Pneumocystis species

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Pneumocystis? What should you expect to find?

Overview:

• The disease entity commonly called “PCP” is caused by Pneumocystis jiroveci. Formerly, this disease was thought to be caused by a different species, P. carinii, which lead to the acronym “PCP” to describe the pneumonia observed in infected patients. However, molecular studies have since shown that the human pathogen is actually P. jiroveci, and P. carinii is a rodent pathogen. However, the acronym PCP can be and is still used, and can now be considered to stand for “Pneumocystis pneumonia.”

• Formerly thought to be a protozoan, molecular studies clearly show that Pneumocystis is a unicellular fungus.

• However, Pneumocystis does not respond to antifungal agents.

• It is an opportunistic pathogen, and is seen in persons with depressed cell-mediated immunity.

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• It is important to recognize severe disease defined as a partial pressure of oxygen in the blood (PaO₂) of less than 70mm Hg or an A-a gradient greater than 35, because the treatment differs for these patients if they are also human immunodeficiency virus (HIV)-infected.

Key symptoms in HIV-infected patients:

• subacute onset of a nonproductive cough

• progressive exertional dyspnea

• fever

Key symptoms in non-HIV patients, including those on steroids and other immunosuppressive agents, with primary immunodeficiencies, hematologic/nonhematologic malignancies and those who are severely malnourished:

• acute onset of nonproductive cough, dyspnea, and fever

• in those on steroids, symptoms often occur during the taper

• lung allograft recipients may be asymptomatic

Key physical findings in all patients:

• tachypnea and tachycardia are noted in most patients

• approximately of adult patients will have fine “cellophane” rales

• a minority of adults will have frank cyanosis; more often observed in children

How did the patient develop Pneumocystis pneumonia? What was the primary source from which the infection spread?

• Pneumocystis jiroveci is a ubiquitous unicellular fungus acquired by the airborne route, and is found in the lungs of approximately 20 to 40% healthy persons but does not cause disease unless immunity wanes; hence it is considered to be an opportunistic pathogen.

• In some patients, disease occurs as a result of activation of a previously controlled infection/colonization.

• Outbreak studies suggest person-to-person transmission also is possible.

• Anyone with compromised cellular immunity is at risk for developing PCP.

Which individuals are of greater risk of developing Pneumocystis pneumonia?

Specific conditions that predispose patients to PCP:

• HIV infection, particularly as the CD4 count drops below 200

• chronic steroid use for any reason, including chronic obstructive pulmonary disease (COPD)

• immunosuppressive medications for any reason, including transplant recipients, patients with vasculitides/connective tissue disorders, or those undergoing cancer chemotherapy

• malignancy (both hematologic and nonhematologic) is associated with PCP even when antineoplastic agents have not been administered

• primary immunodeficiencies affecting the cellular arm of immunity; i.e. severe-combined immunodeficiency and the hyper immunoglobulin M/CD40 ligand/CD40-deficiency syndromes

• protein malnutrition

• prematurity

• smoking

With the recognition that prophylaxis against PCP is necessary in many immunosuppressed patients, including HIV patients, the incidence of disease has fallen greatly since its resurgence in the 1980s when the acquired immunodeficiency syndrome (AIDS) epidemic began. Nonetheless, the majority of PCP occurs in HIV-infected patients who are unaware of their status or who are noncompliant with prophylaxis.

Beware: there are other diseases that can mimic Pneumocystis pneumonia:

Infectious:

• atypical pneumonias due to Mycoplasma, Legionella, Cytomegalovirus, and viruses

• Mycobacterium tuberculosis

• M. avium complex

Noninfectious:

• acute respiratory distress syndrome

• pulmonary embolism (usually multiple emboli)

• lymphocytic interstitial pneumonia

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

• An elevated lactate dehydrogenase (LDH) level is a nonspecific marker of lung damage often seen in PCP.

• Hypoxemia (PaO₂ ≤70mm Hg or O₂ saturation <90%) and/or an increased A-a gradient is characteristically found.

• Pulmonary function tests may reveal a decreased diffusion capacity of carbon monoxide; when it is less than 75% of predicted, the sensitivity is greater than 90%, but the specificity is low (approximately 50%).

• The peripheral white blood cell (WBC) count/differential is not helpful

Results that confirm the diagnosis

• Histopathologic demonstration of P. jiroveci organisms in tissue or a bronchoalveolar lavage (BAL) is required for the diagnosis of PCP.

