Information on the following diseases can be found in the Related Disorders section of this report:

• Paroxysmal Nocturnal Hemoglobinuria
• Cold Antibody Hemolytic Anemia

The typical presentation is that of a child who during the preceding 1-2 weeks had suffered from what appeared to be an undefined or "flu-like" illness. Usually the onset of hemolysis is signaled by a recurrence of fever and then the passage of red-brown urine. This urine contains the iron bearing, oxygen transporting, protein pigment of blood called hemoglobin - which is released when red blood cells are prematurely destroyed. The presence of hemoglobin in the urine (hemoglobinuria) causes the dark brown color of the urine. Hemoglobinuria, jaundice and pallor are common clinical findings in acute PCH and, of particular significance is that hemoglobinuria is found in almost all acute cases in childhood.

Abdominal pain and fever are also common findings. Approximately 25 percent of cases have palpable liver and spleen. Although hemoglobinuria may be induced by exposure to cold, such an occurrence is rare in acute PCH. Hemolysis typically lasts for a few days only and recovery is usually uninterrupted.

PCH is much less common in adults, but may occur in patients of any age. Both the syphilitic and non-syphilitic forms of chronic PCH occur only exceedingly rarely. The older medical literature describes chronic syphilitic PCH as a rather benign disease that rarely caused severe chronic anemia. However, acute attacks of hemolysis and hemoglobinuria were well known and were characterized by the sudden onset of shaking chills, fever, malaise, abdominal distress, aching pains in the back or legs, arid nausea. Usually, hemoglobin was present in the first specimen of urine passed after the onset of symptoms, and the interval between chilling arid the development of symptoms ranged from a few minutes to eight hours. The extent of cold exposure could be surprisingly slight and, in some cases, a history of undue exposure to cold was not elicited.

Individuals with PCH often develop the classic symptoms of anemia- the medical term for low levels of circulating red blood cells. These symptoms may include fatigue, difficulty breathing upon exertion (dyspnea) and abnormal or extreme paleness of the skin (pallor). In addition, affected individuals may develop chills, fever, abdominal pain, and pain or aching in the legs or lower back. Less common findings associated with PCH include headaches, vomiting and diarrhea.

Following an episode, affected individuals usually develop the signs of hemolysis including yellowing of the skin, whites of the eyes and mucous membranes (jaundice). In some cases additional symptoms may occur including tingling in the hands and feet, a condition marked by a feeling of coldness or numbness of the hands, nose and ears in response to cold temperatures (Raynaud's phenomenon), or a skin condition marked by reddening and itching of the skin in response to cold temperatures (cold urticaria). In extremely rare cases, the kidney may become involved and kidney (renal) failure has been reported in a few cases.

In most children, PCH occurs following a viral infection such as measles, mumps or chickenpox and spontaneously resolves once the infection is treated. Usually, PCH does not recur (self-limited) in children, but recurrent cases have been reported in the medical literature. In most adults the cause of PCH is unknown (idiopathic). In the past, most cases of PCH in adults were associated with syphilis. With the dramatic decline in the prevalence of syphilis, PCH in adults has declined, and the current understanding of the adult form of the disease is less clear.

PCH is an autoimmune disorder - a disorder in which the body's natural defenses against invading organisms destroy healthy tissue for unknown reasons. In PCH, antibodies mistakenly attack red blood cells causing the cells to breakdown prematurely, a condition called (hemolysis). When antibodies attack healthy tissue, they are referred to as autoantibodies.

Antibodies (which are also known as immunoglobulins) are specialized proteins that bind to invading organisms and bring about their destruction. There are five main classes of antibodies - IgA, IgD, IgE, IgG, and IgM. In PCH, a specific autoantibody known as the Donath-Landsteiner autoantibody is produced often in response to a viral infection. This autoantibody binds to red blood cells during exposure to cold temperatures. The Donath-Landsteiner autoantibody is a type of IgG antibody.

PCH affects males and females in equal numbers. The disorder is rare in the United States and the prevalence and incidence rates are unknown. Autoimmune hemolytic anemias as a group are estimated to affect 1-3 people per 100,000 in the general population. Anyone may acquire PCH, but it is more common among children than among adults. An individual with a viral infection such as chickenpox or mumps, or anyone affected with syphilis, is at higher risk of contracting the disorder. No known genetic, sex, or racial risk factors exist, although the disease has been reported in families.

PCH was first described as a distinct disorder in the medical literature in 1872. The specific antibody associated with the disorder (Donath-Landsteiner autoantibody) was first described by Drs. Donath and Landsteiner in 1904.

Symptoms of the following disorders can be similar to those of PCH. Comparisons may be useful for a differential diagnosis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is the premature destruction of red blood cells (hemolysis), resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood. Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder. Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective "PNH" blood cells, and a predisposition to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH. (For more information on this disorder, choose "paroxysmal nocturnal hemoglobinuria" as your search term in the Rare Disease Database.)

