Immune reconstitution inflammatory syndrome mimicking relapsing cryptococcal meningitis in a renal transplant recipient

T. Legris, M. Massad, R. Purgus, H. Vacher‐Coponat, S. Ranque, N. Girard, Y. Berland, V. Moal. Immune reconstitution inflammatory syndrome mimicking relapsing cryptococcal meningitis in a renal transplant recipient.
Transpl Infect Dis 2011: 13: 303–308. All rights reserved Abstract: Immune reconstitution inflammatory syndrome (IRIS) is a rare entity that has been described recently in solid organ transplant (SOT) recipients. IRIS is characterized by an exuberant and dysregulated immune response following treatment of opportunistic infections. We describe here the case of a kidney transplant recipient who developed cryptococcal meningitis that was efficiently treated with antifungal therapy and decreased immunosuppression regimen. Eight months later, a paradoxical worsening of neurological symptoms and neuroradiological findings led to the diagnosis of IRIS. A short course of high‐dose steroid therapy allowed complete resolution of neurological symptoms. This report highlights the challenge for physicians to distinguish IRIS from a relapsing cryptococcal infection. Clinical improvement of cryptococcosis‐associated IRIS by anti‐inflammatory drugs needs to be confirmed among SOT recipients.     

A rare case of disseminated Mycobacterium avium complex with colitis in a renal transplant recipient

Mycobacterium avium complex (MAC) colitis is a rare complication of immunosuppression in solid organ transplant (SOT) recipients. Here, we describe a case of disseminated MAC infection with colitis following renal transplantation. Despite common pathways of immunosuppression, SOT recipients and human immunodeficiency virus (HIV)‐infected patients differ in their typical presentations of MAC infection. Intestinal infections have been more commonly reported in HIV‐infected patients than in SOT recipients. The explanation for this difference may be related to HIV's targeted effects on the CD4⁺ T‐cell reservoir in gut‐associated lymphoid tissue.     

Immune reconstitution inflammatory syndrome in an HIV/TB co-infected patient four years after starting antiretroviral therapy

The Immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy for HIV is well known. We describe an HIV seropositive woman, presenting 2 IRIS episodes associated with Mycobacterium tuberculosis. Exceptional was that the last episode occurred 4 years after initiating antiretroviral treatment, when her CD4+ lymphocyte count had been around 300 cells/mm3 for one year.     

Central nervous system involvement in cryptococcal infection in individuals after solid organ transplantation or with AIDS

Background. Cryptococcus neoformans is an important pathogen of immunocompromised hosts. Manifestations of cryptococcal infection have not been compared between populations based on the nature of the underlying immune deficiencies. Methods. The Prospective Antifungal Therapy Alliance (PATH) is a registry that collects clinical data from patients with invasive fungal infections from medical centers in North America. Univariate analyses and group comparisons were conducted from the PATH registry for cases of infection due to Cryptococcus species occurring between March 2004 and April 2008. Results. A total 235 cases of proven infection due to Cryptococcus species were documented, all of which were due to C. neoformans (52 in solid organ transplant [SOT] recipients, 107 in patients infected with the human immunodeficiency virus [HIV], and 76 with neither HIV nor organ transplantation). A total of 140 cases manifested as meningitis (25 in SOT recipients, 88 in HIV‐positive patients, and 27 in those with neither risk factor). Of individuals with cryptococcal infection, 44.2% of SOT recipients had central nervous system (CNS) disease, while 84.1% of those with HIV infection presented with CNS involvement (P=0.0265). SOT recipients receiving calcineurin inhibitors (CNIs) were less likely to have CNS involvement in cryptococcal infection (40.1% versus 66.7%). Overall, 12‐week mortality for patients with cryptococcal infection in the PATH Alliance registry was 22.6% (21.2% for SOT, 15.9% for HIV‐infected patients, and 32.9% for patients with risk factors other than HIV infection or organ transplantation). Conclusions. In a prospectively assembled cohort of individuals with proven infection due to C. neoformans, CNS involvement was more common in individuals with HIV infection than in SOT recipients. The role of CNIs in the reduction of risk for CNS cryptococcosis remains to be defined. Overall survival of patients with cryptococcal infection in immunocompromised hosts has improved over time. Observed differences in the context of various host immune deficits provide a basis for further investigation of cryptococcosis and other opportunistic infections.     

