Infection and Reactive Changes

THREE INFECTION AND REACTIVE CHANGES Infection Bacterial and rickettsial infection The response of the bone marrow to infection Peripheral blood is very variable, depending on the nature and chronicity of the infection, the age of the subject In adults, the usual haematological response to an and the presence of any associated diseases. The acute bacterial infection is neutrophil leucocytosis response differs according to whether the infection with a left shift (an increase of band forms and pos- is bacterial, rickettsial, viral or fungal. The periph- sibly the appearance of neutrophil precursors in the eral blood and bone marrow responses to infec- peripheral blood) (Fig. 3.1). The neutrophils usually tion are non-specific and similar changes occur in show toxic granulation and may show Döhle bodies many other conditions, including trauma and other and cytoplasmic vacuolation. When there is very tissue damage, administration of growth factors, severe bacterial infection and in neonates, alco- carcinoma, Hodgkin’s disease, non-Hodgkin’s holics and patients with reduced bone marrow lymphoma and auto-immune disorders such as reserve, neutrophilia does not occur but there is a systemic lupus erythematosus. Only a minority of left shift with the above ‘toxic’ changes in neu- patients with an infection show peripheral blood or trophils. Certain bacterial infections, specifically bone marrow changes suggestive of a particular typhoid, paratyphoid and tularaemia, are character- micro-organism. ized by neutropenia rather than neutrophilia. In Fig. 3.1 PB, bacterial infection, left shift and toxic granulation. MGG ×940. 90 INFECTION AND REACTIVE CHANGES 91 Fig. 3.2 PB, bacterial infection, monocytosis and neutrophilia. MGG ×940. severe infection, particularly if there is shock or whelming infections, particularly when there is hypoxia, nucleated red blood cells may appear in associated hyposplenism. In relapsing fever, how- the blood, the presence of both granulocyte precur- ever, the characteristic spiral organisms of Borrelia sors and nucleated red cells being referred to as species appear episodically in the bloodstream and leuco-erythroblastosis. The lymphocyte count is are seen lying free between red cells. In ehrlichial reduced but a few atypical lymphocytes, including infections, organisms are often detectable within plasmacytoid lymphocytes, may be present; plasma monocytes or granulocytes. They are detected cells are sometimes seen. The eosinophil count in monocytes in human monocytic ehrlichiosis is reduced during acute infection but eosinophilia (caused by Ehrlichia chaffeensis) and in neutrophils can occur during recovery. Children may respond in human granulocytic ehrlichiosis and human to bacterial infection with lymphocytosis rather infection by Ehrlichia ewingii (the agent responsible than neutrophilia, and certain bacterial infections, for canine granulocytic ehrlichiosis) [1]. The detec- particularly whooping cough and sometimes bru- tion of organisms within leucocytes is facilitated by cellosis, are characterized by lymphocytosis. In bac- examination of buffy coat films. terial infection, the platelet count is often reduced In more chronic infections, there may be but sometimes increased. anaemia, increased rouleaux formation, increased Certain bacterial infections can be complicated by background staining and monocytosis (Fig. 3.2). haemolytic anaemia. Infection by E. coli or Shigella Anaemia is initially normocytic and normochromic species can be followed by a micro-angiopathic but, as the infection becomes increasingly chronic, haemolytic anaemia as part of a haemolytic uraemic the anaemia develops the characteristics of the syndrome. Sepsis due to Clostridium welchii can be anaemia of chronic disease with the cells produced complicated by acute haemolysis with spherocytic being hypochromic and microcytic. red cells. Mycoplasma infection is commonly asso- Pulmonary tuberculosis characteristically causes ciated with the production of cold auto-antibodies anaemia, increased rouleaux formation and, when so that red cell agglutinates are present in blood severe, neutrophilia. Monocytosis occurs in a films made at room temperature and haemolytic minority of patients. Monocytopenia is actually anaemia sometimes occurs. more common than monocytosis. In miliary tuber- Rarely, neutrophils contain phagocytosed bacte- culosis, leucocytosis is uncommon and leucopenia ria. The presence of bacteria, either extracellularly is common. The lymphocyte count is reduced. A or within neutrophils, is usually seen only in over- minority of patients have monocytosis. Pancytopenia 92 CHAPTER THREE Fig. 3.3 BM aspirate film from a patient with severe infection showing heavy toxic granulation and vacuolation of neutrophil precursors. MGG ×940. may occur, sometimes as a consequence of provides evidence of a specific infection. In haemophagocytosis and, less often, in association Whipple’s disease, the causative organisms may be with bone marrow necrosis. seen within bone marrow macrophages [2]. In Rickettsial infections cause varied haematological human monocytic ehrlichiosis, organisms can be effects which may include neutrophilia, neutro- detected in bone marrow monocytes, whereas in penia, lymphocytosis, the presence of atypical human granulocytic ehrlichiosis, caused by a lymphocytes and thrombocytopenia which is some- related organism, they are present in granulocytes times severe. [3]. Bacteria visible within macrophages have also Occasionally, severe infections are associated been reported in bacterial endocarditis. In typhoid with a haematological picture which simulates fever, the bone marrow aspirate shows only non- leukaemia, designated a leukaemoid reaction (see specific features but bone marrow culture can below). be useful since it increases the detection rate by 50% in comparison with culture of the peripheral blood [4]. In brucellosis, the bone marrow is usually Bone marrow cytology hypercellular with prominent haemophagocytosis In severe bacterial infection, the bone marrow fea- and increased eosinophils and plasma cells [5]. tures reflect those of the peripheral blood. There is Bone marrow cultures are occasionally positive granulocytic hyperplasia with associated toxic when blood cultures are negative but, as the diag- changes (Fig. 3.3). In overwhelming infection, the nosis can be made serologically, bone marrow marrow sometimes shows an increase of granulo- aspiration is not indicated for this purpose. cyte precursors but with few maturing cells. In tuberculosis, the bone marrow aspirate shows Erythropoiesis is depressed and erythroblasts show non-specific features such as increased iron stores reduced siderotic granulation. When there is and an increase in macrophages, often with hae- thrombocytosis, megakaryocytes may be increased. mophagocytosis. Mycobacteria may be detected in Macrophages are increased and, in a minority of a minority of cases using specific stains (Ziehl– patients with severe infection, prominent haemo- Neelsen or auramine). Cultures should always be phagocytosis occurs (see page 119). When infection performed when this diagnosis is suspected. In lep- is chronic, an increase of iron stores is apparent. romatous leprosy, bacilli may be apparent as nega- Microscopy or bone marrow culture occasionally tive images within bone marrow macrophages [6]. INFECTION AND REACTIVE CHANGES 93 Fig. 3.4 BM trephine biopsy section, bacterial infection with leukaemoid reaction: there is increased cellularity and granulocytic hyperplasia with left shift; note emperipolesis of a mature neutrophil by a megakaryocyte. Paraffin- embedded, H&E ×195. by three or more plasma cells. The plasma cells have Bone marrow histology mature nuclear and cytoplasmic characteristics Severe bacterial infection leads to an increase in although there are often occasional binucleate marrow cellularity due to granulocytic hyperplasia. forms and cells containing Russell bodies. Chronic There is often left shift of the granulocytic series, i.e. infection is also associated with an increased fre- an increase in the numbers of immature precursors quency of reactive lymphoid aggregates (see page (myelocytes and promyelocytes) in relation to 144). Macrophages may be increased and com- mature polymorphonuclear neutrophils (Fig. 3.4). monly contain ingested granulocytes (Fig. 3.5). A However, the normal topographical arrangement of wide variety of infectious agents, including bacteria, granulopoiesis is retained, with the more immature can cause a secondary haemophagocytic syndrome cells (mainly promyelocytes) found predominantly (see page 119). Stromal changes related to infection in the paratrabecular region [7]. Megakaryocytes include prominent sinusoids, focal reticulin fibrosis are often increased in number [8]; they are mor- and rarely, in very severe chronic infections, gelati- phologically normal, but there may be an increase in nous change (see page 128). A decrease in marrow ‘bare’ megakaryocyte nuclei and increased emperi- cellularity and loss of fat spaces usually accompany polesis. Erythropoiesis is often reduced although gelatinous transformation [10]. morphologically normal. Mycobacterial infections can cause the same In more chronic bacterial infections, changes in reactive changes as infection by other bacteria. other lineages become apparent. Bone marrow However, haemophagocytosis and granuloma for- plasmacytosis is a common but non-specific re- mation are particularly common. Whenever granu- sponse [9]. Very rarely, there may be up to

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