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Infection-associated haemophagocytic syndrome in an infant
Journal of Infection (I988) I7, I67-I7O
CASE REPORT Infection-associated haemophagocytic
syndrome in an infant
H. R. Jenkins and O. P. Gray
Department of Child Health, University of Wales College of Medicine, Heath, Cardiff, U.K Accepted for publication 13 January 1988 Summary We describe the case of an infant with haemophagocytic syndrome initiated by severe infection. The difficulties of diagnosing and managing the condition as well as its pathogenesis are discussed.
Introduction Recent reappraisal of histiocytic syndromes in childhood I has provided a valuable framework for understanding the pathogenesis and aetiology of these complicated diseases. T h i s report of an infant w h o presented with overwhelming septicaemia and p r o f o u n d pancytopenia due to histiocytic infiltration of the bone m a r r o w adds to an understanding of these disorders. T h e investigation and s u b s e q u e n t m a n a g e m e n t of this child highlight some of the difficulties involved in making an accurate diagnosis of the underlying condition.
Case report T h e patient was a female infant b o r n after a normal pregnancy and delivery to a 3o-year-old m o t h e r who had four children b y a previous liaison. T h e r e was no relevant family history of illness. Following excessive p r o d u c t i o n of m u c u s and regurgitation of her first feed, a diagnosis of oesophageal atresia was confirmed. T h i s was successfully corrected surgically. T h e infant s u b s e q u e n t l y thrived without further p r o b l e m s until she was readmitted to hospital on the day before her first birthday with a 24 hours' history of refusing feeds and of fever (4o °C). Some IO days earlier she had suffered a mild u p p e r respiratory tract illness which had lasted for 48 h. O n examination she was seen to be miserable b u t not otherwise unwell. H e r throat and left tympanic m e m b r a n e were inflamed. T h e r e was a suggestion of fullness in the left parotid region b u t the m o u t h appeared normal. A provisional diagnosis of u p p e r respiratory tract viral infection was made. She was treated with antipyretics after b l o o d had been taken for culture, viral antibody titres and haematological assessment. Over the next 4 h the infant's condition deteriorated dramatically; she became shocked and p r o f o u n d l y ill. T h e r e was n o w a m a r k e d swelling o f the left parotid region which rapidly progressed across the face to the midline causing the left eye to close. T h e buccal m u c o u s m e m b r a n e on the left side became tense with exudation of straw-coloured fluid. She developed a serous discharge from her left ear and left nostril. In ot63-4453/88/o5oi67 + 0 4 $02.00/0 7
(~ 1988 T h e British Society for the Study of Infection JIN 17
168
H. R. J E N K I N S AND O. P. GRAY
view of increasing respiratory embarrassment, the infant was transferred to the intensive care unit where direct laryngoscopy revealed grossly swollen supraglottic tissues. Intubation was performed with difficulty. Some 4 h later the swelling had further progressed causing bilateral periorbital oedema. T h e r e was continuous copious discharge of sero-sanguinous fluid from the left auditory meatus and both nostrils. Investigation showed a haemoglobin (Hb) concentration of 7"8 g/d1, white blood cell (WBC) count 2 × I09/1, platelet count 36 × IO9/1; coagulation screen as well as an X-ray of the skull and mandible were normal. Evidence of a recent viral infection derived from subsequently testing paired samples of serum was lacking. Microscopy of the nasal and aural fluids, however, revealed n u m e r o u s Gram-positive cocci and Gram-negative bacilli which proved on culture to be Streptococcus pneumoniae and Haemophilus influenzae respectively. T h e provisional diagnosis was that of rapidly spreading cellulitis and septicaemia with underlying pancytopenia. T h e child was treated with broad-spectrum antibiotics (cefuroxime, gentamicin and metronidazole) and resuscitated with plasma and blood. She required to be paralysed and artificially ventilated. D u r i n g the first 4 days after admission, the massive swelling progressed to involve the