Disease presentation, treatment options and outcomes for myeloid immunodeficiencies

Abstract

Purpose:

Up to date review on various types of immunodeficiencies with a significant myeloid component including some more recently described congenital disorders.

Summary:

Neutrophils (or granulocytes) are a major contributor to infection surveillance and clearance and defective neutrophils characteristically lead to pyogenic infections. Deficiency in numbers, either iatrogenic or congenital, functional defects, and/or inability to target to the sites of infection can all lead to serious morbidity and mortality; however, myeloid based immunodeficiencies are not all the same. Having absent neutrophils, that is neutropenia, has implications different to those of having dysfunctional neutrophils as will become evident as the various disorders are reviewed.

Recent Findings:

While a number of disorders have been described in the past, genetic sequencing has led to the identification of the specific disorders and clarified their pathophysiology. Advances in genetic therapies including genetic editing should provide future treatments beyond hematopoieitic stem cell transplant for patients with these rare disorders

Introduction

A simplified way to classify neutrophilic disorders is by categorizing them based on their primary defect. Although various pathways may be affected, there is often a predominant phenotype that characterizes these disorders based either on 1) compromised mobility, either due to an inability to respond to chemotactants or adhere properly, 2) inadequate ability to phagocytose and/or create the respiratory burst needed to kill various microbes or 3) inadequate numbers (neutropenias). A few genetic mutations though appear to interfere significantly in multiple pathways and therefore do not necessarily fit a specific pattern (See Table 1). However, patients with primarily neutrophilic deficiencies typically present at an early age with a pyogenic infection, or even earlier with signs such as delayed cord healing/separation and omphalitis. Other immunodeficiencies such as Wiskott-Aldrich Syndrome or Hyper IgM’s may also involve the myeloid component either through aberrant cytokine or ligand signaling, defective phagocytosis or even due to decreased granulocytic numbers, so those will also be briefly reviewed here.

Table 1.

Myeloid Immunodeficiencies by phenotype/underlying deficiency. A few genetic mutations appear to interfere significantly in multiple pathways

Type	Disease	Inheritance	Genes	Incidence	Defect	Current Management
Mobility/Signaling	Leukocyte adhesion deficiency I (LAD I)	AR	ITGB2	1 in 1000000	B-2 integrin (CD18) deficiency,	HSCT- gene therapy studies ongoing
	LAD 2 (Congenital disorder of glycosylation CDG)	AR	SLC35Ca	<1 in 1000000	Aberrant GDP fucose transporter leading to lack of selectins needed for rolling.	HSCT- gene therapy studies ongoing
	LAD3 (LAD V1)	AR	FERMT3 (Kindlin 3)	<1 in 1000000	Defective Rap-1 activation leading to loss of tight adherence and Glanzmann’s thrombocytopenia	HSCT- gene therapy studies ongoing
	CARD9 deficiency	AR	CARD9	Rare	CARD9 deficiency, poor cytokine production, impaired phagocytosis	Antifungals, surgical resection, GMCSF, HSCT in selected cases?
	WDR1 deficiency	AR	WDR1	Rare	Abnormal actininteracting protein 1 (Aip1) resulting in abnormal actin depolymerization	Treatment of infections, HSCT
	MyD88/IRAK4 deficiency	AR	MyD88/IRAK4	Rare	Altered signalling through TLRs and IL-1	Prophylactic antibiotics until adulthood
Impaired killing
Respiratory burst	CGD	X-linked, AR	CYBB, CYBA, NCF1, NCF2, NCF4	1 in 250000	Defective respiratory burst- due to NADPH deficiency	Prophylactic Antibiotics, HSCT, Gene therapy
	MPO	AR	MPO	1 in 2--4000 Europeans/NA and 1 in 55000 Japanese	Inability to produce HOCL	Treatment of Infections
	Severe G6PD deficiency	X-linked	G6PD	most common enzyme deficiency	Severe G6PD can cause reduction in the NADPH oxidation	Avoidance of triggers
Granule	Specific granule deficiency	AR	CEBP epsilon	RARE	Lack of myeloid differentiation, altered secondary granule formation, abnormal chemotaxis	HSCT
Miscellaneous	RAC2 deficiency	AR	RAC2 gene	one case	Multiple abnormalities including chemotaxis defects, respiratory burst decrease, adhesion defects	HSCT
Neutropenias	Severe congenital neutropenia (SCN)and Cyclical neutropenias	AR/AD	HAX1, ELANE, CSFR3	1 in 200000	Decreased total or oscillations in numbers of neutrophils- pathways of development or survival affected	GCSF, monitoring for leukemia, occasional HSCT
	Autoimmune neutropenia of infancy		unknown	1 in 100000	Autoimmune mediated clearance of neutrophils	Usually resolves spontaneously
	Glutathione synthetase deficiency (5- oxoprolinuria)	AR	GSS		Accumulation of oxidative damage to neutrophils	Symptomatic management
Myeloid component	Wiskott Aldrich/X-linked Neutropenia	X-linked	WAS/Exon 9 mutations	1 in 1000000	WAS protein mutations affecting actin polymerization	HSCT/gene therapy
	Chediak-Higashi	AR	LYST mutations-	<1 in 1000000	Abnormal granule formation leading to pigment problems, granule malformation, platelet dysfunction	HSCT
	X-linked HyperIgM/CD40 deficiency	X-linked/AR	CD40 ligand, CD40	1 in 250000	Failure to B cell switch	HSCT

