Abstract

Objective.—To review and update the literature on current trends with regard to Pneumocystis carinii (jiroveci ) diagnosis, treatment modalities, and its role in human disease processes.

Data Sources.—Bibliographic databases (PubMed and Ovid) were searched for material and data between 1980 and September 2003 relevant to the review. Indexing terms used were “Pneumocystis carinii pneumonia,” and “Pneumocystis jiroveci,” with the English language as a constraint. Other sources were the PhD thesis of one of the authors (J.F.W., London University, 1993) and the library at the Arabian Gulf University in the Kingdom of Bahrain.

Study Selection.—Acquired immunodeficiency syndrome and organ transplant cases with Pneumocystis carinii pneumonia.

Data Extraction.—Independent extraction by 2 observers.

Data Synthesis.—We reviewed the major characteristics of P carinii (jiroveci ) with special emphasis on the more recently acquired data including the presence of a round pore in the cyst wall, which appears to be used for the release of sporozoites, supporting the hypothesis of sexual reproduction in P carinii (jiroveci ).

Conclusions.—Opportunistic infection with P carinii (jiroveci ) remains a significant cause of morbidity and mortality in human immunodeficiency virus and non-human immunodeficiency virus–associated immunosuppressed patients. Diagnosis may be achieved in the majority of cases by routine cytochemical stains and specialized techniques such as immunocytochemistry and polymerase chain reaction. The incidence of P carinii pneumonia can significantly be reduced with effective use of prophylaxis and early detection of cases at high risk. Immunization for P carinii pneumonia is in the early stages and presents a challenging area for research.

Pneumocystis carinii is a eukaryotic microorganism that is found worldwide. Its host range is wide and includes humans and other mammals such as rabbits,1 dogs,2 goats,3 swine,4 cats,5 chimpanzees,6 owl monkeys,7 and horses.8 ,Pneumocystis carinii was first described as a developmental stage in the life cycle of Trypanosoma cruzi by Chagas in 19099 but was later recognized as a separate entity.10 It was first shown to cause human disease in 1951. The Pneumocystis organism causing disease in human beings is named Pneumocystis jiroveci.11 

In Europe, an epidemic of interstitial plasma cell pneumonia occurred in premature and malnourished children, particularly those in orphanages in the late 1930s and early 1940s.12 A new epidemic of P. carinii pneumonia was described in the 1960s in children with congenital defects of the immune system and in children and adults with acquired defects secondary to malignancy or its treatment. The relationship of P. carinii pneumonia with immunosuppression was established in organ transplant cases. In the 1980s, P. carinii pneumonia was detected in previously healthy men, which led to a search for an underlying cause of immunosuppression, and the pandemic known as acquired immunodeficiency syndrome (AIDS) was defined. Those most at risk from P carinii pneumonia were identified on the basis of the degree of human immunodeficiency virus (HIV)–induced immunosuppression as measured by a CD4 T lymphocyte count less than 200. In the United States, Australia, and Europe, P carinii pneumonia in HIV-infected patients is seen largely in those unaware of their HIV serostatus at presentation or in those noncompliant with or intolerant of prophylaxis and antiretroviral therapy.13 In sub-Saharan Africa, recent illuminating autopsy studies have shown that P carinii pneumonia contributes significantly to the overall death toll in the HIV-infected population, especially children.14,15 In the non-HIV–associated immunosuppressed patients, P carinii infection remains a significant cause of morbidity and mortality.16–18 

TAXONOMY

The taxonomic position of P carinii is still uncertain. Pneumocystis carinii is sometimes called an orphan organism because its phylogenetic position has not yet been established, perhaps because of lack of generally accepted criteria for the classification of fungi and protozoa.19 It has been suggested that it should be classified as fungus, because the ribosomal RNA is homologous to that found in fungi.20,21 A comparative study of small subunits of ribosomal RNA (16S-like rRNA) of P carinii and the fungus Saccharomyces cerevisiae was carried out. The similarities between P carinii and S cerevisiae were consistent with a close evolutionary linkage between Pneumocystis and fungi.20 These small subunits of ribosomal RNA are used to establish phylogenetic relationships, because they have the same functions in all organisms.22 Furthermore, P carinii organisms share staining characteristics of fungi by showing affinity for Grocott's methenamine silver stain.

