Britich Journal of Haematology, 1976,34,
511.
Autoimmune Haemolytic Anaemia in Children B. ~ P A ~ S W. K AEAWKOWICZ, , B. G ~ R S KJ.AKOZEOWSKA, , M. OCHOCKA, R. ROKICKA-MILEWSKA, D. DERULSKA AND D. CIEPIELEWSKA Institute of Haematology, Warsaw, and Institute of Paediatrics, School of Medicine, Warsaw (Received 9 June 1975; acceptedfor publication 18 March 1976) SUMMARY. Forty-four children with autoimmune haemolytic anaemia (AIHA) are described: 3 I had acute, subacute or chronic disease with warm autoantibodies and 13 had acute or chronic anaemia with cold autoantibodies. The commonest forms were the acute and subacute types with warm autoantibodies and these were more frequent in young children, while chronic AIHA occurred mainly among children at puberty. 111 about 16% the anaemia was accompanied by a chronic disorder but in over 50% the anaemia was preceded by an acute infection or immunization. The former gave rise mainly to chronic anaemia, but the latter was associated with the acute and subacute forms. In general the prognosis was good and death was never caused by anaemia per se. The prognosis was worse in patients with clinical features of thrombocytopenia and bleeding and with the immunological findings of free autoantibodies in the serum and a positive direct antiglobulin test. In acute and subacute forms, treatment with corticosteroids and sometimes with blood transfusions was effective. In chronic forms of the disease it was often necessary to give additional immunosuppressive drugs orjand to perform a splenectomy. The autoimmune haemolytic anaemias (AIHA) are not common blood disorders of childhood. In the literature most clinical papers are based on case reports (Andrzejewska et al, 1955; Rowecka-Trzebicka, 1964; Pirofsky, 1969; Paolucci et al, 1970; Lamagnere et al, 1972) and it is only in recent years that reviews of a larger number of children have been published (Zuelzer et al, 1970; Habibi & Schaison, 1973; Carapella de Luca, 1975). Observations on children at the Institute of Pediatrics in Warsaw over 20 years seem to indicate that the clinical course, immunological characteristics and causes leading to the development of AIHA in childhood are somewhat different from those occurring in adults and it thus appeared useful to present our clinical material. MATERIALS AND METHODS In the period from 1955 to 1974, 44 children with AIHA aged 3 months to 14years were seen at the Institute of Pediatrics. All had signs of haemolytic anaemia and either a positive direct antiglobulin test or autoantibodies present in the serum or both. Serological investigations at the Institute of Haematology in Warsaw were performed by conventional methods: polyvalent antiglobulin serum was used for the direct antiglobulin test and eluates were Correspondence: Dr Barbara Zupaliska, Institute of Haematology, 00-791Warsaw, Chocimska 5, Poland. 511
B. Zupabka et a1
Autoimmune Haemolytic Anuemia in Children
513
made by Rubin’s (1963) technique. The patients were classified into two groups: AIHA with warm autoantibodies and AIHA with cold autoantibodies depending on the optional temperature for autoantibody activity. Criteria for serological classification as ‘AIHA with warm autoantibodies’ was based on the presence of a positive direct antiglobulin test and/or the presence of autoantibodies in the serum optionally active at 37°C. Criteria for serological classification as ‘AIHA with cold autoantibodies’ was based on the presence of cold agglutinins with a titre of more than 32 at 12OC and still active at room temperature or higher temperatures up to 34°C. OBSERVATIONS AND RESULTS A I H A with Warm Autoantibodies There were 3 I patients in this group (Table I and Fig r) aged 3 months to 14 years, and 17 were boys and 14girls. Three subgroups were made according to the duration of the disease, whether acute, subacute or chronic. AlHAacute
AIHA chronic
AIHA subacute
654W
Ln 0
,”
3-
0 z
2I-
00
I
5
1015
0
I 5 1015 Age (years)
0
I
5
10 15
FIG I . AIHA with warm antibodies: age at diagnosis.
