Rho(D) immune globulin

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Rho(D) immune globulin
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Trade names WinRho, RhoGAM, others:
Other namesRh0(D) immune globulin, anti-D (Rh0) immunoglobulin, immunoglobulinum humanum anti–D
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Rho(D) immune globulin (RhIG) is a medication used to prevent RhD isoimmunization in mothers who are RhD negative and to treat idiopathic thrombocytopenic purpura (ITP) in people who are Rh positive. [2] It is often given both during and following pregnancy. [2] It may also be used when RhD-negative people are given RhD-positive blood. [2] It is given by injection into muscle or a vein. [2] A single dose lasts 12 weeks. [2] It is made from human blood plasma. [3]

Contents

Common side effects include fever, headache, pain at the site of injection, and red blood cell breakdown. [2] Other side effects include allergic reactions, kidney problems, and a very small risk of viral infections. [2] In those with ITP, the amount of red blood cell breakdown may be significant. [2] Use is safe with breastfeeding. [2] Rho(D) immune globulin is made up of antibodies to the antigen Rho(D) present on some red blood cells. [2] It is believed to work by blocking a person's immune system from recognizing this antigen. [2]

Rho(D) immune globulin came into medical use in the 1960s, [4] following the pioneering work of John G. Gorman. In 1980, Gorman shared the Lasker-DeBakey Clinical Medical Research Award for pioneering work on the rhesus blood group system. [5]

RhIG is on the World Health Organization's List of Essential Medicines. [6] [7]

Medical uses

Prevention of alloimmunization

Alloimmunization: mechanism, timing

Image of a positive Kleihauer-Betke test; the pink smudges are foetal-haemoglobin-containing red blood cells that have entered maternal circulation. Kleihauer Positive.jpg
Image of a positive Kleihauer–Betke test; the pink smudges are foetal-haemoglobin-containing red blood cells that have entered maternal circulation.

Even in normal pregnancies, a small number of fetal blood cells enters the maternal bloodstream (fetomaternal hemorrhage). If a mother is RhD negative, but the fetus is RhD positive, the mother's immune system may develop an immune response (develops antibodies) to the unfamiliar RhD antigens from the fetus. This process is called RhD alloimmunization. Alloimmunization usually has minimal effect on the first such pregnancy; but, in a second such pregnancy, pre-existing maternal RhD IgG antibodies can cross the placenta in enough amounts to damage fetal red blood cells. This condition is called erythroblastosis fetalis and can be fatal to the fetus. [8]

The RhD status of the fetus is determined by genetic inheritance. In a pregnancy where the mother is RhD negative and the father is RhD positive, the probability of the fetus having RhD positive blood is dependent on whether the father is homozygous for RhD (i.e., both RhD alleles are present) or heterozygous (i.e., only one RhD allele is present). If the father is homozygous, the fetus will necessarily be RhD positive, as the father will necessarily pass on a RhD positive allele. If the father is heterozygous, there is a 50% chance that the fetus will be RhD positive, as he will randomly pass on either the RhD positive allele or not. [9] : 130 

Exposure to fetal blood cells that can cause RhD alloimmunization can happen during normal pregnancy and delivery, miscarriage, amniocentesis, cordocentesis, chorionic villus sampling, external cephalic version, trauma. [3] [8] 92% of women who develop an anti-D during pregnancy do so at or after 28 weeks gestation. [10] [9] [11]

In an RhD negative mother, RhIG can temporarily prevent sensitization of the maternal immune system to RhD antigens, with each 100 μg of anti-D being able to neutralize about 4 mL of fetal blood. [12] With the widespread use of RhIG, Rh disease of the fetus and newborn has almost disappeared in the developed world. The risk that an RhD negative mother can be alloimmunized by a RhD positive fetus can be reduced from approximately 16% to less than 0.1% by the appropriate administration of RhIG. [10] [9] [13] In countries without Rh immune globulin (RhIG) protocols, as many as 14% of affected fetuses are stillborn and 50% of live births result in neonatal death or brain injury. [8]

