Each issue of the CoramClick provides an in-depth focus on timely and practical solutions. In this issue of the Click, we are focusing on Blood Diseases and Disorders. Back issues of the Click are available in the CoramClick archive for easy reference!

	IVIg in Blood Cell Transplantation An expected consequence of post-blood cell transplantation is a significantly decreased level of neutrophils, a type of white blood cell essential to fighting against bacterial infection, and T and B cells, critical components of the infection-fighting immune system.	ICD-9 Codes A list of widely used ICD-9 codes relevant to blood diseases and disorders. Resource Center Helpful resources and information focused on blood diseases and disorders. Subscribe to the CoramClick Please include your email address, first and last name, and company name.
	Hemophilia Overview Hemophilia is a hereditary disorder in which one of the proteins that causes blood to clot is missing or reduced. This causes a delay in blood clotting and results in prolonged bleeding. Hemophilia occurs in about one out of every 5,000 U.S. males.
	Lyme Disease – Facts About Borrelia burgdorferi There is significant controversy among clinicians, patients and organizations regarding the incidence and treatment of the long-term effects of Lyme disease. As a result, antibiotic therapy versus only symptomatic therapy is unclear.

IVIg in Blood Cell Transplantation

An expected consequence of post-blood cell transplantation is a significantly decreased level of neutrophils, a type of white blood cell essential to fighting against bacterial infection, and T and B cells, critical components of the infection-fighting immune system. In fact, infection continues to be a leading cause of morbidity and mortality in the blood cell transplant population. It typically takes months for the new immune system to fully take hold, and during that time, infection prevention is a clinical priority. Infection prevention includes: pre-transplant donor selection, prophylactic post-transplant anti-infective administration, isolation precautions, the administration of growth factors and the immunosuppressive medication protocols aimed at preventing acute or chronic graft-versus-host disease (GVHD).

Intravenous immunoglobulin (IVIg) is FDA approved for indicated bone marrow transplant recipients at least 20 years of age to decrease the risk of septicemia and other infections, interstitial pneumonia of infectious or idiopathic causes and acute GVHD in the first 100 days post-blood cell transplant.

For infection, prophylaxis IVIg provides passive immunity against bacteria, fungus and viruses, thus decreasing the risk and potentially the severity of infection. Cytomegalovirus (CMV) is one of the more common causes of viral infection in the blood cell transplant patient, and IVIg that is high in CMV antibodies (Cytogam^®) may be specifically used to prevent and/or treat this infection. IVIg is often indicated for patients with respiratory syncytial virus (RSV) as well.

Increasingly, IVIg is recognized as a valuable infectious prophylaxis in transplant patients who are markedly hypogammaglobunemic (serum IgG levels < 400 mg/dL).

Graft-Verus-Host Disease

IVIg is also considered by some as an immune-modulator capable of decreasing the development of acute graft-versus-host disease (GVHD). Acute GVHD is clinically significant because of its own morbidity and mortality portfolio. Because a history of acute GVHD increases the risk for chronic GVHG, it’s often a debilitating and life-threatening post-allogeneic transplant complication.

IVIg may be indicated for treatment of steroid-resistant GVHD, particularly in patients who are hypogammaglobunemic.

Administration protocols vary, but often include 500mg/kg on transplant day seven and again on day one. Some protocols call for that same dose on the day of transplant. Post-transplant, IVIg is often administered weekly until day 90 to 100. Long-term maintenance administration may be required in patients who remain hypogammaglobunemic.

Hemophilia Overview

Hemophilia is a hereditary disorder in which one of the proteins that causes blood to clot is missing or reduced. This causes a delay in blood clotting and results in prolonged bleeding. Hemophilia occurs in about one out of every 5,000 males born in U.S. A person with hemophilia does not bleed any faster than normal — the bleeding just doesn’t stop, so he bleeds longer than someone without hemophilia.

There are two types of hemophilia:

• Hemophilia A is a deficiency of factor VIII and accounts for 80 percent of the hemophilia population
• Hemophilia B is a deficiency of factor IX and accounts for 20 percent of the hemophilia population
  

Classifying the Severity of Hemophilia

Severity of hemophilia A or B depends on the amount of the factor activity in the blood. The normal range for factor VIII and factor IX is 50 to 150 percent.

• Severe hemophilia causes the person to have less than 1 percent of factor activity. They will have frequent bleeding occurring two to three times per week.
• Moderate hemophilia causes the person to have a factor activity level between 1 and 5 percent. Their bleeding episodes occur less frequently, such as a few times per month.
• Mild hemophilia causes the person to have a factor VIII or IX activity level between 5 and 30 percent. Their bleeding episodes usually occur with trauma or surgery. These patients may not be diagnosed until later in life, such as in their teenage or young adult years.