Long‐term remission in an adult heart transplant recipient with advanced Burkitt’s lymphoma post‐transplant lymphoproliferative disorder after anthracycline‐free chemotherapy: A case report and literature review

Incidence of Burkitt's lymphoma post‐transplant lymphoproliferative disorder (BL‐PTLD) in solid organ transplant (SOT) recipients in 1.4%‐1.6% with unknown cure rate. We report a case of Epstein‐Barr virus (EBV) positive, late‐onset BL‐PTLD in a 24‐year‐old EBV donor positive/recipient negative female. This is the first reported case of advanced BL‐PTLD post‐heart transplant in an adult. This is also the first reported case of treatment of advanced BL‐PTLD in a heart transplant recipient with a combined chemotherapy regimen without anthracyclines to avoid cardiotoxicity. The patient received 6 cycles of R‐COEP (rituximab with cyclophosphamide, vincristine, etoposide, prednisone) over 6 months and subsequently 3 cycles of high‐dose methotrexate (MTX) over 3 months for CNS prophylaxis. She remains without evidence of disease at 19 months post‐treatment. This case demonstrates that an anthracycline‐free regimen can be the therapy option for patients with BL‐PTLD after heart transplantation.     

Fatal herpes simplex virus type 2 hepatitis in a heart transplant recipient: a case report and review of the literature

Herpes simplex virus (HSV) hepatitis is often unrecognized clinically with most untreated cases diagnosed postmortem. HSV hepatitis has been reported in solid organ transplant (SOT) recipients, mostly in kidney and liver transplants, and rarely in heart transplant recipients. We describe a fatal case of community‐acquired HSV‐2 hepatitis in a 24‐year‐old heart transplant recipient occurring 3 years after transplant. We also review the literature summarizing HSV hepatitis and the potential role of quantitative HSV polymerase chain reaction monitoring in the SOT population.     

Management of tuberculosis and latent tuberculosis infection in human immunodeficiency virus‐infected persons

The syndemic of human immunodeficiency virus (HIV)/tuberculosis (TB) co‐infection has grown as a result of the considerable sociogeographic overlaps between the two epidemics. The situation is particularly worrisome in countries with high or intermediate TB burden against the background of a variable HIV epidemic state. Early diagnosis of TB disease in an HIV‐infected person is paramount but suffers from lack of sensitive and specific diagnostic tools. Enhanced symptom screening is currently advocated, and the wide application of affordable molecular diagnostics is urgently needed. Treatment of TB/HIV co‐infection involves the concurrent use of standard antiretrovirals and antimycobacterials during which harmful drug interaction may occur. The pharmacokinetic interaction between rifamycin and antiretrovirals is a case in point, requiring dosage adjustment and preferential use of rifabutin, if available. Early initiation of antiretroviral therapy is indicated, preferably at 2 weeks after starting TB treatment for patients with a CD4 of <50 cells/μL. Development of TB‐immune reconstitution inflammatory syndrome (TB‐IRIS) is however more frequent with early antiretroviral therapy. The diagnosis of TB‐IRIS is another clinical challenge, and cautious use of corticosteroids is suggested to improve clinical outcome. As a preventive measure against active TB disease, the screening for latent TB infection should be widely practiced, followed by at least 6–9 months of isoniazid treatment. To date tuberculin skin test remains the only diagnostic tool in high TB burden countries. The role of alternative tests, for example, interferon‐γ release assay, would need to be better defined for clinical application.     

Immune reconstitution inflammatory syndrome associated with Aspergillus terreus pulmonary infection in an autologous stem cell transplant recipient

S. Antinori, M. Corbellino, A. Necchi, P. Corradini, C. Vismara, V. Montefusco, A.M. Gianni. Immune reconstitution inflammatory syndrome associated with Aspergillus terreus pulmonary infection in an autologous stem cell transplant recipient.
Transpl Infect Dis 2010: 12: 64–68. All rights reserved
Abstract: We describe an autologous stem cell transplant recipient who developed immune reconstitution inflammatory syndrome (IRIS) associated with Aspergillus terreus invasive pulmonary infection after recovery from neutropenia. Clinical and radiological worsening of pulmonary invasive aspergillosis coincident with a robust decline of serum galactomannan values and rising neutrophil counts should be interpreted as IRIS and should not require changes to antifungal therapy.     

