Immune dysfunction during sepsis, malnutrition, HIV/AIDS, and other critical illness states

Malnutrition and immune dysfunction

Worldwide, malnutrition is the most common cause of immune dysfunction. Malnutrition is a serious public health problem observed most frequently in developing countries among children less than 5 years of age, causing stunting in approximately 155 million and wasting in approximately 52 million children. ^, Protein-energy malnutrition (PEM) results from inadequate protein and caloric intake. The reader is directed to a review of malnutrition by Ibrahim et al. 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 5 years of age in developing countries. 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. ^{, ,} It is estimated that one in every five children admitted to the PICU presents with chronic malnutrition or will develop acute malnutrition. Malnourished children and infants have greater numbers of ventilator days, longer ICU stays, increased hospital costs, and increased infectious complications. 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. 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. Loss of the gastrointestinal barrier is associated with the risk of enteric bacterial translocation and chronic inflammation. Recently, an observation cohort related mortality in children with complicated severe acute malnutrition (SAM) to intestinal and systemic inflammation. 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. Despite bone marrow changes, well-nourished children with bacterial infections showed no differences in leukocyte counts or lymphocyte subset numbers compared with malnourished children. However, numbers and responsiveness of dendritic cells in the peripheral blood were observed to be reduced in children with SAM. 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. ^, In addition, gastrointestinal barrier and GALT alterations affect oral vaccine efficacy, as demonstrated with oral vaccines for polio, rotavirus, and cholera.

Dietary lipids and micronutrients have immunomodulatory properties vital to immune function. ω-6 polyunsaturated fatty acid (PUFA) metabolites are mainly inflammatory and a precursor for arachidonic acid and prostaglandin E ₂ synthesis. ω-3 PUFA metabolites are mainly antiinflammatory and a precursor for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Both EPA and DHA inhibit prostaglandin E ₂ synthesis. ^, 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 ω-3 essential fatty acids. Pediatric studies assessing acute lung injury (ALI) and severe burns with associated acute respiratory failure treated with enteral formulas containing antioxidants and ω-3 PUFAs demonstrate formula tolerance, increased antiinflammatory biomarkers, improved oxygenation, and pulmonary compliance. ^, These studies were not designed to assess clinical outcomes. By definition, essential fatty acids, linoleic and α-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. For children in many parts of the world, access to fat other than cow’s milk is severely limited. EPA and DHA, synthesized from α-linolenic acid or obtained from a diet of fish, affects T-lymphocyte signaling and alters cytokine production. ^, Moderate ω-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.

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. Iron is a critical element for hemoglobin production, oxygen delivery, and mitochondrial function. Iron is also critical in innate and adaptive immune cell function. Iron-dependent transcription factors promote NF-κB activation, antimicrobial peptide production in macrophages, and cytokine production. 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. ^,

Zinc is a necessary cofactor for over 200 enzymatic reactions vital for proper growth and development and has many roles in immune function. Thymulin is a zinc-containing hormone important for thymus activity and development, which indirectly affects T-lymphocyte maturation. ^, Zinc promotes CD4 T lymphocyte differentiation, regulates inflammatory cytokine release, and modifies the oxidative burst of neutrophils. ^, Zinc deficiency affects one-fifth of the world’s population and is often associated with PEM. Zinc deficiency results in thymic atrophy, impaired macrophage function, lymphopenia, and reduced inflammatory cytokine production. Zinc supplementation increases CD4 T-lymphocyte numbers, thus improving the CD4/CD8 T-lymphocyte ratio. Zinc supplementation reduces bacteremia, hospitalization rates, and vaso-occlusive crises in patients with sickle cell disease. 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.

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-κB. Selenium supplementation in patients infected with HIV modifies cytokine release, decreasing TNF-α and IL-8, while increasing IL-2. Selenium improves T-lymphocyte proliferation and differentiation. However, selenium supplementation had no impact on severe sepsis in surgical ICU patients. Two single-center studies of plasma selenium levels in children with SIRS found an association between low selenium levels, inflammation, and nutritional status. ^, Enterally fed children whose selenium levels increased by day 5 had more ventilator-free days and ICU-free days than those who did not demonstrate serum selenium increases. Plasma selenium levels respond to adequate nutritional intake, but excessive selenium intake is toxic to the immune system and other organs.

