StemCell Therapy

The first three and half months following a stem cell transplant pose the greatest risk of developing complications associated with a stem cell transplant (whether bone marrow or cord blood). However, the risk of developing stem cell transplant complications varies and depends on several factors. Among these potential stem cell transplant complications is graft failure, which is more likely to occur in some cases than others. The risk of graft failure often depends on the patients medical state prior to a stem cell transplant, the type of stem cell transplant performed, and the type of treatable disease involved.

What is Graft Failure? High-dose chemotherapy which accompanies a stem cell transplant destroys the ability for bone marrow to produce white blood cells, red blood cells and platelets. Graft failure is a condition in which normal bone marrow function does not return following a stem cell transplant.

Following transplant, the graft may fail to grow in the patients body, which will result in bone marrow failure and the absence of new blood cell production. This can lead to side effects such as repeated infections, anemia, bruising and bleeding.

In general, doctors define graft failure as the absence of engraftment forty-two days following a stem cell transplant. In other words, the body does not accept the donated cells; however, total graft failure is considered to be rare.

Graft Failure vs. GVHD Graft failure and graft-versus-host disease (GVHD) represent two different types of potential complications following a stem cell transplant. In the case of GVHD, the patients immune system will respond adversely to the donated stem cells, and white blood cells will begin to destroy the transplanted graft. This differs from the bodys failure to accept the graft and restore blood cell production that occurs in graft failure.

GVHD is a potential side effect associated with allogeneic stem cell transplants, in which stem cells are derived from a donor source such as cord blood. In the case of autologous stem cell transplants in which the patients own stem cells are infused into the body there is generally no risk of GVHD. However, the risk of graft failure following an autologous stem cell transplant is 5%.

Graft Failure Risks There are a number of factors that may contribute to the risk of graft failure in patients undergoing a stem cell transplant. Factors that may contribute to an increased risk of graft failure include the following:

The type pf disease being treated may play a role in the risk of developing graft failure. For example, one study found that the risk of graft failure was much higher (33%) in patients undergoing a stem cell transplant for osteoporosis than in patients being treated for leukemia. This may be due to the fact that leukemia stem cell therapy is a more established treatment procedure.

In leukemia patients, however, graft failure is usually associated with the recurrence of cancer as the leukemic cells may hinder the growth of the transplanted stem cells.

For some patients who develop graft failure, the cause of graft failure is unknown.

Graft Failure Treatment While considered relatively rare, graft failure is a serious and ultimately fatal complication that will likely require a second stem cell transplant. Stem cells used in the second transplant may be derived from either the same donor source or a different stem cell source. In patients undergoing an umbilical cord blood stem cells transplant, the same cord blood unit cannot be used. A different cord blood unit or another adult stem cell source may be used in these cases.

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Stem Cell Transplant Complications: Graft Failure

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Please note: An erratum has been published for this article. To view the erratum, please click here.

Clare A. Dykewicz, M.D., M.P.H. Harold W. Jaffe, M.D., Director Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention

Clare A. Dykewicz, M.D., M.P.H., Chair Harold W. Jaffe, M.D. Thomas J. Spira, M.D. Division of AIDS, STD, and TB Laboratory Research

William R. Jarvis, M.D. Hospital Infections Program National Center for Infectious Diseases, CDC

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Brian R. Edlin, M.D. Division of HIV/AIDS Prevention---Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Robert T. Chen, M.D., M.A. Beth Hibbs, R.N., M.P.H. Epidemiology and Surveillance Division National Immunization Program, CDC

Raleigh A. Bowden, M.D. Keith Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

David Emanuel, M.B.Ch.B. Indiana University Indianapolis, Indiana

David L. Longworth, M.D. Cleveland Clinic Foundation Cleveland, Ohio

Philip A. Rowlings, M.B.B.S., M.S. International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry Milwaukee, Wisconsin

Robert H. Rubin, M.D. Massachusetts General Hospital Boston, Massachusetts and Massachusetts Institute of Technology Cambridge, Massachusetts

Kent A. Sepkowitz, M.D. Memorial-Sloan Kettering Cancer Center New York, New York

John R. Wingard, M.D. University of Florida Gainesville, Florida

John F. Modlin, M.D. Dartmouth Medical School Hanover, New Hampshire

Donna M. Ambrosino, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Norman W. Baylor, Ph.D. Food and Drug Administration Rockville, Maryland

Albert D. Donnenberg, Ph.D. University of Pittsburgh Pittsburgh, Pennsylvania

Pierce Gardner, M.D. State University of New York at Stony Brook Stony Brook, New York

Roger H. Giller, M.D. University of Colorado Denver, Colorado

Neal A. Halsey, M.D. Johns Hopkins University Baltimore, Maryland

Chinh T. Le, M.D. Kaiser-Permanente Medical Center Santa Rosa, California

Deborah C. Molrine, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Keith M. Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.

In 1992, the Institute of Medicine (1) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3--5). Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.

The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.

The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hematopoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals.

For all recommendations, prevention strategies are rated by the strength of the recommendation (Table 1) and the quality of the evidence (Table 2) supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIV-infected persons (3--6). This rating system allows assessments of recommendations to which adherence is critical.

HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) (7--10). Moreover, HSCT has become standard treatment for selected conditions (7,11,12). Data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicate that approximately 20,000 HSCTs were performed in North America during 1998 (Statistical Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia (13) and offer the only curative therapy for persons with chronic myelogenous leukemia (12). Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14--16). Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18). However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19). To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte--depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20).

The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require high-level or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21). Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.

Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22--24). However, immune system function after UCB transplants has not been well-studied.

HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients (25) and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.

GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26) and because of the development of other strategies for GVHD prophylaxis (27). For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.

Although survival rates for certain autologous recipients have improved (28,29), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29). Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987--November 1990, a total of 66% had died by 1991 (15). Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15).**

Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30). In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31).

During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria-carrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.

During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., . coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci) (32,33).

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6--84 days) (15). In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within >2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27). They might also have immunoglobulin G (IgG)2, IgG4, and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32). Immune system recovery might be delayed further by CMV infection (34).

During the first >2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I--IV (32,35,36). Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19). Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38).

Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39). Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41), poor response to vaccination (42--44), and severe mucositis (19). Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40), and a history of acute GVHD (24,45). Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19). Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41), they experience long-lasting IgA, IgG, and IgG subclass deficiencies (41,46,47) and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections (32,39), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.

HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure). Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30--100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information:

Preventing infections among HSCT recipients is preferable to treating infections. How ever, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

Preventing Exposure

Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII).

Preventing Disease

Preventing Early Disease (0--100 Days After HSCT). Routine gut decontamination is not recommended for HSCT candidates (51--53) (DIII). Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients. Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51), infection-related fatality rates are not reduced (52). If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54). Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.

Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG*** use to prevent bacterial infections among the approximately 20%--25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae) (8) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1--10 days) is much shorter than the half-life among healthy adults (generally 18--23 days) (56--58). Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400--500 mg/dl (58) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).

Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60) (DI) as a means of preventing bacterial infections.

Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.

Preventing Exposure

Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae (62,63) (BIII) to prevent exposure among HSCT recipients.

Preventing Disease

Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64--66) (BIII). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, and Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.

As with adults, pediatric HSCT recipients aged >2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Preventing Exposure

Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known.

Preventing Disease

Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia. Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67) (AIII).

Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII). No data were found that demonstrate efficacy of prophylactic antibiotics for this infection. Furthermore, such use might select antibiotic-resistant bacteria, and in fact, penicillin- and vancomycin-resistant strains of Streptococci viridans have been reported (68). However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII). Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII).

HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII). Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69).

Preventing Exposure

Adults with Ha. influenzae type b (Hib) pneumonia require standard precautions (62) to prevent exposing the HSCT recipient to Hib. Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions. Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix). This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72--74). Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII).

Preventing Disease

Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII). This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies >4 months after HSCT (75), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77). HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70) (BIII) (Appendix).

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic-resistance patterns. Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients. Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70) (BIII). Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71) (Appendix).

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII). Only Food and Drug Administration (FDA) licensed or approved tests should be used. HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII).

Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for CMV infections. Therefore, during periods of immuno-compromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).

After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII). CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 106 leukocytes/unit) to prevent transfusion-associated CMV infection (78) (AI). However, insufficient data were found to recommend use of leukocyte-reduced or CMV-seronega tive red cells and platelets among CMV-seronegative recipients who have CMV-seropositive donors (i.e., R-negative or D-positive).

All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients. HSCT patients who are known to excrete CMV should be placed under standard precautions (62) for the duration of CMV excretion to avoid possible transmission to CMV-seronegative HSCT recipients and candidates (AIII). Physicians are cautioned that CMV excretion can be episodic or prolonged.

Preventing Disease and Disease Recurrence

HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI). Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability.

Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT). The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).

Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened >1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).

HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79--81). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82) is very sensitive but has a low positive predictive value (79). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.

Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83) or routine culture (84,85) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require >48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87] or CMV pp67 viral RNA [ribonucleic acid] detection) (88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.

Allogeneic recipients <100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has >2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89--91) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).

Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovir-intolerant should be administered foscarnet instead (93) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked >2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94) or temporarily stopping ganciclovir for >2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is >1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).

Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell--depleted HSCTs who are at high risk (95--99). If CMV is still detectable by routine screening >100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates >5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had >2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.

If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93).

Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102). Acyclovir is not effective in preventing CMV disease after autologous HSCT (103) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).

Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.

Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV-seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80) or quantitative PCR (BII).

Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of >5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.

Preventing Exposure

All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104) (AII).

Preventing Disease

Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell--depleted unrelated or mismatched allogeneic recipients (105,106). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108) (DII).

Preventing Exposure

HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or -approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62) (AI) to prevent transmission of HSV to HSCT recipients.

Preventing Disease and Disease Recurrence

Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109--113) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114), although ganciclovir has not been approved for use against HSV.

Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data among HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).

Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).

Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.

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Guidelines for Preventing Opportunistic Infections Among ...

Overview

Aggressive treatment of malignant disease may produce unavoidable toxicities to normal cells. The mucosal lining of the gastrointestinal tract, including the oral mucosa, is a prime target for treatment-related toxicity by virtue of its rapid rate of cell turnover. The oral cavity is highly susceptible to direct and indirect toxic effects of cancer chemotherapy and ionizing radiation.[1] This risk results from multiple factors, including high rates of cellular turnover for the lining mucosa, a diverse and complex microflora, and trauma to oral tissues during normal oral function.[2] Although changes in soft tissue structures within the oral cavity presumably reflect the changes that occur throughout the gastrointestinal tract, this summary focuses on oral complications of antineoplastic drugs and radiation therapies.

It is essential that a multidisciplinary approach be used for oral management of the cancer patient before, during, and after cancer treatment. A multidisciplinary approach is warranted because the medical complexity of these patients affects dental treatment planning, prioritization, and timing of dental care. In addition, selected cancer patients (e.g., status posttreatment with high-dose head-and-neck radiation) are often at lifelong risk for serious complications such as osteoradionecrosis of the mandible. Thus, a multidisciplinary oncology team that includes oncologists, oncology nurses, and dental generalists and specialists as well as dental hygienists, social workers, dieticians, and related health professionals can often achieve highly effective preventive and therapeutic outcomes relative to oral complications in these patients.

While oral complications may mimic selected systemic disorders, unique oral toxicities emerge in the context of specific oral anatomic structures and their functions.

Frequencies of oral complications vary by cancer therapy; estimates are included in Table 1.

The most common oral complications related to cancer therapies are mucositis, infection, salivary gland dysfunction, taste dysfunction, and pain. These complications can lead to secondary complications such as dehydration, dysgeusia, and malnutrition. In myelosuppressed cancer patients, the oral cavity can also be a source of systemic infection. Radiation of the head and neck can irreversibly injure oral mucosa, vasculature, muscle, and bone, resulting in xerostomia, rampant dental caries, trismus, soft tissue necrosis, and osteonecrosis.

Severe oral toxicities can compromise delivery of optimal cancer therapy protocols. For example, dose reduction or treatment schedule modifications may be necessary to allow for resolution of oral lesions. In cases of severe oral morbidity, the patient may no longer be able to continue cancer therapy; treatment is then usually discontinued. These disruptions in dosing caused by oral complications can directly affect patient survivorship.

Management of oral complications of cancer therapy includes identification of high-risk populations, patient education, initiation of pretreatment interventions, and timely management of lesions. Assessment of oral status and stabilization of oral disease before cancer therapy are critical to overall patient care. Care should be both preventive and therapeutic to minimize risk for oral and associated systemic complications.

Future research targeted at developing technologies is needed to:

Development of new technologies to prevent cancer therapyinduced complications, especially oral mucositis, could substantially reduce the risk of oral pain, oral and systemic infections, and number of days in the hospital; and could improve quality of life and reduce health care costs. New technologies could also provide a setting in which novel classes of chemotherapeutic drugs, used at increased doses, could lead to enhanced cancer cure rates and durability of disease remission.

As has been noted, it is essential that a multidisciplinary approach be used for oral management of the cancer patient before, during, and after cancer treatment. This collaboration is pivotally important for the advancement of basic, clinical, and translational research associated with oral complications of current and emerging cancer therapies. The pathobiologic complexity of oral complications and the ever-expanding science base of clinical management require this comprehensive interdisciplinary approach.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Oral complications associated with cancer chemotherapy and radiation result from complex interactions among multiple factors. The most prominent contributors are direct lethal and sublethal damage to oral tissues, attenuation of immune and other protective systems, and interference with normal healing. Principal causes can be attributed to both direct stomatotoxicity and indirect stomatotoxicity. Direct toxicities are initiated via primary injury to oral tissues. Indirect toxicities are caused by nonoral toxicities that secondarily affect the oral cavity, including the following:

Understanding of mechanisms associated with oral complications continues to increase. Unfortunately, there are no universally effective agents or protocols to prevent toxicity. Elimination of preexisting dental/periapical, periodontal, and mucosal infections; institution of comprehensive oral hygiene protocols during therapy; and reduction of other factors that may compromise oral mucosal integrity (e.g., physical trauma to oral tissues) can reduce frequency and severity of oral complications in cancer patients (refer to the Oral and Dental Management Before Cancer Therapy and the Oral and Dental Management After Cancer Therapy sections of this summary for further information).[1]

Complications can be acute (developing during therapy) or chronic (developing months to years after therapy). In general, cancer chemotherapy causes acute toxicities that resolve following discontinuation of therapy and recovery of damaged tissues. In contrast, radiation protocols typically cause not only acute oral toxicities, but induce permanent tissue damage that result in lifelong risk for the patient.

Risk factors for oral complications (see Table 2) derive from both direct damage to oral tissues secondary to chemotherapy and indirect damage due to regional or systemic toxicity. For example, therapy-related toxicity to oral mucosa can be exacerbated by colonizing oral microflora when local and systemic immune function is concurrently compromised. Frequency and severity of oral complications are directly related to extent and type of systemic compromise.

Ulcerative oral mucositis occurs in approximately 40% of patients receiving chemotherapy. In approximately 50% of these patients, the lesions are severe and require medical intervention including modification of their cytotoxic cancer therapy. Normal oral mucosal epithelium is estimated to undergo complete replacement every 9 to 16 days. Intensive chemotherapy can cause ulcerative mucositis that initially emerges approximately 2 weeks after initiation of high-dose chemotherapy.[2-4]

Chemotherapy directly impairs replication of basal epithelial cells; other factors, including proinflammatory cytokines and metabolic products of bacteria, may also play a role. The labial mucosa, buccal mucosa, tongue, floor of mouth, and soft palate are more severely affected by chemotherapy than are the attached, heavily keratinized tissues such as the hard palate and gingiva; this may be caused by relative rate of epithelial cell turnover among high-risk versus low-risk oral mucosal tissues. Topical cryotherapy may ameliorate mucositis caused by agents such as 5-fluorouracil (5-FU) by reducing vascular delivery of these toxic agents to replicating oral epithelium.[5]

It is difficult to predict whether a patient will develop mucositis strictly on the basis of the classes of drugs that are administered. Several drugs are associated with a propensity to damage oral mucosa:

Anecdotal evidence suggests that patients who experience mucositis with a specific chemotherapy regimen during the first cycle will typically develop comparable mucositis during subsequent courses of that regimen.

Other oral complications typically include infections of the mucosa, dentition/periapices, and periodontium. Prevalence of these infections has been substantiated in multiple studies.[8-11] Specific criteria for determining risk of infectious flare during myelosuppression have not been developed. Guidelines for assessment primarily address both degree of severity of the chronic lesion and whether acute symptoms have recently (i.e., <90 days) developed. However, chronic asymptomatic periodontitis may also represent a focus for systemic infectious complications since bacteria, bacterial cell wall substances, and inflammatory cytokines may translocate into the circulation via ulcerated pocket epithelium.[10] In addition, poor oral hygiene and periodontitis seem to increase the prevalence of pulmonary infections in high-risk patients.[12]

Resolution of oral toxicity, including mucositis and infection, generally coincides with granulocyte recovery. This relationship may be temporally but not causally related. For example, oral mucosal healing in hematopoietic stem cell transplantation patients is only partially dependent on rate of engraftment, especially neutrophils.

Head and neck radiation can cause a wide spectrum of oral complications (refer to the list of Oral Complications of Radiation Therapy). Ulcerative oral mucositis is a virtually universal toxicity resulting from this treatment; there are clinically significant similarities as well as differences compared with oral mucositis caused by chemotherapy.[2] In addition, oral mucosal toxicity can be increased by use of head and neck radiation together with concurrent chemotherapy.

