Posted by: Indonesian Children | June 14, 2009

HIV IN CHILDREN : Complications

 

  • Viral resistance
  • In terms of the mechanisms of resistance development, the rapid turnover rate and high error rate of reverse transcriptase induces 3300 new single mutations per day. When a mutation improves the survival of the virus in an existing drug environment, that quasispecies is selected to reproduce. The higher the viral load and the higher the rate of replication, the greater the number of resistant quasispecies. 
  • Approximately 10-15% of new infections are multidrug resistant in adults. Such drug resistant quasispecies can be transmitted to the fetus or neonate. 
  • HIV resistance develops because of low antiretroviral drug levels due to several factors, including variations in drug absorption and metabolism and lack of compliance because of adverse effects or a poor understanding of the importance of the medication. Virus sanctuary sites may be exposed to lower levels of antiretroviral drugs, and resistant quasispecies may develop.
  • Nonopportunistic infections
  • Like most children, children with HIV are susceptible to common pathogens. Diseases caused by such pathogens should be high in the differential diagnosis list in these children. Of course, the particular medical history of the child guides differential diagnosis. For example, chronic lung disease requires special consideration of atypical respiratory pathogens such as Pseudomonas or Xanthomonas species. 
  • One of the challenges with children who are infected with HIV is that they are more likely to have recurrent infection, which causes them to undergo repeat treatment with many broad-spectrum antibiotics. This antibiotic exposure increases the risk of developing resistant pathogens. Thus, infection with penicillin-resistant Pneumococcus is not uncommon in children with recurrent ear infections. 
  • Common recurrent infections include otitis, sinusitis, and pneumonia. Recurrent otitis is observed in 55% and 35% of HIV-infected children with AIDS and those without AIDS, respectively. 
  • Moderate and severe neutropenia increases the risk for bacterial infection by 2.3- and 7.9-fold, respectively. 
  • Other risk factors for bacterial infection include neutropenia within the last 3 months and central venous line access. 
  • Children with recurrent bacterial infections and CD4 counts less than 200 X 109/L may benefit from monthly IVIG, as discussed previously.
  • Opportunistic infections
  • P carinii infection 
    • PCP was the most common opportunistic infection in children with vertically transmitted HIV prior to universal prophylactic antibiotic treatment. Before prophylactic treatment, PCP commonly occurred in infants aged 3 months. Without prophylactic suppression, infection may develop in children younger than 1 year regardless of the baseline CD4 count because the rapid progression of the immune suppression may precipitate a sharp decrease in CD4 count. 
    • PCP typically occurs in children with moderate immune suppression; this warrants category C classification. 
    • Fever and tachypnea are usually the presenting symptoms. 
    • Chest radiographs may or may not show diffuse interstitial pulmonary infiltrates. 
    • Lung examination may or may not reveal rales. 
    • Diagnosis is confirmed by detecting PCP antigen in a sputum or, preferably, bronchoscopy lavage specimen. 
    • Prophylaxis is the most important measure for decreasing the incidence in this disease, it but does not guarantee protection. Table 4 below delineates the CD4 indications for starting prophylaxis with regard to the patient’s age.

    Table 4. CD4 Indication for Starting PCP Prophylaxis

     

     

     

    Indication CD4 Count, X 109/L CD4, %
    Age 6 wk to 1 y Any Any
    Age 1-2 y <750 <15
    Age 2-5 y <500 <15
    Age >5 y <200 <15
    Previous PCP infection Any Any
  • Prior CMV infection or CMV retinitis requires prophylaxis with ganciclovir 5 mg/kg/d IV, foscarnet 90-120 mg/kg/d IV, or a ganciclovir sustained-release implant. 
  • Severe or frequent recurrences of herpes simplex require prophylaxis with acyclovir 80 mg/kg/d PO bid or qid. 
  • Varicella or zoster infection should be treated with IV acyclovir 500 mg/m2/dose tid for 7 days. 
  • Candida infection 
    • Thrush occurs in a third of patients non–category C disease and half of patients with category C disease. 
    • Candidal esophagitis is an AIDS-defining condition and can result in severe dysphagia and anorexia. 
    • Disseminated systemic fungemia is rare, but indwelling catheters and neutropenia increase a patient’s susceptibility. 
    • Primary prophylaxis is not generally recommended, but prophylaxis after repeated infections may be helpful. 
    • Prophylactic treatment is used in severe recurrent cases, but prolonged prophylaxis can lead to resistance. 
    • Nystatin may not be helpful with repeated thrush or cutaneous infections, and topical clotrimazole or miconazole may be needed. 
    • Fluconazole, itraconazole, or ketoconazole may be needed if topical treatments fail or if candidal esophagitis develops. 
    • Candidal esophagitis recalcitrant to treatment with azole compounds and disseminated disease should be treated with amphotericin.