Acute A I H A . This group contained 13 patients, seven boys and six girls, whose illness lasted 3 months or less. Their ages ranged from 5 months to 13 years and one-third were less than I year old. In six patients an infectious disease (mumps, upper respiratory tract infection, tonsillitis, scarlet fever or pneumonia) preceded the development of anaemia. In two patients the disease developed after immunizations against typhoid fever and poliomyelitis; and with the triple vaccine Diph-Tet-Pert (Table 11). The onset of the illness was acute with fever, general weakness, abdominal pain, vomiting and diarrhoea. In most cases the anaemia was severe with a haemoglobin level below 6 g/dl and blood films showed a high reticulocyte count, nucleated red cells, and the presence of numerous spherocytes. In five patients the leucocyte count was increased and six had thrombocytopenia, although only three patients showed a bleeding tendency. Haenioglobinuria was frequently noted. The bilirubin level was c 30-10o~mol/l.and only in one patient did it reach c 2oopmol/l. A correlation was noted between the intensity of anaemia and the results of the serological tests; when the anaemia was only mild or moderate, the direct antiglobulin test was positive but no free antibody was found in the serum, whereas when the anaemia was severe additional
B. Zupariska et a1
Autoimmune Haemolytic Anaemia in Children
SIS
incomplete autoantibodies were found in the serum. No specificity could be found for any of these autoantibodies. Eleven patients recovered completely, both clinically and serologically. In general, the signs of haemolysis disappeared 1-2 weeks after the onset of the illness and the serological tests became negative after a further 2 weeks. The haemolysis recurred only rarely and the duration of the illness never exceeded 3 months. All children responded well to treatment with corticosteroids and blood transfusions and one child recovered without any treatment. Two patients died. The first was a 9-year-old girl, E.S., who had had scarlet fever 2 weeks before the onset of AIHA. On admission to the hospital she was pale and jaundiced and had enlarged cervical lymph nodes. She was severely anaemic, the haemoglobin level being The platelets were decreased in number under 2 g/dl and the red cell count 0.53 x 10~~11. (31 x 1o9/I.) and purpura developed. During her 2 weeks stay in hospital she remained severely anaemic and she died from bleeding and pneumonia; an autopsy was not done. The second was a 13-year-old boy, R.P., who was brought to hospital 2 weeks after an antityphoid inoculation because he was pale, jaundiced and vomiting blood. He was found to have a low platelet count and a bleeding tendency and during the next 3 weeks severe abdominal pains, temporary oliguria and the biochemical signs of kidney failure were seen. He died with signs of severe haemolysis and increased bleeding. At autopsy the following abnormalities were found : haemosiderosis, necrosis and haemorrhage in the spleen, thrombosis in the splenic arteries, necrosis in the liver, oesophageal and duodenal ulceration with blood in the stomach and a haemothorax. Subacute A I H A . This group contained 12 patients (six boys and six girls) who suffered from AIHA for not longer than 2 years. The age of the children was similar to those in the preceding group and varied between 3 months and 9 years. Seven of the patients had had an acute infection (pneumonia, otitis, tonsillitis or influenza) or an immunization 1-2 weeks before the onset of anaemia (Table 111). The start of the illness was usually acute and the symptoms were similar to those in the previous group. Recovery was slow, relapses were more frequent than in the first group and usually related to an infection or to reduction of the dose of corticosteroids. In eight of the 12 cases the anaemia was severe (Hb below 6 g/dl) and the bilirubin level 4-9 mg/dl. The leucocyte count was usually increased and the platelet count was decreased in three patients but only one bled abnormally. Haemoglobinuria was found not so often as in the previous group. Subacute AIHA was rather homogeneous as far as serological results were concerned. In all patients the direct antiglobulin test was positive and incomplete autoantibodies were present in the serum and eluate. In five patients the autoantibodies were found to have the specificity of anti-e but in the remaining patients specificity could not be demonstrated. Seven patients recovered fully, both clinically and serologically, within a period of 10 months to 2 years. Corticosteroids, immunosuppressive drugs and splenectomy were used to treat these patients. Blood transfusions were given only in cases of severe anaemia. In four patients the clinical signs and serological findings were still present when this survey was completed. However, they are included in this group because their anaemia had not been present for more than 2 years and because their clinical course was similar to the other patients. One girl, M.M., 10 months old at diagnosis, died after 13 years of illness. She had relapsed frequently, not only with severe haemolysis but also with thrombocytopenia and purpura.
Chronic 4
9
6
chronic
ADHA with cold antibodies Acute
IZ
13
No. of cases
Subacute
Acute
AIHA with warm antibodies
Type ofAZHA
Pneumonia
Otitis
Upper respiratory tract infection Pneumonia
-
I I
0
I
3
I
I
I
I
Otitis
2
No. of uses
Upper respiratory tract infection Mumps Scarlet fever Tonsillitis Pneumonia Upper respiratory tract infection Muenza(Hong Kong I :40 Az. England I :20) Pneumonia
Infections
Typhoid fever
Diph-Tet-Pert
Typhoid fever+ poliomyelitis
Immunizafion
o
0
o
I
I
I
No. of cases
SLE Chronic non-specific lymphadenitis
-
SLE Chronic non-specific lymphadenitis
Glomerulonephritis
-
Accompanying diseases
TABLE III. Accompanying diseases and infections or immunization which preceded the onset of AIHA
2
I
0
I
2
0
cases
No. of
E.
2
Autoimmune Huemolytic Anaemia in Children
517
Chronic A I H A . This group contained six patients (four boys and two girls) 12-14 years old. In three children the anaemia was associated with another disease: systemic lupus erythematosus (SLE) or chronic nonspecific lymphadenitis (Table 111). The onset of the disease in all the children was gradual and often masked by the accompanying illness, so that the symptoms were not characteristic. Anaemia was not severe and frequently associated with thrombocytopenia. The bilirubin level was 30-50 pmol/l. and haemoglobinuria was not noticed. Numerous relapses were observed in the course of the illness. In five patients the direct antiglobulin test was positive and in four of these additional autoantibodies were found in the serum. One patient had only autoantibodies in the serum. No specificity was found for any of these autoantibodies. Corticosteroids and immunosuppressive drugs or corticosteroids and splenectomy were used to treat the patients but none recovered fully. One 13-year-old girl, E.O., died after 2 years of anaemia associated with SLE and complicated by thronibocytopenic purpura and uraemia. Autopsy confirmed the diagnosis of SLE with lupus glomerulonephritis.
