1235CHAPTER 104 Acquired Immune Dysfunction Initiation of antiretroviral therapy can result in rapid immune recovery A subset of patients experience an inflammatory re sponse as the immune system is r[.]
CHAPTER 104 Acquired Immune Dysfunction Initiation of antiretroviral therapy can result in rapid immune recovery A subset of patients experience an inflammatory response as the immune system is reconstituted.163 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.164 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.163 Pneumocystis jirovecii Pneumonia PJP occurs in patients with acquired immunodeficiency from HIV, chemotherapy, and immunomodulatory therapies Although increased emphasis on early prophylaxis has reduced its incidence, PJP is still the most common AIDS-defining illness in pediatrics.162,165 Infants not previously recognized to be infected with HIV may present as early as to weeks of age, whereas the median age or presentation to ICUs is between and months of age This coincides with the timing of a natural decline in maternal antibodies In children known to be at risk of HIV infection, PJP prophylaxis is indicated starting at to weeks of age as CD4 lymphocyte counts obtained before the development of infection are not predictive of infection and can drop precipitously Pneumocystis jirovecii is unique to humans and has a predilection for the lung.166 PJP generally presents with cough, fever, tachypnea, and dyspnea of several days Physical examination typically reveals retractions, grunting, rales, rhonchi, or wheezing The chest radiograph generally shows diffuse interstitial infiltrates, but pulmonary infiltrates can be variable in children, in part because infants have a greater propensity for atelectasis.167 Hypoxemia is often out of proportion to clinical and radiographic examinations A selectively elevated serum lactate dehydrogenase level is suggestive, although not diagnostic of PJP.166 For a confirmation of a PJP diagnosis, bronchoalveolar lavage should be performed Flexible fiberoptic bronchoscopy has a diagnostic yield of 90% to 97% and allows one to look for other pathogens as well Nonbronchoscopic bronchoalveolar lavage and sputum induction may also be used in combination with PCR to detect PJP.168,169 Patients in whom no diagnosis is obtained from bronchoalveolar lavage should undergo an open-lung biopsy This procedure has a diagnostic yield for PJP of 97% in the study of patients with underlying malignancy or immunosuppression.166 The preferred antiprotozoal therapy for PJP is the combination of trimethoprim and sulfamethoxazole (TMP-SMX; 20 mg/kg per day TMP).166 Patients in whom this combination agent fails have not been shown to respond to a change in antiprotozoal therapy In fact, higher doses of both components may be required to achieve therapeutic levels in critically ill patients Sulfa allergy as manifested by severe drug eruptions, including StevensJohnson syndrome, is less frequent in children than in adults However, severe drug eruptions may prompt a change of therapy to pentamidine (4 mg/kg per day) When adverse events such as pancreatitis and renal failure occur as a result of pentamidine, atovaquone (40 mg/kg per day) is an alternative treatment.166 Twenty-one days of therapy are followed by prophylactic therapy, for which TMP-SMX is also the agent of choice 1235 Several adult randomized controlled trials showed efficacy of high-dose steroids in HIV-positive adults with moderate PJP Although no controlled studies have been performed in children, improved outcomes in children who received corticosteroids have been described in several case series.170–172 Even in the face of respiratory failure, the survival rates reported with adjunctive corticosteroid therapy are 91% to 100% in a limited number of pediatric studies.171,172 Adults who have respiratory failure despite adjunctive corticosteroids have a high risk of death; failure to improve after days of mechanical ventilation and the development of pneumothorax were strongly predictive of death in adults.173 Pneumocystis pneumonia has also been reported in patients receiving high-dose steroids, transplant-related immunosuppression, and the new monoclonal antibodies that modulate the immune system.174 Cytomegalovirus Pneumonitis Children at risk for vertical transmission of HIV are also at risk for CMV infections Kitchin et al reported that 55% of HIVexposed but untreated children with respiratory failure in South Africa had a CMV viral load in the range consistent with CMV disease.175 Furthermore, the mortality from CMV with and without PJP was over 40% Failure of PJP response to conventional therapy may constitute evidence of concomitant CMV infection The presentation of CMV pneumonitis can closely mimic that of PJP with diffuse interstitial infiltrates and hypoxemia, but there is generally a more insidious onset.176 While the definitive diagnosis of CMV pneumonitis may require identification of characteristic intracellular viral inclusion bodies in pulmonary macrophages or biopsy specimens, because viral shedding is known to occur, the