Infections in the Immunocompromised Host 

An immunocompromised host is a patient who does not have the ability to respond normally to an infection due to an impaired or weakened immune system. This inability to fight infection can be caused by a number of conditions including illness and disease (eg, diabetes, HIV), malnutrition, and drugs.

Essential update: New guidelines from the IDSA recommend vaccination for immunocompromised patients

According to new guidelines from the Infectious Diseases Society of America (IDSA), most immunocompromised patients should be vaccinated. The new guidelines are designed for health care professionals caring for patients with compromised immune systems due to HIV infection or 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. ^{[1, 2]}

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 living with immunocompromised patients can safely receive inactivated vaccines.
• Individuals living with immunocompromised patients 6 months of age or older should receive annual influenza vaccine.

Immunocompromising conditions

Congenital conditions

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

• Syndromes
• B-cell defects
• Combined B-cell and T-cell defects
• T-cell defects
• Macrophage, cytokine, and miscellaneous defects
• Phagocyte deficiency or dysfunction
• Complement deficiencies

Acquired conditions

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

• Malnutrition
• HIV infection
• Trauma
• Medical conditions

Infectious complications

Immunocompromised patients are susceptible to bacterial, fungal, and viral infections that healthy immune systems usually conquer. They are also susceptible to common infections of childhood.

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 combined B- and T-cell defects. Patients often present with failure to thrive, thrush, and/or P jiroveci 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), respiratory viral infections, Toxoplasma species, cryptosporidia, Strongyloides species, and encapsulated bacteria.

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

Phagocyte deficiency or dysfunction predisposes patients to infections with S 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, H influenzae and N meningitidis.

Infectious diarrhea, pneumonia, tuberculosis, measles, malaria, salmonellosis, P jiroveci infection, and HIV are common causes of death among malnourished infants and children.In immunosuppression due to HIV infection a myriad of infections occur, particularly as immune function deteriorates.

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. ^[3] 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. ^{[4, 5]} 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 focusesonevaluation 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 examined in the office because of frequent infections have a series of benign, self-limited, largely viral infections 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 frequently than siblings and others. However, most children with frequent infections are immunologically healthy.

Careful questioning and evaluation frequently reveals antecedent 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, Münchhausen syndrome or Münchhausen syndrome by proxy manifests as frequent or obscure infections (or suspicion of such infections). Secondary, or acquired, immunodeficiency is more common than primary immunodeficiency.

Although the well child with frequent infections is seen in the outpatient office more often than one with immunocompromise, most hospitalized children have some immune-compromising condition.

History

For the outpatient with frequent infections, a thorough history should be obtained. In particular, the following should be identified: ^[6]

• 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 on 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

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

• Plot growth.
• Evaluate development.
• Evaluate for dysmorphology.
• Seek 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.

Congenital Conditions

These most commonly affect the fetus and newborn. Hemoglobinopathy may be noted.

Syndromes

• Partial albinism with immunodeficiency (Griscelli) syndrome ^[7]
• Hemorrhagic hereditary telangiectasia (Rendu-Osler disease) ^[8]
• Immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome
• Kabuki syndrome
• Partial albinism, immunodeficiency, and progressive white matter disease (PAID) syndrome
• Autoimmune polyendocrinopathy syndrome type 1
• Rubinstein-Taybi syndrome ^[9]
• Hermansky-Pudlak-2 syndrome
• CHARGE syndrome ^[10]
• Other dysmorphology or immunodeficiency syndromes
• Stromal interaction molecule 1 mutation ^[11]

B-cell defects ^[12]

• Antibody deficiency with transcobalamin II deficiency
• Antibody deficiency with normal or high immunoglobulin (Ig) levels
• Common variable immunodeficiency ^[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
• Transient hypogammaglobulinemia of infancy or early childhood ^[15]
• Thymoma with agammaglobulinemia
• X-linked (Bruton) agammaglobulinemia
• X-linked hyper-IgM syndrome
• X-linked hypogammaglobulinemia with growth hormone deficiency ^[15]

