INTRODUCTION — The incidence of Pneumocystis jirovecii (previously named Pneumocystis carinii) pneumonia has dramatically declined due to effective antiretroviral therapy (ART) and, to a lesser extent, the use of prophylaxis. Despite this decrease, it remains one of the leading causes of opportunistic infections among persons with HIV and low CD4 cell counts, such as those who are unaware of their HIV diagnoses or are not receiving medical care.
The general features of Pneumocystis pulmonary infection in the patient with HIV, including clinical presentation and diagnosis, will be reviewed here. An overview of extrapulmonary disease due to pneumocystic infection will also be discussed. Treatment and prophylaxis of Pneumocystis infection in individuals with and without HIV are considered elsewhere. (See "Treatment and prevention of Pneumocystis infection in patients with HIV" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)
MICROBIOLOGY AND TERMINOLOGY — Pneumocystis is currently recognized as a fungus based upon ribosomal RNA and other gene sequence homologies, the composition of their cell walls, and the structure of key enzymes [1]. Prior to being identified as a fungus, the taxonomic classification of Pneumocystis as a genus of protozoan organisms had been questioned for several years. However, Pneumocystis organisms are atypical fungi as they do not grow in fungal culture, they respond to some antiparasitic agents, and they have a cell wall that contains cholesterol rather than ergosterol [2]. The life cycle consists of the trophic form, a precystic form, and the cystic form [3]. The trophic form predominates over the cystic form during infection.
The nomenclature for Pneumocystis has also changed; the species that infects rats is called P. carinii; and the one that infects humans, P. jirovecii [4]. P. jirovecii is now designated as the species name to use in publications and references to human infections [4,5]. The abbreviation "PCP" is still often used to refer to the clinical entity of "Pneumocystis pneumonia"; this allows for the retention of the familiar acronym and maintains the accuracy of this abbreviation in older published papers. However, some sources have started using "PJP" as the abbreviation.
PATHOGENESIS
Transmission — The primary mode of transmission of P. jirovecii is via the airborne route. Serologic studies show that primary infection occurs early in life, with 75 percent of humans infected by the age of four years [6]. It was initially believed that PCP remained in a latent state unless the patient became immunosuppressed; however, this may not account for all cases of PCP. Animal and human studies have shown clearance of the organism, and there is increasing evidence of transmission from person to person and possibly through environmental reservoirs [7-11]. The role of colonization in humans may also be of importance to Pneumocystis transmission. (See 'Colonization' below.)
Pathogen-host interaction — Pneumocystis exists almost exclusively within the alveoli of the lung [2]. The trophic forms first attach to the epithelium. Interaction of Pneumocystis with alveolar epithelial cells and alveolar macrophages initiates a cascade of cellular responses in both the organism and lung cells. Attachment of Pneumocystis to lung epithelial cells enhances Pneumocystis proliferation.
Alveolar macrophages are the primary resident phagocytes that mediate the clearance of the organisms from the lung. Phagocytosis, respiratory burst, and inflammatory activation of alveolar macrophages in response to Pneumocystis are impaired in persons with HIV, and may contribute to the pathogenesis of infection. Accumulating evidence indicates that beta-glucan molecules, which are abundant in the cell wall of Pneumocystis are important components that drive the initiation of the inflammatory response during PCP. The most abundant surface protein of Pneumocystis is the major surface glycoprotein (MSG) [12]. Variation of the expressed MSG may facilitate evasion of host immune responses.
Host immunity — Immune control of Pneumocystis involves production of chemokines and inflammatory cytokines by alveolar macrophages and epithelial cells. In healthy individuals, CD4+ T cells coordinate the host inflammatory response by recruiting and activating additional immune effector cells including monocytes and macrophages, which are responsible for elimination of the organism. In contrast to CD4+ T cells, the role of CD8+ T cells in host defense against Pneumocystis is more controversial. However, CD8+ T cells may have some beneficial effect, particularly in a situation of chronic CD4+ depletion. In mice, the T-cell mediated inflammatory response can cause impaired lung compliance and gas exchange; as such, both CD4+ and CD8+ T cells may result in deleterious lung inflammation. In addition to T cells, neutrophils, recruited by CXCL2 and IL-8, also participate in lung inflammation during PCP.
