D25 Pneumocystis pneumonia
Pneumocystis organisms were first reported by Carlos Chagas in 1909. It was initially thought to be a protozoan but reclassified as a fungus in 1988 after DNA sequence analysis. More recently, additional DNA data showed that Pneumocystis organisms from different host species have very different DNA sequences, indicating presence of multiple species. The microbe that causes human Pneumocystis pneumonia is now named Pneumocystis jiroveci (P. jirovecii). However the acronym PCP is still used to designate Pneumocystis pneumonia.
Before the widespread use of chemoprophylaxis, PCP was a major cause of morbidity and mortality in AIDS patients. Some 30-60% of untreated AIDS patients would have PCP at the time of AIDS diagnosis and an additional 20-35% developed PCP sometime after the diagnosis. Incidence of PCP has declined substantially in the HAART (highly active antiretroviral therapy) era; the incidence of which has fallen from 29.9 per 1000 person years between 1994 to 1997 to 3.9 per 1000 person years between 200 to 2007 in United States. A majority of cases now occur among patients who are unaware of their HIV infection or are not receiving ongoing HIV care. PCP is the most common AIDS-defining illness in Hong Kong, accounting for 40%-50% of reported AIDS cases in recent years.
Earlier studies supported the theory of Pneumocystis infection early in life followed by reactivation of latent infection when a person becomes immunocompromised. Primary infection occurs in childhood as evidenced by the detection of antibodies by the age of 4 in a majority of children worldwide. However animal studies have demonstrated that Pneumocystis can be transmitted between animals via an airborne route. Numerous reports of clustered outbreaks of PCP in different immunocompromised populations suggested person-to-person transmission and the recent acquisition of Pneumocystis infection in the pathogenesis of PCP in humans. In addition, molecular typing of P. jirovecii has provided molecular evidence in support of inter-human transmission and recent infection. Although the results of studies in animals and humans favour airborne transmission, respiratory isolation for patients with PCP is not currently recommended.
Clinical manifestations of PCP
As an AIDS-defining illness, PCP usually occurs when CD4 count drops below 200/μL and when one is not receiving PCP prophylaxis. Other risk factors include previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, CD4 cell percentage <14% and a high plasma HIV RNA.
Common symptoms include subacute onset of dyspnoea, nonproductive cough, and low-grade fever. Acute dyspnoea with pleuritic chest pain may indicate the development of pneumothorax. Physical examination typically reveals tachypnoea, tachycardia, and normal findings on lung auscultation. Extra-pulmonary involvement may rarely occur particularly in patients on aerosolised pentamidine prophylaxis. Respiratory failure, as evidenced by parameters such as increased respiratory rate and hypoxaemia, signifies progression of PCP and is associated with high mortality particularly when the alveloar-arterial oxygen gradient ≥50mmHg at presentation.
LDH level is often elevated but non-specific. Typical radiographic features of PCP are bilateral perihilar interstitial infiltrates that become increasingly homogeneous and diffuse as the disease progresses. Less common findings include solitary or multiple nodules, pneumatoceles, pneumothorax, and upper-lobe infiltrates in patients receiving aerosolised pentamidine. PCP may occasionally present with a normal chest radiograph. However, pleural effusions and thoracic lymphadenopathy are rare. High-resolution computed tomography (HRCT) thorax is more sensitive than chest radiography and may reveal extensive ground-glass attenuation or cystic lesions. Although the presence of ground-glass attenuation is nonspecific for PCP, its absence probably rule out the diagnosis.
PCP may be difficult to diagnose from nonspecific symptoms and signs, and that there may be co-infection with other organisms, such as cytomegalovirus (CMV) in the immunocompromised host. Pneumocystis cannot be cultured, and thus the diagnosis of PCP requires microscopic examination of sputum, bronchoalveolar fluid or lung tissue. [Algorithm 25A]
Sputum induction with hypertonic saline has variable sensitivity of 50-90% and should be the initial procedure used. If it fails to yield a diagnosis, bronchoscopy with bronchoalveolar lavage should be performed, which has a diagnostic yield of 90-100%. Trophic forms can be detected with Wright-Giemsa or Papanicolaou stain. Cysts can be detected with methenamine silver stain. Direct and indirect immunofluorescence methods have been shown to have higher sensitivity than the classical staining methods.
