AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Pneumonia in the immunocompromised host involves infection and inflammation of the lower respiratory tract. Regardless of the reason for altered immune function, pneumonia carries a high mortality rate in immunocompromised patients.¹

Human immunodeficiency virus

Patients with human immunodeficiency virus (HIV) are at risk for a number of pulmonary infections. Pneumocystis jiroveci remains the most common opportunistic infection in this group; however, the epidemiology of pulmonary infections among patients with HIV is changing.²

• Bacterial pneumonia: The most common bacterial pathogen causing illness in patients with HIV is Streptococcus pneumoniae. These patients develop pneumonia more frequently than their non-HIV infected counterparts, and they have more severe clinical courses when they are infected.³ For more information, see Pneumonia, Bacterial.
• Tuberculosis: Patients with HIV are more likely to develop active tuberculosis (TB) once infected, and they have a higher risk of death with TB disease. HIV is the most important recognized risk factor for progression from latent to active tuberculosis.⁴ For more information, see Tuberculosis.
• Mycobacterium avium complex: Mycobacterium avium complex (MAC) infection refers to infection with either of two nontuberculous mycobacterial species, either M avium or Mycobacterium intracellulare. These infections can occur in non-HIV infected patients; however, it is much more frequently encountered in the setting of HIV. For more information, see Mycobacterium Avium-Intracellulare.
• Histoplasmosis: For the immunocompetent host, this infection is frequently asymptomatic. In the setting of HIV, this infection is much more common and frequently progresses to disseminated disease. Immunocompromised persons living in endemic areas are at increased risk of disease. For more information, see Histoplasmosis.
• Coccidioidomycosis: This fungal infection is caused by Coccidioides immitis, an organism endemic to large parts of the southwestern United States. Life-threatening infections have been described in patients both with HIV and impaired cellular immunity. For more information, see Coccidioidomycosis.
• Varicella-zoster virus pneumonia: Varicella pneumonia is not a common infection in patients with HIV. Few cases have been reported; these have included both primary and reactivation disease.⁵
• Cryptococcal pneumonia: Cryptococcal pneumonia is more severe in patients with HIV. Patients with pulmonary disease frequently progress to disseminated disease.⁶
• Pneumocystis jiroveci pneumonia: PCP remains the most common opportunistic infection among patients with HIV; however, its epidemiology is changing. Adoption of highly active antiretroviral therapy (HAART) has resulted in lower frequency of this infection. For more information, see Pneumocystis (carinii) jiroveci Pneumonia.

Patients with cystic fibrosis experience progressive lung disease leading to respiratory insufficiency and failure. For more information, see Cystic Fibrosis, Thoracic.

Patients with primary immunodeficiencies are challenged by a number of pulmonary infections. The spectrum of illnesses they face is largely determined by their underlying immune dysfunction: humoral deficiencies, cellular deficiencies, or combined deficiencies.

Both solid organ and bone marrow transplant patients are at heightened risk of pulmonary infections. Timing since transplantation, use of immunosuppressive medications, and the type of transplant are all important for predicting these complications.

Leukemia itself (primarily chronic lymphocytic leukemia) is characterized by frequent infectious episodes. Patients who are undergoing chemotherapy are additionally at risk for severe neutropenia and subsequent pulmonary infections.⁷

When lymphoma compromises airway lumen, secondary postobstructive pneumonias can develop. Patients with lymphoma are often taking steroids, which increase their risk of pulmonary infections.

Patients who are undergoing chemotherapy for solid organ tumors are at increased risk of infections. Pulmonary infections are common.

For many reasons, alcoholics are at increased risk of pneumonias. For more information, see Pneumonia, Aspiration.

Patients who are taking steroids long term are at higher risk of pulmonary infections.⁸ Additionally, patients taking steroids long term for sarcoidosis have the same risk of pulmonary infections as other chronic steroid users, plus complications from postobstructive infections secondary to compressive granulomas.

Both primarily and from immunosuppressive therapies, patients with autoimmune diseases are at higher risk of infectious pulmonary complications.

These patients are at particularly high risk of acquiring infections from encapsulated organisms.⁹ They also have a higher rate of infection from pneumonias overall. For more information, see Asplenia.¹⁰

Functionally immunocompromised

Poorly managed secretions and frequent aspiration are risk factors for pneumonitis and pneumonias. Reasons for a breakdown in this component of pulmonary defense can be functional, resulting in an overwhelmed immune system, include the following: cognitive dysfunction, spinal cord injuries, and neuromuscular disorders. For more information, see Pneumonia, Aspiration.

Both the old and the young are at increased risk of pneumonia. 

