1220 SECTION XI Pediatric Critical Care Immunity and Infection all CGD patients The remaining forms, caused by mutations in the CYBA, NCF1, NCF2, or NCF4 genes, are all autosomal reces sive All mutati[.]
1220 S E C T I O N X I Pediatric Critical Care: Immunity and Infection all CGD patients The remaining forms, caused by mutations in the CYBA, NCF1, NCF2, or NCF4 genes, are all autosomal recessive All mutations affect the formation or function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex on neutrophil phagolysosomes The NADPH oxidase is required to generate a burst of reactive oxygen species in response to phagocytosis of pathogens Reactive oxygen species activate proteases in the phagolysosomes that destroy ingested bacteria In CGD, the oxidative burst cannot be generated, leading to defective processing of ingested organisms and an inability to appropriately eliminate bacterial and fungal pathogens Catalase-positive organisms—including Staphylococcus species, Aspergillus species, Burkholderia cepacia, Serratia marcescens, and others—are the most common pathogens The most common types of infection at presentation are pneumonia, lymphadenitis, osteomyelitis, cellulitis, and hepatic abscesses (particularly with Aspergillus) The most common cause of premature death is Aspergillus infection.22 In addition to the infectious susceptibilities of CGD, a substantial percentage of patients struggle with inflammatory complications that are common to this disorder, including an inflammatory colitis that occurs in approximately 40%, hepatic dysfunction, gingivitis, and others Treatment of CGD revolves around aggressive management of acute infections followed by prophylaxis against future infections using a combination of daily antibiotic (typically, trimethoprimsulfamethoxazole), daily antifungal (typically, itraconazole), and thrice-weekly interferon-g injections This combination has dramatically improved outcomes in CGD However, despite appropriate use of this regimen, some patients ultimately have increasing symptoms that lead to a decline in survival beginning in the late-teens or early 20s The prospects for long-term survival appear to be correlated with the amount of residual oxidative burst activity that can be generated by a particular patient’s phagocytes.23 Many now recommend that for patients who have mutations that severely impact oxidative burst activity, bone marrow transplantation should be considered preemptively, early in life before patients develop comorbidities.24 Specific Disorders: B Cells and Antibodies X-Linked Agammaglobulinemia X-linked agammaglobulinemia (XLA) is the prototypic B-cell disorder It is caused by mutations in the Bruton tyrosine kinase (BTK) gene BTK is a cytoplasmic tyrosine kinase that is required for the maturation of B-cell precursors in the bone marrow.25 Mutations in BTK therefore cause an arrest of B-cell development at the pre2B-cell stage, leading to virtual absence of circulating B cells in the peripheral blood Mutations that only partially interfere with the enzymatic function of BTK have also been described and are associated with milder forms of the disease that have defects only in generation of specific antibody responses XLA is typically suspected in male patients with recurrent bacterial sinopulmonary infections and B-cell lymphopenia Other infections that occur relatively frequently in patients with XLA before the initiation of IgG replacement therapy include skin infections (furunculosis, pyoderma, and cellulitis) and sepsis The diagnosis can be confirmed either by identifying a mutation in the BTK gene or demonstrating absence of the BTK protein in monocytes or platelets A positive family history suggestive of an X-linked recessive mode of inheritance increases the suspicion for XLA It is uncommon for patients with XLA to develop symptoms in the first months of life because newborns are protected from most infections by transplacentally acquired maternal IgG There are few distinguishing physical features of XLA that can provide clues to the diagnosis, but absence of visible tonsils or adenoids (by physical examination, radiograph, or computed tomography [CT] scan) is a useful clue In addition to the common sinopulmonary pathogens, patients with XLA are also susceptible to infections by particular opportunistic organisms that can cause unusual clinical syndromes For example, Helicobacter cinaedi can cause a syndrome of dermatomyositis and cellulitis that presents with cutaneous ulcerations, particularly on the lower legs.26,27 The organism can sometimes be recovered from the blood but is fastidious and difficult to culture using the usual methods A combination of antibiotics is often necessary to effectively clear the infection.28 Similarly, Mycoplasma species, including M hominis, can cause lung, abdominal, or bone infections that are remarkably hard to eradicate and Ureaplasma urealyticum infections are a rare cause of arthritis, urethritis, and pneumonia.29 Before the widespread use of IgG supplementation in these patients, opportunistic viral infections, particularly with viruses that require an extracellular phase, were especially problematic For example, echovirus encephalitis