Congenital or primary immunodeficiency syndromes have demonstrated that specific cellular, soluble, and genetic elements within the human immune system are required for defense against a particular environmental challenge. These “pure” defects of the immune system have been referred to as immunologic “experiments of nature” (1) and have provided significant insight as to how the host is protected from specific organisms. Most typically, they result in frequent or recurrent common infections but, in some cases, predispose to unusual or severe infections. Herein, congenital immunodeficiencies having a predisposition to sepsis are reviewed with a goal of understanding commonalities of human host defense needed for protection from sepsis.
Advances in the understanding of inflammation, infectious disease, and systemic responses to infection have resulted in more specific definitions of sepsis and the infections that can cause sepsis (2). The contributions from multiple authors presented in this volume serve to carry this field even further. Unfortunately, many descriptions of patients with congenital immunodeficiencies in the medical literature do not provide sufficient detail to discern whether systemic inflammatory response syndrome or sepsis has occurred. In a number of congenital immunodeficiencies, however, there are reports as well as case series describing severe infections that would be consistent with sepsis. In some, the label of sepsis is provided without noting the basis of that diagnosis. The rarity of these diagnoses necessitates consideration of these historical cases to estimate the impact of sepsis in patients with congenital immunodeficiencies. With this in mind, my focus is on congenital immunodeficiencies in which sepsis, or descriptions of infectious disease consistent with sepsis, are pervasive, or at least an expected feature in a subset of patients. This undertaking is clearest if a focus is placed on patients experiencing sepsis due to bacteremia, fungemia, or viremia without mention of another nidus of infection. This definition excludes isolated pneumonia, which is certainly a major cause of sepsis and is extraordinarily common in congenital immunodeficiencies (reviewed in Reference 3). Discussion of pneumonia and other organ-specific infectious disease is excluded from this review because it is difficult to discern from the immunodeficiency literature whether individual occurrences of these infections resulted in sepsis. Because of this restrictive definition, however, it is almost certain that the true incidence of sepsis (according to the current broader definition ) in congenital immunodeficiencies will be severely underestimated. Hopefully, future descriptions of expected sequelae of congenital immunodeficiencies will pay greater attention to the specific definition of sepsis (as defined in this volume) to allow a greater understanding of human host factors contributing to susceptibility to sepsis.
An important related consideration is that sepsis may have distinct characteristics in patients with congenital immunodeficiencies. This would presumably be a result because sepsis is an immune-mediated disease. Congenitally impaired immunity could lead to a more mild course of sepsis due to an incomplete inflammatory response or, in a more severe course, due to a lack of regulatory responses. Alternatively, sepsis has the potential to be worse due to a higher pathogen burden resulting from impaired defenses. Identification of congenital immunodeficiencies with an increased incidence of sepsis, however, is a necessary prerequisite in being able to appreciate and consider the immunology underlying these subtleties.
To review congenital immunodeficiencies with a noted predisposition toward sepsis as defined above, it is necessary to divide the clinical disorders for consideration. Rather than use the classic immunologic division of complement, phagocyte, and humoral and cellular components, it will be more useful to view the immune system and defects thereof as primarily affecting innate or adaptive immunity (Table 1). The innate immune system consists of elements that are capable of participating in host defenses immediately on the first exposure to a pathogenic challenge. In contrast, the adaptive immune system requires time after the challenge to develop specificity and effectiveness. This division of defects into innate and adaptive defects has shortcomings as some molecular lesions affect both adaptive and innate immunity. Furthermore, the adaptive and innate responses are interrelated and communicate to appropriately coordinate an effective immune response. Despite this, some of the more recently appreciated congenital immunodeficiencies defy the traditional categorization and are more conducive to this alternative consideration.
Finally, a number of relatively common genetic polymorphisms have been described that affect the immune system. In some cases, these are associative only, but in others, there are definitive functional data demonstrating immunologic impact. This subject is the topic of another part of these proceedings and is only included here as it relates to the broader category of nuclear factor (NF)-κB activation defects. A brief mention of the mannose-binding lectin (MBL) polymorphisms is also included due to their relation to the complement component defects.
Congenital Defects of the Innate Immune System with an Increased Incidence of Sepsis
For the purpose of discussing congenital defects of the immune system affecting innate immunity having susceptibility to sepsis, the disorders are divided into four categories. The first category consists of soluble bactericidal components of immunity and presently includes complement proteins and MBL. The second comprises defects affecting the normal process of NF-κB activation. The third consists of specific defects of phagocyte quantity and quality. The fourth is made up of defects in the so-called type 1 cytokine response axis, which overlap significantly with and will serve as a lead into defects of adaptive immune function.
Complement Proteins and Mannose-Binding Lectin
Complement proteins comprise a multiple functional system that is capable of promoting inflammatory processes as well as mediating the direct destruction of pathogenic organisms. Defects of the individual complement components have been appreciated for many years and can be associated with both infectious susceptibilities and autoimmunity. Classically, deficiencies of the terminal complement components forming the membrane attack complex (C5–9) are associated with infectious disease due to the Neisseria species. In the largest series of patients with complement component deficiencies, this paradigm is substantiated as most of these patients were found to have invasive infection with Neisseria meningitidis or Haemophilus influenzae (4). In deficiencies of earlier complement components, Gram-positive organisms are more common. Of the patients deficient for a complement component, >50% had invasive bacterial disease. Of these, 28% could be clearly identified as having sepsis at some point. When the most common deficiency, C2, is considered by itself, at least 15% can be identified as having experienced sepsis (4).