Pregnancy itself has an immunosuppressive effect. Further, a reluctance to perform imaging in pregnant patients may lead to delayed detection of pneumonias.

Pulmonary complications are common.¹¹ For more information, see Initial Evaluation and Management of the Burn Patient.

Pathophysiology

Many pulmonary pathogens reliably plague the host with a dysfunctional immune system. Others are encountered more frequently with certain causes of immune suppression. Therefore, the pathophysiology can be appreciated in both general and more specific contexts.

Conceptually, pneumonia susceptibility from immunosuppression stems from neutrophil defects, immunoglobulin defects, or T-cell defects. The underlying reason for immune suppression may suggest certain pulmonary pathology.

Malignancy

Neutrophil defects, immunoglobulin defects, and T-cell defects are all seen in patients with cancer.

• Cancer chemotherapy: Many treatment protocols exist. Common adverse reactions are leukopenia and lymphopenia.
• Immune dysfunction: Underlying malignancy itself is a risk factor for subsequent infections.¹²

T-cell dysfunction in the setting of HIV leads to a number of infectious complications.

• TB: HIV is considered to be the greatest risk factor for TB.¹³ Early diagnosis is more difficult because of the lack of specific clinical findings, such as an abnormal chest radiograph or a positive purified protein derivative (PPD) skin test result.
• Bacterial pneumonia: HIV causes dysfunction of cell-mediated as well as humoral immunity. CD4 T cells principally help other cells achieve their effector function. As such, at low CD4 levels, a disruption of B-cell differentiation occurs. Impaired B-cell functions, particularly of memory cells, are postulated to account for increased risk of infection.¹⁴ Even after the initiation of HAART therapy, patients with HIV have reduced marginal zone B-cell percentages.
• PCP: Transmission and infection from P jiroveci is incompletely understood. Traditionally, infection in a patient with HIV has been thought to represent reactivation latent colonization. Now, however, some evidence exists that the epidemiology of this infection is defined on a more local geographical level.¹⁵ As molecular analysis of P jiroveci improves, so will the understanding of the transmission and epidemiology of this opportunistic infection.
• Histoplasmosis: Spores of the mold phase are inhaled and cause a localized or patchy bronchopneumonia. CD4 lymphocytes normally activate macrophages to control the infection. In patients with HIV and low CD4 counts, the likelihood of developing both pulmonary and disseminated histoplasmosis is increased.¹⁶
• Coccidioidomycosis: Spores are inhaled and then ingested by pulmonary macrophages. Impaired cell-mediated immunity in the HIV patient accounts for their increased risk of infection.¹⁷
• Cryptococcus: Most cases are the result of reactivation from a latent infection. Recognition and treatment are important because pulmonary cryptococcus is thought to herald the onset of disseminated disease.
• HSV and VZV: The pathophysiology of these infections in the setting of HIV is not well understood. 
• MAC: This infection is thought to represent a recent acquisition of organisms rather than a reactivation of latent infections.

• Humoral deficiencies: Patients with defects of humoral immunity are unable to create functional antibodies. Their complications are characterized by severe, recurrent upper and lower respiratory tract infections.
• Cellular deficiencies: Cellular deficiencies are rare conditions that affect T-cell development and function. Dysfunction of T cells invariably has an impact on B-cell activity; therefore, most of these conditions manifest as combined deficiencies.
• Combined deficiencies: In combined deficiencies, both T-cell and B-cell function is disturbed. These patients present not only with recurrent episodes of respiratory syncytial virus (RSV), herpes simplex virus (HSV), VZV, influenza, and other viral respiratory infections but also chronic diarrhea and chronic mucocutaneous candidiasis.

Transplant immunosuppression

For both solid organ and bone marrow transplant patients, the time since transplant is a major predictor of infectious complications. Induction regimens are used in the early posttransplant period, while maintenance therapies are long-term later medication strategies.

• Solid organ transplant: A variety of antilymphoproliferative agents are used commonly including cyclosporine, azathioprine, and tacrolimus. Additionally, both monoclonal and polyclonal antibodies to hematopoietic antigens are increasingly being used. The full medication history should be available through the patient’s transplant coordinator.
• Bone marrow transplant: Like solid organ transplant patients, various antilymphoproliferative agents are used commonly. Distinguishing between CMV, idiopathic pneumonia syndrome, and graft-versus-host disease is challenging.¹⁸

Pregnancy

Pregnancy results in immunologic changes that predispose to infections. There is a decrease in helper-T-cell numbers, reduced activity of natural killer cells, and decreased cell-mediated immune function.¹⁹ Cardiopulmonary changes that occur as a part of normal pregnancy may result in a diminished capacity to compensate for the effects of respiratory disease.²⁰ The elevated serum concentrations of progesterone and 17beta-estradiol observed in the latter half of pregnancy can stimulate the growth and maturation of Coccidioides immitis.²¹

