Nonresolving pneumonia

INTRODUCTION — Slow or incomplete resolution of pneumonia despite treatment is a

common clinical problem, estimated to be responsible for approximately 15 percent of
inpatient pulmonary consultations and 8 percent of bronchoscopies [1]. There are a
variety of reasons that a case of pneumonia might resolve slowly or incompletely,
including those relating to the etiology of the pneumonia (misdiagnosis of the pathogen
or the presence of a resistant pathogen); those relating to the host, including
mechanical processes; and the development of complications from the initial infection.
In addition, noninfectious etiologies of pulmonary infiltrates can mimic infectious
pneumonia, thus making it appear that resolution is not following the expected course.
Approximately 20 percent of presumed nonresponding community-acquired pneumonia
is due to noninfectious causes [2]. Despite the frequency of this problem, there has
been a paucity of studies specifically addressing this issue.

In this review, we will use the term "nonresolving pneumonia" to include those cases of
presumed pneumonia that progress, resolve slowly, or fail to achieve complete
resolution despite what is thought to be appropriate therapy. We will first discuss those
factors that normally affect the resolution of pneumonia, and we will then focus on
specific causes of nonresolving pneumonia. Aspiration pneumonia, community-acquired
pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, and the
approach to fever and pulmonary infiltrates in the immunocompromised patient are
discussed separately.

NORMAL VERSUS DELAYED RESOLUTION OF PNEUMONIA — Normal resolution

of pneumonia is not easily defined and may vary depending upon the underlying cause.
Patients typically note subjective improvement within three to five days of treatment;
more specific clinical criteria for resolution include improvement in tachycardia and
hypotension, which are expected to improve in two days; fever, tachypnea, and arterial
oxygenation (PaO2), which are expected to improve within three days; and cough and
fatigue, which may take 14 days or longer to improve [3,4]. The 2009 British Thoracic
Society guidelines for the management of community-acquired pneumonia suggest that
chest x-ray and hospitalization be considered for outpatients with pneumonia who fail to
improve after 48 hours of treatment [5].

Most studies on the natural history of pneumonia have focused upon the resolution of
chest radiographic abnormalities, with "slow resolution" often being defined as the
persistence of radiographic abnormalities for greater than one month in a clinically
improved host [6].

Determining whether a patient has nonresolving or progressive pneumonia must also

take into account several factors that affect the expected rate of resolution. These
include:
 ● Comorbidities – Comorbid conditions often slow the resolution of pneumonia.
Whereas patients without associated medical illnesses usually demonstrate
clearing of radiographic infiltrates by four weeks, only 20 to 30 percent of patients
with a comorbid condition will clear by four weeks [7,8].

● Age – Approximately 90 percent of patients younger than 50 years of age show

radiographic resolution by four weeks, compared with only 30 percent of patients
older than 50, even in the absence of concurrent disease [9].

● Severity – Radiographic resolution of severe pneumonia is estimated at 10 weeks,

compared with three to four weeks for mild to moderate pneumonia.

● Infectious agent – The rate of radiographic and clinical improvement varies with the
particular infectious agent causing the pneumonia. In general, resolution is more
rapid with Mycoplasma pneumoniae, nonbacteremic Streptococcus pneumoniae,
Chlamydia species, and Moraxella catarrhalis than with other organisms [10].

EVALUATION OF NONRESOLVING PNEUMONIA — Evaluation of patients with an

apparent nonresolving pneumonia generally centers around more detailed imaging
studies or obtaining material for microbiologic and pathologic analysis.

Approach to diagnosis — The diagnostic evaluation of treatment failure in

pneumonia begins with a careful history, physical examination, and review of the
medical record. Whether or not the rate of resolution is within the range of expected
norms, taking into account the patient's underlying host factors, comorbidities, severity
of illness, and suspected pathogen must be established. In stable or slowly improving
pneumonia, especially in the presence of comorbidities or host factors that are known
to delay the resolution of pneumonia, careful
observation with or without therapy is warranted for four to eight weeks. If there is no
resolution or progression of disease, a more aggressive diagnostic approach is
appropriate [11,12].

