++
Pneumocystis pneumonia
(PCP) occurs almost exclusively in the severely immunocompromised
host, especially patients with congenital immunodeficiency diseases,
AIDS, and cancer, and those who have had organ transplantation. Once
pneumonia is apparent, the fatality rate is near 100% if
untreated. Effective therapeutic and prophylactic drugs are available. The
causative agent is a protozoan-like fungus known for the past century
as Pneumocystis carinii. Recently, the term Pneumocystis
jirovecii has been proposed for the organism found in humans,1 but
acceptance has not been universal.2
++
Pneumocystis infection is recognized among humans
and lower animals worldwide. The natural habitat and mode of transmission
in man are unknown, but animal studies suggest animal-to-animal
transmission occurs by the airborne route.3-5 Animal-to-human
transmission has not been reported, and available evidence suggests
that human-to-human transmission is possible.11 Symptomatic
infection occurs sporadically in immunocompromised individuals.
++
PCP was first recognized in humans by Van der Meer and Brug in 1942.6 During
this time, epidemics of interstitial plasma cell pneumonitis were
occurring in European infants. In the 1950s, several reports confirmed
that Pneumocystis was the etiology of epidemics
of interstitial plasma cell pneumonitis in European infants.7
++
With the advent of immunosuppressive therapy for cancer and methods
for diagnosing congenital immunodeficiency disorders, PCP became
recognized as a potentially fatal infection in such individuals.8-10
++
Intrauterine transmission of Pneumocystis has
also been reported.12,13 Of eight pregnant women with AIDS
and PCP, one infant had Pneumocystis infection.14,15 Considerable
data show that at least 75% of normal children reaching
4 years of age have acquired antibody to Pneumocystis and
that more than 90% of normal adults have detectable antibody.16-18,19 Furthermore,
a prospective study of otherwise normal infants, ages 2 to 12 weeks,
with pneumonia showed that 10 of 69 babies had detectable antibody
to Pneumocystis and that one of the 10 infants
had PCP.20 In serial observations of 107 normal infants, Pneumocystis DNA
was detected in nasopharyngeal aspirates in 74 of the infants tested.21 In
addition, Pneumocystis has been associated with
sudden infant death syndrome (SIDS), but no cause and effect has
been proven.22,23 The natural course of PCP can be delineated
from studies done before the advent of chemoprophylaxis in 1977
in individuals at high risk for PCP. Data collected at the Centers
for Disease Control (CDC) revealed 194 documented cases of PCP encountered
in the United States during the 3-year period from 1967 to 1970.
Twenty-five (12.9%) of these cases had primary immunodeficiency
disorders; 91 (47%) had leukemia; 41 (21%) had
other malignancies; 22 (11%) were organ transplant recipients,
and 15 (8%) had other immunocompromising conditions.24-26From
1962 to 1971, the incidence of PCP was determined in 1251 children
with malignancies and 379 patients with nonmalignant neoplasms or
immunodeficiency diseases at St. Jude Children’s Research
hospital; PCP was found in 4.1%, 0%, and 0% of
patients, respectively.27 The incidence of PCP in cancer patients
is influenced more by the extent of immunocompromise from treatment
than the primary disease. In a controlled study of 160 children
with acute lymphocytic leukemia without PCP prophylaxis and on intensive antileukemia
therapy, 20% were found to have developed PCP.28Other
at risk populations include those immunosuppressed for solid organ
transplantation30, rheumatoid arthritis, lupus erythematosus,
and other connective tissue diseases in adults with CD4+ T
lymphocyte counts less than 250/mm3.31
++
A 1999 review of 4581 solid organ transplant recipients who were
not receiving prophylaxis found 4.9% had PCP.30 A
2006 report showed PCP is emerging as a complication of immunosuppressive
therapy for patients with rheumatoid arthritis, lupus erythematosus,
and other connective tissue diseases in adults with CD4+ Tlymphocyte
counts less than 250/mm3.31
++
Patients with HIV are ideal targets for PCP because of a profound
defect in their cell-mediated immune responses. Early in the AIDS
epidemic, when no antiviral therapy was available and chemoprophylaxis
for PCP was not applied, some 75% of adults and 39% of
infants with AIDS acquired PCP.32,33,34 In infants and
children with HIV infection, PCP occurs most often in infants between
3 and 6 months of age.33-35 The use of PCP prophylaxis
and highly active antiretroviral therapy (HAART) has profoundly
reduced PCP in patients with AIDS. Before HAART (from 1981–1988),
the incidence of PCP in 3331 HIV-infected children was 1.3 cases
per 100 person-years; after the introduction of HAART (2001–2004), the
incidence of PCP in 2767 HIV-infected patients decreased to less than
0.5 per 100 person-years.36 The Perinatal AIDS Collaborative Transmission
Study showed a 95% decrease in PCP (cases per 100 patient-years),
from 5.8 in the pre-HAART era to 0.3 in the HAART era.37,38
++
While the incidence of PCP has declined in children with AIDS
in the United States, the incidence has increased in Africa. From 1992
to 1993, 16% of children dying with AIDS had PCP39;
29% of those dying from 1997 to 200040 and 44% of
those dying between 2000 and 2001 had PCP.41
++
As with other immunosuppressed states, highly significant risk
factor for PCP in HIV-infected patients is a marked reduction in
the CD4+ T lymphocyte count.