Vitamin A (retinol) has key roles in the proper differentiation of epithelial barriers, secondary lymphoid development, mucus production, and antibody production. ^, 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. Vitamin A deficiency leads to inadequate epithelial barriers, increasing the likelihood of bacterial and viral infections, mainly of the gastrointestinal, respiratory, and urogenital tracts. Maternal intake of vitamin A plays a key role in in utero secondary lymphoid development. Retinol regulates mucin expression by epithelial cells. Vitamin A enhances IgA production of respiratory tract epithelium. 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. 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.

Vitamin C (ascorbic acid) is an important cofactor for numerous enzymes and transcription factors but is popular for its antioxidant activity. Leukocytes have a severalfold higher concentration of ascorbic acid than that of plasma, suggesting a key role for vitamin C in immune function. Low leukocyte ascorbic acid concentrations are associated with impaired immune function. Vitamin C appears to regulate immune cell apoptosis, increase costimulatory molecules of dendritic cells, and attenuate lung injury in preclinical animal models. 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. ^, High-dose vitamin C improves several measures of immune function and does not appear to have any adverse effects.

Vitamin D has a primary role in bone metabolism and calcium homeostasis. Vitamin D receptors (VDRs) are found on numerous cell types, including innate and adaptive immune cells. ^, Vitamin D has both proinflammatory and antiinflammatory functions, highlighting the complexity of its effect on immunity. Vitamin D deficiency is associated with depressed macrophage function and impaired delayed hypersensitivity. 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. In critically ill children, vitamin D deficiency was more likely to occur in winter, in older children, and those with darker skin. 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. 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.

HIV infection and AIDS

HIV is an RNA retrovirus dependent on a reverse transcriptase for DNA integration into the host cell for replication. 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 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). 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. What is unique to pediatric HIV is that the child’s immune system—unlike the adult’s—is relatively naive, with little natural immunity. 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 2 years. Antiretroviral therapy can effectively reverse HIV/AIDS immune dysfunction.

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. 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. 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. 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 severely symptomatic (i.e., AIDS) based on age-specific CD4 T-cell counts, as outlined in Table 104.4 . Stage 3 HIV infection or an AIDS-defining illness in the presence of HIV infection confirms the diagnosis of AIDS. 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. Children younger than 4 years, especially those aged 1 year or less, are more likely to have Pneumocystis jirovecii pneumonia (PJP); have severe progressive encephalopathy, wasting, or both; and die earlier. Older children, 5 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 5 and 8 months if infants do not receive antiretroviral therapy. The density of CCR5 receptors on nonactivated CD4 T lymphocytes directly correlates with CD4 T-lymphocyte decline and prognosis.

Globally, at the end of 2017, the adult prevalence of HIV was 0.8%. Sub-Saharan Africa had the highest incidence of HIV infection, accounting for 66% of the world’s people living with HIV. 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. Ninety percent of children living with HIV reside in sub-Saharan Africa. 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. 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. 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. 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. ^, It is important to extend antiretroviral therapy for the mother during the period of breastfeeding. ^, Although there has been extensive development of appropriate therapies, a major challenge has been overcoming barriers to mother-child transmission. ^,

Combinations of HAART used to treat pediatric HIV-infected patients have dramatically decreased mortality caused from HIV-associated conditions and opportunistic infections. ^, 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 3 years of age for HIV-infected children reached 89%. 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 5 years. 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. 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. Because resistance develops with monotherapy, HAART is preferred for both children and adults. 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. Baseline viral loads are higher in children than in adults and have a slower decay rate after the introduction of HAART. Pediatric studies in which dosage adjustments were directed by pharmacokinetics resulted in superior decreases in viral loads compared with fixed dosages based on weight. 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. 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. ^, Nearly 20% of hospitalized HIV-infected patients require transfer to the ICU. Barbier et al. identified major changes in the clinical presentation, ICU management, and mortality of critically ill HIV-infected adults from 1999 to 2010. 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. Pneumonia is the leading cause of morbidity and death in HIV-infected children worldwide. Comparing low- or middle-income countries to high-income countries, pneumonia accounts for 20% versus 4.3% of the annual deaths in children, respectively. 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. Bacterial pneumonia is common in this population. ^, 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. The incidence of Haemophilus influenzae and pneumococcal infections is declining where vaccination is available. 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.