Conversely, when a series of patients with severe meningococcal disease were evaluated for having deficiency of complement components, the estimated prevalence rates have ranged from 0% to 18%, depending on the population studied (unweighted mean, 7.9% ± 7.9% [sd]) (5–8). The incidence of a defect is substantially higher in patients with recurrent disease or disease due to uncommon serogroups (9, 10).
Deficiencies exclusively affecting the alternative as opposed to the classic pathway of complement activation can also predispose to sepsis and thus should be considered. The most common of these is properdin deficiency, which is X-linked, results in approximately 50% of patients having meningococcal disease, and includes a disproportionate percentage of cases due to unusual N. meningitidis serotypes (11). Importantly, standard tests of the classic complement pathway that are readily available from most clinical laboratories will miss deficiencies of properdin. This defect needs to be evaluated specifically when suspected or screened for by an assessment of alternative complement pathway.
Another proposed deficiency bearing homology to the complement component defects is that of MBL. MBL is a collectin with homology to the assembled first component of complement. It functions in the opsonization of bacteria and subsequent activation of complement. Certain polymorphisms of the MBL genes lead to decreased production of MBL and are associated with an increased incidence of sepsis. In a study comparing MBL genotypes in patients with severe sepsis with a control population, the genotype resulting in the lowest MBL production was statistically overrepresented in the sepsis population 2.8% vs. 5.1% (12). Similarly, a study of pediatric patients with meningococcal disease found those homozygous for an MBL structural variant to be overrepresented relative to controls (7.7% vs. 1.5%) (13). Interestingly, patients with sepsis having MBL genotypes that result in substantially reduced serum MBL had a greater chance of having a more severe presentation (relative risk, 3.21 ; odds ratio, 7.1 ). In contrast, MBL genotypes were not found to be predictive of susceptibility to or outcome during invasive pneumococcal infection (15, 16).
NF-κB Activation Defects
It has been recently shown that a number of specific congenital immunodeficiencies can result from a genetically defective ability to appropriately activate the transcription factor NF-κB after recognition of a pathogenic stimulus. As this system is important in generating early responses against microbial organisms, it is not surprising that there is an increased incidence of sepsis in a number of these disorders. One of the more clearly defined of these conditions is immunodeficiency resulting from mutation of the NF-κB essential modulator (NEMO), the gene for which is encoded on the X-chromosome. NEMO is a component of the kinase required for the activation of NF-κB in the canonical pathway of NF-κB function. A recent series of patients with NEMO mutations reported sepsis in 86%, with pneumococcus and Klebsiella being the most common pathogens (17). These infections typically occurred early in life and are believed to be in part due to impaired function of innate immune receptors that rely on NF-κB activation, such as the Toll-like receptor (TLR) family of pathogen pattern recognition receptors. In this light, impaired TLR-4 responsiveness to lipopolysaccharide has been reported for one patient with a NEMO mutation (18) and has been found in a number of others (19).
Slightly further upstream of NEMO in the activation pathway resulting after TLR ligation lies IRAK4, the mutation of which has also been identified as causing a congenital immunodeficiency. All patients described with mutation of their IRAK4 genes have had severe bacterial illness, and 75% can be distinguished as having had septic events due to Gram-positive organisms (20–22). Similarly, an undefined TLR signaling defect not resulting from mutation of IRAK4 or NEMO has been identified (23). These patients have defective TLR ligand function but normal NF-κB translocation in response to LPS. Both patients described thus far have had recurrent pneumococcal bacteremia.
Even further upstream of IRAK-4 in the innate immunoreceptor pathway to NF-κB activation lie the TLRs themselves. Although it is theoretically conceivable that deviant forms of each of the TLR will result in some infectious susceptibility, the best current evidence supports TLR-4 as a candidate. TLR-4 has been proposed to recognize a variety of microbial components, the most widely appreciated of which is lipopolysaccharides. Population screening has identified an A896G missense alteration in TLR4 predicting a D299G substitution in 6.6% of a control population (24) (which is higher in other control populations ). This alteration was associated with a significantly impaired TLR-4 response to lipopolysaccharide in vitro and endotoxin hyporesponsiveness in vivo (24, 25). Screening for this mutation in 91 patients with septic shock found that 13.8% had the A896G mutation (26) and thus was significantly overrepresented. Furthermore, those that had only this missense alteration had infection with Gram-negative organisms. When the D299G allele was evaluated as a risk factor for sepsis in very low birth weight infants, however, it was not found to predict sepsis (27). The potential importance of TLR-4, however, is highlighted by a study of 355 patients with meningococcal sepsis, in which 14 were identified to have rare coding missense mutations of TLR4 (28). Nine distinct genetic lesions were identified and included one patient with D299G and two with T399I. This series, therefore, probably includes some true mutations of TLR-4. Although the significance of TLR variants and mutants is still a matter of debate, their inclusion is worthwhile when considering patterns of sepsis susceptibility.
