disease Control and Prevention does not express a preference for the high-dose or adjuvanted vaccine, but rather stresses the importance of influenza vaccination with whatever age-appropriate IIV formulation is available at the time of the patient’s visit.

The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23)

All adults who turn 65 years of age should receive the PCV13, followed 1 year later by the PPSV23. For those who already received the PPSV23 after age 65 years of age, they should receive the PCV13 at least 1 year later. “The real bulk of hospitalizations and fatalities from invasive pneumococcal disease are happening to people over 65 year of age,” said Dr. Kelso, who is also a clinical professor of pediatrics and internal medicine at the University of California, San Diego “So there’s a real need here for vaccination.”

Tdap

This should be administered to all adolescents and adults regardless of interval since their last tetanus-diphtheria vaccine. “This includes those age 65 years of age and older in whom the vaccine has been found to be equally safe and immunogenic,” Dr. Kelso said. “This is important not only to prevent pertussis in older adults, but also to prevent them from spreading the disease to infants where it can be fatal.”

Zoster vaccine

One in three adults will develop zoster during their lifetime, he said, and one million episodes occur in the United States each year. Common complications include postherpetic neuralgia and eye involvement that can result in loss of vision. The CDC recommends routine vaccination of all immunocompetent persons over age 60 with one dose of zoster vaccine. “Persons who report a previous episode of zoster can be vaccinated but it is not indicated to treat acute zoster, to prevent persons with acute zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia,” Dr. Kelso said.

He reported having no relevant financial disclosures.

[email protected]

SEATTLE – When men who have sex with men were given doxycycline and told to take it after unprotected sex, the incidence of sexually transmitted infections dropped 47% over about 9 months in France.

“We were quite surprised to see” such a strong effect, especially since it was achieved with “a very low use of doxycycline, less than two pills per week” among the 232 men in the study, said lead investigator Jean-Michel Molina, MD, of St. Louis Hospital, Paris.

Alexander Otto/Frontline Medical News

[email protected]

On Twitter @IDPractitioner

SEATTLE – When men who have sex with men were given doxycycline and told to take it after unprotected sex, the incidence of sexually transmitted infections dropped 47% over about 9 months in France.

“We were quite surprised to see” such a strong effect, especially since it was achieved with “a very low use of doxycycline, less than two pills per week” among the 232 men in the study, said lead investigator Jean-Michel Molina, MD, of St. Louis Hospital, Paris.

Alexander Otto/Frontline Medical News

[email protected]

On Twitter @IDPractitioner

SEATTLE – When men who have sex with men were given doxycycline and told to take it after unprotected sex, the incidence of sexually transmitted infections dropped 47% over about 9 months in France.

“We were quite surprised to see” such a strong effect, especially since it was achieved with “a very low use of doxycycline, less than two pills per week” among the 232 men in the study, said lead investigator Jean-Michel Molina, MD, of St. Louis Hospital, Paris.

Alexander Otto/Frontline Medical News

[email protected]

On Twitter @IDPractitioner

Lymphomas constitute a very heterogeneous group of neoplasms with diverse clinical presentations, prognoses, and responses to therapy. Approximately 80,500 new cases of lymphoma are expected to be diagnosed in the United States in 2017, of which about one quarter will lead to the death of the patient.¹ Perhaps more so than any other group of neoplasms, the diagnosis of lymphoma involves the integration of a multiplicity of clinical, histologic and immunophenotypic findings and, on occasion, cytogenetic and molecular results as well. An accurate diagnosis of lymphoma, usually rendered by hematopathologists, allows hematologists/oncologists to treat patients appropriately. Herein we will describe a simplified approach to the diagnosis and classification of lymphomas (Figure 1).

Lymphoma classification

Lymphomas are clonal neoplasms characterized by the expansion of abnormal lymphoid cells that may develop in any organ but commonly involve lymph nodes. The fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid tissues, published in 2008, is the official and most current guideline used for diagnosis of lymphoid neoplasms.² The WHO scheme classifies lymphomas according to the type of cell from which they are derived (mature and immature B cells, T cells, or natural killer (NK) cells, findings determined by their morphology and immunophenotype) and their clinical, cytogenetic, and/or molecular features. This official classification is currently being updated³ and is expected to be published in full in 2017, at which time it is anticipated to include definitions for more than 70 distinct neoplasms.

Lymphomas are broadly and informally classified as Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs), based on the differences these two groups show in their clinical presentation, treatment, prognosis, and proportion of neoplastic cells, among others. NHLs are by far the most common type of lymphomas, accounting for approximately 90% of all new cases of lymphoma in the United States and 70% worldwide.^1,2 NHLs are a very heterogeneous group of B-, T-, or NK-cell neoplasms that, in turn, can also be informally subclassified as low-grade (or indolent) or high-grade (or aggressive) according to their predicted clinical behavior. HLs are comparatively rare, less heterogeneous, uniformly of B-cell origin and, in the case of classical Hodgkin lymphoma, highly curable.^1,2 It is beyond the scope of this manuscript to outline the features of each of the >70 specific entities, but the reader is referred elsewhere for more detail and encouraged to become familiarized with the complexity, challenges, and beauty of lymphoma diagnosis.^2,3

Biopsy procedure

A correct diagnosis begins with an adequate biopsy procedure. It is essential that biopsy specimens for lymphoma evaluation be submitted fresh and unfixed, because some crucial analyses such as flow cytometry or conventional cytogenetics can only be performed on fresh tissue. Indeed, it is important for the hematologist/oncologist and/or surgeon and/or interventional radiologist to converse with the hematopathologist prior to and even during some procedures to ensure the correct processing of the specimen. Also, it is important to limit the compression of the specimen and the excessive use of cauterization during the biopsy procedure, both of which cause artifacts that may render impossible the interpretation of the histopathologic findings.

Given that the diagnosis of lymphoma is based not only on the cytologic details of the lymphoma cells but also on the architectural pattern with which they infiltrate an organ, the larger the biopsy specimen, the easier it will be for a hematopathologist to identify the pattern. In addition, excisional biopsies frequently contain more diagnostic tissue than needle core biopsies and this provides pathologists with the option to submit tissue fragments for ancillary tests that require unfixed tissue as noted above. Needle core biopsies of lymph nodes are increasingly being used because of their association with fewer complications and lower cost than excisional biopsies. However, needle core biopsies provide only a glimpse of the pattern of infiltration and may not be completely representative of the architecture. Therefore, excisional lymph node biopsies of lymph nodes are preferred over needle core biopsies, recognizing that in the setting of deeply seated lymph nodes, needle core biopsies may be the only or the best surgical option.

Clinical presentation

Accurate diagnosis of lymphoma cannot take place in a vacuum. The hematopathologist’s initial approach to the diagnosis of lymphoid processes in tissue biopsies should begin with a thorough review of the clinical history, although some pathology laboratories may not have immediate access to this information. The hematopathologist should evaluate factors such as age, gender, location of the tumor, symptomatology, medications, serology, and prior history of malignancy, immunosuppression or immunodeficiency in every case. Other important but frequently omitted parts of the clinical history are the patient’s occupation, history of exposure to animals, and the presence of tattoos, which may be associated with certain reactive lymphadenopathies.

Histomorphologic evaluation

Despite the plethora of new and increasingly sophisticated tools, histologic and morphologic analysis still remains the cornerstone of diagnosis in hematopathology. However, for the characterization of an increasing number of reactive and neoplastic lymphoid processes, hematopathologists may also require immunophenotypic, molecular, and cytogenetic tests for an accurate diagnosis. Upon review of the clinical information, a microscopic evaluation of the tissue submitted for processing by the histology laboratory will be performed. The results of concurrent flow cytometric evaluation (performed on fresh unfixed material) should also be available in most if not all cases before the H&E-stained slides are available for review. Upon receipt of H&E-stained slides, the hematopathologist will evaluate the quality of the submitted specimen, since many diagnostic difficulties stem from suboptimal techniques related to the biopsy procedure, fixation, processing, cutting, or staining (Figure 1). If deemed suitable for accurate diagnosis, a search for signs of preservation or disruption of the organ that was biopsied will follow. The identification of certain morphologic patterns aids the hematopathologist in answering the first question: “what organ is this and is this consistent with what is indicated on the requisition?” This is usually immediately followed by “is this sufficient and adequate material for a diagnosis?” and “is there any normal architecture?” If the architecture is not normal, “is this alteration due to a reactive or a neoplastic process?” If neoplastic, “is it lymphoma or a non-hematolymphoid neoplasm?”

Both reactive and neoplastic processes have variably unique morphologic features that if properly recognized, guide the subsequent testing. However, some reactive and neoplastic processes can present with overlapping features, and even after extensive immunophenotypic evaluation and the performance of ancillary studies, it may not be possible to conclusively determine its nature. If the lymph node architecture is altered or effaced, the predominant pattern of infiltration (eg, nodular, diffuse, interfollicular, intrasinusoidal) and the degree of alteration of the normal architecture is evaluated, usually at low magnification. When the presence of an infiltrate is recognized, its components must be characterized. If the infiltrate is composed of a homogeneous expansion of lymphoid cells that disrupts or replaces the normal lymphoid architecture, a lymphoma will be suspected or diagnosed. The pattern of distribution of the cells along with their individual morphologic characteristics (ie, size, nuclear shape, chromatin configuration, nucleoli, amount and hue of cytoplasm) are key factors for the diagnosis and classification of the lymphoma that will guide subsequent testing. The immunophenotypic analysis (by immunohistochemistry, flow cytometry or a combination of both) may confirm the reactive or neoplastic nature of the process, and its subclassification. B-cell lymphomas, in particular have variable and distinctive histologic features: as a diffuse infiltrate of large mature lymphoid cells (eg, diffuse large B-cell lymphoma), an expansion of immature lymphoid cells (lymphoblastic lymphoma), and a nodular infiltrate of small, intermediate and/or mature large B cells (eg, follicular lymphoma).

Immunophenotypic evaluation

Immunophenotypic evaluation is essential because the lineage of lymphoma cells cannot be determined by morphology alone. The immunophenotype is the combination of proteins/markers (eg, CD20, CD3, TdT) expressed by cells. Usually, it is evaluated by immunohistochemistry and/or flow cytometry, which help determine the proportion of lymphoid cells that express a certain marker and its location and intensity within the cells. While immunohistochemistry is normally performed on formalin-fixed and paraffin-embedded tissue, flow cytometry can be evaluated only on fresh unfixed tissue. Flow cytometry has the advantage over immunohistochemistry of being faster and better at simultaneously identifying coexpression of multiple markers on multiple cell populations. However, certain markers can only be evaluated by immunohistochemistry.

The immunophenotypic analysis will in most cases reveal whether the lymphomas is of B-, T- or NK-cell origin, and whether a lymphoma subtype associated immunophenotype is present. Typical pan B-cell antigens include PAX5, CD19, and CD79a (CD20 is less broadly expressed throughout B-cell differentiation, although it is usually evident in most mature B-cell lymphomas), and typical pan T-cell antigens include CD2, CD5, and CD7. The immature or mature nature of a lymphoma can also be confirmed by evaluation of the immunophenotype. Immature lymphomas commonly express one or more of TdT, CD10, or CD34; T-lymphoblastic lymphoma cells may also coexpress CD1a. The majority of NHLs and all HLs are derived from (or reflect) B cells at different stages of maturation. Mature B-cell lymphomas are the most common type of lymphoma and typically, but not always, express pan B-cell markers as well as surface membrane immunoglobulin, with the latter also most useful in assessing clonality via a determination of light chain restriction. Some mature B-cell lymphomas tend to acquire markers that are either never physiologically expressed by normal mature B cells (eg, cyclin D1 in mantle cell lymphoma, or BCL2 in germinal center B cells in follicular lymphoma) or only expressed in a minor fraction (eg, CD5 that is characteristically expressed in small lymphocytic and mantle cell lymphoma). The most common mature B-cell lymphomas include diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (Figures 2 and 3). Classical HLs are also lymphomas of B-cell origin that demonstrate diminished preservation of their B-cell immunophenotype (as evidenced by the dim expression of PAX5 but absence of most other pan B-cell antigens), expression of CD30, variable expression of CD15, and loss of CD45 (Figure 1). In contrast, nodular lymphocyte predominant HL shows a preserved B-cell immunophenotypic program and expression of CD45, typically without CD30 and CD15. Of note, the evaluation of the immunophenotype of the neoplastic cells in HL is routinely assessed by immunohistochemistry because most flow cytometry laboratories cannot reliably detect and characterize the low numbers of these cells.

Mature T-cell lymphomas generally express one or more T-cell markers, and tend to display a T-helper (CD4-positive) or cytotoxic (CD8-positive) immunophenotype and may show loss of markers expressed by most normal T-cells (eg, CD5, CD7; Figure 4). However, a subset of them may express markers not commonly detected in normal T cells, such as ALK. NK-cell lymphomas lack surface CD3 (expressing only cytoplasmic CD3) and CD5 but express some pan T-cell antigens (such as CD2 and CD7) as well as CD16 and/or CD56.

Patients with primary or acquired immune dysfunction are at risk for development of lymphoma and other less clearly defined lymphoproliferative disorders, the majority of which are associated with infection of the lymphoid cells with Epstein-Barr virus (EBV). Therefore, evaluation with chromogenic in situ hybridization for an EBV-encoded early RNA (EBER1) is routinely performed in these cases; it is thus essential that the hematopathologist be informed of the altered immune system of the patient. If lymphoma develops, they may be morphologically similar to those that appear in immunocompetent patients, which specifically in the post-transplant setting are known as monomorphic post-transplant lymphoproliferative disorders (PTLD). If the PTLD does not meet the criteria for any of the recognized types of lymphoma, it may be best characterized as a polymorphic PTLD.

Once the lineage (B-, T-, or NK-cell) of the mature lymphoma has been established, the sum (and on occasion the gestalt) of the clinical, morphologic, immunophenotypic and other findings will be considered for the subclassification of the neoplasm.

Cytogenetic and molecular evaluation

If the morphologic and immunophenotypic analysis is inconclusive or nondiagnostic, then molecular and/or cytogenetic testing may further aid in the characterization of the process. Some of available molecular tests include analyses for the rearrangements of the variable region of the immunoglobulin (IG) or T-cell receptor (TCR) genes and for mutations on specific genes. The identification of specific mutations not only confirms the clonal nature of the process but, on occasion, it may also help subclassify the lymphoma, whereas IG or TCR rearrangement studies are used to establish whether a lymphoid expansion is polyclonal or monoclonal. The molecular findings should not be evaluated in isolation, because not all monoclonal rearrangements are diagnostic of lymphoma, and not all lymphomas will show a monoclonal rearrangement. Other methodologies that can aid in the identification of a clonal process or specific genetic abnormalities include metaphase cytogenetics (karyotyping) and fluorescence in situ hybridization (FISH). If any cytogenetic abnormalities are found in sufficient numbers (and constitutional abnormalities are excluded), their identification indicates the presence of a clonal process. Also, some cytogenetic abnormalities are characteristic of certain lymphomas. However, they may be neither 100% diagnostically sensitive nor diagnostically specific, for example, the hallmark t(14;18)/IGH-BCL2 is not present in all follicular lymphomas and not all lymphomas with this translocation are follicular lymphomas. Whereas FISH is generally performed on a minimum of 200 cells, compared with typically 20 metaphase by “conventional” karyotyping, and is therefore considered to have higher analytical sensitivity, it evaluates only for the presence or absence of the abnormality being investigated with a given set of probes, and therefore other abnormalities, if present, will not be identified. The value of FISH cytogenetic studies is perhaps best illustrated in the need to diagnose double hit lymphomas, amongst other scenarios. The detection of certain mutations can aid in the diagnosis of certain lymphomas, such as MYD88 in lymphoplasmacytic lymphoma, prognosis of others, such as in follicular lymphoma and identify pathways that may be precisely therapeutically targeted.