     

  • Tuberculosis 
    • TB causes primary pulmonary disease in children and is more likely in children with existing lung disease. 
    • Extrapulmonary disease can occur, especially when decreased immune function exists, and it may be present with or without pulmonary disease. 
    • Multidrug-resistant TB is highly prevalent among HIV-infected individuals. 
    • Fever, cough, and tachypnea are common presenting symptoms. 
    • PPD is useful only if its findings are positive, and it should not be used as a diagnostic method. 
    • Gastric aspirates, induced sputum samples, and bronchoalveolar lavage specimens are necessary, and susceptibility testing should be performed. 
    • Initial therapy should involve 4 drugs, including isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol or streptomycin. Therapy should continue for 1 year if the isolate is drug susceptible or longer if the isolate is multidrug resistant. Rifampin and rifabutin interact with protease inhibitors requiring alteration in HAART. Children younger than 4 years should not be treated with ethambutol because of possible optic neuritis. 
    • Multidrug-resistant TB is associated with a poor prognosis.

     

  • MAC infection 
    • Disseminated MAC infection is not uncommon in children with significant disease progression, and a low CD4 count is a major risk factor for MAC disease. MAC infection is second only to PCP as one of the most common opportunistic infections in children with AIDS and occurs in 6-15% of children with HIV infection. This percentage increases to 24% in children with CD4 counts less than 100 X 109/L. In the United States, MAC infection may be more common in the South than elsewhere. 
    • MAC is ubiquitous, commonly existing in water, soil, and household environments. Colonization may occur in some individuals before infection. Person-to-person transmission has not been documented. 
    • Although localized pulmonary disease is the common site of infection in the non–HIV-infected host, localized disease is uncommon in the HIV-infected individual, and disseminated disease is typical. 
    • Disseminated MAC infections commonly cause fever, night sweats, malaise, anorexia, and weight loss. Anemia and elevated alkaline phosphatase levels also are common. 
    • Bone marrow involvement may produce neutropenia. 
    • Gastrointestinal symptoms are common in some presentations. Abdominal pain, hepatosplenomegaly, and diarrhea with associated malabsorption may be common, but elevated transaminase levels are not common. CT or MRI may reveal general intestinal lymphadenopathy. 
    • Sputum, stool, and blood acid-fast cultures should be obtained when the presence of MAC is suspected. The reticuloendothelial system is a common reservoir for mycobacteria, although the bone marrow, gastrointestinal tract, lungs, adrenals, and kidneys also may be affected. 
    • Control of the MAC infection requires at least 2-3 antibiotics, but more may be necessary if clinical symptoms do not resolve. Early detection and treatment is most effective. Exposure to antibiotics before treatment suggests that other agents may be more effective, and the lack of a response to a regimen may indicate the need to change antibiotics empirically instead of simply adding additional antibiotics because drug resistance can develop rapidly. 
    • Although multiantibiotic therapy may be useful, toxicity is more common with this approach. 
    • Initial regimens may include macrolides, rifabutin, and ethambutol, but rifabutin interacts with several protease inhibitors, and ethambutol is not generally used in children younger than 4 years because of the possible development of optic neuritis. However, ethambutol is the only choice in many situations, and it is used when indicated. Amikacin, cefoxitin, ciprofloxacin, ofloxacin, doxycycline, rifampin, and streptomycin also may be used in treatment. 
    • The best treatment is the use of effective HAART with immune reconstitution, which increases the CD4 count. 
    • Blood cultures should be obtained at regular intervals until results are negative and the susceptibilities of identified organisms are determined. Treatment must be continued indefinitely. 
    • Prophylaxis is extremely important. Table 5 below indicates the CD4 count at which prophylaxis should be started with regard to the patient’s age.

