Treatment of WAS
Coping with WAS
Symptoms of WAS
Symptoms of WAS vary significantly between patients and even between patients in the same family. Some patients show symptoms soon after birth whereas in others, symptoms are only seen in late infancy. The severity of the bleeding, infections and eczema correlate with the WASp present in the cells1 i.e. WASp positive patients have milder symptoms whereas WASp negative patients have more serious symptoms. Patients with XLT have a lower incidence of malignancies and autoimmune disorders as compared with patients with Classic WAS1.
Most, but not all patients with WAS, regardless of the severity of the disease have microthrombocytopenia(small platelets and a reduced number of platelets) with a slightly shortened platelet life span. When there is an injury, platelets are the first of several clotting factors that help to stop the bleed. When there is a significant reduction in the number of platelets, the bleeding time is prolonged and these patients can bleed in various parts of the body including the skin, nose, intestines and the brain. The bleeding can be spontaneous or as the result of an injury. The bleeding in the skin is in the form of purpura which are red or purple discolorations measuring 0.3-1cm, under the skin or inside the mouth. Petechiae are purpura which appear as pin-head sized red or blue dots and measure less than 3 mm. Ecchymoses are those discolorations from bleeding that measure greater than 1 cm. These boys can have prolonged bleeding after circumcision, bleeding from the gum especially after the loss of a tooth and prolonged bloody noses. Hematorrhea, especially during infancy is often the presenting symptom. Internal bleeding, such as in the brain, liver or spleen can be life threatening due to serious blood loss.
The number and size of platelets are similar in XLT and Classic WAS, approximately 36 x 10^9/L (36,000/cu.mm)1. Petechiae are usually the first symptom noted in patients with XLT whereas hematorrhea is often the first symptom in patients with Classic WAS. The number of fatal episodes of hemorrhage such as intracranial bleeding or intestinal bleeding was noted to be four times higher in patients who were WASp negative (see table below). In a more recent study of XLT patients2 the incidence of serious hemorrhage was 13% with a sixth of them being fatal.
WASp-positive numbers represent WASp detectable by Western blot. WASp-negative numbers represent WASp found absent or truncated by Western blot. PAlgG indicates platelet-associated lgG; and —, not applicable.
* BM megakaryocyte indicates number of bone marrow megakaryocytes per microliter BM aspirate. For BM megakaryocyte subrows, normal or increased indicates more than 50/µL; decreased, 20-50/µL; and undetectable, less than 20/µL.
+ Not significant.
Patients with Classic WAS have a significant defect in their immune system which affects the function of their T and B lymphocytes. The B lymphocytes are the white blood cells that are responsible for producing antibodies (immunoglobulin) against bacteria and viruses. These patients therefore have frequent and severe bacterial infections ranging from ear infection and sinusitis to more severe infections such as pneumonia, meningitis and bacterial infection of the blood (sepsis). They are particularly susceptible to infections with bacteria that have a capsule covering them (encapsulated) such as the Pneumococcus and Hemophilus influenzae. The infections usually start between 3-6 months of age when the defense acquired from the mother prior to birth begins to wane. The immune function tends to decline over the years with infections becoming more serious and frequent.
The T-lymphocytes help the body to fight off fungal, viral and parasitic infections. T-lymphocytes are also responsible for the regulation and coordination of the immune system. Therefore these children have frequent and recurrent viral infections such as with the herpes virus. One study noted serious infections1 such as encephalitis and hepatitis with cytomegalovirus (CMV). When patients with WAS have infection with Epstein Barr Virus their immune system often is unable to clear the infection completely from the body. Infection with this virus is common, with over 95% of the world population being infected. It causesinfectious mononucleosis, commonly referred to as mono or glandular fever. Patient usually have a sore throat, fever and swollen lymph nodes. Because these patients are unable to clear the virus completely from their immune system, it makes them more susceptible to lymphoma's associated with this virus. They are more susceptible to fungal and opportunistic infections, especially those caused by Candida and Aspergillus and Pneumocystis jirovecii.
Patients who are on preventative medication1 for Pneumocystis (Bactrim), Aspergillus, Candida (oral anti-fungal agent such as fluconazole) and herpes virus (Acyclovir) were noticed to have a reduced rate of infection. This underscores the importance of starting preventative medication early on in infancy in patients with severe WAS.
Patients with XLT have a milder course with a fourth of the number of bacterial infections and viral infections as the severely affected patients and lesser number of infections with fungi as well.
WASP expression and infections
WASP-positive numbers represent WASP detectable by Western blot. WASP-negative numbers represent WASP found absent or truncated by Western blot. — indicates not applicable.
* WASP-positive patients: CMV hepatitis (n = 3), severe varicella (n = 1). WASP-negative patients: CMV encephalomeningitis (n = 2), measles pneumonitis (n = 2), mumps meningitis (n = 2), EBV reactivation (n = 1).
WASP-positive patients: molluscum contagiosum infections (n = 1), recurrent herpes zoster (n = 1). WASP-negative patients: HSV infections (n = 13), molluscum contagiosum infections (n = 4).
Fungal infections: aspergillosis (n = 3), candidiasis (n = 9), and P carinii pneumonia (n = 2).
WASP-positive patients: trimethoprim-sulfamethoxazole (ST) + amphotericin B (AMPH) (syrup) + acyclovir (ACV, orally) + vancomycin (orally). WASP-negative patients: 12 ST + AMPH (syrup), 1 ST, 2 antibiotics (rifampicin, kanamycin), 1 fluconazole, 1 ACV (orally).
|| Not significant.
