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Pneumocystis pneumonia

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Pneumocystis Pneumonia

I. What every physician needs to know

Pneumocystis pneumonia (PCP) is associated with advanced HIV disease (CD4<200), malignancy, rheumatologic or inflammatory conditions, and other forms of immunosuppression.

HIV-associated PCP is by the most common manifestation seen within the United States. For this article, the assumption is made that the patient is HIV-positive unless clarification is given otherwise (although it is also seen in any patient with cell-immunity deficiencies such as solid organ or hematopoietic stem cell tranplants, or any patients taking immunosuppressive drugs).

The organism is historically referred to as Pneumocystis carinii, but more recent taxonomy have identified it as Pneumocystis jirovecii. However, many clinicans will still use the terms interchangably.

Diagnosis begins by identifying a susceptible host with respiratory symptoms, fever, and an abnormal CXR. Extrapulmonary Pneumocystis can also occur, but this is more likely to occur in HIV patients receiving aerosolized pentamidine for prophylaxis.

Debate exists about acquisition and transmission of the disease.

II. Diagnostic Confirmation: Are you sure your patient has Pneumocystis Pneumonia?

See Figure 1 for the diagnosis and workup of a patient with suspected PCP.

Figure 1.

Algorithm for the diagnostic evaluation and management of patients with suspected pneumocystis pneumonia.

Please note that the duration of therapy is suggested to be 14 days in non-HIV patients.

Definitive diagnosis of PCP requires documentation of the organism from a respiratory specimen.

Samples are obtained via either induced sputum (specificity 100%, sensitivity 55-92%) or BAL (sensitivity/specificity 97-100%). Immunofluorescence can increase sensitivity/specificity of sputum induction to 95 and 100% respectively.

PCP prophylaxis (especially inhaled pentamidine) decreases the sensitivity of both tests to ~62%. However, transbronchial biopsy can increase the sensitivity to 100% (although this increases the risk for complications).

Beta-D-glucan levels >80 pg/mL in one study correlate well with a diagnosis of PCP. PCP-positive patients had median levels of 408 pg/mL versus 37 pg/mL in PCP-negative patients. The sensitivity of beta-D-glucan for the diagnosis of PCP was 92% and the specificity was 65%.

Endotracheal aspirates have a good degree of sensitivity of ~92%. Transthoracic biopsies have a very high degree of sensitivity, but has a high incidence of pneumothorax and other less invasive techniques can be used instead.

PCR is a highly sensitive technique currently under investigation for routine use. It may be useful in diagnosis for patients negative on conventional testing or for a screening technique on oral samples (90% sensitivity in one trial).

A. History Part I: Pattern Recognition

The major presenting symptoms are shortness of breath (95%), fever (79-100%), and a nonproductive cough (95%).

Some patients may have sputum production (as much as 30%) or more uncommonly hemoptysis. Patients receiving immunosuppressive drugs may have a delay of 1-2 weeks after steroids taper before symptoms occur.

Other nonspecific symptoms include fatigue, chills, chest pain, and weight loss. About 7% of patients are asymptomatic.

Patients receiving aerosolized pentamidine for PCP prophylaxis are more likely to have atypical and extrapulmonary disease ranging from asymptomatic to multisystem organ dysfunction.

In both AIDS and non-AIDS patients, the clinical picture is quite variable. Disease symptoms can develop subtlely in HIV patients over anywhere from weeks to months.

Symptoms in non-HIV patients tend to be somewhat more fulminant and acute.

Common physical exam findings include fever (84% of patients), tachypnea (62%), and tachycardia. However, the lung exam usually cannot make a specific diagnosis. While crackles are heard in ~33% of patients, a normal exam occurs in 50% of patients.

The classic description of the CXR are bilateral diffuse infiltrates extending from the perihilar region. See Figure 2.

Figure 2.

"Classic" CXR pattern seen in Pneumocystis pneumonia.

