Pneumocystis jirovecii pneumonia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pneumocystis pneumonia (PCP) is a form of pneumonia caused by the yeast-like fungal Pneumocystis jirovecii (Jirovecii is pronounced “yee row vet zee eye”). The causal agent was originally described as a protozoan and spelled P. jiroveci and prior to then was classified as a form of Pneumocystis carinii, a name still in common usage.^[1][2] These names are discussed below. As a result, Pneumocystis pneumonia (PCP) has also been known as Pneumocystis jiroveci[i] pneumonia and as Pneumocystis carinii pneumonia, as is also explained below.^[3][4][5]

It is relatively rare in people with normal immune systems but common among people with weakened immune systems, such as premature or severely malnourished children, the elderly, and especially AIDS patients, in whom it is most commonly observed today.^[6] PCP can also develop in patients who are taking immunosuppressant medications (e.g. patients who have undergone solid organ transplantation) and in patients who have undergone bone marrow transplantation.

The organism is distributed worldwide^[7].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The earliest report of this genus appears to have been that of Carlos Chagas in 1909^[1] who discovered it in experimental animals but confused it with part of the life-cycle of Trypanosoma cruzi (causal agent of Chagas Disease) and later called both organisms ‘Schizotrypanum cruzi’ a form of trypanosome infecting humans.^[2] The rediscovery of Pneumocystis cysts was reported by Antonio Carini in 1910 also in Brazil.^[3] The genus was again discovered in 1912 by Delanoë and Delanoë this time at the Pasteur Institute in Paris, France who found it in rats and who proposed the genus and species name Pneumocystis carinii after Carini.^[4]

Pneumocystis was redescribed as a human pathogen in 1942 by two Dutch investigators, van der Meer and Brug who found it in three new cases: a 3-month-old infant with congenital heart disease and in 2 of 104 autopsy cases – a 4-month-old infant and a 21-year-old adult.^[5] There being only one described species in the genus, they considered the human parasite to be P. carinii. Nine years later (1951) Dr. Josef Vanek at Charles University in Prague in Prague, Czechoslovakia showed in a study of lung sections from sixteen children that the organism labelled “P. carinii” was the causative agent of pneumonia in these children.^[6] The following year (1952) Jírovec reported “P. carinii” as the cause of interstitial pneumonia in neonates.^[7][8][9] Following the realization that Pneumocystis from humans could not infect experimental animals such as rats, and that the rat form of Pneumocystis differed physiologically and had different antigenic properties, Frenkel^[10] was the first to recognize the human pathogen as a distinct species. He named it Pneumocystis jirovecii (see nomenclature above). There has been controversy over the relabeling of P. carinii in humans as P. jirovecii,^[11] which is why both names still appear in publications. However, only the name P. jirovecii is used exclusively for the human pathogen, whereas the name P. carinii has had a broader application to many species.^[12] Frenkel and those before him, believed that all Pneumocystis were protozoans, but soon afterwards evidence began accumulating that Pneumocystis was a fungal genus. Recent studies show it to be an unusual, in some ways a primitive genus of Ascomycota, related to a group of yeasts.^[13] Every tested primate, including humans, appears to have their own type of Pneumocystis that is incapable of cross-infecting other host species and has co-evolved with each mammal species.^[14] Currently only 5 species have been formally named: P. jirovecii from humans, P. carinii as originally named from rats, P. murina from mice,^[15] P. wakefieldiae^[16][17] also from rats, and P. oryctolagi from rabbits.^[18]

Historical and even recent reports of P. carinii from humans are based upon older classifications (still used by many, or those still debating the recognition of distinct species in the genus Pneumocystis) which does not mean that the true P. carinii from rats actually infects humans. In an intermediate classification system, the various taxa in different mammals have been called formae speciales or forms. For example the human “form” was called Pneumocystis carinii f. [or f. sp.] hominis, while the original rat infecting form was called Pneumocystis carinii f. [or f. sp.] carinii. This terminology is still used by some researchers. The species of Pneumocystis species originally seen by Chagas have not yet been named as distinct species. Many other undescribed species presumably exist and those that have been detected in many mammals are only known from molecular sample detection from lung tissue or fluids, rather than by direct physical observation.^[19] As of yet, they are cryptic taxa.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The name P. jirovecii, to distinguish the organism found in humans from physiological variants of Pneumocystis found in other animals, was first proposed in 1976, in honor of Otto Jirovec, who described Pneumocystis pneumonia in humans in 1952. After DNA analysis showed significant differences in the human variant, the proposal was made again in 1999 and has come into common use; P. carinii still describes the species found in rats^[1] and that name is typified by an isolate from rats.^[2] The International Code of Botanical Nomenclature (ICBN) requires that the name to be spelled jirovecii rather than jiroveci. The latter spelling originated when Pneumocystis was believed to be a protozoan, rather than a fungus, and therefore was spelled using the International Code of Zoological Nomenclature; both spellings are commonly used. A change in the ICBN in 2005 now recognizes the validity of the 1976 publication, making the 1999 proposal redundant, and cites Pneumocystis and P. jirovecii as examples of the change in ICBN Article 45, Ex 8. The name P. jirovecii is typified (both lectotypified and epitypified) by samples from human autopsies dating from the 1960s.^[2]