++
The portal of entry for Pneumocystis is believed
to be the respiratory tract via the airborne route. In the infected
lung, the organism is found in both cystic and extracystic forms.
The cyst is a round, oval, or cup-shaped structure approximately
4 to 6 microns in diameter (Fig. 353-1).
Within the mature cyst are as many as eight daughter cells, referred
to as sporozoites, that are pleomorphic and often crescent
shaped. These cells eventually excyst through breaks in the cyst
wall. Outside the cyst, the daughter cell, now termed a trophozoite, varies
from 2 to 5 microns in diameter. These thin-walled trophozoites
tend to cluster in masses.
++
++
In the normal, healthy individual, Pneumocystis may
lie dormant in the alveoli, eliciting no tissue response and leaving
the host asymptomatic.42 In the severely immunocompromised
host, organisms replicate to large numbers and an extensive diffuse
alveolar disease and interstitial infiltration may progress to death.
++
Pneumocystis attaches to the alveolar epithelial cells,
and alveolar macrophages ingest and degrade the organisms; this
provokes neutrophil, lymphocyte, and monocyte infiltration
and cytokine release. Alveolar disruption impedes gas exchange and
leads to respiratory failure.43,44 The CD4+ T
lymphocyte serves to recruit and activate other immune effector cells.45,46There
is an increase in CD8+ lymphocytes in
the lungs.47 Surfactant phospholipids are reduced in PCP,
further impairing pulmonary function.48-51 Although using
surfactant in clinical application in humans has not been adequately
studied, a case report describes immediate improvement in an infant
with respirator-dependent PCP upon administration of synthetic surfactant
via endotracheal tube.52
++
The clinical manifestations of PCP may present abruptly as an
acute febrile episode with respiratory symptoms or a more subtle
subacute illness with little or no fever. In all cases, tachypnea,
cough, dyspnea, and oxygen desaturation occur. Typically, the chest
radiograph shows bilateral, diffuse alveolar disease with symmetric reticular
(interstitial) or granular opacites (eFig. 353.1).
However, by the time pneumonitis is discernible by radiograph, tachypnea,
flaring of nasal alae, intercostal retractions, and even cyanosis
may be evident on examination. Even with diffuse pneumonitis, rales
may not be heard. Once pneumonitis is evident, the infection progresses
to a fatal outcome in nearly 100% of cases if untreated.
++
++
Atypically, lobar, nodular, or miliary lesions
are found. The type of clinical presentation is generally related
to the patient’s age and the underlying primary disease
and its treatment. Infants tend to have the slower subacute course,
and older children have the acute onset. Studies have found that
HIV-infected patients present with a higher arterial oxygen tension
and a lower alveolar-arterial oxygen gradient than other immunocompromised
hosts.42
++
In children with severe protein-calorie malnutrition the onset
is often subtle, with chronic diarrhea and weight loss preceding
the onset of cough, tachypnea, and dyspnea. Fever is often absent,
and symptoms may persist for several days before evidence of pneumonitis
is seen on the chest radiograph.53 By the time pneumonitis
is discernible by radiograph, tachypnea, flaring of nasal alae,
intercostal retractions, and even cyanosis may be evident on examination.
Even with diffuse pneumonitis, rales may not be heard.
++
It is important to note that both the acute and subacute presentation for
PCP may occur in any immunosuppressive disease and in any age group.
Hypoxia, as revealed by decreased arterial oxygen tension, is found
in essentially all cases of PCP.