Initiation of antiretroviral therapy can result in rapid immune recovery. A subset of patients experience an inflammatory response as the immune system is reconstituted. Most cases have another occult infection in addition to HIV. In one study, nearly 50% were associated with mycobacterial infections, such as Mycobacterium avium intracellulare , and herpesviruses, such as Varicella zoster . Enhanced screening and subsequent treatment of opportunistic infections such as TB before beginning HAART may prevent reconstitution inflammatory syndrome. The World Health Organization has recommended prednisone for patients with TB who experience severe paradoxical reactions; however, there are no randomized controlled trials to support this practice.

Upper airway obstruction

Young children and infants exhibit upper airway obstruction with greater frequency than adults. Whereas classic viral laryngotracheitis is the most common cause in the immunocompetent patient, immunocompromised patients are susceptible to a greater variety of infectious entities, including bacterial tracheitis, CMV-related ulceration of the trachea, and Candida infections of the airway oropharynx. Tracheostomy in HIV-infected children is not associated with increased mortality provided initiation of HAART. Given the complexity of the differential diagnosis of stridor in this population, early laryngoscopy and bronchoscopy are indicated.

Cardiovascular complications

Severe sepsis became the most common reason for ICU admission in patients with AIDS after the introduction of PJP prophylaxis. A systematic review demonstrated community-acquired bacterial bloodstream infections occurring of hospitalized HIV patients at 20% and 30% in adults and children, respectively. The main pathogens identified were nontyphoidal salmonella, S. pneumoniae , Escherichia coli , and Staphylococcus aureus . Regional differences were noted, especially for S. pneumoniae , likely due to vaccination availability and combinational HAART access. In one series of pediatric patients with AIDS, 10% of patients had Gram-negative bacillary bacteremia with a risk of death that was greater than 40%; Pseudomonas sepsis accounted for 26% of these episodes. Pseudomonas infection is frequently associated with neutropenia, which may be a cause or effect phenomenon.

Cardiac dysfunction develops in 19% to 25% of HIV-infected children and is the presenting sign in a minority of children. About 10% of a survey population had chronic congestive heart failure, whereas another 10% had transiently decreased ventricular function. ^, Cardiac complications appear to occur more frequently in rapidly progressing patients with encephalitis and other AIDS-defining illnesses. Because tachycardia and hepatomegaly are so common in pediatric AIDS patients with fever, pulmonary infection, and anemia, a clinical diagnosis of cardiac involvement is difficult to make. Enlargement of the cardiac silhouette may not be appreciable even in patients with significant muscle hypertrophy or pericardial effusion. Given these inherent difficulties in the detection of cardiac disease, assessment of a critically ill child with AIDS should include echocardiography. When assessment is prospectively followed by echocardiography, the earliest sign of cardiac involvement is diastolic dysfunction. At autopsy, aside from biventricular dilation, macroscopic evidence of cardiac dysfunction has been difficult to find in adults or children. Microscopically, in a limited number of cases, lymphocytic infiltrates and mild focal interstitial fibrosis are observed, but actual myocyte necrosis is rare. HIV cardiomyopathy likely has several causes: direct myocardial infection by HIV-1, coxsackie B3 virus, CMV, adenovirus, EBV, and Toxoplasma gondii have also been identified as pathogens causing myocardial dysfunction. ^, Selenium deficiency has been documented in severely malnourished children with AIDS whose cardiac function improved after selenium supplementation.

In the ICU, patients with severe cardiac dysfunction respond to management of preload, increasing contractility, and afterload reduction. Endocarditis, myocardial ischemia, and other potentially treatable causes of cardiac dysfunction should be ruled out with repeated blood cultures, electrocardiography, and echocardiography. Pharmacologic afterload reduction should be considered as first-line therapy, with diuretic therapy as appropriate. Other than selenium supplementation, there is no direct therapy available for HIV-related cardiomyopathy. Although survival data following clinically evident congestive heart failure in children undergoing HAART have not been reported, HAART intervention in children and adolescents appears to be cardioprotective. The etiology data on cardioprotective effects are incomplete, and evidence from adult studies link HIV infection as an independent risk factor in developing chronic cardiovascular conditions, such as hypertension, coronary artery disease, myocardial infarction, stroke, and pulmonary artery hypertension. ^, Prior studies demonstrate a potential association between congenital heart defects (CHD), myocardial dysfunction, and ZDV in in utero exposure. A current observational cohort study confirms the association between in utero exposure to ZDV and CHD (adjusted odds ratio, 2.2). In addition, the randomized clinical trial PRIMEVA demonstrated an association between in utero ZDV and long-lasting postnatal myocardial remodeling in girls.

