Delayed Autoimmune Haemolytic Anaemia in Severe Malaria
Delayed Autoimmune Haemolytic Anaemia in Severe Malaria
A 17-year old Ivorian female without remarkable medical history was admitted for fever, chills, headache, and abdominal pain in a French University Hospital Centre (day 1). She had left Ivory Coast seven days earlier to live in France for studying purpose and symptoms began two days before her admission. Initial physical examination showed a temperature of 39°C and pain when palpating right hypocondrium. Blood tests demonstrated a normal leucocyte count, a thrombocyte count of 11,000/mm (normal range 150,000–450,000), a haemoglobin level of 12.6 g/dL (12–16) with abnormalities indicative of haemolysis: rise in lactate dehydrogenase (LDH) at 500 U/L (5–248) and total bilirubin at 105 μmol/L (3–18) with a low haptoglobin of 0.15 g/L (0.3–2). She was diagnosed with uncomplicated malaria as peripheral thin blood film showed P. falciparum trophozoites (0.8% of parasitized erythrocytes). Abdominal ultrasonography ruled out biliary tract or gall bladder infection. A treatment with oral artemether/lumefantrine combination (Riamet©) was initiated with respectively, 80 and 480 mg trice within the first 24 hours of hospitalization (total of 240 mg of artemether and 1440 mg of lumefantrine). On day 2, her clinical condition deteriorated, her blood pressure dropped to 80/40 mmHg together with a pulse rate of 130 bpm. Laboratory tests indicated a fall of thrombocyte count at 6,000/mm and elevation of blood lactate up to 7.4 mmol/L (N < 2). The patient was now classified as complicated malaria and admitted to intensive care unit. Treatment was switched to intravenous artesunate (Malacef®, ACE Pharmaceuticals, The Netherlands), started at three doses of 120 mg (2.4 mg/kg body weight) with 12-hour interval. Concurrently she was managed with supportive care, that was administration of 2 l normal saline solution and two units of packed thrombocytes. The use of norepinephrine up to 0.5 μg/kg/min was required during 24 hours to restore a normal blood pressure. The septic shock condition was managed by a course of empiric antibiotic treatment, i.e., ceftriaxone 2 g/day, gentamycin 3 mg/kg/day and metronidazole 1.5 g/day. Evolution was marked by rapid improvement as blood pressure maintained at normal values, and fever disappeared. Lactate level returned within normal range and parasitaemia declined under 0.1% of red blood cells (RBCs). Twelve hours after the last dose of artesunate (total of three doses, 360 mg), the patient was transferred to a regular ward of tropical medicine (day 4). Anti-malarial treatment was continued orally with two daily doses of 80 mg artemether and 480 mg lumefantrine until day 6 (total of 480 mg of artemether and 2880 mg of lumefantrine). Antibiotics were changed to piperacillin/tazobactam (12 g daily) and ciprofloxacin 500 mgx2/day. Despite initial favourable evolution and total clearance of parasites, fever reappeared on day 8. Of note, a drop in haemoglobin up to 6.3 g/dL was evidenced while thrombocytosis was associated: 489 G/L. The Coombs' test performed at that time was negative. The patient left hospital against medical advice but was re-admitted on day 14 because of persistent fever and marked asthaenia.
Blood analysis confirmed anaemia with a decrease in haemoglobin at 4.6 g/dL and the subsequent criteria for haemolysis: reticulocyte count of 202,000/mm, LDH flare up to 658 U/L and undetectable haptoglobin level. Repeated blood films for malaria as well as for schistocytes (i.e. fragments of RBCs produced by extrinsic mechanical damage within the circulation) were negative. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was promptly ruled out and haemoglobin electrophoresis did not reveal any abnormality. On the other hand, direct Coombs' test revealed positivity for both IgG and complement factor C3d while this test was negative five days earlier. The irregular antibody testing was negative. It was concluded AIHA and complementary aetiological inquiry was performed. Antinuclear antibodies were absent and the investigation was negative for numerous pathogens such as bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, Salmonella typhi and Salmonella paratyphi), viruses (dengue virus, CMV, EBV, parvovirus B19, HBV, HCV, and HIV) or parasites (Leishmania spp, Entamoeba histolytica).
