Pneumocystis pneumonia in children

Paediatric Respiratory Reviews 10 (2009) 192–198

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-Symposium: Fungi and The Paediatric Lung

Pneumocystis pneumonia in children Vasilios Pyrgos 1,2, Shmuel Shoham 2, Emmanuel Roilides 1,3, Thomas J. Walsh 1,* 1

Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA Section of Infectious Diseases, Washington Hospital Center, Washington, DC, USA 3 rd 3 Department of Pediatrics, Aristotle University, Hippokration Hospital, Konstantinoupoleos 49, GR-54642 Thessaloniki, Greece 2

A R T I C L E I N F O

S U M M A R Y

Keywords: pneumocystis pneumonia (pcp) immunocompromised children t-lymphocytes corticosteroids trimethoprim–sulphamethoxazole

Pneumocystis pneumonia (PCP) is a life-threatening infection in immunocompromised children with quantitative and qualitative defects in T lymphocytes. At risk are children with lymphoid malignancies, HIV infection, corticosteroid therapy, transplantation and primary immunodeficiency states. Diagnosis is established through direct examination or polymerase chain reaction (PCR) from respiratory secretions. Trimethoprim–sulphamethoxazole is used for initial therapy in most patients, while pentamidine, atovaquone, clindamycin plus primaquine, and dapsone plus trimethoprim are alternatives. Prophylaxis of high-risk patients reduces but does not eliminate the risk of PCP. Improved understanding of the pathogenesis of PCP is important for future advances against this life-threatening infection. Published by Elsevier B.V.

INTRODUCTION Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality in children and adults with acquired immune deficiency syndrome (AIDS) and other immunosuppressive conditions. The causative agent, Pneumocystis carinii, also termed Pneumocystis jirovecii, is a eukaryotic microorganism with features superficially resembling protozoa and fungi. Phylogenetic analysis of pneumocystis 16S-like rRNA has demonstrated it to be a fungus.1 PCP was initially described as interstitial plasma cell pneumonia in the 1940 s. It was first observed in hospitals and orphanages in premature neonates and malnourished children in the 1940 s. Prior to the AIDS epidemic, Pneumocystis had been increasingly recognized as an opportunistic pathogen in children suffering from various immune compromising conditions. These include allogeneic haematopoietic stem cell transplantation (HSCT), solid organ transplantation, receipt of corticosteroids and other immunosuppressive agents, and congenital immunodeficiency syndromes. Following the introduction and widespread availability of highly active antiretroviral therapy (HAART) and the use of prophylaxis in susceptible populations, the incidence of PCP in children has declined dramatically.2 However, in the absence of appropriate prophylaxis pneumocystis con-

* Corresponding author. Senior Investigator, Chief, Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, CRC 1-5750, 10 Center Drive, Bethesda, MD 20892, USA. Tel.: +301 402 0023; fax: +301 480 2308. E-mail address: [email protected] (T.J. Walsh). 1526-0542/$ – see front matter . Published by Elsevier B.V. doi:10.1016/j.prrv.2009.06.010

tinues to constitute a major threat to the health of severely immunocompromised children and adults. EPIDEMIOLOGY Initial exposure to Pneumocystis generally occurs during the first few months of life and sub-clinical infection in immunocompetent children is very common.3 In a cohort of healthy US children, two-thirds developed Pneumocystis antibodies by the age of 4 years.4 A complete understanding of the epidemiology of Pneumocystis continues to be hampered by the inability reliably to cultivate the organism in vitro. Infection is thought to occur following person-to-person transmission via respiratory secretions and possibly through environmental transmission. Pneumocystis DNA fragments can be found in air, but specific environmental reservoirs have not been definitely identified.5 Pneumocystis DNA is frequently detected in the respiratory tract of immunocompetent individuals, suggesting that the general population could act as a reservoir.6 Molecular epidemiology studies indicate that the airborne route, particularly with personto-person transmission, is the most likely mode of acquiring new infections.7–9 Outbreaks of infection in highly immunosuppressed populations have been described in non-prophylaxed children with cancer, in transplant recipients and in malnourished children living in crowded orphanages.10–12 Primary infection in non-immunocompromised infants is generally asymptomatic, but may present as a self-limiting upper respiratory tract infection, and even as invasive pneumonia in very young infants.13,14 An association between mild primary Pneumocystis infection and sudden infant death syndrome (SIDS) has been