Head and neck radiation can also induce damage that results in permanent dysfunction of vasculature, connective tissue, salivary glands, muscle, and bone. Loss of bone vitality occurs:

These changes can lead to soft tissue necrosis and osteonecrosis that result in bone exposure, secondary infection, and severe pain.[11]

Oral Complications of Radiation Therapy

Unlike chemotherapy, however, radiation damage is anatomically site-specific; toxicity is localized to irradiated tissue volumes. Degree of damage depends on treatment regimen-related factors, including type of radiation utilized, total dose administered, and field size/fractionation. Radiation-induced damage also differs from chemotherapy-induced changes in that irradiated tissue tends to manifest permanent damage that places the patient at continual risk for oral sequelae. The oral tissues are thus more easily damaged by subsequent toxic drug or radiation exposure, and normal physiologic repair mechanisms are compromised as a result of permanent cellular damage.

Poor oral health has been associated with increased incidence and severity of oral complications in cancer patients, hence the adoption of an aggressive approach to stabilizing oral care before treatment.[1,2] Primary preventive measures such as appropriate nutritional intake, effective oral hygiene practices, and early detection of oral lesions are important pretreatment interventions.

There is no universally accepted precancer therapy dental protocol because of the lack of clinical trials evaluating the efficacy of a specific protocol. A systematic review of the literature revealed two articles on oral care protocols prior to cancer therapy.[3] One study examined the benefits of a minimal intervention precancer therapy (mostly chemotherapy) dental protocol, and the other examined the impact of an intensive preventive protocol on patients undergoing chemotherapy. Both studies had several flaws, including small sample size or the lack of comparison groups.[3]

The involvement of a dental team experienced with oral oncology may reduce the risk of oral complications via either direct examination of the patient or in consultation with the community-based dentist. The evaluation should occur as early as possible before treatment.[4,5] The examination allows the dentist to determine the status of the oral cavity before cancer treatment begins and to initiate necessary interventions that may reduce oral complications during and after that therapy. Ideally, this examination should be performed at least 1 month before the start of cancer treatment to permit adequate healing from any required invasive oral procedures. A program of oral hygiene should be initiated, with emphasis on maximizing patient compliance on a continuing basis.

Oral evaluation and management of patients scheduled to undergo myeloablative chemotherapy should occur as early as possible before initiation of therapy (refer to the list on Oral Disease Stabilization Before Chemotherapy and/or Hematopoietic Stem Cell Transplantation). To maximize outcomes, the oncology team should clearly advise the dentist as to the patients medical status and oncology treatment plan. In turn, the dental team should delineate and communicate a plan of care for oral disease management before, during, and after cancer therapy.[5]

Oral Disease Stabilization Before Chemotherapy and/or Hematopoietic Stem Cell Transplantation

The overall goal is to complete a comprehensive oral care plan that eliminates or stabilizes oral disease that could otherwise produce complications during or following chemotherapy. Achieving this goal will most likely reduce risk of oral toxicities with resultant reduced risk for systemic sequelae, reduced cost of patient care, and enhanced quality of life. If the patient is unable to receive the medically necessary oral care in the community, the oncology team should assume responsibility for oral management.

It is important to realize that dental treatment plans need to be realistic relative to type and extent of dental disease and how long it could be before resumption of routine dental care. For example, teeth with minor caries may not need restoration before cancer treatment begins, especially if more conservative disease stabilization strategies can be used (e.g., aggressive topical fluoride protocols, temporary restorations, or dental sealants).

Specific interventions are directed to:

Guidelines for dental extractions, endodontic management, and related interventions (see Table 3) can be used as appropriate.[6,7] Antibiotic prophylaxis prior to invasive oral procedures may be warranted in the context of central venous catheters; the current American Heart Association (AHA) protocol for infective endocarditis and oral procedures is frequently used for these patients.

Stages of assessment have been described relative to the hematopoietic stem cell transplant patient (see Table 4).[5] This model provides a useful classification for neutropenic cancer patients in general. Type, timing, and severity of oral complications represent the interaction of local and systemic factors that culminate in clinical expression of disease. Correlating oral status with systemic condition of the patient is thus critically important.

Selected conditioning regimens characterized by reduced intensity for myelosuppression have been used in patients. These regimens have generally been noted to significantly reduce the severity of oral complications early posttransplant, especially for mucositis and infection risk. The guidelines listed in Table 4 can be adjusted to reflect these varying degrees of risk, based on the specific conditioning regimen to be used.

Phase I: Before Chemotherapy

Oral complications are related to current systemic and oral health, oral manifestations of underlying disease, and oral complications of recent cancer or other medical therapy. During this period, oral trauma and clinically significant infections, including dental caries, periodontal disease, and pulpal infection, should be eliminated. Additionally, patients should be educated relative to the range and management of oral complications that may occur during subsequent phases. Baseline oral hygiene instructions should be provided. It is especially important to note whether patients have been treated with bisphosphonates (e.g., patients with multiple myeloma) and to plan their care accordingly.

Phase II: Neutropenic Phase

Oral complications arise primarily from direct and indirect stomatotoxicities associated with high-dose chemotherapy or chemoradiotherapy and their sequelae. Mucositis, xerostomia, and those lesions related to myelosuppression, thrombocytopenia, and anemia predominate. This phase is typically the period of high prevalence and severity of oral complications.

Oral mucositis usually begins 7 to 10 days after initiation of cytotoxic therapy and remains present for approximately 2 weeks after cessation of that therapy. Viral, fungal, and bacterial infections may arise, with incidence dependent on the use of prophylactic regimens, oral status prior to chemotherapy, and duration/severity of neutropenia. Frequency of infection declines upon resolution of mucositis and regeneration of neutrophils. This phenomenon appears to be more a temporal relation than a causative one, based on the predominant evidence. Despite the initial marrow recovery, however, the patient may remain at risk for infection, depending on status of overall immune reconstitution.

Salivary gland hypofunction/xerostomia secondary to anticholinergic drugs and taste dysfunction is initially detected in this phase; the toxicity typically resolves within 2 to 3 months.

In allogeneic transplant patients, while uncommon, hyperacute graft-versus-host disease (GVHD) can occur and can result in significant oral mucosal inflammation and breakdown that can complicate the oral course for patients. Clinical presentation will often not be sufficiently distinct to diagnosis this lesion. The clinical assessment is typically based on the patient experiencing more-severe-than-expected mucositis that will often not heal within the time line for mucosal recovery associated with oral mucositis caused by chemotherapy.

Phase III: Hematopoietic Recovery

Frequency and severity of acute oral complications typically begin to decrease approximately 3 to 4 weeks after cessation of chemotherapy. Healing of ulcerative oral mucositis in the setting of marrow regeneration contributes to this dynamic. Although immune reconstitution is developing, oral mucosal immune defenses may not be optimal. Generally stated, immune reconstitution will take between 6 and 9 months for autologous transplant patients and between 9 and 12 months for allogeneic transplant patients not developing chronic GVHD. Thus, the patient remains at risk for selected infection, including candidal and herpes simplex virus infections.

Mucosal bacterial infections during this phase occur less frequently unless engraftment is delayed or the patient has acute GVHD or is receiving GVHD therapy. Most centers will use systemic infection prophylaxis throughout this period (and, in many instances, longer) to reduce the risk of infections in general, a practice that positively influences the rate and severity of both systemic and local oral infections.

The hematopoietic stem cell transplant patient represents a unique cohort at this point. For example, risk for acute oral GVHD typically emerges during this time in allogeneic graft recipients.

Phase IV: Immune Reconstitution/Recovery from Systemic Toxicity

Oral lesions are principally related to chronic conditioning regimenassociated (chemotherapy with or without radiation therapy) toxicity and, in the allogeneic patient, GVHD. Late viral infections and xerostomia predominate. Mucosal bacterial infections are infrequent unless the patient remains neutropenic or has severe chronic GVHD.

Risk exists for graft failure, cancer relapse, and second malignancies. The hematopoietic stem cell transplant patient may develop oral manifestations of chronic GVHD during this period.

Phase V: Long-term Survival

Long-term survivors of cancer treated with high-dose chemotherapy alone or chemoradiotherapy will generally have few significant permanent oral complications.

Risk for radiation-induced chronic complications is related to the total dose and schedule of radiation therapy. Regimens that incorporate total body irradiation may result in permanent salivary gland hypofunction/xerostomia,[8] which is the most frequently reported late oral complication. Permanent salivary gland dysfunction can occur in autologous transplant patients in addition to nonautologous recipients. Other significant complications include craniofacial growth and developmental abnormalities in pediatric patients, and emergence of second malignancies of the head/neck region.

Routine systematic oral hygiene is important for reducing incidence and severity of oral sequelae of cancer therapy. The patient must be informed of the rationale for the oral hygiene program as well as the potential side effects of cancer chemotherapy and radiation therapy. Effective oral hygiene is important throughout cancer treatment, with emphasis on oral hygiene beginning before treatment starts.[1]

Management of patients undergoing either high-dose chemotherapy or upper-mantle radiation share selected common principles. These principles are based on baseline oral care (refer to the list of suggestions for Routine Oral Hygiene Care) and reduction of physical trauma to oral mucosa (refer to the list of Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy).

Routine Oral Hygiene Care

Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy [1]

Considerable variation exists across institutions relative to specific nonmedicated approaches to baseline oral care, given limited published evidence. Most nonmedicated oral care protocols use topical, frequent (every 46 hours) rinsing with 0.9% saline. Additional interventions include dental brushing with toothpaste, dental flossing, ice chips, and sodium bicarbonate rinses. Patient compliance with these agents can be maximized by comprehensive overseeing by the health care professional.

Patients using removable dental prostheses or orthodontic appliances have risk of mucosal injury or infection. This risk can be eliminated or substantially reduced prior to high-dose cancer therapy. (Refer to the list of Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy.)

Dental brushing and flossing represent simple, cost-effective approaches to bacterial dental plaque control. This strategy is designed to reduce risk of oral soft tissue infection during myeloablation. Oncology teams at some centers promote their use, while teams at other centers have patients discontinue brushing and flossing when peripheral blood components decrease below defined thresholds (e.g., platelets <30,000/mm3). There is no comprehensive evidence base regarding the optimal approach. Many centers adopt the strategy that the benefits of properly performed dental brushing and flossing in reducing risk of gingival infection outweigh the risks.

Periodontal infection (gingivitis and periodontitis) increases risk for oral bleeding; healthy tissues should not bleed. Discontinuing dental brushing and flossing can increase risk for gingival bleeding, oral infection, and bacteremia. Risk for gingival bleeding and infection, therefore, is reduced by eliminating gingival infection before therapy and promoting oral health daily by removing bacterial plaque with gentle debridement with a soft or ultra-soft toothbrush during therapy. Mechanical plaque control not only promotes gingival health, but it also may decrease risk of exacerbation of oral mucositis secondary to microbial colonization of damaged mucosal surfaces.

Dental brushing and flossing should be performed daily under the supervision of professional staff:

Patients skilled at flossing without traumatizing gingival tissues may continue flossing throughout chemotherapy administration. Flossing allows for interproximal removal of dental bacterial plaque and thus promotes gingival health. As with dental brushing, this intervention should be performed under the supervision of professional staff to ensure its safe administration.

The oral cavity should be cleaned after meals:

Preventing dryness of the lips to reduce risk for tissue injury is important. Mouth breathing and/or xerostomia secondary to anticholinergic medications used for nausea management can induce the condition. GVHD of the lips can also contribute to dry lips in allogeneic transplant patients. Lip care products containing petroleum-based oils and waxes can be useful. Lanolin-based creams and ointments may be more effective in moisturizing/lubricating the lips and thus protecting against trauma.

The terms oral mucositis and stomatitis are often used interchangeably at the clinical level, but they do not reflect identical processes.

Oral Mucositis:

Stomatitis:

Risk of oral mucositis has historically been characterized by treatment-based and patient-based variables.[4] The current model of oral mucositis involves a complex trajectory of molecular, cellular, and tissue-based changes. There is increasing evidence of genetic governance of this injury,[5-8] characterized in part by upregulation of nuclear factor kappa beta and inflammatory cytokines (e.g., tumor necrosis factor-alpha) and interleukin-1 in addition to epithelial basal cell injury. Comprehensive knowledge of the molecular-based causation of the lesion has contributed to targeted drug development for clinical use.[9] The pipeline of new drugs in development (e.g., recombinant human intestinal trefoil factor [10] may lead to strategic new advances in the ability of clinicians to customize the prevention and treatment of oral mucositis in the future.[11]

Erythematous mucositis typically appears 7 to 10 days after initiation of high-dose cancer therapy. Clinicians should be alert to the potential for increased toxicity with escalating dose or treatment duration in clinical trials that demonstrate gastrointestinal mucosal toxicity. High-dose chemotherapy, such as that used in the treatment of leukemia and hematopoietic stem cell transplant regimens, may produce severe mucositis. Mucositis is self-limited when uncomplicated by infection and typically heals within 2 to 4 weeks after cessation of cytotoxic chemotherapy.

Systematic assessment of the oral cavity following treatment permits early identification of lesions.[12-16] Oral hygiene and other supportive care measures are important to minimizing the severity of the lesion.

In an effort to standardize measurements of mucosal integrity, oral assessment scales have been developed to grade the level of stomatitis by characterizing alterations in lips, tongue, mucous membranes, gingiva, teeth, pharynx, quality of saliva, and voice.[12-14] Specific instruments of assessment have been developed to evaluate the observable and functional dimensions of mucositis. These evaluative tools vary in complexity.

Prophylactic measures and treatment options should be employed by practitioners for patients in the appropriate clinical settings. Specific recommendations for minimizing oral mucositis include the following:

Updated guidelines from the American Society of Clinical Oncology for the prevention and treatment of mucositis were published in 2007 [17] and include the following:

Specific recommendations against specific practices include the following:

Oral mucositis in hematopoietic stem cell transplantation patients produces clinically significant toxicities that require multiprofessional interventions.[18-25] The lesion can increase risk of systemic infection,[1] produce clinically significant pain,[26][Level of evidence: II] and promote oral hemorrhage. It can also compromise the upper airway such that endotracheal intubation is required. Use of total parenteral nutrition is often necessary because of the patients inability to receive enteral nutrition.

Once mucositis has developed, its severity and the patients hematologic status govern appropriate oral management. Meticulous oral hygiene and palliation of symptoms are essential. Some established guidelines for oral care include oral assessments twice daily for hospitalized patients and frequent oral care (minimum of every 4 hours and at bedtime) that increases in frequency as the severity of mucositis increases.

Oral care protocols generally include atraumatically cleansing the oral mucosa, maintaining lubrication of the lips and oral tissues, and relieving pain and inflammation. Several health professional organizations have produced evidence-based oral mucositis guidelines. These organizations include but are not limited to the following:

In many cases, there is similarity in recommendations across the organizations. The Cochrane Collaboration, however, uses a meta-analysis approach and thus provides a unique context for purposes of guideline construction.

Palifermin (Kepivance), also known as keratinocyte growth factor-1, has been approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic cancers undergoing conditioning with high-dose chemotherapy, with or without radiation therapy, followed by hematopoietic stem cell rescue.[9][Level of evidence: I] The standard dosing regimen is three daily doses before conditioning and three additional daily doses starting on day 0 (day of transplant). Palifermin has also been shown in a randomized, placebo-controlled trial to reduce the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy.[30][Level of evidence: I] In addition, a single dose of palifermin prevented severe oral mucositis in patients who had sarcoma and were receiving doxorubicin-based chemotherapy.[31][Level of evidence: I]

In two randomized, placebo-controlled trials conducted in head/neck cancer patients undergoing postoperative chemoradiotherapy and in patients receiving definitive chemoradiotherapy for locally advanced head/neck cancer, intravenous palifermin administered weekly for 8 weeks decreased severe oral mucositis,[32,33][Level of evidence: I] as graded by providers using standard toxicity assessments and during multicycle chemotherapy.[31] Patient-reported outcomes related to mouth and throat soreness and to treatment breaks or compliance were not significantly different between arms in either trial. In one study, opioid analgesic use was also not significantly different between arms.[33]

Evidence from several studies has supported the potential efficacy of low-level laser therapy in addition to oral care to decrease the duration of chemotherapy-induced oral mucositis in children.[34][Level of evidence: I][35][Level of evidence: I]

Mucositis Management

Management of oral mucositis via topical approaches should address efficacy, patient acceptance, and appropriate dosing. A stepped approach is typically used, with progression from one level to the next as follows:

Normal saline solution is prepared by adding approximately 1 tsp of table salt to 32 oz of water. The solution can be administered at room or refrigerated temperatures, depending on patient preference. The patient should rinse and swish approximately 1 tbsp, followed by expectoration; this can be repeated as often as necessary to maintain oral comfort. Sodium bicarbonate (12 tbsp/qt) can be added, if viscous saliva is present. Saline solution can enhance oral lubrication directly as well as by stimulating salivary glands to increase salivary flow.

A soft toothbrush that is replaced regularly should be used to maintain oral hygiene.[17] Foam-swab brushes do not effectively clean teeth and should not be considered a routine substitute for a soft nylon-bristled toothbrush; additionally, the rough sponge surface may irritate and damage the mucosal surfaces opposite the tooth surfaces being brushed.

On the basis of nonoral mucosa wound-healing studies, the repeated use of hydrogen peroxide rinses for daily preventive oral hygiene is not recommended, especially if mucositis is present, because of the potential for damage to fibroblasts and keratinocytes, which can cause delayed wound healing.[36-39] Using 3% hydrogen peroxide diluted 1:1 with water or normal saline to remove hemorrhagic debris may be helpful; however, this approach should only be used for 1 or 2 days because more extended use may impair timely healing of mucosal lesions associated with bleeding.[40]

Focal topical application of anesthetic agents is preferred over widespread oral topical administration, unless the patient requires more extensive pain relief. Products such as the following may provide relief:

The use of compounded topical anesthetic rinses should be considered carefully relative to the cost of compounding these products versus their actual efficacy.