prevalence of CMV pneumonitis and its contribution to mortality in immunocompromised children has led many to recommend empiric therapy for pneumonia.176,177 Viral culture and viral nucleic acid detection by PCR performed on tracheal aspirates and blood have all been used to guide treatment.176,177 CMV treatment is ganciclovir mg/kg, administered twice daily, followed by long-term oral suppressive therapy.178 Foscarnet and cidofovir have been used in other immunosuppressed patients, but these drugs have significant nephrotoxicity.178 Although solid-organ transplant recipients receive prophylaxis against CMV with ganciclovir, this approach has not been applied to patients with AIDS Of course, patients with AIDS should also receive HAART Other Viral Pathogens Children with AIDS are more likely to experience lower airway disease and pneumonia when contracting respiratory syncytial virus (RSV) and influenza.179,180 For RSV, the estimated incidence was twofold greater in HIV-infected children; it is not clear that HIV infection increases the likelihood of death.179 The incidence of lower respiratory tract disease requiring hospitalization in influenza was eightfold higher in children with HIV infection.180 HIVinfected children with influenza pneumonia were older and more likely to have another underlying disease or concurrent infection Despite these comorbidities, there was no difference in clinical outcome Other pathogenic viruses recovered from pediatric patients with AIDS include adenovirus, parainfluenza, herpes simplex, and measles In vitro data suggest ribavirin and cidofovir may be effective against some of these viral pathogens However, evidence of in vivo efficacy is limited to anecdotal reports in im- 1236 S E C T I O N X I Pediatric Critical Care: Immunity and Infection munosuppressed patients.181 Immunosuppressed children have been noted to shed viral pathogens such as RSV and influenza for a prolonged period of time; therefore, hospital-acquired viral infections may be a significant problem if infection control practices are not maintained.182,183 Mycobacterial Pathogens Worldwide, approximately one-third of the human population is infected with Mycobacterium bacillus.184 Most of these individuals live in developing countries where the prevalence of HIV infection is high The incidence of M tuberculosis appeared to level off in the United States by 1985 but began rising steadily in 1988—an increase attributed to the AIDS epidemic.185,186 The increased incidence of pediatric TB is likely due to increased exposure to adults with active TB infection HIV-infected children with TB have higher CD4 T-lymphocyte counts than those observed with other classic opportunistic infections.139 Although adults generally acquire HIV infection after acquiring TB, the opposite is true in children Thus, HIV-infected children have not mounted an immunologic response to M tuberculosis In contrast to adults who have apical cavitary lesions, children demonstrate more peripheral lung disease.184 These children also have a high incidence of extrapulmonary manifestations, such as hepatosplenomegaly and meningitis Aggressive efforts to confirm mycobacterium infection by culture are required because anergy obscures Mantoux testing (tuberculin skin test [TST]) Use of PCR to identify M tuberculosis nucleic acids in bronchoalveolar lavage and cerebrospinal fluid (CSF) specimens can accelerate diagnosis.186 Recovery of mycobacterium by sputum induction has been reported in infants and very young children.186 In some regions, organism recovery is necessary for antimicrobial susceptibility determination; approximately 25% of isolates are resistant.187 Children with TB and HIV coinfection who are not treated with HAART have a higher mortality rate than children not infected with HIV.188 They must be treated for a longer time, perhaps because of poor drug absorption and a weakened immune system Patients coinfected with TB and HIV need a specialist familiar with antiretroviral therapies because rifampin, a common anti-TB drug, is contraindicated with protease inhibitors and nonnucleoside reverse transcriptase inhibitors.188 During HAART, reconstitution of the immune system may increase the inflammatory response to pulmonary TB Mycobacterium avium-intracellulare complex (MAC) may also be recovered from the lungs of children with pneumonia.158 Fungal Infections Candida is frequently recovered from sputum and bronchoalveolar lavage samples in children with AIDS.189 Candidiasis of the respiratory or gastrointestinal system is an AIDS-defining illness Aspergillosis has also been reported in older children with multiple opportunistic infections, prolonged hospitalization, neutropenia, and corticosteroid use.190 Cryptococcosis occurs in 5% to 15% of adults but in only 0.6% to 1% of children.191 This ubiquitous organism enters the body through the respiratory tract Therefore, initial symptoms are generally both pulmonary and nonspecific Cryptococcal antigen titers are useful in the evaluation of possible relapse Prophylaxis for the prevention of cryptococcal