Pediatric AIDS Part 1 Praveen Khilnani, Shiv Kumar Rajdev, Rajiv Uttam

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1 IJCCM October-December 2003 Vol 7 Issue 4 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 Review Article Pediatric AIDS Part 1 Praveen Khilnani, Shiv Kumar Rajdev, Rajiv Uttam Abstract Much progress has been made in the therapy of pediatric HIV infection, which has been transformed from a usually fatal disease into that of a chronic disease model. Early, aggressive therapy with the goal of complete suppression of viral replication (undetectable plasma virus) should be the therapeutic goal, b ut this new, more hopeful environment has been created at the cost of complexity and compromises in quality of life. The rapid pace of new developments and therapeutic complexities argue strongly for care in specialized centers or, at least, frequent consultation. Principles of therapy in the pediatric intensive care unit remain unchanged. Efforts are ongoing to develop simpler, more effective therapeutic regimens that suppress and ultimately eradicate infection and that stimulate immune reconstitution and reduces need for frequent hospitalization. AIDS Definition Clinical syndrome resulting from infection by HIV type I which preferentially infects and destroys CD 4 helper/ inducer T cells. This leads to a severe immunodeficiency involving both cell mediated and humoral immunity and makes the patient highly susceptible to life threatening bacterial and opportunistic infections and to certain tumors Magnitude of the problem At the end of 2002, 7.2 million adults and children in the region were living with HIV/AIDS. Of that total, 6.0 million were in South and Southeast Asia. Although India s adult prevalence rate is only 0.70 percent, an estimated 3.7 million Indians were living with HIV/AIDS at the end of 1999, more than in any other country in the world except South Africa. (Note, however, that these data have been the subject of much dispute). Moreover, whereas some states of India show almost no HIV infection, others have reached adult prevalence rates of 2 percent and above. Fr om: Depar tment of Paediatrics, Indraprastha Apollo Hospital, Sar ita Vihar, New Delhi , India. Correspondence: Dr. Pr aveen Khilnani B-42, Panchsheel Enclave, New Delhi , India. pr aveenk@nde.vsnl.net.in Opportunistic infections and other clinical manifestations of HIV disease in children Pneumocystis carinii pneumonia Hallmark opportunistic infection of Pediatrics AIDS epidemic. Known as AIDS pneumonia this opportunistic infection is the most common AIDS defining illness in children. PCP is an infection of early infancy and most children are affected at between 4 and 6 months of age. The risk of PCP in the first year of life for perinatally infected children not receiving prophylaxis is estimated to be approximately 12%. The revised guidelines recommend prophylaxis for all HIV infected infants, independent of CD4 count and HIV infection status starting at 4 to 6 weeks of life until 4 months of age, when a more definite diagnosis of HIV infection can be made using PCR. 1 Pathogenesis of Pneumocystis carinii infection: P. Carinii thought to be protozoan is now believed to be more closely related to fungi. P. Carinii is not easily cultured, making diagnosis dependent on the demonstration of organisms in tissues or secretions. P. Carinii establishes infection within the alveoli, where it proliferates as an extracellular parasite. Clinical and radiological presentation of PCP: Children with PCP present with a tetrad of findings; tachypnea, dyspnea, cough and fever. Physical examination find- 257

2 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 ings include tachycardia and respiratory distress, accelerating tachypnea and diffuse retractions. Pulmonary auscultation is typically non specific. PCP is characerised by rapidly progressive hypoxemia. Early radiographic findings may be normal or can include hyperinflation with peribronchial thickening. As the disease progresses, the chest radiographic findings typically evolve to reveal bilateral alveolar or interstital infiltrates usually spreading peripherally from the perihilar region to involve both lung fields. Further progression results in coalescent bilateral airspace disease with air bronchogram. Less typical radiographic findings include focal or patchy infiltrates, cavities or effusions. Diagnosis A confirmed diagnosis has implications for the measurement of treatment efficacy and decisions regarding secondary prophylaxis. Fibreoptic bronchoscopy with bronchoalveolar lavage has been shown to be a safe and sensitive method for the diagnosis of PCP. Other diagnostic methods include sputum, tracheal wash for intubated children and open lung biopsy. Open lung biopsy is now typically reserved for children with inconclusive results from less invasive procedures and worsening clinical status despite treatment. The wright-geimsa procedure stains trophozoite and intracystic sporozoite forms of P. Carinii and is commonly used as rapid screening test. The Papanicolaou stain which identifies the alveolar exudates of PCP rather than the organism can be used for screening. The Methenamine silver stain and direct immuno- flouroscent staining with monoclonal antibody detect cyst forms of the organism and can be used for the confirmation of screening results. Treatment and prognosis for children with pneumocystis carinii Therapy for PCP should include treatment with trimethoprim-sulphamethoxazole (TMP-SMX) or pentamidine, intravenous steroids and intensive respiratory support. TMP-SMX is the treatment of choice for children with PCP. The dose is 20 mg/kg divided into 4 daily doses for 21 days. Medication can be changed to an oral formulation when clinical improvement is sustained. Pentamidine 4mg/kg given as a single dose for 21 days is generally reserved for children who cannot tolerate TMP-SMX secondary to adverse effects and for those IJCCM October-December 2003 Vol 7 Issue 4 who fail therapy. Several other mediactions (ie. dapsonetrimethoprim, clidamycin-primaquone, atovaquone and trimetrexate-leucovorin) have been approved for the treatment of adults with PCP but none of these medications have been evaluated in children. These medications may provide