In contrast, some investigators think that Pneumocystis is more closely related to protozoa than fungi. Chagas9 and Carinii23 thought P carinii to be a protozoan in view of its association with Trypanosoma cruzi and Trypanosoma lewisi. However, ultrastructural studies of P carinii failed to demonstrate the cytoskeletal elements and complex organelle systems, peculiar to protozoa.24 In addition P carinii shows surface antigenic variation, which occurs in protozoa and bacteria, which has not been described in fungi. The major antigen of P carinii is major surface glycoprotein (MSG), including gpA and gp120.25 The MSG is encoded by a family of approximately 100 genes, each of which expresses a different isoform of MSG.26 The antigenic variation may be important for host immune evasion.

Some workers are of the opinion that P carinii should be recognized by the name of genus of the host species from which it is isolated; for example, P carinii derived from human beings is identified as Pneumocystis carinii hominis and from rats as Pneumocystis carinii rattus.27 The host specificity is further emphasized by the fact that cross-infection between different host species is not possible and that P carinii infection in man is not from other animals.28,29 

MORPHOLOGY

The morphological characteristics of P carinii are quite constant in all mammalian species. Generally, 4 morphological forms are identified: trophozoites, cysts, precysts, and sporozoites (also known as intracystic bodies). The trophozoites are pleomorphic and measure 2 to 4 μm. Under electron microscopy, trophozoites appear as unicellular structures with a thin wall or pellicle and sometimes have 2 or more nuclei.

The cyst is the diagnostic form of P carinii and stains with Giemsa, Papanicolaou, and Grocott methenamine silver nitrate stains and immunocytochemical techniques using monoclonal antibodies. Giemsa- and Papanicolaou- stained smears show an indirect evidence of P carinii infection by the demonstration of foamy exudate in the form of alveolar casts as shown in Figures 1 and 2. This makes the Grocott methenamine silver nitrate and immunocytochemical stains mandatory to confirm the cysts of P carinii (Figures 3 through 5).

Figure 1.

Alveolar casts of Pneumocystis carinii (Giemsa stain, original magnification ×400). Figure 2. Alveolar cast of Pneumocystis carinii in smear prepared from a bronchoalveolar lavage specimen (Papanicolaou stain, original magnification ×400). Figure 3. Cysts of Pneumocystis carinii with capsular dots. Note the position of dots varies in each cyst (Grocott methenamine silver nitrate, original magnification ×1000). Figure 4. Cysts of Pneumocystis carinii in alveolar cast stained positive with 3F6 antibody (immunoperoxidase, original magnification ×1000)

Figure 1.

Alveolar casts of Pneumocystis carinii (Giemsa stain, original magnification ×400). Figure 2. Alveolar cast of Pneumocystis carinii in smear prepared from a bronchoalveolar lavage specimen (Papanicolaou stain, original magnification ×400). Figure 3. Cysts of Pneumocystis carinii with capsular dots. Note the position of dots varies in each cyst (Grocott methenamine silver nitrate, original magnification ×1000). Figure 4. Cysts of Pneumocystis carinii in alveolar cast stained positive with 3F6 antibody (immunoperoxidase, original magnification ×1000)