However, many kinds of abnormalities (unilateral infiltrates, nodules, cavities, pneumatoceles, lymphadenopathy, and effusions) or lack thereof (~25% of patients have a "normal" CXR) have been seen.

If the CXR is normal, consider obtaining a high-resolution CT (HRCT) of the chest to look for ground glass opacities (GGO). A HRCT has both high sensitivity (100%) and specificity (89%) when patchy or nodular GGO are seen. A negative HRCT may help exclude PCP. See Figure 3.

Figure 3.

CT chest with ground opacities.

Hypoxemia is the most frequent lab abnormality found in PCP.

Calculating the A-a gradient can evaluate disease severity and monitor progression (the ABG's pO2 will also determine treatment).

A high LDH is common and improves with therapy. However, this test is non-specific and so its clinical utility is limited.

B. History Part 2: Prevalence

As mentioned previously, patients who are immunosuppressed and especially HIV-infected patients with CD4 counts of <200 are most at risk for this illness. Other factors include a CD4 percentage of <14%, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and a higher HIV viral load. In patients without HIV, systemic steroid use, malignancy, organ transplantation, inflammatory conditions (such as Wegener's & polymyositis/dermatomyositis), and other defects in cell-mediated immunity put patients at a greater risk.

Patients receiving HAART therapy and PCP prophylaxis have been shown to have significantly lower rates of Pneumocystis than those who do not.

C. History Part 3: Competing diagnoses that can mimic Pneumocystis Pneumonia

This is not an exhaustive list because any patient who is immunocompromised can have any number of competing diagnoses.

  • Community-acquired pneumonia

  • Other fungal pheumonias

  • CMV pneumonia

  • Nocardia infections

  • TB

  • Pulmonary embolus

D. Physical Examination Findings

Common physical exam findings include fever (84% of patients), tachypnea (62%), and tachycardia in acutely ill patients. However, the lung exam usually cannot make a specific diagnosis. While rales are heard in ~33% of patients, a normal exam occurs in 50% of patients.

E. What diagnostic tests should be performed?

1. Obtain CXR and if normal, consider HRCT of the chest.

The classic description of the CXR are bilateral diffuse infiltrates extending from the perihilar region. See Figure 2. However, many kinds of abnormalities (unilateral infiltrates, nodules, cavities, pneumatoceles, lymphadenopathy, and effusions) or lack thereof (~25% of patients have a "normal" CXR) have been seen.

HRCT of the chest may reveal ground glass opacities (GGO). A HRCT has both high sensitivity (100%) and specificity (89%) when patchy or nodular GGO are seen. A negative HRCT may help exclude PCP. See Figure 3.

2. A definitive diagnosis of PCP requires documentation of the organism from a respiratory specimen.

Respiratory samples can be obtained via either induced sputum (specificity 100%, sensitivity 55-92%) or BAL. Immunofluorescence can increase sensitivity/specificity of induced sputum to 95 and 100% respectively.

Polymerase chain reaction (PCR) assays can also be used on induced sputum, BAL fluid, blood, or nasopharyngeal aspirates, which may be particularly useful in non-HIV infected patients who usually have lower sensitivity with conventional testing.

PCP prophylaxis (especially inhaled pentamidine) decreases the sensitivity both tests to ~62%. However, transbronchial biopsy can increase the sensitivity to 100% (although this increases the risk for complications).

3. Consider transbronchial biopsy if initial samples are negative and there is still a high suspicion for PCP.

A study in the mid-1990's showed that patients treated empirically for PCP had higher mortality than patients where a specific diagnosis was made by bronchoscopy. Empiric therapy may hinder finding a specific etiology at a later time or could have harmful consequences.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

1. Obtain an ABG and LDH, alongside the usual basic lab work.

Hypoxemia is the most frequent lab abnormality found in PCP. Calculating the A-a gradient can evaluate disease severity and monitor progression (the ABG's pO2 will also determine treatment).