alternative therapies for children who fail or cannot tolerate TMP-SMX or pentamidine. Comprehensive respiratory support, including supplemental oxygen, ventilatory support and good pulmonary toilet is essential to ensure a satisfactory outcome for patients with this disease. Children are at risk for respiratory distress syndrome and secondary complications including pneumothorax. Characteristically oxygen requirement increases inconsistent with radiological correlation of infiltrates necessitating mechanical ventilation with high fio2 and positive endexpiratory pressures. Secondary bacterial complications may also complicate the course of disease. Prophylaxis of PCP Guidelines for PCP Prophylaxis: Prophylaxis should be administered to: All HIV infected and indeterminate children from 4 weeks to 12 months of life (prophylaxis can be stopped if HIV infection has been excluded after 4 months of age); HIV infected children aged: 1 to 5 years with CD4+ count less than 500/µLor CD4+ percentage less than 15% 6 to 12 years with CD4+ count less than 200/µLor CD4+ percentage less than 15% All HIV infected children treated for PCP TMP-SMX given for 3 consecutive days weekly is the therapy of choice but daily dapsone and monthly inhaled or IV pentamidine are acceptable alternatives for children intolerant to TMP-SMX. Recurrent bacterial infections In 1987, recurrent bacterial infections defined as 2 or more bacteriologically documented systemic bacterial infections including septicemia or bacterimia, meningitis, pneumonia, osteomyelitis, septic arthritis, or abscess of an internal organ or body cavity that occurred within a 2-year period were included as AIDS defining illness for children. Recurrent bacterial infection constitute the second most common opportunistic cause of IDS in 258

3 IJCCM October-December 2003 Vol 7 Issue 4 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 children. Also minor and presumed (those without bacteriological confirmation) bacterial infections further contribute to the clinical complexity of pediatric HIV disease. Bacteriological pathogens: Summarising the experience of many investigators, Krasinski 2 noted that the major bacterial pathogens in children with HIV were similar to those in immunologically healthy children and that the spectrum of bacterial isolates can be predicted from the site of infection or the clinical infection syndrome. Clinical manifestations Bacterimia Although the pathogens of bacterial disease are not especially unusual, the incidence of bacterial disease is significantly greater in children with HIV infection compared with uninfected children. Pneumonia-Although bacteremia is the most common laboratory documented bacterial infection, clinically diagnosed bacterial infections, major and minor are far more frequently diagnosed in children with HIV infection. The diagnosis of acute pneumonia was the most common clinically diagnosed severe bacterial infection. Sinusitis was found to be the second most common clinically diagnosed severe infection. Other major bacterial infections- Meningitis, osteomyelitis, septic arthritis, purulent pericarditis and periorbital cellulites have been reported in children with HIV disease. Sinusitis- Sinusitis is the second most common clinically diagnosed bacterial infection. The disease presents as a subacute or chronic indolent process and is commonly recurrent. Radiographic evaluations revealed primary involvement of the maxillary and ethmoid sinuses and one third of cases involved 2 or more sinuses. A history of nasal discharge and persistent cough for more than 2 weeks should prompt the diagnosis of sinusitis. Bacterial infections associated with central venous catheters HIV infected children with central venous catheters like other children with indwelling catheters are at increased risk for bacterial infections with a different array of pathogens. Rollides et al 3 reported that half of all documented bacterial infections in 39 children with indwelling lines were related to the catheter (22% bacteremia and 24% exit site infection). S. Aureus and Staphylococcal epidermidis were the most common bacterial pathogens, although gram negative organisms, including Klebsiella pneumonie, Acinetobacter sp. and pseudomonas sp. were commonly cultured compared with children without catheters. Most catheter infections (88 of 99 episodes) were successfully treated without removing the line. Diagnosis and treatment of bacterial infections The diagnosis of bacterial infections in HIV-infected children should parallel the principles followed for non infected children. Physicians should obtain blood or tissue cultures for laboratory confirmation and antibiotic susceptibility testing. Prophylaxis against bacterial infections: Prophylaxis against bacterial infections should include vaccination against conjugate H. Influenze Type B vaccine during infancy and with the 23-valent polysaccharide at 2 years of age. A second dose of pneumococcal vaccine should be administered after 3 to 5 years for children less than 10 years of age and after 5 years for children more than 10 years of age. Children with recurrent bacterial infections may benefit from daily prophylaxis with TMP-SMX (150 mg/m 2. TMP divided into 2 daily doses). IVIG is indicated for children with hypogammaglobulinemia (400 mg/kg/mo.) and should be considered for children with 2 or more invasive bacterial infections in a 1-year period especially for those who have failed or are intolerant to antibiotic prophylaxis. 4 Mycobacterium avium infection (MAC) Disseminated infection with MAC occurs almost exclusively in children with advanced HIV disease. Disseminated MAC is recognized as a significant cause of morbidity for HIV infected children. Pathogenesis: M. Avium complex includes 2 closely related species, M. Avium and Mycobacter ium Intercellulare. Mycobacteria are intracellular parasites that proliferate within macrophages. A high tissue burden can be found in organs, including lungs, liver, spleen, intestines, bone marrow and lymph nodes. Clinical presentation: Clinical presentation can be indolent and slowly progressive. Most children have a conglomeration of signs and symptoms, including fever, weight loss and poor weight gain, abdominal pain and 259