51
AIHA chronic
AlWocute
4-
8
3-
U
c 0 2z
I-
0-
diL um
0
I
5
10 15
o
i
5
ro IS
Age (years)
FIG2. AIHA with cold antibodies: age at diagnosis.
A I H A with Cold Antibodies This group contained 13 patients (eight boys and five girls) whose ages ranged from 3 months to 11 years (Table I1 and Fig 2). They were classified into two subgroups according to the clinical course. Acute A I H A . This group contained nine patients (five boys and four girls) most of whom were under 5 years, and all of whom recovered within I month. The illness started suddenly with fever and in every case was preceded by infections such as pneumonia or otitis. In one case the pneumonia was found to be due to Mycoplusmu pneumonioe. Most patients were not severely anaemic but the leucocyte count was frequently raised and in one patient thrombocytopenia was found. Three patients had a bilirubinaemia of c 50-120 pmol/l. All nine patients had cold autoantibodies in their serum but only two patients with severe anaemia had a positive direct antiglobulin test. The specificity of the autoantibodies was
518
B. Zupatiska et a1
established as anti-I in only two out of the nine patients. One patient showed polyagglutination. The clinical symptoms and serological abnormalities usually disappeared between the second and fourth week of illness and relapse did not occur. Only three patients were treated with corticosteroids : one received an additional blood transfusion and the other recovered without any treatment. Chronic AIHA. This group contained four patients (three boys and one girl) who had repeated relapses during the 2-5 years of observation. One patient was a 13-year-old girl who after suffering from haemolytic anaemia for 2 years developed overt SLE with skin lesions, kidney involvement and LE cells in the blood. Two other children had chronic enlargement of the lymph nodes histologically described as nonspecific lymphadenitis. As in the preceding group, the two patients who were most anaemic had a positive direct antiglobulin test and autoantibodies in the serum. The other two had only autoantibodies in the serum. In three cases the specificity of autoantibodies was established as anti-I. All patients were treated with corticosteroids and one was splenectomized but none recovered completely.
DISCUSSION In this clinical analysis of children with signs of haemolytic anaemia and serological tests indicating autoantibodies against erythrocytes, only a simple classification into those with warm autoantibodies and those with cold autoantibodies has been used. This is because these observations were made over 20 years and therefore the extent of investigation was variable and for many years only polyvalent antiglobulin serum was available (Wiener et al, 1956). In order to obtain comparable material we have omitted the more comprehensive tests on later patients and thus we cannot use the classifications introduced recently by other authors. These take into account the type of proteins found in the direct antiglobulin test, i.e. the immunoglobulin class of the autoantibody and the presence or absence of complement binding (Wiener et al, 1956; Jenkins et al, 1960; Marsh, 1961; Gerbal et al, 1967; Salmon et al, 1967; Engelfriet et al, 1968, Dacie, 1970). However, it would seem from studies on AIHA in adults that this further classification does not give any very useful information and since the clinical picture of AIHA with warm antibodies differs markedly from that of the same disease with cold antibodies, a simple classification is preferred. In our series, children with AIHA due to warm antibodies (70% of the patients) were commoner than children with AIHA due to cold antibodies (30% of the patients). This last incidence is high compared with that of Habibi & Schaison (1973), who only recorded cold antibodies in 10% of their cases. This difference may be due to differences of selection; Hababi and his colleagues included patients up to 18 years old and our series includes patients who were not severely anaemic. Acute and subacute AIHA with warm antibodies which were the commonest forms of AIHA in our series generally have a good prognosis although the onset is sudden with severe anaemia which needs treatment not only with corticosteroids but often also with blood transfusions. The prognosis is not quite so good in patients who have additional autoantibodies in the serum. The clinical picture of acute AIHA with cold antibodies is quite different. The course of the disease is mild, seldom accompanied by severe anaemia and often there is full recovery
Autoirnmunt Haemolytic Anaemia in Children
5x9
within I month. In contrast to our observations, Bell e t a ! (1973) report deaths in a group of patients with cold antibodies. However, their patients were mainly elderly and some of the deaths might have been due to the complications of steroid therapy. It is known that it may be very difficult to classify cases of AIHA into those that arise de novo and those that may be associated with various well-defined disorders and the figures vary markedly when different authors report on adult patients (Engelfriet et al, 1968; Dzierzkowa-Borodej, 1971). In the present series only seven patients (16%) had an accompanying chronic disease (systemic lupus erythematosus, chronic non-specific lymphadenitis and glomerulonephritis), but more than half had had an acute infection or a vaccination against infectious diseases about 2 weeks prior to the development of symptoms of AIHA. It is interesting that AIHA accompanied by a chronic disease occurred mainly in older children, frequently at the age of puberty, whereas cases preceded by infection or vaccination occurred mainly in younger children. The presence of a preceding infection in acute AIHA and of SLE accompanying chronic AIHA is also mentioned by Habibi and his colleagues, although these authors did not stress that older patients were more likely to have chronic disease. In patients with cold antibodies only pneumonia or otitis preceded the AIHA while in patients with warm antibodies a variety of infections like scarlet fever, mumps and influenza were seen as well as immunizations. This might suggest a different mechanism of autoantibody production in the two groups of anaemia. Like Zuelzer ct a1 (1g70), we have seen patients who suffered from chronic AIHA and lymphadenopathy histologically described as non-specific reactive lymphadenitis. Since in adults Iymphadanopathy associated with AIHA may be due to malignant lympoma, children with non-specific lymphadenitis should be carefully watched to see if malignancy develops. Although prognosis in AIHA is in general good, about 10% of our children died: though in no case was death directly due to severe anaemia. The children died from uncontrollable bleeding caused by thrombocytopenia, uraemia or the accompanying disease such as SLE. The mechanism of thrombocytopenia in patients with AIHA is not clear. Antibodies against antigens common to red cells and platelets might be involved but disseminated intravascular coagulation (DIC) initiated by haemolysis and leading to thrombocytopenia cannot be excluded. It might be useful to determine the level of fibrinogen degradation products to resolve this problem and it might be helpful in planning treatment. It is possible that DIC may play a part in patients suffering from AIHA with uraemia (Lanzkovsky & McGrory, 1967).
