Chronic idiopathic neutropenia

What every physician needs to know:

Chronic idiopathic neutropenia in adults (CINA) describes a heterogeneous group of disorders associated with a decreased number of circulating neutrophils. Although there is some variability, in most studies neutropenia is defined as an absolute neutrophil count (ANC) of less than 1,500/μl. The etiology of CINA is likely heterogeneous, as the term has been used to describe individuals with a wide range of neutrophil counts with evidence of a number of potential causes. In some patients, neutrophil destruction may be immune, in others it may be related to inflammatory mediators, and in others, there are few hints as to the etiology.

A large number of studies have concentrated on patients from Crete, where CINA has a prevalence of about 2%, and evidence suggests that in those patients, neutropenia may be mediated by inflammatory cytokines, suggesting an underlying low-grade inflammatory process. However, the patients in that cohort have very mild neutropenia, with neutrophil counts that are rarely less than 800μl. These patients rarely have any clinical sequelae from their neutropenia and likely represent a unique subset of CINA patients.

There are other patients with CINA that have an ANC that is chronically less than 300/lμ, and indeed some that without cytokine support have an ANC that can be as low as 50/μl. The etiology of CINA in these patients is completely unknown.

Neutropenia may also be familial, with a syndrome that is essentially identical to sporadic CINA, except that the patient has a family history of low neutrophil counts.

The most important thing to know about CINA is that it is a benign disorder. Although some patients may need cytokine support to prevent recurrent aphthous ulcers or recurrent infections, many patients require no therapy at all. Even in those patients who are clinically symptomatic, low doses of granulite colony-stimulating factor (G-CSF) are usually sufficient to maintain an adequate neutrophil count to allow them to live essentially symptom-free. There are as yet no long term sequelae that have been attributed to CINA.

Are you sure your patient has chronic idiopathic neutropenia? What should you expect to find?

CINA is a diagnosis of exclusion. Patients with persistent neutropenia over weeks to months with no identifiable underlying disorder are deemed to have chronic idiopathic neutropenia.

Patients with CINA will often present with the usual signs and symptoms of neutropenia. Clues to the diagnosis of chronic neutropenia include a history of recurrent apthous ulcers, increased dental caries, recurrent bronchitis and/or pneumonia.

Acute fever in the setting of severe neutropenia may often be accompanied by little in the way of localizing signs and symptoms. Because the disease is usually asymptomatic, neutropenia may come to medical attention because of an acute infectious episode in a patient who was not previously known to be neutropenia. In that setting, because acute infections in patients with chronic severe neutropenia are not associated with the predicted level of leukocytosis, it is also not uncommon for patients to suffer complications of undiagnosed infections. If these patients develop appendicitis, for example, they are at high risk of remaining undiagnosed and having perforation and peritonitis before the situation is appropriately recognized.

Beware of other conditions that can mimic chronic idiopathic neutropenia:

The differential diagnosis of chronic neutropenia depends on the acuity and the severity of the decrease in ANC. If the patient has other cytopenias, a diagnosis of idiopathic neutropenia should not be entertained.

In the setting of chronic mild neutropenia, several other diagnoses should be considered:

Constitutional neutropenia
Autoimmune neutropenia related to systemic autoimmune disease
Drug-induced neutropenia
Infection-related neutropenia

granulomatous disease

fungal disease
Myelodysplastic syndrome
Hypersplenism

In the setting of acute mild neutropenia, alternative diagnoses to consider include:

Viral infection
Acute bacterial infection
Laboratory error

Acute severe neutropenia without evidence of other cytopenias should lead you to consider the following:

Acute sepsis
Drug-induced agranulocytosis
Acute leukemia

Chronic severe neutropenia, especially in patients who appear otherwise healthy, should raise the consideration of CINA. Other potential diagnoses include:

Large granular lymphocyte leukemia (LGL), either sporadic or in the setting of underlying autoimmune disease
Familial neutropenia (which is probably a variant of CINA)

Which individuals are most at risk for developing chronic idiopathic neutropenia:

In the setting of familial neutropenia, other family members are at risk of having the same abnormality.

On the island of Crete, there is a markedly increased prevalence of CINA, which is seen about 2% of the population. The neutropenia in this setting tends to be extremely mild, with ANCs less than 800/ul being distinctly rare. Although there has been considerable research documenting a role for chronic inflammation in the neutropenia in this population (see Pathophysiology, below), it seems highly likely that this represents a form of constitutional neutropenia, which may be exacerbated by inflammatory influences.

