Pneumocystis Jirovecii Pneumonia

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Continuing Education Activity

Pneumocystis carinii Pneumonia (PCP), now referred to as Pneumocystis jirovecii pneumonia, is a fungal infection that most commonly affect the immunocompromised and, in some cases, can be severely life-threatening. Typically, patients at risk are those with underlying disease states that alter host immunity, such as cancer, HIV, transplant recipients, or those taking immunosuppressive therapies and medications. Patients presenting with PCP may show signs of fever, cough, dyspnea, and, in severe cases, respiratory failure. This activity reviews the cause, pathophysiology, and presentation of pneumocystis jiroveci pneumonia and highlights the role of the interprofessional team in its management.

Objectives:

  • Describe the pathophysiology of pneumocystis jiroveci.
  • Review the workup of a patient with pneumocystis jiroveci pneumonia.
  • Summarize the treatment options for pneumocystis jiroveci pneumonia.
  • Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by pneumocystis jiroveci pneumonia.

Introduction

Pneumocystis carinii pneumonia (PCP), now referred to as Pneumocystis jirovecii pneumonia, is a fungal infection that most commonly affects the immunocompromised and, in some cases, can be severely life-threatening. Typically, patients at risk are those with underlying disease states that alter host immunity, such as cancer, HIV, transplant recipients, or those taking immunosuppressive therapies and medications. Patients presenting with PCP may show signs of fever, cough, dyspnea, and, in severe cases, respiratory failure.

Pneumocystis is thought to be transmitted from person to person through an airborne route. Asymptomatic lung colonization can occur in people with normal immune systems, and they may unknowingly become reservoirs (asymptomatic carriers) for the spread of Pneumocystis to immunocompromised individuals. Although it is still the most common and serious opportunistic respiratory infection in patients with AIDS, thanks to the widespread use of prophylaxis and antiretroviral therapy, the incidence of infection in this population has declined substantially.[1][2]

Etiology

Pneumocystis was originally thought to be a member of the protozoan class but was reclassified as an ascomycetous fungus in 1988. Its life cycle had been said to resemble that of both a protozoan and a fungus, and the debate over its correct classification led to further studies. Through careful phylogenetic analysis of small subunit ribosomal RNAs, researchers have been able to compare plant, animal, fungi, and protozoan lineages. Ultimately, investigators have concluded with distinct certainty that Pneumocystis is a member of the fungi family based on cell wall composition, the structure of key enzymes, and gene sequencing. The Pneumocystis genus includes several species, including P. carinii and P. jirovecii, which infect rats and humans.[3][4]

Epidemiology

Pneumocystis first appeared in Europe following World War II as a cause of pneumonia in premature and malnourished infants in orphanages. Not much was known about the organism then; after the HIV epidemic during the 1980s, studies into this illness increased significantly. PCP is now known to affect patients worldwide and is spread from person to person via the airborne route. Although typically seen in immunocompromised individuals, PCP is rarely seen in those with functional and competent immune systems. Many risk factors for acquiring and developing PCP exist. Groups at a significantly higher risk of developing PCP are patients with cancer (most specifically hematologic malignancies), transplant patients who have undergone hematopoietic cell or solid organ transplants, patients undergoing treatment for certain inflammatory or rheumatologic conditions, or patients with any condition that results in defects in cell-mediated immunity.[5][6] 

The most significant risk factor for contracting PCP in HIV-uninfected patients is using glucocorticoids combined with immunosuppressive therapy. One study showed that of patients with a first-time PCP, 91% had used glucocorticoids within one month of infection.[7][8]

PCP is most commonly described in HIV-infected individuals as an AIDS-defining illness. At the beginning of the HIV epidemic, rates of infections were documented as high as 20 per 100 persons in patients with CD4+ counts of less than 200 cells/microL. The decline in PCP rates began after 1989 with the introduction of primary prophylaxis and antiretroviral therapy at a rate of 3.4% per year between the1992 and 1995 and most dramatically between 1996 and 1998 at a rate of 21.5% per year. A 2016 published prospective cohort study of HIV-infected individuals calculated incidence rates of PCP per 1000 person-years of 29.9 from 1994 through 1997, 7.7 from 1998 through 2002, and 3.9 from 2003 through 2007. Although the infection rate has declined significantly in the United States and other industrialized countries, this opportunistic infection is a leading cause of significant infection in immunocompromised individuals.[9]

