Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Pneumocystis jiroveci fungal infection transplant recipients. Pneumonia (PJP) may develop via airborne transmission or reactivation of prior infection. Nosocomial clusters of infection have been described among transplant recipients. PJP should not occur during prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX). Without prophylaxis, PJP risk is greatest in the first 6 months after organ transplantation but may develop later. Risk factors include low lymphocyte counts, cytomegalovirus infection (CMV), hypogammaglobulinemia, treated graft rejection or corticosteroids, and advancing patient age (>65). Presentation typically includes fever, dyspnea with hypoxemia, and cough. Chest radiographic patterns generally reveal diffuse interstitial processes best seen by CT scans. Patients generally have PO2  < 60 mm Hg, elevated serum lactic dehydrogenase (LDH), and elevated serum (1 â†’ 3) ß-d-glucan assay. Specific diagnosis uses respiratory specimens with direct immunofluorescent staining; invasive procedures may be required. Quantitative PCR is a useful adjunct to diagnosis. TMP-SMX is the drug of choice for therapy; drug allergy should be documented before resorting to alternative therapies. Adjunctive corticosteroids may be useful early. Routine PJP prophylaxis is recommended for at least 6-12 months post-transplant, preferably with TMP-SMX.

Course of colonization by multidrug-resistant organisms after allogeneic hematopoietic cell transplantation.

Multidrug-resistant organisms (MDRO) have been developing as an emerging problem in allogeneic hematopoietic cell transplantation (HCT). Since no data are available on the course of MDRO colonization after HCT, we investigated in this retrospective, single-center study, persistence and clearance of MDRO after HCT. From June 2010 to December 2015, 121 consecutive HCT patients were included. Patients received a MDRO screening before conditioning as well as surveillance cultures after HCT. In MDRO-colonized patients, surveillance specimens were taken until MDRO were no longer detectable. Thirty-three patients (27%) were found to be colonized by at least one MDRO at any time point until day 100 post HCT. Day 100 (2-year) non-relapse mortality (NRM) and overall survival (OS) of MDRO-colonized (MDRO+) versus non-colonized (MDRO-) patients were essentially the same. NRM is 15% (21%) versus 15% (24%). Two-year OS is 60 versus 55% for MDRO+ versus MDRO- patients. Out of the 33 MDRO+ patients, 21 cleared the MDRO. Median time to non-detectability of MDRO was 6 months. In 12 patients, the MDRO persisted. There was a significant (p < 0.0001) survival difference between patients who cleared the MDRO versus those with MDRO persistence (2-year OS 80 vs 40%). Except for the length of antibiotic therapy as a potential risk factor for MDRO persistence after HCT, no other conventional factors could be identified. (a) colonization by MDRO per se had no negative impact on the outcome, (b) MDRO can be cleared by the majority of patients after allogeneic HCT, and (c) to increase the probability to clear MDRO, the use of antibiotics in MDRO+ patients should be reviewed critically.

Sepsis During Immunosuppression for Sight-threatening Uveitis: The Flip side.

PURPOSE: To highlight the rare but life-threatening infective consequences of immunosuppression or biologic treatment for sight-threatening uveitis. PATIENTS AND METHODS: Retrospective case series of four immunosuppressed patients with uveitis complicated by sepsis. RESULTS: The affected patients were all treated using prednisolone 10 mg/day or greater, together with oral immunosuppression (2 mycophenolate mofetil, 1 azathioprine + ciclosporin, 1 methotrexate) and, in one case, infliximab. All patients survived following intensive treatment. CONCLUSION: Life-threatening infection is a rare but important risk in immunosuppressed patients with uveitis. Complete protection is not possible and prophylaxis regimens are of unproven efficacy. Patients should understand the risks before agreeing to a course of treatment.

[A Case of Pneumocystis Pneumonia Developed during Chemotherapy for Sigmoid Colon Cancer].

A 69-year-old man with multiple liver metastases from sigmoid colon cancer received mFOLFOX6 plus cetuximab(Cmab) chemotherapy. A partial response was observed; hence, we performed an extended left hepatectomy, 3 partial liver resections, and a sigmoidectomy. After 4 courses of CapeOX, a recurrent lesion occurred between S8 and S7 of the liver, and we changed the regimen to FOLFIRI plus bevacizumab(BV). Three months later, he had Grade 3 febrile neutropenia and CT scan findings showed ground glass opacity in the superior lobes of both lungs. We diagnosed pneumocystis pneumonia(PCP)and administered steroids and trimethoprim/sulfamethoxazole. The signs of PCP thus improved. PCP during chemotherapy for gastrointestinal cancer is rarely reported, but recently it has increased.

Pathological and protective immunity to Pneumocystis infection.