++
A recent study of HIV-infected children with pneumonia showed four
clinical factors were independently associated with PCP: respiratory
rate greater than 59 respirations per minute, arterial hemoglobin
saturation (SaO2) less than or equal to 92%, less than
6 months of age, and the absence of vomiting.54
++
In patients with PCP, the disease and the organisms remain localized
to the lungs, even in fatal cases, with rare exception. Rarely Pneumocystis has
been found in extrapulmonary sites, including meninges, spleen, liver,
pancreas, thyroid, brain, kidneys, bone marrow, heart, lymph nodes,
ears, eyes, stomach, intestinal tract, ureter, muscles, adrenal glands,
and peritoneum. Usually no clinical manifestations are associated
with these infected sites.
++
In a recent study of 56 cancer patients with PCP, the clinical
manifestations included fever in 86%, dyspnea in 79%,
and cough in 57% of the cases. The pneumonitis presented
with severe hypoxemia (PaO2 = 50–70 mm
Hg) and bilateral interstitial infiltrates (80%) and bilateral
ground-glass appearance (89%) by computed tomography. Sixteen
(29%) patients required assisted mechanical ventilation and
11 (19.6%) died.55
++
A definitive diagnosis requires the demonstration of Pneumocystis in
infected lung tissue or in material from the lung that is obtained by
bronchoalveolar lavage (BAL); induced sputum; or open lung, transbronchial,
percutaneous, or endobronchial brush biopsies. BAL is usually the
preferred procedure for children, although the lung biopsy remains
the “gold standard,” because it provides histology
of the disease. The
specimen is stained with Gomori, toluidine blue O, calcofluor white, or Giemsa stains (see Fig.
353-1 and eFigs. 353.2, 353.3,
and 353.4). A fluorescence-conjugated
monoclonal antibody (Meriflour, Meridian Bioscience, Cincinnati)
is highly sensitive and specific (eFig. 353.5). Serum antibody titers to Pneumocystis are
of no diagnostic value.
++
++
++
++
++
Pneumocystis DNA/RNA has been detected
in lung tissue, in sputum, and in oral and nasal secretions by polymerase
chain reaction (PCR), but this approach has not been adequately
standardized and studied to adopt for diagnosis. While lung biopsy
is the most sensitive and specific procedure and provides histopathology
on the extent of disease process (eFigs. 353.4 and 353.5), BAL is usually the procedure initially
used because of the possible complications from general anesthesia,
pneumothorax, hemorrhage, and pneumomediastinum with biopsy. The
reported diagnostic sensitivity of BAL ranges from 89% to
greater than 98%.56,57
++
Due to the dearth of data on induced sputum in infants and children,
the sensitivity of the procedure for diagnosis is not known. However,
if microscopic methods find Pneumocystis in the
sputum of a patient of any age who has clinical evidence of pneumonitis,
it can be dependably accepted as diagnostic of PCP. If the first
induced sputum sample is negative, a BAL is warranted.58
++
Because Pneumocystis is highly resistant to
acid and because PCP is associated with a massive number of organisms
in the lungs, gastric lavage might provide a means to obtain diagnostic
specimens (as with acid-fast mycobacteria). The early study of Chan
and colleagues59 found Pneumocystis in
gastric aspirates of 23% of children with PCP, and none
of the uninfected controls yielded the organism. More recently,
a study60found that 48.6% of 35 children with
HIV and respiratory symptoms suggestive of PCP had microscopically
detectable Pneumocystis in nasogastric aspirates.
Also, studies of 105 gastric aspirates from 52 infants and children
in Bangkok showed Pneumocystis in 11 (10%)
of the samples done by immunofluorescence antibody test and showed Pneumocystis DNA
in 13% of the samples done by single-step PCR and 62% done by
nested PCR (eFig. 353.6). There was moderate
agreement with single-step PCR but none with nested PCR.61
++
++
Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred drug for
treating Pneumocystis pneumonia (Table
353-1). The dosage is based
on 20 mg of TMP and 100 mg SMX per kg per day orally, or three fourths
of this dose given IV in 3 or 4 doses. A 2-week course is usually
adequate for patients without AIDS, but at least 3 weeks of treatment
is needed for patients with AIDS.