A high LDH is common and improves with therapy. However, this test is non-specific and so its clinical utility is limited.

2. If the patient is HIV-positive, a CD4 count should also be taken if the patient has not had one in the last 3-4 months. This does not affect the management of PCP as much as determining what sort of prophylaxis the patient will need on discharge (azithromycin if CD4<50 for instance).

3. Definitive diagnosis of PCP requires documentation of the organism from a respiratory specimen. Respiratory samples are obtained via either induced sputum (specificity 100%, sensitivity 55-92%) or BAL (sensitivity/specificity 97-100%). Immunofluorescence can increase sensitivity/specificity of sputum induction to 95 and 100% respectively.

PCP prophylaxis (especially inhaled pentamidine) decreases the sensitivity of both tests to ~62%. However, transbronchial biopsy can increase the sensitivity to 100% (although this increases the risk for complications).

Polymerase chain reaction (PCR) assays can also be used on induced sputum, BAL fluid, blood, or nasopharyngeal aspirates, which may be particularly useful in non-HIV infected patients who usually have lower sensitivity with conventional testing.

See Figure 1 for the diagnosis and workup of a patient with suspected PCP. Please note that the duration of therapy is suggested to be 14 days in non-HIV patients.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

1. Obtain a CXR. The classic description of the CXR are bilateral diffuse infiltrates extending from the perihilar region. See Figure 2.

However, many kinds of abnormalities (unilateral infiltrates, nodules, cavities, pneumatoceles, lymphadenopathy, and effusions) or lack thereof (~25% of patients have a "normal" CXR) have been seen.

2. Consider HRCT of the chest if the CXR is normal, to look for ground glass opacities GGO). A HRCT has both high sensitivity (100%) and specificity (89%) when patchy or nodular GGO are seen. A negative HRCT may help exclude PCP. See Figure 3.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis

This is probably not applicable in the sense that making a diagnosis of pneumonia in an immunocompromised patient requires a fairly broad approach. As always, one wants to avoid any unnecessary tests once a diagnosis is made and avoid unnecessary radiographic tests because of radiation exposure for the patient.

III. Default Management

A definitive microbiologic diagnosis should be attempted instead of simply starting empiric therapy.

If treatment is warranted, start therapy depending on whether the patient has mild-moderate disease versus moderate-severe disease.

If moderate to severe defined as PaO2 <70 mmHg at room air or A-a gradient ≥35:

i. Preferred therapy: TMP 15-20 mg/kg per day and SMX 75-100 mg/kg per day divided q8 or q6 either IV or PO (Bactrim DS (double strength) 2 tabs PO q8).

ii. Pentamidine IV 4 mg/kg q24; avoid aerosolized pentamidine for treatment (it should be used only for prophylaxis and even then other agents are preferred).

iii. Clindamycin-primaquine: Clindamycin 450 mg PO q6 or 600 mg PO q8 (or 900 mg IV q8 or 600 mg IV q6) with primaquine base 30 mg PO q24. Test for G6PD deficiency because of primaquine.

PLUS

iv. Prednisone 40 mg PO bid x 5 days, then 40 mg PO q24 x 5 days, then 20 mg PO q24 x 11 days. IV methylprednisolone at 75% of prednisone dose if unable to take PO.

If the patient as mild to moderate disease PaO2 ≥70 mmHg at room air or A-a gradient <35:

a. TMP 15-20 mg/kg per day and SMX 75-100 mg/kg per day divided q8 or q6 either IV or PO (Bactrim DS (double strength) 2 tabs PO q8). Preferred therapy.

b. TMP-dapsone: TMP 15 mg/kg (to the nearest 100mg) q8 with dapsone 100 mg PO q24. Test for G6PD deficiency because of dapsone.

c. Clindamycin-primaquine: Clindamycin 450 mg PO q6 or 600 mg PO q8 (or 900 mg IV q8 or 600 mg IV q6) with primaquine base 30 mg PO q24. Test for G6PD deficiency because of primaquine.

d. Atovaquone 750 mg PO bid with meals.