Acute peritonitis as presentations of tuberculosis-associated immune reconstitution inflammatory syndrome in an HIV-infected man

Immune reconstitution inflammatory syndrome (IRIS) is particularly observed after the start of therapy for pathogenic antigens in patients infected with human immunodeficiency virus (HIV) and receiving highly active antiretroviral therapy (HAART). Although tuberculosis (TB)-associated IRIS is the most common form, its presentation as a primary feature of acute peritonitis is extraordinarily rare. We report a 43-year-old man diagnosed with acquired immunodeficiency syndrome and pulmonary TB coinfection. His symptoms, sputum quantity, and chest radiologic appearance improved markedly after 3 weeks of antituberculous therapy, and HAART was initiated on the fourth week. However, acute abdomen with peritoneal signs resulting from the established tuberculous peritonitis developed on the seventh day of HAART. His clinical symptoms resolved after maintenance of HAART and antituberculous regimens. Tuberculous peritonitis must be considered in the differential diagnosis of acute abdomen in HIV-infected patients on antiviral therapy, especially in patients with known underlying TB. Early recognition of IRIS is important when managing HIV-infected patients with opportunistic infections.     

Seroprevalence of West Nile virus infection in solid organ transplant recipients

A.G. Freifeld, J. Meza, B. Schweitzer, L. Shafer, A.C. Kalil. A.R. Sambol. Seroprevalence of West Nile virus infection in solid organ transplant recipients.
Transpl Infect Dis 2010: 12: 120–126. All rights reserved Background. Of people infected with mosquito‐borne West Nile virus (WNV), <1% develop neuroinvasive disease (NID). Population studies suggest that people older than 65 years may be at higher risk for neurologic symptoms. It has been suggested that solid organ transplant (SOT) recipients are also at higher risk for WNV NID, but definitive serologic and epidemiologic data are lacking. Methods. A serologic screening survey, using a US Food & Drug Administration‐approved enzyme‐linked immunosorbant assay to detect WNV immunoglobulin‐G (IgG) antibody responses in cohorts of SOT recipients and non‐immunocompromised controls, was undertaken at a large Midwestern university organ transplant center in the aftermath of the summer 2003 WNV regional outbreak. Hemagglutination‐inhibition testing was used to confirm WNV IgG‐positive results and differentiate them from positive results caused by Saint Louis encephalitis virus, another flavivirus that is endemic in the Midwestern US. Findings. The rate of WNV IgG‐seropositive responses did not differ between SOT recipients and non‐immunocompromised controls, and were 12% and 10%, respectively. Retrospective chart review showed no documented WNV NID in the seropositive SOT recipients, suggesting an incidence of WNV NID may be as low as 0.7% in this population. Interpretation. Asymptomatic WNV infection is common among immunocompromised SOT patients, occurring as often as it does in non‐immunocompromised controls. Our data indicated that severe WNV NID is less frequent in SOT patients, contrary to what has been suggested in other studies.     

Acquired hypogammaglobulinemia and pathogen‐specific antibody depletion after solid organ transplantation in human immunodeficiency virus infection: A brief report

Hypogammaglobulinemia (HGG) frequently occurs in recipients after types of (SOT). The incidence and significance of HGG in HIV+ recipients of SOT are just being explored. We reported that 12% of the recipients in the SOT in multi‐center HIV‐TR (HIV‐TR) Study developed moderate or severe HGG at 1 year. In LT recipients, this was associated with serious infections and death. We have now further characterized the decreased antibodies in HIV+ SOT recipients who developed HGG. We measured the levels of pathogen‐specific antibodies and poly‐specific self‐reactive antibodies (PSA) in relation to total IgG levels from serial serum samples for 20 HIV+ SOT recipients who developed moderate to severe HGG following SOT. Serum antibody levels to measles, tetanus toxoid, and HIV‐1 were determined by EIA. Levels of PSAs were determined by incubating control lymphocytes with patient serum, staining with anti‐human IgG Fab‐FITC, and analysis by flow cytometry. Levels of PSA were higher compared to healthy, HIV‐uninfected controls at pre‐transplant baseline and increased by weeks 12 and 26, but the changes were not significant. Likewise, anti‐HIV antibody levels remained unchanged over time. In contrast, antibody levels against measles and tetanus were significantly reduced from baseline by week 12, and did not return to baseline, even after 2 years. For HIV patients who develop moderate to severe HGG after transplant, the reduction in IgG levels is associated with a significant decrease in pathogen‐specific antibody titers, while PSA levels and anti‐HIV antibodies are unchanged. This may contribute to infectious complications and other clinical endpoints.     

Epidemiology,outcomes, and mortality predictors of invasive mold infections among transplant recipients: a 10‐year,single‐center experience

Background

The epidemiology of invasive mold infections (IMI) in transplant recipients differs based on geography, hosts, preventative strategies, and methods of diagnosis.

