Which of the following is a factor that increases a hosts susceptibility in the chain of infection?

Practice Essentials

An immunocompromised host is a patient who does not have the ability to respond normally to an infection because of an impaired or weakened immune system. This inability to fight infection can be caused by a number of conditions, including diseases (eg, diabetes, human immunodeficiency virus [HIV] infection), malnutrition, and drugs. [1]

Immunocompromising conditions

Congenital conditions

Congenital conditions most commonly affect the fetus and newborn. Classes of congenital conditions include the following:

• Genetic syndromes

• Macrophage, cytokine, and miscellaneous defects

• Phagocyte deficiency or dysfunction

Acquired conditions

These conditions may interfere directly with the immune system or may disrupt barrier function. Types of acquired conditions include the following:

• Trauma

• Medical conditions

Infectious complications

Immunocompromised patients are susceptible to bacterial, fungal, viral, and parasitic infections that healthy immune systems usually overcome. They are also more susceptible to complications from common infections.

B-cell defects predispose patients to frequent sinopulmonary and respiratory tract infections and infections with nonenveloped viruses, parvovirus B19, and rotavirus.

Almost any organism can cause infection in patients with combined B-cell and T-cell defects. These patients often present with failure to thrive, thrush, and Pneumocystis jirovecii infection. Other commonly seen pathogens include Streptococcus pneumoniae, Pseudomonas aeruginosa, Legionella pneumophila, Listeria monocytogenes, Nocardia species, Mycobacterium species, fungi, varicella-zoster virus (VZV), herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), viruses that cause respiratory tract infections, Toxoplasma species, cryptosporidia, Strongyloides species, and other encapsulated bacteria.

T-cell defects predispose to infections with Candida species, Mycobacterium avium-intracellulare complex, herpesviruses, and P jirovecii.

Phagocyte deficiency or dysfunction predisposes patients to infections with Staphylococcus aureus, Nocardia species, P aeruginosa, Serratia species, streptococci, other enteric organisms, and Candida, Burkholderia, Aspergillus, and Chromobacterium species.

Complement deficiency is associated with recurrent sinopulmonary infections and invasive infections due to encapsulated bacteria such as S pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.

Infectious diarrhea, pneumonia, tuberculosis, measles, malaria, salmonellosis, P jirovecii infection, and HIV infection are common causes of death among malnourished infants and children. In immunosuppression due to HIV infection, a myriad of opportunistic infections may occur, particularly as immune function deteriorates in the absence of antiretroviral treatment.

IDSA guidelines recommend vaccination for immunocompromised patients

According to guidelines from the Infectious Diseases Society of America (IDSA), most immunocompromised patients should be vaccinated. These guidelines are designed for health care professionals who care for patients with compromised immune systems due to HIV infection or acquired immunodeficiency syndrome (AIDS), cancer, solid organ transplantation, stem cell transplantation, sickle cell disease or asplenia, congenital immune deficiencies, chronic inflammatory conditions, cochlear implants, or cerebrospinal fluid leaks. [2, 3]

Specific recommendations include the following:

• When possible, vaccines should be administered before planned immunosuppression.

• Live vaccines should be administered at least 4 weeks before immunosuppression and should be avoided within 2 weeks of beginning immunosuppression.

• Inactivated vaccines should be administered at least 2 weeks before immunosuppression is initiated.

• Most immunocompromised patients 6 months of age or older should receive annual influenza vaccination as an injection; these patients should not receive live attenuated influenza vaccine administered as a nasal spray.

• Influenza vaccine is unlikely to be of benefit in individuals who are receiving intensive chemotherapy or who have received anti–B-cell antibodies in the preceding 6 months.

• Immunocompetent persons who live with immunocompromised patients can safely receive inactivated vaccines.

• Individuals who live with immunocompromised patients 6 months of age or older should receive annual influenza vaccination.

Overview

Much of the practice of pediatric infectious diseases now focuses on the treatment of the fetus, neonate, infant, child, and adolescent who have infections in the context of immunocompromise. [4] Because of the vast scope of this topic, the interested reader is referred to appropriate reviews for exhaustive treatment of specific immunologic and immune-compromising disorders and infections. [5, 6] Further information is also available in textbooks of pediatric infectious diseases (some of which are devoted exclusively to this topic) as cited in the bibliography.

This review focuses on evaluation of the child with frequent infections (who likely has no immunocompromise), conditions leading to immunocompromise (congenital, acquired, and iatrogenic in broad terms), and the particular infections associated with these conditions.

Most children who have a series of frequent, benign, self-limited, mostly viral infections are examined in the office in the context of parental or familial concern for an underlying immune problem or perception that the child is sickly. The patient often seems to get sick more often than siblings and peers. Nevertheless, most children with frequent infections are immunologically healthy.

Careful questioning and evaluation frequently reveal previous events or problems that predispose the patient to such concerns (eg, the vulnerable child syndrome). Thorough history taking and physical examination, with a review of laboratory and radiographic results (which generally accompany the patient), almost always help in excluding clinically significant immunologic disorders. In rare cases, Munchausen syndrome or Munchausen syndrome by proxy manifests as frequent or obscure infections (or suspicion of such infections). Secondary or acquired immunodeficiency is more common than primary immunodeficiency.