Eczema and Allergies
Patients with WAS tend to have allergies. These can be in the form of food allergies, asthma, hay fever or dermatitis. Patients with Classic WAS tend to have severe eczema which can be persistent and difficult to control whereas patients with XLT have milder and transient eczema which is easier to control. Eczema occurs in up to 80% of patients3 with WAS. Eczema usually starts in infancy as red, dry, itchy, scaly skin with cracks behind the ears and rashes on the cheeks, arms and legs. It can manifest as "cradle cap" on the scalp or a diaper rash. In older boys it may be limited to the skin behind the knees, in front of the elbows and around the neck or it can affect the skin all over the body. There is intense itching associated with this disease and patients can itch until they bleed. Night time itching can disrupt sleep.
Several factors can cause a flare up of eczema such as dry skin, allergens, chemical irritants, stress, heat and sweating. These patients are not tolerant to very high or very low temperatures. High heat and humidity makes them sweat causing a prickly heat like phenomenon. Low temperatures, especially during the winter months when the homes are heated, causes flares. Exercise with the resultant sweating can aggravate the dermatitis. Emotional stresses such as frustration, anger or anxiety can be triggers. Food allergens and chemical irritants are trigger factors and their identification and elimination is important to control of eczema. Courtesy: www.topnews.in/health/files/eczema1.jpg
There is a higher incidence of autoimmune disorders seen in both, the XLT and Classic WAS patients. This is due to the disregulated immune system which reacts against parts of the patients own body. The risk of developing an autoimmune disorder increases with age. In a study of a 154 patients by Sullivan et al3, the incidence of patients with WAS having at least one autoimmune disorder was 40% and 25% had up to five autoimmune disorders. Anotherstudy of 55 patients by duPois, S et al4 , estimated that 72% of WAS patients eventually developed autoimmune or inflammatory disorders. A recent study by Albert et al of 182 XLT patients2 placed the incidence of autoimmune diseases in these patients at 12%. A more consistent pattern has not yet been identified, and a more age specific study needs to be done in order to determine the exact incidence of autoimmunity.
Most commonly seen was autoimmune hemolytic anemia (AIHA) where the patients developed antibodies to their red blood cells causing their destruction. Another frequently seen disorder is vasculitis where there is inflammation of blood vessels. It can affect any part of the body including the skin, gastrointestinal tract, kidneys, brain, heart, liver or gall bladder. In the skin, there can be hives, or purpura, especially around the knees (called Henoch Schonlein Purpura) or there can be inflammation with the destruction of the skin. Also noted were arthritis, autoimmune neutropenia where the patients develop antibodies to their neutrophils causing their neutrophil counts to fall below 1,000 neutrophils/cu.mm. Similarly these patients tend to produce antibodies to platelets causing ITP-idiopathic thrombocytopenic purpura. They can have colitis, an inflammation of the large intestine causing chronic diarrhea or nephropathies which damage the kidneys.
AIHA and vasculitis can be severe and are among the most common indications for a bone marrow transplant5 in patients with WAS. A bone marrow transplant corrects the autoimmune disease. The occurrence of an autoimmune disorder in WAS patients further increases the risk of malignancy. As many as 25% of patients with autoimmunity develop malignancy as compared with just 5% in WAS patients who do not have an autoimmune disorder.
Autoimmune or Inflammatory Manifestations in a Cohort of 55 Patients With WAS
Age distribution of onset of autoimmune complications in 40 patients with autoimmune complications
Malignancies are seen with a higher frequency in Classic WAS patients. Lymphomas are the most common, particularly in patients who have been exposed to the Epstein Barr Virus (EBV). These lymphomas can occur in unusual places such as in the brain, lungs or gastrointestinal tract. Leukemias form the other major type of malignancy in WAS patients. The risk of malignancy increases with age and in the presence of autoimmune disorders. Overall, 5% of patients with Classic WAS develop a malignancy3 and this risk increases to 25%5 in the presence of an autoimmune disorder. These malignancies are more difficult to treat than in the normal population with a higher frequency of relapse or the development of a new malignancy. Malignancies are seen less frequently in XLT patients. A recent survey of XLT patients by Albert, M et al2 places the incidence at 5%.
1. Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, Yata J, Mizutani S, Ochs HD, Nonoyama S. Clinical course of patients with WASP gene mutations. Blood. 2004 Jan 15;103(2):456-64.
2. Albert, MH, Bittner, T, Stachel, D, Nonoyama, S, Notarangelo, L, Burns, S, Pellier, I, Strauss, G, Morio, T, Imai, K, Espanol, T, Gathmann, B, Hönig, M, Noordzij, JG, Nathrath, M, Meindl, A, Wintergerst, U, Fischer, A, Thrasher, A, Belohradsky, BH and Ochs, HD. Clinical Phenotype and Long Term Outcome in a Large Cohort of X-Linked Thrombocytopenia (XLT)/Mild Wiskott-Aldrich-Syndrome Patients. ASH Conference, Dec. 6-9 2008 http://www.hematology.org/meetings/2008/index.cfm
3. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multi institutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994 Dec;125(6 Pt 1):876-85.
4. Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, de Saint Basile G, Delaunay J, Schwarz K, Casanova JL, Blanche S, Fischer A. Autoimmunity in Wiskott-Aldrich Syndrome: Risk Factors, Clinical Features, and Outcome in a Single-Center Cohort of 55 Patients. Pediatrics. 2003 May;111(5 Pt 1):e622-7.
5. Schurman SH, Candotti F. Autoimmunity in Wiskott-Aldrich syndrome. Curr Opin Rheumatol. 2003 Jul;15(4):446-53.