4 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 anemia. Night sweats, diarrhea, malaise, neutropenia and hepatomegaly have also been described. Fever can be quite high C or more and surprisingly well tolerated. Death ois generally not attributed to M. Avium infection but rather to advanced HIV disease or other infectious agents. Diagnosis of disseminated MAC infection: The diagnosis of M. Avium infection requires cultivation from blood or tissue. Blood cultures are usually done using the Bactec radiometric mycobacterial growth system which can yield a positive culture within 2 weeks. DNA hybridization with species specific probes is then used to identify the species of mycobacteria. Bone marrow and lymph nodes biopsies can be useful in the evaluation of M. Avium disease. Characteristic histologic findings of acidfast bacilli within macrophages are highly suggestive of M. Avium infection and may hasten the start of therapy in children with a suspected diagnosis but cultures are imperative to distinguish species. Treatment of disseminated MAC infection: Monotherapy for MAC results in rapid development of resistance,so combination therapy with 2 or more drugs is indicated for the treatment of disseminated MAC infection. The initial regime for the treatment of disseminated MAC infection should include: Clarithromycin 15 mg/kg daily in 2 divided doses; maximum 500mg or Azithromycin 10 mg/kg once daily PO; maximum 500mg with Ethambutol 15 to 20 mg/kg once daily PO; maximum 1600 mg and /or Rifabutin 5-10 mg/kg once daily PO, maximum 300 mg. Ethambutol is not recommended for children less than 12 years old and may cause optic neuritis. Mycobacterium tuberculosis After decades of decline, the late 1980 s and the early 1990 s saw the unexpected increase in the incidence of tuberculosis in the United States. This increased number of cases was coincident with the beginning of the AIDS epidemic. Clinical presentation: Although most children seem to have primary pulmonary infection, extrapulmonary disease has been reported in 10 to 50% of children with tuberculosis. 5 Most children have a history of fever and commonly, cough. Tuberculin skin test results are commonly negative in patients with advanced immunosuppression and chest radiograph findings can be variable. IJCCM October-December 2003 Vol 7 Issue 4 Children with low CD4+ counts may be at highest risk for tuberculosis, but children at all stages of HIV infection can become infected. High rates of resistance to antitubercular drugs have been reported in HIV-infected children with tuberculosis. Diagnosis: The diagnosis of tuberculosis in HIV infected children is complicated by several factors. Clinical manifestations although predominantly pulmonary, commonly involve extrapulmonary sites. For children with pulmonary tuberculosis, chest radiographs are often abnormal, but a wide array of abnormalities have been described, including diffuse interstitial disease and lobar infiltrates. Many children with tuberculosis have a history of chronic lung disease and abnormal chest radiographs further obscuring the diagnosis. A careful medical history with attention to potential household and community contacts may be the first clue to the diagnosis of this infection. The differential diagnosis for any child with pulmonary disease undergoing diagnostic evaluation should include tuberculosis. The Mantoux test, 5 tuberculin units of purified protein derivative, 0.1 ml (5 TU, PPD) should be planted; 5 mm of induration is considered a positive result in HIV infected individuals, but imperative of skin test results, specimens for cultures are imperative if a child is suspected of having tuberculosis. Samples can be obtained with gastric washings or bronchoalveolar lavage. All specimens should be cultured and antimycobacterial susceptibility should be performed on all isolates. Treatment: Investigators recommend that children with tuberculosis disease begin therapy with a 4 drug regimen consisting of Isoniazid (10-20 mg/kg/day; max 300 mg), Rifampicin (10-20 mg/kg/day; max 600 mg), Pyrazinamide (30 mg/kg/day) and Ethambutol (15 mg/ kg/day) or Streptomycin (20-30 mg/kg/dayim). Children with pulmonary disease should be treated for 6 to 12 months whereas those with extrapulmonary disease are likely to require a minimum of 12 months of therapy. Fungal infections Although systemic fungal infection are relatively rare in children with HIV disease, mucosal and cutaneous fungal infections are commonly diagnosed. Most HIV infected children develop oral candidiasis during their lifetime and many children have recurrent episodes. 260

5 IJCCM October-December 2003 Vol 7 Issue 4 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 Candida infections Oral candidiasis: Candidiasis is acquired during passage through the birth canal and is commonly diagnosed in otherwise healthy infants. Severe oral candidiasis may be the first clinical indication of HIV infection in HIV exposed infants. Children may complaint of discomfort and decreased oral intake in the presence of candidiasis. Diagnosis may be made on inspection. Laboratory confirmation is typically unnecessary. Initial treatment should begin with topical nystatin or clotrimazole. Topical Amphoteracin B and intraoral use of vaginal suppositories may also be effective therapies. Children with recurrent disease may benefit from daily prophylaxis with fluconazole. Esophageal candidiasis Children with esophagitis complain of substernal or abdominal pain or burning and difficulty swallowing. Weight loss and oral candidiasis are common findings on physical examination. Endoscopy is generally recommended to confirm the diagnosis of candida esophagitis in children and exclude other pathogens including herpes simplex and CMV. Many clinicians treat children who have oral candidiasis and symptoms consistent with esophagitis and reserve endoscopy for cases unresponsive to therapy. Fluconazole 3-6 mg/kg (max. 200) once daily for 21 days is the treatment of choice for esophageal candidiasis. Other fungal infections Cryptococcus Neoformans, Aspergillius Sp., Histoplasma Capsulatum and Coccidiodes immitis are other fungal pathogens. Toxoplasma gondii infection Toxoplasmosis typically occurs in HIV-infected adults and children with severe