A three year-old boy with back pain, fever and cola-coloured urine

A three year-old boy was assessed at A&E because of abdominal and back pain. A week previously he had had an eye and ear infection and had been treated effectively with penicillin orally and with fucidin eye drops. He now had a fever, back pain and discoloured urine. Urine dipsticks showed haemoglobin 3+, nitrite 1+, protein 1+. C-reactive protein (CRP) was 119 mg/l (< 5 mg/l).

On admission, his previous medical history was reviewed. As a one year-old he had been hospitalised with sepsis with no definite focus of infection. The same year he had received a diagnosis of asthma, and since then had had frequent respiratory tract infections. He used inhalation steroids regularly (fluticasone 50 µg x 2) and an adrenergic drug (salbutamol 0.1 mg x 4). In recent months he had had intermittent pain in both knees and had been referred to Paediatric Outpatients.

Blood tests showed haemoglobin 11.4 g/dl (10.6–13.8 g/dl), leukocytes 10.2 · 10⁹/l (5.5–12.5 · 10⁹/l), thrombocytes 226 · 10⁹/l (228–435 · 10⁹/l) and CRP 142 mg/l. Urine dipsticks showed haemoglobin 1+, leukocytes 1+ and protein 1+. The duty paediatrician assessed it as probably being pyelonephritis and the child was discharged with a course of mecillinam by mouth 10 mg/kg x 3.

Two days later the boy arrived at Outpatients for a scheduled examination to assess his knee pain. He was now icteric and in considerably reduced general condition and was hospitalised. He was afebrile and with stable circulation, but had slight tachycardia with a pulse of 135/minute (70–110/min) and blood pressure 90/50 mm Hg (80–105/40–60). Blood tests showed haemoglobin 7.0 g/dl, CRP 83 mg/l and leukocytes 15.9 · 10⁹/l. Intravenous therapy with ampicillin and gentamicin was started. Several diagnoses were now considered, including glomerulonephritis, haemolytic uraemic syndrome and sepsis.

Ultrasound of the abdomen showed a moderately enlarged spleen. Ultrasound of the knees was normal. Bilirubin was 75 µmol/l (< 19 µmol/l), lactate dehydrogenase 1 700 U/l (< 400 U/l), haptoglobin < 0.10 g/l (0.4–1.9 g/l), thrombocytes 248 · 10⁹/l and reticulocytes 95 · 10⁹/l (36–60 · 10⁹/l). Blood smears showed no schistocytes, as expected with haemolytic uraemic syndrome, but granulocytosis and monocytosis consistent with infection or inflammation. A polyspecific ("simple") direct antiglobulin test was positive. A monospecific ("extended") direct antiglobulin test was positive for C3c and C3d, consistent with autoimmune haemolytic anaemia with complement activation.

The assessment was now that the child had haemolytic anaemia as a complication of infection. New blood tests in the evening showed a further fall in the haemoglobin level from 7.0 g/dl to 6.3 g/dl. This was regarded as probable dilution following addition of fluid.

On day 2 after his admission, the boy's general condition was good, but his pulse rose to 140–150/min in connection with activity. He was reluctant to urinate because of the pain. His urine was cola-coloured, without coagula. The boy was distinctly icteric, but was assessed as being clinically stable, and it was decided to hold off on blood transfusion.

On the third day his general condition had deteriorated, and the boy was now complaining of pain in his joints and head. He was pale and had increasing tachycardia with a pulse of 150/min and blood pressure 74/33 mm Hg. New blood tests showed haemoglobin 4.6 g/dl, and he received a transfusion of erythrocytes 5 ml/kg using a blood warmer. The cause of the autoimmune haemolytic anaemia was now reassessed. A number of conditions were considered, including autoimmune diseases, malignancy and immune defects such as autoimmune lymphoproliferative syndrome (ALPS) or severe combined immune deficiency (SCID). The possibility that the condition might be due to infection or triggered by mecillinam therapy had not been excluded. The following were ordered: rheumatology tests, blood tests for Epstein-Barr virus, cytomegalovirus and parvovirus, testing of a nasopharyngeal specimen for Microplasma pneumoniae, a gastrointestinal pathogen panel, and lymphocyte quantification and flow cytometric subclassification of blood lymphocytes. After conferring with the Department of Immunology and Transfusion Medicine, cold agglutinin titration was ordered, as secondary cold agglutinin syndrome was a possible differential diagnosis. After transfusion, Hb rose to 7.3 g/dl.

Over the next few days, his haemoglobin level fell again, to 6.3 g/dl. Cold agglutinin titration revealed a titre of < 4 (< 32), and this was not consistent with cold agglutinin syndrome. A new, comprehensive assessment of the clinical findings and analytical results led to the conclusion that they might be consistent with an unusual diagnosis, paroxysmal cold haemoglobinuria.

Owing to strong clinical suspicion of paroxysmal cold haemoglobinuria, a Donath-Landsteiner test was ordered. The test had only been carried out at the laboratory a couple of times before, and the test procedure was acquired and reviewed by doctors and bioengineers (6). The test was clearly positive, and confirmed the condition (Figs 1, figs 2). Neither a triggering agent nor an underlying disease was detected.

After the diagnosis had been made, the boy was kept away from the cold, cold drinks and ice cream, and no further haemolysis occurred. His general condition gradually improved. His haemoglobin level rose over the next couple of days to 7.7 g/dl, and there was considerable reticulocytosis. Nine days after admission he was discharged in good health, with the option to return at any time in the event of new anaemia symptoms. Weekly check-ups were agreed upon, with haematology tests, haemolysis tests (Table 1) and a direct antiglobulin test. The parents were instructed that the child should avoid exposure to the cold.

At follow-up eight days after discharge, his haemoglobin level was 11.3 g/dl. Haptoglobin was 0.26 g/l and a direct antiglobulin test was still positive for C3d. Lactate dehydrogenase and bilirubin were normalised. The results of complement factor testing while he was in hospital were now available and showed C3 1.19 g/l (0.83–1.65 g/l), C4 0.2 g/l (0.13–0.36 g/l) and haemolytic activity/CH50 showed 10–50 %, which is somewhat reduced.

The direct antiglobulin test was not negative until six weeks after the onset of the illness, at which point a cold provocation test was conducted. The child was allowed to go outside in 5–10 °C for 10–20 minutes and to eat an ice cream. He was then observed in the department. His haemoglobin remained stable at 13.7 g/dl, and urine dipsticks were negative. At an assessment two days later there was still no clinical change, blood tests were normal and the child was viewed as well.