The term PCP, which was widely used by practitioners and patients, has been retained for convenience, with the rationale that it now stands for the more general Pneumocystis pneumonia rather than Pneumocystis carinii pneumonia.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pneumocystis jirovecii (previously classified as Pneumocystis carinii) was previously classified as a protozoa. Currently, it is considered a fungus based on nucleic acid and biochemical analysis.

The risk of pneumonia due to pneumocystis jirovecii increases when CD4 levels are less than 200 cells/μl. In these immunosuppressed individuals the manifestations of the infection are highly variable.^[1] The disease attacks the interstitial, fibrous tissue of the lungs, with marked thickening of the alveolar septa and alveoli and leading to significant hypoxia which can be fatal if not treated aggressively; ergo, LDH levels increase and gas exchange is compromised. Oxygen is less able to diffuse into the blood, leading to hypoxia. Hypoxia, along with high arterial carbon dioxide (CO₂) levels, stimulates ventilation, thereby causing dyspnea.

The complete life-cycles of any of the species of Pneumocystis are not known, but presumably all resemble the others in the genus. The terminology follows zoological terms, rather than mycological terms, reflecting the initial misdetermination as a protozoan parasite. All stages are found in lungs and because they cannot be cultured, direct observation of living Pneumocystis is difficult. The trophozoite stage is the vegetative state. It is single-celled and appears amoeboid (multilobed) and closely associated with host cells. Globular cysts eventually form that have a thicker wall. Within these ascus-like cysts, eight spores form which are released through rupture of the cyst wall. The cysts often collapse forming crescent-shaped bodies visible in stained tissue. It is not known for certain if meiosis takes place within the cysts, or what the genetic status is of the various cell types – see DPDx life-cycle diagram.

This is a generalized life cycle proposed by John J. Ruffolo, Ph.D. (Cushion, MT, 1988) for the various species of Pneumocystis. These fungi are found in the lungs of mammals where they reside without causing overt infection until the host’s immune system becomes debilitated. Then, an oftentimes lethal pneumonia can result. 1 Asexual phase: trophic forms replicate by mitosis 2 to 3. Sexual phase: haploid trophic forms conjugate 1 and produce a zygote or sporocyte (early cyst) 2. The zygote undergoes meiosis and subsequent mitosis to produce eight haploid nuclei (late phase cyst) 3. Spores exhibit different shapes (such as, spherical and elongated forms). It is postulated that elongation of the spores precedes release from the spore case. It is believed that the release occurs through a rent in the cell wall. After release, the empty spore case usually collapses, but retains some residual cytoplasm 4. A trophic stage, where the organisms probably multiply by binary fission is also recognized to exist. The organism causes disease in immunosuppressed individuals.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pneumocystis jirovecii is a yeast-like fungus of the genus Pneumocystis. The causative organism of Pneumocystis pneumonia, it is an important human pathogen, particularly among immunocompromised hosts. Prior to its discovery as a human-specific pathogen, P. jirovecii was known as P. carinii.

The complete lifecycles of any of the species of Pneumocystis are not known, but presumably all resemble the others in the genus. The terminology follows zoological terms, rather than mycological terms, reflecting the initial misdetermination as a protozoan parasite. It is an extracellular parasite. All stages are found in lungs and because they cannot be cultured ex vivo, direct observation of living Pneumocystis is difficult. The trophozoite stage is thought to be equivalent to the so-called vegetative state of other species (such as Schizosaccharomyces pombe) which, like Pneumocystis belong to the Taphrinomycotina branch of the fungal kingdom.^[1] The trophozoite stage is single-celled and appears amoeboid (multilobed) and closely associated with host cells. Globular cysts eventually form that have a thicker wall. Within these ascus-like cysts, eight spores form which are released through rupture of the cyst wall. The cysts often collapse forming crescent-shaped bodies visible in stained tissue. It is not known for certain if meiosis takes place within the cysts, or what the genetic status is of the various cell types.^[2]

Pneumocystis pneumonia is an important disease of immunocompromised humans, particularly patients with HIV, but also patients with an immune system that is severely suppressed for other reasons; for example, following a bone marrow transplant. In humans with a normal immune system, it is an extremely common silent infection.^[3]

Identified by methenamine silver stain of lung tissue. Type I pneumocytes, so Type II pneumocytes overreplicate and damage alveolar epithelium, causing death by asphyxiation. Fluid leaks into alveoli producing an exudate seen as honeycomb/cotton candy appearance on hematoxylin and eosin stained slides. Drug of choice is TMP-SMX, pentamidine, or dapsone. In HIV patients, most cases occur when the CD4 count is below 200 cells per microliter.

