PAEDIATRIC RESPIRATORY REVIEWS (2004) 5(Suppl A), S225–S233

Pulmonary complications of primary immunodeficiencies

Rebecca H. Buckley°

Departments of Pediatrics and , Duke University Medical Center, Durham, NC 27710, USA

Summary In the fifty years since Ogden Bruton discovered agammaglobulinemia, more than 100 additional immunodeficiency syndromes have been described. These disorders may involve one or more components of the immune system, including T, B, and NK ; phagocytic cells; and complement proteins. Most are recessive traits, some of which are caused by mutations in genes on the X chromosome, others in genes on autosomal chromosomes. Until the past decade, there was little insight into the fundamental problems underlying a majority of these conditions. Many of the primary immunodeficiency diseases have now been mapped to specific chromosomal locations, and the fundamental biologic errors have been identified in more than 3 dozen. Within the past decade the molecular bases of 7 X-linked immunodeficiency disorders have been reported: X-linked immunodeficiency with Hyper IgM, X-linked lymphoproliferative disease, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency, the Wiskott–Aldrich syndrome, nuclear factor úB essential modulator (NEMO or IKKg), and the immune dysregulation polyendocrinopathy (IPEX) syndrome. The abnormal genes in X-linked chronic granulomatous disease (CGD) and deficiency had been identified several years earlier. In addition, there are now many autosomal recessive immunodeficiencies for which the molecular bases have been discovered. These new advances will be reviewed, with particular emphasis on the pulmonary complications of some of these diseases. In some cases there are unique features of lung abnormalities in specific defects. Infections obviously account for most of these complications, but the host reaction to infection often leads to characteristic findings that can be helpful diagnostically. Finally, advances in treatment of the underlying diseases as well as their infectious complications will be covered. © 2004 Elsevier Science Ltd.

HUMORAL such as Haemophilus influenzae, Streptococcus DISORDERS pneumoniae, and Staphylococci. Recurrent pneu- monia, otitis media, sinusitis, and septicemia are Humoral immunodeficiencies, i.e. those character- the most common clinical manifestations. Most ized by defective production, are the patients with defects involving predominantly hu- most common, accounting for about 70% of all moral immunity have the ability to recover from primary immunodeficiencies.1,2 Clinically, affected viral infections because of their normal T-cell individuals are susceptible to infections with pyo- responses. genic agents, particularly the encapsulated ,

* Correspondence to: Rebecca H. Buckley, M.D. X-linked agammaglobulinemia Tel.: +1-(919)-684-2922; Fax: +1-(919)-681-7979; E-mail: [email protected] X-linked agammaglobulinemia (XLA) was the first Correspondence address: Box 2898 or 363 Jones Building, primary immunodeficiency disorder to be recognized Duke University Medical Center, Durham, NC 27710, USA and was reported by Ogden Bruton in 1952.3 The

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Table 1 Locations of faulty genes in primary immunodeficiency diseases

Chromosome Disease

1q21 MCH class II antigen deficiency caused by RFX5 mutation* 1q25 Chronic granulomatous disease (CGD) caused by gp67phox deficiency* 1q42−43 Chediak–Higashi syndrome* 2p11 Kappa-chain deficiency* 2q12 CD8 caused by ZAP70 deficiency* 5p13 SCID due to IL-7 receptor alpha chain deficiency* 6p21.3 MHC class I antigen defect caused by mutations in TAP1 or TAP2* 6p21.3 (?) Common variable immunodeficiency and selective IgA deficiency 6q22−23 Interferon-g R1 mutations* 7q11.23 CGD caused by p47phox deficiency* 8q21 Nijmegen breakage syndrome due to mutations in Nibrin* 9p13 Cartilage hair hypoplasia due to mutations in endoribonuclease RMRP* 10p13 SCID (Athabascan, radiation sensitive) due to mutations in the Artemis gene* 10p13 DiGeorge’s syndrome/velocardiofacial syndrome 11p13 IL-7 receptor alpha chain deficiency* 11p13 SCID caused by RAG-1 or RAG-2 deficiencies* 11q22.3 Ataxia telangiectasia (AT), attributable to AT mutation, causing deficiency of DNA-dependent kinase* 11q23 CD3 gamma- or epsilon-chain deficiency* 12p13 Autosomal recessive Hyper-IgM caused by mutations in the activation-induced cytidine deaminase (AID) gene* 13q MHC class II antigen deficiency caused by RFXAP mutation* 14q13.1 Purine nucleoside phosphorylase (PNP) deficiency* 14q32.3 Immunoglobulin heavy-chain deletion* 16p13 MHC class II antigen deficiency caused by CIITA mutation* 16q24 CGD caused by gp22phox deficiency* 17 Human nude defect* l9p13.1 SCID caused by Janus kinase 3 (Jak3) deficiency* 19p13.2 Agammaglobulinemia caused by mutations in Iga gene* 20q13.11 SCID caused by adenosine deaminase (ADA) deficiency* 21q22.3 Leukocyte adhesion deficiency, type 1 (LAD 1), caused by CD18 deficiency* 22q11.2 Agammaglobulinemia caused by mutations in l5 surrugate light chain gene* 22q11.2 DiGeorge syndrome Xp21.1 CGD caused by gp91phox deficiency* Xp11.23 Wiskott–Aldrich syndrome (WAS) caused by WAS protein (WASP) deficiency* Xp11.3−21.1 Properdin deficiency*

