Development Of Pneumocystis Jirovecii Pneumonia Research Articles

Hidden consequences: Uncovering belimumab's role in the development of Pneumocystis jirovecii pneumonia in a lupus patient.

Pneumocystis jirovecii is an opportunistic fungal organism that can cause fatal pneumonia in immunocompromised individuals. It is a disease associated with CD4+ T cell depletion or high-dose steroids. However, there is increasing evidence that B cell dysfunction may also play a role in this illness. A 33-year-old female with SLE, who was maintained on belimumab and low-dose prednisone (2.5mg daily), presented with progressive cough and shortness of breath. She had been on monthly belimumab and prednisone 2.5mg daily for 19months, and her CD4 count was >200/uL, but her CD19+ B cell was <1% due to the belimumab. She developed a persistent cough and progressive dyspnea that did not respond to empiric antibiotic therapy for pneumonia. She went to the hospital for acute worsening of her dyspnea and cough. An extensive workup was performed, including a VATS procedure and surgical biopsy, which gave a definitive diagnosis of PJP. The patient was treated and discharged on trimethoprim-sulfamethoxazole. She made a complete recovery. Our report demonstrates the first confirmed case of pneumocystis jirovecii pneumonia in a patient with B cell depletion due to chronic maintenance therapy with belimumab. Our patient's diagnosis of PJP was unexpected, given her normal CD4+ count and the use of such a low dose of prednisone. We attribute her susceptibility to PJP infection to her profound B cell depletion in response to her belimumab therapy, supporting previous research indicating the importance of CD4+ T cells and B cells in the protective immune response against PJP. This case may help shape future clinical guidelines concerning PJP prophylaxis, particularly in SLE patients with deficient B lymphocytic activity and B cell depletion.

#6071 RITUXIMAB FOR MAINTENANCE OF REMISSION IN ADULT MINIMAL CHANGE DISEASE

Abstract Background and Aims Maintaining remission in a minority of adult patients with minimal change disease remains challenging. Prolonged corticosteroid use is associated with severe adverse effects. A limited number of observational studies suggest that rituximab may be an alternative therapeutic option for remission maintenance, allowing steroid withdrawal. Method We retrospectively analysed the data of all adult patients with minimal change disease, who received rituximab in our centre between 2017 and 2022. Results A total of 14 adults with minimal change disease were treated with rituximab, six of whom had childhood-onset nephrotic syndrome. Six patients were steroid dependent. The median number of relapses was 6.5 (IQR 4.5-15.2) prior to rituximab. Thirteen patients had received at least ≥ 2 different immunosuppressive agents during their disease. Corticosteroid-related adverse events, including osteopenia, hypertension, cataract and diabetes mellitus were observed in 10 subjects. Rituximab was administered in a median time of 10.6 years (IQR 4.5-16.3) after diagnosis. All patients received 2 doses of 1g rituximab 2 weeks apart. The median age at rituximab administration was 31 years (IQR 18.7-49.0); all patients were in remission. Besides corticosteroids, concomitant immunosuppressive therapy included calcineurin inhibitors (n = 6) and mycophenolate acid analogues (n = 1). The median follow-up time after the first dose of rituximab was 44 months (IQR 9.5-67.2). Relapses occurred in 6/14 patients in a median time of 17.5 months (IQR 10.2-26.5). The number of relapses per year decreased to 0.27 from 0.87 (p &amp;lt; 0.001) after rituximab. Six patients received a repeat course of rituximab. One patient developed Pneumocystis Jirovecii pneumonia, that was successfully treated with cotrimoxazole. At the last follow-up visit, corticosteroids were discontinued in 8 out of 14 patients and calcineurin inhibitors in 3 out of 7 patients. Conclusion Rituximab is a reasonable therapeutic approach for maintaining remission and avoiding steroid toxicity in adult minimal change disease. Randomized controlled studies are needed to further evaluate the safety and efficacy of rituximab in these patients.

Factors Associated with Pneumocystis jirovecii Pneumonia in Patients with Rheumatoid Arthritis Receiving Methotrexate: A Single-center Retrospective Study.