Recommendations for use

The American College of Obstetricians and Gynecologists (ACOG) recommends that all RhD negative mothers, regardless of fetal blood type, receive RhIG at about 28 weeks gestation, and again shortly after delivery in the case of an RhD positive or RhD unknown baby. [14] It should be given within 3 days of a potential exposure to Rh positive blood from the baby such as may occur during second and third trimester miscarriage, amniocentesis, cordocentesis, chorionic villus sampling, external cephalic version, trauma, or delivery (amounts detailed in the next section). [8] It is given by intramuscular injection as part of modern routine antenatal care. Despite excellent results, the medication retains an FDA Pregnancy Category C.[ citation needed ]

RhIG is recommended in the UK after antenatal pathological events that are likely to cause a feto–maternal hemorrhage. Applicable 'pathologic events' include accidents that may induce fetomaternal hemorrhage (motor vehicle accidents, falls, abdominal trauma), following obstetric/gynecologic procedures during pregnancy, and at the time of threatened- or spontaneous-/elective abortions, regardless of gestational age. RhIG is also recommended after normal delivery, with amounts detailed in the next section. [12]

There is insufficient evidence that the use of Rho(D) immune globulin after a spontaneous miscarriage is needed and a Cochrane review recommends that local practices be followed. [15]

Rh immune globulin is composed of IgG antibodies and therefore is able to cross the placenta. In rare cases this can cause a baby to have a weakly positive direct antiglobulin test (DAT) due to sensitization of fetal cells from mothers who have received multiple doses of RhIG. However, no treatment is necessary as the clinical course is benign. [16]

Following delivery

Widespread use of RhIG started with postpartum administration, as delivery is the main source of significant fetomaternal hemorrhage. A D-negative mother who is not alloimmunized to D should also receive an appropriate dose of RhIG after delivery of a D-positive infant. (In older recommendations, the Rh status of the infant is only known at delivery from testing of cord blood.) [9] If the infant is D-positive, the mother should have a postpartum blood sample screened for fetomaternal hemorrhage in order to determine the appropriate dosage of RhIG to be administered. (The presence of residual anti-D from antepartum RhIG administration does not indicate ongoing protection from alloimmunization – repeat administration of RhIG is necessary.) [12]

The rosette test is a sensitive method to detect fetomaternal hemorrhage of 10 cc or more. This qualitative (not quantitative) test will be positive if fetal D-positive cells are present in the maternal sample, indicating a significantly large fetomaternal hemorrhage has occurred. A rosette test may be falsely positive if the mother is positive for the weak D phenotype and falsely negative if the neonate is weak D. If the mother is positive for the weak D phenotype, the rosette test should not be used; instead, a quantitative test such as the Kleihauer–Betke test or flow cytometry should be utilized. If the rosette test is negative, then a dose of 300 micrograms of RhIG is given (sufficient to prevent alloimmunization after delivery in 99% of cases). [10] [17] The RhIG dose suppresses the immune response to up to 30 cc of whole fetal blood (15 cc of red blood cells). If a fetomaternal hemorrhage in excess of 30 cc has occurred, additional testing is mandatory in order to determine the appropriate dosage of RhIG to prevent alloimmunization. A positive rosette test should be followed by a quantitative test such as the Kleihauer–Betke test or an alternative approach such as flow cytometry. See the article on Kleihauer–Betke test for details on how the volume of fetomaternal hemorrhage is calculated. The dosage of RhIG is calculated from the volume of fetal hemorrhage (in mL). Ex: 50 mL fetal hemorrhage / 30 mL = 1.667 (round up to 2) then add 1 = 3 vials of RhIG.[ citation needed ]

Postpartum RhIG should be administered within 72 hours of delivery. If prophylaxis is delayed, the likelihood that alloimmunization will be prevented is decreased. However, ACOG still recommends that RhIG be administered because partial protection still occurs. [10] [11] If the D-type of a newborn or stillborn is unknown or cannot be determined, RhIG should be administered.