Colonization — Healthy individuals, as well as those with HIV infection, underlying lung disease, and immunosuppression, may harbor Pneumocystis in their respiratory tract despite being without any signs or symptoms of disease. These colonized individuals have generally been identified using experimental polymerase chain reaction assays. (See 'Identifying the organism' below.)
The prevalence of Pneumocystis colonization among healthy adults ranges from 0 to 20 percent [2], and it has also been demonstrated to be a common colonizer in hospitalized patients with bacterial and viral pneumonia [13].
The clinical significance of colonization is not well understood, but may be important for several reasons [14]:
●Colonized individuals may be at risk of developing pneumonia or transmitting infection.
●Colonized individuals receiving Pneumocystis prophylaxis may be at risk for developing drug resistance mutations.
●Ongoing colonization may trigger inflammation and local alveolar damage leading to lung diseases, such as chronic obstructive pulmonary disease.
EPIDEMIOLOGY
Incidence — The incidence of PCP has dramatically decreased after the administration of potent ART, and the general adoption of recommendations for PCP prophylaxis [10,15-19]. As examples:
●In a United States cohort of patients with HIV, there was a decrease in PCP incidence from 29.9 per 1000 person years between 1994 to 1997 to 3.9 per 1000 person years between 2003 to 2007 [18].
●In Uganda, the frequency of PCP among patients with HIV hospitalized with suspected pneumonia who had negative sputum acid-fast bacilli smears and underwent bronchoscopy decreased from nearly 40 percent of bronchoscopies in 1999 to 2000 to less than ten percent in 2007 to 2008 [20,21].
The decrease in incidence with ART is due to both immunologic improvement as measured by CD4 cell count increases and the suppression of HIV RNA. For example, in a European cohort of individuals with HIV, the incidence of primary PCP was zero among those with a CD4 count between 100 to 200 cells/microL who were receiving ART and were virologically suppressed, independent of PCP prophylaxis [19].
Despite this decrease, PCP is still one of the leading causes of opportunistic infection in individuals with HIV [18]. Most cases occur in patients who are undiagnosed or are not receiving care [22,23].
Risk factors — The main risk factor for PCP is advanced immunosuppression in patients not taking antiretroviral therapy. Other risk factors include a CD4 cell count less than 200 cells/microL, a CD4 cell percentage of less than 14 percent, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV RNA levels [24].
CLINICAL FEATURES OF PULMONARY DISEASE
Clinical manifestations — The clinical manifestations of PCP are most commonly gradual in onset, and are characterized by fever (80 to 100 percent), cough (95 percent), and dyspnea (95 percent) progressing over days to weeks [25]. The average patient has pulmonary symptoms for about 3 weeks before presentation. Patients may describe fatigue with usual activities (climbing stairs, speaking on the telephone, shaving) that previously were done without difficulty. The cough is generally nonproductive. Other symptoms include fatigue, chills, chest pain, and weight loss. Approximately 5 to 10 percent of patients are asymptomatic.
The most common findings on physical examination are fever (over 80 percent of patients have a temperature exceeding 38.1ºC) and tachypnea (60 percent). The most common adventitial sounds are crackles and rhonchi, but a normal chest examination occurs in 50 percent of cases. Oral thrush is a common co-infection.
Laboratory findings — There are several laboratory findings that are observed in patients with HIV and PCP.
Low CD4 counts — The incidence of PCP in patients with HIV increases as the CD4 count decreases [15,26,27], with most cases occurring when the CD4 count drops below 200 cells/microL [26,28]. A CD4 cell count percentage of less than 14 percent is also commonly observed.
Oxygenation — Hypoxia occurs with progression of PCP. The alveolar-arterial oxygen gradient is widened in more than 90 percent of patients, ranging from mild (alveolar-arterial O2 difference <35 mmHg) to severe (alveolar-arterial O2 difference >45 mmHg) [29]. Oxygen desaturation can occur with exercise and is highly suggestive of a diagnosis of PCP [30-32]. (See "Approach to the HIV-infected patient with pulmonary symptoms", section on 'Pulse oximetry or arterial blood gas analysis'.)
Lactate dehydrogenase level — In studies done before the availability of effective ART, an elevated lactate dehydrogenase (LDH) level was present in 90 percent of patients with HIV and PCP and had some prognostic significance. In one study, the mean LDH of PCP survivors was 340 IU, while the mean level of non-survivors was 447 IU [33]. More importantly, a rising LDH level despite appropriate treatment portends a poor prognosis [33,34].