In the light microscope, the cyst appears as a spherical, cup-shaped, or crescent-shaped object measuring 4 to 8 μm in diameter.30 Some cysts are empty and collapsed; others contain dark bodies or dots in silver-stained preparations as shown in Figure 3. The dark bodies or dots are focal thickenings of the cyst wall (Figure 6). The dark bodies acquire different positions in relation to the cyst depending on the angle of visualization. Hence, dark bodies or dots should not be confused with sporozoites. Serial ultrathin sectioning revealed an irregular round pore in the thickened area of the cyst wall of P carinii, which is thought to be used for the release of sporozoites into external environment (Figure 6).31 Phase contrast and electron microscopy have revealed up to 8 sporozoites in the cyst.24,32 In transmission electron microscopy, the cysts exhibit various shapes depending on whether or not they contain sporozoites (Figure 7). The cysts with sporozoites in them have a spherical structure, with a pellicle (70–140 nm) consisting of 3 layers: the inner plasmalemma, an electron lucent middle layer, and electron dense outer layer (Figure 8). Empty cysts are crescent- or cup-shaped (Figure 7). In contrast to trophozoites, cysts have a smooth surface. However, the cysts might have attached membranotubular extensions from the neighboring trophozoites because of their intimate relationship.

Figure 5.

Positive staining of the Pneumocystis carinii cysts using 3F6 antibody (indirect immunofluorescence, original magnification ×1000). Figure 6. Ultrastructure of a mature cyst of Pneumocystis carinii with ghostly outlines of intracystic bodies (sporozoites). The cyst wall shows a coffee bean–shaped focal thickening with an opening (arrow) (transmission electron micrograph, original magnification ×28 800). Figure 7. Ultrastructure of Pneumocystis carinii by transmission electron microscopy: cysts (C) and trophozoites (T); a crescent-shaped collapsed cyst (arrow) (original magnification ×5400). Figure 8. Ultrastructure of the cyst wall of Pneumocystis carinii with an inner layer of plasmalemma, an electron lucent middle layer, and an electron dense outer layer (arrow) (transmission electron micrograph, original magnification ×59,400)

Figure 5.

Positive staining of the Pneumocystis carinii cysts using 3F6 antibody (indirect immunofluorescence, original magnification ×1000). Figure 6. Ultrastructure of a mature cyst of Pneumocystis carinii with ghostly outlines of intracystic bodies (sporozoites). The cyst wall shows a coffee bean–shaped focal thickening with an opening (arrow) (transmission electron micrograph, original magnification ×28 800). Figure 7. Ultrastructure of Pneumocystis carinii by transmission electron microscopy: cysts (C) and trophozoites (T); a crescent-shaped collapsed cyst (arrow) (original magnification ×5400). Figure 8. Ultrastructure of the cyst wall of Pneumocystis carinii with an inner layer of plasmalemma, an electron lucent middle layer, and an electron dense outer layer (arrow) (transmission electron micrograph, original magnification ×59,400)

CLINICAL DISEASE AND PRESENTATION

Clinical disease was thought to be due to reactivation of childhood latent infection in immunosuppressed cases. In the recent past, studies have shown a de novo infection.33 This is supported by the fact that P carinii infection may be transmitted among animals and human beings by airborne route, as P carinii DNA has been detected in the air.34,35 Using internal transcribed spacers (ITS) genotyping, different ITS types of P carinii were identified in most episodes of P carinii pneumonia. The same ITS types were observed in patients immunosuppressed as a result of HIV infection or malignancies and who were sharing the same room or who had prolonged close ward contact.36 However, there are as yet insufficient data to suggest isolation of P carinii pneumonia cases from susceptible patients.

Pneumocystis carinii causes a potentially severe and fatal pneumonia in patients with compromised immune status caused by HIV infection, chemotherapeutic regimes for malignancies, immunosuppressed therapy in organ transplant cases,37 and congenital immune diseases.38,39 

Clinically, patients with P carinii pneumonia present with several weeks' history of dry cough, fever with sweats, and difficulty in taking a deep breath.40 Haemoptysis has also been recorded as a presenting feature.41 Clinical examination often reveals an increased respiratory rate, tachycardia, cyanosis, and fine crackles on auscultation of the chest.42 Reduced transfer factor and vital capacity and reduction in total lung capacity have been described.43 Arterial blood gas measurement is mandatory in order to determine the presence and indicate extent of respiratory failure.44 A chest radiograph shows diffuse bilateral infiltrates. However, the chest x-ray occasionally shows multiple nodules.45 

Pneumocystis carinii infection is not only confined to the lungs, but may also be disseminated via lymphatics and hematogenous routes.46,47 Disseminated infection most commonly involves thyroid, liver, bone marrow, lymph nodes, and spleen.47,48 

LABORATORY INVESTIGATIONS

Bronchoalveolar lavage (BAL) and induced sputum samples are frequently used for the investigation of P carinii pneumonia.49,50 However, open lung biopsy is considered as a gold standard, but is rarely performed in the current clinical practice.