Since TMP-SMX, TMP-dapsone, and clindamycin-primaquine are well absorbed orally and obtain good levels in the blood and lung, the IV version should be used only in patients who are seriously ill (A-a gradient >45, potential for respiratory failure) or have significant GI problems.

Patient may clinically worsen for the first 2-3 days.

If patients do not improve after ~4-8 days of therapy, consider changing to IV therapy.

If on oral Bactrim, change to IV Bactrim. If already on IV Bactrim, change to pentamidine. If on pentamidine, consider rechallenge with Bactrim as long as the patient did not have a life threatening event.

Consult ID and consider starting HAART in HIV infected patients. Early HAART (within 2 weeks) in patients with AIDS and an opportunistic infection (OI) is associated with lower mortality.

Treatment should be for 21 days in HIV patients and 14 days in non-HIV patients.

A. Immediate management

Please see above.

Make a clinical judgment for whether the patient needs ICU care and intubation or can be managed on a medicine/telemetry floor.

B. Physical Examination Tips to Guide Management

Improved shortness of breath, tachypnea, and fever should occur over time.

Patients may initially clinically deteriorate in the first 2-3 days. If the patient does not improve after 4-8 days, consider changing therapy to IV or use an alternative drug (see default management).

The physical exam may not help much if it was initially unremarkable. If the patient had rales initially, these should improve over time.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management

One should note the patient's overall respiratory status.

Serial ABGs will show improvement in the A-a gradient.

TMP-SMX: BMP, CBC, LFT.

Dapsone or primaquine: G6PD level, CBC, ABG.

Pentamidine: BMP, LFT.

D. Long-term management

Early HAART (within 2 weeks) in patients with AIDS and an OI is associated with lower mortality. The need to be on HAART therapy and be adherent with medications should be stressed. HAART therapy should be coordinated with an ID specialist.

After the patient has completed therapy, Bactrim prophylaxis is preferred. Dosing is 1 DS tab q24 or qMWF. An alternative is 1 SS (single strength) tab q24.

Alternative therapies:

Atovaquone 1500 mg PO q24

Dapsone 50 mg PO q12 or 100 mg PO q24

Aerosolized pentamidine 300mg inhaled q month

Prophylaxis therapy can be stopped if the CD4 count >200 for more than 3 months (however, this would be determined by the patient's outpatient ID specialist).

E. Common Pitfalls and Side Effects of Management

TMP-SMX: rash, fever, GI intolerance, hepatotoxicity, hyperkalemia, and bone marrow suppression.

Ensure that dosing of Bactrim is sufficient as the dosing is higher than what many clinicians use for treatment of CA-MRSA skin infections.

Note that the patient may still be able to take TMP-SMX for prophylaxis even if patient has symptoms on treatment doses unless anaphylaxis or SJS type reaction. Many of the side effects are dose dependent.

Dapsone: Rash, fever, lymphadenopathy, transaminitis, and gastrointestinal upset. Check for G6PD deficiency. Bone marrow suppression and methemoglobinemia can occur.

Clindamycin-primaquine: Clindamycin can cause rash, diarrhea, and C diff diarrhea. Primaquine can cause methemoglobinemia, rash, hemolytic anemia, leukopenia, nausea, and vomiting. Check for G6PD deficiency.

Atovaquone: GI disturbances, rash, and transaminitis.

Pentamidine: hypotension, cardiac arrhythmias (e.g., Torsades de Pointes), azotemia, pancreatitis, hyper/hypokalemia, hypomagnesemia, hypocalcemia, neutropenia, hepatitis, bronchospasm, hyper/hypoglycemia, and nephrotoxicity.

