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Respirology (2009) 14 (Suppl.

2) S44S50

doi: 10.1111/j.1400-1843.2009.01576.x

CHAPTER VII

Pneumonia in immunocompromised patients

SUMMARY
The diagnosis and identification of causative microorganisms of pneumonia are often difficult in
immunocompromised patients.
Immunosuppression can divided into three cate
gories; neutropenia (or neutrophil dysfunction);
humoral immunodeficiency and cellular immunodeficiency. Presumptive pathogen identifications
of pneumonia could be made systematically based
on the type of impaired immune function.
Since there are a number of diseases that must be
differentiated, the collection of respiratory tract
specimens and appropriate serum antigen tests
should be done whenever possible to identify the
causative microorganisms.
Empirical antibiotic therapy should be started as
soon as possible.
If initial treatment proves ineffective, invasive diagnostic procedures, including surgical lung biopsy,
should be considered.

What is immunocompromised?
(Fig. VII-1)
The major categories of immunosuppression are
neutropenia (or neutrophil dysfunction), humoral
immunodeficiency and cellular immunodeficiency.
Immunocompromised patients, however, often
have more than two of those categories of immuno
suppression in clinical settings.
Pneumonia is the most common infectious disease
for the immunocompromised host because the lungs
could be the portal of entry for a wide range of pathogens via respiration. The diagnosis of pneumonia and
identification of causative organisms are often complicated because radiographical imaging findings
and clinical symptoms of pneumonia could be different from those of immunocompetent patients as a
result of immunosuppression.

DIAGNOSIS OF PNEUMONIA IN
IMMUNOCOMPROMISED PATIENTS
1.Diagnosistic problems
Patients are often afeverile or have only a low-grade
fever due to the lack of appropriate immune reaction.

In addition, it is difficult to detect a subtle chest


radiographical changes when immunosuppression is
severe.
Pneumonia that develops in a patient with neutropenia following chemotherapy may suddenly become
obvious and serious as the neutrophil count improves.
The staining of sputum smears is not helpful in
many cases to identify causative organisms, since
patients tend to have little sputum. Patients who
are neutropenic have few neutrophils in the sputum,
and evaluating obtained samples is also difficult.
Antimicrobials are often used in immunocompromised hosts before the onset of pneumonia. In such
cases, there is a high possiblilty of pneumonia caused
by drug-resistant strains of bacteria or fungus. The
possibility of non-infectious pneumonia related to
the primary disease or associated treatment must
always be considered.

2.Tests required for diagnosis


Sputum or other samples derived from the respiratory
tract should be obtained whenever possible.
In cases when sampling is difficult, the inhalation of
hypertonic saline may facilitate specimen collection.
Specimens applied on slide glasses are examined
microscopically at a magnification of 100, and those
with a neutrophil count of more than 25 and epithelial cell count of less than 25 (Geckler classification,
group 5) are judged as the most appropriate samples
for examination. In sputum from neutropenic
patients, however, the specimen is judged to be
appropriate even when almost no neutrophils are
seen if the epithelial cell count is less than 25 (Geckler
classification, group 6).
When pneumonia is suspected, an evaluation of
chest CT findings could be of great help for the estimation of causative microorganisms by the charac
teristics and distribution of the lesions, and also could
give valuable information when invasive procedures,
such as BAL, are performed.1 For example, the diagnosis of Pneumocystis pneumonia (PCP), cytomegalovirus (CMV) pneumonia, pulmonary aspergillosis
and pulmonary tuberculosis could be suspected from
the characteristic CT findings. If the distribution of
lesions is not diffuse, bacterial pneumonia most likely
(Fig. VII-2). In cases where the initial empirical antimicrobial treatment is ineffective, the collection of
BAL specimens should be considered.