Irrigation should be performed before topical medication is applied because removal of debris and saliva allows for better coating of oral tissues and prevents material from accumulating. Frequent rinsing cleans and lubricates tissues, prevents crusting, and palliates painful gingiva and mucosa.

Systemic analgesics should be administered when topical anesthetic strategies are not sufficient for clinical relief. Opiates are typically used;[26][Level of evidence: II] the combination of chronic indwelling venous catheters and computerized drug administration pumps to provide PCA has significantly increased the effectiveness of controlling severe mucositis pain while lowering the dose and side effects of narcotic analgesics. Nonsteroidal anti-inflammatory drugs that affect platelet adhesion and damage gastric mucosa are contraindicated, especially if thrombocytopenia is present.

Although mucositis continues to be one of the dose-limiting toxicities of fluorouracil (5-FU), cryotherapy may be an option for preventing oral mucositis. Because 5-FU has a short half-life (520 minutes), patients are instructed to swish ice chips in their mouths for 30 minutes, beginning 5 minutes before 5-FU is administered.[41][Level of evidence: I] Oral cryotherapy has been studied in patients receiving high-dose melphalan conditioning regimens used with transplantation;[42,43] further research is needed.

Many agents and protocols have been promoted for management or prevention of mucositis.[44-46] Although not adequately supported by controlled clinical trials, allopurinol mouthwash and vitamin E have been cited as agents that decrease the severity of mucositis. Prostaglandin E2 was not effective as a prophylaxis of oral mucositis following bone marrow transplant, although studies indicate possible efficacy when prostaglandin E2 is administered via a different dosing protocol.

Check the list of NCI-supported cancer clinical trials for supportive and palliative care trials about mucositis that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Pain in cancer patients may arise from onset of the disease through survivorship and may be:[1]

Cancer pain causes increased morbidity, reduced performance status, increased anxiety and depression, and diminished quality of life (QOL). Dimensions of acute and chronic pain include the following:

Management of head and neck pain and oral pain may be particularly challenging because eating, speech, swallowing, and other motor functions of the head and neck and oropharynx are constant pain triggers.

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Oral Complications of Chemotherapy and Head/Neck Radiation ...

Sickle cell disease affects the hepatobiliary system in different ways at different ages. Intrinsic disease results from recurrent ischemia and bilirubin stones. These result from the vascular obstruction and red cell hemolysis of sickle cell. Biliary sludge is a common finding that is often clinically unimportant. Viral infections that affect the liver may be independent of or secondary to red cell transfusions. The iron overload that accompanies red cell transfusions can lead to liver dysfunction and fibrosis. Many medications taken by sickle cell patients may cause or worsen hepatobiliary disease. The dysfunction of the liver can affect the lungs, kidneys, and coagulation systems. Treatment is directed at the etiology of the dysfunction as well as the underlying sickle cell disease.

The natural consequences of any hemolytic condition affect both the gallbladder [45] and the liver [46]. The gallbladder is affected by hemoglobin (pigmented) stones [47], biliary sludge [4850], and obstruction [5153]. The liver is affected by vasoocclusive changes (right upper quadrant syndrome) of recurrent ischemia and reperfusion injuries [46, 54], iron overload from transfusions that are used to treat both symptomatic anemia and the complications of sickle cell disease [5559], vascular endothelial dysfunction [60], and the liver consequences of the hypercoagulation of sickle cell [6163].

The challenge physicians caring for sickle cell patients is recognizing the life-threatening course from the more frequent, similar appearing milder, recurrent syndromes. A useful way to consider the protean effects of hepatobiliary issues in sickle cell is to consider the disorders of the presentation and evaluation of abdominal complaints of sickle cell followed by a review of the major disorders. Although hepatobiliary conditions are intimately linked, the embryology of the biliary system and the hepatic system shows these two organs to be histologically and functionally separate [64]. This explains the differential response of these organs to the same insult. However, many conditions may overlap, so a single diagnosis may mask parallel processes.

Acute pain in the right upper quadrant is common in sickle cell patients [6567]. The symptom of hepatobiliary disease often must be separated from the more common symptoms of sickle cell disease. Patients develop sickle cell attacks in a consistent pattern. The patient can often recognize whether the current attack is different from prior sickle cell pains. If the pain is new, especially when accompanied by more jaundice than usual, nausea and vomiting, then further hepatobiliary workup is needed. Increasing nausea and vomiting with food points to the gallbladder. Colic pains point to the gallbladder. Right upper quadrant fullness with dull pains points to the liver. General jaundice points to both.

The liver is often increased in size throughout the life of the patient [68]. If the liver has acutely increased in size, then hepatic congestion or sequestration may be involved. A 1980 clinicopathologic study of 70 autopsies of sickle cell patients found 91% with enlarged livers characterized by distention of Kupffer cells engorged with red cells [69]. In 27% the liver sinusoids were distended with obstruction from sickled red cells. Focal necrosis of liver tissue was present in 34%. 20% of patients had reparative liver changes of portal fibrosis and regenerative nodules. The authors felt that recurrent vascular obstruction, ischemia, necrosis, and repair best explained the pathological findings.

If right upper quadrant pain is severe, then acute swelling or inflammation may be involved. Murphy's sign is often lost in the general pains but, if present, may point to the gallbladder. If the serum bilirubin concentration is over 4mg/dL, then checking whether the fraction of direct bilirubin exceeds 10% would point to the gallbladder as the source of the increase [70, 71]. Some patients have genetic variations in the UDP glucuronyltransferase that will elevate the serum bilirubin concentration [72]. This recurrent or chronic elevation should be evident on review of the patient's records. In most sickle cell presentations the AST is relatively more elevated that the ALT, as the AST also reflects the degree of hemolysis [73]. If the ALT is similarly elevated as the AST, then a hepatocellular process may be occurring. Similarly the alkaline phosphatase will be elevated in biliary disease. However, bone infarcts will also call the alkaline phosphatase to rise. Fractionating the alkaline phosphatase into bone and biliary sources is seldom done. The clinical presentation usually finds bone pain or severe extremity pains with infarcts, and severe right upper quadrant pains prompt imaging, usually ultrasound, of the hepatobiliary system. Measurement of the aPPT and PT may provide evidence of a more severe process beginning.

Initial evaluation is for conditions that need emergent transfusions or treatments.

Pain patterns that differ from a patient's usual pattern need close evaluation.

Having sickle cell does not protect a patient from any other condition.

Hepatic crisis is often used as a general term to describe right upper quadrant pain in a sickle cell patient [80, 81]. However, hepatic crisis is best used to describe a syndrome consisting of pain, elevated ALT (usually less than 300IU/liter), and hepatic enlargement. Another working definition of a hepatic crisis could be painful hepatomegaly and worsened jaundice (usually less than 12mg/dL) [82]. The definition used causes the incidence of this condition to vary in reports. Large series reports that up to 10% of patients admitted to hospital have hepatic involvement rising to their definition of crisis. Other studies with more restrictive definitions concluded hepatic crisis was rare. The rapidity of the onset of symptoms and the rapidity of the correction of ALT may be able to guide therapy. Symptoms that began suddenly are more often typical, self-limited sickle cell conditions. Symptoms that begin over several days to weeks may be from more severe conditions such as viral or autoimmune hepatitis, liver infarct, or gallbladder dysfunction. Severe elevations of bilirubin (over 30mg/dL) may represent acute liver failure of intrahepatic cholestasis (see below).

If the condition is from typical sickle vaso-occlusion and inflammation, then the elevation of ALT decreases after a few days. Severe, persistent elevations may relate to hepatic infarct, characterized by a wedge-shaped, hypointense CT lesions [83]. Hepatic abscess has been rarely reported, but should be suspected in a patient with fever, a course different from their usual sickle cell crisis, right upper quadrant pain, and tender hepatomegaly [8488]. Hepatic ultrasound would delineate the abscess. Prior areas of hepatic infarction give the bacteria a site to invade. Bacteroides species were found in one report [85]. Bilirubin levels decrease to prior values in about two weeks; liver transaminases return to prior values in about three months. If changes persist beyond those times, further evaluation is needed.

Hepatic sequestration is best diagnosed by a rapid enlargement of the liver with a concurrent drop in hemoglobin concentration [8991]. The bilirubin also will be elevated with a high percentage of direct bilirubin. Transfusions, simple or exchange, may help reserve the process. Hepatic sequestration may be a life-threatening event in pediatric patients with sickle cell disease [8991]. Small vessel congestion with red cells leads to a drop in hemoglobin levels. The liver enlarges and becomes tender and inflamed. Treatment is transfusions. Often the hemoglobin level is low enough that given red cell units (matched for ABO, Kell, E, and C antigens) to raise the hemoglobin to 9g/dL often stabilize the process. Manual or automatic red cell exchanges are indicated for more severe cases shown by hepatic dysfunction or a hemoglobin level over 9 to start with. Hepatic sequestration may be part of the multiorgan failure syndromes [74, 75].

Chronic hepatic sequestration has been reported in a 17-year old with SS hemoglobin [92]. After exchange transfusions, his liver size decreased. However it recurred. This recurrence was successfully treated with hydroxyurea for several months.

One report of reverse sequestration occurred following simple transfusions. This syndrome comprises a sudden increase in hemoglobin concentration, sudden onset of hypertension, acute congestive heart failure, neurologic signs of infarct or hemorrhage [93].

Autoimmune hepatitis is reported in sickle cell patients [94, 95]. Interestingly, it also appears in mice models of sickle cell disease (personal communication). We have documented transient positivity of antibodies to smooth muscle (antiactin F). Associated features of autoimmune hepatitis include rashes, skin ulcers, and joint disease. The etiology, natural course, and treatment of autoimmune hepatitis in sickle cell patients are unclear. If a patient has persistent liver symptoms and antibody titers to smooth muscles, then a therapeutic trial of prednisone and azathioprine may be warranted. Referral to a hepatologist is indicated.

Viral hepatitis occurs at least as frequently as in the general population [96]. Hepatitis C, and to a lesser extent, Hepatitis B, occurred more often because of blood product exposure. Improved blood product testing has reduced the incidence of these infections, but they still occur. We screen all our patients yearly for Hepatitis C viral RNA by PCR. In new patients, persistently elevated ALT levels require screening for viral hepatitis. Every sickle cell patient should be vaccinated with two doses of Hepatitis A vaccine from six months to a year apart and three doses of Hepatitis B vaccinations at zero, one, and six months. Quantitative hepatitis B surface antibody tests and total Hepatitis A antibody tests are available to help decide if a patient has been adequately vaccinated if the records are not available. Many practitioners opt to revaccinate in case of any doubt. No vaccine exists for Hepatitis C prevention. Patients with chronic Hepatitis B and Hepatitis C should be treated as any other patients. There has been some concern about using ribavirin because it may cause hemolytic anemia. If a patient on ribavirin does develop worsening anemia, then placing the patient on monthly transfusions would both allow therapy to continue and would decrease sickle cell and anemia symptoms. A recent article showed good results in treating sickle cell patients for chronic hepatitis C [97]. Liver transplants are as successful in patients with sickle cell disease and other patients needing allographic livers [98101].

Hepatic siderosis is a growing area of concern and research [102]. As red cell transfusions become routine for more indications, the inevitable result is the accumulation of liver iron. After about a year of transfusion therapy, serum ferritin levels rise to over 1,000ng/mL. While serum ferritin is a rough guide to total liver iron, values over 1,000 indicate liver iron overload. Other studies have shown significant liver iron accumulation after 13 units of red cells. Each unit of red cells contains nearly a year worth of dietary iron. Over many years, hepatic dysfunction, insufficiency, fibrosis, and cirrhosis may lead to morbidity and even liver death. Many patients on regular transfusions will have hyperintense livers on CT scans or hypointense livers on MRI scanning [103, 104]. These changes have been used to semiquantitate the degree of iron loading. Chelation with deferoxamine [55, 105], deferasirox [106], or deferiprone (recently approved in the US) does reduce total body iron. However, all regimes have issues with compliance and side effects that require appropriate monitoring. When patients with iron overload are admitted to hospital with noninfectious complaints, we often give deferoxamine 3 grams in 500mL normal saline intravenously over 24 hours, repeating continuously during their stay. Giving Vitamin C 250mg orally daily while the patient is on deferoxamine increases iron excretion [107, 108]. Ongoing cohort studies should help define the natural history of iron overload in sickle cell patients [109111].

Hepatic effects on kidneys and lungs are increasingly recognized. Although there are few publications concerning sickle cell patients, such effects are well known in other conditions where the liver is cirrhotic or dysfunctional. The hepatorenal syndrome [112], hepatopulmonary syndrome [113], and the portopulmonary [114] syndrome may complicate the hepatic disease of sickle cell.

Sickle cell intrahepatic cholestasis or sickle cell hepatopathy is a condition with marked hyperbilirubinemia (>50mg/dL) and a high fraction of direct (conjugated) bilirubin (about 50%) [77, 115118]. Other features of right upper quadrant pain and progressive hepatomegaly resemble many of the hepatic crisis syndromes. However, in sickle cell intrahepatic cholestasis, the liver transaminases are nearly at baseline. Coagulopathy as assessed by the PT test is often found. Renal insufficiency is often present, likely from the nephrotoxic effects of bilirubin. Endoscope retrograde cholangiopancreatography has been reported to guide management by diagnosing strictures from ischemic cholangiopathy and defining the presence or absence of common bile duct stones [119]. Some authors consider the presence of acute sickle hepatopathy to contraindicate liver biopsies [120]. Ischemic cholangiopathy has also been described [121].

Early reports indicate that sickle cell intrahepatic cholestasis was a life-threatening condition that mandated exchange transfusions. As clinicians were more aware of the condition, series were reported that had a less severe course [122]. Given the protean causes of intrahepatic cholestasis, it is reasonable to divide cases of cholestasis into those with and those without other evidence of marked hepatic dysfunction and coagulopathy. The milder cases (bilirubin level 10 to 30mg/dL) appear to be more common in children. Patients in the first category should be monitored for worsening hepatic function: encephalopathy, coagulopathy, and rising bilirubin concentrations. For the more severe cases, exchange transfusion may be given, but it is not always effective [77, 79].

Cholelithiasis occurs as early as two years old [47]. About 30% of patients will have gallstones by 18 years of age [52, 123, 124]. The incidence and prevalence of this condition appears to be affected by local diet and possible genetic factors [125]. The coinheritance of -thalassemia may reduce the incidence of stones since it may lessen the degree of hemolysis that is thought to drive stone formation [126]. The cause of cholelithiasis is usually pigmented stones resulting from the breakdown of hemoglobin [45]. Some reports implicate ceftriaxone and other third generation cephalosporins as causing crystallization in the gallbladder [127]. However, these antibiotics are commonly and usefully used in the proper settings. In adults, asymptomatic gallstones are common and are best treated by observation only [52, 53, 68, 123]. Abdominal and right upper quadrant pains are common in sickle cell patients. Cholecystectomy for recurrent right upper quadrant pains often does not relieve the recurrent symptoms. Only if signs of cholecystitis (fever, increased direct bilirubin, and positive imaging) develop, should cholecystectomy be considered after the treatment with supportive care and antibiotics [47, 124]. Laparoscopic cholecystectomy is the procedure of choice for this indication [128, 129]. This also causes less abdominal muscle disruption and decreases postsurgical complications including acute chest syndrome. Ultrasound is the imaging of choice but is not diagnostic in most cases. Reports of pancreatitis from sickling also exist. Biliary scintigraphy is seldom used because of the numerous false positive results [130, 131]. Still, it has a useful negative predictive value if used in the right setting. Technetium scanning may show hyperemia of cholecystitis but its use is not well studied. Liver peliosis and extramedullary erythropoiesis have occasionally been noted as multiple nodules on liver imaging [132].

Biliary sludge is a common finding in sickle cell patients [48, 50]. Biliary sludge is nonshadowing, echogenic intraluminal sediment. This material is calcium bilirubinate, cholesterol crystals, viscous bile, mucus, and proteins. The natural history of biliary sludge in children with sickle cell disease finds that at a mean of 2.1 years of followup, about 65% of such patients do eventually develop gallstones, although not necessarily symptomatic ones. About 40% of patients originally with biliary sludge do not develop gallstones, despite the continued presence of sludge in most [133]. Most authors recommend yearly ultrasounds to access stone formation. They reserve cholecystectomy only for patients with signs and symptoms of acute cholecystitis [133].

Choledocholithiasis also occurs in sickle cell disease [51]. Even in patients with cholecystectomy, recurrent stones may form in the common bile ducts. Symptoms are similar to primary gallbladder disease. Ultrasound may be the best modality to evaluate the common bile duct. Duct obstruction is seldom complete. This may be because pigmented stones are smaller than nonpigmented stones. If the common duct is obstructed, then symptomatic or chemical pancreatitis may be the presentation [134]. After cholecystectomy, the common bile duct is usually dilated, confounding diagnosis of new stones. Given the prevalence of common duct stones, patients with persistent cholestatic jaundice should have imaging to evaluate the ductal system. If surgery is contemplated, some authors suggest ERCP as the best approach to determine management [135].