Alcohol consumption affects both systemic and pulmonary immune function. Current alcohol use is an independent risk factor for severe community-acquired pneumonia. Additionally, patients who are alcoholics are frequently also smokers. The negative effect of these risk factors for pulmonary infections are additive. Chronic alcohol drinkers also have decreased saliva production, an important component of mucosal defense.²²

In cystic fibrosis, abnormal chloride and sodium transport in the respiratory epithelium, leads to thick, viscous secretions. Chronic airway obstruction leads to colonization by pathogenic bacteria, including Pseudomonas aeruginosa.²³

• Systemic lupus erythematosus: Distinguishing infection from an autoimmune flare is important. Treatment with steroids in the setting of infection could be deleterious. Susceptibility to infections derives from therapeutic and disease-related factors. Complement deficiencies and elevated Fc gamma III and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels may contribute to increased susceptibility to infection.²⁴ Deficiencies of functional mannose-binding lectin do not appear to be the reason for increased infection burden.²⁵ Low complement, use of more than 20 mg prednisone daily, and use of cyclophosphamide were important risk factors in multivariate analyses.²⁶ Severe manifestations of disease are treated with immunosuppressive therapies.²⁴
• Connective tissue diseases: Both the primary condition and the use of immunosuppressive medications place patients at increased risk. Of 5,411 cases reviewed, 29% of patients developed a serious infection; 24% died from this infection—most reported as bacteremia or pneumonia.²⁷

Functionally immunocompromised

• Neuromuscular disease: Pneumonia is a leading cause of death. Impairment of cough and swallowing mechanisms contributes to increased risk of pneumonia.²⁸ Gastroesophageal reflux is more common, persistent, and severe in patients with cerebral palsy. Kyphoscoliosis secondary to unequal muscle tone leads to restrictive lung function and predisposes to atelectasis.²⁹
• Cognitive dysfunction: Drooling, feeding problems, and aspiration place these patients at higher risk of pulmonary infections. Asynchrony between swallowing and breathing results in increased risk of aspiration.²⁹
• Spinal cord injury: Muscular weakness may contribute to dysfunctional cough reflex.²⁹

Older patients may complain of fewer symptoms than younger patients, making the diagnosis more challenging.³⁰

Children and infants at risk of RSV infection include those younger than 24 months with chronic lung disease who have required medical therapy within 6 months of RSV season onset, preterm infants born prior to 32 weeks’ gestation, preterm infants born at 32-35 weeks’ gestation with at least 2 additional risk factors, and those with hemodynamically significant heart disease.³¹

Burn

Complications arise from both direct lung injury and indirect pulmonary effects (eg, decreased lung expansion secondary to circumferential burns). Bacterial clearance is impaired in patients with inhalational injury.¹¹ Mechanisms for impaired clearance include impaired cough, impaired mucociliary action, airway plugging, and impaired alveolar macrophage function.

Frequency

United States

The spectrum of diseases in immunocompromised patients has changed in the last 10 years.² Part of this stems from different causes of immunosuppression in the community; part of this reflects other epidemiological trends.

HIV

The rate of bacterial pneumonia is higher in HIV-positive patients than matched HIV-negative controls at all CD4 levels. In HIV-positive patients, the rate of bacterial pneumonia was inversely related to the baseline CD4 lymphocyte count.³ S pneumoniae is the most commonly identified bacterial pathogen; their risk of pneumonia is 10-100 times greater than non-HIV infected persons.⁹

From 2005-2006, among patients with TB with known HIV status, a decline from 13% to 12.4% occurred.⁴ The frequency of extensively resistant (XDR) TB declined in HIV-positive patients from 2000-2006 compared with 1993-1999.⁴ HAART reduces but does not eliminate the risk of TB.³² Globally, 11.4 million adults (aged 15-49 y) are co-infected with HIV and TB.³³

In patients with PCP, risk of infection is strongly correlated with CD4 count. In patients with a CD4 count between 201 and 350, the incidence was 0.5%.³⁴ PCP remains a leading cause of death in patients with HIV.²

In patients with MAC, the risk of infection increases when the CD4 count falls below 50.

In patients with histoplasmosis, the risk of infection increases when CD4 count falls below 150.

Infection with Coccidioides requires specific climatic conditions (ie, a period of moisture, followed by a dry period, followed by dispersal to the host). In Arizona, this is the third most commonly reported opportunistic infection among patients with HIV.

