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Pneumocystis Jirovecii Pneumonia

Synonym: pneumocystosis
Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality among
immunocompromised people. It remains a leading AIDS-defining opportunistic infection in HIVinfected individuals. [1] Pneumocystis is primarily a pulmonary pathogen but extrapulmonary
disease occurs in about 1% of cases.
Pneumocystis organisms from different host species have very different DNA sequences,
indicating multiple species. Because of the genetic and functional distinctness, the organism
that causes human PCP (formerly known as Pneumocystis carinii) is now named
Pneumocystis jirovecii. [2]
P. jirovecii is a unicellular eukaryote which shares characteristics with both protozoa and
fungi.

Epidemiology
The background rate of infection in the general population is extremely low at less than 1 case per
million population per year.
When HIV was first characterised, PCP affected up to 75% of HIV-infected individuals. Current
rates of infection in the HIV-positive population in the developed world are about 1020%.
The incidence of PCP in HIV-positive patients has been significantly reduced by prophylactic
medication and highly active antiretroviral therapy (HAART). [3]
In the developing world, rates of PCP are lower, possibly due to poor survival with HIV,
underdiagnosis and prior pulmonary infection with TB and other organisms.

Risk factors
PCP tends to affect HIV positive patients who have a CD4 count below 200 cells/mm 3
HIV patients with oral thrush or fever, or AIDS-defining diagnosis
Patients taking steroids or other immunosuppressants
Patients with haematological malignancy
Organ-transplant recipients
Congenital immune deficiency, eg thymic aplasia, severe combined immune deficiency (SCID),
hypogammaglobulinaemia
Severe malnutrition (poor nutrition in HIV-positive individuals increases risk)

Presentation
Cough is usually non-productive but productive cough may occur in up to a third of patients
Exertional dyspnoea
Fever
Tachypnoea
Chest pain
There may be signs of AIDS such as thrush, oral hairy leucoplakia or Kaposi's sarcoma
Respiratory examination is highly variable and often normal. Scattered crackles and wheeze may
be present, or rarely signs of focal consolidation
Pulse oximetry may show low SaO 2 at rest

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may show low SaO 2 at rest
Extrapulmonary disease may manifest as hepatosplenomegaly, lymphadenopathy or ocular
disease

Differential diagnosis
Bacterial or viral pneumonia
Mycobacterium avium-intracellulare complex infection
Atypical pneumonia
Pulmonary Kaposi's sarcoma
Tuberculosis
Influenza
Cytomegalovirus infection
Aspergillosis
Measles
Varicella (chickenpox) pneumonitis
Coxiella burnetii (Q fever)
Thoracic actinomycosis
Pulmonary nocardiosis
Lymphocytic interstitial pneumonia (associated with autoimmune disease)
Pulmonary embolism

Investigations
Bloods:
Elevated lactate dehydrogenase is indicative of the diagnosis but not highly specific or
sensitive.
Arterial blood gases may show hypoxia and hypocarbia due to hyperventilation.
The alveolar-arterial oxygen tension gradient may be increased.
The use of serum (1-->3) beta-D-glucan levels (high in PCP) is currently being
investigated as a diagnostic test. [4]
Radiology:
Chest X-ray can be normal or show perihilar fluffy shadows or pneumothorax.
CT imaging shows ground glass infiltrates but has low sensitivity and specificity.
Gallium scanning is highly sensitive but with low and variable specificity.
Microbiology:
The organism cannot be routinely cultured and is detected by staining of the cyst wall or
trophozoite in sputum samples, usually with silver-based stains. Repeated samples may
need to be taken to confirm the diagnosis.
Sputum may be collected following inhalation of nebulised saline and/or chest
physiotherapy and should also be sent for routine and mycobacterial culture.
If sputum is negative but PCP is still suspected, then bronchoscopy with
bronchoalveolar lavage or transbronchial biopsy may detect the organism.
Open lung biopsy may occasionally be employed.
Pulmonary function tests:
May show a modest reduction in the vital capacity (VC) and the total lung capacity (TLC).
Most consistent abnormality is a decrease in the single-breath diffusing capacity for
carbon monoxide (DLCO), which has a sensitivity of 89%.

