Human Immunodeficiency Virus Infection

PART 7 RESPIRATORY INFECTIONS

CHAPTER

37

Human Immunodeficiency Virus Infection Heather J. Zar and Michael R. Bye

EPIDEMIOLOGY TEACHING POINTS ● ● ● ●

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Respiratory illness is the predominant cause of mortality and morbidity in HIV-infected children. Severe pneumonia is often caused by co-infection with more than one pathogen. Streptococcus pneumoniae is the major bacterial pathogen causing pneumonia. Viral respiratory infections account for a lower incidence of pneumonia in HIV-infected compared with HIVnegative children, but are associated with more severe disease and a higher case fatality rate. Pneumocystis jiroveci (formerly Pneumocystis carinii pneumonia, hence [PCP]) is frequently the manifesting illness in infants undiagnosed with HIV; HIV-exposed infants are also at risk of PCP. With use of highly active antiretroviral therapy (HAART), the rate of opportunistic and respiratory infections has declined substantially. Cotrimoxazole prophylaxis may reduce mortality and morbidity in HIV-infected children of all ages, who are not taking HAART. The incidence of chronic lung disease increases with longer survival of HIV-infected children.

A changing pattern in the epidemiology of pediatric HIV and HIV-associated lung disease has emerged in developed countries over the last decade. In these countries, programs to prevent mother-to-child HIV transmission (MTCT), early diagnosis of HIV infection in infants, and use of Pneumocystis prophylaxis and highly active antiretroviral therapy (HAART) have led to a substantial decline in the incidence of pediatric HIV and HIV-associated respiratory infections. Concomitantly, with improved survival of HIV-infected children on HAART, the incidence of HIV-associated chronic lung disease has increased. In contrast, in developing countries, particularly those in sub-Saharan Africa, the HIV epidemic has escalated with a rise in acute and chronic HIV-associated pulmonary diseases. This has been compounded by poor access and unavailability of preventive strategies and of HAART for HIV-infected children. As a result, HIVassociated lung disease is a major cause of childhood morbidity and mortality in developing countries.

The total number of pediatric AIDS cases has declined substantially in developed countries in the last decade owing to a dramatic reduction in perinatal HIV transmission. New cases of HIV infection in children in developed countries occur predominantly in adolescents owing to sexual transmission, but most adolescents will remain asymptomatic until adulthood. 1 However, globally there are approximately 2.3 million HIV-infected children, most of whom live in subSaharan Africa. 2 Approximately 540,000 children are infected with HIV annually; approximately 470,000 of these cases occur in developing countries. 2 In the absence of HAART, up to 90% of HIV-infected children will develop a serious respiratory illness sometime in the course of their HIV disease, resulting in a large increase in the incidence and severity of childhood respiratory illness in developing countries and an exponential increase in infant and under-5 mortality rates. 3 Mortality rates among HIVinfected African children are much higher than those for developed countries; 26% to 59% of HIV-infected African children die within the first year of life and under-5 mortality rates exceed 60% in some countries. 4,5 Respiratory disease, principally pneumonia, is the predominant cause of childhood mortality in children in developing countries— accounting for approximately 2 million deaths annually in children younger than 5 years. 6 Pneumonia is also the most common cause of hospitalization in African HIV-infected children. Pneumonia-specific mortality rates are higher in HIV-infected children with case fatality rates consistently reported as three to six times those of HIV-negative patients. 7 In a U.S. cohort of HIV-infected children in the pre-HAART era followed longitudinally, respiratory infection was the most common cause of death in children under 6 years of age, with 32% caused by pulmonary infection. 8 The frequency of pulmonary disease as the underlying cause of death decreased significantly with increasing age, with 56% of respiratory-related deaths occurring within the first year of life. 8 Clinical Features HIV-associated respiratory involvement may manifest as acute or chronic disease, involving the upper and/or lower respiratory tract. Infections, especially pneumonia, are the major cause of acute lung disease whereas chronic disease

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may manifest as chronic infection, bronchiectasis, or lymphocytic interstitial pneumonia (LIP).

INFECTIOUS DISEASES The rate of acute respiratory infections has decreased dramatically with the use of HAART. 9 In the pre-HAART era, the most common opportunistic infection in children in the United States was serious bacterial infection, principally pneumonia. 10 Other common opportunistic infections (event rates >1 per 100 child-years) involving the respiratory tract were PCP, disseminated Mycobacterium avium complex (MAC) and tracheobronchial candidiasis. 10 Less commonly (event rates <1 per 100 child-years) tuberculosis (TB), cytomegalovirus (CMV) disease, and systemic fungal infections occurred. 10 In the HAART era, the number of opportunistic infections has declined substantially, although the relative prevalence of AIDS-defining infections has remained constant. 11 In children not taking HAART or those resistant to antiretroviral therapy, acute respiratory infections are common and may be severe. Infection of the upper airways may produce sinusitis, ear disease, supraglottitis, epiglottitis, or laryngotracheobronchitis. More severe acute infection may involve the lower airways and manifest as pneumonia, pleural effusion, bronchiolitis, a lung abscess or localized parenchymal disease. A number of bacteria, viruses, or fungi may cause respiratory infections in HIV-infected children (Box 37-1); mixed infections also occur commonly. Bacterial Infections

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Pre-HAART, bacterial pneumonia was the most common serious bacterial infection, with an event rate of 11 per 100 child-years 12 ; this has declined to a rate of 2.2 in the HAART era. 9 Bacterial pneumonia is still a major cause of hospitalization and mortality in HIV-infected children who are unable to access HAART, particularly in developing countries. 3,13 The clinical signs of pneumonia are similar in HIV-infected and uninfected children but bacteremic illness is more common in HIV-infected children, occurring in approximately 15% to 20%, and the case fatality rate is higher. 14,15 The etiology of bacterial pneumonia is similar to that in HIV-uninfected children (see Chapter 35), with S. pneumoniae the most common cause and accounting for more than 50% of associated bacteremic illness. 14-19 The risk of pneumococcal infection or invasive disease is significantly higher in HIV-infected than uninfected children. 14,19 The incidence of Staphylococcus aureus respiratory infection is increasing in HIV-infected children and may manifest as an empyema, pneumatocele, or lung abscess. 20 S. aureus is the most common pathogen occurring in catheter-associated bacteremia. 21 In addition, gram-negative pathogens such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, non-typhoid Salmonella and Escherichia coli may cause pneumonia with or without bacteremia in HIVinfected children. 14,15,22,23 HIV infection has been associated with an increase in the antimicrobial resistance patterns of bacterial pathogens causing pneumonia, with implications for empirical antibiotic therapy. 14 Methicillin-resistant S. aureus has increasingly

BOX 37-1 Etiology of Pneumonia in HIV-Infected Children Bacteria Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Mycobacterium tuberculosis Non-tuberculous Mycobacteria Non-typhoid Salmonella Klebsiella pneumoniae Streptococcus milleri Escherichia coli Moraxella catarrhalis Atypical Bacteria Mycoplasma pneumoniae Chlamydia trachomatis Chlamydia pneumoniae Viruses Respiratory syncytial virus Cytomegalovirus Human meta-pneumovirus Parainfluenza virus types 1 and 3 Adenovirus Influenza virus A or B Measles virus Varicella-zoster virus Human papillomavirus type 6 or 11 Pneumocystis and Fungi Pneumocystis jiroveci (previously Pneumocystis carinii) Candida species Aspergillus species Histoplasma capsulatum Cryptococcus neoformans Coccidioides immitis

emerged as a pathogen in HIV-infected children. There are variable data on the prevalence of penicillin-resistant pneumococcal infection in HIV-infected children but no clear differences in clinical outcome for susceptible and resistant strains have been shown, except for isolates with high level resistance. 24 Immunization with the pneumococcal conjugate vaccine reduces the incidence of pneumonia and invasive disease. 25-27 In HIV-infected children, immunization reduces the incidence of invasive disease due to vaccine strains by 65% and also prevents 13% of radiologically confirmed pneumonia. 25 Although the efficacy is lower than that in HIV-uninfected children, vaccination still offers protection to a substantial proportion of HIV-infected children. Moreover, immunization reduced the incidence of infection with drug-resistant pneumococcal strains. 25 Immunization also reduces the incidence of hospitalization for viral-associated pneumonia, suggesting that more severe pneumonia requiring hospitalization may occur due to viral and S. pneumoniae coinfection. 28