In a survey of 81 HIV-infected children, dysrhythmias occurred in 35%, including atrial and ventricular ectopy, ventricular tachycardia, and ventricular fibrillation. A syndrome of autonomic dysfunction has been reported in adult patients with AIDS; similar lability in blood pressure and heart rate has been noted in a number of HIV-infected children. Catecholamine surges have been described in adults. Additionally, peripheral neuropathy may contribute to altered vascular regulation and a propensity for cardiac arrhythmias.

Pericardial disease is reported in approximately 30% of HIV-infected children undergoing echocardiography or autopsy. The presence of pericardial effusion and a pleural effusion is strongly associated with cardiac disease even with normal cardiac silhouette appearance. A pericardial effusion greater than 5 mm in diameter was detected in 5.4% of prospectively evaluated HIV-infected children, but no episodes of tamponade were reported.

Vasculitis has been reported in patients with HIV infection. However, it is not clear whether HIV causes the condition or is merely an association with immune dysregulation, although there are a variety of suggested mechanisms. Many infections reported in HIV-infected patients, including herpes viruses and mycobacterium, can cause inflammation by direct infection or an immune-mediated response to the endothelium. Several cases of polyarteritis nodosa have been reported. ^, When vasculitis is noted, an infectious agent should be sought.

HIV-associated nephropathy (HIVAN) has many etiologies, from direct infection by HIV to nephrotoxic HAART medications. The complications from HIVAN are proteinuria (often severe, >3.5 g/day), azotemia, interstitial disease, and segmental glomerulosclerosis. Creatinine clearance is usually normal. Proteinuria may be accompanied by hematuria. Immunoglobulins are usually elevated while complement is normal. On ultrasound, the kidneys are enlarged. The course of the disease before HAART was usually fulminant, with end-stage renal disease developing in 8 to 9 months. Effective antiretroviral therapy slows or reverses the course of HIV nephropathy, but HAART risks renal toxicities. Potentially nephrotoxic drugs to which the HIV-infected patient may be exposed are legion. Antiretroviral drugs indinavir and tenofovir are associated with increased risk of chronic renal failure. Pentamidine-induced renal toxicity usually occurs in the second week of therapy, causing proteinuria and hematuria. This may be falsely attributed to HIVAN or catheter-induced trauma. Early recognition and cessation of pentamidine are key to renal recovery; a repeat challenge of pentamidine will prompt an early return of proteinuria and hematuria. Renal toxicity from sulfadiazine during the treatment of toxoplasmosis is also reported and can be reduced by hydration. Amphotericin-induced nephrotoxicity is particularly problematic when the drug is used in combination with aminoglycosides.

In critically ill patients with AIDS, acute tubular necrosis may be precipitated by sepsis, hypovolemia, or hypoperfusion, which is reversible, as in non-HIV-infected patients. However, HIV-infected children presenting with acute kidney injury at admission have a higher in-hospital mortality. The same principles for management and support of a patient with reversible acute renal failure apply to the HIV-infected population. For patients who are seen in the ICU with end-stage renal disease due to HIV nephropathy, the indications for dialysis are the same as in other patient populations. But the decision to undertake dialysis must be made on an individual basis. Peritonitis during ambulatory peritoneal dialysis in pediatric patients with AIDS does not occur with any apparent greater frequency than in immunocompetent patients. Kidney transplantation has been successful in carefully selected HIV-infected patients.

