Haemolytic anaemia precipitated by dengue fever

Abstract

We reported a case of a woman with no past medical illness who presented with a few days’ history of fever, myalgia, arthralgia, hypochromic microcytic anaemia and thrombocytopaenia and who was nonstructural protein 1 antigen (NS1Ag)-positive. Haemolytic anaemia including full blood picture work-up revealed high reticulocyte count and haemolysis with positive direct Coombs test. She was started on prednisolone and was discharged well.

Background

Dengue fever, the most common arthropodborne viral infection in South-East Asia, is increasing in prevalence due to increased awareness and improved diagnostic method. Usually dengue is accompanied by hypotension and haematological manifestations such as thrombocytopaenia and leucopaenia with deranged liver enzymes. However there are only scanty cases of autoimmune haemolytic anaemia (AIHA) precipitated by dengue infection.

Case presentation

A 32-year-old Malay woman with no past medical illness presented with a 4-day history of fever associated with chills and rigor, vomiting, headache, arthralgia, and myalgia. There was no diarrhoea and abdominal pain. There was neither a history of going for camping nor signs of urinary tract and upper respiratory tract infections. She lived in an area previously known to have dengue outbreak. On day 3 of her illness, she went to the nearest clinic and was noted to have positive nonstructural protein 1 antigen (NS1Ag). She was admitted on the next day for dengue fever with warning signs that include intractable vomiting.

On examination, she was pale but afebrile. She had no jaundice. Her hydration was fair, with blood pressure of 109/61 mm Hg and heart rate of 90 beats per minute. Respiratory examination was unremarkable. There was no hepatosplenomegaly and no calf tenderness. Per-rectal examination showed no melaena.

Investigations

Serial full blood count (table 1) showed leucopaenia on admission. Full blood picture (figure 1) revealed anaemia with anisopoikilocytosis. Both indirect and direct Coombs tests were positive. Further tests including autoimmune screening were negative. Complement levels were normal. Coagulation profile revealed isolated prolonged activatedpartial thromboplastin time (APTT) with normal international normalized ratio (INR). Chest X-ray showed minimal bilateral pleural effusion with no cardiomegaly or focal consolidation.

Table 1.

Serial full blood count

Day	3	4	5	6	7	8	9	10 (discharged)	1 month
Total white blood cells (×109/L)	3.8	2.0	2.2	6.2	11.1	7.3	7.9	7.2	7.5
Haemoglobin (g/L)	8.1	7.5	7.5	6.9	6.7	6.3	6.3	7.4	10.0
Mean corpuscular volume(MCV) (fL)	102.1	96.6	95.7	90.2	95.7	100	106.0	107.2	100
Mean corpuscular haemoglobin (MCH) (pg)	33.3	32.8	32.6	32.1	32.1	30.9	31.7	33.3	31
Mean corpuscular haemoglobin concentration(MCHC) (g/dL)	32.7	33.8	34.1	35.6	33.5	30.9	29.9	31.4	30.7
Hematocrit (%)	24.8	22.2	22.0	19.4	20.0	20.4	21.1	23.8	32.6
Platelet (×109/L)	142	47	46	36	70	108	122	152	351
Reticulocyte (%)					8.03	14.6	18.5	22.64	3.9

Figure 1.

Full blood picture revealed anaemia with anisopoikilocytosis. The large arrow shows polychromatic cells, while the small arrow shows spherocytes.

Differential diagnosis

Differential diagnoses for intravascular haemolysis:

• Stress-induced haemolysis (dengue fever).

• AIHA.

  • Connective tissue disease.
  • Haematological malignancies, in particular lymphoma.
  • Infection, that is, Ebstein Bar Virus (EBV) and mycoplasma.

• Drug-induced haemolysis, that is, certain antibiotics (cephalosporin, penicillin derivatives, levofloxacin), quinine, methyldopa, nitrofurantoin and non-steroidal anti-inflammatory drugs.

Differential diagnoses for isolated prolonged APTT:

• Acquired haemophilia due to infection.

• Lupus anticoagulant (antiphospholipid syndrome).

• Heparin exposure.

• Haemophilia A and B (factor VIII and IX deficiency, respectively).

• Factor XI or XII deficiency.

Treatment

The patient was started on intravenous drip at 3 cc/kg/hour and was reduced to 1 cc/kg/hour at the end of the day. Intravenous ceftriaxone 1 g twice daily was started to treat the superimposed bacterial infection.