Combined B-cell and T-cell defects

• Adenosine deaminase deficiency
• Artemis deficiency
• Ataxia-telangiectasia syndrome
• 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, 20, 21]}
• Nijmegen breakage syndrome ^[22]
• Omenn syndrome
• Purine nucleoside phosphorylase deficiency
• Recombination activation gene ( RAG) 1 or 2 deficiency
• Reticular dysgenesis
• Swiss-type severe combined immunodeficiency
• T-cell receptor deficiency
• Wiskott-Aldrich syndrome ^[20]
• 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
• DiGeorge (velocardiofacial) syndrome ^[21]
• Fas defect
• Nezelof syndrome
• Short-limbed dwarfism or cartilage-hair hypoplasia

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
  • STAT1 mutations ^{[18, 25]}
  • NEMO ^[19]
  • CYBB
  • Interferon regulatory factor 8 mutations ^[26]
• IL-1 receptor–associated kinase 4 (IRAK4) deficiency ^{[21, 27]}
• MYD88 deficiency ^{[21, 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 syndrome) ^[33]
• STAT 5 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 Interleukin-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

• Chediak-Higashi syndrome
• Chronic granulomatous disease
• Chronic idiopathic neutropenia
• Cyclic neutropenia
• Glycogen storage disease 1b
• Hyper-IgE/recurrent infection (Job) syndrome (Janus kinase protein tyrosine kinase 2 [Tyk2], signal transducer and activator of transcription [STAT] 3, and STAT 1 mutations) ^{[18, 43, 25, 44]}
• Kostmann syndrome
• Leukocyte adhesion deficiency (including CD11 or CD18 deficiency)
• Myeloperoxidase deficiency
• Neutrophil actin dysfunction
• Papillon-Lefèvre syndrome
• Specific granule deficiency
• Shwachman-Diamond syndrome

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

• Asplenia ^[49]
• Ciliary dyskinesia, Kartagener syndrome, and other disorders
• Galactosemia and other metabolic conditions
• Lymphedema (congenital)
• Trisomy 21 and other genetic disorders
• Other anatomic defects (eg, midline dermal sinus, Mondini defect of the inner ear, fistulae, cysts, duplications, meningeal defects, iron overload, decreased sensation)

Acquired Conditions

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

• Malnutrition
• HIV infection: Although human immunodeficiency virus (HIV) infection is a considerable cause of immunodeficiency worldwide, immunocompromise is most likely to result from common problems, including asthma, diabetes, malnutrition, and cancer, among others.
• Trauma

  • Burns
  • Lacerations and abrasions
• Medical conditions

  • Collagen vascular
  • GI tract
  • Hematologic or oncologic
  • Hepatic
  • Metabolic
  • Pregnancy
  • Pulmonary, particularly atopy, asthma ^[50] , and cystic fibrosis (CF)
  • Renal
  • Skin and mucous membrane
  • Viral infections (eg, cytomegalovirus [CMV] infection ^[51] , measles)
  • Other anatomic or physiologic problems (eg, fistulae, 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

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

Use of drugs and/or therapies (eg, radiation therapy), which may interfere with normal flora, decrease gastric acidity and ciliary motility, and 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 ^[52]
• Major surgery ^[53]

Treatment

• For leukemia or lymphoma
• Bone marrow or stem-cell transplantation
• Solid organ transplantation ^[54]
• Therapy for autoimmune or inflammatory disorders
• TNF-alpha inhibitors ^[55]
• Monoclonal antibodies and related small molecules
• Transfusion (which may lead to iron overload)

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

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

Fetal and Neonatal Immune System

The fetal and neonatal immune systems are immature ^[56] and the aggressive measures frequently needed to care for young patients predispose them to various infections with the following agents:

• Streptococcus agalactiae, 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
• Herpes simplex virus (HSV), HIV, CMV, and varicella zoster virus (VZV)
• Candida albicans ^[57] and other fungi
• Pneumocystis jiroveci

Hemoglobinopathies

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

Asplenia (congenital or acquired) predisposes patients to malaria, babesiosis, and infection by encapsulated organisms, including the following: S pneumoniae, H influenzae, E coli, K pneumoniae, Neisseria meningitidis, and Capnocytophaga canimorsus. ^[49]

Iron overload predisposes patients to Yersinia, Vibrio, and Capnocytophaga infections.