Final remarks

The diagnosis of lymphoma can be complex and usually requires the hematopathologist to integrate multiple parameters. The classification of lymphomas is not static, and new entities or variants are continuously described, and the facets of well-known ones refined. While such changes are often to the chagrin of hematologists/oncologists and hematopathologists alike, we should embrace the incorporation of nascent and typically cool data into our practice, as more therapeutically relevant entities are molded.

Lymphomas constitute a very heterogeneous group of neoplasms with diverse clinical presentations, prognoses, and responses to therapy. Approximately 80,500 new cases of lymphoma are expected to be diagnosed in the United States in 2017, of which about one quarter will lead to the death of the patient.¹ Perhaps more so than any other group of neoplasms, the diagnosis of lymphoma involves the integration of a multiplicity of clinical, histologic and immunophenotypic findings and, on occasion, cytogenetic and molecular results as well. An accurate diagnosis of lymphoma, usually rendered by hematopathologists, allows hematologists/oncologists to treat patients appropriately. Herein we will describe a simplified approach to the diagnosis and classification of lymphomas (Figure 1).

Lymphoma classification

Lymphomas are clonal neoplasms characterized by the expansion of abnormal lymphoid cells that may develop in any organ but commonly involve lymph nodes. The fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid tissues, published in 2008, is the official and most current guideline used for diagnosis of lymphoid neoplasms.² The WHO scheme classifies lymphomas according to the type of cell from which they are derived (mature and immature B cells, T cells, or natural killer (NK) cells, findings determined by their morphology and immunophenotype) and their clinical, cytogenetic, and/or molecular features. This official classification is currently being updated³ and is expected to be published in full in 2017, at which time it is anticipated to include definitions for more than 70 distinct neoplasms.

Lymphomas are broadly and informally classified as Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs), based on the differences these two groups show in their clinical presentation, treatment, prognosis, and proportion of neoplastic cells, among others. NHLs are by far the most common type of lymphomas, accounting for approximately 90% of all new cases of lymphoma in the United States and 70% worldwide.^1,2 NHLs are a very heterogeneous group of B-, T-, or NK-cell neoplasms that, in turn, can also be informally subclassified as low-grade (or indolent) or high-grade (or aggressive) according to their predicted clinical behavior. HLs are comparatively rare, less heterogeneous, uniformly of B-cell origin and, in the case of classical Hodgkin lymphoma, highly curable.^1,2 It is beyond the scope of this manuscript to outline the features of each of the >70 specific entities, but the reader is referred elsewhere for more detail and encouraged to become familiarized with the complexity, challenges, and beauty of lymphoma diagnosis.^2,3

Biopsy procedure

A correct diagnosis begins with an adequate biopsy procedure. It is essential that biopsy specimens for lymphoma evaluation be submitted fresh and unfixed, because some crucial analyses such as flow cytometry or conventional cytogenetics can only be performed on fresh tissue. Indeed, it is important for the hematologist/oncologist and/or surgeon and/or interventional radiologist to converse with the hematopathologist prior to and even during some procedures to ensure the correct processing of the specimen. Also, it is important to limit the compression of the specimen and the excessive use of cauterization during the biopsy procedure, both of which cause artifacts that may render impossible the interpretation of the histopathologic findings.

Given that the diagnosis of lymphoma is based not only on the cytologic details of the lymphoma cells but also on the architectural pattern with which they infiltrate an organ, the larger the biopsy specimen, the easier it will be for a hematopathologist to identify the pattern. In addition, excisional biopsies frequently contain more diagnostic tissue than needle core biopsies and this provides pathologists with the option to submit tissue fragments for ancillary tests that require unfixed tissue as noted above. Needle core biopsies of lymph nodes are increasingly being used because of their association with fewer complications and lower cost than excisional biopsies. However, needle core biopsies provide only a glimpse of the pattern of infiltration and may not be completely representative of the architecture. Therefore, excisional lymph node biopsies of lymph nodes are preferred over needle core biopsies, recognizing that in the setting of deeply seated lymph nodes, needle core biopsies may be the only or the best surgical option.

Clinical presentation

Accurate diagnosis of lymphoma cannot take place in a vacuum. The hematopathologist’s initial approach to the diagnosis of lymphoid processes in tissue biopsies should begin with a thorough review of the clinical history, although some pathology laboratories may not have immediate access to this information. The hematopathologist should evaluate factors such as age, gender, location of the tumor, symptomatology, medications, serology, and prior history of malignancy, immunosuppression or immunodeficiency in every case. Other important but frequently omitted parts of the clinical history are the patient’s occupation, history of exposure to animals, and the presence of tattoos, which may be associated with certain reactive lymphadenopathies.

Histomorphologic evaluation

Despite the plethora of new and increasingly sophisticated tools, histologic and morphologic analysis still remains the cornerstone of diagnosis in hematopathology. However, for the characterization of an increasing number of reactive and neoplastic lymphoid processes, hematopathologists may also require immunophenotypic, molecular, and cytogenetic tests for an accurate diagnosis. Upon review of the clinical information, a microscopic evaluation of the tissue submitted for processing by the histology laboratory will be performed. The results of concurrent flow cytometric evaluation (performed on fresh unfixed material) should also be available in most if not all cases before the H&E-stained slides are available for review. Upon receipt of H&E-stained slides, the hematopathologist will evaluate the quality of the submitted specimen, since many diagnostic difficulties stem from suboptimal techniques related to the biopsy procedure, fixation, processing, cutting, or staining (Figure 1). If deemed suitable for accurate diagnosis, a search for signs of preservation or disruption of the organ that was biopsied will follow. The identification of certain morphologic patterns aids the hematopathologist in answering the first question: “what organ is this and is this consistent with what is indicated on the requisition?” This is usually immediately followed by “is this sufficient and adequate material for a diagnosis?” and “is there any normal architecture?” If the architecture is not normal, “is this alteration due to a reactive or a neoplastic process?” If neoplastic, “is it lymphoma or a non-hematolymphoid neoplasm?”

Both reactive and neoplastic processes have variably unique morphologic features that if properly recognized, guide the subsequent testing. However, some reactive and neoplastic processes can present with overlapping features, and even after extensive immunophenotypic evaluation and the performance of ancillary studies, it may not be possible to conclusively determine its nature. If the lymph node architecture is altered or effaced, the predominant pattern of infiltration (eg, nodular, diffuse, interfollicular, intrasinusoidal) and the degree of alteration of the normal architecture is evaluated, usually at low magnification. When the presence of an infiltrate is recognized, its components must be characterized. If the infiltrate is composed of a homogeneous expansion of lymphoid cells that disrupts or replaces the normal lymphoid architecture, a lymphoma will be suspected or diagnosed. The pattern of distribution of the cells along with their individual morphologic characteristics (ie, size, nuclear shape, chromatin configuration, nucleoli, amount and hue of cytoplasm) are key factors for the diagnosis and classification of the lymphoma that will guide subsequent testing. The immunophenotypic analysis (by immunohistochemistry, flow cytometry or a combination of both) may confirm the reactive or neoplastic nature of the process, and its subclassification. B-cell lymphomas, in particular have variable and distinctive histologic features: as a diffuse infiltrate of large mature lymphoid cells (eg, diffuse large B-cell lymphoma), an expansion of immature lymphoid cells (lymphoblastic lymphoma), and a nodular infiltrate of small, intermediate and/or mature large B cells (eg, follicular lymphoma).

Immunophenotypic evaluation

Immunophenotypic evaluation is essential because the lineage of lymphoma cells cannot be determined by morphology alone. The immunophenotype is the combination of proteins/markers (eg, CD20, CD3, TdT) expressed by cells. Usually, it is evaluated by immunohistochemistry and/or flow cytometry, which help determine the proportion of lymphoid cells that express a certain marker and its location and intensity within the cells. While immunohistochemistry is normally performed on formalin-fixed and paraffin-embedded tissue, flow cytometry can be evaluated only on fresh unfixed tissue. Flow cytometry has the advantage over immunohistochemistry of being faster and better at simultaneously identifying coexpression of multiple markers on multiple cell populations. However, certain markers can only be evaluated by immunohistochemistry.

The immunophenotypic analysis will in most cases reveal whether the lymphomas is of B-, T- or NK-cell origin, and whether a lymphoma subtype associated immunophenotype is present. Typical pan B-cell antigens include PAX5, CD19, and CD79a (CD20 is less broadly expressed throughout B-cell differentiation, although it is usually evident in most mature B-cell lymphomas), and typical pan T-cell antigens include CD2, CD5, and CD7. The immature or mature nature of a lymphoma can also be confirmed by evaluation of the immunophenotype. Immature lymphomas commonly express one or more of TdT, CD10, or CD34; T-lymphoblastic lymphoma cells may also coexpress CD1a. The majority of NHLs and all HLs are derived from (or reflect) B cells at different stages of maturation. Mature B-cell lymphomas are the most common type of lymphoma and typically, but not always, express pan B-cell markers as well as surface membrane immunoglobulin, with the latter also most useful in assessing clonality via a determination of light chain restriction. Some mature B-cell lymphomas tend to acquire markers that are either never physiologically expressed by normal mature B cells (eg, cyclin D1 in mantle cell lymphoma, or BCL2 in germinal center B cells in follicular lymphoma) or only expressed in a minor fraction (eg, CD5 that is characteristically expressed in small lymphocytic and mantle cell lymphoma). The most common mature B-cell lymphomas include diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (Figures 2 and 3). Classical HLs are also lymphomas of B-cell origin that demonstrate diminished preservation of their B-cell immunophenotype (as evidenced by the dim expression of PAX5 but absence of most other pan B-cell antigens), expression of CD30, variable expression of CD15, and loss of CD45 (Figure 1). In contrast, nodular lymphocyte predominant HL shows a preserved B-cell immunophenotypic program and expression of CD45, typically without CD30 and CD15. Of note, the evaluation of the immunophenotype of the neoplastic cells in HL is routinely assessed by immunohistochemistry because most flow cytometry laboratories cannot reliably detect and characterize the low numbers of these cells.

Mature T-cell lymphomas generally express one or more T-cell markers, and tend to display a T-helper (CD4-positive) or cytotoxic (CD8-positive) immunophenotype and may show loss of markers expressed by most normal T-cells (eg, CD5, CD7; Figure 4). However, a subset of them may express markers not commonly detected in normal T cells, such as ALK. NK-cell lymphomas lack surface CD3 (expressing only cytoplasmic CD3) and CD5 but express some pan T-cell antigens (such as CD2 and CD7) as well as CD16 and/or CD56.

Patients with primary or acquired immune dysfunction are at risk for development of lymphoma and other less clearly defined lymphoproliferative disorders, the majority of which are associated with infection of the lymphoid cells with Epstein-Barr virus (EBV). Therefore, evaluation with chromogenic in situ hybridization for an EBV-encoded early RNA (EBER1) is routinely performed in these cases; it is thus essential that the hematopathologist be informed of the altered immune system of the patient. If lymphoma develops, they may be morphologically similar to those that appear in immunocompetent patients, which specifically in the post-transplant setting are known as monomorphic post-transplant lymphoproliferative disorders (PTLD). If the PTLD does not meet the criteria for any of the recognized types of lymphoma, it may be best characterized as a polymorphic PTLD.

Once the lineage (B-, T-, or NK-cell) of the mature lymphoma has been established, the sum (and on occasion the gestalt) of the clinical, morphologic, immunophenotypic and other findings will be considered for the subclassification of the neoplasm.

Cytogenetic and molecular evaluation

If the morphologic and immunophenotypic analysis is inconclusive or nondiagnostic, then molecular and/or cytogenetic testing may further aid in the characterization of the process. Some of available molecular tests include analyses for the rearrangements of the variable region of the immunoglobulin (IG) or T-cell receptor (TCR) genes and for mutations on specific genes. The identification of specific mutations not only confirms the clonal nature of the process but, on occasion, it may also help subclassify the lymphoma, whereas IG or TCR rearrangement studies are used to establish whether a lymphoid expansion is polyclonal or monoclonal. The molecular findings should not be evaluated in isolation, because not all monoclonal rearrangements are diagnostic of lymphoma, and not all lymphomas will show a monoclonal rearrangement. Other methodologies that can aid in the identification of a clonal process or specific genetic abnormalities include metaphase cytogenetics (karyotyping) and fluorescence in situ hybridization (FISH). If any cytogenetic abnormalities are found in sufficient numbers (and constitutional abnormalities are excluded), their identification indicates the presence of a clonal process. Also, some cytogenetic abnormalities are characteristic of certain lymphomas. However, they may be neither 100% diagnostically sensitive nor diagnostically specific, for example, the hallmark t(14;18)/IGH-BCL2 is not present in all follicular lymphomas and not all lymphomas with this translocation are follicular lymphomas. Whereas FISH is generally performed on a minimum of 200 cells, compared with typically 20 metaphase by “conventional” karyotyping, and is therefore considered to have higher analytical sensitivity, it evaluates only for the presence or absence of the abnormality being investigated with a given set of probes, and therefore other abnormalities, if present, will not be identified. The value of FISH cytogenetic studies is perhaps best illustrated in the need to diagnose double hit lymphomas, amongst other scenarios. The detection of certain mutations can aid in the diagnosis of certain lymphomas, such as MYD88 in lymphoplasmacytic lymphoma, prognosis of others, such as in follicular lymphoma and identify pathways that may be precisely therapeutically targeted.

Final remarks

The diagnosis of lymphoma can be complex and usually requires the hematopathologist to integrate multiple parameters. The classification of lymphomas is not static, and new entities or variants are continuously described, and the facets of well-known ones refined. While such changes are often to the chagrin of hematologists/oncologists and hematopathologists alike, we should embrace the incorporation of nascent and typically cool data into our practice, as more therapeutically relevant entities are molded.

Lymphomas constitute a very heterogeneous group of neoplasms with diverse clinical presentations, prognoses, and responses to therapy. Approximately 80,500 new cases of lymphoma are expected to be diagnosed in the United States in 2017, of which about one quarter will lead to the death of the patient.¹ Perhaps more so than any other group of neoplasms, the diagnosis of lymphoma involves the integration of a multiplicity of clinical, histologic and immunophenotypic findings and, on occasion, cytogenetic and molecular results as well. An accurate diagnosis of lymphoma, usually rendered by hematopathologists, allows hematologists/oncologists to treat patients appropriately. Herein we will describe a simplified approach to the diagnosis and classification of lymphomas (Figure 1).

Lymphoma classification

Lymphomas are clonal neoplasms characterized by the expansion of abnormal lymphoid cells that may develop in any organ but commonly involve lymph nodes. The fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid tissues, published in 2008, is the official and most current guideline used for diagnosis of lymphoid neoplasms.² The WHO scheme classifies lymphomas according to the type of cell from which they are derived (mature and immature B cells, T cells, or natural killer (NK) cells, findings determined by their morphology and immunophenotype) and their clinical, cytogenetic, and/or molecular features. This official classification is currently being updated³ and is expected to be published in full in 2017, at which time it is anticipated to include definitions for more than 70 distinct neoplasms.