1). Disorders affecting neutrophil migration or cytokine signaling

Myeloid differentiation primary response 88 (MYD88)/Interleukin 1 receptor associated kinase 4 (IRAK4) deficiencies.

Mutations in MYD88 or its downstream signaling molecule IRAK4 have been described in patients presenting with bacterial infections, the nature and sites of which seem to be well delineated: mostly invasive pneumococcal disease, cutaneous and invasive staphylococcal disease, and Pseudomonas infection of the upper respiratory tract. ^{1, 2}

MYD88 and IRAK4 are required in TLR2, TLR4 and Il-1 signaling but not in TLR3 and TNF-alpha signaling. The phenotype may vary though depending on the type of infection as one patient with a homozygous truncation in MYD88 had decreased TNF-alpha as well as decreased Il-6, and presented with delayed umbilical cord separation as well as BCGitis in addition to a pseudomonal infection. Another set of siblings were also described with a unique homozygous mutation and presented with Salmonellosis along with other more typical infections^3,4. The majority of patients appear to outgrow their infection susceptibility though, possibly due to the development of adaptive T and B cell responses and/or maturation of other innate immune responses.² Thus management consists of antibacterial prophylaxis to cover those specific bacteria in childhood which can be then discontinued in adulthood.

Leukocyte Adhesion Deficiencies (LAD)

The first case series of 6 infants with delayed separation of their umbilical cords was described in 1979. Five of the 6 patients succumbed to severe bacterial infections and ascorbic acid was hypothesized to aid in the immunodeficiency, but was not used.⁵ Subsequently, it was recognized to be a disorder of adhesion attributed to a CR3 deficiency.^6–9 Leukocyte adhesion deficiency (LAD) type I as the disorder is now known results from mutations of the B2 integrin (also known as CD18) gene ITGR2 on Chromosome 21 and is inherited in an autosomal recessive fashion with severity of the phenotype dependent on the level of expression of the protein.¹⁰ CD18 complexes with CD11a to form LFA-1, with CD11b to form MAC-1, and CD11c to form p150,95 which after activation are required for binding to ICAM-1, fibrinogen and other ligands to be able to migrate to and phagocytose bacteria properly.^{11, 12}

LAD type II is a separate disorder due to mutations in the GDP fucose transporter gene resulting in a failure of glycosylation of a fucose leading to lack of a Sialyl-Lewis-X- the carbohydrate ligand for P and E selectins.¹³ However fucose is also required for the carbohydrate structures responsible for ABO typing of blood. Patients thus have a characteristic Bombay (H-) blood phenotype.¹⁴ Patients present with a myriad of problems including neurologic developmental delays, growth retardation, anemia, and bleeding as well as infections. This is a much rarer form of LAD and has been described in only a handful of families.¹⁵

LAD type III is often referred to as a variant of LAD type I as the phenotype is similar. Mutations in the Kindlin3 (or FERMT3) gene result in aberrant integrin binding to selectins on the endothelium.¹⁶ Neutrophils are unable to roll and again do not reach the sites of infection required for their function.¹⁷

