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REVIEW ARTICLE

Human Pneumocystosis

R. Singhal, B.R. Mirdha and R. Guleria1

Departments of Microbiology and Medicine1, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

ABSTRACT
Pneumocystis is an atypical fungus causing pneumonia in immuno-compromised individuals.
Though previously termed as Pneumocystis carinii, the recent taxonomy has considered human
derived Pneumocystis to be a different species Pneumocystis jiroveci. The organism is the most
common cause of opportunistic infections among patients with acquired immunodeficiency
syndrome (AIDS) in developed countries. Incidence of Pneumocystis pneumonia or
pneumocystosis in developing countries including India continues to be low. Microscopy of
appropriate clinical samples has been the mainstay of diagnosis of pneumocystosis.
Amplification techniques are now being evaluated for detection of P. jiroveci. This review
attempts to give a recent update on P. jiroveci with special focus on epidemiology, taxonomy,
current diagnostic modalities and recommended immuno-prophylaxis.

Key words: Pneumocystis jiroveci, Pneumonia, Pneumocystosis, Immunocompromised, Acquired


immuno deficiency syndrome.

[Indian J Chest Dis Allied Sci 2005; 47: 273-283]

INTRODUCTION emergence of the human immunodeficiency


virus (HIV) and the acquired immuno-
Human derived Pneumocystis carinii, an deficiency syndrome (AIDS) in the 1980s. P.
established cause of pneumonia in immuno- jiroveci infection was the first opportunistic
compromised individuals in now considered as illness to be recognised in AIDS patients and has
a different species, Pneumocystis jiroveci. The remained as one of the most common AIDS
clinical spectrum caused by the organism is defining illnesses in the western world1.
termed as Pneumocystis pneumonia (PCP) or
pneumocystosis. It was initially recognised as
the cause of epidemic interstitial pneumonia in CONTROVERSY IN TAXONOMY
premature and malnourished infants. In 1950s
and subsequently in 1960s, it was evident as a Pneumocystis was first identified by Chagas as
respiratory pathogen in persons undergoing a variant stage of Trypanosoma cruzi1. Cyst forms
organ transplantation, receiving chemotherapy of the organism were found in the lungs of rats
for malignant disease and in other immuno- by Antonio Carinii. However, Delanoes 1
compromised population. However, the reported the organism to the distinct from
dynamics of P. jiroveci took a new turn with Trypanosoma and re-named it as Pneumocystis
[Received: May 11, 2004; accepted after revision: September 6, 2004]
Correspondence and reprint request: Dr B.R. Mirdha, Additional Professor, Department of Microbiology, All
India Institute of Medical Sciences, Ansari Nagar, New Delhi-110 029; India; Tele.: 91-11-26593288 (Off.); E-mail:
<mirdhabr@ hotmail.com>.
274 Human Pneumocystosis R. Singhal et al