The routine cytological staining techniques (Giemsa, Papanicolaou, and Grocott's methenamine silver nitrate) are used on BAL and induced sputum samples for the detection of P carinii infection. The specialized techniques such as immunocytochemistry and polymerase chain reaction (PCR) are also used with slightly more promising results. However, these techniques are laborious and not cost-effective. Thus, most of the routine clinical laboratories would resort to such specialized techniques for patients having negative results on routine stained smears and showing high index of suspicion for P carinii pneumonia on clinical grounds. Wazir et al51 carried out a comparative study of the routine cytological techniques and immunocytochemical technique using 3F6 monoclonal antibody for the detection of P carinii in BAL and induced sputum samples. Their specificity, sensitivity, and predictive values were determined. All 4 techniques were highly specific for the detection of P carinii pneumonia. However, the immunocytochemical technique was 2.5% more sensitive than Grocott and 7.6% more sensitive than Giemsa stain.51 A similar study by Tuncer et al52 was performed by comparing the sensitivity of routine cytological staining techniques with immunocytochemistry and PCR using induced sputum samples from 30 immunosuppressed patients. They found P carinii infection in 8 patients using immunocytochemistry and PCR, of whom 4 were also detected by routine staining methods.

In addition, Wazir et al51 had demonstrated that there is an inverse relationship between mean cyst size (measured by micrometers in Grocott methenamine silver nitrate–stained smears) and response to treatment.53 

TREATMENT OF PNEUMOCYSTIS CARINII PNEUMONIA

Co-trimoxazole used in full dose is a first-line treatment of P carinii pneumonia.54 This drug is routinely used for 21 days for the treatment of P carinii pneumonia in HIV-infected cases. However, 14 to 17 days of treatment is recommended for non-HIV–associated P carinii pneumonia. The incidence of adverse drug reaction to co-trimoxazole, such as rash, fever, and abnormalities of liver function tests, is more common in HIV-associated cases compared with non-HIV–associated cases. Patients with solid organ transplantation such as kidney and liver transplants are more likely to develop nephrotoxicity with co-trimoxazole.54 In such cases, second-line treatment with intravenous administration of pentamidine or clindamycine with primaquine or of dapsone with trimethoprim is recommended.54 Atovaquone and trimetrexate with folinic acid may be used as a third line of treatment for P carinii pneumonia.

Some are of the opinion that addition of glucocorticosteroids to the treatment regimes of cases with HIV-associated P carinii pneumonia has shown to reduce the risk of respiratory failure and subsequent need for mechanical ventilation followed by death.3–5 However, Pareja et al55 suggested that all the treatment regimes for P carinii pneumonia must be supplemented by glucocorticosteroid. Such cases treated for P carinii pneumonia by routine drugs in conjunction with glucocorticosteroids have shown shorter duration of mechanical ventilation, length of stay on the intensive care unit, and overall hospitalization compared with patients without glucocorticosteroids in the treatment regimes. Based on these findings, it is suggested that glucocorticosteroids may accelerate recovery in adults with severe non-HIV–associated cases of P carinii pneumonia.55 

The mortality rate among individuals with non-HIV– associated P carinii pneumonia is high, ranging from 34% to 49%, in comparison with patients with HIV-associated Pneumocystis infection.16–18 This may either be due to continuous and effective monitoring of CD4 T-lymphocyte count in HIV-infected cases or the continuous use of glucocorticosteroids in non-HIV–associated cases.