2009 The Japanese Respiratory Society


Journal compilation 2009 Asian Pacific Society of Respirology

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JRS Guidelines for Management of Hospital-Acquired Pneumonia


Humoral
immunodeficiency
-Globulin 500 mg/dL
Dysfunction of specific
antibody production

Neutropenia

Categories (of
immunosuppression)

500/L

Assumed
conditions

Cellular
immunodeficiency

(1) Haematological
malignancy

(1) Haematological
malignancy

(1) In HIV patients,

(2) Anticancer agent


use

(2) After splenectomy

(2) Severity cannot be assessed by the


CD4 count in the following:
Use of immunosuppressants
(steroids etc)
Use of anticancer agents
Haematological malignancy
Diabetes mellitus, renal failure
Use of biological preparations
(anti-TNF- therapy etc)

(3) Drug induced

(3) Anti-CD20
antibody use

*Immunocompromised patients often have more than two of those


categories of immunosuppression in clinical settings.

the CD4 count is 200 cells/L

Figure VII-1 Types of immunosuppression.

Localized infiltration
Initial treatment ineffective or pneumonia
occurring during antimicrobial use

Neutropenia
Aspergillus

Pneumonia of drug-resistant bacteria is


considered

Pneumococcus
Haemophilus influenzae

Pseudomonas aeruginosa
Serratia
Aspergillus
Cryptococcus
Nocardia
Actinomycete
Legionella
Mycobacterium tuberculosis
Non-tuberculosis mycobacteria

Cellular immunosuppression

Humoral immunosuppression

Nocardia
Mycobacterium tuberculosis
Non-tuberculosis mycobacteria
Cryptococcus

Causative microorganisms with a high frequency that should


always be considered
Staphylococcus aureus (MRSA)
Pseudomonas aeruginosa
Klebsiella
Enterobacteria

When treatment is ineffective

Neutropenia
Aspergillus
Pneumocystis
Diffuse infiltration
Cytomegalovirus
Mycobacterium tuberculosis

Humoral immunodeficiency
Pneumococcus
Haemophilus influenzae

The following should always be considered:


Pulmonary lesions related to the underlying disease
Drug-induced pneumonia associated with treatment of the
underlying disease

Cellular immunodeficiency
Pneumocystis
Cytomegalovirus
(rare in HIV patients)
Mycobacterium tuberculosis
Non-tuberculosis mycobacteria
Cryptococcus
Nocardia
Herpes simplex virus
RS virus
Varicella, herpes zoster virus
Adenovirus
Parainfluenza virus
Legionella
Pneumococcus
(considered in HIV patients)

Figure VII-2 Major causative microorganisms in pneumonia among immunocompromised patients.

2009 The Japanese Respiratory Society


Journal compilation 2009 Asian Pacific Society of Respirology

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When lesions are distributed diffusely, invasive


diagnostic procedure, such as BAL collection and
transbronchial lung biopsy (TBLB), should be con
sidered. Such invasive diagnostic procedures have
been shown to be effective in achieving a definitive
diagnosis.2-6
The value of the QuantiFERON test in diagnosing
tuberculosis in immunocompromised patients has
not been yet established.
Surgical lung biopsy is also considered when
treatment with a combination of antimicrobials is
ineffective, particularly in cases with diffuse pul
monary shadows on chest Xp and pneumonia/
pneumonitis related to the underlying disease or
associated treatment cannot be ruled out. A review of
medication history, side-effects from anticancer
agents and sites of exposure to radiation should
be conducted.

CHARACTERISTICS OF PNEUMONIA IN THE


IMMUNOCOMPROMISED HOST
1.Neutropenia (or neutrophil dysfunction)
(1) Background
Haematological malignancies, including leukemia
and lymphoma, and anticancer chemotherapy are
among the most frequent causes of neutropenia.
Drug-induced neutropenia or agranulocytosis is also
a important cause. HIV infection, which mainly leads
to cellular immunodeficiency, could also be a cause
of neutropenia in the advanced stage.
It is known that neutrophil phagocytic capacity and
bactericidal activity are impaired when steroids are
being administered, and that neutrophiil dysfunction
may exist even if the neutrophil count is within the
normal range.
The same neutrophil dysfunction is also known to
occur in patients with diabetes mellitus, uremia or
malignant tumours.

