Pneumocystis (carinii) jirovecii

Authors: M. Patricia George, M.D., Matthew R. Gingo, M.D.Alison Morris, M.D.

Pneumocystis jirovecii is an important cause of pneumonia in immunocompromised hosts, especially those with human immunodeficiency virus (HIV), hematologic malignancies, organ transplants, congenital immunodeficiencies, and those receiving specific immunosuppressive drugs such as high dose corticosteroids and tumor-necrosis factor inhibitors. A dramatic increase in incidence of P. jirovecii pneumonia occurred as the acquired immunodeficiency syndrome (AIDS) epidemic grew. With the more widespread use of specific chemoprophylaxis for the appropriate immunosuppressed patient populations in general, and with the expanded availability of effective combination antiretroviral therapy (CART) for HIV-infected patients in particular, there has been a decline in cases (122); however,Pneumocystis continues to cause morbidity and mortality among non-HIV-infected patients who are immunosuppressed and remains a leading cause of AIDS-associated pneumonia.


Pneumocystis was originally discovered by Carlos Chagas in 1906 and believed by Chagas and Antonio Carini to be a stage in the trypanosome life cycle. Inability to culture Pneumocystis has limited understanding of the biology of the organism. Pneumocystis was recognized by Pierre and Mme. Delanoe to be distinct from trypanosomes six years after Chagas first identified it and was subsequently classified as a separate protozoa. Recent application of molecular techniques demonstrated that the organism shares many characteristics such as cell wall and enzyme structure with fungi (241). Thus, the organism is now considered to be a fungus rather than a protozoan.

Based on morphology, Pneumocystis exists in two main forms: the trophic form (formerly called the trophozoite) and the cyst form (also known as the spore case) (46246). It has been hypothesized that trophic forms can conjugate and form cysts that mature to contain eight nuclei. These cysts rupture, freeing eight trophic forms from the intracystic nuclei. It has also been hypothesized that trophic forms can replicate asexually via binary fission (162246). Although the life-cycle has not been fully elucidated, the organism has been isolated in the alveolar spaces of the host organism, where the trophic form attaches to alveolar epithelial cells (148). This interaction is important for survival of the organism, and the organism has not been successfully maintained in vitro in a cell-free environment. Recent work suggests that formation of a biofilm is also crucial to the organism’s survival and may enable future in vitro experimentation (45).

The cell walls of the cysts are rich in carbohydrate, consisting primarily of ß-1,3-glucan, as well as chitins and proteins (246). The main cell surface antigen is known as the major surface glycoprotein (MSG) or glycoprotein A (gpA). It is highly variable and is distinct among different species of Pneumocystis that infect different mammalian hosts (79150192). MSG interacts with the host by binding to both surfactant protein D, a lung collagenous carbohydrate protein that accumulates in Pneumocystis pneumonia (Vuk-Pavlovic et al. Carbohydrate recognition domain of surfactant protein D mediates interactions with Pneumocystis carinii glycoprotein A. AJRCMB 2001; 24: 475-484), and host macrophages through mannose receptors (192). The ability of the MSG locus to undergo recombination helps the organism evade host defenses (239126). Pneumocystis also contains a kexin-like serine protease, encoded by the Kex1 locus. This protease has been found on the cell surface and is believed to be less antigenically variable than MSG (142200274); however, recent reports have found genetic polymorphisms in this gene as well (69).

Several enzymatic targets have been isolated from Pneumocystis including dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), the target enzymes for sulfonamides and trimethoprim, respectively. Genes encoding these enzymes, as well as the cytochrome B locus (the site of action of atovaquone), have been identified and sequenced. Mutations in these loci are postulated to be linked to drug resistance (62106115155183).

Pneumocystis exhibits host-specific speciation, and the nomenclature was revised to distinguish these different species (Frenkel JK.Pneumocystis jiroveci n. sp. from man: morphology, physiology, and immunology in relation to pathology. Natl Cancer Inst Monogr 1976; 43:13-30). The organism in rats is called P. carinii, but this species does not infect humans. The name of the Pneumocystis species that infects humans was changed from Pneumocystis carinii to Pneumocystis jirovecii after Otto Jirovec, one of the earliest scientists to recognize the organism in humans (80240). P. jirovecii pneumonia is still abbreviated PCP, with the abbreviation standing for Pneumocystis Pneumonia instead of Pneumocystis carinii Pneumonia.

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In 1981, cases of Pneumocystis pneumonia (PCP) were first reported in men who had sex with men and in intravenous drug users (1160). The disease became the first opportunistic infection associated with HIV/AIDS. The advent of effective CART and routine PCP prophylaxis have reduced the incidence of PCP, although it remains the most common serious opportunistic infection in HIV (43117172,245). The EuroSIDA study followed a cohort of over 8,500 HIV-infected patients in Europe and found that incidence of PCP fell from 4.9 cases per 100 person-years before the introduction of combination CART to 0.3 cases per 100 person-years after CART was widely available (266). The prevalence of PCP in the current era in the United States ranges between 6-19% (30). Mortality from PCP has also changed over the course of the AIDS epidemic with the latest mortality of hospitalized patients with PCP reported to be around 7-11% (215129). In one study of PCP in HIV-infected individuals hospitalized in London from 1985-2006, overall mortality was 13.5% (265). Mortality improved over time, from 10.1% from 1985 to 1989, to 16.9% from 1990 to June 1996, and 9.7% from July 1996 through 2006 (265). For patients requiring intensive care, studies performed shortly after the introduction of CART showed a mortality ranging from 53 to 62% (44131,177). Certain clinical factors such as patient age, low serum albumin, need for mechanical ventilation, and development of a pneumothorax have been associated with increased mortality (561652170177265). In a study of HIV-infected individuals admitted to the ICU between 1996 and 2004 with respiratory failure, lower tidal volume ventilation was also independently associated with improved survival (48).

The frequency of PCP among HIV-infected patients in tropical and developing countries has generally been thought to be much lower than in industrialized countries (175). The lower incidence of PCP in places like Africa may be secondary to a high mortality from diseases such as tuberculosis and bacterial pneumonia that occur at higher CD4 cell counts, thus preventing persons from ever becoming at risk for PCP. The apparently lower incidence might also result from geographic or climactic factors that influence PCP risk, or merely reflect an underreporting secondary to a failure to diagnose (1172175251).