Pathophysiology

Pneumocystis jirovecii has a preference for infecting the lung in at-risk individuals. Microscopic examination reveals that Pneumocystis attaches to Type I alveolar epithelium, which allows the fungus to transition from its small trophic form to the larger cystic form. Adherence of Pneumocystis to alveoli is not the singular cause of diffuse alveolar damage, but rather it is the host's inflammatory response that causes significant lung injury and impaired gas exchange, leading to hypoxia and possibly respiratory failure. Pneumocystis is primarily an alveolar pathogen, but in the setting of severely immunocompromised individuals, the rare disseminated form may be seen. Examples of extra-pulmonary manifestations may be seen in patients undergoing non-systemic or second-line prophylaxis, including hepatosplenomegaly and thyroid, ocular, ear, or skin lesions.

Histopathology

Histology is often done on specimens to make a diagnosis of PCP. Stains like Giemsa, crystal violet, and Diff-Quick can be used to detect both the cyst and trophozoite. In addition, the walls can be stained with Toluidine blue or methenamine silver.

History and Physical

Patients presenting with PCP may have subtle or obvious signs of illness. Literature notes that HIV-infected patients will likely have a more indolent and subtle onset of symptoms such as non-productive and dry cough, 95%; low-grade fever, greater than 80%; and progressive dyspnea, 95%, over several weeks.[10] In contrast, those not infected with HIV patients can present similarly but may have a more abrupt onset of symptoms and accompanying respiratory distress or failure. Both patient populations will typically have some degree of hypoxemia and respiratory distress at the time of presentation.

History must be aimed at evaluating the patient for underlying causes of immunodeficiency and, as such, their risk of contracting an opportunistic infection. As mentioned before, PCP is considered an AIDS-defining illness; therefore, a history of HIV infection must be obtained along with whether the patient is undergoing antiretroviral therapy (ART). History may reveal signs and symptoms such as fatigue, weight loss, myalgia/arthralgia, rash, and headache, indicating an undiagnosed and underlying HIV infection. Also necessary during the evaluation is to ascertain if a patient has recently been on glucocorticoids or had a change to their dose of immunosuppressive therapies.

Physical exam findings are important in determining a patient's level of distress. No classic exam findings point directly at a Pneumocystis infection, but many findings indicate a respiratory illness such as pneumonia. The exam may reveal crackles and rhonchi on auscultation, but 50% of cases will have normal and clear lung sounds. Other common physical exam findings include associated dyspnea, tachypnea, and tachycardia. Patients will likely present with a fever, most times greater than 38.1 C (100.6 F). HIV-infected patients often will present with oral thrush as a co-infection; therefore, it is essential to do a thorough head-to-toe examination to evaluate for any other signs that may indicate an underlying immunologic disorder. A study in London, England, has shown that exertional dyspnea, interstitial infiltrates, oral thrush, and granulocyte percentage > 75% are associated with an increased likelihood of PCP compared to tuberculosis or bacterial pneumonia in patients with HIV.[11]

Evaluation

Diagnosis of PCP is multifactorial and may include clinical suspicion, patient risk factors, laboratory evaluations, chest radiograph, chest computed tomography (CT), sputum studies, evaluation of bronchoalveolar lavage fluid, or lung biopsies.[12] Laboratory findings can be nonspecific for PCP, and of most notable mention is an elevated serum lactate dehydrogenase (LDH) in HIV-infected patients. For various reasons, immunocompromised individuals without HIV may have elevated serum LDH; therefore, LDH is not a highly valuable diagnostic tool in this patient population. Most fungi, including Pneumocystis, contain beta-D-glucagon in their cell walls. Elevation of serum beta-D-glucagon in the setting of those with clinical signs and risk factors for pneumonia should raise suspicion for Pneumocystis infection and prompt further diagnostic evaluation. An arterial blood gas analysis should be obtained in hypoxic patients with tachycardia and signs of respiratory distress to assess the severity of their illness, and results will likely show an elevated Alveolar-arterial (A-a) oxygen gradient in the setting of PCP.[13][14]

A chest radiograph will typically reveal diffuse bilateral peri-hilar interstitial infiltrates. These changes become increasingly homogenous as the disease course progresses. Other radiographic findings may include solitary or multiple nodules, which may progress to cavitary lesions, lobar infiltrates such as upper lobe lesions in patients receiving certain antimicrobial medications, and pneumothorax in some cases. If there is a clinical concern for infection with Pneumocystis and a negative chest radiograph, a chest CT should be performed and may show ground glass attenuation or cystic lesions with high sensitivity.