C H A P T E R 37 ■ Human Immunodeficiency Virus Infection

Mycobacterial Infections Mycobacterium tuberculosis is an important cause of acute pneumonia in HIV-infected children living in high TB prevalence areas, with culture-confirmed pulmonary tuberculosis occurring in approximately 8% of children hospitalized with pneumonia. 14,15,29 Pediatric TB infection is usually acquired from an infectious adult contact (see Chapter 39). The incidence of TB and risk of disease are higher in HIV-infected compared to immunocompetent children. 29-31 Primary infection rather than reactivation disease is usual in children. 32 Co-infection with M. tuberculosis and HIV results in more rapid deterioration of immune dysfunction, viral replication, and HIV progression and more frequent and severe other infections. 33-36 HIV-infected children with TB may present with nonspecific signs including weight loss, failure to thrive, and fever or with signs and symptoms of acute pneumonia or airway obstruction. 29,33-36 Pulmonary TB may also manifest as chronic, persistent respiratory symptoms and failure to thrive (see Chapter 39). The clinical presentation is similar in HIVinfected and uninfected children, although more severe disease, cavitary disease, and more rapid progression may occur in HIV-positive children (Fig. 37-1). 29,33-36 Extrapulmonary and miliary disease (Fig. 37-2) occur more commonly and progression to death is more rapid than in HIV-negative children. 29,33-36 Multidrug resistant (MDR) TB is increasingly prevalent in TB-endemic areas; the clinical features are similar to drug susceptible TB, although the prognosis is poorer. 37 In the United States, MDR TB, reported in 2.8% of foreignborn and 1.4% of U.S.-born children with TB, is uncommon. 32 Localized or disseminated Mycobacterium bovis infection including pneumonia has been reported in HIV-infected children who received bacille Calmette-Guérin (BCG) immunization; this may occur weeks to years after vaccination. 38-40 Ulceration at the site of vaccination and localized lymphadenopathy are not uncommon in HIV-infected children; systemic dissemination occurs more rarely. 38-40 The risk of

disseminated BCG disease is increased several hundred-fold in HIV-infected infants compared to HIV-uninfected infants. 38 The clinical presentation of disseminated M. bovis may be indistinguishable from M. tuberculosis infection. 40 Disseminated M. bovis infection has a poor prognosis with a case fatality rate of approximately 50%. 40 Non-tuberculous mycobacteria (NTM), particularly MAC, may cause disseminated disease including pulmonary infection in severely immunosuppressed HIV-infected children; isolated pulmonary disease is rare. 10,41 Children with pulmonary disease are at high risk for developing dissemination; up to 72% develop systemic disease within 8 months. 10 Disseminated MAC appears to be more common in children who have transfusion-acquired HIV than perinatal acquisition. 42 Epidemiologically, disease occurs in adults with CD4 counts less than 50 cells/µL but the threshold has been less well established in young children. 43 Primary and secondary prophylaxis is, therefore, recommended for severely immunosuppressed children based on CD4 counts. 43,44 The incidence of NTM disease has declined significantly with successful use of HAART from a rate of 1.8 per 100 child-years pre-HAART to 0.1 post-HAART. 9,12 With increasing use of HAART, an immune reconstitution syndrome (IRIS) associated with mycobacterial infection has been reported. 45 Immune reconstitution syndrome may occur weeks to months after initiation of HAART therapy and may result either from unrecognized mycobacterial infection or from a florid immune response directed against a mycobacterial antigen in those already on therapy for mycobacterial infection. 45 IRIS has been described with different mycobacterial species including M. tuberculosis, M. bovis, or MAC infection. 46-48 Most cases of IRIS with M. tuberculosis have been described in HIV-infected adults, 49-50 but this is increasingly being recognized in HIV-infected children from high TB-prevalent areas. 51 Clinically, IRIS is characterized by a seemingly paradoxical worsening in signs with increasing lymphadenopathy, new clinical and radiological respiratory signs, and fever (Fig. 37-3). 47,48,50,51 The tuberculin skin test may become positive and chest radiographs may show devel-

A

B Figure 37-1

Anteroposterior (A) and lateral (B) chest radiographs of a young child with cavitary tuberculosis.

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A

A

B Figure 37-2 Chest radiograph (A) and chest CT scan (B) of a child with miliary tuberculosis showing multiple diffuse small nodules.

B

opment of lymphadenopathy or new infiltrates. 50,51 IRIS must be distinguished from other infections, multidrug resistant TB, or non-response to TB therapy because of noncompliance. 50 To minimize the risk of IRIS, HIV-infected children with confirmed or probable TB should be treated with antituberculous drugs for 1 to 2 months before commencing HAART. 50 When IRIS develops in a child who was not known to have TB, therapy for TB should be initiated. If lymphadenopathy or respiratory signs are particularly severe, oral corticosteroids may be beneficial, although there are no controlled trials in children. 50 Viral Infection

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Viral respiratory infection, although accounting for less pneumonia in HIV-infected compared with HIV-negative children, is associated with more severe disease and a higher case fatality rate. 52 The presence of wheezing suggests a viral etiology; however, HIV-infected children with viral lower respiratory infection are more likely to develop pneumonia rather than wheezing. 52 Respiratory syncytial virus (RSV) is the most common cause of viral pneumonia, especially in the first 3 years of life (see Chapter 33). Concurrent bacterial infection has been reported in 30% to 50% of children hospitalized with viral pneumonia. Human meta-pneumovirus (hMPV),

C Figure 37-3 Immune reconstitution in a child with undiagnosed tuberculosis (TB) started on HAART. A, Chest radiograph prior to HAART initiation when a TB work-up was negative. B, Chest radiograph 1 month into HAART therapy showing development of right-sided disease. C, Chest radiograph 2 months into HAART therapy showing extensive right-sided disease and compression of the right bronchus. A gastric lavage culture obtained prior to initiating HAART then grew Mycobacterium tuberculosis and the tuberculin skin test became positive.