PCP has also been reported in non-HIV-infected, immunocompromised patients. The incidence of PCP among patients with cancer varies by diagnosis, ranging from 22-45% for lymphomas, 25% for rhabdomyosarcomas, and 1.3% for solid tumors if patients are receiving at least 20 mg of prednisone or equivalent corticosteroid for over one month (111229230). Bone marrow transplant and solid organ recipients are also at increased risk of PCP, with reported incidences from 2.5% to >25% (5160639193102168272). The incidence of PCP in patients with collagen vascular disease has been reported at < 2%, although patients with Wegener’s granulomatosis have an incidence > 6% (84194). The clinical presentation of PCP differs in HIV-infected and non-HIV-infected individuals with HIV-infected individuals presenting with less severe hypoxemia and a more indolent course than other immunocompromised patients (68135147). Non-HIV-infected individuals have lower parasite numbers and greater BAL neutrophilia than AIDS patients (147).

While overt PCP in immunocompetent hosts is rare, there is a growing body of literature that colonization with Pneumocystisoccurs in both immunocompetent and immunocompromised persons. Pneumocystis colonization is defined as detection of Pneumocystiswithout signs and symptoms of PCP, often requiring use of polymerase chain reaction (PCR) for detection of the organism’s DNA in respiratory secretions (175261). Pneumocystis colonization may be detected in infants and young children (178). Nevez and coworkers reported a 24% prevalence of Pneumocystis colonization in 178 infants with bronchiolitis (188). Similar levels of colonization (between 14% and 25%) have been noted by other investigators in the immunocompetent pediatric population with acute respiratory syndromes or chronic lung diseases (39123249).

As methods of detection improve, prevalence of colonization in normal, non-immunosuppressed adults is somewhat common, with reported colonization ranging from 20 to as high as 64.9% (163210253). In order to detect high prevalence of colonization in the normal host, however, large quantities of lung tissue need to be assayed, suggesting that the organism burden is quite low. The prevalence ofPneumocystis colonization among HIV-infected individuals is higher and has been reported between 10-68.8% (92107143161174185,213262). The wide prevalence range is likely due to differences in subject populations, the type of sample tested, and the PCR technique used. One study reported that the frequency of colonization increased with decreasing CD4 count, although colonization has been reported even in individuals with high CD4 cell counts (143174). The prevalence of colonization among non-HIV infected, immunocompromised individuals is also high, ranging from 15.5 to 58.5% (98158166187258270).

Pneumocystis colonization may be an important phenomenon for several reasons. The role of colonization in risk for PCP is not known, but it is possible that people who are colonized may have an increased risk of developing PCP or may act as a reservoir and transmitPneumocystis to others. Colonization may also play a pathogenic role in other diseases. It has been linked to chronic obstructive pulmonary disease (COPD) in both HIV-infected and non-HIV-infected individuals (28176186). In one study, Pneumocystis colonization was detected in 36.7% of patients with very severe COPD compared to less than 10% of those with other end-stage lung diseases (176). In another study, Pneumocystis colonization in COPD subjects was associated with higher levels of serum proinflammatory cytokines, suggesting a role in disease pathogenesis (28). Animal models also demonstrate that Pneumocystis colonization can promote the development of airway obstruction and emphysema (34190234). In a non-human primate model of HIV, Pneumocystis-colonized animals develop airway obstruction as well as radiographic and anatomic emphysema (234). A rodent model demonstrated that cigarette exposure combined with Pneumocystis murina infection in immunocompetent mice resulted in pulmonary function and pathologic changes consistent with emphysema. In addition, these changes were associated with increased macrophages in the bronchoalveolar lavage fluid as well as alterations of CD4/CD8 ratios similar to humans who develop emphysema (34). Although the link of colonization to these diseases needs to be confirmed, clinicians and researchers should at least consider the possibility that Pneumocystis may cause more clinical manifestations than previously suspected.

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Compared to other diffuse pulmonary processes, there is nothing unique about the presentation of PCP that would allow it to be diagnosed without a specific microbiologic test identifying the organism in pulmonary secretions or tissue. Clinicians must be alert to the possibility of PCP in at-risk patients and the importance of quickly establishing the diagnosis, so that appropriate therapy can be instituted early when the likelihood of response to therapy is greatest. As PCP is currently a common initial presentation of HIV infection, clinicians must consider the diagnosis in patients who are not previously known to be HIV-infected.

PCP typically presents as an acute or subacute pulmonary process with fever, nonproductive cough, dyspnea, and shortness of breath (67). AIDS patients tend to have a more indolent course with a longer duration of symptoms and less hypoxemia than patients immunosuppressed from cytotoxic chemotherapy or corticosteroids (135244). HIV-infected patients typically present after 1-4 weeks of symptoms, while other immunosuppressed patients present within a few days of symptom onset.

Physical examination is often unrevealing except for fever and tachypnea. Chest examination is commonly normal; however, diffuse rales, and eventually signs of consolidation, may be present as the disease progresses.

Routine laboratory testing is also unremarkable. Patients often have nonspecific elevations of serum lactate dehydrogenase (LDH) and hypoxemia. The serum LDH is a reflection of tissue damage, in this case to the lung, rather than a specific marker for PCP. Although LDH is generally elevated, it cannot be used to diagnose PCP, and a normal LDH does not rule out PCP. The peripheral white blood count may be modestly elevated. For patients with HIV infection, clinicians should recognize that a white blood count of 6-10,000 cells/mm3 may represent a marked elevation over baseline. Patients are generally hypoxemic with an elevated alveolar-arterial oxygen gradient, and the degree of hypoxemia is used to determine disease severity.

The chest radiographic manifestations depend on the severity of illness. Early in the course of PCP, especially for patients with HIV, the chest radiograph may be normal despite substantial hypoxemia (55135). In patients with a normal chest radiograph, a high resolution (thin section) computed tomography (CT) scan of the chest will usually demonstrate a characteristic diffuse ground glass appearance; however, this finding is not specific for PCP and further diagnostic testing should be pursued (90). A normal high resolution CT scan makes the diagnosis of PCP highly unlikely. As the disease worsens, diffuse interstitial infiltrates develop which then progress to dense alveolar filling.

A substantial number of patients have atypical chest radiographs. Almost all types of infiltrates have been described with PCP. Asymmetric patterns, upper lobe infiltrates, mediastinal adenopathy, nodules, cavities, and effusions have been attributed to PCP alone, without a concurrent process, but rare findings such as pleural effusions or adenopathy should prompt an evaluation for processes other than PCP. Pneumothorax in a patient with AIDS should raise the suspicion for PCP (167232). Patients may present primarily with a pneumothorax, although the contralateral lung usually has diffuse infiltrates. Images of the liver, spleen, kidneys, or even the brain may occasionally reveal inflammatory masses due to P. jirovecii. These extrapulmonary lesions rarely cause symptomatic disease and appear to resolve with therapy.