right side of the face, the neck and the scalp. In addition, the liver edge became palpable IO cm, and the spleen palpable 6 cm, below the costal margin. Over the same period of time the H b concentration was maintained above I I g/dl following a single transfusion of whole blood. T h e WBC count fell to 0"5 x Iog/1 and the platelet count to I5 x IO9/1. Subsequently, daily granulocyte and platelet transfusions were required for z weeks. T h e bone marrow aspirated on day 4 was hypocellular without specific features, but that aspirated on day IO showed histiocytic infiltration with haemophagocytosis. This was initially felt to be compatible with a diagnosis of Langerhans' cell histiocytosis (LCH) although subsequent expert review of the specimen did not suggest any specific features of this condition. T h e r e was no evidence of neoplasia in either bone marrow aspirate. Because the child remained critically ill, with L C H being a possible diagnosis, steroid therapy was instituted with intravenous hydrocortisone at a dose of 2 m g / k g . T h e child's condition gradually improved and by day 20 the facial swelling had diminished and the W B C and platelet counts were maintained without transfusion. A liver biopsy showed normal liver architecture with evidence of mild cholestasis and no evidence of histiocytic infiltration. Enlargement of the liver and spleen gradually disappeared during the next 3 weeks. T h e child's immunological status was extensively investigated. Initially, concentrations of all i m m u n o globulin classes were low. T h e patient received weekly immunoglobulin infusions for 3 weeks and thereafter her I g G and I g M immunoglobulin concentrations were normal but she remained IgA-deficient. Tests of cellmediated immunity, T-cell function, complement activity and neutrophil function were all abnormal during the acute stage of the illness but were normal on recovery. Tests for H I V antibody were negative on three occasions. T h e child was artificially ventilated for 3 weeks and finally left the intensive care unit 4o days after admission. Steroids had been discontinued and repeated bone marrow aspiration was normal. A computer-assisted tomographic scan of the head showed cerebral atrophy and, although initially she was severely
Haemophagoeytic syndrome in an infant
I69
affected neurologically, she made a remarkable recovery and was almost developmentally normal at the time she left hospital. Subsequently she remained free of infection and her haematological and immunological values were normal except for a low concentration of serum IgA. A year later, however, the child was readmitted to hospital with a purpuric rash and moderate enlargement of the liver and spleen. T h e bone marrow was typical of acute lymphoblastic leukaemia (ALL). T h e child was treated with cytotoxic drugs but died after an episode of Gram-negative bacteraemia. Discussion
Accurate delineation of histiocytic disorders has been fraught with problems of nomenclature and classification, although recently a more rational approach has been proposed. 1 T h e term Langerhans' cell histiocytosis (LCH) embraces disorders previously called 'Histiocytosis X ' and, initially, this diagnosis was entertained in our patient. Definitive proof of L C H was lacking and there was no evidence of the typical skin rash or bony abnormalities often found in this condition. T h e simplest test for L C H is to stain the bone marrow aspirate with alpha-mannosidase but the method requires fresh material and, unfortunately, in our case this opportunity was lost. It is likely, however, that the staining would have been negative, particularly since there was evidence of haemophagocytosis in the specimen from our patient and this is not a feature of Langerhans' cells. Several other histiocytic syndromes feature accumulations of active histiocytes but, crucially, the histiocytes are not Langerhans' cells. T h e two most common of these in childhood are haemophagocytic lymphohistiocytosis, a familial and lethal condition, which is an unlikely diagnosis in our case, and 'infection-associated haemophagocytic syndrome' (IAHS). T h e latter is not familial but is related to various infectious agents. 