Genetics

Hemophilia is carried on the X chromosome; therefore, it is a sex-linked genetic disorder. This manifests in the female being the carrier and males inheriting hemophilia. Both hemophilia A and B are inherited the same way. There is a 30 percent mutation rate; therefore, these patients have no family history of hemophilia.

Bleeds

The most common sites for bleeding to occur are in the joints and muscles, but bleeding can occur anywhere in the body. These bleeding episodes occur internally with only external signs such as swelling, decrease range of motion and pain. Serious and potentially life-threatening bleeding sites are in the head, neck/tongue, spinal cord and abdominal area.

The most important part of treating hemophilia is to recognize bleeding episodes early and to treat them right away. By controlling and stopping the bleed, you can speed up recovery and reduce complications.

Treatment

Since there is no cure for hemophilia, the current treatment is to replace the missing clotting factor in the blood. Factor replacement therapy needs to be given as soon as a bleed is determined to prevent joint destruction and/or to prevent further pressure to the surrounding organs or tissues.

Giving factor as prophylaxis (a preventive measure) is a recommended therapy for pediatrics to preserve the joints from the destruction that occurs when bleeds occur in the joints. Prophylaxis is also useful when there is an activity which might cause a bleed — such as a school field trip or a special occasion.

Factor replacement products are classified as either plasma derived or recombinant. Plasma derived products are manufactured from human plasma which is then purified and made into a freeze-dried concentrated product.

Recombinant products were first approved in 1992, and are classified as non-plasma derived factor. These products are produced in a lab. The new generations of the recombinant products do not use any human plasma products.

Complications

Hemophilic Arthropathy

Hemophilic arthropathy is the result of having repeated bleeds in a given joint. Each time there is a bleed in a joint, damage to the cartilage is caused by the residual iron that is left behind as well as the enzymes that are secreted to break down the blood so it can be reabsorbed out of the joint space. Synovitis is caused by the repeated need to clean up the blood that accumulates in the joint with each bleed. Prophylaxis is the way to prevent bleeds, thereby preserving the joints. Quick and adequate treatment is necessary to prevent increased damage.

Inhibitors

An inhibitor is a major complication to the treatment of bleeds. The body sees the factor as a foreign protein which does not belong in the body; therefore, it neutralizes the factor so it cannot work. This occurs mostly in patients who have severe hemophilia. When a person with an inhibitor has a bleed, their regular dose of factor will not be able to stop the bleed properly, and a special treatment plan is needed.

The incidence of inhibitor development in those with factor VIII is about 30 percent and in the factor IX population it is about three percent. This antibody (inhibitor) is measured in Bethesda units. A routine screening for this antibody is done at the patient’s annual comprehensive visit. An inhibitor can develop at any time which manifest as a bleed that does not respond to treatment.

There are two types of inhibitors — low and high responding. Low responding inhibitors usually can be managed with a higher than normal dose of factor to override the antibody and control the bleeding episode. High responding inhibitors are much more difficult to manage. These patients require the use of special factor products which are manufactured to work in the clotting cascade as a bypassing agent. These products bypass the factor VIII sector of the cascade and activate factor X. This process causes a clot to form — even though it is not a strong, stable clot, it does stop the bleeding.

An immune tolerance program is a process to rid the body of the inhibitor antibody. This program requires daily infusions of factor VIII for over several months to two years. When the inhibitor antibody has disappeared, the patient is has now returned to being “a normal hemophilia person” and can use factor VIII for bleeding episodes. Not all inhibitor antibodies will respond to this program, and these patients will need to continue using the special inhibitor products for their bleeding episodes.

Factor IX inhibitor antibodies are much more difficult to manage and are usually treated with novo VII. These patients have a high incidence of severe reactions to factor IX so they are usually not treated with factor IX. Factor IX babies are given their first 10–20 infusions in a controlled environment because of the possible reaction to the factor IX if they are developing an inhibitor.

Hepatitis

Hepatitis A has a vaccine available and is given to persons with hemophilia. Hepatitis B has a vaccine available and is part of the immunization. Hepatitis C is the most common cause of liver disease in persons with hemophilia. Those who used factor VIII before 1987 and factor IX before 1990 had a higher rate of incidence of Hepatitis C.