If further evaluation is necessary, it should include a chest CT to look for sequestered

areas of infection or for findings that suggest an alternative diagnosis. When
pneumonia fails to resolve or when there is clinical progression, fiberoptic
bronchoscopy should be considered. Patients with a negative bronchoscopic
examination have a good chance of merely having a slowly resolving pneumonia,
particularly if they are smokers or over age 55. Diseases not readily or typically
diagnosed with fiberoptic bronchoscopy include pulmonary vasculitis syndromes,
bronchiolitis obliterans organizing pneumonia, and diffuse alveolar damage of various
etiologies. With a worsening chest radiograph and progressive symptoms accompanied
by a negative bronchoscopy, further evaluation with thoracoscopic or open lung biopsy
may be necessary.

Imaging studies — Chest CT, particularly high resolution chest CT, is the primary
radiographic tool for assessing treatment failure of a presumed pneumonia. Compared
with conventional chest radiography, high resolution chest CT allows superior detection
of parenchymal abnormalities, including emphysema, airspace disease, interstitial
disease, and nodules. Such findings may narrow the differential diagnosis or suggest
new possibilities not previously under consideration. Chest CT also detects
sequestered foci of infection, such as lung abscess and empyema, and helps direct
biopsy procedures

Bronchoscopy — The relative ease and low risk of fiberoptic bronchoscopy make this
the primary diagnostic procedure to obtain specimens from patients with a wide
spectrum of possible infectious and noninfectious etiologies of nonresolving or
progressive pneumonia. However, despite the frequency of its use for this indication,
there are few studies that document the diagnostic yield of fiberoptic bronchoscopy for
nonresolving pneumonia.

Objective data suggest that fiberoptic bronchoscopy with bronchoalveolar lavage and
transbronchial biopsy can successfully diagnose approximately 90 percent of patients
who eventually have a specific diagnosis established. It is most likely to be useful in
younger, nonsmoking patients with multilobar involvement and prolonged disease,
whereas elderly patients, smokers, and those with immunodeficiency are more likely to
have a nondiagnostic bronchoscopy and to have a slowly resolving pneumonia [13].
Bronchoscopy is particularly useful to exclude mycobacteria or fungi if not detected with
expectorated sputum [12]. Development of endobronchial ultrasound has improved
the value of fiberoptic bronchoscopy and should be considered as an alternative to
mediastinoscopy when mediastinal lymph nodes are enlarged.

Thoracoscopic or open lung biopsy — Several factors need to be considered when

deciding to proceed to a more invasive biopsy procedure, such as thoracoscopic or
open lung biopsy. A previous nondiagnostic bronchoscopy, concern about the specific
patient's risk or ability to tolerate bronchoscopy, or the need for obtaining larger
specimens of tissue for certain diagnoses under serious concern, may all support the
need for proceeding to thoracoscopic or open lung biopsy.

INFLUENCE OF SPECIFIC BACTERIAL PATHOGENS — Data are available regarding

resolution of pneumonia caused by different etiologic agents, including factors that
affect the course of particular types of pneumonia. It should be noted that the empiric
approach to treatment of community-acquired pneumonia (CAP) and hospital-acquired
pneumonia (HAP) suggested by most guidelines can result in failure to treat
appropriately when pneumonia is the result of less common pathogens, like anaerobes
and fungi.

Streptococcus pneumoniae — Because pneumococcal pneumonia represents the

most common cause of community-acquired pneumonia, it also is responsible for most
cases of nonresolving pneumonia syndromes that are due to infection. In normal
individuals without predisposing illness, clinical improvement is relatively rapid and
precedes radiographic improvement. The maximum temperature generally decreases
over the first 48 to 72 hours in patients with lobar pneumonia but may not resolve
completely for several more days; however, only 6 percent of patients remain febrile
beyond 20 days [10].

Risk factors for delayed resolution of auscultatory findings and fever include more
severe presentation, multilobar disease, and infection with drug-resistant organisms.
Radiographic improvement is often much slower, with 20 to 30 percent of patients
demonstrating no radiographic improvement after one week. Initial worsening of the
chest radiograph is common. Risk factors for delayed radiographic resolution include
bacteremia, persistent fever or leukocytosis beyond six days, advanced age, chronic
obstructive pulmonary disease, alcoholism, and HIV.