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A specific diagnosis of PCP should be sought because many infectious and non-infectious processes can present almost identically to PCP. Empiric treatment should be begun immediately when PCP is suspected because treatment does not decrease the ability to diagnose PCP, and treatment delay may worsen outcome. In HIV-infected patients, organisms can persist for weeks or months after initiation of effective therapy. For other immunosuppressed patients, there is less information regarding the persistence of organisms, but treatment during the several days that might be required for diagnosis is prudent (218).

The definitive diagnosis of P. jirovecii disease requires the demonstration of cysts or trophozoites in tissue or body fluids since human Pneumocystis cannot be cultured in laboratory animals or in vitro. Before the AIDS epidemic, the diagnosis of P. jirovecii pneumonia typically required an open lung biopsy. With the development of improved diagnostic techniques, diagnoses can now be established by less invasive methods. Virtually all HIV-infected patients can be diagnosed by careful analysis of bronchoalveolar lavage fluid (BAL), although BAL is less sensitive in non-HIV-infected patients (164193). Induced sputum has been shown to be a sensitive, simple and noninvasive means to diagnose P. jirovecii pneumonia in the HIV-infected population and often reduces the need for bronchoscopy (18132137189). Reported yields for recovery of the organism range from 70-95% at various institutions, and utility of the test depends on the laboratory’s familiarity with the technique (18137208). On rare occasions, tissue diagnosis will be necessary. Either transbronchial biopsy, video-assisted thorascopic surgery (VATS) biopsy, or open lung biopsy can be performed. Most often, when bronchoalveolar lavage has failed to reveal Pneumocystis, a biopsy will reveal a pathologic process other than PCP.

The identification of P. jirovecii in sputum or BAL fluid has typically been performed with colorimetric stains such as methenamine silver, toluidine blue-O, Geimsa, and Diff-Quik or by using immunofluorescent assays (direct fluorescent antigen testing). The development of monoclonal antibodies has resulted in a rapid, sensitive and easy-to-perform immunofluorescence assay, which is more efficient than conventional colorimetric stains for detecting Pneumocystis jirovecii in respiratory specimens (82134189). Many hospital laboratories use this immunofluorescent stain in preference to colorimetric stains.

More recently, molecular assays have been developed for detecting P. jirovecii in BAL fluid, induced sputum, or oral wash samples. PCR methods have used a variety of gene targets (196224), but those with the highest sensitivity use either a multicopy gene target, e.g., mitochondrial rRNA or major surface glycoprotein (109264), and/or a nested PCR assay in which two amplification rounds are used to increase sensitivity (719798140151153263). In one study, a quantitative touch-down PCR assay targeting the MSG gene tested had a sensitivity of 88% and a specificity of 85% for diagnosis of PCP in oral wash samples (140). Initiation of PCP treatment prior to oral wash collection decreased the sensitivity of the PCR assay, suggesting that specimens should be collected early if the assay is to be used in clinical settings (140). When PCR is used on induced sputum or BAL, the sensitivity increases, but the specificity decreases as more cases of colonization are detected. In a study of real-time PCR reaction against a single-copy gene (cdc2) rather than a multi-copy gene, detection of Pneumocytis pneumonia in immunosuppressed patients being evaluated for opportunistic respiratory infections was enhanced over direct fluorescent microscopy method, while detection of colonization in non-immunocompromised, asymptomatic individuals was reduced (268). These highly sensitive molecular techniques are not currently available in clinical practice, but they have been useful tools for research to examine drug resistance, to study Pneumocystis colonization, and to address questions regarding the transmission of the disease (108).

Other novel diagnostic techniques for PCP are being investigated. S-Adenosylmethionine (AdoMet) is a molecule thatPneumocystis requires for methylation reactions and polyamine synthesis and is scavenged by Pneumocystis from its hosts. Two studies showed that AdoMet levels are reduced in humans with PCP (235236). With a break point between 59 and 66 nM of AdoMet, the sensitivity and specificity were 0.88 and 1.0 respectively for PCP diagnosis. AdoMet levels rose with successful treatment suggesting that it could be a non-invasive, rapid assay for diagnosing PCP and following response to treatment (236). However, in a subsequent prospective study of 31 HIV-negative patients with and without PCP, AdoMet levels did not reliably distinguish between patients with and without PCP (de Boer MG, Gelinck LB, van Zeist BD, van de Sande WW, Willems LN, van Dissel JT, de Jonge R, Kroon FP. β -d-glucan and S-adenosylmethionine serum levels for the diagnosis of Pneumocystis pneumonia in HIV-negative patients: a prospective study. J Infect 2011; 62:93-100). Another rapid assay that has shown some usefulness is the serum β-D-glucan level. With a cut-off point of 31.1 pg/mL, the sensitivity and specificity of β-D-glucan were 92.3% and 86.1%, respectively (243). In a prospective study of HIV-negative patients, elevated serum β-D-glucan level with a cut-off point of 60 mg/mL had a sensitivity of 0.90 and specificity of 0.89 (50). This molecule is elevated in other fungal infections, and the specificity may be lower if applied more widely.

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Serologic and polymerase chain reaction data indicate that most humans become subclinically infected with P. jirovecii during childhood and that this infection is usually well-contained by an intact immune system (141188203207252). The mode of transmission in humans is likely respiratory (99197255). It was historically thought that PCP results solely from reactivation of latent infection; however, several lines of evidence suggest that de novo infection either from an environmental reservoir or from person-to-person transmission occurs. There have been clusters of PCP cases, and risk of PCP varies by location (4959179). Studies have found thatPneumocystis genotype reflects a patient’s city of residence rather than city of birth and that newly-diagnosed HIV patients with PCP havePneumocystis containing mutations associated with prior use of PCP prophylaxis, in both cases suggesting that disease was recently acquired (1415105). Similarly, some patients have had recurrent episodes of PCP due to genotypically distinct organisms, indicating that their disease resulted from re-infection (1599127128214). In addition, animal models of PCP have shown that Pneumocystis can be transmitted between both immunosuppressed and immunocompetent animals (7314181). Thus, disease can occur after primary infection, re-infection, or after reactivation of latent infection acquired in the distant past.

