Neutropenia

Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood.[4] Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria, bacterial fragments and immunoglobulin-bound viruses in the blood.[5] People with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening (neutropenic sepsis).[6]

Neutropenia
Blood film with a striking absence of neutrophils, leaving only red blood cells and platelets
SpecialtyInfectious disease, Hematology
CausesAplastic anemia, Glycogen storage disease, Cohen syndrome,[1][2] gene mutations
Diagnostic methodCBC[3]
TreatmentAntibiotics, Splenectomy if needed,[3] G-CSF

Neutropenia can be divided into congenital and acquired, with severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) being autosomal dominant and mostly caused by heterzygous mutations in the ELANE gene (neutrophil elastase).[7] Neutropenia can be acute (temporary) or chronic (long lasting). The term is sometimes used interchangeably with "leukopenia" ("deficit in the number of white blood cells").[8]

Signs and symptoms
Otitis

Signs and symptoms of neutropenia include fever, painful swallowing, gingival pain, skin abscesses, and otitis. These symptoms may exist because individuals with neutropenia often have infection.[3]

Children may show signs of irritability and poor feeding.[9] Additionally, hypotension has also been observed in individuals who suffer from this condition.[6]

Causes
Vitamin B12

The causes of neutropenia can be divided between problems that are transient and those that are chronic. Causes can be divided into these groups:[1][2][10][11]

Gram-positive bacteria are present in 60–70% of bacterial infections. There are serious concerns regarding antibiotic-resistant organisms. These would include as methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE).[12])

Other causes of congenital neutropenia are Shwachman–Diamond syndrome, Cyclic neutropenia, bone marrow failure syndromes, cartilage–hair hypoplasia, reticular dysgenesis, and Barth syndrome. Viruses that infect neutrophil progenitors can also be the cause of neutropenia. Viruses identified that have an effect on neutrophils are rubella and cytomegalovirus.[1] Though the body can manufacture a normal level of neutrophils, in some cases the destruction of excessive numbers of neutrophils can lead to neutropenia. These are:[1]

  • Bacterial or fungal sepsis
  • Necrotizing enterocolitis, circulating neutrophil population depleted due to migration into the intestines and peritoneum
  • Alloimmune neonatal neutropenia, the mother produces antibodies against fetal neutrophils
  • Inherited autoimmune neutropenia, the mother has autoimmune neutropenia
  • Autoimmune neutropenia of infancy, the sensitization to self-antigens

Pathophysiology

The pathophysiology of neutropenia can be divided into congenital and acquired. The congenital neutropenia (severe and cyclic type) is autosomal dominant, with mutations in the ELA2 gene (neutrophil elastase) as the most common genetic reason for this condition.[7] Acquired neutropenia (immune-associated neutropenia) is due to anti-neutrophil antibodies that target neutrophil-specific antigens, ultimately altering neutrophil function.[13] Furthermore, emerging research suggests neutropenia without an identifiable etiology (idiopathic neutropenia) may be the result of a low-grade, chronic inflammatory process with an abnormal excessive production of myelosuppressive cytokines in a study conducted in the island of Crete.[14]

Neutropenia fever can complicate the treatment of cancers. Observations of children noted that fungal infections are more likely to develop in those with neutropenia. Mortality increases during cancer treatments if neutropenia is also present.[6] Congenital neutropenia is determined by blood neutrophil counts (absolute neutrophil counts or ANC) < 0.5 × 109/L and recurrent bacterial infections beginning very early in childhood.[15]

Congenital neutropenia is related to alloimmunization, sepsis, maternal hypertension, twin-to-twin transfusion syndrome, and Rh hemolytic disease.[1]

Diagnosis
P anca

Neutropenia can be the result of a variety of consequences, including from certain types of drugs, environmental toxins, vitamin deficiencies, metabolic abnormalities, as well as cancer or infections. Neutropenia itself is a rare entity, but can be clinically common in oncology and immunocompromised individuals as a result of chemotherapy (drug-induced neutropenia). Additionally, acute neutropenia can be commonly seen from people recovering from a viral infection or in a post-viral state. Meanwhile, several subtypes of neutropenia exist which are rarer and chronic, including acquired (idiopathic) neutropenia, cyclic neutropenia, autoimmune neutropenia, and congenital neutropenia.

Neutropenia that is developed in response to chemotherapy typically becomes evident in seven to fourteen days after treatment. Conditions that indicate the presence of neutropenic fever are implanted devices; leukemia induction; the compromise of mucosal, mucociliary and cutaneous barriers; a rapid decline in absolute neutrophil count, duration of neutropenia >7–10 days, and other illnesses that exist in the patient.[12]

Signs of infection can be subtle. Fevers are a common and early observation. Sometimes overlooked is the presence of hypothermia, which can be present in sepsis. Physical examination and accessing the history and physical examination is focussed on sites of infection. Indwelling line sites, areas of skin breakdown, sinuses, nasopharynx, bronchi and lungs, alimentary tract, and skin are assessed.[12]

The diagnosis of neutropenia is done via the low neutrophil count detection on a complete blood count. Generally, other investigations are required to arrive at the right diagnosis. When the diagnosis is uncertain, or serious causes are suspected, bone marrow biopsy may be necessary. Other investigations commonly performed: serial neutrophil counts for suspected cyclic neutropenia, tests for antineutrophil antibodies, autoantibody screen (and investigations for systemic lupus erythematosus), vitamin B12 and folate assays.[16][17] Rectal examinations are usually not performed due to the increased risk of introducing bacteria into the blood stream and the possible development of rectal abscesses. A routine chest X-ray and urinalysis may be can not be relied upon or considered normal due to the absence of neutrophils.[12]

Classification
Neutrophil

Generally accepted reference range for absolute neutrophil count (ANC) in adults is 1500 to 8000 cells per microliter (µl) of blood. Three general guidelines are used to classify the severity of neutropenia based on the ANC (expressed below in cells/µl):[18]

  • Mild neutropenia (1000 <= ANC < 1500): minimal risk of infection
  • Moderate neutropenia (500 <= ANC < 1000): moderate risk of infection
  • Severe neutropenia (ANC < 500): severe risk of infection.

Each of these are either derived from laboratory tests or via the formula below:

ANC = [1][18][19]

Treatment

Recombinant granulocyte-colony stimulating factor preparations, such as filgrastim[20] can be effective in people with congenital forms of neutropenia including severe congenital neutropenia and cyclic neutropenia;[21] the amount needed (dosage) to stabilize the neutrophil count varies considerably (depending on the individual's condition).[22] Guidelines for neutropenia regarding diet are currently being studied.[23]

Most cases of neonatal neutropenia are temporary. Antibiotic prophylaxis is not recommended because of the possibility of encouraging the development of multidrug-resistant bacterial strains.[1]

Neutropenia can be treated with hematopoietic growth factors, granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These are cytokines (inflammation-inducing chemicals) that are present naturally in the body. These factors are used regularly in cancer treatment with adults and children. The factors promote neutrophil recovery following anticancer therapy.[1]

The administration of intravenous immunoglobulins (IVIGs) has had some success in treating neutropenias of alloimmune and autoimmune origins with a response rate of about 50%. Blood transfusions have not been effective.[1]

Prognosis

If left untreated, people with fever and absolute neutrophil count <500 have a mortality of up to 70% within 24 hours.[12] The prognosis of neutropenia depends on the cause. Antibiotic agents have improved the prognosis for individuals with severe neutropenia. Neutropenic fever in individuals treated for cancer has a mortality of 4-30%.[24]

Epidemiology

Neutropenia is usually detected shortly after birth, affecting 6% to 8% of all newborns in neonatal intensive care units (NICUs). Out of the approximately 600,000 neonates annually treated in NICUs in the United States, 48,000 may be diagnosed as neutropenic. The incidence of neutropenia is greater in premature infants. Six to fifty-eight percent of preterm neonates are diagnosed with this auto-immune disease. The incidence of neutropenia correlates with decreasing birth weight. The disorder is seen up to 38% in infants that weigh less than 1000g, 13% in infants weighing less than 2500g, and 3% of term infants weighing more than 2500 g. Neutropenia is often temporary, affecting most newborns in only first few days after birth. In others, it becomes more severe and chronic indicating a deficiency in innate immunity.[1]

Furthermore, the prevalence of chronic neutropenia in the general public is rare. In a study conducted in Denmark, over 370,000 people were assessed for the presence of neutropenia. Results published demonstrated only 1% of those evaluated were neutropenic, and were commonly seen in those suffering from HIV, viral infections, acute leukemias, and myelodsyplastic syndromes. The study concluded the presence of neutropenia is an ominous sign that warrants further investigation and follow-up.[25]

See also

References
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  2. Newburger, Peter E.; Dale, David C. (1 July 2013). "Evaluation and Management of Patients with Isolated Neutropenia". Seminars in Hematology. 50 (3): 198–206. doi:10.1053/j.seminhematol.2013.06.010. ISSN 0037-1963. PMC 3748385. PMID 23953336.
  3. "Neutropenia Clinical Presentation: History, Physical Examination". emedicine.medscape.com. Retrieved 8 December 2015.
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  5. "Neutrophils". National Center for Biotechnology, National Library of Medicine. Retrieved 8 December 2015.
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  7. Marshall S. Horwitz; et al. (2013). "ELANE Mutations in Cyclic and Severe Congenital Neutropenia". Hematology/Oncology Clinics of North America. 27 (1): 19–41. doi:10.1016/j.hoc.2012.10.004. PMC 3559001. PMID 23351986. Retrieved 28 October 2018.
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  13. Schwartzberg, Lee S. (1 January 2006). "Neutropenia: etiology and pathogenesis". Clinical Cornerstone. 8 Suppl 5: S5–11. doi:10.1016/s1098-3597(06)80053-0. ISSN 1098-3597. PMID 17379162. – via ScienceDirect (Subscription may be required or content may be available in libraries.)
  14. Dale, David C.; Bolyard, Audrey Anna (2017). "An update on the diagnosis and treatment of chronic idiopathic neutropenia". Current Opinion in Hematology. 24 (1): 46–53. doi:10.1097/MOH.0000000000000305. PMC 5380401. PMID 27841775.
  15. Makaryan, Vahagn; Rosenthal, Elisabeth A.; Bolyard, Audrey Anna; Kelley, Merideth L.; Below, Jennifer E.; Bamshad, Michael J.; Bofferding, Kathryn M.; Smith, Joshua D.; Buckingham, Kati; Boxer, Laurence A.; Skokowa, Julia; Welte, Karl; Nickerson, Deborah A.; Jarvik, Gail P.; Dale, David C. (2014). "TCIRG1-Associated Congenital Neutropenia". Human Mutation. 35 (7): 824–827. doi:10.1002/humu.22563. ISSN 1059-7794. PMC 4055522. PMID 24753205.
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