AIHA in children presents certain differences from AIHA in adults: the disease in childhood often appears acutely with a violent onset but a good prognosis; a more distinct link with infections is found and the illness is less frequently associated with other chronic diseases, especially malignant lymphomata. These differences have not been explained and require further investigation. REFERENCES ANDRZEJEWSKA, E., CHOJNACKA, J. & SAWICKA, E. (1955) Autoprzeciwcida w niedokrwistoici hemoitycznej. Pediatria Pofska, 6, 521.
BELL, C.A., ZWICKER,H. & SACKS,H.J. (1973)
Autoimmune hemolytic anaemia. Routine serologic evaluation in a general hospital population, American Journal of Clinical Pathology, 60, 903. CARAPELLA DE LUCA,E. (1975)Autoimmune hemolytic
B. Zupatiska et a1 anaemia (AHA) in childhood: a review of 26 cases. Book of Abstracts X I V Congress of the Infernationals Society of Blood Transfusion, p 50. DACIB, J.V. (1970)Autoimmune haemolytic anaemias. British Medical]ournal, 3,381. DZIBRZKOWA-BORODBJ, w. (1971) UMad ant)’genowy I jego rola w immunopatologii. Postepy Higieny i Medyeyny Doswiadczalnej, 25, 789. ENGELFRIBT, C.P., V.D. B O W , A.E.G. KR.,V.D. GmsSEN, M., BACKERS, D O . & VAN LOGHBM, J.J. (1968) Autoimmune haemolytic anaemias. I. Serological studies with pure anti-immunoglobulin reagents. ClinicalandExperimenfalImmunology, 3,605. GERBAL, A., HOMBBRG, J.C., ROCHANT, H., LIBERGE, G., DBLANIE, F. & SALMON,H. (1967) Nouvelle classification immunologique des anemies hemolitiques avec autoanticorps. Nouvelle Revue Franpise d’Hhzfologie, 7 , 401. HABIBI, B. & SCHAISON, G. (1973) AnCmies htmolytiques auto-immunes de l’enfant et de l’adolescent. Actualitis Himatologiques. JBNKINS, W.J., MCH, W.L., NOADBS, J., TIPPET, P., R. & RACE,R.R. (1960) The I antigen and LANGBR, antibody. Vox Sanguinis, 5, 97. LAMAGNERB, J.P., LEROY,J., AVRIL, J., LANGIBR, J. & DBSBUQUOIS, G. (1972) AnCmia hkmolytique aigue transitoire auto-anticorps (gamma M)-C de I’enfant. Pediafrie, a7, 749. LANZKOWSKY, P. & MCCRORY,W.W. (1967) Disseminated intravascular coagulation as a possible factor in the pathogenesis of thrombotic micro-
angiopathy (hemolytic-uremic syndrome). Journal of Pediatrics, 70, 460. MARSH, W.L. (1961) Anti-i: a cold antibody defining the Ii relationship in human red cells. BrifishJournal of Haemafology, 7, zoo. PAOLUCCI, G., ROSITO,P., MANCINI,A., et a1 (1970) Considerazioni clinico-terapeutiche su quattro casi di anemia emolitica autoimmune dell’infanzia Hematologica (Pavia), 55, 509. PIROFSKY. B. (1969) Autoimmunization and the Autoimmune Hemolytic Anemias, p 23. Williams & Wilkins, Baltimore. ROWBCKA-TRZBBICKA, K. (1964) Nabytej Niedokrwostoici hemolitycznej na tle autoimniunizacji u 7-letniego chlopca. Pediatria Polska, 39, 433. RUBIN, H. (1963) Antibody elution from red blood cells. Journal of Clinical Pathology, 16, 70. SALMON,C., GERBAL,A. & HOMBBBG, J.C. (1967) Acquisitions rCcentes sur les auto-anticorps #an& mies htmolytiques acquises. TrunsfHsion (Paris), 10, 143.
WBINER, AS., UNGER, L.J., COHEN,L. & FELDMAN, J. (1956) Type-specific cold auto-antibodies as cause of acquired hemolytic anemia and hemolytic transfusion reactions: biologic test with bovine red cells. Annals of Internal Medicine, 4, 221. ZUELZER, W.W., MASTRANGELO, R., STALBERG, C.S., POLIK,M.D., PAGE,R.H.& THOMPSON, R.I. (1970) Autoimmune hemolytic anemia. Natural history and viral-immunologic interactions in childhood. American Journal of Medicine, 49, 80.