disease is not recommended in children Other fungal infections—such as histoplasmosis, cryptococcosis, coccidiomycosis, and disseminated Talaromyces marneffei (formerly known as Penicillium marneffei)—are reported in patients with AIDS who are living in or traveling through endemic areas.158,192 Lymphocytic Interstitial Pneumonitis LIP is a lymphoproliferative disorder associated with viral infections In children, LIP is almost exclusively seen with Epstein-Barr virus (EBV) and HIV.193 LIP occurs in 30% to 50% of pediatric patients with AIDS, presenting in the second year of life in that patient population, with high antibody titers and recurrent bacterial infections.193 Generally, the children also have diffuse lymphadenopathy and hepatosplenomegaly Children with LIP may have mild pulmonary symptoms, such as dry cough, but generally are admitted to the PICU only when an acute infection is superimposed on their chronic condition When such is the case, maximal therapy of the acute exacerbation is indicated, including mechanical ventilation On chest radiograph, hilar adenopathy and reticulonodular infiltrates are seen Pulmonary function tests reveal reduced lung volumes and diffusing capacity Histologically, peribronchial lymphoid nodules containing plasma cells and lymphocytes are observed Most specimens show predominantly CD8 T lymphocytes Spontaneous radiographic resolution was reported in 65% of children with LIP.194 Patients with hypoxemia are treated with steroids; resolution is seen in most patients in to weeks If the patient is persistently febrile, MAC infection should be ruled out before steroid administration.158 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.195 Tracheostomy in HIV-infected children is not associated with increased mortality provided initiation of HAART.196 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.154 A systematic review demonstrated community-acquired bacterial bloodstream infections occurring of hospitalized HIV patients at 20% and 30% in adults and children, respectively.197 The main pathogens identified were nontyphoidal salmonella, S pneumoniae, Escherichia coli, and Staphylococcus aureus.197 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.198 Pseudomonas infection is frequently associated with neutropenia, which may be a cause or effect phenomenon.198 Cardiac dysfunction develops in 19% to 25% of HIV-infected children and is the presenting sign in a minority of children.199 About 10% of a survey population had chronic congestive heart failure, whereas another 10% had transiently decreased ventricular function.200,201 Cardiac complications appear to occur more frequently in rapidly progressing patients with encephalitis and CHAPTER 104 Acquired Immune Dysfunction 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.199 At autopsy, aside from biventricular dilation, macroscopic evidence of cardiac dysfunction has been difficult to find in adults or children.202 Microscopically, in a limited number of cases, lymphocytic infiltrates and mild focal interstitial fibrosis are observed, but actual myocyte necrosis is rare.202 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.200,203 Selenium deficiency has been documented in severely malnourished children with AIDS whose cardiac function improved after selenium supplementation.204 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.205 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.206,207 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.208 In a survey of 81 HIV-infected children, dysrhythmias occurred in 35%, including atrial and ventricular ectopy, ventricular tachycardia, and ventricular fibrillation.209 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.199 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 HIVinfected children undergoing echocardiography or autopsy.199 The presence of pericardial effusion and a pleural effusion is strongly associated with cardiac disease even with normal cardiac silhouette appearance.210 A pericardial effusion greater than mm in diameter was detected in 5.4% of prospectively evaluated HIVinfected children, but no episodes of tamponade were reported.210 Vasculitis has been reported in patients with HIV infection However, it is not clear whether HIV causes the condition or is 1237 merely an association with immune dysregulation, although there are a variety of suggested mechanisms.211–214 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.211,214 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.215 The course of the disease before HAART was usually fulminant, with end-stage renal disease developing in to months Effective antiretroviral therapy slows or reverses the course of HIV nephropathy, but HAART risks renal toxicities.216–218 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.218 Pentamidineinduced 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.219 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.220 Kidney transplantation has been successful in carefully selected HIV-infected patients.221 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.222 