PROPHYLAXIS

Immunosuppressed patients due to HIV infection or other non-HIV causes of immunosuppression who are at high risk of developing P. carinii pneumonia should be started on prophylactic treatment. Patients with HIV infection showing a CD4 lymphocyte cell count of less than 200 should receive prophylaxis. Sepkowitz and colleagues37,56 suggested that immunosuppression induced by chemotherapy or radiotherapy, or patients with inflammatory diseases receiving glucocorticosteroids 20 mg/day or more for 4 weeks or more should receive prophylaxis.

Co-trimoxazole is the drug of first choice for prophylaxis in daily or intermittent doses.57 In the event of adverse reactions to co-trimoxazole, alternative agents such as dapsone with or without pyrimethamine and nebulized pyrimidine may be used as prophylaxis.58 

The possibility of immunization of patients at high risk of P carinii pneumonia may be used in the future as prophylaxis. This is supported by the fact that successful attempts have been made to elicit protective antibody responses to major surface glycoprotein immunization in an immunosuppressed rat model.59 The immunization with major surface glycoprotein may protect patients at high risk of P carinii pneumonia.59 The candidates for immunization include newly diagnosed cases of malignancy, pre–organ transplant cases, or cases with HIV infection having a CD4 lymphocyte count still in the normal range.59 

CONCLUSIONS

The incidence of P carinii pneumonia can significantly be reduced with effective use of prophylaxis and early detection of cases at high risk of P carinii infection. The experimental work on immunization for P carinii infection is still in the early stages, which may be taken as a research challenge for further investigation into this problem.