Pneumocystis jirovecii is a common opportunistic infection in the HIV-positive population and is re-emerging as a growing clinical concern in the HIV-negative immunosuppressed population. Newer targeted immunosuppressive therapies and the discovery of rare genetic mutations have furthered our understanding of the immunity required to clear Pneumocystis infection. The immune system can also mount a pathologic response against Pneumocystis following removal of immunosuppression and result in severe damage to the host lung. The current review will examine the most recent epidemiologic studies about the incidence of Pneumocystis in the HIV-positive and HIV-negative populations in the developing and developed world and will detail methods of diagnosis for Pneumocystis pneumonia. Finally, this review aims to summarize the known mediators of immunity to Pneumocystis and detail the pathologic immune response leading to Pneumocystis-related immune reconstitution inflammatory syndrome.

Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients.

Pneumocystis jirovecii is the only fungus of its kind to be pathogenic in humans. It is primarily responsible for pneumonia (PJP). The key to understanding immune defences has focused on T-cells, mainly because of the HIV infection epidemic. Patients presenting with PJP all have a CD4 count below 200/mm(3). The introduction of systematic primary prophylaxis and the use of new anti-retroviral drugs have significantly reduced the incidence of this disease in the HIV-infected population, mainly in developed countries. The increasingly frequent use of corticosteroids, chemotherapy, and other immunosuppressive drugs has led to an outbreak of PJP in patients not infected by HIV. These patients presenting with PJP have more rapid and severe symptoms, sometimes atypical, leading to delay the initiation of a specific anti-infective therapy, sometimes a cause of death. However, the contribution of new diagnostic tools and a better understanding of patients at risk should improve their survival.

Risk of Pneumocystis jiroveci pneumonia in patients long after renal transplantation.

BACKGROUND: Pneumocystis jiroveci pneumonia (PCP) is an important cause of morbidity and mortality in renal transplant recipients (RTRs). Chemoprophylaxis with trimethoprim/sulphamethoxazole is recommended during the early post-transplantation period, but the optimal duration has not been determined and a main drawback of chemoprophylaxis is the development of resistance of the commensal faecal flora. A cluster outbreak of PCP occurred in our outpatient Renal Transplant Unit. We aimed to investigate risk factors for PCP in RTRs to determine who should receive long-term chemoprophylaxis. METHODS: In a case-control study, we investigated common demographic variables and immunological parameters. Nine PCP cases diagnosed between August 2006 and April 2007 were matched with 18 control patients, who did not develop PCP, received their transplant in the same time-period and had a similar follow-up period with a comparable immunosuppressive drug regimen. RESULTS: The median time from transplantation to PCP was 19 months. We observed no significant differences in gender, age, donor type or number of rejections. In PCP cases, the median lymphocyte count just before PCP diagnosis was 0.49 (0.26-0.68), which was significantly reduced compared to the control patients after a similar follow-up period (median 1.36, 0.59-3.04, P = 0.002). This lymphocytopaenia was chronic and existed in most patients already for many months. CD4(+) T-cell counts were also significantly reduced in the PCP cases. We found no difference in the Th1, Th2 and Th17 subsets between PCP cases and control patients. CONCLUSION: Long-term prophylactic therapy for PCP may be indicated for RTR with persistent severe lymphocytopaenia.

Pulmonary manifestations of the immune reconstitution inflammatory syndrome.

PURPOSE OF REVIEW: Immune reconstitution inflammatory syndrome (IRIS) is a common occurrence in HIV patients starting antiretroviral therapy (ART), and pulmonary involvement is an important feature of tuberculosis-IRIS and pneumocystis-IRIS. Pulmonologists need an awareness of the timing, presentation and treatment of pulmonary IRIS. RECENT FINDINGS: Case definitions for tuberculosis-IRIS and cryptococcal-IRIS have been published by the International Network for the Study of HIV-associated IRIS (INSHI). A number of studies have addressed validation of clinical case definitions and the optimal time to commence ART after diagnosis of an opportunistic infection in HIV patients. The pathogenesis of IRIS is being assessed at a molecular level, increasing our understanding of mechanisms and possible targets for future preventive and therapeutic strategies. SUMMARY: Tuberculosis-IRIS, nontuberculosis mycobacterial-IRIS and pneumocystis-IRIS occur within days to weeks of starting ART, causing substantial morbidity, but low mortality. Cryptococcal-IRIS usually occurs later in the course of ART, and may be associated with appreciable mortality. Early recognition of unmasking and paradoxical IRIS affecting the lung allows timely initiation of antimicrobial and/or immunomodulatory therapies.

Risk factors for Pneumocystis jiroveci pneumonia (PcP) in renal transplant recipients.