C H A P T E R 37 ■ Human Immunodeficiency Virus Infection

is emerging as an important respiratory pathogen in HIVinfected children and produces a similar spectrum of disease to RSV. 53 Other respiratory viruses that may produce lower respiratory tract infection include parainfluenza virus types 1 and 3, adenovirus and influenza A or B virus (see Box 37-1). 52 Cytomegalovirus (CMV) may produce severe, disseminated disease including pneumonia in HIV-infected children. 10 CMV can cause primary pneumonitis or may be found in association with other pathogens, especially Pneumocystis. Co-infection with CMV and HIV results in more rapid progression of HIV disease. 54 Therefore, CMV prophylaxis should be provided for severely immunosuppressed children or those with a history of CMV disease. The incidence of CMV infection has decreased with the use of HAART. 9 Herpesvirus infections may involve the respiratory tract in HIV-infected children. Oral herpes-simplex virus lesions may spread to involve the larynx and upper airways resulting in croup 55 ; disseminated disease including pneumonia may also occur. Pneumonia may occur as a complication of varicellazoster virus infection. 56 Measles virus infection may result in severe pneumonia; in HIV-infected children infection may occur without a typical skin rash, making diagnosis particularly difficult. 57 Human papillomavirus (HPV) type 6 or type 11 may produce lesions in the oral cavity, pharynx, larynx, and rarely in the lower airways or lungs; the disease has a tendency to recur. 58 Clinically, disease may manifest as progressive hoarseness, stridor, airway obstruction, and respiratory distress. 59 Rarely lung nodules, cysts, recurrent pneumonia, emphysema, or atelectasis have been described in immunocompetent children. 58,59 Little is known about the epidemiologic risk of disease in HIV-infected children. An increased prevalence of HPV in HIV-infected compared with HIVuninfected women has been reported; however, the rate of HPV transmission to children has not been associated with the HIV status of the mother or child. 60,61

deaths. 13 Increasingly PCP has also been reported in older HIV-infected children; 25% of cases in a Zambian postmortem study occurred in those older than 6 months. 13 Symptoms of PCP include tachypnea, fever, dyspnea, and cough. 66 HIV-infected infants under 6 months of age are especially at risk for PCP and have an acute, severe illness characterized by prominent and progressive hypoxia and increasing respiratory difficulty. 67 Auscultation of the lungs is usually normal, although crepitations or wheezing may occur. No specific clinical features can reliably distinguish children with PCP from those with other lower respiratory tract infections; however, disease is characterized by severe, progressive, clinical and radiologic signs and hypoxia (Fig. 37-4). Clinical signs may be compounded by co-infection with bacterial or viral co-pathogens. 68,69 Less commonly, PCP has also been reported to manifest with a pneumothorax, cyst, pneumatocele, or a bronchiolitis-like picture. 70,71 PCP is associated with mortality rates ranging from 35% to 87% with higher rates in children with acute respiratory failure. 63-65,72,73 Timely anti-Pneumocystis therapy may

PNEUMOCYSTIS INFECTION Pneumocystis jiroveci pneumonia (PCP) was the most common opportunistic infection in HIV-infected infants prior to widespread prenatal HIV screening, trimethoprimsulfamethoxazole (TMP-SMX) prophylaxis, and HAART. 12 The incidence of PCP has declined significantly in developed countries following these advances; the rate of PCP was 1.3 per 100 child years pre-HAART, declining to 0.1 with HAART. 9,12 PCP remains the most common AIDS indicator of disease among HIV-infected children, accounting for 57% of AIDS-defining conditions among those younger than 1 year of age. 10 PCP may frequently be the initial clinical presentation of HIV infection in infants; in developed countries, PCP occurs most commonly in infants born to women with unrecognized HIV infection. 62 In developing countries, PCP is a major cause of severe pneumonia and death in HIV-infected children, with the peak incidence at 3 to 6 months of age. 63-65 In these countries, the incidence of PCP varies from 8% to 49% among HIV-infected children hospitalized for pneumonia—depending on the patient population and the methods used for diagnosis. 63-65 PCP is the most common cause of death in African HIV-infected infants younger than 6 months, accounting for approximately 50% of respiratory related

A

B Figure 37-4 Radiologic progression of Pneumocystis jiroveci pneumonia (PCP) in an HIV-infected infant. A, initial radiograph and B, rapid progression of opacification within 24 hours.

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improve outcome as suggested by historical comparisons and adult studies in which early use of corticosteroids for PCP has been associated with better survival. 74-76 Mutations in P. jiroveci dihydropteroate synthase genes (a key enzyme target of TMP-SMX) have been described in HIV-infected patients with PCP—especially with widespread use of TMP-SMX as prophylaxis. 74 However, the clinical importance of mutant strains is unclear and the response to TMP-SMX treatment is variable. 74 HIV-exposed but uninfected children may also be at increased risk of PCP compared to HIV unexposed children. Probable transmission of P. jiroveci from an HIV-infected mother to her HIV-uninfected infant has been reported in a few cases. 77-79 HIV-exposed children may be at risk for PCP owing to close and early exposure to the organism from the mother, reduced passage of functional maternal antibody, impaired cell-mediated immunity, or concomitant malnutrition. Fungal Infections Chronic Candida infection is common in HIV-infected children and may produce oropharyngeal, laryngeal, or esophageal candidiasis and promote the development of gastroesophageal reflux disease. 10,80 Infection of the upper airways may result in Candida supraglottitis, epiglottitis, and a croup-like picture. 81,82 Laryngeal candidiasis may manifest as severe acute airways obstruction. 82 Pulmonary disease may also occur in the context of severe disseminated disease. Other fungal infections including aspergillosis, histoplasmosis, cryptococcosis, and coccidioidomycosis may produce respiratory illness usually in the context of severe immunosuppression and disseminated disease. 10 Pulmonary cryptococcosis without dissemination may manifest with fever, intrathoracic adenopathy, and pulmonary infiltrates. 10 Occasionally, pulmonary cryptococcosis may be asymptomatic and manifest on routine chest radiographs as pulmonary nodules. 10 Pulmonary coccidioidomycosis may produce diffuse reticulonodular infiltrates associated with fungemia and systemic disease. 10 Other pulmonary manifestations include nodules or cavities.

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DIAGNOSIS Diagnosis of the etiology of respiratory infection is difficult because signs are nonspecific and co-infection with more than one organism occurs frequently. For bacterial pneumonia, blood culture may be useful because HIV-infected children have higher rates of bacteremic pneumonia than do HIVuninfected children; approximately 15% of HIV-infected children hospitalized for pneumonia have a positive blood culture. 14 Current evidence suggests that no radiologic or laboratory findings can distinguish the etiology of pneumonia with sufficient sensitivity or specificity. Diagnosis of pulmonary tuberculosis is particularly difficult in HIV-infected children for whom clinical scoring systems have not been developed and in whom anergy may reduce the reliability of the tuberculin skin test (see Chapter 39). Diagnosis is frequently based on a combination of epidemiologic history of a TB contact and suggestive clinical and radiologic findings. A tuberculin skin test of 5 mm or more of induration is regarded as positive. 10 Tests of T lymphocyte

