Category Archives: Pneumocystis Pneumonia (PCP)

Pneumocystis Pneumonia (PCP)

– Christian Hoffmann –

This interstitial pneumonia attributed to the majority of AIDS deaths in the early years of the HIV epidemic. In the last 20 years, there has been significant progress made in understanding this organism, especially through DNA analysis (review: Thomas 2004). Although pneumocystis was previously classified as a protozoan, it was established in 1988 that it is in fact an unusual type of fungus (Edman 1988). In the 1990s, it was recognized that every host, whether rat, mouse, monkey or human, had its own specific pneumocysts. It also became clear that Pneumocystis carinii (P. carinii), which was first described in 1910, does not occur in humans at all, but only in rats. The Pneumocystis species that affects humans is now referred to as Pneumocystis jiroveci, and “carinii” has now been taken out of the name for the pneumonia, although the abbreviation PCP remains the same (Stringer 2002).

Today, the majority of patients diagnosed with PCP are not pre-treated with antiretroviral drugs, because many of them either do not know of their HIV infection status or do not want to know it. In Europe between 1997-2004, among 760 cases of so-called “late presenters” who were diagnosed with HIV infection and AIDS diagnosed at the same time,  PCP was the by far most frequent OI (Mussini 2008).

PCP is a life-threatening disease, which should be treated by an HIV specialist. It often requires mechanical ventilation and then still continues to have a high fatality rate of up to 10% (Morris 2008, Walzer 2008). Factors associated with mortality are older age, low hemoglobin level, and low partial pressure of oxygen breathing room air at hospital admission (Walzer 2008, Miller 2010). Moreover, relapses seen frequently in the past have become rare, thanks to ART and prophylaxis. Scar tissue formation may result in susceptibility to recurring pneumothoraces. While PCP may rarely occur in relation to an immune reconstitution inflammatory syndrome (see below). Extrapulmonary manifestations of pneumocystis infections are also considerably rare. They may affect the liver, but many other organs may be involved.

Signs and symptoms

Every clinician should be familiar with the classic triad of PCP symptoms that include dry cough, subfebrile temperatures, and dyspnea on exertion; should ask patients specifically about their symptoms; and should measure the patients’ respiratory rates. A subacute course that allows differentiation from the productive cough, acutely high fever, pain and less common dyspnea associated bacterial pneumonia is a typical practice. Oral thrush is a frequent symptom in patients with PCP. Also, substantial weight loss of several kilograms in the weeks before PCP diagnosis is also common. These and other symptoms may be more subtle in cases with suboptimal prophylaxis (rare).

Weeks and sometimes even months may go by before the diagnosis of PCP is made. It is noteworthy to state that decompensation – as with all interstitial pneumonias – often occurs much faster than expected. It is not rare for a patient to suddenly require ventilation after weeks of antibiotic therapy prescribed by the primary health care provider, especially when even “broad spectrum” antibiotics do not help. A patient with significant exertional dyspnea or even resting dyspnea should be directed immediately to a hospital.

Diagnosis

If there is clinical suspicion of PCP determined by a physical examination with attention give to respiratory rate, oral thrush, and significant findings on auscultation, then a chest x-ray should follow without delay and, if possible, a high resolution computed tomography (HRCT) of the lungs. The chest x-ray often shows relatively characteristic findings with a butterfly-shaped (perihilar) interstitial infiltrate. In the early stages, the focus is on the mid- and lower fields. Indistinct, diffuse changes are more easily visible on HRCT than on chest x-ray. A CT scan also allows a fairly certain distinction from other pulmonary infections (Hidalgo 2003). However, in cases where nothing pathological is visible on CT scan to an experienced radiologist, then rapid initiation of treatment is still justified even without a definitive diagnosis – particularly in the presence of the classic triad of symptoms, low CD4 T cell count and no previous PCP prophylaxis. Almost always present is partial respiratory insufficiency, which should be confirmed by arterial blood gas analysis. Lactate dehydrogenase (LDH) is often elevated and may have limited use as a predictive parameter for the course of disease. A high LDH is an unfavorable sign and may reflect the severity of the PCP. In contrast, CRP is often normal, provided there are no other concurrent infections.