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

Transfusions predispose to Babesia, Plasmodium ^[59] , and Trypanosoma infections, among others; iron overload may occur (see above).

Humoral Deficiency

B-cell defects predispose patients to frequent sinopulmonary and respiratory tract infections and infections with nonenveloped viruses, parvovirus B19, and rotavirus. They are also at risk for infections with S pneumoniae; H influenzae; S aureus; P aeruginosa; M pneumoniae; Giardia lamblia; and Salmonella, Shigella, and Campylobacter species. Specific B-cell defects and their associated pathogens, signs, and symptoms are listed below: ^[12]

• Antibody deficiency with transcobalamin II deficiency - S aureus infection, failure to thrive, severe diarrhea
• Antibody deficiency with normal or high Ig levels - Recurrent sinopulmonary infections, recurrent pneumococcal septicemia
• Common variable immunodeficiency - Respiratory tract infections; infections with Giardia, Salmonella, or Campylobacter species; infections with Cryptosporidium parvum and P jiroveci; enteroviral infections
• IgG heavy-chain deletion
• IgG subclass deficiency - S pneumoniae, H influenzae, and other encapsulated bacteria; severe pandemic 2009 influenza A H1N1 in IgG ₂ subclass deficiency ^[60]
• Kappa-chain deficiency
• Organic cation transporter 2 deficiency - Recurrent respiratory tract infections
• Selective IgA deficiency - Sinopulmonary and GI infections with bacteria, Giardia; more common with associated IgG ₂ subclass deficiency
• Selective IgM deficiency
• Selective antipolysaccharide antibody deficiency - Encapsulated organisms, especially pneumococcus
• Transient hypogammaglobulinemia of infancy/early childhood - Respiratory tract infections
• Thymoma with agammaglobulinemia - Sinusitis and respiratory tract infections
• X-linked (Bruton) agammaglobulinemia - Sinopulmonary, pneumococcal, and enteroviral (nonenveloped) infections (especially with echovirus) and S pneumoniae, S aureus, G lamblia, P jiroveci, and rotaviral infections
• X-linked hyper-IgM syndrome - Oral ulcers, perirectal abscesses, infections with P jiroveci, recurrent abscesses, mycobacterial infections, infections with Cryptococcus and Salmonella species, Entamoeba histolytica infections, infections with Giardia and Cryptosporidium species, and CMV and adenovirus infections
• X-linked hypogammaglobulinemia with growth hormone deficiency

Combined Humoral and Cellular Deficiency

Almost any organism can cause infection in combined B- and T-cell defects. Patients often present with failure to thrive, thrush, and/or P jiroveci 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), respiratory viral infections ^[61] , Toxoplasma species, cryptosporidia, Strongyloides species, and encapsulated bacteria. Types of combined B- and T-cell defects and their associated conditions and pathogens include the following:

• Adenosine deaminase deficiency
• Artemis deficiency
• Ataxia-telangiectasia syndrome - Severe sinopulmonary infections and bronchiectasis
• Bare lymphocyte syndrome (major histocompatability complex class I/II deficiency) - Overwhelming viral infection
• Caspase-8 mutations - Mucocutaneous HSV
• DOCK8 mutations - Recurrent sinopulmonary infections, S aureus, severe HSV or VZV, severe molluscum contagiosum, and human papillomavirus ^[17]
• IL-2R alpha/gamma deficiency
• Intestinal lymphangiectasia - Encapsulated organisms
• JAK3 deficiency
• NEMO deficiency - Pyogenic bacteria, mycobacteria, herpesviruses, fungi
• Nijmegen breakage syndrome - Recurrent pyogenic infections
• Omenn syndrome
• 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 - S pneumoniae, H influenzae, P jiroveci, Candida species, CMV, HSV, EBV
• X-linked lymphoproliferative syndrome - EBV
• 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 infections. T-cell defects and 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 jiroveci, infections; chronic diarrhea; CMV, HSV, and others
• 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. Defects and associated conditions and pathogens are as follows:

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

  • Interferon-gamma deficiency - Some viral infections; Cryptosporidia
  • Interferon-gamma receptor I or II deficiency - Some viral infections and histoplasmosis, refractory disseminated coccidioidomycosis, and mycobacteriosis ^[64]
  • 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 infection (receptor beta-1 deficiency) ^[67]
  • STAT1 mutations - Chronic mucocutaneous candidiasis ^[68]
  • NEMO
  • CYBB
  • Interferon regulatory factor 8 mutations
• IRAK4 deficiency - S aureus, S pneumoniae, S agalactiae, Shigella ^[69] , P aeruginosa ^{[27, 70]}
• MYD88 deficiency - S pneumoniae, S aureus, P aeruginosa ^{[27, 70]}
• Toll-like receptor 5 mutations - Legionella ^[70]
• Apolipoprotein L-I deficiency - Trypanosoma evansi infection ^[71]
• UNC-93B deficiency - HSV encephalitis ^[72]
• 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 for recurrence ^[29]
• Anti-interferon-gamma antibodies - Nontuberculous Mycobacteria ^[74]
• IL-18 polymorphisms - Severe RSV infection ^[75]
• RANTES promoter gene polymorphisms - Severe RSV infection; upper urinary tract infection ^[76]
• Deficiency of chemokine receptor CCR5 - Severe flaviviral infections, particularly West Nile virus and tick-borne encephalitis virus ^[77]
• Toll-like receptor 4 mutations - Severe RSV, neonatal sepsis, Aspergillus infection following stem-cell transplant ^[41] , CMV, parainfluenza virus, respiratory viruses, meningococcal disease; symptomatic neurocysticercosis ^{[78, 79]}
• IL-8 RA (CXCR1) mutations - Pyelonephritis
• CXCR4 mutations (Whim syndrome) - Papillomavirus infections
• STAT 5 mutations - Severe VZV
• NOD2 gene polymorphisms - Tuberculosis disease in blacks ^[80]
• IL-6 polymorphisms - Chorioamnionitis and neonatal infections in preterm infants ^[81] , severe RSV, and rhinovirus infections ^[82]
• Activating killer immunoglobulinlike receptor gene polymorphisms - CMV after stem-cell transplantation ^[83] , HIV, HCV
• Cytokine polymorphisms have been associated with severe Chlamydia infections and tubal factor infertility ^[84]
• Dectin-1 deficiency - Mucocutaneous candidiasis ^[85] , Trychophyton ^[84] , Aspergillus ^[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 Interleukin-10 - Non-meningitic Haemophilus influenzae type b (Hib) infection and Hib epiglottitis, respectively ^[88]
• Autoantibodies against IL-6 - Recurrent staphylococcal infections ^{[37, 74]}
• Polymorphisms in the IL-8 promoter gene - Recurrent Clostridium difficile infection ^[38]
• IL-12 receptor deficiency - Disseminated coccidioidomycosis ^{[39, 89]}
• 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 or inflammatory disorders predispose patients to infections with P jiroveci and Candida, Aspergillus, and Mucor species.

Congenital or acquired lymphedema predisposes patients to infections with Streptococcus pyogenes.

Trisomy 21 and other genetic disorders are linked to otitis media and upper respiratory infections, as well as to infections with Candida organisms.

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 an emerging mold of significance for those with cystic fibrosis. ^[92]

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

Hemorrhagic hereditary telangiectasia (Rendu-Osler disease) predisposes patients to brain abscess and S aureus extracerebral infections.

Rubinstein-Taybi syndrome predisposes to recurrent respiratory tract infections, apparently because of deficient polysaccharide antibody responses.

