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Pyrexia and pancytopenia with unusual host immune response

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Q1: What cytomorphological phenomenon is shown in fig 1?

Figure 1 shows a proliferation of benign histiocytes in the bone marrow smears. They have abundant foamy to granular cytoplasm and many of them contain phagocytosed blood cells and their precursors. This cytomorphological phenomenon is called haemophagocytic histiocytosis and can be seen in the bone marrow, lymph nodes, spleen and liver in a variety of clinical settings.

Q2: List the conditions with which this cytomorphological phenomenon may be associated

The conditions associated with haemophagocytic histiocytosis are listed in box 1.

Box 1: Clinical states associated with haemophagocytosis

Primary
  • Familial haemophagocytic lymphohistiocytosis

  • Virus-associated haemophagocytosis (with no prior immunodeficiency)

    Secondary/reactive
  • Malignancies, especially T cell lymphomas

  • Acquired and hereditary immunodeficiency

  • Parenteral fat overload

  • Panniculitis

  • Bacterial, parasitic and fungal infections (tuberculosis, typhoid, brucellosis, malaria, leishmaniasis, histoplasma, etc)

Q3: What is the diagnosis in this case?

Figure 2 shows greater detail of the histiocyte. Numerous 2–4 μm round to oval bodies with eccentric to central nuclei and a perinuclear vacuole are identified within the cytoplasm. These were morphologically identified, on silver methenamine and periodic acid Schiff stain, as yeast forms of histoplasma. Figure 2(A) also shows phagocytosed red cell precursors.

Discussion

Haemophagocytic syndrome is a clinicopathological state characterised by fever, blood cytopenias, coagulopathy, hepatosplenomegaly and a systemic proliferation of mature histiocytes showing phagocytosis of blood cells.1 The diagnostic guidelines as laid down by the Histiocytic Society1 are shown in box 2. Haemophagocytosis (HP) is a disorder of the cellular arm of immune response occurring as a consequence of unrestricted monocyte activation that results from marked elevation of inflammatory cytokines produced by dysregulated reactive or neoplastic T lymphocytes.2 Profound cytopenias, which may result from haemophagocytosis or associated coagulopathy, may seriously compromise the already morbid patient.

First described as a familial disease by Farquhar and Claireaux in 1952,3 haemophagocytic syndrome has subsequently been reported to occur in a host of other clinical settings (box 2)5-9; it is also called secondary or reactive haemophagocytosis.5 6 Haematological malignancies, especially T cell lymphomas, have been reported as the most frequent cause of reactive HP in most studies.7 Infections are an important association in tropical countries, in the oriental population6 and, with increasing incidence of AIDS, in the West as well.8 9

Box 2: Diagnostic guidelines for haemophagocytic lymphohistiocytosis1

Clinical and laboratory criteria
  • Fever (⩾7 days; peaks ⩾38.5oC)

  • Splenomegaly (⩾3 cm below costal margin)

  • Cytopenia (affecting ⩾2 of three lineages in the peripheral blood not caused by hypocellular or dysplastic bone marrow)

  • Haemoglobin < 9 g/dl

  • Platelets < 100 × 109/l

  • Neutrophils < 1.0 × 109/l

  • Hypertriglyceridaemia and/or hypofibrinogenaemia*

    Morphological criteria
  • Haemophagocytosis in bone marrow or lymph nodes or spleen

    *
    Some of these guidelines may not apply to a secondary haemophagocytic state2

Histoplasmosis has been sporadically reported from different parts of India. The commonest manifestation in the Indian population is involvement of skin and mucous membranes, with or without systemic involvement.10 The organism has been identified in various sites, including skin, mucous membranes, blood, bone marrow, lymph nodes, and sputum.10 However, HP in a setting of disseminated histoplasmosis has, to the best of our knowledge, not been described previously from India. The few reported cases in English literature have occurred mostly in patients with AIDS.8 9In the wake of an alarming increase in the number of AIDS cases in the sub-continent, the importance of careful laboratory examination in the diagnosis of histoplasmosis cannot be over-emphasised, particularly because, given the high prevalence of tuberculosis in India, cases of pulmonary or disseminated histoplasmosis may be misdiagnosed as tuberculosis. Presence of severe cytopenias in a patient with prolonged pyrexia should alert the physician to the possibility of HP and a meticulous search in the bone marrow and other reticulo-endothelial sites should be made for the underlying cause of HP. An early diagnosis of infection-associated reactive HP is crucial in the management of this potentially reversible condition.

Final diagnosis

Disseminated histoplasmosis with reactive haemophagocytosis.

References

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