Xq13.1 X-linked SCID caused by common gamma-chain (gc) deficiency* Xq22 X-linked agammaglobulinemia caused by Bruton tyrosine kinase (Btk) deficiency* Xq24−26 X-linked lymphoproliferative syndrome caused by mutations in the SH2D1A gene* Xq26 Immunodeficiency with hyper-IgM caused by CD154 (CD40 ligand) deficiency* Xq28 Anhidrotic ectodermal dysplasia with immunodeficiency caused by mutations in the nuclear factor kappa B essential modulator (NEMO)*

° Gene cloned and sequenced; gene product known. PULMONARY COMPLICATIONS OF PRIMARY S227 incidence is unknown, but XLA is thought to be less frequently than Asians or African Americans.9 Both common than IgA deficiency or common variable genetic and environmental factors contribute to the immunodeficiency (CVID).4 Serum immunoglobulins pathogenesis of this disorder. Some children with and of all isotypes are almost completely IgA deficiency may be clinically healthy,2 while others lacking. Those affected have less than 1% circulating are susceptible to respiratory and gastrointestinal B cells. They also lack germinal centers in infections, allergy, autoimmune diseases, and malig- their lymphoid tissue, accounting for their small nancy. Pulmonary complications are predominantly and lymph nodes. There is a block in due to bacterial pneumonias. However, since most differentiation at all stages of B-cell development. can make IgG antibodies, bronchiectasis is not as The responsible mutated gene has been identified common as in XLA. Treatment of this disorder is on the X chromosome and it encodes Bruton’s usually with antibiotics for specific infections. tyrosine kinase, a key regulator of B-cell maturation (Table 1).5,6 T-cell numbers and functions are Common Variable Immunodeficiency normal, as is thymic size and architecture. During the first 6−9 months of life, patients with Common variable immunodeficiency (CVID) is a syndrome encompassing probably several different XLA are protected from infections by maternally 10 derived IgG antibodies. As this source of antibodies genetic disorders. It is characterized by impaired diminishes, patients begin to develop pyogenic antibody production of all major classes. CVID has an estimated incidence of up to 1:10,000.1,13 The bacterial infections, with recurrent sinopulmonary diagnosis is usually made by the finding of low to infections being most common. As a consequence absent serum immunoglobulins but normal numbers bronchiectasis frequently develops before the un- of circulating B cells. Upon antigen stimulation, derlying condition is diagnosed. While most children these B cells do respond and proliferate, but fail develop recurrent bacterial infections during infancy, to differentiate into antibody-secreting plasma cells. 20% of presentations occur from about 3−5 years T-cell-mediated immunity is often intact; however, of age, probably due to the widespread use of T-cell abnormalities have also been noted in up to antibiotics.1 Unfortunately, this often masks the 60% of individuals.1,13 Both males and females are diagnosis until after structural damage to the lungs affected equally, and the pattern of inheritance in has already occurred. Less common complications many cases appears to be autosomal dominant include chronic conjunctivitis, giardiasis, malabsorp- with incomplete penetrance. In contrast to XLA tion, and persistent CNS enteroviral infections with where onset is always in early childhood, onset of resultant chronic meningoencephalitis.7 symptoms may occur in early or late childhood or The standard treatment for XLA is intravenous adulthood. immunoglobulin (IVIG) replacement therapy. Despite Clinically, CVID and XLA share a number of com- apparently adequate treatment with IVIG, however, mon features such as increased susceptibilities to many patients still develop pansinusitis or post- recurrent pyogenic sinopulmonary infection leading infectious chronic lung diseases, most commonly to frequent development of bronchiectasis, gastroin- bronchiectasis. Rotating antibiotics in treatment testinal involvement, and (less often than in XLA) fa- doses are then needed in addition to monthly IVIG tal enteroviral meningoencephalitis.15 Unlike in XLA, infusions. tonsillar tissue is normal in amount in CVID, and Chest radiographs may demonstrate findings 15−25% of individuals develop of pulmonary infection, including atelectasis and or . Lymphoid interstitial pneumonia bronchial wall thickening or bronchiectasis. Bronchi- and nodular follicular lymphoid hyperplasia of the ectasis is most commonly found in the middle gastrointestinal tract are frequently observed as a or lower lobes; upper-lobe distribution is very 16 8 part of a generalized lymphoproliferative process. uncommon. Splenomegaly is not seen and tonsils, CVID is also associated with an increased cancer adenoids and cervical lymph nodes are typically risk, predominantly with lymphoreticular tumors.17 extremely small. Infectious involvement of the Approximately 20% of individuals with CVID will central nervous system may demonstrate diffuse develop autoimmune diseases.10 Treatment for leptomeningeal thickening and enhancement or patients with this group of disorders consists of IVIG encephalitis with MR imaging. replacement and rotating antibiotics if bronchiectasis or pansinusitis is present. IgA deficiency Other humoral deficiencies This is the most common primary immunodeficiency disorder, with an estimated incidence of from 1:333– Other defects characterized by antibody defi- 1:700 in Caucasians, who are affected much more ciency include both X−linked and non-X-linked S228 R.H. BUCKLEY