Radiographic clearing occurs by one to three months in nonbacteremic cases and three
to five months in bacteremic cases. Residual radiographic abnormalities are rare in
nonbacteremic cases but are present in up to 35 percent of bacteremic cases [14].

Legionella infection — Many of the risk factors for development of Legionella are also
risk factors for delayed resolution. These include cigarette smoking, alcoholism, age
greater than 65 years, immunosuppression (especially glucocorticoid use), chronic
kidney disease, and hematopoietic stem cell and solid organ transplantation. As a
result, the rate of resolution for Legionella infection is usually slower than for other
organisms [15].

Radiographic, but not necessarily clinical, deterioration despite treatment is common,

occurring in up to two- thirds of patients with Legionella, compared with 4 percent of
patients with nonbacteremic pneumococcal pneumonia. In addition, after this initial
deterioration, resolution is slow, with clearing beginning only after two to three weeks
and approximately one-half of patients demonstrating residual abnormalities at 10
weeks.
Resolution may take as long as 6 to 12 months, and residual fibrosis may be evident in
up to 25 percent of patients.

In addition to the slowly resolving or residual radiographic abnormalities, patients may

experience generalized weakness and fatigue for months. Residual abnormalities on
pulmonary function testing may be seen as long as two years later.

Mycoplasma pneumoniae — Mycoplasma pneumoniae is a common cause of

respiratory tract infection but a rare cause of severe pneumonia. Resolution is typically
rapid and faster than that with other types of pneumonia [1]. Significant clinical
improvement usually occurs within the first two weeks, which may in part reflect the
predominantly young and otherwise healthy population affected.

Radiographic deterioration after treatment is rare, occurring in less than 25 percent of

cases. The average duration of radiographic abnormalities is two to four weeks,
depending upon the use of antibiotics. Forty percent have complete radiographic
resolution at four weeks and 90 percent at eight weeks. Residual radiographic
abnormalities are distinctly unusual.

Chlamydia pneumoniae — C. pneumoniae infection is an uncommon cause of

pneumonia, but it has been implicated in outbreaks of pneumonia in residents of
long-term care facilities and military recruits. It is a relatively mild disease, and mortality
is rare [16]. Prompt resolution is the rule in younger patients.

Radiographic deterioration is uncommon, with clearing typically occurring in less than

three months. Fifty percent of chest radiographs clear within four weeks, while up to 20
percent take longer than nine weeks. Residual radiographic abnormalities persist in 10
to 20 percent of cases. Much information regarding Chlamydia resolution is derived
from observations of patients with psittacosis [8].

Haemophilus influenzae — Haemophilus influenzae is commonly considered a cause

of pneumonia, especially in elderly adults, in cigarette smokers, and in patients with
chronic obstructive lung disease. However, several large series following the widespread
use of conjugate vaccines against H. influenzae type b in children have shown a
decreasing incidence of infection and a shift to nontypeable strains compared with the
more invasive type b infection [17,18].

The natural history of H. influenzae infection has not been well studied, but there do not
appear to be any unique features regarding its resolution. Based on the propensity for
the organism to infect the immunocompromised and elderly, resolution is often slow,
with many patients having prolonged hospitalization. Only 50 percent of patients return
to their previous level of function by six weeks [17].

MISDIAGNOSIS OF PATHOGENS — Alternative pathogens in addition to the usual

bacterial causes of pneumonia need to be considered in the patient who fails to
respond to treatment. Particularly important pathogens in this category include
mycobacteria (either Mycobacterium tuberculosis or atypical mycobacteria), fungi,
Nocardia, and Actinomyces.

Tuberculosis — Tuberculosis is of significant concern, especially in elderly patients and

in those who have immigrated within the past five years, those who have a history of
intravenous drug use, and those who have other risk factors for the acquired
immunodeficiency syndrome (AIDS).