References

References
Sheldon
,
W. H.
Experimental pulmonary Pneumocystis carinii infection in rabbits.
J Exp Med
1959
.
110
:
147
160
.
Copland
,
J. W.
Canine pneumonia caused by Pneumocystis carinii.
Aust Vet J
1974
.
50
:
515
518
.
McConnell
,
E. E.
,
P. A.
Basson
, and
J. G.
Pienaar
.
Pneumocystic in domestic goat.
Onderstepoort J Vet Res. 1971;38:117–124. [Hughes WT. Pneumocystis carinii Pneumonitis. Vol. 1. Boca Raton, Fla: CRC Press; 1987.]
.
Siebold
,
H. R.
and
J. F.
Munnell
.
Pneumocystis in a pig.
Vet Pathol. 1977;14:89. Hughes WT. Pneumocystis carinii Pneumonitis. Vol. 1. Boca Raton, Fla: CRC Press; 1987
.
Settnes
,
O. P.
and
E.
Hasselager
.
Occurrence of Pneumocystis carinii Delanoe & Delanoe, 1912 in dogs and cats in Denmark.
Nord Vet Med. 1984;36:179–181. [Hughes WT. Pneumocystis carinii Pneumonitis. Vol. 1. Boca Raton, Fla: CRC Press; 1987.]
.
Chandler
,
F. W.
,
H. M.
McClure
,
W. G.
Campbell
, and
J. C.
Watts
.
Pulmonary pneumocystosis in nonhuman primates.
Arch Pathol Lab Med
1976
.
100
:
163
167
.
Long
,
G. G.
,
J. D.
White
, and
J. L.
Stookey
.
Pneumocystis carinii infection in splenectomized owl monkeys.
J Am Vet Med Assoc
1975
.
167
:
651
654
.
Shively
,
J. N.
,
K. K.
Moe
, and
R. W.
Dellers
.
Fine structure of spontaneous Pneumocystis carinii pulmonary infection in foals.
Cornell Vet
1974
.
64
:
72
88
.
Chagas
,
G.
Nova trypanosomiaze humana. Estudos sobre a morphologia e ciclo evolutivo do Schizotrypanum cruzi, n. gen. N. sp; ajente etiologico de nova entidade morbida do homen. Mems Inst Oswaldo Cruz. 1909;1:159–218. [Gutierrez Y. The biology of Pneumocystis carinii.
Semin Diagn Pathol
1989
.
6
3
:
203
211
.
Delanoe
,
A.
and
M.
Delanoe
.
Ser les rapports der kystes de Carinii du pulmon des rats avec Trypanosoma lewisii.
C R Acad Sci Paris. 1912;155:658. [Hughes WT. Pneumocystis carinii Pneumonitis. Vol. 1. Boca Raton, Fla: CRC Press; 1987.]
.
Stringer
,
J. R.
,
C. B.
Beard
,
R. F.
Miller
, and
A. E.
Wakefield
.
A new name (Pneumocystis jiroveci) for Pneumocystis from humans.
Emerg Infect Dis
2002
.
8
:
891
896
.
Hughes
,
W. T.
Prologue to AIDS: the recognition of infectious opportunists.
Medicine (Baltimore)
1998
.
77
:
227
232
.
Day
,
J.
,
I. G.
Williams
,
A.
Zumla
, and
R. F.
Miller
.
Protection from Pneumocystis carinii pneumonia.
Sex Trans Infect
1999
.
75
:
202
203
.
Ansari
,
N. A.
,
A. H.
Kombe
, and
T. A.
Kenyon
.
et al
.
Pathology and causes of death in a series of human immunodeficiency virus-positive and -negative pediatric referral hospital admissions in Botswana.
Pediatr Infect Dis J
2003
.
22
:
43
47
.
Ansari
,
N. A.
,
A. H.
Kombe
, and
T. A.
Kenyon
.
et al
.
Pathology and causes of death in a group of 128 predominately HIV-positive patients in Botswana, 1997–1998.
Int J Tuberc Lung Dis
2002
.
6
:
55
63
.
Sepkowitz
,
K. A.
,
A. E.
Brown
,
E. E.
Telzak
,
S.
Gottleib
, and
D.
Armstrong
.
Pneumocystis carinii pneumonia among patients without AIDS at a Cancer hospital.
JAMA
1992
.
267
:
832
837
.
Arend
,
S. M.
,
F. P.
Kroon
, and
J. W.
Van't Wout
.
Pneumocystis carinii pneumonia in patients without AIDS, 1980 through 1993.
Arch Intern Med
1995
.
155
:
2436
2441
.
Yale
,
S. H.
and
A. H.
Limper
.
Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illnesses and prior corticosteroid therapy.
Mayo Clin Proc
1996
.
71
:
5
13
.
Editorial: Pneumocystis—an orphan organism?
Lancet
1985
.
i
:
676
677
.
Edman
,
J. C.
,
J. A.
Kovacs
,
H.
Masur
,
D. V.
Santi
,
H. J.
Elwood
, and
M. L.
Sogin
.
Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi.
Nature
1988
.
334
:
519
522
.
Stringer