++
++
TMP-SMX is usually administered intravenously at first. When there
is evidence of clinical improvement and the patient can take and
tolerate oral therapy, the drug combination can be given orally, using
either tablets or suspension. The recommended doses provide an effective
therapeutic serum concentration of 5 to 10 mcg/mL of TMP.62 Because
patients who have one episode of PCP and recover are at high risk
for a recurrent episode, all individuals treated for PCP should
be maintained on TMP-SMX at prophylactic doses indefinitely or until
the immunocompromised state is resolved.63 TMP-SMX is generally
well tolerated, but HIV-infected patients have an exceptionally
high rate of adverse reactions.64 These include rash, fever,
anorexia, nausea, vomiting, diarrhea, leukopenia, thrombocytopenia,
anemia, renal toxicity, and exfoliative skin disorders (Stevens-Johnson
syndrome). Unless the reaction is mild and insignificant, TMP-SMX should
be discontinued and therapy continued with another drug, usually
pentamidine. About 15% of HIV-infected children have substantial
adverse reactions to TMP-SMX.65
++
Pentamidine is recommended for patients who cannot tolerate or
who do not respond to TMP-SMX. The drug must be administered parenterally
and is frequently associated with nephrotoxicity, hypoglycemia,
and other adverse effects. Pentamidine is given as a single IV dose
at 4 mg/kg. Pentamidine isethionate is available only by
the intravenous, intramuscular, and aerosol routes. Aerosolized
pentamidine is only minimally effective for therapy and should not
be used. The intravenous route is preferred to avoid the severe
cutaneous reactions encountered from intramuscular administration.
Pentamidine is highly toxic, causing nephrotoxicity, hypokalemia,
hypo- and hyperglycemia, pancreatitis, leukopenia, cardiac arrhythmias,
and cutaneous sterile abscess and necrosis. Adverse reactions occur
in up to 80% of patients receiving pentamidine, and the
drug must be discontinued in half the cases.66-70
++
Other drugs with demonstrated efficacy for treating PCP are atovaquone,
dapsone plus trimethoprim, fansidar, and clindamycin plus primaquine (Table 353-1). Atovaquone offers a safe alternative
to TMP-SMX and is available only as an oral suspension (750 mg per
5 ml). It has been evaluated for treatment of PCP in adults with
AIDS and was found to have therapeutic efficacy related directly
to the plasma concentration of the drug.71 At a mean steady-state
concentration of at least 15 mcg/mL, therapeutic success
was achieved in more than 95% of cases; at levels of 5
to 10 mcg/mL, only 69% had successful outcome.
Thus, it is essential to emphasize the administration of this medication
with food (preferably fatty meals), which will provide a two- to
threefold greater plasma concentration than when administered in
a fasting state. Adverse events with atovaquone therapy include
nausea, vomiting, diarrhea, and rash. No fatal adverse reactions
have been reported.72,73
++
The combination of dapsone and trimethoprim has proven effective in
treating PCP in adults with AIDS. Trimethoprim alone has little,
if any, effect on PCP but is synergistic to enhance therapeutic efficacy
of dapsone. Dapsone alone is effective in only about 61% of
cases, while dapsone plus trimethoprim is effective in 100% of
cases.74,75 Reversible neutropenia is a common adverse
effect of dapsone. Other side effects to dapsone are rash, methemoglobinemia,
anemia, thrombocytopenia, and elevated transaminases.76
++
Lack of data on the use of clindamycin plus primaquine to treat PCP
in children relegates this regimen to cases where the aforementioned
regimens cannot be used.
++
Trimetrexate, a folate antagonist that was once used to treat
PCP in adults, has been removed from the market by the manufacturers
and is no longer available.
++
Supportive measures are important in managing PCP. Administering
oxygen and using assisted mechanical ventilation are indicated with
severe hypoxia. Evidence suggests that using a corticosteroid may
enhance survival in patients with moderate and severe PCP.77-79 With
PaO2 values less than 70 mm Hg or an alveolar-arterial
gradient of greater than 35 mm Hg, the administration of a corticosteroid such
as prednisone is recommended (see Table 353-1 for
doses).
++
Once pneumonitis is evident on chest radiograph, PCP is fatal
in approximately 100% of cases if untreated. When defervescence
reveals signs of clinical improvement from treatment, a decrease
in respiratory rate and an increase in PaO2 may be seen
at a mean of 4.5 ±2.5 days and improvement in chest radiograph may
be seen at 7.7 ±4.5 days after treatment begins.80
++
Pneumocystis pneumonitis can be prevented by the
prophylactic use of TMP-SMX in a dosage of 5 mg of TMP and 25 mg
of SMX per kg per day orally (daily or 3 days a week) in equally divided
doses. For patients who cannot tolerate TMP-SMX, atovaquone, dapsone,
and aerosolized pentamidine are effective alternatives (Table 353-2).76,81-83,84 The host
is protected for only as long as the drug is administered. Updated
CDC and NIH guidelines established for prophylaxis in infants and
children with HIV infection recommend the following individuals
receive PCP prophylaxis: all HIV-infected and indeterminate infants
ages 1 to 12 months; children ages 1 through 5 years with CD4+ T lymphocyte
counts of less than 500/mm3 (or < 15%);
and children age 6 years and older with CD4+ T
lymphocyte counts of less than 200/mm3 (or <
15%).38 Other patients at high risk for PCP and
who warrant prophylaxis are those who have received organ transplants,
those who have certain malignancies and congenital immunodeficiency
syndromes, and those who require prolonged immunosuppressive therapy.