The clinical presentation of tuberculosis as a cause of nonresolving pneumonia is often

atypical, especially in diabetics and in elderly patients, who commonly have
radiographic findings in the middle or lower lung zones. Diagnosis may be difficult, as
sputum is not always available and culture results take weeks after the specimen is
obtained. Polymerase chain reaction testing has been approved for smear-positive
specimens to allow confirmation of tuberculous disease, but its role in smear-negative
cases is uncertain.

Fungi — Both opportunistic and endemic fungal infections can mimic bacterial
pneumonia. In the patient with an apparent nonresolving pneumonia, Aspergillus is a
particularly important pathogen, presenting either as chronic necrotizing or as invasive
aspergillosis. Patients with advanced AIDS are at increased risk of invasive
aspergillosis, while patients with less advanced disease may develop tracheobronchitis.

Although invasive aspergillosis classically occurs in neutropenic patients who have been
on multiple antibiotics for several days, it is increasingly recognized in elderly patients
with chronic lung disease who are on corticosteroids. Aspergillus in this setting may
mimic a bacterial infection, and one series demonstrated that patients with invasive
aspergillosis were treated for an average of 18 days with multiple antibiotics before the
diagnosis was established [14].
Endemic fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis,
and cryptococcosis should be considered as a cause of nonresolving pneumonia in the
appropriate endemic areas (image 2) [19]. These include the Mississippi River valley for
histoplasmosis, the southwestern United States for coccidioidomycosis, and the
southeast and Midwest for blastomycosis. Each of these fungi can cause a nonspecific
acute febrile illness, which may be confused with community-acquired pneumonia.
Histoplasmosis has worldwide distribution and should be considered in travelers to high
prevalence countries.

Nocardia and Actinomyces — Although Nocardia and Actinomyces are higher order
bacteria, the clinical presentation of infection due to these organisms is more consistent
with a fungal etiology. Nocardia infection presents most commonly on chest radiograph
as a localized alveolar infiltrate that is usually homogeneous, nonsegmental, and
cavitary. Infection due to Actinomyces has a similar appearance but with a propensity to
extend across fissures and invade the chest wall.

RESISTANT BACTERIAL PATHOGENS — The presence of a resistant pathogen is an

important consideration for any pneumonia that is not responding appropriately to
antibiotic therapy. Although penicillin- resistant Streptococcus pneumoniae
(pneumococcus) is the organism of most concern, multidrug-resistant Haemophilus
influenzae and Pseudomonas aeruginosa, as well as methicillin-resistant
Staphylococcus aureus, are increasingly recognized in the community setting as
possible causes of a nonresolving or recurrent pneumonia.

HOST FACTORS — A variety of host factors may be associated with delayed resolution
of pneumonia, including alcoholism, older age, and the presence of comorbid diseases,
such as diabetes and chronic obstructive lung disease. In addition, disorders of immune
function, particularly AIDS and syndromes associated with deficient humoral immunity,
can be associated with delayed resolution of pneumonia.

AIDS — Although unrecognized Pneumocystis jirovecii (formerly P. carinii) pneumonia

remains an important diagnostic consideration in patients with AIDS and a CD4 count
<200 cells/mm3, the most common initial lower respiratory tract infection in this patient
population remains bacterial pneumonia, especially pneumococcal pneumonia. It is
important to consider the possibility of underlying HIV infection in patients with
nonresolving or progressive pneumonia. The Infectious Disease Society of America
recommends routine testing for HIV infection in patients with community-acquired
pneumonia between the ages of 15 and 54
occurring in hospitals in which the rate of newly diagnosed HIV infection exceeds 1 case
per 1000 discharges.

Primary humoral immune deficiencies — It is important to identify primary humoral

immune deficiency as an underlying risk factor for pneumonia because of the effect of
treatment with intravenous immune globulin (IVIG) on the incidence and resolution of
pneumonia. Specific disorders commonly associated with hypogammaglobulinemia
include X-linked agammaglobulinemia, common variable immune deficiency, and
selective IgG subset deficiency. The most common pathogens in these patients include
Streptococcus pneumoniae and Haemophilus influenzae, with Mycoplasma pneumoniae
and P. jirovecii being less common.

