Neutropenia - Complications and diseases associated to Neutropenia

Neutropenia is defined as a condition of  abnormally low number of neutrophils, as a  result of granulocyte disorder of that leads to Immunodeficiency with lower than normal  circulating white blood cells. Patients with neutropenia are susceptible to bacterial infections causes of neutropenic sepsis.
Neutropenia is either problems in the production of the cells by the bone marrow and destruction of the cells from somewhere else in the body, if  neutrophil count falls below 1,000 cells per microliter of blood.
Neutropenia can be classified into acute and chronic types, depending to the duration of the illness. Some researchers divided severity of the disease, depending to the absolute neutrophil count (ANC) and is described as follows(a).
1. Mild neutropenia, when the ANC falls below a lower limit of 1500 per mm3 (1.5 x 109 /1), but remains higher than 1000 per mm3 (1.0 x 109 /1).
2. Moderate neutropenia, when the ANC falls between 500 per mm3 and 1000 per mm3 (0.5 x 109 /1 - 1.0 x 109 /1)
3. Severe neutropenia, when the ANC falls below 500 per mm3 (0.5 x 109 /1)
Complications and diseases associated to Neutropenia
C.1. Complications
1. Unstable hemodynamic status, respiratory distress, altered mental status, newly developed arrhythmia that required intervention, and death
In the study to evaluate associations between the risk factors and serious complications in patients presenting to the ED with febrile neutropenia by reviewing the health information system database to identify a retrospective cohort of patients with febrile neutropenia who visited the ED of a tertiary medical hospital from January to December 2008, showed that serious complications during hospitalization were defined as unstable hemodynamic status, respiratory distress, altered mental status, newly developed arrhythmia that required intervention, and death during hospitalization.  Only episodes of febrile neutropenia caused by chemotherapy for underlying cancer were included(22).

2. High risk for septic complications
In the study to evaluate pentraxin 3 as a marker for complications of neutropenic fever in 100 hematologic patients receiving intensive chemotherapy with Pentraxin 3 and C-reactive protein measured at fever onset and then daily to day 3, showed that in comparison to C-reactive protein, pentraxin 3 achieved its maximum more rapidly. Pentraxin 3 correlated not only with the same day C-reactive protein but also with the next day C-reactive protein. High pentraxin 3 on day 0 was associated with the development of septic shock (P=0.009) and bacteremia (P=0.046). The non-survivors had constantly high pentraxin 3 levels(23).

C.2. Diseases associated to Neutropenia
Chronic neutropenia with autoimmune diseases is associated mainly with rheumatoid arthritis (RA), as Felty's syndrome or large granular lymphocyte (LGL) leukemia, and with systemic lupus erythematosus (SLE)(23a).
1.  Rheumatoid arthritis (RA) 
T cell large granular lymphocyte leukemia (T-LGL) is a disease characterized by clonal expansion of cytotoxic T cells (CTLs). It generally follows an indolent course and is notable for an association with chronic inflammation, neutropenia and rheumatoid arthritis (RA), according to the study by the Duke University Medical Center(24).

2. Felty’ssyndrome or large granular lymphocyte (LGL) 
Large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic cells, either CD3(+) (T-cell) or CD3(-) (natural killer, or NK). Both subtypes can manifest as indolent or aggressive disorders. T-LGL leukemia is associated with cytopenias and autoimmune diseases and most often has an indolent course and good prognosis. Rheumatoid arthritis and Felty syndrome are frequent, according to the study by Michal G. Rose, M.D., The Comprehensive Cancer Center (IIID), VA Connecticut Healthcare System(25).

3. Leukemia and related disorders
T-cell large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic T cells, which causes neutropenia, anemia, and/or thrombocytopenia. This condition is often associated with autoimmune disorders, especially rheumatoid arthritis, and other lymphoproliferative disorders(26).

4. Systemic lupus erythematosus (SLE)
In the study of 89 SLE patients (92% females), with their mean (SD) age and disease duration at the study entry of 31.7 (12.2) years and 2.4 (2.9) months, leukopenia was found at the diagnosis in 51.6% of the cases. The cumulative prevalence of leukopenia, lymphopenia, and neutropenia was observed in 57.3%, 96.6%, and 60.7%, respectively(27).

5. Crohn's disease
There is a report of a 29-year-old woman with a 20-year history of Crohn's disease and neutropenia. Because of repeated complications of Crohn's disease, she has undergone three intestinal resections and also has had recurrent skin abscesses, sinusitis, and pneumonia. Persistent neutropenia has been noted throughout the course of her disease, and antineutrophil antibodies have been detected in her serum and that of her younger brother, who also has Crohn's disease and neutropenia(28). 

6. Graves' disease
There is a report of a 38-year-old man with Graves' disease taking propylthiouracil (PTU) for 6 years developed neutropenia and marked splenomegaly(29). 

7. Poikiloderma
Poikiloderma with neutropenia (PN, OMIM 604173) is a rare autosomal-recessive genodermatosis. Mutations in the C16orf57 gene have been recently identified as the cause(29a).

8. without serious complications in children with acquired neutropenia
In the study to to identify the relationship of acquired neutropenia with childhood infections and to assess its clinical course, complications, and outcome of 161 previously healthy children with febrile neutropenia/leukopenia aged (mean ± SD) 3.02 ± 3.86 years (range, 0.1-14). One hundred and thirty-six out of 161 patients (84.5 %) had transient neutropenia (TN), while in 25 patients, neutropenia was chronic (CN) and persisted for ≥180 days, indicated that a infectious agent was isolated in 98/161 (60.9 %) cases, in 68.4 % patients with TN, and in 20 % of those with CN (p = 0.001). Among the patients with CN, seven had positive antineutrophil antibodies (autoimmune neutropenia) and four were eventually diagnosed with hematological malignancy. In all age groups, TN was of short duration (<1 month), of mild to moderate severity, and was predominantly associated with viral infections. Two years after diagnosis, 143/161 children (88.8 %) were available for follow-up. One hundred and thirty-seven of 143 (95.8 %) had recovered completely, while the rest remained neutropenic(30).
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Sources
(a) http://www.neutropenia.ca/about/what-is-neutropenia
(22) http://www.ncbi.nlm.nih.gov/pubmed/23303687
(23) http://www.ncbi.nlm.nih.gov/pubmed/21880642
(23a) http://www.ncbi.nlm.nih.gov/pubmed/11957195
(24) http://www.ncbi.nlm.nih.gov/pubmed/19394280
(25) http://theoncologist.alphamedpress.org/content/9/3/247.full
(26) http://www.ncbi.nlm.nih.gov/pubmed/17596907 
(27) http://www.ncbi.nlm.nih.gov/pubmed/23519174 
(28) http://www.ncbi.nlm.nih.gov/pubmed/2066550 
(29) http://www.ncbi.nlm.nih.gov/pubmed/3841726 
(29a) http://www.ncbi.nlm.nih.gov/pubmed/23823120
(30) http://www.ncbi.nlm.nih.gov/pubmed/23408310