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Pneumocystis Jiroveci Prophylaxis


Pneumocystis Jiroveci Prophylaxis

Article Author:
Juan Melendez Rivera
Article Editor:
Gabriela Ciofoaia
Updated:
8/15/2020 12:09:44 AM
For CME on this topic:
Pneumocystis Jiroveci Prophylaxis CME
PubMed Link:
Pneumocystis Jiroveci Prophylaxis

Introduction

Pneumocystis jirovecii is a common and potentially lethal opportunistic pneumonia-causing fungus in immunocompromised patients. Pneumocystis jirovecii pneumonia (PCP) is classically associated with acquired immunodeficiency syndrome (AIDS), but it also affects patients with malignancy, rheumatologic conditions, or transplantation.

Due to the advent of combined antiretroviral therapy and routine use of chemoprophylaxis for opportunistic infections, there has been a steady decline in PCP among people living with human immunodeficiency virus (PLWHIV). PCP was initially thought to be caused by reactivation of fungal infection during childhood, but recent studies have shown evidence that new-onset infection appears to be more common than previously thought. These findings stress the importance of adequate and effective chemoprophylaxis in immunosuppressed patients.[1][2][3][4]

Etiology

Initially, PCP was believed to be secondary to reactivation of latent infection acquired early in life since antibodies against Pneumocystis jirovecii were found in children. However, the genotypic analysis showed that primary infection is more common than previously thought and that immunocompetent patients can be asymptomatic carriers of the infection. While both means of developing PCP appear to be prevalent, the latter is much more common, especially in immunosuppressed post-transplant patients.[3][5]

Epidemiology

Pneumocystis jirovecii is ubiquitous worldwide, and antibodies against it are widespread in immunocompetent children, with more than 80% of children developing antibodies by age 4 years. During the human immunodeficiency virus (HIV) epidemic, rates up to 60% of patients with AIDS developed this condition. The onset of combined antiretroviral therapy (cART) has made this condition significantly less prevalent among PLWHIV. On the other hand, the advent of novel immunosuppressive therapy for conditions such as cancer, rheumatologic disorders, and the increased number of transplant patients, have made this population the main subset suffering from PCP.[2][3][5][4]

Pathophysiology

Pneumocystis jirovecii adheres to the surface epithelium of type 1 alveolar cells, which stimulates cytokines, chemokines, and cellular infiltrate in the lungs to eradicate the infection. In immunocompetent hosts, this results in a mild inflammatory response with minimal damage to the lung. However, patients with a diminished immune response due to lack or incomplete function of certain immune system components develop hyperinflammatory responses that cause direct damage to the lung.[3]

History and Physical

Pneumocystis jirovecii typically presents with a constellation of nonspecific symptoms such as fever, nonproductive cough, pleuritic chest pain, and shortness of breath. Since it is an opportunistic pathogen, a history of immunosuppression is essential for colonization. Underlying causes of immunodeficiency and their risk of developing an opportunistic infection should be assessed. History can reveal signs and symptoms that can indicate an underlying undiagnosed HIV infection. Also, it is important to evaluate the recent use or any dose changes of immunosuppressive medications, including glucocorticoids. Studies have shown that the presentation of PCP appears to be more severe, often fulminant, in non-HIV-infected patients.

Due to the nonspecific nature of PCP presentation, further evaluation is needed to accurately diagnose. A physical exam can determine the level of respiratory distress with tachypnea, tachycardia, and hypoxia. Lung examination is usually indicative of pneumonia with the presence of crackles or rhonchi, but patients can also present with normal or clear lung sounds. A thorough examination is important as it can reveal other signs that can indicate an underlying infection, immunologic disorder, or malignancy.[6][7]

Evaluation

The evaluation of patients for whom the initiation of PCP prophylaxis is being considered should include a physical examination, complete blood count (CBC) with differential to assess for signs of hematologic malignancy, comprehensive metabolic panel (CMP) to assess electrolytes as determinants of nutritional status, along with serology for infectious etiologies known to cause immunosuppression. In the case of suspected autoimmune disease, serological studies such as an antinuclear antibody (ANA), anti-dsDNA, and other markers should be tested. In the case of organ transplant recipients and other patients with iatrogenic immunosuppression, prophylaxis should be initiated without delay. HIV patients require evaluation of CD4 count, CD4 percent, and viral load before initiation of any sort of prophylaxis unless they are currently suffering from an AIDS-defining illness.[8][9][10][11][12][13][14]

The diagnosis of PCP infection relies on clinical presentation and suspicion, presence of risk factors in combination with laboratory testing, imaging, sputum studies, which include microscopic detention of cysts and trophic form in respiratory secretion, evaluation of bronchoalveolar lavage fluid, or lung biopsy. Laboratory evaluation can be nonspecific, like elevated serum lactate dehydrogenase (LDH) and serum 1-3 beta D glucan. Beta D glucan can be found in the cell wall of most fungi, including Pneumocystis jirovecii. In the appropriate clinical context, serum LDH and 1-3 beta D glucan elevation should raise suspicion of PCP.