The etiologic agent is not identified in approximately half of cases of community-acquired pneumonia in pregnancy.²⁰ Streptococcus pneumoniae and Haemophilus influenzae are the most frequently identified bacterial agents.²⁰

Cystic fibrosis

Cystic fibrosis affects 30,000 persons in the United States and 60,000 persons worldwide. One in 1,900 to 3,700 persons in the US white population are affected; it is less frequent in the Hispanic, Asian, and African American population.

Transplant immunosuppression

The depth and duration of neutropenia are risk factors for infection.³⁵ Risk factors for pulmonary nocardial disease were receipt of high-dose steroids, cytomegalovirus disease in the past 6 months, and high median calcineurin inhibitor level.³⁶

In renal transplant patients, the etiology of pneumonia is 23% bacterial, 20% tuberculosis, 9% fungal, 4% PCP, 4% Nocardia, and 2% viral.³⁷ PCP can occur even in patients who are on prophylactic treatment with trimethoprim-sulfamethoxazole.³⁷

Bacterial infection is the leading cause of death in single and double lung transplant patients in the first 3 months after transplantation.³⁸ CMV is the most common viral cause of morbidity and mortality and usually occurs 1-4 months after transplantation.³⁸ Approximately 50% will have infection or disease.³⁸ Nocardia has the highest frequency in lung transplant patients.³⁶ The incidence of PCP declined with the routine use of prophylaxis.

In heart transplant patients, the overall rate of infections in one 2-year period was 70%, with pneumonia listed as the second most common infection (19%). The etiology of the pneumonias was not described by the authors.³⁹ Another study of 34 patients had 28% with pneumonias during the follow-up period: 16% had community-acquired pneumonia, 9% with a fungal etiology, and 3% with hospital-acquired pneumonia. These infections also tended to occur during the first 6 months after transplantation.⁴⁰

In liver transplant patients, the etiology of pneumonia is 26% bacterial, 15% viral, 11% PCP, and 6% fungal.⁴¹

The depth and duration of neutropenia are risk factors for infection.³⁵

Extremes of age

Adults older than 85 years were 16 times more likely to die from influenza than those aged 65-69 year.⁴⁴ Hospitalization rates for influenza are substantially increased in patients older than 65 years.⁴⁵ Elderly patients have a significantly higher rate of community-acquired pneumonia compared with younger patients.⁴⁶

Chronic steroids

Both the dose and duration of use are predictive of increased risk of pneumonia. Low-dose and short-term use carry minimal additional risk of pneumonia; dosages more than 10 mg/d or cumulatively 700 mg of prednisone increased patients' risk of pulmonary infection.⁴⁷

Alcoholic

The frequency of severe pneumonia (as defined by American Thoracic Society [ATS] criteria), bilateral pneumonia, multilobar pneumonia, mental confusion, admission to ICU, and mechanical ventilation requirements is more common among alcoholic patients.⁴⁸

Asplenic patients

In asplenic patients, the overall incidence of invasive pneumococcal disease is 500 cases per 100,000 per year.⁹

Mortality/Morbidity

Overall, 13.7% of immunocompromised patients with community-acquired pneumonia died in a Canadian study. Mortality correlated with etiology of immunosuppression.⁵⁰

HIV

From 1999-2000, the leading cause of death was from PCP.⁵¹ More than 50% of patients who died were not on or were not adherent to HAART.⁵¹ 

The case-fatality rate in patients with TB is higher in patients co-infected with HIV.⁵²

For community-acquired pneumonia, the in-patient mortality rate is 9.1%.⁵³ Clinical staging system predicts mortality: neurological symptoms, elevated respiratory rate, and elevated creatinine.⁵³

Elderly persons

Pneumonia is the leading cause of infection-related death.⁴⁶ Patients older than 90 years have twice the pneumonia mortality rate of patients aged 65-69 years.⁵⁴ Elderly persons have a disproportionate rate of ICU admission and mechanical ventilation.⁴⁶

Mortality from influenza and RSV disproportionately affects elderly persons.⁴⁴

The traditional pneumonia severity index (PSI) may not be applicable to elderly patients; a modified PSI that incorporates performance status has been described.⁵⁵  

Cognitive impairment

Cognitive impairment, especially in the setting of stroke, is a major risk factor for pulmonary infections.⁵⁶

Sex

An increased male-to-female ratio for pneumococcal disease has been described. This is thought to be related to underlying conditions, such as alcoholism and smoking, which are more common in males.⁹

Age

Patients at the extremes of age should be considered immunocompromised; these patients have increased burden of morbidity and mortality due to pneumonia.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

The underlying cause of immunosuppression is a crucial aspect of the history.

