Infectious mononucleosis with secondary cold agglutinin disease causing autoimmune haemolytic anaemia

Abstract

This case report describes a 20-year-old woman whose initial clinical, laboratory, and radiological presentation suggested obstructive jaundice. However, she was subsequently found to be suffering from autoimmune haemolytic anaemia resulting from an Epstein–Barr virus infection complicated by cold agglutinin disease. The patient went on to make a complete clinical recovery after discharge.

BACKGROUND

The authors document a case of autoimmune haemolytic anaemia (AIHA) associated with cold agglutinin disease secondary to Epstein–Barr Virus (EBV). However, the patient’s symptoms mimicked an obstructive jaundice pattern with gallbladder thickening on ultrasonography. This case elucidates the importance of considering AIHA in infectious mononucleosis (IM) associated with right upper quadrant pain, obstructive pattern on liver blood tests, macrocytic anaemia, and cryoglobulinaemia. Although cold agglutinins develop in more than 60% of patients with IM, haemolytic anaemia is rare.¹

CASE PRESENTATION

A 20-year-old woman was admitted after a brief, 1 min loss of consciousness and right upper quadrant pain. She endorsed progressive fatigue over the prior 2 weeks, as well as mild throat irritation, which developed into a non-productive cough over the previous month. The patient was known to have recently travelled to Spain for 3 months, but returned to the US. She occasionally had unprotected sexual relations with her male partner (who had admitted to having past sexual encounters with prostitutes), but did not smoke tobacco, drink alcohol, or use intravenous drugs. There was no family history of immunodeficiency. On examination, the patient was found to have tender, bilateral, anterior and posterior cervical lymphadenopathy. Additionally, she was found to be dehydrated (dry mouth, sunken eyes, reduced skin turgor), hypotensive (98/58 mm Hg supine, 92/55 mm Hg standing), and tachycardic (106 beats/min). Hepatosplenomegaly were noted on physical examination. On admission, the patient was febrile (38.8°C) and jaundiced with right upper quadrant abdominal tenderness. During hospitalisation, the patient developed cough productive of green sputum and transient fevers.

INVESTIGATIONS

On admission, laboratory testing was remarkable for macrocytic anaemia with a red cell count of 2.96×10¹²/l (normal 4.2–5.4×10¹²/l), erythrocyte sedimentation rate of 94 mm/h (normal 0–20 mm/h), white blood cell count of 16.7×10⁹/l (normal 4.5–11.0×10¹²/l), haemoglobin of 9.7 g/dl (normal 12–16 g/dl), haematocrit of 26.9% (normal 38–47%), reticulocyte count of 35.2% (normal 0.5–1.5%), platelet count of 249×10⁹/l (normal 150–400×10⁹/l), mean corpuscular volume (MCV) of 110 fL (normal 80–96 fL), mean corpuscular haemoglobin (MCH) of 32.5 pg/cell (normal 27–31 pg/cell), and mean corpuscular haemoglobin concentration (MCHC) of 34.3 g/dl (normal 31–36 g/dl).

Peripheral blood smear revealed anisocytosis and nucleated red cells.

Hepatic analysis upon admission revealed abnormal liver blood tests demonstrating an obstructive pattern with a lactate dehydrogenase of >300 U/l (normal 94–250 U/l), peak total bilirubin of 10.6 mg/dl (normal 0.3–1.2 mg/dl), direct bilirubin of 5.0 mg/dl (normal 0–0.4 mg/dl), haptoglobin <6 mg/dl (normal 30–200 mg/dl), alanine aminotransferase (ALT) of 418 U/l (normal 5–31 U/l), aspartate transaminase (AST) of 631 U/l (normal 5–40 U/L), alkaline phosphatase (ALP) of 195 U/l (normal 25–100 U/L), and albumin of 3.8 g/dl (normal 3.5–4.8 g/dl). The patient’s hepatic panel slowly improved throughout hospitalisation, and on the day of discharge, her total bilirubin was 7.4 mg/dl, direct bilirubin was 5.7 mg/dl, ALT 412 U/l, AST 396 U/l, and ALP 158 U/l.