The use of polymerase chain reaction (PCR) to detect Pneumocystis nucleic acids has been an active area of research. PCR has been shown to have higher sensitivity and specificity for the diagnosis of PCP from specimens of induced sputum and bronchoalveolar lavage fluid than conventional staining. Real time quantitative PCR (qPCR), targeting Pneumocystis mitochondrial large subunit ribosomal RNA gene or Pneumocystis major surface glycoprotein primers, using upper respiratory tract specimens such as nasopharyngeal aspirate and oral washes demonstrated high sensitivity (91% -100%) and could possibly reduce the need for invasive procedure. qPCR for Pneumocystis may also become useful in discriminating between colonization and active infection.
1,3-β-D-glucan is a cell-wall component of many medically important fungi including Pneumocystis. A meta-analysis assessing the diagnostic accuracy of the test to detect PCP reported high sensitivity (96%) but lack of specificity and could not differentiate from other invasive fungal infection. It may be useful as a screening tool.
Treatment [Box 25.1][Algorithm 25A]
Trimethoprim-sulfamethoxazole (TMP-SMZ) is the drug of choice for the treatment of PCP and extrapulmonary disease if the patients have no sulfa allergy. It has the advantage of excellent penetration, rapid clinical response (3 to 5 days in patients with mild to moderate disease), and good oral bioavailability. TMP-SMZ is effective in treating PCP of different severities. Unfortunately, adverse events are common in HIV-infected patients due to systemic glutathione deficiency and dosage adjustment for renal impairment is needed. The adverse effects of TMP-SMZ are generally those of sulfa drug: skin rash including Stevens-Johnson syndrome, fever, transaminase level elevation, neutropaenia, thrombocytopaenia, and nephrotoxicity.
If patients develop mild or moderate hypersensitivity reaction to TMP-SMX, strategies include continuing the drug (treating-through) or reintroducing the drug at a later date by desensitisation. Desensitisation is contraindicated in those with a history of life-threatening reaction to TMP-SMX e.g. Steven-Johnson Syndrome.
The widespread use of TMP-SMX for PCP prophylaxis has raised concerns over potential TMP-SMX drug resistance. Owing to the inability to culture Pneumocystis, researchers have performed genotypic testing to detect mutations within the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes, the enzymatic targets of trimethoprim and sulfa (sulfamethoxazole and dapsone) drugs respectively. Todate there have been more studies examining the incidence and clinical correlation of DHPS mutations in patients with PCP. These studies reported a wide range of frequency of DHPS mutations (from 3.7 to 81%) which were significantly associated with sulfa (sulfamethoxazole or dapsone) use as part of PCP prophylaxis. However, studies did not consistently demonstrate the association between DHPS mutations and poor clinical outcomes in HIV-infected persons with PCP.
Clindamycin-primaquine. The combination of clindamycin and primaquine is effective in patients with mild to moderate infection. No significant differences were observed among treatment groups consisting of AIDS patients receiving TMP-SMZ or clindamycin-primaquine for mild to moderate PCP in terms of survival, toxicity or treatment failure. No prospective clinical trials have evaluated the optimal approach to patients who experience therapy failure with TMP-SMX. However a meta-analysis reported that second-line treatment with clindamycin-primaquine in patients who failed or developed toxicity to first-line therapy was associated with a more favourable outcome compared with intravenous pentamidine. This combination was better tolerated than intravenous pentamidine too. Therefore, many clinicians prefer clindamycin-primaquine as an alternative regimen for patients with moderate to severe PCP. The main toxicities of clindamycin include rash (16%), methaemoglobinaemia, anaemia, neutropaenia, and the development of Clostridium difficile colitis. G6PD status should be tested whenever possible before administration of primaquine.
