Next Article in Journal
First Report of the Production of Mycotoxins and Other Secondary Metabolites by Macrophomina phaseolina (Tassi) Goid. Isolates from Soybeans (Glycine max L.) Symptomatic with Charcoal Rot Disease
Next Article in Special Issue
Disseminated Mucormycosis in Immunocompromised Children: Are New Antifungal Agents Making a Difference? A Multicenter Retrospective Study
Previous Article in Journal
Implementation of MALDI-TOF Mass Spectrometry and Peak Analysis: Application to the Discrimination of Cryptococcus neoformans Species Complex and Their Interspecies Hybrids
Previous Article in Special Issue
Candidemia in Children with Malignancies: Report from the Infection Working Group of the Hellenic Society of Pediatric Hematology-Oncology
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JoF
Volume 6
Issue 4
10.3390/jof6040331
jof-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Pneumocystis jirovecii Pneumonia in Children with Hematological Malignancies: Diagnosis and Approaches to Management

by
Elpis Mantadakis
Department of Pediatrics, Hematology/Oncology Unit, University General Hospital of Alexandroupolis, Democritus University of Thrace, 68 100 Alexandroupolis, Thrace, Greece
J. Fungi 2020, 6(4), 331; https://doi.org/10.3390/jof6040331
Submission received: 13 November 2020 / Revised: 1 December 2020 / Accepted: 1 December 2020 / Published: 2 December 2020
(This article belongs to the Special Issue Invasive Fungal Infections in Paediatric Haematology: Accomplishments and Challenges)
Versions Notes

Abstract

:
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that mostly affects children with suppressed cellular immunity. PJP was the most common cause of infectious death in children with acute lymphoblastic leukemia prior to the inclusion of cotrimoxazole prophylaxis as part of the standard medical care in the late 1980s. Children with acute leukemia, lymphomas, and those undergoing hematopoietic stem cell transplantation, especially allogeneic transplantation, are also at high risk of PJP. Persistent lymphopenia, graft versus host disease, poor immune reconstitution, and lengthy use of corticosteroids are significant risk factors for PJP. Active infection may be due to reactivation of latent infection or recent acquisition from environmental exposure. Intense hypoxemia and impaired diffusing capacity of the lungs are hallmarks of PJP, while computerized tomography of the lungs is the diagnostic technique of choice. Immunofluorescence testing with monoclonal antibodies followed by fluorescent microscopy and polymerase chain reaction testing of respiratory specimens have emerged as the best diagnostic methods. Measurement of (1-3)-β-D-glucan in the serum has a high negative predictive value in ruling out PJP. Oral cotrimoxazole is effective for prophylaxis, but in intolerant patients, intravenous and aerosolized pentamidine, dapsone, and atovaquone are effective alternatives. Ιntravenous cotrimoxazole is the treatment of choice, but PJP has a high mortality even with appropriate therapy.

1. Introduction

Pneumocystis jirovecii is an important cause of pneumonitis in immunocompromised children. The organism was initially described by Chagas and Delanoes but was later named in honor of Antonio Carini, who isolated it from infected rats [1]. Since the genus incorporates various species that are host-specific, the organism causing human pneumonia and previously known as P. carinii was renamed as P. jirovecii, in honor of Otto Jirovec, a Czech Professor of Parasitology, who first isolated the organism from humans [2,3].
Pneumocystis was initially misclassified as a trypanosome and later as a protozoan because of the morphologic features of the small trophic form, the larger cyst form, and the rupture of its cyst to release new trophozoites. However, an analysis of the small ribosomal RNA subunit clearly established a phylogenetic linkage to the fungal kingdom, and all subsequent studies have verified that Pneumocystis is a fungus [4].
In 2014, the first successful cultivation and propagation of Pneumocystis directly from bronchoalveolar lavage (BAL) fluid was achieved, using a three-dimensional air–liquid interface culture system formed by a respiratory epithelial cell line [5]. While this represents a breakthrough and provides the potential to perform antifungal susceptibility testing [6], the process still requires cell culture and confirmation of the method by other laboratories, severely limiting its use in everyday diagnostics.

2. P. jirovecii in Human Disease

Pneumocystis first came to attention as a cause of pneumonitis in malnourished infants in the 1940s [7]. Before the 1980s, a few dozen cases of P. jirovecii pneumonia (PJP) were reported annually in USA, almost exclusively in patients with cancer receiving chemotherapy without chemoprophylaxis [8]. Since 1981, PJP has been recognized as an acquired immunodeficiency syndrome (AIDS)-defining illness and the most common opportunistic infection in Human Immunodeficiency Virus (HIV)-positive patients [9].
PJP is almost never observed in immunocompetent persons. In recent years, the diagnosis of PJP has increased among non-HIV patients [10,11], particularly among those who receive immunosuppressive therapy for hematological malignancies [12,13], solid tumors, collagen vascular diseases [14], and hematopoietic or solid organ transplantation [15]. In a single-center study from Denmark of 604 patients with PJP, the ratio of non-HIV versus HIV patients increased from 1.7 to 5.6 during the 9 year study period [16]. A British study also demonstrated that the laboratory-confirmed cases, deaths, and hospital admissions from PJP in England increased by an average of 7% per year from 2000 to 2010, but this surge was limited to patients with hematological malignancies or who had been transplanted [17].
In children with leukemia, PJP was by far the most common cause of infectious death prior to the inclusion of PJP prophylaxis as part of the standard medical care [18]. PJP is one of the 14 acute toxic effects of antileukemic therapy recognized by Delphi consensus by 15 international childhood acute lymphoblastic leukemia (ALL) study groups [19]. Children with brain neoplasms receiving high-dose corticosteroids or methotrexate are also at increased risk for PJP [20,21]. In fact, nowadays, chronic corticosteroid use is the single most important risk factor for patients without AIDS who develop PJP. A daily dose of corticosteroids 16 mg of prednisone equivalent for a period 8 weeks is associated with a significant risk of PJP [22]. In assessing a patient’s overall risk for PJP, the clinician should weigh not only the use of corticosteroids, but also consider the underlying disease itself, and its therapy. For example, methotrexate, an essential antileukemic drug in ALL, is independently associated with increased risk of developing PJP in patients with rheumatoid arthritis [23].
Besides children with AIDS and cancer, PJP is rare, even among children receiving long-term corticosteroid therapy. In a retrospective cohort of patients ≤18 years of age who received at least two prescriptions for a systemic glucocorticoid within a 60-day period and did not have cancer, AIDS or, history of transplantation, the incidence of PJP was 0.61 and 0.53 per 10,000 patient-years in those exposed and unexposed to PJP prophylaxis, respectively [24].
The epidemiology of PJP in children with hematologic malignancies and other types of cancer has not been thoroughly studied. A prospective survey of the regimens adopted for PJP prophylaxis in Italian centers of pediatric hematology–oncology showed the cumulative incidence of PJP at 3 years to be only 0.09% [25]. A retrospective cohort study of children with newly diagnosed cancer between January 2004 and December 2009 at 45 U.S. children’s hospitals disclosed 33,067 cancer patients, 169 (0.5%) of whom developed PJP. Patients with ALL and acute myeloid leukemia (AML) had the highest relative risks of PJP, when compared with other types of cancer [26].
Children with high-risk ALL or high-grade non-Hodgkin lymphomas that receive intensely immunosuppressive regimens are at an exceptionally high risk for PJP [27]. Children with Hodgkin’s lymphoma are also at risk because they are frequently lymphopenic at diagnosis or will become lymphopenic with chemotherapy [28]. Children undergoing hematopoietic stem cell transplantation (HSCT) are also at high risk for developing PJP. The Center for International Blood and Marrow Transplant Research evaluated the incidence, timing, prophylactic agents, risk factors, and mortality of PJP after autologous and allogeneic HSCT. Overall, 0.63% of allogeneic and 0.28% of autologous recipients of their first HSCT developed PJP [29]. Risk factors for PJP infection included lymphopenia and mismatched HSCT. Overall, survival was significantly poorer among cases versus controls; risk factors included graft versus host disease (GVHD) and poor immune reconstitution [29].

3. Clinical Picture and Imaging Findings of PJP

P. jirovecii is transmitted through the airborne route, and most children worldwide have been exposed to the organism before their fourth birthday [30,31]. In children with leukemia, PJP has a high mortality even with prompt therapy [18,32]. Extrapulmonary involvement is rare compared with in patients with advanced AIDS. In the lungs, the trophic form of P. jirovecii attaches to type I alveolar epithelial cells, which allows the fungus to be transformed into its cystic form [33]. Asymptomatic lung colonization is common in patients with normal immunity. Human-to-human spread is well documented [34,35,36], and both asymptomatic colonizers and patients with pneumonia can transmit the fungus to immunocompromised people. Molecular epidemiologic studies have suggested that active infection may be due to reactivation of latent infection or due to recent acquisition from environmental exposure [35,37,38].
PJP is characterized by the presence of intra-alveolar foamy exudate, diffuse alveolar damage, and interstitial lymphoid infiltrates [39]. It is the host’s inflammatory response that causes significant lung injury [40], and this response is more pronounced in children with leukemia than in children with AIDS. All signs and symptoms of PJP are nonspecific, and a high index of suspicion is required for early diagnosis. Leukemic children with PJP at presentation may have fever with or without chills, nonproductive cough, tachypnea, intercostal retractions, nasal flaring, weight loss, and progressive exertional dyspnea [41]. Hemoptysis can occur but is rare, while cyanosis occurs in cases with severe hypoxemia. Physical examination reveals mild crackles and rhonchi, but the results can be surprisingly normal in many patients despite profound dyspnea. Intense hypoxemia—out of proportion to that expected based on the clinical picture—with an increased alveolar–arterial oxygen gradient, respiratory alkalosis, and impaired diffusing capacity of the lungs are hallmarks of PJP. In general, patients with leukemia and PJP have more acute and severe disease compared with patients with AIDS [42,43]. However, as the knowledge of PJP in HIV-uninfected patients has increased and the laboratory diagnosis perfected, it is now more common to see pneumonia in leukemic patients presenting with more indolent course [44].
On chest radiography, diffuse bilateral lung infiltrates extending from the perihilar region are seen in most patients, but unilateral or asymmetric infiltrates can occur. Compared to patients with bacterial pneumonia, patients with PJP are more likely to have bilateral lung disease, higher frequency of hypoxemia, and lower frequency of pleural involvement [41]. However, no radiological findings are pathognomonic of PJP.
Depending on the presenting symptoms and oxygen saturation by pulse oximetry, PJP can be stratified into mild, moderate, and severe [32]. In severe PJP, dyspnea and tachypnea are present at rest, oxygen saturation is 91%, and chest radiography usually demonstrates extensive bilateral interstitial lung changes along with diffuse alveolar shadowing. The need for mechanical ventilation in patients with severe PJP dramatically increases the risk of death [45].
High-resolution computerized tomography (HRCT) is the best radiological method for diagnosis of PJP and should be considered, even if chest radiographs are normal [46]. On HRCT, PJP typically presents with bilateral mosaic regions of ground-glass attenuation and thickening of the interlobar septa [46,47]. Bilateral ground-glass opacities on the upper lobes with peripheral sparing are the typical imaging findings in non-HIV immunocompromised patients [48]. Lymphadenopathy is uncommon. In immunocompromised patients, bronchial wall thickening is more indicative of bacterial pneumonia, presence of nodules is more characteristic of fungal infection, and a mosaic pattern is more indicative of PJP [49]. Different immune reactions to P. jirovecii in patients with and without AIDS lead to different radiographic patterns. Thus, air cysts, pneumothorax, and pneumomediastinum are much less common in patients with leukemia compared with patients with AIDS [50]. In adults, the mean lung attenuation (MLA) on CT scans highly correlates with Acute Physiology and Chronic Health Evaluation II scores and the need for mechanical ventilation, but MLA has limited value in predicting patient mortality [51]. For diagnostic purposes, decreased diffusion capacity of carbon monoxide (DLCO) is useful, since PJP is highly unlikely if DLCO is normal [52]. When the CT findings are unclear, fluorodeoxyglucose positron emission tomography (FDG PET) can be used to diagnose PJP, and it also aids with monitoring response to therapy [53,54,55].
Differences in the laboratory features, clinical presentation, and imagining findings of children with PJP and leukemia versus AIDS are summarized in Table 1.