Imaging evaluation with a chest radiograph can reveal diffuse bilateral interstitial infiltrates. Other radiologic findings can include lobar infiltrates, solitary or multiple nodules that can progress to cavitary lesions, and pneumothorax. A negative chest radiograph with a high clinical suspicion should determine further imaging evaluation, and a chest computed tomography (CT) should be performed to look for findings of ground-glass opacities or cystic lesions. Definitive diagnosis requires organism identification with a polymerase chain reaction assay of respiratory specimens of sputum or bronchoalveolar lavage, fluorescein antibody, or dye staining. Sometimes the definitive diagnosis of PCP may not be possible. However, the treatment should not be delayed, and the patient should be treated accordingly.[7][15]

Treatment / Management

Due to high mortality associated with the disease and potential fulminant course, treatment should be initiated immediately when clinical suspicion is high.

Trimethoprim-sulfamethoxazole (TMP-SMX)

Oral trimethoprim-sulfamethoxazole is the gold standard therapy for PCP infection and prophylaxis. This medication is well tolerated in most patients and has a broad spectrum covering the major opportunistic pathogens, such as Toxoplasma gondii, Listeria monocytogenes, Nocardia species, and encapsulated bacteria. Usual regimens for prophylaxis include daily and three times a week regimen with single or double strength doses. Studies have shown no significant difference in effectivity between these regimens, and selection should be tailored to the specific patient. Trimethoprim-sulfamethoxazole is the treatment of choice for PCP infection. Intravenous therapy is recommended until they are clinically stable with improvement in oxygen requirements. 

The main limitation of TMP-SMX usage is hypersensitivity reactions. Usually, these hypersensitivity reactions are treated with desensitization to good outcomes. Providers must be aware of the more severe but less common side effects of TMP-SMX, such as myelosuppression, drug-induced hepatitis, interstitial nephritis, aseptic meningitis, and pancreatitis. Stevens-Johnson syndrome has also been reported secondary to TMP-SMX administration. Trimethoprim is known to inhibit potassium and creatinine in renal tubules. Therefore, patients’ renal function, cell count, and electrolytes should be routinely monitored. Due to the effectiveness and usually mild side effect profile of TMP-SMX, it remains the first line for PCP prophylaxis.

Dapsone

Dapsone is a second-line treatment for PCP prophylaxis. It is usually the agent of choice for patients that have poor tolerance to TMP-SMX. The most significant side effect of dapsone is hemolytic anemia, specifically in patients suffering from G6PD deficiency. When combined with pyrimethamine, it is an effective treatment for the major opportunistic pathogens affecting immunocompromised patients.

Atovaquone

Atovaquone has been extensively studied in the HIV population as an alternative to TMP-SMX, but data is lacking for other immunocompromised populations. It appears to be as effective as dapsone and other second-line agents for PCP prophylaxis. Atovaquone is well tolerated, with the most common side effects being diarrhea and rash.

Pentamidine

Inhaled pentamidine is a third-line agent for PCP prophylaxis as it appears to be less effective than TMP-SMX, dapsone, and atovaquone. The side effect profile for this medication is mild, most commonly only causing cough or bronchospasm. Intravenous pentamidine has been shown to be effective primary prophylaxis for PCP. However, more studies are needed to assess its efficacy when compared with the first- and second-line agents.[9][10][11][12][13][14]

Glucocorticoids

For patients with moderate to severe PCP infection, the current recommendation suggests patients be initiated on glucocorticoid therapy if there are signs of hypoxemia like oxygen saturation <92 percent, partial pressure of oxygen <70 mmHg, or the alveolar-arterial oxygen gradient is >35 mmHg.[7]

Differential Diagnosis

Due to their poor immune response, patients with HIV and those with immunosuppression for other causes, such as malignancy, autoimmune disease, or iatrogenic due to underlying condition or organ transplant patients, require prophylaxis for numerous pathogens. These pathogens include:

  • Aspergillus species
  • Candida albicans
  • Clostridium difficile
  • Coccidioides immitis
  • Cryptococcus neoformans
  • Cytomegalovirus
  • Histoplasma capsulatum
  • Legionella pneumophila
  • Microsporidium
  • Mycobacterium avium complex
  • Mycobacterium tuberculosis
  • Pseudomonas aeruginosa
  • Salmonella
  • Staphylococcus aureus
  • Streptococcus pneumoniae
  • Streptococcus pyogenes
  • Toxoplasma gondii[2][3][5]

Treatment Planning

Combined antiretroviral therapy (cART) remains the gold standard for the treatment of HIV and opportunistic infection prevention. Primary prophylaxis for Pneumocystis jirovecii pneumonia (PCP) should be initiated when the patient’s CD4 count <200cells/microL, CD4% is <14%, and patients have a detectable viral load. Also, patients that suffer from any AIDS-defining illness should be started on primary prophylaxis for other opportunistic pathogens, such as PCP.