The autoimmune hemolytic anemias are rare disorders characterized by the premature destruction (hemolysis) of red blood cells at a rate faster than they can be replaced. Acquired hemolytic anemias are non-genetic in origin. Idiopathic acquired autoimmune diseases occur when the body's natural defenses against invading organisms destroy its own healthy tissues for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow. Acquired autoimmune hemolytic anemia is a disorder that occurs in individuals who previously had a normal red blood cell system. The disorder may occur as the result of, or in conjunction with, some other medical condition, in which case it is "secondary" to another disorder. Less commonly, it occurs alone without a precipitating factor. Acquired autoimmune hemolytic anemia occurs in different forms, including warm antibody hemolytic anemia and cold antibody hemolytic anemia. In warm antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at body temperature. In contrast, in the cases of cold antibody hemolytic anemia (often called cold agglutinin disease to distinguish it from PCH since both disorders have antibodies that react optimally at cold temperatures), the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures below normal body temperature. (For more information on this disorder, choose "Warm Antibody Hemolytic Anemia" and/or Cold Antibody Hemolytic Anemia as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of PCH may be suspected in some individuals with anemia. In particular, the diagnosis should be suspected in any acutely ill child with hemoglobinuria. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of specialized tests such as a Coombs test, which is used to detect certain antibodies that act against red blood cells. A diagnosis of PCH is confirmed through a Donath-Landsteiner test, which can distinguish PCH from other forms of hemolytic anemia. The test consists of incubating a sample of the patient's serum with normal red blood cells (RBCs) in the cold for 30 minutes and then warming the mixture to body temperature (370C). Hemolysis of the RBCs in this "bi-phasic" test indicates a diagnosis of PCH.

Treatment
Most cases of PCH resolve without treatment (spontaneously) and only require supportive therapy for a few days to weeks after onset. Strict avoidance of cold temperatures is recommended to protect against the premature breakdown of red blood cells and loss of hemoglobin (hemolysis).

In some cases, severe anemia may require a red blood cell transfusion. In such cases, a transfusion should not be delayed. Use of a blood warmer during transfusion is particularly important.

Due to the temporary (transient) nature of the disease in children in most cases, affected children are often in the recovery phase of the illness at the time symptoms become apparent. Most cases that involve children and are linked to a viral infection require only supportive therapy, bed rest, and protection of the affected individual from cold temperatures.

In some cases of chronic PCH additional therapies may be tried to help manage the disease. Steroids have been used with most ineffective results. Researchers are studying drugs that suppress the immune system (immunosuppressive agents) such as Rituximab for the treatment of chronic PCH that does not respond to other therapies (refractory PCH). More research is necessary to determine the long-term safety and effectiveness of immunosuppressive drugs for the treatment of individuals with refractory PCH.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

TEXTBOOKS
Depcik-Smith ND, Brecher ME. Paroxysmal Cold Hemoglobuinuria. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:388-389.

Lichtman MA, Beutler E, Kipps TJ, Selisohn U, et al. Eds. Williams Hematology. 7th ed. McGraw-Hill Companies. New York, NY; 2006:.729-745

Petz LD, Garratty G. Immune Hemolytic Anemias, second edition. Churchill-Livingstone, Philadelphia, 2004;61-62;73-78;191-196.

JOURNAL ARTICLES
Vaglio S, Arista MC, Perrone MP, et al. Autoimmune hemolytic anemia in childhood: serologic features in 100 cases. Transfusion. 2007;47:50-54.

Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion. 2007;47:1902-1904.

Hothi DK, Bass P, Morgan M, et al. Acute renal failure in a patient with paroxysmal cold hemoglobinuria. Pediatr Nephrol. 2007;22:593-596.

Gertz MA. Cold hemolytic syndrome. Hematology. 2006;

Rosse WL, Hillman P, Schreiber AD. Immune-mediated autoimmune anemia. Hematology Am Soc Hematol Educ Program. 2004;48-62.

Petz LD. Treatment of autoimmune hemolytic anemias. Curr Opin Hematol. 2001;8:411-416.

Jeffereies LC. Transfusion therapy in autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 1994;8:1087-1104.

Gottsche B, Salama A, Mueller-Eckhardt C. Donath-Landsteiner autoimmune hemolytic anemia in children: a study of 22 cases. Vox Sang. 1990;58:281-86.

FROM THE INTERNET
Loew T, Camilo NA. Paroxysmal Cold Hemoglobinuria. Emedicine Journal, August 10 2006. Available at: http://www.emedicine.com/PED/topic512.htm Accessed on: March 26, 2008.

Goldberg C, Sacher RA. Paroxysmal Cold Hemoglobinuria. Emedicine Journal, December 7 2007. Available at: http://www.emedicine.com/med/TOPIC977.HTM Accessed on: March 26, 2008.