(2) Characteristics of pneumonia


In neutropenic patients, the severity and duration of
neutropenia are related to the risk of developing
pneumonia, and the longer the neutropenic state
lasts, the higher the risk of fungal infection, particularly pulmonary aspergillosis.
In neutropenic patients, chest radiography shows
some or no abnormal findings, even when the patient
has pneumonia. When pneumonia is highly suspected, performing a chest CT is recommended for
early diagnosis.
The value of a sputum smear examination to identify causative microorganisms is often limited since
purulent sputum is not easily obtained. Clinical
symptoms and radiographical findings of pneumonia
are often recognized just after the neutrophil count
recovers. In such a case, it is important to consider

Respirology (2009) 14 (Suppl. 2)

differentiation of the causative microorganism based


on the period in which the patient was neutropenic,
even if the neutrophil count is normal, The high incidence of non-infectious pneumonia/pneumonitis
related to the underlying disease must also be kept
in mind. The incidence of pulmonary invasion of
malignant cells, heart failure, pulmonary alveolar
haemorrhage and drug-induced pneumonia/
pneumonitis is high.7

(3) Causative microorganisms


X-rays showing localized consolidation usually
indicate an infection of bacteria including MRSA,
Klebsiella or Pseudomonas aeruginosa.8
However, if the disease develops while antimicrobials are being used or the response to initial anti
microbial treatment is poor, the probability of either
pneumonia of drug-resistant bacteria or pulmonary
aspergillosis is high.
In neutropenic states caused by anticancer
agents, cellular immunosuppression is also common
because co-existing severe lymphopenia is seen.
Therefore, in cases where the initial antibiotic treatment is ineffective, further tests and treatment should
be conducted with the possibility of PCP or CMV
pneumonia in mind (Fig. VII-2, 3). An investigation,
using protected BAL or PSB to avoid contaminantions
from the upper respiratory tract, shows that five of 63
neutropenic patients (haematological malignancy)
were diagnosed with viral pneumonia (2 patients with
herpes simplex virus, and one each with cytomegalovirus, RS virus and parainfluenza virus.2

2.Humoral immunodeficiency
(1) Background
Humoral immunodeficiency is often seen in haematological malignancies or following splenectomy.
Since the use of anti-CD20 antibodies has become
more common, particularly as a treatment for haematological malignancies, frequency of hypogam
maglobulinaemia has been increasing due to the
accompanying decrease in the B-cell count. Humoral
immunodeficiency caused by HIV infection is not
common, except in the advanced stage, however, it is
known that the production of specific antibodies is
impaired and that the risk of severe pneumococcal
infection is high in patients with HIV infection.9
Specific antibody production following inoculation
with the influenza vaccine is also impaired in HIVinfected patients.10
In clinical settings, humoral immunodeficiency is
encountered in combination with other types of
immunosuppression. The severity of humoral immunosuppression caused by anti-CD20 antibody treatment can be evaluated by the amount of -globulin.
In other conditions, the severity of humoral immunosuppression is difficult to evaluate by -globulin levels
alone.

2009 The Japanese Respiratory Society


Journal compilation 2009 Asian Pacific Society of Respirology

JRS Guidelines for Management of Hospital-Acquired Pneumonia

Local infiltration

S47

Diffuse infiltration

Sputum smear, culture


(bacteria, mycobacteria)
Chest radiography
Blood culture
Urine antigen test
(Legionella, pneumococcus)

Chest CT (HRCT)
BAL TBLB
CMV antigenemia

Initial treatment ineffective or


pneumonia occurs during antimicrobial
use

PCR or virus isolation (mycobacteria,


pneumocystis, herpes simplex virus)
in specimens derived from the
respiratory tract
Serum antigen test (Cryptococcus,
Aspergillus)
-D-glucan, endotoxin
CD4 count (with HIV)
Particularly when possibility of
pneumonia related to the primary
disease or associated treatment cannot
be ruled out TBLB surgical lung
biopsy

Figure VII-3 Tests conducted for diagnosis in pneumonia in immunocompromised patients.