Methods

We conducted a retrospective observational study to evaluate the epidemiology of proven and probable IMI, using prior definitions, among all adult hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients in the era of “classic” culture‐based diagnostics (2000–2009). Epidemiology was evaluated before and after an initiative was begun to increase bronchoscopy in HSCT recipients after 2005.

Results

In total, 106 patients with one IMI were identified. Invasive aspergillosis (IA) was the most common IMI (69; 65.1%), followed by mucormycosis (9; 8.5%). The overall rate of IMI (and IA) was 3.5% (2.5%) in allogeneic HSCT recipients. The overall incidence for IMI among lung, kidney, liver, and heart transplant recipients was 49, 2, 11, and 10 per 1000 person‐years, respectively. The observed rate of IMI among human leukocyte antigen‐matched unrelated and haploidentical HSCT recipients increased from 0.6% annually to 3.0% after bronchoscopy initiation (P < 0.05). The 12‐week mortality among allogeneic HSCT, liver, kidney, heart, and lung recipients with IMI was 52.4%, 47.1%, 27.8%, 16.7%, and 9.5%, respectively. Among allogeneic HSCT (odds ratio [OR]: 0.07, P = 0.007) and SOT (OR: 0.22, P = 0.05) recipients with IA, normal platelet count was associated with improved survival. Male gender (OR: 14.4, P = 0.007) and elevated bilirubin (OR: 5.7, P = 0.04) were significant predictors of mortality for allogeneic HSCT and SOT recipients with IA, respectively.

Conclusions

During the era of culture‐based diagnostics, observed rates of IMI were low among all transplants except lung transplant recipients, with relatively higher mortality rates. Diagnostic aggressiveness and host variables impact the reported incidence and outcome of IMI and likely account for institutional variability in multicenter studies. Definitions to standardize diagnoses among SOT recipients are needed.     

Fatal case of cutaneous‐sparing orolaryngeal zoster in a renal transplant recipient

Herpesvirus infections in solid organ transplant (SOT) recipients are a significant cause of morbidity and mortality. We report a case of herpes zoster (HZ) in a kidney transplant recipient while receiving belatacept, a CTLA‐4 inhibitor that prevents acute rejection. The patient presented with oropharyngolaryngeal mucosal lesions that subsequently disseminated resulting in pneumonitis and meningo‐encephalitis. Very late‐onset HZ can occur and can present atypically in SOT recipients. Delayed recognition and treatment may result in poor outcomes, as illustrated by this case.     

Leg weakness in a lung transplant patient

Progressive multifocal leukoencephalopathy (PML) is associated with JC polyomavirus (JCV) infection of central nervous system oligodendrocytes resulting in demyelinization and progressive focal neurologic deficits. Reactivation of dormant JCV occurs in the setting of immunosuppression, most commonly in patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) or hematological malignancies. PML has also been reported in solid organ transplant recipients. We report the case of a 61‐year‐old man after bilateral lung transplantation for chronic hypersensitivity pneumonitis who presented with leg weakness, cognitive decline, and expressive aphasia at 5 months post transplantation. Magnetic resonance imaging and brain biopsy were consistent with PML. Treatment attempt with cytarabine was unsuccessful, and immunomodulation resulted in recurrent grade A3 rejection. The difficulty of managing PML in lung transplant patients is highlighted by the lack of directed therapy and risk of graft rejection or failure with attempts at decreasing immunosuppression.     

Human papillomavirus‐related high‐grade squamous intraepithelial lesions of the esophagus,skin, and cervix in an adolescent lung transplant recipient: a case report and literature review

High‐risk (carcinogenic) genotype human papillomavirus (HPV) infections can be associated with significant morbidity in the immunocompromised solid organ transplant (SOT) recipient. Immunosuppression‐associated persistent infection can predispose to the development of rapidly progressive high‐grade squamous intraepithelial lesions (HSIL) in this population. We present a case report of an adolescent bilateral lung transplant recipient who developed HSIL of the esophagus, cervix, and skin secondary to HPV. This review highlights the unique developmental needs of the sexually active adolescent SOT recipient and reviews guidelines for HPV‐related screening and education of this population.     

Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion

Immune reconstitution inflammatory syndrome (IRIS) affects 30-43% of HIV and tuberculosis (TB) co-infected patients after starting highly active antiretroviral therapy (HAART). Pericarditis and pericardial effusion are rare manifestations of IRIS. We report a case of HIV-TB related IRIS that developed pericardial involvement. This complication resolved after treatment with ibuprofen. Antituberculous treatment and HAART were not interrupted.     

