Immune Function and Critical Illness

Critical illness often involves the activation of the inflammatory cascade that must be turned off for the patient to survive.³ In response to stress, proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α); interferon; and interleukin-1 (IL-1), IL-6, and IL-12 are produced along with antiinflammatory agents such as IL-10 and TNF receptor.^3–6 The production of IL-10 is associated with downregulation of major histocompatibility complex class II (human leukocyte antigen [HLA]-DR) molecule expression on the surface of monocytes, but not B cells. If the resulting downregulation of the immune system is prolonged a condition occurs known as immunoparalysis. Suppressed monocyte/macrophage function reduces clearance of immune complexes, impairs antigen-presenting capabilities, and decreases natural killer cell function. Activated T cells are important sources of interferons, which in turn control infection by stimulating nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and nitric oxide production and by increasing adhesion molecule expression. Immunoparalysis is confirmed in the laboratory by reduced expression of HLA-DR antigens on peripheral blood monocytes and decreased TNF-α production in response to lipopolysaccharide (LPS) exposure.⁵ Immunoparalysis and has been shown in patients after trauma, neurosurgical procedures, and cardiopulmonary bypass operations.^7–11 This phenomenon may in part explain the increased incidence of life-threatening nosocomial infections including those considered opportunistic in these patients.^{12, 13}

Absolute lymphocytopenia has often been reported in previously healthy patients in response to critical illness, including burns, neurotrauma, cardiopulmonary bypass, and viral inefections.^14–17 Total lymphocyte counts measured in 22 children fell to a nadir at 6 hours after anesthesia for major surgery with minimal recovery out to 48 hours.¹⁴ Helper cells were most affected. Cardiopulmonary bypass further induced lymphocyte apoptosis compared to surgery alone.¹⁵ Exogenous corticosteroids have long been known to induce lymphocute apoptosis. Because critical illness also evokes a hormonal stress response, elevated endogenous corticosteroids are hypothesized to induce lymphopenia; however, there is no direct correlation between cortisol levels and lymphocyte counts.^16,17 In contrast, prolactin levels have been shown to correlate with lymphopenia in several studies and prolonged suppression of prolactin was associated with lymphocyte depletion, nosocomial infection and death.^17,18 Prolactin is required for lymphocyte proliferation and protects lymphocytes from steroid induced apoptosis. Other drugs used in critically ill patients may contribute to lymphopenia. Dopamine inhibits prolactin release even at very low doses, whereas metoclopramide increases prolactin release.^18,19 Dopamine and dobutamine also affect lymphocyte function directly.²⁰ Growth hormone deficiency is associated with decreased natural killer cell activity.²¹

Critically ill patients frequently receive blood transfusions that are known to modify the immune response see also Chapter 82, Transfusion Medicine. Patients with cancer who receive transfusion at the time of resection have greater risk of dying than those who do not.²² In contrast, certain patients who receive blood transfusion before transplant have a lower incidence of rejection²²; however, transplant recipients who receive an HLA-DR mismatched transfusion have accelerated graft rejection.²³ The long-term effects of transfusions on the immune system and disease susceptibility are unknown, but even 19 years after transfusion, blood recipients have fewer peripheral T cells, particularly helper T cells, than patients who did not undergo transfusion.²⁴ Blood transfusions after trauma or cardiopulmonary bypass are associated with increased infection; however, in major surgery or trauma it is difficult to sort out the effect of transfusion compared with the effect of critical illness.^25,26 The use of autologous transfusion in elective surgery may reduce the risk of immunosuppression.²⁷

In addition to HIV, viruses such as measles, influenza, and human T-cell lymphotrophic virus-1 can suppress the immune response.^28–31 The neutrophils of patients infected with measles are not activated and therefore are unable to phagocytize and kill bacteria.²⁸ Lymphopenia has been associated with measles and respiratory syncyctial virus (RSV) and two paramyxoma viruses that can infect monocytes.^29–32 In both infections, mortality is often related to secondary infections. Okada et al. documented that the measles virus infected only small number of lymphocytes but apoptosis occurred in noninfected lymphocytes.²⁹ The duration of lymphopenia was age dependent and was most prolonged in infants. The same response was not observed in response to a live measles vaccine.³⁰ Absolute lymphocyte counts were lower in hospitalized RSV-infected patients than controls and were lowest in patients admitted to the intensive care unit.³¹ No mortality was observed and lymphocyte counts recovered. In children with a known immunodeficiency such as following cancer therapy and RSV, the development of lower respiratory tract infection was associated with profound lymphopenia (<100 cells/µL) and mortality was 31%.³²

