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Pneumocystis jirovecii Pneumonia

Brijesh Singh Yadav


brijeshbioinfo@gmail.com

Disease Type: Parasitic Disease


Common Name: PCP
Causative Agent: Pneumocystis jirovecii
Disease Discription:
Pneumocystis pneumonia is a form of pneumonia caused by the yeast-like fungus,
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 alsobeen
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][8]

Fig.X-ray of Pneumocystis
jirovecii pneumonia There is
increased white (opacity) in the
lower lungs on both sides,
characteristic of Pneumocystis
pneumonia .
Causes of Disease:

P. carinii, the cause of PCP, usually is classified as a protozoan, although some


investigators consider it more closely related to fungi. The organism exists as a
saprophyte in the lungs of humans and various animals as part of the normal flora in
most healthy people. It becomes an aggressive pathogen in the immunocompromised
patient. Impaired cell-mediated (T-cell) immunity is thought to be more important than
impaired humoral (B-cell) immunity in predisposing the patient to PCP, but the immune
defects involved are poorly understood. P. carinii becomes activated in
immunocompromised patients when the CD4+ T-cell count falls below 200/µl.

P. carinii invades the lungs bilaterally and multiplies extracellularly. As the infestation
grows, alveoli fill with organisms and exudate, impairing gas exchange. The alveoli
hypertrophy and thicken progressively, eventually leading to extensive consolidation.

The primary transmission route seems to be air, although the organism is already present
in most people. The incubation period probably lasts for 4 to 8 weeks.

Risk Factors:

Some patients are at greater risk of developing PCP. These high-risk groups include:

• Premature infants
• Patients with immunodeficiency diseases, including severe combined
immunodeficiency disease (SCID) and acquired immunodeficiency syndrome
(AIDS)
• Patients receiving immunosuppressive drugs, especially cortisone-like drugs
(corticosteroids)
• Patients with protein malnutrition.

AIDS is currently the most common risk factor for PCP in the United States. PCP is,
however, also found in countries with widespread hunger and poor hygiene.

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.[12] 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; therefore, 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.

Causative Agent:
Pathogen Name: Pneumocystis jirovecii
Pathogen Description:
Pneumocystis jirovecii (formerly known as Pneumocystis carinii f. sp. hominis) is the
causative agent of Pneumocystis pneumonia (PCP), one of the most frequent and severe
opportunistic infections in immunocompromised patients . Pneumocystis organisms
represent a large group of species of atypical fungi with universal distribution and
pulmonary tropism, and each species has a strong specificity for a given mammalian host
species.
Taxonoimic Classification:

Kingdom: Fungi
Subkingdom: Dikarya
Phylum: Ascomycota
Subphylum: Taphrinomycotina
Class: Pneumocystidomycetes
Order: Pneumocystidales
Family: Pneumocystidaceae
Genus: Pneumocystis
(Delanoë & Delanoë 1912)
P. jirovecii cysts in tissue

Other Pathogenic speices:


P. carinii
P. jirovecii
P. murina
P. oryctolagi
P. wakefieldiae

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.

Morphology and toxin production:

Pneumocystis Genome Project:

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. The project is described in the
site linked here. Genetic material of other species, such as P. jirovecii can be compared to
the genome of P. carinii. Pneumocystis Genome Project.
History:

The earliest report of this genus appears to have been that of Carlos Chagas in 1909[14]
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.[15] The rediscovery of
Pneumocystis cysts was reported by Antonio Carini in 1910 also in Brazil.[16] 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.[17]

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.[18] 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 Karls-
Universität 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.[19] The following year (1952) Jírovec reported "P. carinii" as the cause of
interstitial pneumonia in neonates.[20][21][22] 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[23]
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,[24][2] 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.[25] 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.[26] 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.[27] Currently only 5 species have been
formally named: P. jirovecii from humans, P. carinii as originally named from rats, P.
murina from mice,[28] P. wakefieldiae[29][30] also from rats, and P. oryctolagi from rabbits.
[31]

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.[2] 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.[32] As of yet, they are cryptic taxa.

Epidemiology:

Pneumocystis pneumonia has been described in all continents except Antarctica.[7] 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).[9] Greater
than 75% of children are seropositive by the age of 4, which suggest a high background
exposure to the organism.

Since the start of the HIV pandemic, 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.[10][11]

Disease Host: Humans and Animals


Disease Transmission:

Life-cycle

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 .

Antipneumocystic medication is used with concomitant steroids in order to avoid


inflammation, which causes an exacerbation of symptoms about four days after treatment
begins if steroids are not used. By far the most commonly used medication is a
combination of trimethoprim and sulfamethoxazole (co-trimoxazole, with the tradenames
Bactrim, Septrin, or Septra), but some patients are unable to tolerate this treatment due to
allergies. Other medications that are used, alone or in combination, include pentamidine,
trimetrexate, dapsone, atovaquone, primaquine, and clindamycin. Treatment is usually for
a period of about 21 days.