At first, the name Pneumocystis carinii was applied to the organisms found in both rats and humans, as it was not yet known that the parasite was host-specific. In 1976 the name “Pneumocystis jiroveci” was proposed for the first time, to distinguish the organism found in humans from variants of Pneumocystis in other animals. The organism was named thus in honor of Czech parasitologist Otto Jirovec, who described Pneumocystis pneumonia in humans in 1952. After DNA analysis showed significant differences in the human variant, the proposal was made again in 1999 and has come into common use.^[4]

The name was spelled according to the International Code of Zoological Nomenclature, since the organism was believed to be a protozoan. After it became clear that it was a fungus, the name was changed to Pneumocystis jirovecii,^[5] according to the International Code of Nomenclature for algae, fungi, and plants (ICNafp), which requires such names be spelled with double i (ii).^[6] Both spellings are commonly used, but according to the IBNafp P. jirovecii is correct.^[7] A change in the ICNafp now recognizes the validity of the 1976 publication, making the 1999 proposal redundant, and cites Pneumocystis and P. jirovecii as examples of the change in ICN Article 45, Ex 7. The name P. jirovecii is typified (both lectotypified and epitypified) by samples from human autopsies dating from the 1960s. ^[8]

The term PCP, which was widely used by practitioners and patients, has been retained for convenience, with the rationale that it now stands for the more general Pneumocystis pneumonia rather than Pneumocystis carinii pneumonia.

The name P. carinii is incorrect for the human variant, but still describes the species found in rats and that name is typified by an isolate from rats.^[8]

Pneumocystis species cannot be grown in culture. Therefore, there is a limitation to the availability of the human disease causing agent, P. jirovecii. Hence, investigation of the whole genome of a Pneumocystis is largely based upon true P. carinii available from experimental rats which can be maintained with infections. Genetic material of other species, such as P. jirovecii can be compared to the genome of P. carinii.^[9]

The genome of P. jirovecii has been sequenced from a bronchoalveolar lavage sample.^[10] The genome is small, low in G+C content and lacks most amino acid biosynthesis enzymes.

The earliest report of this genus appears to have been that of Carlos Chagas in 1909^[11] who discovered it in experimental animals but confused it with part of the life-cycle of Trypanosoma cruzi (causal agent of Chagas disease) and later called both organisms ‘Schizotrypanum cruzi’ a form of trypanosome infecting humans.^[12] The rediscovery of Pneumocystis cysts was reported by Antonio Carini in 1910 also in Brazil.^[13] The genus was again discovered in 1912 by Delanoë and Delanoë this time at the Pasteur Institute in Paris, France who found it in rats and who proposed the genus and species name Pneumocystis carinii after Carini.^[14]

Pneumocystis was redescribed as a human pathogen in 1942 by two Dutch investigators, van der Meer and Brug who found it in three new cases: a 3-month-old infant with congenital heart disease and in 2 of 104 autopsy cases – a 4-month-old infant and a 21-year-old adult.^[15] There being only one described species in the genus, they considered the human parasite to be P. carinii. Nine years later (1951) Dr. Josef Vanek at Charles University in Prague in Prague, Czechoslovakia showed in a study of lung sections from sixteen children that the organism labelled “P. carinii” was the causative agent of pneumonia in these children.^[16] The following year (1952) Jírovec reported “P. carinii” as the cause of interstitial pneumonia in neonates.^[17][18][19] Following the realization that Pneumocystis from humans could not infect experimental animals such as rats, and that the rat form of Pneumocystis differed physiologically and had different antigenic properties, Frenkel^[20] was the first to recognize the human pathogen as a distinct species. He named it “Pneumocystis jiroveci” (corrected to P. jirovecii – see nomenclature above). There has been controversy over the relabeling of P. carinii in humans as P. jirovecii,^[8][21] which is why both names still appear in publications. However, only the name P. jirovecii is used exclusively for the human pathogen, whereas the name P. carinii has had a broader application to many species.^[22] Frenkel and those before him believed that all Pneumocystis were protozoans, but soon afterwards evidence began accumulating that Pneumocystis was a fungal genus. Recent studies show it to be an unusual, in some ways a primitive genus of Ascomycota, related to a group of yeasts.^[1] Every tested primate, including humans, appears to have its own type of Pneumocystis that is incapable of cross-infecting other host species and has co-evolved with each mammal species.^[23] Currently only 5 species have been formally named: P. jirovecii from humans, P. carinii as originally named from rats, P. murina from mice,^[24] P. wakefieldiae^[25][26] also from rats, and P. oryctolagi from rabbits.^[27]