The management for all patients with the LAD subtypes, particularly those with severe disease, is hematopoietic stem cell transplant (HSCT) from an unaffected sibling donor, or if not available, a matched unrelated donor. ^{18, 19} Given the variance in phenotype depending on the expression levels of the proteins, particularly in LAD type I, mixed chimerism may be sufficient for phenotypic resolution in these patients. Centres have been trying reduced toxicity or nonmyeloablative conditioning regimens with some success.²⁰ As with all genetic disorders there are efforts to develop a gene therapy using in vitro gene correction of hematopoietic stem cells. There is a canine model of LAD type I and dogs have been successfully treated with both lentiviral vectors and more recently foamy virus vectors expressing the B2 integrin, providing proof of principal. ^{21, 22} Currently, a clinical study is ongoing for pediatric patients with severe LAD type I in the US with high gene marking, 47% restored CD18 expression (<1% pre-gene therapy), and clinical improvement in inflammatory skin lesions in one patient with at least 6 months followup as presented at the 2020 American Society for Gene and Cell Therapy Annual Meeting.

Caspase recruitment domain-containing protein 9 (CARD9) deficiency

CARD9 deficiency is an unusual myeloid immunodeficiency inherited in an autosomal recessive fashion, whereby patients have a specific susceptibility to fungal infections which can range from chronic mucocutaneous infections due to Candida, to deep invasive infections including extrapulmonary aspergillosis.^{23, 24} Mutations lead to impaired cytokine and chemokine production by macrophages, reduced neutrophil recruitment, impaired fungal killing and a decrease in Th17 cells. Treatment has been antifungals and surgical resection of infected masses as well as GCSF or GMCSF.²⁵ HSCT has been used with varying results. ^{26, 27} Gene therapy using a lentiviral vector is being developed (personal communication).

WDR1 deficiency

This is a very rare disorder initially described in a patient who presented with various infections and an unusual morphology to her neutrophils, wherein her neutrophils migrated abnormally, and extruded their nuclei in cytoplasmic blebs.²⁸ Other patients have also been described with a type of lazy leucocyte syndrome; however the pathophysiology was not understood at the time, although hypothesized to involve altered membrane proteins.^{29, 30} The defect was later characterized as a deficiency in the WDR1 gene which encodes for the Actin-interacting protein 1 (AIP1). HSCT was then used to treat one patient.³¹ Further description of mutations in other patients suggest more profound defects can result in immune dysregulation and inflammasome activation as well as the stomatitis and recurrent infections initially described.³² Overall the prognosis is mixed with some patients seeming to improve symptomatically over time and others succumbing to infection ³¹ (personal communication).

2). Disorders affecting mechanisms of microbial killing

Myeloperoxidase (MPO) deficiency

MPO deficiency is the most common enzymatic disorder affecting white blood cells with an estimated incidence of 1 in 2000 for moderate deficiency. Originally it was thought to be much rarer with a few patients presenting with infectious complications. However biochemical and phenotypic characterization have found the prevalence to be much higher with some variation in ethnic populations (1 in 55000 described in the Japanese population versus 1 in 4000 (severe deficiency) in the European and North American groups).³³ The defect occurs due to mutations in the MPO gene and is inherited in an autosomal recessive manner. MPO is required for the production of hypochlorous acid (HOCL) by oxidation of chloride anions. ³⁴ Although in vitro, this HOCL production appears necessary for the killing of Candida, the vast majority of patients have few to no symptoms, as this HOCL production appears to be redundant as part of the microbial killing pathway in vivo. ³⁵

Treatment of infections as they occur appears adequate with no prophylaxis normally recommended. There are a few case reports of patients presenting with severe/life threatening infections, but these have been described prior to the implementation of whole genome sequencing and therefore there may be adjuvant factors contributing to these rarer presentations.

Chronic Granulomatous Disease (CGD)

CGD is a much rarer disorder of neutrophil function estimated to occur in 1 of 250000 births, but results in significantly more morbidity and mortality.³⁶ CGD is characterized by a failure of neutrophils to produce NADPH oxidase which is crucial to the suppression and killing of certain types of bacteria (most commonly catalase positive) such as Burkholderia and Serratia as well as Staphylococcus aureus in addition to atypical bacteria, most significantly Nocardia. Patients are also very susceptible to fungal infections, particularly aspergillus but with more common use of azoles, there is now an increased incidence of other dematiaceous mold infections. CGD patients however are not particularly susceptible to Candida.^{37, 38}