immunosuppression. Although toxoplasmosis of the CNS is a common opportunistic infection in adults, few cases have been reported in children. Rather, severe congenital toxoplasmosis, although uncommon, seems to be the more common manifestation of this infection in children with HIV CNS Infection: Headache, change in cognitive status, fever, and focal neurologic deficits are the most common clinical findings in patients with CNS toxoplasmosis. Focal neurologic deficits include hemiparesis, ataxia, cranial nerve palsies, and seizures. Diagnosis is usually based on clinical presentation, the presence of IgG antibodies, and characteristic findings on imaging studies. MR imaging and CT scanning typically reveal multiple ring-enhancing lesions located in the frontal, basal ganglia, or parietal regions. Cerebral edema is often present and commonly result in a mass effect. Treatment is typically initiated based on these findings, and the diagnosis is considered confirmed if a patient responds to therapy. Brain biopsy is the only method to provide a definitive diagnosis and is reserved for patients who fail to respond to therapy. Treatment: Therapy for toxoplasmosis in children includes sulfadiazine (85-120/mg/kg/d in two to four divided doses), pyrimethamine (1 mg/kg/d or 15 mg/m 2 /d as a single dose; maximum dose, 25 mg), and folinic acid (5-10 mg every 3 days). Treatment must be continued after the resolution of symptomatic disease to prevent recurrence. Investigators recommend that lifelong suppression be administered at these same doses. Herpes virus infections Cytomegalovirus infections (CMV) CMV infections is a significant cause of morbidity and mortality in HIV infected children. The most common clinical manifestations of CMV in children include chorioretinitis, esophagitis, pneumonitis and colitis. Cytomegalovirus generally occurs in HIV infected children with advanced immunosuppresion. Cytomegalovirus colitis is characterized by non specific complaints of diarrohoea, abdominal pain,weight loss,anemia and fever. Patients with CMV pneumonitis present with cough,shortness of breath and progressive hypoxemia. Clinical, laboratory and radiological findings are simillar to those of PCP. Demonstrations of intracellular inclusions in lung tissue or bronchoalveolar macrophage in the absence of other pulmonary pathogens supports the diagnosis of CMV pneumonitis. Treatment Guidelines for the treatment of CMV in HIV infected children were developed to organize the complex issues around therapy for these diseases. 6 Several therapies are available for CMV. Gancyclovir is the primary medications for CMV retinitis. Foscarnet has been shown to be an effective therapy. Gancyclovir is also indicated for 261

6 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 the treatment of CMV disease of other organ systems. Varicella zoster infections HIV infected children are at risk for persistent, recurrent, chronic infections with VZV. Children with advanced immunosuppression are at risk for advanced disease and more severe manifestations of VZV, but disseminated VZV is unusual and most children can be successfully treated for VZV infections. Investigators recommend that children with varicella start acyclovir therapy as early in the course of infections as possible 7. HIV infected children with low CD4+ counts should receive intravenous therapy (1500 mg/m 2 /d divided into 3 doses) for 7 to 10 days. Oral Acyclovir (80 mg/kg/day divided into 4 doses) is an alternative for mild infections in children with good immune functions. VZV is often painful. Aggressive pain management should be an important component of therapy. Foscarnet has been shown to be active against most Acyclovir resistant VZV and may result in clinical improvement. Prophylaxis: HIV infected children who have not had chicken pox or shingles and who report significant exposure to varicella should receive varicella zoster imune globulin (1 vial /10 kg, 5 vials maximum) within 96 hours. Diagnosis of HIV infection in infants HIV infection can be diagnosed definitively in most infected infants by age 1 month and in virtually all infected infants by age 6 months using viral diagnostic assays. A positive virological test result (i.e. detection of HIV by culture, DNA or RNA polymerase chain reaction [PCR]) indicates possible HIV infection and should be confirmed by a repeat virological test on a second specimen as soon as possible after the results of the second test become available. Diagnostic testing should be performed before the infant is 48 hours of age, at 1 to 2 months and 3 to 6 months. Testing at age 14 days may also be advantageous for early detection of infection. HIV DNA PCR is the preferred virologic method for diagnosing HIV infection during infancy. Assays that detect HIV RNA in plasma also may be useful for diagnosis of perinatal infection. HIV culture has sensitivity similar to that of DNA PCR for diagnosis of infection. However HIV culture is more complex and expensive to perform than is DNA PCR and definitive results may not be available for 2 to 4 weeks. Although use of standard and immune-complex dissociated p-24 antigens tests are specific for HIV IJCCM October-December 2003 Vol 7 Issue 4 infection and have been used to diagnose infection in children, the sensitivity is less than that of other virologic tests. Initial testing is recommended by 48 hours because nearly 40% of infected infants can be identified by this time. Blood samples from the umbilical cord should not be used for diagnostic evaluation. Repeat diagnostic evaluation can also be considered at age 14 days in infants with negative tests at birth, because the diagnostic sensitivity of virologic assays increases rapidly by age 2 weeks and early identification of infection would permit modification of antiretroviral therapy from the standard 6 week course of neonatal ZDV chemoprophylaxis to more aggressive combination antiretroviral therapy. Infants with initially negative virologic results should be retested at 1 to 2 months. With increasing use of ZDV to reduce perinatal transmission, most HIV exposed neonates will receive 6 weeks of antiretroviral chemoprophylaxis. Although antiretroviral chemoprophylaxis could theoretically affect the predictive value of HIV virologic