Although for many previously healthy children immune dysfunction recovers with time, treatment of the underlying condition and/or withdrawal of immuosuppression, for others it does not. This phenomenon is associated with multiple organ failure and death.^12,13,18 For example, an absolute lymphocyte count less than 1000 cells/µL lasting longer than 7 days was associated with a more than sixfold increase risk of death in one pediatric study.¹⁸ For this reason, several investigators have attempted to proactively reverse this process.^33–41 In neutropenic patients with sepsis, granulocyte stimulating factor (G-CSF) reduces the likelihood of death; however, in non-neutropenic patients only one clinical trial has yet shown benefit.³⁶ Adults with severe community-acquired pneumonia treated with G-CSF plus antibiotics had less sepsis-related organ failure than those treated with antibiotics alone.³⁷ During immunoparalysis, interferons, which are major activators of monocytes, are reduced. Exogenous interferon gamma-1b therapy administered to 10 consecutively admitted patients with less than 30% HLA-DR expression restored both HLA-DR expression and production of IL-6 and TNF-α.³⁹ Aerosolized interferon-γ administered to trauma patients with immunoparalysis (defined as suppressed HLA-DR expression on alveolar macrophages) was associated with a lower incidence of ventilator-associated pneumonia.⁴⁰ Monocytes can also be stimulated by granulocyte macrophage colony stimulating factor (GM-CSF). In nine consecutive patients with immunoparalysis documented by reduced mean HLA-DR expression in peripheral blood monocytes, 5 μg/kg of GM-CSF produced a fourfold increase in mean HLA-DR expression and a ninefold increase in TNF-α response to LPS in as little as 24 hours.⁴¹ When given to septic patients with acute respiratory distress syndrome (ARDS), GM-CSF was associated with improved gas exchange and increased neutrophil respiratory burst.³⁸ Clinical investigations aimed at reversing the downregulated immune system are ongoing and not without risk.

Malnutrition and Immune Deficiency

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 intake during their stay in intensive care, implying that many critically ill children will have abnormal immune function secondary to nutritional problems.^42–45 Immune system dysfunction occurs so early in the course of malnutrition that measures of immune competence such as anergy and total T-cell numbers are sensitive indicators of a patient’s nutritional status.⁴⁶ Nutrition influences the course of HIV and tuberculosis, susceptibility to infection in older patients, the body’s ability to respond to vaccines, and many other aspects of immune function.^45–48

Protein or protein-calorie malnutrition is generally only studied in humans in its most severe form. Because of interspecies variability in immunoglobulin synthesis and cytokine regulation, extrapolation of animal data to humans may be inappropriate.⁴⁸ Protein malnutrition alters production of epithelial cell membrane glycoprotein receptors, immunoglobulin A, and mucus, increasing the risk of bacterial colonization.⁴⁸ Mobilization of neutrophils is delayed, natural killer cell lytic activity is reduced, and imbalances in critical T-cell subsets occur. All contribute to increased susceptibility to infection. Severe malnutrition attenuates the acute phase response and interferon production, but other proinflammatory compounds and T-cell subsets are upregulated. The common tautology that protein deficiency reduces all protein synthesis is not supported by available data.⁴⁸ In the human condition, selective protein deficiency without concomitant essential fatty acid and micronutrient deficiency is unlikely.

By definition, essential fatty, linoleic, and alpha-linoleic acids, cannot be synthesized by mammalian cells and must be obtained through the diet.⁴⁹ Linoleic acid is found in plant oils and animal fats, alpha-linolenic acid in plant oils.^49,50 For children in many parts of the world access to fat other than cow’s milk is severely limited. The n-3 polyunsaturated fatty acids (PUFAs), eicosopentaenoic acid and docosahexaenoic acid (DHA), synthesized from alpha-linolenic acid or obtained from a diet of fish, suppress lymphocyte responses to mitogen stimulation.⁴⁸ Accumulating evidence suggests that dietary supplementation with n-3 PUFAs is a “natural” immunosuppressant that may be useful in autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, and diabetes mellitus.⁴⁹ Moderate n-3 PUFA intake can enhance the immune response. For example, supplementation of infant formula with a small amount of DHA accelerates development of T-cell responsiveness in preterm infants (see also Chapter 75).⁵⁰