Abdominal complications

Patients with AIDS have multiple gastrointestinal complaints including dysphagia, abdominal pain, and chronic diarrhea. However, these are generally not important in the ICU except that they affect nutritional status. Other more life-threatening complications include severe dehydration, intraabdominal sepsis, pancreatitis, and hepatic failure. Diarrhea occurs in 40% to 60% of children with AIDS and may produce severe dehydration. Worldwide, acute diarrhea is the most common cause of death in children with AIDS. In underdeveloped countries where poor sanitation increases the risk of diarrheal diseases, HIV-related hypovolemic shock is a common indication for PICU admission. Patients with AIDS may have typical infectious enteritis and enterocolitis caused by Salmonella, Shigella, Giardia, Campylobacter, and rotavirus, but may also have an atypical, prolonged course. The frequent use of systemic antibiotics in HIV-infected children increases the risk of Clostridium difficile colitis. Mycobacterium avium-intracellulare , cryptosporidium, Giardia , Cystoisospora belli (formerly known as Isospora belli ), CMV, and adenovirus may all induce opportunistic small-bowel enteropathy. Patients with MAC, CMV, and Candida infection typically also have extra gastrointestinal infection. A nonspecific enteropathy may arise as a result of the overgrowth of normal gut flora due to the effects of local immunodeficiency and antibiotic use. It is not uncommon to find heavy growth of Candida albicans or Pseudomonas aeruginosa in stool cultures. If findings from stool culture and analysis are negative, a flexible sigmoidoscopy with possible rectal biopsy should be considered in the child with rectal bleeding or tenesmus. Aspiration of duodenal secretions is particularly helpful in evaluation of patients from underdeveloped countries in that the aspirate may reveal infection with C. belli , Cryptosporidium parvum , or helminthic species. Additional evaluation may be desirable, including small-bowel radiography or abdominal computed tomography (CT) scanning. If results of all diagnostic studies are negative, diarrhea may be due to HIV therapy because most antiretroviral agents are associated with diarrhea. Recovery of MAC from the blood generally indicates invasive disease, but percutaneous needle aspiration with CT guidance of enlarged intraabdominal nodes may be confirmatory. ^, Antimicrobial therapy of disseminated MAC infection before HAART was unrewarding, and disseminated MAC is rapidly fatal. Current antimicrobial therapy is a two-drug regimen of a macrolide and ethambutol with the possible addition of a third agent, including rifabutin, ciprofloxacin, or azithromycin. Prophylaxis against MAC with azithromycin is indicated in children with CD4 counts less than 100 cells/μL and in infants with counts less than 200 cells/μL. In patients treated with HAART, diarrhea often persists despite improvements in immunologic function.

The evaluation and management of acute abdominal pain in HIV-infected children is complicated by their immunosuppressed state. Localized signs of infection can be masked by immunosuppression, debilitation, and previous or current use of antibiotics. In fact, a significant intraabdominal abscess may result in minor symptoms, with unremarkable elevations in white blood cell count or temperature. Thus, diagnostic imaging with abdominal CT scan is invaluable for evaluation in children with HIV. Although morbidity after surgical intervention is somewhat higher in patients with AIDS, there is still a significant survival when such intervention is undertaken promptly. ^, Supportive management of these conditions is the same as that for immunocompetent patients, although the appropriate antimicrobial therapy may be different.

Pancreatitis in the AIDS population results from both the disease and its treatment. ^, Pancreatitis presents as acute or persistent midepigastric pain and/or back pain and elevation of serum amylase, lipase, and triglyceride levels. Infectious causative entities include CMV, adenovirus, mycobacterium, fungal infections, cryptococcus, herpes simplex virus (HSV), and protozoal infections, such as by Toxoplasma, Pneumocystis, and Cryptosporidium . The list of drugs known to cause pancreatitis is extensive and includes the antiretroviral agent zalcitabine and the antiprotozoal agent pentamidine. The mechanism by which drugs induce pancreatitis is unknown. Maintaining a high index of suspicion for pancreatitis is important because vomiting, abdominal distension, and malabsorption are common complaints in the HIV-infected child. Evaluation of these patients should include both serum lipase and amylase determinations because parotid inflammation seen in HIV infection can cause isolated elevations of serum amylase concentrations. Abdominal ultrasound is useful only in the detection of a large edematous pancreas and in follow-up assessment for pancreatic pseudocyst.