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Table 1 Differences between AIDS and non-AIDS-associated pneumocystis pneumonia. (Adapted from Kovacs et al65)

Average duration of symptoms prior to presentation Respiratory rate Degree of hypoxaemia TMP–SMX intolerability Cyst load Sensitivity of BAL for diagnosis Corticosteroids for PaO2 < 60 mmHg Mortality

AIDS

Non-AIDS

Weeks ++ ++ +++ High High Proven benefit Lower

Days +++ +++ + Low Moderate Not well defined in this population Higher

BAL, bronchoalveolar lavage; PaO2, partial pressure of oxygen in arterial blood.

noted in a cohort of immunocompetent infants.15 However, the role that Pneumocystis plays in SIDS is unclear and recent data indicate that this pathogen does not directly cause SIDS.16 Invasive disease, usually pneumonia (PCP), may occur due to primary infection, reactivation of latent disease or re-infection with a different strain.17,18 Patients with severe defects in T-cell immunity who are not receiving prophylaxis are at particular risk for developing PCP. Advanced human immunodeficiency virus (HIV) infection is the major risk factor for PCP. In industrialized countries, effective antiretroviral therapy and judicious use of prophylaxis have sharply reduced the incidence of PCP in children. In much of the developing world, however, PCP remains a significant health problem for children with HIV.19 In a study of HIV-infected children in Botswana, PCP was responsible for 31% of all deaths and for 48% of deaths in infants  1 year.20 Most cases in children with perinatal AIDS occur between 3 and 6 months of age.21 In infants younger than 1 year of age CD4+ T-lymphocyte counts are not a good indicator of risk for PCP. Many young infants with PCP have CD4+ T-lymphocyte counts above 1500/ml, and Tcell number can drop rapidly shortly before PCP develops in infants.22 For children older than 1 year of age the risk for PCP increases with progressive decline of CD4+ T-lymphocyte count, particularly when counts are below 200–250 cells/ml. PCP is frequently associated with receipt of immunosuppressive agents in non-AIDS patients with malignancies, organ transplant and collagen vascular diseases.19,23 Differences in features of PCP in AIDS patients versus those not suffering from AIDS are summarized in Table 1. Nearly all non-AIDS cases are associated with antecedent corticosteroid use. Corticosteroid dose and duration, and use of concomitant immunosuppressive therapies, are important variables in determining the risk for PCP. The risk is particularly elevated with daily doses > 30 mg of a prednisone equivalent in adults (or > 0.4 mg/kg/day), and with therapy over many months. However, the risk for PCP is still substantial at a prednisone dose equivalent of 16 mg/day and durations as short as 1 month.24,25 In a meta-analysis, adult patients receiving < 10 mg of prednisone/day or a cumulative dose of 700 mg were not found to be at increased risk of developing PCP. Among recipients of corticosteroids, those with nervous system disorders were found to be at a particularly elevated risk.26 In some studies, the infection becomes clinically apparent only during corticosteroid taper.27,28 The risk for developing PCP in association with malignancy varies by cancer type, and type and intensity of chemotherapy.29 The risk is highest with lymphoid malignancies. Without prophylaxis, rates of infection can range between 22% and 45%.30 Use of the purine analogue fludarabine in combination with corticosteroids has been associated with a significantly elevated risk for developing opportunistic infections including PCP.31 Temozolomide, an orally available antineoplastic agent currently used for the treatment of primary brain tumours and melanoma, may induce CD4+ T cell lymphopenia and has been associated with development of PCP.32 Alemtuzumab, an antiCD52 monoclonal antibody increasingly employed in the treat-