Grading of severity [5]

Mild:
Breathlessness on mild exercise, which may be associated with cough and sweats
Arterial blood gases and oxygen saturation at rest, on air: PaO2 >11 kPa; SaO2 >96%
Chest X-ray: normal or minor perihilar infiltrates

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Moderate:
Breathlessness on minimal exercise, fever (with or without sweats)
Arterial blood gases and oxygen saturation at rest, on air: PaO2 811 kPa; SaO2 91-96%
Chest X-ray: diffuse interstitial shadowing
Severe:
Breathlessness at rest, persistent fever and cough
Arterial blood gases and oxygen saturation at rest, on air: PaO2 <8 kPa; SaO2 <91%
Chest X-Ray: extensive interstitial shadowing, with or without alveolar shadowing

Management
Early diagnosis greatly aids successful therapy.
Mild cases may be treated with oral medication as outpatients. Moderate to severe cases usually
require hospitalisation and intravenous therapy.
Treating empirically without confirmation of the diagnosis may be necessary but is best avoided if
possible, due to the danger of missing other causes for the symptoms.
Patients often deteriorate 35 days after starting treatment. This is thought to be due to
inflammation caused by dead pneumocystis organisms.
Treatment is usually given for 23 weeks.

Mild-to-moderate disease
High-dose co-trimoxazole (trimethoprim-sulfamethoxazole) is the drug of choice. Concomitant
host disease influences susceptibility to adverse drug reactions. HIV increases the risk of toxicity
with many drugs including co-trimoxazole. Adverse effects occur in up to 65% of those receiving
the drug and 50% will discontinue treatment. Hypersensitivity reactions are most common in such
patients and include fever and maculopapular rash. Co-trimoxazole is usually well tolerated in
immunocompetent patients [6] but should be avoided in those with severe hepatic or renal
dysfunction and porphyria. It is also best avoided during pregnancy and breast-feeding. Sideeffects are numerous and include nausea, vomiting, skin reactions, neutropenia,
thrombocytopenia, hepatitis and cholestatic jaundice. [7]
Alternatives if the patient is unable to tolerate co-trimoxazole are:
Atovaquone - this has similar efficacy as pentamidine and is better tolerated than
parenteral pentamidine, co-trimoxazole or dapsone. However, oral atovaquone has
limited and unpredictable bioavailability. [8]
Dapsone with trimethoprim - dapsone is given intravenously or occasionally in nebulised
form in the treatment of PCP.
Clindamycin with primaquine - clindamycin is associated with the development of
antibiotic-associated colitis and treatment must be immediately discontinued if diarrhoea
develops.
Inhaled pentamidine isetionate - this is restricted to specialist care, under careful patient
observation and with laboratory monitoring.

Severe disease
Intravenous high-dose co-trimoxazole is first-line treatment but toxic effects mean it may not be
tolerated.
Pentamidine isetionate:
Given by intravenous infusion, is used for patients who either cannot tolerate cotrimoxazole or who have not responded to it.
Can cause severe hypotension during or immediately after infusion; blood pressure and
glucose should be carefully monitored.

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Oral prednisolone or parenteral hydrocortisone:
Steroids are an important adjunctive therapy for patients with moderate-to-severe
infections associated with HIV infection.
Steroids are usually given in high dosage for 5-7 days and then the dose is reduced and
continued for a further two weeks.
Steroid treatment should be started at the same time as the antimicrobial therapy and
withdrawn before antimicrobial treatment is complete.