carinii. In next two decades, this organism was NOMENCLATURE OF PNEUMOCYSTIS


considered as non-pathogenic. In 1950s, Vanek
Phenotypic differences between Pneumocystis
and Jirovec 1 demonstrated Pneumocystis in
from different mammals and humans were
alveolar exudates of children dying of
noted decades ago. Based on this, Frenkel10 had
interstitial plasma cell pneumonia and
proposed name P. jiroveci (Pronounced “ yee
established its pathogenic role in the disease.
row vet zee”) in 1976 for human-derived
However, the taxonomic status of Pneumocystis
Pneumocystis, in honour of Czech parasitologist
remained unanswered. Ultrastructural studies
Otta Jirovec. Due to the lack of valid publication,
in 1960s and 1970s and biochemical analysis
the new name was not accepted then. Analysis
were unable to conclusively place Pneumocystis
of proteins and deoxyribonucleic acid (DNA)
either in fungi or in protozoa. Morphological
amplification studies have shown that human-
similarity to a sporozoan, i.e., Cryptosporidia and
derived Pneumocystis is distinct. In addition,
pseudopodia like extensions seen in trophic
transfer experiments of Pneumocystis from
forms, prompted Barton and Campbell2 to place
humans to rats and other mammals failed11. In
it in sporozoa group of protozoa. Presence of
1994, a provisional trinomial nomenclature
double membrane in all stages of its life cycle
based on naming the ‘special forms’ of
and lack of ergosterol, further argued against
mammalian host was adopted. Thus,
fungal lineage 3 . In addition, antimicrobials
Pneumocystis from mouse was termed as P.
found to be effective against Pneumocystis were
carinii f.sp. muris where f. sp. stands for ‘formale
antiprotozoals such as pentamidine and
speciales’ 12. This nomenclature was cumber-
trimethoprim-sulphamethoxazole4.
some, inadequate and failed to define the
On the contrary, Vavra 5 noted similarities uniqueness of human-derived Pneumocystis.
between cyst with intracystic bodies with yeast Additional research based on 18S rRNA
ascus and ascospores. Besides, lack of sub - sequence showed considerable differences in
pellicular microtubules, polar rings and human- and rat-derived Pneumocystis13. DNA
cystostomas were not sufficient to justify its amplification studies have detected only
placement in sporozoa. Presence of lamellar human-derived Pneumocystis in human lungs.
rather than vesicular mitochondria was Besides, this DNA sequence remains unique to
consistent with fungi5. In addition, biochemical humans13. Based on all these findings, Frenkel10,
studies showed presence of glucan in cyst wall in the year 1999 published the name P. jiroveci
to further substantiate fungal lineage2. Eviden- for human-derived Pneumocystis according to
ces based on genetic studies have accumulated, guidelines of International Code of Botanical
which conclusively consider Pneumocystis to be Nomenclature (ICBN). In the year 2001, in an
a fungus. Sequencing of small sub-unit International Workshop, it was unanimously
ribosomal 16S ribonucleic acid (RNA) has accepted that the special forms of Pneumocystis
placed Pneumocystis among Ascomycetes yeast6. be termed as species. Thus, the name P. jiroveci
Comparison of portions of mitochondrial gene has been accepted after series of scientific
sequence, thymidylate synthase (TS) gene and deliberations and evidences12,14,15. P. jiroveci has
dihydrofolate reductase (DHFR) gene, have been used instead of P. carinii in the text here-
showed similarity to fungi7,8. Elongation factor after keeping up with the revised nomenclature.
III, a protein unique to fungi among Eukaryotes,
has also been detected in genus Pneumocystis9.
Based on all these evidences, National Center of GENETIC DIVERSITY IN
Biotechnology Information (NCBI), in the year PNEUMOCYSTIS
2002 have proposed classification of
Pneumocystis. Pneumocystis belongs to kingdom Stringer 11 devised a classification system
Fungi; Phylum Ascomycotina; Subphylum among pneumocystis based on percentage of
Ascomycota; Class Pneumocystidomycetes; Order sequence differences among selected loci,
Pneumocystidales; Family Pneumocystidaceae. thymidylate synthase, inter-transcribed spacer
2005; Vol. 47 The Indian Journal of Chest Diseases & Allied Sciences 275

