Immunodeficiencies in Infants and Children

Treating opportunistic infections in HIV-infected children and adolescents

Synonyms

Pediatric AIDS, Pediatric HIV

Related conditions

Mycobacteria [Mycobacterium tuberculosis, Mycobacterium avium complex (MAC)],

Invasive and Recurrent Bacterial Infections,

Fungi [Pneumocystis jirovecii Pneumonia (PCP), Candida species, Cryptococcus neoformans, Histoplasmosis],

Protozoa [Toxoplasmosis] and

Viruses [Cytomegalovirus, Herpes Simplex Virus I and II and Varicella Zoster].

1. Description of the problem

What every physician needs to know

The following summaries reflect current recommendations on the treatment of opportunistic infections (OIs) common to HIV-infected infants, children and adolescents in the U.S. For a more comprehensive summary, the reader is referred to the Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society and the American Academy of Pediatrics. AIDSinfo 2013 Nov 6; Downloaded from http://aidsinfo.nih.gov/guidelines on 5/18/2014.

Due to the widespread use of effective combination antiretroviral therapy (cART) among HIV- infected children, the number of OIs seen in clinical practice has decreased. However, OIs continue to be the presenting symptom of HIV infection in infants due to lack of antenatal testing in mother, or in adolescents who are increasingly infected by horizontal transmission.

Without cART, the most common OIs in children include serious bacterial infections, namely pneumonia and bacteremia. Common co-pathogens and OIs that are difficult to eradicate without successful immune reconstitution include chronic mucosal or disseminated infections with herpes viruses, namely CMV, HSV, and VZV. Primary disseminated and reactivated TB is a major cause of morbidity and mortality among HIV-infected children from communities where infection with the pathogen is endemic.

Disseminated disease with Mycobacterium avian complex (MAC) may occur in HIV-infected children with advanced immunologic deterioration.

Pneumocystis

jiroveci (formerly

carinii) pneumonia (PCP) is a common and serious OI associated with a high mortality. The pneumonia most often manifests between 3-6 months of age in infants with vertically acquired infection.

Candidiasis (topical, oral, esophageal, and tracheobronchial) is the most common fungal infection in HIV-infected children. Causes of acute and chronic CNS infections include

Cryptococcus neoformans and

Toxoplasma gondii. Less commonly observed OIs include cryptosporidiosis and systemic fungal infections.

Clinical features

Clinical presentations include hepatosplenomegaly, failure to thrive, oral candidiasis, recurrent diarrhea, parotitis, cardiomyopathy, hepatitis, nephropathy, developmental delay and encephalopathy, lymphoid interstitial pneumonitis, recurrent bacterial infections, and specific malignancies. The latter include non-Hodgkin’s B-cell Burkitt’s-type lymphomas, leiomyosarcomas and Kaposi’s sarcoma, which is not uncommonly described in HIV-infected children of African ethnicity.

Mycobacterium tuberculosis

The clinical presentation of TB disease among children with HIV infection is similar to that in children without HIV infection. Most tuberculosis infection is usually asymptomatic. Children aged less than 4 years of age and those who are HIV-infected are more likely to develop signs of active TB. Early clinical manifestations of disease include fever, weight loss, cough, night sweats, and chills. Children with pulmonary TB may have few or no symptoms. Chest X-ray may show hilar or mediastinal lymphadenopathy, segmental involvement, cavitary lesions or a miliary pattern. Radiological changes such as diffuse interstitial disease may be less well-defined in HIV-infected children.

Older HIV-infected children and adolescents may have adult-type reactivation pulmonary disease with cavitation. Multiple lobes are involved in up to 25% of children. Extrapulmonary disease in children includes lymphadenitis, disseminated (miliary) disease, TB meningitis, bone/joint disease, and TB in other sites such as peritoneum and pericardium.

Disseminated Mycobacteria avium complex disease

It is difficult to separate the clinical and laboratory features directly attributable to MAC from abnormalities attributable to advanced HIV disease. In early reports of HIV-infected children with disseminated MAC high fever, weight loss with failure to thrive, chronic diarrhea and malabsorption, night sweats, neutropenia and/or severe anemia were most often described. Other features included persistent abdominal pain, intra-abdominal lymphadenopathy, hepatosplenomegaly and elevated alkaline phosphatase. Local manifestations of disseminated MAC and TB may occur in severely immunosuppressed HIV-infected children following immune reconstitution with cART.

Local symptoms develop secondary to an inflammatory response to mycobacterial antigens as cell-mediated immunity is restored. Most often, patients’ exhibit lymphadenopathy occurring 1-12 weeks after initiating cART; abdominal pain and hepatosplenomegaly are also reported. Fever may be present, but other constitutional symptoms (weight loss and night sweats) usually are absent, and blood cultures usually do not grow mycobacteria.

Invasive and recurrent bacterial infections

Prior to the advent of ART, invasive bacterial infections were the most common OIs in HIV-infected children, with pneumonia most often diagnosed followed by bacteremia and urinary tract infection. Other serious bacterial infections include osteomyelitis, meningitis, abscess, and septic arthritis. Signs and symptoms are organ/system-specific and similar in HIV-infected and non-HIV-infected children with an acute presentation, fever, and leukocytosis; the latter may be absent in very immunosuppressed children.

