Shahid Husain

IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia

Emerging evidence supports the concept that T helper type 17 (TH17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the TH17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony–stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the TH17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.

Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.

Background. The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. Methods. Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. Results. Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30–1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12–0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16–0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. Conclusions. Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.

Opportunistic Mycelial Fungal Infections in Organ Transplant Recipients: Emerging Importance of Non-Aspergillus Mycelial Fungi

To determine the spectrum and impact of mycelial fungal infections, particularly those due to non-Aspergillus molds, 53 liver and heart transplant recipients with invasive mycelial infections were prospectively identified in a multicenter study. Invasive mycelial infections were due to Aspergillus species in 69.8% of patients, to non-Aspergillus hyalohyphomycetes in 9.4%, to phaeohyphomycetes in 9.4%, to zygomycetes in 5.7%, and to other causes in 5.7%. Infections due to mycelial fungi other than Aspergillus species were significantly more likely to be associated with disseminated (P=.005) and central nervous system (P=.07) infection than were those due to Aspergillus species. Overall mortality at 90 days was 54.7%. The associated mortality rate was 100% for zygomycosis, 80% for non-Aspergillus hyalohyphomycosis, 54% for aspergillosis, and 20% for phaeohyphomycosis. Thus, non-Aspergillus molds have emerged as significant pathogens in organ transplant recipients. These molds are more likely to be associated with disseminated infections and to be associated with poorer outcomes than is aspergillosis.

Infections Due to Scedosporium apiospermum and Scedosporium prolificans in Transplant Recipients: Clinical Characteristics and Impact of Antifungal Agent Therapy on Outcome

BACKGROUND Unique characteristics, impact of therapy with antifungal agents, and outcome of infections with Scedosporium species were assessed in transplant recipients. METHODS The patients comprised a total of 80 transplant recipients with Scedosporium infections, including 13 patients from our institutions (University of Pittsburgh Medical Center [Pittsburgh, PA], University of Maryland [Baltimore], Duke University Medical Center [Durham, NC], Emory University [Atlanta, GA], and Hospital Gregorio Maranon [Madrid, Spain]) and 67 reported in the literature. The transplant recipients were compared with 190 non-transplant recipients with scedosporiosis who were described in the literature. RESULTS Overall, 69% of the infections in hematopoietic stem cell transplant (HSCT) recipients and 53% of the infections in organ transplant recipients were disseminated. HSCT recipients, compared with organ transplant recipients, were more likely to have infections caused by Scedosporium prolificans (P=.045), to have an earlier onset of infection (P=.007), to be neutropenic (P<.0001), and to have fungemia (P=.04). Time elapsed from transplantation to Scedosporium infection in transplant recipients has increased in recent years (P=.002). The mortality rate among transplant recipients with scedosporiosis was 58%. In a logistic regression model using amphotericin B as comparison treatment, voriconazole was associated with a trend towards better survival (odds ratio [OR], 10.40; P=.08). Presence of disseminated infection (OR, 0.20; P=.03) predicted lower survival, and receipt of adjunctive surgery as treatment (OR, 5.52; P=.02) independently predicted a better survival in this model. CONCLUSIONS Scedosporium infections in transplant recipients were associated with a high rate of dissemination and a poor outcome overall. The use of newer triazole agents warrants consideration as a therapeutic modality for these infections.

Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management

BACKGROUND Invasive aspergillosis is a serious opportunistic infection in lung transplant recipients. It has not been fully discerned whether there are differences in the characteristics, risk factors and outcome of Aspergillus infection in single as compared with bilateral lung transplant recipients. METHODS English-language articles identified by a MEDLINE search through December 2000 and bibliographies were used as data sources to identify cases of Aspergillus infections in lung transplant recipients. The studies selected had to have provided a definition of invasive aspergillosis to distinguish colonization from infection. RESULTS The median incidence of Aspergillus infections in lung transplant recipients was 6.2%. In total, 58% (45 of 78) of the Aspergillus infections were tracheobronchitis or bronchial anastomotic infections, 32% (25 of 78) were invasive pulmonary, and 22% (25 of 78) were disseminated infections. Single lung transplant recipients with Aspergillus infections were significantly older (p = 0.006), more likely to have had chronic obstructive pulmonary disease as an underlying illness (p = 0.05), more likely to have developed Aspergillus infections later after transplantation (p = 0.019), and tended to have a higher incidence of invasive aspergillosis (p = 0.11) than all other lung transplant recipients. Overall mortality in lung transplant recipients with Aspergillus infections was 52%. Single lung transplant recipients (p = 0.03), and patients with late-onset infections (occurring at least 3 months after transplantation ([p = 0.045]) infections had significantly higher mortality. CONCLUSIONS Single lung transplant recipients with Aspergillus infections had an overall greater morbidity and poorer outcome than other types of lung transplant recipients. Recognition of the unique characteristics of Aspergillus infections in single lung (vs bilateral or heart-lung) transplant recipients has implications relevant for the management of lung transplant recipients with aspergillosis.

Risk Factors, Clinical Characteristics, and Outcome of Nocardia Infection in Organ Transplant Recipients: A Matched Case-Control Study

BACKGROUND Risk factors for Nocardia infection in organ transplant recipients have not been formally assessed in the current era of transplantation. METHODS We performed a matched case-control study (1:2 ratio) between January 1995 and December 2005. Control subjects were matched for transplant type and timing. Univariate matched odds ratios were determined and conditional logistic regression was performed to identify independent risk factors. Clinical and microbiological characteristics of all case patients were reviewed. RESULTS Among 5126 organ transplant recipients, 35 (0.6%) were identified as having cases of Nocardia infection. The highest frequency was among recipients of lung transplants (18 [3.5%] of 521 patients), followed by recipients of heart (10 [2.5%] of 392), intestinal (2 [1.3%] of 155), kidney (3 [0.2%] of 1717), and liver (2 [0.1%] of 1840) transplants. In a comparison of case patients with 70 matched control subjects, receipt of high-dose steroids (odds ratio, 27; 95% confidence interval, 3.2-235; P=.003) and cytomegalovirus disease (odds ratio, 6.9; 95% confidence interval, 1.02-46; P=.047) in the preceding 6 months and a high median calcineurin inhibitor level in the preceding 30 days (odds ratio, 5.8; 95% confidence interval, 1.5-22; P=.012) were found to be independent risk factors for Nocardia infection. The majority of case patients (27 [77%] of 35) had pulmonary disease only. Seven transplant recipients (20%) had disseminated disease. Nocardia nova was the most common species (found in 17 [49%] of the patients), followed by Nocardia farcinica (9 [28%]), Nocardia asteroides (8 [23%]), and Nocardia brasiliensis (1 [3%]). Of the 35 case patients, 24 (69%) were receiving trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis. Thirty-one case patients (89%) experienced cure of their Nocardia infection. CONCLUSIONS Receipt of high-dose steroids, history of cytomegalovirus disease, and high levels of calcineurin inhibitors are independent risk factors for Nocardia infection in organ transplant recipients. Our study provides insights into the epidemiology of Nocardia infection in the current era, a period in which immunosuppressive and prophylactic regimens have greatly evolved.

An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients.

