case presentation about pneumonia

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Scenario 1: A Patient with Mild Community-Acquired Pneumonia—Introduction to Clinical Trial Design Issues

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David N. Gilbert, Scenario 1: A Patient with Mild Community-Acquired Pneumonia—Introduction to Clinical Trial Design Issues, Clinical Infectious Diseases , Volume 47, Issue Supplement_3, December 2008, Pages S121–S122, https://doi.org/10.1086/591391

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A prototypical patient is presented to introduce important design issues for clinical trials of antibacterials in the treatment of community-acquired pneumonia.

Of the 4 million or more patients in the United States treated annually for community-acquired pneumonia (CAP), ∼80% are cared for on an outpatient basis [ 1 , 2 ]. Admittedly, the patient population is heterogeneous. However, 2 subgroups constitute a significant percentage of the total.

The first subgroup consists of young, otherwise-healthy individuals who are nonsmokers aged <40 years. “Atypical” pathogens, such as Mycoplasma pneumoniae or Chlamydia pneumoniae , are identified frequently as the etiologic organism. Streptococcus pneumoniae may be the etiologic organism, especially during or after viral tracheobronchitis.

In contrast, individuals in the second group are older. Often, they have used tobacco products for years and meet clinical criteria for chronic bronchitis and/or emphysema.

To focus on clinical trial design issues pertinent to the population of patients with mild pneumonia, a typical clinical-trial candidate patient is described below.

Present illness. A 35-year-old male resident of Boston, Massachusetts, presents with fever and cough. He was well until 3 days earlier, when he suffered the onset of nasal stuffiness, mild sore throat, and a cough productive of small amounts of clear sputum. Today, he decided to seek physician assistance because of an increase in temperature to 38.3°C and spasms of coughing that produce purulent secretions. On one occasion, he noted a few flecks of bright-red blood in his sputum.

Other pertinent history. It is March. He lives in a home in the city with his wife and 3 children, aged 7, 9, and 11 years. The children are fully immunized. The 11-year-old child is recovering from a “nagging” cough that has persisted for 10–14 days.

The family has a pet parakeet who is 5 years old and appears to be well. The patient has not traveled outside the city in the past year. He is an office manager.

The patient smokes 1 pack/day and has done so since the age of 15 years. Several times a month, especially during the winter, on arising from sleep, he produces ∼1 tablespoon of purulent sputum.

Medical history. The patient has no history of familial illness, hospitalizations, or trauma. There are no drug allergies or intolerance. The only medication he takes is acetaminophen occasionally, for headaches. He drinks beer or wine in moderation.

Physical examination. His body temperature is 38.9°C (100°F), his pulse is 110 beats/min and regular, and his respiratory rate is 18 breaths/min. His oxygen saturation is 93% while breathing room air. There is mild erythema of the mucosa of the nose and posterior oropharynx. Inspiratory “rales” are heard at the right lung base.

Laboratory and radiographic findings. His hemoglobin level is 12.5 g/dL, with a hematocrit of 36%. His WBC count is 13,500 cells/µL, with 82% polymorphonuclear cells, 11% band forms, and 7% lymphocytes. His platelet count is 180,000 cells/µL. The results of a multichemistry screen are unremarkable.

Chest radiography documents bilateral lower lobe infiltrates that are more pronounced on the right side. There are no pleural effusions.

Management questions. A validated prediction rule forecasts that this patient's risk of death from his CAP is <1% [ 3 ]. Therefore, he is a candidate for outpatient therapy.

What is the likely microbiological diagnosis? On the basis of the cough of 2 weeks' duration in the patient's 11-year-old child, the pneumonia could be due to M. pneumoniae or another atypical pathogen. However, this illness could represent pneumococcal pneumonia superimposed on a viral upper respiratory tract infection.

Clinical trial design questions. These are the hard questions and illustrate some of the many reasons for this workshop: Is the patient of sufficient reliability to participate in an outpatient clinical trial of antibacterials for mild CAP? Is it ethical or, from a practical standpoint, feasible to conduct a placebo-controlled trial? If an active comparator drug is used, how does one generate a valid and defensible margin of noninferiority?

What are valid, reproducible, and quantifiable clinical end points (outcomes)?

It would help greatly if the etiology of the pneumonia could be determined for the majority of the enrolled patients. What are the current diagnostic tools that can be applied and thereby “enrich” the patient population?

Multiple precautions are necessary to avoid bias in the interpretation of the results of clinical trials. For example, what are acceptable methods in the “blinding” of treatment arms?

How can investigators reliably and with reasonable sensitivity detect adverse drug effects?

The articles that follow address these questions and more. Participants in this workshop uniformly agreed that the interaction of US Food and Drug Administration regulations, industry sponsors, and Infectious Diseases Society of America academics represents an opportunity to modernize future clinical trials for CAP.

Supplement sponsorship. This article was published as part of a supplement entitled “Workshop on Issues in the Design and Conduct of Clinical Trials of Antibacterial Drugs for the Treatment of Community-Acquired Pneumonia,” sponsored by the US Food and Drug Administration and the Infectious Diseases Society of America.

Potential conflicts of interest. D.N.G. serves on the speakers' bureau of Abbott Laboratories, Bayer, GlaxoSmithKline, Lilly, Merck, Pfizer, Roche, Schering-Plough, and Wyeth; and has received consulting fees from Advanced Life Sciences and Pacific Beach Bioscience.

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INTRODUCTION  —  Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. The clinical presentation of CAP varies, ranging from mild pneumonia characterized by fever and productive cough to severe pneumonia characterized by respiratory distress and sepsis. Because of the wide spectrum of associated clinical features, CAP is a part of the differential diagnosis of nearly all respiratory illnesses.

This topic provides a broad overview of the epidemiology, microbiology, pathogenesis, clinical features, diagnosis, and management of CAP in immunocompetent adults. Detailed discussions of each of these issues are presented separately; links to these discussions are provided within the text below.

DEFINITIONS  —  Pneumonia is frequently categorized based on site of acquisition ( table 1 ).

● Community-acquired pneumonia (CAP) refers to an acute infection of the pulmonary parenchyma acquired outside of the hospital.

● Nosocomial pneumonia refers to an acute infection of the pulmonary parenchyma acquired in hospital settings and encompasses both hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).

• HAP refers to pneumonia acquired ≥48 hours after hospital admission.

• VAP refers to pneumonia acquired ≥48 hours after endotracheal intubation.

Health care-associated pneumonia (HCAP; no longer used) referred to pneumonia acquired in health care facilities (eg, nursing homes, hemodialysis centers) or after recent hospitalization. The term HCAP was used to identify patients at risk for infection with multidrug-resistant pathogens. However, this categorization may have been overly sensitive, leading to increased, inappropriately broad antibiotic use and was thus retired. In general, patients previously classified as having HCAP should be treated similarly to those with CAP. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults" .)

EPIDEMIOLOGY

Incidence  —  CAP is one of the most common and morbid conditions encountered in clinical practice [ 1-3 ]. In the United States, CAP accounts for over 4.5 million outpatient and emergency room visits annually, corresponding to approximately 0.4 percent of all encounters [ 4 ]. CAP is the second most common cause of hospitalization and the most common infectious cause of death [ 5,6 ]. Approximately 650 adults are hospitalized with CAP every year per 100,000 population in the United States, corresponding to 1.5 million unique CAP hospitalizations each year [ 7 ]. Nearly 9 percent of patients hospitalized with CAP will be rehospitalized due to a new episode of CAP during the same year.

Risk factors

● Older age – The risk of CAP rises with age [ 7,8 ]. The annual incidence of hospitalization for CAP among adults ≥65 years old is approximately 2000 per 100,000 in the United States [ 7,9 ]. This figure is approximately three times higher than the general population and indicates that 2 percent of the older adult population will be hospitalized for CAP annually ( figure 1 ).

● Chronic comorbidities – The comorbidity that places patients at highest risk for CAP hospitalization is chronic obstructive pulmonary disease (COPD), with an annual incidence of 5832 per 100,000 in the United States [ 7 ]. Other comorbidities associated with an increased incidence of CAP include other forms of chronic lung disease (eg, bronchiectasis, asthma), chronic heart disease (particularly congestive heart failure), stroke, diabetes mellitus, malnutrition, and immunocompromising conditions ( figure 2 ) [ 7,10,11 ].

● Viral respiratory tract infection – Viral respiratory tract infections can lead to primary viral pneumonias and also predispose to secondary bacterial pneumonia. This is most pronounced for influenza virus infection. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Pneumonia' .)

● Impaired airway protection – Conditions that increase risk of macroaspiration of stomach contents and/or microaspiration of upper airway secretions predispose to CAP, such as alteration in consciousness (eg, due to stroke, seizure, anesthesia, drug or alcohol use) or dysphagia due to esophageal lesions or dysmotility.

● Smoking and alcohol overuse – Smoking, alcohol overuse (eg, >80 g/day), and opioid use are key modifiable behavioral risk factors for CAP [ 7,10,12,13 ].

● Other lifestyle factors – Other factors that have been associated with an increased risk of CAP include crowded living conditions (eg, prisons, homeless shelters), residence in low-income settings, and exposure to environmental toxins (eg, solvents, paints, or gasoline) [ 7,10,11,14 ].

Combinations of risk factors, such as smoking, COPD, and congestive heart failure, are additive in terms of risk [ 15 ]. These risk factors and other predisposing conditions for the development of CAP are discussed separately. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Predisposing host conditions' .)

MICROBIOLOGY

Common causes  —  Streptococcus pneumoniae (pneumococcus) and respiratory viruses are the most frequently detected pathogens in patients with CAP [ 8,16 ]. However, in a large proportion of cases (up to 62 percent in some studies performed in hospital settings), no pathogen is detected despite extensive microbiologic evaluation [ 8,17,18 ].

The most commonly identified causes of CAP can be grouped into three categories:

● Typical bacteria

• S. pneumoniae (most common bacterial cause)

• Haemophilus influenzae

• Moraxella catarrhalis

• Staphylococcus aureus

• Group A streptococci

• Aerobic gram-negative bacteria (eg, Enterobacteriaceae such as Klebsiella spp or Escherichia coli )

• Microaerophilic bacteria and anaerobes (associated with aspiration)

● Atypical bacteria ("atypical" refers to the intrinsic resistance of these organisms to beta-lactams and their inability to be visualized on Gram stain or cultured using traditional techniques)

• Legionella spp

• Mycoplasma pneumoniae

• Chlamydia pneumoniae

• Chlamydia psittaci

• Coxiella burnetii

● Respiratory viruses

• Influenza A and B viruses

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

• Other coronaviruses (eg, CoV-229E, CoV-NL63, CoV-OC43, CoV-HKU1)

• Rhinoviruses

• Parainfluenza viruses

• Adenoviruses

• Respiratory syncytial virus

• Human metapneumovirus

• Human bocaviruses

The relative prevalence of these pathogens varies with geography, pneumococcal vaccination rates, host risk factors (eg, smoking), season, and pneumonia severity ( table 2 ).

Certain epidemiologic exposures also raise the likelihood of infection with a particular pathogen ( table 3 ). As examples, exposure to contaminated water is a risk factor for Legionella infection, exposure to birds raises the possibility of C. psittaci infection, travel or residence in the southwestern United States should raise suspicion for coccidioidomycosis, and poor dental hygiene may predispose patients with pneumonia caused by oral flora or anaerobes. In immunocompromised patients, the spectrum of possible pathogens also broadens to include fungi and parasites as well as less common bacterial and viral pathogens. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates" .)

While the list above details some of most common causes of CAP, >100 bacterial, viral, fungal, and parasitic causes have been reported. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Microbiology' .)

Important trends  —  Both the distribution of pathogens that cause CAP and our knowledge of these pathogens are evolving. Key observations that have changed our understanding of CAP and influenced our approach to management include:

● Decline in S. pneumoniae incidence – Although S. pneumoniae (pneumococcus) is the most commonly detected bacterial cause of CAP in most studies, the overall incidence of pneumococcal pneumonia is decreasing. This is in part due to widespread use of pneumococcal vaccination, which results in both a decline in the individual rates of pneumococcal pneumonia and herd immunity in the population. (See "Pneumococcal pneumonia in patients requiring hospitalization", section on 'Prevalence' .)

Because pneumococcal vaccination rates vary regionally, the prevalence of S. pneumoniae infection also varies. As an example, S. pneumoniae is estimated to cause approximately 30 percent of cases of CAP in Europe but only 10 to 15 percent in the United States, where the population pneumococcal vaccination rate is higher [ 8 ].

● The coronavirus disease 2019 (COVID-19) pandemic – SARS-CoV-2 is an important cause of CAP and is discussed in detail elsewhere. (See "COVID-19: Epidemiology, virology, and prevention" .)

● Increased recognition of other respiratory viruses – Respiratory viruses have been detected in approximately one-third of cases of CAP in adults when using molecular methods [ 8 ]. The extent to which respiratory viruses serve as single pathogens, cofactors in the development of bacterial CAP, or triggers for dysregulated host immune response has not been established.

● Low overall rate of pathogen detection – Despite extensive evaluation using molecular diagnostics and other microbiologic testing methods, a causal pathogen can be identified in only half of cases of CAP. This finding highlights that our understanding of CAP pathogenesis is incomplete. As molecular diagnostics become more advanced and use broadens, our knowledge is expected to grow.

● Discovery of the lung microbiome – Historically, the lung has been considered sterile. However, culture-independent techniques (ie, high throughput 16S ribosomal ribonucleic acid [rRNA] gene sequencing) have identified complex and diverse communities of microbes that reside within the alveoli [ 19-21 ]. This finding suggests that resident alveolar microbes play a role in the development of pneumonia, either by modulating the host immune response to infecting pathogens or through direct overgrowth of specific pathogens within the alveolar microbiome. (See 'Pathogenesis' below.)

Antimicrobial resistance  —  Knowledge of antimicrobial resistance patterns and risk factors for infection with antimicrobial-resistant pathogens help inform the selection of antibiotics for empiric CAP treatment ( table 4 ).

● S. pneumoniae may be resistant to one or more antibiotics commonly used for the empiric treatment of CAP.

• Macrolide resistance rates vary regionally but are generally high (>25 percent) in the United States, Asia, and southern Europe. Resistance rates tend to be lower in northern Europe. (See "Resistance of Streptococcus pneumoniae to the macrolides, azalides, and lincosamides" .)

• Estimates of doxycycline resistance are less certain and vary substantially worldwide. In the United States, rates tend to be less than 20 percent but may be rising. (See "Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline, and trimethoprim-sulfamethoxazole" .)