    Table 5. Indication and CD4 Count for MAC Prophylaxis

     

     

    Indication CD4 Count, X 109/L
    Age <1 y <750
    Age 1-2 y <500
    Age 2-6 y <75
    Age >6 y <50
    Previous infection Any

     

  • Cryptosporidium infection 
    • Cryptosporidium infections cause chronic, secretory, watery diarrhea that may be large in volume. 
    • Maintaining an adequate fluid balance is most important and may be challenging. 
    • A unique parasitophorous vacuole within the host cell shelters the parasite from antimicrobial drugs. 
    • Control of the infection can be difficult because no curative therapy exists. 
    • The best treatment is prevention and good immunity. 
    • Clarithromycin administered for MAC prophylaxis may also protect the patient against Cryptosporidium infection. 
    • Avoidance of tap water may have some value in prevention. 
    • Nitazoxanide currently is being investigated for treatment. Other drugs, such as paromomycin, azithromycin, and hyperimmune bovine colostrum have been used with suboptimal results. 
    • Octreotide must be used with caution because it can slow diarrhea but not clear the infection. 
    • Pancreatitis and/or bowel infarction may develop.

     

  • Toxoplasmosis 
    • Toxoplasmosis is a rare CNS infection in children. When it occurs, it is usually acquired congenitally. 
    • Specific IgG and immunoglobulin M (IgM) titers, as well as a head ultrasonography, should be performed in neonates with risk of congenital infection or in whom it is suspected. 
    • Treatment with pyrimethamine, folinic acid, and sulfadiazine or clindamycin is required when infection occurs.
  • Systemic complications
  • Cardiomyopathy 
    • Dysrhythmias, hemodynamic abnormalities, and cardiomyopathy develop in about 20% and 5% of HIV-infected children with AIDS and those without AIDS, respectively. Congestive heart failure is a late manifestation of HIV infection. Children must be treated symptomatically with fluid restriction, diuretics, digitalization, and angiotensin converting–enzyme inhibitor (ACEI). 
    • Study findings have demonstrated that progressive changes in cardiac structure are correlated with disease progression.

     

  • Gastrointestinal 
    • Chronic diarrhea develops in approximately 15% of children with HIV infection. Infectious agents may cause diarrhea. MAC and Cryptosporidium are not uncommon causes of diarrhea in children with low CD4 counts. 
    • Stool examination and cultures for bacteria, fungus, virus, parasites, and acid fast organisms should be performed every day for at least 3 days, with special instruction for Cryptosporidium,Isospora, and microsporidia detection. Clostridium difficile antigen should be requested in those with recent or current antibiotic use. 
    • Bile acid malabsorption, but not bacterial overgrowth, appears to contribute to chronic diarrhea of HIV. Cholestyramine 4-8 g tid may significantly slow diarrhea in some patients. 
    • Pancreatitis can develop from medications, ascending infections, or HIV infection itself. Amylase and lipase levels should be monitored in patients at risk for pancreatitis. 
    • Abdominal pain with associated diarrhea, hepatosplenomegaly, intestinal lymphadenopathy, fever, or anemia is common in disseminated MAC infection.

     

  • Growth 
    • In adults, wasting syndrome is common with advanced disease. 
    • Although older children with advanced disease may have wasting syndrome, younger children have growth failure even without advanced disease. 
    • Undiagnosed HIV infections may present in patients with a failure to thrive diagnosis.

     

  • Hematologic disturbances 
    • Although HIV infects hematopoietic stem cells, the significance is minor. Hematopoietic disturbances are believed to occur as a consequence of changes in the microenvironment of the marrow and a deficiency in local and systemic growth factors. In typical conditions, the marrow’s stroma promotes stem cell proliferation and differentiation by producing G-CSF and interleukin (IL)-3. HIV infected stroma produces less G-CSF and IL-3 and excessive tumor necrosis factor (TNF)-alpha and IFN-gamma. This cytokine dysregulation halts the production of badly needed hematopoietic cell lines and causes apoptosis of committed progenitor cells. HIV also appears to retard the production of thrombopoietin in the liver and erythropoietin in the kidney. In addition to a low serum erythropoietin level, HIV-induced anemia also is a result of a blunted response to erythropoietin. 
    • Thrombocytopenia occurs in 40% of patients with HIV infection during the course of the disease. It is more common in those with advanced disease, IV drug users, African Americans, and those with a history of anemia or lymphoma; its presence suggests a shorter survival time. Immune thrombocytopenia may occur in half of these cases and appears to be the result of molecular mimicry of the platelet glycoprotein (GP)-IIb/IIIa receptor by the HIV-GP 160/120 antigen. Decreased platelet production is common in HIV infection regardless of the platelet count, and it may be associated with the ultrastructure damage in HIV-infected megakaryocytes. 
    • Anemia may be present in as many as 20% of patients at diagnosis and occurs in as many as 80% of patients at some point. Patients with clinical AIDS are more likely to have anemia, as are patients with low CD4 counts. The etiology is probably multifactorial in most patients; common contributing factors include bone marrow suppression, iatrogenic causes, vitamin deficiencies, suppressed erythropoietin production, and a blunted erythropoietin response. Bone marrow infiltration with lymphoma or Kaposi sarcoma (KS); bone marrow suppression by pathogens such as MAC, parvovirus B19, CMV; and disseminated fungemia can cause anemia. 
    • Neutropenia is observed in 10% of early asymptomatic HIV infections and in 50% of patients with AIDS. Neutropenia results from the aforementioned mechanisms, as well as from medications. GM-CSF and G-CSF deficiencies not only reduce neutrophil production but also reduce granulocytic and monocytic function as well. Indeed, GM-CSF and G-CSF promote increased neutrophil function, including superoxide production, phagocytosis, intracellular killing, and antibody-dependent cellular cytotoxicity.