Objective To investigate the risk factors for the development of Pneumocystis jirovecii pneumonia (PCP) in patients with rheumatoid arthritis (RA) undergoing methotrexate (MTX) therapy. Methods This single-center retrospective cohort study included consecutive patients with RA who received MTX for at least one year. The study population was divided into PCP and non-PCP groups, depending on the development of PCP, and their characteristics were compared. We excluded patients who received biologic disease-modifying anti-rheumatic drugs (DMARDs), Janus kinase inhibitors, and anti-PCP drugs for prophylaxis. Results Thirteen patients developed PCP, and 333 did not develop PCP. At the initiation of MTX therapy, the PCP group had lower serum albumin levels, a higher frequency of pulmonary disease and administration of DMARDs, and received a higher dosage of prednisolone (PSL) than the non-PCP group. A multivariate Cox regression analysis revealed that the concomitant use of PSL [hazard ratio (HR) 5.50, p=0.003], other DMARDs (HR 5.98, p=0.002), and serum albumin <3.5 mg/dL (HR 4.30, p=0.01) were risk factors for the development of PCP during MTX therapy. Patients with these risk factors had a significantly higher cumulative probability of developing PCP than patients who lacked these risk factors. Conclusion Clinicians should pay close attention to patients with RA who possess risk factors for the development of PCP during MTX therapy.

Incidence of Pneumocystis jirovecii pneumonia utilizing a polymerase chain reaction-based diagnosis in patients receiving bendamustine.

Background Pneumocystis jirovecii pneumonia (PJP) is a life‐threatening infection occurring in patients receiving bendamustine. The poorly defined incidence, particularly when utilizing polymerase chain reaction (PCR)‐based diagnostic techniques, precipitates unclear prophylaxis recommendations. Our objective was to determine the cumulative incidence of PJP diagnosed by single copy target, non‐nested PCR in patients receiving bendamustine.MethodsPatients were evaluated for PJP from initiation of bendamustine through 9 months after the last administration. The cumulative incidence of PJP was estimated using the Aalen–Johansen method. Cox proportional hazard models were used to demonstrate the strength of association between the independent variables and PJP risk.ResultsThis single‐center, retrospective cohort included 486 adult patients receiving bendamustine from 1 January 2006 through 1 August 2019. Most patients received bendamustine‐based combination therapy (n = 461, 94.9%), and 225 (46.3%) patients completed six cycles. Rituximab was the most common concurrent agent (n = 431, 88.7%). The cumulative incidence of PJP was 1.7% (95% CI 0.8%–3.3%, at maximum follow‐up of 2.5 years), after the start of bendamustine (n = 8 PJP events overall). Prior stem cell transplant, prior chemotherapy within 1 year of bendamustine, and lack of concurrent chemotherapy were associated with the development of PJP in univariate analyses. Anti‐Pneumocystis prophylaxis was not significantly associated with a reduction in PJP compared to no prophylaxis (HR 0.37, 95% CI (0.05, 3.04), p = 0.36).ConclusionsOur incidence of PJP below 3.5%, the conventional threshold for prophylaxis implementation, indicates routine anti‐Pneumocystis prophylaxis may not be necessary in this population. Factors indicating a high‐risk population for targeted prophylaxis require further investigation.

Laparoscopic Bilateral Adrenalectomy Should Be an Early Consideration in Ectopic Adrenocorticopic Hormone Secretion

Introduction: Ectopic ACTH secretion (EAS) causes myriad metabolic derangements which may be effectively managed with laparoscopic bilateral adrenalectomy (LBA) in fit-for-surgery candidates. Clinical Case: A 67-year old woman with a remote 12-pack year smoking history presented with unintentional weight loss, cough, fever and chest pain. Imaging revealed a right-sided lung mass with liver lesions. Liver biopsy confirmed a well-differentiated neuroendocrine tumour (NET). Attempt at palliative lung resection was aborted due to disease extent. She was treated with multiple courses of chemotherapy but her disease progressed. Two years later, she presented with hypokalemia of 2.8 mmol/L (3.5 - 5.0 mmol/L) and uncontrolled hypertension. She was treated with spironolactone and oral potassium. She was notably hyperglycaemic with clinical features of cortisol excess. A random cortisol of 2742 nmol/L (<500 nmol/L), corresponding ACTH of 201 ng/L (5 - 50 ng/L) and lack of diurnal variation in cortisol day curve were in keeping with EAS. Metyrapone and spironolactone normalised blood pressure and biochemical derangement. With her initially high cortisol levels and its associated immunocompromised state, she developed pneumocystis jirovecii pneumonia (PCP), and was briefly admitted to the intensive care unit. In hospital, monitoring her response to EAS management necessitated multiple blood investigations, which proved burdensome for the patient. To effect definitive management of EAS and reduce invasive monitoring, she wished to have LBA and underwent an uneventful procedure. She was discharged on fludrocortisone and hydrocortisone along with lanreotide for primary disease management. Metyrapone and spironolactone were stopped. At initial outpatient follow up, she had normal blood pressure and electrolytes. By her report, her quality of life had improved tremendously, given the reduced need for multiple clinic visits and blood investigations. Unfortunately, her primary disease progressed with gradual deterioration of physical function. She died six months after LBA but, as per her desire, spent her final months with loved ones. Clinical Lesson: In patients with EAS who have unresectable primary disease but otherwise good performance status, LBA is a viable alternative to medical management and should be discussed with patients early after diagnosis.