Organ-specific localizing signs and symptoms may present as a manifestation of disseminated MAC. The most commonly involved organs include the spleen, lymph nodes, liver, intestines, colon, bone marrow, and less commonly, lungs, adrenals, stomach, and central nervous system. Isolated pulmonary disease is rare, although presentation with isolated parenchymal pulmonary disease is a marker of high risk for dissemination. When lung disease does occur, the chest radiograph may reveal alveolar infiltrates, nodules or cavitations.

Pneumocystis jirovecii pneumonia (PCP)

Infants and children may develop a subacute or an abrupt diffuse pneumonitis with non-specific symptoms (mild non-productive cough, dyspnea at rest, poor feeding, weight loss). Clinical signs include tachypnea and respiratory distress, oxygen desaturation, bilateral basal crackles, and fever. The magnitude and prevalence of these signs and symptoms is variable, although tachypnea is universal by the time radiographic changes become apparent. Chest radiographs often show bilateral diffuse interstitial disease with a reticulogranular appearance; rarely, lobar, miliary, pneumothorax or pneumomediastinum, and nodular lesions occur as well.

Occasionally, the chest roentgenogram at the time of diagnosis appears normal. Most children with PCP have substantial hypoxia with low arterial oxygen pressure and an alveolar-arterial oxygen gradient greater than 30 mm/Hg. The disease may be far advanced before it is diagnosed and associated with a high mortality rate (5-40% with treatment, and 100% if untreated).

2. Emergency Management

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3. Diagnosis

Mycobacterium tuberculosis

There should be an increased index of suspicion of TB infection and disease in HIV-infected children. The diagnosis of TB has traditionally relied on microscopy of clinical samples using acid-fast staining and culture to detect the bacilli. Children with pulmonary TB are less likely to have positive smears because they may not produce sputum voluntarily and have lower quantities of bacteria in sputum. Acid-fast stains of early morning gastric aspirates are positive in less than 20% of children with TB. Samples from extrapulmonary sites, such as lymph node, CSF and joint fluid also have lower yields on acid-fast staining.

The microbiological isolation of M.TB on culture represents the gold standard for the diagnosis of TB. Three consecutive morning gastric aspirates yield a positive culture in up to 70% of infants and 30-50% of children with clinical pulmonary TB. Gastric lavage samples, collected on three consecutive mornings, has a higher yield on culture (50%) than a single sample collected by bronchoalveolar lavage (10%).

Sputum induction with hypertonic saline has been shown to be safe and equivalent in terms of culture yield to the collection of three early morning gastric aspirates. The culture yield from other fluids and tissues from extrapulmonary sites is lower, even with optimal samples. Positive culture is more helpful than positive acid fast stain to differentiate M.TB from other mycobacterial strains. Drug sensitivity testing should be performed on all isolates to identify resistant strains.

Tuberculin skin testing (TST) using PPD has traditionally been used as a diagnostic tool for latent TB infection (LTBI) detection and screening in children with HIV. TST suffers from significant false positive and negative results. Approximately 10% of immunocompetent children with culture proven TB disease will have a negative TST. Children with HIV co-infection will be even less likely to have a positive TST, particularly those with CD4 counts less than 15% or 200 cells/mm³. This limits the usefulness of TST as a diagnostic tool.

FDA-approved interferon gamma release assays (IGRA) are currently licensed and available. These assays measure interferon-gamma production by lymphocytes in response to TB antigens and may allow differentiation from atypical mycobacteria and BCG. Data from children with TB disease show better sensitivity than TST, especially in HIV-infected children, although TST is preferred over IGRA in children aged <5 years.

PCR amplification techniques have been used for the rapid identification of TB through amplification of specific regions of mycobacterial DNA in clinical samples. These tests have been adopted at some sites in the United States after local validation, but they are not yet FDA-approved.

Species identification using molecular probes may be useful, particularly in the very immunosuppressed child, in whom atypical mycobacteria can cause clinical disease and which may be difficult to clinically differentiate from M.TB. These tests are most effective when applied to samples in which mycobacteria have been detected microscopically.

Disseminated Mycobacteria avium intracellulare complex (MAC) disease

Although MAC may be identified by microscopy or histology, culture is necessary to determine which non-tuberculous mycobacteria is causing infection and to perform drug-susceptibility testing. The definitive diagnosis of disseminated disease requires isolation of the organism from blood or biopsy specimens from normally sterile sites, including bone marrow. Several mycobacterial blood cultures over time may be required to yield a positive result.

Blood cultures are highly sensitive in recovery of MAC. Caution must be exercised in the interpretation of cultures obtained from non-sterile sites, such as gastric washing specimens, stool, urine or respiratory tract secretions, which may suggest transient colonization and not invasive disease. Repeated isolation of numerous colonies of a single species is more likely to indicate disease than culture contamination or transient colonization.