The cause of hepatic failure in HIV-infected patients differs from that of other adults and is affected by the patient’s degree of immunosuppression. In early stages, hepatic disease is usually a result of drug toxicity or hepatotropic viruses. Drug-induced hepatotoxicity has been reported with sulfa drugs, isoniazid, rifampin, rifabutin, and several antiretroviral agents. If HIV progresses to AIDS, the liver manifests systemic involvement of opportunistic infections. ^, Reviews of hepatic tissue disease in HIV-infected children document that CMV and mycobacterial disease are common in children, whereas classic viral hepatitis is relatively rare. ^, Chronic hepatitis becomes clinically significant as survival increases in patients receiving HAART. Cholangitis and cholecystitis are well described in adult patients with AIDS; biliary tract infections have been attributed to CMV, adenovirus, cryptosporidium, and microsporidia. ^{, ,} Liver biopsy is indicated only when mycobacterial disease is expected or jaundice is present, as most diseases can be diagnosed by serologic testing or PCR. Drug toxicity has no specific biopsy finding. HIV itself can cause a giant cell hepatitis and dense lymphoid infiltrates, similar to those in the lung in LIP. Hepatitis B and C can occur in patients with HIV/AIDS, and it is estimated that 30% of HIV-infected adults worldwide are coinfected with hepatitis C. Hepatitis B can be treated with the antiretrovirals lamivudine in combination with tenofovir or entecovir. Recent advances in hepatitis C therapies demonstrate a greater sustained virologic response; adult patients coinfected with HIV and HCV should be treated with ribavirin, interferon, and sofosbuvir (an oral direct-acting antiviral that inhibits HCV polymerase). ^, Liver transplantation can be successful with proper patient selection. ^,

Hematologic and malignancy complications

Hematologic abnormalities are common in patients with HIV/AIDS. Isolated thrombocytopenia is likely mediated by antiplatelet antibodies and should prompt HIV testing. ^, As with other forms of antibody-mediated thrombocytopenia, this may respond to immunoglobulin, steroids, or subtotal splenectomy. Neutropenia may be antibody mediated, drug related, or secondary to sepsis, and granulocyte colony growth factors have reduced the incidence of sepsis in AIDS patients.

Anemia occurs in 20% to 73% of HIV-infected children and is an independent predictor of death from AIDS. ^, Iron deficiency and other nutritional deficiencies previously discussed, possibly related to malabsorption, account for 10% to 45% of anemia in HIV-infected children. Many medications that are given to patients with AIDS cause anemia, including ZDV, acyclovir, TMP-SMX, and pentamidine. Anemia of chronic disease, mediated by inflammatory cytokines, likely accounts for additional cases. Rarely, antierythrocyte and antierythropoietin antibodies have been reported in patients with AIDS.

Malignancies account for 2% of AIDS-defining illnesses in pediatric patients and are those typically associated with chronic viral infections. In a cohort study of perinatally HIV-infected children, the cancer rate was nearly four times higher in children treated with HAART for less than 2 years when compared with those treated for more than 2 years. The development of cancer was 3 times more likely in those with low CD4 T lymphocyte counts. EBV DNA has been identified in most CNS lymphomas, soft-tissue leiomyosarcomas or rhabdomyosarcomas, and polyclonal, polymorphic B-cell lymphoproliferative disorder similar to that seen in transplant patients receiving immunosuppression. In addition, infection with human herpes virus type 8 (HHV-8) is associated with body cavity–based lymphoma and Kaposi sarcoma. Human papilloma virus is associated with invasive cervical cancer. Hepatitis B infection is associated with the development of hepatocellular carcinoma.

Central nervous system complications

CNS involvement—defined as seizure disorders, cerebral vascular accidents, CNS lymphoma, and aseptic meningitis—presents in 20% to 60% of HIV-infected children. ^, In this situation, treatable conditions must be ruled out before the diagnosis of AIDS encephalopathy can be made. Evaluation of these patients generally requires a series of biochemical and radiologic tests. Imaging studies such as CT and magnetic resonance imaging (MRI) can reveal mass-occupying lesions, such as intracranial hemorrhage, malignancies, or calcifications consistent with infection. Lumbar puncture is necessary to rule out infection and CSF should be routinely cultured and investigated for specific pathogens via culture, direct antigen detection, and nucleic acid detection using PCR.