BACKGROUND We describe an immune reconstitution syndrome (IRS)-like entity in the course of evolution of Cryptococcus neoformans infection in organ transplant recipients. METHODS The study population comprised a cohort of 83 consecutive organ transplant recipients with cryptococcosis who were observed for a median of 2 years in an international, multicenter study. RESULTS In 4 (4.8%) of the 83 patients, an IRS-like entity was observed a median of 5.5 weeks after the initiation of appropriate antifungal therapy. Worsening of clinical manifestations was documented, despite cultures being negative for C. neoformans. These patients were significantly more likely to have received tacrolimus, mycophenolate mofetil, and prednisone as the regimen of immunosuppressive therapy than were all other patients (P = .007). The proposed basis of this phenomenon is reversal of a predominantly Th2 response at the onset of infection to a Th1 proinflammatory response as a result of receipt of effective antifungal therapy and a reduction in or cessation of immunosuppressive therapy. CONCLUSIONS This study demonstrated that an IRS-like entity occurs in organ transplant recipients with C. neoformans infection. Furthermore, this entity may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy in such cases.

Fungal infections in solid organ transplantation

Fungal infections in solid organ transplant recipients continue to be a significant cause of morbidity and mortality. Candida spp. and Aspergillus spp. account for most invasive fungal infections. The incidence of fungal infection varies with type of solid organ transplant. Liver transplant recipients have highest reported incidence of candida infections while lung transplant recipients have highest rate of Aspergillus infections. Recent epidemiological studies suggest the emergence of resistant strains of candida as well as mycelial fungi other than Aspergillus in these patients. The current review incorporates the recent changes in the epidemiology of fungal infections in solid organ transplant recipients and highlights the newer data on the diagnosis, prophylaxis and treatment of fungal infections in these patients.

Prospective Assessment of Platelia™ Aspergillus Galactomannan Antigen for the Diagnosis of Invasive Aspergillosis in Lung Transplant Recipients

The clinical utility of Platelia™Aspergillus galactomannan antigen for the early diagnosis of invasive aspergillosis was prospectively assessed in 70 consecutive lung transplant recipients. Sera were collected twice weekly and tested for galactomannan. Invasive aspergillosis was documented in 17.1% (12/70) of the patients. Using the generalized estimating equation model, at the cutoff value of ≥ 0.5, the sensitivity of the test was 30%, specificity 93% with positive and negative likelihood ratios of 4.2 and 0.75, respectively. Increasing the cutoff value to ≥ 0.66 yielded a sensitivity of 30%, specificity of 95%, and positive and negative likelihood ratios of 5.5 and 0.74. A total of 14 patients had false‐positive tests, including nine who had cystic fibrosis or chronic obstructive pulmonary disease. False‐positive tests occurred within 3 days of transplantation in 43% (6/14) of the patients, and within 7 days in 64% (9/14). Thus, the test demonstrated excellent specificity, but a low sensitivity for the diagnosis of aspergillosis in this patient population. Patients with cystic fibrosis or chronic obstructive pulmonary disease may transiently have a positive test in the early post‐transplant period.

Cryptococcus neoformans in Organ Transplant Recipients: Impact of Calcineurin-Inhibitor Agents on Mortality

Variables influencing the risk of dissemination and outcome of Cryptococcus neoformans infection were assessed in 111 organ transplant recipients with cryptococcosis in a prospective, multicenter, international study. Sixty-one percent (68/111) of the patients had disseminated infection. The risk of disseminated cryptococcosis was significantly higher for liver transplant recipients (adjusted hazard ratio [HR], 6.65; P=.048). The overall mortality rate at 90 days was 14% (16/111). The mortality rate was higher in patients with abnormal mental status (P=.023), renal failure at baseline (P=.028), fungemia (P=.006), and disseminated infection (P=.035) and was lower in those receiving a calcineurin-inhibitor agent (P=.003). In a multivariable analysis, the receipt of a calcineurin-inhibitor agent was independently associated with a lower mortality (adjusted HR, 0.21; P=.008), and renal failure at baseline with a higher mortality rate (adjusted HR, 3.14; P=.037). Thus, outcome in transplant recipients with cryptococcosis appears to be influenced by the type of immunosuppressive agent employed. Additionally, discerning the basis for transplant type-specific differences in disease severity has implications relevant for yielding further insights into the pathogenesis of C. neoformans infection in transplant recipients.