Invasive and Recurrent Bacterial Infections

Lower respiratory tract infection (LRTI) is presumptively diagnosed in young children who most often present with fever, chest symptoms with or without an abnormal chest X-ray unless an accompanying bacteremia is present. Common isolates including Streptococcus pneumoniae, Haemophilus influenzae type B, Staphylococcus aureus and Escherichia coli were more likely to be resistant to common antibiotics in HIV-infected children.

In older children sputum culture may support the diagnosis of an LRTI. The isolation of the pathogen from blood or pleural fluid should be attempted. Other investigations to identify occult foci include CT and ultrasound for bronchiectasis and abscesses.

Pneumocystis jirovecii pneumonia (PCP)

The definitive diagnosis of PCP requires demonstration of the organism in pulmonary tissues or fluids from induced sputum after inhalation of nebulized 3% hypertonic saline. The sensitivity of induced sputum analysis in adults ranges from 25-90%; because negative predictive value is only 48%, it may be necessary to follow a negative induced sputum sample with bronchoscopy and bronchoalveolar lavage – the diagnostic procedure of choice in infants. The sensitivity ranges from 55-97% and might be positive for at least 72 hours after PCP treatment has been initiated; treatment should not be delayed while awaiting results.

Three types of stains can be used to diagnose P. jiroveci organisms in specimens. Gomori’s methenamine-silver stains the cyst wall brown or black. Toluidine blue stains the cyst wall blue or lavender and also stains fungal elements. Giemsa or Wright’s stains stain the trophozoites and intracystic sporozoites pale blue with a punctate red nucleus; unlike the other stains, this does not stain the cyst wall.

Candida species

Candida albicans most often causes mucocutaneous candidiasis in HIV-infected children with low or declining CD4+ T cell number (or percentage). Related risk factors include neutropenia, treatment with corticosteroids and/or broad-spectrum antibiotics, the presence of indwelling vascular catheters and prolonged intravenous infusions, particularly with parenteral alimentation and lipids. Such patients are also at risk of invasive infection.

Complications of disseminated disease include endophthalmitis, hepatosplenic and renal candidiasis, meningitis, candidemia, endocarditis and osteomyelitis. A significant percentage of reported cases of fungemia in HIV-infected children are caused by non-albicans Candida species. Isolates include C. tropicalis, C.pseudotropicalis, C. parapsilosis, C. glabrata, C.krusei, and C. dubliniensis.

Most patients present with pseudomembranous candidiasis or thrush (white curd-like plaques on the buccal mucosa, palate, gums or tongue with inflamed underlying mucosa). Esophageal candidiasis is usually accompanied by the presence of oropharyngeal candidiasis but may be absent. Typically, dysphagia and odynophagia are described, although children may present with nausea and vomiting alone.

Cryptococcus neoformans

More than 75% of cases associated with AIDS develop when the CD4 T-lymphocyte count falls below 50 cells/mm³. Cryptococcus neoformans is an encapsulated oval yeast. Inhalation of unencapsulated forms may result in colonization of the airways and respiratory infection with a propensity to invade the CNS. Meningoencephalitis is the most frequent manifestation of cryptococcosis.

Infection typically presents as a subacute process characterized by headache, fever, and less often, altered mental status; however, presentations characteristic of acute meningitis can occur with up to 70% of children. Cranial nerve palsies and papilledema are the most common ocular manifestations secondary to CNS invasion. Complications include hydrocephalus, motor or sensory deficits, cerebellar dysfunction and seizures.

Cryptococcal pneumonia may be either asymptomatic or symptomatic, with or without evidence of dissemination. It is unclear if disseminated disease represents a progression or reactivation of pulmonary disease. Children with pulmonary cryptococcosis without dissemination present with cough and recurrent fever. Chest radiographs may reveal focal or diffuse infiltrates and intrathoracic lymphadenopathy.

Cutaneous cryptococcosis is a sign of dissemination and may precede life-threatening disease by several weeks. The lesions may appear as papules, tumours, vesicles, plaques, abscesses, cellulitis, purpura, ulcers or bullae, and have previously been misdiagnosed as molluscum contagiosum. Immune Reconstitution syndrome (IRIS) related to cryptococcosis can present within weeks (meningitis) or months (lymphadenitis) after initiating cART.

Cryptococcus neoformans

The CT scan is usually nonspecific but may show signs of increased intracranial pressure, hydrocephalus or focal lesions, especially in the basal ganglia. Abnormal CSF findings, including pleocytosis, low glucose and high protein concentrations, are seen in approximately 40% of patients, although, in HIV-infected children with CNS disease these parameters may be normal. However, the opening pressure is usually elevated. The India ink stain on wet mount preparation that outlines the polysaccharide capsule is positive on direct examination of the CSF in over 80% of patients with cryptococcal meningitis secondary to AIDS.

Cryptococcal antigen can be detected in CSF, serum, or bronchoalveolar lavage fluid by latex agglutination. Cryptococcal antigen detection in the serum is usually indicative of systemic disease but does not correlate with clinical response to treatment. In contrast cryptococcal antigen titres in CSF can be helpful in evaluating response to therapy.

False negative titres may occur as a result of high (prozone effect) or low antigenic concentration, or the presence of nonencapsulated strains. Fungal cultures from CSF, sputum and blood might identify the organism. In selected cases, such as in patients with refractory disease or relapse, susceptibility testing of the C. neoformans isolate can be helpful.

Histoplasmosis

Fungal culture from bone marrow, blood, sputum and tissue specimens is the definitive method of diagnosis. The lysis-centrifugation method is preferred for blood cultures. Identification of H. capsulatum can be shortened in cultures through the use of a DNA probe. Demonstration of typical intracellular yeast forms by examination with Gomori methenamine silver of tissue, blood, bone marrow, or bronchoalveolar lavage specimens strongly support the diagnosis of histoplasmosis when clinical, epidemiologic and other laboratory studies are compatible.

Serologic testing by complement fixation or immunodiffusion is useful in patients with subacute or pulmonary disease. A fourfold rise in yeast- or mycelial-phase titer or a single titer of ≥1:32 in either test is presumptive evidence of active or recent infection.

Detection of H. capsulatum polysaccharide antigen (HPA) in serum, urine or bronchoalveolar lavage fluid by radio or enzyme immunoassay is a rapid, sensitive (particularly during acute pulmonary and disseminated infection) and specific diagnostic method and can be detected before culture positivity and antibody detection; a negative test does not exclude infection. An EIA that rapidly identifies and quantifies histoplasmal antigen in body fluids has been developed.

Antigen concentration can be used to monitor treatment response and to identify relapse. Cross reactivities occur in patients with blastomycosis, coccidioidomycosis, paracoccidioidomycosis and Penicillium marneffei infection. Meningitis can be diagnosed by testing CSF for histoplasma antigen, antibody and culture. Serologic tests are not useful for the diagnosis of acute histoplasmosis and might be undetectable in immunosuppressed patients. Histoplasmin skin tests are not sensitive for the diagnosis of disseminated disease and no longer available.

Histoplasmosis

The incidence of disseminated histoplasmosis in HIV-infected children residing in the United States is 0.4% and remains the most frequently diagnosed systemic fungal disease, with an estimated 500,000 cases per year. The diagnosis of disseminated histoplasmosis should therefore be considered in children with AIDS who have previously resided in endemic regions.

Primary infection in the respiratory tract is commonly asymptomatic in immunocompetent hosts, since cell-mediated immunity prevents dissemination. Infection occurs as a result of either reactivation or newly acquired infection in subjects with severe immunosuppression or during infancy.

Most symptomatic children with acute pulmonary histoplasmosis develop an influenza-like illness with non-pleuritic chest pain, hilar adenopathy, and mild pulmonary infiltrates; symptoms persist for 2 days to 2 weeks. Intense exposure to spores can cause severe respiratory tract symptoms and diffuse nodular pulmonary infiltrates, prolonged fever, fatigue and weight loss. Erythema nodosum can occur in adolescents. Primary cutaneous infections can occur after trauma.

A primary pulmonary focus frequently results in widespread dissemination in children with AIDS most often characterized by prolonged fever in association with weight loss and a non-productive cough. Frequent physical findings include hepatosplenomegaly, diffuse adenopathy and failure to thrive. Cutaneous lesions that are erythematous and nodular may develop.

Mucosal ulceration, pancytopenia, disseminated intravascular coagulopathy and gastrointestinal bleeding can ensue in association with elevated liver transaminases. Manifestations of CNS involvement include chorioretinitis, meningitis and brain abscesses.

Toxoplasmosis

An HIV-infected individual with impaired cell mediated immunity is at risk for reactivation of toxoplasmosis following primary infection, which manifests primarily as encephalitis and usually occurs with CD4+ T cell counts less than 100/mm³. Toxoplasma encephalitis should be considered in all HIV infected children with new neurologic findings. Although focal findings are more typical, the initial presentation can be variable and reflect diffuse CNS disease.

Characteristically toxoplasma encephalitis has a subacute onset with focal neurologic abnormalities often accompanied by headache, altered mental status and fever. Common focal neurologic signs include motor and speech disturbances. Patients can also present with seizures, cranial nerve abnormalities, visual field defects, sensory disturbances, cerebellar dysfunction, meningismus, movement disorders, and neuropsychiatric manifestations.

The manifestations of extracerebral toxoplasmosis in HIV-infected children include ocular toxoplasmosis, which occurs most often in association with toxoplasma encephalitis necessitating neurologic examination. Patients with chorioretinitis present with blurred vision, pain or photophobia. Rarely manifestations of reactivated chronic toxoplasmosis include systemic toxoplasmosis, pneumonitis, hepatitis and cardiomyopathy/myocarditis.

Cytomegalovirus (CMV)

Human CMV remains latent in the infected host throughout life, but rarely reactivates to cause clinical illness except in subjects with impaired cell-mediated immunity. Thus clinical manifestations vary with the age and immunocompetence of the host. Acquisition can occur in infancy, early childhood or adolescence and reflects either vertical or horizontal transmission.