Primary HIV infection of the CNS probably occurs in 4% of HIV-infected children by the age of 12 months. This entity is termed HIV encephalopathy and can generally be divided into two types: static with developmental delay or progressive, similar to AIDS dementia in adults with progressive decline in neurologic functioning. Direct HIV infection of the macrophages and microglia of the CNS is thought to cause release of inflammatory neurotoxins such as TNF or platelet-activating factor. Pathologically, gliosis, microglial nodules, demyelination, and multinucleate giant cells are seen. Diffuse atrophy is noted on CT and bifrontal white matter abnormalities are commonly seen on MRI. ^, One-third of infected children may show calcifications of the basal ganglia. Calcifications observed before age 10 months are more likely due to an infection other than HIV, such as toxoplasmosis or CMV. AIDS encephalopathy is a diagnosis of exclusion—other pathogens must be ruled out. Therefore, evaluation includes imaging of the brain by CT or MRI along with blood and CSF studies in search of specific pathogens, such as Cryptococcus , Mycobacterium spp., CMV, HSV, varicella-zoster virus, and Treponema pallidum .

CNS malignancy, such as high-grade B-cell lymphoma, is found in 4% of HIV-infected children and is the most common mass lesion found in the CNS of children with AIDS. It generally presents between ages 5 and 10 years. Lymphoma can be distinguished from toxoplasmosis by increased uptake of tracer on single-photon emission computed tomography or positron emission tomography imaging. The most frequently affected areas are in periventricular white matter and it is associated with EBV infection.

CNS infection by usual and opportunistic organisms in childhood AIDS accounts for only 13% of neurologic complications. Primary CNS infections in HIV-infected children are caused by the usual etiologic bacterial organisms and M. tuberculosis . The usual presenting signs and symptoms are seen. Opportunistic infections, such as CMV and aspergillosis, are frequently observed at autopsy and generally result from disseminated disease. Toxoplasmic encephalitis occurs in 30% of adult patients with AIDS and is generally seen in only older children. Combination therapy with sulfadiazine and pyrimethamine is generally effective if initiated early. Clindamycin is an appropriate alternative in patients with sulfa allergy. Corticosteroids are sometimes used in addition to first-line therapy to reduce edema. Relapse is common after treatment is stopped and maintenance therapy is necessary. Primary prophylaxis is offered to adults with serologic findings that are positive for toxoplasma and a CD4 count of less than 200.

Although not considered a reactivated infection, cryptococcal meningitis is typically seen in older children. Cryptococcus spreads via the bloodstream to the CNS. Classic presentation includes fever, headache, and preceding alterations in mental status. Focal neurologic signs and meningeal signs are minimal. CSF counts may be normal, although intracranial pressure (ICP) is typically elevated and CT findings are nonspecific.

Progressive multifocal leukoencephalopathy presents with ataxia, aphasia, weakness, and lethargy. CT may be relatively unremarkable, with one or two nonenhancing hypodense areas of demyelination generally in subcortical white matter. MRI is more sensitive than CT for detection of these lesions. The lack of inflammatory findings is believed to be due to the severity of immunosuppression. The only treatment for this condition is HAART in the hopes that the immune system will be reconstituted. However, an inflammatory response during immune reconstitution may cause clinical deterioration and seizures. Death is typically secondary to apnea and, although recovery is possible, residual deficits are likely.

Occupational human immunodeficiency virus exposure

Serious exposure to HIV in the healthcare setting is most likely to occur in the emergency department or ICU. The risk of exposure is 0.3% after a percutaneous exposure and 0.09% after blood or body fluid contact with nonintact skin or mucous membrane. Postexposure prophylaxis should be offered to all persons who have sustained a mucosal or parenteral exposure to HIV from a known infected source within 72 hours. Postexposure prophylaxis regimen should consist of the US Public Health Service preferred regimen: raltegravir plus Truvada (tenofovir plus emtricitabine). Women who receive postexposure prophylaxis should be offered emergency contraception to prevent pregnancy. Repeat HIV antigen testing should be done 3 months after completion of the postexposure prophylaxis regimen.

Other selected causes of secondary immune dysfunction

Neonatal period

The impaired immunity of the neonate is related to the immaturity of lymphoid tissues, innate cells, and T/B lymphocytes. This immune system immaturity increases the neonate’s susceptibility to infectious organisms and is inversely associated with prematurity. Neonates have an absence of memory T lymphocytes because of the protective in utero environment. The lymphoid tissues are undeveloped, lacking marginal zones that support B-lymphocyte maturation. This includes the lymphoid tissue of the respiratory and gastrointestinal tracts. Neutrophils and NK lymphocytes have reduced activity, especially phagocytosis, cytokine production, and toll-like receptor signaling.