4. Laboratory Diagnosis of PJP

Serum lactate dehydrogenase (LDH) is typically elevated in patients with AIDS and PJP, but a single-center retrospective analysis identified initial LDH values as a tool to identify patients at high risk of death irrespective of HIV status [57]. As mentioned previously, culturing P. jirovecii has proven very difficult and is not a routine diagnostic investigation. This creates a major problem with PJP diagnosis since there is a lack of a true gold standard diagnostic assay. In the past, the best assay for confirming a diagnosis of PJP was the histological identification of its trophic forms and cysts in clinical specimens using a variety of different stains. Giemsa, Diff-Quik (a modified Giemsa stain with very short preparation time), crystal violet, Wright, Gomori methenamine silver (GMS), and Toludine blue O (TBO) have traditionally been used, but have decreased sensitivity compared with immunofluorescence antibody testing (IFAT) [58,59]. Giemsa, Diff-Quik, crystal violet, and Wright stains can detect both the trophozoite and cyst forms of the fungus, while GMS and TBO selectively stain the wall of Pneumocystis cysts [60]. IFAT with labelled monoclonal antibodies followed by fluorescent microscopy has surpassed conventional microscopy due to its superior sensitivity [61], especially when testing BAL fluid as compared with samples from the upper airways. If IFAT is unavailable, Giemsa or TBO should be used as the primary staining method, with confirmation of the results with GMS [62]. All staining methods are limited by the quality of the respiratory specimens and the experience of the laboratory personnel. The isolated use of microscopy for diagnosis should be avoided due to its low sensitivity and specificity and its inability to differentiate colonization from true pneumonia. Interpretation of IFAT assays may be difficult due to artifacts that can easily be confused with trophic forms or cysts by inexperienced laboratory staff [32]. Moreover, microscopy and cyst-staining assays can fail to detect PJP infection with mostly trophic forms of the fungus. Finally, microscopy is less sensitive to detect P. jirovecii in children with leukemia, who typically carry lower fungal loads than patients with AIDS [63].
Over the last decades, polymerase chain reaction (PCR) has been developed for the diagnosis of PJP in HIV and non-HIV patients, and PCR is currently included in the guidelines for the diagnosis of PJP in febrile neutropenic patients with hematological malignancies [64]. It can be used in fresh or formalin-fixed, paraffin-embedded samples [65]. It has superior sensitivity compared with immunofluorescent microscopy, but its specificity varies. By combining multiple tests, PJP can be more confidently excluded if all tests are negative and confirmed if all tests are positive in children with leukemia and HSCT recipients [66]. Positive PCR results need careful interpretation if microscopy is negative, while negative PCR results in the face of positive microscopy are technically inconsistent and likely represent artifacts or false-negative results due to the presence of PCR inhibitors in respiratory samples [66,67].
The use of conventional and nested PCR techniques has for the most part been replaced by real-time PCR, which allows quantification in clinical samples and improved specificity [68]. PCR has close to 100% negative predictive value, and a negative result can reliably exclude PJP [69,70]. Efforts are ongoing to improve the specificity of this molecular method in differentiating PJP from colonization. While successful attempts have been made to define a threshold to distinguish between pneumonia and colonization [71], these are hindered by the various molecular targets, type of sample, and volume of BAL obtained. Many gene targets have been used, but the mitochondrial large subunit of ribosomal RNA has been the most commonly used target [72]. Other targets include the short subunit of ribosomal RNA, the major surface glycoprotein [73,74], and the enzymes dihydrofolate reductase and dihydropteroate synthetase, which, however, are more commonly used for genotyping in epidemiological studies or in patients who fail cotrimoxazole therapy [75]. In summary, quantitative PCR can reliably exclude PJP, but a positive result should be interpreted in the context of the clinical signs and the patient’s immune suppression.
(1-3)-β-D-glucan (BDG) is a cell wall polysaccharide present in most fungi, including Candida spp., Aspergillus spp., and P. jirovecii (but not the Zygomycetes) that can be detected in serum/plasma using various commercially available assays [76,77]. Although it lacks specificity, patients negative by BDG or both BDG and PCR are extremely unlikely to have PJP [78]. BDG testing of BAL fluid does not add to the testing of serum and is not recommended [79]. In 31 HIV-negative, immunocompromised patients suspected of PJP on the basis of clinical presentation and chest imaging, elevated serum BDG was a reliable indicator of PJP with a sensitivity of 90% and a specificity of 89% at the 60 pg/mL cut-off [80]. In PJP- positive patients, BDG serum levels decrease during effective treatment. Preferably, BDG positivity should be combined with one of the P. jirovecii-specific assays described above, because many other fungal pathogens in children with hematological malignancies can provide high BDG serum concentrations. Surfactant protein-D is another biomarker of PJP that continues to increase after failure of treatment and may be associated with clinical outcome in non-HIV patients with PJP [81].
Open lung biopsy is the most sensitive and specific diagnostic procedure [82] but is rarely performed nowadays, especially in children with leukemia that are frequently severely ill, thrombocytopenic, and/or suffer from coagulopathy, when they present with a new-onset pulmonary infiltrate.

5. Differential Diagnosis of PJP

The differential diagnosis of PJP in a child with leukemia is extensive and includes cytomegalovirus (CMV) and other viral pneumonias, lymphocytic interstitial pneumonia, atypical bacterial pneumonia due to Mycoplasma pneumoniae and Chlamydia pneumoniae, legionellosis, lung infection by M. tuberculosis or by nontuberculous mycobacteria, pulmonary embolism, and pulmonary GVHD. PJP can occur in conjunction with CMV in non-HIV immunocompromised patients with respiratory failure, and mortality may be increased in the setting of coinfection [83]. Coinfection with CMV was significantly more common in adult patients who were receiving corticosteroids and T-cell immunosuppressants, compared with corticosteroids alone [84].