testing, ZDV monotherapy did not delay the detection of HIV by culture in infants in PACTG 076 and has not decreased the sensitivity and predictive value of many virologic assays. HIV exposed children with repeated negative virologic assays at birth and at age 1 to 2 months should be retested at 3 to 6 months of age. HIV infection is diagnosed by two positive HIV virologic test results from separate blood samples. HIV infection can be reasonably excluded among children with 2 or more negative results, Two performed at age 1 month and one performed at age 4 months. Two or more negative HIV IgG antibody test results obtained at age >6 months with an interval of at least 1 month between tests also can be used to reasonably exclude HIV infection in children with no clinical evidence of HIV infection. HIV infection can be excluded definitively if HIV IgG antibody is negative in the absence of hypogamma-globulinemia at age 18 months and if the child has both no clinical symptoms of HIV infection and negative HIV virologic assays. Immunologic parameters in children Clinicians interpreting CD4+ T lymphocyte number in children must consider age as a variable. CD4+ T lymphocyte count and percentage values in healthy infants who are not infected with HIV are considerably higher than those observed in uninfected adults and slowly decline to adult values by age 6. A pediatric clini- 262

7 IJCCM October-December 2003 Vol 7 Issue 4 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 cal and immunologic staging system for HIV infection has been developed that includes age-related definitions of immune suppression (Table 1). 8 Although the CD4+ absolute number that identifies a specific level of immune suppression changes with age, the CD4+ percentage that defines each immunologic category does not. Thus, a change in CD4+ percentage, not number, may be a better marker to identify disease progression in children. In infected children and adults, CD4+ cell count declines as HIV infection progresses, and patients with lower CD4+ cell counts have a poorer prognosis than do patients with higher counts. Because knowledge of immune status (i.e. CD4+ T lymphocyte count and percentage) is essential when caring for HIV -infected infants and children, CD4+ T -lymphocyte values should be obtained as soon as possible after a child has a positive virologic test for HIV and every 3 months thereafter. The CD4+ T lymphocyte count or percentage value is used in conjunction with other measurements to guide antiretroviral treatment decisions and primary prophy- Table 1: 1994 revised HIV pediatric classification system Clinical Categories Category N: Not symptomatic Children who have signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in Category A Category A: Mildly Symptomatic Children with two or more of the conditions listed below but none of the conditions listed in categories B and C. Lymphadenopathy (³0. 5 cm at more than two sites; bilateral =one site) Hepatomegaly Splenomegaly Dermatitis Parotitis Recurrent or persistent upper respiratory infection, sinusitis or otitis media Category B: Moderately Symptomatic Children who have symptomatic conditions other than those listed for category A or C that are attributed to HIV infection. Examples of conditions in clinical category B include but are not limited to: Anemia (<8 gm/dl), neutropenia (<1000/mm3) or thrombocytopenia (< /mm 3 ) persisting >30 days Bacterial meningitis, pneumonia, or sepsis (single episode) Candidiasis, oropharyngeal (thrush) persisting (>2 months) in children >6 m Cardiomyopathy. Cytomegalovirus infection, with onset before 1 month of age Diarrhea, recurrent or chronic Hepatitis, HSV stomatitis, recurrent (more than two episodes within 1 year) HSV bronchitis, pneumonitis, or esophagitis with onset before 1 month of age Her pes zoster (shingles) involving at least two distinct episodes or more than one dermatome Leiomyosarcoma. LIP or pulmonary lymphoid hyperplasia complex Nephropathy, Nocardiosis Persistent fever (lasting > 1 month) Toxoplasmosis, onset before 1 month of age Varicella, disseminated (complicated chickenpox) Category C: Severely Symptomatic Children who have any condition listed in the 1987 surveillance case definition for AIDS, with the exception of LIP (which is a category B condition) Serious bacterial infections, multiple or recurrent (ie, any combination of at least two culture-confirmed infections within a 2-year period) of the following types: Septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses, and in-dwelling catheter-related infections) Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs) Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes) Cryptococcosis, extrapulmonary Cryptosporidiosis or isosporiasiswith diarrhea persisting >1 month Cytomegalovirus disease with onset of symtoms at age > 1 month (at a site other than liver; spleen, or lymph nodes) Encephalopathy (at least one of the following progressive findings present for at least 2 months in the absence of a concurrent illness other than HIV infection that could explain the findings: 1) failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests; 2) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophx demonstrated by CT or MRI (serial imaging is required for children <2 years of age); 3) acquired symmetric motor deficit manifested by two or more of the following: paresis,pathologic reflexes, ataxia, or gait disturbance HSV infection causing a mucocutaneous ulcer that persists for > 1 month; or bronchitis, pneumonitis, or esophagitis for any duration affecting a child > 1 month of age Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes) Kaposi s sarcoma Lymphoma, primary, in brain Lymphoma, small, noncleaved cell (Burkitt s), or immunoblastic or large cell lymphoma of B-cell or unknown immunologic Modified from Centers for Disease Control Re vised classification system for human immunodeficiency virus infection in children less than 13 y ears of age. MMWR. 1994;43(No. RR-12):