(2) Characteristics of pneumonia


Since antibody-mediated phagocytosis promotion
and complement activation are impaired, pneumonia
caused by Streptcoccus pneumoniae showing resistance to phagocytosis tends to become more serious.

(3) Causative microorganisms


Streptcoccus pneumoniae, Haemophilus influenzae
and Klebsiella pneumoniae are important causative
microorganisms.

3.Cellular immunodeficiency
(1) Background
HIV infection is a typical condition that gives rise to
cellular immunodeficiency. Other common causes in
clinical settings are related to the use of anticancer
agents, steroids and immunosuppressants.
Diabetes mellitus is one of the main diseases
causing cellular immunosuppression; the relative
risk of tuberculosis in terms of prevalence is reported
to be 23.6 times higher than non-diabetic groups.11
Renal failure can also cause cellular immunosuppres-

sion and is associated with decreased reactivity


to the tuberculin skin test with a high prevalence of
tuberculosis.

(2) Characteristics of pneumonia


The severity of cellular immunosuppression caused
by HIV infection can be accurately assessed with the
CD4 count as an indicator. Likely pathogens can
often be predicted on the basis of CD4 counts, and
even with the same pathogen, radiographical and
clinical findings may differ according to the severity
of immunosuppression. Even with HIV infection,
opportunistic pathogens seldom give rise to pneumonia in cases where the CD4 count is 200/L or more.
With immunosuppression related to steroids or
other immunosuppressants, the general experience
has been that pneumonia, particularly PCP, appears
rapidly as cellular immunity recovers after immunosuppressants are decreased.

(3) Causative microorganisms


PCP, CMV pneumonia, pulmonary cryptococcosis,
tuberculosis and Legionella pneumonia are particularly important differential diagnoses. CMV pneumonia, however, is rare in patients with HIV infection. It

2009 The Japanese Respiratory Society


Journal compilation 2009 Asian Pacific Society of Respirology

S48

should be noted that CMV pneumonia often develops


in conjunction with PCP. The risk of subsequent
secondary bacterial pneumonia, as well as severe
primary influenza virus pneumonia, is high in the
bone marrow transplant patients, and the mortality
rate is reportedly high.12
The risk of bacterial pneumonia is high in patients
infected with HIV, and the incidence of communityacquired pneumonia is 5-times that in people without
HIV infection.13 The risk of pneumococcal pneumonia is particularly high.9 The radiograph of bacterial
pneumonia in HIV-infected patients often shows
bilateral shadows, identical to those seen in PCP.14 In
cases when cavitary pulmonary lesions are seen in
HIV-infected patients, bacterial pneumonia is more
likely than tuberculosis, and the causative organisms
are often Pseudomonas aeruginosa or Staphylococcus
aureus.15 In addition, in patients with HIV infection,
the CD4 count at the time of onset is the most impor
tant indicator in narrowing down the differential
diagnosis (Table VII-1). Image findings also
tend to be atypical depending upon the severity of
immunosuppression. Differential diseases that
should be considered with X-ray findings in HIV
patients are summarized in Table II-2.

DIAGNOSIS OF COMMON CAUSES OF


PNEUMONIA IN
IMMUNOCOMPROMISED HOST
1. PCP
In terms of incidence and mortality, PCP is the most
important opportunistic infection seen in patients
with cellular immunosuppression.