Pentamidine is less often used as its major limitation is the high frequency of side effects.
These include acute pancreatitis, renal failure, hepatotoxicity, leukopenia, rash, fever and
hypoglycaemia.
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.
Asexual phase: trophic forms replicate by mitosis to . Sexual phase: haploid
trophic forms conjugate and produce a zygote or sporocyte (early cyst) . The
zygote undergoes meiosis and subsequent mitosis to produce eight haploid nuclei
(late phase cyst) . 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 . A trophic stage, where the organisms probably multiply by
binary fission is also recognized to exist. The organism causes disease in
immunosuppressed individuals.

Signs and symptoms of disease:

Symptoms of PCP include fever, non-productive cough,


shortness of breath (especially on exertion), weight loss and
night sweats. There is usually not a large amount of sputum with PCP unless the patient
has an additional bacterial infection. The fungus can invade other visceral organs, such as
the liver, spleen and kidney, but only in a minority of cases.

X-ray of Pneumocystis jirovecii

Diagnosis:

The diagnosis can be confirmed by


the characteristic appearance of the
chest x-ray which shows widespread
pulmonary infiltrates, and an arterial
oxygen level (pO2) strikingly lower
than would be expected from
symptoms. The diagnosis can be
definitively confirmed by pathologic
identification of the causative
organism in induced sputum or
bronchial washings obtained by
bronchoscopy with coloration by
toluidine blue or
immunofluorescence assay, which
will show characteristic cysts [1].

Pneumocystis infection can also be


diagnosed by immunofluorescent or
histochemical staining of the
specimen, and more recently by
molecular analysis of polymerase
chain reaction products comparing
DNA samples. Notably, simple
molecular detection of Pneumocystis jirovecii in lung fluids does not mean that a person
has Pneumocystis pneumonia or infection by HIV. The fungus appears to be present in
healthy individuals also in the general population.[13]

Treatment:

Antipneumocystic medication is used with concomitant steroids in order to avoid


inflammation, which causes an exacerbation of symptoms about four days after treatment
begins if steroids are not used. By far the most commonly used medication is a
combination of trimethoprim and sulfamethoxazole (co-trimoxazole, with the tradenames
Bactrim, Septrin, or Septra), but some patients are unable to tolerate this treatment due to
allergies. Other medications that are used, alone or in combination, include pentamidine,
trimetrexate, dapsone, atovaquone, primaquine, and clindamycin. Treatment is usually for
a period of about 21 days.

Pentamidine is less often used as its major limitation is the high frequency of side effects.
These include acute pancreatitis, renal failure, hepatotoxicity, leukopenia, rash, fever and
hypoglycaemia.

Prevention of disease:
Lifestyle modifications

Patients who have previously had PCP often experience a recurrence. Healthy lifestyle
choices, including exercising, eating well, and giving up smoking may keep the disease at
bay.

Medications

For patients at serious risk for PCP infection, low doses of TMP-SMX, given daily or
three times a week, are effective in preventing PCP. The drug is, however, highly toxic.
Researchers are currently evaluating the effectiveness and toxicity of aerosol pentamidine
and dapsone in preventing PCP.

Geographical Distribution:
The organism is distributed worldwide.

Disease Statistics:
Most patients with PCP are between ages 50 and 60. Incidence is equally divided
between men and women. A smoking history doesn’t seem to increase the risk of
developing PCP.

Molecular Evidence of Interhuman Transmission of Pneumocystis Pneumonia


among Renal Transplant Recipients Hospitalized with HIV-Infected Patients
Figure. Pneumocystis jirovecii pneumonia (PCP) cases in HIV-infected patients
(white bars) and in transplant recipients (black bars) at building A of Edouard-
Herriot Hospital. Solid lines show the number of hospital patient-days for
transplant recipients (filled squares), for HIV-infected patients (filled triangles),
and for the patients during their PCP episode (crosses), as well as the num-ber of
renal transplantations performed (white squares). HAART, highly active
antiretroviral therapy.
Figure. Frequency distribution of Pneumocystis jirovecii types observed
in different cities and hospitals. Each type was considered as one isolate.
The number of isolates followed by the number of specimens analyzed are
indicated in the parenthesis for each geographic location. Data from
Switzerland and other European cities are reproduced with permission
from Hauser et al. 2001, AIDS 15(4):461-6 (27).
Figure. Frequency distribution of Pneumocystis jirovecii types observed
in 30 HIV-infected patients and nine renal transplant recipients from 1994
through 1996 at building A of the Edouard-Herriot Hospital.
Figure . Potential encounters compatible with nosocomial interhuman
transmission of Pneumocystis jirovecii at building A of the Edouard-
Herriot Hospital (see Methods). Thicker parts of solid lines rep-resent
periods of hospitalization. Each encounter or consecutive encounters are
figured by an arrow with the head indicat-ing the direction of the
presumed trans-mission, the number of encounters being indicated close to
each arrow. *Anti-PCP prophylaxis was suboptimal. D, death. G, graft. R,
rejection episode. RTR, renal transplant recipient. PCPnoso, nosocomi-al
case.

Refrence:

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