P14.128 Lack of development of Pneumocystis Jirovecii Pneumonia in a cohort of 103 Italian glioblastoma patients not receiving prophylaxis during post-surgical chemoradiotherapy

Abstract BACKGROUND Patients diagnosed with high grade gliomas (HGG) usually receive surgery, radiation, temozolomide (TMZ) and corticosteroids. A major concern in patients who receive chemoradiotherapy (CRT) is the risk of developing secondary myelosuppression and a related infection during treatment. CRT may also lead to a long-lasting reduction of WBC, associated with early death from tumor progression. Among treatment-related infections, Pneumocystis Jirovecii Pneumonia (PJP) has been reported, since then, PJP prophylaxis has been required by the FDA. However, evidence for PJP during CRT is very limited limited and the rate of PJP still low. MATERIAL AND METHODS We did a retrospective, Institutional Review Board-approved cohort study in 103 patients (60 men and 43 women), who were consecutively diagnosed with GBM in “A. Manzoni” Hospital in Lecco during the period May 2007 to December 2013. All of these patients were treated with CRT according to the Stupp protocol without PJP prophylaxis. Haematological toxicities of CRT were assessed according to Common Terminology Criteria for Adverse Events (CTCAE, version 5.0; November 27, 2017). The objective of our study was to investigate the association between CRT and myelosuppression and we evaluated the types of infection contracted on CRT and in particular if the absence of a proper PJP prophylaxis led to an increased rate of PJP. RESULTS In our cohort, among 103 patients receiving CRT, 18% developed severe lymphopenia. Among all the subjects enrolled, a total of 9 patients (8.7%) had documented infectious complications during the CRT. Three patients developed community acquired pneumonia. Moreover, we documented three cases of fever without source, two urinary tract infections, one herpes zoster, one herpes simplex 1, one phlegmon and one purulent otitis. However, no one of these patients was diagnosed as PJP despite PJP prophylaxis was not given. CONCLUSION In conclusion, our data seem to support a lack of undisputable evidence for a favorable risk/benefit profile in the use of PJP prophylaxis for all newly diagnosed GBM patients undergoing the CRT, also considering the rate of adverse reactions (15.2%) and severe adverse reactions (around 3%, mainly leukopenia) in non-HIV adults receiving trimethoprim/sulphametoxazole for prolonged periods.

Risk factors and clinical characteristics of Pneumocystis jirovecii pneumonia in lung cancer

Solid malignancies are associated with the development of Pneumocystis jirovecii pneumonia (PJP). This study aimed to evaluate the risk factors for PJP among patients with lung cancer. This retrospective case-control study compared patients who had lung cancer with PJP (n = 112) or without PJP (n = 336) matched according to age, sex, histopathology, and stage. PJP definition was based on (i) positive PCR or direct immunofluorescence results for pneumocystis, (ii) clinical symptoms and radiological abnormalities that were consistent with a pneumonic process, and (iii) received targeted PJP treatment. The development of PJP was associated with radiotherapy (RTx), concurrent chemoradiotherapy (CCRTx), lymphopenia, and prolonged high-dose steroid therapy (20 mg of prednisolone equivalent per day for ≥3 weeks). Multivariate analysis revealed independent associations with prolonged high-dose steroid therapy (odds ratio [OR]: 1.96, 95% confidence interval [CI]: 1.06–3.63; p = 0.032) and CCRTx (OR: 2.09, 95% CI: 1.27–3.43; p = 0.004). Steroid use was frequently related to RTx pneumonitis or esophagitis (29 patients, 43.3%). Prolonged high-dose steroid therapy and CCRTx were risk factors for PJP development among patients with lung cancer. As these patients had a poor prognosis, clinicians should consider PJP prophylaxis for high-risk patients with lung cancer.