CHARGE syndrome may present like SCID. ^[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, and 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 - Primarily catalase-positive organisms, including S aureus, S marcescens, Burkholderia cepacia, Granulibacter bethesdensis ^[94] , Candida species ^[95] , Aspergillus species ^{[96, 97]} , Nocardia species, Chromobacterium species, G argillacea, ^{[98, 99]} Aspergillus nidulans ^[100]
• Chronic idiopathic neutropenia - Helicobacter pylori, CMV
• Cyclic neutropenia - Gingivostomatitis, perirectal abscesses, fever of unknown origin
• Glycogen storage disease 1b - Recurrent skin and soft tissue infections
• 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 - S agalactiae, S aureus, E coli, P aeruginosa, fungi
• Leukocyte adhesion deficiency (including CD11/CD18 deficiency) - Recurrent necrotic skin and soft-tissue infection, 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]
• Leukocyte glucose-6-phosphate dehydrogenase deficiency - Toxoplasmosis
• Myeloperoxidase deficiency - Disseminated candidiasis
• Neutrophil actin dysfunction - Recurrent skin infections with S aureus and Candida infections
• Papillon-Lefèvre syndrome - Herpesviruses, periodontic infection, pyogenic liver abscess
• Specific granule deficiency - S aureus, P aeruginosa, streptococci
• Shwachman-Diamond syndrome - P aeruginosa

Complement Deficieny

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

• Mannose-binding lectin (Mannan-binding protein) deficiency ^[70] - Cryptosporidia ^[102] or Burkholderia species, meningococcal infections ^[103] , respiratory viruses, frequent respiratory tract infections in infancy and childhood, invasive aspergillosis in immunocompromised patients ^[104] , Bancroftian filariasis, neonatal gram-negative sepsis ^[105] , schistosomiasis ^[106]
• Deficiency of C1q, C1r, C1rs, C4, C2, C3, or C5-9 - Recurrent sinopulmonary infections, S pneumoniae, H influenzae, Neisseria species, chronic meningococcemia ^{[107, 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 immunocompromising condition worldwide. Those affected are less able than others to tolerate infection. Infectious diarrhea, pneumonia, tuberculosis, measles, malaria, salmonellosis, P jiroveci infection, and HIV 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 HIV infection a myriad of infections occur, particularly as immune function deteriorates. Conditions and organisms related to HIV infection are as follows:

• S pneumoniae, S aureus, ^[109] M tuberculosis, ^[110] M avium-intracellulare complex, other mycobacteria, P aeruginosa, Salmonella, ^[111] Bartonella species, syphilis, Nocardia species, Rhodococcus equi ^[112] , Tsukamurella species, other gram-positive organisms, other gram-negative organisms, anaerobes
• Hepatitis C, CMV, VZV, HSV, molluscum contagiosum, human papilloma virus, EBV, measles, JC virus
• Tinea and infections with Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Candida species, and Blastomyces dermatitidis
• Infections with Toxoplasma gondii, P jiroveci, C parvum, Cyclospora cayetanensis, and Isospora belli; amebiasis; scabies; leishmaniasis; microsporidiosis; and other protozoal infections ^[113]

Barrier Deficiency

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

Medical conditions lead to infectious complications as follows:

• 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 ^[114]
• GI tract - Enteric organisms, Leuconostoc species, Pediococcus species
• Hematologic or oncologic complications

  • Coagulase-negative staphylococci, viridans streptococci, S aureus, P aeruginosa, S pneumoniae, S pyogenes, Aeromonas species, mycobacteria, other gram-positive and gram-negative organisms
  • Candida, Aspergillus, Mucor, Rhizopus, Fusarium, Pseudoallescheria, Alternaria, Scedosporium, and Trichosporon species ^{[115, 116]}
  • CMV, HSV, VZV, or community respiratory viruses
  • P jiroveci, Strongyloides species, Toxoplasma specie
• Hepatic complications - Enteric organisms, enterococci, streptococci, anaerobes, S aureus, P aeruginosa, Vibrio vulnificans, Aeromonas species
• Metabolic complications - S aureus infection, candidiasis, mucormycosis
• Pregnancy complications - S agalactiae, 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]
  • CF predisposes to infections 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 -S aureus, S pyogenes, and corynebacteria, among othersInjections predispose to skin and soft t issue infections. Int ravascular infections may follow contaminated IV access. Organisms include P aeruginosa and Gemella speciesWound infections may complicate incisions and other breaks in the skin.Access 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, and mycobacteria.