Acute cholecystitis presents as it does in patients without sickle cell disease [53, 136]. Right upper quadrant pain, fever, nausea, and vomiting have a long and diverse differential diagnosis. When the diagnosis is suspected, then ultrasound is the usual next step. Imaging signs of acute inflammation or obstructing stones prompt treatment for pain, hydration, and the assessment for infection. Laparoscopic cholecystectomy is deferred until the acute episode is over. If all the stones and sludge have cleared, then surgery may not be indicated. Some authors prefer a conservative approach. Intraoperative cholangiography is reported to have a 25% false positive rate. Some authors recommend intraoperative ERCP. A detailed intraoperative evaluation of the biliary system is important as symptoms often persist or recur after cholecystectomy [124].

Chronic cholecystitis may be related to persistent gallstones or persistent biliary sludge. Recurrent symptoms consistent with colic warrant screening with blood work and imaging. If the blood work shows increases in conjugated (direct) bilirubin during the attacks, and there are ultrasonographic signs of a thickened gallbladder wall, then cholecystectomy may decrease these symptoms. However, just as in chronic cholecystitis in the general population, the symptoms may recur several months after surgery.

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Beyond the Definitions of the Phenotypic Complications of ...

Description

An in-depth report on the causes, diagnosis, and treatment of sickle cell disease.

Sickle cell anemia

What is Sickle Cell Disease?

Sickle cell disease is an inherited blood disorder in which the body produces abnormally shaped red blood cells. In sickle cell disease, the hemoglobin in red blood cells clumps together. This causes red blood cells to become stiff and C-shaped. These sickle cells block blood and oxygen flow in blood vessels. Sickle cells break down more rapidly than normal red blood cells, which results in anemia.

What Causes Sickle Cell Disease?

Sickle cell disease is a genetic disorder. People who have sickle cell disease are born with two sickle cell genes, one from each parent. If one normal hemoglobin gene and one sickle cell gene are inherited, a person will have sickle cell trait. People who have sickle cell trait do not develop sickle cell disease, but they are carriers who can pass the abnormal gene on to their children.

Complications of Sickle Cell Disease

Sickle cell disease can block the flow of blood in arteries in many parts of the body, causing many complications. The hallmark of sickle cell disease is the sickle cell crisis, which causes sudden attacks of severe pain. Acute chest syndrome, which is triggered by an infection or by blockage of blood vessels in the lungs, is another common and serious occurrence. Additional medical complications include:

New Recommended Vaccine

Infants with sickle cell disease should receive a new vaccine that protects against bacterial meningitis, according to recommendations from the Centers for Disease Control. The MenHibrix vaccine protects against both Neisseria meningitidis and Haemophilus influenza, the bacterial strains most often associated with life-threatening meningitis and bloodstream infections. The vaccine is given as a 4-dose series starting when the baby is 6 - 8 weeks old. The FDA approved the Menhibrix vaccine in 2012.

Sickle cell disease (also called sickle cell anemia) is an inherited blood disorder that affects red blood cells. The sickle cell gene causes the body to produce abnormal hemoglobin. In sickle cell disease, the hemoglobin clumps together, causing red blood cells to become stiff and develop a C-shaped (sickle) form. These sickled red blood cells can block blood vessels, reducing blood flow in many parts of the body. This process results in tissue and organ damage.

Each red blood cell contains about 280 million hemoglobin molecules. Hemoglobin is the most important component of red blood cells. It is composed of protein (globulin) and a molecule (heme), which binds to iron.

In the lungs, the heme component takes up oxygen and releases carbon dioxide. The red blood cells carry the oxygen to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide, and the cycle repeats. The oxygen is essential for all cells in the body to function.

Sickle cell disease reduces or denies adequate oxygen to many parts of the body. This contributes to the severe pain experienced as a sickle cell crisis and both short- and long-term organ damage.

Sickle cell disease occurs from genetic changes that cause abnormalities in hemoglobin molecules:

Hemoglobin is the most important component of red blood cells. It is composed of a protein called heme, which binds oxygen. In the lungs, oxygen is exchanged for carbon dioxide. Abnormalities of an individual's hemoglobin value can indicate defects in red blood cell balance. Both low and high values can indicate disease states.

The symptoms and problems of sickle cell disease are a result of the hemoglobin S (HbS) molecule:

The sickle cell gene for hemoglobin S (HbS) is the most common inherited blood condition in the United States. About 70,000 - 100,000 Americans -- mostly African-Americans -- have sickle cell disease. About 2 million Americans have sickle cell trait.

Sickle cell disease is inherited. People at risk for inheriting the gene for sickle cell descend from people who are or were originally from Africa or parts of India and the Mediterranean. The sickle cell gene also occurs in people from South and Central America, the Caribbean, and the Middle East. The high prevalence of the sickle cell gene in these regions of the world is due to the sickle cell's ability to make red blood cells resistant to the malaria parasite.

People inherit a pair of genes that regulate hemoglobin, with one gene coming from each parent:

The risk of a child inheriting sickle cell disease or sickle cell trait is as follows:

If both parents have sickle cell trait (each have one normal hemoglobin gene and one sickle cell gene), the child has a 50% chance of inheriting sickle cell trait (one normal gene, one sickle cell gene), 25% chance of inheriting sickle cell disease (two sickle cell genes), and 25% chance of not inheriting either the trait or the disease (two normal genes).

If one parent has sickle cell trait (one normal gene and one sickle cell gene) and the other parent has two normal hemoglobin genes, the child has a 50% chance of inheriting sickle cell trait (one normal gene and one sickle cell gene) and a 50% of inheriting neither the trait nor the disease (two normal genes). The child is not at risk of inheriting sickle cell disease.

If one parent has sickle cell disease (two sickle cell genes) and the other parent has sickle cell trait (one normal gene, one sickle cell gene), the child has a 50% chance of inheriting sickle cell trait and a 50% chance of inheriting sickle cell disease.

If one parent has sickle cell disease and the other parent has two normal hemoglobin genes, the child has a 100% chance of inheriting sickle cell trait, but not the disease.

If both parents have sickle cell disease, the child has a 100% chance of inheriting the disease.

General Symptoms in Infants. In infants, symptoms do not usually appear until late in the baby's first year. Most commonly, they include:

General Symptoms in Children. Pain is the most common complaint. It can be acute and severe or chronic, usually from orthopedic problems in the legs and low back. Other symptoms include:

Additional Symptoms in Adolescence or Adulthood. Symptoms from childhood continue in adolescence and adulthood. In addition, patients may have:

Sickle cell crises are episodes of pain that occur with varying frequency and severity in different patients and are usually followed by periods of remission. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. It most commonly occurs in the lower back, leg, abdomen, and chest, usually in two or more locations. Episodes usually recur in the same areas. (See "Pain and Acute Sickle Cell Crisis" in Complications section of this report.)

Blood tests can determine whether an individual has sickle cell trait or sickle cell disease.

In the United States, hospitals routinely screen newborn babies for sickle cell disease. To perform the test, a blood sample is taken from the baby's heel using a simple needle prick. Early detection of sickle cell disease can help reduce the risk of life-threatening infections and increase the odds for survival. Babies who are diagnosed with sickle cell disease are given daily antibiotics to help prevent infections.

Prenatal diagnosis is also possible through amniocentesis. The amniotic fluid is tested for the presence of the sickle cell gene.

Unfortunately, no tests can definitely determine which children are at highest risk for a stroke and, therefore, would be candidates for ongoing blood transfusions. The following are diagnostic tools currently used or under investigation:

New and aggressive treatments for sickle cell disease are prolonging life and improving its quality. As recently as 1973, the average lifespan for people with sickle cell disease was only 14 years. Today, life expectancy for these patients can reach 50 years and beyond. Women with sickle cell usually live longer than their male counterparts.

The damage of sickle cell disease occurs because of the logjam that sickle cells cause in the capillaries. Sickle cell disease slows the flow of blood and reduces the supply of oxygen to various tissues. Not only does pain occur when body tissues are damaged by lack of oxygen, but serious and even life-threatening complications can result from severe or prolonged oxygen deprivation.

Sickle cell disease is referred to in some African languages as "a state of suffering," but the disease has a wide spectrum of effects, which vary from patient to patient. In some people, the disease may trigger frequent and very painful sickle cell crises that require hospitalization. In others, it may cause less frequent and milder attacks.

Children with sickle cell disease are very susceptible to infections,mostly because their damaged spleens are unable to protect the body from bacteria. Signs of impaired lung function may occur even in very early years. Because children with sickle cell disease are living longer, older patients are now facing medical problems related to the long-term adverse effects of the disease process. The most serious dangers are acute chest syndrome, long-term damage to major organs, stroke, and complications during pregnancy such as high blood pressure in the mother and low birth weight in the infant.

There is still no cure for sickle cell disease other than experimental transplantation procedures, but treatments for complications of sickle cell have prolonged the lives of many patients who are now living into adulthood.

The hallmark of sickle cell disease is the sickle cell crisis (also calledvaso-occlusive crisis), which is an episode of pain. It is the most common reason for hospitalization in sickle cell disease. The pattern may occur as follows:

Episodes cannot be predicted, and they vary widely among different individuals. Episodes sometimes become less frequent with increasing age. Generally, people can resume a relatively normal life between crises. Most patients are pain-free between episodes although pain can be chronic in some cases.

Acute chest syndrome (ACS) occurs when the lung tissues are deprived of oxygen during a crisis. It can be very painful, dangerous, and even life threatening. It is a leading cause of illness among patients with sickle cell disease and is the most common condition at the time of death. At least one whole segment of a lung is involved, and the following symptoms may be present:

Pain often lasts for several days. In about half of patients, severe pain develops about 2 - 3 days before there are any signs of lung or chest abnormalities. Acute chest syndrome is often accompanied by infections in the lungs, which can be caused by viruses, bacteria, or fungi. Pneumonia is often present. A dull, aching pain usually follows, which most often ends after several weeks, although it may persist between crises.

Air is breathed in (inhaled) through the nasal passageways, and travels through the trachea and bronchi to the lungs.

Causes of Acute Chest Syndrome. Primary causes of acute chest syndrome include:

Some cases of acute chest syndrome may result from treatments of the crisis, including from administration of opioid pain killers (which can reduce breathing and oxygen uptake) or excessive use of intravenous fluids. Other lung diseases may also trigger ACS.

Severity of Acute Chest Syndrome. The mortality rates for ACS are around 2% in children and 4% in adults. The syndrome and its long-term complications are the major causes of death in older patients. The longer a patient survives, the more repetitive sickle cell crises damage the chest and lungs.

The following destructive effects can occur:

Infections are common and an important cause of severe complications. Before early screening for sickle cell disease and the use of preventive antibiotics in children, 35% of infants with sickle cell died from infections. Fortunately, with screening tests for sickle cell now required for newborns, and with the use of preventive antibiotics and immunizations in babies who are born with the disease, the mortality rate has dropped significantly.

Infections in Infants and Toddlers with Sickle Cell Disease. The most common organisms causing infection in children with sickle cell disease include:

Such infections pose aserious threat to infants and very young children with sickle cell disease. They can progress to fatal pneumonia with devastating speed in infants, and death can occur only a few hours after onset of fever. The risk for pneumococcal meningitis, a dangerous infection of the central nervous system, is also significant.

Infections in Children and Adults. Infections are also common in older children and adults with sickle cell disease, particularly respiratory infections such as pneumonia, kidney infections, and osteomyelitis, a serious infection in the bone. (The organisms causing them, however, tend to differ from those in young children.) Infection-causing organisms include:

About 30% of patients with sickle cell disease have pulmonary hypertension. Pulmonary hypertension is a serious and potentially deadly condition that develops when pressure in the arteries of the lungs increases. It is an often unrecognized complication and a significant cause of death in sickle cell disease. Many doctors recommend that all adults with sickle cell disease have echocardiographic testing to identify if they are at risk for pulmonary hypertension and need treatment.

The primary symptom of pulmonary hypertension is shortness of breath, which is often severe. Pulmonary hypertension can be very serious and life threatening in the short- and long-term. If pulmonary hypertension develops suddenly it can cause respiratory failure, which is life threatening. Over time, pulmonary hypertension may cause a condition called cor pulmonale, in which the right side of the heart increases in size. In some cases, this enlargement can lead to heart failure.

After acute chest syndrome, stroke is the most common killer of patients with sickle cell disease who are older than 3 years old. Between 8 - 10% of patients suffer strokes, typically at about age 7. Patients may also suffer small strokes that may not be immediately noticeable. However, patients who have many of these small strokes may over time start behaving differently or have worsening mental functioning.

Strokes are usually caused by blockages of vessels carrying oxygen to the brain. Patients with sickle cell disease are also at high risk for stokes caused by aneurysm, a weakened blood vessel wall that can rupture and hemorrhage. Multiple aneurysms are common in sickle cell patients, but they are often located where they cannot be treated surgically.

Anemia is a significant characteristic in sickle cell disease (which is why the disease is commonly referred to as sickle cell anemia).

Severe worsening of anemia. Children, adolescents, and possibly young adults may experience what is called splenic sequestration. This happens when a large number of sickled red blood cells collect in the patient's spleen. Symptoms may include pain in the right abdomen below the ribs and a large mass (the swollen spleen) may be felt.

Chronic Anemia. Because of the short lifespan of the sickle red blood cells, the body is often unable to replace red blood cells as quickly as they are destroyed. This causes a particular form of anemia called hemolytic anemia. Most patients with sickle cell disease have hemoglobin levels of about 8 g/dL, much lower than healthy people. Chronic anemia reduces oxygen levels and increases the demand on the heart to pump more oxygen-bearing blood through the body. Eventually, this can cause the heart to become dangerously enlarged, with an increased risk for heart attack and heart failure.

Sometimes patients may have what is called an aplastic crisis. This happens when the cells in the bone marrow that are normally trying to make new red blood cells suddenly stop working. This sudden stopping is often triggered by a virus called human parvovirus B19.

The kidneys are particularly susceptible to damage from the sickling process. Persistent injury can cause a number of kidney disorders, including infection. Problems with urination are very common, particularly uncontrolled urination during sleep. Patients may have blood in the urine, although this is usually mild and painless and resolves without damaging consequences. Kidney failure is a major danger in older patients and accounts for 10 - 15% of deaths in sickle cell patients. Renal medullary carcinoma is an aggressive, rapidly destructive tumor in the kidney that is rare but can occur in association with sickle cell disease.

About 40% of males, including children, with sickle cell disease suffer from priapism. Priapism causes prolonged and painful erections that can last from several hours to days. If priapism is not treated, permanent partial or complete erectile dysfunction can occur.

Enlargement of the liver occurs in over half of sickle cell patients, and acute liver damage occurs in up to 10% of hospitalized patients. Because sickle cell patients often need transfusions, they are at higher risk for viral hepatitis, an infection of the liver. This risk, however, has decreased since screening procedures for donated blood have been implemented.

About 30% of children with sickle cell disease have gallstones, and by age 30, 70% of patients have them. In most cases, gallstones do not cause symptoms for years. When symptoms develop, patients may feel overly full after meals, have pain in the upper right quadrant of the abdomen, or have nausea and vomiting. Acute attacks can be confused with a sickle cell crisis in the liver. Ultrasound is usually used to confirm a diagnosis of gallstones. If the patient does not have symptoms, no treatment is usually necessary. If there is recurrent or severe pain from gallstones, the gallbladder may need to be removed. Minimally invasive procedures (using laparoscopy) reduce possible complications. [For more information, see In-Depth Report #10: Gallstones.]

The spleen of most adults with sickle cell anemia is nonfunctional due to recurrent episodes of oxygen deprivation that eventually destroy it. Injury to spleen increases the risk for serious infection. Acute splenic sequestration crisis (sudden spleen enlargement) can occur when the spleen suddenly becomes enlarged from trapped blood.

In some children with sickle cell disease, excessive production of blood cells in the bone marrow causes bones to grow abnormally, resulting in long legs and arms or misshapen skulls. Sickling that blocks oxygen to the bone can also cause bone loss and pain. Sickling that affects the hands and feet of children causes a painful condition called hand-foot syndrome. A condition called avascular necrosis of the hip occurs in about half of adult sickle cell patients when oxygen deprivation causes tissue death in the bone. Eventually adult patients may need surgery to remove diseased and dead bone tissue. Patients with severe cases may need joint replacement.

Leg sores and ulcers may occur. They usually affect patients older than 10 years.

Sickle cell disease can damage blood vessels in the eye and cause scarring and detachment of the retina, which can lead to blindness.

Women with sickle cell disease who become pregnant are at higher risk for complications such as miscarriage and premature birth, and their babies may have low birth weight. Sickle cell disease symptoms often worsen during pregnancy and pain crises become more frequent. However, with careful prenatal care and monitoring, serious problems can be avoided. Maternal mortality rates have dropped significantly over the past decades. Most women with sickle cell disease can now anticipate favorable pregnancy outcomes.

Older children and adult patients with sickle cell are subject to other medical problems, including impaired physical development and gum disease. In severe cases, sickle cell disease can cause multiple organ failure.

Treatment goals for sickle cell disease aim to relieve pain, prevent infections, and manage complications. [For specific information on complications, see Treatment of Complications section in this report.] Patients should seek care from a doctor who specializes in blood disorders (hematologist) or a clinic that is experienced in treating sickle cell disease.

Bone marrow transplantation is the only potential cure, but it is used in only a small number of casesbecause few patients are able to find donors who are suitable genetic matches. Blood transfusions are given to prevent worsening anemia and prevent stroke.

Drug treatments for sickle cell disease include:

Antibiotics, usually penicillin, are commonly given to infants and young children, as well as adults, to help prevent infections.

Pain relief medications ranging from nonprescription nonsteroidal anti-inflammatory drugs (NSAIDs) to opiods are given to control pain.