Table VII-1 Possible cause of pneumonia in HIV infected


patients based on the CD4 count
CD4 >200/L
Bacterial pneumonia (risk elevated with CD4 )
Tuberculosis (cavitation in upper lung field)
Non-Hodgkins lymphoma
CD4 <200
Pneumocystis pneumonia
Pulmonary cryptococcosis
Tuberculosis (infiltrative shadows, mediastinal
lymphadenopathy)
CD4 <100
Kaposis sarcoma
Toxoplasmic pneumonia
CD4 <50
Cytomegalovirus pneumonia
Mycobacterium avium complex (pulmonary lesions only are
rare)
Pulmonary aspergillosis (rare)
Disseminated histoplasmosis (rare in Japan)
Disseminated coccidioidomycosis (rare in Japan)

Respirology (2009) 14 (Suppl. 2)

The preventive effects of prophylaxis with trimethoprim-sulfamethoxazole 80/400mg once/day is


extremely high and almost enough to rule out the
the probability of the development of PCP under the
prophylactic regimen.
The diagnosis of PCP should be suspected from the
presence of cellular immunosuppression, elevated
level of LDH and typical chest X-ray findings
(which characteristically show diffuse, bilateral perihilar infiltrates).

Table VII-2 Differentiation of pneumonia in HIV-infected


patients base on radiographical findings
Alveolar shadows
Pneumocystis pneumonia
Bacterial pneumonia
Pulmonary tuberculosis (CD4 < 200/L)
Non-Hodgkins lymphoma
Miliary shadow
Miliary tuberculosis
Pulmonary cryptococcosis
Pneumocystis pneumonia
Mediastinal lymphadenopathy
Pulmonary tuberculosis (necrosis in central region with
contrast)
Kaposis sarcoma
Mycobacterium avium complex
Non-Hodgkins lymphoma
Linear, reticular shadows
Pneumocystis pneumonia
Cytomegalovirus pneumonia
Bacterial pneumonia
Non-Hodgkins lymphoma
Kaposis sarcoma
Nodular, mass shadows
Pulmonary tuberculosis (CD4 > 200/L)
Kaposis sarcoma (margin irregularity)
Cytomegalovirus pneumonia
Non-Hodgkins lymphoma (regular margin)
Pulmonary cryptococcosis
Pneumothorax
Pneumocystis pneumonia
Pleural effusion
Pleural tuberculosis
Kaposis sarcoma (bloody)
Bacterial pneumonia
Non-Hodgkins lymphoma (primary effusion lymphoma)
Cavitation
Pulmonary tuberculosis (CD4 >200/L)
Mycobacterium avium complex (immune reconstitution
syndrome)
Pulmonary abscess (Staphylococcus aureus, Pseudomonas
aeruginosa)
Cyst
Pneumocystis pneumonia

*Only representative differential diseases are listed.


*Bold type indicates particular importance according to
frequency.

2009 The Japanese Respiratory Society


Journal compilation 2009 Asian Pacific Society of Respirology

JRS Guidelines for Management of Hospital-Acquired Pneumonia

Measuring the serum level of beta-D-glucan is very


useful in the diagnosis of PCP, which has high sensitivity and specificity. The diagnosis of PCP, however,
cannot be completely ruled out, even if the serum
level of beta-D glucan is within normal range.
Bronchoscopic examination is recommended,
especially in people with HIV infection. Confirmation
of diagnosis requires demonstration of P. jiroveci
with Diff-Quik stain on Cytospin specimens prepared
from BAL fluid. Since people infected with HIV can be
pneumocystis carriers and remain asymptomatic,
taking sputum PCR positivity as grounds for diagnosis may lead to misdiagnosis. With PCP in HIVinfected patients, characteristic cystic changes in
chest X ray are often seen (1030%),16 and the finding
strongly suggests the diagnosis of PCP. (Table VII-2).
Unlike in HIV-infected patients, it is often difficult
to demonstrate P. jirovecii on the stained BAL specimen in non-HIV infected patients because of the
relatively small burden of the organisms in the lung.
Rapid progression to respiratory failure also makes it
difficult to conduct a invasive diangnositic approach,
such as bronchoscopy. However, differing from HIV
patients, there is a high probability of PCP when
sputum shows positive results on PCR.

