on 08-Mar-2023 (Wed)

Autoimmune and inflammatory conditions — Patients with autoimmune diseases, antibody deficiencies (eg, glomerulonephritis with proteinuria, Goodpasture syndrome, or receipt of chimeric antigen receptor-modified T [CAR-T] therapy), and some hematologic malignancies are susceptible to bacterial infections (ie, bacteremia) and to a lesser extent to opportunistic infections similar to those of cancer and transplant patients. Infections (eg, Pneumocystis, Nocardia spp) may result from deficiencies in opsonization and phagocytosis, notably during corticosteroid or cyclophosphamide therapies.

Infections following CAR-T cell therapy are most often related to cytopenia from prior cancer therapies or following glucocorticoid, IL-6 inhibitor, and/or TNF-alpha inhibitor treatment for cytokine release syndrome (CRS) [45,46]. CAR-T cell therapy can be associated with B cell aplasia and hypogammaglobulinemia. As with other immunosuppressive treatments, infections that occur early after therapy are often nosocomial, whereas those that occur later can be opportunistic related to prolonged immune defects.

In one case series evaluating 53 patients treated with CD19 CAR-T cell therapy for relapsed acute B cell leukemia, treatment was complicated by infection in 22 patients (42 percent) in the first 30 days following therapy [ 46]. A total of 26 infections were reported, 17 bacterial, 4 fungal, and 5 viral, occurring at a median of 18, 23, and 48 days post-CAR-T cell infusion, respectively.

Biologic agents and targeted therapies — Inhibitors of tumor necrosis factor (TNF)-alpha and blockade of other mediators of inflammation (cytokines and chemokines) predispose to infection with intracellular pathogens (mycobacteria, Legionella species) as well as systemic viral and fungal infections, including those caused by molds (Aspergillus spp), yeasts (Cryptococcus spp), dimorphic fungi (Histoplasma capsulatum, Coccidioides spp), and P. jirovecii [47].

Certain cancer therapies such as ibrutinib have unique cellular targets (Bruton’s tyrosine kinase in B-cell malignancies) and are associated with an excess incidence of invasive fungal infections [48].

Inhibitors of cytokine-mediated cell processes including the JAK/STAT pathway are achieving broad use in oncology and in autoimmune and inflammatory diseases. Use of these agents in organ transplantation resulted in increased rates of infection and post-transplant lymphoproliferative disorder compared with calcineurin inhibitor-based immunosuppression [ 49].

Concomitant viral infection — The observation that pulmonary or systemic viral infection is associated with subsequent pneumonia has been described best for cytomegalovirus (CMV), influenza, and severe acute respiratory syndrome coronavirus 2. Factors that predispose to superinfection vary with the specific virus and include systemic and local immune responses (eg, in the lung transplant recipient), decreased mucociliary function, impaired recruitment of and phagocytosis by macrophages and neutrophils, neutropenia, or injury to type 2 pneumocytes [50]. Thus, pulmonary fungal infections (eg, Pneumocystis pneumonia, Aspergillosis) are not uncommon in the weeks following viral infection.

Infection — The etiology of infectious pneumonitis in immunocompromised patients, when documented, is diverse [2,3,40,52-59]. The spectrum of infection is altered by antimicrobial prophylaxis. The frequency of identification of common organisms varies with the nature of the host and with the aggressiveness of diagnostic approach.

In one series using invasive diagnostic approaches for pulmonary infiltrates in immunocompromised hosts, a specific diagnosis was obtained in 162 of the 200 cases evaluated (81 percent) [ 60]. An infectious etiology was found in 125 patients (77 percent) and a noninfectious etiology in 37 (23 percent); 38 (19 percent) remained undiagnosed. Among infectious causes, bacteria were documented in 24 percent, fungi in 17 percent, and viruses in 10 percent. In 7 percent, the etiology was polymicrobial. There were no statistically significant associations between the specific underlying immunosuppressive state and the etiology of the pulmonary infiltrates.