Children who require hospitalization for management of a common infection should raise suspicion of an immunocompromising condition.

The Child with Frequent Infections

History

For the outpatient with frequent infections, a thorough history should be obtained. In particular, the following should be identified [1] :

• More than 10 episodes of acute otitis media in a year

• More than 2 episodes of consolidated pneumonia in a year

• More than 2 life-threatening infections

• Infections with unusual pathogens

• Unusual response to usual pathogens

• Recurrent autoimmune phenomena

• Exacerbation of chronic disorders by infections

• Infections with vaccine pathogens despite adequate vaccination

• Family history of recurrent infections or immunodeficiency

• Chronic eczema, diarrhea, or thrush

• Developmental delay

• Growth problems

A complete history should be obtained for all patients, with attention to the following:

• Travel history

• Dietary and medication history (including nonprescription medications and supplements)

• Animal, insect, and tick exposure

• Other exposures or risk factors

Physical examination

A thorough physical examination should be performed for the outpatient with frequent infections, with particular attention to the following:

• Growth chart

• Developmental milestones

• Evaluation for dysmorphology

• Evidence of normal physiology and functioning between episodes of fever

Thorough physical examination often provides clues to the presence and etiology of infectious complications of immunocompromise.

Immunocompromising Conditions

Congenital conditions

Congenital conditions most commonly affect the fetus and newborn.

Syndromes

• Immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome

• Kabuki syndrome

• Partial albinism, immunodeficiency, and progressive white matter disease (PAID) syndrome

• Autoimmune polyendocrinopathy syndrome type 1

• CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome [10]

• Other dysmorphology or immunodeficiency syndromes

• Stromal interaction molecule 1 (STIM1) mutation [11]

B-cell defects [12]

• Antibody deficiency with transcobalamin II deficiency

• Antibody deficiency with normal or high immunoglobulin (Ig) levels

• GATA2 deficiency [13]

• IgG heavy-chain deletion

• IgG subclass deficiency

• Kappa-chain deficiency

• Organic cation transporter 2 deficiency [14]

• Selective IgA deficiency

• Selective IgM deficiency

• Selective antipolysaccharide antibody deficiency

• Thymoma with agammaglobulinemia

• X-linked hypogammaglobulinemia with growth hormone deficiency [15]

Combined B-cell and T-cell defects

• Adenosine deaminase deficiency

• Artemis deficiency

• Bare lymphocyte syndrome (major histocompatability complex class I/II deficiency)

• Caspase-8 mutations [16]

• DOCK8 mutations [17]

• Interleukin (IL)-2R alpha or gamma deficiency

• Intestinal lymphangiectasia

• Janus kinase 3 (JAK3) deficiency [18]

• Nuclear factor-kappaB essential modifier (NEMO) deficiency [19]

• Nijmegen breakage syndrome [21]

• Purine nucleoside phosphorylase deficiency

• Recombination activation gene (RAG) 1 or 2 deficiency

• Reticular dysgenesis

• Swiss-type severe combined immunodeficiency

• X-linked lymphoproliferative syndrome

• X-linked severe combined immunodeficiency

• Zeta-associated protein of 70 kDa (ZAP-70) tyrosine kinase deficiency

T-cell defects

• Biotin-dependent multiple carboxylase deficiency

• Chronic mucocutaneous candidiasis

• Fas defect

• Nezelof syndrome

• Short-limbed dwarfism or cartilage-hair hypoplasia

• T-cell receptor deficiency

Macrophage, cytokine, and miscellaneous defects

• Mendelian susceptibility to mycobacterial diseases (MSMD)

  • Interferon-gamma deficiency [23]

  • Interferon-gamma receptor I or II deficiency [24]

  • IL-12 deficiency

  • IL-12 receptor deficiency

  • Signal transducer and activator of transcription (STAT) 1 (STAT1) mutations [18, 25]

  • NEMO deficiency [19]

  • CYBB deficiency

  • Interferon regulatory factor 8 mutations [26]

• IL-1 receptor–associated kinase 4 (IRAK4) deficiency [27]

• MYD88 deficiency [27]

• Toll-like receptor 5 mutations

• Apolipoprotein L-I deficiency

• UNC-93B deficiency

• Toll-like receptor 3 mutations [28]

• TRIF and TRAF3 mutations

• Plasminogen activator inhibitor-1 4G/4G promoter genotype [29]

• Anti–interferon-gamma antibodies

• IL-18 polymorphisms

• RANTES promoter gene polymorphisms [30]

• Deficiency of chemokine receptor CCR5 [31, 32]

• Toll-like receptor 4 mutations

• IL-8 RA (chemokine CXC motif receptor 1 [CXCR1]) mutations

• CXCR4 mutations (WHIM [warts, hypogammaglobulinemia, immunodeficiency, myelokathexis] syndrome) [33]

• STAT5 mutations [18, 34]

• NOD2 gene polymorphisms

• IL-6 polymorphisms [35]

• Activating killer immunoglobulinlike receptor gene polymorphisms

• Dectin-1 deficiency [36]

• CARD9 mutations [36]

• Polymorphisms in cytokine-inducible SRC homology 2 domain protein (CISH)