Immune thrombocytopenia

Primary immune thrombocytopenia (ITP) is an acquired immune-mediated disorder characterized by isolated thrombocytopenia, defined as a peripheral blood platelet count less than 100 x 109/L, and the absence of any obvious initiating and/or underlying cause of the thrombocytopenia. Symptoms of ITP include abnormal bleeding and bruising due to the reduction in platelet count. [18] Rho(D) Immune Globulin Intravenous [Human; Anti-D] is indicated for use in non-splenectomized, Rho(D)-positive children with chronic or acute ITP, adults with chronic ITP, and children and adults with ITP secondary to HIV infection. Anti-D must be administered via the intravenous route when used in clinical situations requiring an increase in platelet count. The mechanism of action of anti-D is not fully understood; however, after administration the anti-D coated red blood cell complexes saturate Fcγ receptors sites on macrophages, resulting in preferential destruction of red blood cells (RBCs), therefore sparing antibody-coated platelets. [19] Anti-D is recommended as a first-line therapy for ITP, along with corticosteroids and intravenous immune globulin (IVIG). [18] [20] [WinRho SDF is an anti-D manufactured, distributed and marketed by Cangene in the US. There is a black box warning on WinRho SDF due to the risk of potentially fatal intravascular hemolysis when used in the treatment of ITP. [19] Life-threatening anemia, kidney failure, and disseminated intravascular coagulation (DIC) have occurred in people treated with WinRho SDF for ITP.[ citation needed ]

Contraindications

The following females are not candidates for RhIG:

History

The first Rho(D) immune globulin treatment "skymed" was introduced by Ortho Clinical Diagnostics, a subsidiary holding of Jskymed, and was first administered on May 29, 1968, to Marianne Cummins in Teaneck, New Jersey. [22]

In 1996, ZLB Bioplasma (part of CSL Behring) was given approval to sell Rhophylac in Europe. Effectiveness was demonstrated in a clinical trial in 2003 and in 2004 Rhophylac was approved in the United States. [23]

Society and culture

Manufacturing and safety

Human plasma

Conventional Rho(D) immune globulin is extracted from human blood plasma. Excluding autoimmunity, only people who are themselves Rho(D) negative can make the anti-D antibody. As a result, there is a limited pool of people from which to draw plasma that can contain the desired IgG. Special anti-D donation programs are set up to account for this rarity. [24] Volunteers are given an injection containing the D antigen in order to make their immune system start producing the antibody (alloimmunization) or to boost the amounts. Only men and women who have no ability to become pregnant may apply. [25]

The most common way anti-D products are manufactured is by a form of the Cohn cold ethanol fractionation process developed in the 1950s. Variations of the Cohn method developed in the 1950s may not completely clear aggregates of immunoglobulins, which can cause problems for patients if administered intravenously, and is a primary reason why most anti-Ds are for intramuscular use only. A non-Cohn manufacturing variation is ChromaPlus process approved by the U.S. Food and Drug Administration (FDA) that is used to make Rhophylac. [26] Rho(D) immune globulin may trigger an allergic reaction. Steps are taken in the plasma-donor screening process and the manufacturing process to eliminate bacterial and viral contamination, although a small, residual risk may remain for contamination with small viruses. There is also a theoretical possibility of transmission of the prion responsible for Creutzfeldt–Jakob disease, or of other, unknown infectious agents. [27]

Cell culture

There has been continual attempts to produce a monoclonal anti-D IgG formulation suitable for replacing the current polyclonal formulation. [28] A monoclonal antibody can be produced without requiring human donors (and associated supply and disease risks) and would be more consistent from batch to batch. [8]

India has approved a monoclonal formulation called Rhoclone (Bharat Serums and Vaccines Ltd.), [29] made from hybridoma cultures. The country has also tested a recombinant version of Rhoclone expressed in CHO cells. [30]