hyper-IgM (both characterized by recurrent bacterial with cellular immunodeficiencies, are susceptible to infections).12,18 X-linked lymphoproliferative disease infections with opportunistic organisms (i.e., (an inadequate response to Epstein–Barr viral and Pneumocystis carinii), and to graft-versus- infection) results in either death from acute infectious host disease (GVHD) from non-irradiated blood mononucleosis, malignancy or severe antibody or blood-product transfusions. Viral pneumonias or deficiency.11 These conditions have the same PCP pneumonia are the most common pulmonary pulmonary complications as seen in XLA and CVID. complications. Chest radiographs may reveal narrow upper mediastinal contour and retrosternal lucency due to absence of the . Cardiovascular CELLULAR AND COMBINED anomalies such as right-side aortic arch, interrupted IMMUNODEFICIENCY DISORDERS aortic arch, truncus arteriosus, tetralogy of Fallot, Patients with inadequate cellular immunity are atrial or ventricular septal defects are frequently 19 highly susceptible to opportunistic infections with present. viruses, such as the herpes viruses (herpes Immunologic treatment is usually unnecessary in simplex, varicella zoster, and cytomegalovirus). the partial form. However, the cardiac defects may They often have progressive pneumonia caused by need early correction. Thymic epithelial transplants parainfluenza 3 , respiratory syncytial virus, or unfractionated HLA-identical sibling bone-marrow cytomegalovirus, varicella, or Pneumocystis carinii. transplantation are recommended only for those with T-cell immunodeficiencies are also accompanied by the complete DiGeorge syndrome.20 abnormalities in antibody production, because B-cell function is T-cell dependent. Hence, patients with Severe combined immunodeficiency these defects may also have infections with high- grade pathogens, similar to those with primarily Severe combined immunodeficiency (SCID) is a antibody deficiencies. syndrome characterized by the absence of T- and B-cell (and sometimes ) function.21 Recently, several molecular defects responsible for DiGeorge syndrome SCID have been identified. X-linked SCID accounts DiGeorge syndrome () is a typical for 46% of all cases and is caused by defects example of a primary T-cell deficiency.1 DiGeorge in the chain (gc) common to the IL-2, IL-4, IL-7, syndrome is most often due to gene defects IL-9, IL-15 and IL-21 receptors.22−26 Mutations in on chromosome 22, which lead to abnormal the genes encoding adenosine deaminase,27 Janus development of the third and fourth pharyngeal kinase 3 (Jak3),28 the a chain of the IL-7 receptor,29 pouches during early embryogenesis.19 As a result, recombinase activating genes 1 or 2,30 CD4531 the organs that develop from these structures, most or the Artemis gene32 also result in SCID and importantly the thymus, parathyroid glands, and are inherited in an autosomal recessive pattern the heart, can be affected. Impaired functions of (Table 1). Regardless of the molecular cause, SCID these organs account for a unique constellation patients with this syndrome are similar in many of of clinical presentations including variably severe their clinical and histopathological features. T-cell deficiencies secondary to hypoplasia (most Affected children frequently start to develop severe common) or aplasia of the thymus, neonatal infections with opportunistic organisms soon after hypocalcemic tetany due to hypoparathyroidism, and the neonatal period. Typical presenting features congenital cardiovascular anomalies, especially of include failure to thrive, chronic diarrhea, persistent the great vessels and septa. Another distinctive oral thrush, severe diaper rash or other skin rashes, abnormality associated with this syndrome is facial pneumonia, and sepsis. Due to lack of graft- dysmorphology, which presents as micrognathia, rejection capability, these infants are also at risk low-set ears, shortened philtrum of the upper lip, for severe GVHD from transfusion of non-irradiated and hypertelorism.19 B cells are present in normal blood products. Immunization with live attenuated numbers. Nevertheless, antibody responses may still viruses, such as poliovirus, bacille Calmette–Guerin be affected due to an inadequate number of T cells, (BCG), measles or varicella vaccines must be which is highly variable depending on the degree avoided due to risk of severe or systemic infection of thymic hypoplasia. In up to 80% of patients, which can be fatal. Pulmonary manifestations of the immunodeficiency is mild (partial DiGeorge SCID include recurrent severe pneumonias due to syndrome). However, those with more severe forms Pneumocystis carinii, Parainfluenza 3, respiratory of this disease (complete DiGeorge syndrome) may syncytial virus, adenovirus, cytomegalovirus, or resemble children with severe combined immunode- bacterial organisms. The pneumonias may be ficiency. These children, as is the case for all children due to multiple organisms. Pneumocystis typically PULMONARY COMPLICATIONS OF PRIMARY IMMUNODEFICIENCIES S229