region (ITS), β tubulin and arom. Highest level recipients of organ or bone marrow transplants
of divergence (15-50%), designated as class III, or persons on steroid therapy 16. Occasional
was seen among Pneumocystis from different reports are from patients without any
mammalian hosts. Class II divergence (4-7%) abnormalities in immune system17.
has been observed between two populations of
Pneumocystis inhabiting rat or ferret lung P. jiroveci in HIV-negative Patients
described as ‘prototype’ or ‘variant’. The rate
prototype and variant populations have been In a study from Netherlands18, it was shown
named as P. carinii f. sp. carinii and P. carinii f.sp. that all HIV-negative patients with P. jiroveci
ratii, respectively12. Among rat ‘prototype’, eight infection had underlying disorders resulting in
forms have been identified based on electro- immunosuppression. These included haemo-
phoretic karyotyping. Class I divergence is 0-4% tological malignancies (49%), immunological
and has been noted among Pneumocystis from disorders (22%), solid organ transplantations
human lung. Based on these variations, at least (20%) and bone marrow transplantation (9%)18.
59 human types have been identified so far11. Attack rates of P. jiroveci have been found to
vary from less then one percent in renal
transplant patients to 6.2-12% in patients with
MORPHOLOGY AND LIFE CYCLE immunological disorders 16 . Prophylactic
regimen has played an important role in
Three developmental forms are recognised. bringing down the attack rate. In India, various
Trophic form is the vegetative form and is studies have reported association of P. jiroveci in
smallest of the stages (1-5µ). It is amoeboid with HIV-negative cases with underlying diseases,
filopodia and is covered by a double membrane, such as Hodgkin's 19 lymphoma and renal
a characteristic morphology found on all stages transplant patients20.
of the organism. It is thought to reproduce by
primary fission. Ultrastructural studies have P. jiroveci in HIV-positive Patients
been found to interdigitate with type I
Before 1989, 60-80% of HIV-positive patients
Pneumocystis within mammalian lung alveoli.
in developed countries presented with P. jiroveci
Pre-cyst or sporocyte is the intermediate stage,
pneumonia. Furthermore, P. jiroveci accounted
4-8 µ in size and undergoes sexual reproduction
for 20-25% of all AIDS related deaths21-23. Now,
to produce spores. Cyst stage is spherical and is
the incidence of PCP has declined by 75% with
bound by thick cell wall unlike other two stages.
prompt diagnosis, effective prophylaxis and
Upto eight spores, 1µ in diameter can be seen
institution of highly active antiretroviral
which may be released by excystation 4. A
therapy (HAART) in AIDS patients 21. In USA,
localised thickening at one pole is often seen
the incidence has declined from 9 per 100
and is presumed to play role in release of spores.
person-years in 1991 to 5.3 per 100 person-years
in 1996 as per Centers for Disease Control and
Prevention (CDC) 22. In a large multi-centric
EPIDEMIOLOGY AND study conducted on 1,42,447AIDS cases during
TRANSMISSION OF P. JIROVECI 1993-2003, pneumocystosis was found to be the
most common AIDS defining illness in Western
Highest incidence of pneumocystosis is seen Europe 23 . In the 1980s, pneumocystosis
in HIV positive patients with CD4+ count less accounted for 0-11% infections in AIDS
than 200 cells/µl. Amongst non-HIV group, patients24. However, recent studies have shown
persons at highest risk include, severely an increasing trend in Africa with higher
malnourished and premature infants less than percentage of AIDS patients developing
three months of age, children with primary pneumocystosis; 33% in Zimbabwe and 22% in
immunodeficiency disorders, patients with Zambia in the year 1995 and 2002,
haematological and other malignancies, respectively25,26.
276 Human Pneumocystosis R. Singhal et al

