Mini-Symposium: Fungi and The Paediatric Lung
Pneumocystis pneumonia in children

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Summary

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.

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 continues to constitute a major threat to the health of severely immunocompromised children and adults.

Section snippets

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

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

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

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

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

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

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 prophylaxis should be continued through the first year of life unless the child

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,

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