6. Prophylaxis against PJP

The Centers for Disease Control and Prevention recommends patients with PJP not to have direct contact with other immunosuppressed patients [85]. Protective isolation decreases but does not eliminate the risk of PJP, as shown by a retrospective survey in which 12 of 55 adults with hematological malignancies who developed PJP were on protective isolation in a laminar airflow room [86].
Without chemoprophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop PJP [18]. Pioneering studies in the 1970s demonstrated the central role of cotrimoxazole in the prevention of this serious infection [87]. Cotrimoxazole prophylaxis for PJP is so successful that nowadays noncompliance with drug-taking is the main reason for pneumonia. This is more common in older children and adolescents with cancer and poor obedience with the administered therapy [88]. Hughes et al., in a double-blinded, placebo-controlled clinical trial conducted at St. Jude Children’s Research Hospital (SJCRH), randomized 160 children and young adults with cancer to receive placebo or 150 mg of trimethoprim and 750 mg of sulfamethoxazole per square meter of body surface area per day. Remarkably enough, 17 of 80 patients receiving placebo developed PJP versus none of the 80 patients given cotrimoxazole [89]. The same investigators conducted a two-year randomized clinical trial in children and adolescents with ALL to assess the efficacy of cotrimoxazole for PJP prophylaxis when given on three consecutive days per week versus daily. PJP did not develop in any of the 92 patients receiving the drug daily or in any of the 74 patients who received it on three consecutive days per week [90]. These results were confirmed by a study of the University of Milan, Italy [91]. Since cotrimoxazole intolerance with the above regimen, especially hematological toxicity, can occur and may interfere with the administration of methotrexate and 6-mercaptopurine in children receiving maintenance chemotherapy for ALL, lower doses of cotrimoxazole, that is, 18 mg/kg/day, daily or on three consecutive days per week have been successfully used for PJP prophylaxis in the Netherlands [92].
PJP prophylaxis should be considered for all allogeneic HSCT recipients and for autologous recipients who have leukemia or lymphoma, are receiving intense conditioning, or have recently received fludarabine or 2-chlorodeoxyadenosine [93]. Balanced against serious adverse events of cotrimoxazole, PJP prophylaxis in children is indicated at very low PJP incidence rates, while in adults when the risk for pneumonia exceeds >3.5% [94].
According to the European Conference on Infections in Leukemia (ECIL) guidelines, standard indications for PJP prophylaxis are as follows: ALL patients from induction to end of maintenance chemotherapy, allogeneic HSCT recipients from engraftment to 6 months and as long as receiving immunosuppressive therapy, recipients of alemtuzumab, and recipients of corticosteroids >0.4 mg/kg/day or 16 mg/day of prednisone equivalent for >1 month. Optional indications are lymphoma patients treated with R-CHOP14 or escalated BEACOPP, patients on fludarabine, cladribine, or mycophenolate mofetil, patients with primary brain tumors or brain metastases on high-dose corticosteroids, and patients with AML and solid tumors throughout the duration of chemotherapy [95].
Intermittent dosing of cotrimoxazole on two instead of three consecutive or nonconsecutive days per week is also effective in children with leukemia and lymphoma [96,97,98,99]. A prospective survey of the regimens adopted for PJP prophylaxis in all children with cancer treated at Italian centers of Pediatric Oncology showed that even a single-day per week course of prophylaxis with cotrimoxazole at 5–10 mg/kg/week for trimethoprim may be sufficient to prevent PJP in children with cancer undergoing intensive chemotherapy [25].
In spite of the above, occasionally patients with hematological malignancies still fail prophylaxis and develop pneumonia [56]. A systematic review of children with ALL and adults with acute leukemia, solid organ transplantation, and autologous bone marrow transplantation estimated that the number of patients needed to treat to prevent PJP is 19 (95% confidence intervals 17 to 42) [100].
Intravenous or aerosolized pentamidine, oral dapsone, and atovaquone are acceptable alternatives for children unable to tolerate cotrimoxazole due to an allergic reaction or hematological toxicity. Table 2 summarizes studies of children with cancer who underwent HSCT and received intravenous pentamidine for PJP prophylaxis [101,102,103,104,105,106,107,108,109].
Similar results for adults undergoing HSCT have been published illustrating efficacy, safety, and patient approval of intravenous pentamidine for PJP prophylaxis [110,111], although some have questioned the efficacy of intravenous pentamidine in children undergoing chemotherapy [112].
Regarding aerosolized pentamidine for PJP prophylaxis, beyond the SJCRH study [101], limited data are available. Aerosolized pentamidine was administered to 22 children with acute leukemia during maintenance chemotherapy or post-Bone Marrow Transplantation (BMT) and was adequately tolerated and efficacious, since none of the patients developed PJP during the 3.5 years of close observation [113]. Investigators at the University of Texas Southwestern Medical Center at Dallas administered monthly aerosolized pentamidine 200 mg/m2 to 60 children with malignancies who had experienced severe adverse reactions to cotrimoxazole; they found that none of the treated patients developed PJP during more than a year of observation. However, adverse reactions including bronchospasm, cough, vomiting, and nausea occurred during 10% of the treatments, although only three patients (5%) discontinued therapy [114]. In adults, two large studies show that aerosolized pentamidine is clearly inferior to cotrimoxazole in preventing PJP in the post-transplantation setting for hematologic malignancies, aplastic anemia, or myelodysplasia and is associated with a higher mortality at one year after transplantation [115,116]. Besides, aerosolized pentamidine is frequently avoided in children <5 years of age due to concerns regarding their ability to inhale the entire dose.
Considering dapsone, its weekly oral administration has been feasible and effective for prevention of PJP because of its prolonged plasma half-life and the long incubation period and replication cycle of P. jirovecii [117]. Maltezou et al. reviewed 33 children who underwent BMT in whom dapsone 50 mg/m2 once a week was used for PJP prophylaxis due to cotrimoxazole intolerance. After a median follow-up of one-year post-BMT, no proven cases of PJP were diagnosed [118]. Sangiolo et al. compared 155 HSCT recipients on dapsone prophylaxis with 310 matched control patients who received cotrimoxazole throughout the post-transplantation course. Two of 155 patients developed PJP versus 0 of 310 controls [119]. Souza et al. evaluated the effectiveness of dapsone prophylaxis 50 mg orally twice daily for three days per week to twice weekly cotrimoxazole in preventing PJP after allogeneic HSCT in 646 adults who received allogeneic transplantation. The incidence of PJP was 0.37% for cotrimoxazole versus 7.2% for dapsone, a highly significant difference that was not accounted for by age, donor source, chronic GVHD, or disease relapse [120]. Hence, extreme caution is required in the transplantation setting when using an alternative to cotrimoxazole regimens for PJP prophylaxis. If dapsone is used, the patient should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency because the drug can cause hemolysis [121]. Moreover, heterozygosity for cytochrome b5 reductase deficiency may predispose children with leukemia to methemoglobinemia even on a thrice-weekly regimen of dapsone [122,123]. Finally, the drug is metabolized via the hepatic P-450 system; thus, it can interfere with cyclosporine metabolism in transplanted patients and in children with leukemia who receive prophylactic or therapeutic antifungal azoles.
Another alternative to cotrimoxazole for PJP prophylaxis in children with leukemia is atovaquone. A SJCRH study reviewed 86 children with ALL or AML who received atovaquone daily for PJP prophylaxis due to intolerance to cotrimoxazole. PJP was not diagnosed in any patient [124]. Atovaquone is very expensive and requires ingestion with fatty foods for optimal absorption. Common side effects include headache, skin rash, and gastrointestinal disturbances, but bone marrow toxicity is uncommon. Prophylactic regimens for PJP in children with leukemia and HSCT recipients are summarized in Table 3 [95,125].
Notably, guidelines have been published that recommend all children with malignancies undergoing chemotherapy, including those with solid tumors, receive prophylaxis with cotrimoxazole, unless well-defined contraindications exist [126].

7. Treatment of PJP

Early diagnosis and treatment of PJP are crucial for survival [127]. P. jirovecii is extremely resistant to traditional antifungal agents, including polyenes and azoles [128]. On the other hand, animal and limited clinical data indicate that echinocandins have activity against P. jirovecii [129,130]. The European Organization for Research and Treatment of Cancer, the International Immunocompromised Host Society, and The European LeukemiaNet have jointly published guidelines for the treatment of PJP in non-HIV-infected hematology patients [131]. Treatment of choice for PJP remains intravenous cotrimoxazole, that is, trimethoprim 15–20 mg/kg/day and sulfamethoxazole 75–100 mg/kg/day divided in two to four daily doses. Treatment should be initiated immediately after obtaining appropriate samples, that is, nasopharyngeal aspirates in infants [132], sputum in adolescents, and BAL with fiberoptic bronchoscopy in children of all ages [66]. Fiberoptic bronchoscopy is generally a safe and highly diagnostic procedure in the immunocompromised host with pneumonia due to opportunistic pathogens [133].
Documenting the serum levels of trimethoprim or sulfamethoxazole is useful in critically ill patients receiving intravenous cotrimoxazole therapy. In individual patients with persistent PJP despite adequate therapy with cotrimoxazole, search for mutations in the genes for dihydropteroate synthase or dihydrofolate reductase may be justified [134]. However, P. jirovecii genotypes are unlikely to have clinical relevance in most cases [135,136].
Treatment with intravenous cotrimoxazole is continued for three weeks, and clinical improvement is usually apparent after seven days of therapy. If clinical improvement does not develop within a week, a second infection or resistance to cotrimoxazole should be considered, and the diagnostic procedures repeated. In case of allergy to sulfa drugs or clinical deterioration on cotrimoxazole, second-line agents should be used, including primaquine plus clindamycin [137], atovaquone, or intravenous pentamidine. Primaquine should not be used in children with G6PD deficiency due to the risk of hemolysis [138], while clindamycin can cause pseudomembranous colitis [139]. Aerosolized pentamidine should only be reserved for children with mild disease who cannot tolerate other therapies. Therapeutic regimens for PJP in children with leukemia and HSCT recipients are summarized in Table 4.
Patients who have been successfully treated for PJP should receive secondary prophylaxis to prevent recurrence. Drugs of choice for secondary PJP prophylaxis are intermittent oral cotrimoxazole or monthly aerosolized pentamidine.
Adjunctive corticosteroids in addition to cotrimoxazole are of substantial benefit to HIV-infected patients with moderate-to-severe PJP defined by the degree of hypoxemia. In one retrospective study of non-HIV adults with severe PJP, a dose of prednisone 60 mg/day was also associated with better outcome [140]. However, other observational studies do not support the use of corticosteroids in HIV-uninfected immunocompromised patients [141]. Hence, given the lack of randomized controlled clinical trials, the decision regarding the use of corticosteroids in children with hematological malignancies and PJP should be individualized. The American Thoracic Society advises adding corticosteroids into the treatment of HIV-uninfected patients with moderate-to-severe PJP [142], but the German Society of Hematology and Medical Oncology does not recommend corticosteroids in this setting [64]. Finally, extracorporeal membrane oxygenation [143] and adjunctive surfactant treatment [144] have been successfully used in carefully selected children with PJP.

8. Conclusions

PJP is a life-threatening opportunistic infection in children with hematological malignancies receiving chemotherapy [101]. In high-risk children with leukemia, the clinical and radiological findings are usually enough for initiating empirical therapy, but every effort should be made to achieve a mycological diagnosis. IFAT and PCR of respiratory samples are now the reference diagnostic methods, but serum BDG testing is invaluable to rule out P. jirovecii as a cause of pneumonia. Oral cotrimoxazole two or three days per week is highly effective for prevention of PJP. However, given its potential for allergic reactions and hematological toxicity, other alternative drugs should be carefully considered for PJP prophylaxis in selected children with leukemia. Antimicrobial resistance of P. jirovecii appears to be clinically rare, and although in vitro cultivation of the organism for susceptibility testing has been feasible since 2014, it remains unavailable for everyday clinical diagnostics. Finally, the population of children at risk for PJP will likely increase in the future beyond children with hematological malignancies to include pediatric patients with a variety of autoimmune and inflammatory disorders treated with corticosteroids, anti-Tumor Necrosis Factor agents, and calcineurin inhibitors [145,146,147].

Funding

This manuscript received no external funding.

Acknowledgments

The author would like to thank Theoklis Zaoutis for critically reviewing the manuscript.

Conflicts of Interest

The author reports no conflict of interest. The conclusions of this article are those of the author.