Outcome and follow-up

On day 5 of illness, the patient was still febrile and slightly tachypnoeic with bilateral pleural effusion and ascites. Intravenous drip was ceased as she was able to tolerate fluid orally. She was planned for packed cell transfusion should she became symptomatic of anaemia. During night review, she developed worsening shortness of breath due to fluid overload requiring oxygen Ventimask 6 L/min, which was improved after she was given intravenous frusemide 20 mg. On day 7 of illness, entering the reabsorptive phase, her condition was significantly improving. She was able to wean off oxygen to nasal prong at 3 L/min. Lactate also improved from 5.3 to 2.5.

However her haemoglobin further dropped from 8.1 to 6.5 g/L. The full blood picture sent 2 days prior was reported as reticulocytosis with the presence of spherocytes suggestive of haemolysis. Intravenous hydrocortisone 100 mg was commenced thrice daily. She was discharged with prednisolone 60 mg daily after a week of admission. During her last follow-up in the clinic, her haemoglobin level was raised, from 6.5 to 10 g/dL, with reticulocyte count reduced to 3.0%.

Discussion

Haemolytic anaemia is a rare manifestation of dengue fever. Few cases have been reported, in a British traveller as well as in Sri Lanka and India as cold agglutinin-induced haemolytic anaemia in a dengue patient.^1–3 Our patient is a case of severe dengue fever with impending shock and plasma leakage, who later developed haemolysis on day 4 of illness. Although clinically detectable haemolysis occurred on day 2 of admission (day 4 of illness), asymptomatic haemolysis was already present since the first day of admission. Our patient had a sudden drop in haemoglobin without evidence of blood loss, reticulocytosis and positive direct Coombs test (table 1). Since the first day of admission, asymptomatic haemolysis was already present. Aspartate aminotransferase (AST) and lactic acid dehydogenase (LDH) were noted to be elevated (table 2), and indirect bilirubin was higher than direct bilirubin. Of note, only 15% of cases in India reported higher indirect than direct bilirubin in dengue fever.⁴

Table 2.

Serial liver function test

Day	4	5	6	7	8	9	10 (discharged)	1 month
Aspartate aminotransferase (AST)	1155	1277	729	442	370	198	180	30
Alkaline phosphatase (ALP)	107	108	100	120	139	113	104	117
Alanine aminotranferase (ALT)	456	478	323	288	288	215	162	57
Total Bilirubin (TB)	25			21	19	17	14	6
Lactic acid dehydrogenase (LDH)				3395	3444	2600		746

Severe dengue fever can be prognosticated by early changes in biochemical markers such as raised LDH, creatinine kinase (CK) and AST, and reduced levels of albumin, total cholesterol and triglycerides.^{5 6} Raised LDH cannot be used as the only parameter for haemolysis in dengue haemorrhagic fever as ischaemic tissue injury may cause significantly increased LDH, CK and AST in severe dengue cases. In our patient, the concomitantly raised indirect bilirubin, reticulocytosis and positive direct Coombs test indicated the presence of haemolysis. In addition, our case developed a positive direct Coombs test, differing from other cases that were Coombs-negative. Mires et al reported a similar case of haemolysis anaemia in dengue with positive direct Coombs test.⁷

Elevated LDH, CK and AST may also suggest biochemical features of rhabdomyolysis.^{8 9} Our case however has no clinical symptoms or signs to suggest rhabdomyolysis. Her renal profile was normal.

Leucopaenia is a common presentation of dengue fever as demonstrated in our patient. In Malathesha and Ashwini,¹⁰ leucopaenia was seen in 27.6% of cases, lymphocytosis (>45%) in 66%, monocytosis (>10%) in 84.6%, basophilia (>2%) in 52.9% and 44.4% had platelet count below 50×10⁹/L. Previous studies have shown that the dengue virus in vitro invades and replicates poorly in resting lymphocytes but well in stimulated transformed B lymphoblast cells.¹¹ It has been postulated that, in an attempt to control the spread of dengue virus-infected cells, the augmented immune response may be represented by atypical lymphocytes in secondary dengue infection.¹²

In all patients with sudden anaemia and prolonged APTT, disseminated intravascular coagulopathy needs to be considered. However, it was unlikely in this case as the peripheral blood film showed evidence of haemolysis without microangiopathic features. Although dengue fever is commonly presented by either single or multiple cytopaenias (thrombocytopaenia and/or leucopaenia), sepsis caused by bacterial or other viraemias may also have similar peripheral blood film features.

Learning points.

• Immune haemolytic anaemia is a potential clinical feature of severe dengue.

• Haemolysis, other than gastrointestinal bleeding, is an important differential diagnosis of blood loss in dengue.

• The list of infective causes of immune haemolytic anaemia should include dengue virus infection, in addition to other atypical infections such as Mycoplasma pneumoniae and others.

• Drug-induced haemolysis should also be considered in the differential diagnosis of haemolysis anaemia.