,
S. L.
,
K.
Hudson
,
M. A.
Blasé
,
P. D.
Walzer
,
M. T.
Cushion
, and
J. R.
Stringer
.
Sequence from ribosomal RNA of Pneumocystis carinii compared to those of four fungi suggests an ascomycetous affinity.
J Protozool
1989
.
36
:
14S
16S
.
Fitch
,
W. M.
and
E.
Margoliash
.
Construction of phylogenetic trees.
Science
1967
.
155
:
279
284
.
Carinii
,
A.
Formas de eschizogonia do Trypanosoma lewisi. Arch Soc Med (Sao Paulo). August 16, 1910. [Gutierrez Y. The biology of Pneumocystis carinii.
Semin Diagn Pathol
1989
.
6
3
:
203
211
.
Bedrossian
,
C. W. M.
Rapid cytologic diagnosis of pneumocystis: a comparison of effective techniques.
Semin Diagn Pathol
1989
.
6
3
:
245
261
.
Benfield
,
T. L.
and
J. D.
Lundgren
.
The Pneumocystis carinii major surface glycoprotein (MSG): its potential involvement in the pathophysiology of pneumocystosis.
FEMS Immunol Med Microbiol
1998
.
22
:
129
134
.
Garbe
,
T. R.
and
J. R.
Stringer
.
Molecular characterisation of clustered variants of genes encoding major surface antigens of human Pneumocystis carinii.
Infect Immunol
1994
.
62
:
3092
3101
.
Hughes
,
W. T.
and
F.
Gigliotti
.
Nomenclature for Pneumocystis carinii.
J Infect Dis
1988
.
157
3
:
432
433
.
Wakefield
,
A. E.
Genetic heterogeneity in Pneumocystis carinii: an introduction.
FEMS Immunol Med Microbiol
1998
.
22
:
5
13
.
Stringer
,
J. R.
and
P. D.
Walzer
.
Molecular biology and epidemiology of Pneumocystis carinii infection in AIDS.
AIDS
1996
.
10
:
561
571
.
Beals
,
T. F.
Appropriate terminology for the features of Pneumocystis carinii.
Acta Cytologica
1991
.
35
2
:
250
251
.
Wazir
,
J. F.
Cytological, ultrastructural and immunocytochemical studies of Pneumocystis carinii infection in patients infected with human immunodeficiency virus.
[PhD thesis]. London University; 1993
.
Cushion
,
M. T.
,
J. J.
Ruffolo
, and
P. D.
Walzer
.
Analysis of the developmental stages of Pneumocystis carinii, in vitro.
Lab Invest
1988
.
58
:
324
331
.
Stringer
,
J. R.
and
P. D.
Walzer
.
Molecular biology and epidemiology of Pneumocystis carinii infection in AIDS.
AIDS
1996
.
10
:
561
571
.
Wakefield
,
A. E.
DNA sequences identical to Pneumocystis carinii f. sp. carinii and Pneumocystis carinii f. sp. hominis in samples of air spora.
J Clin Microbiol
1996
.
34
:
1754
1759
.
Olsson
,
M.
,
C.
Lidman
, and
S.
Latouche
.
et al
.
Identification of Pneumocystis carinii f. sp. hominis gene sequences in filtered air in hospital environments.
J Clin Microbiol
1998
.
36
:
1737
1740
.
Helweg-Larsen
,
J.
,
A. G.
Tsolaki
,
R. F.
Miller
,
B.
Lundgren
, and
A. E.
Wakefield
.
Clusters of Pneumocystis carinii pneumonia: analysis of person-to-person transmission by genotyping.
Q J Med
1998
.
91
:
813
820
.
Sepkowitz
,
K. A.
,
A. E.
Brown
, and
D.
Armstrong
.
Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome: more patients, same risk.
Arch Intern Med
1995
.
155
:
1125
1128
.
Hughes
,
W. T.
,
S.
Feldman
,
R. J. A.
Aur
,
M. S.
Verzoza
,
H. O.
Hustu
, and
J. V.
Simone
.
Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.
Cancer
1975
.
36
:
2004
2009
.
Saulsbury
,
F. T.
,
M. T.
Bernstein
, and
J. A.
Winkelstein
.
et al
.
Pneumocystis carinii pneumonia as the presenting infection in congenital hypogamaglobulinaemia.
J Pediatr
1979
.
95
:
559
561
.
Francis
,
N. D.
,
R. D.
Goldin
, and
S. M.
Forster
.
et al
.
Diagnosis of lung disease in acquired immune deficiency syndrome: biopsy or cytology and implications for management.
J Clinical Pathol
1987
.
40
:
1269
1273
.
Mascarenhas
,
D. A.
,
V. P.
Vasudevan
, and
K. P.
Vaidya
.
Pneumocystis carinii pneumonia. Rare cause of haemoptysis.