produces interstitial infiltrates, which progress to that is expressed in lymphocytes, megakaryocytes, alveolar infiltrates. However, viral pneumonitis can , and thymus.37 The function of this protein, be indistinguishable from Pneumocystis pneumonia. however, is still unclear, but it is thought to have a An important feature to recognize in children with major role in actin polymerization.38 Immunologically, SCID, as opposed to immunocompetent children or serum IgA and IgE levels are elevated, the IgM level children with other immunodeficiencies with an acute is decreased, and the IgG level remains normal or pulmonary infection, is that the thymic shadow is slightly decreased. However, despite the presence of absent. normal or elevated levels of immunoglobulins, includ- ADA-deficient SCID is noteworthy from a radio- ing IgG subclasses, there are consistently impaired logic standpoint due to skeletal abnormalities and antibody responses to polysaccharide antigens and because infants and children with this disorder a moderately impaired response to protein antigens. usually have more profound lymphopenia than Therefore, such patients are particularly susceptible other infants with SCIDs.27 Skeletal abnormalities, to infection with polysaccharide-encapsulated organ- while not present in all cases, are unique to isms (e.g., pneumococcus, Haemophilus influenzae, this form of SCID and are usually limited to meningococcus). T-cell function is also impaired, the axial skeleton. These abnormalities include resulting in a partial combined immunodeficiency. cupping and flaring at the costochondral junctions Clinically, affected infants often first present with anteriorly, metaphyseal cupping, and irregularity at prolonged bleeding from the circumcision site, the costovertebral junction with increased separation bruising, or bloody diarrhea during infancy. Pyogenic between the rib head and vertebral body. In addition, infections usually start before 1 year of age and a “bone-in-bone” appearance of the vertebral bodies, may include meningitis, otitis media, pneumonia, and squaring of the scapula tip have also been and sepsis. Pulmonary infections with agents such reported.33 as pneumococci, Pneumocystis carinii and herpes SCID is fatal without immune reconstitution. viruses are common. Imaging findings include recur- Current therapy is most commonly bone-marrow rent pneumonia, sinusitis and mastoiditis. Patients transplantation, which has been highly successful.25 rarely survive beyond teenage years without bone- The first successful gene therapy for X-linked SCID marrow transplantation. Death usually results from was reported from France and was successful in 9 massive bleeding, infection, vasculitis, autoimmune such patients.34 However, 2 of the 9 developed a cytopenias or lymphoreticular malignancy. -like complication and gene therapy trials Therapy includes monthly IVIG infusions to are currently on hold. compensate for the antibody deficiency and trans- fusions of fresh irradiated platelets for acute bleeding episodes. transplantation has Purine nucleoside phosphorylase deficiency completely corrected both the hematological and Purine nucleoside phosphorylase (PNP) is an immunologic abnormalities in many patients.39 If enzyme deficiency affecting function no HLA-identical donor is available, splenectomy somewhat similar to the mechanism in ADA may improve platelet count and reduce bleeding deficiency.35 Clinically, immunodeficiency associated complications.40 with PNP deficiency varies in age of onset of symptoms. The infections are similar to those Ataxia telangiectasia experienced by patients with SCID. Milder forms may present later with diverse neurologic findings such as Ataxia telangiectasia (AT) is an autosomal recessive developmental delay, hypotonia, and spasticity. How- disorder characterized by progressive cerebellar ever, PNP deficiency is uniformly fatal in childhood ataxia (evident as the child begins to walk), unless corrected by bone-marrow transplantation.36 oculocutaneous telangiectasia (evident beginning Unlike ADA deficiency, this disorder is not associated at 3−6 years of age), recurrent bronchopulmonary with skeletal anomalies. infections (in approximately 80% of individuals), and a high incidence of malignancy. The mutated gene (ATM) responsible for this defect is on the Wiskott–Aldrich syndrome long arm of chromosome 11 (11 q22−23) and was Wiskott–Aldrich syndrome is an X-linked recessive cloned.41 The gene product is a DNA-dependent immunodeficiency disorder characterized by a triad protein kinase localized predominantly to the nucleus of eczema, thrombocytopenia with small defective and believed to be involved in mitogenic signal platelets, and recurrent infections.1,2 The responsible transduction, meiotic recombination, and cell cycle gene on the X chromosome encodes a protein called control.42−44 Defects in the AT gene compromise the Wiskott–Aldrich syndrome protein (or WASP) DNA repair mechanisms thus rendering the affected S230 R.H. BUCKLEY