Immune reconstitution inflammatory syndrome (IRIS) of the small bowel in an immunocompromised patient suffering from systemic lupus erythematosus and non-tuberculous mycobacteriosis

An overwhelming immune reaction resulting in granulomatous inflammation after infection with opportunistic pathogens is termed immune reconstitution inflammatory syndrome (IRIS). It has mainly been described in patients with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy (HAART) who show a significant increase of low CD4 T cells (initially <50/microl). IRIS may lead to organ damage and differential diagnosis is often difficult. We report the case of a 38-year-old female patient who developed a Mycobacteria genavense infection of the liver and the bowel after several immunosuppressive therapies for systemic lupus erythematosus. CD4 T cell counts as low as 17/microl were found and immunosuppressive therapy was stopped. Despite several courses of antibiotic treatment and rising CD4 T cell counts, severe malabsorption persisted. Upper endoscopy revealed a continuous inflammation with pseudopolyps of the small bowel and histologically, a granulomatous infiltrate was detected. After exclusion of a persisting infection by Mycobacteria genavense, IRIS of the small bowel was suspected and treatment with prednisolone was started. The clinical and histological picture improved significantly, the number of CD25(+)CD4(+) cells decreased in the lamina propria of the duodenum under treatment with prednisolone and Foxp3+ regulatory T cells (Treg) accumulated around granulomas. This case shows that IRIS is not restricted to HIV patients but may also occur in otherwise immunosuppressed patients. Due to different treatment strategies, distinguishing IRIS from infectious diseases is essential. The role of Treg in IRIS has to be elucidated.     

Later onset of herpes zoster-associated immune reconstitution inflammatory syndrome

Objectives

The aim of the study was to determine whether immune reconstitution inflammatory syndrome (IRIS) associated with herpes zoster occurs on a different time frame from other instances of IRIS.

Methods

Statistical analysis of onset times of herpes zoster‐associated IRIS and other cases of IRIS was carried out in a retrospective cohort starting antiretroviral therapy at advanced stages of HIV infection.

Results

Herpes zoster‐associated IRIS was significantly more frequent after the first 3 months of successful highly active antiretroviral therapy (HAART), than other instances of IRIS (IRIS associated with tuberculosis, Mycobacterium avium complex, Kaposi's sarcoma, etc.) which mainly occurred during the first 3 months of treatment.

Conclusions

The characteristic onset time pattern of herpes zoster‐associated IRIS, coincident with the second phase of immune recovery under HAART, suggests that the immune recovery events underlying herpes zoster‐associated IRIS are different from those underlying other types of IRIS. Our findings may be useful in improving the follow‐up of individuals who start HAART at an advanced stage of HIV infection.

     

Soft tissue abscess and lymphadenitis due to Mycobacterium avium complex as an expression of immune reconstitution inflammatory syndrome after a second scheme of highly active antiretroviral therapy

Immune reconstitution inflammatory syndrome (IRIS) is an atypical and unexpected reaction related to highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infected patients. IRIS includes an atypical response to an opportunistic pathogen (generally Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus and herpes varicella-zoster), in patients responding to HAART with a reduction of plasma viral load and evidence of immune restoration based on increase of CD4+ T-cell count. We reported a case of a patient with AIDS which, after a first failure of HAART, developed a subcutaneous abscess and supraclavicular lymphadenitis as an expression of IRIS due to Mycobacterium avium complex after starting a second scheme of HAART.     

Bartonella henselae‐mediated disease in solid organ transplant recipients: two pediatric cases and a literature review

Bartonella henselae, the etiologic agent of cat‐scratch disease, causes a well‐defined, self‐limited syndrome of fever and regional lymphadenopathy in immunocompetent hosts. In immunocompromised hosts, however, B. henselae can cause severe disseminated disease and pathologic vasoproliferation known as bacillary angiomatosis (BA) or bacillary peliosis. BA was first recognized in patients infected with human immunodeficiency virus. It has become more frequently recognized in solid organ transplant (SOT) recipients, but reports of pediatric cases remain rare. Our review of the literature revealed only one previously reported case of BA in a pediatric SOT recipient. We herein present 2 pediatric cases, one of which is the first reported case of BA in a pediatric cardiac transplant recipient, to our knowledge. In addition, we review and summarize the literature pertaining to all cases of B. henselae‐mediated disease in SOT recipients.