511.
Autoimmune Haemolytic Anaemia in Children B. ~ P A ~ S W. K AEAWKOWICZ, , B. G ~ R S KJ.AKOZEOWSKA, , M. OCHOCKA, R. ROKICKA-MILEWSKA, D. DERULSKA AND D. CIEPIELEWSKA Institute of Haematology, Warsaw, and Institute of Paediatrics, School of Medicine, Warsaw (Received 9 June 1975; acceptedfor publication 18 March 1976) SUMMARY. Forty-four children with autoimmune haemolytic anaemia (AIHA) are described: 3 I had acute, subacute or chronic disease with warm autoantibodies and 13 had acute or chronic anaemia with cold autoantibodies. The commonest forms were the acute and subacute types with warm autoantibodies and these were more frequent in young children, while chronic AIHA occurred mainly among children at puberty. 111 about 16% the anaemia was accompanied by a chronic disorder but in over 50% the anaemia was preceded by an acute infection or immunization. The former gave rise mainly to chronic anaemia, but the latter was associated with the acute and subacute forms. In general the prognosis was good and death was never caused by anaemia per se. The prognosis was worse in patients with clinical features of thrombocytopenia and bleeding and with the immunological findings of free autoantibodies in the serum and a positive direct antiglobulin test. In acute and subacute forms, treatment with corticosteroids and sometimes with blood transfusions was effective. In chronic forms of the disease it was often necessary to give additional immunosuppressive drugs orjand to perform a splenectomy. The autoimmune haemolytic anaemias (AIHA) are not common blood disorders of childhood. In the literature most clinical papers are based on case reports (Andrzejewska et al, 1955; Rowecka-Trzebicka, 1964; Pirofsky, 1969; Paolucci et al, 1970; Lamagnere et al, 1972) and it is only in recent years that reviews of a larger number of children have been published (Zuelzer et al, 1970; Habibi & Schaison, 1973; Carapella de Luca, 1975). Observations on children at the Institute of Pediatrics in Warsaw over 20 years seem to indicate that the clinical course, immunological characteristics and causes leading to the development of AIHA in childhood are somewhat different from those occurring in adults and it thus appeared useful to present our clinical material. MATERIALS AND METHODS In the period from 1955 to 1974, 44 children with AIHA aged 3 months to 14years were seen at the Institute of Pediatrics. All had signs of haemolytic anaemia and either a positive direct antiglobulin test or autoantibodies present in the serum or both. Serological investigations at the Institute of Haematology in Warsaw were performed by conventional methods: polyvalent antiglobulin serum was used for the direct antiglobulin test and eluates were Correspondence: Dr Barbara Zupaliska, Institute of Haematology, 00-791Warsaw, Chocimska 5, Poland. 511
B. Zupabka et a1
Autoimmune Haemolytic Anuemia in Children
513
made by Rubin’s (1963) technique. The patients were classified into two groups: AIHA with warm autoantibodies and AIHA with cold autoantibodies depending on the optional temperature for autoantibody activity. Criteria for serological classification as ‘AIHA with warm autoantibodies’ was based on the presence of a positive direct antiglobulin test and/or the presence of autoantibodies in the serum optionally active at 37°C. Criteria for serological classification as ‘AIHA with cold autoantibodies’ was based on the presence of cold agglutinins with a titre of more than 32 at 12OC and still active at room temperature or higher temperatures up to 34°C. OBSERVATIONS AND RESULTS A I H A with Warm Autoantibodies There were 3 I patients in this group (Table I and Fig r) aged 3 months to 14 years, and 17 were boys and 14girls. Three subgroups were made according to the duration of the disease, whether acute, subacute or chronic. AlHAacute
AIHA chronic
AIHA subacute
654W
Ln 0
,”
3-
0 z
2I-
00
I
5
1015
0
I 5 1015 Age (years)
0
I
5
10 15
FIG I . AIHA with warm antibodies: age at diagnosis.