Possibly due to the ineffective killing, patients also develop granulomas, hence the name of the disease. These often involve tubular organs, such as the urinary tract, or esophagus and can become obstructive but respond quickly to a course of steroids. Patients also develop microabscesses that resemble small microtumours and the addition of steroids to treat these infections has proven helpful if somewhat paradoxically in the setting of an immunodeficiency.³⁹ Patients can also develop hyperinflammatory response to exposure of microbial elements such as aspergillus or nocardia and require steroids in addition to aggressive antifungal treatment for resolution. ⁴⁰

Distinct from the granulomas and the hyperinflammation, a significant proportion of patients also have autoinflammatory disorders, such as pneumonitis, arthritides and lupus, with estimates of 40 to 50% having inflammatory bowel disease (IBD) alone.⁴¹ Their innate immunity appears relatively intact with good responses to vaccines and normal immunoglobulin levels and the cause of the autoinflammation is not well understood although there may be some genetic factors.⁴²

There are 5 subtypes of CGD with the most common form being the X-linked involving the CYBB gene, resulting in a failure to produce GP91phox. Autosomal recessive forms consist of P22, P47 and P67 deficiencies due to mutations in the CYBA, NCF1 and NCF2 genes respectively. ⁴³ A 5^th type has been more recently described, with mutations in the NCF4 gene affecting expression of the P40phox; however these patients presented with significant inflammatory disease and not infection. In fact, their respiratory burst appears mostly intact and laboratory diagnosis using Dihydrorhodamine (DHR) based flow cytometry is equivocal. ^{44, 45} DHR however is the preferred method of diagnosis as it can be quantitative, and even diagnostic for the various forms. Of course genetic sequencing is also helpful, but nitroblue tetrazolium staining should no longer be used. Patients who produce some oxidase (more commonly in the P47 form) appear to have better prognosis than those with little to no oxidase production.⁴⁶ Significant skewing of the X-chromosome lyonization in female carriers, has resulted in CGD specific infections when levels of 10% to 20% or less of oxidase expression are reached. ⁴⁷ Treatment for patients was traditionally prophylaxis with Bactrim (or ciprofloxacin in sulfa allergic patients) and itraconazole; however now more often third generation azoles such as posaconazole or voriconazole. ⁴⁸ Interferon gamma was also shown to be useful in a randomized trial, but is not necessarily well tolerated.^49–51 It is usually held during an active infection. Pioglitazone has also been suggested to improve infection responses.⁵²

Corticosteroids are very successful in the treatment of the granulomas but less so for the autoimmune type disorders seen, with many patients requiring high doses or the use of other agents such as monoclonal antibodies/biologics for steroid reduction. These alternate therapies can be effective but may increase the risk of infection in this immunocompromised population.^{53, 54}

HSCT has become much more common and overall survival ranges from 80–90% in various studies. ⁵⁵ Regimens vary but the majority now are of a reduced intensity/reduced toxicity. Graft rejection rates are higher than many of the other ‘classical immunodeficiencies’ with rates ranging from 12–20% often occurring late.^56–60 With improving outcomes using matched donors, various centres have been exploring the use of mismatched donors to expand the donor pool for appropriate patients with mixed results. ^{61, 62} Transplant has also been used successfully in a few rare cases for carriers with skewed lyonization (personal experience). As mentioned, data from X-linked carriers suggests that for phenotypic correction of the infection susceptibility, 10–20% oxidase positivity is sufficient. Thus mixed myeloid chimerism may be sufficient for cure; however the threshold required for reversal of autoimmunity is less clear. ⁶³ The Primary Immune Deficiency Treatment Consortium (PIDTC) evaluated a number of patients treated within North America with HSCT and found that IBD resolves in all patients, but there were no patients who had myeloid engraftment of less than 85%. Also of note, patients with inflammatory bowel disease did not have a statistically higher rate of GvHD nor was there an impact on survival thus supporting the use of HSCT for management of patients with recalcitrant inflammatory disease. ⁶⁴

Given the benefits of mixed chimerism, CGD is a natural candidate for gene modification of hematopoietic stem cells and was in fact one of the first immunodeficiencies to be studied clinically. Results were encouraging, but without conditioning, gene marking did not persist. ^{65, 66} The addition of busulfan improved results; however, the use of a retroviral vector was complicated by the development of myelodysplasia with activation of genes causing clonal outgrowth in one trial and eventual silencing and in other studies, inadequate marking for long term clinical benefit. ^{67, 68}