ment of haematological malignancies and as an antirejection agent in organ transplantation, has also been associated with lymphopenia and PCP.33 Transplantation is a major risk factor for PCP. The level of risk depends upon the type of transplant and intensity of immunosuppression. Without prophylaxis, PCP develops in 5–15% of patients who undergo solid organ or allogeneic stem cell transplantation. Among heart–lung transplant and lung transplant recipients this rate may approach 25%.30 The risk for PCP is elevated with multiple rejection episodes, highly potent immunosuppressive regimens and cytomegalovirus (CMV) infection.34 Infrequently, PCP occurs in association with rheumatic diseases, especially Wegener granulomatosis.35 Receipt of multiple immunosuppressive agents and lymphopenia are important risk factors in this population.36 Recently, PCP has been reported in patients receiving anti-tumour necrosis factor (TNF) therapy, usually in combination with other immunosuppressive agents.37–39 Rarely, non-AIDS PCP is associated with primary immunodeficiency states, including HLA class II combined immunodeficiency, severe combined immune deficiency, the Wiskott–Aldrich syndrome, X-linked agammaglobulinaemia and X-linked hyper-IgM syndrome.40–43 PATHOGENESIS – IMMUNE RESPONSE For infection to occur, the inhaled organism must first evade the upper respiratory tract defenses and settle in alveoli. Within alveoli, Pneumocystis trophozoites attach to respiratory epithelia, proliferate and inhibit epithelial repair processes.44 If not checked by host defense mechanisms, the infection progresses to cause severe lung damage and ultimately respiratory failure and death. Effective host defenses against Pneumocystis are mediated by a combination of innate, T-cell mediated, and humoral immune responses. In normal hosts, infections are cleared with minimal disease-associated lung damage. By contrast, in patients with defective immunity, the infection may progress and can be further complicated by an exuberant, but dysfunctional immune response that results in diffuse lung injury suggestive of adult respiratory distress syndrome. Alveolar macrophages play a critical role in clearance of Pneumocystis from the lung.45 Macrophage responses to this organism are enhanced by serum opsonization, including opsonization by surfactant protein, fibronectin, vitronectin, immunoglobulin and complement.46–48 Additionally, pattern recognition receptors, including Toll-like receptors, mannose receptors and ßglucan receptors help macrophages to sense the organism’s presence. These cell surface receptors mediate direct killing of the organism by phagocytosis and activation of the immune system via secretion of pro-inflammatory cytokines.49–51 HIV infection, particularly with low CD4 count, is associated with impaired mannose receptor-mediated binding and phagocytosis of the organism. This may contribute to the susceptibility of HIVinfected individuals to this pathogen.52

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The importance of CD4+ T lymphocytes in Pneumocystis infection is clinically apparent. The majority of susceptible children and adults have defects in T-cell number and/or function. With the exception of children < 1 year old and those receiving prophylaxis, the risk for developing PCP in AIDS is directly related to the absolute number of CD4+ T lymphocytes.53 Under normal conditions antigen-presenting cells migrate to draining lymph nodes. There, these cells present Pneumocystis antigen to CD4+ T lymphocytes, induce their activation and direct their migration to the lungs. When the interaction between antigen-presenting cells and T lymphocytes is dysfunctional, as in some neonates and in the X-linked hyper-IgM syndrome, clearance of the organism is impaired and PCP can ensue.54,55 When functional CD4+ T lymphocytes are recruited to the lungs, Pneumocystis infection is effectively cleared with minimal associated inflammation. Conversely, mice depleted of CD4+ T lymphocytes develop persistent Pneumocystis infection and an exuberant but ineffective inflammatory response composed of mononuclear cells, CD8+ T lymphocytes and activated alveolar macrophages.56 With recovery of CD4+ T cells the infection can be cleared.57 Within this milieu CD8+ T lymphocytes are significant contributors to immune-mediated lung injury. Whether CD8+ T lymphocytes have a protective role in this setting is controversial, but emerging data suggest that some CD8+ T-cell subsets (Tc1) are protective, while others (Tc0 and Tc2) mediate immune lung injury in Pneumocystis infection.58 Furthermore, regulatory CD4+ T cells (which are decreased in patients with HIV) appear to play a role in controlling the extent of inflammation and lung injury with Pneumocystis infection.59 Although T cells and macrophages play a central role in the host response to Pneumocystis, intact B-lymphocyte function and effective interactions between B and T lymphocytes are also important. Mice deficient in B lymphocytes are susceptible to PCP. These lymphocytes provide protection by regulating CD4+ T-cellmediated immune responses and, possibly, by producing opsonizing antibodies.60,61 The role of naturally occurring anti-pneumocystis antibodies in humans is not fully understood and infection can progress despite their presence. However, a protective role for immunoglobulin has been demonstrated in immunocompromised animals treated with passive anti-Pneumocystis monoclonal antibody.62 CLINICAL AND RADIOLOGICAL MANIFESTATIONS The most common presentation of Pneumocystis infection is pneumonia. Rarely, in highly immunocompromised patients, who do not receive systemic Pneumocystis prophylaxis, pneumocystosis may present as extrapulmonary disease with reticuloendothelial, auditory and ophthalmic involvement.63 Although PCP was originally described in the 1940 s as interstitial plasma cell pneumonia, a disease of young, malnourished children living in crowded conditions, almost all cases in the developed world and an increasing number of cases in the developing world, are associated with immunosuppression.64 The symptoms of PCP in AIDS are typically insidious with gradual progression over several weeks prior to presentation to medical care.65 Non-AIDS-associated PCP typically presents in a more acute fashion with symptoms progressing over several days and respiratory compromise being more severe at presentation.65 The most common symptoms are shortness of breath, fever and non-productive cough. Less commonly, there is chest pain and productive cough. There is a spectrum of clinical presentations ranging from mild disease with minimal signs and symptoms of infection to advanced disease with profound respiratory compromise, sometimes with concomitant spontaneous pneumothorax.66 In younger children the symptoms can be non-specific and may