Acute A I H A . This group contained 13 patients, seven boys and six girls, whose illness lasted 3 months or less. Their ages ranged from 5 months to 13 years and one-third were less than I year old. In six patients an infectious disease (mumps, upper respiratory tract infection, tonsillitis, scarlet fever or pneumonia) preceded the development of anaemia. In two patients the disease developed after immunizations against typhoid fever and poliomyelitis; and with the triple vaccine Diph-Tet-Pert (Table 11). The onset of the illness was acute with fever, general weakness, abdominal pain, vomiting and diarrhoea. In most cases the anaemia was severe with a haemoglobin level below 6 g/dl and blood films showed a high reticulocyte count, nucleated red cells, and the presence of numerous spherocytes. In five patients the leucocyte count was increased and six had thrombocytopenia, although only three patients showed a bleeding tendency. Haenioglobinuria was frequently noted. The bilirubin level was c 30-10o~mol/l.and only in one patient did it reach c 2oopmol/l. A correlation was noted between the intensity of anaemia and the results of the serological tests; when the anaemia was only mild or moderate, the direct antiglobulin test was positive but no free antibody was found in the serum, whereas when the anaemia was severe additional
B. Zupariska et a1
Autoimmune Haemolytic Anaemia in Children
SIS
incomplete autoantibodies were found in the serum. No specificity could be found for any of these autoantibodies. Eleven patients recovered completely, both clinically and serologically. In general, the signs of haemolysis disappeared 1-2 weeks after the onset of the illness and the serological tests became negative after a further 2 weeks. The haemolysis recurred only rarely and the duration of the illness never exceeded 3 months. All children responded well to treatment with corticosteroids and blood transfusions and one child recovered without any treatment. Two patients died. The first was a 9-year-old girl, E.S., who had had scarlet fever 2 weeks before the onset of AIHA. On admission to the hospital she was pale and jaundiced and had enlarged cervical lymph nodes. She was severely anaemic, the haemoglobin level being The platelets were decreased in number under 2 g/dl and the red cell count 0.53 x 10~~11. (31 x 1o9/I.) and purpura developed. During her 2 weeks stay in hospital she remained severely anaemic and she died from bleeding and pneumonia; an autopsy was not done. The second was a 13-year-old boy, R.P., who was brought to hospital 2 weeks after an antityphoid inoculation because he was pale, jaundiced and vomiting blood. He was found to have a low platelet count and a bleeding tendency and during the next 3 weeks severe abdominal pains, temporary oliguria and the biochemical signs of kidney failure were seen. He died with signs of severe haemolysis and increased bleeding. At autopsy the following abnormalities were found : haemosiderosis, necrosis and haemorrhage in the spleen, thrombosis in the splenic arteries, necrosis in the liver, oesophageal and duodenal ulceration with blood in the stomach and a haemothorax. Subacute A I H A . This group contained 12 patients (six boys and six girls) who suffered from AIHA for not longer than 2 years. The age of the children was similar to those in the preceding group and varied between 3 months and 9 years. Seven of the patients had had an acute infection (pneumonia, otitis, tonsillitis or influenza) or an immunization 1-2 weeks before the onset of anaemia (Table 111). The start of the illness was usually acute and the symptoms were similar to those in the previous group. Recovery was slow, relapses were more frequent than in the first group and usually related to an infection or to reduction of the dose of corticosteroids. In eight of the 12 cases the anaemia was severe (Hb below 6 g/dl) and the bilirubin level 4-9 mg/dl. The leucocyte count was usually increased and the platelet count was decreased in three patients but only one bled abnormally. Haemoglobinuria was found not so often as in the previous group. Subacute AIHA was rather homogeneous as far as serological results were concerned. In all patients the direct antiglobulin test was positive and incomplete autoantibodies were present in the serum and eluate. In five patients the autoantibodies were found to have the specificity of anti-e but in the remaining patients specificity could not be demonstrated. Seven patients recovered fully, both clinically and serologically, within a period of 10 months to 2 years. Corticosteroids, immunosuppressive drugs and splenectomy were used to treat these patients. Blood transfusions were given only in cases of severe anaemia. In four patients the clinical signs and serological findings were still present when this survey was completed. However, they are included in this group because their anaemia had not been present for more than 2 years and because their clinical course was similar to the other patients. One girl, M.M., 10 months old at diagnosis, died after 13 years of illness. She had relapsed frequently, not only with severe haemolysis but also with thrombocytopenia and purpura.
Chronic 4
9
6
chronic
ADHA with cold antibodies Acute
IZ
13
No. of cases
Subacute
Acute
AIHA with warm antibodies
Type ofAZHA
Pneumonia
Otitis
Upper respiratory tract infection Pneumonia
-
I I
0
I
3
I
I
I
I
Otitis
2
No. of uses
Upper respiratory tract infection Mumps Scarlet fever Tonsillitis Pneumonia Upper respiratory tract infection Muenza(Hong Kong I :40 Az. England I :20) Pneumonia
Infections
Typhoid fever
Diph-Tet-Pert
Typhoid fever+ poliomyelitis
Immunizafion
o
0
o
I
I
I
No. of cases
SLE Chronic non-specific lymphadenitis
-
SLE Chronic non-specific lymphadenitis
Glomerulonephritis
-
Accompanying diseases
TABLE III. Accompanying diseases and infections or immunization which preceded the onset of AIHA
2
I
0
I
2
0
cases
No. of
E.
2
Autoimmune Huemolytic Anaemia in Children
517
Chronic A I H A . This group contained six patients (four boys and two girls) 12-14 years old. In three children the anaemia was associated with another disease: systemic lupus erythematosus (SLE) or chronic nonspecific lymphadenitis (Table 111). The onset of the disease in all the children was gradual and often masked by the accompanying illness, so that the symptoms were not characteristic. Anaemia was not severe and frequently associated with thrombocytopenia. The bilirubin level was 30-50 pmol/l. and haemoglobinuria was not noticed. Numerous relapses were observed in the course of the illness. In five patients the direct antiglobulin test was positive and in four of these additional autoantibodies were found in the serum. One patient had only autoantibodies in the serum. No specificity was found for any of these autoantibodies. Corticosteroids and immunosuppressive drugs or corticosteroids and splenectomy were used to treat the patients but none recovered fully. One 13-year-old girl, E.O., died after 2 years of anaemia associated with SLE and complicated by thronibocytopenic purpura and uraemia. Autopsy confirmed the diagnosis of SLE with lupus glomerulonephritis.