Pneumocystis jiroveci pneumonia in kidney and simultaneous pancreas kidney transplant recipients in the present era of routine post-transplant prophylaxis: risk factors and outcomes

BackgroundThe goal of this study was to identify predictors for development of Pneumocystis jirovecii pneumonia (PJP) in kidney and simultaneous kidney and pancreas transplant recipients in the present era of universal primary prophylaxis.MethodsWe reviewed adult recipients of kidney transplant or simultaneous pancreas and kidney transplant at the University of Wisconsin between January 1, 1994 and December 31, 2016. Patients diagnosed with PJP during this time frame were included. Controls were randomly selected from among those whose post-transplant course was not complicated by PJP, matched on time since transplant through incidence density sampling with a 3:1 ratio.Results28 (0.45%) of 6270 recipients developed PJP between 1994 and 2016. Median time since transplant was 4.6 years (interquartile range (IQR): 1.4–9.6 years). Affected recipients were older, had more HLA mismatches, and were more likely to have had BK viremia, CMV viremia and invasive fungal infections than matched controls. CMV viremia remained the only significant risk factor in multivariate analysis, and was a strong predictor (OR 6.27; p = 0.002). Ninety percent of the cases with prior CMV viremia had been diagnosed in the year preceding the diagnosis of PJP; among these, median time from diagnosis of CMV to diagnosis of PJP was 3.4 months (IQR: 1.74–11.5 months) and median peak CMV viral load prior to diagnosis of PJP was 3684.5 IU/mL (IQR: 1034–93,300 IU/mL). Additionally, 88.9% of patients with CMV in the preceding year had active infection at time of PJP diagnosis. Patient and graft survival were significantly worse at 2 years in recipients with PJP than our control group (42.4% vs. 88.5, and 37.9% vs. 79.9%; p < 0.001).ConclusionsDespite the low overall incidence of PJP in the era of universal prophylaxis, outcomes are poor. We suggest extending or re-initiating PJP prophylaxis for at least 6 months in the setting of CMV viremia due to the relatively low risk of therapy and potential significant impact on disease prevention.

Investigation of the Pathophysiology and Diagnostic Methods Through a Case of Acute HIV Infection in which the Western Blot Method Remained Negative Over the Long Term and the 4th Generation Screening Assay Became Negative for a Certain Period of Time after Initiating Antiretroviral Therapy

A man in his early twenties previously visited a hospital because of fever in October 2012. Laboratory data revealed leukocytopenia, thrombocytopenia and increased serum ferritin, suggesting hemophagocytic syndrome (HPS). During that visit, he tested positive for a 4thGIA, but negative for HIV-1 WB and his result of HIV-1 RNA result was detected invalid because of the presence of some inhibitory material in his RNA preparation. Thereafter, he was diagnosed as having cytomegalovirus-associated HPS treatment was for which initiated. In January 2013, he developed Pneumocystis jirovecii pneumonia, and his HIV-1 RNA viral load was 7.7 × 105 copies/mL in February 2013. Acute HIV infection was suspected, because the HIV-1 WB remained negative. He was started on antiretroviral therapy in April 2013. His 4thGIA was converted to negative in May 2013 and was reconverted to positive in August 2013. HIV-1 WB, however, continued to be indeterminant until February 2014, in which it turned positive for the first time according to the CDC criteria. The genetic analyses of HIV-1 were done on the gag, env, nef and pol region of the HIV-1 gene from the patient. There was no clear element to delay antibody production on the virus side. Preserved specimens of the patient were measured with eight kinds of HIV screening assay. It was thought that the fourth generation assay was positive only by the presence of the antigen until March 2013 because the antibody had not been detected. We encountered a case of acute HIV infection in which the WB result was negative for 10 months after the first positive response of the 4thGIA. The 4thGIA is essential for the early diagnosis and early treatment of HIV infection; therefore, the 4thGIA should be strictly recommended to avoid the use of older generations of immunoassay in the diagnostic guidelines. The role of the WB test should be examined closely from various aspects for use as a confirmatory test under recent laboratory situations in which highly sensitive and specific methods, e.g. the 4th GIA, have become available. In addition, unnecessary confusion due to the diversities of antibody formation should be avoided. The antibody detection tests for HIV are still necessary and indispensable for the confirmation of the disease or the diagnosis of the acute infection stage. Therefore development of a newer antibody measuring method which could achieve an easier operation and should have a higher sensitivity and specificity for HIV confirmation is strongly expected.

Pneumocystis jirovecii pneumonia developed in a patient with rheumatoid arthritis after 14 weeks of iguratimod add-on to treatment with methotrexate and etanercept

A 66-year-old woman who had rheumatoid arthritis and underwent a long-term treatment with methotrexate and etanercept developed Pneumocystis jirovecii pneumonia (PCP) 3 months after iguratimod add-on. Although most rheumatologists might have the impression that iguratimod has less toxicity and immunosuppressive effect compared with methotrexate and biologic disease-modifying antirheumatic drugs, this case suggests that iguratimod may increase the risk of PCP, especially in combination with other drugs.