DEVELOPMENT OF COMPLICATIONS FROM THE INITIAL PNEUMONIA —

Sequestered foci of infection may prevent adequate concentrations of antibiotic agents
from reaching the site of infection. The two main forms of sequestered focus preventing
adequate resolution of pneumonia are empyema and lung abscess.

Empyema — Empyema is now a rare complication of community-acquired pneumonia

(CAP). This was illustrated in a review of 3675 patients with CAP in which empyema
was diagnosed by the attending physician in 1.3 percent and by strict laboratory criteria
in 0.7 percent [20]. The patients with empyema were more likely to be younger and to
be illicit drug users. The most common cultured pathogen was Streptococcus milleri,
suggesting a role for aspiration.

Evaluation of a possible empyema is initially facilitated by imaging techniques such as

computed tomography (CT) and ultrasound. In a patient with nonresolving pneumonia,
demonstration of any significant amount of pleural fluid should prompt consideration of
a diagnostic thoracentesis to rule out empyema.

Lung abscess — Predisposing factors that should raise the suspicion of abscess
formation include alcoholism, seizures, poor oral hygiene, and previous aspiration.
Chest radiography typically demonstrates an air-liquid level , but chest CT is more
sensitive and can confirm the diagnosis in difficult cases. Most patients with lung
abscess do well with conservative management and a prolonged course of antibiotics.
However, several factors are associated with increased abscess-related mortality and
may warrant a more aggressive approach. These include age-related factors (pediatric
or elderly populations), large cavity size, longer duration of symptoms prior to therapy,
lower lobe location, association with malignant disease, and the presence of multiple
abscesses. The development of infection in preexisting bullae may be mistaken for lung
cancer.

NONINFECTIOUS ETIOLOGIES — A variety of noninfectious etiologies of pulmonary

infiltrates can mimic pneumonia and therefore represent causes of presumed
nonresolving pneumonia. These fall into the categories of neoplastic, inflammatory,
drug-induced, and vascular disease. Some of these noninfectious etiologies may also
be associated with nonresolving pneumonia through other pathophysiologic
mechanisms, such as endobronchial obstruction by bronchogenic carcinoma.

Neoplastic disorders — Neoplasms may be associated with nonresolving pneumonia

either by compromise of the airway lumen and secondary postobstructive pneumonia or
abscess, or by mimicking an infiltrative process. Bronchogenic carcinoma and carcinoid
tumors are the most common cause of endobronchial obstruction leading to
pneumonia, whereas bronchioloalveolar cell carcinoma and lymphoma are the most
common causes of an alveolar infiltrate mimicking pneumonia.

● Bronchogenic carcinoma compromises the airway lumen either through

endobronchial involvement or extrinsic compression. However, the frequency of
endobronchial carcinoma as a cause of nonresolving pneumonia is relatively low,
ranging from 0 to 8 percent in most series [13].
 ● Endobronchial obstruction by a carcinoid tumor is an important predisposing factor
for a postobstructive pneumonia and should be considered as a possible etiology
for endobronchial obstruction in a young nonsmoking patient.

● Bronchioloalveolar cell carcinoma may present as a focal infiltrate, often with air
bronchograms, and ground glass infiltrates with a "subsolid" appearance, thus
mimicking the radiographic appearance of pneumonia. Patients with
bronchioloalveolar cell carcinoma may present with a discrepancy between the
size of the infiltrate and the paucity of systemic symptoms [21].

● Lymphoma in the lung may also present with focal alveolar infiltrates with air
bronchograms, mimicking the radiographic appearance of pneumonia.
Lymphoma affecting the lung parenchyma may occur either as part of a systemic
disease or as primary pulmonary lymphoma. Three categories of clonal lymphoid
proliferation are now recognized as producing pulmonary parenchymal
involvement: low grade B cell lymphoma arising from mucosal tissue (MALT),
high grade B cell lymphoma, and lymphomatoid granulomatosis. Primary
pulmonary lymphoma is unusual, with only 10 percent of Hodgkin lymphoma
and 4 percent of non-Hodgkin lymphomas presenting with an alveolar infiltrate.
As the disease progresses, lung involvement becomes more common, occurring
in 38 percent of patients with Hodgkin lymphoma and 24 percent with
non-Hodgkin lymphoma. Chest CT may be particularly useful in patients with
suspected Hodgkin lymphoma, since mediastinal lymphadenopathy is common
[22].