1-3-beta-D-glucan — Elevated plasma levels of 1-3-beta-D-glucan, a component of the cell wall of P. jirovecii, have been found in patients with HIV and PCP. In a study of 282 patients with HIV, those with a diagnosis of PCP had significantly higher median beta-D-glucan levels than patients without the disease (408 versus 37 pg/mL) [35]. The use of this assay in supporting the diagnosis of PCP is discussed elsewhere. (See 'Presumptive diagnosis' below.)
Diffusion capacity — PCP is highly unlikely if the diffusion lung capacity for carbon monoxide (DLCO) is normal (eg 70 percent of the predicted value or greater). One prospective study of 306 HIV-positive patients with 467 episodes of worsening respiratory symptoms found that PCP pneumonia was present in less than 2 percent of patients with a normal or unchanged chest x-ray and a single breath DLCO >75 percent of the predicted value [36].
Radiographic manifestations
Chest radiographs — Chest x-rays are initially normal in up to one-fourth of patients with PCP. The most common radiographic abnormalities are diffuse, bilateral, interstitial, or alveolar infiltrates [37] (image 1). Upper lobe infiltrates and pneumothoraces can also be seen; however, a higher incidence of both of these findings can be seen in patients using aerosolized pentamidine prophylaxis [38-40].
Other less common radiographic presentations include [25,39,41]:
●Lobar or segmental infiltrates
●Cysts
●Nodules
●Pleural effusions
High resolution computed tomography — High resolution computed tomography (HRCT) has a high sensitivity for PCP among HIV-positive patients [42-44]. One study, for example, evaluated 51 patients with suspected PCP and normal, equivocal, or nonspecific chest x-ray findings; HRCT had a sensitivity of 100 percent and a specificity of 89 percent when the presence of patchy or nodular ground-glass attenuation was used to indicate possible PCP [43]. While such findings are suggestive, they are not diagnostic. However, a negative high resolution computed tomography scan makes the diagnosis of PCP highly unlikely.
Gallium-67 citrate scanning — Gallium-67 citrate scanning is sometimes used to screen for PCP in suspected individuals with a normal chest radiograph but in whom a HRCT cannot be obtained. Nuclear scanning is a highly sensitive test in patients with PCP, demonstrating intense, diffuse bilateral uptake [45]. This test is rarely used for diagnosis today.
EVALUATION AND DIAGNOSIS — The initial approach to the patient with HIV and pulmonary symptoms is discussed separately (see "Approach to the HIV-infected patient with pulmonary symptoms"). If PCP is a consideration, we measure CD4 cell counts, oxygen saturation, and 1-3-beta-D-glucan levels (if available). We also obtain a chest radiograph and, if the plain film is nondiagnostic, a high resolution CT scan of the lung.
PCP is strongly suspected in the patient with HIV and a CD4 cell count less than 200 cells/microL, 1-3-beta-D-glucan levels greater than 80 pg/mL (especially if markedly elevated), and symptoms/signs characteristic of the infection; particularly dyspnea, hypoxemia, and cough, and diffuse, bilateral, interstitial, or alveolar infiltrates on chest radiograph or HRCT.
Definitive diagnosis — A definitive diagnosis of PCP requires visualization of the cystic or trophic forms in respiratory secretions. Obtaining a definitive diagnosis of PCP is usually important since treatment requires a prolonged course of possibly toxic therapy, and a significant percentage of patients with PCP have an alternative or co-occurring infection/disease. Approximately 15 percent have a concurrent cause of disease [24]; this rate may be higher in resource-limited settings where coinfection with Mycobacterium tuberculosis is more likely to occur [46]. However, some clinicians may elect to forego obtaining a definitive diagnosis if the clinical presentation and radiographic findings are highly consistent with PCP, especially if the beta glucan is markedly elevated. (See 'Presumptive diagnosis' below and "Treatment and prevention of Pneumocystis infection in patients with HIV".)
Empiric treatment should be initiated in acutely ill patients in whom there is a high clinical suspicion for PCP. This is because:
●The definitive diagnosis of PCP can be problematic since obtaining appropriate specimens may be difficult to obtain and quickly process. Processing and interpretation of an adequate specimen may require several days.
●Many patients are acutely ill due to PCP and require definitive therapy before a diagnosis can be confirmed.