Lymphomas are broadly and informally classified as Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs), based on the differences these two groups show in their clinical presentation, treatment, prognosis, and proportion of neoplastic cells, among others. NHLs are by far the most common type of lymphomas, accounting for approximately 90% of all new cases of lymphoma in the United States and 70% worldwide.^1,2 NHLs are a very heterogeneous group of B-, T-, or NK-cell neoplasms that, in turn, can also be informally subclassified as low-grade (or indolent) or high-grade (or aggressive) according to their predicted clinical behavior. HLs are comparatively rare, less heterogeneous, uniformly of B-cell origin and, in the case of classical Hodgkin lymphoma, highly curable.^1,2 It is beyond the scope of this manuscript to outline the features of each of the >70 specific entities, but the reader is referred elsewhere for more detail and encouraged to become familiarized with the complexity, challenges, and beauty of lymphoma diagnosis.^2,3

Biopsy procedure

A correct diagnosis begins with an adequate biopsy procedure. It is essential that biopsy specimens for lymphoma evaluation be submitted fresh and unfixed, because some crucial analyses such as flow cytometry or conventional cytogenetics can only be performed on fresh tissue. Indeed, it is important for the hematologist/oncologist and/or surgeon and/or interventional radiologist to converse with the hematopathologist prior to and even during some procedures to ensure the correct processing of the specimen. Also, it is important to limit the compression of the specimen and the excessive use of cauterization during the biopsy procedure, both of which cause artifacts that may render impossible the interpretation of the histopathologic findings.

Given that the diagnosis of lymphoma is based not only on the cytologic details of the lymphoma cells but also on the architectural pattern with which they infiltrate an organ, the larger the biopsy specimen, the easier it will be for a hematopathologist to identify the pattern. In addition, excisional biopsies frequently contain more diagnostic tissue than needle core biopsies and this provides pathologists with the option to submit tissue fragments for ancillary tests that require unfixed tissue as noted above. Needle core biopsies of lymph nodes are increasingly being used because of their association with fewer complications and lower cost than excisional biopsies. However, needle core biopsies provide only a glimpse of the pattern of infiltration and may not be completely representative of the architecture. Therefore, excisional lymph node biopsies of lymph nodes are preferred over needle core biopsies, recognizing that in the setting of deeply seated lymph nodes, needle core biopsies may be the only or the best surgical option.

Clinical presentation

Accurate diagnosis of lymphoma cannot take place in a vacuum. The hematopathologist’s initial approach to the diagnosis of lymphoid processes in tissue biopsies should begin with a thorough review of the clinical history, although some pathology laboratories may not have immediate access to this information. The hematopathologist should evaluate factors such as age, gender, location of the tumor, symptomatology, medications, serology, and prior history of malignancy, immunosuppression or immunodeficiency in every case. Other important but frequently omitted parts of the clinical history are the patient’s occupation, history of exposure to animals, and the presence of tattoos, which may be associated with certain reactive lymphadenopathies.

Histomorphologic evaluation

Despite the plethora of new and increasingly sophisticated tools, histologic and morphologic analysis still remains the cornerstone of diagnosis in hematopathology. However, for the characterization of an increasing number of reactive and neoplastic lymphoid processes, hematopathologists may also require immunophenotypic, molecular, and cytogenetic tests for an accurate diagnosis. Upon review of the clinical information, a microscopic evaluation of the tissue submitted for processing by the histology laboratory will be performed. The results of concurrent flow cytometric evaluation (performed on fresh unfixed material) should also be available in most if not all cases before the H&E-stained slides are available for review. Upon receipt of H&E-stained slides, the hematopathologist will evaluate the quality of the submitted specimen, since many diagnostic difficulties stem from suboptimal techniques related to the biopsy procedure, fixation, processing, cutting, or staining (Figure 1). If deemed suitable for accurate diagnosis, a search for signs of preservation or disruption of the organ that was biopsied will follow. The identification of certain morphologic patterns aids the hematopathologist in answering the first question: “what organ is this and is this consistent with what is indicated on the requisition?” This is usually immediately followed by “is this sufficient and adequate material for a diagnosis?” and “is there any normal architecture?” If the architecture is not normal, “is this alteration due to a reactive or a neoplastic process?” If neoplastic, “is it lymphoma or a non-hematolymphoid neoplasm?”

Both reactive and neoplastic processes have variably unique morphologic features that if properly recognized, guide the subsequent testing. However, some reactive and neoplastic processes can present with overlapping features, and even after extensive immunophenotypic evaluation and the performance of ancillary studies, it may not be possible to conclusively determine its nature. If the lymph node architecture is altered or effaced, the predominant pattern of infiltration (eg, nodular, diffuse, interfollicular, intrasinusoidal) and the degree of alteration of the normal architecture is evaluated, usually at low magnification. When the presence of an infiltrate is recognized, its components must be characterized. If the infiltrate is composed of a homogeneous expansion of lymphoid cells that disrupts or replaces the normal lymphoid architecture, a lymphoma will be suspected or diagnosed. The pattern of distribution of the cells along with their individual morphologic characteristics (ie, size, nuclear shape, chromatin configuration, nucleoli, amount and hue of cytoplasm) are key factors for the diagnosis and classification of the lymphoma that will guide subsequent testing. The immunophenotypic analysis (by immunohistochemistry, flow cytometry or a combination of both) may confirm the reactive or neoplastic nature of the process, and its subclassification. B-cell lymphomas, in particular have variable and distinctive histologic features: as a diffuse infiltrate of large mature lymphoid cells (eg, diffuse large B-cell lymphoma), an expansion of immature lymphoid cells (lymphoblastic lymphoma), and a nodular infiltrate of small, intermediate and/or mature large B cells (eg, follicular lymphoma).

Immunophenotypic evaluation

Immunophenotypic evaluation is essential because the lineage of lymphoma cells cannot be determined by morphology alone. The immunophenotype is the combination of proteins/markers (eg, CD20, CD3, TdT) expressed by cells. Usually, it is evaluated by immunohistochemistry and/or flow cytometry, which help determine the proportion of lymphoid cells that express a certain marker and its location and intensity within the cells. While immunohistochemistry is normally performed on formalin-fixed and paraffin-embedded tissue, flow cytometry can be evaluated only on fresh unfixed tissue. Flow cytometry has the advantage over immunohistochemistry of being faster and better at simultaneously identifying coexpression of multiple markers on multiple cell populations. However, certain markers can only be evaluated by immunohistochemistry.

The immunophenotypic analysis will in most cases reveal whether the lymphomas is of B-, T- or NK-cell origin, and whether a lymphoma subtype associated immunophenotype is present. Typical pan B-cell antigens include PAX5, CD19, and CD79a (CD20 is less broadly expressed throughout B-cell differentiation, although it is usually evident in most mature B-cell lymphomas), and typical pan T-cell antigens include CD2, CD5, and CD7. The immature or mature nature of a lymphoma can also be confirmed by evaluation of the immunophenotype. Immature lymphomas commonly express one or more of TdT, CD10, or CD34; T-lymphoblastic lymphoma cells may also coexpress CD1a. The majority of NHLs and all HLs are derived from (or reflect) B cells at different stages of maturation. Mature B-cell lymphomas are the most common type of lymphoma and typically, but not always, express pan B-cell markers as well as surface membrane immunoglobulin, with the latter also most useful in assessing clonality via a determination of light chain restriction. Some mature B-cell lymphomas tend to acquire markers that are either never physiologically expressed by normal mature B cells (eg, cyclin D1 in mantle cell lymphoma, or BCL2 in germinal center B cells in follicular lymphoma) or only expressed in a minor fraction (eg, CD5 that is characteristically expressed in small lymphocytic and mantle cell lymphoma). The most common mature B-cell lymphomas include diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (Figures 2 and 3). Classical HLs are also lymphomas of B-cell origin that demonstrate diminished preservation of their B-cell immunophenotype (as evidenced by the dim expression of PAX5 but absence of most other pan B-cell antigens), expression of CD30, variable expression of CD15, and loss of CD45 (Figure 1). In contrast, nodular lymphocyte predominant HL shows a preserved B-cell immunophenotypic program and expression of CD45, typically without CD30 and CD15. Of note, the evaluation of the immunophenotype of the neoplastic cells in HL is routinely assessed by immunohistochemistry because most flow cytometry laboratories cannot reliably detect and characterize the low numbers of these cells.

Mature T-cell lymphomas generally express one or more T-cell markers, and tend to display a T-helper (CD4-positive) or cytotoxic (CD8-positive) immunophenotype and may show loss of markers expressed by most normal T-cells (eg, CD5, CD7; Figure 4). However, a subset of them may express markers not commonly detected in normal T cells, such as ALK. NK-cell lymphomas lack surface CD3 (expressing only cytoplasmic CD3) and CD5 but express some pan T-cell antigens (such as CD2 and CD7) as well as CD16 and/or CD56.

Patients with primary or acquired immune dysfunction are at risk for development of lymphoma and other less clearly defined lymphoproliferative disorders, the majority of which are associated with infection of the lymphoid cells with Epstein-Barr virus (EBV). Therefore, evaluation with chromogenic in situ hybridization for an EBV-encoded early RNA (EBER1) is routinely performed in these cases; it is thus essential that the hematopathologist be informed of the altered immune system of the patient. If lymphoma develops, they may be morphologically similar to those that appear in immunocompetent patients, which specifically in the post-transplant setting are known as monomorphic post-transplant lymphoproliferative disorders (PTLD). If the PTLD does not meet the criteria for any of the recognized types of lymphoma, it may be best characterized as a polymorphic PTLD.

Once the lineage (B-, T-, or NK-cell) of the mature lymphoma has been established, the sum (and on occasion the gestalt) of the clinical, morphologic, immunophenotypic and other findings will be considered for the subclassification of the neoplasm.

Cytogenetic and molecular evaluation

If the morphologic and immunophenotypic analysis is inconclusive or nondiagnostic, then molecular and/or cytogenetic testing may further aid in the characterization of the process. Some of available molecular tests include analyses for the rearrangements of the variable region of the immunoglobulin (IG) or T-cell receptor (TCR) genes and for mutations on specific genes. The identification of specific mutations not only confirms the clonal nature of the process but, on occasion, it may also help subclassify the lymphoma, whereas IG or TCR rearrangement studies are used to establish whether a lymphoid expansion is polyclonal or monoclonal. The molecular findings should not be evaluated in isolation, because not all monoclonal rearrangements are diagnostic of lymphoma, and not all lymphomas will show a monoclonal rearrangement. Other methodologies that can aid in the identification of a clonal process or specific genetic abnormalities include metaphase cytogenetics (karyotyping) and fluorescence in situ hybridization (FISH). If any cytogenetic abnormalities are found in sufficient numbers (and constitutional abnormalities are excluded), their identification indicates the presence of a clonal process. Also, some cytogenetic abnormalities are characteristic of certain lymphomas. However, they may be neither 100% diagnostically sensitive nor diagnostically specific, for example, the hallmark t(14;18)/IGH-BCL2 is not present in all follicular lymphomas and not all lymphomas with this translocation are follicular lymphomas. Whereas FISH is generally performed on a minimum of 200 cells, compared with typically 20 metaphase by “conventional” karyotyping, and is therefore considered to have higher analytical sensitivity, it evaluates only for the presence or absence of the abnormality being investigated with a given set of probes, and therefore other abnormalities, if present, will not be identified. The value of FISH cytogenetic studies is perhaps best illustrated in the need to diagnose double hit lymphomas, amongst other scenarios. The detection of certain mutations can aid in the diagnosis of certain lymphomas, such as MYD88 in lymphoplasmacytic lymphoma, prognosis of others, such as in follicular lymphoma and identify pathways that may be precisely therapeutically targeted.

Final remarks

The diagnosis of lymphoma can be complex and usually requires the hematopathologist to integrate multiple parameters. The classification of lymphomas is not static, and new entities or variants are continuously described, and the facets of well-known ones refined. While such changes are often to the chagrin of hematologists/oncologists and hematopathologists alike, we should embrace the incorporation of nascent and typically cool data into our practice, as more therapeutically relevant entities are molded.

ORLANDO – The quality of life of someone with treated hypothyroidism is worse than that of the general population and requires endocrinologists to think “outside the pill box,” said Anna M. Sawka, MD, PhD, of the University of Toronto, at a spring symposium presented by the American Thyroid Association.

While issues such as whether monotherapy with T4 is the treatment of choice or whether there is a subset of patients who might benefit from treatment with either T4/T3 in combination or even with extract of dessicated thyroid, many patients with treated hypothyroidism continue to feel bad, judging from discussion during the symposium.

[email protected]

ORLANDO – The quality of life of someone with treated hypothyroidism is worse than that of the general population and requires endocrinologists to think “outside the pill box,” said Anna M. Sawka, MD, PhD, of the University of Toronto, at a spring symposium presented by the American Thyroid Association.

While issues such as whether monotherapy with T4 is the treatment of choice or whether there is a subset of patients who might benefit from treatment with either T4/T3 in combination or even with extract of dessicated thyroid, many patients with treated hypothyroidism continue to feel bad, judging from discussion during the symposium.

[email protected]

ORLANDO – The quality of life of someone with treated hypothyroidism is worse than that of the general population and requires endocrinologists to think “outside the pill box,” said Anna M. Sawka, MD, PhD, of the University of Toronto, at a spring symposium presented by the American Thyroid Association.

While issues such as whether monotherapy with T4 is the treatment of choice or whether there is a subset of patients who might benefit from treatment with either T4/T3 in combination or even with extract of dessicated thyroid, many patients with treated hypothyroidism continue to feel bad, judging from discussion during the symposium.

[email protected]

SAN DIEGO – The way the president of the American Board of Internal Medicine, Richard J. Baron, MD, sees it, maintenance of certification is more important than ever, because trust in the medical profession “is under assault right now in all kinds of ways.”

So, to help “bring clarity to uncertainty,” ABIM is continuing its makeover of the maintenance of certification (MOC) process. Beginning in 2018, an open-book option to test every 2 years will be available for physicians who are certified in internal medicine and for those in the subspecialty of nephrology.

Doug Brunk

Linking MOC and trust

Speaking at the annual meeting of the American College of Physicians, Dr. Baron said that false and misleading information circulated widely on Facebook and other social media channels runs the gamut of health issues, from falsified studies about purported links between vaccines and autism and public health scares on impostor websites, to stories of miracle cures for any number of ailments.

“It’s not just vaccines people are questioning,” said Dr. Baron, ABIM’s president and CEO. “There are erosions of trust in government, and there’s the tenacity and power of wildly inaccurate information. You will be dealing with patients who tenaciously believe things that you know not to be true. You will need to find ways to build trust, credibility, and relationships based on their trusting that what you’re saying is really in their interest.”

U.S. physicians aren’t secure in the shaky trust landscape. In fact, globally, the United States ranks 24th in public trust level of physicians by country (N. Eng. J. Med. 2014 Oct 23;371[17]:1570-2).

“The confidence in the medical system today is lower than the confidence in police or in small business,” Dr. Baron said. “That’s [the view] people are bringing into your offices every day. I don’t think we can assume that deference and trust are given to doctors, that the privileged role that society affords us is something that we’re going to have forever. We all have to think how trust is built in the new world.”