manifest as poor feeding, malaise, progressive respiratory distress, cyanosis and apnoea. In recent years a new syndrome of Pneumocystis-associated pneumonitis has emerged in AIDS patients with a previous history of PCP who were then treated with HAART. The pneumonitis is attributed to reconstitution of host immune function, with rapid recruitment of fully competent immune and inflammatory cells to the lungs and an exuberant response to persistent Pneumocystis antigens.67,68 A somewhat analogous situation is seen in some non-AIDS patients where PCP only becomes clinically apparent at the time of steroid taper. This pattern of PCP was especially prevalent in paediatric patients receiving chemotherapy for acute lymphoblastic leukaemia. The radiological findings in PCP are generally similar for AIDSand non-AIDS-associated disease. The most common radiological manifestation is diffuse bilateral interstitial pulmonary infiltrates, which may be characterized as finely granular, reticular or groundglass opacities. In a patient with AIDS and exertional dyspnoea, a finding of interstitial infiltrates is highly suggestive of PCP.69 With milder disease the chest roentgenogram may be normal or equivocal. In such cases high-resolution computed tomography (CT), which is more sensitive than chest radiography for detecting PCP, can be helpful.70 In such equivocal cases, hypoxaemia (oxygen saturation < 90% at room air), as measured by pulse oximetry, can assist in making a presumptive diagnosis of PCP. The typical CT finding is extensive ground-glass attenuation.71 However, it is important to note that the radiological presentations of PCP can be extremely diverse and include localized infiltrates, nodules, cavities, upper lobe predominance, asymmetric patterns, cystic or honeycomb lesions, pneumothorax, pleural effusion and hilar enlargement.66,72 PROGNOSIS AND OUTCOME The prognosis of children with HIV-associated PCP depends upon multiple factors, including degree of hypoxaemia at presentation, need for mechanical ventilation and access to medical care (including HAART). Survival following PCP infection in HIV-infected infants in the UK and Ireland improved significantly with advances in medical care.73 This is in contrast to the situation in developing countries where PCP-associated mortality rates among children continue to be 40% or higher.74 Mortality rates for non-HIV associated PCP also are high and may approach 50% in patients with neoplastic disease.75 DIAGNOSIS The signs and symptoms of PCP are frequently non-specific and the organism is not cultivable. Therefore, definitive diagnosis relies on microscopic identification of Pneumocystis from specimens such as sputum, bronchoalveolar lavage (BAL) fluid and lung tissue. Typical pathology findings are alveolar foamy eosinophilic proteinaceous material in association with Pneumocystis cysts and trophozoites. Methods for detection of infection include histological visualization using Papanicolaou, Gomori’s methenamine silver, toluidine blue O, Wright-Giemsa and calcofluor white stains, and/or immunofluorescence using anti-Pneumocystis monoclonal antibodies. Sputum induction is a non-invasive procedure for diagnosis of PCP. A meta-analysis in patients with HIV found this technique to be associated with 98.6%, specificity for infection but only 55.5% sensitivity.76 The sensitivity improves when immunofluorescence rather than cytochemical staining is used (67.1% versus 43.1%). However, the procedure for induced sputum requires inhalation of nebulized 3% hypertonic saline. This may be difficult to perform in young children because of their small airways and poor ability to