INDIAN PERSPECTIVE histopathology report revealed P. jiroveci cysts


with no tuberculosis34.
As in African countries, with low incidence,
pneumocystosis is fifth commonest infection in
TRANSMISSION OF PNEUMOCYSTIS
AIDS patients in India27,28. In 1993, P. jiroveci was
JIROVECI
first reported in three AIDS patients in India29.
In one of the initial study from Mumbai 28, 5%
Reactivation of Latency
autopsy cases from AIDS patients had evidence
of P. jiroveci infection. Another study showed Traditional theories have maintained that
that, five among 34 AIDS autopsies had pneumocystosis results from reactivation of
evidence of pneumocystosis30. In a North Indian latent infection acquired during childhood 40.
study, among 134 HIV-positive patients, 12 were Detectable antibodies are present in majority of
found to have pneumocystosis as the terminal children by four years of age. In addition,
event31. Merchant et al32 conducted study on 285 occurrence of P. jiroveci in respiratory samples
children and found pneumocystosis in 3.9% of from clinically normal population supports the
cases. In a study from South India33, 6% of AIDS reactivation theory 41. Besides, host immune
patients has pneumocystosis. In this study34, evasion by variation of major suface
pneumocystosis was observed to be the second glycoprotein (MSG), species specificity of P.
most common opportunistic infection. Several jiroveci and difficult in vitro cultivation are
case reports of P. jiroveci infection among HIV- consistent with long term carriage or latency in
positive individuals have been reported from the host42,43.
India 34-36 . In a systematic study from North
India 37, P. jiroveci was found in 6.1% of HIV- Over the years, data have accumulated
positive and 1.5% of HIV-negative immuno- against reactivation theory as well. Many
compromised patients. studies have been unable to find P. jiroveci in
immunocompetent hosts 44. Study on severe
The reasons for these variations are several combined immunodeficiency (SCID) mouse
fold. First, rampant tuberculosis in Indian model showed that mice infected with P. jiroveci
subcontinent seems to be the most possible were able to clear organisms after immune
reason of lower prevalence of pneumocystosis24. reconstitution45. P. jiroveci genotypes in patients
Secondly, role of climatic changes has been with recurrent P. jiroveci often differ from
reported in few studies 38,39 . Countries with original genotype and correlates better with
warmer climate such as Portugal and Italy had palce of infection than with place of birth45.
relatively lower frequency of P. jiroveci than
countries with colder climates such as Germany Active Acquisition
and United Kingdom38. Similar trends have also
been noted in United States 39. Thirdly, some All attempts to transfer P. jiroveci from one
genotypic differences have been observed animal species to another have been
between P. jiroveci from different geographic unsuccessful. In natural environment, P. jiroveci
regions39. At present, significance of genotypic deoxyribonucleic acid (DNA) has been detected
diversity with respect to virulence, infectivity in water, air and in soil samples however, whole
and drug susceptibility is still at evolving stage. organism has been never detected from these
Lastly, but most importantly, initial lack of sources46-48. Navin et al48 found that patients with
awareness, lack of appropriate diagnostic P. jiroveci were more likely to have history of
facilities and non-specific signs and symptoms recent gardening, thus suggesting soil
may be the cause of under-reporting of exposure 48 . Outbreaks in oncology and
pneumocystosis in developing world. Arora et transplant units have raised the possibility of
al34 have reported a HIV infected patient whose person to person transmission49. Besides clinical
chest radiograph showed signs of pulmonary cases, sub-clinical cases and a small number of
tuberculosis. However, post-mortem immunocompetent persons with no evidence of
2005; Vol. 47 The Indian Journal of Chest Diseases & Allied Sciences 277

clinical disease harbor P. jiroveci, forming the patients with late stage AIDS, P. jiroveci
reservoir. This source cannot be ignored in the disseminates from lung to other organs where
absence of other evidences. In any case, the they induce secondary lesions. Almost any
transmission takes place via an airborne route as organ may be affected but spleen, kidney lymph
alveoli is the site of infection24. Rare reports of node, liver and bone marrow are the most
vertical transmission of infection are there but commonly affected sites55,56.
animal experiments have been unable to
document this finding50. DIAGNOSIS OF PNEUMOCYSTOSIS
CLINICAL ASPECTS OF It is challenging to diagnose pneumocystosis
PNEUMOCYSTOSIS on the basis of signs and symptoms only. Curtis
et al57 made an interesting observation that only
Four clinical forms of pneumocystosis have 77% physicians included pneumocystosis in
been recognised, namely, asymptomatic, their differential diagnosis on the basis of
infantile or epidemic interstitial pneumonia, symptoms, chest radiograph and arterial blood
child-adult sporadic pneumonitis of gas values only. Specific microbiological
immunocompromised and extra-pulmonary diagnosis, based on conventional or antibody
pneumocystosis21. Infantile form was commonly stains or nucleic acid detection methods is,
observed during world-war II in Europe and it therefore, imperative. Sputum induction with
primarily affected premature and malnourished hypertonic saline has been found to be sensitive
infants. Infected infants presented with procedure for P. jiroveci recovery with a
dyspnoea, anorexia, weight loss and diarrhoea. diagnostic yield of 50-90 percent58. Results are
Cough and fever were uncommon. much better than expectorated sputum 59 .
Immunocompromised hosts typically present Bronchoalveolar lavage (BAL) of two or more
with a triad of progressive dyspnoea of many segments may increase the yield to 90-99% and
weeks, non-productive cough or with clear is considered as the gold standard 60. In our
sputum and low-grade fever. On examination, earlier study37, 7.5% BAL samples were positive
tachypnoea, tachycardia, cyanosis and fine dry for P. jiroveci whereas no induced sputum
rales may be present 51 . Chest radiography samples from same patients were positive. Lack
usually shows diffuse interstitial or peri-hilar of facilities for bronchoscopy at most places in
infiltrates but may be normal in one-third of our country could be the reason for under-
cases. Other findings, such as spontaneous reporting of P. jiroveci. Bijur et al60 detected cysts
pneumothorax, effusions or cavitary lesions can of P. jiroveci in BAL and transbronchial lung
be seen in less number of cases52. Increased biopsy (TBLB) samples in five patients.
serum lactate dehydrogenase (LDH) > 460 IU/L However, no organism was found in induced
has been found to be a sensitive test for this sputum. Though TBLB has sensitivity of 95-
disease, but a number of pathological conditions 100%, it carries the risk of pneumothorax. TBLB
involving lungs show increased serum LDH is considered useful when BAL fails to reveal P.
level53. Partial pressure of arterial oxygen (PaO2) jiroveci in patients with compatible clinical
measurement offers a good negative predictive presentation or when other diseases, such as
value for exclusion of P. jiroveci infection as PaO2 tuberculosis, neoplasms or fungal infections61.
< 75 mmHg correlates with the disease54. Diagnostic yield of these procedures is lower in
HIV-negative group due to lower organism
Acute respiratory failure has been described
load. Rarely, lung biopsy whose yield is close to
in 20-25% HIV-positive patients and more than
100% may be indicated in such cases62.
40% HIV-negative patients with pneumo-
cystosis. The higher mortality rate of 20-40% is Microscopy constitutes the mainstay of
seen in HIV-negative patients with diagnosis and involves visualisation of
pneumocystosis could probably be due to more trophozoites or cyst forms. Giemsa stains the
profound inflammatory response21. In 2-3% of trophozoites as deep blue with no staining of
278 Human Pneumocystosis R. Singhal et al