Hydroxyurea (Droxia) is prescribed for patients with moderate-to-severe sickle cell disease to help reduce the frequency of pain episodes and acute chest syndrome.

HbF, also called fetal hemoglobin, is the form of hemoglobin present in the fetus and young infants. Most HbF disappears early in childhood, although some HbF may persist. Fetal hemoglobin is able to block the sickling action of red blood cells. Because of this, infants with sickle cell disease do not develop symptoms of the illness until HbF levels have dropped. Adults who have sickle cell disease but still retain high levels of hemoglobin F generally have mild disease.

Hydroxyurea (Droxia) is a drug that reduces the severity of sickle cell disease by stimulating production of HbF. It is currently the only drug in general use to prevent acute sickle cell crises.

Hydroxyurea is recommended as first-line therapy to treat adults and adolescents with moderate-to-severe recurrent pain (occurring three or more times a year). Hydroxyurea reduces the frequency of acute pain crises and episodes of acute chest syndrome. It is taken daily by mouth. Hydroxyurea can be taken indefinitely and the benefits appear to be long-lasting.

Hydroxyurea is not a cure-all. Not all patients respond to hydroxyurea, and the best candidates for the treatment are not yet clear. Many patients who could benefit fromthis medicationare not receiving it. Hydroxyurea is still being investigated for younger patients. To date, the response to the drug in children with sickle cell disease is similar to the response in adults, and few severe adverse effects are being reported. Recent research also suggests that hydroxyurea is safe for infants.

Side effects include constipation, nausea, drowsiness, hair loss, and inflammation of the mouth. More severe side effects include reduction of white blood cells (neutropenia) and the cells responsible for normal blood clotting (thrombocytopenia). Hydroxyurea should not be taken by women because it can cause birth defects. There have been concerns that long-term use of hydroxyurea may increase the risk of developing leukemia, but the significance of this risk remains unclear. Still, formany patients the risks of untreated sickle cell disease may outweigh the risks of hydroxyureas side effects.

Patients should handle hydroxyurea with care and wash their hands before and after touching the bottle or capsules. Household members who are not taking hydroxyurea (such as caregivers) should wear disposable gloves when handling the medicine or its bottle.

Blood transfusions are often critical for treating sickle cell disease. Transfusions may be used either as treatment for specific episodes or as chronic transfusion therapy to prevent life-threatening complications Ongoing transfusions can also help improve height and weight in children with sickle cell disease. Normal hemoglobin levels for patients with sickle cell disease are around 8 g/dL. Doctors will try to keep the hemoglobin level no higher than 10 g/dL after transfusion.

Episodic Transfusions. Episodic transfusions are needed in the following situations:

Chronic Transfusions. Chronic (on-going) transfusions are used for:

Stroke prevention for first or recurrent strokes. Evidence shows that regular (every 3 - 4 weeks) blood transfusions can reduce the risk of a first stroke by 90% in high-risk children. In addition, studies indicate that as many as 90% of patients who have experienced a stroke do not experience another stroke after 5 years of transfusions. The U.S. National Institutes of Health strongly recommends that doctors do not stop regular transfusions for children with sickle cell disease who are at high risk for stroke.

Chronic blood transfusions carry their own risks, including iron overload, alloimmunization (an immune response reaction), and exposure to bloodborne microbes. Still, data from large-scale trials suggest that the risks for stroke outweigh the risks associated with transfusions. Researchers are working on ways to reduce the side effects associated with transfusion treatment.

Kinds of Transfusions. Transfusions may be either simple or exchange.

Iron Overload and Chelation Therapy. Iron overload increases risk for damage to the liver, heart, and other organs. A liver biopsy accurately determines whether excess iron levels are present.

Chelation therapy is used to remove excess iron stores in the body. The drug deferoxamine (Desferal) is commonly used during such therapy. Unfortunately, deferoxamine has some severe side effects and must be used with a pump for about 12 hours each day. Many patients do not continue treatment. A newer drug deferasirox (Exjade) is approved for the treatment of transfusion-related iron overload in patients ages 2 and older. It is taken once a day by mouth. Patients mix the pills in liquid and drink the mixture. This new treatment may make chelation therapy much easier and less painful for patients.

Other Complications of Transfusion Therapy.

At this time, the only chance for cure for sickle cell disease is bone marrow or stem cell transplantation. The bone marrow nurtures stem cells, which are early cells that mature into red and white blood cells and platelets. By destroying the sickle cell patient's diseased bone marrow and stem cells and transplanting healthy bone marrow from a genetically-matched donor, normal hemoglobin may be produced.

Bone marrow transplantations have been performed successfully in select children with sickle cell disease. However, due to a lack of available donors and the risks of potential complications, bone marrow transplantations for sickle cell disease are not routinely performed. Complications can include the immune systems rejection of the transplant (a condition called graft-versus-host-disease) and serious infections. Patients can suffer serious neurological damage if the procedure triggers bleeding in the brain. In general, younger children are considered better candidates for bone marrow transplantation than older children.

Before a bone marrow transplant can be performed, the patient must undergo chemotherapy to completely destroy their own bone marrow. Bone marrow transplantation is considered too risky for adults with sickle cell disease, because they cannot tolerate the chemotherapy regimen as well as children and they tend to have long-term organ damage as a result of the condition.

Researchers are investigating new types of bone marrow transplants for children and adults with sickle cell disease. Several new approaches appear promising. They include giving less intense doses of chemotherapy prior to the transplant (a regimen known as reduced-intensity conditioning), or using low doses of immunosuppressive drugs or radiation in place of chemotherapy.

In 2012, researchers reported some success with a study of half-matched marrow transplants (haploidentical transplant is the medical term), which used donors who shared only 50% of the recipients genes. While this approach may potentially help expand donor options for patients, the research is still very preliminary. Bone marrow transplant with a fully matched donor remains the best choice at this time.

Nitric Oxide. Nitric oxide is a natural chemical in the body that relaxes smooth muscles and widens blood vessels. Patients with sickle cell disease are deficient in nitric oxide. This lack of nitric oxide constricts blood vessels and causes sickle cell pain. Some studies have indicated that inhaling nitric oxide may slow the disease process and improve symptoms in acute sickle cell crises. Other studies report that nitric oxide is of no benefit. In addition, nitric oxide is difficult to administer. More studies are needed to determine if nitric oxide should have a role in sickle cell therapy. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)

Arginine. Arginine is an amino acid involved in producing nitric oxide. Because a lack of arginine may contribute to the development of pulmonary hypertension, (a leading cause of death in patients with sickle cell disease), arginine is being studied as a potential drug treatment. Some research is also being conducted on arginine nutritional supplements. Patients should talk to their doctors before taking these or any other supplements.

Drugs to Prevent Dehydration. Researchers are studying various drugs, as well as mineral supplements such as magnesium pidolate and zinc sulfate, that may help prevent potassium loss and red blood cell dehydration.

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Sickle cell disease | University of Maryland Medical Center

Not to be confused with cortisone, a metabolite from cortisol, with a similar name, genesis, and function. Cortisol Systematic (IUPAC) name

(11)-11,17,21-trihydroxypregn-4-ene-3,20-dione

O=C4C=C2/[C@]([C@H]1[C@@H](O)C[C@@]3([C@@](O)(C(=O)CO)CC[C@H]3[C@@H]1CC2)C)(C)CC4

Cortisol is a steroid hormone, in the glucocorticoid class of hormones, and is produced in humans by the zona fasciculata of the adrenal cortex within the adrenal gland.[1] It is released in response to stress and low blood-glucose concentration.

It functions to increase blood sugar through gluconeogenesis, to suppress the immune system, and to aid in the metabolism of fat, protein, and carbohydrates.[2] It also decreases bone formation.[3]

Hydrocortisone (INN, USAN, BAN) is a name for cortisol when it is used as a medication. Hydrocortisone is used to treat people who lack adequate naturally generated cortisol. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[4]

In the early fasting state, cortisol stimulates gluconeogenesis (the formation of glucose), and activates anti-stress and anti-inflammatory pathways.[5] Cortisol also plays an important, but indirect, role in liver and muscle glycogenolysis, the breaking down of glycogen to glucose-1-phosphate and glucose. This is done through its passive influence on glucagon.[clarification needed] Additionally, cortisol facilitates the activation of glycogen phosphorylase, which is necessary for epinephrine to have an effect on glycogenolysis.[6][7]

In the late fasting state, the function of cortisol changes slightly and increases glycogenesis. This response allows the liver to take up glucose that is not being used by the peripheral tissue and turn it into liver glycogen stores to be used if the body moves into the starvation state.[citation needed]

Elevated levels of cortisol, if prolonged, can lead to proteolysis (breakdown of proteins) and muscle wasting.[8] Several studies have shown that cortisol can have a lipolytic effect (promote the breakdown of fat). Under some conditions, however, cortisol may somewhat suppress lipolysis.[9]

Cortisol prevents the release of substances in the body that cause inflammation. It is used to treat conditions resulting from over activity of the B-cell-mediated antibody response. Examples include inflammatory and rheumatoid diseases, as well as allergies. Low-potency hydrocortisone, available as a non-prescription medicine in some countries, is used to treat skin problems such as rashes, and eczema.

It inhibits production of interleukin (IL)-12, interferon (IFN)-gamma, IFN-alpha and tumor-necrosis-factor (TNF)-alpha by antigen-presenting cells (APCs) and T helper (Th)1 cells, but upregulates IL-4, IL-10, and IL-13 by Th2 cells. This results in a shift toward a Th2 immune response rather than general immunosuppression. The activation of the stress system (and resulting increase in cortisol and Th2 shift) seen during an infection is believed to be a protective mechanism which prevents an over activation of the inflammatory response.[10]

Cortisol can weaken the activity of the immune system. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor (IL-2).[11] Cortisol also has a negative-feedback effect on interleukin-1.[12]

Though IL-1 is useful in combating some diseases; however, endotoxic bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels (forcing the secretion of CRH hormone, thus antagonizing IL-1). The suppressor cells are not affected by glucosteroid response-modifying factor (GRMF),[13] so the effective setpoint for the immune cells may be even higher than the setpoint for physiological processes (reflecting leukocyte redistribution to lymph nodes, bone marrow, and skin). Rapid administration of corticosterone (the endogenous Type I and Type II receptor agonist) or RU28362 (a specific Type II receptor agonist) to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are affected by cortisol.[14]

Cortisol stimulates many copper enzymes (often to 50% of their total potential), probably to increase copper availability for immune purposes.[15]:337 This includes lysyl oxidase, an enzyme that cross-links collagen and elastin.[15]:334 Especially valuable for immune response is cortisol's stimulation of the superoxide dismutase,[16] since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria.

Cortisol counteracts insulin, contributes to hyperglycemia-causing hepatic gluconeogenesis[17] and inhibits the peripheral utilization of glucose (insulin resistance)[17] by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.[18] However, cortisol increases glycogen synthesis (glycogenesis) in the liver.[19] The permissive effect of cortisol on insulin action in liver glycogenesis is observed in hepatocyte culture in the laboratory, although the mechanism for this is unknown.

Cortisol reduces bone formation,[3] favoring long-term development of osteoporosis (progressive bone disease). It transports potassium out of cells in exchange for an equal number of sodium ions (see above).[20] This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine.[21]

Collagen is an important component of connective tissue. It is vital for structural support and is found in muscles, tendons, and joints, as well as throughout the entire body. Cortisol down regulates the synthesis of collagen.[22]

Cortisol raises the free amino acids in the serum. It does this by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis.[23] Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves.[24] Cortisol also inhibits IgA in serum, as it does IgM; however, it is not shown to inhibit IgE.[25]

Cortisol and the stress response have known deleterious effects on the immune system. High levels of perceived stress and increases in cortisol have been found to lengthen wound healing time in healthy, male adults. Those who had the lowest levels of cortisol the day following a 4mm punch biopsy had the fastest healing time.[26] In dental students, wounds from punch biopsies took an average of 40% longer to heal when performed three days before an examination as opposed to biopsies performed on the same students during summer vacation.[27] This is in line with previous animal studies that show similar detrimental effects on wound healing, notably the primary reports showing that turtles recoil from cortisol.[28]

Cortisol acts as a diuretic, increasing water diuresis, glomerular filtration rate, and renal plasma flow from the kidneys, as well as increasing sodium retention and potassium excretion. It also increases sodium and water absorption and potassium excretion in the intestines.[29]

Cortisol promotes sodium absorption through the small intestine of mammals.[30] Sodium depletion, however, does not affect cortisol levels[31] so cortisol cannot be used to regulate serum sodium. Cortisol's original purpose may have been sodium transport. This hypothesis is supported by the fact that freshwater fish utilize cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium.[32]

A sodium load augments the intense potassium excretion by cortisol. Corticosterone is comparable to cortisol in this case.[33] For potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell.[20] This should make pH regulation much easier (unlike the normal potassium-deficiency situation, in which two sodium ions move in for each three potassium ions that move outcloser to the deoxycorticosterone effect).

Cortisol stimulates gastric-acid secretion.[34] Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate the excretion of ammonium ions by deactivating the renal glutaminase enzyme.[35]

Cortisol works with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future.[36] However, long-term exposure to cortisol damages cells in the hippocampus;[37] this damage results in impaired learning. Furthermore, it has been shown that cortisol inhibits memory retrieval of already stored information.[38][39]

Diurnal cycles of cortisol levels are found in humans.[6] In humans, the amount of cortisol present in the blood undergoes diurnal variation; the level peaks in the early morning (approximately 8 a.m.) and reaches its lowest level at about midnight-4 a.m., or three to five hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. This pattern is not present at birth; estimates of when it begins vary from two weeks to nine months of age.[40]

Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and physiological stressors such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion, or temperature extremes. Cortisol levels may also differ for individuals with autism or Asperger's syndrome.[41] There is also significant individual variation, although a given person tends to have consistent rhythms.[42]

During human pregnancy, increased fetal production of cortisol between weeks 30 and 32 initiates production of fetal lung surfactant to promote maturation of the lungs. In fetal lambs, glucocorticoids (principally cortisol) increase after about day 130, with lung surfactant increasing greatly, in response, by about day 135,[43] and although lamb fetal cortisol is mostly of maternal origin during the first 122 days, 88 percent or more is of fetal origin by day 136 of gestation.[44] Although the timing of fetal cortisol concentration elevation in sheep may vary somewhat, it averages about 11.8 days before the onset of labor.[45] In several livestock species (e.g. the cow, sheep, goat and pig), the surge of fetal cortisol late in gestation triggers the onset of parturition by removing the progesterone block of cervical dilation and myometrial contraction. The mechanisms yielding this effect on progesterone differ among species. In the sheep, where progesterone sufficient for maintaining pregnancy is produced by the placenta after about day 70 of gestation,[46][47] the pre-partum fetal cortisol surge induces placental enzymatic conversion of progesterone to estrogen. (The elevated level of estrogen stimulates prostaglandin secretion and oxytocin receptor development.)

Exposure of fetuses to cortisol during gestation can have a variety of developmental outcomes, including alterations in prenatal and postnatal growth patterns. In marmosets, a species of New World primates, pregnant females have varying levels of cortisol during gestation, both within and between females. Mustoe et al. (2012) showed that infants born to mothers with high gestational cortisol during the first trimester of pregnancy had lower rates of growth in body mass indices (BMI) than infants born to mothers with low gestational cortisol (approximately 20% lower). However, postnatal growth rates in these high-cortisol infants was more rapid than low-cortisol infants later in postnatal periods, and complete catch-up in growth had occurred by 540 days of age. These results suggest that gestational exposure to cortisol in fetuses has important potential fetal programming effects on both pre- and post-natal growth in primates.[48]

Cortisol is produced in the human body by the adrenal gland in the zona fasciculata,[1] the second of three layers comprising the adrenal cortex. The cortex forms the outer "bark" of each adrenal gland, situated atop the kidneys. The release of cortisol is controlled by the hypothalamus, a part of the brain. The secretion of corticotropin-releasing hormone (CRH) by the hypothalamus[49] triggers cells in the neighboring anterior pituitary to secrete another hormone, the adrenocorticotropic hormone (ACTH), into the vascular system, through which blood carries it to the adrenal cortex. ACTH stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids and dehydroepiandrosterone (DHEA).

Normal values indicated in the following tables pertain to humans (normals vary among species). Measured cortisol levels, and therefore reference ranges, depend on the analytical method used and factors such as age and sex. Test results should, therefore, always be interpreted using the reference range from the laboratory that produced the result.

Using the molecular weight of 362.460g/mole, the conversion factor from g/dl to nmol/L is approximately 27.6; thus, 10g/dl is approximately equal to 276 nmol/L.