Will patients value MOC?

During a question and answer session at the ACP session, Anne Cummings, MD, an internist who practices in Greenbrae, Calif., asked the ABIM for support in educating the general public about what it means to be treated by a board-certified physician.

“I had a naturopath tell me the other day that she had the same training as I had,” Dr. Cummings said. “I was floored, but I think that patients don’t know the difference [between board-certified and not board-certified].”

Dr. Baron agreed ABIM needs to do more to promote the value of certification among patients. But he also called on board-certified physicians to deliver the value message directly to their own patients.

Other attendees recommended that ABIM expand the number of ways physicians can earn MOC points, and they expressed concern about the time MOC takes away from their daily practice.

For regular updates on the MOC process, physicians can subscribe to the ABIM’s blog at transforming.abim.org.

[email protected]

SAN DIEGO – The way the president of the American Board of Internal Medicine, Richard J. Baron, MD, sees it, maintenance of certification is more important than ever, because trust in the medical profession “is under assault right now in all kinds of ways.”

So, to help “bring clarity to uncertainty,” ABIM is continuing its makeover of the maintenance of certification (MOC) process. Beginning in 2018, an open-book option to test every 2 years will be available for physicians who are certified in internal medicine and for those in the subspecialty of nephrology.

Doug Brunk

Linking MOC and trust

Speaking at the annual meeting of the American College of Physicians, Dr. Baron said that false and misleading information circulated widely on Facebook and other social media channels runs the gamut of health issues, from falsified studies about purported links between vaccines and autism and public health scares on impostor websites, to stories of miracle cures for any number of ailments.

“It’s not just vaccines people are questioning,” said Dr. Baron, ABIM’s president and CEO. “There are erosions of trust in government, and there’s the tenacity and power of wildly inaccurate information. You will be dealing with patients who tenaciously believe things that you know not to be true. You will need to find ways to build trust, credibility, and relationships based on their trusting that what you’re saying is really in their interest.”

U.S. physicians aren’t secure in the shaky trust landscape. In fact, globally, the United States ranks 24th in public trust level of physicians by country (N. Eng. J. Med. 2014 Oct 23;371[17]:1570-2).

“The confidence in the medical system today is lower than the confidence in police or in small business,” Dr. Baron said. “That’s [the view] people are bringing into your offices every day. I don’t think we can assume that deference and trust are given to doctors, that the privileged role that society affords us is something that we’re going to have forever. We all have to think how trust is built in the new world.”

Will patients value MOC?

During a question and answer session at the ACP session, Anne Cummings, MD, an internist who practices in Greenbrae, Calif., asked the ABIM for support in educating the general public about what it means to be treated by a board-certified physician.

“I had a naturopath tell me the other day that she had the same training as I had,” Dr. Cummings said. “I was floored, but I think that patients don’t know the difference [between board-certified and not board-certified].”

Dr. Baron agreed ABIM needs to do more to promote the value of certification among patients. But he also called on board-certified physicians to deliver the value message directly to their own patients.

Other attendees recommended that ABIM expand the number of ways physicians can earn MOC points, and they expressed concern about the time MOC takes away from their daily practice.

For regular updates on the MOC process, physicians can subscribe to the ABIM’s blog at transforming.abim.org.

[email protected]

SAN DIEGO – The way the president of the American Board of Internal Medicine, Richard J. Baron, MD, sees it, maintenance of certification is more important than ever, because trust in the medical profession “is under assault right now in all kinds of ways.”

So, to help “bring clarity to uncertainty,” ABIM is continuing its makeover of the maintenance of certification (MOC) process. Beginning in 2018, an open-book option to test every 2 years will be available for physicians who are certified in internal medicine and for those in the subspecialty of nephrology.

Doug Brunk

Linking MOC and trust

Speaking at the annual meeting of the American College of Physicians, Dr. Baron said that false and misleading information circulated widely on Facebook and other social media channels runs the gamut of health issues, from falsified studies about purported links between vaccines and autism and public health scares on impostor websites, to stories of miracle cures for any number of ailments.

“It’s not just vaccines people are questioning,” said Dr. Baron, ABIM’s president and CEO. “There are erosions of trust in government, and there’s the tenacity and power of wildly inaccurate information. You will be dealing with patients who tenaciously believe things that you know not to be true. You will need to find ways to build trust, credibility, and relationships based on their trusting that what you’re saying is really in their interest.”

U.S. physicians aren’t secure in the shaky trust landscape. In fact, globally, the United States ranks 24th in public trust level of physicians by country (N. Eng. J. Med. 2014 Oct 23;371[17]:1570-2).

“The confidence in the medical system today is lower than the confidence in police or in small business,” Dr. Baron said. “That’s [the view] people are bringing into your offices every day. I don’t think we can assume that deference and trust are given to doctors, that the privileged role that society affords us is something that we’re going to have forever. We all have to think how trust is built in the new world.”

Will patients value MOC?

During a question and answer session at the ACP session, Anne Cummings, MD, an internist who practices in Greenbrae, Calif., asked the ABIM for support in educating the general public about what it means to be treated by a board-certified physician.

“I had a naturopath tell me the other day that she had the same training as I had,” Dr. Cummings said. “I was floored, but I think that patients don’t know the difference [between board-certified and not board-certified].”

Dr. Baron agreed ABIM needs to do more to promote the value of certification among patients. But he also called on board-certified physicians to deliver the value message directly to their own patients.

Other attendees recommended that ABIM expand the number of ways physicians can earn MOC points, and they expressed concern about the time MOC takes away from their daily practice.

For regular updates on the MOC process, physicians can subscribe to the ABIM’s blog at transforming.abim.org.

[email protected]

Click here to access the April 2017 Digital Edition.

Table of Contents

• Write for Us, Right for You
• A Heart Failure Management Program Using Shared Medical Appointments
• Suspected Clozapine-Induced Cardiomyopathy and Heart Failure With Reduced Ejection Fraction
• Military Sexual Trauma and Sexual Health: Practice and Future Research for Mental Health Professionals
• Veterans as Caregivers: Those Who Continue to Serve
• Conjoint Sessions With Clinical Pharmacy and Health Psychology for Chronic Pain
• Hypoperfusion Retinopathy
• William Beaumont: A Pioneer of Physiology

 

Click here to access the April 2017 Digital Edition.

Table of Contents

• Write for Us, Right for You
• A Heart Failure Management Program Using Shared Medical Appointments
• Suspected Clozapine-Induced Cardiomyopathy and Heart Failure With Reduced Ejection Fraction
• Military Sexual Trauma and Sexual Health: Practice and Future Research for Mental Health Professionals
• Veterans as Caregivers: Those Who Continue to Serve
• Conjoint Sessions With Clinical Pharmacy and Health Psychology for Chronic Pain
• Hypoperfusion Retinopathy
• William Beaumont: A Pioneer of Physiology

 

Click here to access the April 2017 Digital Edition.

Table of Contents

• Write for Us, Right for You
• A Heart Failure Management Program Using Shared Medical Appointments
• Suspected Clozapine-Induced Cardiomyopathy and Heart Failure With Reduced Ejection Fraction
• Military Sexual Trauma and Sexual Health: Practice and Future Research for Mental Health Professionals
• Veterans as Caregivers: Those Who Continue to Serve
• Conjoint Sessions With Clinical Pharmacy and Health Psychology for Chronic Pain
• Hypoperfusion Retinopathy
• William Beaumont: A Pioneer of Physiology

 

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to Coversin™ for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in patients who have polymorphisms conferring eculizumab resistance.

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is a second-generation complement inhibitor that acts on complement component C5, preventing release of C5a and formation of C5b-9, and also independently inhibits LTB4 activity.

Coversin is being developed by Akari Therapeutics.

Akari is evaluating Coversin in a pair of phase 2 trials.

In the first trial, researchers are evaluating Coversin in patients with PNH who have never received a complement-blocking therapy. Interim results from this ongoing trial are scheduled to be presented at Akari’s Research and Development Day on April 24 in New York, New York.

In the second phase 2 trial, researchers are evaluating Coversin in patients with PNH who have C5 polymorphisms that confer resistance to eculizumab.

One patient has been enrolled in this trial and has received Coversin for over a year. The treatment has resulted in significant lactate dehydrogenase reduction and complete complement blockade.

About fast track designation

The FDA created the fast track program to facilitate the development and expedite the review of drugs that show promise for treating serious or life-threatening diseases and address unmet medical needs.

Companies developing drugs that receive fast track designation benefit from more frequent communications and meetings with the FDA to review their drug’s development plan, including the design of proposed clinical trials, use of biomarkers, and the extent of data needed for approval.

Drugs with fast track designation may qualify for priority review as well, if relevant criteria are met. Priority review shortens the FDA review process from 10 months to 6 months.

Fast track designation also allows for a rolling review process, whereby completed sections of the investigational new drug application can be submitted for FDA review as they become available, instead of waiting for all sections to be completed.

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to Coversin™ for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in patients who have polymorphisms conferring eculizumab resistance.

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is a second-generation complement inhibitor that acts on complement component C5, preventing release of C5a and formation of C5b-9, and also independently inhibits LTB4 activity.

Coversin is being developed by Akari Therapeutics.

Akari is evaluating Coversin in a pair of phase 2 trials.

In the first trial, researchers are evaluating Coversin in patients with PNH who have never received a complement-blocking therapy. Interim results from this ongoing trial are scheduled to be presented at Akari’s Research and Development Day on April 24 in New York, New York.

In the second phase 2 trial, researchers are evaluating Coversin in patients with PNH who have C5 polymorphisms that confer resistance to eculizumab.

One patient has been enrolled in this trial and has received Coversin for over a year. The treatment has resulted in significant lactate dehydrogenase reduction and complete complement blockade.

About fast track designation

The FDA created the fast track program to facilitate the development and expedite the review of drugs that show promise for treating serious or life-threatening diseases and address unmet medical needs.

Companies developing drugs that receive fast track designation benefit from more frequent communications and meetings with the FDA to review their drug’s development plan, including the design of proposed clinical trials, use of biomarkers, and the extent of data needed for approval.

Drugs with fast track designation may qualify for priority review as well, if relevant criteria are met. Priority review shortens the FDA review process from 10 months to 6 months.

Fast track designation also allows for a rolling review process, whereby completed sections of the investigational new drug application can be submitted for FDA review as they become available, instead of waiting for all sections to be completed.

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to Coversin™ for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in patients who have polymorphisms conferring eculizumab resistance.

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is a second-generation complement inhibitor that acts on complement component C5, preventing release of C5a and formation of C5b-9, and also independently inhibits LTB4 activity.

Coversin is being developed by Akari Therapeutics.

Akari is evaluating Coversin in a pair of phase 2 trials.

In the first trial, researchers are evaluating Coversin in patients with PNH who have never received a complement-blocking therapy. Interim results from this ongoing trial are scheduled to be presented at Akari’s Research and Development Day on April 24 in New York, New York.

In the second phase 2 trial, researchers are evaluating Coversin in patients with PNH who have C5 polymorphisms that confer resistance to eculizumab.

One patient has been enrolled in this trial and has received Coversin for over a year. The treatment has resulted in significant lactate dehydrogenase reduction and complete complement blockade.

About fast track designation

The FDA created the fast track program to facilitate the development and expedite the review of drugs that show promise for treating serious or life-threatening diseases and address unmet medical needs.

Companies developing drugs that receive fast track designation benefit from more frequent communications and meetings with the FDA to review their drug’s development plan, including the design of proposed clinical trials, use of biomarkers, and the extent of data needed for approval.

Drugs with fast track designation may qualify for priority review as well, if relevant criteria are met. Priority review shortens the FDA review process from 10 months to 6 months.

Fast track designation also allows for a rolling review process, whereby completed sections of the investigational new drug application can be submitted for FDA review as they become available, instead of waiting for all sections to be completed.

CE/CME No: CR-1704

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Recognize patients who are at risk for tetanus.
• Describe the clinical presentation of tetanus.
• Discuss proper treatment for a patient with tetanus.
• Promote widespread vaccination against tetanus.

FACULTY
Timothy W. Ferrarotti is the Director of Didactic Education and Assistant Professor in the PA Studies Program at the University of Saint Joseph, West Hartford, Connecticut.

The author has no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of April 2017.

Article begins on next page >>

Tetanus is a devastating disease that can be prevented by proper immunization and wound care. Although the incidence is low in the United States due to widespread routine vaccination, immunization coverage remains below target, especially in older adults. Since outcome is influenced by the clinician's ability to make a timely diagnosis and initiate appropriate care, continued appreciation of tetanus is warranted.

Tetanus is a neurologic disorder resulting from infection by the gram-positive, spore-forming anaerobic bacillus Clostridium tetani. The bacterium, in spore form, typically enters the body through a contaminated soft-tissue wound. Ubiquitous in the environment, C tetani spores are found throughout the world—in soil as well as in animal feces and saliva—and are resistant to temperature extremes and antiseptics. Tetanus is infectious but not contagious (not transmitted person-to-person).¹ Wounds with devitalized tissue or those supporting anaerobic conditions, such as bites, puncture wounds, burns, and gangrene, are conducive to the development of tetanus. Infection can also occur following dental extractions, abortions, and illicit drug injection.¹ Although vaccination programs have decreased the incidence of tetanus in the United States, C tetani infection remains an ongoing clinical concern because the spores are omnipresent, universal vaccination coverage has not been achieved, and vaccine-immunity wanes over time, placing individuals at risk.

PATHOPHYSIOLOGY

C tetani produces two toxins: tetanolysin and tetanospasmin (tetanus toxin). Tetanolysin may have a role in promoting the diffusion of tetanospasmin in soft tissues.² Tetanospasmin is a highly potent toxin, with a lethal dose in humans of less than 2.5 ng/kg of body weight.³ The toxin enters the peripheral nerve at the site of injury and migrates to the central nervous system (CNS). There, it causes unopposed α-motor neuron firing by preventing the release of inhibitory neurotransmitters such as γ-aminobutyric acid (GABA), resulting in muscle spasms and excess reflexive response to sensory stimuli.⁴ It also leads to excessive catecholamine release from the adrenal medulla.¹

Tetanospasmin binds to neurons in the spinal cord and brainstem. Because toxin binding is irreversible, resolution of tetanus requires the neurons to grow new axon terminals. The effects of tetanus can persist for six to eight weeks until new terminals develop.^3,5 Patients often require several weeks of ventilator support during this time.³

EPIDEMIOLOGY

Tetanus continues to be a serious cause of morbidity and mortality worldwide. The majority of cases (80%) occur in Africa and Southeast Asia.⁶ Incidence is much lower in the United States (0.1 cases per million persons annually) because of widespread vaccination, with only 233 cases of tetanus reported between 2001 and 2008.⁷ However, in the absence of confirmatory tests, the diagnosis is a clinical one; furthermore, there is no laboratory reporting program for tetanus. As a result, more cases may occur in the US than are detected or reported.