Pentamidine is the main alternative parenteral agent for the treatment of PCP. It achieves therapeutic levels in the lungs slowly (5 to 7 days) due to high levels of extrapulmonary tissue binding. Slow accumulation of pentamidine in pulmonary tissue may account for the delayed onset of activity when compared with TMP-SMZ. Pentamidine is useful for infection in patients with adverse reactions to TMP or sulfonamides. It should be noted however that aerosolised pentamidine is less effective and may result in more frequent treatment relapse than intravenous pentamidine for the treatment of PCP. Side effects of intravenous pentamidine include transient hypoglycaemia, pancreatitis, diabetes, pancytopaenia, hypotension, and renal dysfunction. These side effects occur more frequently in patients with existing renal impairment. Renal function, electrolytes, blood glucose and blood pressure should be monitored closely during therapy. Due to its toxicities, it is recommended to consider switching to a safer regimen when patients’ condition improved clinically.
Dapsone-trimethoprim. Dapsone in combination with TMP is an effective oral therapy for mild to moderate PCP. The efficacy of dapsone-trimethoprim is similar to that of TMP-SMZ, but dapsone-trimethoprim was reported to be associated with a lower frequency of major toxicities (30% compared with 57%). In a subsequent randomised trial, however, the rates of dose-limiting toxicity among patients receiving these regimens were similar. Toxicities include neutropaenia, anaemia, fever, haemolysis in patients with G6PD deficiency, rash and hepatitis.
Atovaquone is approved by the US FDA for the treatment of mild to moderately severe PCP. Side effects are relatively uncommon and are generally mild. It has been reported that up to 7% of HIV-infected patients develop dose-limiting toxicity while on atovaquone (versus 20% for those on TMP-SMZ therapy). However, significantly more patients on atovaquone failed therapy compared to TMP-SMZ. Toxic effects include rash, diarrhoea, nausea, vomiting, fever, and deranged liver function.
Studies have shown that the concurrent use of corticosteroids with anti-Pneumocystis treatment can prevent deterioration in oxygenation, intubation and mortality (50% reduction). Steroid therapy is recommended in patients with moderate-to-severe PCP. Criteria include a partial arterial O2 pressure (PaO2) of less than 70 mmHg in room air or an alveolar-arterial oxygen gradient of greater than 35 mmHg. Gradual tapering of dosage (usually over 2 weeks) is necessary to avoid relapse of pulmonary inflammation. Adverse drug reactions and complications of steroid therapy are relatively rare.
Box 25.1. Treatment of PCP
Trimethoprim 15-20 mg/kg/day + sulfamethoxazole 75-100 mg/kg/day PO or IV x 21 days in 3-4 divided doses
Clindamycin 600 mg IV q8h or 300-450 mg PO q6h + primaquine 30 mg base/day PO x 21 days
Trimethoprim 15 mg/kg/day PO + dapsone 100 mg/day x 21 days
Pentamidine 4 mg/kg/day IV x 21 days
Atovaquone 750 mg suspension PO bid
Corticosteroids (for moderate to severe disease)
Prednisolone 40 mg bid x 5 days, then 40 mg qd x 5 days, then 20 mg qd x 11 days
Response to therapy and HAART-related issues
Response to therapy is generally excellent in patients whose infection is diagnosed prior to respiratory failure. Failure to observe clinical improvement by day 4 to 5 (for those receiving TMP-SMZ) or day 5 to 7 (for those receiving pentamidine) should warrant a search for other pathology. The optimal duration of therapy has not been evaluated, but the general recommendation is 21 days. Residual viable organisms may persist after treatment for up to a year.
Treatment failure with a recommended regimen is uncommon. While some patients may do better on one agent instead of another, it is commoner to discover a second process (new infection, allergy, adult respiratory distress syndrome, immune reconstitution inflammatory syndrome (IRIS) [Chapter C17]) complicating PCP than resistance that has emerged. The chest radiograph is less reliable than the level of arterial blood oxygenation as an indicator of treatment failure.
The optimum timing to initiate HAART in patients with PCP who are treatment naive have been evaluated in both observational studies and randomised controlled trials. The collective findings of these trials concluded that patients with CD4 cell counts less than 200/μL who started HAART within the first 2 weeks of treatment for opportunistic infections including PCP had lower mortality compared to patients starting treatment at later time-points. However it is important to be aware that early initiation of HAART is associated with the risk of IRIS, complex drug interactions and overlapping toxicities, and a high pill burden. Patients should be closely monitored for treatment efficacy and toxicities.