More recently, lentiviral based gene therapy has had more success, with levels of greater than 10% oxidase positive cells detectable in many of the patients persisting for more than 2 years. However, again the level of correction necessary for autoimmune disease resolution is not clear, and patients in these trials did not have significant inflammation. Further a few patients have appeared to reject the grafts despite high dose busulfan. ⁶⁹

Patients with large mutations of the CYBB gene may also present with McLeod’s syndrome due to the gene’s proximity which can complicate transplant but does not preclude it. Other genetic disorders affecting neighbouring genes have also been seen in conjunction with CGD such as the dystrophin gene, Ornithine transcarbamylase, and retinitis pigmentosa GTPase.⁷⁰ Patients with severe Glucose 6 phosphate dehydrogenase (G6PD) deficiency can also have a CGD like phenotype as NADPH oxidase production is dependent upon the glycolytic pathway.

Specific granule deficiency (SGD)

First described in a young male presenting with infections from birth, the patient had bilobed nuclei with abnormal appearing specific granules and was found to have a lack of lactoferrin production. The disorder was ultimately found to be due to a mutation in the CCAAT/enhancer binding protein epsilon which is expressed exclusively in myeloid and T cell lineages. This class of proteins are key regulators of cellular differentiation and the myeloid cells appear to be blocked in their differentiation, resulting in decreased numbers with the few neutrophils having poor chemotaxis, impaired phagocytosis and microbial killing. ^{71–73, 74, 75} A consideration for HDAC1 inhibitor use has been proposed for specific mutations based on invitro studies; however these have not been used clinically to date. ⁷⁶ This is a rare autosomal recessive disorder but there is a report of one patient being successfully transplanted. ⁷⁷

RAC2 deficiency

Probably the rarest disorder of neutrophils, this has been described in a patient who presented with a severe bacterial infection at 5 weeks of age. Genetic analysis revealed a point mutation in the RAC2 gene whose protein is a member of the Rho GTPAse family. The patient’s mutation resulted in an aspartic acid to asparagine change at the GTP binding site. The resulting neutrophils had defects in chemotaxis due to actin abnormalities, as well as a deficiency in respiratory burst formation as RAC 2 is necessary for NADPH formation. This patient successfully underwent allogeneic transplantation.^{78, 79} No other cases have been described to date, but this disorder points to other pathways and/or proteins that should be considered when evaluating for genetic defects involving myeloid based immunodeficiencies. ^{80, 81}

3). Disorders affecting neutrophil numbers

Congenital Neutropenias

Severe congenital neutropenias (SCN) as well as cyclical neutropenias arise from the same genetic defects and are differentiated simply by the chronicity of the neutropenia and whether the counts oscillate. Mutations in ELANE, the gene responsible for neutrophil elastase production, accounts for the majority of patients with either SCN or cyclical neutropenia.⁸² HAX 1 mutations (also known as Kostmann’s) are the second most common cause of congenital neutropenias. Other genes that have been described include CSFR3,GF11, and G6PC3, which function in various pathways of myeloid development.⁸³

Patients often present at birth or early age with low neutrophil counts, and a pyogenic infection or omphalitis similar to patients with LAD.

Management is typically with GCSF.⁸⁴ A number of patients have also undergone allogeneic hematopoietic stem cell transplant with the Europeans reporting an overall survival of 82%.⁸⁵ There is an increased predisposition to the development of myeloid leukemias in patients with these disorders, and there was concern that this might be related to the chronic GCSF use; however this may in fact be intrinsic to the diseases and not necessarily due to stimulation by the growth factor. ^86–88

Autoimmune neutropenia of infancy (AIN)

Another neutropenia diagnosed early in life is AIN. Due to the presence of autoimmune antibodies to neutrophils, patients can present with a congenital neutropenia type picture and are typically diagnosed within the first 7 to 9 months of life. In the vast majority of cases, the antibody titres wane and the neutropenia resolves by the 1^st year of life. ^{89, 90} The development of these antibodies appears idiopathic and is not well understood.

Glutathione synthetase deficiency (GSD)

Finally, a very rare cause of congenital neutropenia has been attributed to GSD, although not a typical myeloid immunodeficiency per se as patients present with a multitude of symptoms. There has been a description of a patient being diagnosed with GSD after developing bacterial infections in the setting of neutropenia. The buildup of oxolopurine within the neutrophils leads to their destruction and thus reduced numbers and increased susceptibility to infections. ⁹¹ There is currently no treatment available.

4). Immunodeficiency Syndromes involving the myeloid lineage.