Chest
1991
.
99(1)
:
251
253
.
Mitchell
,
D. M.
Diagnostic problems in AIDS and lung.
Res Med
1989
.
83
:
9
14
.
Curtis
,
J.
,
P.
Goodman
, and
P. C.
Hopewell
.
Non-invasive tests in the diagnostic evaluation of Pneumocystis carinii pneumonia in patients with or suspected of having AIDS.
Am Rev Respir Dis
1986
.
133A
:
132
.
Murray
,
J. F.
,
C. P.
Felton
, and
S.
Garay
.
et al
.
Pulmonary complications of the acquired immunodeficiency syndrome: report of the National heart, lung, and blood institute workshop.
N Engl J Med
1984
.
310
:
1682
1688
.
Wulf
,
G. G.
,
U.
Reichard
,
B.
Wormann
, and
W.
Hiddemann
.
Pneumocystis carinii pneumonia with peripheral modular infiltrates in a patient with T-acute lymphoblastic leukaemia.
J Clin Oncol
1998
.
16
:
3476
3477
.
Ravinglione
,
M. C.
Extrapulmonary pneumocystosis: the first 50 cases.
Rev Infect Dis
1990
.
12
:
1127
1138
.
Amin
,
M. B.
,
M. P.
Abrash
, and
E.
Mezger
.
et al
.
Systemic dissemination of Pneumocystis carinii in a patient with acquired immunodeficiency syndrome.
Henry Ford Hosp Med J
1990
.
38
:
68
71
.
Battan
,
R.
,
P.
Mariuz
, and
M. C.
Ravinglione
.
et al
.
Pneumocystis carinii infection of the thyroid in a hypothyroid patient with AIDS: diagnosis by fine needle aspiration biopsy.
J Clin Endocrinol Metab
1991
.
72
:
724
726
.
Broadus
,
C.
,
M. D.
Dake
, and
M. S.
Stulbarg
.
et al
.
Bronchoalveolar lavage and transbronchial biopsy for the diagnosis of pulmonary infections in the acquired immunodeficiency syndrome.
Ann Intern Med
1985
.
102
:
747
752
.
Leigh
,
T. R.
,
P.
Parsons
, and
C.
Hume
.
et al
.
Sputum induction for diagnosis of Pneumocystis carinii pneumonia.
Lancet
1989
.
ii
:
205
206
.
Wazir
,
J. F.
,
S. G.
Macrorie
, and
D. V.
Coleman
.
Evaluation of sensitivity, specificity, and predictive value of monoclonal antibody 3F6 for the detection of Pneumocystis carinii pneumonia in bronchoalveolar lavage and induced sputum specimens.
Cytopathology
1994
.
5
:
82
90
.
Tuncer
,
S.
,
S.
Erguven
,
S.
Kocagoz
, and
S.
Unal
.
Comparison of cytochemical staining, immunoflourescence and PCR for diagnosis of Pneumocystis carinii on sputum samples.
Scand J Infect Dis
1998
.
30
:
125
128
.
Wazir
,
J. F.
,
G.
Woodward
, and
D. V.
Coleman
.
Correlation of cyst size with response to treatment.
Cytopathology
1994
.
5
:
90
92
.
Fishman
,
J. A.
Treatment of infection due to Pneumocystis carinii.
Antimicrob Agents Chemother
1998
.
42
:
1309
1314
.
Pareja
,
J. G.
,
R.
Garland
, and
H.
Koziel
.
Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia.
Chest
1998
.
113
:
1215
1224
.
Sepkowitz
,
K. A.
Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome: who should receive prophylaxis?
Mayo Clin Proc
1996
.
71
:
102
103
.
Fishman
,
J. A.
Prevention of infection due to Pneumocystis carinii.
Antimicrob Agents Chemother
1998
.
42
:
995
1004
.
Machado
,
C. M.
,
M. C. A.
Macedo
, and
R. S. S.
Medeiros
.
et al
.
Primary Pneumocystis carinii prophylaxis with aerosolized pentamidine after bone marrow transplantation.
Acta Haematol
1998
.
99
:
54
56
.
Theus
,
S. A.
,
A. G.
Smulian
,
P.
Steele
,
M. J.
Linke
, and
P. D.
Walzer
.
Immunisation with the major surface glycoprotein of Pneumocystis carinii elicits a protective response.
Vaccine
1998
.
16
:
1149
1157
.

The authors have no relevant financial interest in the products or companies described in this article.

Author notes

Reprints: Javed F. Wazir, MBBS, PhD, MRCPath, Department of Pathology, Arabian Gulf University, PO Box-22979, Kingdom of Bahrain (javedfw@agu.edu.br or jfwazir@hotmail.com)