51
AIHA chronic
AlWocute
4-
8
3-
U
c 0 2z
I-
0-
diL um
0
I
5
10 15
o
i
5
ro IS
Age (years)
FIG2. AIHA with cold antibodies: age at diagnosis.
A I H A with Cold Antibodies This group contained 13 patients (eight boys and five girls) whose ages ranged from 3 months to 11 years (Table I1 and Fig 2). They were classified into two subgroups according to the clinical course. Acute A I H A . This group contained nine patients (five boys and four girls) most of whom were under 5 years, and all of whom recovered within I month. The illness started suddenly with fever and in every case was preceded by infections such as pneumonia or otitis. In one case the pneumonia was found to be due to Mycoplusmu pneumonioe. Most patients were not severely anaemic but the leucocyte count was frequently raised and in one patient thrombocytopenia was found. Three patients had a bilirubinaemia of c 50-120 pmol/l. All nine patients had cold autoantibodies in their serum but only two patients with severe anaemia had a positive direct antiglobulin test. The specificity of the autoantibodies was
518
B. Zupatiska et a1
established as anti-I in only two out of the nine patients. One patient showed polyagglutination. The clinical symptoms and serological abnormalities usually disappeared between the second and fourth week of illness and relapse did not occur. Only three patients were treated with corticosteroids : one received an additional blood transfusion and the other recovered without any treatment. Chronic AIHA. This group contained four patients (three boys and one girl) who had repeated relapses during the 2-5 years of observation. One patient was a 13-year-old girl who after suffering from haemolytic anaemia for 2 years developed overt SLE with skin lesions, kidney involvement and LE cells in the blood. Two other children had chronic enlargement of the lymph nodes histologically described as nonspecific lymphadenitis. As in the preceding group, the two patients who were most anaemic had a positive direct antiglobulin test and autoantibodies in the serum. The other two had only autoantibodies in the serum. In three cases the specificity of autoantibodies was established as anti-I. All patients were treated with corticosteroids and one was splenectomized but none recovered completely.
DISCUSSION In this clinical analysis of children with signs of haemolytic anaemia and serological tests indicating autoantibodies against erythrocytes, only a simple classification into those with warm autoantibodies and those with cold autoantibodies has been used. This is because these observations were made over 20 years and therefore the extent of investigation was variable and for many years only polyvalent antiglobulin serum was available (Wiener et al, 1956). In order to obtain comparable material we have omitted the more comprehensive tests on later patients and thus we cannot use the classifications introduced recently by other authors. These take into account the type of proteins found in the direct antiglobulin test, i.e. the immunoglobulin class of the autoantibody and the presence or absence of complement binding (Wiener et al, 1956; Jenkins et al, 1960; Marsh, 1961; Gerbal et al, 1967; Salmon et al, 1967; Engelfriet et al, 1968, Dacie, 1970). However, it would seem from studies on AIHA in adults that this further classification does not give any very useful information and since the clinical picture of AIHA with warm antibodies differs markedly from that of the same disease with cold antibodies, a simple classification is preferred. In our series, children with AIHA due to warm antibodies (70% of the patients) were commoner than children with AIHA due to cold antibodies (30% of the patients). This last incidence is high compared with that of Habibi & Schaison (1973), who only recorded cold antibodies in 10% of their cases. This difference may be due to differences of selection; Hababi and his colleagues included patients up to 18 years old and our series includes patients who were not severely anaemic. Acute and subacute AIHA with warm antibodies which were the commonest forms of AIHA in our series generally have a good prognosis although the onset is sudden with severe anaemia which needs treatment not only with corticosteroids but often also with blood transfusions. The prognosis is not quite so good in patients who have additional autoantibodies in the serum. The clinical picture of acute AIHA with cold antibodies is quite different. The course of the disease is mild, seldom accompanied by severe anaemia and often there is full recovery
Autoirnmunt Haemolytic Anaemia in Children
5x9
within I month. In contrast to our observations, Bell e t a ! (1973) report deaths in a group of patients with cold antibodies. However, their patients were mainly elderly and some of the deaths might have been due to the complications of steroid therapy. It is known that it may be very difficult to classify cases of AIHA into those that arise de novo and those that may be associated with various well-defined disorders and the figures vary markedly when different authors report on adult patients (Engelfriet et al, 1968; Dzierzkowa-Borodej, 1971). In the present series only seven patients (16%) had an accompanying chronic disease (systemic lupus erythematosus, chronic non-specific lymphadenitis and glomerulonephritis), but more than half had had an acute infection or a vaccination against infectious diseases about 2 weeks prior to the development of symptoms of AIHA. It is interesting that AIHA accompanied by a chronic disease occurred mainly in older children, frequently at the age of puberty, whereas cases preceded by infection or vaccination occurred mainly in younger children. The presence of a preceding infection in acute AIHA and of SLE accompanying chronic AIHA is also mentioned by Habibi and his colleagues, although these authors did not stress that older patients were more likely to have chronic disease. In patients with cold antibodies only pneumonia or otitis preceded the AIHA while in patients with warm antibodies a variety of infections like scarlet fever, mumps and influenza were seen as well as immunizations. This might suggest a different mechanism of autoantibody production in the two groups of anaemia. Like Zuelzer ct a1 (1g70), we have seen patients who suffered from chronic AIHA and lymphadenopathy histologically described as non-specific reactive lymphadenitis. Since in adults Iymphadanopathy associated with AIHA may be due to malignant lympoma, children with non-specific lymphadenitis should be carefully watched to see if malignancy develops. Although prognosis in AIHA is in general good, about 10% of our children died: though in no case was death directly due to severe anaemia. The children died from uncontrollable bleeding caused by thrombocytopenia, uraemia or the accompanying disease such as SLE. The mechanism of thrombocytopenia in patients with AIHA is not clear. Antibodies against antigens common to red cells and platelets might be involved but disseminated intravascular coagulation (DIC) initiated by haemolysis and leading to thrombocytopenia cannot be excluded. It might be useful to determine the level of fibrinogen degradation products to resolve this problem and it might be helpful in planning treatment. It is possible that DIC may play a part in patients suffering from AIHA with uraemia (Lanzkovsky & McGrory, 1967).