Pneumocystis is presumably inhaled into the alveolar space. The organism has a unique tropism for the lung, where it exists primarily as an alveolar pathogen without invading the host. Following primary infection in an immunologically intact individual, the organism can be completely cleared or can colonize the airways, possibly allowing the person to act as a reservoir for transmission or increasing the risk of developing PCP in the future. Clinically apparent pneumonia occurs only if an individual develops specific types of immunosuppression. At that point, latent organisms reactivate, or an acute infection/re-infection produces acute disease. Organisms proliferate, evoking a mononuclear cell response. Alveoli become filled with proteinacous material and clinical pneumonia occurs. The disease is fatal if untreated.

CD4+ T lymphocytes are pivotal in the host’s defenses against Pneumocystis in both animals and humans. For patients with HIV infection, the degree of depletion of CD4+ T lymphocytes strongly correlates with the likelihood of developing PCP. About 95% of PCP cases in patients with HIV infection have been seen in HIV-infected patients with recent CD4+ T lymphocyte counts under 200 cells/μL (237). The majority of these cases occur at CD4+ T lymphocyte counts less than 100 cells/μL (237). About 10-15% of patients develop PCP at CD4+ T lymphocyte cell counts greater than 200 cells/mm3 (35). For HIV-infected patients who have benefited from therapy with antiretroviral drugs, considerable evidence supports the concept that CD4+ T lymphocyte cell counts continue to be an accurate indicator of susceptibility to PCP, and those who experience sustained increases of CD4+ T lymphocytes above 200 cells/μL are at much lower risk of PCP (6177121152). The nadir of the CD4+ T lymphocyte cell count fall prior to the institution of CART does not influence the predictive value of counts after response to CART (38128137). For patients with immunosuppressive disorders other than HIV, CD4+ T lymphocyte cell counts are less helpful (157). They should not be used to determine which non-HIV-infected patients are susceptible to PCP or which patients need prophylaxis.

PCP has also been recognized in patients with B cell defects, children with severe combined immunodeficiency disease, premature or debilitated infants, oncology patients receiving immunosuppressive drugs, and organ transplant recipients (2627111205231242,250). In one retrospective study, a corticosteroid dose equivalent to 16 mg of prednisone per day or more for a period of weeks was associated with a significant risk for PCP in patients who did not have AIDS (271). In a non-human primate model of Pneumocystiscolonization in HIV, Kling demonstrated that low anti-Pneumocystis-kexin protein (KEX1) antibody titers were associated with increased risk of Pneumocystis colonization (133). A study in persons with HIV also found that low KEX1 titers were an early independent predictor of future PCP risk (Gingo in press), and vaccination against KEX1 in mice is protective against PCP (274). Thus, it appears that both humoral and cell-mediated immunity are important host defenses against this infection (47108219).

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Human P. jirovecii cannot be grown in vitro, so conventional susceptibility testing cannot be performed. Molecular techniques permit detection of mutations in the target enzymes for various drugs (130139), but the clinical significance of these mutations is currently unknown.

Because P. jirovecii has been widely exposed to sulfonamides, it is reasonable to expect that this organism might develop sulfonamide resistance. Both dapsone and TMP/SMX act by inhibiting the folate biosynthesis enzyme DHPS. Sulfonamide resistance could theoretically result from point mutations in the DHPS gene. DHPS mutations seem to be occurring more commonly in recent years than one or two decades ago and are more often detected among patients with heavy prior exposure to sulfonamides (4296124184). Interestingly, no trimethoprim resistance has been detected, implying that perhaps trimethoprim exerts no selective pressure because it has so little activity.In vivo rodent studies support this concept (155).

Whether the degree of sulfonamide resistance currently recognized is clinically sufficient to cause treatment or prophylaxis failure has not been conclusively determined (4296105124125165184). A Danish study reported that patients with mutant DHPS were less likely to survive PCP, although the response to TMP-SMX was not specifically addressed (96). A more recent study found that although the majority of patients with mutant genotype survived when given treatment doses of TMP-SMX, there was a trend for these patients to be more likely to require mechanical ventilation and to die (42). Moreover, two other trials reported that there was no effect on survival or response to therapy in those who had mutant DHPS (124184). There is concern that higher level resistance will occur in the future and diminish the effectiveness of sulfonamides and sulfones.

Recommendations for Treatment

Once the diagnosis of P. jirovecii is made, outpatient therapy with oral TMP-SMX for 21 days is recommended for mild to moderate disease (PaO2 >70 mm Hg, A-a gradient ≤35 mm Hg) (121149). Other alternatives for oral outpatient therapy include TMP-dapsone, clindamycin-primaquine, and atovaquone. Patients who are more severely ill with moderate to severe disease or who cannot tolerate oral medications should be hospitalized and given intravenous TMP-SMX. In sulfonamide-intolerant patients, intravenous pentamidine or clindamycin-primaquine should be administered.

As patients often worsen within the first several days of treatment, treatment failure is considered only if the patient has worsening clinical status after at least 4-8 days of therapy. Alternative treatment regimens include clindamycin-primaquine or IV pentamidine. Pentamidine has more evidence of efficacy than clindamycin-primaquine for first line therapy; however, a systematic review found that clindamycin-primaquine had a higher response rate than IV pentamidine for second-line salvage therapy for suspected treatment and can be considered for those failing TMP-SMX (17).

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The efficacy of chemotherapy for PCP depends on several factors: the degree of hypoxia at the time therapy is started, the degree of immunosuppression, co-morbid conditions, and the ability of the patient to tolerate the most effective agents (923). As with other infectious diseases, the earlier therapy is started, the better the prognosis is likely to be (220222247).

Trimethoprim-sulfamethoxazole (TMP-SMX) is the agent of choice for initial therapy of acute PCP regardless of severity (23112,121149159220222). TMP-SMX is as potent as intravenous pentamidine, and it is less toxic (226). If a patient has mild disease (PaO2 greater than 70 mm Hg and alveolar-arterial oxygen gradient less than 35 mmHg) and is able to tolerate oral medications, TMP-SMX may be given in the dosage of two oral double strength (DS) tablets (160 mg TMP and 800 mg SMX) every 8 hours. With more severe disease or if the patient is unable to tolerate oral medication reliably, intravenous TMP-SMX (15-20mg/kg TMP and 75-100 mg/kg SMX divided into three or four doses) should be given. Total duration of therapy is 21 days. Intravenous therapy can be switched to the oral dosing when the patient is clinically improved.