Sputum specimens are generally not useful (review: Cruciani 2002), so that a bronchoalveolar lavage (BAL) is usually necessary. This can lead to detection of pneumocysts even after several days of treatment. Therefore, it is not essential to wait for the BAL to start treatment. The laboratory should be specifically alerted to the suspicion of PCP. The routine test for detecting Pneumocystis in the BAL is direct immunofluorescence assay (DFA). A real-time PCR assay also seems to be an accurate diagnosis method and could replace the DFA (Fillaux 2008).

Performing the BAL as early as possible also allows for the timely diagnosis of co-infections (CMV, pneumococci). It should be noted that respiratory insufficiency can deteriorate with BAL. Full blood count, transaminases and kidney function must be monitored during treatment and baseline values should be determined at this point. Newer diagnostic approaches include antibody testing (Bishop 2003) and measurement of S-adenosylmethionine, a agent that pneumocysts require but cannot produce. S-adenosylmethionine levels are significantly reduced in patients with PCP (Skelly 2008). It is currently not foreseeable, whether these tests, which spare patients the discomfort of bronchoscopy, will be available for routine diagnostic testing in the future. This also applies to other serum markers such as beta-d glucan or antibody tests (Desmet 2009, Watanabe 2009, Djawe 2010, Gingo 2011).

Treatment

General

Treatment should be initiated immediately if there is clinical suspicion. In cases of mild PCP (BGA: PO2 > 70-80 mm Hg), ambulatory treatment can be attempted. In very mild cases, even oral medication can be considered. This may well be possible in cooperation with a competent HIV nursing service. If such monitoring is not possible, if respiratory deterioration occurs, and in every case with resting dyspnea, immediate hospitalization is advised. If ventilation becomes necessary, patients have a poor prognosis, even today (Crothers 2005, Walzer 2008). Non-invasive methods (like CPAP) may be beneficial if used from an early stage. This helps particularly in prevention of pneumothoraces (Confalonieri 2002).

While with ART naïve patients initiation of ART was mostly deferred until PCP was cured, a randomized study showed advantages of an early start (Zolopa 2009, see above). Another retrospective study showed improved survival in patients who began ART while hospitalized (Morris 2003). Possible cumulative toxicities and allergies with this approach, which may necessitate discontinuation of both PCP and HIV treatment can be largely avoided today (Watson 2002).

Drugs

Acute therapy should last for 21 days. The drug of choice is co-trimoxazole. The dose of three 960 mg tablets three times daily is possible in milder cases. However, these higher oral doses are also associated with poor gastrointestinal tolerability. Some case reports have observed positive effects with lower doses, but controlled studies are missing (Thomas 2009). All severe cases should be treated intravenously in hospital. Due to possible clinical deterioration, which is probably a result of the bursting of pneumocysts in the alveoli, 1 mg/kilogram prednisone bid should always be simultaneously co-administered with the PCP therapy for 5-10 days. There should be no hesitation to use steroids especially in patients with poor blood gases. On steroids, significantly less patients need intubation (Briel 2006). Important: clinical deterioration during the first week of treatment is still not uncommon. Initial treatment should be re-evaluated after one week at the earliest, and only after exclusion of co-infections such as CMV.

The high doses of co-trimoxazole require monitoring of full blood count, electrolytes, renal function parameters and transaminases at least three times weekly. The main problems in addition to myelotoxicity as well as liver and kidney problems include a rash that usually occurs after the middle of the second week of treatment and is often accompanied by drug fever. The rash occurred in up to 30% of patients (Fisk 2009) – patients should be checked daily for skin changes! If an exanthema occurs, one can attempt to interrupt treatment for one or two days, and then continue with half the dose under steroids. Otherwise, co-trimoxazole must be discontinued and replaced with alternative treatments.