Overall, including both invasive and noninvasive approaches to diagnosis, approximate rates of infection include [ 60-62]:

● Conventional bacteria – 37 percent (higher with neutropenia and mucositis and early after lung transplantation)

● Fungi – 14 percent (higher with prolonged neutropenia)

● Viruses – 15 percent (common with T cell suppression)

● P. jirovecii (formerly P. carinii) – 5 to 15 percent (without prophylaxis)

● Nocardia spp – 7 percent (including sulfa-resistant strains)

● Mycobacterium tuberculosis – 1 percent (higher in endemic regions)

● Mixed infections – 20 percent

T he spectrum of pulmonary fungal infection includes infection with non-fumigatus Aspergillus spp, Fusarium spp, Scedosporium spp, and the Mucorales in patients with neutropenia and/or in association with graft-versus-host disease (GVHD) [35,63,64].

Mixed infections with combinations of respiratory viruses, cytomegalovirus (CMV), Aspergillus spp, and/or gram-negative bacilli are common in neutropenic hosts and hematopoietic cell transplant (HCT) recipients [65-69]. Pneumocystis pneumonia (PCP) is most common in patients receiving glucocorticoids as a part of a chemotherapeutic or maintenance regimen [38].

Invasive CMV disease may be difficult to distinguish from viral shedding (or activation in the setting of severe systemic illness) in the immunocompromised host with pulmonary infiltrates. Confirmation of invasive CMV pneumonitis can be achieved using assays from blood samples (eg, CMV viral load by nucleic acid testing) and/or tissue histology (image 2).

In HCT recipients, CMV pneumonitis occurs most commonly in seropositive individuals (CMV donor seronegative, recipient seropositive; CMV D-/R+) after the completion of prophylaxis (late infection) [ 70,71]. This contrasts with the risk profile of CMV pneumonitis in solid organ transplantation, which is greatest in seronegative recipients of seropositive organs (CMV D+/R-). Antiviral resistance may allow CMV infection to break through antiviral prophylaxis.

The lungs in systemic infections — Some infections, especially those due to tuberculosis, Nocardia spp, and Cryptococcus spp, generally enter via the lungs but metastasize to other sites. These other sites may be more accessible than the lungs for establishing a microbiologic diagnosis.

The lungs can also be a site for hematogenous spread of infection (eg, septic emboli due to Staphylococcus aureus or gram-negative bacteremia). Peripheral pulmonary lesions in the lungs can be a clue that there is important disease elsewhere (eg, line sepsis, hepatosplenic candidiasis, infective endocarditis) (image 3).

Noninfectious — Noninfectious etiologies for pulmonary infiltrates are common in immunocompromised patients, including pulmonary embolus, tumor, radiation pneumonitis, cancer, fibrosis, atelectasis with pulmonary edema, drug allergy or toxicity, and pulmonary hemorrhage [72-74]. Often, the resolution of fever in response to a trial of antibiotics is the only evidence suggesting that infection was present.

Drug toxicities (bleomycin, cyclophosphamide, and sulfonamides), leukoagglutinin reactions, radiation injury, pulmonary emboli, pulmonary hemorrhage, and cancer metastases may coexist with opportunistic infections.

Radiation-induced injury — Clinically apparent injury due to radiation therapy can occur acutely (typically 4 to 12 weeks following irradiation) or more than six months after the initial exposure to a dose of >2000 rads. Vascular damage, mononuclear infiltrates, and edema are seen histologically at 3 to 12 months. The severity of lung injury due to drugs or radiation appears to correlate with the rapidity of the withdrawal of glucocorticoid therapy. However, this timing may also reflect the emergence of the underlying inflammatory response rather than enhanced injury. Radiation fibrosis may occur (usually after six to nine months) and will amplify radiologic findings with other processes; lung function may not stabilize for up to two years.

Drug-induced injury — Acute, drug-induced lung disease may reflect hypersensitivity to chemotherapeutic agents, sulfonamides, or other agents.

● Methotrexate, bleomycin, and procarbazine can cause a syndrome of nonproductive cough, fever, dyspnea, and pleurisy with skin rash and blood eosinophilia. Chest radiographs generally demonstrate diffuse reticular infiltrates. (See "Methotrexate-induced lung injury" and "Bleomycin-induced lung injury".)

● Cyclophosphamide may cause a syndrome of pulmonary disease with interstitial inflammation and pulmonary fibrosis that occurs subacutely over weeks to months. (See "Cyclophosphamide pulmonary toxicity".)

