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Pneumocystis Pneumonia

SERGIO L. VARGAS

University of Chile School of Medicine, Santiago,Chile

SynonymsP. carinii pneumonia; P. jiroveci pneumonia; P. cariniif. sp. hominis pneumonia; PcP; PCP

Definition and CharacteristicsPneumocystis pneumonia (PcP) is a life-threateningpulmonary infection that affects immunocompromisedpersons. Clinically, it is characterized by marked pro-gressive hypoxemia and dyspnea with relative absenceof auscultatory signs. Infiltrates are normally present inthe chest radiography. Paradoxically, the clinical courseis more abrupt and severe in less immunocompro-mised individuals, suggesting that the clinical presenta-tion and outcome of the disease is more dependent onthe type and extent of the immune response mountedby the patient than the pathogenic potential ofPneumocystis itself [1–5].

PrevalencePcP occurs in direct proportion to the number ofimmunocompromised susceptible individuals not recei-ving anti-Pneumocystis prophylaxis. Without chemo-prophylaxis, the risk of PcP is 5–25% in transplantpatients, 2–6% in patients with collagen vasculardisease, and 1–25% in oncology patients [2]. Histori-cally, PcP remained as an occasional disease ofundernourished infants since it was first reported,during World War II, to 1956 when reports on adultsbegan to appear as a result of progressive implementa-tion of anti-cancer chemotherapy. Numbers increaseddramatically with the AIDS epidemic. HIV-infectedpersons are the highest risk group, as over half ofAIDS patients developed PcP, before chemoprophylaxis

and highly active antiretroviral agents (HAART) wereadopted in 1989 and1996, respectively [3]. Theprevalence in industrialized countries decreased after1998 to 0.3 cases/100 person-years. Despite thisachievement, PcP remains the most common severeopportunistic infection of AIDS. Available data onprevalence of PcP in non-industrialized countries islimited, and the number of reported cases may be lowowing to shorter patient survival and/or difficultiesin diagnosis [2].

GenesPcP is an airborne-transmissible infectious disease.Phylogenetic analysis of the Pneumocystis 16S-likesmall-ribosomal RNA subunit indicates Pneumocystisis a fungus. The Pneumocystis genome is being sequen-ced and comprises�8million base pairs of DNAdividedinto 15 linear chromosomes. A few genes coding forimportant host–pathogen interaction processes havebeen cloned [1].

Molecular and Systemic PathophysiologyAn underlying T-lymphocyte defect is the main factorpredisposing to PcP. Adult patients are at risk when theirT cell CD4+ lymphocyte count falls below 300–200cells per mm. This generally occurs as a result of HIVinfection or administration of immunosuppressive agentsincluding corticosteroids that affect T-lymphocyte num-ber or function. In addition, a variety of genetic immunedefects like Severe Combined Immunodeficiency Syn-drome (SCIDS) T-B− and T-B+, hyper-immunoglobulinE syndrome or X-linked hyper-IgM syndrome maypredispose to PcP [3]. Molecularly, Pneumocystisattaches to alveolar pneumocyte type I cells inducingcellular immune responses with participation of innateand adaptive immune mechanisms [4,5]. Contactwith alveolar macrophages and pneumocyte type IIcells activate complex and expanding, CD 4+ T cells,CD8+ T cells, neutrophils, host proteins, and otherinteractions that lead to cytokine and chemokine expres-sion and inflammation. BalancedCD4+ andCD8+T-cellresponses and B-cell lymphocytes are required to clearthe infection (Fig. 1) [4].


