BlueCross and BlueShield of Montana Medical Policy/Codes
Natural Killer (NK) Cells
Chapter: Medicine: Tests
Current Effective Date: February 01, 2014
Original Effective Date: October 25, 2013
Publish Date: January 15, 2014
Revised Dates: January 15, 2014
Description

The organs of the immune system, called lymphoid organs, work together to clear infection from the body. Lymphoid organs include lymph nodes, lymphatic vessels, and lymphocytes (white blood cells), as well as the spleen, bone marrow, tonsils, adenoids, and thymus gland. There are two major classes of lymphocytes—B cells and T cells. B cells grow to maturity in the bone marrow, and produce antibodies that attach to foreign antigens, marking them for destruction by other immune cells; this is the antibody-mediated response, or humoral immunity. T cells mature in the thymus gland. They attack and destroy diseased cells that they recognize as foreign, as well as regulate and coordinate the overall immune response; this is cell-mediated response, or cellular immunity. 

Natural killer (NK) cells are a type of lymphocyte that provide the first line of defense against pathogens by containing infections while the adaptive immune response is generating antigen specific cytotoxic T cells that can clear the infection. NK cells target a wide variety of infectious microbes, tumor cells, and other abnormal cells; they do not need to recognize a specific antigen before they attack and destroy a target cell. Unlike phagocytes, they do not engulf and ingest target cells, but attach to them and inject chemicals that erode the membranes of the target cell and lead to cellular destruction. 

The exact mechanism NK cells use to determine which cells to target is not certain; one theory involves recognition of “altered self.” Major histocompatibility complex (MHC) molecules are anchored in cell membranes, where they display short polypeptides to T cells, via the T cell receptor (TCRs). The polypeptides may be "self," that is, originating from a protein created by the organism itself, or they may be foreign, originating from bacteria, viruses, pollen, etc. By design of the MHC-TCR interaction, T cells should ignore “self” peptides while reacting appropriately to the foreign peptides. Foreign peptides that provoke an immune response are termed antigens. NK cells have two types of surface receptors, “activating receptors” and “inhibitory receptors.” The inhibitory receptors recognize MHC class I alleles, which could explain why NK cells kill cells with low levels of MHC class I molecules; this is known as “missing self” recognition.

Natural killer cell activity can be an important indicator of disease progression and patient prognosis, and may be involved in how the immune system relates to such conditions as infertility, cancer, HIV, leukemia, chronic fatigue syndrome, infections and other diseases.

Policy

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan or contract, the benefit plan or contract will govern.

Coverage

Measurement of natural killer (NK) cells is considered experimental, investigational and unproven for any indication.

Rationale

Natural killer (NK) cell count has been studied in relation to a variety of conditions, including cancer, HIV, leukemia, chronic fatigue syndrome, infections and other diseases. One area of interest, the relationship between NK cells and reproductive failure is a controversial area in reproductive medicine. Vaquero et al. conducted a study to propose a set of tests to clarify the diagnosis of repeated implantation failure in patients undergoing in vitro fertilization (IVF); they concluded that thyroid abnormalities, antiphospholipid antibodies, and increased NK levels are more prevalent in women experiencing IVF failure. However, regarding NK cells and reproductive failure, Rai et al. contend that there is no scientific basis for NK testing in routine practice, and the use of immunosuppressant agents based on the results of such testing may be potentially harmful. Ghazeeri and Kutteh noted that the roles alloimmunity and autoimmunity may play in reproductive failure, including recurrent pregnancy loss and failed IVF, have not been clearly established, and they concluded that large, well-constructed studies examining the benefit of immunological evaluation and treatment are needed before definite recommendations can be made.

Tratkiewicz and Szer studied the loss of NK activity as an indicator of relapse in acute leukemia. They concluded that there was a marked reduction in NK activity in patients with active leukemia when compared with healthy controls, and that NK activity substantially improved in complete remission. All patients who relapsed had significantly reduced NK activity, which in some significantly preceded the time of relapse. Their data suggest that regular assessment of NK activity may be a useful diagnostic tool in patients with acute leukemia.

NK cells are a promising area of immunology and cancer research. Experiments are being done on mice to learn how NK cells cause the immune system to respond to cancer cells. Also, Iwao et al. studied the prognostic value of NK cell infiltration in resected pulmonary adenocarcinoma, and concluded that NK cell infiltration may contribute to regulation of tumor progression, and can serve as a useful prognostic marker in overall and stage I pulmonary adenocarcinoma.

NK cell activity has been evaluated for a variety of other prognostic and diagnostic uses. El-Sameea et al. evaluated NK cells as diagnostic markers of early onset neonatal sepsis; they reported that their data raised the possibility that adding NK cell activity to the standard workup of critically ill patients with suspected sepsis could increase the diagnostic certainty and generate improved patient management. Zeman et al. studied the prognostic value of NK cells in monitoring the course of IFN-alpha (Interferon-alpha) therapy in children with chronic hepatitis and concluded that increased NK cells in these children may be determinant of IFN therapy. Researchers at the University of Miami reported that preliminary evidence suggests that measuring NK activity may support identification of chronic fatigue syndrome in a subgroup of patients with more severe symptoms. Researchers at the Mayo Clinic in Rochester, Minnesota are devising a way to manipulate NK cells to destroy cells containing HIV virus (“latent” or “resting” cells). While their experiments have been successful in laboratory test tubes, they have not been tested on patients in clinical trials.