A potentially related but somewhat poorly understood genetic variant affecting the normal NF-κB activation process associated with sepsis susceptibility is that of homozygous long form of caspase-12. Caspase-12 has been proposed to function in cytokine maturation and/or cellular apoptosis and involves the activation of NF-κB after cellular exposure to tumor necrosis factor-α. The homozygous long form of caspase-12 is a genotype found exclusively in Africans and is overrepresented among those with severe sepsis = 10.5 (n = 23) vs. 1.8% (n = 499) in the control group (29). This variant of capsase-12 results in less NF-κB activation after tumor necrosis factor-α exposure and thus may interfere with the normal regulation of inflammation during sepsis.
Inherent Phagocyte Defects
Defects directly affecting either the quantity or quality of phagocytes can result in susceptibility to sepsis. The best appreciated of the defects in quality is chronic granulomatous disease (CGD), which results from a mutation of one of the components of the reduced nicotinamide dinucleotide phosphate oxidase complex. Phagocytes from patients with CGD mount an abnormal respiratory burst when challenged with microbial pathogens. Remarkably, 21% (54/259) of patients with the X-linked variety of the disease have experienced bacterial or fungal sepsis (30). This occurrence is reduced to 10% (8/81) in the autosomal recessive cases. Of the causative organisms identified, Salmonella species were most common (18%), followed by Burkholderia cepacia (12%), Candida species (11%), Staphylococcus species (9%), Pseudomonas species (9%), Serratia species (6%), and a variety of others (28%). Sepsis was identified as the cause of death in 21% (13/61) of patients with CGD.
Another, rare but well-defined defect in phagocyte quality resulting in an increased susceptibility to sepsis is the leukocyte adhesion deficiency. This disorder most commonly results from a defect in one of the integrin chains commonly employed by leukocytes to create a functioning integrin complex. The oxidative killing function of theses cells is normal, but they are unable to localize to sites of inflammation where this function would be required. As a result, neutrophil numbers in the peripheral blood are typically markedly elevated. In the most comprehensive yet small series of patients with leukocyte adhesion deficiency, sepsis can be identified in 28% (31). The most common responsible organism identified was Pseudomonas aeruginosa.
A final qualitative disorder of phagocytes associated with an increased sepsis risk is specific granule deficiency. This disorder is also extremely rare and is caused by a mutation in the CCAAT/enhancer binding protein-ε resulting in an absence of neutrophil secondary granules. The resulting neutrophils have characteristic abnormal bilobed nuclei. Although an organized series of these patients has not been recorded, severe bacterial illness and sepsis are described in the majority of reported patients (32–34).
The quantitative disorders of neutrophils all are associated with some degree of sepsis susceptibility and can result from at least two distinct genetic lesions. Kostmann’s (severe congenital neutropenia) and cyclic neutropenia are both caused by mutations of the same gene, ELA2, and thus represent a spectrum of disease affecting neutrophil development. Severe neutropenia also occurs as an X-linked form due to an unusual mutation of the Wiskott-Aldrich syndrome protein (WASp) gene. There are also a relatively large number of neutropenic disorders that are still defined as idiopathic. Anecdotal reports and other sources attest to a significant frequency of sepsis in the neutropenic disorders (35–37). Unfortunately detailed sepsis data of patients enrolled in the Severe Chronic Neutropenia International Registry (SCNIR) have not been published. A recent query, however, of the European SCNIR data of patients enrolled between 1990 and 2004 (n = 378) reveals an incidence of sepsis of 2.9% (Dr. B. Schwinzer, personal communication). A similar query of the North American SCNIR reveals an incidence of sepsis of 2.4% and bacteremia of 15% (Dr. D. C. Dale and A. A. Boylard, R.N., personal communication). The incidence of sepsis in the North American registry was similar in severe congenital and cyclic neutropenia, but lower in idiopathic neutropenia. These low occurrences of sepsis, however, are probably not a true estimate of sepsis susceptibility and more a reflection of the excellent clinical care provided to patients in the registries. In this regard, of the patients included in the original description of severe congenital neutropenia, 64% of the 14 can be inferred to have had sepsis (38).
Type 1 Cytokine Axis Defects
A number of genetic defects in the type-1 cytokine axis defined by the interleukin (IL)-12/interferon (IFN)-γ pathway have been delineated (39). They include defects in the IL-12 receptor, IL-12 p40 subunit, IFN-γ receptors, and the signal transducer and activator of transcription-1 (STAT1). All of these result in susceptibility to infectious diseases, and some have been determined to have an increased risk of sepsis. IL-12rβ deficiency results in impaired secretion of IFN-γ and increased susceptibility to mycobacterial infections and salmonellosis. In the largest series of patients, 19 of 29 had disseminated salmonella infections (40). Some of these have been defined as having “severe” disease and are thus presumed to have been septic (41, 42), but it is unclear as to whether true criteria for sepsis were fulfilled. IFN-γ receptor deficiency, in contrast, primarily results in mycobacterial susceptibility that can lead to pervasive and severe infection (43, 44), even resulting in sepsis (45). A subset of these patients, however, has experienced severe viral disease, including what is inferred to be viral sepsis (46). Patients having congenital deficiency of STAT1 are also predisposed to mycobacterial infections similar to patients with other type-1 cytokine axis disorders, but a subset who are deficient in IFN-α/β signaling die of disseminated viral disease consistent with viral sepsis (47).
Congenital Defects of the Adaptive Immune System with an Increased Incidence of Sepsis
Congenital defects of the adaptive immune system that have been associated with an increased risk of sepsis include disorders having clear molecular etiologies as well as some that are still diagnosed and categorized phenotypically. Deeper understanding of the basic immunology underlying these disorders has led to an appreciation that most include effects on both B cells and T cells to some extent. Thus, these diseases are discussed as a group.