Diagnostic PrinciplesClinical diagnosis of PcP is difficult due to non-specificsigns and symptoms. Therefore, the diagnosis neces-sarily relies on the demonstration of Pneumocystis cystor trophozoite forms in respiratory specimens bymicroscopy. Molecular tools like the polymerase chainreaction (PCR; real-time PCR) detect nucleic acids ofPneumocystis, and their use for diagnosis needs betterdefinition. More immunocompromised individuals mayharbor larger numbers of Pneumocystis organisms perdiagnostic specimen than less immunocompromisedindividuals, implying that the sensitivity and specificityof the diagnostic tests is highly dependent on the typeand quality of the diagnostic specimen and onthe patient’s underlying immunodeficiency condition.This way, the sampling procedure and the diagnosticspecimen volume and processing in the laboratory arecritical, especially when specimens are from non-AIDSpatients. The most frequently used stains for microsco-py are Gomori Grocott methenamine silver andToluidine Blue O that stain the cyst form, Wright-Giemsa that stains trophozoites, and fluoresceine-conjugated monoclonal antibodies may stain both

forms depending on the monoclonal antibody that isused. Other stains used for diagnosis are calco-fluor white, cresyl echt violet, Gram-Weigert, andPapanicolaou.

Therapeutic PrinciplesPcP is uniformly fatal if untreated. Anti-PcP drugs inchemoprophylaxis schemes aiming to prevent thedisease should be indicated to susceptible immunocom-promised patients at risk and can be discontinued inAIDS patients with sustained response to HAART, andin other patients, if predisposing factors are resolved.Treatment of PcP aims to decrease the Pneumocystisburden with therapeutic doses of an anti-Pneumocystisagent for 2–3 weeks, to control hypoxemia withsupportive oxygen, and to modulate the host immuneresponse with steroids when more severe disease ispresent. The preferred prophylactic and therapeuticdrug scheme is the combination of Trimethoprim andSulfamethoxazole. These drugs target enzymes thatparticipate in the folic acid cycle pathway and produce aPneumocystis-“static” effect. Anti-Pneumocystis drugalternatives are few, and no “cydal” drugs are available

Pneumocystis Pneumonia. Figure 1 Schematic representation of the progression of immune-mediated lung injuryduring PcP. Direct activation of Pneumocyte type II in the alveolar epithelium by Pneumocystis leads to NF-κBactivation and the release of proinflamatory signals. PcP progresses differently in the absence of CD4+ lymphocyteimmune response (as in AIDS), than when residual immune response is present, as may be the case inchemotherapy-mediated immunodeficient cancer patients (adapted from [4] with permission).

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(Table 1). Given access to standard of care, the outcomeis better in AIDS patients than in patients withimmunosuppression resulting from chemotherapy orother disorders [1,4].

References

1. Thomas C, Limper A (2007) Nature Rev Microbiol5:298–308

2. Morris A, Lundgren JD,Masur H,Walzer PD, Hanson DL,Frederick T, Huang L, Beard CB, Kaplan JE (2004) EmergInfect Dis 10:1713–1720

3. Hughes WT (2005) In: Walzer PD, Cushion MT (eds)Pneumocystis pneumonia, 3rd edn. Marcel Dekker, NewYork, pp 1–37

4. Gigliotti F, Wright TW (2005) Expert Rev Mol Med7:1–16

5. Steele C, Shellito JE, Kolls JK (2005) MedMycol 43:1–19

Pneumocystis Pneumonia. Table 1 Anti-Pneumocystis drugs and their metabolic targets

Agent Therapeutic use Prophylactic use Primary moleculartarget

Trimethoprimsulfamethoxazole

First choice First choice DHPS/DHFR

Primaquinclindamycin

Second choice Not used Uncertain/proteinsynthesis inhibition

Pentamidine Alternative choice Aerosolized/rarely used DNA synthesis

Atovaquone Alternative choicea (for mild tomoderate infection)

Alternative choice Cytochrome bcomplex

Dapsonetrimethoprim

Alternative choiceb Dapsone alone or dapsone with pyri-methamine and leucovorin

DHPS/DHFR

Adapted from [1] with permission.aAdminister with high-fat meals to maximize absorption.bHemolysis can occur with G6PD deficiency.

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