Iron analysis showed total serum iron of 194 μg/dl (normal 40–160 μg/dl), total iron binding capacity of 230 μg/dl (normal 240–450 μg/dl), and ferritin of 2.0 μg/l (normal 12–200 μg/L).

Viral hepatitis serologies, sexually transmitted infections screen and blood cultures were negative. A Monospot test was positive. Antibody titres to EBV were 20× for virus capsid antigen (VCA) IgM, 300× for the VCA IgG and <20× for Epstein–Barr Nuclear Antigen (EBNA), confirming the diagnosis of IM. Direct Coomb’s test was positive for presence of cold autoantibody.

Upon the development of a productive cough, sputum culture with gram staining was taken, revealing a polymorphic neutrophil count of >25 cells/mm³ with gram positive cocci and gram negative rods.

Abdominal ultrasound revealed non-distended gallbladder without cholelithiasis. Non-specific gallbladder wall thickening and fluid layering dependently in the gallbladder fossa was also present.

DIFFERENTIAL DIAGNOSIS

Initial presentation of hyperbilirubinaemia with elevated AST, ALT, and ALP on the hepatic analysis, as well as subsequent ultrasonography demonstrating gallbladder wall thickening, formed a differential diagnosis of obstructive jaundice (cholelithiasis, acalculous cholecystitis, primary biliary sclerosis, primary sclerosing cholangitis), hepatitis, and haemolytic anaemia.

The patient was noted to be progressively anaemic. Workup revealed immune mediated haemolysis (elevated lactate dehydrogenase (LDH), elevated total bilirubin, and decreased haptoglobin values, along with consistent peripheral blood smear findings) in the setting of cold autoantibody. Such findings were suggestive of cryoglobulinaemia.

Direct Coombs’ test was consistent with cold agglutinin haemolysis, which was likely secondary to her known IM. As the direct Coomb’s test is highly specific for patients with immune haemolytic anaemia, this finding strongly suggests that immune haemolysis mediated by cold autoantibody was the source of the anaemia. HIV infection is associated with a positive direct Coombs’ test in 18–43% of patients. Such a diagnosis would also be plausible in this patient upon consideration of her sexual history. However, this was ruled out with the negative sexually transmitted infections screen.² Moreover, haemolysis is usually mild, and AIHA is usually seen without reticulocytosis, in HIV infected patients; thus, the severity of anaemia in this patient makes this diagnosis less likely.²

Anaemia, secondary to haemolytic anaemia, was an initial clinical sign in this patient. However, anaemia is not diagnostic in infectious mononucleosis. The constellation of abnormal haematological findings should be used for the diagnosis of AIHA secondary to infectious mononucleosis.

Hepatocyte damage, secondary to EBV, likely caused a reduction in the liver’s conjugation and excretory capacity. This resulted in increased concentrations of direct bilirubin along with increased indirect bilirubin from AIHA. As the hepatic function returned, hepatic excretory capacity increased and total bilirubin concentrations were reduced.

A raised erythrocyte sedimentation rate in the patient suggests an underlying infectious disease. As the erythrocyte sedimentation rate is inversely proportional to the haemoglobin level, sedimentation rate is more rapid in many patients with severe anaemia.³ The findings of macrocytic anaemia suggest a new cell population produced in a compensatory response to the haemolysis. This is also consistent with the markedly elevated reticulocyte count findings.

The diagnosis of EBV causing IM was made with consistent findings on clinical history and laboratory results. The diagnosis was confirmed with positive titres of VCA IgM, IgG, and EBNA, with secondary diagnosis of cold agglutinin disease (positive Coomb’s test) causing AIHA.

A mixed organism throat infection was noted on sputum culture. Pharyngitis is commonly associated with IM, with rates of co-infection with EBV ranging from 3–33%.^4–6

TREATMENT

Following clinical history and physical examination, the patient was commenced on normal saline infusion. Acetaminophen (paracetamol) (650 mg) was administered orally every 6 h. Subsequent management of the patient was supportive after the diagnosis was made.

