NK cell deficiency syndromes: Treatment

INTRODUCTION — Natural killer (NK) cell deficiency syndromes are rare disorders in which NK cells are absent, deficient, or dysfunctional in the absence of any other identifiable immunodeficiency, genetic disorder, or medication known to affect NK cells. These disorders are categorized as classical NK cell deficiency (CNKD) and functional NK cell deficiency (FNKD).

●In CNKD, NK cell developmental status or survival is abnormal, often leading to decreased NK cell numbers in the peripheral blood.

●In FNKD, NK cells are appropriately developed and present but are functionally impaired.

The management of patients with these disorders is discussed here. The biology of NK cells, the clinical manifestations of NK cell disorders, and the evaluation of patients suspected of having NK cell defects are presented separately. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)

OVERVIEW — Therapy for patients with NK cell deficiency syndromes is largely empiric due to the small numbers of cases described in the literature [1]. Active infections must be identified and treated aggressively, as with any immunodeficiency. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

The use of specific therapies is based either on theoretical utility or anecdotal reports of benefit (table 1).

ANTIVIRAL PROPHYLAXIS — NK cell disorders are characterized clinically by susceptibility to severe and/or recurrent infection with herpes viruses, including varicella-zoster virus (VZV), herpes simplex virus (HSV) I and II, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). There is also a marked susceptibility in some patients to human papillomaviruses (HPV).

In patients who are suspected or known to have classical NK cell deficiency type 1 (CNKD1) with GATA-binding protein 2 (GATA2) deficiency, prophylaxis for Mycobacterium avium-intracellulare should be considered as the risk for this infection is increased in some patients with this genetic defect. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis' and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)

Prophylactic antiviral regimens should be tailored to the infectious history of the individual patient. Serologic tests should be performed to determine if an NK cell-deficient individual has experienced infections with known herpesviruses. Nucleic acid polymerase chain reaction (PCR) tests of peripheral blood should also be performed to ensure that a patient does not have active and inadequately controlled infection. In our clinic, we assess for past exposure to the following viruses:

●VZV

●HSV I and II

●CMV

●EBV

●Human herpesvirus 6 (HHV-6)

Evidence of past exposure without detectable viral nucleic acid in peripheral blood or active/recurrent viral disease indicates that the patient is able to contain that particular pathogen to some extent and thus does not require prophylaxis against that pathogen.

If a patient with NK cell deficiency is naïve to HSV or CMV, however, then we suggest administering permanent prophylaxis with an appropriate antiviral agent (eg, acyclovir or valacyclovir for HSV, valganciclovir for CMV). There are no studies assessing the risk/benefit ratio of such an approach, but, in the absence of this information, the author would suggest indefinite prophylaxis.

In those for whom they are prescribed, the prophylactic regimens are continued indefinitely. Doses are reviewed elsewhere. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)

Breakthrough infectious episodes should be treated with higher-dose treatment regimens or with the intravenous form of the drug, where appropriate. For patients who may have or have had central nervous system viral disease, a more specific treatment and subsequently conservative prophylactic approach is warranted. This suggestion is based upon anecdotal clinical experiences described in case reports. (See "Viral encephalitis in adults".)

IMMUNIZATIONS — The administration of recombinant human papillomavirus (HPV) vaccine to both female and male patients is suggested due to the potential risk of severe disease in those with NK cell defects. (See "Human papillomavirus vaccination".)

In contrast, we would not recommend the live-attenuated virus varicella vaccine, since it could place the patient at risk for disseminated infection. Instead, the subunit vaccine for shingles could be given. Although not routinely recommended for immunocompetent children, this vaccine is a non-live recombinant glycoprotein E vaccine (designed recombinant zoster vaccine; sold as Shingrix [brand name]) and is a more logical choice for children with NK cell deficiency. (See "Vaccination for the prevention of chickenpox (primary varicella infection)", section on 'Choice of vaccine'.)