Historical and even recent reports of P. carinii from humans are based upon older classifications (still used by many, or those still debating the recognition of distinct species in the genus Pneumocystis) which does not mean that the true P. carinii from rats actually infects humans. In an intermediate classification system, the various taxa in different mammals have been called formae speciales or forms. For example the human “form” was called Pneumocystis carinii f. [or f. sp.] hominis, while the original rat infecting form was called Pneumocystis carinii f. [or f. sp.] carinii. This terminology is still used by some researchers. The species of Pneumocystis originally seen by Chagas have not yet been named as distinct species.^[8] Many other undescribed species presumably exist and those that have been detected in many mammals are only known from molecular sample detection from lung tissue or fluids, rather than by direct physical observation.^[28][29] Currently, they are cryptic taxa.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pneumocystis jirovecii pneumonia exists worldwide, in humans and animals. Serologic evidence indicates that most healthy children have been exposed by age 3 to 4. Pneumocystis pneumonia (PCP) occurs in immunosuppressed individuals and in premature, malnourished infants.

Pneumocystis pneumonia has been described in all continents except Antarctica.^[1] It was originally described as a rare cause of pneumonia in neonates. It is believed to be an environmental organism, and human-to-human transmission is thought not to occur (although in one outbreak of 12 cases among transplant patients in Leiden it was postulated, but not proven, that human-to-human spread may have occurred).^[2] Greater than 75% of children are seropositive by the age of 4, which suggest a high background exposure to the organism.

The disease PCP is relatively rare in people with normal immune systems, but common among people with weakened immune systems, such as premature or severely malnourished children, the elderly, and especially persons living with HIV/AIDS, in whom it is most commonly observed.^[3] PCP can also develop in patients who are taking immunosuppressive medications. It can occur in patients who have undergone solid organ transplantation or bone marrow transplantation and after surgery.^[4] Infections with Pneumocystis pneumonia are also common in infants with hyper IgM syndrome, an X-linked or autosomal recessive trait.

The causative organism of PCP is distributed worldwide^[1] and Pneumocystis pneumonia has been described in all continents except Antarctica.^[1] Greater than 75% of children are seropositive by the age of 4, which suggest a high background exposure to the organism. A post-mortem study conducted in Chile of 96 persons who died of unrelated causes (suicide, traffic accidents, and so forth) found that 65 (68%) of them had pneumocystis in their lungs, which suggests that asymptomatic pneumocystis infection is extremely common.^[5]

Pneumocystis jirovecii was originally described as a rare cause of pneumonia in neonates. It is commonly believed to be a commensal organism (dependent upon its human host for survival). The possibility of person-to-person transmission has recently gained credence, with supporting evidence coming from many different genotyping studies of Pneumocystis jirovecii isolates from human lung tissue.^[6][7] For example, in one outbreak of 12 cases among transplant patients in Leiden, it was suggested as likely, but not proven, that human-to-human spread may have occurred.^[8]

Since the start of the AIDS epidemic, PCP has been closely associated with AIDS. Because it only occurs in an immunocompromised host, it may be the first clue to a new AIDS diagnosis if the patient has no other reason to be immunocompromised (e.g. taking immunosuppressive drugs for organ transplant). An unusual rise in the number of PCP cases in North America, noticed when physicians began requesting large quantities of the rarely used antibiotic pentamidine, was the first clue to the existence of AIDS in the early 1980s.^[9][10]

Prior to the development of more effective treatments, PCP was a common and rapid cause of death in persons living with AIDS. Much of the incidence of PCP has been reduced by instituting a standard practice of using oral co-trimoxazole to prevent the disease in people with CD4 counts less than 200/mm³. In populations that do not have access to preventive treatment, PCP continues to be a major cause of death in AIDS.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

This type of pneumonia is caused by the fungus Pneumocystis jiroveci. This fungus is common in the environment and does not cause illness in healthy people. However, it can cause a lung infection in people with a weakened immune system due to:

• Cancer
• Chronic use of corticosteroids or other medications that weaken the immune system
• HIV/AIDS
• Organ or bone marrow transplant

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Pneumocystis pneumonia can be life threatening, causing respiratory failure that can lead to death. People with this condition need early and effective treatment. For moderate to severe pneumocystis pneumonia in people with AIDS, the short term use of corticosteroids has decreased death.

• Pleural effusion (extremely rare)
• Pneumothorax (collapsed lung)
• Respiratory failure (may require breathing support)

Typically, in untreated PCP increasing pulmonary involvement leads to death.

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