was estimated to be the cause of death in ,10% of boys with XLA in the 1970s, but that number has fallen dramatically with aggressive use of IgG supplementation There continue to be rare cases of echovirus encephalitis in patients with XLA, even in those on adequate IgG replacement therapy However, these are thought to be caused by viral strains for which there may not be high antibody titers in the particular IgG preparation being used.30,31 Similarly, a mink astrovirus strain was identified by deep sequencing from the brain of an XLA patient who developed a neurodegenerative disorder as a teen.32 Interestingly, he had lived next to a mink farm as a child but was started on immunosuppression early in his teens for inflammatory bowel disease (IBD), which may have allowed the virus to escape control Lastly, infections with vaccine-strain poliovirus were pathogenic in undiagnosed patients with XLA who were immunized with the live-viral vaccine after transplacentally acquired maternal antibody had waned The shift from live attenuated to killed poliovirus for immunization has essentially eliminated new cases Inflammatory conditions are associated with XLA Even though autoantibodies are not produced, up to 25% of patients had complaints consistent with autoinflammation, such as arthritis, hypothyroidism, or IBD Hyperimmunoglobulin M Syndromes Under normal circumstances, binding of antigen to cell surface IgM on naïve B cells induces activation of the B cell Classic laboratory findings include elevated IgM with very low serum IgG and IgA levels Specific antibody responses to vaccine antigens are decreased and patients lack switched memory B cells (CD27 IgM IgD 2) due to failed class-switch recombination The overwhelming majority of patients with hyper-IgM syndrome have the X-linked form caused by X-linked recessive mutations in CD40 ligand (CD40L/CD154), which is encoded by the CD40L gene on the X chromosome.33 CD40L and its receptor CD40 are members of the tumor necrosis factor superfamily of ligands and receptors In lymphocytes, CD40L is expressed only on activated T cells but is also expressed on platelets, where its role is unknown Neutropenia may also be found in these patients Affected boys may present with recurrent bacterial sinopulmonary infections caused by hypogammaglobulinemia B lymphocytes are 1220.e1 B-Cell Activation The antigen that is bound to surface IgM on the B cell is ingested and proteolytically digested Antigenic peptide fragments are displayed on the B-cell surface in MHC class II molecules Antigen-specific T cells then engage the B cell via MHC II/ T-cell receptor (TCR) interactions Once engaged, the activated helper T cell (Th) provides additional costimulatory signals to the B cell that are critical to promote immunoglobulin classswitching from IgM to IgG, IgA, and IgE The most important of these costimulatory signals comes via the interaction of CD40 ligand on activated T cells with CD40 on B cells Activation of the B cell through CD40 and cytokines that are secreted by the Th cause it to undergo class-switch recombination (CSR), during which the µ-heavy chain gene segment within the immunoglobulin gene is replaced by either a g, a, or e gene segment This is accomplished by nicking and double-strand breakage of the deoxyribonucleic acid (DNA) in the immunoglobulin heavy-chain locus, which requires a series of enzymatic steps that involve activation-induced cytidine deaminase (AID), uracil DNA glycosylase (UNG), and others Therefore, genetic defects that affect CD40 ligand (CD40L), CD40, AID, or UNG can prevent class-switch recombination, thus thwarting the B cells’ ability to make significant amounts of any antibody isotype besides IgM CHAPTER 103 Congenital Immunodeficiency present, and T-cell numbers are generally normal In almost all cases, the diagnosis can be made by using flow cytometry to evaluate the expression and function of the CD40L protein on activated T cells Expression is evaluated using antibodies specific to the CD40L protein, and the function is evaluated by measuring the binding of a CD40-Ig heavy chain fusion protein to the expressed CD40L Gene sequencing can then be performed in order to identify a specific mutation In addition to the usual bacterial pathogens, patients with CD40L mutations also demonstrate unique susceptibilities to fungal infections, particularly Pneumocystis jirovecii, which causes pneumonia, and to a protozoan, Cryptosporidium parvum, which causes bowel infections, discussed online at ExpertConsult.com CD40 deficiency is clinically similar to CD40L deficiency It is inherited as an autosomal recessive defect that has been described primarily in two cohorts from Italy and the Middle East It results in a syndrome that is almost identical to CD40L deficiency in which both sexes are affected.39 Autosomal recessive mutations in activation-induced cytidine deaminase (AID) and uracil DNA glycosylase (UNG) also cause a hyper-IgM phenotype, but it tends to be milder than either CD40L or CD40 deficiency, likely because the defect is limited to B cells, whereas CD40L/CD40 signaling plays a role in other cell types, including dendritic cells and monocytes.40,41 Patients with AID