In a prospective study in which 30 hospitalized patients with postobstructive pneumonia

due to malignancy were compared with 60 patients with bacterial pneumonia, those
with postobstructive pneumonia due to malignancy had a longer duration of symptoms
(14 versus 5 days) and were more likely to have weight loss and cavitary lesions but
were less likely to have leukocytosis [23].

Inflammatory disorders — Numerous inflammatory disorders can mimic and be

misdiagnosed as pneumonia. Because these disorders do not respond to antibiotics,
they should be considered in the evaluation of patients with an apparently
nonresolving pneumonia.

● Systemic vasculitis or connective tissue disorders may cause fever, dyspnea, and
pulmonary infiltrates, and therefore can be easily mistaken for pneumonia.
Granulomatosis with polyangiitis (Wegener’s) and the alveolar hemorrhage
syndromes are the most frequent vasculitides to mimic pneumonia (image 3).
Bronchoscopy and bronchoalveolar lavage are useful to establish the diagnosis of
alveolar hemorrhage.

● Bronchiolitis obliterans organizing pneumonia (BOOP/Cryptogenic organizing

pneumonia) presents typically with a subacute onset, with 75 percent of patients
having symptoms less than two months at the time of diagnosis. Idiopathic BOOP
usually begins with a flu-like illness mimicking an atypical (community- acquired)
pneumonia, with fever, malaise, fatigue, dyspnea, and dry cough. Patients may
 have an elevated sedimentation rate and leukocytosis. Patchy alveolar infiltrates
are typically present on chest radiograph, often mimicking a pneumonia.

● Eosinophilic pneumonias, including both chronic and acute forms, are characterized
by collections of eosinophils in the interstitial and alveolar spaces [24,25]. Chronic
eosinophilic pneumonia typically presents as a subacute illness with cough, fever,
dyspnea, weight loss, wheezing, night sweats, and radiographic infiltrates
appearing over weeks to months. Chest radiographs often demonstrate patchy,
nonsegmental alveolar infiltrates that predominantly affect the periphery of the
lungs, sparing the central and basilar regions. Patients typically have a rapid
clinical and radiographic response to treatment with corticosteroids.
Acute eosinophilic pneumonia has a more rapid onset of fever, nonproductive
cough, dyspnea, and pleuritic chest pain. Chest radiograph early in the course
may show only subtle reticular or ground-glass infiltrates, which can progress to
bilateral diffuse alveolar disease and acute respiratory distress syndrome (ARDS).
As in chronic eosinophilic pneumonia, response to corticosteroids is often
dramatic. Data suggest significant clinical overlap between eosinophilic
pneumonia syndromes [26].

● Acute interstitial pneumonia is a rare, idiopathic form of diffuse alveolar damage,

thus corresponding to a clinical picture compatible with idiopathic ARDS [27,28].
Patients typically present after a prodromal period of up to 14 days with the onset
of fever, cough, and dyspnea. Chest radiographs usually demonstrate bilateral
airspace disease, and chest CT characteristically shows patchy or diffuse areas of
ground-glass attenuation. The effectiveness of corticosteroids is not clear, and
mortality is approximately 70 percent.

● Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized

by the abnormal accumulation of lipoproteinaceous fluid in the distal airspaces [29].
Patients typically present with the insidious onset of dyspnea, fatigue, weight loss,
and low-grade fever. Chest radiographs often demonstrate nonspecific central
alveolar opacities in the lower and mid-lung zones with sparing of the areas
adjacent to the diaphragm and heart. High-resolution CT commonly has a "crazy
paving" appearance, characterized by a ground glass pattern with thickening of the
intralobular and interlobular septa to produce polygonal shapes.

● Sarcoidosis may be confused with a nonresolving pneumonia when patients

have pulmonary parenchymal disease without intrathoracic adenopathy and in
the absence of clinically apparent extrapulmonary involvement.