In developed countries, tetanus is primarily a disease of the elderly or the unvaccinated. Older persons, especially non-veterans, are less likely to have received the primary series. Because immunity decreases with age, even those who completed the primary series but have not received booster doses are at increased risk.⁸ Home-schooled children, who are not subject to school-entry vaccination requirements, are also at risk if unvaccinated.⁹

Neonatal tetanus is an ongoing problem in undeveloped countries that lack maternal vaccination programs. (Maternal immunization successfully reduces neonatal tetanus via passive immunity, and maternal tetanus via active immunity.) Unvaccinated women who undergo nonmedical abortions or unhygienic childbirth are at increased risk for tetanus.^3,10

Other risk factors for tetanus include wound contamination with soil, saliva, or devitalized tissue; injection drug use; and exposure to anthropogenic or natural disasters.¹ C tetani spores can contaminate heroin and may grow in abscesses of heroin users.⁴ Small outbreaks of tetanus among injection drug users have been reported, even among younger adults who had some immunity from childhood vaccination.^7,11 In addition, patients with diabetes are at increased risk for tetanus. These patients may have chronic wounds due to slowed healing and poor vascularity, which can lead to lower oxygen tension in their wounds and create an environment conducive to anaerobic infection. These chronic wounds are often ignored as a potential nidus for tetanus; instead, focus is placed on plantar puncture wounds or lacerations.⁷

Though tetanus risk is greatest for those who were never fully immunized, cases have been reported in persons who were immunized in the remote past but had not received a recent booster. Such cases show that tetanus immunity is not absolute and does wane over time.^12-14 Among the 233 tetanus cases reported in the US during 2001-2008, vaccination status was reported for 92. Of these, 24 patients had a complete series and 31 patients had at least one prior dose of tetanus vaccine.⁷ Furthermore, six cases occurred in patients known to have had the four-dose series and a booster within 10 years of diagnosis. Similarly, a 14-year-old boy who was fully vaccinated developed cephalic tetanus from a stingray wound.¹⁴ Given these data, clinicians should not assume that a patient who reports having had “a tetanus shot” is completely protected; a full series and regular boosters are required, and, in rare cases, tetanus can occur despite full vaccination.

PATIENT PRESENTATION AND TETANUS TYPES

The CDC describes tetanus as “the acute onset of hypertonia and/or painful muscle contractions (usually of the muscles of the jaw and neck) and generalized muscle spasms without other apparent medical cause.”¹⁵ Clinicians should always consider tetanus in patients with dysphagia and trismus, especially if the patient has a wound, had not received primary vaccination, or has not had a booster in several decades. Tetanus cannot be ruled out based on the lack of a wound, however, since up to 25% of patients who develop tetanus have no obvious site of inoculation.¹⁶ The incubation period ranges from 3 to 21 days, with more severe cases having shorter incubation periods (< 8 days).¹⁰ The closer the site of inoculation is to the CNS, the more serious the disease usually is—and the shorter the incubation period will be.¹

Presentation depends on the time elapsed since inoculation, the severity of illness (determined by the Ablett classification; see Table 1), and the form of tetanus involved. The patient may present early when the infection and toxin are localized to the wound and have not progressed to the CNS (localized tetanus). There may be a wound with signs of infection, including erythema, induration, edema, warmth, tenderness, and drainage. If the injury is on the head or neck, cephalic tetanus may occur, causing the patient to present with painful spasms of the extra-ocular, facial, and/or neck muscles; trismus; dysphagia; or even a Horner-like syndrome. The patient with more advanced, generalized tetanus may have decorticate posturing, abdominal wall rigidity, or opisthotonus.^1,2,5,17

Four types of tetanus have been described: generalized, localized, cephalic, and neonatal.

Generalized tetanus is the most common form, accounting for approximately 80% of cases.¹⁰ It may involve contractions of the masseter muscles, producing trismus; facial muscles, producing risus sardonicus (sardonic smile); neck and shoulder muscles; abdominal wall muscles, mimicking guarding; and back muscles, producing opisthotonus (arching of the back, neck, and head; see Figure 1) and decorticate posturing (flexion and adduction of the arms, clenched fists, and extension of the lower extremities).^1,5,6 Patients with generalized tetanus often exhibit hyperresponsiveness to the environment. As a result, noises and sudden light changes may result in acute spasms. In addition, patients may experience painful spasms when affected muscles are palpated. Affected reflex arcs are usually hyperresponsive to stimuli.¹ Intermittent spasms of the thoracic, pharyngeal, and/or laryngeal muscles may cause periods of apnea. Autonomic effects of tetanus mimic those associated with the catecholamine excess of pheochromocytoma. Patients exhibit restlessness, irritability, diaphoresis, fever, excessive salivation, gastric stasis, hypertension, tachycardia, and arrhythmia. There may be interposed hypotension and bradycardia.^1,5,17

Localized tetanus involves painful spastic contraction of muscles at or near the site of inoculation. It often evolves into generalized tetanus as the toxin spreads further into the CNS.

Cephalic tetanus involves facial and laryngeal muscles. It is rare, accounting for 1% to 3% of tetanus cases.⁶ Patients may initially have flaccid paralysis, mimicking stroke, rather than spasm, because the toxin has not completely migrated up the peripheral nerve into the CNS. As the toxin enters the CNS and induces the typical spasm (trismus), the diagnosis will be more obvious. The presence of trismus or a subacute wound on the head may be used to discriminate tetanus from stroke. Cephalic tetanus often evolves into generalized tetanus, affecting more of the body in a caudal direction.⁵

Neonatal tetanus develops within one week after birth. The neonate with tetanus is usually born to a mother lacking immunization. Typically, the infant sucks and feeds for the first couple of days, then develops inability/refusal to suck/feed, has difficulty opening his/her mouth, becomes weak, and develops muscle spasms.³ The affected child may develop risus sardonicus, clenched hands, dorsiflexion of the feet, and opisthotonus.³

DIFFERENTIAL DIAGNOSIS

The clinician should consider other CNS conditions in the differential diagnosis (see Table 2). Although similar to generalized seizures, tetanus causes painful spasms and does not produce a loss of consciousness.^1,17 Tetanus, intracranial bleed, and meningitis all can cause meningismus; meningitis, however, is more likely to manifest with other symptoms of infection, such as headache and fever. Although the autonomic dysfunction of tetanus can cause pyrexia, fever would usually coincide with other sympathetic symptoms, such as hypertension, tachycardia, and diaphoresis. Intracranial bleeding tends to have a more rapid onset than tetanus and produces headache and mental status changes. Seventh nerve palsy produces muscle flaccidity, not spasm, and is usually painless unless associated with herpetic inflam­mation.^1,5,6,14,17

Poisoning and medication effects should also be considered. Strychnine poisoning manifests similar to tetanus but occurs without a wound.⁵ Blood and urine assays for strychnine can be diagnostic. Dystonic reactions resulting from neuroleptic medications—such as phenothiazines—include torticollis, oropharyngeal muscle spasms, and deviation of the eyes. Unlike tetanus, drug-induced dystonia does not cause reflex spasms and often resolves with benztropine or diphenhydramine administration.¹ Neuroleptic malignant syndrome can also cause muscular rigidity and autonomic instability, but unlike tetanus, it often causes altered mental status; it should be considered in patients who recently received a causative medication.^5,17

Tetanus often manifests with reflexive muscle spasms similar to those seen in electrolyte and acid-base abnormalities. Hypocalcemia may produce a reflexive spasm of the facial muscles when the facial nerve is percussed (Chvostek sign), while alkalemia may produce reflexive spasm of the hand and wrist muscles (Trousseau sign).¹ Lab tests can rule out these diagnoses.^1,5

A patient with an odontogenic abscess may have pain and muscle spasm/trismus, but the infection is usually easily detected on exam. The clinician should be cautious in attributing the trismus solely to the swelling, however, as C tetani has been found in odontogenic abscesses and the patient may have both.^1,17 Peritonsillar abscess will often produce trismus. When abscess is the cause, careful examination of the oropharynx will usually demonstrate tonsillar exudate, hypertrophy, soft tissue erythema, and tenderness, as well as a misplaced uvula.¹

DIAGNOSIS

Tetanus is a clinical diagnosis, usually made based on the findings described. Confirmatory lab tests are not readily available. The organism is infrequently recovered in cultures of specimens from suspected wounds (30% of cases).^10,11 Serologic testing on specimens drawn before administration of tetanus immunoglobulin (TIG) may indicate very low or undetectable antitetanus antibody levels, but tetanus can still occur when “protective” levels of antibodies are present.¹¹ Detection of tetanus toxin in plasma or a wound with bioassays and polymerase chain reaction might be possible, but these tests are only available in a few settings.³

THE MULTIFACETED CARE PLAN

The primary care provider should refer a patient with suspected tetanus to an emergency department, preferably a tertiary care center with the necessary specialists. Patients are likely to require prolonged hospitalization. In a recent series of tetanus cases in California, the median length of hospitalization was 18 days.¹² Treatment is multifaceted; interventions include immunization, wound care, administration of antibiotics and other pharmacologic agents, and supportive therapy (see Table 3).

Immunization

All patients with suspected tetanus should immediately receive both passive (with TIG) and active (tetanus toxoid–containing vaccines) immunization. Because of the extremely high potency of tetanus toxin, the very small amount of toxin that is required to cause tetanus is insufficient to prompt an immune response that would confer immunity. Therefore, treatment is the same regardless of whether the patient had prior disease.¹⁰

TIG binds to and neutralizes unbound tetanospasmin, preventing progression of the disease. As noted, TIG will not reverse the binding of the toxin to nerve structures.⁵ Due to a lack of prospective studies, there is disagreement regarding TIG dosage: Doses as high as 3,000-6,000 U have been recommended, but case studies indicate that the dosage recommended by the CDC (500 U) is likely effective.¹³ The full CDC recommendation is 500 U of human-derived TIG intramuscularly administered at locations near and away from the wound (but always away from the tetanus toxoid injection site).^10,17 Outside the US, equine-based TIG may be the only option. Animal-derived TIG is less desirable because of increased allergy risk; when used, a small amount (0.1 mL) should be first administered as an intradermal test.¹⁷

Tetanus toxoid immunization produces active immunity. It is currently available in combination antigen forms (tetanus and diphtheria vaccine [Td], tetanus-diphtheria-acellular pertussis [Tdap] vaccine). The dose of either is 0.5 mL. Patients with tetanus should receive three doses given intramuscularly: immediately, at 4 weeks, and at 6 to 12 months.¹⁰

Wound care

Wound care should include incision and drainage, removal of foreign bodies, debridement, and irrigation. These steps are taken in order to ensure an aerobic environment in the wound, ultimately decreasing C tetani survival.¹

Antibiotics

The preferred antimicrobial agent for treating tetanus infection is metronidazole 500 mg intravenously (IV) every 6 hours.^1,3,17 Penicillin (2 to 4 million U IV every 4 to 6 hours) is effective against C tetani, but it is a GABA-receptor antagonist and may worsen tetanus by further inhibiting the release of GABA.^1,14,18 GABA-receptor antagonism may also occur with cephalosporins; however, these broader-spectrum agents may be necessary to treat mixed infections.¹⁷ Alternatives include doxycycline, macrolides, and clindamycin.¹

Other pharmacologic treatment

Benzodiazepines (eg, diazepam 10 to 30 mg IV) can help control rigidity and muscle spasms and are a mainstay of tetanus treatment.¹⁸ Benzodiazepines and propofol both act on GABA receptors, producing sedation in addition to controlling muscle spasms.¹⁹ Traditionally, more severe spasms, such as opisthotonus, have required induction of complete paralysis with nondepolarizing paralytics, such as pancuronium or vecuronium. However, paralysis is not optimal therapy since it necessitates sedation, intubation, and mechanical ventilation. Because tetanus does not resolve for 6 to 8 weeks, patients who require mechanical ventilation will also require tracheostomy to prevent laryngotracheal stenosis. Paralysis and mechanical ventilation can also lead to deep venous thrombosis, decubitus ulcers, and pneumonia.⁵ The ideal treatment would reduce the spasms and autonomic instability without the risks associated with deep sedation and paralysis.⁵

Other agents used in the treatment of tetanus include magnesium sulfate, which can decrease muscle spasm and ameliorate the effects of autonomic dysfunction, and intrathecal baclofen, which can decrease muscle spasm.^19,20 Patients with persistent autonomic dysfunction may require combined α- and ß-adrenergic receptor blockade.^1,17-20

Supportive care

It is important to implement supportive care, including limiting auditory and tactile stimulation, as well as providing adequate hydration and nutritional support. IV fluids, parenteral feeding, and enteral feeding are required. Measures should be taken to prevent complications of prolonged immobility, paralysis, and mechanical ventilation, including deep venous thrombosis, pulmonary embolism, and pressure ulcers. The quality of supportive care and the swiftness with which the diagnosis is made and appropriate treatment is initiated are key factors that determine an individual patient’s outcome.²¹

COMPLICATIONS AND MORTALITY

Tetanus can lead to many complications, including long bone and spine fractures from severe muscle spasms, as well as renal failure and aspiration. Most spinal fractures involve the thoracic spine, but lumbar spine fractures have been reported.²² Burst-type fractures of the vertebrae may cause cauda equina syndrome or directly injure the spinal cord if fragments are retropulsed.²² Persistent muscle spasm can also cause rhabdomyolysis and renal failure. Lab test results, including elevated levels of creatine phosphokinase and myoglobin (rhabdomyolysis) as well as blood urea nitrogen and creatinine (renal failure), can indicate presence of complications. Muscle relaxation and hydration are key to prevention.

Patients with trismus are often unable to swallow and maintain oral hygiene, leading to caries and dental abscess. The trismus itself can also cause dental or jaw fractures.^2,13 Aspiration can occur when laryngeal muscles are affected, resulting in pneumonia in 50% to 70% of autopsied cases of tetanus.¹⁰ Additionally, the paralyzed patient receiving ventilatory support can develop pneumonia, deep vein thrombosis, and pulmonary embolism.^5,13 Neonatal tetanus often results in complications such as cerebral palsy or cognitive delay.¹

A number of factors influence the severity and outcome of tetanus. Untreated tetanus is typically fatal, with respiratory failure the most common cause of death in settings where mechanical ventilation is unavailable.¹ Where mechanical ventilation is accessible, autonomic dysfunction accounts for most deaths.²⁰ Ventilation aside, the case-fatality rate varies according to the medical system. The rate is often less than 20% where modern ICUs are available but can exceed 50% in undeveloped countries with limited facilities.^1,5 A review of outcomes data for 197 of the 233 tetanus cases reported in the US during 2001-2008 (modern medical care was provided in all) showed an overall case-fatality rate of 13.2%.⁷

Age and vaccination status also affect outcomes, with higher case-fatality rates seen in older (18% in those ≥ 60, 31% in those ≥ 65) and unvaccinated (22%) patients. ^7,10 In the study of tetanus cases from 2001-2008, the fatality rate was five times higher in patients ages 65 or older compared with patients younger than 65.⁷ This study also showed that severity of tetanus may be inversely related to the number of vaccine doses the individual has received, and that having previous vaccination was associated with improved survival, as only four of the 26 deaths occurred in patients with prior vaccination.⁷

Patients who survive the first two weeks of tetanus have a better chance of recovery. Those with multiple chronic comorbidities, such as chronic obstructive pulmonary disease (COPD), diabetes, or cardiovascular disease, are more likely to die because of the physiologic stress of the illness and its treatment.^1,7,12 The provision of ventilator support is more complicated in those with COPD; similarly, the autonomic effects of tetanus can be more problematic for patients with chronic cardiac disease or neurologic complications of chronic diabetes.¹³

PATIENT EDUCATION

Widespread vaccination against tetanus, which began in the US in the mid-20th century, has greatly reduced disease incidence.⁷ However, vaccination coverage rates remain below target.