• Beta-lactam resistance rates also vary regionally but to a lesser extent than macrolide and doxycycline resistance. In the United States, <20 percent of isolates are resistant to penicillin and <1 percent to cephalosporins. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics" .)

• Fluoroquinolone resistance tends to be <2 percent in the United States but varies regionally and with specific risk factors such as recent antibiotic use or hospitalization. (See "Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline, and trimethoprim-sulfamethoxazole" .)

Because resistance rates vary even at local levels, clinicians should refer to local antibiograms to guide antibiotic selection when available. General epidemiologic data can be obtained through sources such as the OneHealthTrust (formerly the Center for Disease Dynamics, Economics & Policy [CDDEP]).

● Methicillin-resistant S. aureus (MRSA) is an uncommon cause of CAP. Risk factors for MRSA have two patterns: health care associated and community acquired. The strongest risk factors for MRSA pneumonia include known MRSA colonization or prior MRSA infection, particularly involving the respiratory tract. Gram-positive cocci on sputum Gram stain are also predictive of MRSA infection. Other factors that should raise suspicion for MRSA infection include recent antibiotic use (particularly receipt of intravenous antibiotics within the past three months), recent influenza-like illness, the presence of empyema, necrotizing/cavitary pneumonia, and immunosuppression ( table 4 ).

In contrast with health care-associated MRSA, community-acquired MRSA (CA-MRSA) infections tend to occur in younger healthy persons [ 22 ]. Risk factors for CA-MRSA infection include a history of MRSA skin lesions, participation in contact sports, injection drug use, crowded living conditions, and men who have sex with men. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology" .)

CAP caused by CA-MRSA can be severe and is associated with necrotizing and/or cavitary pneumonia, empyema, gross hemoptysis, septic shock, and respiratory failure. These features may be attributable to infection with toxin-producing CA-MRSA strains. In the United States, these strains tend to be methicillin resistant and belong to the USA300 clone. (See "Methicillin-resistant Staphylococcus aureus (MRSA): Microbiology and laboratory detection" .)

● Pseudomonas is also an uncommon cause of CAP and tends to occur more frequently in patients with known colonization or prior infection with Pseudomonas spp, recent hospitalization or antibiotic use, underlying structural lung disease (eg, cystic fibrosis or advanced chronic obstructive pulmonary disease [bronchiectasis]), and immunosuppression. Antibiotic resistance is common among pseudomonal strains, and empiric therapy with more than one agent that targets Pseudomonas is warranted for at-risk patients with moderate to severe CAP ( table 4 ). (See "Pseudomonas aeruginosa pneumonia" and 'Inpatient antibiotic therapy' below.)

PATHOGENESIS  —  Community-acquired pneumonia (CAP) pathogenesis Figure 3 Traditionally, CAP has been viewed as an infection of the lung parenchyma, primarily caused by bacterial or viral respiratory pathogens. In this model, respiratory pathogens are transmitted from person to person via droplets or, less commonly, via aerosol inhalation (eg, as with Legionella or Coxiella species). Following inhalation, the pathogen colonizes the nasopharynx and then reaches the lung alveoli via microaspiration. When the inoculum size is sufficient and/or host immune defenses are impaired, infection results. Replication of the pathogen, the production of virulence factors, and the host immune response lead to inflammation and damage of the lung parenchyma, resulting in pneumonia ( figure 3 ).

With the identification of the lung microbiome, that model has changed [ 19-21 ]. While the pathogenesis of pneumonia may still involve the introduction of respiratory pathogens into the alveoli, the infecting pathogen likely has to compete with resident microbes to replicate. In addition, resident microbes may also influence or modulate the host immune response to the infecting pathogen. If this is correct, an altered alveolar microbiome (alveolar dysbiosis) may be a predisposing factor for the development of pneumonia.

In some cases, CAP might also arise from uncontrolled replication of microbes that normally reside in the alveoli. The alveolar microbiome is similar to oral flora and is primarily comprised of anaerobic bacteria (eg, Prevotella and Veillonella ) and microaerophilic streptococci [ 19-21 ]. Hypothetically, exogenous insults such as a viral infection or smoke exposure might alter the composition of the alveolar microbiome and trigger overgrowth of certain microbes. Because organisms that compose the alveolar microbiome typically cannot be cultivated using standard cultures, this hypothesis might explain the low rate of pathogen detection among patients with CAP.

In any scenario, the host immune response to microbial replication within the alveoli plays an important role in determining disease severity. For some patients, a local inflammatory response within the lung predominates and may be sufficient for controlling infection. In others, a systemic response is necessary to control infection and to prevent spread or complications, such as bacteremia. In a minority, the systemic response can become dysregulated, leading to tissue injury, sepsis, acute respiratory distress syndrome, and/or multiorgan dysfunction.

The pathogenesis of CAP is discussed in greater detail separately. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults" .)

CLINICAL PRESENTATION  —  The clinical presentation of CAP varies widely, ranging from mild pneumonia characterized by fever, cough, and shortness of breath to severe pneumonia characterized by sepsis and respiratory distress. Symptom severity is directly related to the intensity of the local and systemic immune response in each patient.

● Pulmonary signs and symptoms – Cough (with or without sputum production), dyspnea, and pleuritic chest pain are among the most common symptoms associated with CAP. Signs of pneumonia on physical examination include tachypnea, increased work of breathing, and adventitious breath sounds, including rales/crackles and rhonchi. Tactile fremitus, egophony, and dullness to percussion also suggest pneumonia. These signs and symptoms result from the accumulation of white blood cells (WBCs), fluid, and proteins in the alveolar space. Hypoxemia can result from the subsequent impairment of alveolar gas exchange. On chest radiograph, accumulation of WBCs and fluid within the alveoli appears as pulmonary opacities ( image 1A-B ).

● Systemic signs and symptoms – The great majority of patients with CAP present with fever. Other systemic symptoms such as chills, fatigue, malaise, chest pain (which may be pleuritic), and anorexia are also common. Tachycardia, leukocytosis with a leftward shift, or leukopenia are also findings that are mediated by the systemic inflammatory response. Inflammatory markers, such as the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin may rise, though the latter is largely specific to bacterial infections. CAP is also the leading cause of sepsis; thus, the initial presentation may be characterized by hypotension, altered mental status, and other signs of organ dysfunction such as renal dysfunction, liver dysfunction, and/or thrombocytopenia [ 23 ].

Although certain signs and symptom such as fever, cough, tachycardia, and rales are common among patients with CAP, these features are ultimately nonspecific and are shared among many respiratory disorders (see 'Differential diagnosis' below). No individual symptom or constellation of symptoms is adequate for diagnosis without chest imaging. For example, the positive predictive value of the combination of fever, tachycardia, rales, and hypoxia (oxygen saturation <95 percent) among patients with respiratory complaints presenting to primary care was <60 percent when chest radiograph was used as a reference standard [ 24 ].

Signs and symptoms of pneumonia can also be subtle in patients with advanced age and/or impaired immune systems, and a higher degree of suspicion may be needed to make the diagnosis. As examples, older patients may present with mental status changes but lack fever or leukocytosis [ 25 ]. In immunocompromised patients, pulmonary infiltrates may not be detectable on chest radiographs but can be visualized with computed tomography.

The clinical and diagnostic features of CAP and sepsis are discussed in detail separately. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Clinical presentation' .)

Making the diagnosis  —  The diagnosis of CAP generally requires the demonstration of an infiltrate on chest imaging in a patient with a clinically compatible syndrome (eg, fever, dyspnea, cough, and sputum production) [ 26 ].

● For most patients with suspected CAP, we obtain posteroanterior and lateral chest radiographs. Radiographic findings consistent with the diagnosis of CAP include lobar consolidations ( image 1C ), interstitial infiltrates ( image 1D-E ), and/or cavitations ( image 2 ). Although certain radiographic features suggest certain causes of pneumonia (eg, lobar consolidations suggest infection with typical bacterial pathogens), radiographic appearance alone cannot reliably differentiate among etiologies.

● For selected patients in whom CAP is suspected based on clinical features despite a negative chest radiograph, we obtain computed tomography (CT) of the chest. These patients include immunocompromised patients, who may not mount strong inflammatory responses and thus have negative chest radiographs, as well as patients with known exposures to epidemic pathogens that cause pneumonia (eg, Legionella ). Because there is no direct evidence to suggest that CT scanning improves outcomes for most patients and cost is high, we do not routinely obtain CT scans when evaluating patients for CAP.

The combination of a compatible clinical syndrome and imaging findings consistent with pneumonia are sufficient to establish an initial clinical diagnosis of CAP. However, this combination of findings is nonspecific and is shared among many cardiopulmonary disorders. Thus, remaining attentive to the possibility of an alternate diagnosis as a patient's course evolves is important to care. (See 'Differential diagnosis' below.)

Defining severity and site of care  —  For patients with a working diagnosis of CAP, the next steps in management are defining the severity of illness and determining the most appropriate site of care. Determining the severity of illness is based on clinical judgement and can be supplemented by use of severity scores ( algorithm 1 ).

The most commonly used severity scores are the Pneumonia Severity Index (PSI) and CURB-65 [ 27,28 ]. We generally prefer the PSI, also known as the PORT score ( calculator 1 ), because it is the most accurate and its safety and effectiveness in guiding clinical decision-making have been validated [ 29-32 ]. However, the CURB-65 score is a reasonable alternative and is preferred by many clinicians because it is easier to use ( calculator 2 ).

The three levels of severity (mild, moderate, and severe) generally correspond to three levels of care:

● Ambulatory care – Most patients who are otherwise healthy with normal vital signs (apart from fever) and no concern for complication are considered to have mild pneumonia and can be managed in the ambulatory setting. These patients typically have PSI scores of I to II and CURB-65 scores of 0 (or a CURB-65 score of 1 if age >65 years).

● Hospital admission – Patients who have peripheral oxygen saturations <92 percent on room air (and a significant change from baseline) should be hospitalized. In addition, patients with PSI scores of ≥III and CURB-65 scores ≥1 (or CURB-65 score ≥2 if age >65 years) should also generally be hospitalized.

Because patients with early signs of sepsis, rapidly progressive illness, or suspected infections with aggressive pathogens are not well represented in severity scoring systems, these patients may also warrant hospitalization in order to closely monitor the response to treatment.

Practical concerns that may warrant hospital admission include an inability to take oral medications, cognitive or functional impairment, or other social issues that could impair medication adherence or ability to return to care for clinical worsening (eg, substance abuse, homelessness, or residence far from a medical facility).

● Intensive care unit (ICU) admission – Patients who meet either of the following major criteria have severe CAP and should be admitted to the ICU [ 26 ]:

• Respiratory failure requiring mechanical ventilation

• Sepsis requiring vasopressor support

Recognizing these two criteria for ICU admission is relatively straightforward. The challenge is to identify patients with severe CAP who have progressed to sepsis before the development of organ failure. For these patients, early ICU admission and administration of appropriate antibiotics improve outcomes. To help identify patients with severe CAP before development of organ failure, the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) suggest minor criteria [ 1,26 ].

The presence of three of these criteria warrants ICU admission:

• Altered mental status

• Hypotension requiring fluid support

• Temperature <36°C (96.8°F)

• Respiratory rate ≥30 breaths/minute

• Arterial oxygen tension to fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio ≤250

• Blood urea nitrogen (BUN) ≥20 mg/dL (7 mmol/L)

• Leukocyte count <4000 cells/microL

• Platelet count <100,000/microL

• Multilobar infiltrates

Although several other scores for identifying patients with severe CAP and/or ICU admission have been developed, we generally use the ATS/IDSA major and minor criteria because they are well validated [ 33-35 ].

Detailed discussion on assessing severity and determining the site of care in patients with CAP is provided separately. (See "Community-acquired pneumonia in adults: Assessing severity and determining the appropriate site of care" .) (Related Pathway(s): Community-acquired pneumonia: Determining the appropriate site of care for adults .)

Triage of patients with known or suspected COVID-19 is also discussed elsewhere. (See "COVID-19: Evaluation of adults with acute illness in the outpatient setting", section on 'Disposition' .)

Microbiologic testing  —  The benefit of obtaining a microbiologic diagnosis should be balanced against the time and cost associated with an extensive evaluation in each patient.

Generally, we take a tiered approach to microbiologic evaluation based on CAP severity and the site of care ( table 5 ):

● Outpatients − For most patients with mild CAP being treated in the ambulatory setting, microbiologic testing is not needed (apart from testing for SARS-CoV-2 during the pandemic). Empiric antibiotic therapy is generally successful, and knowledge of the infecting pathogen does not usually improve outcomes.

● Patients with moderate CAP admitted to the general medicine ward − For most patients with moderate CAP admitted to the general medical ward, we obtain the following:

• Blood cultures

• Sputum Gram stain and culture

• Urinary antigen testing for S. pneumoniae

• Testing for Legionella spp (polymerase chain reaction [PCR] when available, urinary antigen test as an alternate)

• SARS-CoV-2 testing

During the pandemic, we test all patients for COVID-19. During respiratory virus season (eg, late fall to early spring in the northern hemisphere), we also test for other respiratory viruses (eg, influenza, adenovirus, parainfluenza, respiratory syncytial virus, and human metapneumovirus). When testing for influenza, PCR is preferred over rapid antigen testing. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis" .)

For these patients, making a microbiologic diagnosis allows for directed therapy, which helps limit antibiotic overuse, prevent antimicrobial resistance, and reduce unnecessary complications, such as Clostridioides difficile infections.

● Patients with severe CAP (including ICU admission) − For most hospitalized patients with severe CAP, including those admitted to the ICU, we send blood cultures, sputum cultures, urinary streptococcal antigen, and Legionella testing. In addition, we obtain bronchoscopic specimens for microbiologic testing when feasible, weighing the benefits of obtaining a microbiologic diagnosis against the risks of the procedure (eg, need for intubation, bleeding, bronchospasm, pneumothorax) on a case-by-case basis. When pursuing bronchoscopy, we usually send specimens for aerobic culture, Legionella culture, fungal stain and culture, and testing for respiratory viruses.

The type of viral diagnostic tests used (eg, PCR, serology, culture) vary among institutions. In some cases, multiplex PCR panels that test for a wide array of viral and bacterial pathogens are used. While we generally favor using these tests for patients with severe pneumonia, we interpret results with caution as most multiplex assays have not been approved for use on lower respiratory tract specimens. In particular, the detection of single viral pathogen does not confirm the diagnosis of viral pneumonia because viruses can serve as cofactors in the pathogenesis of bacterial CAP or can be harbored asymptomatically.