Wiskott-Aldrich Syndrome (WAS)

WAS is an X-linked disorder whose hallmark is that of thrombocytopenia with small platelets, but in which the defect affects multiple hematopoietic lineages and presents in a very heterogeneous manner. Patients are categorized as having mild disease (often referred to as X-linked thrombocytopenia) to severe, based on the development of infections, autoimmunity and/or malignancy.⁹² However patients can also progress from mild to severe disease and thus patients need lifelong monitoring particularly as patients with mild disease have a similar life expectancy to those with severe disease. ⁹³

The WAS protein is part of a family of actin nucleation-promoting factors which is required for actin polymerization and cytoskeletal remodeling. Neutrophils are thus unable to respond to chemotactants, phagocytose adequately and also have reduced integrin-induced respiratory bursts. ^94–97 As all the white blood cell lineages are affected, patients can develop a wide variety of infections, including viral, bacterial, fungal, and opportunistic. They can also have significant problems from atopy, autoimmunity, and an increased risk of malignancy probably as a result of their disordered immune surveillance and regulation.

Notably there is a condition referred to as X-linked Neutropenia (XLN) that occurs from mutations in exon 9 of the WAS gene and these patients present with neutropenia and myelodysplasia without the other manifestations of Wiskott-Aldrich syndrome.^{98, 99}

Allogeneic transplantation can be curative and is recommended for those with severe disease. It is less commonly considered in those with mild disease particularly as there appears to be a relatively high rate of autoimmune complications post-transplant, and mixed chimerism is not sufficient for full phenotypic reversion. ^{100, 101, 102, 103, 104, 105} Gene therapy has been hampered by the development of malignancies in a retroviral vector study; however the use of lentiviral vectors appears promising. ^106–110

Chediak-Higashi Syndrome

Chediak-Higashi patients have mutations in the LYST gene which is required for lysosomal granule formation. Patients have albinism, platelet dysfunction with a bleeding diathesis but also develop infections related to a neutrophilic granule defect where the neutrophils are characterized by abnormally large azurophilic granules. A number of patients will develop an accelerated phase of the disease which resembles hemophagocytic lymphohistiocytosis and may be related to macrophage or Natural Killer cell dysfunction. Patients have a shortened life expectancy and the majority are treated with HSCT including cord blood transplants. ^{111, 112}

Hyper IgM Syndrome

HIGM syndromes are a group of disorders that are characterized by failure of B cells to class switch, leading to decreased IgG and IgA serum levels, but normal or elevated serum IgM. The X-linked form (XHIGM) is the most common subtype and arises from mutations in the CD40 ligand gene. These patients are particularly susceptible to Pneumocystis carinii pneumonia, diarrhea secondary to Cryptosporidium and 67% of patients will also present with neutropenia. ^113,114 Despite intravenous immunoglobulin supplementation, use of GCSF and antibiotic prophylaxis, patients do not do well with an estimated 20% survival beyond the age of 25 in one European study.¹¹³ Cryptosporidial infections are particularly significant for development of chronic cholangitis and liver failure; thus patients are restricted to boiled water.¹¹⁴ Most patients are offered HSCT using a variety of type of donors; however outcomes are better when using a matched donor and patients are transplanted prior to infection.^{115, 116} CD40 deficiency which is a rare autosomal recessive form of the disease presents similarly in patients; however transplantation is less successful as the CD40 deficiency is not corrected in the nonhematopoietic cell lineages by HSCT.^117,118 Although gene therapy has been considered, dominant negative effects have been shown in in vitro modeling and unregulated expression may be detrimental, thus therapies may depend on the success of gene editing as opposed to gene addition. ^{119, 120}

Conclusions

As this review demonstrates, myeloid based immunodeficiencies are varied in their pathophysiology but present similarly with recurrent bacterial infections early in life and therefore should be considered in any patient presenting with a pyogenic infection within the first or second year of life. Genetic sequencing has significantly helped with the elucidation of many of the pathophysiologies; however, genetic mutations do not always explain the variety of phenotypes and presentations. As gene therapy and eventually gene editing improve and become more available clinically, the barriers of transplantation including availability of donors and the toxicities of conditioning regimens as well as the risks of graft versus host disease will hopefully be replaced by curative treatments with less adverse effects and better outcomes overall. Finally, as further research continues to elucidate the pathways of neutrophil function, novel therapies such as small molecule adjuncts or monoclonal antibodies will mostly likely be developed.