1230 e2 eTABLE 104 2 Cytokines in Sepsis Cytokine Main Immune Functions Sources Other Effects TNF a Differentiation and activation of macrophages, endothelial, and neutrophils, causing fever and coagu[.]
1230.e2 eTABLE 104.2 Cytokines in Sepsis Cytokine Main Immune Functions Sources Other Effects TNF-a Differentiation and activation of macrophages, endothelial, and neutrophils, causing fever and coagulation activation Macrophages, lymphocytes, and fibroblasts The release of additional proinflammatory cytokines (IL-6/IL-8/MIF) IL-1b Differentiation and activation of macrophages, endothelial, and neutrophils, causing fever and coagulation activation Macrophages The release of additional proinflammatory cytokines (IL-6/IL-8/MIF) IL-6 Acute-phase reactant causing fever/leukocytosis, coagulation activation, complement release, and B/T-lymphocyte activation Macrophages, dendritic cells, lymphocytes, and endothelium Pro- and antiinflammatory actions Promotes sTNFR/IL-1RA/TGF-b release IL-12 Induces T-lymphocyte and NK-cell production of INF-g Macrophages and neutrophils Helper T (Th1) cytokine responses INF-g Enhances phagocyte bactericidal activity and may reverse immunoparalysis state in sepsis T lymphocytes and NK cells Enhances phagocyte bactericidal activity MIF Increases macrophage survival and promotes macrophage recruitment Monocytes and macrophages Elevates TLR4 expression and downstream cytokine production (TNF-a/IL-1b) IL-4 Promotes helper T lymphocyte differentiation to a Th2 phenotype and inhibits helper T (Th1) lymphocyte differentiation Th2 lymphocytes, mast cells, basophils and eosinophils Induces macrophage release of IL-4 and IL-13 IL-10 Suppresses TNF-a, IL-1b, IL-6, INF-g and GM-CSF proinflammatory mediators and impairs phagocytosis/antigen presentation Macrophages, NK cells, lymphocytes, and APCs Promotes sTNFR/IL-1RA/TGF-b release TGF-b Suppresses TNF-a, IL-1b, and HMGB1 proinflammatory mediators Inhibits T-lymphocyte activation via reduced IL-2 secretion Macrophages and smooth muscle cells Promotes sTNFR/IL-1RA/TGF-b release and fibrosis APCs, Antigen presenting cells; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; INF, interferon; MIF, macrophage migration inhibitory factor; sTNFR, soluble tumor necrosis factor receptor; TGF, transforming growth factor; TNF, tumor necrosis factor CHAPTER 104 Acquired Immune Dysfunction 1231 TABLE 104.3 Infectious Diseases Associated With Broad Categorical Immune Defects Common Less Common Bacteria Staphylococcus aureus, Streptococcus pneumonia, Klebsiella, Pseudomonas Enterobacter, Acinetobacter, Stenotrophomonas Fungi/molds Candida, aspergillosis, zygomycosis Granulocytopenia Parasites/viruses HSV1 or HSV2, VZV Cellular Defects Bacteria Legionella, Nocardia Fungi/molds Pneumocystis, Cryptococcus, mucormycosis Parasites/viruses Toxoplasma/CMV, EBV, adenovirus, VZV Mycobacterium tuberculosis Humoral Defects Bacteria S pneumonia, Haemophilus influenzae Fungi/molds Pneumocystis Parasites/viruses Giardia lamblia/VZV Combined Defects Bacteria S aureus, S pneumonia, Klebsiella, Pseudomonas Mycobacterium tuberculosis, Listeria monocytogenes, Legionella Fungi/molds Pneumocystis, aspergillosis, Cryptococcus Zygomycosis, mucormycosis Parasites/viruses Toxoplasma/CMV, VZV, influenza, parainfluenza, RSV, adenovirus HSV1 or HSV2 CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; VZV, varicella zoster virus Modified from Safdar A, Armstrong D Infectious morbidity in critically ill patients with cancer Crit Care Clin 2001;17:531-570 responses and autoimmunity.50,51 There is an inverse linear correlation between IL-10 serum concentrations and HLA-DR expression.52 After CPB, children with elevated IL-10 serum levels demonstrate ex vivo LPS hyporesponsiveness.53 Among children with septic shock who went on to develop hospital-acquired infections, early serum IL-10 levels were significantly higher than similar children who did not experience hospital acquired infections.3 IL-10 is capable of suppressing T-lymphocyte production of IL-2 and interferon (INF)-g and monocyte/macrophage production of IL-12 and tumor necrosis factor-a (TNF-a), meaning that IL-10 directly reduces adaptive and innate immune responses.51,54 TGFb is an important stimulator of fibrosis and scar formation In addition, TGF-b suppresses B- and T-lymphocyte proliferation and induces apoptosis The primary producer of TGF-b are regulatory T cells (Tregs) Tregs are a subfamily of CD4 T lymphocytes critical in maintaining tolerance of self-antigens Malnutrition and Immune Dysfunction Worldwide, malnutrition is the most common cause of immune dysfunction.8 Malnutrition is a serious public health problem observed most frequently in developing countries