Treatment Products

Lyme Disease – Facts About Borrelia burgdorferi

Lyme disease is a bacterial infection, caused by the spirochete Borrelia burgdorferi and transmitted by a tick bite. It is the most common tick-borne disease and the most rapidly emerging of all vector-borne diseases. Lyme disease can invade multiple systems in the human body, giving rise to a wide variation of symptoms and disabilities.

Nature’s reservoir for B. burgdorferi is the white-footed mouse. The deer tick acquires the spirochete by feeding on the mouse. B. burgdorferi is transferred to humans when the infected tick attaches to the person’s skin (transmission of infection typically requires attachment for more than 36 hours). The B. burgdorferi spirochete can then cause infection in the person, i.e. Lyme disease.

The numbers of reported cases of Lyme disease have increased dramatically over the decades. For example, in 1992 when the Centers for Disease Control and Prevention (CDC) first started tracking Lyme disease, about 10,000 cases were reported. That number has increased to 28,921 confirmed cases (plus 6,277 probable) cases in 2008, a 5 percent increase in confirmed cases as compared to 2007. It is estimated that only about 10 percent of the cases of Lyme disease are actually reported to the CDC, thus the incidence is likely much higher.

Lyme disease has been reported in every state in the US, with the greatest numbers (approximately 95 percent) seen in 10 key states: along the east coast and in Minnesota and Wisconsin.

Risk Factors for Lyme Disease

Life Cycle of the Deer Tick Ticks have a two-year life cycle from egg to adult. Nymphs and adults are primarily responsible for transmission of B. burgdorferi to susceptible hosts. In the spring, a tick’s eggs hatch into a larvae. Larvae feed and molt into nymphs. Nymphs feed and molt into adults. So, nymphs that feed in the fall and spring, become feeding adults throughout the next year.

Since Lyme disease is transmitted via the deer tick, risk factors for infection center on exposure.

• Growing populations of deer that support the tick
• Increased residential development of wooded areas where Lyme disease is endemic
• Outdoor work and/or recreational activities in areas where Lyme disease is endemic

Infections are most likely to occur in the spring and summer with the greatest spike in June and July. Fewer cases are reported in the cooler months (October–April) for a number of probable reasons:

• In the spring , there are a greater number of nymphs feeding, and therefore, infecting
• People tend to be outdoors more in the spring and summer so they have a greater risk of exposure
• While adult ticks are twice as likely to be infected — since they fed as nymphs and again as adults — they are larger than the nymphs and more likely to be spotted and removed prior to spirochete invasion

Diagnosis

There are no completely reliable diagnostics for Lyme disease. The results of serological testing, e.g.: indirect immunoflourescence assay (IFA), enzyme-linked immunosorbant assay (ELISA), a Western blot, and/or polymerase chain reaction (PCR), are often unreliable and should be used to support rather than make a diagnosis. Diagnosis is primarily based on clinical symptoms and a history, if known, of a tick bite.

Clinical Symptoms

Signs and symptoms of Lyme disease vary between individuals and depending on the stage of infection.

• Stage 1 – asymptomatic tick bite
• Stage 2 – early, localized infection. Within a few days to a month:
  • Erythema migrans
  • Recurrent flu-like symptoms
  • Head, muscle and joint aches
  • Nausea and vomiting
  • Sore throat, swollen glands, stiff neck
• Stage 3 – early, disseminated infection. Several weeks to months after infection:
  • Skin
  • Headache, stiff neck
  • Musculoskeletal
  • Joint, muscle, tendon pain
  • Neurological
  • Cranial neuropathy
• Stage 4 – late, persistent infection. Four months to years later:
  • Musculoskeletal
  • Central/peripheral nervous system
  • Subacute encephalopathy
  • Nerve tingling or pain
  • Neurosensory sensations
  • Panic, anxiety, depression

Treatment

Treatment decisions depend on the stage of illness and presenting symptoms; however, there is no cure for Lyme disease. Fortunately, prompt recognition and antibiotic treatment almost always assure rapid improvement with minimal likelihood of later complications.

The Infectious Disease Society of America (IDSA) has developed guidelines to support treatment decisions which include the following:

1. No antibiotic treatment or single dose doxycycline if:
   • An identifiable tick was attached for more than 36 hours and treatment was initiated within 72 hours
   • Monitored closely for 30 days, treat if symptoms development
2. Oral antibiotic treatment for 10 to 21 days if it is still early in the disease process:
   • Tetracyclines (doxycycline) most common
   • Amoxacillin or cefuroxime are also options
3. IV antibiotics for 14 to 28 days for patients who do not respond to oral antibiotics or who have multi-systemic effects:
   • Ceftriaxone, cefuroxime, penicillin G
   • Combination therapy is increasingly used for refractory Lyme disease
4. Combination therapy is increasingly used for refractory Lyme disease

Some clinicians recommend that the duration of therapy be guided by clinical, not by a prescribed treatment course, and in cases of persistent Lyme disease, several months of antibiotics may be required.