1'~ IAHS is a systemic disease affecting many organs with a predilection for bone-marrow, lymphoid tissue, spleen, liver and meninges. T h e r e appears to be an infection-provoked proliferation of histiocytes in these organs causing pancytopenia, although the mechanism by which infectious agents cause this disorder is not known and the relationship to haemophagocytic lymphohistiocytosis is not clear. In Risdall's series of 19 patients with IAHS 2 there was evidence of a recent viral infection, particularly a virus of the herpes group or an adenovirus, in 15 of them, most being immuno-incompetent children. Furthermore, the association of viral infections with reversible histiocytic proliferation and haemophagocytosis was suggested as a cause of transient histiocytosis by Chandra et al.fl who also described similar findings in a patient with tuberculosis. Although it appears that many different types of infective agent may precipitate IAHS, it may be impossible to identify the initial offending pathogen as was so in our case. Our patient's immunological status was carefully studied but the only permanent abnormality that we could demonstrate was IgA deficiency. This might have resulted in increased vulnerability to infection. It seems likely that the child's initial illness was IAHS with an apparently mild infection IO days before admission to hospital causing proliferation of histiocytes in liver, spleen and bone marrow. T h e 7-2
x7o
H.R. JENKINS AND O.P. GRAY
consequent pancytopenia and immunological paresis could explain the s u b s e q u e n t overwhelming cellulitis and septicaemia which p r o b a b l y had originated in the middle ear or paranasal sinuses. T h e condition i m p r o v e d either coincidentally with, or as a consequence of, the use of corticosteroids. T h e r e was no evidence of leukaemia in any of the three bone m a r r o w aspirates obtained during the first admission and there is no reported association b e t w e e n I A H S and malignant disease. It is, however, tempting to speculate that the two illnesses were linked in some way, and it is possible that I A H S in our child m a y have been a manifestation of an early pre-leukaemic phase of A L L . T o our knowledge, this association, whether fortuitous or causal, has not been previously reported. T h i s case illustrates the fact that apparently mild infections m a y have a p r o f o u n d effect u p o n a child w h o is not fully i m m u n o c o m p e t e n t . It also illustrates the potential difficulties in accurately diagnosing states of histiocytic proliferation in childhood and again emphasises that infection-associated haemophagocytic s y n d r o m e should be considered in the differential diagnosis. (We thank Dr N. Matthews for performing the immunological investigations as well as Dr J. Pritchard for his review of the bone marrow specimens and assistance with the diagnosis.) References Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet I987; i: 208-2o9. 2. Risdall RJ, McKenna RW, Nesbitt ME et al. Virus-associated hemophagocytic syndrome. A benign histiocytic proliferation distinct from malignant histiocytosis. Cancer x979; 44: 993-IOO2. 3. Chandra P, Chaudhery SA, Rosner F, Kagen M. Transient histiocytosis with striking phagocytosis of platelets, leukocytes and erythrocytes. Arch lntern M e d I975; I35: 989-99 r.
r.
CASE REPORT Infection-associated haemophagocytic
syndrome in an infant
H. R. Jenkins and O. P. Gray
Department of Child Health, University of Wales College of Medicine, Heath, Cardiff, U.K Accepted for publication 13 January 1988 Summary We describe the case of an infant with haemophagocytic syndrome initiated by severe infection. The difficulties of diagnosing and managing the condition as well as its pathogenesis are discussed.
Introduction Recent reappraisal of histiocytic syndromes in childhood I has provided a valuable framework for understanding the pathogenesis and aetiology of these complicated diseases. T h i s report of an infant w h o presented with overwhelming septicaemia and p r o f o u n d pancytopenia due to histiocytic infiltration of the bone m a r r o w adds to an understanding of these disorders. T h e investigation and s u b s e q u e n t m a n a g e m e n t of this child highlight some of the difficulties involved in making an accurate diagnosis of the underlying condition.