among children less than years of age, causing stunting in approximately 155 million and wasting in approximately 52 million children.14,55 Protein-energy malnutrition (PEM) results from inadequate protein and caloric intake The reader is directed to a review of malnutrition by Ibrahim et al.8 as well as Chapter 99 Malnutrition influences the course of HIV and tuberculosis, susceptibility to infection in older patients, vaccine responsiveness, intestinal microbiota, and many other aspects of both innate and adaptive immune functions It has been estimated that malnutrition contributed to more than 45% of deaths among children younger than years of age in developing countries.57 Critical illness often causes initial hypermetabolism followed by macro- and micronutrient malnutrition exacerbating nutritional deficiencies in children already affected by undernutrition or malnutrition (see Chapter 99) A significant proportion of children admitted to ICUs (even in affluent countries) have been noted to be malnourished, whereas many others will receive inadequate nutritional support during their stay in the ICU, implying that many critically ill children will have abnormal immune function secondary to nutritional deficits.56,58,59 It is estimated that one in every five children admitted to the PICU presents with chronic malnutrition or will develop acute malnutrition.56 Malnourished children and infants have greater numbers of ventilator days, longer ICU stays, increased hospital costs, and increased infectious complications.60 Immune dysfunction occurs early in the course of malnutrition because of changes to epithelial barriers, hematopoiesis, and innate and adaptive immune function Because of high enterocyte proliferation rates, PEM and micronutrition deficiencies impair the gastrointestinal epithelial integrity.61 Diets deficient in zinc, vitamin A, and vitamin D or PEM alter the villous structure of the small intestine, disrupting intestinal permeability, gut-associated lymphoid tissue (GALT), and normal intestinal bacterial flora.6 Loss of the gastrointestinal barrier is associated with the risk of enteric bacterial translocation and chronic inflammation.62 Recently, an observation cohort related mortality in 1232 S E C T I O N X I Pediatric Critical Care: Immunity and Infection children with complicated severe acute malnutrition (SAM) to intestinal and systemic inflammation.63 PEM was associated with risk of bacterial overgrowth, altered mucosal defenses, increased epithelial permeability, and reduced immunoglobulin A (IgA) secretion Malnutrition has multiple effects on hematopoietic and lymphoid organs Progenitor cells of the bone marrow are sensitive to nutritional deficiencies because of high proliferation rates and enzymatic processes dependent on micronutrients and trace elements for proper growth and differentiation PEM and iron deficiency alter erythropoiesis and arrest progenitor cell cycle progression, affecting both myeloid and erythroid cell lines.64–66 Despite bone marrow changes, well-nourished children with bacterial infections showed no differences in leukocyte counts or lymphocyte subset numbers compared with malnourished children.67 However, numbers and responsiveness of dendritic cells in the peripheral blood were observed to be reduced in children with SAM.68 Secondary lymphoid tissues (spleen and lymph nodes) have not been studied in children with malnutrition, and preclinical animal studies modeling PEM provide evidence of lymphocyte and dendritic cell dysfunction GALT in children with malnutrition demonstrates reduced intestinal luminal IgA and plasma cell numbers secreting IgA.69,70 In addition, gastrointestinal barrier and GALT alterations affect oral vaccine efficacy, as demonstrated with oral vaccines for polio, rotavirus, and cholera.71–73 Dietary lipids and micronutrients have immunomodulatory properties vital to immune function v-6 polyunsaturated fatty acid (PUFA) metabolites are mainly inflammatory and a precursor for arachidonic acid and prostaglandin E2 synthesis v-3 PUFA metabolites are mainly antiinflammatory and a precursor for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) Both EPA and DHA inhibit prostaglandin E2 synthesis.74,75 Adult studies demonstrate improved clinical outcomes (ventilator-free days and mortality) in the setting of ARDS and severe sepsis when patients are given an enteral formula containing antioxidants plus v-3 essential fatty acids.76–78 Pediatric studies assessing acute lung injury (ALI) and severe burns with associated acute respiratory failure treated with enteral formulas containing antioxidants and v-3 PUFAs demonstrate formula tolerance, increased antiinflammatory biomarkers, improved