IRIS can occur in patients with PCP though only limited data are available. There were case reports of transient clinical deterioration in patients with confirmed PCP soon after the introduction of HAART (3 to 17 days). In these cases, patients initially responded to PCP treatment but developed acute respiratory failure shortly after the initiation of antiretroviral therapy. They normally improved after systemic steroid.
PCP Prophylaxis [Algorithm 25B]
HIV-infected patients should receive primary prophylaxis against PCP if they have a CD4+ T-lymphocyte count <200 cells/μL or a history of oropharyngeal candidiasis. Patients who have a history of PCP should be put on secondary prophylaxis (chronic maintenance therapy) for life unless immune reconstitution occurs as a result of HAART.
Regimens for prophylaxis
TMP-SMZ is the first choice for the prevention of PCP. Alternative prophylactic regimens are available for patients intolerant of TMP-SMZ.
- A variety of prophylactic regimens for TMP-SMZ have been studied. There is no difference between single- and double-strength TMP-SMZ in reducing mortality (12% versus 15%). No new PCP was observed in either group when the patients were compliant with treatment. Intermittent therapy (double strength TMP-SMZ 3 times per week) has also been found to be equally effective. Toxicities of TMP-SMZ generally occur within the first month of chemoprophylaxis unless they are masked by immune suppression. AIDS patients with mild adverse effects often tolerate the reintroduction of the drugs at a lower dose after resolution of symptoms (such as rash). Rapid oral desensitisation is possible and is well tolerated in up to 86% of patients tested in small series.
- Pentamidine aerosol prophylaxis is effective when it is administered by experienced personnel with a nebuliser (e.g. Fisons or Respirgard II) which produces droplets in the 1- to 3-mm range. Breakthrough infection is seen in 10 to 23% of compliant patients, most often in those with rapidly progressive AIDS or CD4 counts less than 50/μL. As aerosolised drug may not reach the upper lobes, breakthrough infection of the upper lobes has been more commonly observed. Side effects of aerosolised pentamidine are usually minimal. Cough and bronchospasm are common and are generally reversible with bronchodilator therapy.
- Dapsone was shown to be as effective as TMP-SMZ for PCP prophylaxis if use in high dose (50-100mg/day) but not in lower dose (equivalent of 25mg/day) in a meta-analysis of 35 randomised trials. TMP-SMZ and dapsone have similar anti-Toxoplasma efficacies. One major concern on the use of dapsone for prophylaxis is the Dapsone Hypersensitivity Syndrome (DHS), which develops in about 0.5-3.6% of individuals using dapsone. DHS is characterised by the development of fever, rash and multi-organ involvement, usually 4-6 weeks after the initiation of dapsone and is a life-threatening condition with mortality up to 9.9%. Study has identified the association of HLA-B*1301 and DHS among Chinese patients with leprosy. The frequency of this allele varies across ethnic populations, with rate lowest (0%) in European and African and highest (28%) among Papuan and Australian, whereas the rate in Northern China is 2-5% and southern China it’s 5-20%. The incidence of intolerance to dapsone is roughly equivalent to that to TMP-SMZ (65 to 70%). Switching from TMP-SMZ to dapsone cannot be recommended for individuals with severe side effects including desquamation, neutropaenia, severe nephritis, or hepatitis or in patients with documented G6PD deficiency.
Discontinuation of prophylaxis
Primary and secondary PCP prophylaxis can be discontinued in patients who have responded to HAART with an increase of CD4+ count to >200/μL for at least 3 months. Studies have confirmed the safety of the recommended practice. Besides, discontinuation of prophylaxis can reduce pill burden, potential toxicity and interactions, and selection of drug-resistant pathogens. Prophylaxis should be reintroduced if CD4 count drops below 200/μL.
Emerging data suggest that PCP incidence is low in HIV-infected persons with CD4 cell counts between 100 to 200/μL but with fully suppressed HIV RNA levels, suggesting that it may be safe to stop prophylaxis earlier in such situation, though additional data are needed.