There are many specific nutrients now identified as vital to immune function. Vitamin A has essential functions in immune cells and indirectly contributes to protection from infection through maintenance of vital epithelial cell differentiation and barrier function of the lung and intestine.⁵¹ Vitamin A deficiency occurs in an estimated 100 million children worldwide⁵² and is a risk factor for increased death from pneumonia and diarrhea.⁴⁵ A survey of hospitalized children in Malawi showed that one third had severe vitamin A deficiency and one third had moderate deficiency.⁵² Paradoxically, these children exhibited monocytes with preferential synthesis of TNF-α as compared with IL-10. This shift was perhaps triggered by the underlying disease that prompted hospitalization. Results of several randomized, double-blinded, placebo-controlled trials conducted in malnourished children have shown improved antibody response to vaccines and fewer diseases of the gastrointestinal and respiratory systems after vitamin A supplementation.^45,51,52 Vitamin A supplementation in individuals who are not deficient has no benefit, whereas high retinal levels are associated with an increased diarrhea and pneumonia.⁵³ Vitamin C (ascorbic acid) is highly concentrated in leukocytes, and low leukocyte vitamin C concentrations are associated with reduced immune function.⁵⁰ Epidemiological data suggest that higher vitamin C consumption lowers the risk of cancer and cardiovascular disease, but despite numerous clinical trials with participants of both sexes and varying ages, no definitive evidence that vitamin C supplementation reduces the frequency or symptoms of upper respiratory infections exists. High-dose vitamin C does improve several measures of immune function and does not appear to have any side effects.⁴⁵ Vitamin D receptors are found on numerous immune cell types.⁵⁴ Vitamin D deficiency is associated with depressed macrophage function and impaired delayed hypersensitivity.⁵³ Vitamin E (-tocopherol) is a potent lipid-soluble antioxidant. Study results of vitamin E supplementation ranging from 200 to 800 mg/day in healthy adults showed increasing CD4/CD8 ratios, mitogen responsiveness, antibody production, and decreasing free radical production; however, a dosage of 300 mg/day for 3 weeks resulted in suppressed bactericidal activity in humans.⁴⁶ Optimal daily requirements of these nutrients in health and disease remain to be determined.

Of the trace elements that may affect the immune system, selenium, zinc, and iron have been the most widely studied. Selenium balances redox states and suppresses inflammation through its vital role in several antioxidant enzymes and intranuclear factors, including the glucocorticoid receptor, activator protein-1, and nuclear factor-κB.⁴⁷ In HIV infection, selenium supplementation modifies cytokine release, decreasing TNF and IL-8 while increasing IL-2. Selenium improves T-cell proliferation and differentiation. Selenium deficiency in the host enhances the mutation rate of Coxsackie and influenza viruses, but excessive selenium intake is toxic to the immune system and other organs.⁴⁷ Zinc, as with selenium, is required for the activity of more than 100 enzymes.⁵² Zinc supplementation increases the number of CD4+ T cells; thus, the CD4/CD8 T-cell ratio is improved. Zinc deficiency has been documented in alcoholics and in patients with burns and gastrointestinal disorders.⁵³ Zinc supplementation reduces bacteremia, hospitalization rates, and vaso-occlusive crises in patients with sickle cell anemia.⁴⁷ In young children, zinc supplementation reduced the duration of diarrhea and frequency of respiratory infections.⁴⁷ Worldwide, 20% to 25% of the population has iron deficiency, that results in impaired cell mediated immunity, particularly in neutrophil and natural killer cell function.⁵⁶ Although an association between iron availability and susceptibility to certain bacterial infections exists, there is little evidence that iron supplementation in deficient individuals inhibits immune responses or increases susceptibility to infections.⁴⁷

Human Immunodeficiency Virus Infection and Acquired Immune Deficiency Syndrome

Acquired immune deficiency syndrome (AIDS) is a clinical syndrome resulting from infection by HIV-1 (and very rarely HIV-2), an RNA retrovirus dependent on a reverse transcriptase for replication.⁵⁷ Surrounding the RNA and its reverse transcriptase are core proteins p24 and p18. A viral envelope is composed of the host cell membrane studded with glycoproteins gp120 and gp40. Entry of HIV into cells is mediated by the binding of gp120 to the CD4 membrane protein of the host’s T-helper cells in the presence of a host coreceptor of the chemokine family, either CCR5 on macrophages or CXCR4 on other cell lines. After HIV replication, the host’s T-helper cells undergo apoptosis resulting in severe deficiency of both cell-mediated and humoral immunity. Because pediatric HIV infection is most commonly transmitted from mother to infant, the acquired immunodeficiency is occurring in a host whose immune system, unlike the adult’s immune system, is relatively naive and has developed little natural immunity.^57,58 This may in part explain the shorter time required for progression of HIV infection to AIDS in perinatally infected children when compared with children infected after the age of 2 years.⁵⁹ Antiretroviral therapy can effectively reverse this immune dysfunction.⁶⁰