OUTCOME AND FOLLOW-UP

On the day of discharge, the patient’s haematocrit was 19.6%, but had remained stable over several readings. The patient was discharged with iron and folic acid supplementation, azithromycin (10 day course), and ibuprofen, and was advised to have sufficient bed rest. She was asked to have a follow-up complete blood count, particularly for her haematocrit values, and a hepatic analysis in 1–2 weeks. Upon return and clinical history and examination, the patient was found to be fully recovered. Additionally, her haematological and hepatic parameters had returned to baseline at follow-up. At the time of this submission, the patient has fully recovered and is doing well.

DISCUSSION

IM is a self limiting, clinical, lymphoproliferative syndrome most commonly found in adolescents and young adults following EBV infection.^7,8 Typical manifestation of IM is a fever, cervical lymphadenopathy and pharyngitis progressive over weeks.⁹ Additionally, fatigue and right upper quadrant (RUQ) pain can be seen commonly.¹⁰ Atypical lymphocytosis and positive heterophile antibody tests are diagnostic.¹¹ Complications of IM are rare, but are potentially life threatening, and can include hepatitis, mild thrombocytopenia, haemolytic anaemia, splenic rupture, aplastic anaemia, and neutropenia among others.^12–14

AIHA occurs in 0.5–3% of IM patients, and has been associated with cold reactive antibodies, anti-I antibodies, and autoantibodies to triphosphate isomerase.^15–17 It has been reported to occur in the first 2–3 weeks of disease, and usually resolves in the following 2 weeks.¹⁸ High titres of cold agglutinins, with particular specificity to anti-I, have previously been reported in the literature.^19,20 Documented literature demonstrating hepatitis with cryglobulinaemia mediated AIHA during the course of an EBV infection have been fairly limited.^21–23

This patient’s hyperbilirubinaemia resulted from AIHA, which was likely precipitated by cold agglutinin disease secondary to IM. It was important to distinguish this from an obstructive cause of the hyperbilirubinaemia, as the hepatic panel was suggestive of obstructive jaundice, and the management of these two conditions differs substantially.

Additionally, the patient was found to have gallbladder wall thickening on ultrasonography in the absence of cholelithiasis. Thickening of the gallbladder wall has been recognised as a non-specific sign that may be seen in acute cholecystitis, acute hepatitis, as well as IM in an adult.²⁴ Although a rare finding, gallbladder wall thickening in IM is considered a worrisome sign, and has been associated with severe hepatic dysfunction and pulmonary oedema.^25,26 However, self resolution was seen in our patient and she had a rapid and complete recovery.

Thickening of the gallbladder wall may be attributed to an immunological reaction analogous to that which occurs in the liver in episodes of hepatitis associated with IM. Another plausible explanation described includes obstruction of the lymphatic flow secondary to enlarged lymph nodes at the porta hepatitis.²⁷ Reduced bile flow due to hepatic dysfunction resulting in incomplete distension of the gallbladder may also contribute.

The authors report a case of AIHA associated with cold agglutinin disease, self limiting hepatitis, and gallbladder wall thickening with an obstructive pattern on liver function tests, as complications of IM.

LEARNING POINTS

• Hyperbilirubinaemia with elevated AST, ALT, and ALP on hepatic panel may also have pre-hepatic causes, indicating the importance of clinical history and examination of the patient.

• Although rare, cold agglutinin disease can complicate infectious mononucleosis (IM), leading to a potentially fatal haemolytic anaemia and should be considered in the differential diagnosis.

• Febrile illness, right upper quadrant pain, pharyngitis, cervical lymphadenopathy and fatigue in a young individual are major clinical exam findings highly suggestive of IM. However, IM can present atypically, as seen in our case, where it may be mimicked by hepatitis and gallbladder wall thickening.