Methaemoglobinaemia associated with trimethoprim/sulfamethoxazole treatment on a background of leflunomide‐induced pneumonitis

AbstractBackgroundImmunomodulating drugs such as leflunomide are known to be associated with immunosuppression and infection. Off‐label use of such agents may place patients at increased risk of potentially unforeseen adverse effects not commonly observed in clinical trials.AimTo describe a case of leflunomide‐induced pneumonitis, which may have contributed to the development of Pneumocystis jirovecii pneumonia (PJP). Treatment of the infection with trimethoprim/sulfamethoxazole (TMP‐SMX) in this case was associated with the development of methaemoglobinaemia, a relatively rare adverse effect associated with this agent.Clinical detailsA 72‐year‐old female presented with a 2‐week history of progressive dyspnoea and orthopnoea with a background of newly diagnosed, biopsy proven, membranous glomerulonephropathy. She had recently started leflunomide and prednisolone for resistant proteinuria. Soon after admission, her respiratory status deteriorated with tachypnoea (30–40/min) and hypoxia requiring large amounts of supplemental oxygen (oxygen saturation (SaO2) 95%, partial pressure of oxygen (PO2) 68 mmHg with 10 L/min of oxygen). A chest X‐ray and computed tomography revealed diffuse bilateral ground glass opacities with multimodal consolidation. Sputum polymerase chain reaction testing was positive for P. jirovecii, and a diagnosis of PJP was made. Subsequent treatment with primaquine and TMP‐SMX was linked to the development of drug‐induced methaemoglobinaemia (MeHb).OutcomeThe antimicrobial regime was changed to intravenous (IV) pentamidine as an alternative treatment for P. jirovecii pneumonia. Despite this, there was further deterioration associated with a suspected secondary bacterial pneumonia. Additional IV antibiotics were added, including piperacillin/tazobactam and vancomycin. Following failure to respond to this treatment, active interventions were withdrawn after family discussions. Palliative care measures were implemented and she died 4 days later.ConclusionPharmacists should be aware of the potential for serious, rare adverse effects associated with immunomodulating drugs. Patients must be informed of the risks associated with treatment and the evidence for benefit when these drugs are prescribed for off‐label use. PJP pneumonia prophylaxis should be considered for patients commencing high dose, chronic corticosteroid therapy. Methaemoglobin should be measured for patients who become significantly hypoxic after treatment with trimethoprim/sulfamethoxazole.

A case of spontaneous pneumothorax, pneumomediastinum &amp; subcutaneous emphysema in Pneumocystis jirovecii pneumonia complicating HIV

Spontaneous pneumothorax and subcutaneous emphysema are well-known but less common complications of pneumocystis pneumonia, whereas pnuemomediastinum is rare. We had a patient known to be HIV seropositive, who developed Pneumocystis jirovecii pneumonia. During the course of treatment, he developed spontaneous pneumothorax, pneumomediastinum and subcutaneous emphysema. He had no predisposing factors known to cause this complication

Once weekly trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis in children with cancer

Journal of Paediatrics and Child HealthVolume 50, Issue 6 p. 491-491 Heads UpFree Access Once weekly trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis in children with cancer First published: 01 June 2014 https://doi.org/10.1111/jpc.12556_3AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Before the use of trimethoprim-sulfamethoxazole prophylaxis, up to 43% of children with cancer developed Pneumocystis jirovecii pneumonia (PCP). Current recommendations for prophylaxis vary considerably, from daily dosing to thrice weekly dosing. A multi-centre Italian prospective survey compared treatment regimens in 2466 children with newly diagnosed cancer from 2009 to 2011, including 1093 with solid tumours and 1373 with leukaemia/lymphoma.1 Of these patients, 1371 received the 3-day/week prophylaxis regimen, 406 received the 2-day/week regimen and 689 received the 1-day/week regimen (5–10 mg/kg/day in two doses). Only two cases of PCP (0.08%) were reported, both in the 2-day/week group, and both had ceased prophylaxis. The authors concluded that a 1 day per week regimen of trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in immunosuppressed children with cancer. Take home message: 1 day per week trimethoprim/sulfamethoxazole dosing for PCP prophylaxis appears sufficient to prevent PCP in immunosuppressed children with cancer, is simpler than twice or thrice weekly dosing and may improve adherence. This regimen merits consideration in children with cancer and potentially in children at risk of PCP from primary immunodeficiency, transplantation or other medical immunosuppression. Reference 1 Caselli D et al. J. Pediatr. 2014; 164: 389– 392. Reviewer: Brendan McMullan, Sydney Children's Hospital, Randwick, brendan.mcmullan@sesiahs.health.nsw.gov.au Volume50, Issue6June 2014Pages 491-491 ReferencesRelatedInformation