Toxicity associated with TMP-SMX continues to hinder its use in many patients and occurs more frequently in HIV-infected patients than in patients without HIV infection (86113). Toxicities include fever, rash, headache, nausea, vomiting, pancytopenia, hepatitis, aseptic meningitis, and renal dysfunction. Trimethoprim can also cause hyperkalemia. Patients with bone marrow suppression have predictable difficulty tolerating TMP-SMX, and anemia and neutropenia are common. Some toxicities of TMP-SMX can be life threatening, including Stevens-Johnson syndrome and a distributive shock syndrome that presents similarly to anaphylaxis. Treatment-limiting toxicities usually occur between day 6 and day 10 of therapy. For AIDS patients, trials suggest that approximately 25% of patients are unable to tolerate a full course of TMP-SMX (94212228). Minor laboratory abnormalities should not be an indication to switch to a less effective alternative therapy. Clinicians must recognize that providing optimal therapy for this life-threatening pneumonia should be the therapeutic priority compared to mild or moderate toxicities that are reversible.

Alternative Therapy

Intravenous pentamidine is the most potent alternative agent to TMP-SMX (226267). The standard dose of pentamidine is 4 mg/kg/day, given intravenously (IV) over at least one hour for a minimum of 14-21 days (121149). Small studies suggest that a lower dose of 3 mg/kg/day may be less toxic, but equally effective (36). Pentamidine can only be given parenterally because aerosolized pentamidine is not effective for acute therapy (149). Pentamidine is difficult to administer because of the incidence of substantial toxicities including renal dysfunction, dysglycemias, pancreatitis, and Torsades de pointes. An elevated creatinine commonly occurs and must be monitored closely, but dosages do not need to be adjusted for renal dysfunction. Because pentamidine can cause initial islet cell destruction that results in insulin release followed by insufficient insulin production, patients often develop both hypo- and hyperglycemia, and glucose levels should be monitored. Patients also need to be carefully assessed to determine if they are receiving other drugs that prolong the QT interval in order to reduce the likelihood that Torsades will occur. Although initially used before intravenous pentamidine was shown to be safe, intramuscular pentamidine is rarely, if ever, used because it causes large, painful sterile abscesses.

The combination of clindamycin and primaquine is another reasonable alternative for the treatment of PCP in both mild and more severe disease (21121149220247). A randomized trial assessing initial therapy found the combination to be comparable in efficacy to TMP-SMX or TMP-dapsone in mild to moderate disease (222). Clindamycin-primaquine has also been used as a salvage regimen in patients with Pneumocystis-induced respiratory failure (191), although many authorities are reluctant to use an oral agent (i.e. primaquine) in this setting. Investigators report success rates of 75-80% in open, noncomparative trials with patients who are intolerant to or have failed standard treatment (220247). Primaquine is given orally at a dose of 30 mg per day. Clindamycin is given either orally (300 mg to 450 mg every 6 to 8 hours) or intravenously (600 mg to 900 mg every 6 to 8 hours). Primaquine has been associated with methemoglobinemia and hemolytic anemia especially in patients with glucose-6-phosphate dehydrogenase deficiency (G-6-PD), and therefore patients should be checked for G-6-PD deficiency prior to being started on primaquine.

Dapsone, as a single agent, is not as effective as other alternatives in the treatment of P. jirovecii pneumonia. Failure rates are approximately 40% in patients with HIV infection (171223). In combination with trimethoprim (15 mg/kg/day), however, its efficacy is comparable to TMP-SMX (145222). TMP-dapsone is used as an alternative oral regimen in mild to moderate disease for patients intolerant of TMP-SMX. Approximately 50% of sulfonamide-intolerant patients tolerate dapsone. This regimen can only be given orally and is therefore not suitable for patients with severe disease or gastrointestinal dysfunction. In addition, the combination of trimethoprim and dapsone is not formulated into one pill and is not as convenient to use as trimethoprim-sulfamethoxazole. Dapsone has also been associated with methemoglobinemia and hemolytic anemia, especially in patients with G-6-PD deficiency, and patients should be checked for G-6-PD deficiency prior to initiation of dapsone.

Oral atovaquone, another approved agent for treating P. jirovecii pneumonia, is effective and well tolerated. Atovaquone has a role as therapy for patients with mild, stable, disease who have no evidence of gastrointestinal dysfunction (121). If neither TMP-SMX nor TMP-dapsone is tolerable for patients with mild disease, atovaquone is a reasonable option. Atovaquone is not as effective as TMP-SMX (110), but atovaquone and intravenous pentamidine were found to have similar success rates in mild and moderate P. jirovecii pneumonia in AIDS patients who were intolerant to TMP-SMX (58). Atovaquone was better tolerated, but patients receiving atovaquone more frequently failed to respond to therapy, and patients receiving pentamidine had more treatment-limiting adverse drug toxicities (58). Low plasma atovaquone levels are due in part to poor bioavailability of the drug and are associated with a poor response (110). Even with the liquid formulation of the drug, absorption can be unpredictable and steady state may not be reached for several days. Absorption can be improved with ingestion of a fatty meal. Atovaquone levels are also reduced when used concurrently with rifampin of rifabutin. The combination of these drugs should be avoided. The standard dose of atovaquone is 750 mg orally twice a day.

Trimetrexate in combination with leucovorin has been assessed in patients with moderate to severe disease (227). Although this drug is very effective, it is less effective and associated with more relapses than TMP-SMX (227). Trimetrexate was an alternative agent for patients who were intolerant of TMP-SMX and who could not tolerate or did not respond to intravenous pentamidine (227), but it is no longer commercially available.

Other agents under investigation include analogs of primaquine, analogs of pentamidine, albendazole, and echinocandins or pneumocandins. There is interest in the activity of caspofungin against the cyst form of Pneumocystis, but there is scant clinical evidence that this drug is useful for treating or preventing human disease (856).

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The use of corticosteroids in conjunction with anti-Pneumocystis agents has become the standard of care in the treatment of moderate-severe PCP in AIDS patients (2). Three randomized studies revealed that corticosteroids significantly decreased the frequency of early deterioration in oxygenation and improved survival in patients who had an initial room air PO2 <70mm Hg or an A-a gradient >35mm Hg (22278). Glucocorticoids should be given to patients with moderate to severe PCP at a dose of 40 mg of prednisone twice daily for 5 days, then 40 mg daily for 5 days and then 20 mg daily through day 21 (if the patient is unable to take medication by mouth, methylprednisolone can be given intravenously at 75% of the prednisone dose) (121149). Corticosteroids should be administered with initiation of anti-PCP therapy if possible, even if therapy is empiric, and at least within 72 hours of treatment initiation (121). Although corticosteroids hasten the symptomatic resolution of mild PCP and prevent early deterioration in oxygenation (often subclinical) in this population, they are rarely used in mild disease because of concern regarding the metabolic complications of corticosteroids and possible potentiation of osteonecrosis (169). Corticosteroid therapy is logical to use in patients with underlying immunodeficiency disorders other than HIV, although no prospective trials have documented this efficacy (54202). Most clinicians would introduce corticosteroid therapy, or augment the dose if their patient had severe PCP.