Case report T h e patient was a female infant b o r n after a normal pregnancy and delivery to a 3o-year-old m o t h e r who had four children b y a previous liaison. T h e r e was no relevant family history of illness. Following excessive p r o d u c t i o n of m u c u s and regurgitation of her first feed, a diagnosis of oesophageal atresia was confirmed. T h i s was successfully corrected surgically. T h e infant s u b s e q u e n t l y thrived without further p r o b l e m s until she was readmitted to hospital on the day before her first birthday with a 24 hours' history of refusing feeds and of fever (4o °C). Some IO days earlier she had suffered a mild u p p e r respiratory tract illness which had lasted for 48 h. O n examination she was seen to be miserable b u t not otherwise unwell. H e r throat and left tympanic m e m b r a n e were inflamed. T h e r e was a suggestion of fullness in the left parotid region b u t the m o u t h appeared normal. A provisional diagnosis of u p p e r respiratory tract viral infection was made. She was treated with antipyretics after b l o o d had been taken for culture, viral antibody titres and haematological assessment. Over the next 4 h the infant's condition deteriorated dramatically; she became shocked and p r o f o u n d l y ill. T h e r e was n o w a m a r k e d swelling o f the left parotid region which rapidly progressed across the face to the midline causing the left eye to close. T h e buccal m u c o u s m e m b r a n e on the left side became tense with exudation of straw-coloured fluid. She developed a serous discharge from her left ear and left nostril. In ot63-4453/88/o5oi67 + 0 4 $02.00/0 7
(~ 1988 T h e British Society for the Study of Infection JIN 17
168
H. R. J E N K I N S AND O. P. GRAY
view of increasing respiratory embarrassment, the infant was transferred to the intensive care unit where direct laryngoscopy revealed grossly swollen supraglottic tissues. Intubation was performed with difficulty. Some 4 h later the swelling had further progressed causing bilateral periorbital oedema. T h e r e was continuous copious discharge of sero-sanguinous fluid from the left auditory meatus and both nostrils. Investigation showed a haemoglobin (Hb) concentration of 7"8 g/d1, white blood cell (WBC) count 2 × I09/1, platelet count 36 × IO9/1; coagulation screen as well as an X-ray of the skull and mandible were normal. Evidence of a recent viral infection derived from subsequently testing paired samples of serum was lacking. Microscopy of the nasal and aural fluids, however, revealed n u m e r o u s Gram-positive cocci and Gram-negative bacilli which proved on culture to be Streptococcus pneumoniae and Haemophilus influenzae respectively. T h e provisional diagnosis was that of rapidly spreading cellulitis and septicaemia with underlying pancytopenia. T h e child was treated with broad-spectrum antibiotics (cefuroxime, gentamicin and metronidazole) and resuscitated with plasma and blood. She required to be paralysed and artificially ventilated. D u r i n g the first 4 days after admission, the massive swelling progressed to involve the right side of the face, the neck and the scalp. In addition, the liver edge became palpable IO cm, and the spleen palpable 6 cm, below the costal margin. Over the same period of time the H b concentration was maintained above I I g/dl following a single transfusion of whole blood. T h e WBC count fell to 0"5 x Iog/1 and the platelet count to I5 x IO9/1. Subsequently, daily granulocyte and platelet transfusions were required for z weeks. T h e bone marrow aspirated on day 4 was hypocellular without specific features, but that aspirated on day IO showed histiocytic infiltration with haemophagocytosis. This was initially felt to be compatible with a diagnosis of Langerhans' cell histiocytosis (LCH) although subsequent expert review of the specimen did not suggest any specific features of this condition. T h e r e was no evidence of neoplasia in either bone marrow aspirate. Because the child remained critically ill, with L C H being a possible diagnosis, steroid therapy was instituted with intravenous hydrocortisone at a dose of 2 m g / k g . T h e child's condition gradually improved and by day 20 the facial swelling had diminished and the W B C and platelet counts were maintained without transfusion. A liver biopsy showed normal liver architecture with evidence of mild cholestasis and no evidence of histiocytic infiltration. Enlargement of the liver and spleen gradually disappeared during the next 3 weeks. T h e child's immunological status was extensively investigated. Initially, concentrations of all i m m u n o globulin classes were low. T h e patient received weekly immunoglobulin infusions for 3 weeks and thereafter her I g G and I g M immunoglobulin concentrations were normal but she remained IgA-deficient. Tests of cellmediated immunity, T-cell function, complement activity and neutrophil function were all abnormal during the acute stage of the illness but were normal on recovery. Tests for H I V antibody were negative on three occasions. T h e child was artificially ventilated for 3 weeks and finally left the intensive care unit 4o days after admission. Steroids had been discontinued and repeated bone marrow aspiration was normal. A computer-assisted tomographic scan of the head showed cerebral atrophy and, although initially she was severely