Since Pneumocystis cannot be cultured, definitive diagnosis requires detecting and identifying the organism by polymerase chain reaction assays of respiratory specimens, dye staining, or fluorescein antibody staining.[15] Testing in this manner requires a microscopic examination of a patient's sputum or bronchoalveolar lavage fluid. These samples should only be obtained when safe and if the patient is stable. A definitive diagnosis of PCP may not always be possible. For example, patients with HIV/AIDS will have fewer neutrophils and a higher number of organisms present in their sputum and bronchoalveolar lavage fluid, making the diagnosis easier or more likely attainable. In contrast, patients with immunosuppression and without HIV infection will likely have a lower organism burden in their sputum or bronchoalveolar lavage fluid samples, making diagnosing difficult. Regardless, if there is clinical concern or suspicion for PCP in a high-risk patient, the practitioner should treat the patient accordingly, irrespective of whether a definitive diagnosis has or can be made.

Treatment / Management

Treatment for a presumed PCP should not be withheld while diagnostic measures are pending. Treatment should be initiated in patients with known risk factors and when clinical suspicion of infections exists. Most studies for PCP treatment have been performed in HIV-infected versus HIV-uninfected patients. Treatment in mild cases can be performed with oral therapies on an outpatient basis unless, of course, the patient cannot tolerate oral MEDICATIONS, has a moderate or severe case that requires corticosteroids, or the patient requires a drug regimen that may only be given intravenously.[16]

Due to its efficacy, the first-line treatment choice for HIV-infected and uninfected patients is 21 days of trimethoprim-sulfamethoxazole (TMP-SMX).[17] For mild to moderate treatment, TMP 15 to 20 mg/kg/day and SMX 75 to 100 mg/kg/day, given orally in 3 or 4 divided doses or TMP-SMX DS, two tablets three times per day. For moderate to severe cases (e.g., PaO ≤ 60 mmHg, respiratory rate > 25), TMP 15 to 20 mg/kg/day and SMX 75-100 mg/kg/day are given intravenously (IV) every 6 to 8 hours with a switch to oral when the patient shows clinical improvement. In patients with a mild allergy to TMP-SMX, desensitization should be attempted as this is the most effective drug of choice. In patients with severe allergies to TMP-SMX, desensitization is no longer recommended, and choosing a different drug regimen is more appropriate.

Alternative drug regimens for the treatment of PCP in those with sulfa allergies and mild to moderate disease include:

  • Atavaquone 750 mg, orally twice daily for 21 days (must be taken with food).[18]
  • Trimethoprim 15 mg/kg/day by mouth twice daily plus dapsone 100 mg by mouth every day
  • Primaquine 30 mg daily, plus clindamycin by mouth 450 mg every 6 hours or 600 mg every 8 hours.

Alternative treatments for moderate to severe cases include:

  • Pentamidine 4 mg/kg IV once daily over 60 minutes
  • Primaquine 30 mg by mouth every day plus clindamycin IV 600 mg every 6 hours or 900 mg every 8 hours.

Primaquine can only be orally administered, and patients who cannot tolerate oral medications should be given IV pentamidine, but caution should be used due to its increased toxicity and side effects when compared to primaquine. In addition, caution must be used in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency if dapsone or primaquine are used, as they can cause an increased risk of hemolytic anemia.

In HIV-infected patients with moderate or severe disease, current recommendations suggest the addition of glucocorticoids to the treatment regimen, as their use has been shown to improve clinical outcomes and mortality. In addition, HIV-infected patients with a room air arterial blood gas partial pressure of oxygen less than or equal to 70 mm Hg, an alveolar-arterial (A-a) gradient greater than or equal to 35 mm Hg, or hypoxia on pulse oximetry should receive steroids.

