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Case of the Month

October 2011

Dr Gary Reubenson and Dr Gillian Sorour, Dept of Paediatrics and Child Health, University of Witwatersrand

A 13 year old girl was referred from a district hospital to an academic secondary level hospital. She had been born in South Africa, but had lived in Mozambique continuously for the last 5 years. She had recently returned to South Africa as she was unwell and her mother lived here.

According to the referral note, she had been ill for 14 days with high fevers and chills, headaches and a distended abdomen. The doctors at the referring hospital had also identified pancytopenia.

She had apparently been previously well with no prior hospital admissions. Initial investigations included two reactive Rapid-HIV tests, a negative falciparum malaria antigen test and a negative malaria smear.

On examination, she was ill-looking, her weight plotted on the 3rd percentile and her height on the 10th percentile. Her temperature was 40°C, she had marked pallor and generalized significant cervical, axillary and inguinal lymphadenopathy. She also had bilateral pedal and peri-orbital oedema.

On abdominal examination her liver was palpable 5cm and her spleen 18cm below the costal margin. There was no ascites or prominent abdominal wall veins. Her initial investigations showed:

* Plasmodium falciparum antigen and pan-malarial antigen

CXR – Normal

Abdominal CT

  • Hepatosplenomegaly
  • Spleen is inhomogenous with multiple peripherally based wedge-shaped hypodensities consistent with infarcts
  • Splenic and portal veins dilated (in keeping with portal hypertension)
  • Horseshoe kidneys with normal excretory function
  • Significant coeliac nodes
  • No free fluid

Progress in the ward:

Spiked high temperatures (up to 40 °C) throughout her admission

Started on intravenous quinine, but stopped after 2 days

7 days ceftriaxone

Transfused packed cells repeatedly

Started on empiric 4-drug TB treatment

ARVs started 12 days after TB treatment initiated

Cotrimoxazole changed to dapsone in view of persistent anemia

She underwent a bone marrow examination:

The aspirate showed a hypercellular marrow with hemopoietic activity in all 3 cell lines. The trephine was of sub-optimal quality, but confirmed hypercellularity. There was some evidence of non-refractile pigment noted in macrophages and an abnormal infiltrate could not be excluded.

The conclusion of the test was that her pancytopenia was probably multifactorial due to a combination of dyshaemopoiesis (infection and/or nutritional), reticul-endothelial iron blockade, DIC and hypersplenism. The child was sent to a paediatric haematology-oncology subspecialty unit for biopsy and unfortunately demised unexpectedly the night before the scheduled procedure.

A postmortem was performed:

  • Lung consolidation – no evidence of tuberculosis; possibility of ARDS; extramedullary haematopoiesis
  • Massive hepatosplenomegaly – large amounts of refractile hemosiderin and finer, non-refractile haemozoin pigment (highly suggestive hyperreactive malarial splenomegaly)
  • Significant and severe generalised lymphadenopathy – extramedullary haematopoiesis
  • Membranous nephropathy
  • No evidence of malignancy

Question 1: What is the differential diagnosis for massive splenomegaly in this child?

Answer to Q1

  1. Malaria (Hyper-reactive malarial splenomegaly) – most likely
  2. Schistosomiasis (Serology not suggestive, but no rectal snip etc. done)
  3. Gaucher Disease (but bone marrow not suggestive)
  4. Kala-Azar (Visceral Leishmaniasis) – from incorrect geographical area
  5. CML (unusual age)
  6. Haemophagocytic Syndrome – (BMAT not suggestive)

Question 2: What additional blood test(s) would have confirmed hyperreactive malarial splenomegaly?

Answer to Q2

  • Hyper-reactive tropical splenomegaly used to be known as “tropical splenomegaly”
  • The splenomegaly is distinct from splenomegaly associated with malarial parasitaemia.
  • It is thought to be due to a disturbance in the T-lymphocyte control of the humoral response to recurrent malaria (?related to HLA Class H antigens)
  • This leads to the gross overproduction of IgM antibodies which leads to the formation of high molecular weight immune complexes, persistent gross splenomegaly, recurrent episodes of profound anaemia and an increased susceptibility to infections (bacterial and viral).
  • Typical lab findings:
    • Pancytopaenia
    • Very high IgM
    • High malarial antibody titres
    • Malarial parasites are NOT seen during the acute episodes

Question 3: What are the diagnostic criteria for hyperreactive malarial splenomegaly?

Answer to Q3

  • Major criteria:
    • Gross splenomegaly (10 cm or more below the costal margin in adults) for which no other cause can be found
    • Elevated serum IgM level (2 standard deviations or more above the local mean)
    • Clinical and immunologic responses to antimalarial therapy
    • Regression of splenomegaly by 40% by 6 months after start of therapy
    • High antibody levels of Plasmodium species (≥ 1:800) – this test is not routinely offered by NHLS
  • Minor Criteria:
    • Hepatic sinusoidal lymphocytosis
    • Normal cellular and humoral responses to antigenic challenge
    • Hypersplenism
    • Lymphocytic proliferation
    • Familial occurrence

Question 4: What are the possible causes for her nephrotic syndrome?

Answer to Q4

  • HIV-associated nephropathy (usually FSGS)
  • Related to Plasmodium malariae coinfection (usually membranous glomerulonephritis)
  • Membranous nephropathy:
    • Primary
    • Secondary:
  • Hepatitis B
  • Syphilis
  • SLE
  • Some malignancies
  • Schistosomiasis

References:

  1. Hyper-reactive Malarious Splenomegaly (Tropical Splenomegaly Syndrome); G.G. Crane; Parastitology Today, vol. 2, no. I, 1986
  2. Case Report: Hyper-reactive Malarial Splenomegaly in a Patient with Human Immunodeficiency Virus; G. De Iaco, N. Saleri et al; Am. J. Trop. Med. Hyg., 78(2), 2008, pp. 239–240
  3. Fakunle Y.Tropical splenomegaly. In: Luzzatto L, ed. Clinics in haematology.London:WB Saunders, 1981: 963–75
Lesson learnt

This tragic case illustrates the importance of considering non-HIV related pathology in HIV-infected patients. In addition, it demonstrates the difficulty in diagnosing this condition particularly as widely available malaria tests are typically negative. Finally, this case highlights the value of post-mortem evaluation when patients die of incompletely explained causes.

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