or UNG typically live into adulthood and not demonstrate the same susceptibility to PJ pneumonia and CP bowel infections Patients with mutations in AID do, however, have a significant propensity to develop autoimmunity affecting various organ systems Patients are typically treated with IgG replacement therapy and antibiotics for acute infections There are no reports of bone marrow transplantation for AID or UNG deficiency Common Variable Immunodeficiency Syndromes Common variable immunodeficiency (CVID) is a heterogeneous disorder that is likely caused by a variety of molecular mechanisms that ultimately lead to a similar clinical phenotype The International Consensus Document (ICON) for CVID has proposed diagnostic criteria in an effort to standardize the diagnosis of CVID These include (1) plasma IgG levels that are less than standard deviations below the mean for age combined with a marked decrease in either IgM or IgA, (2) age of onset of immunodeficiency greater than years, (3) absent isohemagglutinins or poor responses to vaccines, and (4) defined causes of hypogammaglobulinemia have been excluded The peak age of onset of CVID is in the second or third decade of life and 50% to 60% of patients have a clinical phenotype consisting almost exclusively of increased bacterial sinopulmonary infections With IgG supplementation, this group of patients has a relatively benign course with long-term survival that is not unlike the normal population The other half of patients have a complicated disease course with autoimmunity or lymphoproliferative disease that can involve the hematopoietic system, lungs, lymph nodes, liver, and bowel The long-term outcome of this population is significantly worse, approaching only 40% survival over 40 years.42 Among the disorders seen in this population, granulomatous, lymphoproliferative, interstitial lung disease (GLILD) affects approximately 30% to 40% of patients.43 This often presents with decreasing lung function that is manifested by cough, decreased exercise tolerance, and, sometimes, hypoxemia Typical findings on chest CT scan include diffuse nodules within the lung, opacities that have a ground-glass appearance, bronchial wall thickening, and, sometimes, bronchiectasis Lung biopsy generally demonstrates a 1221 lymphocytic interstitial pneumonitis with noncaseating granulomas and a follicular bronchiolitis with lymphoid aggregates of both B and T cells This pattern is sometimes mistaken for sarcoidosis, although there are differences Over time, this inflammatory process in the lungs will cause destruction of alveoli and contribute to development of bronchiectasis and emphysematous changes If left unchecked, there is evidence that irreversible damage and fibrosis develop in many patients High-dose corticosteroids are often used as first-line therapy to treat this process In many cases, they are effective but not typically lead to a lasting remission on their own A recent study using a combination of anti-CD20 monoclonal antibody (rituximab) therapy and azathioprine in a small cohort of CVID patients with GLILD demonstrated dramatic responses, with a prolonged remission of disease in many patients.44 In addition to pulmonary symptoms, gastrointestinal complaints are common in CVID, affecting 20% to 30% of patients.42 Patients who develop disease demonstrate a hypertrophic lymphoproliferation of Peyer patches that causes a nodular lymphoid hyperplasia in the bowel This is associated with abdominal discomfort, diarrhea, malabsorption, and weight loss and can cause significant morbidity A variety of approaches have been taken to treat this process, but none have offered particularly dramatic results, although nonabsorbable steroid preparations have shown some benefit with minimal side effects A more troubling complication observed in 5% to 10% of patients is hepatitis, which can cause severe hepatic dysfunction with development of hepatosplenomegaly and ascites.42 Infectious causes are almost never identified, and liver biopsy demonstrates a nodular lymphoid hyperplasia in the liver parenchyma, not unlike that observed in the bowel Liver disease is among the complications associated with a poor outcome Some 20% of subjects have additional clinical findings that are suggestive of autoimmunity/immune dysregulation, including immune thrombocytopenia and hemolytic anemia, neuropathy, endocrinopathies, and skin disease Skin involvement ranges from alopecia and vitiligo to psoriasis and granuloma annulare.45,46 In most cases of CVID, the molecular etiology of disease is unknown However, there has been some progress in identifying genetic defects associated with a CVID phenotype, which is detailed online at ExpertConsult.com B-cell numbers in peripheral blood are typically normal, but a subset of CVID patients has B-cell lymphopenia In those patients with normal B-cell numbers, B-cell maturation, memory development, and immunoglobulin class-switching are often abnormal and can be assessed by detailed flow cytometry–based immunophenotyping of B cells Varying classification schemes have been proposed to subtype patients according to their B-cell phenotype; these subsets have been correlated with differences in