Roledumab and Rozrolimupab are two other formulations that have undergone some clinical trials. The former is a monoclonal IgG. The latter is a recombinant mixture of 25 IgGs. [8]

Routes of administration

RhIG can be administered by either intramuscular (IM) or intravenous (IV) injection, depending on the preparation. The IM-only preparation should never be administered IV due to the risk of complement system activation. Multiple IM doses should be given at different sites or at different times within the 72-hour window. Or, multiple IV doses can be administered according to the instructions in the package insert.[ citation needed ]

Names

Rho(D) immune globulin is also spelled Rh0(D) immune globulin (letter o and digit zero are both widely attested; more at Rh blood group system - Rh nomenclature).

Rhophylac is manufactured by CSL Limited. RhoGAM and MICRhoGam are brand names of Kedrion Biopharma. Other brand names are BayRHo-D, Gamulin Rh, HypRho-D Mini-Dose, Mini-Gamulin Rh, Partobulin SDF (Baxter), Rhesonativ (Octapharma), and RhesuGam (NBI). KamRho-D I.M. is a brand name of Kamada Ltd.

The United States distribution rights for WinRho SDF (another brand name) were transferred from Baxter to the manufacturer, Cangene, in 2010; they had been held by Baxter since 2005. [31] Sales of WinRho fell every year under the agreement with Baxter, the supposition being that Baxter was favoring the sale of its own product over WinRho; according to one analyst, "WinRho was always an afterthought for a big company like Baxter." [32]

See also

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses, including those that cause disease. Antibodies, however, can be generated to recognize virtually any molecule in existence. Each antibody recognizes one or more specific antigens. This term literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Blood type</span> Classification of blood based on antibodies and antigens on red blood cell surfaces

A blood type is a classification of blood, based on the presence and absence of antibodies and inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates, glycoproteins, or glycolipids, depending on the blood group system. Some of these antigens are also present on the surface of other types of cells of various tissues. Several of these red blood cell surface antigens can stem from one allele and collectively form a blood group system.

<span class="mw-page-title-main">Amniocentesis</span> Sampling of amniotic fluid done mainly to detect fetal chromosomal abnormalities

Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is necessary to conclusively diagnose the majority of genetic disorders, with amniocentesis being the gold-standard procedure after 15 weeks' gestation.

<span class="mw-page-title-main">Immune thrombocytopenic purpura</span> Medical condition with rash and bleeding risk

Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura characterized by a low platelet count in the absence of other causes, and accompanied by a red-purple rash called purpura. It leads to an increased risk of bleeding. ITP manifests in two distinct clinical syndromes: an acute form observed in children, and chronic conditions observed in adults. The acute form often follows an infection and typically resolves within two months, while chronic immune thrombocytopenia persists for longer than six months and its specific cause is unknown.

Rh disease is a type of hemolytic disease of the fetus and newborn (HDFN). HDFN due to anti-D antibodies is the proper and currently used name for this disease as the Rh blood group system actually has more than 50 antigens and not only the D-antigen. The term "Rh Disease" is commonly used to refer to HDFN due to anti-D antibodies, and prior to the discovery of anti-Rho(D) immune globulin, it was the most common type of HDFN. The disease ranges from mild to severe, and occurs in the second or subsequent pregnancies of Rh-D negative women when the biologic father is Rh-D positive.

<span class="mw-page-title-main">Hemolytic disease of the newborn</span> Fetal and neonatal alloimmune blood condition

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis.

The direct and indirect Coombs tests, also known as antiglobulin test (AGT), are blood tests used in immunohematology. The direct Coombs test detects antibodies that are stuck to the surface of the red blood cells. Since these antibodies sometimes destroy red blood cells they can cause anemia; this test can help clarify the condition. The indirect Coombs test detects antibodies that are floating freely in the blood. These antibodies could act against certain red blood cells; the test can be carried out to diagnose reactions to a blood transfusion.