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.223 Worldwide, acute diarrhea is the most common cause of death in children with AIDS.144 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 1238 S E C T I O N X I Pediatric Critical Care: Immunity and Infection enterocolitis caused by Salmonella, Shigella, Giardia, Campylobacter, and rotavirus, but may also have an atypical, prolonged course.222–224 The frequent use of systemic antibiotics in HIVinfected 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.224 Patients with MAC, CMV, and Candida infection typically also have extra gastrointestinal infection.225 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.209,211 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.226 Prophylaxis against MAC with azithromycin is indicated in children with CD4 counts less than 100 cells/mL and in infants with counts less than 200 cells/mL.226 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.227,228 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.140,229 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.226 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 followup 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.230 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.231,232 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.230,232 Chronic hepatitis becomes clinically significant as survival increases in patients receiving HAART.233 Cholangitis and cholecystitis are well described in adult patients with AIDS; biliary tract infections have been attributed to CMV, adenovirus, cryptosporidium, and microsporidia.232,234,235 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.230 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.233 Hepatitis B can be treated with the antiretrovirals lamivudine in combination with tenofovir or entecovir 233 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).233,236 Liver transplantation can be successful with proper patient selection.237,238 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.239,240 As with other forms of antibody-mediated thrombocytopenia, this may respond to immunoglobulin, steroids, or subtotal splenectomy.241 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.242 Anemia occurs in 20% to 73% of HIV-infected children and is an independent predictor of death from AIDS.243,244 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.245 Malignancies account for 2% of AIDS-defining illnesses in pediatric patients and are those typically associated with chronic CHAPTER 104 Acquired Immune Dysfunction viral infections.246 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 years when compared with those treated for more than years.247 The development of cancer was 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 (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.233 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.248,243 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.249 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.250 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.251–253 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.254,255 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.255 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, varicellazoster 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.247 It generally presents between ages 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 1239 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.256 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.257 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.258 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.259 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.260 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.257 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.261 Postexposure prophylaxis regimen should consist of the US Public Health Service preferred regimen: raltegravir plus Truvada (tenofovir plus emtricitabine).261 Women who receive postexposure prophylaxis should be offered emergency contraception to prevent pregnancy.261 Repeat HIV antigen testing should be done months after completion of the postexposure prophylaxis regimen.261 Other Selected Causes of Secondary Immune Dysfunction Immunosuppressive Medications The use of medications to alter immune responses is becoming common in clinical practice, treating broad categories of diseases, such as autoimmune disorders, allergic disorders, transplant ... control practices are not maintained.182,183 Mycobacterial Pathogens Worldwide, approximately one-third of the human population is infected with Mycobacterium bacillus.184 Most of these individuals... corticosteroid use.190 Cryptococcosis occurs in 5% to 15% of adults but in only 0.6% to 1% of children.191 This ubiquitous organism enters the body through the respiratory tract Therefore, initial symptoms... provided initiation of HAART.196 Given the complexity of the differential diagnosis of stridor in this population, early laryngoscopy and bronchoscopy are indicated Cardiovascular Complications