Haemophagoeytic syndrome in an infant
I69
affected neurologically, she made a remarkable recovery and was almost developmentally normal at the time she left hospital. Subsequently she remained free of infection and her haematological and immunological values were normal except for a low concentration of serum IgA. A year later, however, the child was readmitted to hospital with a purpuric rash and moderate enlargement of the liver and spleen. T h e bone marrow was typical of acute lymphoblastic leukaemia (ALL). T h e child was treated with cytotoxic drugs but died after an episode of Gram-negative bacteraemia. Discussion
Accurate delineation of histiocytic disorders has been fraught with problems of nomenclature and classification, although recently a more rational approach has been proposed. 1 T h e term Langerhans' cell histiocytosis (LCH) embraces disorders previously called 'Histiocytosis X ' and, initially, this diagnosis was entertained in our patient. Definitive proof of L C H was lacking and there was no evidence of the typical skin rash or bony abnormalities often found in this condition. T h e simplest test for L C H is to stain the bone marrow aspirate with alpha-mannosidase but the method requires fresh material and, unfortunately, in our case this opportunity was lost. It is likely, however, that the staining would have been negative, particularly since there was evidence of haemophagocytosis in the specimen from our patient and this is not a feature of Langerhans' cells. Several other histiocytic syndromes feature accumulations of active histiocytes but, crucially, the histiocytes are not Langerhans' cells. T h e two most common of these in childhood are haemophagocytic lymphohistiocytosis, a familial and lethal condition, which is an unlikely diagnosis in our case, and 'infection-associated haemophagocytic syndrome' (IAHS). T h e latter is not familial but is related to various infectious agents. 1'~ IAHS is a systemic disease affecting many organs with a predilection for bone-marrow, lymphoid tissue, spleen, liver and meninges. T h e r e appears to be an infection-provoked proliferation of histiocytes in these organs causing pancytopenia, although the mechanism by which infectious agents cause this disorder is not known and the relationship to haemophagocytic lymphohistiocytosis is not clear. In Risdall's series of 19 patients with IAHS 2 there was evidence of a recent viral infection, particularly a virus of the herpes group or an adenovirus, in 15 of them, most being immuno-incompetent children. Furthermore, the association of viral infections with reversible histiocytic proliferation and haemophagocytosis was suggested as a cause of transient histiocytosis by Chandra et al.fl who also described similar findings in a patient with tuberculosis. Although it appears that many different types of infective agent may precipitate IAHS, it may be impossible to identify the initial offending pathogen as was so in our case. Our patient's immunological status was carefully studied but the only permanent abnormality that we could demonstrate was IgA deficiency. This might have resulted in increased vulnerability to infection. It seems likely that the child's initial illness was IAHS with an apparently mild infection IO days before admission to hospital causing proliferation of histiocytes in liver, spleen and bone marrow. T h e 7-2
x7o
H.R. JENKINS AND O.P. GRAY
consequent pancytopenia and immunological paresis could explain the s u b s e q u e n t overwhelming cellulitis and septicaemia which p r o b a b l y had originated in the middle ear or paranasal sinuses. T h e condition i m p r o v e d either coincidentally with, or as a consequence of, the use of corticosteroids. T h e r e was no evidence of leukaemia in any of the three bone m a r r o w aspirates obtained during the first admission and there is no reported association b e t w e e n I A H S and malignant disease. It is, however, tempting to speculate that the two illnesses were linked in some way, and it is possible that I A H S in our child m a y have been a manifestation of an early pre-leukaemic phase of A L L . T o our knowledge, this association, whether fortuitous or causal, has not been previously reported. T h i s case illustrates the fact that apparently mild infections m a y have a p r o f o u n d effect u p o n a child w h o is not fully i m m u n o c o m p e t e n t . It also illustrates the potential difficulties in accurately diagnosing states of histiocytic proliferation in childhood and again emphasises that infection-associated haemophagocytic s y n d r o m e should be considered in the differential diagnosis. (We thank Dr N. Matthews for performing the immunological investigations as well as Dr J. Pritchard for his review of the bone marrow specimens and assistance with the diagnosis.) References Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet I987; i: 208-2o9. 2. Risdall RJ, McKenna RW, Nesbitt ME et al. Virus-associated hemophagocytic syndrome. A benign histiocytic proliferation distinct from malignant histiocytosis. Cancer x979; 44: 993-IOO2. 3. Chandra P, Chaudhery SA, Rosner F, Kagen M. Transient histiocytosis with striking phagocytosis of platelets, leukocytes and erythrocytes. Arch lntern M e d I975; I35: 989-99 r.
r.