<span class="mw-page-title-main">Hydrops fetalis</span> Human disease of fetuses

Hydrops fetalis or hydrops foetalis is a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. By comparison, hydrops allantois or hydrops amnion is an accumulation of excessive fluid in the allantoic or amniotic space, respectively.

<span class="mw-page-title-main">Kleihauer–Betke test</span> Blood test used to measure the amount of fetal hemoglobin

The Kleihauer–Betke ("KB") test, Kleihauer–Betke ("KB") stain, Kleihauer test or acid elution test is a blood test used to measure the amount of fetal hemoglobin transferred from a fetus to a mother's bloodstream. It is usually performed on Rh-negative mothers to determine the required dose of Rho(D) immune globulin (RhIg) to inhibit formation of Rh antibodies in the mother and prevent Rh disease in future Rh-positive children. It is named after Enno Kleihauer and Klaus Betke who described it in 1957.

In ABO hemolytic disease of the newborn maternal IgG antibodies with specificity for the ABO blood group system pass through the placenta to the fetal circulation where they can cause hemolysis of fetal red blood cells which can lead to fetal anemia and HDN. In contrast to Rh disease, about half of the cases of ABO HDN occur in a firstborn baby and ABO HDN does not become more severe after further pregnancies.

Hemolytic disease of the newborn (anti-Kell1) is the second most common cause of severe hemolytic disease of the newborn (HDN) after Rh disease. Anti-Kell1 is becoming relatively more important as prevention of Rh disease is also becoming more effective.

Hemolytic disease of the newborn (anti-Rhc) can range from a mild to a severe disease. It is the third most common cause of severe HDN. Rh disease is the most common and hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe HDN. It occurs more commonly in women who are Rh D negative.

<span class="mw-page-title-main">Rh blood group system</span> Human blood group system involving 49 blood antigens

The Rh blood group system is a human blood group system. It contains proteins on the surface of red blood cells. After the ABO blood group system, it is the most likely to be involved in transfusion reactions. The Rh blood group system consisted of 49 defined blood group antigens in 2005. As of 2023, there are over 50 antigens among which the five antigens D, C, c, E, and e are the most important. There is no d antigen. Rh(D) status of an individual is normally described with a positive (+) or negative (−) suffix after the ABO type. The terms Rh factor, Rh positive, and Rh negative refer to the Rh(D) antigen only. Antibodies to Rh antigens can be involved in hemolytic transfusion reactions and antibodies to the Rh(D) and Rh antigens confer significant risk of hemolytic disease of the newborn.

Neonatal alloimmune thrombocytopenia is a disease that affects babies in which the platelet count is decreased because the mother's immune system attacks her fetus' or newborn's platelets. A low platelet count increases the risk of bleeding in the fetus and newborn. If the bleeding occurs in the brain, there may be long-term effects.

Hemolytic disease of the newborn (anti-RhE) is caused by the anti-RhE antibody of the Rh blood group system. The anti-RhE antibody can be naturally occurring, or arise following immune sensitization after a blood transfusion or pregnancy.

Erythrocyte rosetting or E-rosetting is a phenomenon seen through a microscope where red blood cells (erythrocytes) are arranged around a central cell to form a cluster that looks like a flower. The red blood cells surrounding the cell form the petal, while the central cell forms the stigma of the flower shape. This formation occurs due to an immunological reaction between an epitope on the central cell's surface and a receptor or antibody on a red cell. The presence of E-rosetting can be used as a test for T cells although more modern tests such as immunohistochemistry are available. Rosetting is caused by parasites in the genus Plasmodium and is a cause of some malaria-associated symptoms.

Fetal-maternal haemorrhage is the loss of fetal blood cells into the maternal circulation. It takes place in normal pregnancies as well as when there are obstetric or trauma related complications to pregnancy.

Immune tolerance in pregnancy or maternal immune tolerance is the immune tolerance shown towards the fetus and placenta during pregnancy. This tolerance counters the immune response that would normally result in the rejection of something foreign in the body, as can happen in cases of spontaneous abortion. It is studied within the field of reproductive immunology.