Asymptomatic infections are the most common, particularly in children. An infectious mononucleosis-like syndrome with prolonged fever and mild hepatitis occurring in the absence of heterophile antibody production can occur in adolescents and adults. In the immunocompromised host, infection may occur secondary to reactivation of latent viral infection or may be newly acquired. Viral dissemination results in multiple organ system involvement, with the most important clinical manifestations consisting of pneumonitis, gastrointestinal disease and retinitis.

CMV retinitis is the most frequent severe manifestation of CMV disease in HIV-infected children, accounting for approximately 25% of CMV AIDS-defining illnesses. Peripheral lesions are frequently asymptomatic, and even advanced disease does not cause pain. The disease can progress to total blindness and retinal detachment if left untreated. CMV produces a necrotic rapidly progressing retinitis with characteristic white perivascular infiltrate and retinal hemorrhages. Older HIV-infected children with CD4+ T cell counts less than 100/mm³ are more likely to develop CMV retinitis but CD4+ number is less predictive in young infants.

CMV gastrointestinal disease. GI tract disease caused by CMV can include esophagitis, gastritis, pyloric obstruction, hepatitis, pancreatitis, colitis, ascending cholangitis and cholecystitis. Signs and symptoms may include nausea, vomiting, dysphagia, epigastric pain, icterus, and watery diarrhea. Stools may be bloody. Sigmoidoscopy in CMV colitis is nonspecific, showing diffuse erythema, submucosal hemorrhage, and diffuse mucosal ulcerations.

CMV pneumonitis. CMV in pulmonary disease is often isolated with other organisms (PCP). CMV pneumonitis begins with fever and a dry, non-productive cough that can progresses acutely, resulting in retractions, dyspnea, and hypoxia. Bilateral interstitial infiltrates are noted radiographically.

CNS manifestations. Co-infection with CMV appears to accelerate HIV disease progression and associated neurological disease. Manifestations include subacute encephalopathy and myelitis. CSF findings are nonspecific and may show a polymorphonuclear predominance, elevated protein and low glucose. Many children have normal CSF.

CMV-associated IRIS. Uveitis may occur after the initiation of effective cART and is a paradoxical immunologic reaction to CMV associated with inflammation in the anterior chamber and/or the vitreous. Ocular complications of uveitis include macular edema and the development of epiretinal membranes, which can cause loss of vision. Immune recovery uveitis may respond to periocular corticosteroids or a short course of systemic steroids.

Cytomegalovirus

It is often difficult to distinguish asymptomatic infection from disease. CMV can be isolated by viral culture from virtually any body fluid or tissue. A positive blood buffy-coat culture establishes a diagnosis of CMV infection and increases the likelihood that disease or symptoms are caused by CMV because children with positive blood cultures are at higher risk for developing end-organ disease. Viral antigen (specifically pp65 antigen) or DNA can be detected directly by qualitative and quantitative PCR and DNA hybridization.

These techniques are more sensitive than buffy-coat or cultures for detecting CMV and can be used to identify patients at higher risk of disease. Quantitation by DNA PCR can be used as a marker of disease progression and to monitor response to therapy. Histopathology demonstrates characteristic “owl’s eye” intranuclear and smaller intracytoplasmic inclusion bodies in biopsy specimens.

Herpes Simplex virus 1 and 2

(HSV 1 & 2)

In immunosuppressed HIV-infected children, primary HSV coinfection is associated with extensive tissue destruction, poor healing of ulcerative lesions, prolonged viral shedding and occasional dissemination. The latter includes visceral involvement and generalized skin lesions. Other sites of involvement include the esophagus, genitalia, liver, adrenals, lung, kidney, spleen and CNS.

Varicella Zoster virus

(VZV)

A generalized severe pruritic vesicular rash and fever is diagnostic. Lesions appear first and are most numerous on the trunk, neck and face. The vesicles contain fluid, rest on an erythematous base, and ulcerate and dry to form crusts and scabs. Lesions in all stages of development (macules, papules, vesicles, ulcers and crust) are characteristic of varicella. Lesions during chronic VZV infection are varicelliform at onset but may evolve into non-healing, necrotic and crusted ulcers that become hyperkeratotic.

The classical clinical presentation of zoster (a painful localized cutaneous vesicular eruption along one or more contiguous dermatomes) is diagnostic. Lesions evolve over 1-2 days to form vesicles, pustules, and crusts. In HIV-infected patients, zoster may be bullous, hemorrhagic, necrotic, and particularly painful. Blisters and crusts usually last 2-3 weeks, although necrotic lesions may last up to 6 weeks and heal with severe scarring. Zoster in HIV-infected children may also present as an atypical rash that extends beyond dermatomal boundaries or is bilaterally distributed or generalized, or as multiple episodes of a disseminated rash more similar in appearance to chickenpox than zoster.

Varicella pneumonitis in HIV-infected children is associated with severe pulmonary manifestations resulting in hypoxemia and diffuse reticulo-nodular densities on radiography. Encephalitis occurs more frequently with zoster in the ophthalmic distribution, and cerebellar findings are typical; prominent symptoms include ataxia, tremors and dizziness. Cerebral involvement results in fever, headache, vomiting and lethargy. Progressive outer retinal necrosis associated with VZV typically occurs among HIV-infected individuals with CD4 counts fewer than 50 cells/mm³.