• Polymorphisms in Mal/TIRAP and IL-10

• Autoantibodies against IL-6 [37]

• Polymorphisms in the IL-8 promoter gene [38]

• IL-12 receptor deficiency [39]

• Macrophage migration inhibitory factor deficiency

• IL-17 defects [40, 41]

• Toll-like receptor 9 polymorphisms [42]

Phagocyte deficiency or dysfunction

• Chronic idiopathic neutropenia

• Cyclic neutropenia

• Hyper-IgE/recurrent infection (Job) syndrome (Janus kinase protein tyrosine kinase 2 [Tyk2], STAT3, and STAT1 mutations) [18, 25, 43, 44]

• Neutrophil actin dysfunction

• Papillon-Lefèvre syndrome

• Specific granule deficiency

Complement deficiencies [45]

• Mannose-binding lectin (Mannan-binding protein) deficiency [46, 47]

• Deficiencies of C1q, C1r, C1rs, C4, C2, C3, or C5-9

• Deficiencies of factor D, factor P, factor I, factor H, or properdin

• Ficolin-3 (H-ficolin) deficiency [48]

Other conditions

• Lymphedema (congenital)

• Trisomy 21 and other genetic disorders

• Other anatomic defects (eg, midline dermal sinus, Mondini defect of the inner ear, fistulas, cysts, duplications, meningeal defects, iron overload, decreased sensation)

Acquired conditions

Acquired conditions may interfere directly with the immune system or may disrupt barrier function.

• HIV infection: Although human immunodeficiency virus (HIV) infection is a considerable cause of immunodeficiency worldwide, immunocompromise is most likely to result from other common chronic problems such as asthma, diabetes, malnutrition, and cancer. Adequate viral control in persons living with HIV lowers the risk of acquiring opportunistic infections.

• Trauma

  • Burns

  • Lacerations and abrasions

• Medical conditions

  • Collagen vascular disorders

  • Gastrointestinal (GI) tract disorders

  • Hematologic or oncologic conditions

  • Hepatic disorders

  • Metabolic disorders

  • Pregnancy

  • Pulmonary disorders, particularly atopy, asthma, [50]  and cystic fibrosis (CF)

  • Renal disorders

  • Skin and mucous membrane conditions

  • Viral infections (eg, cytomegalovirus [CMV] infection, [51]  measles)

  • Other anatomic or physiologic problems (eg, fistulas, cysts, obstructions, iron overload, decreased sensation)

• Acquired asplenia [45]

• Acquired lymphedema

• Other conditions that injure or bypass barrier function

  • Parasitic infections

  • Animal and insect bites or scratches

Iatrogenic or self-inflicted conditions

Iatrogenic or self-inflicted conditions may directly interfere with the immune system or may disrupt barrier function.

Use of certain drugs or therapies (eg, radiation therapy) may interfere with normal flora, decrease gastric acidity and ciliary motility, and also may be directly immunomodulating. [52]

Trauma

• Injections (eg, insulin injections, intravenous [IV] drug use, others)

• Operative and other incisions

• Vascular, osseous, tracheal, gastric, bladder, joint, peritoneal, wound, or ventricular access or drainage devices

• Internal foreign bodies

• Major surgery [53]

Treatment

• Therapies for leukemia or lymphoma

• Bone marrow or stem-cell transplantation

• Solid organ transplantation [54]

• Therapy for autoimmune or inflammatory disorders

• Tumor necrosis factor (TNF)-alpha inhibitors [55]

• Monoclonal antibodies and related small molecules

• Transfusion (which may lead to iron overload)

Alternate Diagnoses

Table. Differential Diagnoses (Open Table in a new window)

Infections

In general, infectious complications can be seen with almost any immune-compromising condition. The following discussion includes infections most frequently associated with the immunocompromising conditions enumerated above, with particular attention to the distinctive infections for each condition. Refer to the reviews of the specific infections for further details.

Fetal and neonatal immune systems

The fetal and neonatal immune systems are not fully developed, [56] and the aggressive measures frequently needed to care for young patients may predispose them to various infections with the following agents:

• Streptococcus agalactiae (group B streptococcus, or GBS), Escherichia coli, Listeria monocytogenes, Chlamydia trachomatis, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Ureaplasma urealyticum, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Chryseobacterium meningosepticum, Mycobacterium tuberculosis, viridans streptococci, other gram-negative bacilli, other gram-positive organisms, Treponema pallidum, lactobacilli, and anaerobes

Hemoglobinopathies and other predisposing conditions

Hemoglobinopathies predispose patients to infections that are also seen in those with congenital or acquired asplenia. Some infectious agents associated with hemoglobinopathies include encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria species. Other organisms include Salmonella species, E coli, K pneumoniae, and Edwardsiella species.

Asplenia (congenital or acquired) predisposes patients to parasitic infections, such as malaria and babesiosis, and also to infections by encapsulated organisms, such as S pneumoniae, H influenzae, E coli, K pneumoniae, Neisseria meningitidis, and Capnocytophaga canimorsus. [49]

Iron overload increases the susceptibility of patients to Yersinia, Vibrio, and Capnocytophaga infections.

