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Human Pneumocystosis
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.
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
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
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