cyst walls. Its modifications such as Diff-Quick, DHFR gene had amplified many non-specific
which is a rapid Giemsa technique taking only products and had a low sensitivity 70. Subse-
30 seconds and May-Grunwald have shown quently, primers to mitochondrial large subunit
better sensitivity and specificity ranging from rRNA gene (Mt LS rRNA) showed better sensi-
50-84 percent63,64. Papanicolaou, hematoxyline tivity and specificity using nested PCR71. Studies
and eosin stains are employed in histopathology on P. jiroveci DNA detection in non-invasive
but stained poorly for both cysts and samples such as sputum, oral washes and naso-
trophozoites. However, foamy intra-alveolar pharyngeal aspirate have provided encouraging
eosinophilic exudate may be seen which has results. Caliendo et al72 have reported 100% and
high predictive value in the presence of typical 95% sensitivity with BAL and induced sputum
clinical profile63. respectively, using 18S rRNA sequence. Another
favoured candidate for PCR with reported
Gomori methanamine silver (GMS),
higher sensitivity compared to Mt LS rRNA has
Toluidine blue ‘O’ and Calcofluor white are the
been the MSG sequence73.
various stains, those outline the cyst wall.
Sensitivities of these stains varies from 49-60%,
with Calcofluor white being most sensitive 63, 65.
IN VITRO CULTIVATION
Cysts are seen as ovoid or cup-shaped grey
black stucture with GMS and blue coloured Mono-layer systems have shown only ten-
with Toluidine blue ‘O’ 64 . Cysts show light fold increase in the yield of P. jiroveci. Tissue
bluish-white fluorescence upon ultra-voilet culture systems used so far include human lung
light exposure at 346-365 nm with Calcofluor carcinoma cell line A 549, human lung fibroblast
white. Specificity of these staining techniques is line HEL and mink lung cell line Mv 1 Lu. In cell
close to 100 percent67. In a study66, only hyaline lines, P. jiroveci may be detected with
masses of 50-500 µ in size with rounded spaces
conventional or antibody stains74.
were appreciated in centrifuged unstained BAL
fluid and this methodology claimed 80% Very few studies have attempted to use cell
sensitivity as compared to direct immuno- free systems for cultivation of P. jiroveci. Acidic
fluorescene and high specificity in the hands of neo-peptone based medium, DMEM and RPMI
an experienced microbiologist. and 1640 have been found to maintain P. jiroveci
for four to seven days. Successful continuous
Fluorescence conjugated monoclonal anti-
axenic cultivation of P. jiroveci in minimal
bodies have been employed in detecting cyst
essential medium with defined supplements
and trophozoite forms of the organism from
has been reported. P. jiroveci growth could be
sputum, BAL, naso-pharyngeal aspirate and
detected by measurement of both ATP and PCR
lung tissue 58,67 . Monoclonal antibodies
based methods75.
developed so far are directed against 50-60 kDa
(group A) or 104 kDa MSG, present on all forms
of P. jiroveci 68. Flouroscent technique has higher PROPHYLAXIS AND TREATMENT
sensitivity as compared to conventional tests.
Similar results were also reported in an Indian As per guidelines laid down by Infectious
study in AIDS patients69. This test may be very Diseases Society of America regarding P. jiroveci
helpful in diagnosing pneumocystosis in prophylaxis 76 , HIV patients including those
patients without AIDS due to lower organism receiving HAART should receive primary
load 58,67. However, flouroscent technique is prophylaxis against P. jiroveci if the CD4+ T-
expensive and is of concern in most of the lymphocyte count is less than 200 cells/µl or
developing countries. there is history of oral candidiasis. Prophylaxis
Role of polymerase chain reaction (PCR) in should be also given to patients with CD4+ T-
detection of P. jiroveci nucleic acid has been lymphocytes less than 14% of total lymphocyte
studied extensively. Initial attempts at using the count or presence of AIDS defining illnesses.
2005; Vol. 47 The Indian Journal of Chest Diseases & Allied Sciences 279