Corticosteroids also may be recommended in HIV-uninfected patients with PCP due to the potential for high mortality and fulminant course of illness, but data are limited on whether there are benefits or a decrease in in-hospital mortality. Dosing for prednisone should be started as soon as possible or within 72 hours of starting treatment for PCP and is as follows: 40 mg by mouth twice per day on days 1 through 5, 40 mg by mouth daily on days 6 through 10, and 20 mg orally daily on days 11 through 21. IV methylprednisone can be given at 75% of the prednisone dose if oral therapy cannot be tolerated. HIV-infected patients who are not already on them should have antiretroviral therapy (ART) initiated within two weeks of Pneumocystis treatment or as soon as they are stable enough to begin treatment. Patients usually show slightly worsening clinical signs around days 3 to 4 due to the host's inflammatory response to dying organisms and then improvement afterward.

Prophylaxis treatment guidelines have been established for certain patient populations. Patients who are immunocompromised, such as those with malignancy and who are taking glucocorticoid doses greater than 20 mg daily for one month or longer, patients who have received bone marrow suppressive therapies or antineoplastic therapies, and those who have undergone hematopoietic cell or solid organ transplantation should receive primary prophylaxis for Pneumocystis. Prophylaxis is generally not required if the patient receives pyrimethamine-sulfadiazine to suppress or treat toxoplasmosis.

  • First-line prophylaxis treatment is trimethoprim-sulfamethoxazole, one double-strength tablet by mouth daily or one single-strength tablet by mouth daily.
  • For those with sulfa allergies, recommended prophylaxis includes:
    • Dapsone 100 mg by mouth daily or 50 mg by mouth twice each day
    • Dapsone 50 mg by mouth daily plus pyrimethamine 50 mg plus leucovorin 25 mg by mouth weekly
    • Dapsone 200 mg plus pyrimethamine 75 mg plus leucovorin 25 mg by mouth weekly
    • Atovaquone 1500 mg by mouth daily
    • Atovaquone 1500 mg plus pyrimethamine 25 mg plus leucovorin 10 mg by mouth daily
    • Aerosolized pentamidine 300 mg monthly via Respigard II nebulizer.

HIV-infected individuals should receive prophylaxis with the same medications recommended above when a CD4+ count is below 200 cells/microL or CD4+ less than 14%, the presence of oropharyngeal candidiasis, and a CD4+ of 200-250 cells/microL when ART cannot be started or if monitoring of CD4+ counts every three months is not possible. In pregnant patients, the same chemoprophylaxis for PCP should be given. However, aerosolized pentamidine or oral atovaquone should be avoided during the first trimester due to some concerns of possible teratogenicity.

The treatment prognosis depends on many factors, including the degree of hypoxia at presentation, age, prior PCP, elevated serum LDH, low CD4+ count, and the presence of other opportunistic infections, such as cytomegalovirus (CMV). The presence of any of the factors mentioned above carries a higher risk of mortality and poor outcome. Mild to moderate disease has overall mortality rates as high as 65%. Patients with severe disease and respiratory failure who require mechanical ventilation and intensive care unit (ICU) admission have mortality rates as high as 84%.

Patients should be monitored for adverse reactions and signs of treatment failure when started on antimicrobial therapies. Monitoring should include vital signs (most notably oxygen saturation), labs such as complete blood counts, liver function enzymes, renal function, glucose, and electrolytes. Treatment is considered failed if the patient does not show signs of clinical improvement after 4 to 8 days. No definitive studies exist regarding the guidelines for treatment failure management, but most studies agree that combination treatment with primaquine plus clindamycin may be the most effective regimen for salvage therapy. It is important to also search for concurrent infections that may be causing illness besides Pneumocystis and treat those accordingly.[19]

Differential Diagnosis

  • Acute respiratory distress syndrome
  • Viral or bacterial pneumonia
  • Tuberculosis
  • Legionella pneumonia
  • Mycoplasma infections
  • COVID-19 pneumonia