For patients with HIV-related PCP who are not receiving CART, clinicians often consider starting such therapy soon after the PCP is improving. A recent randomized, multicenter trial of initiating CART early during opportunistic infections including PCP found a benefit in the combined secondary endpoint of progression to AIDS and death (273). Although this study included patients hospitalized with PCP, it did not include any patients with PCP requiring intensive care. Some retrospective studies have found that that continuing or starting CART in PCP patients or general HIV-infected patients requiring intensive care has a survival benefit (40177), but some evidence suggests that improvements in mortality in the CART era have resulted from use of low tidal volume ventilation and improved supportive techniques rather than the actual use of antiviral therapies (48211). If antiretroviral therapy is initiated during PCP treatment, the immune reconstitution inflammatory syndrome (IRIS) may occur and may result in worsening hypoxemia, increased radiographic infiltrates, and, in some cases, respiratory failure (121138269). Low CD4 cell counts and higher pre-CART HIV viral levels are associated with an increased risk of IRIS (87).

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Survival from an episode of PCP correlates most closely with the pretreatment arterial-alveolar gradient < 55 as well as with pre-existing co-morbidities (70). Other factors that influence outcome include the number of trophic forms in bronchoalveolar lavage, degree of chest radiograph abnormality, level of LDH elevation, and (for patients with HIV infection) low CD4+ T lymphocyte cell counts (23119,135). For a patient with an initial PaO2 of greater than 70 mm Hg while breathing room air, expected survival rates are 60 to 80% in non-AIDS patients and 90-95% in patients with AIDS (23226).

Respiratory rate, arterial oxygenation, temperature and chest imaging should be assessed to determine initial clinical status and then followed to assess response to therapy. Arterial blood gases provide more precise measurement of oxygenation than percutaneous oxygen saturation monitoring, but the latter can be used, especially with mild disease. The median time to clinical response to therapy is 4 to 10 days (135). During that time, the temperature should return to normal, and the respiratory rate and oxygen saturation should unequivocally improve. As with most infectious pulmonary processes, the chest radiograph or CT scan often do not improve for several weeks. The use of bronchoscopy to assess response to drug therapy is not helpful since cysts and trophozoites are difficult to quantitate, and P. jirovecii will be present in bronchoalveolar lavage specimens for many weeks after initiation of therapy, even in patients who rapidly improve (233).

Causes of Clinical Worsening After Initiation of Therapy

There are several reasons why patients with PCP may fail to improve (Table 1). During the initial two to five days of therapy, many HIV-infected patients worsen with a decline in partial pressure of oxygen by 10-30 mmHg (121). This decline has been attributed to dying organisms, which elicit an intense inflammatory response. The precise causes and mechanisms of this intensified inflammatory response have not been well-delineated. The benefit of corticosteroids appears to be the ability to blunt this “paradoxical” inflammatory response. After this initial worsening, patients should demonstrate clinical improvement.

 Another cause of worsening during PCP treatment is development of a pneumothorax. Patients with PCP, especially HIV-related PCP, develop pneumatocoeles that can rupture, resulting in a pneumothorax. If a patient with PCP, especially one receiving mechanical ventilation, experiences a sudden deterioration, clinical and radiographic assessment for a pneumothorax should be performed immediately.

The initial therapeutic regimen should be continued for at least 4 to 8 days before considering a change in therapy due to treatment failure (121). If patients do not improve or if they worsen, other causes of clinical deterioration should also be sought. Fluid status should be monitored carefully, because P. jirovecii pneumonia may cause increased permeability of alveolar capillary membranes, which can lead to accumulation of interstitial and alveolar fluid and respiratory failure. Intravenous TMP-SMX may be an unrecognized source of fluids. Concomitant congestive heart failure due to processes unrelated to Pneumocystis may also occur. Cardiovascular comorbidities are a particular consideration as patients with HIV infection live to an older age, and certain antiretroviral regimens have been association with accelerated atherosclerosis (20747576). In addition, HIV-related or chemotherapy-related cardiomyopathy may not be evident until the patient is challenged with large volumes of fluid.

Clinicians also need to assess for other concurrent pulmonary processes in patients who appear to be failing PCP treatment. Cytomegalovirus (CMV), fungi, mycobacteria, respiratory viruses, or agents of atypical pneumonia may be present. Most clinicians would perform bronchoalveolar lavage if patients are not responding promptly, especially if the initial diagnosis was established by sputum examination. In desperate situations, an open or video-assisted thoracoscopic biopsy would be warranted to determine if a treatable cause of deterioration had been missed by bronchoalveolar lavage. Tissue is especially helpful to determine if CMV is present and if it should be treated. Non-infectious causes such as congestive heart failure, embolic disease or alveolar hemorrhage should also be considered. Evaluation may thus require CT scan for pulmonary emboli, an echocardiogram, or placement of a pulmonary artery catheter.

Patients started on CART shortly after PCP treatment may also worsen due to IRIS (1253101138216269). The exact incidence of IRIS in PCP is unknown (101269). In this syndrome, as viral load declines and CD4+ T lymphocyte count increases, a more robust inflammatory response can occur at sites of recent infection or may be seen in response to latent or subclinical infection. IRIS is more common in patients with very low CD4+ T cells (< 50 cells/μL) and high serum HIV viral levels (>100,000 copies/μL) (216). IRIS can occur within days or weeks of instituting therapy. In patients with PCP, the syndrome manifests as deteriorating oxygenation, worsening cough, fever, and shortness of breath, and worsening chest imaging. The diagnosis of IRIS is one of exclusion. Patients must be reevaluated to determine which process in causing their deterioration, i.e. IRIS, another infection, or another non-infectious syndrome (101). Management of IRIS is not well-defined, but CART should be continued whenever possible. Non-steroidal agents and corticosteroids have been used (66,269). Decisions regarding treatment or withdrawal of CART should be influenced by the severity of the syndrome, the robustness of the virologic and CD4+ T lymphocyte response to CART and the specific pathogen involved.

Management of the PCP Patient Who Fails to Improve

When patients deteriorate, possible causes discussed above should be evaluated and empiric treatment of immediately life-threatening diagnoses initiated. Echocardiography, CT scanning, or placement of a pulmonary artery catheter may help evaluate for other causes of worsening. Empiric therapy for community-acquired or hospital-acquired pneumonia with consideration of bronchoscopy may also be a reasonable strategy. Prednisone should be added to the regimen if not already initiated. A change in therapy to a different anti-PCP agent is usually reserved until the patient has had 4 to 8 days of first-line therapy and after other pulmonary processes have been investigated. Most recommend a switch first from TMP-SMX to clindamycin-primaquine or intravenous pentamidine (121). If a patient is deteriorating or failing to improve on a regimen other than TMP-SMX, strong consideration should be given to using TMP-SMX, even if desensitization is required in the intensive care setting.