• Tissue samples obtained by transbronchial or open lung biopsy have the highest sensitivity, but such an invasive approach is not a feasible approach for most patients.

• Bronchoscopy to obtain BAL specimens is a reasonable alternative, with a sensitivity approaching 90% when multiple lobes are sampled.

• The sensitivity of BAL is decreased in patients receiving aerosolized pentamidine, so biopsy may be required to make the diagnosis.

• The sensitivity of finding organisms in induced sputum is variable, ranging from 50 to 90%; therefore, a negative result does not rule out the diagnosis. The specificity, however, is very high at 99%.

What imaging studies will be helpful in making or excluding the diagnosis of Pneumocystis pneumonia?

• A chest X-ray (CXR, $) should be performed first. While no particular lung finding is pathognomonic, diffuse, patchy infiltrates extending out from the perihilar area is a common pattern. In patients with a clinically compatible syndrome and an abnormal CXR, no further imaging is required.

• In patients who received aerosolized pentamidine for prophylaxis, patchy infiltrates in the apices only may be seen.

• If the CXR is normal but the clinical suspicion remains high, high resolution chest computed tomography (CT, $$) provides a high sensitivity for the diagnosis of PCP when the characteristic finding of patchy, ground glass opacities is seen. A normal or unchanged CXR and a CT lacking ground glass opacities strongly militates against a diagnosis of PCP.

• While a gallium scan ($$) is very sensitive for the diagnosis of PCP (approaching 100%), its poor specificity (20–30%) and time delay limit its clinical usefulness.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has Pneumocystis pneumonia, what therapies should you initiate immediately?

Patients suspected of having or diagnosed with PCP should be evaluated by:

• an infectious disease specialist, since underlying HIV infection is common in these patients

• a pulmonologist should be consulted if the diagnosis is in doubt, so that a BAL or other invasive study can be done

Key principles of therapy:

• Even though P. jiroveci is a fungus, it does not respond to antifungal agents

• Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred treatment for all severities of PCP, including in pregnancy, and should be given intravenously in severe cases.

• If a patient develops a mild rash or low-grade fever while on TMP-SMX, supportive treatment with antihistamines and antipyretics should be attempted before changing therapy, since TMP-SMX is the preferred treatment for PCP.

• TMP-SMX must be adjusted in renal insufficiency (Table I).

• The usual course is 21 days in HIV patients and 14 days in all others; this is because the organism burden in HIV-infected patients is usually much higher than in non-HIV infected patients.

• For HIV patients: severe PCP, defined as a PaO₂ of less than 70mm Hg or an A-a gradient greater than 35, also requires adjunctive corticosteroids, which should be started within 72 hours of anti-PCP treatment. The lower organism burden in non-HIV infected patients provokes less inflammation when antimicrobial therapy is begun, thereby obviating the need for corticosteroids in most cases.

• For patients with mild to moderate disease and with a sulfa allergy, TMP with dapsone is an acceptable regimen once glucose-6-phosphate dehydrogenase (G-6-PD) deficiency has been ruled out.

• For patients with moderate to severe disease or who are both sulfa allergic and G-6-PD deficient, clindamycin and primaquine has similar efficacy to TMP-SMX.

• Intravenous pentamidine is about as effective as TMP-SMX but its use is limited by toxicity (nephrotoxicity, arrhythmias, and metabolic disturbances).

• Atovaquone is inferior TMP-SMX for the treatment of PCP and should only be used for mild to moderate disease if no other options exist; it should not be used for the treatment of severe PCP (although atovaquone is used for prophylaxis).

• Aerosolized pentamidine is inferior to TMP-SMX and should not be used for the treatment of PCP.

• Trimetrexate is no longer available; it was found to be inferior to TMP-SMX.

Table I.n

Pregnancy categories:

• TMP-SMX, atovaquone, primaquine, and dapsone are Category C.

• Clindamycin is Category B.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

If there is a clinical suspicion of PCP, treatment should not be delayed; TMP-SMX, if possible, should be initiated immediately while the work-up for PCP ensues.

Treatment options are summarized in Table I.

2. Other key therapeutic modalities

• For HIV-infected patients with moderate to severe PCP (PaO₂<70mm Hg and A-a gradient >35), corticosteroids should be started within 72 hours of the first dose of anti-PCP medication to prevent an overwhelming inflammatory response to dying organisms.