●The initiation of empiric therapy does not preclude obtaining a definitive diagnosis since cysts may persist for days to weeks after appropriate therapy has been administered [47,48].
Identifying the organism — Since Pneumocystis cannot be cultured, the diagnosis relies upon the visualization of the cystic or trophic forms in appropriate specimens. Stains that have commonly been used selectively stain the cell wall of the cystic form, and include Gomori-methenamine silver (picture 1), cresyl violet, Gram-Weigert and toluidine blue O. Wright-Giemsa and Diff-Quick detect both the cystic and trophic forms, but does not stain the cell wall (picture 2). Other agents that can be useful include the Papanicolaou stain and Calcofluor white. Immunofluorescent staining using fluorescein-labeled monoclonal antibodies represents the preferred technique for the diagnosis of PCP and is more sensitive than the general stains [2,24,29].
Polymerase chain reaction (PCR) of respiratory fluid, in particular bronchoalveolar lavage (BAL), is increasingly used to make the diagnosis of PCP in both patients with and without HIV [29,49-51], and several clinical laboratories offer this test. Advantages to PCR testing include confirming the diagnosis in clinically suspect cases with negative sputum or BAL smears, and using alternative specimens such as oral washes and nasopharyngeal aspirates [51-53]. A disadvantage is that PCR cannot distinguish between colonization and disease [10]. In a retrospective study that compared rates of P. jirovecii detection before and after the introduction of PCR testing at a tertiary care center, Pneumocystis was detected in 11 of 1583 (0.69 percent) specimens by toluidine blue staining of microbiology, cytology, and/or pathology specimens in the year prior to the introduction of PCR testing, whereas 44 of 1457 (3 percent) of specimens were positive for Pneumocystis when PCR testing was used [54]. Of those with a positive PCR test, only three had low quantities of Pneumocystis DNA detected and were likely colonized; the remainder had evidence of true disease.
PCR testing of BAL fluid can also be useful when evaluating patients with possible PCP and an elevated 1-3-beta-D-glucan. In this setting, a negative test strongly supports a non-pneumocystic cause of the high beta-D-glucan level. A discussion of the diagnostic utility of 1-3-beta-D-glucan levels for diagnosing PCP is found below. (See 'Presumptive diagnosis' below.)
Optimal specimens — There are several respiratory and lung tissue specimens that are optimal for immunofluorescent staining. The type of specimen that should be obtained depends on the respiratory status of the patient, concern for alternative pathogens, the institution where the specimen is being processed, and the risks of the various procedures. In most cases, sputum induction is the initial step in the attempt to obtain an adequate specimen. In many cases, however, bronchoalveolar lavage (BAL) specimens are required to make the diagnosis of PCP. The ability to detect Pneumocystis can be reduced in patients receiving prophylactic therapy, particularly those receiving aerosolized pentamidine [38,55].
Infrequently, a more invasive technique, such as a lung biopsy, is necessary. However, most patients are treated empirically without resorting to these more invasive methods because of the significant morbidity associated with their use. In patients in whom an alternative diagnosis is likely, the use of these techniques may be necessary.
Sputum induction — The least invasive method of definitively diagnosing PCP in individuals with HIV is by analysis of sputum induced via the inhalation of hypertonic saline. While the specificity of this method can approach 100 percent, the sensitivity is highly variable, ranging from 55 to approximately 90 percent [56-58]. Factors that affect the accuracy of sputum induction include the type of staining that is used, the quality of the specimen, the burden of organisms (particularly in the setting of prophylactic therapy), and the expertise of the laboratory in interpreting the specimen.
Bronchoalveolar lavage — In individuals with HIV, bronchoalveolar lavage (BAL) is highly sensitive for the diagnosis of PCP. Therefore, if sputum induction is nondiagnostic or cannot be performed (eg, the patient cannot cooperate, is too dyspneic, or is unable to produce a specimen), fiberoptic bronchoscopy with BAL is the next recommended step.
BAL alone has a diagnostic yield of 90 to 100 percent in patients with HIV. To increase its sensitivity, site-directed lavage can be used in patients with focal infiltrates; this involves sampling the most heavily involved lobes on chest radiograph. One group has shown that the combination of site-directed lavage and immunofluorescent antibody staining increased the sensitivity of BAL from 80 to 98 percent [59]. Transbronchial biopsy, which has a diagnostic yield of up to 100 percent, can be added if necessary. PCR may further add to the sensitivity of BAL. (See 'Identifying the organism' above.)