Prognosis

Although most patients will improve with appropriate treatment, some develop progressive respiratory failure.[20] The mortality among patients requiring intensive care admission or mechanical ventilation is reported to be as high as 60%.[21] As reported, patients with mild to moderate disease have a case fatality rate of <10%, whereas patients with more severe illness have a case fatality of >20%.[22][23]

Particularly in patients with HIV, factors that correlate with poor prognosis include:

  • Increasing age
  • Prior episode of PCP
  • Presence of cytomegalovirus in bronchoalveolar lavage fluid
  • Elevated serum lactate dehydrogenase concentration
  • Low CD4 cell count[24]

Complications

  • Lymphadenopathy
  • Bone marrow involvement leading to pancytopenia
  • Involvement of the gastrointestinal tract and thyroid gland
  • Acute respiratory distress syndrome
  • Respiratory failure

Consultations

The patients usually present with respiratory symptoms to internists, emergency practitioners, and ambulatory care providers. In addition, patients often require consultations with infectious disease specialists, microbiologists, and intensive care specialists, for further illness management.

Deterrence and Patient Education

Patients with a history of HIV should get thorough counseling on the disease's course and cell counts that may warrant prophylactic treatment. Patients managed as outpatients should be informed that if their symptoms worsen or if they do not feel better in 4 to 7 days, they may need intravenous treatment and should come back for follow-up.

Pearls and Other Issues

Pneumocystis was once considered an AIDS-defining illness, but due to prophylaxis and antiretroviral therapy, the incidence of disease in HIV-infected individuals has been drastically reduced.

Symptoms include fever, exertional dyspnea, and dry cough, and the diagnosis should be suspected in anyone with compromised immunity, such as cancer, transplant patients, or those on immunosuppressive therapies.

Treatment is trimethoprim-sulfamethoxazole, although other lines of therapy exist for those with allergies or severe illness.

Prevention is also with trimethoprim-sulfamethoxazole and recommended in certain populations such as HIV- infected individuals with CD4+ counts less than 200 cells/microL or CD4+ less than 14%, presence of oropharyngeal candidiasis, and a CD4+ of 200-250 cells/microL when ART cannot be started or if monitoring of CD4+ counts every three months is not possible. 

The illness can be categorized as mild, moderate, or severe, and new recommendations suggest the use of glucocorticoids in HIV-infected patients with a room air arterial blood gas partial pressure of oxygen that is less than or equal to 70 mm Hg, an alveolar-arterial (A-a) gradient greater than or equal to 35 mm Hg, or hypoxia on pulse oximetry should receive steroids.

Any patients needing corticosteroids should be admitted to the hospital for monitoring and into the ICU for respiratory failure and continued monitoring.

Enhancing Healthcare Team Outcomes

PCP is best managed by an interprofessional team that includes a pulmonologist, infectious disease expert, pharmacist, intensivist, nurse, respiratory therapist, and dietitian. Once the diagnosis of PCP is made, the patient should be urged to discontinue smoking, as nicotine worsens the symptoms and complicates therapy. Since most patients with PCP are frail, a dietary consult should be sought to increase calorie intake. The pharmacist should educate the patient on the importance of medication compliance. Patients receiving corticosteroids should be followed closely to monitor the side effects, which both nursing and pharmacy can do, reporting any concerns to the prescriber. Finally, these patients need lifelong follow-up by monitoring CD 4 counts, viral load, and disease progression.[25] The interprofessional approach to care will result in the best patient outcomes. [Level 5]

Outcomes

In the past, PCP carried high mortality, but over the past two decades, the mortality rates have dropped because of earlier diagnosis and treatment. Currently, at least 10 to 20% of patients with PCP will die. PCP carries an even worse prognosis in patients without HIV infection, with mortality rates over 50%. In general, the mortality rates are much higher when there is an underlying lung disorder and in patients who require mechanical ventilation.[16][26] [Level 5]



(Click Image to Enlarge)
Lung X-ray of patient showing infection with pneumocystis carinii, Pneumonia
Lung X-ray of patient showing infection with pneumocystis carinii, Pneumonia
Contributed by The National Institutes of Health (NIH)
Article Details

Article Author

Justina Truong

Article Editor:

John V. Ashurst

Updated:

1/21/2023 5:13:14 PM

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