Leukemia and lymphoma predispose patients to infections with S aureus, coagulase-negative staphylococci, Pseudomonas aeruginosa, enteric organisms, fungi, [58]  S pneumoniae, H influenzae, mycobacteria, and viruses.

Transfusions may increase the susceptibility of patients to infections caused by Babesia, Plasmodium, [59]  and Trypanosoma species.

Humoral deficiency

B-cell defects may predispose patients to frequent sinopulmonary and respiratory tract infections. Common causes of infections are nonenveloped viruses, parvovirus B19, and rotavirus. Patients are also at risk for infections with S pneumoniae, H influenzae, S aureus, P aeruginosa, M pneumoniae, and enteric pathogens such as Giardia lamblia and Salmonella, Shigella, and Campylobacter species. Specific B-cell defects and their associated pathogens and conditions are listed below [12] :

• Antibody deficiency with transcobalamin II deficiency: S aureus infection, failure to thrive, severe persistent diarrhea

• Antibody deficiency with normal or high immunoglobulin (Ig) levels: Recurrent sinopulmonary infections, recurrent pneumococcal septicemia

• Common variable immunodeficiency: Recurrent respiratory tract infections; infections with Giardia, Salmonella, or Campylobacter species; infections with Cryptosporidium parvum and P jirovecii; recurrent enteroviral infections

• IgG subclass deficiency: Infections with S pneumoniae, H influenzae, and other encapsulated bacteria; severe pandemic 2009 influenza A H1N1 in IgG2 subclass deficiency [60]

• Organic cation transporter 2 deficiency: Recurrent respiratory tract infections

• Selective IgA deficiency: Recurrent sinopulmonary viral and bacterial GI infections; more common with associated IgG2 subclass deficiency

• Selective IgM deficiency

• Selective antipolysaccharide antibody deficiency: Infections with encapsulated organisms, especially pneumococcus

• Transient hypogammaglobulinemia of infancy/early childhood: Recurrent respiratory tract infections

• Thymoma with agammaglobulinemia: Sinusitis and respiratory tract infections

• X-linked (Bruton) agammaglobulinemia: Sinopulmonary, pneumococcal, and enteroviral (nonenveloped) infections (especially with echovirus); infections with S aureus, G lamblia, P jirovecii, and rotavirus

• X-linked hyper-IgM syndrome: Recurrent abscesses, oral ulcers, perirectal abscesses, infections with P jirovecii, mycobacterial infections, infections with Cryptococcus and Salmonella species; enteric infections with Entamoeba histolytica, Giardia, and Cryptosporidium species; CMV and adenovirus infections

• X-linked hypogammaglobulinemia with growth hormone deficiency

Combined humoral and cellular deficiency

Almost any organism can cause infection in patients with combined B-cell and T-cell defects. These patients often present with failure to thrive, thrush, and P jirovecii infection. Other commonly seen pathogens include S pneumoniae, P aeruginosa, Legionella pneumophila, L monocytogenes, Nocardia species, Mycobacterium species, fungi, VZV, HSV, CMV, Epstein-Barr virus (EBV), viruses that cause recurrent respiratory tract infections, [61] Toxoplasma species, cryptosporidia, Strongyloides species, and encapsulated bacteria. Types of combined B-cell and T-cell defects and their associated conditions and pathogens include the following:

• Adenosine deaminase deficiency

• Artemis deficiency

• Bare lymphocyte syndrome (major histocompatability complex class I/II deficiency): Overwhelming viral infection

• Caspase-8 mutations: Mucocutaneous HSV infection

• DOCK8 mutations: Recurrent sinopulmonary infections, S aureus infection, severe HSV or VZV infection, severe molluscum contagiosum, and human papillomavirus (HPV) infection [17]

• IL-2R alpha/gamma deficiency

• Intestinal lymphangiectasia: Encapsulated organisms

• Janus kinase 3 (JAK3) deficiency

• Nuclear factor-kappaB essential modifier (NEMO) deficiency: Pyogenic infections with bacteria, mycobacteria, herpesviruses, fungi

• Nijmegen breakage syndrome: Recurrent pyogenic infections

• Purine nucleoside phosphorylase deficiency

• RAG1 or RAG2 deficiency: Granulomas in skin, [62]  mucous membranes, and internal organs; EBV-associated lymphoma; overwhelming viral infections

• Reticular dysgenesis: Overwhelming gram-negative infection

• Swiss-type severe combined immunodeficiency

• T-cell receptor deficiency

• Wiskott-Aldrich syndrome: Infections with S pneumoniae, H influenzae, P jiroveci, and Candida species; CMV, HSV, and EBV infections

• X-linked lymphoproliferative syndrome: EBV infection

• X-linked severe combined immunodeficiency

• ZAP-70 tyrosine kinase deficiency

Cellular deficiency

T-cell defects predispose to infections with Candida, Mycobacterium avium-intracellulare complex, herpesviruses, and P jiroveci. Specific T-cell defects and their associated conditions and pathogens are as follows:

• Biotin-dependent multiple carboxylase deficiency

• Chronic mucocutaneous candidiasis: Candida organisms

• DiGeorge (velocardiofacial) syndrome: Recurrent chronic S pneumoniae, Candida species, and P jirovecii infections; chronic diarrhea; CMV and HSV infections