oxygenation, and pulmonary compliance.79,80 These studies were not designed to assess clinical outcomes By definition, essential fatty acids, linoleic and a-linoleic acids, cannot be synthesized by mammalian cells and must be obtained through the diet Linoleic acid is found typically in fish, shellfish, plant seeds/oils, and tree nuts.75 For children in many parts of the world, access to fat other than cow’s milk is severely limited.57 EPA and DHA, synthesized from a-linolenic acid or obtained from a diet of fish, affects T-lymphocyte signaling and alters cytokine production.81,82 Moderate v-3 PUFA intake can enhance the immune response For example, supplementation of formula with a small amount of DHA accelerates T-lymphocyte development and responsiveness in preterm infants.83 Micronutrient deficiencies may cause unnoticed clinical manifestations when severe or chronic; these deficiencies have profound effects on immune function Worldwide, approximately 25% of the population has iron deficiency.84 Iron is a critical element for hemoglobin production, oxygen delivery, and mitochondrial function.85 Iron is also critical in innate and adaptive immune cell function.86 Iron-dependent transcription factors promote NF-kB activation, antimicrobial peptide production in macrophages, and cytokine production.87–89 The direct impact of iron deficiency and susceptibility to infections is difficult to determine An association between iron availability and susceptibility to certain bacterial infections exists However, there is little evidence that iron supplementation in deficient individuals inhibits immune responses or increases infection susceptibility.90,91 Zinc is a necessary cofactor for over 200 enzymatic reactions vital for proper growth and development and has many roles in immune function.8 Thymulin is a zinc-containing hormone important for thymus activity and development, which indirectly affects T-lymphocyte maturation.92,93 Zinc promotes CD4 T lymphocyte differentiation, regulates inflammatory cytokine release, and modifies the oxidative burst of neutrophils.8,94 Zinc deficiency affects one-fifth of the world’s population and is often associated with PEM.8 Zinc deficiency results in thymic atrophy, impaired macrophage function, lymphopenia, and reduced inflammatory cytokine production.94 Zinc supplementation increases CD4 T-lymphocyte numbers, thus improving the CD4/CD8 T-lymphocyte ratio.95 Zinc supplementation reduces bacteremia, hospitalization rates, and vaso-occlusive crises in patients with sickle cell disease.96 For young children (infants to toddlers), zinc supplementation has been demonstrated to reduce the frequency and duration of diarrheal disease and frequency of respiratory infections.97–99 Selenium is a necessary cofactor for enzymatic processes that balance oxidative states (antioxidant activity) and antiinflammation effects through intranuclear factors, including the glucocorticoid receptor, activator protein-1, and NF-kB.100–103 Selenium supplementation in patients infected with HIV modifies cytokine release, decreasing TNF-a and IL-8, while increasing IL-2.104 Selenium improves T-lymphocyte proliferation and differentiation However, selenium supplementation had no impact on severe sepsis in surgical ICU patients.105 Two single-center studies of plasma selenium levels in children with SIRS found an association between low selenium levels, inflammation, and nutritional status.106,107 Enterally fed children whose selenium levels increased by day had more ventilator-free days and ICU-free days than those who did not demonstrate serum selenium increases.107 Plasma selenium levels respond to adequate nutritional intake, but excessive selenium intake is toxic to the immune system and other organs.8 Vitamin A (retinol) has key roles in the proper differentiation of epithelial barriers, secondary lymphoid development, mucus production, and antibody production.108,109 Retinol is the primary active metabolite of vitamin A, which is absorbed by enterocytes and stored in the liver Vitamin A deficiency occurs in an estimated 100 million children and is the leading cause of blindness worldwide.110 Vitamin A deficiency leads to inadequate epithelial barriers, increasing the likelihood of bacterial and viral infections, mainly of the gastrointestinal, respiratory, and urogenital tracts.109 Maternal intake of vitamin A plays a key role in in utero secondary lymphoid development.111 Retinol regulates mucin expression by epithelial cells.112 Vitamin A enhances IgA production of respiratory tract epithelium.113 Several randomized, double-blinded controlled trials assessing vitamin A supplementation have been conducted Most demonstrate associations