For recipients of solid organ transplant, guidelines recommend primary prophylaxis for a minimum of 6 months after transplant. Some patients, such as lung and small bowel transplant recipients or those with a history of PCP infection or chronic cytomegalovirus infection, have indications for lifelong prophylaxis. Patients with a kidney transplant are recommended to receive prophylaxis during and after treatment of acute rejection, but guidelines are not universally delineated.

Guidelines for PCP prophylaxis in non-HIV immunocompromised patients due to other conditions are not well established. For patients undergoing stem-cell transplantation guidelines recommend primary prophylaxis for at least 6 months after graft transplant, and longer if patients are receiving immunosuppressive therapy for a longer period. For patients with hematologic and solid malignancies, specifically patients with acute lymphocytic leukemia (ALL), prolonged CD4 count <200cells/microL, or on long-term steroid therapy, primary prophylaxis is usually continued until CD4 count >200cells/microL or while on chemotherapy. For other malignancies, the risk is not well-established, and usually, it is given for the duration of chemotherapy. For patients suffering from rheumatologic conditions and connective tissue diseases, there are no guidelines, but the general recommendations are to initiate prophylaxis if patients are on long-term steroid treatment or other immunosuppressive therapy.

Other populations that experts agree would benefit from initiation of primary prophylaxis are patients with severe protein malnutrition, primary immune deficiencies, and a persistent CD4 count of <200cells/microL.[8][9][10][11][12][13]

Prognosis

Infection with opportunistic pathogens in patients with diminished immune response can have severe consequences for the patients, including death. Rates of infection for patients treated with gold standard regimens are very low. With the advent of cART, HIV positive patients are less likely to die from AIDS-related complications.

Complications

Trimethoprim-sulfamethoxazole (TMP-SMX)

Trimethoprim-sulfamethoxazole (TMP-SMX) is usually well-tolerated with gastrointestinal disturbances and rashes being the most common side effects. TMP-SMX is known to cause nephrotoxicity, usually, renal tubular acidosis, but it is uncommon. Usually, the increased creatinine after initiation of this antibiotic is due to its effect on the reduction of tubular secretion of creatinine. Other side effects include hypoglycemia, hyponatremia, hepatitis. The most severe side effects of TMP-SMX are Steven-Johnson syndrome/toxic epidermal necrolysis, leukopenia, hyperkalemia, and lactic acidosis.

Dapsone

Dapsone is known to cause hemolytic anemia, especially in patients with G6PD deficiency, lupus-like syndrome, peripheral nephropathy, along with less severe side effects, usually of the GI tract and skin.[9][10][11][12]

Deterrence and Patient Education

Pneumocystis jirovecii is an opportunistic pathogen, classically associated with AIDS, that can have serious health consequences, including death. Due to the advent of cART, Pneumocystis pneumonia has become less common in this population. However, HIV patients should be encouraged to follow with their infectious disease specialists to optimize their treatment and monitor their immune response closely. When indicated, prophylaxis, for this and other pathogens, should be initiated without delay.

In other immunocompromised populations, the guidelines are not as defined, and recommendations by specific societies and health institutions should be followed. Clinicians should always be considering and adjusting the regimen according to the patient’s comorbidities and response to previous therapies.

Enhancing Healthcare Team Outcomes

Due to the possible long-lasting effects of Pneumocystis pneumonia, prophylaxis should be initiated without delay, when clinically indicated. Pneumocystis jirovecii primarily affects immunocompromised individuals; therefore, the underlying etiology of the patient’s immunosuppression should be first addressed. In cases of patients with AIDS, an infectious disease specialist should be on board. Markers of T cell integrity and function should be closely monitored, tailoring the specific treatment and prophylaxis to the patient’s CD4 count, CD4%, and HIV viral load.

In other populations, immunosuppression may be indicated due to solid organ transplant and rheumatologic conditions, to name a few. Therefore, prophylaxis should be initiated in these patients on a case by case basis. This requires an interprofessional team approach incorporating clinicians from several specialties, such as rheumatology, nephrology, pulmonology, hematology, and oncology. Furthermore, in cases where compliance with medication regimen has been compromised, behavioral health and psychiatry could be involved to better assess the patient’s reasoning. On the other hand, nutrition, social work, and other non-clinician personnel should be involved to maximize response to treatment.


References

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