Trimethoprim and dapsone may be used in combination for mild-to-moderate PCP, although unlicensed. [7]
An alternative regimen should be used in patients with G6PD deficiency. [7]

Drug resistance
Prior to the HIV epidemic, co-trimoxazole was rarely used in developed countries due to concerns
regarding toxicity. Resistance to co-trimoxazole in such countries was therefore very low. However since the
use of co-trimoxazole and dapsone [9] for the treatment and long-term prophylaxis of PCP and
toxoplasmosis, increased levels of resistance have been detected. [10]
A number of single base polymorphisms have been demonstrated in the P. jirovecii nucleotide sequence
that codes for dihydropteroate synthetase. These mutations may affect substrate binding and be
associated with the emergence of resistance to sulphonamides and dapsone. [11] Mutations in the
cytochrome b gene have been demonstrated in atovaquone-resistant P. jirovecii isolates, which are likely to
represent mechanisms of resistance. [8]
Findings linking mortality rates to the acquisition of the mutated P. jirovecii organism are inconsistent, which
is not surprising, since survival in HIV-positive patients depends on many other factors. However, it does
make assessment of the impact of drug resistance in such patients difficult and more research is required
to develop strategies to prevent the emergence of further resistance strains. [1] [9]

The impact of highly active antiretroviral therapy

Before the introduction of HAART, the two-year probability of developing PCP in HIV-positive patients was
40%. HAART has reduced the rate of opportunistic infections and so the absolute benefit of prophylactic
treatment in those taking HAART is less significant. Recent studies have suggested that in HIV patients
taking HAART with CD4 T-cell counts above 200 cells/mm3, discontinuation of prophylaxis does not
increase the incidence of PCP. Current guidelines recommend that persons who meet these criteria can
discontinue PCP prophylaxis and remain off prophylaxis as long as the CD4 T-cell count remains above
200 cells/mm3. [1] For more information see separate article Antiretroviral Agents.

New drugs
New drugs against P. jirovecii are in development. Sordarin derivatives are a novel class of antifungal
compounds that inhibit protein synthesis. Animal models of infection have shown promising activity against
PCP with limited toxicity. Echinocandins and pneumocandins, which inhibit beta-glucan synthesis are also
being investigated. [12] [13] The promise of future new targets is expected with the annotation of the
pneumocystis genome. [14]

Prophylaxis
Drug prophylaxis reduces the incidence of PCP and lengthens the disease-free intervals between
episodes.
It should be considered for:
All patients with a history of the pneumocystis infection.
Severely immunocompromised patients.
All HIV-positive individuals once their CD4 T-cell count falls below 200 cells/mm 3. [7]
Prophylaxis should continue until immunity recovers sufficiently.

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Oral co-trimoxazole by mouth is the drug of choice.
Intermittent inhalation of pentamidine isetionate is used for patients unable to tolerate cotrimoxazole but it doesn't suppress extrapulmonary pneumocystosis.
Dapsone and atovaquone have also been used for prophylaxis.
Patients (particularly children) who start HAART and attain low HIV viral load and improved CD4
counts may have prophylactic therapy safely discontinued. [15] [16]

Complications
Respiratory failure
Acute respiratory distress syndrome
Worsening of condition after starting therapy
Pulmonary cyst formation
Pneumothorax
Haematogenous spread
Extrapulmonary infection (typically affects bone marrow, liver, spleen, lymph nodes, gut and eyes)

Prognosis
The use of HAART has made significant changes to the prognosis of HIV-related pulmonary infections.
Mortality is about 1020% in mild-to-moderate cases, [17] rising to 4050% in patients who require artificial
ventilation. Due to restricted access to optimal medical care, PCP remains a common AIDS-defining illness
in developed nations and is associated with significant morbidity and mortality. [18]