of improved antibody response to oral vaccines, reductions in the incidence and severity of diarrheal disease and measles, and reductions in mortality.114–116 Vitamin A supplementation in individuals who are not deficient has no benefit, whereas high retinol levels are associated with an increase in diarrhea and pneumonia.117 Vitamin C (ascorbic acid) is an important cofactor for numerous enzymes and transcription factors but is popular for its antioxidant activity.118 Leukocytes have a severalfold higher concentration of ascorbic acid than that of plasma, suggesting a key role for vitamin C in immune function.118 Low leukocyte CHAPTER 104 Acquired Immune Dysfunction ascorbic acid concentrations are associated with impaired immune function.83 Vitamin C appears to regulate immune cell apoptosis, increase costimulatory molecules of dendritic cells, and attenuate lung injury in preclinical animal models.119–121 Recently, intravenous ascorbic acid was used to treat septic shock in adults; this treatment was associated with significantly reduced inflammatory biomarkers and an attenuation of progressive organ dysfunction.122,123 High-dose vitamin C improves several measures of immune function and does not appear to have any adverse effects.122 Vitamin D has a primary role in bone metabolism and calcium homeostasis.124 Vitamin D receptors (VDRs) are found on numerous cell types, including innate and adaptive immune cells.125,126 Vitamin D has both proinflammatory and antiinflammatory functions, highlighting the complexity of its effect on immunity.8 Vitamin D deficiency is associated with depressed macrophage function and impaired delayed hypersensitivity.125 While vitamin D deficiency is present on admission in many ICU patients, an association between low vitamin D levels and length of mechanical ventilation and mortality has been reported in several but not all studies.127–132 In critically ill children, vitamin D deficiency was more likely to occur in winter, in older children, and those with darker skin.129 A correlation between vitamin D levels and severity of illness of septic shock was identified Patients who were receiving vitamin D supplementation prior to admission had higher serum concentrations, with increasing dosing being more protective.129 Vitamin D supplementation appears to be inexpensive, easily accomplished, and without overt risk However, to date, there is no convincing evidence that vitamin D supplementation improves outcomes in critically ill patients.133 HIV Infection and AIDS HIV is an RNA retrovirus dependent on a reverse transcriptase for DNA integration into the host cell for replication.134 HIV is transmissible through blood and other body fluids (semen, vaginal fluid, or breast milk) HIV RNA and its reverse transcriptase form a viral envelope composed of the host cell membrane 1233 studded with viral glycoproteins (gp) gp120 and gp40 HIV mainly targets host cells expressing CD4, a cell surface glycoprotein expressed on helper T lymphocytes, macrophages, and dendritic cells After gp120-CD4 binding, HIV entry into cells is aided by the presence of host cell surface coreceptors, chemokine receptors (CCR5) on macrophages, or on other cell lines (CXCR4).135 Once HIV gains entry into a host cell and replication occurs, virus-mediated destruction of the host cell reduces CD4 T-lymphocyte counts and results in AIDS over time Table 104.4 summarizes age-specific CD4 counts, stages of HIV infection, and specific infection risks AIDS is a clinical syndrome caused by opportunistic infections because of severe deficiencies of both cell-mediated and humoral immunity Pediatric HIV infection is most commonly transmitted vertically from mother to infant either during pregnancy, delivery, or breastfeeding.136 What is unique to pediatric HIV is that the child’s immune system—unlike the adult’s—is relatively naive, with little natural immunity.137 This may explain, in part, the shorter time required for progression to AIDS after HIV infection in perinatally infected infants when compared with children infected after the age of years.138 Antiretroviral therapy can effectively reverse HIV/AIDS immune dysfunction.139 The diagnosis of HIV infection in adults and children older than 24 months is accomplished by identification of antibodies specific to HIV-1 or HIV-2 viral proteins and confirmed by a second test using a different methodology.140 Because infants carry acquired maternal antibodies that have crossed the placenta, HIV infection in infants younger than 24 months must be documented by HIV DNA polymerase chain reaction (PCR) or HIV RNA assays.140 Generally, viral testing is repeated three times (between 14 and 21 days, 1–2 months, and 4–6 months