• Fas defect: EBV, mycobacteria

• Nezelof syndrome: Herpesviruses, mycobacteria

• Short-limbed dwarfism or cartilage-hair hypoplasia: Enteric viruses

Macrophage, cytokine, and miscellaneous deficiencies

Macrophage, cytokine, and miscellaneous defects are associated with mycobacterial infections and infections with Salmonella and Listeria species. Specific defects and their associated conditions and pathogens are as follows:

• Mendelian susceptibility to mycobacterial diseases (MSMD): mycobacterial infections; Salmonella, Histoplasma, Listeria, Legionella, HSV, [63]  VZV, respiratory syncytial virus (RSV), human herpesvirus (HHV)-8, and CMV infections

  • Interferon-gamma deficiency: Some viral infections, Cryptosporidia

  • Interferon-gamma receptor I or II deficiency: Some viral infections, histoplasmosis, refractory disseminated coccidioidomycosis, and mycobacteriosis [64]

  • Interleukin (IL)-12 deficiency: Infections with intracellular organisms and paracoccidioidomycosis, pyogenic bacterial infections, mycobacterial infections

  • IL-12 receptor deficiency: Recurrent leishmaniasis [65] ; mycobacterial osteomyelitis is typical; disseminated Mycobacterium avium infection [66] ; Klebsiella infections (receptor beta-1 deficiency) [67]

  • STAT1 mutations: Chronic mucocutaneous candidiasis [68]

  • NEMO

  • CYBB

  • Interferon regulatory factor 8 mutations

• IL-1 receptor–associated kinase 4 (IRAK4) deficiency: S aureus, S pneumoniae, S agalactiae, Shigella, [69]  P aeruginosa infections [27, 70]

• MYD88 deficiency: S pneumoniae, S aureus, P aeruginosa infections [27, 70]

• Toll-like receptor 5 mutations: Legionella [70]

• Apolipoprotein L-I deficiency: Trypanosoma evansi infection [71]

• Toll-like receptor 3 mutations: HSV encephalitis [73]

• TRIF and TRAF3 mutations: HSV encephalitis

• Plasminogen activator inhibitor-1 4G/4G promoter genotype: Delayed healing following otitis media with increased risk of recurrence [29]

• Anti–interferon-gamma antibodies: Nontuberculous Mycobacteria infection [74]

• IL-18 polymorphisms: Severe RSV infection [75]

• RANTES promoter gene polymorphisms: Severe RSV infection; urinary tract infections [76]

• Deficiency of chemokine receptor CCR5: Severe flaviviral infections, particularly with West Nile virus; tick-borne encephalitis [77]

• Toll-like receptor 4 mutations: Severe RSV infection; neonatal sepsis; Aspergillus infection after stem-cell transplantation [41] ; infection with CMV, parainfluenza virus, and respiratory viruses; meningococcal disease; symptomatic neurocysticercosis [78, 79]

• CXCR4 mutations (WHIM [warts, hypogammaglobulinemia, immunodeficiency, myelokathexis] syndrome): HPV infections

• STAT5 mutations: Severe VZV infections

• NOD2 gene polymorphisms: Tuberculosis in African American patients [80]

• IL-6 polymorphisms: Neonatal infections in preterm infants, [81]  severe RSV and rhinovirus infections [82]

• Activating killer immunoglobulinlike receptor gene polymorphisms: CMV infection after stem-cell transplantation, [83]  HIV and hepatitis C virus infections

• Cytokine polymorphisms have been associated with severe Chlamydia infections and tubal factor infertility [84]

• Dectin-1 deficiency: Mucocutaneous candidiasis, [85]  Trichophyton [84]  and Aspergillus infections [86]

• CARD9 mutations: Fungal infections [87]

• Polymorphisms in cytokine-inducible SRC homology 2 domain protein (CISH): Bacteremia, tuberculosis, severe malaria

• Polymorphisms in Mal/TIRAP and IL-10: Non-meningitic Haemophilus influenzae and Hib epiglottitis, respectively [88]

• Autoantibodies against IL-6: Recurrent staphylococcal infections [37, 74]

• Macrophage migration inhibitory factor deficiency: Klebsiella pneumoniae sepsis [90]

• IL-17 defects: Chronic mucocutaneous candidiasis [40, 41]

• Toll-like receptor 9 polymorphisms: Bacterial meningitis [42]

Autoimmune and inflammatory disorders predispose patients to infections with P jirovecii and Candida, Aspergillus, and Mucor species. Congenital or acquired lymphedema increases the susceptibility of patients to Streptococcus pyogenes infections.

Midline dermal sinuses, Mondini defects of the inner ear, and meningeal defects predispose patients to recurrent meningitis.

Disorders of ciliary function predispose patients to frequent sinopulmonary and other respiratory tract infections. [91]  Geosmithia argillacea is a mold of significance for those with cystic fibrosis. [92]

Decreased sensation can contribute to recurrent skin and soft tissue infections.

