Neutropenia in primary care

Consider ethnicity

Before embarking on further investigation, however, it is necessary to determine whether the neutrophil count is genuinely abnormal. Benign ethnic neutropenia affects 25-50% of people of African or Afro-Caribbean ancestry, as well as some of Arabic-Middle Eastern origin, and has no clinical significance.4 Normal ranges specific to ethnic groups are not reported; however, a population study from Uganda suggests that the mean neutrophil count for healthy black African adults is lower than that seen in white people, at 1.8×10⁹/L (90% confidence interval 0.84 to 3.37).5 Similar findings were reported in a study of four ethnic groups in the United Kingdom,6 with a mean neutrophil count of 2.6×10⁹/L (1.1 to 6.1) being reported for black Africans. The average neutrophil count for white people was 3.6×10⁹/L (1.7-7.5). In patients of African or Afro-Caribbean ancestry, we therefore recommend investigating neutropenia only in those who have counts persistently less than 1.0×10⁹/L.

Review the drug history

The underlying cause of neutropenia is often evident from the history. The incidence of drug induced severe neutropenia or agranulocytosis is 2.4-15.4 per million population per year,7 and, although a temporal association with drug treatment is typical, delayed neutropenia can occur in patients who have been taking a stable dose of a drug for years (table 2⇓).8

A systematic review of more than 900 published reports of agranulocytosis identified 125 “definite or probable” causative agents and highlighted a 10% mortality rate in patients with a neutrophil nadir of less than 0.1×10⁹/L.9 In such severe cases, the drug usually needs to be discontinued and granulocyte colony stimulating factor is often needed to speed neutrophil recovery. Drug induced neutropenia is more often mild or moderate, however, and a clinical decision must be made regarding the relative benefits of drug treatment and the risks of neutropenic sepsis. If a decision is made to continue treatment, the neutrophil count should be carefully monitored.

Ask for a blood film

For moderate or severe unexplained neutropenia, inspection of a blood film is an important investigation. Figures 1 and 2⇓ ⇓ highlight some of the abnormalities that may be detected.

Fig 1 Large granular lymphocytes with azurophilic granules may be seen in viral infection. More rarely, they are seen in the T cell chronic lymphoproliferative disorder, large granulocytic leukaemia

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Fig 2 “Pelger form” neutrophil (top right), and a hypogranular, poorly segmented neutrophil (bottom left), both with typical dysplastic features; some variation in red cell size and shape is also seen

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The presence of reactive T cells may suggest acute viral infection. Neutropenia is seen in 50% of cases of infectious mononucleosis10 and may also be seen in acute cytomegalovirus infection and toxoplasmosis. A suitable history (perhaps including fever, sore throat, or general malaise) and the blood film shown in fig 1 should prompt a monospot test or specific viral serology. Neutropenia in this context usually resolves in three to four weeks.

Large granular lymphocytes, similar to those in fig 1, are also seen in many autoimmune or reactive conditions. Less commonly, a persistent lymphocytosis suggests an underlying lymphoproliferative disease, with the rare T cell disorder large granular lymphocytic leukaemia manifesting as an isolated neutropenia in 60-85% of cases.11

A myelodysplastic syndrome may be suggested by typical blood film findings (fig 2), although these are observer dependent and usually extend to cell lines other than granulocytes.12

Occasionally, the blood film suggests haematinic deficiency. Vitamin B₁₂ and folate deficiency are often cited as possible causes of isolated neutropenia,13 14 although few if any cases of neutropenia in the absence of anaemia or macrocytosis are reported. Iron deficiency may also rarely cause neutropenia.15 16 Because haematinic deficiency is readily testable and easily remedied, vitamin B₁₂, folate, and ferritin assays are justifiable in the investigation of patients presenting with unexplained neutropenia. Other nutritional deficiencies are also worth considering: neutropenia caused by deficiencies of trace elements (such as copper) has also been described, although other haemopoietic cell lines are usually affected.17 Extreme energy restriction—in patients with anorexia nervosa, for example—can also cause neutropenia, partly due to haematinic deficiencies and partly through serous atrophy of the marrow.

In many cases, however, the blood film provides no clues to the underlying cause. For these patients, further testing is determined on a case by case basis.

Chronic viral serology (HIV, hepatitis B and C)

Neutropenia has been described in 50% of patients with HIV, and is seen in 5-10% of asymptomatic patients with early infection.18 19 It may also be seen in treatment naive patients with hepatitis C, with a minority of cases being severe.20 A prospective study of patients undergoing a structured investigation in primary care for isolated neutropenia identified chronic hepatitis in 6% of patients,16 confirming chronic viral serology as a useful test in the investigation of persistent unexplained neutropenia.

Antinuclear antibodies (ANA) and rheumatoid factor

Autoimmune spectrum disorders are often associated with neutropenia. Although most cases of severe neutropenia in systemic lupus erythematosus are caused by drug induced myelosuppression,21 one study reports that 50% of patients with this condition have mild to moderate neutropenia, usually with an immunological pathophysiology.22 Fewer data are available on neutropenia in rheumatoid arthritis (except for the well described, but rare, Felty’s syndrome), Sjögren’s syndrome, or mixed connective tissue disorders.

Other articles in this series have discussed the limited sensitivity of ANA testing for the diagnosis of systemic lupus erythematosus.23 Systematic studies are lacking, but pragmatically we support testing for ANA, rheumatoid factor, or antibodies to extractable nuclear antigens only when there are additional features consistent with these disorders. For isolated neutropenia in an otherwise well person, a positive ANA or rheumatoid factor result is unlikely to inform diagnosis or management.

Antineutrophil antibodies

Primary immune neutropenia in the absence of any systemic immunological disease is also well described. In infancy and early childhood, this is the most common cause of acquired neutropenia, with antineutrophil antibodies being detected in more than 98% of cases.24 However, it is less clear whether adults with neutropenia should be tested for these antibodies because the correlation between a positive test and clinically detectable neutropenia in adults is poor.25 26 This makes it difficult to assess the prevalence of primary immune neutropenia in primary care; testing for antineutrophil antibodies is not recommended in this setting.

When to refer?

Primary care doctors are perhaps most worried that patients with isolated neutropenia may have an underlying haematological malignancy. However, this is a relatively unusual explanation. One study in primary care that reported the results of a panel of investigations, including bone marrow examination, in 97 patients with isolated neutropenia detected a clonal haematological disorder in only seven (three cases of myelodysplastic syndrome and four chronic B cell lymphoproliferative disorders).16 Of note, a potentially helpful inspection of the peripheral blood film was not mentioned as part of the diagnostic investigation of these patients.

Referral to secondary care is warranted whenever there is suspicion of progressive or serious disease of any kind. This takes account of features beyond the blood count alone, but the development of anaemia or thrombocytopenia in a patient with previously isolated neutropenia may suggest a primary bone marrow disorder and is a strong indication for a referral for haematological opinion. More severe neutropenia is also more likely to prompt referral, particularly if a downward trend in the absolute neutrophil count is also seen. Although evidence based clinical guidelines are lacking, these are the patients in whom a bone marrow examination is likely to be performed. Any patient with unexplained neutropenia consistently less than 1×10⁹/L warrants a discussion with the haematology service to establish the utility of further investigation in secondary care.

In one prospective study, no cause was found in a third of patients with isolated neutropenia, even after comprehensive investigation.16 27 However, doctors in primary and secondary care should be aware that disease specific symptoms may become apparent with time and periodic re-evaluation may be needed.