Neutropenia

Referencia médica Neutropenia

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Angel A. Justiz Vaillant

Editor del artículo:

Patrick M. Zito

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8/25/2022 2:12:05

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Actividad de Educación Continua

Los neutrófilos juegan un papel esencial en las defensas inmunes porque ingieren, matan y digieren microorganismos invasores, incluidos
hongos y bacterias. El fracaso en llevar a cabo este papel conduce a la inmunodeficiencia, que se caracteriza principalmente por la presencia de
infecciones recurrentes. Los defectos en la función de los neutrófilos pueden ser cuantitativos, como se ve en la neutropenia o cualitativos,
como se ve en la disfunción de los neutrófilos. El recuento estándar de neutrófilos circulantes es superior a 1,5 x 10/L. La neutropenia se puede
clasificar en asintomática (leve), moderada y grave, y por lo tanto, la progresión a la infección con respecto al número. La neutropenia, con
disminución de la producción con hipoplasia medular, puede ser primaria y debida a neutropenia benigna crónica, neutropenia cíclica y otras
neutropenias congénitas y familiares. Puede ser secundaria a fármacos citotóxicos, anemia aplásica, leucemia, reacciones a medicamentos e
infecciones. La neutropenia, con mayor destrucción con hiperplasia medular, se debe al hiperesplenismo y la neutropenia inmune. Las causas
secundarias son las más comunes. Por ejemplo, neutropenia causada como efecto secundario de la quimioterapia para neoplasias malignas.
Esta actividad revisa la etiología, presentación, evaluación y manejo/prevención de la neutropenia, y revisa el papel del equipo interprofesional
en la evaluación, diagnóstico y manejo de la afección.

Objetivos:

Explicar la fisiopatología de la neutropenia.

Describir los criterios de presentación y examen para evaluar la neutropenia.
Revisar las consideraciones de tratamiento y manejo para pacientes con neutropenia crónica.
Describir las estrategias del equipo interprofesional para mejorar la coordinación y colaboración de la atención con el fin de emplear una
mejor identificación, detección y tratamiento de la neutropnea para mejorar los resultados de los pacientes y mejorar las posibilidades
de supervivencia y recuperación.

Introducción
Los neutrófilos juegan un papel esencial en las defensas inmunes porque ingieren, matan y digieren microorganismos invasores, incluidos
hongos y bacterias. El fracaso en llevar a cabo este papel conduce a la inmunodeficiencia, que se caracteriza principalmente por la presencia de
infecciones recurrentes. [1] Los defectos en la función de los neutrófilos pueden ser cuantitativos, como se observa en la neutropenia, o
cualitativos, como se observa en la disfunción de los neutrófilos. El recuento estándar de neutrófilos circulantes es superior a 1,5 x 10/L. La
neutropenia se puede clasificar en asintomática (leve), moderada y grave, y por lo tanto, la progresión a la infección con respecto al número.

La neutropenia, con disminución de la producción con hipoplasia medular, puede ser primaria y debida a neutropenia benigna crónica,
neutropenia cíclica y otras neutropenias congénitas y familiares. Puede ser secundaria a fármacos citotóxicos, anemia aplásica, leucemia,
reacciones a medicamentos e infecciones. La neutropenia, con mayor destrucción con hiperplasia medular, se debe al hiperesplenismo y la
neutropenia inmune. Las causas secundarias son las más comunes. Por ejemplo, neutropenia causada como efecto secundario de la
quimioterapia para neoplasias malignas. Las formas congénitas son raras y varían en gravedad; algunos de ellos son afecciones potencialmente
mortales que incluyen deficiencia de adhesión leucocitaria, síndrome de Chediak-Higashi, hiper-IgE, síndrome de infección recurrente y
enfermedad granulomatosa crónica. [2] [3]
Etiología
Las causas de los defectos primarios de la función de los neutrófilos incluyen la falla de lo siguiente[3][4]:

Adherirse a las células endoteliales

Migran a los sitios inflamatorios (quimiotaxis anormal)
Ingerir y matar bacterias
Producir compuestos microbicidas para matar hongos y otros patógenos
Forma fagolisosomas
Producir altas concentraciones de especies tóxicas reactivas de oxígeno

Los niveles bajos de neutrófilos pueden deberse a médula ósea hipoplásica, una infección, exposición a la radiación, infiltración tumoral de la
médula ósea, mielofibrosis, exposición prolongada a un medicamento o un trastorno hereditario. La neutropenia congénita o síndrome de
Kostmann se adquiere de forma autosómica recesiva.

Los medicamentos que se sabe que causan neutropenia incluyen:

Quinidina
Aminopyrine
Cephalosporin
Sulfonamides
Hydralazine
Penicillins
Heavy metals
Phenothiazine

Antineutrophil or autoimmune neutropenia has been observed in:

Rheumatoid arthritis (Felty syndrome)

Inflammatory bowel disease
Chronic autoimmune hepatitis
Granulomatosis with polyangiitis
Hodgkin lymphoma
Sjogren syndrome

Almost any infection can cause neutropenia. The condition is also seen with folate, vitamin B12, and copper deficiency.

Epidemiology
Hsieh and collaborators reported that in the United States, the prevalence of neutropenia was 0.38% among Mexican-Americans, 0.79% among
whites, and 4.5% among black participants.[5] Weycker and collaborators reported that the risk of febrile neutropenia during the chemotherapy
regimen course for treating solid tumor was 16.8%.[6] Severe neutropenia was present in 1 of every 2 patients with lymphoma receiving
chemotherapy with a higher risk of febrile neutropenia, and it was found in approximately 1 of every 10 breast cancer patients in Spain.[7]

Pathophysiology
Neutrophils play a role in the immune defense against extracellular bacteria, including Staphylococci, Streptococci, and Escherichia coli, among
others. They also protect against fungal infections, including those produced by Candida albicans. Once their count is below 1 x 10/L recurrent
infections start. As compensation, the monocyte count may increase. In primary neutropenia disorders such as chronic granulomatous disease
presents with recurrent infections affecting many organs since childhood. It is caused from a failure to produce toxic reactive oxygen species so
that the neutrophils can ingest the microorganisms, but they are unable to kill them, as a significant consequence granuloma can obstruct
organs such as the stomach, esophagus, or bladder. Patients with this disease are very susceptible to opportunistic infections by certain
bacteria and fungi, especially with Serratia and Burkholderia.[8]

Leukocyte adhesion deficiency has an autosomal recessive inheritance, and its functional defect is a failure of neutrophils to adhere to
endothelial cells and so to traverse into tissues to ingest and kill bacteria. Chediak-Higashi syndrome is also an autosomal recessive problem,
characterized by abnormal chemotaxis, so neutrophils fail to reach bacteria, and reduced microbicidal activity as lysosomes fail to fuse with
phagosomes.[9]
Histopathology
In Chediak-Higashi syndrome, histologically present with giant lysosomal granules in secretory cells.[9] The chronic granulomatous disease is
characterized by the presence of granulomas, which are composed of histiocytes that can fuse to form multinucleated giant cells and might be
surrounded by other immune cells such as lymphocytes and cover with collagen.

History and Physical

In neutropenia, there is a history of[9][10][11]:

Recurrent infections
Infections caused by rare bacteria and fungi
Opportunistic infections
Frequent use of antibiotics and antifungals

The physical findings include[12][10][9][13][14]:

Delayed separation of umbilical cord

Skin infections
Gingivitis
Deep abscesses
Peritonitis
Osteomyelitis
Lung abscesses
Pneumatoceles
Sinus and lung infections, e.g., pneumonia
Otitis media
Meningitis
Septicemia
Arthritis
Bacteremia
Fever
Coarse facial features
Mucocutaneous candidiasis
Cough
Malaise
Intestinal malabsorption
Bronchiectasis
Recurrent tonsillitis
Extensive cutaneous bacterial (Staphylococcal) infections
Sore throat
Purulent conjunctivitis
Granuloma with catalase-positive organisms
Skin abnormalities, e.g., pyodermitis
Splenomegaly 
Diarrhea    
Recurrent abscess       
Aphthous stomatitis
Urinary sepsis
Vasculitis
Poor wound healing  

Evaluation
The immunological investigation of a patient with neutropenia includes the assessment of immunoglobulins, complement system, and
phagocytes.[15][16]

Quantitative Serum Immunoglobulins

IgG
 IgM
IgA
IgE

Blood Lymphocyte Subpopulations

B lymphocytes (CD19 and CD20)

Phagocytic Function  

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

Unstimulated
Stimulated

Neutrophil mobility

In medium alone
In presence of chemoattractant

Complement System Evaluation

Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting

C3 serum levels
C4 serum levels

Hemolytic assays

CH50

Complement system functional studies

Classical pathway assay (using IgM on a microtiter plate)

Alternative pathway assay (using LPS on a microtiter plate)
Mannose pathway assay (using mannose on a microtiter plate)

Microbiological studies

Blood culture
Urine culture
Stool culture 
Sputum culture
Cerebrospinal fluid (culture, chemistry, and histopathology)

Other investigations of immunodeficiency disorders 

Complete blood cell count    

Bone marrow biopsy
Histopathological studies
Blood chemistry
Tumoral markers
Levels of cytokines (granulocyte-colony stimulating factor)
Chest x-ray
Diagnostic ultrasound
CT scan
Fluorescent in situ hybridization (FISH)
DNA testing (for most congenital disorders)

Treatment / Management
Application of granulocyte-colony stimulating factor (G-CSF) can improve neutrophil functions and number.[17][7] Prophylactic use of antibiotics
and antifungals is reserved for some forms of alteration in neutrophil function such as chronic granulomatous disease CGD).[13][18] The
utilization of antimicrobials is compulsory if recurrent infections exist. Interferon-gamma has been successfully used to improve the quality of
life of the patient suffering from neutropenia. Allogenic bone marrow transplantation from an HLA-matched related donor can cure CGD but
has a high mortality rate [19], and gene therapy is also a therapeutic option for treating disorders with neutropenia. Furthermore, intravenous
immunoglobulins can be another option in the management of these disorders.[13]
Differential Diagnosis
Neutropenia can differentiate from antibody deficiency disorders, where a class or different classes of immunoglobulins are below the normal
range or absence. These disorders may present clinically by recurrent infections with bacteria and fungi; some of them are opportunistic
pathogens, so the use of antimicrobials to treat infectious diseases is a norm.[20] A patient with neutropenia may have an intact acquired
immune response but a low number or impaired function of neutrophils. Some complement system deficiency, e.g., C3 deficiency manifests
with multiple extracellular bacterial infections and may resemble neutropenia, but can rule out by quantification and functional assessment of
the complement system.[1][21]

Prognosis
The prognosis of neutropenia disorders depends on the cause and organs involved. CGD has a better prognosis if allogeneic bone marrow
transplantation can successfully achieve. Neutropenia due to chemotherapy or drugs may cause remission once the treatment is over. Some
primary defects of neutrophil functions affect the prognosis, where devastating fatal diseases can lead to death at a young age.[22]

Serious infections occur in a significant number of patients with neutropenia, and many require repeated admissions. Without treatment,
neutropenia is associated with a high risk of death.

Complications
Recurrent and fatal bacterial and fungal infections[13]
Bacteremia
Septic shock
Premature death
Failure to thrive
Protein-energy malnutrition
Multiorgan failure

Enhancing Healthcare Team Outcomes

Neutropenia is a serious life-threatening disorder with high morbidity and mortality. Thus the condition is best managed by an interprofessional
team that includes physicians, nurses, and pharmacists. A specialist in infectious diseases, internal medicine specialists, or pediatricians should
recommend treatment options, including antibiotics and antifungal. A patient with severe neutropenia is considered to have a life-threatening
disorder and should be monitored regularly for complete blood cell count, blood chemistry, infectious disease markers, and immunotherapy.
Nurses looking after these patients should know what signs and symptoms to monitor for and when to call the specialist. They educate the
patient about precautions and warning signs. Pharmacists review the prescription for dose, contraindications, and interactions. They, too,
provide patient education.

Further, these patients should avoid exposure to people and wear a face mask in public. The pharmacist should assess the medications and
immediately recommend discontinuation of those associated with neutropenia. Those who are undergoing chemotherapy should be educated
about handwashing and symptoms to watch for.

The use of neutrophil colony-stimulating factors should be monitored by an immunologist or hematologist to treat the side effects of this
cytokine efficiently.

Only through such a team approach can the morbidity of neutropenia be lowered. [Level 5]

References

[1] Immunodeficiency, Justiz Vaillant AA,Qurie A,,, 2018 Jan     [PubMed PMID: 29763203]

[2] Rezaei N,Moazzami K,Aghamohammadi A,Klein C, Neutropenia and primary immunodeficiency diseases.
International reviews of immunology. 2009     [PubMed PMID: 19811314]