IMMUNOGLOBULIN REPLACEMENT — For patients with classical NK cell deficiency (CNKD) or functional NK cell deficiency (FNKD) who have experienced a life-threatening infection with one of the viruses that pose a threat to these patients and are naïve to others, it is reasonable to consider regular immune globulin replacement therapy [2]. Theoretically, the antiviral antibodies contained in gammaglobulin would provide some protection against these viruses, including herpesviruses for which there are no specific prophylactic antiviral therapies. (See "Immune globulin therapy in inborn errors of immunity".)

POSSIBLE ADJUNCTIVE THERAPIES — There are relatively few therapies that are known to increase NK cell activities, but interleukin (IL) 2 and interferon alfa-2b are of potential value in both functional NK cell deficiency (FNKD) and classical NK cell deficiency (CNKD):

●In patients with FNKD, these therapies might increase NK cell function.

●In CNKD, certain biologic therapies can promote some additional development or survival of NK cells.

Interleukin 2 — One biologic agent that is capable of increasing NK cell activities is IL-2 [3]. IL-2 has been used in individuals with malignancy and human immunodeficiency virus (HIV) infection and has been shown to increase NK cell activity. It has also been reported to have clinical benefit in diseases having impaired NK cell function [4-6].

Based upon these observations, the in vitro responsiveness of NK cells to IL-2 in a patient with FNKD can be evaluated. If there is a convincing in vitro response, as determined by a greater than twofold increase in NK cell cytolytic activity, then low-dose IL-2 therapy may be considered as an experimental adjunctive treatment. We suggest that this be administered only by clinicians with experience in the use of this agent.

As demonstrated in other diseases, there are a variety of successful IL-2 treatment regimens that increase NK cell function [4,7,8]:

●In the author's unpublished, anecdotal experience, IL-2 (at a dose of 0.5 to 1 million units/m² given subcutaneously daily for five consecutive days) can induce an increase in NK cell cytotoxic activity in those patients who have been shown to respond in vitro [9]. If the patient appears to improve, the treatment can be repeated every seven to eight weeks.

●Alternatively, a dose of 0.5 to 1 million units/m² can be given subcutaneously three times per week as continuous therapy. This can help induce and sustain NK cell function in some patients. Aside from injection-site reactions, either regimen is relatively well tolerated.

Interferon alfa — Interferon alfa-2b enhances the cytotoxic activity of NK cells, and systemic treatment of a patient with refractory periungual warts and NK cell dysfunction resulted in dramatic improvement [10,11]. There is also preliminary experience with use of interferon alfa in patients with classical NK cell deficiency type 1 (CNKD1 due to GATA-binding protein 2 [GATA2] deficiency), with clinical improvement of warts as well as increased NK cell numbers and functional activity [12]. This agent warrants further study since its use is only anecdotal. However, side effects include potentially severe cytopenias, flu-like syndrome, and depression. Aside from use in patients with NK cell dysfunction and intractable warts, use of interferon alfa-2b is not recommended outside of investigational protocols.

Interferon alfa-2b is likely to become gradually less available in the United States and globally and at some point is likely to be unavailable for clinical use. Other type-I interferons (alpha and beta) should have similar activity upon NK cells, although direct evidence for use in NK cell deficiency is not available. However, there is substantive evidence in other disease states that interferon alfa-2a and possibly interferon beta can enhance NK cell function, although the latter is most clearly associated with increasing CD56bright NK cells [13-17].

HEMATOPOIETIC CELL TRANSPLANTATION — For patients with particularly severe past infections and acceptably matched donors, hematopoietic cell transplantation may be considered in an attempt to correct the presumed hematopoietic defect. The severity of the patient's illness must be balanced against the risks of transplant.

●Successful hematopoietic cell transplantation from a matched, unrelated donor was reported in a seven-year-old girl who had suffered severe disseminated varicella infection at the age of four years, which was complicated by encephalitis, vasculitis, and macrophage activation syndrome with multiple-organ involvement [18]. Laboratory evaluation prior to transplantation revealed an absence of both NK cells and B cells. The child was free of infections and had a normal lymphocyte profile four years after transplantation.