• Corticosteroids are not usually necessary in non-HIV infected patients as they usually have a much lower organism burden than HIV-infected patients.

What complications could arise as a consequence of Pneumocystis pneumonia?

What should you tell the family about the patient's prognosis?

• Most patients with mild PCP recover fully, but those who remain immunosuppressed are at risk for recurrent disease and may warrant prophylaxis.

• Prognosis is directly related to the degree of hypoxemia on presentation; those who present with an A-a gradient greater than 45 have a worse prognosis, with mortality exceeding 50%.

• In HIV-infected patients, other poor prognostic markers include:

  second episode of PCP

  age less than 60 years

  biopsy-proven interstitial fibrosis

  extensive infiltrates on CXR

  elevated neutrophils and/or interleukin-8 in BAL specimens

  serum LDH less than 500

  decreased serum albumin

  pulmonary cytomegalovirus or human herpes virus (HHV)-8 infection

• In non-HIV infected patients, prior lung damage is an additional poor prognostic marker

• Untreated patients develop fatal respiratory failure; therefore prompt diagnosis and treatment is essential

Immune reconstitution inflammatory syndrome

• Immune reconstitution inflammatory syndrome (IRIS) occurs when an HIV-infected patient’s immune system begins to recover secondary to highly active antiretroviral therapy (HAART), or when immunosuppressive therapy is diminished in non-HIV infected patients.

• The mechanism can be:

  reaction to viable Pneumocystis organisms—these patients require treatment for PCP

  reaction to residual Pneumocystis organisms from past, cured disease—these patients require transient immunosuppression (prednisone, usually) until the immune system is able to remove the proinflammatory, residual antigens

• The distinction between these two mechanisms is not always straightforward, but the occurrence of fever, cough, and dyspnea in a patient whose immune system is recovering and has not been treated for PCP in the past should raise suspicion for the disease.

• In contrast, a patient with fever, cough, and dyspnea who is on prophylaxis for prior PCP may be suffering from IRIS due to residual Pneumocystis antigens rather than recurrent disease.

• In both situations, the patient requires close clinical monitoring so that steroids or PCP treatment is initiated should symptoms worsen.

• Other complications are primarily related to medical therapy:

  atovaquone: diarrhea, rash, vomiting, headache, hyponatremia, hyperglycemia

  clindamycin: diarrhea, pseudomembranous colitis (due to Clostridium difficile infection), rash

  dapsone: methemoglobinemia and hemolytic anemia particularly in G-6-PD-deficient patients; neutropenia, rash, liver function test elevation/hepatotoxicity, hyperkalemia, peripheral neuropathy, fever

  pentamidine

  intravenous: nephrotoxicity, infusion-related hypotension, cardiac arrhythmia, pancreatitis/diabetes, hypoglycemia, hepatitis, deranged electrolytes

  aerosolized: bronchospasm, cough, dyspnea, taste dysgeusia (metallic), pneumothorax

  primaquine: methemoglobinemia and hemolytic anemia particularly in G-6-PD-deficient patients, nausea, vomiting, abdominal cramping

  pyrimethamine: pancytopenia, rash

  TMP-SMX: rash, Stevens–Johnson syndrome, bone marrow suppression, renal insufficiency, hepatotoxicity, hyperkalemia

What-if scenario:

• If the patient has progressive disease despite 4 to 5 days of TMP-SMX therapy, treatment should be changed to clindamycin/primaquine or pentamidine. In addition, consideration of dual infection should be considered, including Cytomegalovirus and HHV-8 (the agent of Kaposi sarcoma).

• Extrapulmonary Pneumocystis infection is unusual but when it occurs, involved sites include:

  lymph nodes

  gastrointestinal tract

  reticuloendothelial system (pancytopenia, hepatosplenomegaly)

  eyes (retinal cotton wool spots)

  thyroid and adrenal glands (gland enlargement results)

  kidneys

• Biopsy of affected sites may yield a foamy eosinophilic material and possibly Pneumocystis organisms.

How do you contract Pneumocystis pneumonia and how frequent is this disease?

• P. jiroveci is a ubiquitous fungus, and humoral studies show that approximately 67% of children have been exposed by age 4 years. However, it is not clear that it causes illness in otherwise healthy children.