‘Once weekly trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis in children with cancer’

Journal of Paediatrics and Child HealthVolume 50, Issue 5 p. 415-415 Heads UpFree Access ‘Once weekly trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis in children with cancer’ First published: 15 April 2014 https://doi.org/10.1111/jpc.12549_2AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Before the use of trimethoprim-sulfamethoxazole prophylaxis, up to 43% of children with cancer developed Pneumocystis jirovecii pneumonia (PCP). Current recommendations for prophylaxis vary considerably, from daily dosing to thrice weekly dosing. A multi-centre Italian prospective survey compared treatment regimens in 2466 children with newly diagnosed cancer from 2009 to 2011, including 1093 with solid tumours and 1373 with leukaemia/lymphoma.1 Of these patients, 1371 received the 3-day/week prophylaxis regimen, 406 received the 2-day/week regimen, and 689 received the 1-day/week regimen (5–10 mg/kg/day in two doses). Only two cases of PCP (0.08%) were reported, both in the 2-day/week group, and both had ceased prophylaxis. The authors concluded that a one-day-per-week regimen of trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in immunosuppressed children with cancer. Take home message: One-day-per-week trimethoprim-sulfamethoxazole dosing for PCP prophylaxis appears sufficient to prevent PCP in immunosuppressed children with cancer, is simpler than twice or thrice weekly dosing, and may improve adherence. This regimen merits consideration in children with cancer and potentially in children at risk of PCP from primary immunodeficiency, transplantation or other medical immunosuppression. Reference 1 Caselli D et al. J. Pediatr. 2014; 164: 389– 392. Reviewer: Brendan McMullan, Sydney Children's Hospital, Randwick ([email protected]) Volume50, Issue5May 2014Pages 415-415 ReferencesRelatedInformation

Late‐onset Pneumocystis jirovecii pneumonia post–fludarabine, cyclophosphamide and rituximab: implications for prophylaxis

ObjectiveFludarabine, cyclophosphamide and rituximab (FCR) therapy for lymphoid malignancies has historically been associated with a low reported incidence of Pneumocystis jirovecii pneumonia (PJP). However, prophylaxis was routinely used in early studies, and molecular diagnostic tools were not employed. The objective of this study was to review the incidence of PJP during and post‐FCR in the era of highly sensitive molecular diagnostics and 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET)–computerised tomography (CT).MethodsAll patients treated with standard FCR at the Peter MacCallum Cancer Centre (March 2009 to June 2012) were identified from a medications management database. Laboratory‐confirmed PJP cases during this time were identified from an electronic database.ResultsOverall, 66 patients were treated with a median of 5.5 FCR cycles. Eight PJP cases were identified, 6 of whom had received chemotherapy prior to FCR. In 5 cases, 18F‐FDG PET demonstrated bilateral ground‐glass infiltrates. Median CD4+ lymphocyte counts at time of PJP diagnosis and 9–12 months following FCR were 123 and 400 cells/μL, respectively. In patients receiving no prophylaxis, 9.1% developed PJP during FCR. The rate following FCR was 18.4%, with median onset at 6 months (2.4–24 months).ConclusionGiven the high rate of late‐onset PJP, consideration should be given for extended PJP prophylaxis for up to 12 months post‐FCR, particularly in pretreated patients. Further evaluation of the role of CD4+ monitoring is warranted to quantify risk of disease development and to guide duration of prophylaxis.

Pneumocystis jirovecii pneumonia associated with etanercept treatment in patients with rheumatoid arthritis: a retrospective review of 15 cases and analysis of risk factors

Objectives The association of anti-tumor necrosis factor therapy with opportunistic infections in rheumatoid arthritis (RA) patients has been reported. The goal of this study was to clarify the clinical characteristics and the risk factors of RA patients who developed Pneumocystis jirovecii pneumonia (PCP) during etanercept therapy.Methods We conducted a multicenter, case–control study in which 15 RA patients who developed PCP were compared with 74 RA patients who did not develop PCP during etanercept therapy.Results PCP developed within 26 weeks following the first injection of etanercept in 86.7% of the patients. All PCP patients presented with a rapid and severe clinical course and the overall mortality was 6.7%. Independent risk factors were identified using multivariate analysis and included age ≥ 65 years [hazard ratio (HR) 3.35, p = 0.037], coexisting lung disease (HR 4.48, p = 0.009), and concomitant methotrexate treatment (HR 4.68, p = 0.005). In patients having a larger number of risk factors, the cumulative probability of developing PCP was significantly higher (p < 0.001 for patients with two or more risk factors vs. those with no risk factor, and p = 0.001 for patients with one risk factor vs. those with no risk factor).Conclusion Physicians must consider the possibility of PCP developing during etanercept therapy in RA patients, particularly if one or more risk factors are present.