Trisomy 21 and other genetic disorders are linked to otitis media and upper respiratory tract infections, as well as to infections with Candida organisms. Hemorrhagic hereditary telangiectasia (Osler-Weber-Rendu disease) predisposes patients to brain abscesses and S aureus infections. Rubinstein-Taybi syndrome increases the susceptibility of patients to recurrent respiratory tract infections, apparently because of deficient polysaccharide antibody responses.

CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome may have a presentation similar to that of severe combined immunodeficiency. [10]

Phagocyte deficiency

Phagocyte deficiency [93] or dysfunction predisposes patients to infections with S aureus, Nocardia species, P aeruginosa, Serratia species, streptococci, other enteric organisms, Candida, Burkholderia, Aspergillus, and Chromobacterium species. Immunocompromising conditions and associated pathogens and infections are as follows:

• Chediak-Higashi syndrome: Infections with S aureus and streptococci, recurrent skin and mucosal infections

• Chronic granulomatous disease: Infections with primarily catalase-positive organisms, including S aureus, Serratia marcescens, Burkholderia cepacia, Granulibacter bethesdensis, [94]  Candida species, [95]  Nocardia species, Chromobacterium species, G argillacea, [96, 97]  and Aspergillus nidulans [98]  and other Aspergillus species [99, 100]

• Cyclic neutropenia: Gingivostomatitis, perirectal abscesses, recurrent fever of unknown origin

• Granulocyte colony-stimulating factor receptor mutation

• Hyper-IgE/recurrent infection (Job) syndrome: S aureus infections, recurrent staphylococcal furuncles; infections with streptococci or Candida or Aspergillus species

• Kostmann syndrome: Infections with S agalactiae, S aureus, E coli, P aeruginosa, and fungi

• Leukocyte adhesion deficiency (including CD11/CD18 deficiency): Recurrent necrotic skin and soft-tissue infections; poor wound healing; delayed separation of the umbilicus; omphalitis; gingivitis; periodontal disease; infections with P aeruginosa, S aureus, E coli, B cepacia, Serratia species, Klebsiella species, Candida species, Aspergillus species, and Fusarium solani [101]

• Neutrophil actin dysfunction: Recurrent skin infections with S aureus and Candida infections

• Papillon-Lefèvre syndrome: Herpesvirus infections, periodontal infection, pyogenic liver abscess

• Specific granule deficiency: Infection with S aureus, P aeruginosa, streptococci

Complement deficiency

Complement deficiencies and their associated conditions and infections are as follows [45] :

• Mannose-binding lectin (Mannan-binding protein) deficiency [70] : Infections with Cryptosporidia [102] or Burkholderia species, meningococcal infections, [103]  frequent viral respiratory tract infections in infancy and childhood, invasive aspergillosis in immunocompromised patients, [104]  Bancroftian filariasis, neonatal gram-negative sepsis, [105]  schistosomiasis [106, 107]

• Deficiency of C1q, C1r, C1rs, C4, C2, C3, or C5-9: Recurrent sinopulmonary infections; infections with S pneumoniae, H influenzae, and Neisseria species; chronic meningococcemia [108]

• Deficiency of factor D, factor P, factor I, factor H, or properdin: Meningococcal infections

• Ficolin-3 (H-ficolin) deficiency: Recurrent infections, bronchiectasis, [48] neonatal gram-positive sepsis

Nutritional deficiency

Malnutrition is a significant condition that leads to immunocompromise and reduces the ability of those affected to manage infections. Infectious processes that cause diarrhea, pneumonia, tuberculosis, measles, malaria, salmonellosis, and P jirovecii infection are common causes of death among malnourished infants and children.

Galactosemia predisposes patients to infections with E coli.

Human immunodeficiency virus

In immunosuppression due to human immunodeficiency virus (HIV) infection a myriad of infections occur, particularly as the immune function deteriorates in patients without antiretroviral treatment. Conditions and organisms related to HIV infection are as follows:

• Infections with S pneumoniae, S aureus, [109] M tuberculosis, [110] M avium-intracellulare complex, and other mycobacteria; infections with P aeruginosa and Salmonella [111]  and Bartonella species; syphilis; infections with Nocardia species, Rhodococcus equi, [112]  Tsukamurella species, and other gram-positive and gram-negative organisms, including anaerobes

• Hepatitis C; CMV, VZV, HSV, HPV, EBV, and JC virus infections; measles

• Tinea and infections with Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Candida species, and Blastomyces dermatitidis

Barrier deficiency

Any break in the barrier function of the skin and other epithelium predisposes to wound infections and complications, such as tetanus; wound botulism; P aeruginosa infection; and infection with staphylococci, streptococci, gram-negative bacilli, and Mycobacterium marinum.