of age) with sensitivity increasing over time.140 High-risk infants should be tested at birth Absence of HIV infection can be confirmed by serology at 12 to 18 months of age, but positive serology may still reflect maternal antibody presence and should be confirmed by nucleic acid assays In 2014, the CDC modified an earlier classification system for HIV infection ranging from indeterminate to asymptomatic to TABLE Age-Specific CD4 T-Lymphocyte Count (%) Based on HIV Infection Stage and Opportunistic Diseases 104.4 Associated With Different Stages ,1 y Stage 1–5 y y Cells/mL % Cells/mL % Cells/mL % 1500 33 1000 29 500 25 750–1499 26–33 500–999 22–29 200–499 14–25 ,750 ,26 ,500 ,22 ,200 ,14 Stage Stage Severe CD4 Depletion Pulmonary TB Herpes zoster Oral candidiasis Kaposi sarcoma Thrombocytopenia purpura LIP Pneumocystis jirovecii pneumonia CNS toxoplasmosis Cryptosporidium/ Microsporidia diarrhea Oropharyngeal candidiasis Miliary/extrapulmonary TB HIVAN Mucocutaneous herpes simplex Cryptococcal meningitis Primary CNS lymphoma Lymphoma HIV encephalopathy CMV enteritis/retinitis Disseminated Mycobacterium avium-intracellulare Progressive multifocal leukoencephalopathy CMV, Cytomegalovirus; CNS, central nervous system; HIV, human immunodeficiency virus; HIVAN, HIV-associated nephropathy; LIP, lipopolysaccharide; TB, tuberculosis 1234 S E C T I O N X I Pediatric Critical Care: Immunity and Infection severely symptomatic (i.e., AIDS) based on age-specific CD4 Tcell counts, as outlined in Table 104.4.141 Stage HIV infection or an AIDS-defining illness in the presence of HIV infection confirms the diagnosis of AIDS.141 AIDS-defining illnesses include recurrent bacterial infections, fungal and/or mycobacterium infection, cytomegalovirus (CMV), lymphoma, encephalopathy or progressive multifocal leukoencephalopathy, wasting syndrome, and associated malignancies These categories aside, there appear to be at least two patterns of response to HIV infection in untreated children.142 Children younger than years, especially those aged year or less, are more likely to have Pneumocystis jirovecii pneumonia (PJP); have severe progressive encephalopathy, wasting, or both; and die earlier Older children, years or greater, tend to have a less serious course, characterized by recurrent bacterial infections, lymphocytic interstitial pneumonia (LIP), nephropathy, and thrombocytopenia The time course for vertically transmitted HIV infection to progress to AIDS in children is variable and may be more than 10 years However, in children, AIDS is most commonly seen between and months if infants not receive antiretroviral therapy.139 The density of CCR5 receptors on nonactivated CD4 T lymphocytes directly correlates with CD4 T-lymphocyte decline and prognosis.143 Globally, at the end of 2017, the adult prevalence of HIV was 0.8%.144 Sub-Saharan Africa had the highest incidence of HIV infection, accounting for 66% of the world’s people living with HIV.144 As of 2017, 1.8 million children (,15 years of age) are living with HIV worldwide; 180,000 were newly infected and 190,000 died annually.144 Ninety percent of children living with HIV reside in sub-Saharan Africa.144 The majority of pediatric HIV infections are from mother to child (vertical transmission) during pregnancy, delivery, or breastfeeding Vertical transmission of HIV infection from untreated mother to fetus occurs at a rate of 15% to 40% but is reduced by 66% when antiretroviral monotherapy (zidovudine [ZDV]) is taken during pregnancy, delivery, and the newborn period.145 Prior to 2010, even though simple inexpensive monotherapy can reduce vertical transmission by 40% to 50%, only 33% of infected pregnant women received such treatment.145 As of 2017, 80% of pregnant women living with HIV had access to antiretroviral therapies; thus, new HIV infections among children has declined 35% since 2010.144 When used in combination with elective cesarean delivery and formula feeding, perinatal antiretroviral therapy has reduced the vertical transmission of HIV to less than 2% in the United States Currently, trials suggest that highly active antiretroviral therapy (HAART) in pregnancy may be more effective in preventing transmission than monotherapy.146,147 It is important to extend antiretroviral therapy for the mother during the period of breastfeeding.148,149 Although there has been extensive development of appropriate therapies, a major challenge has been overcoming barriers to mother-child transmission.150,151 Combinations of HAART used to treat pediatric HIV-infected patients have dramatically decreased mortality caused from HIVassociated conditions and opportunistic infections.150,152 Because of cultural, economic, and political