• Fever
• Exertional dyspnea, followed by dyspnea at rest with progression of disease
• Cough, most often nonproductive in patients with AIDS
• Pleuritic chest pain
• Anorexia and weight loss
• Abdominal pain

Physical

Pulmonary findings may be nonspecific or nonexistent in immunocompromised patients.

Findings at physical examination may include the following:

• Fever
• Tachypnea
• Tachycardia or bradycardia
• Rales or crackles
• Rhonchi
• Decreased breath sounds
• Dullness to percussion
• Egophony

Causes

The etiologic agents responsible for pneumonias in immunocompromised patients are often different than those found in immunocompetent patients.

Infectious causes

• Bacterial pneumonia
• Coccidioides species
• CMV
• TB
• Histoplasma species
• Aspergillus species
• MAC
• PCP
• Influenza
• HSV
• VZV
• Legionella species
• Nocardia species
• Cryptococcus neoformans
• Mucoraceae species
• Strongyloides species
• Toxoplasma species
• Capnocytophaga species

Noninfectious causes

• Pulmonary hemorrhage
• Pneumonitis
• Congestive heart failure
• Pulmonary embolism
• Myocardial infarction
• Pneumothorax
• Drug-induced injury
• Radiation-induced injury

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• The following laboratory studies should be obtained: WBC count, arterial blood gas (ABG) level, and lactate dehydrogenase (LDH) level. Sputum culture, sputum Gram stain, acid-fast bacillus (AFB) smear, and AFB culture should be collected with caution in the emergency department. If there is even a remote suspicion of tuberculosis, these specimens should be obtained after the patient is placed in isolation.
• Blood cultures, despite low yield and rarely having an impact on care, are considered standard of care.^{57, 58}
• In severe community-acquired pneumonia, urinary antigen testing for Legionella pneumophila and Streptococcus species should be performed early.
• Other routine laboratory studies as are clinically indicated.
• Specialized testing
• • Selective use of polymerase chain reaction (PCR) in suspected TB may be indicated.
  • Selective testing for coccidioidomycosis with direct examination and culture of respiratory secretions or CSF or by biopsy of suspicious pulmonary or cutaneous lesions, which may reveal characteristic double-contoured spherules with endospores and without budding, may be indicated.
  • PCR or VZV-IgM for VZV pneumonia may be performed.
  • Aspergillus galactomannan antigen testing improves diagnostic yield of invasive pulmonary aspergillosis.¹
  • If feasible, sputum culture in the emergency department could help tailor in-patient antibiotic therapy.²³

Imaging Studies

• Chest radiography is the initial imaging study.
• • Chest radiograph findings may be normal, or they may show infiltrates with consolidation, peribronchovascular, or nodular lesions.
  • As many as 14% of chest radiograph findings are normal in AIDS patients with pulmonary TB.⁵⁹
• Chest CT
• • A chest CT identifies pneumonic infiltrates not seen on chest radiograph and may facilitate diagnosis days sooner.¹
  • A negative chest radiograph finding should prompt a chest CT in patients suspected of having a pulmonary infection. CT results can help facilitate optimal sampling in later invasive procedures or for planning bronchoscopy.

Procedures

• Diagnostic yield of bronchoalveolar lavage (BAL) is high in immunocompromised patients with respiratory complaints.²
• BAL is rarely performed in the emergency department, CT scanning can facilitate more efficient in-patient evaluation.
• The frequent need for invasive diagnostic testing in immunocompromised patients should support early pulmonary consultation on these patients from the emergency department (particularly in transplant recipients).¹
• CMV immunostaining of BAL specimens is useful for the diagnosis of CMV pneumonitis in immunocompromised patients.⁶⁰
• Diffusing capacity of lung for carbon monoxide (DLCO): Some authors have supported obtaining a DLCO measurement in HIV-infected patients who have normal findings on chest radiograph as an algorithm for evaluation of PCP.⁶¹

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Prehospital Care

• Oxygen administration
• Establishment of intravenous access
• Oxygen saturation and cardiac monitoring

Emergency Department Care

• Oxygen administration
• Oxygen saturation and cardiac monitoring
• Empiric antimicrobial therapy
• Chest physiotherapy

Consultations

• Pulmonologist and/or critical care specialist
• Infectious disease specialist
• Immunologist in cases of known or suspected primary immunodeficiency

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The 2 goals of pharmacologic therapy are eradication of infections and prophylaxis against common pathogens in high-risk patients.