cells highly susceptible to radiation-induced chro- on long-term anti-staphylococcal antibiotic prophy- mosomal damage. Immunologic features include laxis. selective IgA deficiency, and moderately severe T-cell dysfunction. The degree of immunodeficiency is highly variable. The DISORDERS OF PHAGOCYTIC CELLS thymus is markedly hypoplastic. AND ADHESION MOLECULES Pulmonary complications include recurrent sino- Phagocytic cells are of great importance in host pulmonary infections with bronchiectasis and fibro- defence against pyogenic bacteria and fungi as sis. Because of the increased risk of cancer well as other intracellular microorganisms. Defects from radiation exposure, imaging studies utilizing in phagocyte production and/or function predispose ionizing radiation should be performed sparingly. affected patients to recurrent pyogenic and fungal Children that survive the first decade are at high infections. Common organisms include bacteria such risk for both solid (i.e., adenocarcinoma) and as Pseudomonas, Serratia marcescans, Staphylo- lymphoproliferative malignancies. Patients usually coccus aureus, and fungi such as Aspergillus and die from chronic pulmonary disease, neurologic Candida. Phagocytic disorders are not associated deterioration, or malignancy by early adulthood. Both with increased susceptibility to viral or protozoal in- AT and Wiskott–Aldrich syndrome have the highest fections, nor is there an increased risk of malignancy. malignancy rates of all of the primary immunodefi- Disorders include chronic granulomatous disease, ciencies. Treatment is limited to antibiotics, IVIG if leukocyte adhesion deficiency, and Chediak–Higashi hypogammaglobulinemic and other supportive care. syndrome. No cure is available. Bone-marrow transplantation has not been successful and would likely not correct the neurologic defect. Chronic granulomatous disease Chronic granulomatous disease (CGD) is the most The hyper-IgE syndrome common phagocytic disorder, affecting roughly 1 in 125,000 live births.50 This disorder is inherited in The hyperimmunoglobulinemia E (hyper-IgE) syn- an X-linked fashion in two-thirds of cases, but drome is a condition characterized by staphylococcal three forms of autosomal recessive CGD exist as abscesses of the skin, lungs, viscera or other sites well. beginning in infancy in association with markedly Diagnosis of this disorder is established with elevated serum IgE concentrations.45,46 The mode a respiratory burst assay. CGD is actually a of inheritance appears to be autosomal dominant collection of four different molecular defects that with variable penetrance.46,47 No gender or racial result in defective NADPH oxidase activity in discrepancy in incidence has been noted. The leukocytes.51 NADPH oxidase catalyses a reaction most common infectious agent is staphylococci. producing important bactericidal products following Eczema, mucocutaneous candidiasis, and coarse phagocytosis: superoxide radical, singlet oxygen and facial features are frequently associated with this hydrogen peroxide. Catalase-negative organisms syndrome.45,46 Delayed eruption of teeth, scoliosis such as streptococci and pneumococci provide and osteopenia leading to fractures are also unique oxidative products and can be killed. However, features of this .46,47 catalase-positive bacteria such as Staphylococcus Pulmonary complications include recurrent staphy- aureus and Serratia marcescens, and some fungi lococcal pneumonias with subsequent and usually such as Aspergillus destroy the very oxygen radicals persistent pneumatocoele formation.45,46 The pres- they produce. Prolonged intracellular existence of ence of persistent single or multiple pneumatocoeles these catalase-positive microorganisms in CGD is the most striking radiographic feature of this triggers a cell-mediated response, resulting in syndrome. These lung cysts may persist, expand, granuloma formation. and become superinfected with bacteria and fungi, The onset of symptoms usually occurs before and may require surgical excision. Osteoporosis 1 year of age. In a recent review of the US CGD involving predominantly the spine and, to a lesser registry, pulmonary infection was the most frequent degree, the limbs in the epiphyseal-metaphyseal occurrence (79%), and fungal organisms accounted regions may also occur with resultant recurrent for the majority. Other features included suppurative fractures.49 (53%), subcutaneous abscess (42%), The mechanism of this osteoporosis is not liver abscess (27%), osteomyelitis (25%), and known. The underlying molecular defect is unknown. sepsis (18%). Gastric outlet obstruction, urinary Treatment is usually supportive, with an emphasis tract obstruction, and enteritis or colitis occur in PULMONARY COMPLICATIONS OF PRIMARY IMMUNODEFICIENCIES S231