8 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 laxis of PCP after age 1 year. Medical management of HIV disease in children Efforts are shifting from caring for children with advanced immunosuppression and severe opportunistic infections to early Highly Active Anti Retroviral Therapy (HAART), maintenance of the immune system, and prevention of opportunistic infections. Physicians who have been working with this population have observed a dramatic improvement in the quality of life and length of survival of these patients. Unfortunately, this progress is not shared by developing countries where resources are minimal and antiretroviral agents are commonly unavailable. Although efforts to develop a vaccine to prevent HIV infection are ongoing, progress has been slow. Education and awareness continue to be the most powerful weapons against HIV. Pediatric HIV infection in the United States has evolved from a rapidly progressive, fatal disease in the early years of the epidemic to a chronic infection with prolonged survival. Many children with perinatally acquired infection survive to 8 years of age and older. Management of infants at risk for HIV infection Obstetric standards and published guidelines strongly recommend offering HIV testing to all pregnant women 9 This allows women to become informed about HIV, receive care for their disease, and participate in decision making regarding mode of delivery and chemoprophylaxis to reduce the risk for the perinatal transmission of HIV. These women and their families should be counseled about the schedule of care visits; diagnostic testing for HIV; and chemoprophylaxis with zidovudine (ZDV) and trimethoprim-sulfamethoxazole (TMP-SMX), which are recommended for at-risk infants (Table 2). 10,11 Table 2: Management of children exposed to HIV in utero Age Management Birth HIV DNA PCR; start zidovudine 2 wk HIV DNA PCR; CBC (monitor for anemia) 6 wk HIV DNA PCR; CBC; discontinue zidovudine(if HIV DNA PCR negative); start PCP prophylaxis; start immunizations 4 mo Continue PCP prophylaxis 6 mo Discontinue PCP prophylaxis if tests for HIV remain negative mo HIV-1 ELISA PCR = polymerase chain reaction, CBC = complete blood count, PCP = Pneumocystis carinii pneumonia; ELISA = enzyme linked imm unosorbent assay. IJCCM October-December 2003 Vol 7 Issue 4 A DNA polymerase chain reaction for the detection of HIV is recommended before hospital discharge. Diagnostic tests for HIV in the infants detects 30% to 50% of infected infants at birth, with more than 95% diagnosed by 2 months of age, so physicians should follow up these infants closely during the first several months of life. Their mothers should be counseled against breast-feeding their infants because of the additional risk for transmission of HIV to infants. If the HIV DNA PCR was not done at birth, it is performed at this visit. During the second visit, at 6 weeks of age, ZDV is discontinued if the HIV DNA PCR tests have been negative. At this visit, complete blood count, T-cell subsets, and DNA HIV PCR results are obtained. TMP-SMX is begun at a dose of 150 mg/ m 2 /dose given three times a week for prophylaxis against Pneumocystis carinii pneumonia (PCP), and the first set of immunizations is given. PCP prophylaxis is started empirically in at-risk infants less than 1 year of age, independent of the CD4+ cell count and percentage, because HIV status may be uncertain and, in infected infants with rapid progression of disease, CD4+ cell counts can decrease precipitously in the first months of life, predisposing to PCP. At-risk infants are seen at 4 and 6 months of age for routine care and immunizations and appropriate immune and diagnostic tests. When an atrisk infant has had two negative HIV DNA PCR test results after 2 months of age and is clinically and immunologically normal, PCP prophylaxis is discontinued. These children are considered presumptively HIV negative, but an HIV enzyme-linked immunosorbent assay test is performed after 1 year of age to monitor for the disappearance of maternal antibody. If the HIV enzyme-linked immunosorbent assay and western blot are negative, the ELISA test is repeated and, if the result is negative, the child is considered uninfected and a seroreverter. Care of HIV-infected children Children with HIV should receive routine pediatric care and monitoring of their HIV disease status. Experts recommend that HIV-infected children have consultation with an HIV specialist. HIV-infected children should be seen at least every 3 months. The medications should be reviewed, doses adjusted for growth, and compliance assessed. Children should be assigned a classification (Table 1) and laboratory studies done to monitor the immunologic and virologic status of the disease. Table 3 264

9 IJCCM October-December 2003 Vol 7 Issue 4 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 Table 3: Medical mana gement of children with HIV infection Evaluation Interval Complete history and physical examination 3 mo Review of systems 3 mo Developmental examination 0-12 mo 3 mo 1-3 y 6 mo > 3 y Annually CT scan of the brain Baseline and as indicated Chest radiography Annually Laboratory values Complete blood count 3 mo T-cell subsets 3 mo HIV RNA PCR (quantitative) 3 mo Liver enzymes 3 mo Pancreatic enzymes 3 mo Electrolytes, BUN, and creatinine Baseline and as indicated Quantitative immunoglobulins 6 mo Urine analysis Annually Serology Cytomegalovirus Baseline, annually if negative Epstein-Barr virus Baseline, annually if negative Toxoplasmosis Baseline, annually if negative Rubella Baseline Varicella-zoster Baseline Herpes simplex Baseline Hepatitis B, C Baseline Tuberculin skin test and control Annually * Referrals Ophthalmologic examination Annually Dental examination 6 mo Cardiology (echocardiogram) If clinically indicated Gynecologic examination Puber ty, ann ually thereafter PCR = polymerase chain reaction BUN = blood urea nitrogen. *For control use mumps or tetanus antigen if the patient has already been immunized; otherwise use candida antigen. Every 6 mo if severely immunosuppressed. outlines the clinical and laboratory studies and assessments that should be done at baseline and thereafter at periodic intervals. These studies are done to identify any acute problems and to assess the risk for opportunistic infections or other HIV-related complications and monitoring for medication side effects. Studies have shown that prognosis in children is related independently to viral burden and immune status. 