The major concerns with using BAL are the potential risks of the procedure. These include respiratory failure (rare) and fever (common). Transbronchial biopsy can be complicated by hemoptysis and pneumothorax (the latter occurring in less than 2 percent).
Tissue biopsy — If sputum induction, BAL, and a transbronchial biopsy are nondiagnostic or cannot be performed, more invasive techniques may be necessary to diagnose PCP. Options include transthoracic needle biopsy or lung biopsy performed either via thoracotomy or by video-associated thoracoscopic surgery. However, the risks with these procedures, which are significant, must be weighed against the need for an accurate and definitive diagnosis:
●Transthoracic needle biopsy, which has a high diagnostic yield, is associated with a 30 percent incidence of pneumothorax.
●Lung biopsy, either by thoracotomy or by video-assisted thoracoscopic surgery, can be performed with a sensitivity of 95 to 100 percent for the diagnosis of PCP [24]. Histology on lung biopsy demonstrates the formation of a foamy, eosinophilic alveolar exudate; severe cases are associated with edema and interstitial fibrosis [60].
Endotracheal aspirates — Endotracheal aspirates from intubated and mechanically ventilated patients have a high sensitivity for the detection of PCP. As an example, one study of 31 intubated patients found that endotracheal aspirates examined with immunostaining techniques had a sensitivity of 92 percent for PCP, with immunostained BAL specimens serving as the reference standard [61]. Thus, examination of endotracheal aspirates in intubated patients may obviate the need for bronchoscopy in many cases.
Presumptive diagnosis — There are times when a definitive diagnosis cannot be made due to a low burden of organisms and/or the inability to obtain the necessary specimen. In those situations, a decision must be made whether or not to continue treatment.
Clinical and radiographic findings can be highly suggestive of a diagnosis of PCP in patients with low CD4 cell counts. Increasingly, elevated levels of 1-3-beta-D-glucan are used to help support this diagnosis. Thus, some clinicians may choose to forego obtaining a definitive diagnosis if beta-glucan levels are markedly elevated and the clinical presentation and radiographic findings are highly consistent with PCP. Others, however, recommend obtaining a definitive diagnosis if possible [24].
Support for the diagnostic utility of 1-3-beta-d-glucan levels is provided by a study of 282 patients with HIV in which levels greater than 80 pg/mL were associated with a sensitivity and specificity of 92 and 65 percent for the diagnosis of PCP, respectively [35]. Further analysis showed that, among individuals with advanced immunosuppression and respiratory symptoms, the positive and negative predictive values for PCP of a beta-glucan level of greater than 80 pg/mL was 96 and 60 percent, respectively [62]. Elevated levels can also be observed in patients infected with other fungi (in particular histoplasmosis), and false positives can be seen as a result of other clinical variables. Therefore, potential confounding factors must be considered when interpreting the results of this test. (See "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)
In patients without evidence of an alternative and/or concurrent diagnosis, we continue therapy for presumed PCP in individuals with all of the following clinical features:
●Advanced immunosuppression (CD4 cell count less than 200 cells/microL)
●Clinical signs and symptoms such as cough, fever, dyspnea, hypoxemia (especially with exercise)
●Radiographic findings consistent with PCP on chest x-ray (interstitial, or alveolar infiltrates) or HRCT (patchy or nodular ground-glass attenuation)
●An elevated 1-3-beta-D-glucan level (defined as greater than 80 pg/mL) [62].
These patients must be closely monitored for failure to respond to treatment or clinical deterioration. In those cases, a more extensive work up may be indicated. (See 'Optimal specimens' above and 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS
Overview — Patients with HIV may have symptoms and/or signs that mimic PCP which are due to a wide variety of disease processes. Considerations include acute bronchitis, pneumonia due to bacteria, fungi, viruses and mycobacteria, neoplasm, drug hypersensitivity, pulmonary hypertension, and cardiomyopathy. These diseases may present with atypical signs and/or symptoms in patients with advanced immunosuppression and the clinician must be diligent in ensuring that they are not responsible for the underlying clinical presentation. This is discussed separately. (See "Approach to the HIV-infected patient with pulmonary symptoms".)