Periodic BMP, CBC, and LFTs should be checked.

IV. Management with Co-Morbidities

Caution with renal insufficiency if using TMP-SMX, TMP plus dapsone (because of the TMP), or pentamidine.

A. Renal Insufficiency

Dose adjustment is required for TMP-SMX, TMP plus dapsone (because of the TMP), and pentamidine depending on renal insufficiency.

Pentamidine must also be dose adjusted if creatinine clearance is <10.

B. Liver Insufficiency

No significant recommendations other than watch for transaminitis with high dose TMP-SMX.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

Start HAART therapy as soon as possible if HIV is underlying immunosuppressive state.

H. Primary Lung Disease (COPD, Asthma, ILD)

Patient with lower threshold for sending to ICU.

I. Gastrointestinal or Nutrition Issues

Higher consideration for IV therapy if patient with poor GI absorption.

J. Hematologic or Coagulation Issues

Avoid dapsone and primaquine in G6PD deficient patients.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized

If the patient has signs of worsening respiratory distress, perform an ABG and calculate A-a gradient alongside clinical evaluation. Determine if the patient requires ICU observation or intubation.

B. Anticipated Length of Stay

Variable depending on patient's clinical improvement.

C. When is the Patient Ready for Discharge?

Able to take oral medications, no significant hypoxemia.

D. Arranging for Clinic Follow-up

For HIV patients, ensuring follow up is vital for management of PCP as well as starting HAART therapy, which will prevent future OIs as the CD4 count improves.

1. When should clinic follow up be arranged and with whom?

ID follow up within 2 weeks.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

HIV patients not on HAART therapy should have an HIV genotype performed, but this should be coordinated with the ID physician (the ID physician may opt to have it performed at the office follow up).

Consider giving influenza and pneumococcal vaccine.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

HIV patients not on HAART therapy should have an HIV genotype performed, but this should be coordinated with the ID physician (the ID physician may opt to have it performed at the office follow up).

Toxoplasma IgM/IgG, CMV IgM/IgG, Hepatitis A total antibody, Hep B surface Ag, Hep B surface antibody, Hep C Ab, HIV viral load.

E. Placement Considerations

Patients can generally be discharged home unless the patient has become significantly deconditioned.

F. Prognosis and Patient Counseling

Non-HIV PCP patients have ~35-50% mortality compared to 10-20% mortality in HIV patients.

Severe PCP and a high APACHE III score are also associated with higher mortality.

If the patient is HIV-positive, emphasize the need to follow up and become adherent with medications both for HIV and PCP.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission

If the patient is HIV-positive with a CD4 <50, ensure that the patient is on MAC prophylaxis (Azithromycin 1200 mg po qweek or other alternative if allergic).

VII. What's the evidence?

"Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medical Association of the Infectious Diseases Society of America". http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.

Ponce, CA, Gallo, M, Bustamante, R, Vargas, SL. "Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population". Clinical Infectious Diseases. vol. 50. 2010. pp. 347.

Sax, PE, Komarow, L, Finkelman, MA, Grant, PM. "AIDS Clinical Trials Group Study A5164 Team. Blood (1->3)-beta-D-glucan as a diagnostic test for HIV-related Pneumocystis jirovecii pneumonia". Clinical Infectious Diseases.. vol. 53. 2011 Jul. pp. 197-202.

Stringer, JR, Beard, CB, Miller, RF, Wakefield, AE. "A new name (Pneumocystis jiroveci) for Pneumocystis from humans". Emerging Infectious Diseases. vol. 8. 2002. pp. 891.

Walzer, PD, Smulian, AG, Bennett, Dolin. "Pneumocystis species. Mandell". Principles and Practice of Infectious Diseases 6th ed. Churchill Livingstone. 2004. pp. 975-1022.

Zolopa, A, Andersen, J, Powderly, W. "Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial". PLoS ONE. vol. 4. 2009. pp. e5575.

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