Severe Combined Immunodeficiency (SCID)
In many ways the clearest defect of the adaptive immune system is SCID, which is characterized by a complete or partial failure of lymphocytes to proliferate. Without treatment, SCID is a uniformly fatal disease, as infants cannot protect themselves from their environment. There are a relatively large number of molecular defects that can result in the SCID phenotype. When considered in total from a group of 116 SCID patients, sepsis was described in 5.4% (48). Interestingly, sepsis was more common in infants with Omenn syndrome (16%) and less common in those with adenosine deaminase deficiency (0%). Similarly, in what is believed to be the most severe form of SCID, reticular dysgenesis, 30% had sepsis, typically within the first few days of life (49). Unusual microorganisms can be causative agents, and sepsis from mycobacteria and fungi have been noted (49, 50).
Agammaglobulinemia can be defined as absent immunoglobulins (Igs) resulting from a failure of B cell development and has been identified to result from at least five distinct molecular defects. In a series of 96 children presumed to have the most common variety of agammaglobulinemia, 10% had sepsis as a presenting manifestation (51). This percentage does not include cases of septic arthritis or meningoencephalitis, which were the presenting manifestation in another 24%. Of the sepsis cases, the majority were due to the Pseudomonas species. An additional 4% of patients had sepsis after their diagnosis, most commonly due to Gram-positive bacteria, and one of the 17% of patients who died suffered terminal bacterial sepsis. Unusual organisms can be identified as the causative agents in these patients, and there is a predisposition to the Ureaplasma species in those with arthritis (52). Fortunately, regular replacement therapy with intravenous immunoglobulin (IVIG) reduces the incidence of sepsis in patients with agammaglobulinemia. In a separate series, 10% of patients experienced sepsis before IVIG treatment, with an annual incidence of 0.037 (cases per patient per year), which was reduced to 0.003 after IVIG treatment (53).
The hyper IgM syndrome is characterized by ineffective immunoglobulin class switching resulting from interrupted B cell co-stimulation. There are at least five molecular defects that can give rise to this phenotype. Children with hyper-IgM have ineffective production of specific IgG and are susceptible to infection and sepsis. In a series of 79 patients believed to have the most common and X-linked variety of hyper-IgM, 13% had sepsis, the majority of which were due to pneumococcus or the Pseudomonas species (54). A similar series from Israel reported sepsis in 14% of patients, half of which, however, were caused by Escherichia coli (55). Sepsis susceptibility may be a distinct feature of certain molecular variants of hyper-IgM as there were no cases of sepsis reported in a series of 29 patients having a more recently appreciated autosomal recessive form of hyper-IgM due to mutation of the activation-induced cytidine deaminase (56).
Common Variable Immunodeficiency (CVID)
CVID is defined as hypogammaglobulinemia with impaired production of specific antibody. Although several molecular defects have been identified, the majority of patients with CVID do not presently have an identifiable molecular etiology. Importantly, CVID is the most common primary immunodeficiency presenting in adults, and there are peaks of diagnosis in the first and fourth decades of life. In the single largest series of 248 patients with CVID, sepsis was identified in 1.2% before the initiation of therapy (57). In patients with a variant of CVID, known as Good syndrome, however, the incidence of sepsis appears to be higher. A review of 51 patients with this diagnosis identified 16% as having experienced sepsis and included a number of sepsis episodes caused by fungal pathogens (58).
Transient Hypogammaglobulinemia of Infancy
Transient hypogammaglobulinemia of infancy is a transient humoral immunodeficiency of uncertain etiology that affects infants. It is defined by IgG <2 sds below the mean for age. It may represent a delay in immunoglobulin production after the maternal IgG supply has been exhausted and has been suggested to result from a T cell abnormality (59). Historically, children have normal production of specific antibody, but in actuality, the majority demonstrate some impairment (60). Sepsis has been reported in these patients (61–64), but other series have found a lack of sepsis (65). This paucity of septic events probably speaks to an importance of quality as opposed to quantity of IgG.
IgG Subclass Deficiency
Relative IgG subclass deficiency is defined as an IgG subclass level of <2 sds below the age-adjusted mean and, as such, is relatively common. Therefore, recurrent infection in the setting of a relative IgG subclass deficiency may not necessarily be a feature of the deficient subclass. The true deficiency of an IgG subclass resulting from germline deletion of heavy chain immunoglobulin loci has been described, but these patients have only an increased incidence of respiratory infections (66, 67). It is also possible that the true immunologic defect in patients with relative subclass deficiency may cause the IgG subclass deviations, thus making IgG subclass deficiency a surrogate marker of aberrant immune responses. As an example, some patients who have been previously labeled as having IgG subclass deficiency, who have experienced sepsis, have ultimately been given a different genetic immunodeficiency diagnosis (17). There are, however, reports of patients having IgG subclass deficiency and no evidence of other immunodeficiency who have had sepsis (68, 69). In one series of 119 patients with IgG subclass deficiency initially evaluated because of recurrent infection, 1.7% had sepsis. This population, however, was highly preselected and not indicative of relative IgG subclass deficiencies in the general population. Thus, there are probably subpopulations of patients with IgG subclass deficiency who have sepsis susceptibility, but current technologies do not allow for the specific identification of these groups.