10−17% of individuals. Trimethoprim sulfamethoxa- often mimic those of the antibody deficiency zole prophylaxis and recombinant human interferon disorders. On the other hand, some patients with gamma, in addition to chronic antifungal therapy, are deficiencies in C2, C4, or C9, can remain completely standards of care for this disorder.51 asymptomatic. Treatment usually involves prophy- Chest radiographs or CT may demonstrate lactic antibiotics and specific vaccination against chronic or recurrent pneumonia, pleural reaction, os- encapsulated organisms. Complement replacement teomyelitis from chest wall invasion (e.g., aspergillus, therapy is not effective in treating these disorders. candida), hilar or mediastinal adenopathy, and esophagitis or esophageal stricture. Radionuclide imaging is indicated when clinical signs of infection CONCLUSIONS are present without a source. The sedimentation rate Primary immunodeficiency diseases include a broad is a useful clinical barometer, since this is elevated spectrum of disorders with enormously diverse with acute, occult or persistent infection. intrinsic defects involving one or multiple compo- nents of the immune system. Immunodeficiency is Leukocyte adhesion deficiency characterized clinically by an increased susceptibility to infection, malignancy, and autoimmunity. The Leukocyte adhesion deficiency type 1 (LAD 1) is pulmonologist can play an important role in the attributable to mutations in the gene on chromo- child with a primary immunodeficiency. 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