factors, HIV prevention and treatment have been slowly introduced in resource-limited regions In Malawi, without antiretroviral therapy, the mortality rate at years of age for HIV-infected children reached 89%.153 This high mortality rate may be related to the burden of infectious diseases and malnutrition, as is seen in resource-limited parts of the world Resource-limited areas have a higher frequency of tuberculosis (TB), CMV, hepatitis, and gastroenteritis contributing to a greater disease burden In the United States, 75% of HIV-infected children are alive at age years.152 Most data regarding outcome and survival of HIV-infected children presented in this chapter are derived from patients who did not receive antiretroviral therapy from the time of birth and may have never received it Such data are still applicable to developing countries, given that only 59% of adults and 52% of children are accessing HAART despite a global increase in HAART access.144 As of February 2019, 31 HIV antiretroviral agents were approved and available for use in the United States, 17 of which have a pediatric indication.140 Because resistance develops with monotherapy, HAART is preferred for both children and adults.140 There are six classes of agents available and three drugs are typically selected from at least two different classes Measurement of both HIV viral load (by RNA PCR) and the number of CD4 T lymphocytes are used to monitor the effectiveness of HAART.140 Baseline viral loads are higher in children than in adults and have a slower decay rate after the introduction of HAART.150 Pediatric studies in which dosage adjustments were directed by pharmacokinetics resulted in superior decreases in viral loads compared with fixed dosages based on weight.140 Each antiretroviral therapy has its own toxicity and potential for drug interactions Antiretroviral therapy is rapidly evolving and should be directed by a specialized practitioner.140 Overall, HIV-infected patients are living longer and developing non-HIV-associated comorbidities While the rate of hospitalizations decreased for HIV patients treated with HAART, the rate of ICU admission has not changed and in some studies increased.154,155 Nearly 20% of hospitalized HIV-infected patients require transfer to the ICU.156 Barbier et al identified major changes in the clinical presentation, ICU management, and mortality of critically ill HIV-infected adults from 1999 to 2010.156 AIDS-defining opportunistic infections decreased while non-HIV-associated comorbidities increased The use of life-sustaining therapies has increased as the short-term mortality in HIV-infected patients continues to decline Mechanical ventilation remains the predominant support modality for HIV-infected adults and children, but renal and cardiovascular modalities, including transplantation, have been increasing Pulmonary Complications and Respiratory Failure Pulmonary complications remain the most frequent indication for admission of children with AIDS to an ICU.157–159 Pneumonia is the leading cause of morbidity and death in HIV-infected children worldwide.157 Comparing low- or middle-income countries to high-income countries, pneumonia accounts for 20% versus 4.3% of the annual deaths in children, respectively.157 Comparing HIV-infected children on HAART to uninfected children, pneumonia is more likely to be severe, with high treatment failure rates and increased risk of death.157 Bacterial pneumonia is common in this population.160,161 Along with the usual pathogens frequently seen in childhood, such as Streptococcus pneumoniae and mycoplasma, immunodeficient children are also susceptible to pseudomonal and staphylococcal infections.162 The incidence of Haemophilus influenzae and pneumococcal infections is declining where vaccination is available.160 Empiric therapy for pneumonia in such children should cover the most common pathogens and should be based on hospital-specific susceptibility profiles However, it is important to note that children with HIV infections may not respond to standard antibiotic therapies for lower respiratory tract infections.162 ... animal models.119–121 Recently, intravenous ascorbic acid was used to treat septic shock in adults; this treatment was associated with significantly reduced inflammatory biomarkers and an attenuation... child’s immune system—unlike the adult’s—is relatively naive, with little natural immunity.137 This may explain, in part, the shorter time required for progression to AIDS after HIV infection... antiretroviral therapy, the mortality rate at years of age for HIV-infected children reached 89%.153 This high mortality rate may be related to the burden of infectious diseases and malnutrition, as