Recurrent disease can develop, most likely due to a failure to eradicate the organisms. Early and aggressive antibiotic treatment is indicated for recurrence.

Prevention

The best method for disease prevention is, of course, to avoid a tick bite. Preventive activities include:

• Avoiding endemic areas, especially during spring and summer months
• Appropriate clothing — light-colored; long-sleeved shirts; long pants tucked into high rubber boots
• Age appropriate concentrations and application of DEET
• Self-inspection
• Safe, effective tick removal

Chronic Lyme Disease: The Controversy Behind Treatment Regimens

There is significant controversy among clinicians, patients and organizations regarding the incidence and treatment of long-term effects of Lyme disease. Unfortunately, there is no consensus on the definition of chronic Lyme disease, making scientific conclusions regarding incidence, prevalence and pathogenesis difficult. As a result, the impact of long-term antibiotic therapy versus only symptomatic therapy is unclear.

Symptoms

Often termed Post-Lyme Disease Syndrome (PLDS), post-treatment chronic Lyme disease or chronic Lyme disease, there are a significant number of patients whose symptoms do not abate, even months to years after antibiotic treatment. The course is typically variable with indolent onset. The challenge is in determining if the symptoms are in fact secondary to a previous Lyme disease infection or are simply complaints typical of and no less frequently reported than the general population.

It is expected that with appropriate treatment of Lyme disease there will be no long-term negative sequelae. When patients continue to present with late and/or persistent symptoms, several contributing factors have been proposed, including:

• Non-compliance with prescribed antibiotic treatment
• Delayed diagnosis and/or treatment of initial B. burgdorferi infection
• Residual damage
• Slow resolution of the inflammatory process
• Tick-borne co-infections

Multiple studies have shown that long-term antibiotic use does not improve symptoms. Given the lack of evidence to support symptom improvement, organizations such as the IDSA and the National Institute of Allergy and Infectious Diseases (NIAID) do not consider longer-term antibiotic therapy to be effective, and therefore, we do not recommend it.

Conversely, a notable group of patients and clinicians consider Lyme disease in some patients to remain an active infection and become persistent, recurrent and/or refractory, even after initial antibiotic therapy. Many experts believe that persistent disease may require treatment with repeated and prolonged antibiotics and, in fact, the duration of antibiotics should be lengthened to prevent or delay recurrent or refractory Lyme disease. They report notable symptom improvement when long-term antibiotics are administered. The controversy will likely not be settled until a clear definition of “chronic” Lyme disease is made and specific controlled studies support evidence-based treatment decisions.

Common ICD-9 Codes

The following ICD-9 codes are associated with diagnosing blood diseases and disorders. Please note, this information is not all-inclusive and ICD-9 codes are updated on a regular basis. Always check that you are using the current and correct code by visiting our ICD-9 Code resource page.

Resource Center

• Basic Concepts of Hemophilia: A Self-Study and Planning Workbook for Families with a New Diagnosis of Hemophilia (PDF): www.cdc.gov/ncbddd/hbd/documents/ProviderGuide.pdf
• Hemophilia Handbook, published by Hemophilia of Georgia:
  www.hog.org/publications/page/the-hemophilia-handbook-2
• Infectious Disease Society of America: www.idsociety.org
• International Lyme and Associated Diseases Society: www.ilads.org
• National Hemophilia Foundation: www.hemophilia.org
• National Institute of Allergy and Infectious Diseases at the National Institutes of Health:
  www.niaid.nih.gov
• The Centers for Disease Control and Prevention (CDC): www.cdc.gov
• The Lyme Disease Foundation: www.lyme.org

References

• ¹Wormser, GP, Dattwyler, RJ, Shapiro, ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical practice guidelines by the Infectious Disease Society of America. Clinical Infectious Diseases, 2006; 43:1089-1134.
  
• ²www.guideline.gov/summary/summary.aspx?doc_id=4836&nbr-3481&string=Lyme. Retrieved 4/21/2009.
  
• ³www.canlyme.com/treatment.html. Retrieved 4/21/09.
  
• ⁴www3.niaid.nih.gov/topics/lymeDisease/understanding/chronic.htm Retrieved 4/21/09
  
• ⁵www.cdc.gov. Retrieved 4/21/09.

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