All alternatives to co-trimoxazole are less effective. In cases of intolerability or history of sulfonamide allergy, intravenous pentamidine is recommended as the drug of second choice. An induction therapy is administered over the first few days (200-300 mg in 500 ml 5% glucose or 0.9% NaCl), and half the dose can then be given from day 6. This treatment is very toxic, which is why we have not used it for many years. Severe decompensations of electrolyte and blood glucose levels (both hyper- and hypoglycemia) are possible, as well as pancreatitis, arrhythmia and renal failure. Initially, daily monitoring of blood glucose, electrolytes and renal parameters is necessary.

In very mild cases of PCP, inhalative treatment with daily pentamidine inhalations (300-600 mg daily for three weeks) can be attempted (Arasteh 1990, Montgomery 1995). However, the experiences have not all been positive (Conte 1990, Soo 1990), and the current US-guidelines advise against inhalatory acute therapy (Benson 2004). Instead of pentamidine, treatment with atovaquone suspension (better than the tablets used in the past) or a combination of clindamycin and primaquine is possible. However, data on these alternative therapies is only available for mild to moderately severe cases of PCP (Hughes 1993, Dohn 1994, Toma 1998). According to a meta-analysis, clindamycin-primaquine seems very promising as second-line treatment for PCP in patients who fail treatment with co-trimoxazole (Benfield 2008) and is superior to pentamidine (Helweg-Larsen 2009).

In the past few years, these alternative agents (intravenous pentamidine, atovaquone, clindamycin, primaquine) have been used only in exceptional cases. It should be mentioned that a 10-day initial therapy of a high dose co-trimoxazole is achievable in almost all patients, most of whom are then already significantly better. If exanthema or toxicity forces the interruption of co-trimoxazole between day 10 and 14, daily pentamidine inhalation is called into question in the third and last week of acute therapy. As this is not toxic, it can usually be started in parallel to ART. However, a study on this strategy has yet to be published.

Prophylaxis

Patients with less than 200 CD4 T cells/µl (<14%) are at high risk of PCP. Above these values, the occurrence of PCP is rare. Therefore, these patients are treated prophylactically, ideally with co-trimoxazole. Daily dosages may be slightly more effective than giving the dosages three times weekly (El Sadr 1999). The gradual lead-in administration over a period of 14 days is supposed to prevent allergic reactions, but is cumbersome (Para 2000). In cases of a mild or moderate allergy to co-trimoxazole, desensitization after several weeks is possible (Leoung 2001), and should definitely be attempted. Although dapsone and pentamidine inhalations are almost equally effective (Bozzette 1995, Bucher 1997), co-trimoxazole prophylaxis is better for preventing bacterial infections such as enteritis, sinusitis and pneumonia (DiRienzo 2002). More importantly, co-trimoxazole simultaneously provides reliable protection for cerebral toxoplasmosis. Pediatric co-trimoxazole suspension can be used for desensitization, by slowly increasing exposure within six days from 12.5, 25, 37.5, 50 and 75 to 100% of the dose in the 480 mg tablet. In a study of almost 200 patients, no cases of severe allergy occurred, and there was a reduction of fever and headaches. Approximately three quarters of all patients are thus able to tolerate co-trimoxazole again. However, re-exposure should only be attempted after an interval of eight weeks (Leoung 2001).

Monthly inhalation of pentamidine is a well-tolerated alternative. However, coughing may occur. Asthma attacks are rare, and pneumothoraces are even rarer. A suitable inhalation system should be used, after administration of a beta-sympathomimetic to dilate the bronchi. The loading dose (300 mg tid for the first 5 days) frequently used in the past is no longer a universal standard. In patients with severe pulmonary disease, inhalation is probably less effective.

Further options are problematic. Dapsone has poor gastrointestinal tolerability, is quite myelotoxic and often leads to elevation of LDH. LDH, an important diagnostic parameter, can therefore not be utilized under treatment with dapsone (Ioannidis 1996). Atovaquone was proven to be of comparable efficacy to co-trimoxazole, dapsone and pentamidine in two multicenter studies (El-Sadr 1998, Chan 1999), and since then, is considered to be a good alternative for PCP prophylaxis. The oral suspension has better tolerability than the tablet formulation (Rosenberg 2001). A significant disadvantage of atovaquone for long-term prophylaxis is the disproportionately high cost (in some European countries approximately 1,000 Euro/month).