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There are no vaccines available.



TMP-SMX is always the drug of choice for PCP prophylaxis for patients who can tolerate this agent (121). This drug has a long history of consistent efficacy in a wide variety of patient populations. Hughes demonstrated that TMP-SMX was almost completely protective against PCP in a randomized, placebo-controlled trial of children with acute lymphocytic leukemia in the mid 1970s (112). Smaller trials, especially in patients with HIV (64114136), and non-randomized studies have demonstrated that TMP-SMX is safe and highly effective in other patient populations when compared to patients receiving no prophylaxis. True breakthroughs of PCP are unusual for patients who are adherent to the recommended regimens of TMP-SMX. There are data in patients with HIV infection to suggest that intermittent regimens (one DS tablet thrice weekly) may be less effective than daily regimens, though lower doses of TMP-SMX are better tolerated than higher doses (64). Such differences were not observed in children with malignant neoplasms (101). Reported side effects of prophylactic doses include cytopenias, skin rashes, hepatitis, pancreatitis, and nephritis.

TMP-SMX has advantages not provided by alternative drugs such as aerosolized pentamidine including low cost, oral preparation and probable protective effect against disseminated Pneumocystis. In addition, because of its broad spectrum of antimicrobial activity, it offers protection against toxoplasmosis and enteric pathogens (29). It is also apparent that TMP-SMX confers protection against Haemophilus influenzae and Streptococcus pneumoniae, although it is not indicated for bacterial prophylaxis alone.

Alternative Therapy

Aerosolized pentamidine, dapsone, dapsone-trimethoprim, dapsone-pyrimethamine, and atovaquone also have a high degree of efficacy. Each of these regimens has some disadvantages, and none is likely to be as effective as TMP-SMX. In European and American trials evaluating primary and secondary prophylaxis for patients with HIV infection, either high dose (1 DS per day) or low dose (1 single strength [SS] per day) TMP-SMX was found to be significantly more effective in preventing PCP than aerosolized pentamidine (2195116,228). The rate of discontinuation of study drug because of toxicity was higher in the TMP-SMX groups than in the aerosolized pentamidine group. The incidence and types of adverse reactions were similar in both TMP-SMX groups, but the toxic effects occurred significantly sooner in the group receiving the higher dose (228). Thus, many clinicians prefer lower dose regimens. However, for patients with the most severe immunosuppression, higher doses may be somewhat more effective, leaving clinicians to use their best judgment when choosing between high dose and low dose regimens.

In a large trial (ACTG 081), 843 patients with HIV infection were randomized to TMP-SMX (1 DS tablet bid), dapsone (50 mg bid) or aerosolized pentamidine (300 mg once monthly). Fewer episodes of PCP occurred among patients receiving TMP-SMX than in the other two arms when patients with CD4+ T lymphocyte counts less than 100 cells/μL were considered, but not when patients with higher CD4+ T lymphocyte counts were assessed. In this trial, the efficacy of dapsone appeared to be better than aerosolized pentamidine. Dapsone given at doses of 50 mg per day or less was not as effective as 50 mg bid (21).

A secondary prophylaxis study in the United States involving 310 patients with HIV infection randomly assigned administration of aerosolized pentamidine by a Respirgard II nebulizer or one oral double-strength tablet of TMP-SMX daily (94). When analyzed by intent-to-treat method, the recurrence rate of PCP was significantly higher among the patients assigned to aerosolized pentamidine (18%) than among those who received TMP-SMX (4%). As expected, patients who received TMP-SMX experienced frequent toxicity resulting in discontinuation of the agent.

 Aerosolized pentamidine is usually well-tolerated when delivered by the Respirgard II nebulizer in the indicated dosing regimens. Coughing or wheezing occurs in 30-40% of patients, but this reaction may be diminished or prevented by the administration of beta-adrenergic agonist such as albuterol (144). Bronchospasm rarely necessitates discontinuation of prophylaxis with aerosolized pentamidine treatment. Patients with reactive airway disease or bullous lung disease may not distribute aerosolized pentamidine effectively and thus may not obtain maximum protection. There have been reports of disseminated pneumocystosis in patients receiving aerosolized pentamidine for prophylaxis (95).

There is concern about transmission of Mycobacterium tuberculosis between health-care workers and HIV-infected patients associated with the coughing induced by aerosol pentamidine. Before administering aerosolized pentamidine, all patients should be screened for tuberculosis, and health-care workers should follow guidelines provided by the Centers for Disease Control and Prevention to minimize the risk of spread of tuberculosis to other patients and health-care workers (19118). Ideally, aerosolized pentamidine should be administered in individual booths or rooms with negative pressure ventilation and direct exhaust to the outside. After the administration of aerosolized pentamidine, patients should not return to common waiting areas until coughing has subsided.

Dapsone is an attractive alternative to aerosolized pentamidine because it is oral, convenient, and inexpensive. It is considered by some experts to be the best alternative for patients who cannot tolerate TMP-SMX (21116). It is estimated that 50-80% of patients who are TMP-SMX intolerant will be able to tolerate dapsone (104). Dose reduction to improve tolerability is not recommended, because doses less than 100 mg daily are considerably less effective than the full dose regimen. A case-control study in bone marrow transplants showed the efficacy of daily dapsone was similar to TMP-SMX. Dapsone did not seem to cause hematologic toxicity among TMP-SMX allergic patients (225).

Weekly doses of dapsone (200 mg) and pyrimethamine (75 mg) are well-tolerated, but less effective than TMP-SMX. Dapsone-pyrimethamine has efficacy as a prophylactic regimen against P. jirovecii pneumonia that is similar to aerosol pentamidine, but less effective than TMP-SMX. This combination has been assessed as a daily regimen (dapsone 50 mg po qd plus pyrimethamine 75 mg weekly) or as a weekly regimen (dapsone 200 mg plus pyrimethamine 75 mg) (83199). It is not clear if pyrimethamine truly adds potency against PCP (21). Dapsone alone has no antibacterial activity, and it is not clear if it has adequate anti-toxoplasma activity when used without pyrimethamine.

Atovaquone is another option for prophylaxis. Two trials in patients with HIV infection demonstrated that a daily atovaqone dose of 1500 mg of the liquid suspension has comparable efficacy to aerosolized pentamidine or oral dapsone (3265). Atovaquone does have activity against toxoplasma, but the relative efficacy of this regimen for preventing toxoplasmosis has not been adequately studied. Atovaqone has no antibacterial activity. This regimen is also much more expensive than other drug regimens. Atovaquone has not been extensively evaluated in patients with immunosuppressive disease other than HIV, but there is no reason to believe it would be less effective as long as it is absorbed and there are no substantial drug interactions.

Other potential prophylactic agents that have been used empirically or evaluated in small clinical trials include pyrimethamine-sulfadoxine (Fansidar), trimethoprim-dapsone, parenteral pentamidine, and primaquine-clindamycin. Pyrimethamine-sulfadoxine is effective, but its high rate of adverse reactions and long half-life make this an unattractive option, and one that has little benefit over TMP-SMX. Small trials with parenteral pentamidine and clindamycin-primaquine have been surprisingly disappointing in terms of efficacy.

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Recommendations for Prophylaxis

For patients with HIV infection, primary prophylaxis is indicated when the patient's absolute CD4+ T lymphocyte cell count falls below 200 cells/μL (121) and for patients with oropharyngeal candidiasis regardless of CD4+ T lymphocyte cell count. Other indications include a CD4+% <14% or a history of an opportunistic infection (121). It may also be indicated to give PCP prophylaxis to HIV-infected patients whose CD4 count is between 200 and 250 cells/µl when frequent laboratory evaluation is not possible (121). Secondary prophylaxis is indicated in any patient with a history of PCP.

The recommended agent for prophylaxis is TMP-SMX, ideally one double strength tablet daily (121). In patients who have had an adverse reaction to TMP-SMX, the preferred option is desensitization or lower dose TMP-SMX (121146201). In those who cannot tolerate TMP-SMX, alternative regimens include: dapsone or monthly aerosolized pentamidine (228) or daily atovaquone (3265). In patients who are seropositive for Toxoplasma gondii, the preferred regimen is TMP-SMX (121). If TMP-SMX is not tolerated, then alternatives include daily dapsone combined with weekly pyrimethamine and leucovorin (83199209), or atovaquone with or without pyrimethamine and leucovorin (121).

Prior to the era of CART, prophylaxis was recommended to be life-long (3136159206). However, there are now convincing data that chemoprophylaxis can be stopped if the CD4+ T lymphocyte count rises above 200 cells/μL for at least 3 months because of CART (88152). A recent study showed the incidence of primary PCP in patients with CD4+ T lymphocyte count > 100 cells/μL was low regardless of prophylaxis use (Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) et al. Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200 cells/microL. Clin Infect Dis. 2010 Sep 1;51(5):611-9). It is currently recommended to discontinue primary prophylaxis if patients have responded to CART with a CD4 count greater than 200 cells/μL (121), as there is no known added benefit after immune restoration (88152182). Discontinuing primary prophylaxis lowers pill burden and reduces risk of adverse drug reactions. Even with CD4+ T lymphocyte counts > 200 cells/μL, it may be prudent to continue prophylaxis in some high-risk patients. Those with high viral loads (i.e. > 50,00-100,000 copies/μL), rapidly declining CD4+ T lymphocyte cell counts (especially if frequent monitoring is not possible), wasting, oral candidiasis or a prior episode of PCP may still benefit from prophylaxis.

For non-HIV-infected patients, most authorities believe that it is reasonable to institute primary prophylaxis for groups of patients felt to be at high risk (8991100217). Most clinicians would provide chemoprophylaxis for allogeneic bone marrow transplant recipients, human stem cell transplant recipients, solid organ transplant recipients, and patients receiving antineoplastic chemotherapy, high dose corticosteroids, or certain other immunosuppressive agents (89103111156168180195). Fludarabine and 2-chlorodeoxyadenosine have an especially strong association with PCP (2627). Recent reports link development of PCP with the use of anti-tumor necrosis factor therapy, and prophylaxis should be considered in these patients (120173).

It is generally recommended that prophylaxis should be continued for as long as the immunosuppressive condition continues. Defining this period of immunosuppression may be challenging in non-HIV-infected patients. CD4+ T cell counts are not reliable, nor are any other clinical or laboratory markers (3351). Thus, factors such as the temporal relationship to immunosuppressive drugs, time since transplantation, induction therapy used at transplant, or time since the occurrence of graft versus host disease are used to estimate the period of susceptibility. For recipients of allogeneic bone marrow transplants and human stem cell transplants, it is routine to administer prophylaxis from the time of engraftment to at least 6 months after transplant for all recipients (224). Prophylaxis should be continued for more than 6 months after transplant for all persons who are receiving increased immunosuppression for graft versus host disease or for rejection. Decisions about duration of prophylaxis are made on the basis of estimates of susceptibility rather than objective clinical data. Cases of PCP in bone marrow transplant recipients usually occurred when prophylaxis was stopped too early (51). As transplant regimens change in terms of drugs, intensity, and underlying disease, the indications for PCP prophylaxis need to be readdressed.

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Table 1. Reasons for Failure to Improve with PCP Therapy

 Paradoxical response (initial worsening with effective treatment)

 Pulmonary edema



 Undiagnosed or new infection
  Pulmonary embolism
  Alveolar hemorrhage
  Immune reconstitution inflammatory syndrome
 PCP treatment failure


What's New

Choukri F, Menotti J, Sarfati C, Lucet JC, Nevez G, Garin YJ, Derouin F, Totet A. Spread of Pneumocystis jirovecii in the surrounding air of patients with Pneumocystis pneumonia. Clin Infect Dis. 2010 Aug 1;51(3):259-65.

Skelly MJ, et al.  S-Adenosylmethionine levels in the Diagnosis of Pneumocystis carinii Pneumonia in Patients with HIV Infection. Clin Infect Dis 2008;46(3):467-471.

Walzer PD et al. Early Predictors of Mortality from Pneumocystis jirovecii Pneumonia in HIV-infected Patients: 1985-2006.Clin Infect Dis. 2008 Feb 15;46(4):625-33.

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Clinical Manifestations

Laboratory Diagnosis




Review Articles

Adhikari P, Mietzner T.  Cell Mediated Immunity.

Huang L, Morris A, Limper AH, Beck JM; ATS Pneumocystis Workshop Participants.  An Official ATS Workshop Summary: Recent advances and future directions in pneumocystis pneumonia (PCP). Proc Am Thorac Soc. 2006;3(8):655-64.

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Clinical Manifestations