Pulmonary infections with specific organisms are a significant concern in patients with HIV and CD4 counts less than 200 cells/microL. These include tuberculosis, nontuberculous mycobacteria, several different fungi, toxoplasma, cytomegalovirus, and influenza. Kaposi’s sarcoma involving the lung is also a concern, particularly in patients with CD4 counts less than 100 cells/microL.
Tuberculosis — Patients with tuberculosis (TB) present with fever, cough, weight loss, night sweats and malaise. As immunity declines, the frequency of pulmonary cavitation, which is the hallmark of pulmonary TB in adults, becomes progressively less common [63,64]. In individuals with HIV and advanced immunosuppression, the findings on chest radiographs can vary, ranging from no evidence of disease to a miliary pattern. (See "Diagnosis of pulmonary tuberculosis in adults".)
Compared with PCP, tuberculosis is associated with more severe constitutional symptoms. The incidence of TB in individuals with HIV varies markedly depending on epidemiology. Most cases in the United States now occur in individuals originally from countries where TB is highly endemic, or in those with risk factors for exposure (eg, prisoners, injection drug users, household contacts of active TB cases).
Nontuberculous mycobacteria — There are a variety of nontuberculous mycobacteria (NTM) that can cause disease in patients with HIV, especially in those with CD4 cell counts less than 50 cells/microL. Most disease in HIV secondary to NTM presents as disseminated disease, without respiratory symptoms or pulmonary involvement; this is particularly the case for Mycobacterium avium complex (MAC). This manifestation of MAC is different from the multifocal nodular disease (with "tree in bud" radiographic opacities) seen in immunocompetent hosts, such as those with bronchiectasis. However, on rare occasions disease due to M. kansasii and M. xenopi can present with localized pulmonary findings.
Fungi — Patients with HIV who are from regions known to have endemic fungal infections can present with disseminated diseases that may mimic PCP. The most important of these is disseminated histoplasmosis. Both diagnoses should be considered in a patient with fever, cough, and diffuse interstitial infiltrates who is from a histoplasmosis-endemic area. Elevated beta-glucan levels are observed in both PCP and histoplasmosis. Findings suggestive of histoplasmosis include adenopathy, hepatosplenomegaly, and/or the presence of oral or other mucosal ulcerations. The diagnosis is confirmed with histoplasmosis antigen testing. Other fungi, including cryptococcus and coccidioides, can also mimic PCP. (See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV" and "Cryptococcus neoformans infection outside the central nervous system", section on 'HIV-positive patients'.)
Toxoplasma — Pneumonitis, as an extracerebral manifestation of toxoplasmosis, presents with fever, dyspnea and non-productive cough [65]. Chest radiographs typically have reticulonodular infiltrates. The clinical picture may therefore be indistinguishable from PCP. Toxoplasma, which is a much less common respiratory pathogen than Pneumocystis in patients with HIV and low CD4 counts, can be identified in bronchoalveolar lavage (BAL) fluid [65,66]. (See "Toxoplasmosis in patients with HIV", section on 'Pneumonitis'.)
Cytomegalovirus — Pneumonitis due to Cytomegalovirus (CMV) typically occurs in patients with HIV and CD4 cell counts less than 50 cells/microL. CMV pneumonitis and PCP have similar clinical presentations, but CMV pneumonitis is much less common in patients with HIV. A definitive diagnosis of CMV pneumonitis requires observing CMV inclusion bodies on biopsy.
Influenza — Individuals with HIV are considered at high risk for complications of influenza, one of which is primary influenza pneumonia. This presents with the acute onset of a severe viral syndrome (fever, myalgias, headache) followed by progressive respiratory symptoms such as dyspnea and possibly cyanosis. Typical radiographic manifestations include bilateral reticular or reticulonodular opacities with or without superimposed consolidation. High-resolution computed tomography (CT) may show multifocal peribronchovascular or subpleural consolidation and/or ground glass opacities. Unlike the acute onset of influenza pneumonia, symptoms associated with PCP occur in a subacute fashion. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Pneumonia'.)