γ-interferon production are promising. A study of African children with suspected TB reported that the T cell–based enzyme-linked immunospot assay (ELISPOT) had a higher sensitivity than the tuberculin skin test, particularly in HIVinfected children in whom the ELISPOT sensitivity was 73% compared with 36% for the skin test. 83 Definitive diagnosis requires culture confirmation of M. tuberculosis from sputum, bronchoalveolar lavage (BAL), gastric lavage, or lung or lymph node biopsy. A concerted effort should be made to obtain diagnostic specimens in children in whom TB is suspected because this may provide diagnostic confirmation and drug susceptibility. 84 Recently, induced sputum examination has been reported to be effective and safe for culture confirmation in infants and children; approximately 25% of HIVinfected children hospitalized with suspected pulmonary TB were culture-positive from sputum. 85 The yield from a single induced sputum sample was equivalent to that obtained from three gastric lavages. 85 Therefore, a single induced sputum sample should be the primary diagnostic procedure in a child with suspected pulmonary TB. In contrast, the culture yield from a single BAL is lower than that from three properly performed consecutive gastric lavages. 86 The efficacy of polymerase chain reaction (PCR) has been disappointing with sensitivity on gastric aspirates varying from 45% to 83% in HIV uninfected children. 84 Definitive diagnosis of Mycobacterium bovis or MAC relies on isolation of the organism from the blood or from biopsy specimens from normally sterile sites. 10 If lymphadenopathy is present, an aspirate and culture can be diagnostic. Multiple mycobacterial blood cultures may be necessary to improve the yield. 10 Culture is essential to differentiate nontuberculous mycobacteria from M. tuberculosis and to determine the drug susceptibilities. Diagnosis of PCP should be based on the clinical presentation and empirical treatment initiated. 67 PCP should be suspected in any infant presenting with acute, severe pneumonia who has signs of HIV infection or who comes from an area of high HIV prevalence, particularly if Pneumocystis prophylaxis is not being given. In such infants, a presumptive diagnosis of PCP should be based on a history of acute respiratory decompensation, lack of auscultatory signs, and hypoxemia. In HIV-infected children not taking HAART, four clinical variables have been reported to be associated with PCP—age less than 6 months, a respiratory rate >59 breaths per minute, arterial hemoglobin saturation less than 92%, and absence of a history of vomiting. 67 Most children have significant hypoxemia with an alveolar-arterial oxygen gradient >30 mm Hg. Serum lactate dehydrogenase (LDH) may be markedly elevated (>1000 IU/L) but this is nonspecific and may reflect the extent of lung involvement. 87,88 The chest radiograph usually shows a diffuse interstitial pattern which progresses to alveolar opacification; however, hyperinflation, focal infiltrates, cavities, a miliary pattern, pneumothoraces, pleural effusion, or a normal appearance may also occur. 70,71,89 Definitive diagnosis requires identification of P. jiroveci from lower respiratory tract secretions including BAL, lung biopsy, or induced sputum tests. 74 Bronchoscopy with BAL is the diagnostic procedure of choice in young children, with reported sensitivity ranging from 55% to 97%. 10 Transbronchial biopsy is not recommended unless BAL is nondiagnos-

C H A P T E R 37 ■ Human Immunodeficiency Virus Infection

tic. 10 Transbronchial biopsy may be positive up to 10 days after starting therapy; the sensitivity of biopsy is 87% to 95%. 10 Induced sputum analysis using hypertonic nebulized saline may be useful; a positive yield has been described in infants as young as 1 month of age. 64 Nasopharyngeal secretions may also yield P. jiroveci in cases of severe infection. 63,65 Induced sputum in combination with nasopharyngeal aspiration (NPA) may provide a higher yield than either specimen alone; the sensitivity and specificity for induced sputum and NPA for diagnosis of PCP compared to the yield on autopsy have been reported to be 75% and 80%, respectively. 65 As P. jiroveci cannot be cultured, identification of the organism requires special stains. 66 Silver methenamine, toluidine-blue or calcofluor white are useful for staining cyst forms, whereas Giemsa, modified Wright-Giemsa, or modified Papanicolaou stains identify trophozoites. 66,74 Fluorescein-conjugated monoclonal antibodies provide greater sensitivity, detecting both the cyst and trophozoite forms. 74 Polymerase chain reaction techniques, with a high sensitivity and specificity and potential to improve diagnostic accuracy, are not widely available and are currently mainly a research tool. 74 Nasopharyngeal secretions may be useful for detection of respiratory viruses or atypical organisms such as Chlamydia trachomatis.

TREATMENT (Table 37-1) Bacterial Infections Empirical antibiotic therapy for pneumonia should be broad spectrum and consider the local prevalence of antimicrobial resistance and recent use of prophylactic or therapeutic antibiotics. 10 A combination of a β-lactam with an aminoglycoside antibiotic or a second or third generation cephalosporin

Table 37-1 Recommended Therapy of Lower Respiratory Infections in HIV-Infected Children by Etiology Infection

First Line Therapy

Bacterial pneumonia

Broad-spectrum antibiotic—β-lactam with an aminoglycoside or a second or third generation cephalosporin Add methicillin or vancomycin if Staphylococcus aureus is suspected Trimethoprim-sulfamethoxazole Corticosteroids if hypoxic

PCP Mycobacterial infections Mycobacterium tuberculosis

Mycobacterium bovis

Cytomegalovirus

INH, rifampicin, pyrazinamide as induction for 2 months (add 4th drug if suspected drug resistance or severe disease); then maintenance with INH, rifampicin for at least 7 months for pulmonary TB Corticosteroids if endobronchial disease or airway compression Surgical excision of localized disease; four-drug therapy for disseminated disease (INH, rifampicin, ethambutol, ofloxacin, or ciprofloxacin) Clarithromycin plus ethambutol Ganciclovir

INH, isoniazid; PCP, Pneumocystis jiroveci pneumonia (formerly Pneumocystis carinii pneumonia); TB, tuberculosis.

alone is appropriate empirical therapy. The choice of antimicrobial agent should be modified according to culture results and susceptibility testing. MYCOBACTERIAL INFECTIONS Treatment of pulmonary TB is similar to that in HIV uninfected children although the response to standard therapy in HIV-positive children is poorer than in HIV-negative children with lower cure rates and higher mortality. 36,37 Mortality is particularly high within the first 2 months of treatment. Optimal therapy for HIV-infected children with TB has not been tested in well-designed studies. Empirical therapy for pulmonary TB in HIV-infected children should include three drugs (isoniazid [INH], rifampicin, and pyrazinamide) daily for a 2-month induction period; a fourth drug (either ethambutol, ethionamide, or streptomycin) should be added if drug resistance is suspected or for severe disease. 10,35,90 Following a 2-month induction phase, therapy with two drugs (INH, rifampicin) should be continued either daily or three times a week in drug susceptible isolates. Directly observed therapy (DOT) is advised to promote adherence and reduce the rate of treatment relapse or failure; for the induction phase DOT should be administered daily, whereas for the continuation phase, two to three times weekly is sufficient. 91 However, children with severe immunosuppression should receive therapy daily or three times weekly during the continuation phase because less intense regimens have been associated with the acquisition of resistance in adults with CD4 counts <100 cells/µL. 92 High rates of treatment failure have occurred in children treated for 6 months; therefore, a minimum of 9 months of therapy is advised. 10,93,94 For extrapulmonary TB, the duration of therapy should be at least 12 months. 10 Therapy for drug resistant TB should be individualized, using a minimum of three drugs, at least two of which are bactericidal (see Chapter 39). 10 Adjunctive corticosteroids may be beneficial for children with an endobronchial lesion and airway compression; a suggested regimen is 1 to 2 mg/kg/day prednisone tapered over 6 to 8 weeks. 10 For children on HAART, the antiretroviral regimen should be reviewed to ensure optimal TB and HIV therapy and minimize potential toxicity and drug interactions. 35 Rifampicin induces hepatic cytochrome P450 enzymes and may, therefore, reduce levels of antiretroviral agents, particularly the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTI). Therefore, rifampicin should not be used in conjunction with single protease inhibitors except for ritonavir. 10 Alternatively rifampicin may be used in conjunction with ritonavir-boosted saquinavir, provided that high-dose ritonavir boosting is used. 10 Concurrent rifampicin with the NNRTI delavirdine is not recommended; however, use with efavirenz is possible. Use with nevirapine is recommended only when there are no other options because of the potential decrease in nevirapine levels. 10 Rifabutin is a less potent inducer of the P450 enzymes and is, therefore, a suitable alternative to rifampicin, but there is limited experience of its use in children. 10 Adjustments in dosage of rifabutin and co-administered antiretroviral drugs may be necessary because some drugs (e.g., efavirenz) lower rifabutin levels, whereas others (e.g., the PIs, ritonavir, indinavir, nelfinavir, ritonavirboosted saquinavir) increase levels. 10 For antiretroviral-naïve children, TB therapy should be given for 4 to 8 weeks before

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starting HAART to minimize the risk of immune reconstitution syndrome, optimize adherence, and differentiate potential side effects due to TB or antiretroviral drugs. 48-51 Monitoring of HIV-infected children on TB treatment should include regular evaluation of clinical response, monitoring for drug adverse effects and liver enzyme measurements (at baseline and monthly for the first few months), particularly in the initial months of therapy owing to the potential for hepatotoxicity. 10,91 Elevations of transaminase levels of two to three times normal do not require discontinuation of drugs. A chest radiograph should be done at baseline and repeated 2 to 3 months into therapy to evaluate response; however, the chest radiograph may remain abnormal for months to years and a normal chest radiograph is not a criterion for discontinuing therapy. Management of BCG disease is difficult. Treatment is complicated by the inherent resistance of M. bovis to pyrazinamide, inherent intermediate resistance of some BCG strains to isoniazid, and the emergence of resistance during inappropriate therapy. 95 In immunocompetent children, localized BCG disease is usually self-limiting. However, in HIV-infected children, treatment is warranted because of the risk of dissemination and poor outcome. 40 Surgical excision of localized lymphadenopathy is one strategy. Alternatively, medical therapy with four drugs (INH, rifampicin, ethambutol, ofloxacin or ciprofloxacin) in high doses is recommended. 40 The optimal duration of therapy is not known but at least 9 months of treatment is recommended, based on adult experience. 96 Treatment of MAC should comprise combination therapy with a minimum of two drugs because monotherapy with a macrolide leads to rapid evolution of resistance. 10 Initial recommended therapy is clarithromycin or azithromycin plus ethambutol. 10 Rifabutin may be added as a third drug in

patients with severe disseminated infection; addition of ciprofloxacin, amikacin, or streptomycin may be considered depending on the severity of illness. 10 Viral Infections Treatment of CMV disease focuses on preventing disease progression and not on cure. Ganciclovir is most widely used, with drug dosing separated into induction and maintenance dosage (see Chapter 33). Other possible agents include valganciclovir, foscarnet, or cidofovir. 10 These drugs may produce significant side effects including bone marrow depression and renal toxicity. For children with CMV disease who have sustained immune reconstitution on HAART, there are no data on when maintenance therapy may be safely discontinued; this should be considered on an individual basis. Laryngeal HPV lesions are difficult to treat. Therapy is directed at maintaining airway patency, so obstructing papillomas should be removed. Adjuvant therapy using intralesional cidofovir has been reported to result in regression and reduced need for surgery in HIV-uninfected children. 97 Pneumocystis and Fungal Infections Empirical therapy for Pneumocystis should be given to any child with suspected PCP because untreated infection is usually fatal. 66 The most effective therapy is TMP-SMX (15 mg/kg/day TMP) intravenously three to four times a day for 21 days (Table 37-2). 10,66,74 Oral treatment can be used if intravenous therapy is not feasible, if disease is mild or when clinical improvement occurs. The response to therapy may be slow with clinical improvement occurring only after 3 to 5 days. 66 Adverse reactions to TMP-SMX occur in approximately 15% of cases, but treatment should be discontinued only if reactions are severe—such as neutropenia or a

Table 37-2 Treatment of PCP in Children Drug

Dose

Route

Comments

Trimethoprim-sulfamethoxazole (TMP-SMX)

15-20 mg/kg TMP with 75-100 mg/kg SMX per day given q6h

Intravenous or oral

Pentamidine

4 mg/kg daily

Intravenous

Atovaquone Trimetrexate glucuronate with leucovorin

30 to 45 mg/kg/day No studies of established doses in children Adult dose 45 mg/m2/day trimetrexate glucuronate with leucovorin 20 mg/m2 q6h No studies of established doses in children Adult dose is 100 mg dapsone daily (pediatric equivalent 2 mg/kg) and 15 mg/kg TMP No studies of established doses in children Primaquine adult dose is 30 mg daily orally Pediatric equivalent is 0.3 mg/kg daily orally Clindamycin adult dose is 600 mg intravenously q6h for 10 days; then 300-450 mg orally q6h for 11 days. Pediatric equivalent is 10 mg/kg q6h orally or intravenously

Oral Intravenous

First choice Oral therapy only if mild disease or when clinical improvement occurs In those who cannot tolerate TMP-SMX or where no response after 5 to 7 days High incidence of side effects. Should not be administered with didanosine due to risk of pancreatitis Limited experience in children Limited experience in children

Oral

Limited experience in children

Oral/intravenous

Limited experience in children Most effective alternate therapy for adults with PCP unresponsive to primary therapy

Dapsone and trimethoprim (TMP) Primaquine and clindamycin

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Corticosteroids should be added in moderate or severe Pneumocystis jiroveci pneumonia. PCP, Pneumocystis jirovecii.

C H A P T E R 37 ■ Human Immunodeficiency Virus Infection

severe dermatologic reaction. 66,98 Intravenous pentamidine (4 mg/kg) may be an alternative drug for children who cannot tolerate TMP-SMX or who have not responded after 5 to 7 days of TMP-SMX (see Table 37-2). 10 Pentamidine is associated with a high incidence of adverse reactions including pancreatitis, alterations in blood glucose, renal dysfunction, cardiac dysrhythmias, fever, neutropenia, and hypotension. 99 Patients who show clinical improvement after 7 to 10 days of intravenous pentamidine may be switched to an oral drug to complete 21 days of therapy. Other alternative antiPneumocystis agents include atovaquone, dapsone with trimethoprim, trimetrexate glucuronate with leucovorin and clindamycin with primaquine, but there is little information on the efficacy or tolerability of these regimens in children (see Table 37-2). 10,91 Corticosteroids are recommended in hypoxic children with moderate to severe PCP. Although no controlled trials on the use of corticosteroids in children have been performed, use has been reported to reduce the need for mechanical ventilation and to improve survival compared with historical controls. 75,76,100 Data from adult studies has found that corticosteroids are beneficial, improving oxygenation and reducing the incidence of respiratory failure when used within 72 hours of commencing anti-Pneumocystis therapy in hypoxic HIV-infected adults. 74 Corticosteroids are, therefore, recommended for a PaO2 < 70 mm Hg or an alveolar-arterial oxygen gradient of >35 mm Hg. 10 The optimal dose and duration have not been determined, but a recommended regimen is prednisone 2 mg/kg for 5 to 7 days with tapering doses over the next 10 to 14 days. 75 A few case reports have described use of surfactant to improve pulmonary function in children with severe PCP. 101,102 Children with PCP may be co-infected with bacterial or viral pathogens 68,69 ; additional antimicrobial therapy for these should be used when appropriate. Specifically, CMV coinfection has been associated with more severe disease requiring mechanical ventilation and a poor outcome. The effect of corticosteroid therapy for PCP on CMV pneumonitis is unclear. Uncomplicated oropharyngeal candidiasis can be treated with topical therapy. 103 Oral fluconazole, itraconazole, or ketoconazole are effective alternative agents. 10,104 For esophageal disease fluconazole or itraconazole is recommended. 10 Children with severe pulmonary cryptococcosis should be treated with amphotericin B; maintenance therapy with fluconazole or itraconazole can be substituted when improvement has occurred. 10 Mild or moderate pulmonary cryptococcosis can be treated with oral fluconazole or itraconazole. 10 Life-long suppressive therapy with fluconazole or itraconazole is necessary to prevent relapse. 10 There are little data on treatment of pulmonary coccidioidomycosis in children and recommendations are based on adult data with amphotericin B recommended for the acute illness followed by chronic suppressive therapy with fluconazole or itraconazole. 105 Alternatively, in mild disease, therapy may be initiated with fluconazole or itraconazole. 10

PREVENTION Prevention of HIV-associated lung disease is an important goal. Although the efficacy of preventive measures such as

immunization is reduced in HIV-infected children, efficacy may depend on the degree of immunosuppression and use of antiretroviral therapy. General and specific preventive measures (Table 37-3) are discussed subsequently. General Measures General preventive strategies such as avoidance of passive smoke exposure, preventing exposure to indoor biomass fuels, and improved nutrition and growth may reduce the incidence and severity of respiratory infections. 106 Micronutrient supplementation, particularly the use of vitamin A to prevent measles-associated pneumonia and daily prophylactic elemental zinc (10 mg to infants, 20 mg to older children) may substantially reduce the incidence of pneumonia, particularly in malnourished children. 106,107 CHEMOPROPHYLAXIS Prevention of Pneumocystis jirovecii Pneumonia

Prophylaxis against Pneumocystis infection is very effective if initiated in HIV-exposed infants within the first few months of life. The most effective prophylactic agent is oral TMPSMX, a widely available, well tolerated, and inexpensive drug. A randomized controlled study of TMP-SMX prophylaxis in HIV-infected Zambian children reported that this treatment reduced mortality by 43% and morbidity, including hospitalization, by 23%. 108 The impact on mortality occurred in children of all ages. 108 Although most children were not investigated for P. jiroveci or other pathogens, the authors hypothesize that the effect of TMP-SMX prophylaxis may also provide protection against bacterial infection. Current recommendations for PCP prophylaxis include (Table 37-4): 91,109 1. All infants born to HIV-infected mothers from 6 weeks of age until HIV infection has been excluded in the child and the mother is no longer breastfeeding 2. All HIV-infected children from 6 weeks until 1 year of age. HIV-infected children older than 1 year should receive prophylaxis if their CD4 counts are less than 15% of lymphocytes or if they have symptomatic HIV disease. However, a higher CD4 threshold for providing prophylaxis may be applicable in developing countries, as evidenced by a trial in Zambia where prophylaxis reduced mortality in children even in those with higher CD4 counts. 108,109 Prophylaxis should be continued indefinitely irrespective of age or CD4 counts when HAART is unavailable. 109 3. Prophylaxis should be continued in children taking HAART for at least 6 months. There is little information on the safety of discontinuing prophylaxis once immune reconstitution has occurred. Discontinuation of prophylaxis may be considered in those with confirmed immune restoration for 6 months or more as indicated by two measurements of CD4 > 25% at least 3 to 6 months apart in children 2 to 6 years of age. 110 4. Lifelong prophylaxis should be given to all children who have had an episode of PCP; the safety of discontinuing secondary prophylaxis in the context of immune reconstitution has not been established.

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P A R T 7 ■ RESPIRATORY INFECTIONS Table 37-3 Preventive Measures and Indications Intervention

Indications

General Vitamin A Zinc Avoidance of passive smoke exposure Adequate nutrition

Malnourished children Measles-associated pneumonia Malnourished children All All

Immunization Routine EPI immunizations (DPT, inactivated poliovirus, measles, HiB) Pneumococcal conjugate Influenza vaccine Measles, mumps, rubella vaccine (MMR) Varicella vaccine

All All All Mild or moderately immunocompromised children (CDC immune category 1 or 2) Asymptomatic or mildly symptomatic children without immunosuppression (CDC category N1 or A1)

Chemoprophylaxis PCP prophylaxis in all infants and in children >1 year with moderate or severe immunosuppression or if clinically symptomatic Secondary prophylaxis in children with prior PCP Children exposed to a close contact with TB once TB disease has been excluded in the child Tuberculin skin test–positive children Prophylaxis for nontuberculous mycobacteria in severely immunosuppressed children Lifelong secondary prophylaxis in children with prior infection Prophylaxis for CMV in severely immunosuppressed children Lifelong secondary prophylaxis in children with prior CMV disease

TMP-SMX

INH prophylaxis Azithromycin/clarithromycin Ganciclovir

Immune Prophylaxis Intravenous immunoglobulin (IVIG) Varicella-zoster globulin Measles immunoglobulin RSV immunoglobulin

HAART

Consider to prevent bacterial infections in children with hypogammaglobulinemia or recurrent, severe infections or inability to form antibodies to common antigens Children exposed to varicella or zoster without a prior history of varicella infection or immunization within 2 weeks of exposure Children exposed to measles Children at risk for severe RSV (premature infants, those <2 years with chronic lung disease, or severely immunosuppressed children) monthly for the duration of the RSV season At appropriate stage of immune suppression

CDC, Centers for Disease Control and Prevention; CMV, cytomegalovirus; DPT, diphtheria pertussis tetanus; HAART, highly active antiretroviral therapy; INH, isoniazid; RSV, respiratory syncytial virus; TMP/SMX, trimethoprim sulfamethoxazole.

Table 37-4 Indications for PCP Prophylaxis in HIV-Infected Children Age

*CD4 T-Lymphocyte Count

†

All patients irrespective of CD4 count <500/mm3 or if percentage is less than 15% <200/mm3 or if percentage is less than 15%

4-6 weeks to 12 months 1-5 years >5 years

*If CD4 measurements are unavailable, then prophylaxis should be given to all symptomatic children indefinitely.109 † HIV-exposed children should receive prophylaxis from 4-6 weeks to 4 months; thereafter prophylaxis may be discontinued if HIV infection has been excluded and the mother is not breastfeeding. PCP, Pneumocystis jiroveci pneumonia.

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TMP-SMX prophylaxis (150 mg/m2/day of TMP) may be given three times a week (single dose on 3 consecutive days, or two divided doses on consecutive or alternate days or 7 divided doses each dag for a week). 91 If TMP/SMX is not tolerated or cannot be used, alternatives include dapsone (2 mg/kg once daily), atovaquone (30-45 mg/kg once daily) or aerosolized pentamidine (300 mg via Respigard II inhaler every 4 weeks) if the child is older than 5 years of age. 91,111-114 Safety and efficacy concerns regarding aerosolized pentamidine preclude its use in young children. A study of the safety

of inhaled pentamidine in young children reported cough, wheeze, or oxygen desaturation in five of seven infants. 114 Prevention of Mycobacterial Disease INH prophylaxis is currently not routinely recommended for HIV-infected children, except if a child has been exposed to a household contact with TB (see Chapter 39), when INH prophylaxis (5-10 mg/kg) should be given daily for 6 to 9 months once active tuberculosis disease has been excluded (see Table 37-3). Prophylaxis should also be given to HIVinfected children with TB infection (tuberculin skin test >5 mm induration) but not disease. A recent study in a high TB prevalence area reported that INH prophylaxis given to HIV-infected children, irrespective of tuberculin skin reactivity or a household TB contact, substantially reduced mortality and TB incidence; however, further studies are needed before this can be widely recommended. 115 Primary prophylaxis for NTM with azithromycin or clarithromycin should be considered for severely immunosuppressed children (see Table 37-3) as follows: for children younger than 1 year, CD4 < 750/uL; children 1 to 2 years CD4 < 500/uL; children 2 to 6 years, CD4 < 75/uL; children 6 years or older CD4 < 50/uL. 91 Rifabutin may be an alternative agent in children older than 6 years. 91 Secondary prophylaxis should be given to children with a history of dis-

C H A P T E R 37 ■ Human Immunodeficiency Virus Infection

seminated MAC to prevent recurrence. 91 Lifelong prophylaxis is indicated; the safety of discontinuing secondary prophylaxis in the context of sustained immune restoration following HAART has not been well studied in children. Prevention of Cytomegalovirus Infection Oral ganciclovir or valganciclovir may be used for primary prophylaxis in severely immunosuppressed HIV-infected children as reflected by a CD4 count less than 50 cells/µL (see Table 37-3). 116 Secondary lifelong prophylaxis should be given to children with a history of disseminated CMV disease to prevent recurrence; there are little data on the safety of discontinuing prophylaxis once sustained immune reconstitution on HAART has occurred. Immunization The nature and degree of immunosuppression determine the safety and efficacy of vaccination in HIV-infected children. The efficacy of immunization may be substantially reduced in symptomatic HIV-infected subjects who are not on HAART. Immunization with inactivated vaccines (diphtheria, pertussis, tetanus toxoids; inactivated poliovirus, H. influenzae b, hepatitis B, and pneumococcal conjugate vaccine) should be given to HIV-infected children at the usual recommended age as for uninfected children (see Table 37-3). 91 Although the pneumococcal conjugate vaccine has lower efficacy in HIV-infected children who are not on HAART compared with HIV-uninfected children, it reduces the incidence of invasive disease and pneumonia in a substantial proportion of HIV-infected children. In a large South African study, the nine valent vaccine prevented 13% of radiologically diagnosed pneumonia and 65% of invasive pneumococcal disease in HIV-infected children. 25 A booster dose of the vaccine may be required during the second year in HIV-infected children. Measles, mumps, rubella vaccine (MMR), a live attenuated vaccine, should be given to HIV-infected children at 12 months of age, unless they are severely immunocompromised. 91 Varicella vaccine should be considered at 12 to 15 months for asymptomatic or mildly symptomatic HIVinfected children without immunosuppression (CDC categories N1 and A1); vaccine should not be administered to symptomatic immunosuppressed children due to the potential for disseminated disease. 91 Influenza vaccine should be given annually to all HIV-infected children at the start of the influenza season. 91 BCG vaccine is not recommended in HIV infected infants due to the risk of disseminated disease. Immune Prophylaxis PREVENTION OF BACTERIAL INFECTIONS Intravenous immunoglobulin (IVIG) for prevention of bacterial infections including pneumonia may be indicated for HIV-infected children who have hypogammaglobulinemia (IgG < 4 g/L) or recurrent, severe infections (two or more bacterial infections including pneumonia in 1 year) or inability to form antibodies to common antigens. 16,17,91,117 However, IVIG may not offer additional protection if children are taking TMP-SMX prophylaxis. 17 Moreover, there is no evidence to suggest that immunoglobulin offers additional

protection in children taking HAART. Children with bronchiectasis may benefit from monthly immunoglobulin. 91 Immunoglobulin is usually given as a monthly injection. PREVENTION OF VARICELLA Administration of varicella-zoster globulin should be considered for HIV-infected children exposed to varicella or zoster who have no history of varicella infection or immunization and who have not received immunoglobulin within 2 weeks of exposure. 91 PREVENTION OF MEASLES HIV-infected children exposed to measles should receive a dose of intramuscular immunoglobulin irrespective of immunization status. 91 PREVENTION OF RESPIRATORY SYNCYTIAL VIRUS The efficacy of the humanized monoclonal specific antibody against RSV (palivizumab) or RSV immune globulin (RSVIVIG) has not been well studied in HIV-infected children. Nevertheless, those at risk for severe RSV infection such as premature HIV-infected infants, those under 2 years of age with chronic lung disease, or severely immunosuppressed children may benefit from prophylaxis. 91 A dose should be given monthly for the duration of the RSV season. 91

CHRONIC LUNG DISEASE Chronic lung radiologic changes are common among HIVinfected children with increasing age 118,119 ; a longitudinal birth cohort study reported that the cumulative incidence of chronic radiographic lung changes in HIV-infected children was 33% by 4 years old. 118 The most common chronic radiologic changes are increased bronchovascular markings, reticular densities, or bronchiectasis. 118,119 Chronic changes are associated with lower CD4 cell counts and higher viral loads; radiologic resolution of these may reflect declining immunity. 118 The spectrum of chronic HIV-associated lung disease includes lymphocytic interstitial pneumonia (LIP), chronic infections, bronchiectasis, malignancies, bronchiolitis obliterans, and interstitial pneumonitis. Lymphocytic Interstitial Pneumonia and Pulmonary Lymphoid Hyperplasia Lymphocytic interstitial pneumonia (LIP) and pulmonary lymphoid hyperplasia (PLH) represent a spectrum of chronic lymphocytic infiltrative diseases of the lungs, occurring commonly in HIV-infected children. The etiology is unknown; evidence suggests that infection with Epstein-Barr virus may initiate a lymphoproliferative response in the presence of HIV infection. 120 Clinically children develop insidious, chronic respiratory symptoms—principally cough and mild tachypnea. 121 Lymphoproliferation, occurring in other organs, may produce associated generalized lymphadenopathy, digital clubbing, bilateral nontender parotid enlargement and hepatosplenomegaly. 121-123 Hypoxemia, if present, is usually mild. Children may survive for years with a course characterized by recurrent episodes of acute lower respiratory tract infections. 124 Long-term cor pulmonale or bronchiectasis may develop. 125

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P A R T 7 ■ RESPIRATORY INFECTIONS

Children with LIP have moderately elevated serum IgG and LDH levels and titers to viral capsid antigen of EpsteinBarr virus. 120 Chest radiographs often show a diffuse reticulonodular pattern, more pronounced centrally (Fig. 37-5A) and bilateral hilar adenopathy which may be difficult to distinguish from pulmonary or miliary TB. 123 Clinically, relatively mild respiratory illness, the presence of parotid enlargement, and a reticulonodular pattern on chest radiograph or CT scan may help to distinguish children with LIP from those with miliary TB. 123 Peribronchiolar thickening alone or normal chest radiographs may also occur. 122,123 Radiographic lesions may resolve in association with worsening immune status. 126,127 Respiratory status may improve with the use of HAART 127 ; among HIV-infected adults with LIP, HAART has been reported to result in resolution of radiographic abnormalities. 128 High-resolution CT may improve diagnostic certainty; typical features include micronodules of 1 to 3 mm in diameter, with a perilymphatic distribution and subpleural nodules

(see Fig. 37-5B). 129 The role of nuclear scanning in confirming the diagnosis has not been well studied, but diffuse pulmonary gallium uptake has been reported in an HIV-infected child with LIP. 130 Children with LIP have marked BAL lymphocytosis, but this is nonspecific. Definitive diagnosis requires open lung biopsy. 122 Lung biopsies revealed collections of lymphoid aggregates, often with germinal centers, surrounding the airways and a significant interstitial infiltrate composed primarily of lymphocytes (Fig. 37-6). Treatment is symptomatic, including antibiotics for acute infections and inhaled bronchodilators. Although there are no trials of efficacy, case reports indicate a response to systemic corticosteroids. 131-133 Oral corticosteroids are, therefore, recommended for children with hypoxemia. 133 A suggested regimen is prednisone, 2 mg/kg/day for 2 to 4 weeks, until the partial pressure of oxygen increases. Corticosteroids are then tapered to 0.5 to 0.75 mg/kg alternate days provided that the partial pressure remains adequate. 133 Further tapering may be possible as long as adequate oxygenation is maintained. No data exist on the use of inhaled corticosteroids. LIP is categorized as a World Health Organization (WHO) stage 3 AIDS-defining illness and is thus an indication for initiating HAART in children who are not yet taking antiretroviral therapy. 134 Chronic Pulmonary Infections

A

Chronic infection resulting from recurrent or persistent pneumonia may produce chronic lung disease. Infectious causes of chronic lung disease include many of the bacterial, viral, or fungal pathogens in Box 37-1. Infection with M. tuberculosis is a particularly important and prevalent cause of chronic lung disease in developing countries. 29,30,33-36,123 Distinguishing pulmonary or miliary M. tuberculosis from LIP may be difficult; in general, children with LIP are older and less severely ill, enlarged parotid glands may occur, and chest radiology demonstrates a reticulonodular pattern. 123 A few case reports have described chronic Pneumocystis jiroveci infection occurring in HIV-infected children, usually manifesting with cystic disease or with pneumatocele formation. 71,135

B

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Figure 37-5 A, Chest radiograph of a child with lymphocytic interstitial pneumonia (LIP) with multiple nodular densities throughout all lung fields. The nodules are larger centrally than peripherally. Also noted are hilar adenopathy and widening of the mediastinum. B, High resolution chest CT scan of a child with LIP showing a diffuse micronodular pattern. (A, Courtesy Henry Pritzker, Bronx, NY.)