PCP prophylaxis regimens can be discontinued fairly safely with sufficient immune reconstitution: more than 200 CD4 T cells/µl for three months (Schneider 1999, Weverling 1999, Lopez 2001, Ledergerber 2001). PCP has only rarely been described in cases with CD4 T-cell counts greater than 200 cells/µl after stopping prophylaxis (Degen 2002, Mussini 2003). If the viral load is suppressed, even lower CD4 cells are possible. In an analysis of 23,412 patients from 12 European cohorts who started taking ART after 1997, the incidence of primary PCP was low among patients who had virologically suppressed HIV infection, were receiving ART, and who had CD4 cell counts >100 cells/µl. Discontinuation of prophylaxis may be safe in patients with CD4 counts of 101-200 cells/µL and suppressed viral load (COHERE 2010). However, there a no controlled studies addressing this issue.

Treatment/Prophylaxis of PCP (daily doses, if not specified otherwise)

Acute therapy

Duration: always at least three weeks

Severe to moderately severe PCP

Co-trimoxazole

Co-trimoxazole 5-6 amp. at 480 mg tid plus

prednisolone 2–2–0 tbl. at 20 mg (5-10 days)

Mild PCP

Co-trimoxazole

Co-trimoxazole 3 tbl. at 960 mg tid

Alternatives

Pentamidine

Pentamidine 200-300 mg i.v. for 5 days (4 mg/kg), then halve dose

In very mild cases: daily inhalations with 300 mg

Atovaquone

Atovaquone suspension 5-10 ml bid (750–1500 mg bid)

Clindamycin + Primaquine

Clindamycin 1 amp. at 600 mg i.v. q 6-8 h plus primaquine 1 tbl. at 30 mg qd

Prophylaxis

Below 200 CD4 T cells/µl; after PCP episode

First choice

Co-trimoxazole

Co-trimoxazole 1 tbl. at 480 mg qd or

co-trimoxazole 1 tbl. at 960 mg 3 x/week

Alternatives

Pentamidine

Pentamidine inhalation 300 mg 1-2 x/month

Dapsone

Dapsone 2 tbl. at 50 mg qd

Dapsone + Pyrimethamine

Dapsone  1 tbl. at 50 mg qd plus pyrimethamine 2 tbl. at 25 mg/week plus leucovorin 2 tbl. at 15 mg/week

Atovaquone

Atovaquone suspension 5 ml bid (750 mg bid)

Resistance issues, current controversies

Stopping prophylaxis not only reduces side effects and costs, but also avoids other negative developments: the proportion of co-trimoxazole-resistant bacteria is constantly increasing among HIV infected patients (Martin 1999). The worldwide use of co-trimoxazole has also affected pneumocysts. Resistance analyses were previously difficult since this particular organism, even almost 100 years after its discovery, can still not be cultured. However, it is now possible to sequence sections of the genome encoding for dihydropteroate synthetase (DHPS). DHPS is an important enzyme involved in the folate metabolism of many organisms, and is targeted by sulfonamides such as sulfamethoxazole (SMX) and dapsone. The first mutations in the DHPS gene in pneumocysts were discovered in 1997. A further study showed DHPS mutations in 43%, while the gene region for dihydrofolate reductase (DHFR), targeted by trimethoprim (TMP) and pyrimethamine, did not show a single relevant mutation. In contrast to SMX, there seems to be no selective pressure associated with TMP – a suspicion that has to be analyzed, that TMP is not effective against pneumocysts (Ma 1999). Recently, however, even DHFR-mutations have been proven (Nahimana 2004). In addition, studies in large groups of patients have demonstrated that the frequency of sulfa resistance mutations has significantly increased in recent years. Resistance correlated significantly with the duration of prior prophylaxis and its failure (Helweg-Larsen 1999). However, it remains unclear, whether DHPS mutations should affect decisions on PCP therapy or lead to a change in treatment (Review: Matos 2010).