References

  1. Chagas, C. Uber eine neue Trypoanosomiasis des Menschen. Mem. Inst. Oswaldo Cruz 1909, 3, 1–218. [Google Scholar]
  2. Vanek, J.; Jirovec, O. Parasitic pneumonia. Interstitial plasma cell pneumonia of premature, caused by pneumocystis Carinii. Zent. Bakteriol. Parasit. Infekt. Hygiene 1952, 158, 120–127. [Google Scholar]
  3. Stringer, J.R.; Beard, C.B.; Miller, R.F.; Wakefield, A.E. A New Name forPneumocystisfrom Humans and New Perspectives on the Host-Pathogen Relationship. Emerg. Infect. Dis. 2002, 8, 891–896. [Google Scholar] [CrossRef]
  4. Edman, J.C.; Kovacs, J.A.; Masur, H.; Santi, D.V.; Elwood, H.J.; Sogin, M.L. Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the Fungi. Nat. Cell Biol. 1988, 334, 519–522. [Google Scholar] [CrossRef]
  5. Schildgen, V.; Mai, S.; Khalfaoui, S.; Lüsebrink, J.; Pieper, M.; Tillmann, R.L.; Brockmann, M.; Schildgen, O. Pneumocystis jirovecii Can Be Productively Cultured in Differentiated CuFi-8 Airway Cells. mBio 2014, 5, e01079-14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Song, Y.; Ren, Y.; Wang, X.; Li, R. Recent Advances in the Diagnosis of Pneumocystis Pneumonia. Med. Mycol. J. 2016, 57, E111–E116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Gajdusek, D.C. Pneumocystis carinii as the cause of human disease: Historical perspective and magnitude of the problem: Introductory remarks. Natl. Cancer Inst. Monogr. 1976, 43, 1–11. [Google Scholar] [PubMed]
  8. Hallett, J.J.; Fickenscher, L.G.; Ablin, A.R. Pneumocystis Carinii Pneumonia in Children. West. J. Med. 1977, 126, 441–444. [Google Scholar]
  9. Mansell, P.W.A. Acquired Immune Deficiency Syndrome, Leading to Opportunistic Infections, Kaposi’s Sarcoma, and Other Malignancies. CRC Crit. Rev. Clin. Lab. Sci. 1984, 20, 191–204. [Google Scholar] [CrossRef]
  10. Saltzman, R.W.; Albin, S.; Russo, P.; Sullivan, K.E. Clinical conditions associated with PCP in children. Pediatr. Pulmonol. 2011, 47, 510–516. [Google Scholar] [CrossRef]
  11. Russian, D.A.; Levine, S.J. Pneumocystis carinii Pneumonia in Patients without HIV Infection. Am. J. Med. Sci. 2001, 321, 56–65. [Google Scholar] [CrossRef]
  12. Sepkowitz, K.A. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome. More patients, same risk. Arch. Intern. Med. 1995, 155, 1125–1128. [Google Scholar] [CrossRef]
  13. Pagano, L.; Caira, M.; Fianchi, L. Pulmonary fungal infection with yeasts andpneumocystisin patients with hematological malignancy. Ann. Med. 2005, 37, 259–269. [Google Scholar] [CrossRef]
  14. Aoki, Y.; Iwamoto, M.; Kamata, Y.; Nagashima, T.; Yoshio, T.; Okazaki, H.; Minota, S. Prognostic indicators related to death in patients with Pneumocystis pneumonia associated with collagen vascular diseases. Rheumatol. Int. 2009, 29, 1327–1330. [Google Scholar] [CrossRef]
  15. Martin, S.I.; Fishman, J.A.; the AST Infectious Diseases Community of Practice. Pneumocystis Pneumonia in Solid Organ Transplantation. Arab. Archaeol. Epigr. 2013, 13, 272–279. [Google Scholar] [CrossRef]
  16. Bienvenu, A.-L.; Traore, K.; Plekhanova, I.; Bouchrik, M.; Bossard, C.; Picot, S. Pneumocystis pneumonia suspected cases in 604 non-HIV and HIV patients. Int. J. Infect. Dis. 2016, 46, 11–17. [Google Scholar] [CrossRef] [Green Version]
  17. Maini, R.; Henderson, K.L.; Sheridan, E.A.; Lamagni, T.; Nichols, G.; Delpech, V.; Phin, N. Increasing Pneumocystis Pneumonia, England, UK, 2000–2010. Emerg. Infect. Dis. 2013, 19, 386–392. [Google Scholar] [CrossRef] [Green Version]
  18. Hughes, W.T.; Price, R.A.; Kim, H.-K.; Coburn, T.P.; Grigsby, D.; Feldman, S. Pneumocystis carinii pneumonitis in children with malignancies. J. Pediatr. 1973, 82, 404–415. [Google Scholar] [CrossRef]
  19. Schmiegelow, K.; Attarbaschi, A.; Barzilai, S.; Escherich, G.; Frandsen, T.L.; Halsey, C.; Hough, R.; Jeha, S.; Kato, M.; Liang, D.-C.; et al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: A Delphi consensus. Lancet Oncol. 2016, 17, e231–e239. [Google Scholar] [CrossRef]
  20. Mahindra, A.K.; Grossman, S.A. Pneumocystis carinii pneumonia in HIV negative patients with primary brain tumors. J. Neuro-Oncol. 2003, 63, 263–270. [Google Scholar] [CrossRef]
  21. Sepkowitz, K.A.; Brown, A.E.; Telzak, E.E.; Gottlieb, S.; Armstrong, D. Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital. JAMA 1992, 267, 832–837. [Google Scholar] [CrossRef]
  22. Yale, S.H.; Limper, A.H. Pneumocystis carinii Pneumonia in Patients Without Acquired Immunodeficiency Syndrome: Associated Illnesses and Prior Corticosteroid Therapy. Mayo Clin. Proc. 1996, 71, 5–13. [Google Scholar] [CrossRef] [PubMed]
  23. Hashimoto, A.; Suto, S.; Horie, K.; Fukuda, H.; Nogi, S.; Iwata, K.; Tsuno, H.; Ogihara, H.; Kawakami, M.; Komiya, A.; et al. Incidence and Risk Factors for Infections Requiring Hospitalization, Including Pneumocystis Pneumonia, in Japanese Patients with Rheumatoid Arthritis. Int. J. Rheumatol. 2017, 2017, 1–8. [Google Scholar] [CrossRef]
  24. Basiaga, M.L.; Ross, M.E.; Gerber, J.S.; Ogdie, A. Incidence of Pneumocystis jirovecii and Adverse Events Associated with Pneumocystis Prophylaxis in Children Receiving Glucocorticoids. J. Pediatr. Infect. Dis. Soc. 2018, 7, 283–289. [Google Scholar] [CrossRef]
  25. Caselli, D.; Petris, M.G.; Rondelli, R.; Carraro, F.; Colombini, A.; Muggeo, P.; Ziino, O.; Melchionda, F.; Russo, G.; Pierani, P.; et al. Single-Day Trimethoprim/Sulfamethoxazole Prophylaxis for Pneumocystis Pneumonia in Children with Cancer. J. Pediatr. 2014, 164, 389–392. [Google Scholar] [CrossRef]
  26. Naz, N.; Chiu, Y.; Edwards, M.; Redfern, A. 333. Evaluating the Risk of Pneumocystis Jirovecii Pneumonia (PCP) in Renal and Non-Remal Vasculitis Patints. Rheumatology 2019, 58, 2004–2009. [Google Scholar] [CrossRef] [Green Version]
  27. Poulsen, A.; Demeny, A.K.; Plum, C.B.; Nielsen, K.G.; Schmiegelow, K. Pneumocystis carinii pneumonia during maintenance treatment of childhood acute lymphoblastic leukemia. Med. Pediatr. Oncol. 2001, 37, 20–23. [Google Scholar] [CrossRef]
  28. Jayshree, R.S.; Appaji, L.; Sridhar, H. Pneumocystis carinii pneumonia in two patients with Hodgkin’s disease. Indian J. Cancer 1995, 32, 74–76. [Google Scholar]
  29. Williams, K.M.; Ahn, K.W.; Chen, M.; Aljurf, M.D.; Agwu, A.L.; Chen, A.R.; Walsh, T.J.; Szabolcs, P.; Boeckh, M.J.; Auletta, J.J.; et al. The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: A CIBMTR analysis. Bone Marrow Transplant. 2016, 51, 573–580. [Google Scholar] [CrossRef] [Green Version]
  30. Pifer, L.L.; Hughes, W.T.; Stagno, S.; Woods, D. Pneumocystis carinii infection: Evidence for high prevalence in normal and immunosuppressed children. Pediatrics 1978, 61, 35–41. [Google Scholar]
  31. Vargas, S.L.; Hughes, W.T.; Santolaya, M.E.; Ulloa, A.V.; Ponce, C.A.; Cabrera, C.E.; Cumsille, F.; Gigliotti, F. Search for Primary Infection by Pneumocystis carinii in a Cohort of Normal, Healthy Infants. Clin. Infect. Dis. 2001, 32, 855–861. [Google Scholar] [CrossRef] [Green Version]
  32. White, P.L.; Backx, M.; Barnes, R.A. Diagnosis and management of Pneumocystis jirovecii infection. Expert Rev. Anti-Infect. Ther. 2017, 15, 435–447. [Google Scholar] [CrossRef]
  33. Walzer, P.D. Attachment of microbes to host cells: Relevance of Pneumocystis carinii. Lab. Investig. 1986, 54, 589–592. [Google Scholar] [PubMed]
  34. Gianella, S.; Haeberli, L.; Joos, B.; Ledergerber, B.; Wüthrich, R.; Weber, R.; Kuster, H.; Hauser, P.; Fehr, T.; Mueller, N. Molecular evidence of interhuman transmission in an outbreak ofPneumocystis jiroveciipneumonia among renal transplant recipients. Transpl. Infect. Dis. 2010, 12, 1–10. [Google Scholar] [CrossRef]
  35. Morris, A.; Beard, C.; Huang, L. Update on the epidemiology and transmission of Pneumocystis carinii. Microbes Infect. 2002, 4, 95–103. [Google Scholar] [CrossRef]
  36. Nevez, G.; Chabe, M.; Rabodonirina, M.; Virmaux, M.; Dei-Cas, E.; Hauser, P.M.; Totet, A. Nosocomial Pneumocystis jirovecii infections. Parasite 2008, 15, 359–365. [Google Scholar] [CrossRef] [Green Version]
  37. Kovacs, J.A.; Gill, V.J.; Meshnick, S.; Masur, H. New Insights into Transmission, Diagnosis, and Drug Treatment of Pneumocystis carinii Pneumonia. JAMA 2001, 286, 2450–2460. [Google Scholar] [CrossRef]
  38. Fréalle, E.; Valade, S.; Guigue, N.; Hamane, S.; Chabé, M.; Le Gal, S.; Damiani, C.; Totet, A.; Aliouat, E.M.; Nevez, G.; et al. Diffusion of Pneumocystis jirovecii in the surrounding air of patients with Pneumocystis colonization: Frequency and putative risk factors: Table 1. Med. Mycol. 2016, 55, 568–572. [Google Scholar] [CrossRef] [Green Version]