Disorders of cortisol production, and some consequent conditions, are as follows:

The primary control of cortisol is the pituitary gland peptide, adrenocorticotropic hormone (ACTH). ACTH probably controls cortisol by controlling the movement of calcium into the cortisol-secreting target cells.[58] ACTH is in turn controlled by the hypothalamic peptide corticotropin-releasing hormone (CRH), which is under nervous control. CRH acts synergistically with arginine vasopressin, angiotensin II, and epinephrine.[59] (In swine, which do not produce arginine vasopressin, lysine vasopressin acts synergistically with CRH.[60])

When activated macrophages start to secrete interleukin-1 (IL-1), which synergistically with CRH increases ACTH,[12]T-cells also secrete glucosteroid response modifying factor (GRMF or GAF) as well as IL-1; both increase the amount of cortisol required to inhibit almost all the immune cells.[13] Immune cells then assume their own regulation, but at a higher cortisol setpoint. The increase in cortisol in diarrheic calves is minimal over healthy calves, however, and falls over time.[61] The cells do not lose all their fight-or-flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1[12]especially useful to treat diseases that force the hypothalamus to secrete too much CRH, such as those caused by endotoxic bacteria. The suppressor immune cells are not affected by GRMF,[13] so the immune cells' effective setpoint may be even higher than the setpoint for physiological processes. GRMF (known as GAF in this reference) affects primarily the liver (rather than the kidneys) for some physiological processes.[62]

High-potassium media (which stimulates aldosterone secretion in vitro) also stimulate cortisol secretion from the fasciculata zone of canine adrenals [63][64] unlike corticosterone, upon which potassium has no effect.[65]

Potassium loading also increases ACTH and cortisol in humans.[66] This is probably the reason why potassium deficiency causes cortisol to decline (as mentioned) and causes a decrease in conversion of 11-deoxycortisol to cortisol.[67] This may also have a role in rheumatoid-arthritis pain; cell potassium is always low in RA.[68]

[80][81]

Hydrocortisone is the pharmaceutical term for cortisol used in oral administration, intravenous injection, or topical application. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients needing steroid treatment but unable take oral medication, and perioperatively in patients on long-term steroid treatment to prevent Addisonian crisis. It may also be injected into inflamed joints resulting from diseases such as gout.

Compared to hydrocortisone, prednisolone is about four times as strong and dexamethasone about forty times as strong, in their anti-inflammatory effect.[96] Prednisolone can also be used as cortisol replacement, and at replacement dose levels (rather than anti-inflammatory levels), prednisolone is about eight times more potent than cortisol.[97] For side effects, see corticosteroid and prednisolone.

It may be used topically for allergic rashes, eczema, psoriasis, pruritis (itchyness) and other inflammatory skin conditions. Topical hydrocortisone creams and ointments are available in most countries without prescription in strengths ranging from 0.05% to 2.5% (depending on local regulations) with stronger forms available by prescription only. Covering the skin after application increases the absorption and effect. Such enhancement is sometimes prescribed, but otherwise should be avoided to prevent overdose and systemic impact.

Most serum cortisol (all but about 4%) is bound to proteins, including corticosteroid binding globulin (CBG) and serum albumin. Free cortisol passes easily through cellular membranes, where they bind intracellular cortisol receptors.[98]

Cortisol is synthesized from cholesterol. Synthesis takes place in the zona fasciculata of the adrenal cortex. (The name cortisol is derived from cortex.) While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion in humans and several other species. (However, in cattle, corticosterone levels may approach[99] or exceed[6] cortisol levels.). The medulla of the adrenal gland lies under the cortex, mainly secreting the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation.

The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH); ACTH production is in turn stimulated by corticotropin-releasing hormone (CRH), which is released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane, via regulation of the STAR (steroidogenic acute regulatory) protein. It also stimulates the main rate-limiting step in cortisol synthesis, in which cholesterol is converted to pregnenolone and catalyzed by Cytochrome P450SCC (side-chain cleavage enzyme).[100]

Cortisol is metabolized by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2.

Overall, the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically active cortisol in a given tissue; 11-beta HSD2 serves to decrease local concentrations of biologically active cortisol.

Cortisol is also metabolized into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), reactions for which 5-alpha reductase and 5-beta reductase are the rate-limiting factors, respectively. 5-Beta reductase is also the rate-limiting factor in the conversion of cortisone to tetrahydrocortisone (THE).

An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance known as metabolic syndrome.[101]

An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME).

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Cortisol - Wikipedia, the free encyclopedia

I received a disturbing call from a woman in Texas recently. She was having some complications from the stem cell treatment that she received in her hometown.

In what is becoming a more common email or call from people not our patients, she revealed that she believed that her doctor was inexperienced in the Stem Cell procedure and did not know how to address her complications.

Even though I did not have the luxury of examining her, I tried to ask some questions to help her with her situation.

It seems, that she had received placental cells.They were injected into her knee and it caused a severe inflammatory response that left her with a great deal of pain. I did wish her the best and try to offer some advice, but also let her know that it is not legal nor recommended to inject placental cells into a patient.

While we have found the use of stem cells for the symptomatic treatment of arthritis and pain to be very helpful in our practice, one must be very cautious as to know what they are receiving.

As I mentioned, placental cells are not only illegal, but are immature cells that can have mutagenic properties. That is, they have the ability to turn into cancer cells and furthermore it is uncertain if the body can reject them since they are not harvested from the person who is receiving the treatment. These cells, also differentiate to form both blood cells and tissue cells so there is a great deal of insufficiency if you are looking to heal damaged tissue.

Bone marrow derived stem cells also have this same property of containing cell lines that turn into blood cells. There are certain areas, like the tibia, where the bone marrow contains many more blood cells then areas such as the hip, which contain more mesenchymal cells. Certain doctors have recommended tibial bone marrow draws for the use of bone marrow prolotherapy from the tibia, but this has very little scientific backing to be included as a stem cell source. There is also no research whatsoever showing its efficacy.

Many other doctors use bone marrow from the hip in their stem cell procedure. While this is a richer source of mesenchymal cells when compared to the tibia it is still a very poor source of stem cells.

Results from stem cell procedures not only depend on the cell type and where they are injected, but also the diagnostic skill and approach of the physician. While stem cells may have amazing properties, they are not so magical where we can just inject stem cells into a joint and hope for good results. As a physician, it is our job to evaluate and treat any problem surrounding, above and below the joint using a very careful physical examination. A comprehensive approach, not a single sided approach, will yield the best results for the patient.

Growth hormone has also been touted by one physician as useful in a stem cell mixture. That physician is conducting a study on this, but it still remains unproven. We had used this in power injection solution well over 10 years ago and stopped because it did not produce any significant clinical benefit. Furthermore, stem cells do need to be combined with a variety of growth factors in order to further their differentiation into new tissue. This can be achieved by using specialized forms of PRP along with the stem cell mixture. Both ourselves with our partners at Kensey and Dr. Centeno from Regenexx has done laboratory tests to look at the importance of this. There is a large variation in how stem cells perform based upon the environment that they are given with the PRP.

In summary, while these procedures have tremendous potential, we need to follow in the best of our knowledge base and follow our outcomes. Eventually, our technology will expand, and in the future we will have the capability to harvest stem cells in less than a half hour But this will take several years of development.

Scott Greenberg MD

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Stem Cell Therapy dangers and risks the wrong stem cells

Some of the promise of stem cell therapy has been realized. A prime example is bone marrow transplantation. Even here, however, manyproblems remain to be solved.

Challenges facing stem cell therapy include the following:

Adult stem cells Tissue-specific stem cells in adult individuals tend to be rare. Furthermore, while they can regenerate themselves in an animal or person they are generally very difficult to grow and to expand in the laboratory. Because of this, it is difficult to obtain sufficient numbers of many adult stem cell types for study and clinical use. Hematopoietic or blood-forming stem cells in the bone marrow, for example, only make up one in a hundred thousand cells of the bone marrow. They can be isolated, but can only be expanded a very limited amount in the laboratory. Fortunately, large numbers of whole bone marrow cells can be isolated and administered for the treatment for a variety of diseases of the blood. Skin stem cells can be expanded however, and are used to treat burns. For other types of stem cells, such as mesenchymal stem cells, some success has been achieved in expanding the cellsin vitro, but application in animals has been difficult. One major problem is the mode of administration. Bone marrow cells can be infused in the blood stream, and will find their way to the bone marrow. For other stem cells, such as muscle stem cells, mesenchymal stem cells and neural stem cells, the route of administration in humans is more problematic. It is believed, however, that once healthy stem cells find their niche, they will start repairing the tissue. In another approach, attempts are made to differentiate stem cells into functional tissue, which is then transplanted. A final problem is rejection. If stem cells from the patients are used, rejection by the immune system is not a problem. However, with donor stem cells, the immune system of the recipient will reject the cells, unless the immune system is suppressed by drugs. In the case of bone marrow transplantation, another problem arises. The bone marrow contains immune cells from the donor. These will attack the tissues of the recipient, causing the sometimes deadly graft-versus-host disease.

Pluripotent stem cells All embryonic stem cell lines are derived from very early stage embryos, and will therefore be genetically different from any patient. Hence, immune rejection will be major issue. For this reason, iPS cells, which are generated from the cells of the patient through a process of reprogramming, are a major breakthrough, since these will not be rejected. A problem however is that many iPS cell lines are generated by insertion of genes using viruses, carrying the risk of transformation into cancer cells. Furthermore, undifferentiated embryonic stem cells or iPS cells form tumors when transplanted into mice. Therefore, cells derived from embryonic stem cells or iPS cells have to be devoid of the original stem cells to avoid tumor formation. This is a major safety concern.

A second major challenge is differentiation of pluripotent cells into cells or tissues that are functional in an adult patient and that meet the standards that are required for 'transplantation grade' tissues and cells.

A major advantage of pluripotent cells is that they can be grown and expanded indefinitely in the laboratory. Therefore, in contrast to adult stem cells, cell number will be less of a limiting factor. Another advantage is that given their very broad potential, several cell types that are present in an organ might be generated. Sophisticated tissue engineering approaches are therefore being developed to reconstruct organs in the lab.

While results from animal models are promising, the research on stem cells and their applications to treat various human diseases is still at a preliminary stage. As with any medical treatment, a rigorous research and testing process must be followed to ensure long-term efficacy and safety.

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Stem Cell FAQ

Harvard stem cell researchers today announced that they have made a giant leap forward in the quest to find a truly effective treatment for type 1 diabetes, a condition that affects an estimated 3 million Americans at a cost of about $15 billion annually:

With human embryonic stem cells as a starting point, the scientists are for the first time able to produce, in the kind of massive quantities needed for cell transplantation and pharmaceutical purposes, human insulin-producing beta cells equivalent in most every way to normally functioning beta cells.

Doug Melton, who led the work and who 23 years ago, when his then infant son Sam was diagnosed with type 1 diabetes, dedicated his career to finding a cure for the disease, said he hopes to have human transplantation trials using the cells to be underway within a few years.

We are now just one pre-clinical step away from the finish line, said Melton, whose daughter Emma also has type 1 diabetes.

A report on the new work has today been published by the journal Cell.

Felicia W. Pagliuca, Jeff Millman, and Mads Gurtler of Meltons lab are co-first authors on the Cell paper. The research group and paper authors include a Harvard undergraduate.

You never know for sure that something like this is going to work until youve tested it numerous ways, said Melton, Harvards Xander University Professor and a Howard Hughes Medical Institute Investigator. Weve given these cells three separate challenges with glucose in mice and theyve responded appropriately; that was really exciting.

It was gratifying to know that we could do something that we always thought was possible, he continued, but many people felt it wouldnt work. If we had shown this was not possible, then I would have had to give up on this whole approach. Now Im really energized.

The stem cell-derived beta cells are presently undergoing trials in animal models, including non-human primates, Melton said.

Elaine Fuchs, the Rebecca C. Lancefield Professor at Rockefeller University, and a Howard Hughes Medical Institute Investigator who is not involved in the work, hailed it as one of the most important advances to date in the stem cell field, and I join the many people throughout the world in applauding my colleague for this remarkable achievement.

For decades, researchers have tried to generate human pancreatic beta cells that could be cultured and passaged long term under conditions where they produce insulin. Melton and his colleagues have now overcome this hurdle and opened the door for drug discovery and transplantation therapy in diabetes, Fuchs said.

And Jose Oberholzer, MD, Associate Professor of Surgery, Endocrinology and Diabetes, and Bioengineering at the University of Illinois at Chicago, and its Director of the Islet and Pancreas Transplant Program and the Chief of the Division of Transplantation, said work described in todays Cell will leave a dent in the history of diabetes. Doug Melton has put in a life-time of hard work in finding a way of generating human islet cells in vitro. He made it. This is a phenomenal accomplishment.

Melton, co-scientific director of the Harvard Stem Cell Institute, and the Universitys Department of Stem Cell and Regenerative Biology both of which were created more than a decade after he began his quest said that when he told his son and daughter they were surprisingly calm. I think like all kids, they always assumed that if I said Id do this, Id do it, he said with a self-deprecating grin.

Type 1 diabetes is an autoimmune metabolic condition in which the body kills off all the pancreatic beta cells that produce the insulin needed for glucose regulation in the body. Thus the final pre-clinical step in the development of a treatment involves protecting from immune system attack the approximately 150 million cells that would have to be transplanted into each patient being treated. Melton is collaborating on the development of an implantation device to protect the cells with Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology, Associate Professor in theDepartment of Chemical Engineering, the Institute of Medical Engineering and Science, and the Koch Institute at MIT.

Melton said that the device Anderson and his colleagues at MIT are currently testing has thus far protected beta cells implanted in mice from immune attack for many months. They are still producing insulin, Melton said.

Cell transplantation as a treatment for diabetes is still essentially experimental, uses cells from cadavers, requires the use of powerful immunosuppressive drugs, and has been available to only a very small number of patients.

MITs Anderson said the new work by Meltons lab is anincrediblyimportant advance for diabetes. There is no question that ability to generate glucose-responsive, human beta cells through controlled differentiation of stem cells will accelerate the development of new therapeutics. In particular, this advance opens to doors toan essentially limitless supply oftissue for diabetic patients awaiting cell therapy."

RichardA.Insel, MD, chief scientific officer of the JDRF, a funder of Meltons work, said the JDRF is thrilled with thisadvancementtoward large scale production of mature, functional human beta cells by Dr. Melton and his team. This significant accomplishmenthas the potentialto serve as a cell source for islet replacement in people with type 1 diabetes and mayprovide a resource for discovery of beta cell therapies that promote survival or regeneration of beta cells and development of screening biomarkers to monitor beta cell health and survival to guidetherapeutic strategies for all stages of the disease.

Melton expressed gratitude to both the Juvenile Diabetes Research Foundation and the Helmsley Charitable Trust, saying their support has been, and continues to be essential. I also need to thank Howard and Stella Heffron, whose faith in our vision got this work underway, and helped get us where we are today.

While diabetics can keep their glucose metabolism under general control by injecting insulin multiple times a day, that does not provide the kind of exquisite fine tuning necessary to properly control metabolism, and that lack of control leads to devastating complications from blindness to loss of limbs.

About 10 percent of the more than 26 million Americans living with type 2 diabetes are also dependent upon insulin injections, and would presumably be candidates for beta cell transplants, Melton said.

There have been previous reports of other labs deriving beta cell types from stem cells, no other group has produced mature beta cells as suitable for use in patients, he said. The biggest hurdle has been to get to glucose sensing, insulin-secreting beta cells, and thats what our group has done.

In addition to the institutions and individual cited above, the work was funded by the Harvard Stem Cell Institute, the National Institutes of Health, and the JPB Foundation.

Cited: Pagliuca, F., Millman, J. and Grtler, M, et. al. Generation of functional human pancreatic beta cells in vitro. Cell. October 9, 2014.

Dr. Melton has made an author's proof available. Click here to download the PDF.

The beginning shows a spinner flask containing red culture media and cells, the cells being too small to see. Inside the flask you can see a magnetic stir bar and the flask is being placed on top of a magnetic stirrer.

This is followed by a time course series of images, magnified, showing how cells tart of as single cells and then grow very quickly into clusters over the next few days. The size of the clusters is the same as the size of human islets at the end.

The final image shows 6 flasks, enough for 6 patients, spinning away. If you look closely, you can see particles spinning around, the white dust or dots are clusters of cells, each containing about 1000 cells.

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From stem cells to billions of human insulin-producing ...

By: Brenda Neugent

By Brenda Neugent

Despite a degree of controversy surrounding stem cell therapy, more scientists are starting to discover that adult stem cells are like tiny superheroes with the potential to ease the symptoms of a multitude of serious health problems.

Among the most effective uses for stem cells include inflammation-based diseases such as type 2 diabetes as well as autoimmune disorders like type 1 diabetes and rheumatoid arthritis.

Traditionally, the disease and its complication are treated with insulin as well as drugs that help reduce pain, protect organs and prevent additional damage by helping regulate blood glucose levels.

Adult stem cell therapy removes a patients stem cells stored in body fat and injects them into the abdomen where the majority of the immune system lives and helps treats most of the complications associated with diabetes.

Stem cells are like a small but powerful medical team, according to Dr. Todd Malan, the chief cell therapy at Okyanos, one of the leaders in stem cell technology. They are blank slates that can serve a wide range of purposes, including:

Repairing the lining of blood vessels so blood flows more smoothly. Because they increase blood flow, stem cells can also reverse damage to the beta cells of the pancreas tasked with making insulin, so there is more of the hormone available naturally; Improving the communication between cells, so cells are better able to take in glucose, reducing the amount of sugar in the blood; Restoring nerve function, so the pain of peripheral neuropathy is reduced; and Alleviating inflammation, lessening stress on the body and reducing the release of abnormal levels of inflammatory messengers.

Once the stem cells enter the body, they immediately realize where the bodys inflammation exists and heads there to fix it. This includes tissue repair, the creation of new blood vessels, building cartilage or muscles to fix the damage.

Adult stem cells can reverse, prevent and slow down much of the damage caused by high blood sugar levels.

Stem cells from your body are much better at the cell to cell communication, said Malan, and immediately realize they have a lot of jobs to do.

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Adult Stem Cell Therapy Tackles Diabetes Complications ...

A stem cell transplant poses many risks of complications, some potentially fatal. The risk can depend on many factors, including the type of disease or condition, the type of transplant, and the age and health of the person. Although some people experience few problems with a transplant, others may develop complications that may require treatment or hospitalization. Some complications could even be life-threatening.