Ataxia telangiectasia results from a genetic defect in DNA repair machinery and leads to immunodeficiency and cancer susceptibility. The immunologic defects are varied and affect T cells, B cells, and other immunologic components. The vast majority of patients experience recurrent and often severe infections. In a series of 100 children with ataxia telangiectasia, however, sepsis was reported in only 5% (70). The majority of these episodes of sepsis were due to Gram-positive bacteria.
Immunodysregulation, Polyendocrinopathy, Enteropathy–X-Linked (IPEX)
IPEX is a syndrome of autoimmunity and ineffective host defense, presumably resulting from a dysfunction of regulatory T cells caused by a mutant FoxP3 transcription factor. Severe infections are quite common and are typically found in the context of severe diarrhea. In a clinical review of 55 patients with IPEX, sepsis was identified as the cause of death in 15% (71). It is unclear if this susceptibility results from a specific immunologic defect or a breakdown of mucosal barriers.
Wiskott-Aldrich Syndrome (WAS)
WAS is characterized by infectious susceptibility, thrombocytopenia, and eczema. The disease is caused by mutations in the gene encoding WASp and leads to an ineffective ability to rearrange the actin cytoskeleton in immune cells. As a result, there is most typically impairment of specific antibody production, as well as immunologic defenses. Two comprehensive series of WAS patients have defined an increased sepsis risk (72, 73). One study identified sepsis in 11% of patients before diagnosis and in 36% of patients after diagnosis (72). In addition, 13% of WAS patients experience recurrent sepsis. In the second series, sepsis was identified as the cause of death in 18% (73).
When to Consider a Congenital Immunodeficiency.
It is quite likely that patients who become septic with a given organism have some genetic element or combination of genetic elements that result in their susceptibility to an extreme infection. However, at the present time, the ability to discern subtle or polygenic propensities toward severe infection with a common organism is in its infancy, and many occurrences are still ascribed to “bad luck.” Thus, careful consideration of the septic patient must be given for a cost-effective and high-yield evaluation for primary immunodeficiency to occur. A decision to pursue a diagnosis of a congenital immune defect in patients with sepsis needs to focus on the patient’s personal and family history. Patients with congenital immunodeficiency often have clinical histories of repeated or unusual infections. An expert panel formed by the Jeffrey Modell foundation with support from the American Red Cross and Centers for Disease Control and Prevention have arrived at ten warning signs that should raise concern for a congenital immunodeficiency (Table 2). In addition, there are occasional findings at physical or radiologic examination that are suggestive of immunodeficiency. Examples include absent tonsillar tissue as found in agammaglobulinemia, an absent thymus as found in certain types of SCID, and cutaneous scarring from recurrent abscesses as found in CGD. Unfortunately, however, sepsis can certainly be a presenting feature of the immunodeficiency disorders discussed above and their consideration should certainly not be excluded by a lack of historical features.
The aforementioned primary immunodeficiencies that are associated with a susceptibility to sepsis are all quite rare. Given that the incidence of primary immunodeficiency excluding (IgA deficiency and IgG subclass deficiency) is higher than 1:10,000, an approximate incidence of these diseases among live births can be estimated from evaluation of several existing registries (74–78). Alternatively, the incidence of some of these disorders has been specifically estimated in disease-specific series (17, 30, 54, 64, 79). Using these sources, the primary immunodeficiencies with a notably increased susceptibility to sepsis have the following approximate incidence among live births: complement component defect, 1:10,000; NEMO deficiency, 1:250,000; chronic granulomatous disease, 1:200,000; leukocyte adhesion deficiency, 1:1,000,000; severe congenital neutropenia 1:400,000; agammaglobulinemia, 1:150,000; hyper-IgM, 1:435,000; CVID 1:55,000, ataxia telangiectasia, 1:20,000; WAS, 1:400,000. It is important to realize, however, that the population of children with severe infections and sepsis is highly preselected for those with immunologic defects, so these disorders should be carefully considered in this setting. The diagnosis of congenital immunodeficiency is likely underreported, and it is likely that a subset of deaths due to sepsis occurs in undiagnosed patients.
Testing for a Congenital Immunodeficiency in the Setting of Sepsis.
The current laboratory approach to patients suspected to have congenital immunodeficiencies has been the subject of several manuscripts and thus is comprehensively discussed elsewhere (80, 81). Given present technology, however, it can be quite difficult to identify previously unidentified patients with congenital immunodeficiency during septic episodes as many immunologic tests are unreliable in the setting of severe infection. The best strategy might be to target particular infants for immunologic evaluation should they survive their septic episode. Despite this, there may be certain laboratory assessments that can be useful, even in the setting of severe illness. Although a complete blood count can be significantly affected in the setting of a major infection, serial assessments displaying extremes such as absent neutrophils may be cause for concern and suggestive of a congenital neutropenia. Particularly in the setting of bacteremia, neutrophils should be elevated. If the patient survives the initial presentation of sepsis, persistently very low lymphocyte counts should also be of concern. Lymphocytes, which are typically depressed in the setting of bacteremia, typically recover after several days (82, 83). A lack of recovery of lymphocyte populations over time should be considered abnormal and prompt additional evaluation for SCID. Immunoglobulin levels are also affected by severe sepsis, and the typical pattern is normal to decreased IgG, elevated IgM, and normal IgA (84). Immunoglobulin levels can be useful, especially if they are all absent and thus suggestive of agammaglobulinemia. Alternatively the pattern of very low IgG with elevated IgM and absent IgA can be suggestive of hyper-IgM or NEMO deficiency and indicates the need for further evaluation. Finally an absent classic or alternative total hemolytic complement functional assay can be suggestive of a complement component defect. Although the values are affected by sepsis (85), a level of zero would be unusual and the test may be a consideration in certain types of meningococcal disease as discussed above.