++
++
When deciding which patients should receive chemoprophylaxis, the
following high-risk factors should be considered: all HIV-infected
patients as defined above; lymphoproliferative malignancies; prolonged
corticosteroid therapy; extensive impairment of cell-mediated immunity
(eg, severe combined immunodeficiency syndrome, S-linked CD 40 ligand deficiency);
CD4+ T lymphocyte counts less than 200/mm3 (15%);
severe malnutrition; bone marrow transplant recipients; certain
solid organ transplant recipients; previous episode of PCP; brain
tumor; and Wegener’s granulomatosis.
++
Trimethoprim-sulfamethoxazole has been the preferred drug for PCP
prophylaxis for 3 decades and has been thoroughly evaluated in children
with AIDS and in those with non-AIDS immunosuppressive diseases.
In a recent randomized, placebo-controlled study of 534 HIV-infected
children in Zambia, patients received TMP-SMX or placebo for prophylaxis along
with antiretroviral therapy (ART). The mortality rate was 14 deaths
per 100 child-years in the TMP-SMX group and 23 deaths per 100 child-years
in the placebo group, showing prophylaxis reduced fatalities and
prevented PCP.85 Generally what is observed with PCP in
AIDS patients is somewhat similar to what occurs in non-AIDS patients,
except adverse reactions to TMP-SMX are more frequent in HIV-infected
patients than in those without HIV.When non-life-threatening adverse
effects occur, TMP-SMX can be discontinued; when the reaction has resolved,
the drug combination can be restarted with a desensitizing scheme.86 If
the initial adverse reaction is life-threatening, stop TMP-SMX and
use an alternative drug. Usually atovaquone or dapsone is the drug
of second choice.
++
Atovaquone is effective and safe for PCP prophylaxis. A major
disadvantage of atovaquone is its cost. A month of prophylaxis with atovaquone
costs about 40 times that of TMP-SMX. Unlike TMP-SMX, atovaquone
has no antibacterial activity but is effective against Toxoplasma
gondii, Babesia species, and malaria.
A prospective controlled study compared atovaquone plus azithromycin
with TMP-SMX in 366 HIV-infected children at high risk for PCP.81 Results
showed the regimens were equally effective in preventing PCP and
bacterial infections. In a recent study, 86 children with leukemia
who were intolerant to TMP-SMX received atovaquone prophylaxis over
a period of 172 patient-years. No cases of PCP occurred, and no
significant adverse effects were found.87 Daily atovaquone
prophylaxis has been shown to be as effective as dapsone82 and
aerosolized pentamidine.88 Dapsone is as effective as atovaquone
or aerosolized pentamidine for prophylaxis but is possibly less effective
than TMP-SMX.76,82 Similarly, no cases of PCP were encountered
in peripheral blood stem cell transplant recipients receiving either
TMP-SMX or atovaquone, while treatment-limiting adverse reactions
occurred in 40% of those on TMP-SMX and none of those given
atovaquone.89
++
Dapsone is a sulfone with several known adverse effects; however,
it has been proven relatively safe for PCP prophylaxis. The long
plasma half-life of dapsone allows its use as a once-a-day or once-a-week dosage
administration.90 This drug is as effective as atovaquone
or aerosolized pentamidine for prophylaxis but is possibly less effective
than TMP-SMX.76,82
++
The pediatric dosage for aerosolized pentamidine is 300 mg once
a month; the same dose is recommended for adults.91 This
drug is somewhat more cumbersome to administer than dapsone or atovaquone
but has the advantage of compliance through direct observational
therapy once a month.92 During and following administration
with the Respirgard II nebulizer, patients should be observed for
cough and bronchospasm.84
++
Once PCP prophylaxis has been started, it should be continued
as long as the susceptible immunocompromised state exists. Usually within
3 to 6 months after completion of chemotherapy, the prophylaxis
can be stopped. Recent studies in both adults and children with
AIDS show that those on HAART who achieve immune reconstitution
of CD4+ T lymphocyte to greater than
15% may have PCP prophylaxis discontinued if monitoring
with CD4+ T lymphocyte count is continued.38,65,93,95-97