In the context of unusual immunohaematological haemolysis, no transfusion was attempted and corticosteroids were introduced. Methylprednisolone pulses of 60 mg per day during seven days were performed. The haemoglobin level gradually improved (Figure 1). On discharge (day 24), haemoglobin was 8.8 g/dL and treatment was continued with 50 mg of oral prednisone per day. The corticosteroids dosage was progressively tapered during the two following months before discontinuation. Haemoglobin level slowly increased and from day 52 it was measured above the 12 g/dl threshold. At that time haptoglobin and LDH were within normal limits. Consistently, direct Coombs' test was negative, both for IgG and C3d. During the follow-up, the patient completely recovered and her condition remained stable 12 months later.
(Enlarge Image)
Figure 1.
Evolution of an auto-immune haemolytic anaemia developed during severe malaria treated with intravenous artesunate and other antimicrobial chemotherapy. Ar = artemether; As = artesunate; CFTX = ceftriaxone; CPFX = ciprofloxacin; DAT = direct antiglobulin test; LDH = lactate dehydrogenase; Lu = lumefantrine; PTZ = piperacillin and tazobactam
Concurrently, she was additionally tested for drug-dependent antibodies by ex vivo antigen testing. Serum samples were screened during the convalescent phase, i.e. 12 months, as no biological sample of the acute phase could be retrieved. The test used the main suspected medication substrates, namely ceftriaxone, and three different pharmaceutics specialties containing derivative of artemisin: Riamet®, artemether alone and Malacef (artesunate). This testing was conducted according to a home-made method developed by the French Blood Institute according to standardized reports and detailed in the method section.
Among all tested drugs, the test was positive only with artesunate in the papain-pretreatment condition (Table 1). Thus, no other drug could induce haemolysis, even with papain-treated RBCs. This positivity was obtained using two distinct procedures, applied with the three required concentrations of artesunate. This was indicative of the persistence of drug antibodies related to artesunate, even one year after the episode of haemolytic anaemia.
Case Report
A 17-year old Ivorian female without remarkable medical history was admitted for fever, chills, headache, and abdominal pain in a French University Hospital Centre (day 1). She had left Ivory Coast seven days earlier to live in France for studying purpose and symptoms began two days before her admission. Initial physical examination showed a temperature of 39°C and pain when palpating right hypocondrium. Blood tests demonstrated a normal leucocyte count, a thrombocyte count of 11,000/mm (normal range 150,000–450,000), a haemoglobin level of 12.6 g/dL (12–16) with abnormalities indicative of haemolysis: rise in lactate dehydrogenase (LDH) at 500 U/L (5–248) and total bilirubin at 105 μmol/L (3–18) with a low haptoglobin of 0.15 g/L (0.3–2). She was diagnosed with uncomplicated malaria as peripheral thin blood film showed P. falciparum trophozoites (0.8% of parasitized erythrocytes). Abdominal ultrasonography ruled out biliary tract or gall bladder infection. A treatment with oral artemether/lumefantrine combination (Riamet©) was initiated with respectively, 80 and 480 mg trice within the first 24 hours of hospitalization (total of 240 mg of artemether and 1440 mg of lumefantrine). On day 2, her clinical condition deteriorated, her blood pressure dropped to 80/40 mmHg together with a pulse rate of 130 bpm. Laboratory tests indicated a fall of thrombocyte count at 6,000/mm and elevation of blood lactate up to 7.4 mmol/L (N < 2). The patient was now classified as complicated malaria and admitted to intensive care unit. Treatment was switched to intravenous artesunate (Malacef®, ACE Pharmaceuticals, The Netherlands), started at three doses of 120 mg (2.4 mg/kg body weight) with 12-hour interval. Concurrently she was managed with supportive care, that was administration of 2 l normal saline solution and two units of packed thrombocytes. The use of norepinephrine up to 0.5 μg/kg/min was required during 24 hours to restore a normal blood pressure. The septic shock condition was managed by a course of empiric antibiotic treatment, i.e., ceftriaxone 2 g/day, gentamycin 3 mg/kg/day and metronidazole 1.5 g/day. Evolution was marked by rapid improvement as blood pressure maintained at normal values, and fever disappeared. Lactate level returned within normal range and parasitaemia declined under 0.1% of red blood cells (RBCs). Twelve hours after the last dose of artesunate (total of three doses, 360 mg), the patient was transferred to a regular ward of tropical medicine (day 4). Anti-malarial treatment was continued orally with two daily doses of 80 mg artemether and 480 mg lumefantrine until day 6 (total of 480 mg of artemether and 2880 mg of lumefantrine). Antibiotics were changed to piperacillin/tazobactam (12 g daily) and ciprofloxacin 500 mgx2/day. Despite initial favourable evolution and total clearance of parasites, fever reappeared on day 8. Of note, a drop in haemoglobin up to 6.3 g/dL was evidenced while thrombocytosis was associated: 489 G/L. The Coombs' test performed at that time was negative. The patient left hospital against medical advice but was re-admitted on day 14 because of persistent fever and marked asthaenia.