risk for autoimmunity and other factors.49–51 Thus, B-cell immunophenotyping has become a useful clinical tool in caring for patients with CVID In addition to the humoral immunodeficiency, many patients with CVID have impaired T-cell function with decreased CD4 or CD8 T-cell numbers as well as abnormal T-cell proliferative responses in vitro to mitogens and antigens Regulatory T-cell numbers and function have also been found to be decreased in patients with CVID.52–56 Selective Immunoglobulin A Deficiency Selective IgA deficiency (SIgAD) is common in the general population, with an incidence as high as in 300 individuals in blood bank studies The majority (.50%) of patients with selective IgA deficiency have no apparent symptoms that can be directly linked to their immune defect Severe infections as a consequence of IgA 1221.e1 Pneumocystis jirovecii and Cryptosporidium parvum Infections Among Patients With Hyperimmunoglobulin M and CD40L Mutations The susceptibility to Pneumocystis and possibly other fungal pathogens has been somewhat of a puzzle because patients not have other signs of a significant cellular immune defect, such as severe or recurrent viral infections Interestingly, the susceptibility to Pneumocystis jirovecii (PJ) pneumonia appears to go away in most patients by the age of years PJ pneumonia is almost always diagnosed by staining bronchoalveolar lavage fluid for the presence of the organism PJ pneumonia can be readily prevented by prophylactic trimethoprim-sulfamethoxazole administration; active disease is amenable to treatment using higher doses of the same drug Recent data have suggested that the fungal susceptibility in CD40L deficiency may be a result of defective CD40L signaling into dendritic cells and monocytes that express CD40.34 Cryptosporidium parvum (CP) bowel infections are more difficult to diagnose and manage in patients with CD40L deficiency CP may cause abdominal pain, bloating, diarrhea, malabsorption, and weight loss It may require multiple stool samples to identify the oocysts; occasionally, the diagnosis can be made only on endoscopically obtained biopsy specimens Treatment with paromomycin or nitazoxanide can clear the infection, although prolonged courses are typically needed in hyper-IgM patients and treatment failures are not uncommon CP infections can result in chronic inflammation of the gut and biliary tree, which seems a likely contributor to the high incidence of bile duct cancers seen in these patients.35,36 Treatment involves the use of IgG replacement therapy combined with prophylactic antibiotics for prevention of PJ pneumonia at least until the age of years The role of bone marrow transplantation for CD40L deficiency is still being evaluated Even though a number of patients have undergone successful bone marrow transplantation, its role remains somewhat controversial in this disease, although in patients with ongoing CP infection, the prognosis for the patients who develop sclerosing cholangitis is so poor that the risks of transplantation are well justified.37,38 1221.e2 Genetic Defects Associated With a Common Variable Immunodeficiency Phenotype The most common mutations identified are autosomal recessive defects in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which are found in 7% to 10% of patients with CVID Unfortunately, even in patients who have mutations that abrogate protein expression, the penetrance of disease seems to be highly variable, with individuals from one family harboring the same mutation, having either a CVID phenotype, a selective IgA deficiency phenotype, or no disease at all This inability to correlate disease phenotype or prognosis with the presence of a TACI mutation has raised the question of whether TACI genotyping offers clinical value In addition to TACI, autosomal recessive mutations in the genes encoding the Baff receptor (BAFFR), the inducible T-cell costimulator (ICOS), CD19, CD20, CD21, CD81, the LPS-responsive vesicle trafficking, beach and anchor containing protein (LRBA) and cytotoxic Tlymphocyte-associated protein (CTLA4) have been identified in some patients with features of CVID These mutations have provided insight into basic immune mechanisms in humans but explain only a handful of all patients with CVID.47,48 Lastly, hypomorphic mutations in BTK (X-linked agammaglobulinemia), CD40L (X-linked hyper-IgM syndrome), SAP/SH2D1A (X-linked lymphoproliferative syndrome), and RAG1/RAG2 can be associated with a CVID-like phenotype and, according to the diagnostic criteria for CVID, need to be excluded before making this diagnosis.47 ... recombination (CSR), during which the µ-heavy chain gene segment within the immunoglobulin gene is replaced by either a g, a, or e gene segment This is accomplished by nicking and double-strand breakage... second or third decade of life and 50% to 60% of patients have a clinical phenotype consisting almost exclusively of increased bacterial sinopulmonary infections With IgG supplementation, this group... liver, and bowel The long-term outcome of this population is significantly worse, approaching only 40% survival over 40 years.42 Among the disorders seen in this population, granulomatous, lymphoproliferative,