In all cases, we modify this approach based on epidemiologic exposures, patient risk factors, and clinical features regardless of CAP severity or treatment setting ( table 3 ). As examples:

● For patients with known or probable exposures to epidemic pathogens such as Legionella or epidemic coronaviruses, we broaden our evaluation to include tests for these pathogens. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Important pathogens' .)

● For patients with cavitary pneumonia, we may include testing for tuberculosis, fungal pathogens, and Nocardia .

● For immunocompromised patients, we broaden our differential to include opportunistic pathogens such as Pneumocystis jirovecii , fungal pathogens, parasites, and less common viral pathogens such as cytomegalovirus. The approach to diagnostic testing varies based on the type and degree of immunosuppression and other patient-specific factors. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Epidemiology of pulmonary infections in immunocompromised patients" .)

When defining the scope of our microbiologic evaluation, we also take the certainty of the diagnosis of CAP into consideration. Because a substantial portion of patients hospitalized with an initial clinical diagnosis of CAP are ultimately found to have alternate diagnoses [ 17 ], pursuing a comprehensive microbiologic evaluation can help reach the final diagnosis (eg, blood cultures obtained as part of the evaluation for CAP may help lead to a final diagnosis of endocarditis).

Detailed discussion on the microbiologic evaluation of CAP is provided separately. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Sputum cultures for the evaluation of bacterial pneumonia" .)

The diagnosis of COVID-19 during the pandemic is also discussed in detail elsewhere. (See "COVID-19: Diagnosis" .)

DIFFERENTIAL DIAGNOSIS  —  CAP is a common working diagnosis and is frequently on the differential diagnosis of patients presenting with a pulmonary infiltrate and cough, patients with respiratory tract infections, and patients with sepsis. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Differential diagnosis' .)

Noninfectious illnesses that mimic CAP or co-occur with CAP and present with pulmonary infiltrate and cough include:

• Congestive heart failure with pulmonary edema

• Pulmonary embolism

• Pulmonary hemorrhage

• Atelectasis

• Aspiration or chemical pneumonitis

• Drug reactions

• Lung cancer

• Collagen vascular diseases

• Vasculitis

• Acute exacerbation of bronchiectasis

• Interstitial lung diseases (eg, sarcoidosis, asbestosis, hypersensitivity pneumonitis, cryptogenic organizing pneumonia)

For patients with an initial clinical diagnosis of CAP who have rapidly resolving pulmonary infiltrates, alternate diagnoses should be investigated. Pulmonary infiltrates in CAP are primarily caused by the accumulation of white blood cells (WBCs) in the alveolar space and typically take weeks to resolve. A pulmonary infiltrate that resolves in one or two days may be caused by accumulation of fluid in the alveoli (ie, pulmonary edema) or a collapse of the alveoli (ie, atelectasis) but not due to accumulation of WBCs.

Respiratory illnesses that mimic CAP or co-occur with CAP include:

• Acute exacerbations of chronic obstructive pulmonary disease

• Influenza and other respiratory viral infections

• Acute bronchitis ( figure 4 )

• Asthma exacerbations

Febrile illness and/or sepsis can also be the presenting syndrome in patients with CAP; other common causes of these syndromes include urinary tract infections, intraabdominal infections, and endocarditis.

TREATMENT  —  For most patients with CAP and excluding COVID-19, the etiology is not known at the time of diagnosis, and antibiotic treatment is empiric, targeting the most likely pathogens. The pathogens most likely to cause CAP vary with severity of illness, local epidemiology, and patient risk factors for infection with drug-resistant organisms.

As an example, for most patients with mild CAP who are otherwise healthy and treated in the ambulatory setting, the range of potential pathogens is limited. By contrast, for patients with CAP severe enough to require hospitalization, potential pathogens are more diverse, and the initial treatment regimens are often broader. (Related Pathway(s): Community-acquired pneumonia: Empiric antibiotic selection for adults in the outpatient setting and Community-acquired pneumonia: Empiric antibiotic selection for adults admitted to a general medical ward and Community-acquired pneumonia: Empiric antibiotic selection for adults admitted to the intensive care unit .)

The management of COVID-19 is discussed in detail elsewhere. (See "COVID-19: Management in hospitalized adults" and "COVID-19: Management of adults with acute illness in the outpatient setting" .)

Outpatient antibiotic therapy  —  For all patients with CAP, empiric regimens are designed to target S. pneumoniae (the most common and virulent bacterial CAP pathogen) and atypical pathogens. Coverage is expanded for outpatients with comorbidities, smoking, and recent antibiotic use to include or better treat beta-lactamase-producing H. influenzae , M. catarrhalis , and methicillin-susceptible S. aureus . For those with structural lung disease, we further expand coverage to include Enterobacteriaceae, such as E. coli and Klebsiella spp ( algorithm 2 ).

Selection of the initial regimen depends on the adverse effect profiles of available agents, potential drug interactions, patient allergies, and other patient-specific factors.

● For most patients aged <65 years who are otherwise healthy and have not recently used antibiotics, we typically use oral amoxicillin (1 g three times daily) plus a macrolide (eg, azithromycin or clarithromycin ) or doxycycline . Generally, we prefer to use a macrolide over doxycycline.

This approach differs from the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA), which recommend monotherapy with amoxicillin as first line and monotherapy with either doxycycline or a macrolide (if local resistance rates are <25 percent [eg, not in the United States]) as alternatives for this population [ 26 ]. The rationale for each approach is discussed separately. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting", section on 'Empiric antibiotic treatment' .)

● For patients who have major comorbidities (eg, chronic heart, lung, kidney, or liver disease, diabetes mellitus, alcohol dependence, or immunosuppression), who are smokers, and/or who have used antibiotics within the past three months, we suggest oral amoxicillin-clavulanate (875 mg twice daily or extended release 2 g twice daily) plus either a macrolide (preferred) or doxycycline .

Alternatives to amoxicillin-based regimens include combination therapy with a cephalosporin plus a macrolide or doxycycline or monotherapy with lefamulin .

● For patients who can use cephalosporins, we use a third-generation cephalosporin (eg, cefpodoxime ) plus either a macrolide or doxycycline .

● For patients who cannot use any beta-lactam, we select a respiratory fluoroquinolone (eg, levofloxacin , moxifloxacin , gemifloxacin ) or lefamulin . For those with structural lung disease, we prefer a respiratory fluoroquinolone because its spectrum of activity includes Enterobacteriaceae.

In the absence of hepatic impairment or drug interactions, lefamulin is a potential alternative to fluoroquinolones for most others. However, clinical experience with this agent is limited. Use should be avoided in patients with moderate to severe hepatic dysfunction, known long QT syndrome, or in those taking QT-prolonging agents, pregnant and breastfeeding women, and women with reproductive potential not using contraception. There are drug interactions with CYP3A4 and P-gp inducers and substrates; in addition, lefamulin tablets are contraindicated with QT-prolonging CYP3A4 substrates. Refer to the drug interactions program included within UpToDate.  

Omadacycline is another newer agent that is active against most CAP pathogens, including Enterobacteriaceae. It is a potential alternative for patients who cannot tolerate beta-lactams (or other agents) and want to avoid fluoroquinolones. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'New antimicrobial agents' .)

Modifications to these regimens may be needed for antibiotic allergy, drug interactions, specific exposures, and other patient-specific factors. In particular, during influenza season, patients at high risk for poor outcomes from influenza may warrant antiviral therapy ( table 6 ).

We treat most patients for five days. However, we generally ensure that all patients are improving on therapy and are afebrile for at least 48 hours before stopping antibiotics. In general, extending the treatment course beyond seven days does not add benefit. Studies supporting this approach are discussed separately. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting", section on 'Duration of therapy' .)

Detailed discussion on the treatment of CAP in the outpatient setting, including antibiotic efficacy data, is provided separately. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" .) (Related Pathway(s): Community-acquired pneumonia: Empiric antibiotic selection for adults in the outpatient setting .)

Inpatient antibiotic therapy

General medical ward  —  For patients with CAP admitted to the medical ward, empiric antibiotic regimens are designed to treat S. aureus , gram-negative enteric bacilli (eg, Klebsiella pneumoniae ) in addition to typical pathogens (eg, S. pneumoniae , H. influenzae , and M. catarrhalis ) and atypical pathogens (eg, Legionella pneumophilia , M. pneumoniae , and C. pneumoniae ).

We generally start antibiotic therapy as soon as we are confident that CAP is the appropriate working diagnosis and, ideally, within four hours of presentation. Delays in appropriate antibiotic treatment that exceed four hours have been associated with increased mortality [ 36 ].

The key factors in selecting an initial regimen for hospitalized patients with CAP are risk of infection with Pseudomonas and/or methicillin-resistant S. aureus (MRSA). The strongest risk factors for MRSA or Pseudomonas infection are known colonization or prior infection with these organisms, particularly from a respiratory tract specimen. Recent hospitalization (ie, within the past three months) with receipt of intravenous (IV) antibiotics is also a risk factor, particularly for pseudomonal infection. Suspicion for these pathogens should otherwise be based on local prevalence (when known), other patient-specific risk factors, and the overall clinical assessment ( algorithm 3 and table 4 ):

● For patients without suspicion for MRSA or Pseudomonas , we generally use one of two regimens: combination therapy with a beta-lactam plus a macrolide or monotherapy with a respiratory fluoroquinolone [ 26 ]. Because these two regimens have similar clinical efficacy, we select among them based on other factors (eg, antibiotic allergy, drug interactions). For patients who are unable to use either a macrolide or a fluoroquinolone, we use a beta-lactam plus doxycycline .

● For patients with known colonization or prior infection with Pseudomonas, recent hospitalization with IV antibiotic use, or other strong suspicion for pseudomonal infection , we typically use combination therapy with both an antipseudomonal beta-lactam (eg, piperacillin-tazobactam , cefepime , ceftazidime , meropenem , or imipenem ) plus an antipseudomonal fluoroquinolone (eg, ciprofloxacin or levofloxacin ). The selection of empiric regimens should also be informed by the susceptibility pattern for prior isolates.

● For patients with known colonization or prior infection with MRSA or other strong suspicion for MRSA infection , we add an agent with anti-MRSA activity, such as vancomycin or linezolid , to either of the above regimens. We generally prefer linezolid over vancomycin when community-acquired MRSA is suspected (eg, a young, otherwise healthy patient who plays contact sports presenting with necrotizing pneumonia) because of linezolid's ability to inhibit bacterial toxin production [ 37 ]. Ceftaroline is a potential alternative for the treatment of MRSA pneumonia but is not US Food and Drug Administration approved. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Community-acquired MRSA' .)

Modifications to initial empiric regimens may be needed for antibiotic allergy, potential drug interactions, current epidemics, specific exposures, resistance patterns of known colonizing organisms or organisms isolated during prior infections, and other patient-specific factors. In particular, antiviral treatment (eg, oseltamivir ) should be given as soon as possible for any hospitalized patient with known or suspected influenza. (See "Seasonal influenza in nonpregnant adults: Treatment" .)

Detailed discussion about antibiotic therapy, including use of new agents (eg, lefamulin , omadacycline ) for patients hospitalized to a general medical ward is provided separately. (See "Treatment of community-acquired pneumonia in adults who require hospitalization" .) (Related Pathway(s): Community-acquired pneumonia: Empiric antibiotic selection for adults admitted to a general medical ward .)

ICU admission

Antibiotic selection  —  For patients with CAP admitted to the intensive care unit (ICU), our approach to antibiotic selection is similar to that used for patients admitted to the general medical ward. However, because of the severity of illness in this population, we do not use monotherapy ( algorithm 4 ). In addition, we start antibiotic therapy within one hour of presentation for patients who are critically ill.

The spectrum of activity of the empiric regimen should be broadened in patients with risk factors for Pseudomonas infection or MRSA infection ( table 4 ).

● For most patients without suspicion for MRSA or Pseudomonas , we treat with a beta-lactam (eg, ceftriaxone , cefotaxime , ceftaroline , ampicillin-sulbactam , ertapenem ) plus a macrolide (eg, azithromycin or clarithromycin ) or a beta-lactam plus a respiratory fluoroquinolone (eg, levofloxacin or moxifloxacin ) [ 26 ].

For patients with penicillin hypersensitivity reactions, we select an appropriate agent (eg, later-generation cephalosporin, carbapenem, or a beta-lactam alternative) based on the type and severity of reaction ( algorithm 5 ). For patients who cannot use any beta-lactam (ie, penicillins, cephalosporins, and carbapenems), we typically use combination therapy with a respiratory fluoroquinolone and aztreonam .

● For patients with known colonization or prior infection with MRSA, recent hospitalization with IV antibiotic use, or other strong suspicion for MRSA infection , we add an agent with anti-MRSA activity, such as vancomycin or linezolid , to either of the above regimens [ 26 ].

● For patients with known colonization or prior infection with Pseudomonas , recent hospitalization with IV antibiotic use, or other strong suspicion for pseudomonal infection , we typically use combination therapy with both an antipseudomonal beta-lactam (eg, piperacillin-tazobactam , cefepime , ceftazidime , meropenem , or imipenem ) plus an antipseudomonal fluoroquinolone (eg, ciprofloxacin or levofloxacin ) for empiric treatment [ 26 ].

For patients with penicillin hypersensitivity reactions, we select an appropriate agent based on the type and severity of penicillin reaction ( algorithm 5 ) and prior pseudomonal susceptibility testing.

Modifications to initial empiric regimens may be needed for antibiotic allergy, potential drug interactions, current epidemics, specific exposures, resistance patterns of colonizing bacteria or bacteria isolated during prior infections, and other patient-specific factors. In particular, antiviral treatment (eg, oseltamivir ) should be given as soon as possible for any hospitalized patient with known or suspected influenza. (See "Seasonal influenza in nonpregnant adults: Treatment" .)

Detailed discussion about antibiotic treatment for patients with CAP admitted to the ICU and patients with sepsis and/or respiratory failure are provided separately. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Intensive care unit' and "Evaluation and management of suspected sepsis and septic shock in adults" .) (Related Pathway(s): Community-acquired pneumonia: Empiric antibiotic selection for adults admitted to the intensive care unit .)

Adjunctive glucocorticoids  —  The role of adjunctive glucocorticoid treatment for CAP is evolving. The rationale for use is to reduce the inflammatory response to pneumonia, which may in turn reduce progression to lung injury, ARDS, and mortality. Based on randomized trials, the greatest benefit is for patients with impending respiratory failure or those requiring mechanical ventilation, particularly when glucocorticoids are given early in the course.