2.CMV pneumonia
CMV pneumonia develops in association with other
causes of pneumonia, mainly PCP, than by itself.
Because the prognosis of CMV pneumonia is very
poor and confirmation of the diagosis is mostly difficult, treatment should be considered immediately
when CMV pneumonia is suspected by positive
result of CMV antigenaemia and clinical findings.
CMV pneumonia is the most common viral cause
of morbidity and mortality in patients with cellular
immunosuppression, but is exceptionally rare in
patients with HIV infection. Therefore, even if CMV
is detected from BAL fluid or blood in HIV patients,
initiation of CMV treatment is not generally
recommended.
In organ transplant patients, on the other hand,
CMV pneumonia is an important differential disease
and mortality is high unless treatment is started
immediately. Diagnosis should be made clinically as
soon as possible under some circumstances; the
positve result of CMV antigenemia, bilateral diffuse
infiltrations on chest X-ray, hypoxemia and the detection of CMV in BAL. The incidence of CMV pneumonia in organ transplant patients is reported to differ
depending on the transplanted organ.17 Incidence is
high with lung transplants (50%) and low with kidney
transplants (210%) (Table VII-3).

3. Pulmonary mycosis (except for PCP)


Pulmonary aspergillosis should be suspected first in
neutropenic patients, especially when initial antimicrobial treatment is ineffective. The following typical

S49

Table VII-3 Risks for CMV pneumonia


Allogeneic stem cell transplant
Lung transplant
Liver, heart transplant
Kidney transplant
Advanced HIV/AIDS
Autologous peripheral blood stem cell transplant
High-dose chemotherapy
Autoimmune disease

+++
+++
++
++
++
+
+
+

From Reference 21.

CT findings are useful in the diagnosis of pulmonary


aspergillosis:
(1)Ground-glass opacity surrounding the dense
nodular shadow (halo sign).
(2)Appearance of necrotic lung balls in infiltrations.
Both elevated level of surum beta-D-glucan and
positive serum Aspergillus antigen tests are suggestive for the diagnosis, but their sensitivity are
not high enough. The histopathological demonstration of hypha of Aspergillus spp. in the TBLB
specimen can confirm the definitive diagnosis.
In pulmonary cryptococcosis, the serum cryptoc
occus antigen test is highly sensitive and specific
(8090%) and is very useful in diagnoses . Among HIV
patients in particular, attention is needed for the frequent complications in PCP. Serum beta-D-glucan
level is not elevated in pulmonary cryptococcosis.
Multiple nodular shadows just below the pleurae are
thought to be characteristic radiographical findings,
but they can be diverse and the possibility of cryptococcosis should not be excluded based on image findings alone. Pathological diagnoses with TBLB or BAL
are also useful.

4.Tuberculosis
Diabetes mellitus is the most common risk factor of
tuberculosis. According to a report by Yamagishi
et al.,18 the rate of complications with diabetes in
pulmonary tuberculosis patients was 14.6% in 2001,
increasing each year afterward to reach 28.2% in
2005. Many reports have described higher rates of
cavitation in diabetic patients than in non-diabetic
patients. Nakamoto et al.,19 reported cavitation in
71.4% of a diabetes mellitus group, higher than the
rate of 53.8% in all patients.
Dialysis patients are also vulnerable to tuberculosis, with rates 6.4 times higher in males and 16 times
higher in females compared with general populations
matched for age and sex, and mortality is also high.20
Image findings of tuberculosis in HIV patients are
known to vary depending on CD4 count (VII-1, 2), and
clinical findings are also atypical in HIV-infected
patients, which make the diagnosis often difficult. In
cellular immunosuppression with CD4 counts below
200/L, infiltrations in the inferior lobes are often
presented, and swelling of mediastinal and hilar
lymph nodes together with enhanced periphery and
internal low density on contrast CT are useful findings

2009 The Japanese Respiratory Society


Journal compilation 2009 Asian Pacific Society of Respirology

S50

for diagnosis. In cases of pneumonia in HIV patients,


sputum smears and cultures should always be performed to exclude the possibility of tuberculosis.

Conflict of Interest
No conflict of interest has been declared by The
Committee for the Japanese Respiratory Society
guidelines for the management of respiratory
infections.
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2009 The Japanese Respiratory Society


Journal compilation 2009 Asian Pacific Society of Respirology