The sequencing of the Pneumocystis genome has uncovered other possibly relevant findings: it seems highly likely that PCP is caused by a new infection, rather than the reactivation of an existing infection as previously assumed (Wakefield 2003). Asymptomatic HIV patients with frequent detection of pneumocysts may be reservoirs (Wakefield 2003), but also HIV-negative patients on corticosteroid therapy (Maskell 2003) and patients with active PCP. Reports also exist on nosocomial infection with pneumocysts (Schmoldt 2008). However, other authors doubt patient-to-patient transmission (Wohl 2002), and isolation of PCP patients is still not generally recommended (Thomas 2004).

Pneumocysts do not always cause a manifest pneumonia: in healthy patients pneumocystis colonization has been observed (Ponce 2010, Vargas 2010), which also play a role in chronic obstructive lung diseases (Morris 2008).

References

Arasteh K, Heise W, L’age M. Treatment of mild to moderately severe pneumocystis carinii pneumonia with cotrimoxazole versus pentamidine aerosol. Med Klin 1990, 85 Suppl 2:260-3.

Benfield T, Atzori C, Miller RF, Helweg-Larsen J. Second-Line Salvage Treatment of AIDS-Associated Pneumocystis jirovecii Pneumonia: A Case Series and Systematic Review. J AIDS 2008.

Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the NIH, and the IDSA. MMWR Recomm Rep 2004, 53(RR-15):1-112.

Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced HIV. N Engl J Med 1995, 332:693-9.

Briel M, Bucher HC, Boscacci R, Furrer H. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Cochrane Database Syst Rev 2006, 19;3:CD006150.

Bucher HC, Griffith L, Guyatt GH, Opravil M. Meta-analysis of prophylactic treatments against Pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients. J AIDS Hum Retrovirol 1997, 15:104-14.

Chan C, Montaner J, Lefebvre EA, et al. Atovaquone suspension compared with aero-solized pentamidine for prevention of PCP in HIV-infected subjects intolerant of trimethoprim or sulfonamides. J Infect Dis 1999, 180:369-76.

COHERE. 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, 51:611-9.

Confalonieri M, Calderini E, Terraciano S, et al. Noninvasive ventilation for treating acute respiratory failure in AIDS patients with Pneumocystis carinii pneumonia. Intensive Care Med 2002, 28:1233-8.

Conte JE Jr., Chernoff D, Feigal DW Jr., Joseph P, McDonald C, Golden JA. Intravenous or inhaled pentamidine for treating PCP in AIDS. A randomized trial. Ann Intern Med 1990, 113:203-9.

Crothers K, Beard CB, Turner J, et al. Severity and outcome of HIV-associated Pneumocystis pneumonia containing Pneumocystis jirovecii dihydropteroate synthase gene mutations. AIDS 2005, 19:801-5.

Cruciani M, Marcati P, Malena M, et al. Meta-analysis of diagnostic procedures for Pneumocystis carinii pneumonia in HIV-1-infected patients. Eur Respir J 2002, 20:982-9.

Degen O, van Lunzen J, Horstkotte MA, Sobottka I, Stellbrink HJ. Pneumocystis carinii pneumonia after the discontinuation of secondary prophylaxis. AIDS 2002, 16:1433-4.

Desmet S, Van Wijngaerden E, Maertens J, et al. Serum (1-3)-beta-D-glucan as a tool for diagnosis of Pneumocystis jirovecii pneumonia in patients with human immunodeficiency virus infection or hematological malignancy. J Clin Microbiol 2009, 47:3871-4.

DiRienzo AG, van Der Horst C, Finkelstein DM, et al. Efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced HIV infection. AIDS Res Hum Retroviruses 2002, 18:89-94.

Djawe K, Huang L, Daly KR, et al. Serum antibody levels to the Pneumocystis jirovecii major surface glycoprotein in the diagnosis of P. jirovecii pneumonia in HIV+ patients. PLoS One 2010, 5:e14259.

Dohn MN, Weinberg WG, Torres RA, et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1994;121:174-80.

Edman JC, Kovacs JA, Masur H, et al. Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. Nature 1988, 334:519-522.

El-Sadr WM, Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of PCP in HIV-infected persons. Clin Infect Dis 1999, 29:775-783.

El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med 1998, 339:1889-95.

Fillaux J, Malvy S, Alvarez M, et al. Accuracy of a routine real-time PCR assay for the diagnosis of Pneumocystis jirovecii pneumonia. J Microbiol Methods 2008, 75:258-61.

Fisk M, Sage EK, Edwards SG, Cartledge JD, Miller RF. Outcome from treatment of Pneumocystis jirovecii pneumonia with co-trimoxazole. Int J STD AIDS 2009, 20:652-3.

Gingo MR, Lucht L, Daly KR, et al. Serologic responses to Pneumocystis Proteins in Human Immunodeficiency Virus Patients With and Without Pneumocystis jirovecii Pneumonia. J AIDS 2011 Mar 3. [Epub ahead of print]

Helweg-Larsen J, Benfield T, Atzori C, Miller RF. Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. J Antimicrob Chemother 2009, 64:1282-90.

Helweg-Larsen J, Benfield TL, Eugen-Olsen J, Lundgren JD, Lundgren B. Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated PCP. Lancet 1999, 354:1347-51.

Hidalgo A, Falco V, Mauleon S, et al. Accuracy of high-resolution CT in distinguishing between Pneumocystis carinii pneumonia and non-Pneumocystis carinii pneumonia in AIDS patients. Eur Radiol 2003, 13:1179-84.

Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumo-nia in patients with AIDS. N Engl J Med 1993, 328:1521-7.

Ioannidis JP, Cappelleri JC, Skolnik PR, Lau J, Sacks HS. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med 1996, 156:177-88.

Leoung GS, Stanford JF, Giordano MF, et al. Trimethoprim-sulfamethoxazole dose escalation versus direct rechallenge for PCP prophylaxis in HIV-infected patients with previous adverse reaction to TMP-SMZ. JID 2001, 184:992-7.

Lopez Bernaldo de Quiros JC, Miro JM, Pena JM, et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against PCP after HAART in patients with HIV infection. NEJM 2001, 344:159-67.

Ma L, Borio L, Masur H, Kovacs JA. Pneumocystis carinii dihydropteroate synthase but not dihydrofolate reductase gene mutations correlate with prior trimethoprim-sulfamethoxazole or dapsone use. J Inf Dis 1999, 180:1969-78.

Martin JN, Rose DA, Hadley WK, et al. Emergence of trimethoprim-sulfamethoxazole resistance in the AIDS Era. J Infect Dis 1999, 180:1809-18.

Maskell NA, Waine DJ, Lindley A, et al. Asymptomatic carriage of Pneumocystis jiroveci in subjects undergoing bronchoscopy: a prospective study. Thorax 2003, 58:594-7.

Matos O, Esteves F. Epidemiology and clinical relevance of Pneumocystis jirovecii Frenkel, 1976 dihydropteroate synthase gene mutations. Parasite 2010, 17:219-32.

Miller RF, Evans HE, Copas AJ, Huggett JF, Edwards SG, Walzer PD. Seasonal variation in mortality of Pneumocystis jirovecii pneumonia in HIV-infected patients. Int J STD AIDS 2010, 21:497-503.

Montgomery AB, Feigal DW Jr., Sattler F, et al. Pentamidine aerosol versus trimethoprim-sulfamethoxazole for Pneumocystis carinii in AIDS. Am J Respir Crit Care Med 1995;151:1068-74.

Morris A, Sciurba FC, Norris KA. Pneumocystis: a novel pathogen in chronic obstructive pulmonary disease? COPD 2008;5:43-51.

Morris A, Wachter RM, Luce J, Turner J, Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS 2003, 17:73-80.

Morris A. Is there anything new in Pneumocystis jirovecii pneumonia? Changes in P. jirovecii pneumonia over the course of the AIDS epidemic. Clin Infect Dis 2008;46:634-6.

Mussini C, Manzardo C, Johnson M, et al. Patients presenting with AIDS in the HAART era: a collaborative cohort analysis. AIDS 2008, 22:2461-9.

Mussini C, Pezzotti P, Antinori A, et al. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in HIV-infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis 2003, 36:645-51.

Nahimana A, Rabodonirina M, Bille J, et al. Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother 2004; 48:4301-5.

Para MF, Finkelstein D, Becker S, et al. Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia. J AIDS 2000, 24:337-43.

Ponce CA, Gallo M, Bustamante R, Vargas SL. Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population. Clin Infect Dis 2010, 50:347-53.

Rosenberg DM, McCarthy W, Slavinsky J, et al. Atovaquone suspension for treatment of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 2001, 15:211-4.

Schmoldt S, Schuhegger R, Wendler T, et al. Molecular evidence of nosocomial Pneumocystis jirovecii transmission among 16 patients after kidney transplantation. J Clin Microbiol 2008; 46:966-71.

Schneider MM, Borleffs JC, Stolk RP, Jaspers CA, Hoepelman AI. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with HAART. Lancet 1999, 353: 201-3.

Skelly MJ, Holzman RS, Merali S. S-adenosylmethionine levels in the diagnosis of Pneumocystis carinii pneumonia in patients with HIV infection. Clin Infect Dis 2008;46:467-71.

Soo Hoo GW, Mohsenifar Z, Meyer RD. Inhaled or intravenous pentamidine therapy for Pneumocystis carinii pneumonia in AIDS. A randomized trial. Ann Intern Med 1990;113:195-202.

Stringer JR, Beard CB, Miller RF, Wakefield AE. A new name (Pneumocystis jiroveci) for Pneumocystis from humans. Emerg Infect Dis 2002, 8:891-6.

Thomas CF Jr, Limper AH. Pneumocystis pneumonia. NEJM 2004, 350: 2487-98.

Thomas M, Rupali P, Woodhouse A, Ellis-Pegler R. Good outcome with trimethoprim 10 mg/kg/day-sulfamethoxazole 50 mg/kg/day for Pneumocystis jirovecii pneumonia in HIV infected patients. Scand J Infect Dis 2009,17:1-7.

Toma E, Thorne A, Singer J, et al. Clindamycin with primaquine vs. Trimethoprim-sulfamethoxazole therapy for mild and moderately severe PCP in patients with AIDS: a multicenter, double-blind, randomized trial (CTN 004). Clin Infect Dis 1998, 27:524-30.

Vargas SL, Pizarro P, López-Vieyra M, et al. Pneumocystis colonization in older adults and diagnostic yield of single versus paired noninvasive respira-tory sampling. Clin Infect Dis 2010, 50:e19-21.

Wakefield AE, Lindley AR, Ambrose HE, Denis CM, Miller RF. Limited asymptomatic carriage of pneumocystis jiroveci in HIV-infected patients. J Infect Dis 2003, 187: 901-8.

Walzer PD, Evans HE, Copas AJ, et al. Early predictors of mortality from Pneumocystis jirovecii pneumonia in HIV-infected patients: 1985-2006. Clin Infect Dis 2008;46:625-33.

Watanabe T, Yasuoka A, Tanuma J, et al. Serum (1–>3) beta-D-glucan as a noninvasive adjunct marker for the diagnosis of  Pneumocystis pneumonia in patients with AIDS. Clin Infect Dis 2009, 49:1128-31.

Watson J. Pneumocystis carinii: where are we now? J HIV Ther 2002, 7:8-12.

Weverling GJ, Mocroft A, Ledergerber B, Kirk O, et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of HAART in HIV-1 infection. Lancet 1999, 353:1293-8.

Wohl AR, Simon P, Hu YW, Duchin JS. The role of person-to-person transmission in an epidemiologic study of Pneumocystis carinii pneumonia. AIDS 2002, 16:1821-5.

Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS 2009, 4:e5575.

 

Leave a comment

Filed under 11. Opportunistic Infections, Part 3 - AIDS, Pneumocystis Pneumonia (PCP)