BACKGROUND: Pneumocystis jiroveci pneumonia (PcP) is a potentially life-threatening complication in renal transplant recipients with increased reports during the past few years. Individual risk factors for susceptibility to PcP are incompletely understood. METHODS: We retrospectively analysed 60 cases of confirmed PcP, diagnosed in six German transplant centres between 2004 and 2008, as well as 60 matched controls. RESULTS: Compared with controls, PcP cases revealed the following significant differences: PcP cases had a poorer renal function (eGFR 31 vs. 42 mL/min in controls), more biopsy-proven rejections (18 vs. 5 patients), more frequent treatment with mycophenolate mofetil (53 vs. 44 patients) and less frequent treatment with interleukin-2 receptor antagonist (20 vs. 32 patients). According to centre policy, in those years, none of the patients or controls had received PcP prophylaxis after transplantation. Of the 60 patients with PcP, 30% developed the disease after the currently recommended duration of prophylactic treatment, 27% died in the course of the disease and 45% required treatment in the ICU. CONCLUSIONS: Our case-control study reveals a novel risk profile for PcP. Renal transplant recipients with more pronounced renal insufficiency following rejection episodes and treated with intensified immunosuppression are at particular risk for PcP.

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.

Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.

Pneumocystis jiroveci pneumonia in a patient with Wegener's granulomatosis treated efficiently with caspofungin.

A patient with Wegener's granulomatosis was on steroids (20 mg prednisolone per day) when he fell ill with an atypical pneumonia caused by Pneumocystis, which was diagnosed by detection of antigen in repeated bronchial lavage specimens. Because other treatment options were contraindicated, he received intravenous caspofungin starting with a loading dose of 70 mg and a maintenance dose of 50 mg daily over 3 weeks thereafter. The patient's complaints subsequently resolved within days after initiation of treatment. Tolerability of the drug was excellent. No relapse occurred during the ongoing 4 years, although immunosuppressive therapy continued.

Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency.

The ATP-dependent DNA helicase Q4 (RECQL4) belongs to a family of conserved RECQ helicases that are felt to be important in maintaining chromosomal integrity (Kitao et al., 1998, Genomics: 54 (3): 443-452). Deletions in the RECQL4 gene located on chromosome 8 region q24.3 have been associated with Rothmund-Thomson syndrome (RTS, OMIM 268400), a condition characterized by poikiloderma, sparse hair, small stature, skeletal abnormalities, cataracts and an increased risk of malignancy. We present a patient with a molecularly confirmed diagnosis of RTS with two unique genetic alterations in RECQL4 (IVS16-2A>T and IVS2+27_51del25), who at the age of 7 months nearly succumbed to Pneumocystis carinii pneumonia. Evaluation of his immune system demonstrated a T- B+ NK- phenotype with agammaglobulinemia consistent with combined immunodeficiency (CID). Studies to evaluate for known genetic causes of CID were not revealing. The patient received an umbilical cord blood (UCB) transplant with complete immune reconstitution. This report represents the first description of a CID phenotype and UCB transplantation in a patient with RTS.

Cryptogenic organizing pneumonia associated with Pneumocystis carinii infection and sirolimus therapy in a renal transplant patient.

We present the case of a renal transplant patient on sirolimus (rapamycin) therapy who developed cryptogenic organizing pneumonia in association with Pneumocystis carinii infection. To our knowledge, such a case has not been previously reported.

Pneumocystis colonization, airway inflammation, and pulmonary function decline in acquired immunodeficiency syndrome.

As a result of improved diagnosis, treatment, and supportive care for HIV-infected patients, AIDS in developed countries has now become a chronic infection with prolonged survival time, but longterm complications are increasing contributors to morbidity and mortality. HIV-infected patients are at increased risk for the development of pulmonary complications, including chronic obstructive pulmonary disease (COPD); however, the mechanisms associated with this increased susceptibility have not been defined. Infectious agents may contribute to the development of COPD by upregulating inflammatory mediators in the lung that act in concert with cigarette smoke to promote lung pathology. Studies in human subjects and non-human primate models of AIDS suggest that the inflammatory response to asymptomatic carriage or colonization by the opportunistic pathogen, Pneumocystis sp. (Pc), is similar to that of COPD, which is characterized by influx of CD8+ T cells, neutrophils, and macrophages into the lungs. We have shown a high frequency of Pc colonization among asymptomatic HIV-infected subjects and in non-HIV infected subjects with COPD. To investigate the role of Pc in the progression of obstructive lung disease in HIV infections, we developed a non-human primate model of Pc colonizatoin and infection in simian immunodeficiency virus (SIV)-infected macaques. These animals develop a prolonged colonization state characterized by a persistent influx of CD8+ T cells and neutrophils, and local increases in IL-8, IFN-gamma, and TNF-alpha. SIV-infected Pc-colonized monkeys show progressive decline in pulmonary function compared to SIV-infected monkeys. We hypothesize that in the context of AIDS-immune dysfunction, Pc colonization induces inflammatory responses leading to changes in pulmonary function and architecture similar to that seen in emphysema. Information gained from these studies will lead to the development of interventions to prevent lung injury associated with Pc colonization and the development of HIV-associated COPD.