Drug-induced lung disease — Drug-induced lung disease can be confused with an

infectious pneumonia, and a careful evaluation of medication history should be done in
patients with an apparent nonresolving pneumonia to rule out a drug-related etiology.
Amiodarone toxicity is a particularly important mimic of nonresolving pneumonia, as it
may have an acute presentation with focal alveolar infiltrates. Other drugs of concern
include methotrexate, nitrofurantoin, and bleomycin

In addition to traditional antineoplastic agents, many new, increasingly-used biologic

modifiers are associated with significant respiratory symptoms and radiograph
abnormalities. Anti-tumor necrosis factor-alpha agents have been associated with an
increased risk of tuberculosis as well as other bacterial and fungal infections. These
may have unusual or atypical features. Tyrosine kinase inhibitors like erlotinib, now
frequently used in advanced adenocarcinoma of the lung, may be associated with
interstitial lung disease and acute lung injury. Everolimus, which is used to treat
progressive renal cell carcinoma, has been associated with interstitial pneumonitis in up
to one-third of patients [30].

Pulmonary embolism — Pulmonary embolism can rarely mimic pneumonia, based on

the radiographic findings of pulmonary infiltrates in up to 30 percent and pleural
effusions in approximately 20 percent of cases. Infiltrates, representing areas of
pulmonary infarction, may take several weeks to resolve and are easily mistaken for
slowly resolving pneumonia.

Hydrostatic pulmonary edema — Unusual or focal radiographic patterns of

hydrostatic pulmonary edema can occasionally mimic pneumonia. Pulmonary edema
can have a focal presentation limited to areas of increased perfusion, as in patients
with bullous lung disease or mitral regurgitation. Because pulmonary edema appears
most prominent in areas of maximal perfusion, patients with severe chronic obstructive
pulmonary disease may manifest asymmetric patterns of pulmonary edema.

SUMMARY AND RECOMMENDATIONS

● Slow or incomplete resolution of pneumonia despite treatment is a common clinical

problem, estimated to be responsible for approximately 15 percent of inpatient
pulmonary consultations and 8 percent of bronchoscopies.

● Normal resolution of pneumonia is not easily defined and may vary depending upon
the underlying cause. Patients typically note subjective improvement within three
to five days of treatment; more specific clinical criteria for resolution include
improvement in fever, cough, crackles, leukocytosis, arterial oxygenation (PaO2),
and level of C-reactive protein. Determining whether a patient has nonresolving or
progressive pneumonia must also take into account several factors that affect the
expected rate of resolution, including comorbidities, age, severity, and etiology

● Evaluation of patients with an apparent nonresolving pneumonia generally

centers around more detailed imaging studies or obtaining material for
microbiologic and pathologic analysis

● Data are available regarding resolution of pneumonia caused by different

etiologic agents, including factors that affect the course of particular types of
pneumonia.

● Alternative pathogens, in addition to the usual bacterial causes of pneumonia, need

to be considered in the patient who fails to respond to treatment . Particularly
important pathogens in this category include mycobacteria (either Mycobacterium
tuberculosis or atypical mycobacteria), fungi, Nocardia, and Actinomyces.

● The presence of a resistant pathogen is an important consideration for any

pneumonia that is not responding appropriately to antibiotic therapy.
● A variety of host factors may be associated with delayed resolution of pneumonia,
including alcoholism, older age, and the presence of comorbid diseases such as
diabetes and chronic obstructive lung disease. In addition, disorders of immune
function, particularly AIDS and syndromes associated with deficient humoral
immunity, can be associated with delayed resolution of pneumonia.
● Sequestered foci of infection may prevent adequate concentrations of antibiotic
agents from reaching the site of infection. The two main forms of sequestered
focus preventing adequate resolution of pneumonia are empyema and lung
abscess.
● A variety of noninfectious etiologies of pulmonary infiltrates can mimic
pneumonia and therefore represent causes of presumed nonresolving
pneumonia. These fall into the categories of neoplastic, inflammatory,
drug-induced, and vascular disease