Consult the 2007 Infectious Diseases Society of America (IDSA)/Chest guidelines for optimal care.⁵⁸

• Inpatient, non-ICU treatment
• • Respiratory fluoroquinolone
  • Beta-lactam plus a macrolide
• Inpatient, ICU treatment
• • Beta-lactam plus either azithromycin or fluoroquinolone
  • For Pseudomonas infection, use an antipneumococcal, antipseudomonal beta-lactam plus either ciprofloxacin or levofloxacin (750-mg dose) or beta-lactam plus an aminoglycoside and azithromycin or a beta-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone.
  • For community-acquired methicillin-resistant Staphylococcus aureus infection, add vancomycin or linezolid.

Special considerations

• HIV: Medication choices should be based on CD4 count and should be made in consultation with an infectious disease specialist.
• TB treatment: Initiation of medications for TB rarely occurs in the ED. Infectious disease consultation should be obtained prior to initiating pharmacotherapy for TB in the immunocompromised patient.
• Elderly patients: Moxifloxacin is associated with faster clinical recovery than levofloxacin.⁶²
• Vitamin C: Some evidence suggests that in vitamin C–deficient persons supplementation can lower the risk of pneumonia. Further study is needed; however, it is promising, as it has a low cost and low risk.⁶³
• Cystic fibrosis: Addition of tobramycin to an antipseudomonal semisynthetic penicillin (eg, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin).
• Burn
• • Selective oral decontamination in burn patients has been advocated in some burn centers. Reduced oral carriage of organisms responsible for pulmonary infections is speculated to account for a lower frequency of pneumonias in these patients.⁶⁴
  • Drug pharmacokinetics in burn patients are complex and incompletely understood.⁶⁵ Broadly, treatment can be conceptualized into 2 groups:
  • • First 48-hour acute phase: Protein-rich fluid is lost from intravascular space. This leads to hypovolemia and a drop in cardiac output, which results in tissue hypoperfusion and a fall in renal blood flow.
    • Beyond 48 hours⁵⁶: Complex changes frequently occur in drug metabolism at the level of the liver, and renal function can be variable in these patients.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Tobramycin (Nebcin)
Description	Usually combined with one of the penicillins used to treat pseudomonad infections in patients with cystic fibrosis (CF).
Adult Dose	CF: 3 mg/kg/dose IV q8h
Pediatric Dose	CF: Administer as in adults Aim for peak levels of 10-12 mcg/mL, with trough levels of <2 mcg/mL
Contraindications	Documented hypersensitivity
Interactions	Increases effects of neuromuscular blockers and potentiates effect of extended-spectrum penicillins; concurrent administration with amphotericin B, cephalosporins, and loop diuretics increases risk of nephrotoxicity
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Caution in renal impairment, in preexisting auditory or vestibular impairment, and in neuromuscular disorders; aminoglycosides are associated with nephrotoxicity and ototoxicity

Drug Name	Levofloxacin (Levaquin)
Description	Used to treat community-acquired pneumonia caused by S aureus, S pneumoniae (including penicillin-resistant strains), H influenzae, H parainfluenzae, Klebsiella pneumoniae, M catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae. Fluoroquinolones should be used empirically in patients likely to develop exacerbation due to resistant organisms to other antibiotics. Rapidly becoming a popular choice in pneumonia. This is the L stereoisomer of the D/L parent compound ofloxacin, the D form being inactive. Good monotherapy with extended coverage against Pseudomonas species, as well as excellent activity against pneumococcus. Agent acts by inhibition of DNA gyrase activity. PO form has bioavailability that reportedly is 99%.
Adult Dose	750 mg PO/IV qd for 7-14 d
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Piperacillin and Tazobactam sodium (Zosyn)
Description	Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.
Adult Dose	4.5 g IV q6h for severe infections; adjust for renal function
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis should not be treated with an oral penicillin during the acute stage
Interactions	Tetracyclines may decrease effects of piperacillin; high concentrations of piperacillin may physically inactivate aminoglycosides if administered in same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels; high-dose parenteral penicillins may result in increased risk of bleeding
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Perform CBCs prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT levels during therapy; exercise caution in patients with hepatic insufficiencies; perform urinalysis and BUN and creatinine determinations during therapy, and adjust dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions

Drug Name	Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS, Cotrim, Cotrim DS, Septra, Septra DS)
Description	Inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid; inhibits folic acid synthesis; inhibits of bacterial growth.
Adult Dose	2 tab q8h for 21 d, in patients tolerating PO Alternatively, 15-20 mg/kg/d PO based on TMP
Pediatric Dose	<2 months: Do not administer >2 months: 15-20 mg/kg/d PO based on TMP
Contraindications	Documented hypersensitivity; megaloblastic anemia due to folate deficiency; age <2 mo
Interactions	May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly persons; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Do not use during last trimester of pregnancy due to potential toxicity to newborn (eg, jaundice, hemolytic anemia, kernicterus); discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, chronic alcoholics, elderly persons, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in G-6-PD deficient individuals; AIDS patients may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation Dosage adjustments (adult adjustments) CrCl (mL/min) 80-50: Recommended IV dose q18h CrCl 50-10: Recommended IV dose q24h CrCl <10: Not recommended Hemodialysis: 4-5 mg/kg after HD During peritoneal dialysis: 0.16-0.8 g q48h

Drug Name	Azithromycin (Zithromax)
Description	Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Treats mild-to-moderate microbial infections.
Adult Dose	500 mg IV q24h for 3 d, then 500 mg/d PO for 7-10 d
Pediatric Dose	<6 months: Not established >6 months: Day 1: 10 mg/kg PO once; not to exceed 500 mg/d Days 2-5: 5 mg/kg PO qd; not to exceed 250 mg/d
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function or prolonged QT intervals

Drug Name	Ceftriaxone (Rocephin)
Description	Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin-binding proteins. Exerts antimicrobial effect by interfering with synthesis of peptidoglycan, a major structural component of bacterial cell wall. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested. Highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of dose excreted unchanged in urine, and remainder secreted in bile and ultimately in feces as microbiologically inactive compounds. Reversibly binds to human plasma proteins, and binding has been reported to decrease from 95% bound at plasma concentrations <25 mcg/mL to 85% bound at 300 mcg/mL. Used because of increasing prevalence of penicillinase-producing microorganisms.
Adult Dose	1-2 g IV qd or divided bid depending on type and severity of infection; not to exceed 4 g/d
Pediatric Dose	<7 days: Not established >7 days: 25-50 mg/kg/d IV; not to exceed 125 mg/d Infants and children: 50-75 mg/kg/d IV divided q12h; not to exceed 2 g/d
Contraindications	Documented hypersensitivity; hyperbilirubinemic neonates, particularly those who are premature
Interactions	Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy; caution in breastfeeding women; may displace bilirubin from albumin binding sites increasing the risk of kernicterus; caution with gallbladder, biliary tract, liver, or pancreatic disease or in patients with history of colitis or penicillin hypersensitivity

Drug Name	Vancomycin (Lyphocin, Vancocin, Vancoled)
Description	Classified as glycopeptide agent that has excellent gram-positive coverage, including methicillin-resistant S aureus. To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to next dosing. Use creatinine clearance to adjust dose in patients with renal impairment.
Adult Dose	500 mg IV q6h or 1 g IV q12h; not to exceed 10 mg/min
Pediatric Dose	40 mg/kg/d IV divided tid/qid
Contraindications	Documented hypersensitivity
Interactions	Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in renal failure, neutropenia; red man syndrome is caused by too rapid IV infusion (dose given over a few min) but rarely happens when dose given IV over 2 h administration or as PO or IP administration; red man syndrome is not an allergic reaction

Drug Name	Amikacin (Amikin)
Description	Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in protein synthesis; causes growth inhibition. For gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin. Effective against Pseudomonas aeruginosa. Use patient's IBW for dosage calculation. The same principles of drug monitoring for gentamicin apply to amikacin.
Adult Dose	15 mg/kg/d IV/IM divided bid/tid; not to exceed 1.5 g/d regardless of higher BW Many patient groups are not candidates for single-day dosing methodology including elderly persons, CrCl less than <30, dialysis, pregnancy, endocarditis, cystic fibrosis, ascites, neutropenia, infants, 20% or greater BSA burns, history of hearing loss or vestibular dysfunction, gram-positive positive infections (when aminoglycoside is used for synergy), or mycobacterial infections
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration with other aminoglycosides, penicillins, cephalosporins, and amphotericin B increases nephrotoxicity; enhances effects of neuromuscular blocking agents; causes respiratory depression; irreversible hearing loss may occur with coadministration of loop diuretics
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Not intended for long-term therapy; caution in patients with renal failure (not on dialysis), hypocalcemia, myasthenia gravis, and conditions that depress neuromuscular transmission

Drug Name	Pentamidine (NebuPent, Pentacarinat, Pentam-300)
Description	Inhibits growth of protozoa by blocking oxidative phosphorylation and inhibiting incorporation of nucleic acids into RNA and DNA, causing inhibition of protein and phospholipid synthesis.
Adult Dose	4 mg/kg/d IV qd for 21 d
Pediatric Dose	150 mg/m2 IV qd for 5 d, then 100 mg/m2 IV qd for 16 d
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cidofovir increases risk of nephrotoxicity; concomitant use of foscarnet may decrease serum calcium level; risk of pancreatitis with zalcitabine may be additive; coadministration with other drugs that prolong QT interval (eg, dofetilide) increases risk
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in diabetes mellitus, hypertension or hypotension, hepatic dysfunction, hypoglycemia, leukopenia, and thrombocytopenia

Drug Category: Antimalarial Agents

These agents are active against parasites that cause malaria.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Antiprotozoal Agents

These agents are active against protozoa.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

Immunocompromised patients frequently require inpatient care.