● For most immunocompetent patients with respiratory failure due to CAP who require invasive or non-invasive mechanical ventilation or with significant hypoxemia (ie, PaO2:FIO2 ratio <300 with an FiO 2 requirement of ≥50 percent and use of either high flow nasal cannula or a nonrebreathing mask), we suggest continuous infusion of hydrocortisone 200 mg daily for 4 to 7 days followed by a taper. Because mortality benefit appears to be greatest with early initiation, hydrocortisone should ideally be started as soon as possible. The decision to taper glucocorticoids at day 4 or 7 is based on clinical response.

● Because glucocorticoid use may impair the immune control of influenza, tuberculosis, and fungal pathogens, we avoid hydrocortisone use in patients with CAP caused by these pathogens or for patients with concurrent acute viral hepatitis or active herpes viral infection, which may also be worsened with glucocorticoid use.

● For immunocompromised patients, we weigh the risks and benefits of use on an individual basis.

● While we do not treat CAP with adjunctive glucocorticoids in most other circumstances, we do not withhold glucocorticoids when they are indicated for other reasons, including:

• Refractory septic shock (see "Glucocorticoid therapy in septic shock in adults" )

• Acute exacerbations of COPD (see "COPD exacerbations: Management", section on 'Glucocorticoids in moderate to severe exacerbations' )

• COVID-19 (see "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids' )

Additional detail on the use of glucocorticoids for CAP and review of the evidence are discussed separately. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Adjunctive glucocorticoids' .)

Disposition  —  Once a patient with CAP is hospitalized, further management will be dictated by the patient's response to initial empiric therapy. Clinical response should be assessed during daily rounds. While various criteria have been proposed to assess clinical response [ 38-40 ], we generally look for subjective improvement in cough, sputum production, dyspnea, and chest pain. Objectively, we assess for resolution of fever and normalization of heart rate, respiratory rate, oxygenation, and white blood cell count. Generally, patients demonstrate some clinical improvement within 48 to 72 hours ( table 7 ).

Antibiotic de-escalation  —  For patients in whom a causative pathogen has been identified, we tailor therapy to target the pathogen [ 41 ]. If coverage for MRSA was added empirically, and MRSA was not identified as a pathogen nor on a screening nasal swab and the patient is improving, we typically discontinue the anti-MRSA agent (eg, vancomycin ). However, for the majority of patients hospitalized with CAP, a causative pathogen is not identified. For these patients, we continue empiric treatment for the duration of therapy, provided that the patient is improving. Intravenous antibiotic regimens can be transitioned to oral regimens with a similar spectrum activity as the patient improves ( algorithm 6 ) [ 42,43 ].

Duration of therapy  —  We generally determine the duration of therapy based on the patient's clinical response to therapy.

For all patients, we treat until the patient has been afebrile and clinically stable for at least 48 hours and for a minimum of five days. Patients with mild infection generally require five to seven days of therapy. Patients with severe infection or chronic comorbidities generally require 7 to 10 days of therapy. Extended courses may be needed for immunocompromised patients, patients with infections caused by certain pathogens (eg, P. aeruginosa) , or those with complications. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Duration of therapy' .)

In accord with the ATS/IDSA, we do not use procalcitonin to help determine whether to start antibiotics [ 26 ]. However, we sometimes use procalcitonin thresholds as an adjunct to clinical judgment to help guide antibiotic discontinuation in clinically stable patients. We generally obtain a level at the time of diagnosis and repeat the level every one to two days in patients who are clinically stable. We determine the need for continued antibiotic therapy based on clinical improvement and serial procalcitonin levels ( algorithm 7 ). (See "Procalcitonin use in lower respiratory tract infections" .)

Discharge  —  Hospital discharge is appropriate when the patient is clinically stable, can take oral medication, has no other active medical problems, and has a safe environment for continued care. Patients do not need to be kept overnight for observation following the switch to oral therapy. Early discharge based on clinical stability and criteria for switching to oral therapy is encouraged to reduce risk associated with prolonged hospital stays and unnecessary cost.

Immunocompromised patients  —  The spectrum of potential pathogens expands considerably in immunocompromised patients to include invasive fungal infections, less common viral infections (eg, cytomegalovirus), and parasitic infections (eg, toxoplasmosis) [ 44 ].

The risk for specific infections varies with the type and degree of immunosuppression and whether the patient is taking prophylactic antimicrobials. As examples, prolonged neutropenia, T cell immunosuppression, and use of tumor necrosis factor-alpha inhibitors predispose to invasive fungal infections (eg, aspergillosis, mucormycosis) as well as mycobacterial infections. Advanced human immunodeficiency virus (HIV) infection (eg, CD4 cell count <200 cells/microL), prolonged glucocorticoid use (particularly when used with certain chemotherapeutics), and lymphopenia each should raise suspicion for pneumocystis pneumonia. Multiple infections may occur concurrently in this population, and the likelihood of disseminated infection is greater. Because signs and symptoms of infection can be subtle and nonspecific in immunocompromised patients, diagnosis can be challenging and invasive procedures are often required for microbiologic diagnosis. Broad-spectrum empiric therapy may be needed prior to obtaining a specific microbiologic diagnosis [ 45 ].

Because management is complex, drug interactions are common, adjustments in immunosuppressive regimens may be needed, and empiric treatment options (eg, amphotericin B) can be associated with significant toxicity, we generally involve a multidisciplinary team of specialists when caring for immunocompromised patients with pneumonia. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" .)

FOLLOW-UP IMAGING  —  Follow-up imaging for immunocompetent adults who have recovered from community-acquired pneumonia Algorithm 8 Most patients with clinical resolution after treatment do not require a follow-up chest radiograph, as radiographic response lags behind clinical response. However, follow-up clinic visits are good opportunities to review the patient's risk for lung cancer based on age, smoking history, and recent imaging findings ( algorithm 8 ).

This approach is similar to that outlined by the ATS/IDSA, which recommend not obtaining a follow-up chest radiograph in patients whose symptoms have resolved within five to seven days [ 26 ]. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Follow-up chest radiograph' .)

COMPLICATIONS AND PROGNOSIS  —  While most patients with CAP will recover with appropriate antibiotic treatment, some will progress and/or develop complications despite appropriate therapy (ie, clinical failure) and some will remain symptomatic (ie, nonresolving pneumonia).

Clinical failure  —  Clear indicators of clinical failure include progression to sepsis and/or respiratory failure despite appropriate antibiotic treatment and respiratory support. Other indicators include an increase in subjective symptoms (eg, cough, dyspnea) usually in combination with objective criteria (eg, decline in oxygenation, persistent fever, or rising white blood cell). Various criteria have been proposed to define clinical failure but none widely adopted [ 46-48 ].

Reasons for clinical failure generally fall into these categories:

● Progression of the initial infection – For some patients, CAP can lead to overwhelming infection despite appropriate antibiotic treatment. In some, this indicates a dysregulated host immune response. In others, this may indicate that the infection has spread beyond the pulmonary parenchyma (eg, empyema, lung abscess, bacteremia, endocarditis).

Other possibilities include infection with a drug-resistant pathogen or an unusual pathogen not covered by the initial empiric antibiotic regimen. Alternatively, failure to respond to treatment may signify the presence of an immunodeficiency (eg, new diagnosis of HIV infection).

● Development of comorbid complications – Comorbid complications may be infectious or noninfectious. Nosocomial infections, particularly hospital-acquired pneumonia (HAP), are common causes of clinical failure. In addition to HAP, others include catheter-related bloodstream infections, urinary tract infections, and C. difficile infection [ 49 ].

Cardiovascular events are also common complications and include acute myocardial infarction, cardiac arrhythmias, congestive heart failure, pulmonary embolism, and stroke [ 50-52 ]. Older age, preexisting cardiovascular disease, severe pneumonia, and infection with certain pathogens (ie, S. pneumoniae and influenza) have each been associated with increased risk of cardiovascular events [ 50,53-55 ]. Recognition that cardiovascular events and other systemic complications can occur during the acute phase of CAP is also changing our view of CAP from an acute pulmonary process to an acute systemic disease. (See "Morbidity and mortality associated with community-acquired pneumonia in adults", section on 'Cardiac complications' .)

Because of these possibilities, we generally broaden our initial antibiotic regimen for patients who are progressing despite appropriate empiric treatment and evaluate for alternate diagnoses, less common or drug-resistant pathogens, and/or infectious and cardiovascular complications. (See 'Differential diagnosis' above and "Morbidity and mortality associated with community-acquired pneumonia in adults" .)

Nonresolving CAP  —  For some patients, initial symptoms will neither progress nor improve with at least seven days of appropriate empiric antibiotic treatment. We generally characterize these patients as having nonresolving pneumonia. Potential causes of nonresolving CAP include:

● Delayed clinical response – For some patients, particularly those with multiple comorbidities, severe pneumonia, bacteremia, and infection with certain pathogens (eg, S. pneumoniae ), treatment response may be slow. Eight or nine days of treatment may be needed before clinical improvement is evident.

● Loculated infection – Patients with complications such as lung abscess, empyema, or other closed space infections may fail to improve clinically despite appropriate antibiotic selection. Such infections may require drainage and/or prolonged antibiotic treatment. (See "Lung abscess in adults" and "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults" .)

● Bronchial obstruction – Bronchial obstruction (eg, by a tumor) can cause a postobstructive pneumonia that may fail to respond or slowly respond to standard empiric antibiotic regimens for CAP.

● Pathogens that cause subacute/chronic CAP – Mycobacterium tuberculosis , nontuberculous mycobacteria (eg, Mycobacterium kansasii ), fungi (eg, Histoplasma capsulatum , Blastomyces dermatitidis ), or less common bacteria (eg, Nocardia spp, Actinomyces israelii ) can cause subacute or chronic pneumonia that may fail to respond or may incompletely respond to standard empiric antibiotic regimens for CAP.

● Incorrect initial diagnosis – Failure to improve despite seven days of treatment also raises the possibility of an alternate diagnosis (eg, malignancy or inflammatory lung disease). (See 'Differential diagnosis' above.)

Once a patient is characterized as having nonresolving CAP, a complete new physical examination, laboratory evaluation, imaging studies, and microbiologic workup will be necessary to define the etiology of nonresolving CAP [ 49 ]. Initiation of workup for nonresolving CAP should not be automatically associated with a change in initial empiric antibiotic therapy. (See "Nonresolving pneumonia" .)

Long-term complications and mortality  —  Although the majority of patient with CAP recover without complications, CAP is a severe illness and among the leading causes of mortality worldwide. Mortality can be directly attributable to CAP (eg, overwhelming sepsis or respiratory failure) or can result indirectly from cardiovascular events or other comorbid complications (eg, advanced chronic obstructive pulmonary disease [COPD]) [ 56 ].

Long-term complications resulting from pneumonia are increasingly recognized and there is a shift in the medical community to define pneumonia as a systemic illness that can lead to chronic disease [ 57 ]. While the precise incidence of long-term complications is not known, the more common long-term sequelae involve the respiratory tract and cardiovascular system [ 58 ].

In the United States, pneumonia (combined with influenza) is among the top 10 most common causes of death [ 5 ]. Thirty-day mortality rates vary with disease severity, ranging from less than 1 percent in ambulatory patients to approximately 20 to 25 percent in patients with severe CAP. In addition to disease severity, older age, comorbidities (eg, COPD, diabetes mellitus, cardiovascular disease), infection with certain pathogens (eg, S. pneumoniae ), and acute cardiac complications are each associated with increased short-term mortality [ 50,59,60 ].

CAP is also associated with increased long-term mortality [ 7,61-63 ]. In one population-based study evaluating 7449 patients hospitalized with CAP, mortality rates were 6.5 percent during hospitalization, 13 percent 30 days after hospitalization, 23 percent at six months after hospitalization, and 31 percent at one year after hospitalization [ 7 ]. During the same study year, an estimated 1,581,860 patients were hospitalized in the United States. Extrapolating mortality data to these patients, the number of deaths in the United States population will be 102,821 during hospitalization, 205,642 at 30 days, 370,156 at six months, and 484,050 at one year [ 7 ]. Causes of long-term mortality are primarily related to comorbidities and include malignancy, COPD, and cardiovascular disease [ 56 ].

Data associating CAP with long-term mortality indicate that CAP is not only a common cause of acute morbidity and mortality but also a disease with important chronic health outcomes.

PREVENTION  —  The three primary pillars for the prevention of CAP are [ 64-66 ]:

● Smoking cessation (when appropriate)

● Influenza vaccination for all patients

● Pneumococcal vaccination for at-risk patients

Each is discussed in detail separately. (See "Overview of smoking cessation management in adults" and "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults" .)

SOCIETY GUIDELINE LINKS  —  Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Community-acquired pneumonia in adults" .)

INFORMATION FOR PATIENTS  —  UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Pneumonia in adults (The Basics)" )

● Beyond the Basics topic (see "Patient education: Pneumonia in adults (Beyond the Basics)" )

SUMMARY AND RECOMMENDATIONS

● Background – Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. (See 'Incidence' above.)

● Risk factors – Risk factors include age ≥65 years, chronic comorbidities, concurrent or antecedent respiratory viral infections, impaired airway protection, smoking, alcohol abuse, and other lifestyle factors (eg, crowded living conditions). (See 'Risk factors' above.)

● Microbiology – The most commonly identified causes of CAP include respiratory viruses (particularly severe acute respiratory syndrome coronavirus 2 during the pandemic), typical bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis ) and atypical bacteria (eg, Legionella spp, Mycoplasma pneumoniae, Chlamydia pneumoniae ). Pseudomonas and methicillin-resistant Staphylococcus aureus (MRSA) are less common causes that predominantly occur in patients with specific risk factors. (See 'Microbiology' above and 'Pathogenesis' above.)

● Making the diagnosis – Diagnosis requires demonstration of an infiltrate on chest imaging in a patient with a clinically compatible syndrome (eg, fever, dyspnea, cough, and leukocytosis). For most patients, a posteroanterior and lateral chest radiograph is sufficient. Computed tomography scan is reserved for selected cases. (See 'Clinical presentation' above and 'Making the diagnosis' above.)

● Alternate and concurrent diagnoses – While the combination of a compatible clinical syndrome and an infiltrate on chest imaging are sufficient to establish an initial clinical diagnosis of CAP, these findings are nonspecific. Remaining attentive to the possibility of an alternate or concurrent diagnosis as a patient's course evolves is important to care. (See 'Differential diagnosis' above.)

● Determining severity of illness – For patients with a working diagnosis of CAP, the initial steps in management are defining the severity of illness and determining the most appropriate site of care ( algorithm 1 ). For most patients, we determine our approach to microbiologic testing based on this assessment ( table 5 ). (See 'Microbiologic testing' above.)