The diagnosis of HIV-1 infection in adults and children older than 18 months is accomplished by identification of antibodies specific to viral proteins: first through a rapid enzyme-linked immunosorbent assay and then confirmed by the more time-consuming Western blot analysis.⁶⁰ Because infants carry transplacentally acquired maternal antibodies, HIV infection in infants younger than 18 months must be documented by HIV DNA polymerase chain reaction (PCR) or HIV RNA assay.⁶⁰ Generally DNA PCR is repeated three times (between 14 and 21 days, at 1 to 2 months, and at 4 to 6 months of age) with sensitivity increasing over time.⁵⁷ Some centers also perform testing at birth. Subtypes of HIV have been identified with subtype B predominating in the United States.⁵⁷ The DNA PCR assays are less sensitive for non-B subtypes than are RNA assays. If either test is positive, the child’s HIV enzyme-linked immunosorbent assay can be repeated at 1 year to document seroconversion.⁵⁷

The diagnosis of AIDS requires confirmation of both HIV infection and an AIDS-defining illness.⁶¹ AIDS-defining illnesses include nonspecific findings such as fever; weight loss; lymphadenopathy or diarrhea for more than 2 months; and specific findings such as encephalopathy, lymphoid interstitial pneumonitis (LIP), opportunistic infections, recurrent infections, and associated malignancies. In 1994 the United States Centers for Disease Control and Prevention modified an earlier classification system for HIV infection ranging from indeterminate to asymptomatic to severely symptomatic (i.e., AIDS) in an effort to stratify the severity or progression of the disease, by adding age specific CD4+ T cell counts and percentages.⁶¹ These categories aside, there appear to be at least two patterns of response to HIV infection in untreated children.^59,62 Children younger than 4 years, especially those aged 1 year or younger, are more likely to have Pneumocystis carinii pneumonia (PCP); have severe progressive encephalopathy, wasting, or both; and die earlier. Older children tend to have a less serious course, characterized by recurrent bacterial infections, 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 5 and 8 months.⁶³ The density of CCR5 receptor on nonactivated T cells correlates with the decline of CD4+ T cells and prognosis.⁶⁴

Epidemiology

In North America at the end of 2007, the adult prevalence of HIV was 0.6% compared with 5% in sub-Saharan Africa.⁶⁵ Ninety-six percent of individuals living with HIV reside in low and middle income countries. Sub-Saharan Africa had the highest incidence of HIV infection accounting for 67% of the world’s cases with young women three times more likely than men to be infected. East Africa and Central Africa have reduced the prevalence of HIV infection through educational programs. In Western Europe many new cases of HIV/AIDS are reported from persons who emigrated from or traveled to countries with a high HIV prevalence.

As of December 2007, 2 million children lived with HIV/AIDS worldwide, of which 370,000 were newly infected and 270,000 died annually.⁶⁵ Vertical transmission of HIV infection from untreated mother to fetus occurs at a rate of 20% to 35% but is reduced by 66% when antiretroviral therapy monotherapy (zidovudine [ZDV]) is taken during pregnancy, delivery, and the neonatal period.^65,66 Even though simple inexpensive monotherapy can reduce vertical transmission by 40% to 50%, only 33% of infected pregnant women receive treatment.^65,66 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.^67,68 It may also be important to extend antiretroviral therapy for the mother during the period of breastfeeding.^67,69,70 Although there has been extensive development of appropriate therapies, a major challenge has been actual delivery of programmes to prevent mother to child transmission.^71–73

Pulmonary Complications and Respiratory Failure

Pulmonary complications remain the most frequent indication for admission of children with AIDS to an ICU.^82,83 Bacterial pneumonia is common in this population.^84,85 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.^66,67 The incidence of Haemophilus influenzae infection is declining where vaccination is available, whereas immunization against pneumococcal infections has been associated with a significant drop in pneumococcal disease in HIV infected children.⁸⁶ Empiric therapy for pneumonia in such children should cover the most common pathogens and be based on hospital-specific susceptibility profiles, but it is important to note that children with HIV infections may not respond to standard antibiotic therapies for lower respiratory tract infections.⁸⁷