• A Canadian study proposed stratifying these patients into “high-risk” and “low-risk” groups based on the etiology of their immunosuppression. Those in the low-risk group could then be stratified according to the pneumonia severity index (PSI). This application of the PSI has not been validated outside of this study.⁵⁰ 
• A staging system specifically for predicting mortality in HIV-associated pneumonia has been described. This model was developed by using classification tree analysis, and it relies on 3 commonly available clinical variables: neurologic symptoms, respiratory rate more than 25, and serum creatinine level. However, this study has not been subsequently validated in the era of HAART.⁵³

Further Outpatient Care

If outpatient management is possible, arrange for follow-up with a primary care practitioner within 24 hours.

Deterrence/Prevention

• General influenza vaccination recommendations for immunocompromised persons
• • All persons 50 years old or older⁴⁵
  • Women who will be pregnant during influenza season⁴⁵
  • Adults and children who have any condition that can compromise respiratory function or handling of secretions⁴⁵
  • Residents of nursing homes or other long-term care facilities⁴⁵
  • Adults and children who have immunosuppression from medications or from HIV⁴⁵
  • All children aged 6 months to 4 years⁴⁵

Those in close contact to immunocompromised persons should also be vaccinated, as the immunocompromised person may not have a good response to the flu vaccine.⁴⁵ 

• HIV
• • MAC - Weekly azithromycin or daily clarithromycin for patients with CD4 count less than 50⁶⁶
  • Histoplasmosis - Persons at high risk because of occupational exposure or those who live in a community with a hyperendemic rate are recommended to consider prophylaxis with itraconazole for CD4 counts less than 100.⁶⁷
  • PCP - Prophylaxis recommendations are different for children younger than 1 year who have HIV; these recommendations are not based on CD4 count.^{68, 69, 70} In HIV-infected patients on HAART, PCP prophylaxis can be safely discontinued after the CD4 count has increased to more than 200 for more than 3 months.⁷¹
• Cystic fibrosis - Chronic therapy with azithromycin for those who were clinically infected with Pseudomonas⁷²
• Autoimmune diseases
• • SLE -  Pneumococcal and influenza vaccines are recommended.
  • Rheumatoid arthritis -  Pneumococcal vaccine is recommended for patients with rheumatoid arthritis. The vaccine does not appear to trigger exacerbations of rheumatoid arthritis, and it induces adequate humoral response to pneumococcus.⁷³ Influenza vaccination is recommended for patients with rheumatoid arthritis.
• High-risk infants and children - Children and infants at risk of RSV infection include those younger than 24 months with chronic lung disease who have required medical therapy within 6 months of RSV season onset, preterm infants born prior to 32 weeks’ gestation, preterm infants born 32-35 weeks’ gestation with at least 2 additional risk factors, and those with hemodynamically significant heart disease. These patients should be considered for immune prophylaxis.³¹
• Chemotherapy -  American Society of Clinical Oncology has guidelines on the use of hematopoietic colony-stimulating factors. These chemotherapy regimens have decreased the incidence of febrile neutropenia by more than 40%; however, the guidelines are still controversial. The use of colony-stimulating factors should be made in collaboration with the patient’s treating oncologist and will rarely be indicated in the emergency department. The Infectious Disease Society of America has guidelines on use of antimicrobial medications in neutropenic patients with cancer.
• Pneumococcal vaccination -  A Cochrane Database of Systematic Reviews article indicates pneumococcal vaccination does not reduce deaths or hospitalizations from streptococcus; however, there could be a benefit to those at greatest risk of serious infection.⁷⁴

Complications

• Pneumothorax
• Hypoglycemia (may occur with pentamidine)
• Respiratory failure/ventilatory dependence
• Acute respiratory distress syndrome
• Superinfection
• Pleural effusion
• Empyema
• Death

Prognosis

The prognosis varies depending on the etiology and the degree of immunosuppression.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

Immunocompromised patients are by definition high-risk. Proper documentation of medical decision-making is essential to reduce liability.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Christopher MB Fernandes, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clini