  39. Luna, M.A.; Cleary, K.R. Spectrum of pathologic manifestations of Pneumocystis carinii pneumonia in patients with neoplastic diseases. Semin. Diagn. Pathol. 1989, 6, 262–272. [Google Scholar]
  40. Wright, T.W.; Gigliotti, F.; Finkelstein, J.N.; McBride, J.T.; An, C.L.; Harmsen, A.G. Immune-mediated inflammation directly impairs pulmonary function, contributing to the pathogenesis of Pneumocystis carinii pneumonia. J. Clin. Investig. 1999, 104, 1307–1317. [Google Scholar] [CrossRef]
  41. Bollée, G.; Sarfati, C.; Thiéry, G.; Bergeron, A.; de Miranda, S.; Menotti, J.; de Castro, N.; Tazi, A.; Schlemmer, B.; Azoulay, E. Clinical Picture of Pneumocystis jiroveci Pneumonia in Cancer Patients. Chest 2007, 132, 1305–1310. [Google Scholar] [CrossRef]
  42. Salzer, H.J.; Schäfer, G.; Hoenigl, M.; Günther, G.; Hoffmann, C.; Kalsdorf, B.; Alanio, A.; Lange, C. Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and Non-HIV-Infected Immunocompromised Patients with Pneumocystis jirovecii Pneumonia. Respiration 2018, 96, 52–65. [Google Scholar] [CrossRef]
  43. Kovacs, J.A.; Hiemenz, J.W.; Macher, A.M.; Stover, D.; Murray, H.W.; Shelhamer, J.; Lane, H.C.; Urmacher, C.; Honig, C.; Longo, D.L. Pneumocystis carinii pneumonia: A comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann. Intern. Med. 1984, 100, 663–671. [Google Scholar] [CrossRef]
  44. Fillatre, P.; Decaux, O.; Jouneau, S.; Revest, M.; Gacouin, A.; Robert-Gangneux, F.; Fresnel, A.; Guiguen, C.; Le Tulzo, Y.; Jégo, P.; et al. Incidence of Pneumocystis jiroveci Pneumonia among Groups at Risk in HIV-negative Patients. Am. J. Med. 2014, 127, 1242.e11–1242.e17. [Google Scholar] [CrossRef] [Green Version]
  45. Liu, Y.; Su, L.; Jiang, S.-J.; Qu, H. Risk factors for mortality from pneumocystis carinii pneumonia (PCP) in non-HIV patients: A meta-analysis. Oncotarget 2017, 8, 59729–59739. [Google Scholar] [CrossRef] [Green Version]
  46. Kanne, J.P.; Yandow, D.R.; Meyer, C.A. Pneumocystis jiroveci Pneumonia: High-Resolution CT Findings in Patients with and Without HIV Infection. Am. J. Roentgenol. 2012, 198, W555–W561. [Google Scholar] [CrossRef] [Green Version]
  47. Toma, P.; Bertaina, A.; Castagnola, E.; Colafati, G.S.; D’Andrea, M.L.; Finocchi, A.; Lucidi, V.; Mastronuzzi, A.; Granata, C. Fungal infections of the lung in children. Pediatr. Radiol. 2016, 46, 1856–1865. [Google Scholar] [CrossRef]
  48. Vogel, M.N.; Vatlach, M.; Weissgerber, P.; Goeppert, B.; Claussen, C.; Hetzel, J.; Horger, M.S. HRCT-features of Pneumocystis jiroveci pneumonia and their evolution before and after treatment in non-HIV immunocompromised patients. Eur. J. Radiol. 2012, 81, 1315–1320. [Google Scholar] [CrossRef]
  49. Kunihiro, Y.; Tanaka, N.; Kawano, R.; Yujiri, T.; Kubo, M.; Ueda, K.; Gondo, T.; Kobayashi, T.; Matsumoto, T. Differential diagnosis of pulmonary infections in immunocompromised patients using high-resolution computed tomography. Eur. Radiol. 2019, 29, 6089–6099. [Google Scholar] [CrossRef]
  50. Hardak, E.; Brook, O.; Yigla, M. Radiological Features of Pneumocystis jirovecii Pneumonia in Immunocompromised Patients with and Without AIDS. Lung 2010, 188, 159–163. [Google Scholar] [CrossRef]
  51. Chou, C.-W.; Chao, H.-S.; Lin, F.-C.; Tsai, H.-C.; Yuan, W.-H.; Chang, S.-C. Clinical Usefulness of HRCT in Assessing the Severity of Pneumocystis jirovecii Pneumonia. Medicine 2015, 94, e768. [Google Scholar] [CrossRef]
  52. Hopewell, P.C. Diagnosis of Pneumocystis carinii pneumonia. Infect. Dis. Clin. N. Am. 1988, 2, 409–418. [Google Scholar] [CrossRef]
  53. Kono, M.; Yamashita, H.; Kubota, K.; Kano, T.; Mimori, A. FDG PET Imaging in Pneumocystis Pneumonia. Clin. Nucl. Med. 2015, 40, 679–681. [Google Scholar] [CrossRef]
  54. Nakazato, T.; Mihara, A.; Sanada, Y.; Suzuki, K.; Aisa, Y.; Iwabuchi, M.; Kakimoto, T. Pneumocystis jiroveci pneumonia detected by FDG-PET. Ann. Hematol. 2010, 89, 839–840. [Google Scholar] [CrossRef]
  55. Win, Z.; Todd, J.; Al-Nahhas, A. FDG-PET Imaging in Pneumocystis carinii Pneumonia. Clin. Nucl. Med. 2005, 30, 690–691. [Google Scholar] [CrossRef]
  56. Cordonnier, C.; Cesaro, S.; Maschmeyer, G.; Einsele, H.; Donnelly, J.P.; Alanio, A.; Hauser, P.M.; Lagrou, K.; Melchers, W.J.G.; Helweg-Larsen, J.; et al. Pneumocystis jirovecii pneumonia: Still a concern in patients with haematological malignancies and stem cell transplant recipients. J. Antimicrob. Chemother. 2016, 71, 2379–2385. [Google Scholar] [CrossRef] [Green Version]
  57. Schmidt, J.J.; Lueck, C.; Ziesing, S.; Stoll, M.; Haller, H.; Gottlieb, J.; Eder, M.; Welte, T.; Hoeper, M.M.; Scherag, A.; et al. Clinical course, treatment and outcome of Pneumocystis pneumonia in immunocompromised adults: A retrospective analysis over 17 years. Crit. Care 2018, 22, 307. [Google Scholar] [CrossRef] [Green Version]
  58. Aderaye, G.; Woldeamanuel, Y.; Asrat, D.; Lebbad, M.; Beser, J.; Worku, A.; Fernandez, V.; Lindquist, L. Evaluation of Toluidine Blue O Staining for the Diagnosis of Pneumocystis jiroveci in Expectorated Sputum Sample and Bronchoalveolar Lavage from HIV-infected Patients in a Tertiary Care Referral Center in Ethiopia. Infection 2008, 36, 237–243. [Google Scholar] [CrossRef]
  59. Cregan, P.; Yamamoto, A.; Lum, A.; Vanderheide, T.; Macdonald, M.; Pulliam, L. Comparison of four methods for rapid detection of Pneumocystis carinii in respiratory specimens. J. Clin. Microbiol. 1990, 28, 2432–2436. [Google Scholar] [CrossRef] [Green Version]
  60. Walker, J.; Conner, G.; Ho, J.; Hunt, C.; Pickering, L. Giemsa staining for cysts and trophozoites of Pneumocystis carinii. J. Clin. Pathol. 1989, 42, 432–434. [Google Scholar] [CrossRef]
  61. Gonzalez, A.A.; Hamele-Bena, D.; Wood, T.; Valladares-Silva, S.; Wasserman, P.G. Pneumocystis jirovecii immunostain versus Gomori/Grocott methenamine silver stain of bronchoalveolar lavage in cell blocks: An institutional experience. J. Am. Soc. Cytopathol. 2017, 6, 242–247. [Google Scholar] [CrossRef]
  62. Homayouni, M.M.; Rostami, A.; Gholizadeh, H.; Mehbod, A.S.A.; Ebrahimi, M.; Mehravar, S. Comparison of three cost effective staining methods for detection of Pneumocystis jirovecii. J. Parasit. Dis. 2016, 41, 298–301. [Google Scholar] [CrossRef] [Green Version]
  63. Alanio, A.; Bretagne, S. Pneumocystis jirovecii detection in asymptomatic patients: What does it natural history tell us? F1000Research 2017, 6, 739. [Google Scholar] [CrossRef] [Green Version]
  64. Maschmeyer, G.; Carratalà, J.; Buchheidt, D.; Hamprecht, A.; Heussel, C.; Kahl, C.; Lorenz, J.; Neumann, S.; Rieger, C.; Ruhnke, M.; et al. Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients (allogeneic SCT excluded): Updated guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). Ann. Oncol. 2015, 26, 21–33. [Google Scholar] [CrossRef]
  65. de Leeuw, B.H.; Voskuil, W.S.; Maraha, B.; van der Zee, A.; Westenend, P.J.; Kusters, J.G. Evaluation of different real time PCRs for the detection of Pneumocystis jirovecii DNA in formalin-fixed paraffin-embedded bronchoalveolar lavage samples. Exp. Mol. Pathol. 2015, 98, 390–392. [Google Scholar] [CrossRef]
  66. Alanio, A.; Hauser, P.M.; Lagrou, K.; Melchers, W.J.G.; Helweg-Larsen, J.; Matos, O.; Cesaro, S.; Maschmeyer, G.; Einsele, H.; Donnelly, J.P.; et al. ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J. Antimicrob. Chemother. 2016, 71, 2386–2396. [Google Scholar] [CrossRef]
  67. Döşkaya, M.; Caner, A.; Değirmenci, A.; Wengenack, N.L.; Yolasığmaz, A.; Turgay, N.; Töz, S.Ö.; Gürüz, Y. Degree and frequency of inhibition in a routine real-time PCR detecting Pneumocystis jirovecii for the diagnosis of Pneumocystis pneumonia in Turkey. J. Med. Microbiol. 2011, 60, 937–944. [Google Scholar] [CrossRef] [Green Version]
  68. Guegan, H.; Robert-Gangneux, F. Molecular diagnosis of Pneumocystis pneumonia in immunocompromised patients. Curr. Opin. Infect. Dis. 2019, 32, 314–321. [Google Scholar] [CrossRef]
  69. Summah, H.; Zhu, Y.-G.; Falagas, M.E.; Vouloumanou, E.K.; Qu, J.-M. Use of real-time polymerase chain reaction for the diagnosis of Pneumocystis pneumonia I immunocompromised patients: A meta-analysis. Chin. Med. J. 2013, 126, 1965–1973. [Google Scholar]
  70. Fan, L.-C.; Lu, H.-W.; Cheng, K.-B.; Li, H.-P.; Xu, J.-F. Evaluation of PCR in Bronchoalveolar Lavage Fluid for Diagnosis of Pneumocystis jirovecii Pneumonia: A Bivariate Meta-Analysis and Systematic Review. PLoS ONE 2013, 8, e73099. [Google Scholar] [CrossRef] [Green Version]
  71. Fauchier, T.; Hasseine, L.; Gari-Toussaint, M.; Casanova, V.; Marty, P.M.; Pomares, C. Detection of Pneumocystis jirovecii by Quantitative PCR To Differentiate Colonization and Pneumonia in Immunocompromised HIV-Positive and HIV-Negative Patients. J. Clin. Microbiol. 2016, 54, 1487–1495. [Google Scholar] [CrossRef] [Green Version]