Pneumocystis jirovecii pneumonia associated with etanercept treatment in patients with rheumatoid arthritis: a retrospective review of 15 cases and analysis of risk factors

The association of anti-tumor necrosis factor therapy with opportunistic infections in rheumatoid arthritis (RA) patients has been reported. The goal of this study was to clarify the clinical characteristics and the risk factors of RA patients who developed Pneumocystis jirovecii pneumonia (PCP) during etanercept therapy. We conducted a multicenter, case-control study in which 15 RA patients who developed PCP were compared with 74 RA patients who did not develop PCP during etanercept therapy. PCP developed within 26weeks following the first injection of etanercept in 86.7% of the patients. All PCP patients presented with a rapid and severe clinical course and the overall mortality was 6.7%. Independent risk factors were identified using multivariate analysis and included age ≥65years [hazard ratio (HR) 3.35, p=0.037], coexisting lung disease (HR 4.48, p=0.009), and concomitant methotrexate treatment (HR 4.68, p=0.005). In patients having a larger number of risk factors, the cumulative probability of developing PCP was significantly higher (p<0.001 for patients with two or more risk factors vs. those with no risk factor, and p=0.001 for patients with one risk factor vs. those with no risk factor). Physicians must consider the possibility of PCP developing during etanercept therapy in RA patients, particularly if one or more risk factors are present.

A Case of Pneumocystis Jirovecii Pneumonia in a Patient with Rheumatoid Arthritis

We report a 67-year-old woman who developed Pneumocystis jirovecii pneumonia (PJP) as a complication of treatment with immunosuppressant, such as methotrexate and leflunomide, for rheumatoid arthritis. She had mild fever and non-productive cough, but there was neither symptoms of dyspnea nor typical X-ray findings at initial presentation. However, rapid progression on a chest X-ray, respiratory symptoms and findings of high-resolution chest computed tomography in a few days suggested a possibility of PJP infection. A polymerase chain reaction-based detection of Pneumocystis jirovecii in induced sputum allowed us an early diagnosis of PJP. Through a preemptive treatment with Trimethoprim-sulfamethoxazole, she fully recovered from PJP.

Penetration of Anti-Infective Agents into PulmonaryEpithelial Lining Fluid

Epithelial lining fluid (ELF) is often considered to be the site of extracellular pulmonary infections. During the past 25 years, a limited number of studies have evaluated the intrapulmonary penetration of antifungal, antitubercular, antiparasitic and antiviral agents. For antifungal agents, differences in drug concentrations in ELF or bronchoalveolar lavage (BAL) fluid were observed among various formulations or routes of administration, and between agents within the same class. Aerosolized doses of deoxycholate amphotericin B, liposomal amphotericin B and amphotericin B lipid complex resulted in higher concentrations in ELF or BAL fluid than after intravenous administration. The mean concentrations in ELF following intravenous administration of both anidulafungin and micafungin ranged between 0.04 and 1.38 μg/mL, and the ELF to plasma concentration ratios (based on the area under the concentration-time curve for total drug concentrations) were between 0.18 and 0.22 during the first 3 days of therapy. Among the azole agents, intravenous administration of voriconazole resulted in the highest mean ELF concentrations (range 10.1-48.3 μg/mL) and ratio of penetration (7.1). The range of mean ELF concentrations of itraconazole and posaconazole following oral administration was 0.2-1.9 μg/mL, and the ELF to plasma concentration ratios were <1. A series of studies have evaluated the intrapulmonary penetration of first- and second-line oral antitubercular agents in healthy adult subjects and patients with AIDS. The ELF to plasma concentration ratio was >1 for isoniazid, ethambutol, pyrazinamide and ethionamide. For rifampicin (rifampin) and rifapentine, the ELF to plasma concentration ratio ranged between 0.2 and 0.32, but in alveolar macrophages the concentration of rifampicin was much higher (145-738 μg/mL compared with 3.3-7.5 μg/mL in ELF). No intrapulmonary studies have been conducted for rifabutin. Sex, AIDS status or smoking history had no significant effects on the magnitude of ELF concentrations of antitubercular agents. Subjects who were slow acetylators had higher plasma and ELF concentrations of isoniazid than those who were fast acetylators. Penetration of dapsone into ELF was very good, with the range of mean ELF to plasma concentration ratios being 0.65-2.91 at individual sampling times over 48 hours. Once-daily dosing of aerosolized pentamidine resulted in higher concentrations in BAL fluid than after intravenous administration. The mean BAL concentrations at 15-32 days after once- or twice-monthly administration of aerosolized pentamidine 300 and 600 mg ranged from 6.5 to 28.4 ng/mL. No differences in pentamidine BAL concentrations were observed in symptomatic patients who developed Pneumocystis jirovecii pneumonia compared with patients who did not. Zanamivir concentrations in ELF were similar in magnitude (range 141-326 ng/mL) following administration by continuous intravenous infusion (3 mg/hour), oral inhalation (10 mg every 12 hours) and intravenous bolus (200 mg every 12 hours). Data from case reports have suggested that concentrations of nelfinavir and saquinavir in ELF are undetectable, whereas tipranavir and lopinavir had measureable ELF concentrations (2.20 μmol/L and 14.4 μg/mL, respectively) when these protease inhibitors were co-administrated with ritonavir. While the clinical significance of ELF or BAL concentrations remains unknown for this group of anti-infective agents, the knowledge of drug penetration into the extracellular space of the lung should assist in re-evaluating and designing specific dosing regimens for use against potential pathogens.