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Table 2 Current recommendations for treatment of pneumocystis pneumonia Compound(s)

Dosage

Comments

TMP–SMX Pentamidine

TMP: 15–20 mg/kg/day + SMX: 75–100 mg/kg/day 4 mg/kg/day intravenously

Preferred therapy for all cases Alternative in patients not responding to or intolerant of TMP–SMX

Alternative therapy for mild to moderate disease Atovaquone* 30–40 mg/kg/day Clindamycin–primaquine* 10 mg/kg every 6 h + 0.3 mg/kg/day Dapsone–trimethoprim* Dapsone: > 13 years: 100 mg/day < 13 years: 2 mg/kg/day TMP: 15 mg/kg/day divided in three doses

Texture and taste may be unpalatable Primaquine contraindicated in G6PD deficiency Caution advised with dapsone use in G6PD deficiency

(Adapted from US Department of Health and Human Services/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus, 2004.). G6PD, glucose-6-phosphate deficiency; TMP–SMX, trimethoprim–sulphamethoxazole. * Limited pediatric data available.

produce sputum. Fibre-optic bronchoscopy with BAL is extremely accurate for the detection of pneumocystis in patients with AIDS and has a sensitivity ranging from 55% to 97%.22,77,78 BAL fluid is expected to show organisms for at least 72 h after PCP treatment has been initiated; thus treatment should not be delayed while awaiting results. Although generally safe, the procedure is invasive and possible complications include haemoptysis, pneumothorax, transient worsening of hypoxaemia or pulmonary infiltrates at the lavage site, and post-bronchoscopy fever.22 In one study, use of bronchoscopy for BAL and transbronchial biopsy resulted in 100% sensitivity for PCP in AIDS.79 Routine transbronchial biopsy is not recommended for children, unless BAL is negative or nondiagnostic despite a high suspicion for PCP. Potential complications of transbronchial biopsy include pneumothorax and haemorrhage. This combined approach may be particularly useful in non-HIV patients with suspected PCP since the organism burden may be lower in that population. Lung biopsy, although supplanted by BAL, remains the ‘gold standard’ and may be required in cases where the diagnosis is unclear, particularly in non-HIV patients.80 The procedure is now commonly performed via video-assisted thoracoscopic surgery and complications may include pneumothorax, pneumomediastinum and haemorrhage. Several polymerase chain reaction (PCR) assays applied to BAL, induced sputum and non-invasive oral wash specimens have been developed for diagnosis of PCP. In general, these assays have been more sensitive, but also less specific for PCP when compared to traditional methods.81 A prospective study of PCR applied to oralwash samples in patients with HIV found sensitivity to be 88% and specificity 85%.82 If possible, specimens should be collected prior to the initiation of therapy since the sensitivity of PCR declines with anti-PCP treatment. A variety of serum markers have been studied for evaluation of patients with suspected PCP. Serum lactate dehydrogenase (LDH) is very frequently elevated in PCP and its level is generally higher than that in tuberculosis and bacterial pneumonias. However, this test lacks specificity and its diagnostic value for individual patients may be limited.83 Measurement of serum beta-D-glucan may have a role in diagnosis of PCP, but further study is needed to validate this approach.84–86 TREATMENT Various antimicrobial agents, including sulphonamides, pentamidine, dapsone, atovaquone and clindamycin, have activity against Pneumocystis. Current recommendations for treatment are summarized in Table 2. Folate antagonists, particularly trimethoprim–sulphamethoxazole (TMP–SMX), are the most commonly used agents. Pneumocystis cannot effectively import