4. Specific Treatment

Mycobacterium tuberculosis

The basic principles of treatment of a child with TB infection or disease with HIV will be the same as that for an HIV-uninfected child. Due to drug-drug interactions between some antituberculous and antiretroviral drugs, the treatment of children being treated for both HIV and TB may be complex and require specialist care. It is recommended that the initial empiric treatment of a child with active TB disease should consist of a daily 4-drug regimen including isoniazid, rifampin, pyrazinamide and ethambutol (the latter due to the possibility of a drug-resistant isolate). Ethionamide can be used as an alternative to ethambutol in cases of TB meningitis because of better CNS penetration. Prothionamide is interchangeable with ethionamide and may be better tolerated than ethionamide.

Disseminated Mycobacteria avium complex disease

Combination therapy with a minimum of 2 drugs is recommended: clarithromycin or azithromycin plus ethambutol. In patients with more severe symptoms rifabutin can be added as a third drug but can cause a number of drug interactions by increasing CYP3A activity. If rifabutin cannot be administered, ciprofloxacin, levofloxacin and/or amikacin or streptomycin can be considered. Clinical improvement is usually noted during the first 4-6 weeks of therapy, with fever resolution during the first 2 weeks. Treatment failure is defined as the absence of clinical response and the persistence of mycobacteremia after 7 to 12 weeks of treatment.

Invasive and recurrent bacterial infections

If an organism is identified, antibiotic susceptibility testing should be performed and therapy based on the results of susceptibility testing. HIV-infected children who are not severely immunosuppressed or neutropenic can be expected to respond similarly to HIV-uninfected children and should be treated with antimicrobial agents recommended for the most likely bacterial isolates. Severely immunocompromised children presenting with invasive or recurrent bacterial infections may require empiric antimicrobial treatment covering a broad range of resistant organisms pending results of diagnostic evaluations and cultures.

Pneumocystis jirovecii pneumonia

Co-trimoxazole or Trimethoprim-sulfamethoxazole (TMP/SMX) is the treatment of choice for PCP. After the acute pneumonitis has resolved, children with mild to moderate disease who do not have malabsorption or diarrhea can be given oral treatment with the same dose of TMP/SMX in 3-4 divided doses to complete a 21-day course.

Adverse reactions to TMP/SMX reported in children include rash (including erythema multiforme and rarely Stevens Johnson syndrome), hematologic abnormalities (neutropenia, thrombocytopenia, megaloblastic or aplastic anemia), gastrointestinal complaints, hepatitis and renal disorders. For mild or moderate skin rash, TMP/SMX can be temporarily discontinued and re-started when the rash has resolved. If an urticarial rash or Stevens-Johnson syndrome occur, TMP/SMX should be discontinued and not re-administered.

Pentamidine isothionate is recommended for patients intolerant of TMP/SMX or who demonstrate clinical treatment failure after 5-7 days of TMP/SMX therapy. In patients with clinical improvement after 7-10 days of intravenous therapy with pentamidine, an oral regimen (atovaquone) might be considered to complete a 21-day course.

The most common adverse drug reaction to pentamidine is renal toxicity, which usually occurs after 2 weeks of therapy and can be averted by adequate hydration and careful monitoring of renal function and electrolytes. Severe hypotension (particularly if infused rapidly), prolonged QT interval (torsades de pointes), and cardiac arrhythmias can occur. Hypoglycemia (usually after 5-7 days of therapy) or hyperglycemia, hypercalcemia, hyperkalemia, pancreatitis and insulin-dependent diabetes mellitus have also been reported.

A course of corticosteroids started within 72 hours of diagnosis might be beneficial in some cases of PCP of moderate or great severity. Several studies in children have demonstrated a reduction in acute respiratory failure, decreased need for ventilation, and a decrease in mortality with early use of corticosteroids. Indications for corticosteroid include a PaO2 value of less than 70 mm Hg or an alveolar-arterial gradient of less than 35 mm Hg. A few case reports in children have documented improved pulmonary function with use of surfactant in cases of severe disease.

Candida species

Data from studies using echinocandins including caspofungin, micafungin, and anidulafungin are now sufficient to recommend these agents as alternatives to fluconazole for esophageal candidiasis and as first-line therapy for disseminated candidiasis.

Esophageal candidiasis

Systemic therapy with fluconazole for 14-21 days is effective. For refractory disease, alternative agents include oral itraconazole, low-dose intravenous amphotericin B for a minimum of 7 days, oral or intravenous voriconazole, micafungin, and caspofungin.

Invasive disease

The treatment of choice for invasive disease in HIV-infected children depends on severity of disease, previous azole exposure, and Candida isolate obtained (if known). Despite the frequency of mucosal candidiasis, invasive disease is uncommon in HIV-infected subjects. Central venous catheters should always be removed when feasible in HIV-infected children with candidemia.