The use of tests for congenital immunodeficiency in the setting of sepsis should be guided by the patient’s history and any suspicion raised by a particularly unusual organism. A concerning clinical history might even prompt directed genetic testing. In the absence of historical or microbiological clues, it would not be practical to pursue a diagnosis of immunodeficiency in all patients who are septic. Tests such as a complete blood count, however, are routinely obtained and should not be ignored. On the other hand, the consideration of patients for clinical trials of sepsis interventions is a distinct issue, and a more comprehensive evaluation of patients for congenital immunodeficiency may be warranted. In this case, it might be reasonable to perform all of the tests referred to above. The reason for doing so is that sepsis is likely to be different in patients with congenital immunodeficiency. In some cases, it could be more severe due to incomplete host defense, leading to higher pathogen loads. In other cases, sepsis could be less severe in these patients, perhaps due to blunted inflammation. As an example, patients with terminal complement component deficiencies and meningococcemia have a mortality of only 5% compared with 19% with a normal complement system (4). For these reasons, it is probably best to identify patients with congenital immunodeficiency in clinical trials of sepsis and either exclude them from analysis or consider them as a specific subset. The failure to do so could result in the introduction of an artificial bias into clinical trial data. Finally, as the mechanistic understanding of immunodeficiency improves, it is likely that additional clinical tests will become available that are capable of providing insight into the prospects of a septic patient having a congenital immunodeficiency associated with increased sepsis risk.
Therapeutic Considerations in Patients with Congenital Immunodeficiency
As the majority of infections in immunodeficient patients represent an inability to protect against the environment, therapeutic measures above and beyond those effective in immunocompetent patients may not be required. Some immunodeficiencies would theoretically result in higher pathogen loads, but this could be offset by the organism being relatively more benign. Thus, standard antimicrobial therapies should be considered adequate, but unusual organisms should also be suspected. Although IVIG is an important part of therapy for many congenital immunodeficiencies, its utility in the treatment of an established infection is controversial. Meta-analyses, however, have demonstrated modestly beneficial effects in patients presumed to be immunocompetent (86, 87). As a result, IVIG should be provided to immunodeficient patients who are septic, as would be indicated by their diagnosis. In addition, it is reasonable to administer IVIG to a patient with a congenital immunodeficiency experiencing sepsis who is at the end of his or her usual monthly IVIG infusion cycle. Finally, as sepsis leads to decreased IgG levels in immunocompetent patients, it is important to ensure that a patient with a congenital immunodeficiency dependent on IVIG infusions has trough IgG levels monitored after a septic event. In this case, adjustment of the regular infusion cycle may be needed to insure adequate IgG levels.
Conclusion and Lessons Learned
Consideration of sepsis risk in the human congenital immunodeficiencies highlights two immunologic themes that are important in protection against sepsis. A first theme is the importance of the host’s ability to recognize a pathogen. This is exemplified by the number of congenital immunodeficiencies that impair the normal ability to mediate this function, including the absence of opsonizing antibody, deficiencies of complement, deficiencies of MBL, and impaired function of pattern recognition receptors. The second theme is the need to destroy an organism after recognition and is exemplified by terminal complement component deficiency and quantitative and qualitative phagocyte defects. As severe sepsis is an extreme presentation of infectious disease, congenital immunodeficiencies stress the importance of pathogen recognition and eradication in host defense. Future studies of infection in congenital immunodeficiencies will certainly benefit from paying greater attention to the specific characteristics of sepsis in these patients. This will lead to an even greater appreciation of the host-defense elements required for protection against sepsis. Similarly, greater attention to congenital immunodeficiencies in studies of sepsis will help in the understanding of sepsis pathogenesis. In this light, although specific evaluation for primary immunodeficiency in a septic patient without a characteristic infection or history is not necessarily indicated, specific screening tests should be considered in the design of future clinical trials involving septic patients.