  72. Dimonte, S.; Berrilli, F.; D’Orazi, C.; D’Alfonso, R.; Placco, F.; Bordi, E.; Perno, C.; di Cave, D. Molecular analysis based on mtLSU-rRNA and DHPS sequences of Pneumocystis jirovecii from immunocompromised and immunocompetent patients in Italy. Infect. Genet. Evol. 2013, 14, 68–72. [Google Scholar] [CrossRef]
  73. Rudramurthy, S.M.; Sharma, M.; Sharma, M.; Rawat, P.; Ghosh, A.K.; Venkatesan, L.; Aggarwal, R.; Singh, P.; Chakrabarti, A. Reliable differentiation of Pneumocystis pneumonia from Pneumocystis colonisation by quantification of Major Surface Glycoprotein gene using real-time polymerase chain reaction. Mycoses 2017, 61, 96–103. [Google Scholar] [CrossRef]
  74. Maillet, M.; Maubon, D.; Brion, J.P.; François, P.; Molina, L.; Stahl, J.; Epaulard, O.; Bosseray, A.; Pavese, P. Pneumocystis jirovecii (Pj) quantitative PCR to differentiate Pj pneumonia from Pj colonization in immunocompromised patients. Eur. J. Clin. Microbiol. Infect. Dis. 2013, 33, 331–336. [Google Scholar] [CrossRef]
  75. Suárez, I.; Roderus, L.; van Gumpel, E.; Jung, N.; Lehmann, C.; Fätkenheuer, G.; Hartmann, P.; Plum, G.; Rybniker, J. Low prevalence of DHFR and DHPS mutations in Pneumocystis jirovecii strains obtained from a German cohort. Infection 2017, 45, 341–347. [Google Scholar] [CrossRef]
  76. Desoubeaux, G.; Chesnay, A.; Mercier, V.; Bras-Cachinho, J.; Moshiri, P.; Eymieux, S.; de Kyvon, M.; Lemaignen, A.; Goudeau, A.; Bailly, É. Combination of β-(1, 3)-D-glucan testing in serum and qPCR in nasopharyngeal aspirate for facilitated diagnosis of Pneumocystis jirovecii pneumonia. Mycoses 2019, 62, 1015–1022. [Google Scholar] [CrossRef]
  77. Groll, A.H.; Castagnola, E.; Cesaro, S.; Dalle, J.-H.; Engelhard, D.; Hope, W.W.; Roilides, E.; Styczynski, J.; Warris, A.; Lehrnbecher, T. Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol. 2014, 15, e327–e340. [Google Scholar] [CrossRef]
  78. Morjaria, S.; Frame, J.; Franco-Garcia, A.; Geyer, A.; Kamboj, M.; Babady, N.E. Clinical Performance of (1,3) Beta-D Glucan for the Diagnosis of Pneumocystis Pneumonia (PCP) in Cancer Patients Tested With PCP Polymerase Chain Reaction. Clin. Infect. Dis. 2019, 69, 1303–1309. [Google Scholar] [CrossRef]
  79. Rose, S.R.; Vallabhajosyula, S.; Velez, M.G.; Fedorko, D.P.; van Raden, M.J.; Gea-Banacloche, J.C.; Lionakis, M.S. The utility of bronchoalveolar lavage beta-D-glucan testing for the diagnosis of invasive fungal infections. J. Infect. 2014, 69, 278–283. [Google Scholar] [CrossRef] [Green Version]
  80. de Boer, M.G.; Gelinck, L.B.; van Zelst, B.; van de Sande, W.W.; Willems, L.N.; van Dissel, J.T.; de Jonge, R.; Kroon, F.P. β-d-Glucan and S-adenosylmethionine serum levels for the diagnosis of Pneumocystis pneumonia in HIV-negative Patients: A prospective study. J. Infect. 2011, 62, 93–100. [Google Scholar] [CrossRef]
  81. Urabe, N.; Sakamoto, S.; Sano, G.; Ito, A.; Sekiguchi, R.; Homma, S. Serial change in serum biomarkers during treatment of Non-HIV Pneumocystis pneumonia. J. Infect. Chemother. 2019, 25, 936–942. [Google Scholar] [CrossRef]
  82. Geelhoed, G.W. Open lung biopsy in the diagnosis of Pneumocystis carinii pneumonia. Natl. Cancer Inst. Monogr. 1976, 43, 141–147. [Google Scholar]
  83. Ekren, P.K.; Töreyin, Z.N.; Nahid, P.; Doskaya, M.; Caner, A.; Turgay, N.; Zeytinoğlu, A.; Toz, S.; Bacakoğlu, F.; Guruz, Y.; et al. The association between Cytomegalovirusco-infection withPneumocystispneumonia and mortality in immunocompromised non-HIV patients. Clin. Respir. J. 2018, 12, 2590–2597. [Google Scholar] [CrossRef]
  84. Yu, Q.; Jia, P.; Su, L.; Zhao, H.; Que, C. Outcomes and prognostic factors of non-HIV patients with pneumocystis jirovecii pneumonia and pulmonary CMV co-infection: A Retrospective Cohort Study. BMC Infect. Dis. 2017, 17, 392. [Google Scholar] [CrossRef] [Green Version]
  85. Sehulster, L.; Chinn, R.Y.W. Guidelines for environmental infection control in health-care facilities. Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR. Recomm. Rep. 2003, 52, 1–42. [Google Scholar]
  86. Pagano, L.; Fianchi, L.; Mele, L.; Girmenia, C.; Offidani, M.; Ricci, P.; Mitra, M.E.; Picardi, M.; Caramatti, C.; Piccaluga, P.; et al. Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years’ experience of infection in GIMEMA centres. Br. J. Haematol. 2002, 117, 379–386. [Google Scholar] [CrossRef] [Green Version]
  87. Warren, E.; George, S.; You, J.; Kazanjian, P. Advances in the treatment and prophylaxis of Pneumocystis carinii pneumonia. Pharmacother. J. Hum. Pharmacol. Drug Ther. 1997, 17, 900–916. [Google Scholar]
  88. Castagnola, E.; Zarri, D.; Caprino, D.; Losurdo, G.; Micalizzi, C. Cotrimoxazole prophylaxis of Pneumocystis carinii infection during the treatment of childhood acute lymphoblastic leukemia-beware non compliance in older children and adolescents. Support. Care Cancer 2001, 9, 552–553. [Google Scholar] [CrossRef]
  89. Hughes, W.T.; Kuhn, S.; Chaudhary, S.; Feldman, S.; Verzosa, M.; Aur, R.J.; Pratt, C.; George, S.L. Successful Chemoprophylaxis for Pneumocystis carinii Pneumonitis. N. Engl. J. Med. 1977, 297, 1419–1426. [Google Scholar] [CrossRef]
  90. Hughes, W.T.; Rivera, G.K.; Schell, M.J.; Thornton, D.; Lott, L. Successful Intermittent Chemoprophylaxis for Pneumocystis carinii Pneumonitis. N. Engl. J. Med. 1987, 316, 1627–1632. [Google Scholar] [CrossRef]
  91. Rossi, M.R.; Banfi, P.; Cappuccilli, M.; Conter, V.; de Poli, D.; Piacentini, G.; Zurlo, M.G.; Masera, G. Prospective randomized comparison of two prophylactic regimens with trimethoprim-sulfamethoxazole in leukemic children: A two year study. Eur. J. Cancer Clin. Oncol. 1987, 23, 1679–1682. [Google Scholar] [CrossRef]
  92. Postma, A.; Kamps, W. Prevention of Pneumocystis carinii pneumonia with cotrimoxazole 18 mg/kg. Support. Care Cancer 1998, 6, 300. [Google Scholar] [CrossRef]
  93. Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm. Rep. 2000, 49, 1–125. [Google Scholar]
  94. Green, H.; Paul, M.; Vidal, L.; Leibovici, L. Prophylaxis of Pneumocystis Pneumonia in Immunocompromised Non-HIV-Infected Patients: Systematic Review and Meta-analysis of Randomized Controlled Trials. Mayo Clin. Proc. 2007, 82, 1052–1059. [Google Scholar] [CrossRef] [PubMed]
  95. Maertens, J.; Cesaro, S.; Maschmeyer, G.; Einsele, H.; Donnelly, J.P.; Alanio, A.; Hauser, P.M.; Lagrou, K.; Melchers, W.J.G.; Helweg-Larsen, J.; et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell. J. Antimicrob. Chemother. 2016, 71, 2397–2404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Lindemulder, S.; Albano, E. Successful Intermittent Prophylaxis with Trimethoprim/Sulfamethoxazole 2 Days per Week for Pneumocystis carinii (jiroveci) Pneumonia in Pediatric Oncology Patients. Pediatrics 2007, 120, 2397–2404. [Google Scholar] [CrossRef]
  97. Ohata, Y.; Ohta, H.; Hashii, Y.; Tokimasa, S.; Ozono, K.; Hara, J. Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation. Pediatr. Blood Cancer 2009, 52, 142–144. [Google Scholar] [CrossRef]
  98. Muto, T.; Takeuchi, M.; Kawaguchi, T.; Tanaka, S.; Tsukamoto, S.; Sakai, S.; Takeda, Y.; Abe, D.; Ohwada, C.; Sakaida, E.; et al. Low-dose trimethoprim–sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011, 46, 1573–1575. [Google Scholar] [CrossRef] [Green Version]
  99. Agrawal, A.K.; Chang, P.P.; Feusner, J. Twice Weekly Pneumocystis jiroveci Pneumonia Prophylaxis with Trimethoprim-Sulfamethoxazole in Pediatric Patients with Acute Lymphoblastic Leukemia. J. Pediatr. Hematol. 2011, 33, e1–e4. [Google Scholar] [CrossRef]
  100. Stern, A.; Green, H.; Paul, M.; Vidal, L.; Leibovici, L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst. Rev. 2014, 2014, CD005590. [Google Scholar] [CrossRef]
  101. Quinn, M.; Fannin, J.T.; Sciasci, J.; Bragg, A.; Campbell, P.K.; Carias, D.; Crews, K.R.; Gregornik, D.; Jeha, S.; Maron, G.; et al. Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy. Antimicrob. Agents Chemother. 2018, 62, 00173. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Kruizinga, M.D.; Bresters, D.; Smiers, F.J.; Lankester, A.C.; Bredius, R.G.M. The use of intravenous pentamidine for the prophylaxis of Pneumocystis pneumonia in pediatric patients. Pediatr. Blood Cancer 2017, 64, e26453. [Google Scholar] [CrossRef]
  103. Levy, E.R.; Musick, L.; Zinter, M.S.; Lang, T.; Cowan, M.J.; Weintrub, P.S.; Dvorak, C.C. Safe and Effective Prophylaxis with Bimonthly Intravenous Pentamidine in the Pediatric Hematopoietic Stem Cell Transplant Population. Pediatr. Infect. Dis. J. 2016, 35, 135–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Solodokin, L.J.; Klejmont, L.M.; Scipione, M.R.; Dubrovskaya, Y.; Lighter-Fisher, J.; Papadopoulos, J. Safety and Effectiveness of Intravenous Pentamidine for Prophylaxis of Pneumocystis jirovecii Pneumonia in Pediatric Hematology/Oncology Patients. J. Pediatr. Hematol. 2016, 38, e180–e185. [Google Scholar] [CrossRef]