●An illustrative case of a man with interleukin 2 receptor subunit gamma (IL2RG) severe combined immunodeficiency (SCID) and T cell reversion was left with residual NK cell abnormalities and suffered from recurrent skin and mucosal human papillomavirus (HPV) [19]. He received hematopoietic cell transplantation and had restoration of his NK cell function and amelioration of his HPV disease, including dysplastic lesions.

●Experience with transplantation has been accumulating in GATA-binding protein 2 (GATA2) deficiency (although some patients demonstrate immunologic changes outside of NK cells) [20,21]. In a series of 59 patients, event-free survival was 82 percent at four years [22].

●Other case reports have described patients who survived initial transplantation but reportedly succumbed to complications. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

ANTIVIRAL CELL THERAPY — While only available experimentally, antiviral cell therapy, in which cytotoxic T cells are generated in vitro from the individual patient or a human leukocyte antigen (HLA) compatible donor, presents a potential therapeutic option for classical NK cell deficiency (CNKD) or functional NK cell deficiency (FNKD) patients who have significant morbidity from an otherwise difficult-to-control infection. This is a consideration in centers where this option is available as a bridge to hematopoietic cell transplantation. In this context, antiviral cell therapy can be used to reduce viral loads prior to transplant, to rescue a patient from increased viral replication after transplant, or potentially as a viral load-reducing therapy on its own. A single patient with CNKD was reported in a series of inborn error of immunity (previously "primary immunodeficiency") patients treated with antiviral cell therapy [23,24]. This patient had substantive Epstein-Barr virus (EBV) viremia after transplant and received antiviral cell therapy developed from the cells of the hematopoietic cell transplantation donor. EBV loads were reduced, and the patient survived.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●Approach to therapy – In patients with classical natural killer cell deficiency (CNKD) or functional NK cell deficiency (FNKD), the use of specific therapies is based either on theoretical utility or anecdotal reports of benefit (table 1). (See 'Overview' above.)

●Antiviral prophylaxis – In patients with CNKD who have no evidence of exposure or immunity to herpes simplex virus (HSV) or cytomegalovirus (CMV), we suggest lifelong prophylaxis with antiviral agents for protection against these infections (Grade 2C). (See 'Antiviral prophylaxis' above.)

●Vaccination – In patients with CNKD or FNKD, we suggest administration of recombinant human papillomaviruses (HPV) vaccine (Grade 2C). The non-live recombinant glycoprotein E vaccine for prevention of varicella zoster can also be given, if available. (See 'Immunizations' above.)

●Indications for immune globulin – In patients with CNKD or FNKD who have experienced a life-threatening infection with one herpesvirus and are naïve to other herpesviruses, we suggest immune globulin replacement therapy because the antiviral antibodies it contains should provide some protection against viral infections (Grade 2C). (See 'Immunoglobulin replacement' above.)

●Indications for IL-2 therapy – In the patient with FNKD in whom there is a convincing in vitro response to interleukin (IL) 2 (ie, a greater than twofold increase in NK cell cytolytic activity), low-dose IL-2 therapy is an experimental therapy that may augment NK cell function. The optimal dose is not known, although the author has successfully administered 0.5 to 1 million units of IL-2/m², subcutaneously, using two different schedules. (See 'Interleukin 2' above.)

●Other therapies – For patients with severe and refractory warts, we suggest the administration of interferon alfa-2b (Grade 2C). The use of this agent for other conditions associated with NK cell deficiencies should be limited to investigational protocols. (See 'Possible adjunctive therapies' above.)

●Hematopoietic cell transplantation – For patients with particularly severe histories and acceptably matched donors, hematopoietic cell transplantation may correct the presumed hematopoietic defect. (See 'Hematopoietic cell transplantation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.