An Intrauterine transfusion (IUT) is a procedure that provides blood to a fetus, most commonly through the umbilical cord. It is used in cases of severe fetal anemia, such as when fetal red blood cells are being destroyed by maternal antibodies. IUTs are performed by perinatologists at hospitals or specialized centers.

<span class="mw-page-title-main">Blood compatibility testing</span> Testing to identify incompatibilities between blood types

Blood compatibility testing is conducted in a medical laboratory to identify potential incompatibilities between blood group systems in blood transfusion. It is also used to diagnose and prevent some complications of pregnancy that can occur when the baby has a different blood group from the mother. Blood compatibility testing includes blood typing, which detects the antigens on red blood cells that determine a person's blood type; testing for unexpected antibodies against blood group antigens ; and, in the case of blood transfusions, mixing the recipient's plasma with the donor's red blood cells to detect incompatibilities (crossmatching). Routine blood typing involves determining the ABO and RhD type, and involves both identification of ABO antigens on red blood cells and identification of ABO antibodies in the plasma. Other blood group antigens may be tested for in specific clinical situations.

References

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  18. 1 2 Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, et al. (January 2010). "International consensus report on the investigation and management of primary immune thrombocytopenia". Blood. 115 (2): 168–186. doi: 10.1182/blood-2009-06-225565 . PMID   19846889.
  19. 1 2 "Winrho SDF prescribing information" (PDF). www.winrho.com.
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  23. ↑ "History of HDN Treatment". CSL Behring. Archived from the original on 2008-11-21.
  24. ↑ "Anti-D donor Steve Gansberg is just happy to help". Lifeblood.com.au. 9 June 2022.
  25. ↑ "Anti-D: Rh-negative Plasma Donation". CSL Plasma .
  26. ↑ "ChromaPlus Manufacturing Process". rhophylac.com. Archived from the original on 2008-11-21.
  27. ↑ "RhoGAM Ultra-Filtered PLUS Rho(D) Immune Globulin (Human) Information Site". Johnson & Johnson Services, Inc. Archived from the original on 2006-03-11.
  28. ↑ Béliard R (March 2006). "Monoclonal anti-D antibodies to prevent alloimmunization: lessons from clinical trials". Transfusion Clinique et Biologique. 13 (1–2): 58–64. doi:10.1016/j.tracli.2006.03.013. PMID   16580863.
  29. ↑ Chauhan AR, Nandanwar YS, Ramaiah A, Yelikar KA, Rashmi MD, Sachan R, et al. (October 2019). "A Multicenter, Randomized, Open-Label Trial Comparing the Efficacy and Safety of Monoclonal Anti-Rh (D) Immunoglobulin with Polyclonal Anti-Rh (D) Immunoglobulin for the Prevention of Maternal Rh-Isoimmunization". Journal of Obstetrics and Gynaecology of India. 69 (5): 420–425. doi: 10.1007/s13224-019-01234-2 . PMC   6765035 . PMID   31598044.
  30. ↑ Mayekar RV, Paradkar GV, Bhosale AA, Sachan R, Beeram S, Anand AR, et al. (May 2020). "Recombinant anti-D for prevention of maternal-foetal Rh(D) alloimmunization: a randomized multi-centre clinical trial". Obstetrics & Gynecology Science. 63 (3): 315–322. doi: 10.5468/ogs.2020.63.3.315 . PMC   7231934 . PMID   32489976.
  31. ↑ Staff (5 May 2010). "Cangene assumes U.S. commercialization rights for WinRho SDF". Biotech Week . United States. Archived from the original on 29 March 2015. Retrieved 28 December 2014.
  32. ↑ Cash M (16 June 2010). "Cangene Corp. begins transformation project". Winnipeg Free Press . Archived from the original on 29 March 2015. Retrieved 28 December 2014.
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