     

  • Nephropathy 
    • In approximately 15% and 5% of HIV-infected children with AIDS and those without AIDS, respectively, the disease progresses to HIV nephropathy. 
    • HIV nephropathy is more common in black children than in others. 
    • Proteinuria and hyponatremia with elevation in the blood urea nitrogen (BUN) and creatinine levels and slight increase in blood pressure develop early and are not uncommon. 
    • Renal biopsy most often reveals focal segmental glomerulosclerosis or, less often, mesangial hyperplasia. Necrotizing glomerulonephritis and minimal histologic changes also are observed. 
    • ACEIs appear to have renal sparing effects and are being studied. 
    • Symptomatic treatment with fluid restriction, low-salt diet, and diuretics may be needed in frank nephrosis. 
    • Non-HIV nephropathy may develop, especially in children who are treated with repeat courses of nephrotoxic medications. 
    • Some children have chronic renal failure with electrolyte wasting. Electrolyte levels should be monitored closely, and these patients should receive appropriate supplementation.

     

  • Neurologic 
    • HIV exhibits tropism for the central nervous system, especially microglia. As many as 10% of children with AIDS have progressive encephalopathy, and the CSF viral load is correlated with cognitive dysfunction. Progressive white matter degeneration and brain atrophy may develop; imaging studies are helpful. Neurologic symptoms develop along with developmental delay. Severe encephalopathy in infants younger than 1 year indicates a poor prognosis. Restoration of immune function and viral suppression is required to prevent and reverse progression. Zidovudine and stavudine have good CNS penetration, and protease inhibitors improve neurologic function with indirect viral suppressive effects in the periphery. Children with central nervous system insults require rehabilitation to maintain or recover function. 
    • Cryptococcal meningitis is uncommon in children, although it should be ruled out when meningeal signs exist or when fever without a clear source cause severe headache. CSF should be examined with India ink stain, and the presence of cryptococcal antigen should be determined. Treatment with amphotericin and flucytosine is necessary, followed by maintenance therapy with fluconazole or itraconazole.
  • Pulmonary 
    • Lymphoid interstitial pneumonitis (LIP) is the second most common AIDS-defining illness in children. LIP most commonly occurs in children with a relatively high CD4 count. Chest radiography demonstrates a reticulonodular pattern with or without hilar adenopathy that persists for longer than 2 months despite treatment. Patients are usually asymptomatic initially, but cough and shortness of breath develops as LIP progresses. Hypoxia usually responds to a 2-week course of steroids, but oxygen dependence develops if an underlying chronic lung disease exists. LIP increases the risk of bacterial pneumonia, especially with Haemophilus influenzae and pneumococcus species. 
    • Recurrent pneumonia causes lung tissue destruction that leads to chronic lung disease. Chest radiographs demonstrate chronic changes, including areas of chronic atelectasis. This condition necessitates management by a pulmonologist. Chronic respiratory therapy may be required, including home oxygen therapy.

 

resource : emedicine

 

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Editor in Chief :

DR WIDODO JUDARWANTO

email : judarwanto@gmail.com,

 

Copyright © 2009,  FIGHT AGAINST  AIDS, SAVE  INDONESIAN CHILDREN  Information Education Network. All rights reserved.


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