● Sirolimus (rapamycin) used for immune suppression may be associated with a form of interstitial pneumonitis in transplant recipients [76]. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Rapamycin and analogs'.)

● Other common drugs causing lung injury include cytarabine, but fever is less often associated with these other drug-induced forms of pneumonitis.

Drug toxicity may be related to the cumulative dose of the agent (eg, bleomycin over 450 mg, carmustine [BCNU], lomustine [CCNU]) and to the age of the patient. Synergistic pulmonary toxicity is seen when certain chemotherapeutic agents are used in combination with radiation therapy (eg, bleomycin, mitomycin, busulfan) or oxygen (bleomycin).

Idiopathic pneumonia syndrome — The idiopathic pneumonia syndrome (IPS) is an important noninfectious complication of HCT, which typically occurs within the first several weeks following transplant [77]. IPS is less common following nonmyeloablative HCT. IPS is a clinical syndrome characterized by widespread alveolar injury plus signs and symptoms of pneumonia plus evidence of abnormal pulmonary physiology (an increased alveolar-arterial oxygen gradient or the need for supplemental oxygen) in the absence of lower respiratory tract infection. IPS may represent a heterogeneous group of disorders that result in the common pathologic findings of interstitial pneumonitis and/or diffuse alveolar damage.

Engraftment syndrome — The engraftment syndrome is generally suspected when a patient develops fever and rash approximately 9 to 16 days following autologous HCT (and more rarely following allogeneic HCT) [27]. The engraftment syndrome is associated with increased systemic capillary permeability that occurs during the neutrophil recovery phase. It is attributed to release of proinflammatory cytokines that precedes neutrophil engraftment. Clinical manifestations include fever without infection, maculopapular rash mimicking acute GVHD, diffuse pulmonary opacities, and/or diarrhea.

Checkpoint inhibitor therapy may cause pneumonitis in up to 6 percent of patients receiving programmed cell death receptor 1 (PD-1) or PD-1 ligand (PD-1L) antagonists and up to 12 percent with combined PD-1/PD-1L and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade [78-80].

Pulmonary immune-related adverse events (irAEs) following immune checkpoint inhibitor therapy have a median onset of three months but may occur within a week [ 81,82]. PD-1/PD-1L therapies are more often associated with pneumonitis (or thyroiditis) than CTLA-4 antibodies. Pneumonitis may occur with or without other irAEs including mild skin, endocrine, or autoimmune manifestations or severe inflammatory processes including colitis, myocarditis, or shock.

CAR-T cell therapies may induce toxicities including cytokine-release syndrome with fevers and multiorgan dysfunction, CAR-T cell-related encephalopathy syndrome with altered mental status and neurologic dysfunction, or hemophagocytic lymphohistiocytosis-macrophage-activation syndrome [41].

Recognition of infection in immunocompromised hosts is often delayed because the usual signs of infection are missing due to the muted inflammatory response. As an example, sputum production and radiographic changes may be absent in the neutropenic patient with pneumonia. In one series of cancer patients with pneumonia, neutropenic patients produced purulent sputum far less often than those without neutropenia (8 versus 84 percent) [58].

Many infections are recognized only when fever, clinical symptoms (eg, cough, pleurisy, confusion), unexplained hypotension, or radiologic abnormalities develop after immune suppression or neutropenia is reversed. Blood, urine, and sputum cultures (and cerebrospinal fluid if relevant) should be obtained before starting antimicrobial therapy.

While symptoms may be muted, a low threshold for hospitalization must exist if the patient “looks sick.” Immunocompromised patients with fever without a clear etiology are at high risk for rapid progression.

Certain subgroups of immunocompromised patients are highly susceptible to infection. Symptoms may continue to evolve despite therapy. These include patients with:

● Aggressive tumors (eg, new or relapsed leukemia or lymphoma or uncontrolled metastatic cancer)

● Recent hematopoietic cell transplant recipients, especially those with severe graft-versus-host disease, or delayed engraftment, such as after umbilical cord blood transplantation

● Recent infections, especially due to cytomegalovirus (CMV) or respiratory viruses, or with known colonization with fungi or resistant bacteria [84,85]

● Absolute neutrophil count (ANC) below 500/microL, and especially those below 100/microL, or those in whom the ANC is falling rapidly or expected to fall below 100/microL

● High-dose glucocorticoid therapy or recent intensification of immunosuppression (eg, in solid organ transplant recipients being treated for rejection)

Patients with pneumonitis following checkpoint inhibitor therapy may progress over hours to days.

Travel and occupation – Exposures to tuberculosis, endemic fungi (eg, H. capsulatum, Coccidioides spp), Rhodococcus equi (horse breeders), Cryptococcus neoformans (eg, pigeon breeders), Strongyloides stercoralis (residence in or prolonged travel to endemic areas, even quite distant in time), or exposure to soil (eg, Aspergillus spp or Nocardia spp in landscapers and gardeners)

Prolonged duration of neutropenia (higher risk for gram-negative infections, Aspergillus spp, and Fusarium spp)

Past history of frequent antimicrobial exposure (increased risk for organisms with resistance to antimicrobials used previously)

Recent intensification of immunosuppression for graft rejection (cytomegalovirus [CMV], Pneumocystis) or graft-versus-host disease (Aspergillus or molds) or change in prophylaxis

Potential or witnessed aspiration (risk for anaerobic infection)

Presence of potential pulmonary pathogens in prior cultures, particularly molds (Aspergillus spp, Fusarium spp), Pseudomonas spp, or Stenotrophomonas spp

Cardiac abnormalities (endocarditis), indwelling catheters, or intravascular clot (bacteremic seeding of the lungs)

Obstructing metastatic tumors, particularly intrathoracic malignancies (which can lead to postobstructive pneumonia)

Diabetes mellitus with sinopulmonary infection (mucormycosis)

The specific immune defects and their associated infections (table 1)

Diagnostic approach — The initial evaluation for immunocompromised patients with fever with or without pulmonary findings, at a minimum, should include:

● Rapid assessment of vital signs, including oxygen saturation

● Complete blood count with differential

● Electrolytes, blood urea nitrogen, and creatinine

● Blood cultures (minimum of two sets, with at least one peripheral set and one set from any indwelling catheter)

● Urine sediment examination and culture

● Sputum for Gram stain, fungal smears, and cultures

● Imaging of the lungs (chest radiography or, if possible, chest computed tomographic scanning) and imaging of any symptomatic site (eg, abdomen)

● Skin examination, looking for evidence of metastatic infection

● CMV quantitative molecular testing is often valuable; other viral polymerase chain reaction (PCR) assays as appropriate to the individual (adenovirus, parvovirus B19, severe acute respiratory syndrome coronavirus 2)

● Consideration of sample collection for nonculture-based diagnostic tools (eg, specific molecular and antigen tests such as Aspergillus or Pneumocystis PCR, cryptococcal antigen), Aspergillus galactomannan, beta-1,3,-glucan, whole genome sequencing) [86]

Hypoxemia — The presence or absence of hypoxemia can assist in the differential diagnosis of pulmonary infiltrates in immunocompromised patients. Hypoxemia with an elevation in lactic dehydrogenase or beta-1,3-glucan and minimal radiographic findings are common in Pneumocystis pneumonia (PCP), whereas the absence of hypoxemia with pulmonary consolidation is more common in nocardiosis, tuberculosis, and fungal infections until later in the course.

Three types of pulmonary infiltrates are common:

● Consolidation, with a substantial replacement of alveolar air by tissue density material, typically with air bronchograms and a peripheral location of the abnormality (image 4)

● Peribronchovascular (or interstitial) distribution, in which the infiltrate is predominantly oriented along the peribronchial or perivascular bundles (image 5)

● Nodular space-occupying nonanatomic lesions with well-defined, more or less rounded edges surrounded by aerated lung

This classification system for radiographs can be combined with information about the rate of progression of the illness to generate a differential diagnosis. Several examples are illustrative:

● A focal or multifocal consolidation of acute onset will probably be caused by a bacterial infection. In contrast, similar multifocal lesions with a subacute to chronic progression are more commonly due to fungal, tuberculous, or nocardial infections.

● Large nodules are usually a sign of fungal or nocardial infection in this patient population, particularly if they are subacute to chronic in onset.

● Subacute disease with diffuse abnormalities, either of the peribronchovascular type or miliary micronodules, are usually caused by viruses (especially CMV or respiratory viruses), P. jirovecii, or, in the lung transplant recipient, rejection (image 7).

● The presence of cavitation suggests a necrotizing infection, which can be caused by filamentous fungi, Nocardia spp, mycobacteria, certain gram-negative bacilli (most commonly Klebsiella pneumoniae and Pseudomonas aeruginosa), and anaerobes [5].

● The appearance of invasive pulmonary aspergillosis is heterogeneous [90]. The most common features include patchy infiltrates, nodules, cavitation, and pleural-based wedge-shaped lesions with associated pleurisy [69]. In some patients, including those with neutropenia, the initial appearance may be nodules with surrounding hypoattenuation (the "halo sign") followed by cavitation (the "air-crescent sign") following the return of neutrophils. The halo sign may also be observed with other infections that cause infarction (eg, other angioinvasive fungi, Nocardia spp, P. aeruginosa) and malignancies.

The depressed inflammatory response of the immunocompromised transplant patient may modify or delay the appearance of a pulmonary lesion on radiography, especially if neutropenia is present. As an example, fungal invasion, which causes a less exuberant inflammatory response than does bacterial infection, will often be very slow to appear on conventional chest radiography. By contrast, immune reconstitution (eg, leukocytes after hematopoietic cell transplantation or chemotherapy or HIV therapy) or immune stimulation (with checkpoint inhibitors) may reveal previously unrecognized pulmonary infiltrates.

The following table reviews the radiographic appearances of pulmonary disorders in immunocompromised patients (table 2).

Chest CT — Computed tomography (CT) frequently reveals abnormalities even when the chest radiograph is negative or has only subtle findings. CT can also help to define the extent of the disease. Knowledge of the extent of infection at the time of diagnosis allows for subsequent assessment of the response to therapy. This is especially relevant for opportunistic fungal and nocardial infections. Therapy should be continued until evidence of infection is eliminated; reversal of immunosuppression may accelerate radiologic progression (immune reconstitution) while enhancing clinical recovery.

The morphology of the abnormalities found on CT scan can be useful in developing a differential diagnosis; few lesions are sufficiently specific to obviate the need for microbiologic diagnosis [25]:

● Cavitary CT lesions are suggestive of infections with mycobacteria, Nocardia spp, Cryptococcus spp, Aspergillus spp, and some gram-negative bacilli (P. aeruginosa, Klebsiella spp).

● Rapidly expanding pulmonary lesions with cavitation and/or hemorrhage are associated with the Mucorales, especially in diabetics, and Scedosporium spp.

● Opacified secondary pulmonary lobules in the lung periphery are suggestive of bland pulmonary infarcts or septic or hemorrhagic Aspergillus infarcts (especially if cavitary).

● Opacities in a peribronchial (or interstitial) distribution are suggestive of fluid overload, viral infection such as CMV (image 8), or P. jirovecii infection (image 9), and, in the lung transplant recipient, allograft rejection.

● Dense regional or lobar consolidation on CT is usually seen in bacterial pneumonia or invasive fungal infection.

● Lymphadenopathy is not a common finding in immunosuppressed patients other than in those with lymphoma or posttransplant lymphoproliferative disorder associated with Epstein-Barr virus. Lymphadenopathy may be observed with some acute viral infections (CMV), sarcoidosis, and infections due to mycobacteria and Cryptococcus spp and with drug reactions (eg, trimethoprim-sulfamethoxazole). Positron emission tomography-CT (PET-CT) may differentiate infection from tumor.

CT can also help to predict whether bronchoscopy is likely to be useful. As an example, the demonstration of a feeding bronchus that communicates with a pulmonary nodule greatly increases the diagnostic yield when bronchoscopy is performed (60 versus 30 percent when the feeding bronchus is not visible). If CT demonstrates centrally located diffuse opacities, a bronchoscopic approach is the procedure of choice.

Invasive procedures — Invasive procedures are frequently required to obtain tissue or respiratory samples for specific diagnoses. Decisions regarding invasive procedures are best made early in the course; patients may become too ill or develop contraindications (eg, coagulopathy, hypoxemia) that prevent procedures [60,62,98,99].

Skin and CSF sampling — As discussed above, several infections, especially those due to M. tuberculosis, Nocardia spp, and Cryptococcus spp, generally enter via the lungs but metastasize to other sites. These other sites may be more accessible than the lungs for establishing a microbiologic diagnosis. Thus, skin lesions or cerebrospinal fluid (CSF) may demonstrate Cryptococcus spp or mycobacterial infection before microbiologic data from sputum or lung biopsy specimens are available.

Lung sampling — An invasive diagnostic procedure such as bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsy, percutaneous needle biopsy, video-assisted thorascopic biopsy (VATS), or open lung biopsy is frequently required to obtain a sample of sputum or lung tissue [92-96,98-105].

The sensitivity of BAL is improved by early (days 1 to 2) over later sampling and is reduced by antimicrobial treatment [ 98,105,106]. The yield of invasive procedures varies between 25 and approximately 60 percent depending on the patient population studied. In 199 patients with hematologic malignancy and fever, BAL was performed 246 times and produced a microbiologic diagnoses in 118 patients [107].

It is reasonable to obtain an induced sputum for certain studies (eg, acid-fast bacilli, Pneumocystis, cytology, and routine stains and cultures) while awaiting more invasive procedures [108]. Positive results may allow for more invasive procedures to be avoided. The yield of induced sputum samples is higher than routine sputum samples only for mycobacteria, PCP, and cytology [108].

The diagnostic yield of BAL is greatest in untreated HIV-infected patients due to the large numbers of organisms (eg, P. jirovecii, mycobacteria) compared with other compromised individuals [109]. Conversely, transbronchial biopsy may be considered with BAL in HIV-uninfected immunocompromised hosts without specific contraindications to avoid the need for multiple sequential procedures.

BAL alone is less often useful for the diagnosis of invasive fungal infection than for PCP or bacterial processes. BAL samples should be coupled to microbiologic studies (cultures, polymerase chain reaction, Aspergillus galactomannan antigen) to improve sensitivity [110-112].

Post-BAL sputum samples are often revealing.

Forty-six percent of patients who underwent bronchoscopy with BAL, 50 percent of the eight patients who underwent transbronchial biopsy, and 50 percent of patients who underwent needle aspiration had specific diagnoses made after lung biopsy.

Various antigen detection and nucleic acid-based assays can be performed using blood samples as well as CSF and BAL fluid. Examples include CMV viral loads (nucleic acid testing [NAT]) or antigenemia, serum cryptococcal antigen (particularly if any signs of meningitis), syphilis serology, human herpesvirus 6 NAT, Aspergillus galactomannan antigen [111,114], Histoplasma antigen, and 1,3-beta-D-glucan. The A. galactomannan antigen assay can also be performed on BAL samples.

Detection of certain common organisms (eg, Aspergillus spp, CMV) in respiratory tract specimens may represent colonization rather than infection. Thus, it is important to interpret positive test results in clinical context (eg, whether there is a compatible clinical syndrome and radiographic findings). The presence of CMV viremia may indicate CMV reactivation; viremia in the context of a compatible pulmonary syndrome is suggestive of invasive disease. The absence of CMV viremia may mitigate against the diagnosis of invasive CMV pneumonitis.

Serologic techniques are generally of little use in the diagnosis of active infection in immunocompromised patients because such patients may be unable to generate an adequate immune response to a new pathogen or they may have made a response to a previous infection before they became immunocompromised. Thus, both a negative and a positive result may be uninterpretable.

Pursuit of a unifying diagnosis — While it is always appealing to make a single diagnosis and initiate therapy, it is important to remember that multiple simultaneous processes are common in the immunocompromised patient. The occurrence of multiple simultaneous infections or conditions can complicate and delay appropriate therapy (image 10). As an example, CMV infection may complicate the treatment of graft rejection or venoocclusive disease or contribute to the pathogenesis of PCP or Aspergillus pneumonia.

Antimicrobial agents used for prophylaxis should be avoided in empiric therapy as resistance may emerge.

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].

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].

The rate of 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 (table 1) [3,4].

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 [6,7].

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 (table 2). 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 [8,9].

● 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 [10].

● 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 [11].

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 [13,14].

When pneumonia fails to resolve or when there is clinical progression, 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 bronchoscopy include pulmonary vasculitis syndromes, cryptogenic organizing pneumonia, and diffuse alveolar damage of various etiologies

Imaging studies — The initial diagnosis of pneumonia will generally have been made on a chest radiograph. Three general patterns can be seen: (1) focal segmental or lobar, (2) multifocal, and (3) focal or diffuse interstitial changes, each with a different differential diagnosis [15].

However, despite the frequency of its use for this indication, there are few studies that document the diagnostic yield of bronchoscopy for nonresolving pneumonia.

Objective data suggest that bronchoscopy with bronchoalveolar lavage and transbronchial biopsy can successfully diagnose approximately 90 percent of patients who eventually have a specific diagnosis established [16]. It is most likely to be useful in younger nonsmoking patients with multilobar involvement and prolonged disease, whereas older adult patients, smokers, and those with immunodeficiency are more likely to have a nondiagnostic bronchoscopy and to have a slowly resolving pneumonia [16].

However, causes of nonresolving pneumonia vary considerably with geography. Bronchoscopy is particularly useful to exclude mycobacteria or fungi if not detected with expectorated sputum [14].

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 CAP, 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.

"Pneumococcal pneumonia in patients requiring hospitalization".)

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 [19].

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 [20].

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 — M. 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 — Chlamydia 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 [21]. Prompt resolution is the rule in younger patients. (See "Pneumonia caused by Chlamydia pneumoniae in adults".)

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 [9].

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 older adults, 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 [22].

Alternative pathogens in addition to the usual bacterial causes of pneumonia need to be considered in the patient who fails to respond to treatment (table 3). 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 older adult 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 AIDS.

The clinical presentation of tuberculosis as a cause of nonresolving pneumonia is often atypical, especially in diabetics and in older adult 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 and may present with "rounded" or mass-like densities with or without cavitation. 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 (image 1).

Although invasive aspergillosis classically occurs in neutropenic patients who have been on multiple antibiotics for several days, it is increasingly recognized in older adult 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 [19]. (See "Epidemiology and clinical manifestations of invasive aspergillosis".)

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) [24]. 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 H. 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.

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.

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 [25]. The patients with empyema were more likely to be younger and to use illicit drugs. The most common cultured pathogen was Streptococcus milleri, suggesting a role for aspiration.

Lung abscess — Anaerobes are the dominant flora of the upper airways and common pathogens in aspiration pneumonia and its sequelae: necrotizing pneumonia and lung abscess. The major pathogens are Peptostreptococcus spp, Bacteroides melaninogenicus, and Fusobacterium nucleatum. These infections are often subtle in onset and relatively slow in progression. Patients typically present with fever, night sweats, weight loss, cough, dyspnea, and putrid sputum with or without pleurisy.

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 in a dependent segment (posterior segment of an upper lobe or posterior segment of a lower lobe), 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 older adult populations), large cavity size, longer duration of symptoms prior to therapy, lower lobe location, association with malignant disease, and the presence of multiple abscesses.

However, the frequency of endobronchial carcinoma as a cause of nonresolving pneumonia is relatively low, ranging from 0 to 8 percent in most series [16].

Lung adenocarcinoma 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 [26].

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 [27].

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 [28].

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

Cryptogenic organizing pneumonia (previously called bronchiolitis obliterans 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. (See "Cryptogenic organizing pneumonia".)

Eosinophilic pneumonias, including both chronic and acute forms, are characterized by collections of eosinophils in the interstitial and alveolar spaces [29,30]. 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. (See "Chronic eosinophilic pneumonia".)

Acute interstitial pneumonia is a rare, idiopathic form of diffuse alveolar damage, thus corresponding to a clinical picture compatible with idiopathic ARDS [32,33]. 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. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by the abnormal accumulation of lipoproteinaceous fluid in the distal airspaces [34]. 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 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 (see "Amiodarone pulmonary toxicity"). Other drugs of concern include methotrexate (see "Methotrexate-induced lung injury"), nitrofurantoin (see "Nitrofurantoin-induced pulmonary injury"), bleomycin (see "Bleomycin-induced lung injury"), and systemic antineoplastic therapy (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)

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 (table 5) [35]. Although uncommon, persistent infiltrates resulting from newer antineoplastic checkpoint inhibitors is increasingly seen and may be confused with a prolonged resolution of an infectious pneumonia.

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. Fluid may be trapped in a fissure and look like a mass (“pseudotumor”); this is more common in patients with pre-existing pleural abnormalities.