While measurement of NK cells may support certain diagnoses or conditions, specific studies are scattered, small, and inconclusive. Therefore, measurement of NK cells is not supported by evidence in the peer-reviewed medical literature that permits conclusions on the effect of NK cell measurement on health outcomes, or that demonstrates an improvement in net health outcome through use of NK cell measurement.

2008 Update

A literature search of online and MedLine database was performed through August 2008. No articles were identified that would change the coverage position of this medical policy.

2010 Update

A literature search was performed through August 2010. No articles were identified that would change the coverage position of this medical policy.

2013 Update

A search of peer reviewed literature through September 2013 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy (15-18).

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

Experimental, investigational and unproven for all diagnoses.

ICD-10 Codes

Experimental, investigational and unproven for all diagnoses.

Procedural Codes: 86357
References
  1. Tratkiewicz, J.A. and J. Szer. Loss of natural killer activity as an indicator of relapse in acute leukaemia. Clinical and Experimental Immunology (1990 May) 80(2):241-6.
  2. Wozniakowska-Gesicka, T., Wisniewska-Ligier, M., et al. Prognostic value of natural killer cells monitoring in the course of IFN-alpha therapy in children with chronic hepatitis. Pol Merkuriusz Lek (2000 June) 8(48):376-7.
  3. Ghazeeri G.S. and W.H. Kutteh. Immunological testing and treatment in reproduction: frequency assessment of practice patterns at assisted reproduction clinics in the USA and Australia (2001 October) 16(10):2130-5.
  4. Kenner, Dan. Treatment of immune dysfunction from post-traumatic stress disorder and chronic disease with AHCC. Townsend Letter for Doctors (2001 December) 68-72, accessed 7/17/2006. http://www.ahccpublishedresearch.com .
  5. Takanami, Iwao, Takeuchi, Ken, et al. The prognostic value of natural killer cell infiltration in resected pulmonary adenocarcinoma. Journal of Thoracic Cardiovascular Surgery (2001) 121:1058-63.
  6. El-Sameea, E.R., Metwally, S.S., et al. Evaluation of natural killer cells as diagnostic markers of early onset neonatal sepsis: comparison with C-reactive protein and interleukin-8. Egyptian Journal of Immunology (2004) 11(1):91-102.
  7. Nellis, Bob. Researchers devise method for natural killer cells to destroy hiding HIV. Mayo Clinic I Rochester (2004 May 17) http:www.mayoclinic.org .
  8. Rai, R., Sacks, G., et al. Natural killer cells and reproductive failure—theory, practice and prejudice. Human Reproduction (2005) 20(5):1123-6.
  9. Possible CFS subgroups identified: Test results indicative of symptom severity. ImmuneSupport.com (2006 July 10) accessed 7/18/2006 http://www.immunesupport.com .
  10. Wodnar-Filipowicz, A. and Chriatian P. Kalberer. Function of natural killer cells in immune defense against human leukemia. Swiss Medical Weekly (2006) 136:359-364.
  11. Greenwood, Addison. Spotlight:  Natural killer cells power immune system response to cancer. National Cancer Bulletin (2006):3 http://www.cancer.gov .
  12. Vaquero, E., Lazzarin, N., et al. Diagnostic evaluation of women experiencing repeated in vitro fertilization failure. European Journal of Obstetrics, Gynecology, and Reproductive Biology (2006 March) 125(1):79-84.
  13. Major histocompatibility complex. Accessed 7/20/2006 http://www.reference.com .
  14. The Immune System. National Institute of Allergy and Infectious Diseases. NIAIDNetNews.  Accessed 7/21/2006 http://www.niaid.nih.gov .
  15. Nakata, A. Takahashi, M., et al. Association of overtime work with cellular immune markers among healthy daytime white-collar employees. Scand J Work Environ Health. 2012 Jan;38(1):56-64.doi:10.5274sjweh.3183.
  16. Nakata, A. Takahashi, M., et al. Job satisfaction is associated with elevated natural killer cell immunity among healthy white-collar employees. Brain Behav Immun. 2010 Nov; 24(8):1268-75. Doi: 10.1016/j.bbi.2010.05.004.
  17. Borzoueisileh, S. Monfared, AS., et al. The assessment of cytotoxic T cell and natural Killer cells activity in residents of high and ordinary background radiation areas of Ramsar-Iran. J Med Phys. 2013 Jan; 38(1):30-3. Doi:10.4103/0971-6203.106602.
  18. Zhang, Q. Xiao,HP., et al. Significant increase in  natural-killer T cells in patients with tuberculosis complicated by type 2 diabetes mellitus. J. Int Med Res. 2011;39(1):105-11.
History
July 2013  New 2013 BCBSMT medical policy.  Measurement of natural killer (NK) cells is considered experimental, investigational and unproven for any indication. 
February 2014 Document updated with literature review. Coverage unchanged.
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Natural Killer (NK) Cells