In severely ill children with candidemia, an echinocandin-like micafungin or caspofungin is recommended because of the fungicidal nature of these agents as well as the lack of adverse events. In less severely ill children who have not had previous azole therapy, fluconazole can be used. Alternatively, an initial course of amphotericin B therapy can be administered and then followed by completion of a course of fluconazole therapy. The duration of therapy is determined by the presence of deep tissue foci, patient clinical response, and presence of neutropenia. For candidemia, treatment is recommended until 2 weeks after the last positive blood culture and signs and symptoms have resolved with resolution of neutropenia

In patients with persistent candidemia, despite appropriate therapy, investigation for a deep tissue focus of infection should be conducted, including echocardiogram, renal or abdominal ultrasound, and ophthalmologic evaluation.

Adverse effects of amphotericin B are primarily related to nephrotoxicity with hypokalemia from renal tubular damage. Permanent nephrotoxicity is related to cumulative dose. Nephrotoxicity can be ameliorated by hydration with 0.9% saline intravenously over 30 minutes before infusion. Infusion-related fevers, chills, nausea, and vomiting can occur. Pretreatment with acetaminophen and/or diphenhydramine may alleviate such reactions. Lipid preparations appear to be as efficacious as conventional amphotericin B for treatment of invasive disease and associated with fewer toxicities, but their use is limited by cost.

High dose fluconazole is an alternative to amphotericin B for treatment of invasive disease in patients with uncomplicated candidemia with albicans species who have not recently received azole therapy or prophylaxis. For patients infected with Candida glabrata or Candida krusei, an echinocandin is recommended. For patients infected with Candida parapsilosis, fluconazole or amphotericin B is recommended.

Candida species

The diagnosis is usually suggested by a characteristic clinical appearance. The recovery of an organism is not diagnostic since colonization is common. However a 10% potassium hydroxide (KOH) slide preparation of a scraping of an active lesion can be confirmatory. Pseudohyphae and budding yeast are characteristic findings. In patients with poorly responsive mucosal candidiasis, a culture should be obtained to look for drug-resistant yeast or identification of isolates that respond poorly to azoles C. kruseii or C. glabrata).

Barium swallow or upper GI endoscopy can confirm a suspicion of esophageal involvement. The latter should be performed to rule out other causes of esophagitis (HSV, CMV, MAC). The diagnosis of candidemia can be made with blood cultures. Additional investigations include retinal examination for endophthalmitis, echocardiogram for cardiac vegetations, abdominal CT or ultrasound for hepatic or renal involvement, and bone scans if osteomyelitis is suspected.

Cryptococcus neoformans

Recommendations for treatment of severe cryptococcal disease in children have been extrapolated from adult data to include induction therapy with amphotericin B deoxycholate (or liposomal amphotericin B) combined with a minimum of 2 weeks of flucytosine. Lipid formulations of amphotericin B are preferred in patients with impaired renal function. Fluconazole can be substituted for flucytosine as initial therapy in instances when this drug is not tolerated by the patient or is unavailable. Echinocandins are not active against cryptococcal infections and should not be used.

Consolidation therapy involves replacement of amphotericin B and flucytosine with high dose IV or oral fluconazole for a minimum of 8 weeks or until CSF cultures are stable.

Following induction and maintenance therapy, maintenance suppressive therapy with a low oral dose of fluconazole is recommended. The aggressive management of acute cerebral edema and increased intracranial pressure is pivotal in the management of acute cryptococcal meningitis.

Monitoring mycologic responses to antifungal therapy in patients with CNS cryptococcosis is recommended by repeat CSF examination after 2 weeks of treatment, with continuation of induction therapy if the culture is positive until negative cultures are obtained.

Children with severe pulmonary disease can be treated with amphotericin B induction therapy combined with flucytosine for 2 weeks. Following acute treatment, maintenance therapy with fluconazole or itraconazole is recommended. For children with mild-to-moderate pulmonary cryptococcosis, fluconazole alone can be used for treatment followed by lifelong suppressive therapy with fluconazole (in the absence of immune reconstitution). Itraconazole is a suitable alternative.

The optimal management of cryptococcal IRIS has not been defined. Antifungal therapy should be initiated and cART continued. Many cases resolve spontaneously, although anti-inflammatory therapy (short-course corticosteroids) may be beneficial in patients with severely symptomatic IRIS.

Histoplasmosis

Erythema nodosum, arthritis, and pericarditis do not necessitate therapy. Pericarditis is treated with indomethacin. HIV-infected patients should always receive antifungal therapy.

Untreated disseminated histoplasmosis is usually fatal. Amphotericin B is most often administered as induction therapy usually for ≥2 weeks and is followed by long-term (consolidation) therapy with itraconazole for at least 12 months. Itraconazole is also effective in the treatment of mild disseminated histoplasmosis in HIV-infected patients and immunocompetent children.

For severe or moderately severe acute primary pulmonary histoplasmosis, amphotericin B should be administered for at least 1 to 2 weeks (and clinical improvement). After treatment with amphotericin, patients with intact immunity should receive itraconazole for at least 12 weeks. Adults with CD4 T lymphocyte (CD4) cell counts <150 cells/mm³ and HIV-infected children with severe immunosuppression should receive itraconazole consolidation therapy for at least 12 months.