folate and must therefore synthesize this molecule de novo.87,88 Trimethoprim and sulphamethoxazole impair dihydrofolate reductase and dihydropteroate synthase, two enzymes of the folate synthesis pathway. The treatment of choice for PCP in children over 2 months of age is TMP–SMX at 15–20 mg/kg/day of the trimethoprim component, divided into three to four doses.22,89 Therapy should initially be given intravenously; in children with mild to moderate disease who do not have malabsorption or diarrhoea, after the acute pneumonitis has resolved, there can be a transition to oral TMP–SMX to complete a course of therapy (usually 21 days). Adverse reactions to TMP–SMX are common, particularly with concomitant HIV infection, where they are seen in up to 40% of children.90 The most common adverse reactions are rashes. When the rash is severe, as in erythema multiforme, urticaria or Stevens– Johnson syndrome, TMP–SMX should be permanently discontinued. In cases of mild or moderate rashes, consideration can be given temporarily to discontinuing the medication and restarting it when the rash has resolved. Alternatively, a TMP–SMX desensitization protocol may be employed in such mild cases. Other common toxicities of TMP–SMX include haematological, gastrointestinal, hepatic and renal abnormalities. Pneumocystis carrying mutations in the dihydropteroate synthetase (DHPS) and dihydrofolate reductase (DHF) genes have been reported in patients with AIDS. An increase in the rate of these mutations has been associated with exposure to TMP–SMX and pyrimethamine. Such strains have been linked to prophylaxis and treatment failures; however, the clinical relevance of these mutations remains unclear.91,92 Intravenous pentamidine isothionate is an option for patients intolerant of or who demonstrate clinical treatment failure after 5– 7 days of TMP–SMX therapy.22 Pentamidine is associated with considerable toxicities. The most common is renal dysfunction, which usually occurs after 2 weeks of therapy. Cardiovascular toxicities include severe hypotension, especially with rapid infusion of drug, prolonged QT interval and cardiac arrhythmias. Electrolyte abnormalities including hypercalcaemia and hyperkalaemia may occur with pentamidine use. Pancreatitis with or without dysglycaemia can be a severe life-threatening complication of pentamidine use in children.93 Hypoglycaemia due to inappropriately high plasma insulin levels can be a life-threatening complication. The mechanism is presumed toxicity to the islet bcells. Patients may present with hypoglycaemia alone, hypoglycaemia and then diabetes mellitus, or diabetes mellitus alone. This toxicity is associated with drug accumulation due to excessive doses, multiple courses and/or renal impairment.94 Risk for development of pentamidine toxicity can be reduced with intravenous hydration, close electrolyte monitoring and

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V. Pyrgos et al. / Paediatric Respiratory Reviews 10 (2009) 192–198 Table 3 Prophylaxis for pneumocystis pneumonia in children Compound(s)

Prophylaxis

Comments

TMP–SMX

150/750 mg/m2/day:  Three times weekly in two divided doses on consecutive days, or  Single dose three times a week on consecutive days  Two divided doses daily  Two divided doses three times a week on alternate days  For adolescents/adults: one double dose tablet orally daily or three times weekly

Preferred prophylaxis regimen

Atovaquone

 1–3 months 45 mg/kg/day

Dapsone

 3–24 months 30 mg/kg/day  > 24 months 45 mg/kg/day  2 mg/kg/day (max. 100 mg)  4 mg/kg (max. 200 mg) weekly 300 mg every month via Respigard IITM nebulizer

Used for mild to moderately severe disease in adults Pediatric data are limited

Aerosolized pentamidine

Children > 1 month For children > 5 years

(Adapted from U.S. Department of Health and Human services/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus, 2002.). TMX–SMX, trimethoprim–sulphamethoxazole.