Algorithm 25A. Diagnosis and treatment of PCP
Algorithm 25B. PCP prophylaxis
- Buchacz K, Baker RK, Palella FJ Jr, Chmiel JS, Lichtenstein KA, Novak RM, Wood KC, Brooks JT; HOPS Investigators. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study. AIDS 2010;24(10):1549-59. link
- Wolff AJ, O’Donnell AE. Pulmonary manifestations of HIV infection in the era of highly active antiretroviral therapy. Chest 2001;120(6):1888-93. link
- Fei MW, Kim EJ, Sant CA, Jarlsberg LG, Davis JL, Swartzman A, Huang L. Predicting mortality from HIV-associated Pneumocystis pneumonia at illness presentation: an observational cohort study. Thorax 2009;64(12):1070-6. link
- To KK, Wong SC, Xu T, Poon RW, Mok KY, Chan JF, Cheng VC, Chan KH, Hung IF, Yuen KY. Use of nasopharyngeal aspirate for diagnosis of pneumocystis pneumonia. J Clin Microbiol 2013;51(5):1570-4. link
- Fischer S, Gill VJ, Kovacs J, Miele P, Keary J, Silcott V, Huang S, Borio L, Stock F, Fahle G, Brown D, Hahn B, Townley E, Lucey D, Masur H. 2001. The use of oral washes to diagnose Pneumocystis carinii pneumonia: a blinded prospective study using a polymerase chain reaction-based detection system. J Infect Dis 2001;184:1485-1488. link
- Alanio A, Desoubeaux G, Sarfati C, Hamane S, Bergeron A, Azoulay E, Molina JM, Derouin F, Menotti J. Real-time PCR assay-based strategy for differentiation between active Pneumocystis jirovecii pneumonia and colonization in immunocompromised patients. Clin Microbiol Infect 2011;17(10):1531-7. link
- Onishi A, Sugiyama D, Kogata Y, Saegusa J, Sugimoto T, Kawano S, Morinobu A, Nishimura K, Kumagai S. Diagnostic accuracy of serum 1,3-β-D-glucan for Pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol 2012;50(1):7-15. link
- Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, Cheung T, Soeiro R, Hojczyk P, Black JR. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group. Ann Intern Med 1996;124(9):792-802. link
- 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 Acquir Immune Defic Syndr 2008;48(1):63-7. link
- Medina I, Mills J, Leoung G, Hopewell PC, Lee B, Modin G, Benowitz N, Wofsy CB. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med 1990;323(12):776-82. link
- Lawn SD, Török ME, Wood R. Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections. Curr Opin Infect Dis 2011;24(1):34-42. link
- Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H; Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58(RR-4):1-207. link
- 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(2):177-88. link
- Zhang FR, Liu H, Irwanto A, Fu XA, Li Y, Yu GQ, Yu YX, Chen MF, Low HQ, Li JH, Bao FF, Foo JN, Bei JX, Jia XM, Liu J, Liany H, Wang N, Niu GY, Wang ZZ, Shi BQ, Tian HQ, Liu HX, Ma SS, Zhou Y, You JB, Yang Q, Wang C, Chu TS, Liu DC, Yu XL, Sun YH, Ning Y, Wei ZH, Chen SL, Chen XC, Zhang ZX, Liu YX, Pulit SL, Wu WB, Zheng ZY, Yang RD, Long H, Liu ZS, Wang JQ, Li M, Zhang LH, Wang H, Wang LM, Xiao P, Li JL, Huang ZM, Huang JX, Li Z, Liu J, Xiong L, Yang J, Wang XD, Yu DB, Lu XM, Zhou GZ, Yan LB, Shen JP, Zhang GC, Zeng YX, de Bakker PI, Chen SM, Liu JJ. HLA-B*13:01 and the dapsone hypersensitivity syndrome. N Engl J Med 2013;369:1620-1628. link
- Chaiwarith R, Praparattanapan J, Nuntachit N, Kotarathitithum W, Supparatpinyo K. Discontinuation of primary and secondary prophylaxis for opportunistic infections in HIV-infected patients who had CD4+ cell count <200 cells/mm(3) but undetectable plasma HIV-1 RNA: an open-label randomized controlled trial. AIDS Patient Care STDS 2013;27(2):71?76.