12 Also, a direct relationship exists between the development of certain opportunistic infections and the degree of immune suppression. Complications Anemia Anemia in patients with HIV is multifactorial. The most common causes include nutritional deficiencies; iron; folic acid; and, less commonly, vitamin B 12 ; immune hemolysis; hemorrhage; drug toxicities; and bone marrow suppression caused by the HIV virus, other infectious agents, or malignancy. Anemia with few or absent reticulocytes is common. When secondary to iron deficiency, iron sulfate at 6 mg/kg/d of elemental iron is usually sufficient to correct the hemoglobin level, but sometimes the solution is not that easy. If the erythropoietin level is less than 500 IU/L, a trial of erythropoietin at 100 U/kg/dose, three times a week, is suggested. On the other hand, if the erythropoietin is more than 500 IU/L, no evidence of iron, vitamin B 12 or folic acid deficiency is present, and the patient is reticulocytopenic, alternative diagnoses need to be investigated. Parvovirus B-19 infection can cause an aplastic anemia with a low or absent reticulocyte count and normal or high erythropoietin levels. If this infection is confirmed, IV immunoglobulin (IVIG), 1 g/kg/dose for 5 to 10 days, should be administered. This initial therapy is followed by monthly doses of IVIG at 400 mg/kg/dose. Another common opportunistic infection that causes bone marrow suppression and anemia is disseminated infection with Mycobacterium avium complex (MAC) infection. When a specific cause for anemia cannot be elucidated, a bone marrow aspiration may be necessary. Neutropenia Neutropenia is defined as an absolute neutrophil count of less than 1500 cells/ml. This is a common finding in HIV-infected children and may occur secondary to infection, nutritional deficiencies, or drug toxicity. Some drugs used to treat HIV infection, such as ZDV and TMP- SMX, are associated with the development of neutropenia. In some cases, neutropenia responds to initiation or a change of antiretroviral therapy. If the absolute neutrophil count is less than 500 cells/ml, a trial of granulocyte colony-stimulating factor starting at 5 to 10 mug/kg/dose is begun. Granulocyte colony-stimulating factor is a cytokine that increases circulating neutrophils and improves their functioning. Unlike erythropoietin, the response to granulocyte colony-stimulating factor is immediate, with demargination of the leukocytes, and the dose should be titrated to maintain an absolute neutrophil count of more than 1500 cells/ml. Thrombocytopenia Thrombocytopenia is a common problem among HIVinfected children. It may occur in the absence of other symptoms and, in some patients, is the initial presenting illness. Although a specific cause is usually not found, 265

10 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 it should be investigated. Antibodies against platelet glycoproteins have been identified in some HIV-infected patients with thrombocytopenia. Intervention is not required, especially if the platelet count exceeds 50,000 platelets/ml. In some cases, the thrombocytopenia has responded to the initiation or change of antiretroviral therapy. ZDV has been shown to be beneficial in the treatment of patients with thrombocytopenia. The role of other antiretroviral agents is less clear. When the platelet count is less than 20,000 platelets/ml or when bleeding is present, treatment should be instituted. Platelets are short-lived cells, and transfused platelets have even a shorter life span. The use of platelet transfusions is reserved for patients who are actively bleeding. IVIG has been beneficial in the treatment of immune thrombocytopenia. A total of 2 g/kg is administered over 2 to 4 days. If a response to the IVIG occurs, then this is given at 3-week or 4-week intervals. If a patient has maintained a normal platelet count for 6 to 12 months, the interval between doses is increased, and the treatment is eventually discontinued. Corticosteroids are another alternative treatment. Prednisone is usually started at a dose of 2 mg/kg/d for 2 to 4 weeks and then tapered and discontinued, but the thrombocytopenia may relapse when the steroids have been discontinued. Interferon alfa is reported to be effective in patients with severe thrombocytopenia that is resistant to antiretroviral therapy. Splenectomy is an option to consider if other treatments fail and usually results in the resolution of thrombocytopenia, but the lack of a spleen will predispose these children to encapsulated bacterial infections. Gastrointestinal complications The occurrence of ulcers in the oral cavity presents a diagnostic dilemma because viral infections, such as HSV, CMV, and Coxsackie A infection, as well as bacteria, may be causative agents. Biopsy and culture of lesions that are persistent or increasing in size or number is recommended. Cultures are tested for viral, bacterial (aerobic and anerobic cultures), mycobacterial and fungal infection. If results are negative and the biopsy is not diagnostic, it is assumed that these are aphthous ulcerations and treat patients accordingly. Most cases of esophagitis are diagnosed by clinical symptoms and confirmed with a barium swallow study. IJCCM October-December 2003 Vol 7 Issue 4 In such cases, treatment is begun empirically for candida esophagitis, especially in the presence of oral candidiasis. Fluconazole is the drug of choice and is given at a dose of 6 mg/kg/d in once daily dose. If a patient does not respond to empiric treatment after 3 days, then endoscopy with biopsy and culture of the esophageal mucosa should be done. If the biopsy results are compatible with fungal infection, parenteral amphotericin B is the drug of choice because some Candida albicans and Torulopsis glabrata and Candida krusei are resistant to fluconazole. Esophagitis secondary to HSV is treated with IV acyclovir, 750 mg/m 2 /d divided into three doses. If CMV is the cause, then IV ganciclovir is used. Patients with recurrent esophagitis are at risk for esophageal stenosis. Development of chronic bilateral enlargement of the parotid glands may occur in as many as 15% of children with HIV infection and usually does not require any treatment, but sometimes parotid pain and fever develop in these patients. In this instance, infection is suspected, frequently with Staphylococcus aureus, although mouth flora may also be present. This complication is easily managed with a course of oral antibiotics, using antistaphylococcal agents. On the rare occasion when suppuration is suspected, an otolaryngologist should be consulted to evaluate the need for surgical treatment. Lymphomas and other tumors should be included in the differential diagnosis, especially in children with increasing parotid size. Diarrhea is a common manifestation of HIV infection. 