Amphotericin B therapy should be continued for 12-16 weeks in children with histoplasma meningitis. Liposomal amphotericin B for 4 to 6 weeks is the preferred initial treatment in the presence of focal brain lesions. Thereafter, children should receive itraconazole consolidation therapy for at least 12 months and until cerebrospinal fluid abnormalities, including histoplasma antigen, have resolved.

When antigenuria is demonstrated, antigen levels should be monitored during therapy and for 1 year thereafter to identify relapse.

Toxoplasmosis

A presumptive diagnosis of toxoplasma encephalitis is based on clinical symptoms, serologic evidence of infection and the presence of a space occupying lesion on imaging studies.

Individuals with AIDS who are infected latently with T. gondii have variable IgG titres and rarely possess IgM antibody. Although seroconversion and fourfold increases in IgG antibody titres may occur, the ability to diagnose active disease in patients with AIDS is commonly impaired by immunosuppression. IgM antibodies typically disappear a few months after infection but can remain elevated for more than 1 year, confounding the differentiation of acute and remote infection.

Additional investigations to support the diagnosis of toxoplasma encephalitis include CT scanning of the brain that might indicate multiple, bilateral, hypodense, focal ring-enhancing lesions especially in the basal ganglia and cerebral corticomedullary junction in 70-80% of patients. Magnetic resonance imaging is more sensitive and will confirm basal ganglia lesions in most patients. Although toxoplasmic encephalitis can occasionally cause a single brain lesion on MRI, such a finding suggests an alternative diagnosis (primarily CNS lymphoma and tuberculoma).

The definitive diagnosis of toxoplasma encephalitis requires histologic confirmation by brain biopsy and can be considered when early neurologic deterioration is present despite empiric treatment or in children who fail to respond to anti-toxoplasma therapy after 10-14 days. Ocular toxoplasmosis is diagnosed on the basis of observation of characteristic retinal lesions in conjunction with serum specific antibodies.

Herpes Simplex virus 1 and 2

The diagnosis is clinically based on the appearance of vesicles and ulcers. The virus can be isolated from mucocutaneous lesions by culture or PCR. Other sensitive detection methods include direct staining of infected cells for virus antigen, antibody detection and identification of virus particles by electron microscopy. The shell vial assay uses staining with fluorescein-conjugated monoclonal antibodies to detect synthesis of early HSV proteins, thereby providing an etiologic diagnosis after 24 hours. HSV serology is not useful because prevalence rates of HSV antibodies in subjects with HIV are high. For children with suspected HSV encephalitis, detection of HSV DNA by PCR in the CSF is the diagnostic test of choice since CSF cultures for HSV are usually negative. Detection of HSV DNA by PCR, which is very sensitive and specific, is the gold standard method for diagnosis of HSV invection. Definitive diagnosis of HSV esophagitis requires endoscopy with biopsy and culture.

Varicella Zoster virus

The diagnosis of VZV infection is often suspected from the clinical presentation.

Direct immunofluorescence expressed on the surface of infected cells from scrapings obtained from the base of skin, conjunctiva or mucosal lesions allow VZV antigen detection and is the diagnostic procedure of choice. Direct and indirect immunofluorescence or immunoperoxidase methods can also detect antigen in VZV-infected cells in tissue sections of lung, liver, brain, or other organs. PCR can be used to detect VZV and in some places has replaced culture because of superior sensitivity and specificity from direct lesion, blood, cerebrospinal fluid, and pharyngeal conjunctival swabs.

Cytomegalovirus

IV ganciclovir therapy (6 mg/kg/dose administered every 12 hours) for 6 weeks should be offered to HIV-infected infants who have symptomatic congenital CMV disease involving the CNS. If, during the 6 weeks of therapy, an infant is confirmed as HIV-infected, some experts would recommend longer duration of treatment (>6 weeks). This is also the drug of choice for initial treatment of CMV retinitis – and for other end-organ disseminated CMV disease (colitis, hepatitis, esophagitis, and CNS disease). Prolonged therapy is associated with the emergence of ganciclovir-resistant CMV strains. Transition from IV ganciclovir to valganciclovir oral solution can be considered for younger patients who improve on IV therapy. Major side effects of ganciclovir include myelosuppression (anemia, neutropenia, and thrombocytopenia which may necessitate dose reduction or interruption or the use of granulocyte colony-stimulating factor) and renal toxicity. Foscarnet is an alternative drug to treat CMV disease or for use in ganciclovir-resistant infection.

CMV infections

Foscarnet should be given slowly over the course of 2 hours (no faster than 1 mg/kg/minute). Infusing foscarnet with saline fluid loading can minimize renal toxicity. Doses should be modified in patients with renal insufficiency. Major side effects include renal toxicity and electrolyte imbalances.

Combination therapy with ganciclovir and foscarnet may delay progression of retinitis in certain patients in whom monotherapy is unsuccessful and can be considered as initial therapy among children with sight-threatening disease. Combination treatment with IV ganciclovir and foscarnet may also be preferable as initial therapy to stabilize CMV neurologic disease and maximize response. Combination ganciclovir and foscarnet can also be considered in treatment failure but is accompanied by greater toxicity.

Drugs and dosages

Mycobacterium tuberculosis.

See

Table I.