The following medical conditions lead to infectious complications with the agents listed below:

• Collagen vascular complications: S aureus, P aeruginosa, Listeria species, Serratia species, Nocardia species, Candida species, Aspergillus species, Cryptococcus species, Mucor species, P jiroveci, diphtheroids, streptococci, Strongyloides species, CMV, VZV, polyomaviruses [113]

• Gastrointestinal (GI) tract complications: Enteric organisms, Leuconostoc species, Pediococcus species

• Hematologic or oncologic complications:

  • Coagulase-negative staphylococci; viridans streptococci; S aureus, P aeruginosa, S pneumoniae, S pyogenes, and Aeromonas species; mycobacteria; other gram-positive and gram-negative organisms

  • Candida, Aspergillus, Mucor, Rhizopus, Fusarium, Pseudallescheria, Alternaria, Scedosporium, and Trichosporon species [114, 115]

  • CMV, HSV, VZV, and community respiratory viruses

  • P jirovecii, Strongyloides species, and Toxoplasma species

• Hepatic complications: Enteric organisms; enterococci; streptococci; enteric anaerobic bacteria; S aureus, P aeruginosa, and Aeromonas species; Vibrio vulnificans

• Metabolic complications: S aureus infection, candidiasis, mucormycosis

• Pregnancy complications: S agalactiae (GBS), Candida species, Listeria species, hepatitis E virus

• Pulmonary complications:

  • Asthma predisposes patients to invasive pneumococcal infections.

  • Asthma and atopy predispose to viral infections (rhinovirus). [50]

  • Cystic fibrosis (CF) predisposes to infection with S aureus, H influenzae, P aeruginosa (mucoid in CF), S marcescens, B cepacia, Stenotrophomonas maltophilia, mycobacteria, and fungi.

  • Exposure to cigarette smoke predisposes patients to meningococcal carriage and infection, infection with nontuberculous mycobacteria, and respiratory tract infections.

• Renal complications: S aureus, S pneumoniae, E coli, enterococci, viridans streptococci

Skin and mucous membrane complications increase the susceptibility of patients to infections with S aureus, S pyogenes, corynebacteria, and other pathogens. Injections predispose to skin and soft tissue infections. Contamination while obtaining intravenous (IV) access may lead to intravascular infections. Wound infections may complicate incisions and other breaks in the skin. Intravascular or drainage devices predispose patients to infections with coagulase-negative staphylococci, S aureus, viridans streptococci, enteric organisms, Corynebacterium species, Bacillus species, Malassezia furfur, Acinetobacter species, P aeruginosa, Candida species, Gemella species, and mycobacteria.

Internal foreign bodies predispose to infections with coagulase-negative staphylococci; diphtheroids; corynebacteria; and Leuconostoc, Tsukamurella, and Pediococcus species.

Human, animal, and insect bites or scratches may transmit systemic diseases, such as tick- and arthropod-borne infections, or may become complicated by infections with Pasteurella multocida, C canimorsus, Bartonella species, S aureus, S pyogenes, Eikenella corrodens, gram-negative bacilli, anaerobes, and rabies virus. [116]

Pathogens that cause infections in burn wounds vary according to the body tissue and location and the hospital environment. Pathogens that have been implicated in burn wound infections include the following:

• Gram-positive bacteria: Staphylococcus species, Micrococcus species, Streptococcus species, Pediococcus species, Enterococcus species [1]

• Gram-negative bacteria: E coli, Enterobacter cloacae complex, K pneumoniae, S marcescens, P aeruginosa

Complications from medication

Drugs that interfere with the normal flora may predispose patients to candidiasis and Clostridioides difficile infection.

Drugs that decrease gastric acidity predispose to infections with Salmonella species and Vibrio cholerae, other enteric infections, and community-acquired pneumonia. [102]

Other treatments and medications may interfere directly with immune function. For example, neutropenic patients are particularly at risk for infections with bacteria such as E coli, K pneumoniae, Enterobacter species, Citrobacter species, P aeruginosa, S aureus, Clostridium septicum, coagulase-negative staphylococci, streptococci, enterococci, anaerobes, and a variety of yeasts and fungi (especially Candida and Aspergillus). [117]

Corticosteroid therapy predisposes patients to infections with many organisms, including S aureus, S pneumoniae, Legionella species, Listeria species, P jirovecii, Nocardia species, Strongyloides species, and VZV. Inhaled corticosteroid therapy increases the susceptibility of patients to thrush and community-acquired pneumonia. [102]

Inhibitors of tumor necrosis factor (TNF) predispose to tuberculosis, [55]  atypical mycobacterial infections, HSV encephalitis and infections, [118] histoplasmosis, [119]  Listeria infection, [120] and severe Plasmodium falciparum malaria. [121]

Other monoclonal antibodies and related small molecules have been associated with numerous infections. [122] For example, therapy with eculizumab, a C5 inhibitor, is associated with invasive meningococcal infection. Similarly, treatment with natalizumab (for multiple sclerosis) is associated with progressive multifocal leukoencephalopathy. [123, 124] Treatment with infliximab has been associated with disseminated cutaneous VZV infection. [121, 125]

Transplant complications

Bone marrow or stem cell transplant predisposes to infections with multiple organisms. [126]  The pre-engraftment period poses the highest risk of bacterial bloodstream infections. [1]  Among the pathogens that have caused infections after bone marrow or stem cell transplant are the following:

• Gram-positive organisms from the skin or GI tract: coagulase-negative staphylococci, streptococci, S aureus, C difficile

• Gram-negative enteric rods translocating from the GI tract

• Candida, Aspergillus, [127] and Fusarium species; fungi that cause zygomycosis; other molds, [128] such as Pseudallescheria species [129, 130, 131]