Complications that can arise with a stem cell transplant include:

Your doctor can explain your risk of complications from a stem cell transplant. Together you can weigh the risks and benefits to decide whether a stem cell transplant is right for you.

If you receive a transplant that uses stem cells from a donor (allogeneic stem cell transplant), you may be at risk of graft-versus-host disease (GVHD). This disease happens when the donor stem cells that make up your new immune system see your body's tissues and organs as something foreign and attack them.

GVHD may happen at any time after your transplant. However, it's more common after your marrow has started to make healthy cells. Many people who have an allogeneic stem cell transplant get GVHD at some point. The risk of GVHD is a bit greater with unrelated donors, but it can happen to anyone who gets a stem cell transplant from a donor.

There are two kinds of GVHD: acute and chronic. Acute GVHD usually happens earlier, during the first months after your transplant. It typically affects your skin, digestive tract or liver. Chronic GVHD typically develops later and can affect many organs.

GVHD signs and symptoms include:

.

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Stem cell transplant Risks - Mayo Clinic

Before the transplant, I was in constant pain and it was always a struggle whether to stay at home or go to the emergency room, said Adeyinka Taiwo. Because it was just constant pain all the time. But now I actually have mornings when I wake up with absolutely no painIm trying my best to wean myself off of the [pain medications] and not automatically reach for the drugs that are a part of me. Its a big change, definitely.

How is your daily life different now? Fitzhugh asked.

I walked from the elevators to here and Im not out of breath, Taiwo replied, smiling and gesturing toward the Lipsett Amphitheater staircase. Three years ago, I would never have been able to move up and down these steps and have a conversation like this. I would have been out of breath and I would have had to stop many times to catch my breath, and to rest.

Her simple, heartfelt words prompted spontaneous applause.

Clinicopathologic (CPC) Grand Rounds are presented several times a year. Dr. Michail Lionakis of NIAID described the unique format of CPC talks, which bring together multiple presenters from various disciplines.

The sickle cell session was presented jointly by researchers from the National Heart, Lung, and Blood Institute; National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Diseases; and the NHLBI-Inova Advanced Lung Disease Program.

Team work. Gathering after the lecture are (from l) senior investigator Dr. John Tisdale, who serves as medically responsible investigator on the sickle cell study; NIDDK director Dr. Griffin Rodgers, associate investigator; Dr. Swee Lay Thein, NHLBI senior investigator and head of the Sickle Cell Branch; assistant clinical investigator Fitzhugh, principal investigator on the study; Dr. Nargues Weir, co-director of research development at the NIH-Inova Advanced Lung Disease Program and pulmonary consultant; and staff clinician Dr. Matthew Hsieh, lead associate investigator.

Lionakis said the CPC series has two missions: One is educationalThrough presentation of interesting cases that have interesting clinical, diagnostic and therapeutic features, we all learnand the other is to showcase programs established at NIH that demonstrate the superb clinical care and translational research that occurs in the Clinical Center.

SCD is a common genetic blood disorder that affects about 100,000 people in the U.S. The disease is diagnosed in 1 of every 500 black or African-American births, and 1 in every 36,000 Hispanic-American births. The disease causes misshapensickle-shapedred blood cells, which are the oxygen-carrying cells.

Sickled cells do not circulate freely throughout the body like normally shaped cells. As a result, patients can develop any of several conditions including chronic anemia, pain, infections and failure of such vital organs as liver, lungs and heart. Average age of death for someone with SCD is 45 years old.

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Can Stem Cell Transplant Relieve Sickle Cell Problems ...

IMAGE:Amir Toor, M.D., hematologist-oncologist and member of the Developmental Therapeutics research program at VCU Massey Cancer Center is pictured. view more

Credit: VCU Massey Cancer Center

Researchers at VCU Massey Cancer Center's Bone Marrow Transplant Program have recently published findings from a phase 2 clinical trial that demonstrate lymphocyte recovery in related and unrelated stem cell transplant recipients generally falls into three patterns that are significantly associated with survival. This first-of-its-kind research continues the efforts of principal investigator Amir Toor, M.D., to understand the immune system as a dynamical system that can be modeled to improve stem cell transplantation.

"We began considering lymphocyte reconstitution following stem cell transplantation as similar to population growth models. So, we graphed the lymphocyte counts of our patients at various times following their transplant as a logistic function and observed distinct patterns that correlated with clinical outcomes," says Toor, the lead investigator of the study and hematologist-oncologist and member of the Developmental Therapeutics research program at VCU Massey Cancer Center. "Our goal is to use this data to develop models that can predict complications from stem cell transplantation. Then, we may be able to intervene at key points in times with appropriate clinical treatments that will make the most positive impact on patients' outcomes."

The study, recently published in the journal Biology of Blood & Marrow Transplantation, retrospectively examined lymphocyte recovery and clinical outcome data from a recent phase 2 clinical trial (Clinical trials.gov identifier - NCT00709592) in which 41 patients received a stem cell transplant from related or unrelated donors. As part of the clinical trial protocol, the patients underwent low-dose radiation therapy and received one of two different doses of anti-thymocyte globulin (ATG), an immune-modulating drug given to guard against graft-versus-host-disease (GVHD) before transplantation. GVHD is a condition where the donor's immune system attacks the recipient's body. Following transplantation, the researchers observed that the patients' lymphocytes recovered in one of three general patterns that correlated significantly with survival, relapse, GVHD and the need for further donor immune cell infusions to treat the cancer.

Group A experienced fast, early lymphoid expansion, culminating in a high absolute lymphoid count (ALC) within two months of transplantation. Group B experienced a slower, but steady lymphoid expansion that peaked much later than group A with a lower ALC. Group C experienced very poor lymphocyte recovery that demonstrated an early, but brief lymphoid expansion with a very low ALC. Group B had the best clinical outcomes with a survival rate of 86 percent, followed by group A with a survival rate of 67 percent and group C with 30 percent survival. Relapse rates between groups A and B were similar at 33 and 29 percent, respectively, while group C experienced a 90 percent relapse rate. GVHD was observed in 67 percent of patients in group A, 43 percent of patients in group B and 10 percent of patients in group C. Finally, adoptive immunotherapy with donor cell infusions was required for 13 percent of patients in group A, 21 percent in group B and 70 percent in group C.

The discovery of these patterns in lymphocyte recovery build on prior research by Toor and his team that supports the concept of the immune system working as a dynamical system. In 2013, the Massey Bone Marrow Transplant Program's research team and Massey researcher Masoud Manjili*, D.V.M., Ph.D., sequenced DNA from the T cells of 10 stem cell transplant recipients and their donors and found a fractal, self-repeating pattern in the participants' T cell repertoires. This discovery suggested that physicians could potentially sequence the DNA of patients after they undergo stem cell transplantation and predict potential GVHD complications based on the pattern in which their T cell repertoire is developing. Another study of the same participants in 2014 also used whole exome sequencing and found significant variation in minor histocompatability antigens (mHA, which are receptors on the cellular surface of donated organs that are known to give an immunological response in some organ transplants) between the donor-recipient pairs. This variation represents a large and previously unmeasured potential for developing GVHD for which conventional human leucocyte antigen (HLA) testing, the test that matches stem cell transplants with donors, does not measure. This large library of immune targets, in turn, can serve to drive immune complications of transplantation such as GVHD or graft rejection.

Currently, physicians use stochastic models to determine the probability of a patient developing GVHD based on HLA test results. Stochastic models are not precise because they estimate probability by allowing for random variation in one or more variables. Dynamical system modeling, on the other hand, would account for the key variables influencing transplant outcomes and their evolution over time, allowing physicians to personalize therapy based on the extent of a patient's immune recovery following transplantation.

"We've uncovered order in the structure of the immune system, we've found new variables influencing GVHD and we've now shown patterns in lymphocyte reconstitution that identify at-risk patients," says Toor. "Now, we are working to put it all together and develop a model of immune system reconstruction following stem cell transplantation that will allow physicians to make more informed treatment decisions."

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Massey researchers identify patients at risk for stem cell ...

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek , meaning of the body), they can be found in juvenile as well as adult animals and human bodies.

Scientific interest in adult stem cells is centered on their ability to divide or self-renew indefinitely, and generate all the cell types of the organ from which they originate, potentially regenerating the entire organ from a few cells. Unlike embryonic stem cells, the use of human adult stem cells in research and therapy is not considered to be controversial, as they are derived from adult tissue samples rather than human 5 day old embryos generated by IVF (in vitro fertility) clinics designated for scientific research. They have mainly been studied in humans and model organisms such as mice and rats.

A stem cell possesses two properties:

To ensure the safety of others, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells, both endowed with stem cell properties, whereas asymmetric division produces only one of those stem cells and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before finally differentiating into a mature cell. It is believed that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.

Adult stem cells express transporters of the ATP-binding cassette family that actively pump a diversity of organic molecules out of the cell.[2] Many pharmaceuticals are exported by these transporters conferring multidrug resistance onto the cell. This complicates the design of drugs, for instance neural stem cell targeted therapies for the treatment of clinical depression.

Adult stem cell research has been focused on uncovering the general molecular mechanisms that control their self-renewal and differentiation.

Discoveries in recent years have suggested that adult stem cells might have the ability to differentiate into cell types from different germ layers. For instance, neural stem cells from the brain, which are derived from ectoderm, can differentiate into ectoderm, mesoderm, and endoderm.[5] Stem cells from the bone marrow, which is derived from mesoderm, can differentiate into liver, lung, GI tract and skin, which are derived from endoderm and mesoderm.[6] This phenomenon is referred to as stem cell transdifferentiation or plasticity. It can be induced by modifying the growth medium when stem cells are cultured in vitro or transplanting them to an organ of the body different from the one they were originally isolated from. There is yet no consensus among biologists on the prevalence and physiological and therapeutic relevance of stem cell plasticity. More recent findings suggest that pluripotent stem cells may reside in blood and adult tissues in a dormant state.[7] These cells are referred to as "Blastomere Like Stem Cells" (Am Surg. 2007 Nov;73:1106-10) and "very small embryonic like" - "VSEL" stem cells, and display pluripotency in vitro.[7] As BLSC's and VSEL cells are present in virtually all adult tissues, including lung, brain, kidneys, muscles, and pancreas[8] Co-purification of BLSC's and VSEL cells with other populations of adult stem cells may explain the apparent pluripotency of adult stem cell populations. However, recent studies have shown that both human and murine VSEL cells lack stem cell characteristics and are not pluripotent.[9][10][11][12]

Stem cell function becomes impaired with age, and this contributes to progressive deterioration of tissue maintenance and repair.[13] A likely important cause of increasing stem cell dysfunction is age-dependent accumulation of DNA damage in both stem cells and the cells that comprise the stem cell environment.[13] (See also DNA damage theory of aging.)

Hematopoietic stem cells are found in the bone marrow and give rise to all the blood cell types.

Mammary stem cells provide the source of cells for growth of the mammary gland during puberty and gestation and play an important role in carcinogenesis of the breast.[14] Mammary stem cells have been isolated from human and mouse tissue as well as from cell lines derived from the mammary gland. Single such cells can give rise to both the luminal and myoepithelial cell types of the gland, and have been shown to have the ability to regenerate the entire organ in mice.[14]

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Adult stem cell - Wikipedia, the free encyclopedia

Abstract

Non-malignant late effects after hematopoietic stem cell transplantation (HSCT) are heterogeneous in nature and intensity. The type and severity of the late complications depend on the type of transplantation and the conditioning regimen applied. Based on the most recent knowledge, we discuss three typical non-malignant complications in long-term survivors after HSCT, namely pulmonary, cardiovascular and renal complications. These complications illustrate perfectly the great diversity in respect of frequency, time of appearance, risk factors, and outcome. Respiratory tract complications are frequent, appear usually within the first two years, are closely related to chronic graft-versus-host disease (GVHD) and are often of poor prognosis. Cardiac and cardiovascular complications are mainly related to cardiotoxic chemotherapy and total body irradiation, and to the increase of cardiovascular risk factors. They appear very late after HSCT, with a low magnitude of risk during the first decade. However, their incidence might increase significantly with longer follow-up. The chronic kidney diseases are usually asymptomatic until end stage disease, occur within the first decade after HSCT, and are mainly related with the use of nephrotoxic drugs such as calcineurin inhibitors. We will discuss the practical screening recommendations that could assist practitioner in the follow-up of long-term survivors after HSCT.

Late complications are conditions appearing after the early phase of hematopoietic stem cell transplantation (HSCT) with clinical consequences on the long-term survivorship. Depending on the type of complication, the threshold between early and late might be set at different time points. Some of the complications with relevant late consequences can start as early as 3 months after HSCT, and other events will become apparent only years or even decades later. Here, we define as late complications all events occurring beyond 3 months (Figure 1), and separate them into delayed (3 months to 2 years), late (2 to 10 years) and very late events (>10 years). Late complications after HSCT are the consequence of the conditioning regimen, chronic graft-versus-host disease (GVHD) and its treatment, infectious complications, the treatments used before transplantation, and the pretransplant comorbidity. Many late complications, such as secondary cancer, cataracts, infertility, endocrine dysfunctions, or late bone and joint complications, have been well described. In theory, any organ can be the target of a late effect, and frequently multiple causes are involved. This review will focus on late pulmonary, cardiac and cardiovascular as well as renal consequences after HSCT. It will consider the involved risk factors and the recommended screening practices (Table 1).

Clinical manifestations, risk factors and interventions in pulmonary, cardiac, cardiovascular and renal late complications after hematopoietic stem cell transplantation (HSCT).

Sequence of appearance of pulmonary, cardiac, cardiovascular and renal complications after hematopoietic stem cell transplantation (HSCT), and main risk factors. Late complications are subdivided into delayed events (between 3 months and 2 years), late events (between 2 and 10 years), and very late events (> 10 years).

Delayed onset pulmonary complications involving both the airway and lung parenchyma are frequent after HSCT. They include infectious complications in immunocompromised hosts and noninfectious complications of the lung. The most common noninfectious late complications include bronchiolitis obliterans (BO), bronchiolitis obliterans organizing pneumonia (BOOP), and idiopathic pneumonia syndrome (IPS).1 BOOP/COP has also been termed cryptogenic organizing pneumonia (COP) in order to avoid confusion with airway diseases such as bronchiolitic obliterans syndrome (BOS).2 These pulmonary complications, belonging to the delayed events, appear usually within 3 months to 2 years after HSCT. However, the functional consequences often persist for years after HSCT. There are differences between autologous and allogeneic HSCT, particularly in respect of time of appearance. In autologous but not in allogeneic HSCT, pulmonary complications are unusual after 3 months. In a retrospective analysis, the 2-year cumulative incidence of delayed onset noninfectious pulmonary complications was 10% among 438 patients surviving more than 3 months, and 15.6% among those with chronic GVHD.3 The 5-year overall survival was significantly worse in patients with a pulmonary complication, compared to those without. In the unrelated HSCT setting, the incidence of delayed onset noninfectious pulmonary complications is higher and the clinical outcome of these patients worse.4 Chronic extensive GVHD and advanced-stage disease is associated with the development of delayed onset pulmonary complications.

Restrictive and obstructive ventilatory defects and gas transfer abnormalities are common after HSCT. A decrease in forced expiratory volume in 1 second (FEV1) and the FEV1/forced vital capacity (FVC) ratio is the hallmark of airflow obstruction. Restrictive defects are measured by the total lung capacity (TLC) and may be associated with impaired diffusing capacity for carbon monoxide (DLCO). Pulmonary function evaluated retrospectively in 69 patients with a minimum of 5-year follow-up after allogeneic HSCT showed a late decrease from baseline in 31 (45%) of the patients, with a restrictive pattern in 25, and an obstructive pattern in 6. Twelve of the 31 (38%) patients with abnormal pulmonary function were symptomatic.5 Abnormal pulmonary function before transplantation and chronic GVHD were independently associated with late decrease in pulmonary function compared with baseline. In children, a significant proportion have abnormal function tests after HSCT.6 They involve mainly abnormalities of DLCO and TLC, implying restrictive lung disease and diffusion abnormalities. Obstructive abnormalities are less frequently observed. In a prospective study of the Late Effects Working Party of the EBMT, cumulative incidence of lung impairment evaluated in 162 children by pulmonary function was 35% at 5 years. Chronic GVHD was the major risk factor for reduced lung function. In most children the deterioration of pulmonary function was asymptomatic.7

Bronchiolitis obliterans is a severe pulmonary manifestation characterized by a nonspecific inflammatory injury affecting primarily the small airways. At the initial stage, it is typically an obstructive respiratory disease (Figure 2A/ 2B; see Color Figures, page 495). At a more advanced stage, due to the progressive peribronchiolar fibrosis, BO often presents obstructive and restrictive functional changes. The incidence of BO varies widely in different reports, ranging between 0 and 48%. Among 2152 allogeneic HSCT recipients reported in 9 studies the incidence of BO was 8.3%.8 BO is strongly associated with chronic GVHD, suggesting that BO is a pulmonary manifestation of chronic GVHD.9 However, despite the fact that BO rarely develops in patients without GVHD, single cases of BO have been reported after autologous HSCT. Following peripheral blood progenitor cell transplantation patients were shown to have a 3-fold increase in the risk of BO compared with those who had bone marrow transplantation.10 Other potential risk factors include the use of methotrexate for GVHD prophylaxis, older age of the recipient and/or the donor, busulfan-based myeloablative conditioning, antecedent respiratory viral infection, and low levels of serum immunoglobulin.

The presentation of BO is usually insidious, with a median onset approximately 1 year post-HSCT. The main symptoms are dry cough, progressive dyspnea, and wheezing. Fever does usually not occur, unless there is a concomitant infection. Asymptomatic presentation with abnormal functional tests is observed in 20% of the cases. In the early stage chest X-ray is normal; thus, the presence of parenchymal changes suggests an infection or an unrelated process. In more advanced phases, evidence of hyperinflation may be found. High resolution computed tomography (HRCT) of the chest with inspiratory and expiratory images is the radiological procedure of choice to assess the structural changes in the lung with suspected BO. Pulmonary lobules with normal airways increase their density during expiration, while areas with obstructed airways and air trapping remain radiolucent. This provides a characteristic mosaic image that is highly suggestive of BO. The sensitivity to detect air trapping for the diagnosis of BO ranges between 74% and 91% and specificity between 67% and 94%.1113 The predictive negative value is higher than 90%. Hence, when no air trapping is seen on expiratory HRCT the diagnosis of BO is very unlikely. At the early stage, pulmonary function tests show air flow obstruction with decreased FEV1, normal TLC and DLCO. A > 20% decline in FEV1 from the pretransplant value, or < 80% of the predicted FEV1 should alert clinicians. Recently, an international workshop on chronic GVHD by the National Institutes of Health defined biopsy-proven BO as the only diagnostic criteria of chronic GVHD in the lung (Figure 2C; see Color Figures, page 495). BO is clinically diagnosed when the following conditions are met: (1) FEV1/FVC ratio < 0.7 and FEV1 < 75% of predicted value; (2) evidence of air trapping or small airway thickening or bronchiectasis in HRCT; and (3) absence of infection in the respiratory tract.14

There are no prospective clinical trials on the treatment of BO. So far, the therapeutical recommendations are mainly derived from retrospective studies and from expert opinion.8,15,16 The management is based on the treatment of chronic GVHD. Early detection and prompt immunosuppressive treatment are likely to contribute to a more favorable outcome. Inhaled corticosteroids with bronchodilatator have shown some utility in the management of obstructive airway disease after HSCT.17,18 Further treatment consists of high-dose, systemic corticosteroids and the institution or augmentation of immunosuppressive therapy. Corticosteroids in a dose of 1 to 2 mg/kg/day for 2 to 6 weeks remain the mainstay of the treatment. Higher doses of corticosteroids have not shown higher efficacy. Cyclosporine is often used concomitantly. The addition of a third immunosuppressive agent such as azathioprine, thalidomide, anti-thymocyte globulin, anti TNF-, or the use of macrolide antibiotics have been shown to be beneficial in some cases. Prevention of Pneumocystis jirovecii and the early treatment of superinfection is an important component of the treatment strategy. However, prognosis of patients with BO remains poor, and mortality remains high. In a majority of cases, death is attributed to progressive respiratory failure or opportunistic infections.

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Late Pulmonary, Cardiovascular, and Renal Complications ...

MD Stem Cells and Stem Cell Treatments

MD Stem Cellsis aconsultancy providing information, education, facilitationand access to advanced Stem Cell and Alternative Medicine treatments in the United States and Europe. We are now Collaborator and Study Director for the Stem Cell Ophthalmology Treatment Study- SCOTS - the largest and most comprehensive stem cell eye study registered with the National Institutes of Health. Please see the NIH website http://www.clinicaltrials.gov Identifier NCT 01920867. SCOTS is now recruiting and accepting patients.

Conditions eligible for the SCOTS trial include retinal diseases such as age-related macular degeneration (AMD), myopic macular degeneration, hereditary retinopathies such as Retinitis Pigmentosa and Stargardts, as well as selected inflammatory, vascular and traumatic conditions. Optic nerve diseases considered eligible include glaucoma, ischemic optic neuropathy, optic atrophy, optic neuritis and some trauma. The study is focused on the ocular tissue that has sustained damage and its potential for improvement rather than a specific disease entity.

MD Stem Cells and its staff do not provide medical evaluation, diagnosis, advice or treatment but rather act to connect interested patients with leading physicians and centers of excellence. We encourage you to carefully review the material presented and, should you have interest, complete the Contact Us form and we will be in touch shortly.

Disclaimer: The Stem Cell Ophthalmology Treatment Study or SCOTS is an open label, non-randomized efficacy study and no guarantees of specific improvements or visual results are being made. Any medical procedure carries risks as well as potential benefits. The SCOTS study has different treatment arms and our principle investigator assigns patients to minimize risk and maximize potential benefit. Depending on the arm chosen the risk of potential complications has been calculated to be from approximately 0.0008% to 5%.

Disclaimer: The Stem Cell Ophthalmology Treatment Study or SCOTS is an open label, non-randomized efficacy study and no guarantees of specific improvements or visual results are being made. Any medical procedure carries risks as well as potential benefits. The SCOTS study has different treatment arms and our principle investigator assigns patients to minimize risk and maximal potential benefit. Depending on the arm chosen the risk of potential complications has been calculated to be from approximately 0.0008% to 5%. - See more at: http://www.mdstemcells.com/SCOTSQuestionsonstemcells.html#sthash.VO6wDC9d.dpuf

Disclaimer: The Stem Cell Ophthalmology Treatment Study or SCOTS is an open label, non-randomized efficacy study and no guarantees of specific improvements or visual results are being made. Any medical procedure carries risks as well as potential benefits. The SCOTS study has different treatment arms and our principle investigator assigns patients to minimize risk and maximal potential benefit. Depending on the arm chosen the risk of potential complications has been calculated to be from approximately 0.0008% to 5%. - See more at: http://www.mdstemcells.com/SCOTSQuestionsonstemcells.html#sthash.VO6wDC9d.dpu

MD Stem Cells 412 Main Street, Suite I Ridgefield, CT 06877 USA Tel:203-423-9494 Fax: 203-905-6800 Email: info@mdstemcells.com

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MD Stem Cells

June 26, 2015

Lymphocyte recovery in related and unrelated stem cell transplant recipients generally falls into three patterns that are significantly associated with survival, according to findings from a phase 2 clinical trial published in Biology of Blood & Marrow Transplantation (2015; 21[7]:1237-1245).

This first-of-its-kind research continues the efforts of principal investigator Amir Toor, MD, of the Virginia Commonwealth University Massey Cancer Center in Richmond, to understand the immune system as a dynamical system that can be modeled to improve stem cell transplantation.

"We began considering lymphocyte reconstitution following stem cell transplantation as similar to population growth models. So, we graphed the lymphocyte counts of our patients at various times following their transplant as a logistic function and observed distinct patterns that correlated with clinical outcomes," said Toor.

"Our goal is to use this data to develop models that can predict complications from stem cell transplantation. Then, we may be able to intervene at key points in times with appropriate clinical treatments that will make the most positive impact on patients' outcomes."

The study retrospectively examined lymphocyte recovery and clinical outcome data from a recent phase II clinical trial (Clinical trials.gov identifier NCT00709592) in which 41 patients received a stem cell transplant from related or unrelated donors.

As part of the clinical trial protocol, the patients underwent low-dose radiation therapy and received one of two different doses of antithymocyte globulin (ATG), an immune-modulating drug given before transplantation to guard against graft-versus-host-disease (GVHD). GVHD is a condition that occurs when immune cells from the donor attack the recipient's body.

Following transplantation, the researchers observed that the patients' lymphocytes recovered in one of three general patterns that correlated significantly with survival, relapse, GVHD, and the need for further donor immune cell infusions to treat the cancer.

Group A experienced fast, early lymphoid expansion, culminating in a high absolute lymphoid count (ALC) within 2 months of transplantation. Group B experienced a slower, but steady lymphoid expansion that peaked much later than group A with a lower ALC. Group C experienced very poor lymphocyte recovery that demonstrated an early, but brief lymphoid expansion with a very low ALC.

Group B had the best clinical outcomes with a survival rate of 86%, followed by group A with a survival rate of 67% and group C with 30% survival. Relapse rates between groups A and B were similar at 33% and 29%, respectively, while group C experienced a 90% relapse rate.

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Patients at risk for stem cell transplant complications ...

Amir Toor, M.D., hematologist-oncologist and member of the Developmental Therapeutics research program at VCU Massey Cancer Center is pictured. Credit: VCU Massey Cancer Center

Researchers at VCU Massey Cancer Center's Bone Marrow Transplant Program have recently published findings from a phase 2 clinical trial that demonstrate lymphocyte recovery in related and unrelated stem cell transplant recipients generally falls into three patterns that are significantly associated with survival. This first-of-its-kind research continues the efforts of principal investigator Amir Toor, M.D., to understand the immune system as a dynamical system that can be modeled to improve stem cell transplantation.

"We began considering lymphocyte reconstitution following stem cell transplantation as similar to population growth models. So, we graphed the lymphocyte counts of our patients at various times following their transplant as a logistic function and observed distinct patterns that correlated with clinical outcomes," says Toor, the lead investigator of the study and hematologist-oncologist and member of the Developmental Therapeutics research program at VCU Massey Cancer Center. "Our goal is to use this data to develop models that can predict complications from stem cell transplantation. Then, we may be able to intervene at key points in times with appropriate clinical treatments that will make the most positive impact on patients' outcomes."

The study, recently published in the journal Biology of Blood & Marrow Transplantation, retrospectively examined lymphocyte recovery and clinical outcome data from a recent phase 2 clinical trial (Clinical trials.gov identifier - NCT00709592) in which 41 patients received a stem cell transplant from related or unrelated donors. As part of the clinical trial protocol, the patients underwent low-dose radiation therapy and received one of two different doses of anti-thymocyte globulin (ATG), an immune-modulating drug given to guard against graft-versus-host-disease (GVHD) before transplantation. GVHD is a condition where the donor's immune system attacks the recipient's body. Following transplantation, the researchers observed that the patients' lymphocytes recovered in one of three general patterns that correlated significantly with survival, relapse, GVHD and the need for further donor immune cell infusions to treat the cancer.

Group A experienced fast, early lymphoid expansion, culminating in a high absolute lymphoid count (ALC) within two months of transplantation. Group B experienced a slower, but steady lymphoid expansion that peaked much later than group A with a lower ALC. Group C experienced very poor lymphocyte recovery that demonstrated an early, but brief lymphoid expansion with a very low ALC. Group B had the best clinical outcomes with a survival rate of 86 percent, followed by group A with a survival rate of 67 percent and group C with 30 percent survival. Relapse rates between groups A and B were similar at 33 and 29 percent, respectively, while group C experienced a 90 percent relapse rate. GVHD was observed in 67 percent of patients in group A, 43 percent of patients in group B and 10 percent of patients in group C. Finally, adoptive immunotherapy with donor cell infusions was required for 13 percent of patients in group A, 21 percent in group B and 70 percent in group C.

The discovery of these patterns in lymphocyte recovery build on prior research by Toor and his team that supports the concept of the immune system working as a dynamical system. In 2013, the Massey Bone Marrow Transplant Program's research team and Massey researcher Masoud Manjili, D.V.M., Ph.D., sequenced DNA from the T cells of 10 stem cell transplant recipients and their donors and found a fractal, self-repeating pattern in the participants' T cell repertoires. This discovery suggested that physicians could potentially sequence the DNA of patients after they undergo stem cell transplantation and predict potential GVHD complications based on the pattern in which their T cell repertoire is developing. Another study of the same participants in 2014 also used whole exome sequencing and found significant variation in minor histocompatability antigens (mHA, which are receptors on the cellular surface of donated organs that are known to give an immunological response in some organ transplants) between the donor-recipient pairs. This variation represents a large and previously unmeasured potential for developing GVHD for which conventional human leucocyte antigen (HLA) testing, the test that matches stem cell transplants with donors, does not measure. This large library of immune targets, in turn, can serve to drive immune complications of transplantation such as GVHD or graft rejection.

Currently, physicians use stochastic models to determine the probability of a patient developing GVHD based on HLA test results. Stochastic models are not precise because they estimate probability by allowing for random variation in one or more variables. Dynamical system modeling, on the other hand, would account for the key variables influencing transplant outcomes and their evolution over time, allowing physicians to personalize therapy based on the extent of a patient's immune recovery following transplantation.

"We've uncovered order in the structure of the immune system, we've found new variables influencing GVHD and we've now shown patterns in lymphocyte reconstitution that identify at-risk patients," says Toor. "Now, we are working to put it all together and develop a model of immune system reconstruction following stem cell transplantation that will allow physicians to make more informed treatment decisions."

Explore further: Predicting the storm: Can computer models improve stem cell transplantation?

More information: Biology of Blood & Marrow Transplantation, http://www.sciencedirect.com/science/ ii/S1083879115001834

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Researchers identify patients at risk for stem cell ...

Submitted By:JasonWaterman, M.D.

Published online: January 2009

Autologous stem cell transplantation (ASCT) is now commonly used to treat a variety of illnesses including multiple myeloma, Hodgkins lymphoma, and non-Hodgkins lymphoma (see Stem Cell Transplant by Dr. Matt Kalaycio http://www.cancernews.com/data/Article/258.asp). The transplant process has multiple steps including preparation prior to transplant, the transplant with post-transplant hospital observation, and long-term observation. Each step in the process has its own complications, and thus requires close monitoring to quickly identify and treat any problems. This article focuses specifically on the identification and management of complications of ASCT.

Prior to autologous transplantation a thorough evaluation will take place by an oncologist including a history and physical examination, lab testing, imaging, bone marrow biopsy, and a social work consultation to determine a patients readiness for transplantation. Once a decision to pursue transplantation is made, a sufficient number of the patients stem cells are collected in order to have enough stem cells to reestablish the immune system after transplantation.

To make the collection of stem cells easier, the patient is given a medication called granulocyte-colony stimulating factor (G-CSF) for 4-5 days prior to collection to stimulate the bone marrow to produce and release more stem cells into the blood stream. Certain chemotherapy agents may also be used in this process to ensure that the highest possible number of stem cells are collected. The stem cells can be taken from the bone marrow or from the peripheral blood.

Collection of stem cells from the bone marrow proceeds just like a bone marrow biopsy and the extracted liquid marrow then undergoes processing to isolate the stem cells needed for transplantation. The process used to collect the stem cells from the blood is called leukopheresis. Leukopheresis involves taking blood from a patients vein and passing it through a machine that will remove the stem cells needed for transplant before returning the blood back to the patient through the vein. Either process takes a few hours and may need to be repeated in order to collect enough stem cells.

Stem cell collection is most often done as an outpatient procedure and generally results in few complications, which are mostly mild and easily reversible. The most common complications of leukopheresis include a drop in blood pressure (hypotension), dizziness, numbness and tingling, nausea, vomiting, and fever. Bone marrow collection can also be complicated by soreness and bleeding at the site of collection, which rarely requires blood transfusion. Treatment for hypotension and dizziness is usually accomplished by giving the patient intravenous fluids to bolster the blood pressure during the collection. Calcium is infused if numbness and tingling occur. Nausea and vomiting are common and multiple medications are available for treatment. Fevers are common, generally mild, and most often short-lived. Fevers associated with stem cell collection frequently respond to acetaminophen, although a small number of patients may need to have their blood evaluated to make sure there is no underlying blood stream infection.

When enough stem cells have been collected and it is time for transplantation, the patient is admitted to the hospital and begins a process called conditioning, or myeloablation. The goal of conditioning is to destroy the cancer cells in the body by administering high doses of chemotherapy with or without radiation therapy. The most dangerous side effect of conditioning is that the patients natural immune system is destroyed in the process. This is the portion of the transplant process which is the most important in terms of outcome for the patient, because complications at this stage of transplant are potentially fatal. The next step is then the infusion of stored stem cells back into the patients blood stream to regenerate the patients natural immune system.

Short-term side effects from the actual transplantation of stem cells include fever, chills, hives, chest tightness, hypotension, and coughing. Usually these are mild, and the transplant is rarely stopped because of these symptoms. Once in the blood stream, the stem cells travel to the bone marrow where they will stay and begin to produce all the bodys different blood cells in a process called engraftment. The process of engraftment can take 2-4 weeks, and full reestablishment of the immune system may take several months. The common complications during engraftment revolve around the lack of appropriate numbers of blood cells from the conditioning process, as well as toxicities from the conditioning agents themselves.

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Complications of Autologous Stem Cell Transplantation

By Judith Sachs WebMD Feature

Reviewed by Arnold Wax, MD

WebMD Archive

Having a stem-cell transplant is a major challenge for your body. As you recover in the first weeks and months, you are likely to feel fatigued and weak. Certain side effects, like flu-like symptoms, nausea, and a changed sense of taste, are common. Try to be patient: You're building a brand-new immune system, and this takes time. Your doctors will monitor you closely and give you medications to prevent problems.

Along with these typical side effects, you may experience complications. Some come from the high-dose chemotherapy and radiation that may be part of the transplant process. (These may be less likely if you have had a "mini-transplant" with low-dose chemotherapy and radiation.) Other complications are caused by your body's attempts to reject donor stem cells.

Overview

Laetrile is a compound that contains a chemical called amygdalin. Amygdalin is found in the pits of many fruits, raw nuts, and plants (see Question 1). It is believed that the active anticancer ingredient in laetrile is cyanide (see Question 1). Laetrile is given by mouth as a pill or by intravenous injection (see Question 4). Laetrile has shown little anticancer effect in laboratory studies, animal studies, or human studies (see Question 5 and Question 6). The side effects of laetrile...

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The most common complications are:

Less often, some patients experience cataracts, infertility (if total-body radiation is given), and new, secondary cancers, sometimes as long as a decade after the original cancer.

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Complications of Stem Cell Transplants - WebMD