Blood analysis confirmed anaemia with a decrease in haemoglobin at 4.6 g/dL and the subsequent criteria for haemolysis: reticulocyte count of 202,000/mm, LDH flare up to 658 U/L and undetectable haptoglobin level. Repeated blood films for malaria as well as for schistocytes (i.e. fragments of RBCs produced by extrinsic mechanical damage within the circulation) were negative. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was promptly ruled out and haemoglobin electrophoresis did not reveal any abnormality. On the other hand, direct Coombs' test revealed positivity for both IgG and complement factor C3d while this test was negative five days earlier. The irregular antibody testing was negative. It was concluded AIHA and complementary aetiological inquiry was performed. Antinuclear antibodies were absent and the investigation was negative for numerous pathogens such as bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, Salmonella typhi and Salmonella paratyphi), viruses (dengue virus, CMV, EBV, parvovirus B19, HBV, HCV, and HIV) or parasites (Leishmania spp, Entamoeba histolytica).
In the context of unusual immunohaematological haemolysis, no transfusion was attempted and corticosteroids were introduced. Methylprednisolone pulses of 60 mg per day during seven days were performed. The haemoglobin level gradually improved (Figure 1). On discharge (day 24), haemoglobin was 8.8 g/dL and treatment was continued with 50 mg of oral prednisone per day. The corticosteroids dosage was progressively tapered during the two following months before discontinuation. Haemoglobin level slowly increased and from day 52 it was measured above the 12 g/dl threshold. At that time haptoglobin and LDH were within normal limits. Consistently, direct Coombs' test was negative, both for IgG and C3d. During the follow-up, the patient completely recovered and her condition remained stable 12 months later.
(Enlarge Image)
Figure 1.
Evolution of an auto-immune haemolytic anaemia developed during severe malaria treated with intravenous artesunate and other antimicrobial chemotherapy. Ar = artemether; As = artesunate; CFTX = ceftriaxone; CPFX = ciprofloxacin; DAT = direct antiglobulin test; LDH = lactate dehydrogenase; Lu = lumefantrine; PTZ = piperacillin and tazobactam
Concurrently, she was additionally tested for drug-dependent antibodies by ex vivo antigen testing. Serum samples were screened during the convalescent phase, i.e. 12 months, as no biological sample of the acute phase could be retrieved. The test used the main suspected medication substrates, namely ceftriaxone, and three different pharmaceutics specialties containing derivative of artemisin: Riamet®, artemether alone and Malacef (artesunate). This testing was conducted according to a home-made method developed by the French Blood Institute according to standardized reports and detailed in the method section.
Among all tested drugs, the test was positive only with artesunate in the papain-pretreatment condition (Table 1). Thus, no other drug could induce haemolysis, even with papain-treated RBCs. This positivity was obtained using two distinct procedures, applied with the three required concentrations of artesunate. This was indicative of the persistence of drug antibodies related to artesunate, even one year after the episode of haemolytic anaemia.
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