13 Although an infectious cause is frequently suspected, other important causes include side effects of medications, malignancies, and HIV enteropathy. Antibacterial agents are indicated in the treatment of diarrhea associated with enteric pathogens, such as shigelle, salmonelle, and campylobacter. Adult patients commonly improve with fluoroquinolones, but in children, other alternatives (e.g., ampicillin, third-generation cephalosporins, or TMP- SMX) are used. HIV-infected patients, especially those with low CD4+ cell counts and frequent exposure to antibiotics, are at risk for diarrhea caused by Clostridium difficile. The treatment of choice is metronidazole with orally administered vancomycin used as an alternative drug. Relapse should not be considered a treatment failure because as many as 20% of patients relapse, and these patients should be retreated with metronidazole. 266

11 IJCCM October-December 2003 Vol 7 Issue 4 Indian J Crit Care Med October-December 2003 Vol 7 Issue 4 Many viruses, including rotavirus, calicivirus, adenovirus, coronavirus, and astrovirus, can cause diarrhea. Specific treatment is available only for colitis associated with CMV (ganciclovir) or HSV (acyclovir). When pathogens cannot be identified, a consultation with a pediatric gastroenterologist is indicated for possible endoscopy and biopsy. Children who are immunosuppressed and have high viral loads benefit from HAART. Pulmonary complications Lymphoid interstitial pneumonitis is a chronic lymphocytic infiltrative disease of the lung. 14 The diagnosis of LIP in children is usually based on a typical chest radiograph with persistent reticulondular bilateral infiltrates. In more severe cases, significant clubbing occurs. In asymptomatic children with LIP and normal oxygen saturation, a chest radiograph should be obtained at least once a year, and the oxygen saturation should be monitored using pulse oximetry at each clinic visit. If a patient is hypoxic, steroids are indicated. Prednisone is given at a dose of 2 mg/kg/d for 2 to 4 weeks, with subsequent tapering to 1 mg/kg/d, and therapy is continued until the oxygen saturation becomes normal. Most children respond to this treatment within the first few weeks. In general, when an adequate response has occurred, the steroids may be weaned and discontinued. In some cases, repeated courses of steroids may be warranted. A few children with severe, advanced lung disease may not respond to steroid therapy, and if no response occurs after 4 to 6 months, the steroids should be discontinued. In addition, bronchodilators and chest physical therapy are helpful adjunctive therapies. The use of low doses of diuretics may also improve the respiratory status. When dealing with suspected bacterial pneumonia, an aggressive approach should be taken in patients with chronic lung disease. When possible, the treatment should be directed to the specific pathogen causing the infection. Treatment is usually empiric because noninvasive diagnostic procedures, such as blood and sputum cultures, yield an organism in approximately 30% of cases. Therapy is directed at the usual pathogens (i.e., Streptococcus pneumonie, H. influenze, and Staphylococcus aureus), but in patients with chronic lung disease, gram-negative organisms, especially P. eruginosa, must be considered potential pathogens. If a patient does not improve or his or her condition deteriorates on treatment, a bronchoalveolar lavage is indicated for diagnosis. The length of therapy is dependent on the cause and severity of the illness. Although 10 to 14 days of systemic antibiotic therapy is usually recommend, some children benefit from a longer course of treatment. In patients with chronic lung disease, pulmonary function tests may be beneficial at the onset of treatment and can be used as an indicator for length of therapy. If the pulmonary function tests continue to improve after 14 days of antibiotic therapy, treatment is continued until a return to baseline or a new plateau is reached. Children with HIV infection who have bronchiectasis or frequent episodes of bacterial pneumonia may benefit from daily prophylaxis with TMP-SMX. If this is not successful in decreasing the frequency of infection, monthly infusions of IVIG at 400 mg/kg/d may be beneficial. HIV nephropathy HIV-associated nephropathy in children presents as a spectrum of disease that ranges from mild to moderate proteinuria that is persistent, hematuria, renal tubular acidosis, and end-stage renal disease (ESRD). Because a timed urine collection is difficult to perform in children, the ratio of urine creatinine and urine protein is used to calculate the degree of proteinuria. A normal creatineprotein ratio is less than 0.2. A ratio more than 0.2 is abnormal and is consistent with nephrotic range proteinuria. If this finding persists, it can lead to hypoalbuminemia and edema but without elevation of serum triglycerides as occurs in patients with idiopathic nephrotic syndrome. Renal function deteriorates more slowly in children than in adults. Renal sonography shows increased echogenicity and provides details of the function of the kidneys. Biopsy of the kidney usually shows focal segmental glomerulosclerosis or diffuse mesangial hyperplasia and, less frequently, minimal change or systemic lupus erythematous-like nephropathy. Renal tubular acidosis is corrected with alkalinizing agents. Sodium or potassium citrate can be used depending on other electrolyte abnormalities. One milliequivalent of citrate is equivalent to one milli-equivalent of bicarbonate. Start with 2 to 3 meq/kg/d divided in 2 or 3 doses and adjust the dose to maintain a normal serum Ph. Patients with renal tubular acidosis may also need supplements of other minerals, such as calcium, 267