Figure 37-6 Lung biopsy specimen of a patient with lymphocytic interstitial pneumonia. There is a diffuse lymphocytic infiltrate present throughout. An aggregate of cells into a germinal center is also seen in the center of the field. (Courtesy Sumi Mitsudo, Bronx, NY.)

C H A P T E R 37 ■ Human Immunodeficiency Virus Infection

BRONCHIECTASIS Bronchiectasis may occur following recurrent bacterial infection, secondary to chronic infection including M. tuberculosis and as a consequence of LIP. 125,136 The clinical presentation is similar in HIV-infected and uninfected children (see Chapter 69). Clinical features include sputum production, halitosis, digital clubbing, and abnormalities on chest auscultation. Development of bronchiectasis may be associated with the degree of immunosuppression; among 23 HIVinfected children (median age of 7.5 years) with bronchiectasis, all had CD4 T cell counts less than 100 cells/mm3. 136 Therapy includes physiotherapy and aggressive treatment of intercurrent infections. MALIGNANCY Children with HIV have an increased risk of malignancy, which is reported in 2.5% of children with AIDS in the United States. 137 The most common malignancy is nonHodgkin lymphoma (NHL) followed by Kaposi sarcoma (KS), leiomyosarcoma, and Hodgkin lymphoma. 137,138 Infection with EBV virus has been associated with the development of NHL in HIV-infected children—including those with mild immunosuppression. 138 Primary NHL may arise in a lymph node or be extranodal. 137,138 AIDS-related NHL may occur in almost any extranodal site including the lungs; in addition, pulmonary disease may result from dissemination from a primary focus. In African HIV-infected children, KS is the most common AIDS-defining malignancy. 139 The epidemiology of childhood HIV-associated KS is probably related to the prevalence of human herpes virus-8 infection, which may be transmitted from an infected mother. 139-141 The most common clinical presentation is that of violaceous plaques on the skin. 142 Pulmonary dissemination may produce chronic progressive dyspnea, cough, and fever. Kaposi sarcoma may also produce upper airway obstruction. Hemoptysis may occur with endobronchial lesions. 140,142 Chest radiograph abnormalities include bilateral adenopathy, perihilar infiltrates, pleural effu-

sion, or combinations of interstitial, alveolar, or nodular patterns. The finding of poorly marginated discrete lesions on CT scan may be specific for KS. 143 Thoracentesis may reveal serosanguineous or hemorrhagic exudates, but is nonspecific for KS. The diagnosis is best made by open lung biopsy. The outcome is generally poor. MISCELLANEOUS Desquamative interstitial pneumonitis, bronchiolitis obliterans, and nonspecific interstitial pneumonitis occur in children with AIDS. The manifestations are progressive dyspnea, hypoxemia, cough, and sometimes fever; radiographs reveal interstitial pneumonitis. These conditions may be difficult to distinguish from LIP or miliary TB without open lung biopsy, 123 which is required for definitive diagnosis.

PITFALLS AND CONTROVERSIES ●

●

●

●

●

HIV-infected children are at higher risk for pneumococcal pneumonia or bacteremia than HIV-uninfected children; but the efficacy of the pneumococcal conjugate vaccine is lower in HIV-infected children. Diagnosis of TB in HIV-infected children is difficult owing to anergy, nonspecific signs and radiologic changes, and difficulty in obtaining microbiologic confirmation. An immune reconstitution inflammatory syndrome (IRIS) characterized by a paradoxical worsening in clinical signs occurs with mycobacterial infections and is difficult to distinguish from other infections, multidrug resistant mycobacterial infections, or nonresponse to mycobacterial therapy. The use of corticosteroids in PCP has not been tested in any randomized trials in children but historical comparisons and adult studies report efficacy. However, the impact of corticosteroids on CMV pneumonitis, which may coexist with PCP, is unclear. Chronic pulmonary TB or miliary TB may be difficult to distinguish clinically or radiologically from LIP.

SUGGESTED READINGS American Academy of Pediatrics: Human immunodeficiency virus infection. In: Pickering LK, Baker CJ, Long SS, McMillan JA (eds): Red Book 2006. Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2006.

Chintu C, Mwaba P: Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis 9(5):477-484, 2005. Chintu PC, Bhat G, Walker A, et al: Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): A double-blind randomised placebo-controlled trial. Lancet 364(9448):1865-1871, 2004. Dankner WM, Lindsey JC, Levin MJ: Pediatric AIDS Clinical Trials Group Protocol Teams 051, 128, 138, 144, 152, 179, 190, 220, 240, 245, 254, 300 and 327. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 20(1):40-48, 2001. Gona P, Van Dyke RB, Williams PL, et al: Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 296(3):292-300, 2006.

Gonzalez CE, Samakoses R, Boler AM, et al: Lymphoid interstitial pneumonitis in pediatric AIDS. Natural history of the disease. Ann N Y Acad Sci 918:358-361, 2000. Hesseling AC, Schaaf HS, Marais B, et al: Bacille Calmette-Guérin vaccine-induced disease in HIV infected and HIV-uninfected children. Clin Infect Dis 42(4):548-558, 2006. Hughes WT: Pneumocystis carinii pneumonia: New approaches to diagnosis, treatment and prevention. Pediatr Infect Dis J 10:391399, 1991. Jeena PM, Coovadia HM, Thula SA, et al: Persistent and chronic lung disease in HIV-1 infected and uninfected African children. AIDS 12(10):1185-1193, 1998. Klugman KP, Madhi SA, Huebner RE, et al: A trial of 9-valent pneumococcal conjugate vaccine in children with and without HIV infection. N Engl J Med 349:1341-1348, 2003. Lawn SD, Bekker LG, Miller RF: Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 5(6):361-373, 2005. Mofenson LM, Oleske J, Serchuck L, et al: Treating opportunistic infections among HIV-exposed and infected children: Recom-

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P A R T 7 ■ RESPIRATORY INFECTIONS mendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. Clin Infect Dis 40: S1-S84, 2005. Nachman S, Gona P, Dankner W, et al: The rate of serious bacterial infections among HIV-infected children with immune reconstitution who have discontinued opportunistic infection prophylaxis. Pediatrics 115(4):e488-e494, 2005. Norton KI, Kattan M, Rao JS, et al: Chronic radiographic lung changes in children with vertically transmitted HIV-1 infection. Am J Roentgenol 176(6):1553-1558, 2001. Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. Clin Infect Dis 40:S1-S84, 2005.

Sheikh S, Madiraju K, Steiner P, Rao M: Bronchiectasis in pediatric AIDS. Chest 112(5):1202-1207, 1997. Thomas CF, Limper AH: Pneumocystis pneumonia. N Engl J Med 350(24):2487-2498, 2004. Zar HJ: Pneumonia in HIV-infected and uninfected children in developing countries—epidemiology, clinical features and management. Curr Opin Pulm Med 10(3):176-182, 2004. Zar HJ: Prevention of HIV-associated respiratory disease in developing countries: Potential benefits. Int J Tuberc Lung Dis 7(9):820827, 2003.

REFERENCES The references for this chapter can be found at www.pedrespmedtext.com.

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