• P jirovecii, T gondii, Mycobacterium species

• Respiratory [132] and enteric viruses, CMV, VZV, HSV, EBV, HHV 6 or 7 [133] , parvovirus B19, polyomaviruses, [134, 135] rotavirus, adenovirus

Solid organ transplant predisposes to infections with the following organisms [136] :

• P jirovecii, Toxoplasma species (heart or heart-lung transplant)

• Nocardia, Listeria, mycobacteria, other bacteria (early posttransplant)

• Respiratory viruses, influenza virus, CMV, VZV, HSV, EBV, BK virus, JC virus, lymphocytic choriomeningitis virus [137]

• Adenovirus and BK virus after renal transplant

• Candida (early posttransplantation period), Aspergillus, [127] Cryptococcus, [138] other molds, [128] endemic fungi, and fungi that cause zygomycosis [139, 131, 130]

• Strongyloides species [140]

Evaluation

Laboratory studies at initial presentation

Obtain a complete blood cell count, chemistry profile, and erythrocyte sedimentation rate or C-reactive protein level. Order other diagnostic tests as directed by the presentation and underlying condition.

Blood cultures may be indicated depending on the patient's illness. Initial and serial cultures might be performed by using samples obtained from peripheral sites and from an access device.

Obtain routine aerobic and anaerobic, fungal, viral, and mycobacterial stains and cultures of samples of various sources or locations: blood, urine, cerebrospinal fluid (CSF), throat, wound, synovial fluid, pleural fluid, peritoneal fluid, genitourinary tract, conjunctiva, nares, or skin. The patient's presenting infection and underlying immunocompromise dictate the tests and samples needed.

Order rapid antigen or molecular testing as appropriate. These may include tests for group A streptococci, pneumococci, C difficile, Cryptococcus species, RSV, influenza virus, adenovirus, parainfluenza, human metapneumovirus, and rotavirus.

Laboratory studies of immune function

Evaluation of numbers and function of B cells includes the following:

• Total immunoglobulin levels (IgA, IgM, IgG, IgE)

• IgG subclass levels

• Isohemagglutinins

• Lymphocyte subpopulations (CD19 or CD20)

• Antibody production after vaccination (eg, diphtheria, meningococcus, pneumococcus, tetanus, H influenzae)

Evaluation of numbers and function of T cells includes the following:

• Lymphocyte subpopulations

• Assessment of delayed-type hypersensitivity reactions

• Mitogen-stimulation assays

Evaluation of phagocyte numbers and function includes the following:

• Numbers of CD11a, CD11b, CD11c, and CD18 beta receptor

• Neutrophil oxidative burst (dihydrorhodamine [DHR] fluorescence) or assay for chronic granulomatous disease (formerly nitroblue tetrazolium and Oil red O testing)

Evaluation of complement status includes the following:

• Total hemolytic complement (CH50)

• Measuring mannose-binding lectin levels has been suggested [46]

• Measurements of specific components as needed

Imaging studies at initial presentation

Chest radiography may demonstrate infiltrates or other pulmonary disease. [141] Other radiographic studies should be performed as warranted.

Imaging studies of immune system anatomy and function

Chest radiography or computed tomography of the chest can be used to identify the thymus or lymphoid tissue. Other imaging studies are indicated by the particular immunocompromising conditions and infectious complications.

Therapeutics for Empiric Use

Table. Empiric Antimicrobials for Common Pathogens in Immunocompromised Children (Open Table in a new window)

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Author

Fernando J Bula-Rudas, MD, FAAP Assistant Professor of Pediatrics, Pediatric Infectious Diseases Specialist, Sanford Children's Hospital/Specialty Clinic; Director of Pediatric Infectious Diseases Rotation, Pediatrics Residency Program, Pediatric Clerkship Director, Sanford School of Medicine, The University of South Dakota

Fernando J Bula-Rudas, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Healthcare Epidemiology of America, South Dakota State Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa

Disclosure: Received research grant from: Pfizer;GlaxoSmithKline;AstraZeneca;Merck;American Academy of Pediatrics, Novavax, Regeneron, Diassess, Actelion<br/>Received income in an amount equal to or greater than $250 from: Sanofi Pasteur.

Chief Editor

Russell W Steele, MD Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, Southern Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

Itzhak Brook, MD, MSc Professor, Department of Pediatrics, Georgetown University School of Medicine

Itzhak Brook, MD, MSc is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Microbiology, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Immunocompromised Host Society, International Society for Infectious Diseases, Medical Society of the District of Columbia, New York Academy of Sciences, Pediatric Infectious Diseases Society, Society for Experimental Biology and Medicine, Society for Pediatric Research, Southern Medical Association, Society for Ear, Nose and Throat Advances in Children, American Federation for Clinical Research, Surgical Infection Society, Armed Forces Infectious Diseases Society

Disclosure: Nothing to disclose.

Archana Chatterjee, MD, PhD Professor and Chair, Department of Pediatrics, Senior Associate Dean for Faculty Development, Sanford School of Medicine, The University of South Dakota

Archana Chatterjee, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, International Society for Infectious Diseases, Pediatric Infectious Diseases Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Rebecca Schreier, DO Resident Physician, Department of Pediatrics, Sanford Children’s Hospital

Disclosure: Nothing to disclose.

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