Secondary prophylaxis is also recommended for unsuccessful as immunisation using injections


immunosuppressed individuals with history of of P. jiroveci cyst and Freund’s adjuvant failed to
previous attacks of P. jiroveci regardless of T-cell be protective81. Subsequently, it was shown that
count. HIV negative patients with immune immunisation of mother mice with P. jiroveci
dysfunction induced by inflammatory diseases, resulted in transfer of antibodies to pups. These
chemotherapy, radiotherapy and intake of pups cleared the P. jiroveci challenge
prednisolone more than 20 mg per day, should successfully82. Good protective responses were
also receive prophylaxis76. also noted in immunosuppressed rats
immunised with recombinant MSG antigen.
Trimethoprim-sulphamethoxazole (960 mg
However, naive antigen found to be
daily) is the regimen of choice for pneumo-
unsatisfactory83. Dendritic cells pulsed with P.
cystosis prophylaxis77. Alternative agents found
jiroveci P55 antigens have also been tried with
to be comparatively less effective in HIV-
good results 84 . An intra-nasal vaccine
infected individuals, include dapsone,
comprising P55 antigen with cholera toxin
nebulised pentamidine and atovaquone 78 .
factor B (PC-CTB) has also given encouraging
Prophylactic regime has had a major impact on
results85. However, these trials have been carried
incidence of P. jiroveci. Due to effective
out in experimental animals only. Human trials
prophylaxis, CDC Atlanta, reported conside-
are expected to provide better insight of their
rable reduction in incidence of P. jiroveci from
usefuleness in future.
1991 to 1996 based on data from 90 centers in
USA22. In conclusion, success in in vitro cultivation of
P. jiroveci would give further insights into the life
Trimethoprim–sulphamethoxazole is the
cycle, pathogenesis and basic biology of this
drug of choice for treatment 79 . Pentamidine
organism. This would help to understand the
(both aerosolised and intravenous), dapsone,
undetermined epidemiology and spread of
clindamycin, primaquin, trimethoprim-dapsone
pneumocystosis. Numerous options available
are the other commonly used drugs.
for diagnosis of P. jiroveci are seldom available in
Aerosolised pentamidine is less toxic but may
developing countries such as ours. A clear
not prevent or treat dissemination of P. jiroveci.
assessement of P. jiroveci profile in our country
Atovaquone, a newer anti-protozoal agent, has
would serve to reduce mortality in both AIDS
been approved for use in mild to moderate
and other immunosuppressed patients
pneumocystosis. It interferes with mitochon-
Furthermore, research towards better treatment
drial electron transfer80.
and prophylactic options is highly desirable in
Trimetraxate and eflonithine are other the wake of emerging resistance of P. jiroveci to
alternative agents used in moderate to severe trimethoprim-sulphamethoxazole.
pneumocystosis. Trimetraxate is a folic acid
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