• Analyses of case clusters suggest that Pneumocystis is spread via the airborne route.

• Disease is therefore due to new infection or reactivation of a previously controlled infection when cell-mediated immunity wanes.

• Before the era of HAART, greater than 70% of HIV-infected patients developed PCP; however, now the rate is less than 3 cases per 100 person years. Nonetheless, PCP is still the most common opportunistic infection in HIV-infected patients.

There is no seasonal variation.

PCP is the most common opportunistic infection in HIV-infected patients, and is an AIDS-defining illness.

Pneumocystis is spread by the airborne route. However, there is not sufficient evidence to recommend as standard practice the isolation of PCP patients from persons at risk for PCP.

Pneumocystis is not thought to be transmitted zoonotically.

What pathogens are responsible for this disease?

P. jiroveci is the Pneumocystis species that is responsible for human infections. Previously, it was thought that P. carinii was the agent of human disease, but molecular studies have clearly shown that P. carinii is a rodent pathogen, not a human pathogen.

How does this pathogen cause Pneumocystis pneumonia?

• In normal hosts, the presence of Pneumocystis organisms triggers the release of proinflammatory cytokines and the activation of alveolar macrophages, leading to clearance of the organisms and absence of disease.

• In the lungs of immunocompromised hosts, alveolar macrophages do not become properly activated by CD4 cells, allowing P. jiroveci organisms to proliferate unchecked.

• Their numbers can reach high levels such that the organisms fill the alveolar lumen in addition to a foamy, eosinophilic exudate that stains well with a Papanicolaou stain (although the organisms themselves don’t stain well with this).

• As this process continues, hyaline membranes form and interstitial fibrosis occurs.

• Consequent to these changes, compliance decreases, the diffusion capacity becomes impaired, and dyspnea and hypoxemia ensue.

• Occasionally, atypical responses occur and lead to cavitation, calcification, and granuloma formation.

• In the absence of proper treatment, lung damage continues until respiratory failure and death occurs.

What other clinical manifestations may help me to diagnose and manage Pneumocystis pneumonia?

Presentation:

• Although the organism burden is lower in non-HIV infected patients, this population tends to have a more fulminant presentation and comes to clinical attention after 1 or 2 weeks of illness, often in the setting of a prednisone taper.

• An exception to the above is lung transplant recipients; these patients are often asymptomatic when diagnosed, so the clinician must actively seek the diagnosis in these patients.

• HIV-infected patients usually have a much higher organism load but have a more indolent presentation until their respiratory capacity becomes severely compromised.

• For both populations, a nonproductive cough, dyspnea, and fever are the most common symptoms.

• A minority of patients may develop hemoptysis or chest pain

Physical exam:

• fever

• tachypnea

• tachycardia

• normal lung exam in majority of patients; fine “cellophane” rales in approximately one third of adults

What other additional laboratory studies may be ordered?

• Polymerase chain reaction is currently investigational and so is not recommended for diagnostic purposes at this time.

• Several stains can be used to identify P. jiroveciin patient samples but also stain other fungi:

  methenamine silver, toluidine blue, cresyl violet–stains the wall of organisms

  Wright–Giemsa stain stains the organism as well as host cells

  calcofluor white stains P. jiroveciwell

• Immunofluorescence using monoclonal antibodies against P. jiroveci is the most widely used technique to definitively identify P. jiroveci.

How can Pneumocystis pneumonia be prevented?

• Although smoking cessation cannot prevent disease, smoking does lead to more severe disease.

• Strong evidence exists for the prophylaxis recommendations for HIV-infected patients shown in Table II.

• For other immunosuppressed populations, the recommendations in Table II are based on expert opinions since there are no published guidelines.

• If an HIV-infected patient developed PCP while the CD4 count was greater than or equal to 200 cells/uL, they should receive prophylaxis for life, even if the CD4 count eventually rises to greater than 200 for >3 months.

• May consider prophylaxis for a CD4 percentage less than 14 or a history of other AIDS-defining illness.

• Pyrimethamine plus sulfadoxine is rarely used for prophylaxis because of its potential for severe cutaneous reactions included Stevens–Johnson syndrome.

• The following regimens have been shown to be inferior and should not be used: oral clindamycin plus primaquine; intermittent intravenous pentamidine; and aerosolized pentamidine administered by a nebulization device other than Respirgard II.

• There is no vaccine available.