Internal foreign bodies predispose to infections with coagulase-negative staphylococci; diphtheroids; corynebacteria; and Leuconostoc, Tsukamurella, and Pediococcus species.Various infections may complicate animal or insect bites or scratches.

• Tick-borne and arthropod-borne infections
• Pasteurella multocida, C canimorsus, Bartonella species, S aureus, S pyogenes, Eikenella corrodens, gram-negative bacilli, anaerobes, rabies virus

Complications From Medication

Drugs that interfere with the normal flora may predispose patients to candidiasis and Clostridium difficile infection, among others.

Drugs that decrease gastric acidity predispose to infections with Salmonella species and Vibrio cholerae. They also predispose to community-acquired pneumonia. ^[102]

Other treatments and medications may interfere directly with immune function.

• 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).
• Corticosteroid therapy predisposes patients to infections many organisms, including S aureus, S pneumoniae, Legionella species, Listeria species, P jiroveci, Nocardia species, Strongyloides species, and VZV. Inhaled corticosteroid therapy predisposes to thrush and community-acquired pneumonia. ^[102]
• Inhibitors of tumor necrosis factor predispose to tuberculosis ^[55] , atypical mycobacterial infections, HSV encephalitis and infections, ^[117] histoplasmosis, ^[118] Listeria infection, ^[119] and severe falciparum malaria. ^[120]
• Other monoclonal antibodies and related small molecules have been associated with numerous infections. ^[121] 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. ^{[122, 123]} Treatment with infliximab has been associated with disseminated cutaneous varicella zoster virus infection. ^{[120, 124]}

Transplant Complications

Bone marrow or stem cell transplant predisposes to infections with the following: ^[125]

• Aerobic gram-negative rods, coagulase-negative staphylococci, streptococci, S aureus, C difficile
• Candida, Aspergillus, ^[126] and Fusarium species ; zygomycosis; other molds, ^[127] such as Pseudoallescheria species ^{[128, 129, 130]}
• P jiroveci, T gondii
• Respiratory ^[131] and enteric viruses, CMV, VZV, HSV, EBV, HHV 6 or 7 ^[132] , parvovirus B19, polyomaviruses, ^{[133, 134]} rotavirus, adenovirus

Solid organ transplant predisposes to infections with the following: ^[135]

• P jiroveci, Toxoplasma species (heart or heart-lung transplant)
• Nocardia, Listeria, mycobacteria, ^[14] other bacteria (early posttransplant) ^[76]
• Respiratory viruses, ^[31] influenza, ^[128] CMV, VZV, HSV, EBV, BK virus, JC virus, lymphocytic choriomeningitis virus ^[136]
• Adenovirus and BK virus after renal transplant
• Candida (early posttransplantation period), aspergillosis, ^[126] cryptococcosis, ^[137] other molds, ^[127] endemic fungi, and zygomycosis ^{[138, 130, 129]}
• Strongyloides species ^[139]

Laboratory studies at initial presentation

Obtain a Complete Blood Count, chemistry profile, erythrocyte sedimentation rate and/or C-reactive protein, and others, as directed by presentation and underlying condition.

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

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, conjunctivae, nares, or skin. The patient's presenting infection and underlying immunocompromise dictate the tests and samples needed.

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

Laboratory studies of immune function

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

• Ig levels
• IgG subclass levels
• Isohemagglutinins
• Lymphocyte subpopulations (CD19 or CD20)
• Antibody production after vaccination (eg, diphtheria, meningococcus, pneumococcus, tetanus)

Evaluation of numbers and function 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:

• Absolute neutrophil count (see the Absolute Neutrophil Count calculator)
• Numbers of CD11a, CD11b, CD11c, CD18 beta receptor
• Assay for chronic granulomatous disease (formerly nitroblue tetrazolium and Oil red O testing)

Evaluation of complement status includes the following:

• Total hemolytic complement
• 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. ^[140] Other radiographic studies should be performed as warranted.

Imaging studies of immune system anatomy and/or function

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

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