Further reading & references

Bennett NJ et al; Pneumocystis (carinii) jiroveci Pneumonia, eMedicine, Aug 2010
Wilkin A and Feinberg J; Pneumocystis carinii Pneumonia: A Clinical Review.; Am Fam Phys 1999 Oct 15;60(6):1699-1712.
Hoffmann C, Rockstroh JK, Kamps BS; HIV Medicine 2007; 15th edition.
1. Huang L, Morris A, Limper AH, et al; An Official ATS Workshop Summary: Recent advances and future directions in
pneumocystis pneumonia (PCP). Proc Am Thorac Soc. 2006 Nov;3(8):655-64. [abstract]
2. Stringer JR, Beard CB, Miller RF, et al; A new name (Pneumocystis jiroveci) for Pneumocystis from humans. Emerg Infect Dis.
2002 Sep;8(9):891-6. [abstract]
3. Porter K, Fairley CK, Wall PG, et al; AIDS defining diseases in the UK: the impact of PCP prophylaxis and twelve years of
change. Int J STD AIDS. 1996 Jul;7(4):252-7. [abstract]
4. Persat F, Ranque S, Derouin F, et al; Contribution of the (1-->3)-beta-D-glucan assay for diagnosis of invasive fungal J Clin
Microbiol. 2008 Mar;46(3):1009-13. Epub 2007 Dec 26. [abstract]
5. Adler MW (Ed); ABC of AIDS 4th Ed (1997) BMJ Publishing Group ISBN 0-7279-1137-6.
6. Masters PA, O'Bryan TA, Zurlo J, et al; Masters PA, O'Bryan TA, Zurlo J, et al; Trimethoprim-sulfamethoxazole revisited. Arch
Intern Med. 2003 Feb 24;163(4):402-10. [abstract]
7. British National Formulary; login required
8. Baggish AL, Hill DR; Antiparasitic agent atovaquone. Antimicrob Agents Chemother. 2002 May;46(5):1163-73.
9. Miller RF; Pneumocystis carinii infection in non-AIDS patients. Curr Opin Infect Dis. 1999 Aug;12(4):371-7. [abstract]
10. Grimwade K, Gilks C; Cotrimoxazole prophylaxis in adults infected with HIV in low-income countries. Curr Opin Infect Dis. 2001
Oct;14(5):507-12. [abstract]
11. Wakefield A; Pneumocystis carinii. British Medical Bulletin, 2002; 61: 175-188.
12. Martinez A, et al; Activities of sordarins in experimental models of candidiasis, aspergillosis and pneumocystosis. Antimicrob
Agents Chemother, 2000; 44: 33893394.
13. Patel N, Koziel H; Pneumocystis jiroveci pneumonia in adult patients with AIDS: treatment strategies and emerging challenges to
antimicrobial therapy. Treat Respir Med. 2004;3(6):381-97. [abstract]
14. Cushion MT, Walzer PD; Preclinical drug discovery for new anti-pneumocystis compounds. Curr Med Chem. 2009;16(20):251430. [abstract]
15. Esposito S, Bojanin J, Porta A, et al; Discontinuation of secondary prophylaxis for Pneumocystis pneumonia in human
immunodeficiency virus-infected children treated with highly active antiretroviral therapy. Pediatr Infect Dis J. 2005
Dec;24(12):1117-20. [abstract]
16. Urschel S, Ramos J, Mellado M, et al; Withdrawal of Pneumocystis jirovecii prophylaxis in HIV-infected children under highly
active antiretroviral therapy. AIDS. 2005 Dec 2;19(18):2103-8. [abstract]
17. Di Lorenzo G; Update on classic Kaposi sarcoma therapy: new look at an old disease. Crit Rev Oncol Hematol. 2008
Dec;68(3):242-9. Epub 2008 Jul 25. [abstract]
18. Hull MW, Phillips P, Montaner JS; Changing global epidemiology of pulmonary manifestations of HIV/AIDS. Chest. 2008
Dec;134(6):1287-98. [abstract]
Original Author: Dr Colin Tidy

Current Version: Dr Laurence Knott

Peer Reviewer: Prof Cathy Jackson

Last Checked: 14/03/2012

Document ID: 2623 Version: 23

EMIS

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