avoiding the co-administration of drugs with the potential to cause renal or pancreatic injury. If possible, consideration should be given to switching to a less toxic agent for completion of the course of therapy in patients with clinical improvement after 7–10 days of intravenous pentamidine therapy. Mild to moderate PCP can be treated with alternative regimens. In a randomized double blind study, the combinations of oral TMP– SMX, TMP–dapsone, and clindamycin–primaquine yielded similar outcomes in patients with mild to moderately severe AIDS-related PCP.95 Both clindamycin–primaquine and TMP–dapsone are associated with rashes, gastrointestinal symptoms and haematological disorders, including methemoglobinaemia and haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency.96 Atovaquone, which selectively inhibits electron transport at the mitochondrial cytochrome bc(1) complex and reduces mitochondrial membrane potential, has been studied as an alternative agent for PCP. The response to oral atovaquone was found to be inferior to oral TMP–SMX (80% vs 93%, P = 0.002), but similar to intravenous pentamidine (57% vs 40%, P = 0.085) for AIDS-associated PCP.97,98 Atovaquone is generally better tolerated than TMP–SMX and intravenous pentamidine, but may cause rashes, fever, gastrointestinal symptoms and abnormal liver function tests. The respiratory status of patients with PCP may decline precipitously following the initiation of effective anti-pneumocystis therapy. For patients with advanced PCP, this may lead to severe respiratory compromise, the need for mechanical ventilation and even death. This complication may be prevented with early initiation of systemic corticosteroids, which has become an important adjunct in the therapy of AIDS-associated moderate to severe PCP.99,100 Corticosteroids are generally added when the PaO2 is < 70 mmHg or the alveolar–arterial gradient exceeds 35 mmHg. The role of adjunctive corticosteroids in non-AIDSassociated PCP is less clear, with some studies suggesting a benefit, while others have found none.101,102 PROPHYLAXIS The highest risk period for development of PCP in children with vertically acquired HIV is between 3 and 6 months of age.21 However, CD4 counts are an imprecise indicator of the risk for development of PCP in HIV-infected children < 1 year old.103 Children born to HIV-infected mothers should be administered prophylaxis with TMP–SMX beginning at age 6 weeks after discontinuation of neonatal zidovudine treatment, and prophy-

laxis should be continued through the first year of life unless the child is determined during their first year not to be infected with HIV (three negative HIV-PCR tests up to 6 months of age).104 Between the ages of 1 and 5 years primary prophylaxis should be used in children with CD4 counts <500 cells/ml (or 15%). Beyond that age, primary prophylaxis is indicated for CD4 counts of <200 cells/ml. Prophylaxis should also be considered in patients with other AIDS-defining illnesses and in those with oropharyngeal candidiasis. Secondary prophylaxis should also be used in children who have a history of PCP to prevent recurrences. Currently PCP prophylaxis is discontinued in adult and adolescent AIDS patients whose CD4+ T-lymphocyte cell counts have risen above 200 cells/ ml for >3 months as a result of HAART. Whether this strategy can be applied to children is unclear, but evidence to suggest that this approach may be safe is accumulating.104–106 The benefit of Pneumocystis prophylaxis in non-HIV infected patients depends upon the intensity and duration of immunosuppression. Among transplant recipients the risk is greatest after lung transplants, in individuals with invasive cytomegalovirus disease, during intensive immunosuppression for allograft rejection and during periods of neutropenia.107 Prophylaxis has been advocated in solid organ and allogeneic stem cell transplant recipients in programmes with an institutional incidence of > 5%. Also, prophylaxis may be beneficial in transplant recipients receiving intensified immunosuppression, particularly with T-cell depleting therapies, and in those with a history of PCP or frequent opportunistic infections, invasive CMV infection, receipt of fludarabine or 2-CDA, and prolonged neutropenia. Corticosteroids are a major risk for development of PCP and consideration should be given to prophylaxis when doses of 20 mg of prednisone/day for 2–3 weeks are used.108 Current recommendations for prophylaxis against PCP in children are summarized in Table 3. The preferred agent for prophylaxis is TMP–SMX. In addition to its activity against pneumocystis, TMP–SMX also confers protection against many bacterial infections and toxoplasmosis. For patients unable to tolerate TMP–SMX, other prophylactic strategies include dapsone, dapsone with pyrimethamine and leucovorin, aerosolized pentamidine and atovaquone. While important advances have been achieved in the diagnosis, treatment and prevention of PCP during the past three decades, many children are afflicted with breakthrough infections, delayed diagnosis and intolerability to prophylactic agents. Improved understanding of the pathogenesis of PCP is critical for future advances against this life-threatening infection.109

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PRACTICE POINTS  Pneumocystis pneumonia (PCP) occurs in immunocompromised children with quantitative and qualitative defects in T lymphocytes, especially those with lymphoid malignancies, HIV infection, and corticosteroid therapy.  Diagnosis is established through direct examination by Wright-Giemsa, fluoroscent dye, fluorescent antibody, or polymerase chain reaction (PCR) from respiratory secretions.  Trimethoprim–sulphamethoxazole (TMP–SMX), is used for initial therapy in most patients.  Pentamidine, atovaquone, clindamycin plus primaquine, and dapsone plus trimethoprim are alternatives for therapy.  Prophylaxis of high-risk patients significantly reduces but does not eliminate PCP.

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