COVID-19 — Patients with coronavirus disease 2019 (COVID-19) and Pneumocystis pneumonia can present with dry cough and oxygen desaturation with ambulation. In addition, both can have ground-glass opacities on chest CT. Given these similarities, the diagnosis of Pneumocystis may not be considered, especially when COVID-19 incidence is high [67]. Although chest CT findings are more likely to involve the upper lobes in patients with Pneumocystis pneumonia, whereas chest CT abnormalities often have a peripheral distribution and involve the lower lobes in patients with COVID-19, there are no pathognomonic radiographic findings that would lead to the exclusion of either diagnosis without further testing. In some patients, concurrent COVID-19 and Pneumocystis pneumonia have been reported [68]. The diagnosis of COVID-19 is typically based on the results of polymerase chain reaction (PCR) testing from a nasopharyngeal swab. (See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)
Kaposi sarcoma — Kaposi sarcoma may cause a multifocal nodular disease in individuals with HIV and CD4 counts less than 100 cells/microL. Although most patients with pulmonary symptoms have skin findings, up to 20 percent have no evidence of cutaneous disease. Direct visualization of characteristic lesions on bronchoscopy remains the gold standard for diagnosis; if bronchoscopy cannot be performed, findings with nuclear scans can help differentiate KS from PCP. (See "Pulmonary involvement in AIDS-related Kaposi sarcoma".)
EXTRAPULMONARY DISEASE — Extrapulmonary manifestations of Pneumocystis infection are rare and have been observed in patients with very advanced HIV infection, as well as in those receiving second-line therapy for PCP prevention, including dapsone and aerosolized pentamidine. Current or prior PCP does not need to be present at the time of presentation, and disease can be restricted to a single site. However, when multiple noncontiguous sites are involved, pulmonary disease is often present [69].
Extrapulmonary Pneumocystis has been reported to involve the eye (typically the choroid layer), ear, thyroid, spleen, bone marrow, as well as multiple other sites. In most cases, the diagnosis is made by detection of cysts in GMS-stained, formalin fixed tissue. In some situations, such as when disease is localized to the eye, the diagnosis is based on the characteristic appearance of the lesion on exam and supported by the appropriate response to therapy. The prognosis is better when disease is limited to the eye or ear compared with disseminated disease at noncontiguous sites [69].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Pneumocystis pneumonia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Although the incidence is decreasing, Pneumocystis pneumonia (PCP) remains one of the leading causes of opportunistic infection in individuals with HIV. Most cases occur in patients who are not receiving antiretroviral therapy (ART), either because they are newly diagnosed with HIV or not engaged in care. (See 'Epidemiology' above.)
●Pneumocystis is currently recognized as a fungus based upon ribosomal RNA and other gene sequence homologies, the composition of their cell walls, and the structure of key enzymes. (See 'Microbiology and terminology' above.)
●Risk factors include not receiving ART, a CD4 cell count less than 200 cells/microL, a CD4 cell percentage of less than 14 percent, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV RNA levels. (See 'Risk factors' above.)
●The clinical manifestations, which are most commonly gradual in onset, are characterized by fever, cough, and dyspnea progressing over days to weeks. (See 'Clinical manifestations' above.)
●If PCP is a consideration, we measure CD4 counts, oxygen saturation, and 1-3-beta-D-glucan levels (if available). We also obtain a chest radiograph and, if the plain film is nondiagnostic, a high resolution CT scan of the lung. (See 'Evaluation and diagnosis' above.)
●A definitive diagnosis of PCP requires visualization of the cystic or trophic forms in respiratory secretions. Empiric treatment should be initiated in acutely ill patients in whom there is a high clinical suspicion for PCP. (See 'Evaluation and diagnosis' above.)
●In most cases, sputum induction is the initial step in the attempt to obtain an adequate specimen. In many cases, however, bronchoalveolar lavage (BAL) specimens are required to make the diagnosis of PCP. (See 'Optimal specimens' above.)
●There are times when a definitive diagnosis is unable to be made due to a low burden of organisms and/or the inability to obtain the necessary specimen. In those situations, we make a presumptive diagnosis of PCP in the patient with a clinical presentation and radiographic findings that are highly consistent with PCP, particularly if beta-glucan levels are marked elevated. (See 'Presumptive diagnosis' above.)
●The differential diagnosis is broad, and includes acute bronchitis, pneumonia due to bacteria, fungi, viruses and mycobacteria, neoplasm, drug hypersensitivity, pulmonary hypertension, and cardiomyopathy. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Patricia Tietjen, MD, who contributed to an earlier version of this topic review.
We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges Dr. Bartlett's role as section editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases, and his dedicated and longstanding involvement with the UpToDate program.