In 2012, only 82.5% of children ages 19 to 35 months received the recommended four doses of diphtheria-tetanus-pertussis (DTaP) vaccine, and 94.3% received at least three doses.²³ Only 84.6% of teens ages 13 to 17 years received the primary four doses as well as the recommended booster dose.²⁴ The same year, only 55% of patients ages 65 and older and 64% of adults ages 19 to 64 had received a tetanus booster within the previous 10 years.²⁵

Vaccination rates are lower for black, Hispanic, and Asian adults in the US.²⁵ Clinicians should proactively recommend tetanus booster immunization to all adults.

CONCLUSION

Although few clinicians in developed countries will see a case of tetanus, all should be alert for it. Elderly patients and those not fully vaccinated are at risk. Routine immunization decreases but does not eliminate the risk. Tetanus differs from other illnesses controlled by national immunization efforts in that unvaccinated persons do not benefit from herd immunity, because the disease is not contagious. The diagnosis is clinical and should always be considered in patients with trismus, dysphagia, and/or adrenergic excess. Wounds that place a patient at risk for tetanus involve devitalized tissues and anaerobic conditions. Prompt diagnosis is essential, because it allows for early neutralization of unbound tetanospasmin. Wound care including debridement, antibiotic therapy, control of muscle spasms and the effects of autonomic instability, and airway care are fundamental to the treatment of tetanus. 

CE/CME No: CR-1704

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Recognize patients who are at risk for tetanus.
• Describe the clinical presentation of tetanus.
• Discuss proper treatment for a patient with tetanus.
• Promote widespread vaccination against tetanus.

FACULTY
Timothy W. Ferrarotti is the Director of Didactic Education and Assistant Professor in the PA Studies Program at the University of Saint Joseph, West Hartford, Connecticut.

The author has no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of April 2017.

Article begins on next page >>

Tetanus is a devastating disease that can be prevented by proper immunization and wound care. Although the incidence is low in the United States due to widespread routine vaccination, immunization coverage remains below target, especially in older adults. Since outcome is influenced by the clinician's ability to make a timely diagnosis and initiate appropriate care, continued appreciation of tetanus is warranted.

Tetanus is a neurologic disorder resulting from infection by the gram-positive, spore-forming anaerobic bacillus Clostridium tetani. The bacterium, in spore form, typically enters the body through a contaminated soft-tissue wound. Ubiquitous in the environment, C tetani spores are found throughout the world—in soil as well as in animal feces and saliva—and are resistant to temperature extremes and antiseptics. Tetanus is infectious but not contagious (not transmitted person-to-person).¹ Wounds with devitalized tissue or those supporting anaerobic conditions, such as bites, puncture wounds, burns, and gangrene, are conducive to the development of tetanus. Infection can also occur following dental extractions, abortions, and illicit drug injection.¹ Although vaccination programs have decreased the incidence of tetanus in the United States, C tetani infection remains an ongoing clinical concern because the spores are omnipresent, universal vaccination coverage has not been achieved, and vaccine-immunity wanes over time, placing individuals at risk.

PATHOPHYSIOLOGY

C tetani produces two toxins: tetanolysin and tetanospasmin (tetanus toxin). Tetanolysin may have a role in promoting the diffusion of tetanospasmin in soft tissues.² Tetanospasmin is a highly potent toxin, with a lethal dose in humans of less than 2.5 ng/kg of body weight.³ The toxin enters the peripheral nerve at the site of injury and migrates to the central nervous system (CNS). There, it causes unopposed α-motor neuron firing by preventing the release of inhibitory neurotransmitters such as γ-aminobutyric acid (GABA), resulting in muscle spasms and excess reflexive response to sensory stimuli.⁴ It also leads to excessive catecholamine release from the adrenal medulla.¹

Tetanospasmin binds to neurons in the spinal cord and brainstem. Because toxin binding is irreversible, resolution of tetanus requires the neurons to grow new axon terminals. The effects of tetanus can persist for six to eight weeks until new terminals develop.^3,5 Patients often require several weeks of ventilator support during this time.³

EPIDEMIOLOGY

Tetanus continues to be a serious cause of morbidity and mortality worldwide. The majority of cases (80%) occur in Africa and Southeast Asia.⁶ Incidence is much lower in the United States (0.1 cases per million persons annually) because of widespread vaccination, with only 233 cases of tetanus reported between 2001 and 2008.⁷ However, in the absence of confirmatory tests, the diagnosis is a clinical one; furthermore, there is no laboratory reporting program for tetanus. As a result, more cases may occur in the US than are detected or reported.

In developed countries, tetanus is primarily a disease of the elderly or the unvaccinated. Older persons, especially non-veterans, are less likely to have received the primary series. Because immunity decreases with age, even those who completed the primary series but have not received booster doses are at increased risk.⁸ Home-schooled children, who are not subject to school-entry vaccination requirements, are also at risk if unvaccinated.⁹

Neonatal tetanus is an ongoing problem in undeveloped countries that lack maternal vaccination programs. (Maternal immunization successfully reduces neonatal tetanus via passive immunity, and maternal tetanus via active immunity.) Unvaccinated women who undergo nonmedical abortions or unhygienic childbirth are at increased risk for tetanus.^3,10

Other risk factors for tetanus include wound contamination with soil, saliva, or devitalized tissue; injection drug use; and exposure to anthropogenic or natural disasters.¹ C tetani spores can contaminate heroin and may grow in abscesses of heroin users.⁴ Small outbreaks of tetanus among injection drug users have been reported, even among younger adults who had some immunity from childhood vaccination.^7,11 In addition, patients with diabetes are at increased risk for tetanus. These patients may have chronic wounds due to slowed healing and poor vascularity, which can lead to lower oxygen tension in their wounds and create an environment conducive to anaerobic infection. These chronic wounds are often ignored as a potential nidus for tetanus; instead, focus is placed on plantar puncture wounds or lacerations.⁷

Though tetanus risk is greatest for those who were never fully immunized, cases have been reported in persons who were immunized in the remote past but had not received a recent booster. Such cases show that tetanus immunity is not absolute and does wane over time.^12-14 Among the 233 tetanus cases reported in the US during 2001-2008, vaccination status was reported for 92. Of these, 24 patients had a complete series and 31 patients had at least one prior dose of tetanus vaccine.⁷ Furthermore, six cases occurred in patients known to have had the four-dose series and a booster within 10 years of diagnosis. Similarly, a 14-year-old boy who was fully vaccinated developed cephalic tetanus from a stingray wound.¹⁴ Given these data, clinicians should not assume that a patient who reports having had “a tetanus shot” is completely protected; a full series and regular boosters are required, and, in rare cases, tetanus can occur despite full vaccination.

PATIENT PRESENTATION AND TETANUS TYPES

The CDC describes tetanus as “the acute onset of hypertonia and/or painful muscle contractions (usually of the muscles of the jaw and neck) and generalized muscle spasms without other apparent medical cause.”¹⁵ Clinicians should always consider tetanus in patients with dysphagia and trismus, especially if the patient has a wound, had not received primary vaccination, or has not had a booster in several decades. Tetanus cannot be ruled out based on the lack of a wound, however, since up to 25% of patients who develop tetanus have no obvious site of inoculation.¹⁶ The incubation period ranges from 3 to 21 days, with more severe cases having shorter incubation periods (< 8 days).¹⁰ The closer the site of inoculation is to the CNS, the more serious the disease usually is—and the shorter the incubation period will be.¹

Presentation depends on the time elapsed since inoculation, the severity of illness (determined by the Ablett classification; see Table 1), and the form of tetanus involved. The patient may present early when the infection and toxin are localized to the wound and have not progressed to the CNS (localized tetanus). There may be a wound with signs of infection, including erythema, induration, edema, warmth, tenderness, and drainage. If the injury is on the head or neck, cephalic tetanus may occur, causing the patient to present with painful spasms of the extra-ocular, facial, and/or neck muscles; trismus; dysphagia; or even a Horner-like syndrome. The patient with more advanced, generalized tetanus may have decorticate posturing, abdominal wall rigidity, or opisthotonus.^1,2,5,17

Four types of tetanus have been described: generalized, localized, cephalic, and neonatal.

Generalized tetanus is the most common form, accounting for approximately 80% of cases.¹⁰ It may involve contractions of the masseter muscles, producing trismus; facial muscles, producing risus sardonicus (sardonic smile); neck and shoulder muscles; abdominal wall muscles, mimicking guarding; and back muscles, producing opisthotonus (arching of the back, neck, and head; see Figure 1) and decorticate posturing (flexion and adduction of the arms, clenched fists, and extension of the lower extremities).^1,5,6 Patients with generalized tetanus often exhibit hyperresponsiveness to the environment. As a result, noises and sudden light changes may result in acute spasms. In addition, patients may experience painful spasms when affected muscles are palpated. Affected reflex arcs are usually hyperresponsive to stimuli.¹ Intermittent spasms of the thoracic, pharyngeal, and/or laryngeal muscles may cause periods of apnea. Autonomic effects of tetanus mimic those associated with the catecholamine excess of pheochromocytoma. Patients exhibit restlessness, irritability, diaphoresis, fever, excessive salivation, gastric stasis, hypertension, tachycardia, and arrhythmia. There may be interposed hypotension and bradycardia.^1,5,17

Localized tetanus involves painful spastic contraction of muscles at or near the site of inoculation. It often evolves into generalized tetanus as the toxin spreads further into the CNS.

Cephalic tetanus involves facial and laryngeal muscles. It is rare, accounting for 1% to 3% of tetanus cases.⁶ Patients may initially have flaccid paralysis, mimicking stroke, rather than spasm, because the toxin has not completely migrated up the peripheral nerve into the CNS. As the toxin enters the CNS and induces the typical spasm (trismus), the diagnosis will be more obvious. The presence of trismus or a subacute wound on the head may be used to discriminate tetanus from stroke. Cephalic tetanus often evolves into generalized tetanus, affecting more of the body in a caudal direction.⁵

Neonatal tetanus develops within one week after birth. The neonate with tetanus is usually born to a mother lacking immunization. Typically, the infant sucks and feeds for the first couple of days, then develops inability/refusal to suck/feed, has difficulty opening his/her mouth, becomes weak, and develops muscle spasms.³ The affected child may develop risus sardonicus, clenched hands, dorsiflexion of the feet, and opisthotonus.³

DIFFERENTIAL DIAGNOSIS

The clinician should consider other CNS conditions in the differential diagnosis (see Table 2). Although similar to generalized seizures, tetanus causes painful spasms and does not produce a loss of consciousness.^1,17 Tetanus, intracranial bleed, and meningitis all can cause meningismus; meningitis, however, is more likely to manifest with other symptoms of infection, such as headache and fever. Although the autonomic dysfunction of tetanus can cause pyrexia, fever would usually coincide with other sympathetic symptoms, such as hypertension, tachycardia, and diaphoresis. Intracranial bleeding tends to have a more rapid onset than tetanus and produces headache and mental status changes. Seventh nerve palsy produces muscle flaccidity, not spasm, and is usually painless unless associated with herpetic inflam­mation.^1,5,6,14,17

Poisoning and medication effects should also be considered. Strychnine poisoning manifests similar to tetanus but occurs without a wound.⁵ Blood and urine assays for strychnine can be diagnostic. Dystonic reactions resulting from neuroleptic medications—such as phenothiazines—include torticollis, oropharyngeal muscle spasms, and deviation of the eyes. Unlike tetanus, drug-induced dystonia does not cause reflex spasms and often resolves with benztropine or diphenhydramine administration.¹ Neuroleptic malignant syndrome can also cause muscular rigidity and autonomic instability, but unlike tetanus, it often causes altered mental status; it should be considered in patients who recently received a causative medication.^5,17

Tetanus often manifests with reflexive muscle spasms similar to those seen in electrolyte and acid-base abnormalities. Hypocalcemia may produce a reflexive spasm of the facial muscles when the facial nerve is percussed (Chvostek sign), while alkalemia may produce reflexive spasm of the hand and wrist muscles (Trousseau sign).¹ Lab tests can rule out these diagnoses.^1,5

A patient with an odontogenic abscess may have pain and muscle spasm/trismus, but the infection is usually easily detected on exam. The clinician should be cautious in attributing the trismus solely to the swelling, however, as C tetani has been found in odontogenic abscesses and the patient may have both.^1,17 Peritonsillar abscess will often produce trismus. When abscess is the cause, careful examination of the oropharynx will usually demonstrate tonsillar exudate, hypertrophy, soft tissue erythema, and tenderness, as well as a misplaced uvula.¹

DIAGNOSIS

Tetanus is a clinical diagnosis, usually made based on the findings described. Confirmatory lab tests are not readily available. The organism is infrequently recovered in cultures of specimens from suspected wounds (30% of cases).^10,11 Serologic testing on specimens drawn before administration of tetanus immunoglobulin (TIG) may indicate very low or undetectable antitetanus antibody levels, but tetanus can still occur when “protective” levels of antibodies are present.¹¹ Detection of tetanus toxin in plasma or a wound with bioassays and polymerase chain reaction might be possible, but these tests are only available in a few settings.³

THE MULTIFACETED CARE PLAN

The primary care provider should refer a patient with suspected tetanus to an emergency department, preferably a tertiary care center with the necessary specialists. Patients are likely to require prolonged hospitalization. In a recent series of tetanus cases in California, the median length of hospitalization was 18 days.¹² Treatment is multifaceted; interventions include immunization, wound care, administration of antibiotics and other pharmacologic agents, and supportive therapy (see Table 3).