Serum (1→3)-β- d -Glucan Assay for the Diagnosis of Pneumocystis jiroveci Pneumonia

We read with interest the recent article by Del Bono et al. (2), and we would appreciate your taking into account the following observations. (i) Current diagnosis of Pneumocystis jirovecii pneumonia (PJP) relies on direct visualization of Pneumocystis from stained respiratory specimens (1, 3, 4, 6, 8). No combination of symptoms, signs, radiological findings, and blood chemistry results is diagnostic of PJP (4, 5), and consequently, all new adjunct diagnostic techniques such as the (1,3)-β-d-glucan (BG) assay should be validated prospectively in cases of proven PJP and not in clinically presumptive cases. (ii) We agree that invasive diagnostic procedures are sometimes (but not always) difficult to perform due to the severe clinical status of patients, but other alternative noninvasive diagnostic procedures are possible, such as oral washes combined with PCR (1, 3, 4). PCR has been shown to have greater sensitivity and specificity, but the interpretation of results may be conflicting, because asymptomatic P. jiroveci carriage is possible in both immunocompetent and immunocompromised individuals (4, 7, 8). (iii) When using matched control groups, it is important to define the risk factors accurately, since the possible development of PJP is dependent on the host's risk factor(s) for disease (4, 8). From our point of view, in this setting, the control group(s) should include, exclusively, immunocompromised patients with pneumonia of known etiology (different from PJP); healthy volunteers are inadequate. Although a second control group was immunocompromised patients with non-PJP pneumonia, there are not data about the type of immunosuppression, the CD4 cell counts, and the etiology of their pneumonia. (iv) In an autopsy study of 328 miners with PJP (9), 32.6% had concomitant respiratory infection with Cryptococcus neoformans, other fungi, viruses, and bacteria. Of note, PJP was unsuspected prior to death in 89% of cases. Del Bono et al. (2) state that they exclude patients with no evidence of bacterial pneumonia, although the methodology is not described and they do not provide data on other possible confounding etiologies and on long-term follow-up with patients. (v) Although the accuracy of a diagnostic test is defined by calculating the sensitivity, specificity, and positive and negative predictive values, Del Bono et al. (2) do not report these data. (vi) The diagnostic criterion for PJP based on a favorable response to specific therapy is not widely admitted (9). Furthermore, clinical response to treatment of one infection may make clinicians less likely to look for coinfection with other organisms (9). We agree with Wong et al. (9) that in populations with high HIV prevalence rates, PJP should always be considered in a differential diagnosis, even when tuberculosis or bacterial pneumonia is suspected. In this setting, a highly elevated serum BG value adds to the suspicion of PJP (3). While this may be adequate for empirical or preemptive therapy initiation, quantitative diagnostic performance assessment requires a higher standard of evidence. We maintain that evidence-based prospective studies with different patient subpopulations, in which BG levels are sequentially quantified, are needed for further evaluation of the usefulness of BG detection in PJP.