● Empiric antibiotic selection – The selection of an empiric antibiotic regimen is based on the severity of illness, site of care, and most likely pathogens. We generally start antibiotics as soon as we are confident that CAP is the appropriate working diagnosis and, ideally, within four hours of presentation for inpatients and within one hour of presentation for those who are critically ill (see 'Treatment' above):

• For most outpatients, we prefer to use combination therapy with a beta-lactam and either a macrolide (preferred) or doxycycline . Alternatives to beta-lactam-based regimens include monotherapy with either a fluoroquinolone or, alternatively, lefamulin or omadacycline (newer agents). Selection among these agents depends on patient comorbidities, drug interactions, allergies, and other intolerances. Clinical experience with lefamulin and omadacycline are limited; warnings and contraindications exist ( algorithm 2 ).

This approach differs from the American Thoracic Society/Infectious Diseases Society of America, which recommend monotherapy with amoxicillin as first line and monotherapy with either doxycycline or a macrolide (if local resistance rates are <25 percent [eg, not in the United States]) as alternatives for this population.

• For most inpatients admitted to the general medical ward, treatment options include either intravenous (IV) combination therapy with a beta-lactam plus a macrolide or doxycycline or monotherapy with a respiratory fluoroquinolone ( algorithm 3 ). These regimens should be expanded for patients with risk factors for Pseudomonas or MRSA ( table 4 ).

• For most patients admitted to the intensive care unit (ICU), treatment options include IV combination therapy with a beta-lactam plus either a macrolide or a respiratory fluoroquinolone ( algorithm 4 ). As with other hospitalized patients, regimens should be expanded for patients with risk factors for Pseudomonas or MRSA ( table 4 ).

● Adjunctive glucocorticoids – The benefit of adjunctive glucocorticoids appears greatest in patients with impending respiratory failure or requiring mechanical ventilation, particularly when they are given early in the course. Generally, we add hydrocortisone for most immunocompetent patients with respiratory failure due to CAP who require invasive or non-invasive mechanical ventilation or with significant hypoxemia (ie, PaO2:FIO2 ratio <300 with an FiO 2 requirement of ≥50 percent and use of either high flow nasal cannula or a nonrebreathing mask), unless there are reason to avoid their use (eg, infection with certain pathogen [influenza, fungi, tuberculosis, or immunocompromise]). (See 'Adjunctive glucocorticoids' above.)

● Directed antibiotic therapy – For patients in whom a causative pathogen has been identified, we tailor therapy to target the pathogen. (See 'Antibiotic de-escalation' above.)

● Duration of antibiotics – For all patients, we treat until the patient has been afebrile and clinically stable for at least 48 hours and for a minimum of five days. Patients with mild infection generally require five to seven days of therapy; those with severe infection or chronic comorbidities generally require 7 to 10 days of therapy. (See 'Duration of therapy' above.)

● Lack of response to antibiotics – Failure to respond to antibiotic treatment within 72 hours should prompt reconsideration of the diagnosis and empiric treatment regimen as well as an assessment for complications. (See 'Clinical failure' above and 'Nonresolving CAP' above.)

● Prevention – Key preventive measures include smoking cessation (when appropriate), influenza vaccination for the general population, and pneumococcal vaccination for at-risk populations. (See 'Prevention' above.)

ACKNOWLEDGMENT  —  UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

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• Liapikou A, Ferrer M, Polverino E, et al. Severe community-acquired pneumonia: validation of the Infectious Diseases Society of America/American Thoracic Society guidelines to predict an intensive care unit admission. Clin Infect Dis 2009; 48:377.
• Mandell LA. Severe community-acquired pneumonia (CAP) and the Infectious Diseases Society of America/American Thoracic Society CAP guidelines prediction rule: validated or not. Clin Infect Dis 2009; 48:386.
• Chalmers JD, Taylor JK, Mandal P, et al. Validation of the Infectious Diseases Society of America/American Thoratic Society minor criteria for intensive care unit admission in community-acquired pneumonia patients without major criteria or contraindications to intensive care unit care. Clin Infect Dis 2011; 53:503.
• Lim WS, Woodhead M, British Thoracic Society. British Thoracic Society adult community acquired pneumonia audit 2009/10. Thorax 2011; 66:548.
• Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 2012; 54:621.
• Aliberti S, Zanaboni AM, Wiemken T, et al. Criteria for clinical stability in hospitalised patients with community-acquired pneumonia. Eur Respir J 2013; 42:742.
• Halm EA, Fine MJ, Marrie TJ, et al. Time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines. JAMA 1998; 279:1452.
• Menéndez R, Torres A, Rodríguez de Castro F, et al. Reaching stability in community-acquired pneumonia: the effects of the severity of disease, treatment, and the characteristics of patients. Clin Infect Dis 2004; 39:1783.
• van der Eerden MM, Vlaspolder F, de Graaff CS, et al. Comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study. Thorax 2005; 60:672.
• Ramirez JA, Srinath L, Ahkee S, et al. Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia. Arch Intern Med 1995; 155:1273.
• Ramirez JA, Vargas S, Ritter GW, et al. Early switch from intravenous to oral antibiotics and early hospital discharge: a prospective observational study of 200 consecutive patients with community-acquired pneumonia. Arch Intern Med 1999; 159:2449.
• Di Pasquale MF, Sotgiu G, Gramegna A, et al. Prevalence and Etiology of Community-acquired Pneumonia in Immunocompromised Patients. Clin Infect Dis 2019; 68:1482.
• Ramirez JA, Musher DM, Evans SE, et al. Treatment of Community-Acquired Pneumonia in Immunocompromised Adults: A Consensus Statement Regarding Initial Strategies. Chest 2020; 158:1896.
• Menéndez R, Torres A, Zalacaín R, et al. Risk factors of treatment failure in community acquired pneumonia: implications for disease outcome. Thorax 2004; 59:960.
• Aliberti S, Amir A, Peyrani P, et al. Incidence, etiology, timing, and risk factors for clinical failure in hospitalized patients with community-acquired pneumonia. Chest 2008; 134:955.
• Rosón B, Carratalà J, Fernández-Sabé N, et al. Causes and factors associated with early failure in hospitalized patients with community-acquired pneumonia. Arch Intern Med 2004; 164:502.
• Arancibia F, Ewig S, Martinez JA, et al. Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic implications. Am J Respir Crit Care Med 2000; 162:154.
• Violi F, Cangemi R, Falcone M, et al. Cardiovascular Complications and Short-term Mortality Risk in Community-Acquired Pneumonia. Clin Infect Dis 2017; 64:1486.
• Eurich DT, Marrie TJ, Minhas-Sandhu JK, Majumdar SR. Risk of heart failure after community acquired pneumonia: prospective controlled study with 10 years of follow-up. BMJ 2017; 356:j413.
• Ramirez J, Aliberti S, Mirsaeidi M, et al. Acute myocardial infarction in hospitalized patients with community-acquired pneumonia. Clin Infect Dis 2008; 47:182.
• Perry TW, Pugh MJ, Waterer GW, et al. Incidence of cardiovascular events after hospital admission for pneumonia. Am J Med 2011; 124:244.
• Warren-Gash C, Blackburn R, Whitaker H, et al. Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland. Eur Respir J 2018; 51.
• Viasus D, Garcia-Vidal C, Manresa F, et al. Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia. J Infect 2013; 66:27.
• Bruns AH, Oosterheert JJ, Cucciolillo MC, et al. Cause-specific long-term mortality rates in patients recovered from community-acquired pneumonia as compared with the general Dutch population. Clin Microbiol Infect 2011; 17:763.
• Dela Cruz CS, Wunderink RG, Christiani DC, et al. Future Research Directions in Pneumonia. NHLBI Working Group Report. Am J Respir Crit Care Med 2018; 198:256.
• Corrales-Medina VF, Alvarez KN, Weissfeld LA, et al. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JAMA 2015; 313:264.
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• Lepper PM, Ott S, Nüesch E, et al. Serum glucose levels for predicting death in patients admitted to hospital for community acquired pneumonia: prospective cohort study. BMJ 2012; 344:e3397.
• Peyrani P, Ramirez JA. One-year mortality in patients with community-acquired pneumonia. Univ Louisville J Respir Infect 2017; 1.
• Eurich DT, Marrie TJ, Minhas-Sandhu JK, Majumdar SR. Ten-Year Mortality after Community-acquired Pneumonia. A Prospective Cohort. Am J Respir Crit Care Med 2015; 192:597.
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• Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014; 63:822.
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• Patient Care & Health Information
• Diseases & Conditions

• Pneumonia and your lungs

Most pneumonia occurs when a breakdown in your body's natural defenses allows germs to invade and multiply within your lungs. To destroy the attacking organisms, white blood cells rapidly accumulate. Along with bacteria and fungi, they fill the air sacs within your lungs (alveoli). Breathing may be labored. A classic sign of bacterial pneumonia is a cough that produces thick, blood-tinged or yellowish-greenish sputum with pus.

Pneumonia is an infection that inflames the air sacs in one or both lungs. The air sacs may fill with fluid or pus (purulent material), causing cough with phlegm or pus, fever, chills, and difficulty breathing. A variety of organisms, including bacteria, viruses and fungi, can cause pneumonia.

Pneumonia can range in seriousness from mild to life-threatening. It is most serious for infants and young children, people older than age 65, and people with health problems or weakened immune systems.

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The signs and symptoms of pneumonia vary from mild to severe, depending on factors such as the type of germ causing the infection, and your age and overall health. Mild signs and symptoms often are similar to those of a cold or flu, but they last longer.

Signs and symptoms of pneumonia may include:

• Chest pain when you breathe or cough
• Confusion or changes in mental awareness (in adults age 65 and older)
• Cough, which may produce phlegm
• Fever, sweating and shaking chills
• Lower than normal body temperature (in adults older than age 65 and people with weak immune systems)
• Nausea, vomiting or diarrhea
• Shortness of breath

Newborns and infants may not show any sign of the infection. Or they may vomit, have a fever and cough, appear restless or tired and without energy, or have difficulty breathing and eating.

When to see a doctor

See your doctor if you have difficulty breathing, chest pain, persistent fever of 102 F (39 C) or higher, or persistent cough, especially if you're coughing up pus.

It's especially important that people in these high-risk groups see a doctor:

• Adults older than age 65
• Children younger than age 2 with signs and symptoms
• People with an underlying health condition or weakened immune system
• People receiving chemotherapy or taking medication that suppresses the immune system

For some older adults and people with heart failure or chronic lung problems, pneumonia can quickly become a life-threatening condition.

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Many germs can cause pneumonia. The most common are bacteria and viruses in the air we breathe. Your body usually prevents these germs from infecting your lungs. But sometimes these germs can overpower your immune system, even if your health is generally good.

Pneumonia is classified according to the types of germs that cause it and where you got the infection.

Community-acquired pneumonia

Community-acquired pneumonia is the most common type of pneumonia. It occurs outside of hospitals or other health care facilities. It may be caused by:

• Bacteria. The most common cause of bacterial pneumonia in the U.S. is Streptococcus pneumoniae. This type of pneumonia can occur on its own or after you've had a cold or the flu. It may affect one part (lobe) of the lung, a condition called lobar pneumonia.
• Bacteria-like organisms. Mycoplasma pneumoniae also can cause pneumonia. It typically produces milder symptoms than do other types of pneumonia. Walking pneumonia is an informal name given to this type of pneumonia, which typically isn't severe enough to require bed rest.
• Fungi. This type of pneumonia is most common in people with chronic health problems or weakened immune systems, and in people who have inhaled large doses of the organisms. The fungi that cause it can be found in soil or bird droppings and vary depending upon geographic location.
• Viruses, including COVID-19 . Some of the viruses that cause colds and the flu can cause pneumonia. Viruses are the most common cause of pneumonia in children younger than 5 years. Viral pneumonia is usually mild. But in some cases it can become very serious. Coronavirus 2019 (COVID-19) may cause pneumonia, which can become severe.

Hospital-acquired pneumonia

Some people catch pneumonia during a hospital stay for another illness. Hospital-acquired pneumonia can be serious because the bacteria causing it may be more resistant to antibiotics and because the people who get it are already sick. People who are on breathing machines (ventilators), often used in intensive care units, are at higher risk of this type of pneumonia.

Health care-acquired pneumonia

Health care-acquired pneumonia is a bacterial infection that occurs in people who live in long-term care facilities or who receive care in outpatient clinics, including kidney dialysis centers. Like hospital-acquired pneumonia, health care-acquired pneumonia can be caused by bacteria that are more resistant to antibiotics.

Aspiration pneumonia

Aspiration pneumonia occurs when you inhale food, drink, vomit or saliva into your lungs. Aspiration is more likely if something disturbs your normal gag reflex, such as a brain injury or swallowing problem, or excessive use of alcohol or drugs.

Risk factors

Pneumonia can affect anyone. But the two age groups at highest risk are:

• Children who are 2 years old or younger
• People who are age 65 or older

Other risk factors include:

• Being hospitalized. You're at greater risk of pneumonia if you're in a hospital intensive care unit, especially if you're on a machine that helps you breathe (a ventilator).
• Chronic disease. You're more likely to get pneumonia if you have asthma, chronic obstructive pulmonary disease ( COPD ) or heart disease.
• Smoking. Smoking damages your body's natural defenses against the bacteria and viruses that cause pneumonia.
• Weakened or suppressed immune system. People who have HIV / AIDS , who've had an organ transplant, or who receive chemotherapy or long-term steroids are at risk.

Complications

Even with treatment, some people with pneumonia, especially those in high-risk groups, may experience complications, including:

• Bacteria in the bloodstream (bacteremia). Bacteria that enter the bloodstream from your lungs can spread the infection to other organs, potentially causing organ failure.
• Difficulty breathing. If your pneumonia is severe or you have chronic underlying lung diseases, you may have trouble breathing in enough oxygen. You may need to be hospitalized and use a breathing machine (ventilator) while your lung heals.
• Fluid accumulation around the lungs (pleural effusion). Pneumonia may cause fluid to build up in the thin space between layers of tissue that line the lungs and chest cavity (pleura). If the fluid becomes infected, you may need to have it drained through a chest tube or removed with surgery.
• Lung abscess. An abscess occurs if pus forms in a cavity in the lung. An abscess is usually treated with antibiotics. Sometimes, surgery or drainage with a long needle or tube placed into the abscess is needed to remove the pus.

To help prevent pneumonia:

• Get vaccinated. Vaccines are available to prevent some types of pneumonia and the flu. Talk with your doctor about getting these shots. The vaccination guidelines have changed over time so make sure to review your vaccination status with your doctor even if you recall previously receiving a pneumonia vaccine.
• Make sure children get vaccinated. Doctors recommend a different pneumonia vaccine for children younger than age 2 and for children ages 2 to 5 years who are at particular risk of pneumococcal disease. Children who attend a group child care center should also get the vaccine. Doctors also recommend flu shots for children older than 6 months.
• Practice good hygiene. To protect yourself against respiratory infections that sometimes lead to pneumonia, wash your hands regularly or use an alcohol-based hand sanitizer.
• Don't smoke. Smoking damages your lungs' natural defenses against respiratory infections.
• Keep your immune system strong. Get enough sleep, exercise regularly and eat a healthy diet.
• Pneumonia. National Heart, Lung, and Blood Institute. http://www.nhlbi.nih.gov/health/health-topics/topics/pnu. Accessed April 15, 2016.
• AskMayoExpert. Community-acquired pneumonia (adult). Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2014.
• Goldman L, et al., eds. Overview of pneumonia. In: Goldman-Cecil Medicine. 25th ed. Philadelphia, Pa.: Saunders Elsevier; 2016. http://www.clinicalkey.com. Accessed April 18, 2016.
• Schauner S, et al. Community-acquired pneumonia in children: A look at the IDSA guidelines. Journal of Family Practice. 2013;62:9.
• Attridge RT, et al. Health care-associated pneumonia: An evidence-based review. American Journal of Medicine. 2011;124:689.
• Hunter JD. Ventilator associated pneumonia. BMJ. 2012;344:e3325.
• Dockrell DH, et al. Pneumococcal pneumonia: Mechanisms of infection and resolution. Chest. 2012;142:482.
• Reynolds RH, et al. Pneumonia in the immunocompetent patient. British Journal of Radiology. 2010;83:998.
• Remington LT, et al. Community-acquired pneumonia. Current Opinion Pulmonary Medicine. 2014;20:215.
• Centers for Disease Control and Prevention. Adults: Protect yourself with pneumococcal vaccines. http://www.cdc.gov/features/adult-pneumococcal/. Accessed April 15, 2016.
• Marrie TJ, et al. Pneumococcal pneumonia in adults. http://www.uptodate.com/home. Accessed April 15, 2016.
• Barbara Woodward Lips Patient Education Center. Care following hospitalization for community-acquired pneumonia. Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2013.
• AskMayoExpert. Community-acquired pneumonia (pediatric). Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2014.
• Barson WJ. Community-acquired pneumonia in children: Outpatient treatment. http://www.uptodate.com/home. Accessed April 15, 2016.
• File TM. Treatment of community-acquired pneumonia in adults in the outpatient setting. http://www.uptodate.com/home. Accessed April 20, 2016.
• Chang CC, et al. Over-the-counter ( OTC ) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults. Cochrane Database of Systematic Reviews. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006088.pub4/full. Accessed April 20, 2016.
• Mycoplasma pneumoniae infection. Centers for Disease Control and Prevention. http://www.cdc.gov/pneumonia/atypical/mycoplasma/. Accessed April 20, 2016.
• Barson WJ. Community-acquired pneumonia in children: Clinical features and diagnosis. http://www.uptodate.com/home. Accessed April 20, 2016.
• Olson EJ (expert opinion). Mayo Clinic, Rochester, Minn. May 1, 2016.
• AskMayoExpert. COVID-19: Outpatient. Mayo Clinic; 2020.
• Chest X-ray showing pneumonia
• Walking pneumonia

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• Case Report
• Open access
• Published: 22 April 2024

Post-COVID reactivation of latent Bartonella henselae infection: a case report and literature review

• Yanzhao Dong 1 ,
• Ahmad Alhaskawi 1 ,
• Xiaodi Zou 2 ,
• Haiying Zhou 3 ,
• Sohaib Hasan Abdullah Ezzi 4 ,
• Vishnu Goutham Kota 5 ,
• Mohamed Hasan Abdulla Hasan Abdulla 5 ,
• Alenikova Olga 6 ,
• Sahar Ahmed Abdalbary 7 &

BMC Infectious Diseases volume  24 , Article number:  422 ( 2024 ) Cite this article

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Cat scratch disease (CSD) is caused by Bartonella henselae ( B. henselae ) and presents as lymphadenopathy following close contact with cats. However, in context of the global COVID-19 pandemic, clinical manifestations of CSD may vary, posing new challenges for healthcare professionals. Here we describe a case of a 54-year-old male with painful left upper arm mass, which gradually resolved until he was infected with COVID-19. The mass then rapidly progressed before admission. Meanwhile, pulmonary symptoms including pleural effusion emerged simultaneously. The cause was undetermined with routine blood culture and pathological test until the next generation sequencing (NGS) confirmed the presence of B. henselae . We believe this case is the first to report localized aggravation of CSD after COVID-19 infection and hopefully, offers treatment experience for clinicians worldwide.

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Introduction

Cat-scratch disease (CSD), an uncommon infection often observed in households with domestic cats, is first described in 1950 by Debré R. et al. [ 1 ]. The causative pathogen of CSD is Bartonella henselae ( B. henselae ), a Gram-negative rod that can be detected by immunohistochemistry and several silver staining methods including Warthin-Starry stain, Steiner stain and Dieterle stain [ 2 ]. At the early stage of infection, CSD normally presents as non-specific lymphadenopathy affecting both adults and children [ 3 ]. As an infectious disease, CSD has been reported worldwide and higher incidents are reported in the autumn and winter, perceivably associated the seasonal breeding of domestic cats [ 4 ].

CSD is commonly seen among young adults and children, and the major clinical manifestations of CSD include a papule at the site of microbe entrance and axillary node lymphadenopathy, which could progress to fever, aches, nausea, abdominal pain and malaise [ 5 ]. Diagnosis of CSD is usually dependent on both history of cat contact and primary lesions followed by regional lymphadenopathy, which can be further confirmed via serological evidence, blood or suppuration culture, and the next generation sequencing (NGS). However, B. henselae is a slow-growing bacterium, and bacterial culture could take up to 21 days, with a high false-negative rate. While serological tests could aid in the diagnosis, they often fail to differentiate between B. henselae and other Bartonella species. Furthermore, positive serological results may persist for years after treatment. In contrast, NGS is a highly accurate method for identifying various pathogens including B. henselae . Additionally, NGS can provide quantitative data regarding the detected pathogen, serving as an indicator of the infection’s severity. This quantitative information can be invaluable in monitoring the status of the infection. Approximately 90% of untreated lymphadenitis and lymph node enlargement following CSD gradually regress to normal size in immunocompetent patients over a period of several months, while the remaining 10% patients could progress to cutaneous erythema and result in spontaneous suppuration [ 6 ]. In these cases, the combined use of azithromycin and rifampin orally or intravenously is recommended, although the dosage and course may vary [ 7 , 8 ].

While CSD is the most common manifestation of bartonellosis and over 90% cases of CSD are benign and self-limiting, the spectrum of bartonellosis is expanding as several studies and cases have elucidated association between Bartonella infection and cardiovascular, neurological, psychiatric, ocular and rheumatic disorders [ 9 , 10 , 11 , 12 , 13 ]. For immunocompromised patients, B. henselae infection elicits vasoproliferative responses instead of localized lymphadenopathy, and manifests as a cutaneous angiogenic lesion with inflammatory cell infiltrates [ 1 ]. What is causing this phenomenon, however, is still under debate. Moreover, disseminated bartonellosis has been observed in several cases of patients with human immunodeficiency virus (HIV) infection, and one of the cases reported rapid exacerbation to respiratory failure and ultimately, death of the patient [ 14 , 15 , 16 ]. As our understanding grows, it is being increasing acknowledged that bartonellosis is a major public health issue, and efforts made to better comprehend its reservoir and vector can be assimilated into solving this problem [ 17 ].

Since its discovery, CSD has been studied comprehensively by research groups across the world. Nevertheless, little is known about CSD progression in the context of Coronavirus disease 2019 (COVID) infection, with only one case report available on coinfection of COVID and B. henselae in 2021 [ 18 ]. We believe that this is the first case to report reactivation of B. henselae post COVID infection.

Case presentation

On January 31, 2023, a previously healthy male was admitted with a one-month history of red and swollen mass on the ulnar side of left upper arm. At the onset of the swollen mass, he visited the local clinic and ultrasound (US) examination was ordered, indicating inflammation with abscess formation. Therefore, he was prescribed with oral administration of cefuroxime (250 mg, BID) for 7 days and pain relief treatment (irecoxib, 100 mg, BID). The mass gradually resolved until shortly progression complicated with symptoms of fever (Tmax = 39.5 °C), cough, fatigue, myalgia, shortness of breath and anorexia, which was confirmed to be COVID infection by local hospital. During this period, he observed rapid progression of the original mass with both an increase in size and the formation of a purulent spot. In search of second medical opinion, he visited our out-patient clinic. Prehospital magnetic resonance imaging (MRI) indicated soft tissue swelling on the ulnar side of the left upper arm, with an internal mass-like elongated T2 signal and cellulitis-like enhancement on the enhancement imaging. He recalled no history of distant travel, animal bites or scratches. As a construction worker, he was generally well and the only significant medical history was lumbar disc herniation microdiscectomy he received 10 years ago.

On admission, the patient complained of coughing with white sputum, severe anorexia and nausea. Worse even, the mass had ruptured on the way to hospital, and he had to covered it with some gauze. During the dressing change, it was observed that the mass was swollen with a sinus tract, and approximately 15 mL exudate was drained. The exudate was initially purulent and became hemopurulent on pressure. Physical examination revealed lymphadenopathy in the unilateral axillary and supratrochlear lymph nodes, with local redness and tenderness around the abscess. Subcutaneous edema on the ulnar side of the left upper arm and forearm was observed. Lung auscultation showed scattered rales in both lungs, occasionally with wheezing. Pre-operative blood tests showed elevated white blood cell count (WBC) of 13.08*10 9 /L (normal range 4.0–10.0*10 9 /L), elevated C reactive protein (CRP) of 37.54 mg/L (normal range 0.00–8.00 mg/L) and negative result of HIV infection. Meanwhile, the patient showed no signs of fever (Temperature = 36.6 °C). Pulmonary CT scan showed inflammation on both lungs with interlobular and pleural effusion. Therefore, the patient was started empirically on intravenous infusion of piperacillin/tazobactam for the lesion and possible lower respiratory tract infection. On day 2 of admission, the first surgery was performed, where an extended incision was made to expose the subcutaneous fascia, revealing large amount of inflamed granulation tissue. The ulnar nerve was intact but adherent to surround tissue, and careful dissection was performed to free the ulnar nerve and avoid nerve damage. After excision of necrotic tissue, the abscess cavity was repeatedly irrigated and covered with vacuum sealing drainage (VSD) device. The excised tissue was then set for NGS, pathological tests and bacterial culture (Fig.  1 ).

( A) : MRI image of the mass on admission; ( B ): Preoperative view of the mass, the pus head has ruptured; ( C) : Intra-operative view of the mass, most necrotic or infected tissue have been removed; ( D) : Post-operative histopathological results showing acute and chronic inflammation of subcutaneous soft tissue with histiocytes infiltration (marked by green triangle and magnification on the upper right corner), regional inflammatory granulation tissue hyperplasia (marked by red star)

In the meantime, on day 4 of hospitalization, the patient complained of shortness of breath with decreased blood oxygen saturation levels, and an urgent pulmonary CT scan was ordered. The repeated CT report showed progressed bilateral pleural and interlobar effusions with atelectasis of both lower lobes, and a new ground-glass opacity in the apical segment of the right upper lobe, suggestive of inflammatory changes. At consultation in respiratory medicine experts, bilateral thoracentesis and placement of chest drainage tubes was ordered, and a total of 1100 mL yellow clear pleural effusion was drained on the first day. The pleural drainage was collected and underwent routine, biological examination and bacterium culture, indicating Non-septic Exudative Pleural Effusion. Multiple tissue sample were sent for testing and culture, and the NGS result on day 5 reported presence of B. henselae in the abscess, which confirmed the diagnosis of CSD. Further inquiry on medical history revealed that the patient owned a rural warehouse where he kept clothing and bed sheets, and a pet cat, although he remembered frequent visit of local feral cats. The warehouse was relatively poor in terms of air flow, where he would take occasional naps. After alteration of antibiotic plan to doxycycline combined with azithromycin, the pulmonary distress gradually resolved and inflammatory indicators reduced to normal level on day 8 (CRP: 0.49 mg/L; WBC 5.02*10 9 /L).

On day 8 of admission, the patient reported relief from chest tightness and shortness of breath, and a repeated CT showed interstitial changes in both lungs without pleural effusion on day 8 of admission (Fig.  2 ). The bilateral chest drainage tubes were then removed.

Pulmonary CT scan results with effusion indicated by red arrows. A : Taken 2 days prior to admission, showing interstitial changes, pneumonia with minor amount of pleural effusion; ( B) : Taken on day 4 of admission, showing progressed pneumonia with increased pleural effusion; ( C) : Taken on day 8 of admission, showing alleviated pneumonia, and previous pleural effusion absorbed; ( D) : Taken 2 weeks after discharge with normal result

Meanwhile, as the pulmonary symptoms relieved, the patient underwent secondary debridement, which showed localized inflammation and limited residual granulation tissue, and the remaining necrotized tissue was removed before suturing. The patient was generally well after the second surgery and discharged on day 11 of admission.

On out-patient follow-up 2 weeks later, the patient recovered from the previous symptoms. Physical examination showed negative pulmonary signs, and the incision healed without further inflammation.

CSD has been reported to cause pleural effusion possibly due to obstructed lymphatic drainage from the lungs [ 19 ]. In this case, the pulmonary CT scan on day 4 of admission showed interstitial inflammation with bilateral pulmonary effusion, indicating a possible role of COVID infection. This phenomenon was also observed in canine, as reported by Cherry N. et al. in 2009 [ 20 ]. Interestingly, a canine study led by Weeden A. et al. indicated positive B. henselae DNA in pleural and peritoneal effusion while pericardial effusion showed negative results [ 21 ]. In our case, the recurrence of localized mass and subsequent pleural effusion was parallel to COVID infection, possibly due to disrupted immune response.

As a zoonotic pathogen, B. henselae is transmitted to cats by flea feces contamination and ingested while grooming, therefore transmission to human is often achieved by cat scratches and bites [ 22 , 23 ]. This was corroborated by Chomel B. et al. in 1996, where they observed transmission of B. henselae to specific-pathogen-free (SPF) cats through contact with infected flea. They also noted that highly bacteremic cats, in absence of fleas, were unable to infect SPF cats [ 24 ]. The seasonality of CSD diagnosis, interestingly, has also been extensively studied by Nelson A., Saha S. and Mead P. in the United States spanning from 2005 to 2013 [ 25 ]. It was observed that the largest proportion of CSD diagnosis was made during January, followed by August and November, which they attributed to adoption pattern and age susceptibility of kittens, and peaking of fleas during fall and winter [ 26 ]. This is in line with our patient, who was also admitted in January.

In terms of source of infection, our patient denied cat scratch or bite on admission, whereas indirect contact with cats was found possible in his warehouse. The indirect mode of B. henselae transmission in this case was recently reported by Bush J. et al. in 2023, and they revealed the ability of B. henselae to exist stably in several biological and non-biological fluids [ 27 ]. While the discovery is exhilarating, the possibility of indirect B. henselae transmission poses a challenge for clinicians in face of similar patients without relevant history of feline contact.

Infection of B. henselae could cause diverse clinical symptoms depending on the age group, where children and younger individuals are prone to develop lymphadenitis while the elderly are more likely to suffer from endocarditis, and combined with B. quintana account for over 90% Bartonella endocarditis cases [ 28 ]. While it is necessary to consider infection of Bartonella species in the differential diagnosis in patients with fever of unknown causes, CSD is often misdiagnosed since the diagnosis is critically dependent on serological tests or polymerase chain reaction (PCR) assay as routine blood culture methods fails to detect B. henselae [ 5 ]. While serological test often shows high sensitivity, it fails to distinguish from ongoing infection and past infection. On the other hand, PCR assay has been shown to detect B. henselae in fresh tissue or purulent sample with high sensitivity and specificity, as reported by Gaoz S. et al. in 2022 [ 29 ]. The major challenge for clinicians and microbiologists is that PCR requires specific target, which is sometimes unidentified initially. Another factor for PCR sensitivity is the type of sample, since Khalfe N. and Lin D. observed decreased PCR sensitivity in paraffin embedded sample fixed by formalin [ 30 ]. In comparison, NGS could detect the species of pathogen with a quantity profile, offering assistance for clinicians to narrow down suspected pathogens at an early stage of diseases.

COVID has been characterized as a highly transmissible emerging pathogen, causing mild to severe respiratory symptoms with or without systematic complications and spreading fast across the world [ 31 ]. In context of the global pandemic of COVID, the incidence of various disease has surged due to a variety of reasons. A national study in Argentina in 2022 reported that COVID pandemic is associated with increased incidence of CSD, which was attributed to the prolonged cat contact due to quarantine, and higher rates of systematic CSD, which is yet to be explained [ 32 ].

In conclusion, we present a case underscoring the importance of vigilance in diagnosing and managing unusual presentations of less common diseases, especially in the context of the COVID-19 pandemic. While CSD is typically a self-limiting condition, this case was complicated by COVID-19, leading to unique challenges in both diagnosis and treatment. The co-occurrence of these two conditions highlights the complexity of managing infectious diseases in a time of a global pandemic. Clinicians, hence, should consider multiple diagnostic possibilities and adapt treatment strategies accordingly.

Availability of data and materials

The dataset supporting the conclusions of this article is included with the article.

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Yanzhao Dong, Ahmad Alhaskawi & Hui Lu

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Hui Lu designed the study; Yanzhao Dong and Ahmad Alhaskawi drafted the manuscript, Xiaodi Zou and Haiying Zhou performed literature selection and drew the figures; Sohaib Hasan Abdullah Ezzi and Vishnu Goutham Kota collected patient data, Sahar Ahmed Abdalbary, Alenikova Olga and Mohamed Hasan Abdulla Hasan Abdulla revised the manuscript. The authors have read and approved the final manuscript.

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Dong, Y., Alhaskawi, A., Zou, X. et al. Post-COVID reactivation of latent Bartonella henselae infection: a case report and literature review. BMC Infect Dis 24 , 422 (2024). https://doi.org/10.1186/s12879-024-09336-7

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Prosecutor: A tabloid pact led to Trump faking business records

A deal to quash stories about sex scandals and boost trump’s candidacy allegedly led to hush money crimes.

NEW YORK — Donald Trump oversaw a “planned, coordinated, long-running conspiracy to influence the 2016 election,” which included hush money payments to an adult-film actress, prosecutors told a jury Monday in the opening salvo of the first criminal trial of a former U.S. president.

“It was election fraud, pure and simple,” Assistant District Attorney Matthew Colangelo told the jury inside a packed and heavily guarded courtroom, illustrating the sky-high stakes of a criminal trial in which the defendant is also the presumptive GOP nominee for president in the November election.

In the hallway outside the courtroom, Trump denounced the case, and other legal battles he is fighting, with his usual bluster and vitriol against a system that he claims is targeting him unfairly for political reasons.

“I should be in Georgia now. I should be in Florida now,” Trump said.

Colangelo spent about 40 minutes Monday morning describing the evidence that he said would show Trump broke the law. The prosecutor’s delivery was calm and measured throughout — never raising his voice and keeping his hands in his suit pockets for much of the time he spoke.

Trump’s crimes, the prosecutor said, arose out of his secret election-year deal with the National Enquirer to squelch bad stories about his sex life — a conspiracy launched in a meeting between Trump, the tabloid’s then-CEO David Pecker and Michael Cohen, Trump’s then-lawyer and fixer.

That pact ultimately led Cohen to arrange a $130,000 payment to adult-film actress Stormy Daniels to keep her from going public about an alleged sexual encounter she had with Trump years earlier, the prosecutor said.

Cohen is expected to testify that Trump purposely misrepresented reimbursements to Cohen to conceal what the money was for.

Cohen’s testimony will be “damning” and convincing, Colangelo said.

“I suspect the defense will go to great lengths to get you to reject his testimony, precisely because it is so damning,” Colangelo said, though he acknowledged that Cohen “has made mistakes.”

Throughout the prosecutor’s presentation, Trump showed little emotion, often not looking at Colangelo and occasionally writing short notes to his lawyers.

The Trump Trials

Trump lawyer Todd Blanche countered when it was his turn to address the panel that the prosecutor’s case would collapse because it was built on Cohen’s lies.

“Unbeknownst to President Trump, in all the years that Mr. Cohen worked for him, Mr. Cohen was also a criminal,” Blanche said. “He cheated on his taxes, he lied to banks, he lied about side businesses.”

Blanche said that when the FBI began investigating Cohen, he tried to “blame Trump for virtually all of his problems” and continues to do so.

“Michael Cohen was obsessed with President Trump. He’s obsessed with President Trump even to this day,” Blanche said.

Cohen weighed in on social media later in the day, using a profanity to refer to Trump and saying: “Your attacks of me stink of desperation. We are all hoping that you take the stand in your defense.”

Cohen, an admitted perjurer and felon, is considered central to the prosecution’s case, and how jurors view him may ultimately decide whether they convict Trump. Colangelo said the jury will be convinced Cohen is telling the truth about the hush money payments because his statements will be “backed up by testimony from other witnesses” as well as bank records, emails and text messages.

Trump will provide some of the evidence that will prove his guilt, Colangelo said, because jurors will hear “Donald Trump’s own words on tape, in social media posts, in his own books and in video of his own speeches.”

Manhattan District Attorney Alvin Bragg (D) charged Trump with 34 counts of falsifying business records for categorizing the reimbursement payments to Cohen as legal expenses. Trump denies the charges.

The payment from Cohen to Daniels, whose real name is Stephanie Clifford, was done “at Donald Trump’s direction and for his benefit, and he did it with the specific goal of influencing the outcome of the election,” said Colangelo.

“No politician wants bad press. But the evidence at trial will show this was not spin or strategy,” he said. “This was a planned, coordinated long-running conspiracy to influence the 2016 election, to help Donald Trump get elected through illegal expenditures, to silence people who had something bad to say about his behavior, using doctored corporate records.”

Blanche struck back at that characterization, saying the district attorney is trying to make legal conduct sound like a criminal conspiracy.

“There’s nothing illegal about what happened between AMI, Mr. Pecker, Mr. Cohen and President Trump,” Blanche said, referring to American Media Inc., the Enquirer’s parent company at the time. “This sort of thing happens regularly, where newspapers make decisions about what to publish, how to publish. It happens all the time with famous people, wealthy people. It doesn’t matter if it’s a scheme — it’s not against the law.”

Prosecutors said Trump was motivated to keep Daniels from speaking publicly in part because in October 2016, The Washington Post revealed the existence of an “Access Hollywood” tape in which Trump made graphic comments about grabbing women’s genitalia. Afraid of the damage more stories about sexual impropriety could do to his candidacy, Trump and his allies set out to keep more scandalous stories from surfacing, Colangelo said.

After opening statements, prosecutors called Pecker as their first witness — suggesting his testimony may serve as a kind of tour guide to help the jury understand the seamy world of tabloid sex scandals and Trump’s alleged role in preventing some of those stories from coming to light.

Pecker said in his role as CEO of the company that ran the National Enquirer and other celebrity-focused publications, he approved any payment of more than $10,000 for a story.

“We use checkbook journalism and we paid for stories,” said Pecker, describing a practice that is common at American tabloids and in some other countries, but is not generally part of mainstream journalism.

Prosecutors do not contend that Pecker was part of the scheme to pay off Daniels, but rather, that the deal he struck with Trump and Cohen to “catch and kill” bad stories about the presidential candidate showed Trump was motivated to keep such tales quiet because of the election.

To buttress the point, Colangelo said that when it seemed Trump might have to pay Daniels, he first tried to put the entire issue off until after the election, when it wouldn’t have mattered as much. But when Daniels’s representative made clear they would go public before Election Day, Trump decided to pay, the prosecutor said.

Pecker only spoke for about 20 minutes on the witness stand Monday before court ended for the day. He is expected back in court Tuesday to continue testifying, and a key element to his account will be what specific statements he says were made by Trump, and how the two of them — the witness and the accused — interact in court.

Before Pecker takes the stand, however, New York Supreme Court Justice Juan Merchan plans to hold a morning hearing on the prosecutors’ request that Trump be found in contempt for at least 10 alleged instances of violating a gag order .

Trump has been ordered not to publicly criticize the witnesses or the family members of the judge or prosecutor. Prosecutors say he has brazenly and repeatedly violated that order, and they are asking the judge to impose a fine of $1,000 for each violation.

Trump’s lawyers have argued it’s unfair to insist Trump remain silent about Cohen when Cohen repeatedly publicly criticizes him.

Trump New York hush money case

Former president Donald Trump’s criminal hush money trial is underway in New York. Follow live updates from the trial .

Jury selection: A full jury of 12 jurors and six alternates has been seated. Here’s what we know about the jurors .

The case: The investigation involves a $130,000 payment made to Stormy Daniels, an adult-film actress , during the 2016 presidential campaign. It’s one of many ongoing investigations involving Trump . Here are some of the key people in the case .

The charges: Trump is charged with 34 felony counts of falsifying business records. Falsifying business records is a felony in New York when there is an “intent to defraud” that includes an intent to “commit another crime or to aid or conceal” another crime. He has pleaded not guilty . Here’s what to know about the charges — and any potential sentence .

Can Trump still run for president? The short answer, legal experts said, is yes. The U.S. Constitution does not forbid Trump, or anyone else, from serving as president if convicted of a felony.

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• The jurors in Trump’s New York hush money trial April 19, 2024 The jurors in Trump’s New York hush money trial April 19, 2024

Prosecutors at hush money trial say Trump led 'porn star payoff' scheme to 'corrupt' 2016 election

Donald Trump "orchestrated a criminal scheme to corrupt the 2016 presidential election," a prosecutor told jurors Monday during opening statements in the first criminal trial of a former president.

"This case is about a criminal conspiracy and a cover-up,” prosecutor Matthew Colangelo told the 12-person jury and six alternates. Trump, he said, conspired to corrupt the 2016 presidential election by scheming with his lawyer Michael Cohen and David Pecker, who was the publisher of the National Enquirer at the time.

“Then, he covered up that criminal conspiracy by lying in his New York business records over and over and over again,” Colangelo said.

Pecker was called as the prosecution's first witness following opening statements from both sides. Trump's lawyer Todd Blanche told the jury his client was not guilty because no crime was committed.

Trump, who had his eyes closed for periods during the morning proceedings, seemed much more engaged when his old ally and friend Pecker was taking the stand. Trump craned his neck when Pecker walked in, almost as if to see whether Pecker would meet his eye. Trump also poked at his attorney Emil Bove and whispered something as Pecker, 72, got situated, and he leaned forward attentively when he began testifying.

Pecker did not get to his relationship with Trump by the time the court day ended. The proceedings ended early because a juror had an emergency dental appointment.

Trump told reporters afterward that the case was "unfair" and launched into an attack against Cohen, who's expected to be called as witness.

"When are they going to look at all the lies that Cohen did in the last trial? He got caught lying in the last trial. Pure lying," Trump said, apparently referring to Cohen's statement in the civil fraud case against Trump that he lied under oath during part of his 2018 guilty plea. "When are they going to look at that?” Trump said.

The comments are likely to come up at a hearing Tuesday morning, when Manhattan District Attorney Alvin Bragg's office is scheduled to argue that Trump has repeatedly violated a partial gag order barring him from making "public statements about known or reasonably foreseeable witnesses concerning their potential participation in the investigation or in this criminal proceeding."

Prosecutors have said Cohen and Pecker, the longtime former publisher of the Enquirer, are central figures in the alleged scheme to bury claims from women who said they had had affairs with Trump.

Colangelo told the jurors they will hear about a 2015 meeting at Trump Tower with Trump, Cohen and Pecker. Both Cohen and Pecker had specific roles to play in the scheme, Colangelo said. “Cohen’s job really was to take care of problems for the defendant,” he said. “He was Trump’s fixer.” Pecker, meanwhile, would act as “the eyes and ears” for Trump and would let him and Cohen know about any allegations that could hurt his campaign.

The DA alleges the three conspired to hide “damaging information from the voting public.” That included allegations from a former Playboy model named Karen McDougal who said she had a 10-month sexual relationship with Trump that ended in April 2007. Pecker’s AMI agreed to pay her $150,000 in a deal to essentially buy her silence — a practice that was referred to as “catch and kill.” Trump has denied McDougal's claims.

The situation took on a greater sense of urgency for Trump in October 2016. That's when The Washington Post published the " Access Hollywood " tape, which caught Trump on a hot mic saying he could grope women without their consent because "when you're a star, they let you do it."

Judge Juan Merchan barred the DA from playing the tape for the jury for fear it would be too prejudicial, but he did allow prosecutors to use a transcript of Trump's remarks.

Colangelo said the impact of the tape was “immediate and explosive.”

“The defendant and his campaign were concerned that it would irrevocably damage him with female voters,” he said, and "the campaign went into immediate damage control mode."

It was around that time that the Enquirer heard that adult film actress Stormy Daniels was interested in coming forward with a claim that she had a sexual encounter with Trump in 2006. Trump was "adamant" he didn't want that claim, which he denies, to become public for fear it would be "devastating" to his campaign, Colangelo said.

Cohen then struck a deal to buy Daniels' silence for $130,000, Colangelo said.

"It was election fraud, pure and simple," Colangelo said, adding “We’ll never know, and it doesn’t matter, if this conspiracy was a difference maker in the close election.”

Colangelo said the Trump Organization, Trump’s company, couldn’t cut Cohen a check with the memo “reimbursement for porn star payoff” so "they agreed to cook the books" and make it look like the reimbursement was income.

"The defendant said in his business records that he was paying Cohen for legal services pursuant to a retainer agreement. But, those were lies. There was no retainer agreement," Colangelo said.

“It was instead what they thought was a clever way to pay Cohen back without being too obvious about it,” he said. But what they did was a crime, Colangelo said. “Donald Trump is guilty of 34 counts of falsifying business records in the first degree,” he concluded.

Trump's attorney Blanche countered in his opening statement that his client hasn’t committed any crimes. “The story you just heard, you will learn, is not true,” he said. "President Trump is innocent. President Trump did not commit any crimes."

He said the only thing Trump did was sign checks for legal services rendered by his lawyer.

“The invoice is processed, somebody at Trump Tower generated a check, the check was ultimately signed, and there was a record in the ledger,” Blanche said. “He’s the only signatory on his personal checking account, which is why he signed the check.

"So what on Earth is a crime? What’s a crime, of what I just described?” Blanche said. "None of this is a crime," he said, adding that nondisclosure agreements like the one Daniels signed are legal.

As for the election interference argument, Blanche said, “I have a spoiler alert: There’s nothing wrong with trying to influence an election. It’s called democracy.”

In a preview of his trial strategy, Blanche also attacked Daniels' and Cohen's character and credibility. He accused Daniels, whom he described as "extremely biased," of trying to "extort" Trump, a word that the judge ordered stricken from the record. Blanche then said what Daniels had been threatening to do by going public with her allegation was "sinister" and "damaging to [Trump] and damaging to his family.”

Blanche also said Daniels' testimony, while salacious, doesn't matter because she doesn't know anything about how Cohen was repaid.

The bulk of Blanche's attacks were reserved for Cohen, who pleaded guilty in 2018 to numerous crimes, including some that he said he carried out on Trump's behalf.

“Michael Cohen was obsessed with President Trump. He’s obsessed with President Trump, even to this day,” Blanche said, calling him a "convicted felon" and a "convicted liar."

“He has talked extensively about his desire to see President Trump go to prison,” Blanche said, including in public on Sunday.

He told the jurors that if they listen to the evidence, they'll return "a very swift not guilty verdict."

Cohen said in a statement afterward, “The facts will come out at the time of trial that contradicts Todd Blanche’s mischaracterizations of me.”

Trump faces 34 counts of falsifying business records related to the hush money payment to Daniels. Trump, who has pleaded not guilty , could face up to four years in prison if he is convicted.

On his way into the courtroom Monday morning, he told reporters: “It’s a very, very sad day in America. I can tell you that.”

The day got off to a rough start for Trump, with Merchan, the judge, ruling that if he winds up taking the stand in his own defense, prosecutors can cross-examine him about another New York judge's finding that he and his business committed "persistent" fraud and violated a gag order, juries' finding him civilly responsible for sexual abuse and defamation in the E. Jean Carroll cases and a settlement in a case that found he used his now- shuttered foundation to improperly further his campaign in the 2016 election. Trump's attorneys had argued that all of those topics should be out of bounds.

Trump didn't show concern — he sat with his eyes closed through much of Merchan's ruling. He briefly opened his eyes when the jury was brought in for the judge's instructions and then closed them again.

Bragg was sitting in the front row of the courtroom ahead of opening statements.

Cohen, Daniels and McDougal are also expected to testify during the trial, which is estimated to take six weeks.

The jury consists of seven men and five women. The final day of jury selection, Friday, was particularly intense , as some potential jurors broke down in tears and said they were too anxious to be seated. They were excused. A man also set himself on fire outside the courthouse.

Trial proceedings Tuesday will be abbreviated, ending at 2 p.m. ET because of the Passover holiday.

Adam Reiss is a reporter and producer for NBC and MSNBC.

Dareh Gregorian is a politics reporter for NBC News.

Jonathan Allen is a senior national politics reporter for NBC News, based in Washington.

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Case report: Streptococcus pneumoniae pneumonia characterized by diffuse centrilobular nodules in both lungs

Associated data.

The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Streptococcus pneumoniae ( S. pneumoniae ) is the most common pathogen in community-acquired pneumonia (CAP) and takes the form of lobar pneumonia as typical computed tomography (CT) findings. Various patterns of radiological manifestation have also been reported in patients with S. pneumoniae pneumonia; however, the appearance of diffuse centrilobular nodules in both lungs is rarely reported.

Case presentation

We report the case of a patient with a history of chronic lymphocytic leukemia (CLL) for 9 years who presented with new-onset fever, cough, excess sputum, and shortness of breath for 1 week. He was given intravenous antibacterial (cephalosporin) treatment for 4 days, but his condition did not improve and dyspnea became more serious. The chest CT indicated diffuse centrilobular nodules in both lungs at admission. Patient’s bronchoalveolar (BAL) fluid was sent for metagenomic next-generation sequencing, which only supported a diagnosis of S . pneumoniae infection. His condition improved gradually after antimicrobial treatment (moxifloxacin) and a follow-up CT showed that the diffuse centrilobular nodules in both lungs were absorbed completely.

This case highlights a rare CT presentation of S. pneumoniae pneumonia that should alert clinicians, so as to avoid taking unnecessary treatment measures.

Introduction

Streptococcus pneumoniae ( S. pneumoniae ) remains one of the most common causes of bacterial community-acquired pneumonia (CAP), encompassing infections mild enough to be treated on an outpatient basis, as well as those requiring hospital care, or even intensive care unit admission ( 1 ). Pneumolysin is the major protein virulence factor of the S. pneumoniae and possesses both cytotoxic and proinflammatory properties ( 2 ). The toxin is located in the cytoplasm of the S. pneumoniae , as well as on the cell wall, and is released extracellularly following the autolysis of the pathogen during the later stages of growth, which resulted in the development of pneumonia restricted to the lobe ( 2 , 3 ). Therefore, S. pneumoniae pneumonia takes the form of lobar pneumonia as typical computed tomography (CT) findings ( 4 ). Various patterns and distributions of radiological manifestation have also been reported in patients with S. pneumoniae pneumonia owing to the widespread use of antibiotics ( 5 ). Bronchopneumonia and associated centrilobular nodules were also not uncommon in CT findings of S. pneumoniae pneumonia cases ( 6 , 7 ). However, these nodules were usually at the periphery of consolidation, or the lesions were localized to lung segment or lobe.

Herein, we report a rare case of S. pneumoniae pneumonia characterized by diffuse centrilobular nodules in both lungs, which adds to the body of knowledge about S. pneumoniae .

A 66-year-old man presented with fever, cough, excess sputum, and shortness of breath for 1 week. He was given intravenous antibacterial (cephalosporin) treatment for 4 days, but his condition did not improve and dyspnea became more serious. Therefore, the patient came to our hospital where chest CT showed diffuse centrilobular nodules in both lungs, some with a “tree-in-bud” appearance ( Figure 1 ), and multiple enlarged lymph nodes in mediastinum and bilateral axilla ( Figure 2 ). He was then admitted to the hospital.

Patient’s computed tomography (CT) scan images at three time points. Initial CT scan (Day 0) showed that bilateral diffuse nodules separated by the fissures and pleura. Some of the nodules have a “tree-in-bud” appearance. After treatment, CT scan (Day 9) showed visible absorption of diffuse nodules in both lungs. Follow-up CT scan (Day 31) showed that the bilateral diffuse nodules absorbed completely.

Mediastinal window of patient’s initial computed tomography (CT) scan showed multiple enlarged lymph nodes in mediastinum and bilateral axilla.

The patient had a history of CLL for 9 years and had received several chemotherapies in the past. His condition was stable in the past year. He has a history of smoking for 30 years. Other medical history was denied. He had no bird exposure and no history of travel outside Wuhan, Hubei, where he lived.

At admission, physical examination revealed that temperature was 37.8°C, peripheral blood oxygen saturation (SpO2) was 87% on room air, respiratory rate was 31 breaths/min, and wet rales could be heard on auscultation of both lungs. Multiple soy-sized enlarged lymph nodes could be palpable on both sides of the neck and armpits. Laboratory tests revealed that arterial blood gases at 29% fraction of inspiration O2 (FiO2) showed partial pressure of oxygen (PaO2) 65.6 mmHg, partial arterial pressure of carbon dioxide (PaCO2) 22.8 mmHg, pH 7.43, and oxygenation index (OI; PaO2/FiO2) 226 mmHg. Blood cell analyses, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were examined ( Table 1 ). T-cell spots of tuberculosis infection (T-SPOT.TB) were positive. The detection of mycobacterium tuberculosis in bronchoalveolar (BAL) fluid by polymerase chain reaction (PCR) was negative. Sputum and BAL fluid acid-fast staining were negative. Procalcitonin, immunoglobulin (Ig) E, Mycoplasma pneumoniae IgM, Chlamydia pneumoniae IgM, and 1, 3-beta-D glucan/galactomannan tests were normal. No pathogenic bacteria or fungi were detected in blood, sputum, and BAF fluid cultures. Lymphocyte typing were noted as follows: total T cell 6% (normal, 50–87%), total T-cell number 803/μl (normal, 955–2,860/μl), CD4 + Th-cell proportion 1% (normal, 21–51%), CD4 + Th-cell number 151/μl (normal, 550–1,440/μl), total B-cell 89% (normal, 3–19%), and total B-cell number 12,603/μl (normal, 90–560/μl).

Laboratory parameters of patients at admission and before discharge.

SpO2, peripheral blood oxygen saturation; WBC, white blood cell; EOS, eosinophil; NEU, neutrophil; LYM, lymphocyte; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

The patient was diagnosed with severe pneumonia and type 1 respiratory failure. BAL fluid was collected and sent to the Shenzhen BGI Medical Test Laboratory for metagenomic next-generation sequencing (mNGS), which only supported a diagnosis of S. pneumoniae infection.

After admission, the patient’s condition improved gradually by giving antimicrobial treatment (moxifloxacin injection, 0.4 g, qd) and other comprehensive treatment measures, including airway clearance and oxygen support. Before discharge, SpO2, blood cell analyses, and related inflammatory markers were reexamined ( Table 1 ), in which SpO2, CRP, and ESR were normal finally, and reexamination of the chest CT showed visible absorption of diffuse centrilobular nodules in both lungs ( Figure 1 ). Three weeks after discharge, a follow-up CT showed that the diffuse centrilobular nodules in both lungs absorbed completely ( Figure 1 ).

The differential diagnosis of diffuse centrilobular nodules is extensive but small airway diseases are by far the most likely cause, including infectious bronchiolitis, aspiration, hypersensitivity pneumonitis, respiratory bronchiolitis (RB), and follicular bronchiolitis ( 8 ). “Tree-in-bud” indicates the presence of dilated centrilobular bronchioles with lumen impacted by mucus, fluid, or pus and is associated with peribronchiolar inflammation ( 9 ). Centrilobular nodules showing “tree-in-bud” appearance are associated with airway infection in majority of patients, and the common pathogens include mycobacterium tuberculosis, non-tubercular mycobacteria (typically MAC), Haemophilus influenzae , M. pneumoniae , Chlamydia , and viral and airway invasive aspergillus. In this case, however, the patient’s BAL fluid was detected by mNGS, which only supported a diagnosis of S. pneumoniae infection. Although pathogens mNGS can detect bacteria, viruses, fungi, and parasites without bias, there may be some omissions in RNA virus due to sample storage and transportation problems. The possibility of co-infection with virus cannot be ruled out. However, in the absence of antiviral treatment, the rapid improvement in symptoms and CT imaging in patients with an impaired immune system suggests that the possibility of virus infection is unlikely.

Streptococcus pneumoniae pneumonia typically presents the form of homogeneous airspace consolidation, whereby alveolar lumens are filled with exudates containing leukocytes and alveolar walls are thickened by capillary congestion and edema ( 4 , 5 ). Associated centrilobular nodules were not uncommon. Previous reports have found that 27–48% of patients with S. pneumoniae pneumonia exhibited centrilobular nodules on CT scans ( 6 , 7 ); however, centrilobular nodules were usually at the periphery of consolidation or the lesions were localized to lung segment or lobe. To the best of our knowledge, no cases presenting diffuse centrilobular nodules in both lungs of patients with S. pneumoniae pneumonia have been published.

The patient had a history of CLL for 9 years and smoking for 30 years. CLL is characterized by the clonal proliferation and accumulation of mature and typically CD5 + B-cells within the blood, bone marrow, lymph nodes, and spleen ( 10 ). With an impaired immune system, patients with CLL often develop infectious complication, in which S. pneumoniae pneumonia is not uncommon. Unfortunately, the information of imaging patterns available about S. pneumoniae infection in a patient with CLL is limited. Cigarette smoking is also a common risk factor for S. pneumoniae pneumonia ( 1 ). The mechanisms of this association possibly include altered ciliary motility, increased nasopharyngeal carriage of organisms, altered alveolar macrophage function, and increased epithelial permeability ( 11 ). Meanwhile, there is strong evidence supporting a causal role of cigarette smoking in the development of RB and RB-associated interstitial lung disease (RB-ILD), which are also characterized by diffuse centrilobular nodules ( 12 , 13 ). However, it is unknown whether these comorbid conditions contribute to this rare imaging appearance in a patient with S. pneumoniae infection. We hypothesize that this may have been implicated in this patient, and further studies are warranted.

Data availability statement

Ethics statement.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

FZ and LL generated the concept. FZ and SQ drafted the manuscript. FZ was the consultant in charge of the patient. FX, CM, and LL revised the original draft critically for important intellectual content. All authors contributed to the article and approved the submitted version.

Acknowledgments

We would like to thank the patient for the consent to participate in this study and the nurses and clinical staff who provided care for the patient.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.