  105. Curi, D.A.; Duerst, R.E.; Badke, C.; Bell, J.; Chaudhury, S.; Kletzel, M.; Schneiderman, J.; Tse, W.T.; Muller, W.J.; Hijiya, N. IV pentamidine for Pneumocystis jiroveci pneumonia prophylaxis in pediatric allogeneic stem cell transplant patients. Bone Marrow Transplant. 2016, 51, 1394–1396. [Google Scholar] [CrossRef]
  106. Clark, A.; Hemmelgarn, T.; Teusink, A.; Danziger-Isakov, L. Intravenous pentamidine forPneumocystis carinii/jirovecipneumonia prophylaxis in pediatric transplant patients. Pediatr. Transplant. 2015, 19, 326–331. [Google Scholar] [CrossRef]
  107. Orgel, E.; Rushing, T. Efficacy and Tolerability of Intravenous Pentamidine Isethionate for Pneumocystis Jiroveci Prophylaxis in A Pediatric Oncology Population. Pediatr. Infect. Dis. J. 2014, 33, 319–321. [Google Scholar] [CrossRef]
  108. Demasi, J.M.; Cox, J.A.; Leonard, D.; Koh, A.Y.; Aquino, V.M. Intravenous Pentamidine Is Safe and Effective as Primary Pneumocystis Pneumonia Prophylaxis in Children and Adolescents Undergoing Hematopoietic Stem Cell Transplantation. Pediatr. Infect. Dis. J. 2013, 32, 933–936. [Google Scholar] [CrossRef]
  109. Kim, S.Y.; Dabb, A.A.; Glenn, D.J.; Snyder, K.M.; Chuk, M.K.; Loeb, D.M. Intravenous pentamidine is effective as second linePneumocystis pneumonia prophylaxis in pediatric oncology patients. Pediatr. Blood Cancer 2008, 50, 779–783. [Google Scholar] [CrossRef] [Green Version]
  110. Sweiss, K.; Anderson, J.; Wirth, S.; Oh, A.; Quigley, J.G.; Khan, I.; Saraf, S.; Haaf, C.M.; Rondelli, D.; Patel, P. A prospective study of intravenous pentamidine for PJP prophylaxis in adult patients undergoing intensive chemotherapy or hematopoietic stem cell transplant. Bone Marrow Transplant. 2017, 53, 300–306. [Google Scholar] [CrossRef] [Green Version]
  111. Lim, M.J.; Stebbings, A.; Lim, S.J.; Foor, K.; Hou, J.-Z.; Farah, R.; Raptis, A.; Marks, S.; Weber, D.; Im, A.; et al. IV pentamidine for primary PJP prophylaxis in adults undergoing allogeneic hematopoietic progenitor cell transplant. Bone Marrow Transplant. 2015, 50, 1253–1255. [Google Scholar] [CrossRef] [Green Version]
  112. Prasad, P.; Nania, J.J.; Shankar, S.M. Pneumocystis pneumonia in children receiving chemotherapy. Pediatr. Blood Cancer 2008, 50, 896–898. [Google Scholar] [CrossRef]
  113. Weinthal, J.; Frost, J.D.; Briones, G.; Cairo, M.S. Successful Pneumocystis carinii pneumonia prophylaxis using aerosolized pentamidine in children with acute leukemia. J. Clin. Oncol. 1994, 12, 136–140. [Google Scholar] [CrossRef]
  114. Mustafa, M.M.; Pappo, A.; Cash, J.; Winick, N.J.; Buchanan, G.R. Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole. J. Clin. Oncol. 1994, 12, 258–261. [Google Scholar] [CrossRef]
  115. Vasconcelles, M.; Bernardo, M.; King, C.; Weller, E.; Antin, J. Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections. Biol. Blood Marrow Transplant. 2000, 6, 35–43. [Google Scholar] [CrossRef]
  116. Marras, T.K.; Sanders, K.; Lipton, J.H.; Messner, H.A.; Conly, J.; Chan, C.K.; Marras, T.K.; Sanders, K.; Lipton, J.H.; Messner, H.A.; et al. Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation: Marras et al. Pentamidine for PCP prophylaxis post BMT. Transpl. Infect. Dis. 2002, 4, 66–74. [Google Scholar] [CrossRef]
  117. Hughes, W.T. Use of Dapsone in the Prevention and Treatment of Pneumocystis carinii Pneumonia: A Review. Clin. Infect. Dis. 1998, 27, 191–204. [Google Scholar] [CrossRef] [Green Version]
  118. Maltezou, H.C.; Petropoulos, D.; Choroszy, M.; Gardner, M.; Mantzouranis, E.C.; Rolston, K.V.; Chan, K.W. Dapsone for Pneumocystis carinii prophylaxis in children undergoing bone marrow transplantation. Bone Marrow Transplant. 1997, 20, 879–881. [Google Scholar] [CrossRef] [Green Version]
  119. Sangiolo, D.; Storer, B.; Nash, R.; Corey, L.; Davis, C.; Flowers, M.; Hackman, R.C.; Boeckh, M. Toxicity and Efficacy of Daily Dapsone as Pneumocystis jiroveci Prophylaxis after Hematopoietic Stem Cell Transplantation: A Case-Control Study. Biol. Blood Marrow Transplant. 2005, 11, 521–529. [Google Scholar] [CrossRef] [Green Version]
  120. Souza, J.P.; Boeckh, M.; Gooley, T.A.; Flowers, M.E.D.; Crawford, S.W. High Rates of Pneumocystis carinii Pneumonia in Allogeneic Blood and Marrow Transplant Recipients Receiving Dapsone Prophylaxis. Clin. Infect. Dis. 1999, 29, 1467–1471. [Google Scholar] [CrossRef]
  121. Fanello, C.; Karema, C.; Avellino, P.; Bancone, G.; Uwimana, A.; Lee, S.J.; D’Alessandro, U.; Modiano, D. High Risk of Severe Anaemia after Chlorproguanil-Dapsone+Artesunate Antimalarial Treatment in Patients with G6PD (A-) Deficiency. PLoS ONE 2008, 3, e4031. [Google Scholar] [CrossRef] [Green Version]
  122. Williams, S.; Macdonald, P.; Hoyer, J.D.; Barr, R.D.; Athale, U.H. Methemoglobinemia in children with acute lymphoblastic leukemia (ALL) receiving dapsone forpneumocystis carinii pneumonia (PCP) prophylaxis: A correlation with cytochrome b5 reductase (Cb5R) enzyme levels. Pediatr. Blood Cancer 2004, 44, 55–62. [Google Scholar] [CrossRef]
  123. Esbenshade, A.J.; Ho, R.H.; Shintani, A.; Zhao, Z.; Smith, L.-A.; Friedman, D.L. Dapsone-induced methemoglobinemia. Cancer 2011, 117, 3485–3492. [Google Scholar] [CrossRef] [Green Version]
  124. Ms, R.M.M.; Pui, C.-H.; Hughes, W.T.; Flynn, P.M.; Leung, W. Prophylaxis ofPneumocystis carinii pneumonia with atovaquone in children with leukemia. Cancer 2007, 109, 1654–1658. [Google Scholar] [CrossRef]
  125. Shankar, S.M.; Nania, J.J. Management of Pneumocystis jiroveci Pneumonia in Children Receiving Chemotherapy. Pediatr. Drugs 2007, 9, 301–309. [Google Scholar] [CrossRef]
  126. Proudfoot, R.; Phillips, B.; Wilne, S. Guidelines for the Prophylaxis of Pneumocystis jirovecii Pneumonia (PJP) in Children with Solid Tumors. J. Pediatr. Hematol. 2017, 39, 194–202. [Google Scholar] [CrossRef]
  127. Asai, N.; Motojima, S.; Ohkuni, Y.; Matsunuma, R.; Nakashima, K.; Iwasaki, T.; Nakashita, T.; Kaneko, N.; Otsuka, Y. Early diagnosis and treatment are crucial for the survival of Pneumocystis pneumonia patients without human immunodeficiency virus infection. J. Infect. Chemother. 2012, 18, 898–905. [Google Scholar] [CrossRef]
  128. Bartlett, M.S.; Queener, S.F.; Shaw, M.M.; Richardson, J.D.; Smith, J.W. Pneumocystis carinii is resistant to imidazole antifungal agents. Antimicrob. Agents Chemother. 1994, 38, 1859–1861. [Google Scholar] [CrossRef] [Green Version]
  129. Lee, W.-S.; Hsueh, P.-R.; Hsieh, T.-C.; Chen, F.-L.; Ou, T.-Y.; Jean, S.-S. Caspofungin salvage therapy in Pneumocystis jirovecii pneumonia. J. Microbiol. Immunol. Infect. 2017, 50, 547–548. [Google Scholar] [CrossRef] [Green Version]
  130. Ceballos, M.E.; Ortega, M.; Andresen, M.; Wozniak, A.; García, P.; Balcells, M.E. Successful treatment with echinocandin in an HIV-infected individual failing first-line therapy for Pneumocystis jirovecii pneumonia. AIDS 2011, 25, 2192–2193. [Google Scholar] [CrossRef]
  131. Maschmeyer, G.; Helweg-Larsen, J.; Pagano, L.; Robin, C.; Cordonnier, C.; Schellongowski, P.; Akova, M.; Aljurf, M.; Averbuch, D.; Barnes, R.; et al. ECIL guidelines for treatment of Pneumocystis jirovecii pneumonia in non-HIV-infected haematology patients. J. Antimicrob. Chemother. 2016, 71, 2405–2413. [Google Scholar] [CrossRef]
  132. Richards, C.G.; E Wakefield, A.; Mitchell, C.D. Detection of pneumocystis DNA in nasopharyngeal aspirates of leukaemic infants with pneumonia. Arch. Dis. Child. 1994, 71, 254–255. [Google Scholar] [CrossRef] [Green Version]
  133. Eroglu-Ertugrul, N.G.; Yalcin, E.; Oguz, B.; Ocal, T.; Kuskonmaz, B.; Emiralioglu, N.; Dogru-Ersoz, D.; Ozcelik, U.; Tezcan, I.; Kiper, N. The value of flexible bronchoscopy in pulmonary infections of immunosuppressed children. Clin. Respir. J. 2019, 14, 78–84. [Google Scholar] [CrossRef]
  134. le Gal, S.; Robert-Gangneux, F.; Pépino, Y.; Belaz, S.; Damiani, C.; Guéguen, P.; Pitous, M.; Virmaux, M.; Lissillour, E.; Pougnet, L.; et al. A misleading false-negative result of Pneumocystis real-time PCR assay due to a rare punctual mutation: A French multicenter study. Med. Mycol. 2016, 55, 180–184. [Google Scholar] [CrossRef] [Green Version]
  135. Matsumura, Y.; Shindo, Y.; Iinuma, Y.; Yamamoto, M.; Shirano, M.; Matsushima, A.; Nagao, M.; Ito, Y.; Takakura, S.; Hasegawa, Y.; et al. Clinical characteristics of Pneumocystis pneumonia in non-HIV patients and prognostic factors including microbiological genotypes. BMC Infect. Dis. 2011, 11, 76–79. [Google Scholar] [CrossRef] [Green Version]