There are otherwise no predictive features conferring increased risk for this rare and sporadic disease.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Bone marrow aspirate and biopsy

Patients with persistent neutropenia on multiple complete blood counts (CBCs), with no identifiable underlying cause should undergo bone marrow examination. In addition to histologic examination of the aspirate and biopsy slides, marrow should be analyzed by flow cytometry to rule out LGL or other lymphoproliferative disease and by cytogenetics, to rule out myelodysplastic syndrome. Once a marrow examination has been performed and been shown to be unrevealing, there is little utility to repeated marrow examinations. The likelihood of evolution to a more concerning disorder is extremely low. Consequently, marrow examination should be repeated only if the patient develops worrisome new findings such as other accompanying cytopenias or abnormal morphology on the peripheral smear that might suggest the acquisition of an independent marrow disorder.

Testing for cyclic neutropenia

Patients can be evaluated to determine whether they have cycling of their counts by having biweekly CBCs for 3 to 6 weeks. This has been in large measure supplanted by sequencing of the neutrophil elastase (ELANE) gene, since virtually 100% of patients with cyclic neutropenia have mutations in ELANE.

Testing for severe congenital neutropenia

There is little utility in testing for the mutations associated with severe congenital neutropenia (SCN) in an adult patient, since SCN usually presents in the first year of life with life-threatening neutropenia requiring cytokine support for survival. However, in an occasional adolescent patient with profound neutropenia, one might consider testing for ELANE, HAX-1, and G6PC3. Two patients in the literature with CINA have been described to have mutations in Gfi-1, which can also be evaluated by sequencing.

Testing for immune neutropenia

Flow cytometry on the peripheral blood should be performed to rule out LGL. Testing for antineutrophil antibodies is of low utility, since they are unreliable predictors of immune neutropenia and have poor specificity. Testing for autoimmune disease in the appropriate clinical setting may allow the presumptive diagnosis of immune neutropenia.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of chronic idiopathic neutropenia?

No imaging studies contribute to the diagnosis of CINA. Patients who present with fever in the setting of profound neutropenia, require appropriate imaging studies in aid of diagnosing the source of potential infection.

If you decide the patient has chronic idiopathic neutropenia, what therapies should you initiate immediately?

CINA is a benign disorder that frequently requires no therapy. If the patient is asymptomatic and does not have a history of infections, they do not require therapy in response to their neutrophil number. Patients with profound neutropenia and recurrent apthous ulcers or recurrent febrile episodes do require therapy.

The backbone of therapy is G-CSF. Patients should be treated with G-CSF at a dose and frequency that will maintain their neutrophil count above 500-1000. This can often be maintained with a once or twice weekly dose of G-CSF. Treatment with long-acting G-CSF preparations is not recommended in this population, since it is associated with excessive side effects including severe bone pain, nausea, vomiting, diarrhea, abdominal pain, and occasional splenomegaly.

It is recommended that patients with severe neutropenia be instructed that they should contact their physician immediately in the event of the development of fever. Febrile, neutropenic patients should be hospitalized for intravenous broad spectrum antibiotics (see chapter on Leukopenia). It is advisable to give patients a supply of a broad spectrum antibiotic (for example, a fluoroquinolone) to take in the event of fever, while they are seeking medical attention.

Patients who are discovered to have LGL or autoimmune neutropenia should be managed with appropriate immunosuppressive therapy, as outlined in the chapters dealing with those two diseases.

More definitive therapies?

Further therapy should not be required. G-CSF should remain the cornerstone of therapy if any therapy is required.

What other therapies are helpful for reducing complications?

N/A

What should you tell the patient and the family about prognosis?

It is important to counsel the patient and the family that this is a benign disorder and that is not a prelude to a hematologic malignancy. While it is important to be vigilant with regard to episodes of fever, the patient should be unrestricted in his or her activities. Those patients with febrile episodes can be easily and completely managed with appropriate cytokine support.

"What if" scenarios.

The patient presents with fever

As previously described, patients with fever in the setting of severe neutropenia require immediate hospitalization for intravenous antibiotics. Management of CINA patients with fever and neutropenia is identical to the management of other febrile neutropenic patients.

The patient wants to have a child

There is no contraindication to pregnancy in this patient population. G-CSF therapy should be carefully monitored to maintain counts in a safe range.

The patient wants to travel to the third world

Many patients express anxiety about travel because of the limits on available medical care in some regions of the world. If the patient has had a benign course, as most of these patients do, there is no reason to limit activities or to avoid travel. Patients should continue on G-CSF support if they are taking it, and should definitely be supplied with a broad spectrum antibiotic, such as a fluoroquinolone, to have available in the event of an episode of fever. Should the patient develop a febrile episode while abroad, they should seek medical attention. However, this is rarely necessary.

Pathophysiology

The pathophysiology of CINA is not well defined. This is partly a reflection of the heterogeneity of the disorder. Available information is discussed briefly below.

Familial neutropenia

The original English language description of familial neutropenia (FN) described three generations of affected individuals with an ANC of 400-900/μl. Pedigree analysis suggested an autosomal dominant mode of inheritance affecting multiple individuals across three generations. Although the disease was generally benign, there was a range of manifestations ranging from asymptomatic to repeated dental caries and skin infections, to episodic febrile episodes. At least one family member had died of acute peritonitis.

As noted, acute abdominal catastrophes can result in patients in whom diagnosis is delayed, in part because of the absence of leukocytosis as a marker for acute infection. The gene responsible for this and other cases of FN is unknown. A case report has reported a familial syndrome associated with a deletion at a fragile site on chromosome 16, but the relationship between the cytogenetic lesion and the neutropenia is unknown.

CINA in Crete

The predominant literature on this syndrome is based on an intensive study of a cohort of patients with CINA on the island of Crete. It should be noted that in this population, neutropenia was defined as an ANC less than 1,800/μl, and that the median neutrophil count in these patients was 1,214 +/- 358.

These patients follow a uniformly benign course and virtually never require cytokine support. In this population, neutropenia has been associated with a TGF-β polymorphism, increased Fas-mediated apoptosis of bone marrow (BM) progenitors, and aberrant T-cell expansions. The investigators have proposed that CINA in this population represents a subclinical proinflammatory state affecting the bone marrow microenvironment. Whether this inflammatory response is superimposed on a potential constitutional neutropenia within this population has not been explored.

CINA with severe neutropenia

Very little data are available bearing on the etiology of neutropenia in patients with CINA and severe neutropenia. One study of a small number of patients has demonstrated that peripheral blood neutrophils of six patients with severe neutropenia (though some were treated with G-CSF and had higher neutrophil counts) had no increase in constitutive and death receptor-mediated apoptosis. The authors propose that this suggests that the defect is not intrinsic to the neutrophil.

Whether apoptosis was increased in marrow precursors was not addressed, so it remains uncertain whether the defect is one of abnormal neutrophil maturation and survival or a reflection of an abnormal bone marrow microenvironment. Another study of 20 patients with CINA, identified a significant percentage of patients with immunodominant non-LGL T cell clones, although their functional impact on neutrophil proliferation and survival was not examined. The patients in this study had a wide range of ANC, although only 4 of the twelve patients with immunodominant clones had an ANC of less than 500/ul.

Further study is required to determine whether a significant portion of these patients have subtle T-cell cytotoxic clones mediating their disease.

What other clinical manifestations may help me to diagnose chronic idiopathic neutropenia?

N/A

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

Cutting, HO, Lan, JE. “Familial benign chronic neutropenia”. Annals Int Med. vol. 61. 1964. pp. 876-887. [Early description of familial neutropenia.]

Eliopoulos, DG, Mavroudi, I, Pontikoglou, C. “The -509C/T polymorphism of the transforming growth factor-β1 is associated with increased risk for development of chronic idiopathic neutropenia”. Eur J Haematol. vol. 83. 2009. pp. 535-540. [Role of TGF-β polymorphism in CINA in Crete.]

Garwicz, D, Palmblad, Fadeel, B. “Normal levels of constitutive and death receptor-mediated apoptosis of peripheral blood neutrophils from patients with chronic idiopathic neutropenia”. Clin Immunol. vol. 122. 2007. pp. 349-355. [Data demonstrating normal rates of apoptosis of neutrophils in CINA supporting that neutropenia is not cell intrinsic (in contrast to congenital neutropenia).]

Glasser, L, Meloni-Ehrig, A, Joseph, P, Mendiola, J. “Benign chronic neutropenia with abnormalities involving 15q22, affecting mother and daughter”. Amer J Hematol. vol. 81. 2006. pp. 262-270. [Description of familial neutropenia associated with a chromosomal abnormality, possibly related to a fragile site.]

Papadaki, HA, Palmblad, J, Eliopoulos, GD. “Non-immune chronic idiopathic neutropenia of adult: an overview”. Eur J Haematol. vol. 67. 2001. pp. 35-44 . [Review of CINA in Crete.]

Spanoudakis, M, Koutala, H, Ximeri, M. “T-cell receptor Vβ repertoire analysis in patients with chronic idiopathic neutropenia demonstrates the presence of aberrant T-cell expansions”. Clin. Immunol. vol. 137. 2010. pp. 384-395. [Suggestion that CINA have aberrant T cell clones that underlie the development of neutropenia. Note these patients have only mild neutropenia with ANCs of 800-1,400.]

Wlodarski, MW, Nearman, Z, Jiang, Y, Lichtin, A, Maciejewski, JP. “Clonal predominance of CD8+ T cells in patients with unexplained neutropenia”. Experimental Hematol. vol. 36. 2008. pp. 293-300. [Novel mechanism proposed for some cases of chronic idiopathic neutropenia.]

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