Immunization

All patients with suspected tetanus should immediately receive both passive (with TIG) and active (tetanus toxoid–containing vaccines) immunization. Because of the extremely high potency of tetanus toxin, the very small amount of toxin that is required to cause tetanus is insufficient to prompt an immune response that would confer immunity. Therefore, treatment is the same regardless of whether the patient had prior disease.¹⁰

TIG binds to and neutralizes unbound tetanospasmin, preventing progression of the disease. As noted, TIG will not reverse the binding of the toxin to nerve structures.⁵ Due to a lack of prospective studies, there is disagreement regarding TIG dosage: Doses as high as 3,000-6,000 U have been recommended, but case studies indicate that the dosage recommended by the CDC (500 U) is likely effective.¹³ The full CDC recommendation is 500 U of human-derived TIG intramuscularly administered at locations near and away from the wound (but always away from the tetanus toxoid injection site).^10,17 Outside the US, equine-based TIG may be the only option. Animal-derived TIG is less desirable because of increased allergy risk; when used, a small amount (0.1 mL) should be first administered as an intradermal test.¹⁷

Tetanus toxoid immunization produces active immunity. It is currently available in combination antigen forms (tetanus and diphtheria vaccine [Td], tetanus-diphtheria-acellular pertussis [Tdap] vaccine). The dose of either is 0.5 mL. Patients with tetanus should receive three doses given intramuscularly: immediately, at 4 weeks, and at 6 to 12 months.¹⁰

Wound care

Wound care should include incision and drainage, removal of foreign bodies, debridement, and irrigation. These steps are taken in order to ensure an aerobic environment in the wound, ultimately decreasing C tetani survival.¹

Antibiotics

The preferred antimicrobial agent for treating tetanus infection is metronidazole 500 mg intravenously (IV) every 6 hours.^1,3,17 Penicillin (2 to 4 million U IV every 4 to 6 hours) is effective against C tetani, but it is a GABA-receptor antagonist and may worsen tetanus by further inhibiting the release of GABA.^1,14,18 GABA-receptor antagonism may also occur with cephalosporins; however, these broader-spectrum agents may be necessary to treat mixed infections.¹⁷ Alternatives include doxycycline, macrolides, and clindamycin.¹

Other pharmacologic treatment

Benzodiazepines (eg, diazepam 10 to 30 mg IV) can help control rigidity and muscle spasms and are a mainstay of tetanus treatment.¹⁸ Benzodiazepines and propofol both act on GABA receptors, producing sedation in addition to controlling muscle spasms.¹⁹ Traditionally, more severe spasms, such as opisthotonus, have required induction of complete paralysis with nondepolarizing paralytics, such as pancuronium or vecuronium. However, paralysis is not optimal therapy since it necessitates sedation, intubation, and mechanical ventilation. Because tetanus does not resolve for 6 to 8 weeks, patients who require mechanical ventilation will also require tracheostomy to prevent laryngotracheal stenosis. Paralysis and mechanical ventilation can also lead to deep venous thrombosis, decubitus ulcers, and pneumonia.⁵ The ideal treatment would reduce the spasms and autonomic instability without the risks associated with deep sedation and paralysis.⁵

Other agents used in the treatment of tetanus include magnesium sulfate, which can decrease muscle spasm and ameliorate the effects of autonomic dysfunction, and intrathecal baclofen, which can decrease muscle spasm.^19,20 Patients with persistent autonomic dysfunction may require combined α- and ß-adrenergic receptor blockade.^1,17-20

Supportive care

It is important to implement supportive care, including limiting auditory and tactile stimulation, as well as providing adequate hydration and nutritional support. IV fluids, parenteral feeding, and enteral feeding are required. Measures should be taken to prevent complications of prolonged immobility, paralysis, and mechanical ventilation, including deep venous thrombosis, pulmonary embolism, and pressure ulcers. The quality of supportive care and the swiftness with which the diagnosis is made and appropriate treatment is initiated are key factors that determine an individual patient’s outcome.²¹

COMPLICATIONS AND MORTALITY

Tetanus can lead to many complications, including long bone and spine fractures from severe muscle spasms, as well as renal failure and aspiration. Most spinal fractures involve the thoracic spine, but lumbar spine fractures have been reported.²² Burst-type fractures of the vertebrae may cause cauda equina syndrome or directly injure the spinal cord if fragments are retropulsed.²² Persistent muscle spasm can also cause rhabdomyolysis and renal failure. Lab test results, including elevated levels of creatine phosphokinase and myoglobin (rhabdomyolysis) as well as blood urea nitrogen and creatinine (renal failure), can indicate presence of complications. Muscle relaxation and hydration are key to prevention.

Patients with trismus are often unable to swallow and maintain oral hygiene, leading to caries and dental abscess. The trismus itself can also cause dental or jaw fractures.^2,13 Aspiration can occur when laryngeal muscles are affected, resulting in pneumonia in 50% to 70% of autopsied cases of tetanus.¹⁰ Additionally, the paralyzed patient receiving ventilatory support can develop pneumonia, deep vein thrombosis, and pulmonary embolism.^5,13 Neonatal tetanus often results in complications such as cerebral palsy or cognitive delay.¹

A number of factors influence the severity and outcome of tetanus. Untreated tetanus is typically fatal, with respiratory failure the most common cause of death in settings where mechanical ventilation is unavailable.¹ Where mechanical ventilation is accessible, autonomic dysfunction accounts for most deaths.²⁰ Ventilation aside, the case-fatality rate varies according to the medical system. The rate is often less than 20% where modern ICUs are available but can exceed 50% in undeveloped countries with limited facilities.^1,5 A review of outcomes data for 197 of the 233 tetanus cases reported in the US during 2001-2008 (modern medical care was provided in all) showed an overall case-fatality rate of 13.2%.⁷

Age and vaccination status also affect outcomes, with higher case-fatality rates seen in older (18% in those ≥ 60, 31% in those ≥ 65) and unvaccinated (22%) patients. ^7,10 In the study of tetanus cases from 2001-2008, the fatality rate was five times higher in patients ages 65 or older compared with patients younger than 65.⁷ This study also showed that severity of tetanus may be inversely related to the number of vaccine doses the individual has received, and that having previous vaccination was associated with improved survival, as only four of the 26 deaths occurred in patients with prior vaccination.⁷

Patients who survive the first two weeks of tetanus have a better chance of recovery. Those with multiple chronic comorbidities, such as chronic obstructive pulmonary disease (COPD), diabetes, or cardiovascular disease, are more likely to die because of the physiologic stress of the illness and its treatment.^1,7,12 The provision of ventilator support is more complicated in those with COPD; similarly, the autonomic effects of tetanus can be more problematic for patients with chronic cardiac disease or neurologic complications of chronic diabetes.¹³

PATIENT EDUCATION

Widespread vaccination against tetanus, which began in the US in the mid-20th century, has greatly reduced disease incidence.⁷ However, vaccination coverage rates remain below target.

In 2012, only 82.5% of children ages 19 to 35 months received the recommended four doses of diphtheria-tetanus-pertussis (DTaP) vaccine, and 94.3% received at least three doses.²³ Only 84.6% of teens ages 13 to 17 years received the primary four doses as well as the recommended booster dose.²⁴ The same year, only 55% of patients ages 65 and older and 64% of adults ages 19 to 64 had received a tetanus booster within the previous 10 years.²⁵

Vaccination rates are lower for black, Hispanic, and Asian adults in the US.²⁵ Clinicians should proactively recommend tetanus booster immunization to all adults.

CONCLUSION

Although few clinicians in developed countries will see a case of tetanus, all should be alert for it. Elderly patients and those not fully vaccinated are at risk. Routine immunization decreases but does not eliminate the risk. Tetanus differs from other illnesses controlled by national immunization efforts in that unvaccinated persons do not benefit from herd immunity, because the disease is not contagious. The diagnosis is clinical and should always be considered in patients with trismus, dysphagia, and/or adrenergic excess. Wounds that place a patient at risk for tetanus involve devitalized tissues and anaerobic conditions. Prompt diagnosis is essential, because it allows for early neutralization of unbound tetanospasmin. Wound care including debridement, antibiotic therapy, control of muscle spasms and the effects of autonomic instability, and airway care are fundamental to the treatment of tetanus. 

CE/CME No: CR-1704

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Recognize patients who are at risk for tetanus.
• Describe the clinical presentation of tetanus.
• Discuss proper treatment for a patient with tetanus.
• Promote widespread vaccination against tetanus.

FACULTY
Timothy W. Ferrarotti is the Director of Didactic Education and Assistant Professor in the PA Studies Program at the University of Saint Joseph, West Hartford, Connecticut.

The author has no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of April 2017.

Article begins on next page >>

Tetanus is a devastating disease that can be prevented by proper immunization and wound care. Although the incidence is low in the United States due to widespread routine vaccination, immunization coverage remains below target, especially in older adults. Since outcome is influenced by the clinician's ability to make a timely diagnosis and initiate appropriate care, continued appreciation of tetanus is warranted.

Tetanus is a neurologic disorder resulting from infection by the gram-positive, spore-forming anaerobic bacillus Clostridium tetani. The bacterium, in spore form, typically enters the body through a contaminated soft-tissue wound. Ubiquitous in the environment, C tetani spores are found throughout the world—in soil as well as in animal feces and saliva—and are resistant to temperature extremes and antiseptics. Tetanus is infectious but not contagious (not transmitted person-to-person).¹ Wounds with devitalized tissue or those supporting anaerobic conditions, such as bites, puncture wounds, burns, and gangrene, are conducive to the development of tetanus. Infection can also occur following dental extractions, abortions, and illicit drug injection.¹ Although vaccination programs have decreased the incidence of tetanus in the United States, C tetani infection remains an ongoing clinical concern because the spores are omnipresent, universal vaccination coverage has not been achieved, and vaccine-immunity wanes over time, placing individuals at risk.

PATHOPHYSIOLOGY

C tetani produces two toxins: tetanolysin and tetanospasmin (tetanus toxin). Tetanolysin may have a role in promoting the diffusion of tetanospasmin in soft tissues.² Tetanospasmin is a highly potent toxin, with a lethal dose in humans of less than 2.5 ng/kg of body weight.³ The toxin enters the peripheral nerve at the site of injury and migrates to the central nervous system (CNS). There, it causes unopposed α-motor neuron firing by preventing the release of inhibitory neurotransmitters such as γ-aminobutyric acid (GABA), resulting in muscle spasms and excess reflexive response to sensory stimuli.⁴ It also leads to excessive catecholamine release from the adrenal medulla.¹

Tetanospasmin binds to neurons in the spinal cord and brainstem. Because toxin binding is irreversible, resolution of tetanus requires the neurons to grow new axon terminals. The effects of tetanus can persist for six to eight weeks until new terminals develop.^3,5 Patients often require several weeks of ventilator support during this time.³

EPIDEMIOLOGY

Tetanus continues to be a serious cause of morbidity and mortality worldwide. The majority of cases (80%) occur in Africa and Southeast Asia.⁶ Incidence is much lower in the United States (0.1 cases per million persons annually) because of widespread vaccination, with only 233 cases of tetanus reported between 2001 and 2008.⁷ However, in the absence of confirmatory tests, the diagnosis is a clinical one; furthermore, there is no laboratory reporting program for tetanus. As a result, more cases may occur in the US than are detected or reported.

In developed countries, tetanus is primarily a disease of the elderly or the unvaccinated. Older persons, especially non-veterans, are less likely to have received the primary series. Because immunity decreases with age, even those who completed the primary series but have not received booster doses are at increased risk.⁸ Home-schooled children, who are not subject to school-entry vaccination requirements, are also at risk if unvaccinated.⁹

Neonatal tetanus is an ongoing problem in undeveloped countries that lack maternal vaccination programs. (Maternal immunization successfully reduces neonatal tetanus via passive immunity, and maternal tetanus via active immunity.) Unvaccinated women who undergo nonmedical abortions or unhygienic childbirth are at increased risk for tetanus.^3,10

Other risk factors for tetanus include wound contamination with soil, saliva, or devitalized tissue; injection drug use; and exposure to anthropogenic or natural disasters.¹ C tetani spores can contaminate heroin and may grow in abscesses of heroin users.⁴ Small outbreaks of tetanus among injection drug users have been reported, even among younger adults who had some immunity from childhood vaccination.^7,11 In addition, patients with diabetes are at increased risk for tetanus. These patients may have chronic wounds due to slowed healing and poor vascularity, which can lead to lower oxygen tension in their wounds and create an environment conducive to anaerobic infection. These chronic wounds are often ignored as a potential nidus for tetanus; instead, focus is placed on plantar puncture wounds or lacerations.⁷

Though tetanus risk is greatest for those who were never fully immunized, cases have been reported in persons who were immunized in the remote past but had not received a recent booster. Such cases show that tetanus immunity is not absolute and does wane over time.^12-14 Among the 233 tetanus cases reported in the US during 2001-2008, vaccination status was reported for 92. Of these, 24 patients had a complete series and 31 patients had at least one prior dose of tetanus vaccine.⁷ Furthermore, six cases occurred in patients known to have had the four-dose series and a booster within 10 years of diagnosis. Similarly, a 14-year-old boy who was fully vaccinated developed cephalic tetanus from a stingray wound.¹⁴ Given these data, clinicians should not assume that a patient who reports having had “a tetanus shot” is completely protected; a full series and regular boosters are required, and, in rare cases, tetanus can occur despite full vaccination.

PATIENT PRESENTATION AND TETANUS TYPES

The CDC describes tetanus as “the acute onset of hypertonia and/or painful muscle contractions (usually of the muscles of the jaw and neck) and generalized muscle spasms without other apparent medical cause.”¹⁵ Clinicians should always consider tetanus in patients with dysphagia and trismus, especially if the patient has a wound, had not received primary vaccination, or has not had a booster in several decades. Tetanus cannot be ruled out based on the lack of a wound, however, since up to 25% of patients who develop tetanus have no obvious site of inoculation.¹⁶ The incubation period ranges from 3 to 21 days, with more severe cases having shorter incubation periods (< 8 days).¹⁰ The closer the site of inoculation is to the CNS, the more serious the disease usually is—and the shorter the incubation period will be.¹

Presentation depends on the time elapsed since inoculation, the severity of illness (determined by the Ablett classification; see Table 1), and the form of tetanus involved. The patient may present early when the infection and toxin are localized to the wound and have not progressed to the CNS (localized tetanus). There may be a wound with signs of infection, including erythema, induration, edema, warmth, tenderness, and drainage. If the injury is on the head or neck, cephalic tetanus may occur, causing the patient to present with painful spasms of the extra-ocular, facial, and/or neck muscles; trismus; dysphagia; or even a Horner-like syndrome. The patient with more advanced, generalized tetanus may have decorticate posturing, abdominal wall rigidity, or opisthotonus.^1,2,5,17

Four types of tetanus have been described: generalized, localized, cephalic, and neonatal.

Generalized tetanus is the most common form, accounting for approximately 80% of cases.¹⁰ It may involve contractions of the masseter muscles, producing trismus; facial muscles, producing risus sardonicus (sardonic smile); neck and shoulder muscles; abdominal wall muscles, mimicking guarding; and back muscles, producing opisthotonus (arching of the back, neck, and head; see Figure 1) and decorticate posturing (flexion and adduction of the arms, clenched fists, and extension of the lower extremities).^1,5,6 Patients with generalized tetanus often exhibit hyperresponsiveness to the environment. As a result, noises and sudden light changes may result in acute spasms. In addition, patients may experience painful spasms when affected muscles are palpated. Affected reflex arcs are usually hyperresponsive to stimuli.¹ Intermittent spasms of the thoracic, pharyngeal, and/or laryngeal muscles may cause periods of apnea. Autonomic effects of tetanus mimic those associated with the catecholamine excess of pheochromocytoma. Patients exhibit restlessness, irritability, diaphoresis, fever, excessive salivation, gastric stasis, hypertension, tachycardia, and arrhythmia. There may be interposed hypotension and bradycardia.^1,5,17

Localized tetanus involves painful spastic contraction of muscles at or near the site of inoculation. It often evolves into generalized tetanus as the toxin spreads further into the CNS.

Cephalic tetanus involves facial and laryngeal muscles. It is rare, accounting for 1% to 3% of tetanus cases.⁶ Patients may initially have flaccid paralysis, mimicking stroke, rather than spasm, because the toxin has not completely migrated up the peripheral nerve into the CNS. As the toxin enters the CNS and induces the typical spasm (trismus), the diagnosis will be more obvious. The presence of trismus or a subacute wound on the head may be used to discriminate tetanus from stroke. Cephalic tetanus often evolves into generalized tetanus, affecting more of the body in a caudal direction.⁵

Neonatal tetanus develops within one week after birth. The neonate with tetanus is usually born to a mother lacking immunization. Typically, the infant sucks and feeds for the first couple of days, then develops inability/refusal to suck/feed, has difficulty opening his/her mouth, becomes weak, and develops muscle spasms.³ The affected child may develop risus sardonicus, clenched hands, dorsiflexion of the feet, and opisthotonus.³

DIFFERENTIAL DIAGNOSIS

The clinician should consider other CNS conditions in the differential diagnosis (see Table 2). Although similar to generalized seizures, tetanus causes painful spasms and does not produce a loss of consciousness.^1,17 Tetanus, intracranial bleed, and meningitis all can cause meningismus; meningitis, however, is more likely to manifest with other symptoms of infection, such as headache and fever. Although the autonomic dysfunction of tetanus can cause pyrexia, fever would usually coincide with other sympathetic symptoms, such as hypertension, tachycardia, and diaphoresis. Intracranial bleeding tends to have a more rapid onset than tetanus and produces headache and mental status changes. Seventh nerve palsy produces muscle flaccidity, not spasm, and is usually painless unless associated with herpetic inflam­mation.^1,5,6,14,17

Poisoning and medication effects should also be considered. Strychnine poisoning manifests similar to tetanus but occurs without a wound.⁵ Blood and urine assays for strychnine can be diagnostic. Dystonic reactions resulting from neuroleptic medications—such as phenothiazines—include torticollis, oropharyngeal muscle spasms, and deviation of the eyes. Unlike tetanus, drug-induced dystonia does not cause reflex spasms and often resolves with benztropine or diphenhydramine administration.¹ Neuroleptic malignant syndrome can also cause muscular rigidity and autonomic instability, but unlike tetanus, it often causes altered mental status; it should be considered in patients who recently received a causative medication.^5,17

Tetanus often manifests with reflexive muscle spasms similar to those seen in electrolyte and acid-base abnormalities. Hypocalcemia may produce a reflexive spasm of the facial muscles when the facial nerve is percussed (Chvostek sign), while alkalemia may produce reflexive spasm of the hand and wrist muscles (Trousseau sign).¹ Lab tests can rule out these diagnoses.^1,5

A patient with an odontogenic abscess may have pain and muscle spasm/trismus, but the infection is usually easily detected on exam. The clinician should be cautious in attributing the trismus solely to the swelling, however, as C tetani has been found in odontogenic abscesses and the patient may have both.^1,17 Peritonsillar abscess will often produce trismus. When abscess is the cause, careful examination of the oropharynx will usually demonstrate tonsillar exudate, hypertrophy, soft tissue erythema, and tenderness, as well as a misplaced uvula.¹

DIAGNOSIS

Tetanus is a clinical diagnosis, usually made based on the findings described. Confirmatory lab tests are not readily available. The organism is infrequently recovered in cultures of specimens from suspected wounds (30% of cases).^10,11 Serologic testing on specimens drawn before administration of tetanus immunoglobulin (TIG) may indicate very low or undetectable antitetanus antibody levels, but tetanus can still occur when “protective” levels of antibodies are present.¹¹ Detection of tetanus toxin in plasma or a wound with bioassays and polymerase chain reaction might be possible, but these tests are only available in a few settings.³

THE MULTIFACETED CARE PLAN

The primary care provider should refer a patient with suspected tetanus to an emergency department, preferably a tertiary care center with the necessary specialists. Patients are likely to require prolonged hospitalization. In a recent series of tetanus cases in California, the median length of hospitalization was 18 days.¹² Treatment is multifaceted; interventions include immunization, wound care, administration of antibiotics and other pharmacologic agents, and supportive therapy (see Table 3).

Immunization

All patients with suspected tetanus should immediately receive both passive (with TIG) and active (tetanus toxoid–containing vaccines) immunization. Because of the extremely high potency of tetanus toxin, the very small amount of toxin that is required to cause tetanus is insufficient to prompt an immune response that would confer immunity. Therefore, treatment is the same regardless of whether the patient had prior disease.¹⁰

TIG binds to and neutralizes unbound tetanospasmin, preventing progression of the disease. As noted, TIG will not reverse the binding of the toxin to nerve structures.⁵ Due to a lack of prospective studies, there is disagreement regarding TIG dosage: Doses as high as 3,000-6,000 U have been recommended, but case studies indicate that the dosage recommended by the CDC (500 U) is likely effective.¹³ The full CDC recommendation is 500 U of human-derived TIG intramuscularly administered at locations near and away from the wound (but always away from the tetanus toxoid injection site).^10,17 Outside the US, equine-based TIG may be the only option. Animal-derived TIG is less desirable because of increased allergy risk; when used, a small amount (0.1 mL) should be first administered as an intradermal test.¹⁷

Tetanus toxoid immunization produces active immunity. It is currently available in combination antigen forms (tetanus and diphtheria vaccine [Td], tetanus-diphtheria-acellular pertussis [Tdap] vaccine). The dose of either is 0.5 mL. Patients with tetanus should receive three doses given intramuscularly: immediately, at 4 weeks, and at 6 to 12 months.¹⁰

Wound care

Wound care should include incision and drainage, removal of foreign bodies, debridement, and irrigation. These steps are taken in order to ensure an aerobic environment in the wound, ultimately decreasing C tetani survival.¹

Antibiotics

The preferred antimicrobial agent for treating tetanus infection is metronidazole 500 mg intravenously (IV) every 6 hours.^1,3,17 Penicillin (2 to 4 million U IV every 4 to 6 hours) is effective against C tetani, but it is a GABA-receptor antagonist and may worsen tetanus by further inhibiting the release of GABA.^1,14,18 GABA-receptor antagonism may also occur with cephalosporins; however, these broader-spectrum agents may be necessary to treat mixed infections.¹⁷ Alternatives include doxycycline, macrolides, and clindamycin.¹

Other pharmacologic treatment

Benzodiazepines (eg, diazepam 10 to 30 mg IV) can help control rigidity and muscle spasms and are a mainstay of tetanus treatment.¹⁸ Benzodiazepines and propofol both act on GABA receptors, producing sedation in addition to controlling muscle spasms.¹⁹ Traditionally, more severe spasms, such as opisthotonus, have required induction of complete paralysis with nondepolarizing paralytics, such as pancuronium or vecuronium. However, paralysis is not optimal therapy since it necessitates sedation, intubation, and mechanical ventilation. Because tetanus does not resolve for 6 to 8 weeks, patients who require mechanical ventilation will also require tracheostomy to prevent laryngotracheal stenosis. Paralysis and mechanical ventilation can also lead to deep venous thrombosis, decubitus ulcers, and pneumonia.⁵ The ideal treatment would reduce the spasms and autonomic instability without the risks associated with deep sedation and paralysis.⁵

Other agents used in the treatment of tetanus include magnesium sulfate, which can decrease muscle spasm and ameliorate the effects of autonomic dysfunction, and intrathecal baclofen, which can decrease muscle spasm.^19,20 Patients with persistent autonomic dysfunction may require combined α- and ß-adrenergic receptor blockade.^1,17-20

Supportive care

It is important to implement supportive care, including limiting auditory and tactile stimulation, as well as providing adequate hydration and nutritional support. IV fluids, parenteral feeding, and enteral feeding are required. Measures should be taken to prevent complications of prolonged immobility, paralysis, and mechanical ventilation, including deep venous thrombosis, pulmonary embolism, and pressure ulcers. The quality of supportive care and the swiftness with which the diagnosis is made and appropriate treatment is initiated are key factors that determine an individual patient’s outcome.²¹

COMPLICATIONS AND MORTALITY

Tetanus can lead to many complications, including long bone and spine fractures from severe muscle spasms, as well as renal failure and aspiration. Most spinal fractures involve the thoracic spine, but lumbar spine fractures have been reported.²² Burst-type fractures of the vertebrae may cause cauda equina syndrome or directly injure the spinal cord if fragments are retropulsed.²² Persistent muscle spasm can also cause rhabdomyolysis and renal failure. Lab test results, including elevated levels of creatine phosphokinase and myoglobin (rhabdomyolysis) as well as blood urea nitrogen and creatinine (renal failure), can indicate presence of complications. Muscle relaxation and hydration are key to prevention.

Patients with trismus are often unable to swallow and maintain oral hygiene, leading to caries and dental abscess. The trismus itself can also cause dental or jaw fractures.^2,13 Aspiration can occur when laryngeal muscles are affected, resulting in pneumonia in 50% to 70% of autopsied cases of tetanus.¹⁰ Additionally, the paralyzed patient receiving ventilatory support can develop pneumonia, deep vein thrombosis, and pulmonary embolism.^5,13 Neonatal tetanus often results in complications such as cerebral palsy or cognitive delay.¹

A number of factors influence the severity and outcome of tetanus. Untreated tetanus is typically fatal, with respiratory failure the most common cause of death in settings where mechanical ventilation is unavailable.¹ Where mechanical ventilation is accessible, autonomic dysfunction accounts for most deaths.²⁰ Ventilation aside, the case-fatality rate varies according to the medical system. The rate is often less than 20% where modern ICUs are available but can exceed 50% in undeveloped countries with limited facilities.^1,5 A review of outcomes data for 197 of the 233 tetanus cases reported in the US during 2001-2008 (modern medical care was provided in all) showed an overall case-fatality rate of 13.2%.⁷

Age and vaccination status also affect outcomes, with higher case-fatality rates seen in older (18% in those ≥ 60, 31% in those ≥ 65) and unvaccinated (22%) patients. ^7,10 In the study of tetanus cases from 2001-2008, the fatality rate was five times higher in patients ages 65 or older compared with patients younger than 65.⁷ This study also showed that severity of tetanus may be inversely related to the number of vaccine doses the individual has received, and that having previous vaccination was associated with improved survival, as only four of the 26 deaths occurred in patients with prior vaccination.⁷

Patients who survive the first two weeks of tetanus have a better chance of recovery. Those with multiple chronic comorbidities, such as chronic obstructive pulmonary disease (COPD), diabetes, or cardiovascular disease, are more likely to die because of the physiologic stress of the illness and its treatment.^1,7,12 The provision of ventilator support is more complicated in those with COPD; similarly, the autonomic effects of tetanus can be more problematic for patients with chronic cardiac disease or neurologic complications of chronic diabetes.¹³

PATIENT EDUCATION

Widespread vaccination against tetanus, which began in the US in the mid-20th century, has greatly reduced disease incidence.⁷ However, vaccination coverage rates remain below target.

In 2012, only 82.5% of children ages 19 to 35 months received the recommended four doses of diphtheria-tetanus-pertussis (DTaP) vaccine, and 94.3% received at least three doses.²³ Only 84.6% of teens ages 13 to 17 years received the primary four doses as well as the recommended booster dose.²⁴ The same year, only 55% of patients ages 65 and older and 64% of adults ages 19 to 64 had received a tetanus booster within the previous 10 years.²⁵

Vaccination rates are lower for black, Hispanic, and Asian adults in the US.²⁵ Clinicians should proactively recommend tetanus booster immunization to all adults.

CONCLUSION

Although few clinicians in developed countries will see a case of tetanus, all should be alert for it. Elderly patients and those not fully vaccinated are at risk. Routine immunization decreases but does not eliminate the risk. Tetanus differs from other illnesses controlled by national immunization efforts in that unvaccinated persons do not benefit from herd immunity, because the disease is not contagious. The diagnosis is clinical and should always be considered in patients with trismus, dysphagia, and/or adrenergic excess. Wounds that place a patient at risk for tetanus involve devitalized tissues and anaerobic conditions. Prompt diagnosis is essential, because it allows for early neutralization of unbound tetanospasmin. Wound care including debridement, antibiotic therapy, control of muscle spasms and the effects of autonomic instability, and airway care are fundamental to the treatment of tetanus. 

The obesity epidemic has reached critical proportions. A new practice guide from the American Gastroenterological Association aims to help gastroenterologists engage in a multidisciplinary effort to tackle the problem.

The guide, entitled “POWER: Practice Guide on Obesity and Weight Management, Education and Resources,” includes a comprehensive clinical process for assessing and safely and effectively managing patients with obesity, as well as a framework focused on helping practitioners navigate the business operational issues related to the management of obesity. Both are in press for the May issue of Clinical Gastroenterology and Hepatology (2016. doi: 10.1016/j.cgh.2016.10.023).

The POWER model recognizes obesity as an epidemic and as an economic and societal burden that should be embraced as a chronic, relapsing disease best managed across a flexible care cycle using a team approach.

[email protected]

The obesity epidemic has reached critical proportions. A new practice guide from the American Gastroenterological Association aims to help gastroenterologists engage in a multidisciplinary effort to tackle the problem.

The guide, entitled “POWER: Practice Guide on Obesity and Weight Management, Education and Resources,” includes a comprehensive clinical process for assessing and safely and effectively managing patients with obesity, as well as a framework focused on helping practitioners navigate the business operational issues related to the management of obesity. Both are in press for the May issue of Clinical Gastroenterology and Hepatology (2016. doi: 10.1016/j.cgh.2016.10.023).

The POWER model recognizes obesity as an epidemic and as an economic and societal burden that should be embraced as a chronic, relapsing disease best managed across a flexible care cycle using a team approach.

[email protected]

The obesity epidemic has reached critical proportions. A new practice guide from the American Gastroenterological Association aims to help gastroenterologists engage in a multidisciplinary effort to tackle the problem.

The guide, entitled “POWER: Practice Guide on Obesity and Weight Management, Education and Resources,” includes a comprehensive clinical process for assessing and safely and effectively managing patients with obesity, as well as a framework focused on helping practitioners navigate the business operational issues related to the management of obesity. Both are in press for the May issue of Clinical Gastroenterology and Hepatology (2016. doi: 10.1016/j.cgh.2016.10.023).

The POWER model recognizes obesity as an epidemic and as an economic and societal burden that should be embraced as a chronic, relapsing disease best managed across a flexible care cycle using a team approach.

[email protected]

Outpatient visits for influenza-like illness (ILI) held steady for the week ending March 25, but the number of states at the “high” range of activity dropped from 12 from 10 the previous week, according to the Centers for Disease Prevention and Control.

The proportion of outpatient visits for ILI was 3.2% for the second consecutive week, which halted the slowdown in activity that began the week ending Feb. 18. That 3.2% represents just under 25,000 visits for ILI of the almost 747,000 total visits reported to the Outpatient Influenza-like Illness Surveillance Network (ILINet) for the week ending March 25. By age, the largest groups with ILI visits for the week were individuals aged 5-24 years (41%) and those aged 4 years and under (20%), the CDC reported.

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Outpatient visits for influenza-like illness (ILI) held steady for the week ending March 25, but the number of states at the “high” range of activity dropped from 12 from 10 the previous week, according to the Centers for Disease Prevention and Control.

The proportion of outpatient visits for ILI was 3.2% for the second consecutive week, which halted the slowdown in activity that began the week ending Feb. 18. That 3.2% represents just under 25,000 visits for ILI of the almost 747,000 total visits reported to the Outpatient Influenza-like Illness Surveillance Network (ILINet) for the week ending March 25. By age, the largest groups with ILI visits for the week were individuals aged 5-24 years (41%) and those aged 4 years and under (20%), the CDC reported.

[email protected]

Outpatient visits for influenza-like illness (ILI) held steady for the week ending March 25, but the number of states at the “high” range of activity dropped from 12 from 10 the previous week, according to the Centers for Disease Prevention and Control.

The proportion of outpatient visits for ILI was 3.2% for the second consecutive week, which halted the slowdown in activity that began the week ending Feb. 18. That 3.2% represents just under 25,000 visits for ILI of the almost 747,000 total visits reported to the Outpatient Influenza-like Illness Surveillance Network (ILINet) for the week ending March 25. By age, the largest groups with ILI visits for the week were individuals aged 5-24 years (41%) and those aged 4 years and under (20%), the CDC reported.

[email protected]