1. Good RA, Zak SJ: Disturbances in gamma globulin synthesis as experiments of nature. Pediatrics
2. Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med
3. Buckley RH: Pulmonary complications of primary immunodeficiencies. Paediatr Respir Rev
2004;5 (Suppl A): S225–S233
4. Figueroa JE, Densen P: Infectious diseases associated with complement deficiencies. Clin Microbiol Rev
5. Ellison RT 3rd, Kohler PF, Curd JG, et al: Prevalence of congenital or acquired complement deficiency in patients with sporadic meningococcal disease. N Engl J Med
6. Leggiadro RJ, Winkelstein JA: Prevalence of complement deficiencies in children with systemic meningococcal infections. Pediatr Infect Dis J
7. Platonov AE, Beloborodov VB, Vershinina IV: Meningococcal disease in patients with late complement component deficiency: Studies in the U.S.S.R. Medicine
) 1993; 72:374–392
8. Hogasen K, Michaelsen T, Mellbye OJ, et al: Low prevalence of complement deficiencies among patients with meningococcal disease in Norway. Scand J Immunol
9. Fijen CA, Kuijper EJ, Hannema AJ, et al: Complement deficiencies in patients over ten years old with meningococcal disease due to uncommon serogroups. Lancet
10. Merino J, Rodriguez-Valverde V, Lamelas JA, et al: Prevalence of deficits of complement components in patients with recurrent meningococcal infections. J Infect Dis
11. Linton SM, Morgan BP: Properdin deficiency and meningococcal disease—Identifying those most at risk. Clin Exp Immunol
12. Garred P, J JS, Quist L, Taaning E, et al: Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. J Infect Dis
13. Hibberd ML, Sumiya M, Summerfield JA, et al: Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet
14. Fidler KJ, Wilson P, Davies JC, et al: Increased incidence and severity of the systemic inflammatory response syndrome in patients deficient in mannose-binding lectin. Intensive Care Med
15. Kronborg G, Weis N, Madsen HO, et al: Variant mannose-binding lectin alleles are not associated with susceptibility to or outcome of invasive pneumococcal infection in randomly included patients. J Infect Dis
16. Roy S, Knox K, Segal S, et al: MBL genotype and risk of invasive pneumococcal disease: A case-control study. Lancet
17. Orange JS, Jain A, Ballas ZK, et al: The presentation and natural history of immunodeficiency caused by nuclear factor κB essential modulator mutation. J Allergy Clin Immunol
18. Orange JS, Levy O, Brodeur SR, et al: Human nuclear factor κB essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol
19. Orange JS, Levy O, Geha RS: Human disease resulting from gene mutations that interfere with appropriate nuclear factor-κB activation. Immunol Rev
20. Medvedev AE, Lentschat A, Kuhns DB, et al: Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med
21. Day N, Tangsinmankong N, Ochs H, et al: Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses. J Pediatr
22. Picard C, Puel A, Bonnet M, et al: Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science
23. Currie AJ, Davidson DJ, Reid GS, et al: Primary immunodeficiency
to pneumococcal infection due to a defect in Toll-like receptor signaling. J Pediatr
24. Arbour NC, Lorenz E, Schutte BC, et al: TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet
25. Michel O, LeVan TD, Stern D, et al: Systemic responsiveness to lipopolysaccharide and polymorphisms in the Toll-like receptor 4 gene in human beings. J Allergy Clin Immunol
26. Lorenz E, Mira JP, Frees KL, et al: Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med
27. Ahrens P, Kattner E, Kohler B, et al: Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants. Pediatr Res
28. Smirnova I, Mann N, et al: Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Nat Acad Sci U S A
29. Saleh M, Vaillancourt JP, Graham RK, et al: Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature
30. Winkelstein JA, Marino MC, Johnston RB Jr, et al: Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine
) 2000; 79:155–169
31. Anderson DC, Schmalsteig FC, Finegold MJ, et al: The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: Their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis
32. Breton-Gorius J, Mason DY, Buriot D, et al: Lactoferrin deficiency as a consequence of a lack of specific granules in neutrophils from a patient with recurrent infections: Detection by immunoperoxidase staining for lactoferrin and cytochemical electron microscopy. Am J Pathol
33. Shiohara M, Gombart AF, Sekiguchi Y, et al: Phenotypic and functional alterations of peripheral blood monocytes in neutrophil-specific granule deficiency. J Leukoc Biol
34. Gombart AF, Koeffler HP: Neutrophil specific granule deficiency and mutations in the gene encoding transcription factor C/EBP(epsilon). Curr Opin Hematol
35. Welte K, Dale D: Pathophysiology and treatment of severe chronic neutropenia. Ann Hematol
36. Dale DC, Bolyard AA, Aprikyan A: Cyclic neutropenia. Semin Hematol
37. Devriendt K, Kim AS, Mathijs G, et al: Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet
38. Kostmann R: Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria. Acta Paediatr
39. Rosenzweig SD, Holland SM: Congenital defects in the interferon-gamma/interleukin-12 pathway. Curr Opin Pediatr
40. Fieschi C, Dupuis S, Catherinot E, et al: Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: Medical and immunological implications. J Exp Med
41. Altare F, Lammas D, Revy P, et al: Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J Clin Invest
42. de Jong R, Altare F, Haagen IA, et al: Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science
43. Jouanguy E, Altare F, Lamhamedi-Cherradi S, et al: Infections in IFNGR-1-deficient children. J Interferon Cytokine Res
44. Jouanguy E, Lamhamedi-Cherradi S, Lammas D, et al: A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet
45. Cunningham JA, Kellner JD, Bridge PJ, et al: Disseminated bacille Calmette-Guerin infection in an infant with a novel deletion in the interferon-gamma receptor gene. Int J Tuberc Lung Dis
46. Dorman SE, Uzel G, Roesler J, et al: Viral infections in interferon-gamma receptor deficiency. J Pediatr
47. Dupuis S, Jouanguy E, Al-Hajjar S, et al: Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet
48. Stephan JL, Vlekova V, Le Deist F, et al: Severe combined immunodeficiency: A retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr
49. Bertrand Y, Muller SM, Casanova JL, et al: Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients. Bone Marrow Transplant
50. Parent LJ, Salam MM, Appelbaum PC, et al: Disseminated Mycobacterium marinum infection and bacteremia in a child with severe combined immunodeficiency. Clin Infect Dis
51. Lederman HM, Winkelstein JA: X-linked agammaglobulinemia: An analysis of 96 patients. Medicine
) 1985; 64:145–156
52. Asmar BI, Andresen J, Brown WJ: Ureaplasma urealyticum arthritis and bacteremia in agammaglobulinemia. Pediatr Infect Dis J
53. Quartier P, Debre M, De Blic J, et al: Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: A retrospective survey of 31 patients. J Pediatr
54. Winkelstein JA, Marino MC, Ochs H, et al: The X-linked hyper-IgM syndrome: Clinical and immunologic features of 79 patients. Medicine
) 2003; 82:373–384
55. Levy J, Espanol-Boren T, Thomas C, et al: Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr
56. Quartier P, Bustamante J, Sanal O, et al: Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency. Clin Immunol
57. Cunningham-Rundles C, Bodian C: Common variable immunodeficiency: Clinical and immunological features of 248 patients. Clin Immunol
58. Tarr PE, Sneller MC, Mechanic LJ, et al: Infections in patients with immunodeficiency with thymoma (Good syndrome): Report of 5 cases and review of the literature. Medicine
) 2001; 80:123–133
59. Siegel RL, Issekutz T, Schwaber J, et al: Deficiency of T helper cells in transient hypogammaglobulinemia of infancy. N Engl J Med
60. Dalal I, Reid B, Nisbet-Brown E, et al: The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr
61. Benderly A, Pollack S, Etzioni A: Transient hypogammaglobulinemia of infancy with severe bacterial infections and persistent IgA deficiency. Isr J Med Sci
62. Kosnik EF, Johnson JP, Rennels MB, et al: Streptococcal sepsis presenting as acute abdomen in a child with transient hypogammaglobulinemia of infancy. J Pediatr Surg
63. Simon JL, Bosch J, Puig A, et al: Two relapses of group B streptococcal sepsis and transient hypogammaglobulinemia. Pediatr Infect Dis J
64. Tiller TL Jr, Buckley RH: Transient hypogammaglobulinemia of infancy: Review of the literature, clinical and immunologic features of 11 new cases, and long-term follow-up. J Pediatr
65. McGeady SJ: Transient hypogammaglobulinemia of infancy: Need to reconsider name and definition. J Pediatr
66. Terada T, Kaneko H, Li AL, et al: Analysis of Ig subclass deficiency: First reported case of IgG2, IgG4, and IgA deficiency caused by deletion of C alpha 1, psi C gamma, C gamma 2, C gamma 4, and C epsilon in a mongoloid patient. J Allergy Clin Immunol
67. Smith CI, Hammarstrom L, Henter JI, et al: Molecular and serologic analysis of IgG1 deficiency caused by new forms of the constant region of the Ig H chain gene deletions. J Immunol
68. Bass JL, Nuss R, Mehta KA, et al: Recurrent meningococcemia associated with IgG2-subclass deficiency. N Engl J Med
69. Lacombe C, Aucouturier P, Preud’homme JL: Selective IgG1 deficiency. Clin Immunol Immunopathol
70. Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, et al: Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr
71. Wildin RS, Smyk-Pearson S, Filipovich AH: Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet
72. Sullivan KE, Mullen CA, Blaese RM, et al: A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr
73. Perry GS 3rd, Spector BD, Schuman LM, et al: The Wiskott-Aldrich syndrome in the United States and Canada (1892–1979). J Pediatr
74. Stray-Pedersen A, Abrahamsen TG, Froland SS: Primary immunodeficiency
diseases in Norway. J Clin Immunol
75. Aghamohammadi A, Moein M, Farhoudi A, et al: Primary immunodeficiency
in Iran: First report of the National Registry of PID in Children and Adults. J Clin Immunol
76. Golan H, Dalal I, Garty BZ, et al: The incidence of primary immunodeficiency
syndromes in Israel. Isr Med Assoc J
77. Zelazko M, Carneiro-Sampaio M, Cornejo de Luigi M, et al: Primary immunodeficiency
diseases in Latin America: First report from eight countries participating in the LAGID. J Clin Immunol
78. Stiehm ER, Ochs HD, Winkelstein JA: Immunodeficiency disorders: General considerations. In:
Immunologic Disorders in Infants and Children. Fifth Edition. Stiehm ER, Ochs HD, Winkelstein JA (Eds). Philadelphia, Elsevier Saunders, 2004, pp 289–355
79. Swift M, Morrell D, Cromartie E, et al: The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet
80. Folds JD, Schmitz JL: 24. Clinical and laboratory assessment of immunity. J Allergy Clin Immunol
81. Tangsinmankong N, Bahna SL, Good RA: The immunologic workup of the child suspected of immunodeficiency. Ann Allergy Asthma Immunol
82. Holub M, Kluckova Z, Helcl M, et al: Lymphocyte subset numbers depend on the bacterial origin of sepsis. Clin Microbiol Infect
83. Wyllie DH, Bowler IC, Peto TE: Relation between lymphopenia and bacteraemia in UK adults with medical emergencies. J Clin Pathol
84. Ahmed I, Rahman KM, Miah RA, et al: Serum immunoglobulin profiles of septicemic versus healthy neonates. Bangladesh Med Res Counc Bull
85. Nakae H, Endo S, Inada K, et al: Chronological changes in the complement system in sepsis. Surg Today
86. Jenson HB, Pollock BH: The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis. Semin Perinatol
87. Alejandria MM, Lansang MA, Dans LF, et al: Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Database Syst Rev