AIHA in children presents certain differences from AIHA in adults: the disease in childhood often appears acutely with a violent onset but a good prognosis; a more distinct link with infections is found and the illness is less frequently associated with other chronic diseases, especially malignant lymphomata. These differences have not been explained and require further investigation. REFERENCES ANDRZEJEWSKA, E., CHOJNACKA, J. & SAWICKA, E. (1955) Autoprzeciwcida w niedokrwistoici hemoitycznej. Pediatria Pofska, 6, 521.
BELL, C.A., ZWICKER,H. & SACKS,H.J. (1973)
Autoimmune hemolytic anaemia. Routine serologic evaluation in a general hospital population, American Journal of Clinical Pathology, 60, 903. CARAPELLA DE LUCA,E. (1975)Autoimmune hemolytic
B. Zupatiska et a1 anaemia (AHA) in childhood: a review of 26 cases. Book of Abstracts X I V Congress of the Infernationals Society of Blood Transfusion, p 50. DACIB, J.V. (1970)Autoimmune haemolytic anaemias. British Medical]ournal, 3,381. DZIBRZKOWA-BORODBJ, w. (1971) UMad ant)’genowy I jego rola w immunopatologii. Postepy Higieny i Medyeyny Doswiadczalnej, 25, 789. ENGELFRIBT, C.P., V.D. B O W , A.E.G. KR.,V.D. GmsSEN, M., BACKERS, D O . & VAN LOGHBM, J.J. (1968) Autoimmune haemolytic anaemias. I. Serological studies with pure anti-immunoglobulin reagents. ClinicalandExperimenfalImmunology, 3,605. GERBAL, A., HOMBBRG, J.C., ROCHANT, H., LIBERGE, G., DBLANIE, F. & SALMON,H. (1967) Nouvelle classification immunologique des anemies hemolitiques avec autoanticorps. Nouvelle Revue Franpise d’Hhzfologie, 7 , 401. HABIBI, B. & SCHAISON, G. (1973) AnCmies htmolytiques auto-immunes de l’enfant et de l’adolescent. Actualitis Himatologiques. JBNKINS, W.J., MCH, W.L., NOADBS, J., TIPPET, P., R. & RACE,R.R. (1960) The I antigen and LANGBR, antibody. Vox Sanguinis, 5, 97. LAMAGNERB, J.P., LEROY,J., AVRIL, J., LANGIBR, J. & DBSBUQUOIS, G. (1972) AnCmia hkmolytique aigue transitoire auto-anticorps (gamma M)-C de I’enfant. Pediafrie, a7, 749. LANZKOWSKY, P. & MCCRORY,W.W. (1967) Disseminated intravascular coagulation as a possible factor in the pathogenesis of thrombotic micro-
angiopathy (hemolytic-uremic syndrome). Journal of Pediatrics, 70, 460. MARSH, W.L. (1961) Anti-i: a cold antibody defining the Ii relationship in human red cells. BrifishJournal of Haemafology, 7, zoo. PAOLUCCI, G., ROSITO,P., MANCINI,A., et a1 (1970) Considerazioni clinico-terapeutiche su quattro casi di anemia emolitica autoimmune dell’infanzia Hematologica (Pavia), 55, 509. PIROFSKY. B. (1969) Autoimmunization and the Autoimmune Hemolytic Anemias, p 23. Williams & Wilkins, Baltimore. ROWBCKA-TRZBBICKA, K. (1964) Nabytej Niedokrwostoici hemolitycznej na tle autoimniunizacji u 7-letniego chlopca. Pediatria Polska, 39, 433. RUBIN, H. (1963) Antibody elution from red blood cells. Journal of Clinical Pathology, 16, 70. SALMON,C., GERBAL,A. & HOMBBBG, J.C. (1967) Acquisitions rCcentes sur les auto-anticorps #an& mies htmolytiques acquises. TrunsfHsion (Paris), 10, 143.
WBINER, AS., UNGER, L.J., COHEN,L. & FELDMAN, J. (1956) Type-specific cold auto-antibodies as cause of acquired hemolytic anemia and hemolytic transfusion reactions: biologic test with bovine red cells. Annals of Internal Medicine, 4, 221. ZUELZER, W.W., MASTRANGELO, R., STALBERG, C.S., POLIK,M.D., PAGE,R.H.& THOMPSON, R.I. (1970) Autoimmune hemolytic anemia. Natural history and viral-immunologic interactions in childhood. American Journal of Medicine, 49, 80.