  136. Vanspauwen, M.J.; Knops, V.E.J.; Bruggeman, C.A.; van Mook, W.N.K.A.; Linssen, C.F.M. Molecular epidemiology of Pneumocystis jiroveci in human immunodeficiency virus-positive and -negative immunocompromised patients in The Netherlands. J. Med. Microbiol. 2014, 63, 1294–1302. [Google Scholar] [CrossRef] [Green Version]
  137. Kay, R.; Dubois, R.E. Clindamycin/Primaquine Therapy and Secondary Prophylaxis Against Pneumocystis carinii Pneumonia in Patients With AIDS. South. Med. J. 1990, 83, 403–404. [Google Scholar] [CrossRef]
  138. Belfield, K.D.; Tichy, E.M. Review and drug therapy implications of glucose-6-phosphate dehydrogenase deficiency. Am. J. Heal. Pharm. 2018, 75, 97–104. [Google Scholar] [CrossRef]
  139. Riley, T.V.; Golledge, C.L. Clindamycin and pseudomembranous colitis. Lancet 1995, 346, 639. [Google Scholar] [CrossRef]
  140. Pareja, J.G.; Garland, R.; Koziel, H. Use of Adjunctive Corticosteroids in Severe Adult Non-HIV Pneumocystiscarinii Pneumonia. Chest 1998, 113, 1215–1224. [Google Scholar] [CrossRef]
  141. Delclaux, C.; Zahar, J.-R.; Amraoui, G.; Leleu, G.; Lebargy, F.; Brochard, L.; Schlemmer, B.; Brun-Buisson, C. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in non-human immunodeficiency virus-infected patients: Retrospective study of 31 patients. Clin. Infect. Dis. 1999, 29, 670–672. [Google Scholar] [CrossRef]
  142. Limper, A.H.; Knox, K.S.; Sarosi, G.A.; Ampel, N.M.; Bennett, J.E.; Catanzaro, A.; Davies, S.F.; Dismukes, W.E.; Hage, C.A.; Marr, K.A.; et al. An Official American Thoracic Society Statement: Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients. Am. J. Respir. Crit. Care Med. 2011, 183, 96–128. [Google Scholar] [CrossRef] [Green Version]
  143. Rilinger, J.; Staudacher, D.L.; Rieg, S.; Duerschmied, D.; Bode, C.; Wengenmayer, T. Extracorporeal membrane oxygenation in Pneumocystis jirovecii pneumonia: Outcome in HIV and non-HIV patients. Crit. Care 2019, 23, 356. [Google Scholar] [CrossRef] [Green Version]
  144. Slater, A.; Nichani, S.H.; Macrae, D.; Wilkinson, K.A.; Novelli, V.; Tasker, R.C. Surfactant adjunctive therapy for Pneumocystis carinii pneumonitis in an infant with acute lymphoblastic leukaemia. Intensiv. Care Med. 1995, 21, 261–263. [Google Scholar] [CrossRef]
  145. Lawrence, S.J.; Sadarangani, M.; Jacobson, K. Pneumocystis jirovecii Pneumonia in Pediatric Inflammatory Bowel Disease: A Case Report and Literature Review. Front. Pediatr. 2017, 5, 161. [Google Scholar] [CrossRef]
  146. Tragiannidis, A.; Kyriakidis, I.; Zündorf, I.; Groll, A.H. Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors. Mycoses 2017, 60, 222–229. [Google Scholar] [CrossRef]
  147. Kyriakidis, I.; Tragiannidis, A.; Zündorf, I.; Groll, A.H. Invasive fungal infections in paediatric patients treated with macromolecular immunomodulators other than tumour necrosis alpha inhibitors. Mycoses 2017, 60, 493–507. [Google Scholar] [CrossRef]
Table
Table 1. Differences in laboratory features, clinical presentation, and imagining findings of children with Pneumocystis jirovecii pneumonia (PJP) and underlying leukemia versus AIDS.
Table 1. Differences in laboratory features, clinical presentation, and imagining findings of children with Pneumocystis jirovecii pneumonia (PJP) and underlying leukemia versus AIDS.
FeaturePJP in Children with LeukemiaPJP in Children with AIDS
Number of organisms in BAL fluidLowHigh
Clinical presentationAcute, severeSubacute
Air cysts, spontaneous Pneumothorax and pneumomediastinumUncommonCommon
Possible diagnostic delayUsually longerShorter
Mortality *28–53%17–30%
* From Table 2 of reference [56]. BAL: bronchoalveolar lavage.
Table
Table 2. Series of pediatric patients with malignancies or who underwent hematopoietic stem cell transplantation (HSCT) and received pentamidine intravenously for PJP prophylaxis.
Table 2. Series of pediatric patients with malignancies or who underwent hematopoietic stem cell transplantation (HSCT) and received pentamidine intravenously for PJP prophylaxis.
Ref.CountryStudy PeriodNumber of PatientsNumber of PJP Cases
1Quinn M, et al.[101]Memphis, TN, USA1/2007–8/2014508 (158 HSCT, 262 ST, 88 L/L) *0 cases of probable or proven PJP, 4 cases (0.8%) of possible PJP
2Kruizinga MD, et al.[102]The Netherlands5/2011–9/20161061 case of PJP
3Levy ER, et al.[103]San Francisco, CA, USA12/2006–6/2013111 (all HSCT)0 cases of PJP
4Solodokin LJ, et al.[104]Valhalla, NY, USA1/2009–7/20141210 cases of PJP
5Curi DA, et al.[105]Chicago, IL, USA1/2007–12/2012142 (all HSCT)0 cases of PJP
6Clark A, et al.[106]Cincinnati, OH, USA1/2010–7/2013333 (all HSCT)1 case of PJP
7Orgel E, et al.[107]Los Angeles, CA, USA1/2005–12/20101171 case of possible PJP, 1 case of proven PJP
8DeMasi JM, et al.[108]Dallas, TX, USA1/2005–10/2011137 (all HSCT, 167 transplants **)0 cases of PJP
9Kim SY, et al.[109]USA, Baltimore MA1/2001–12/2006232 (106 HSCT)3 cases of PJP, 2 in HSCT recipients
* HSCT: recipients of HSCT, ST: patients with solid tumors, including central nervous system (CNS) tumors, L/L: patients with leukemia and lymphoma. ** Some patients underwent >1 transplantation procedure.
Table
Table 3. Prophylactic regimens for PJP in children with leukemia and HSCT recipients.
Table 3. Prophylactic regimens for PJP in children with leukemia and HSCT recipients.
Cotrimoxazole per os (A-I level of evidence per ECIL-5) * [95]As trimethoprim (TMP) 5 mg/kg (150 mg/m2) and sulfamethoxazole (SMX) 25 mg/kg (750 mg/m2), divided once or twice/day for two to three days per week. Maximum daily dose is 320 mg TMP and 1600 mg SMX. ** Duration of prophylaxis is from induction to end of maintenance (ALL), from engraftment to 6 months and while immunosuppression is ongoing (HSCT recipients), and through the duration of chemotherapy in patients with AML and solid tumors.
Pentamidine aerosolized (B-II level of evidence per ECIL-5)300 mg once a month. To be avoided in children <5 years of age due to concerns of inability to inhale the entire dose. The drug needs to be administered through a Respirgard II jet or similar nebulizer that generates drug particles <4 µm in diameter. Duration of prophylaxis, as per cotrimoxazole.
Pentamidine intravenously (C-II level of evidence per ECIL-5)4 mg/kg/day, once/day every 28 days. Duration of prophylaxis, as per cotrimoxazole.
Dapsone per os (C-II level of evidence per ECIL-5)2–4 mg/kg/day. Maximum daily dose 100 mg divided twice/day (50 mg bid). Duration of prophylaxis, as per cotrimoxazole.
Atovaquone per os (B-II level of evidence per ECIL-5)30 mg/kg/day for patients aged 1–3 months and 3–12 years. In infants aged 4–24 months, the dose is 45 mg/kg/day. It is administered with a meal as a single daily dose. For adolescents ≥13 years and adults, the dose is 1500 mg once/day. Duration of prophylaxis, as per cotrimoxazole.
* ECIL-5: European Conference on Infections in Leukemia, Version 5, ** Smaller doses, that is, TMP 3 mg/kg (90 mg/m2) and SMX 15 mg/kg (450 mg/m2) divided twice/day have been successfully used daily or three days per week in the Netherlands.
Table
Table 4. Therapeutic regimens for PJP in children with leukemia and HSCT recipients.
Table 4. Therapeutic regimens for PJP in children with leukemia and HSCT recipients.
Cotrimoxazole (TMP/SMX)15–20 mg/kg/day trimethoprim (TMP) (maximum TMP dose 960 mg/day) and 75–100 mg/kg/day sulfamethoxazole (SMX) orally or intravenously divided every 6–8 h for 21 days
Clindamycin plus primaquineClindamycin 30–40 mg/kg/day orally or intravenously divided every 6–8 h (maximum single dose 600 mg) and primaquine 0.25 mg/kg/day (maximum 15 mg/day) for 21 days
Pentamidine4 mg/kg/day IV once/day (maximum 300 mg/day) for 21 days
Atovaquone30 mg/kg/day orally once/day in children <3months and >24 months and 45 mg/kg/day orally divided every 12 h in children 4–24 months for 21 days
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Mantadakis, E. Pneumocystis jirovecii Pneumonia in Children with Hematological Malignancies: Diagnosis and Approaches to Management. J. Fungi 2020, 6, 331. https://doi.org/10.3390/jof6040331

AMA Style

Mantadakis E. Pneumocystis jirovecii Pneumonia in Children with Hematological Malignancies: Diagnosis and Approaches to Management. Journal of Fungi. 2020; 6(4):331. https://doi.org/10.3390/jof6040331

Chicago/Turabian Style

Mantadakis, Elpis. 2020. "Pneumocystis jirovecii Pneumonia in Children with Hematological Malignancies: Diagnosis and Approaches to Management" Journal of Fungi 6, no. 4: 331. https://doi.org/10.3390/jof6040331

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop