Adenovirus Pneumonia Research Articles

Adenovirus in Solid Organ Transplant Recipients

Adenoviruses are nonenveloped, double-stranded DNAviruses associated with a wide range of clinical syndromesin humans (1). There are 52 immunologically distinct typesof adenoviruses that are further classified into one of7 (A–G) subgroups based on hemagglutinin properties,DNA homology, oncogenic potential in rodents and clin-ical disease (Table 1) (2,3). Adenoviruses typically causeself-limited respiratory, gastrointestinal or conjunctival dis-ease throughout the year without significant seasonal vari-ation. Adenovirus infections are most common amongchildren, people living in close quarters (such as collegestudents and military recruits), and immunocompromisedpatients (1).Adenovirus is the third most important viral infection fol-lowing liver transplantation in children, occurring in 10%of 484 pediatric liver transplant recipients in one series(4). A single series has reported an incidence of 5.8%of 191 adult liver transplant recipients (5). Symptomaticdisease (ranging from self-limited fever, gastroenteritis orcystitis to devastating illness with necrotizing hepatitis orpneumonia) occurred in over 60% of the infected patients.Symptomatic infections typically occurred within the first3 months after transplantation. The frequency of invasiveadenovirus infections after pediatric liver transplantationappeared to decrease with use of tacrolimus-based im-munosuppression(6);similardataarenotavailableforadultliver transplant recipients.Adenovirus infection in other organ recipients is less wellcharacterized. A recent prospective study in adult SOT re-cipients demonstrated measurable adenovirus DNAemiain 7.2% of 263 recipients in the first posttransplant year;nearly 60% of these patients were completely asymp-tomatic with the remaining patients manifesting gastroin-testinal (primarily diarrhea), respiratory or vague, nonspe-cific symptoms (7). In contrast to outcomes found in thisprospective study, case reports and small series identifythe fact that adenoviral infection can be clinically signif-icant in these patients. Severe adenoviral infection hasbeen reported after lung transplantation often leading tofatal disease (8–10). The presence of adenovirus DNA incardiac biopsies after pediatric heart transplantation wassignificantly associated with poor graft survival in one se-ries (11). Adenovirus also has been associated with hemor-rhagiccystitisandgraftdysfunctioninadultrenaltransplantrecipients (12). It has also been found in high rates after pe-diatric intestinal transplantation, though frequently in theabsence of obvious clinical disease or associated pathol-ogy (13). As adenovirus, like cytomegalovirus (CMV), canbe latent and can reactivate asymptomatically, ascribing acausative role in the pathologic process may sometimesbe difficult.Sites and clinical manifestations of adenoviral disease intransplant recipients appear to vary according to the typeof organ transplanted, with frequent involvement of theallograft. In liver transplant recipients, infection with aden-ovirusserotype5typicallyresultsinhepatitiswithamedianonset of 55 days after transplant (4,5), while serotypes 1and 2 are more commonly associated with pneumonia.Adenoviral pneumonia is associated with graft loss, deathor progression to obliterative bronchiolitis for lung trans-plant recipients (8). In one study of pediatric heart trans-plant recipients, detection of adenoviral genome copies inmyocardial biopsy specimens was predictive of adverseclinical events including coronary vasculopathy and graftloss (OR 4.7 compared to adenovirus negative patients;95% confidence interval 1.3–17.1) (11). The strength ofthis association and its pathogenesis remain to be clari-fied. Enterocolitis occurs more commonly in small bowelrecipients and may mimic rejection (7,14). Hemorrhagiccystitis and nephritis are described in renal transplant re-cipients (15). Disease in other organ recipients has beendescribed rarely.

50 Years Ago in The Journal of Pediatrics: Adenovirus pneumonia

Blattner RJ. J Pediatr 1958;53:631-3It is now known that the spectrum of disease manifestations of human adenovirus infection can be quite variable, depending on the serotype. Blattner described an outbreak of adenovirus pneumonia that occurred in France in 1955. At that time, only 18 serotypes of adenovirus were known. Today, more than 52 serotypes have been identified, and the disease spectrum extends from asymptomatic infection through pharyngoconjunctival fever, pneumonia, epidemic keratoconjunctivitis, acute hemorrhagic cystitis, gastroenteritis, meningoencephalitis, hepatitis, myocarditis, and life-threatening disseminated disease. Severe or even fatal infections can occur in immunocompromised persons.Advances in molecular biology have enhanced our understanding of this virus. To allow easy and rapid identification, serotypes are classified into subgroups or species (A to G) according to genomic DNA sequence, tissue tropism, and other biological properties. Quantitative polymerase chain reaction technology has become the state-of-the-art approach to providing early diagnosis, tracking the course of infection, and monitoring response to treatment. For adenoviral disease in recipients of bone marrow transplantation, treatment with cidofovir (a selective viral DNA synthesis inhibitor) has decreased viremia and produced concomitant clinical improvement in case series. Oral adenovirus vaccine (Ad4 and Ad7), which is no longer manufactured, had been used in military populations for decades to prevent adenovirus infection. The vaccine was demonstrated to be safe, and with increasing incidence and severity of adenovirus infection, interest in an adenovirus vaccine has been rekindled.The past 50 years have seen the development of rapid molecular assays for early detection of adenovirus in clinical settings. These assays allow for further research aimed at discovering new antiviral agents and type-specific vaccines that hopefully will substantially decrease adenovirus-associated morbidity and mortality in vulnerable populations. Blattner RJ. J Pediatr 1958;53:631-3 It is now known that the spectrum of disease manifestations of human adenovirus infection can be quite variable, depending on the serotype. Blattner described an outbreak of adenovirus pneumonia that occurred in France in 1955. At that time, only 18 serotypes of adenovirus were known. Today, more than 52 serotypes have been identified, and the disease spectrum extends from asymptomatic infection through pharyngoconjunctival fever, pneumonia, epidemic keratoconjunctivitis, acute hemorrhagic cystitis, gastroenteritis, meningoencephalitis, hepatitis, myocarditis, and life-threatening disseminated disease. Severe or even fatal infections can occur in immunocompromised persons. Advances in molecular biology have enhanced our understanding of this virus. To allow easy and rapid identification, serotypes are classified into subgroups or species (A to G) according to genomic DNA sequence, tissue tropism, and other biological properties. Quantitative polymerase chain reaction technology has become the state-of-the-art approach to providing early diagnosis, tracking the course of infection, and monitoring response to treatment. For adenoviral disease in recipients of bone marrow transplantation, treatment with cidofovir (a selective viral DNA synthesis inhibitor) has decreased viremia and produced concomitant clinical improvement in case series. Oral adenovirus vaccine (Ad4 and Ad7), which is no longer manufactured, had been used in military populations for decades to prevent adenovirus infection. The vaccine was demonstrated to be safe, and with increasing incidence and severity of adenovirus infection, interest in an adenovirus vaccine has been rekindled. The past 50 years have seen the development of rapid molecular assays for early detection of adenovirus in clinical settings. These assays allow for further research aimed at discovering new antiviral agents and type-specific vaccines that hopefully will substantially decrease adenovirus-associated morbidity and mortality in vulnerable populations.

Severe adenovirus community-acquired pneumonia mimicking Legionella

Dear Editor, I read with interest the report of Drs. Hakim and Tleyjah on severe adenovirus pneumonia in your journal [1]. Their literature review reminds us of the reemergence of adenoviral community-acquired pneumonia (CAP) and that it may mimic other causes of CAP, particularly the atypical pneumonias, e.g., Legionnaire’s disease [2, 3]. As the authors correctly state, adenovirus is the only viral cause of CAP that may resemble bacterial pneumonia with focal/ lobar infiltrates or consolidation. However, as with other viral causes of pneumonia, early the chest X-ray in adenoviral CAP may be normal, even when the patient is short of breath and hypoxemic. The two most likely radiologic presentations of adenovirus is a completely normal chest X-ray with hypoxemia and symptoms of pneumonia or with lobar infiltrate/consolidation. Unlike influenza, routinely associated with leukopenia, adenoviral CAP is associated with a normal or elevated white blood cell (WBC) count, excluding viral influenza. An important clue noted by the authors, which has been our experience as well is the presence of conjunctival suffusion when present. Another important point is that viral pneumonias are ordinarily not accompanied by loose stools/diarrhea [4]. Adenovirus is most likely to be confused in this respect with Mycoplasma pneumoniae or Legionnaire’s disease, which is a common feature of both. Adenoviral CAP in patients with lobar infiltrates mimic Legionnaire’s disease, which may be differentiated from Legionella by the absence of hyponatremia, hypophosphatemia, and highly elevated serum levels [5]. As with conjunctival suffusion, an important clue to adenoviral pneumonia is wheezing, more common in children that, if present, should suggest adenovirus [1]. Recently, we have had a case of adenoviral CAP in a normal host different to that reported by the authors. The patient was a 36-year-old immunocompetent male who presented with severe CAP with a prominent dry cough and headache. On physical examination, he had a questionable faint truncal rash and conjunctival suffusion. Auscultation of the chest revealed no rales. His WBC count was 7.3 K/ mm with monocytosis. Relative lymphopenia was not present. His platelet count was 280,000 K/mm. Because of his headache and possible rash, the question of aseptic meningitis was raised and a lumbar puncture was performed. His cerebrospinal fluid (CSF) showed 8 WBCs/hpf with a normal glucose, protein, and lactic acid level. Head magnetic resonance imaging (MRI) was negative. He was hypoxemic on room air. Both his erythrocyte sedimentation rate (ESR) and liver function tests (LFTs) were unelevated and cold agglutinin titers were negative. His creatine phosphokinase (CPK) was unelevated. Titers for Legionella, M. pneumoniae, and Chlamydia pneumoniae were negative. His Legionella urinary antigen test was negative. His adenovirus titer was elevated 1:128 (normal<1:8). As the authors suggest, adenoviral CAP is probably more common than recognized. It is an easily missed diagnosis and should be included in the differential diagnosis of severe CAP in patients. Early on, in immunocompetent CAP patients without pulmonary infiltrates, the differential diagnosis should include influenza and cytoEur J Clin Microbiol Infect Dis (2009) 28:313–315 DOI 10.1007/s10096-008-0611-6

Necrotizing adenoviral pneumonia: Manifestation of nosocomial infection in pediatric intensive care unit

A 5-year-old child admitted in the pediatric intensive care unit developed fever and crepitations in the chest on 6(th) day of admission. She succumbed to her illness depite administration of adequate supportive and ventilatory care and anti-microbial therapy. At autopsy, she was diagnosed to have chronic ligneous type of tuberculous meningitis and necrotizing adnoviral pneumonia. There are hardly any reports of nosocomial adenoviral pneumonia from Indian centers. The case serves to remind intensivists to consider this diagnosis so that appropriate therapeutic adjustments and measures to prevent the spread of infection to other critically ill subjects are initiated.

Survival after prolonged pediatric extracorporeal membrane oxygenation support for adenoviral pneumonia

Adenoviral pneumonia can cause significant pulmonary morbidity leading to extracorporeal membrane oxygenation (ECMO) rescue. Reported survival of adenoviral pneumonia requiring ECMO has been poor, and prolonged time on ECMO is associated with increased mortality. We present 2 pediatric cases of adenoviral pneumonia in patients who survived after greater than 30 days on ECMO and review the Extracorporeal Life Support Organization (ELSO) registry to describe the collective experience of children with viral pneumonia requiring prolonged ECMO. Although survival has improved over the past decade for pediatric adenoviral pneumonia, the ELSO database previously has had no surviving children reported with a primary diagnosis of adenovirus after more than 4 weeks on ECMO. Our experience suggests that there may be use for prolonged ECMO support in children despite severe adenoviral pneumonia.

Bronchiolitis obliterans in children

In this review, we discuss recent advances in our understanding of the etiology, pathology and pathogenesis, clinical presentation, diagnosis, treatment, and outcome of bronchiolitis obliterans in the nontransplant, pediatric population. The diagnosis of bronchiolitis obliterans in children can be made with confidence based on clinical presentation, particularly with a history of adenovirus bronchiolitis or pneumonia, fixed obstructive lung disease on pulmonary function testing, and characteristic changes of mosaic perfusion, vascular attenuation, and central bronchiectasis on chest high-resolution computed tomography, thus avoiding the need for lung biopsy in most patients. Patients with postinfectious bronchiolitis obliterans generally have chronic, nonprogressive disease; in contrast, patients with bronchiolitis obliterans from Stevens-Johnson syndrome often have progressive disease that may require lung transplantation. Bronchiolitis obliterans is a rare form of chronic obstructive lung disease that follows a severe insult to the lower respiratory tract, resulting in fibrosis of the small airways. In the nontransplant pediatric population, adenovirus infection is the most common cause. Treatment is largely supportive and prognosis is mainly related to the underlying cause and to the severity of the initial insult.

Bronchiolitis obliterans in children: Clinical presentation, therapy and long‐term follow‐up

To delineate the predisposing factors, clinical, radiological features and outcomes of bronchiolitis obliterans (BO) in children for minimising morbidity and mortality. Ten children who had BO from July 1995 to July 2005 were retrospectively reviewed at a tertiary paediatric facility in northern Taiwan. Bronchiolitis obliterans complicated by infections, Stevens-Johnson syndrome was found in eight and two patients, respectively. In children with post-infectious BO, adenoviruses were the most common etiologic agents (7/8). Among them, six patients needed intensive management and five patients needed mechanical ventilation. All patients presented persistent dyspneic respirations and wheezing since the initial lung infection. Initial focal atelectasis (n = 3) on chest radiographs progressed to atelectasis/lobar collapse (n = 8) when the diagnosis of BO was made. After adequate supportive management, atelectatic bronchiectasis was the most common complication (n = 5). Severe adenovirus bronchiolitis and/or pneumonia appear to have higher risk of development of BO in children. In order to minimise associated complications of BO, meticulous respiratory care for preventing pulmonary collapse may be considered in such instances.

Treatment of Adenovirus Pneumonia With Cidofovir in Pediatric Lung Transplant Recipients

Adenovirus pneumonia results in significant morbidity and mortality in lung transplant recipients. Cidofovir allows for directed therapy but can result in nephrotoxicity. We report our experience with cidofovir for the treatment of adenovirus pneumonia in pediatric lung transplant recipients. In a retrospective review, we identified four cases of culture-proven adenovirus pneumonia in children who underwent lung transplantation at Texas Children's Hospital (TCH). All patients received cidofovir 1 mg/kg every other day or three times a week for a total of 4 weeks. Probenecid and intravenous hydration were administered in conjunction with the cidofovir. Intravenous immunoglobulin (IVIg) was given as adjunctive therapy, and immunosuppression was not modified during the treatment course. The four cases of adenovirus pneumonia comprised 4 of the 54 (7%) lung transplantations performed at TCH from 2002 to 2006, and all were in children <3 years of age. All patients developed pneumonia within 2 months after transplantation. With cidofovir treatment, three of the four children survived. Among the survivors, two developed early bronchiolitis obliterans within 1 year after transplant, and one has continued to have good graft function at 2 years after transplant. All patients maintained normal renal function throughout the treatment course. Pediatric lung transplant recipients <3 years of age are at increased risk of adenovirus pneumonia early after transplantation. Cidofovir, when used in the modified dosing regimen and in combination with IVIg and renal protection measures, is a safe and potentially effective treatment option for adenovirus pneumonia in lung transplant recipients.

Complications pulmonaires précoces des allogreffes de cellules souches hématopoïétiques

Pneumonia is one of the main causes of mortality following allogenic stem cell transplantation, especially in the first months after the transplant has been performed. Pneumonia is the most common infection occurring after transplant and the infection with the highest mortality. Following the classical, myeloablative approach to transplant, two thirds of the pneumonias that occur are of infectious origin. Their causes roughly follow the timing of the immune reconstitution, and may depend on the type of transplant, the match between donor and recipient, and, overall, the occurrence of graft-versus-host disease. Most bacterial pneumonias occur during the initial neutropenic phase. The 2nd and 3rd month post transplant are mainly complicated by viral pneumonia, especially respiratory virus and adenovirus pneumonia in deeply immunosuppressed patients. Preemptive and prophylactic strategies have considerably reduced the incidence of cytomegalovirus pneumonia. Pneumonia due to encapsulated bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae, usually considered to be late infections, may actually be observed from the second month post-transplant. The increasing use of reduced-intensity conditioning regimens has modified the time course of the main adverse events following transplantation, including the timing of the infectious pneumonias. The pneumonias that are specifically related to allogenic transplant are idiopathic interstitial pneumonia, bronchiolitis obliterans, and bronchiolitis obliterans organizing pneumonia, which are all considered to be pulmonary manifestations of graft-versus-host disease, and treated as such. Prophylaxis for many of these infectious pneumonias (i.e., P jiroveci, S pneumoniae, toxoplasmosis) are well standardized. Much remains to be done to decrease the incidence of pneumonia in these patients and to understand their mechanisms.

164: Successful treatment of adenovirus pneumonia in pediatric lung transplant recipients with cidofovir

Purpose: Adenovirus pneumonia results in high mortality in transplant recipients. Cidofovir (5 mg/kg once a week) has been used with moderate success in the treatment of adenovirus pneumonia in hematopoietic stem cell and other solid organ transplant recipients with a significant rate of renal toxicity. In this study, we evaluated the efficacy and safety of cidofovir administered under a modified dosing regimen for the treatment of adenovirus pneumonia in pediatric lung transplant recipients.

Invasive adenoviral infections in T‐cell‐depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir

Adenovirus (ADV) infection occurs in 5-21% of allogeneic hematopoietic stem cell transplants (HSCT). Symptomatic enteritis and hemorrhagic cystitis may be encountered but are seldom fatal. In contrast, mortality rates of up to 75% are reported for adenoviral pneumonia or hepatitis. Cidofovir is currently being increasingly used for treatment of adenoviral infections after HSCT. The efficacy of cidofovir in patients with invasive adenoviral infection is not established. We reviewed 687 adult and pediatric patients who received allogeneic HSCT at our institution from 1998 through June 2005. ADV was isolated from 64 (9.3%) patients. Eleven patients received cidofovir for invasive disease occurring at median 39 days (range 3-145) post HSCT. The median age was 40 (range 6-61) years. Seventy-three percent received a T-cell-depleted graft and 18% had grade 3-4 graft-versus-host disease (GVHD) of the gut. Three out of 3 (100%) patients with adenoviral pneumonia died. One patient with hepatitis, cholecysitis, and viremia cleared the infection after 3 months. Two out of 7 (28.6%) patients with hemorrhagic colitis or cystitis died of ADV (1 with extensive GVHD). Mortality rates of ADV pneumonitis after allogeneic HSCT remain high in the era of cidofovir. Clinical trials are needed to evaluate management strategies for this life-threatening infection.

212: Adenovirus (ADV) infections following allogeneic stem cell transplant (alloSCT) in children and adolescent recepients

ADV is a serious cause of morbidity and mortality in patients undergoing alloSCT. ADV infection rates are 4-6% in adults and as high as 47% in children following alloSCT (Hoffman et al BBMT 2001). The reported mortality rate for disseminated ADV ranges from 8-54 % with higher rates reported in patients with ADV pneumonia (73%) and disseminated disease (61%) (Ljungman, Eur J Clin Microbiol & Infect Dis, 2004). We sought to determine the incidence, demographics, site of disease, treatment course, and outcome of ADV infection in children and adolescents following alloSCT from 1/1/2000-12/31/04. Eighty three children and adolescents underwent 91 alloSCT. Median age 6.5 (0.5 – 21.75) years, sex: M/F (52/39). AlloSCT donors included: Matched Family Donor (MFD), Bone Marrow (BM)/Peripheral Blood (PB) – 34 (37.4%), Unrelated Cord Blood(UCB) – 51 (56%), Related Cord Blood(RCB) - 3 (3.3%), Matched Unrelated Donor(MUD) – 3 (3.3%). Conditioning: 36 (40%) ablative conditioning, 55 (60%) reduced intensity conditioning. The majority (>90%) received Mycophenolate Mofetil/Tacrolimus GVHD prophylaxis (Osunkwo/Cairo et al, BBMT 2004). Recipients at risk for CMV received Foscarnet/Ganciclovir prophylaxis (Shereck/Cairo et al PBC 2006). ADV swabs and tissue biopsies samples cultured in remel microtest viral media. Ten (11%) systemic and/or invasive ADV infections were identified. Underlying diagnosis: 5 malignant (1ALL, 1 AML, 1 NHL, 2 NBL), 5 non-malignant (1WAS, 4 SAA). Donor source: 4 UCB, 1 MUD, 2 MFDPB, 1 MFDBM, 2 MFDBM + PB. Sites of ADV + culture: Gastroenteritis (GE) – 4, GE/Pneumonitis – 3, GE/Nasopharyngeal – 2, Cystits – 1. Treatment (Tx): cidofovir (CDV) (1mg/kg TIW) [n=8], observation [n=1], ADV found on post-mortem culture [n=1]. Outcome: 8 expired (6 non-ADV infection, 1 GVHD, 1 CNS hemorrhage); 2 survivors (1 post tx with no evidence of ADV, 1 ADV + no tx.) There were no ADV related deaths for 0% mortality. Adenovirus infection is an important contributor to post alloSCT morbidity and mortality. In patients transplanted at our center from 1/2000 –12/31/04 there was an 11 % incidence of adenovirus infection. Tx with CDV improves the outcome of patients with ADV infection in the post-transplant period. More rapid diagnosis with PCR-based technology will allow earlier diagnosis of systemic disease in alloSCT recipients resulting in prompt therapeutic intervention which may lead to improved outcomes. ADV is a serious cause of morbidity and mortality in patients undergoing alloSCT. ADV infection rates are 4-6% in adults and as high as 47% in children following alloSCT (Hoffman et al BBMT 2001). The reported mortality rate for disseminated ADV ranges from 8-54 % with higher rates reported in patients with ADV pneumonia (73%) and disseminated disease (61%) (Ljungman, Eur J Clin Microbiol & Infect Dis, 2004). We sought to determine the incidence, demographics, site of disease, treatment course, and outcome of ADV infection in children and adolescents following alloSCT from 1/1/2000-12/31/04. Eighty three children and adolescents underwent 91 alloSCT. Median age 6.5 (0.5 – 21.75) years, sex: M/F (52/39). AlloSCT donors included: Matched Family Donor (MFD), Bone Marrow (BM)/Peripheral Blood (PB) – 34 (37.4%), Unrelated Cord Blood(UCB) – 51 (56%), Related Cord Blood(RCB) - 3 (3.3%), Matched Unrelated Donor(MUD) – 3 (3.3%). Conditioning: 36 (40%) ablative conditioning, 55 (60%) reduced intensity conditioning. The majority (>90%) received Mycophenolate Mofetil/Tacrolimus GVHD prophylaxis (Osunkwo/Cairo et al, BBMT 2004). Recipients at risk for CMV received Foscarnet/Ganciclovir prophylaxis (Shereck/Cairo et al PBC 2006). ADV swabs and tissue biopsies samples cultured in remel microtest viral media. Ten (11%) systemic and/or invasive ADV infections were identified. Underlying diagnosis: 5 malignant (1ALL, 1 AML, 1 NHL, 2 NBL), 5 non-malignant (1WAS, 4 SAA). Donor source: 4 UCB, 1 MUD, 2 MFDPB, 1 MFDBM, 2 MFDBM + PB. Sites of ADV + culture: Gastroenteritis (GE) – 4, GE/Pneumonitis – 3, GE/Nasopharyngeal – 2, Cystits – 1. Treatment (Tx): cidofovir (CDV) (1mg/kg TIW) [n=8], observation [n=1], ADV found on post-mortem culture [n=1]. Outcome: 8 expired (6 non-ADV infection, 1 GVHD, 1 CNS hemorrhage); 2 survivors (1 post tx with no evidence of ADV, 1 ADV + no tx.) There were no ADV related deaths for 0% mortality. Adenovirus infection is an important contributor to post alloSCT morbidity and mortality. In patients transplanted at our center from 1/2000 –12/31/04 there was an 11 % incidence of adenovirus infection. Tx with CDV improves the outcome of patients with ADV infection in the post-transplant period. More rapid diagnosis with PCR-based technology will allow earlier diagnosis of systemic disease in alloSCT recipients resulting in prompt therapeutic intervention which may lead to improved outcomes.

Adenoviral Pneumonia During Etanercept Treatment in a Patient with Rheumatoid Arthritis

Inhibitors of tumor necrosis factor-alpha (TNF-α) have been approved for treating rheumatoid arthritis. As one of the biological response modifiers, etanercept has also been used in the treatment of psoriatic arthritis and inflammatory bowel disease. While etanercept is effective, certain infectious complications, such as tuberculosis, fungus, and cytomegalovirus, have been reported. We report the first Korean case of adenoviral pneumonia in a 55-year-old female who developed disseminated adenoviral infection following etanercept treatment, which resolved after anti-TNF-α discontinuation.

Pre-Transplant 5-Azacitidine (Vidaza®) May Improve Outcome of Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Myelodysplastic Syndrome (MDS).

Most patients with MDS are older than 60 yrs and, because of age, many have previously been excluded from HCT due to the high risk of transplant related mortality. Reduced intensity conditioning has decreased regimen related mortality in HCT and has increased the age of patients for whom this treatment is offered. There remains substantial risk of relapse after HCT especially in patients with > Int-1 MDS who benefit the most from immediate HCT. One strategy to suppress leukemia burden and potentially decrease the risk of relapse is pre-transplant treatment with 5-azacitidine (Vidaza®). This DNA hypomethylating drug is FDA approved for the treatment of MDS. We analyzed the outcome for 34 MDS patients who received a myeloablative HCT from an HLA compatible sibling or unrelated donor from July 2004 through June of 2006, to investigate the potential impact of pre-transplant 5-azacitidine on response and post-transplant relapse. Fourteen of thirty-four patients received a median of 2 (1–7) cycles of 5-azacitidine prior to HCT. Median age was 59 (49 – 69) yrs. Diagnosis and IPSS category included MDS (8) [Int-1 (1) and Int-2 (7)], MDS-AML (5) and CMML (1). Two patients had induction chemotherapy with residual MDS prior to 5-azacitidine. Subsequent to 5-azacitidine: ten responded [CR (2), PR (1) improvement (7)] three progressed and one was not evaluable. The IPSS category after 5-azacitidine treatment and prior to HCT was Int-2(1), Int-1 (4), and Low (5; 3 in CR) in addition to AML (2) and CMML (1). One was unable to assess. The median follow-up in the survivors is 191 (47 – 524) days. Of the fourteen 5-azacitidine treated patients, none have relapsed post-HCT including patients who progressed on 5-azacitidine. Four have died from non-Hodgkins lymphoma (1), DAH (1), adenovirus pneumonia (1) and chronic GVHD (1). Ten are alive in remission, two for greater than one year. Twenty patients did not receive 5-azacitidine. Diagnosis and IPSS category included MDS (9) [Int-1 (3) and Int-2 (6)], MDS-AML (9) and CMML (1) and one not determined due to lack of cytogenetics. Their median age was 53 (33 – 68) yrs. Treatment included supportive care, induction chemotherapy (9) and SCIO-469 (1). IPSS distribution prior to HCT was Int-2 (7), Int-1 (5) Low (5; 4 in CR); in addition to AML (1) and CMML (1). One was unable to assess. The median follow-up in the survivors is 420 (21 – 742) days. Ten of twenty are alive without relapse and eight have relapsed. Five have died, with relapse (3), fungal pneumonia (1) or multi-organ failure (1). The 1 year K-M estimates of overall and progression free survivals are 64% (SEM 15%) and 64% (SEM 15%), respectively for 5-azacitidine group and 70% (SEM 11%) and 51% (SEM 13%) for non-5-azacytidine group. We conclude from this preliminary analysis that pre-HCT conditioning treatment with 5-azacitidine may reduce the risk for MDS relapse after allogeneic transplant in higher risk patients. In addition to its direct anti-tumor effect, 5-azacitidine may sensitize neoplastic cells to the effects of high dose chemotherapy or promote the expression of antigens critical to effective graft-vs-tumor response. This treatment strategy will be evaluated in a prospective trial to investigate the role of pre-transplant 5-azacitidine on transplant outcomes in patients with higher risk MDS.

T Cell Immunotherapy for Adenoviral Infections of Stem Cell Transplant Recipients.

Adenoviruses remain a major cause of mortality and morbidity in hematopoietic stem cell transplant (HSCT) recipients. To date, no effective anti-adenoviral treatment is available, presenting a potential role for adoptive T cell therapy, as an increased risk of infection may be correlated with lack of endogenous T cell immunity. Therefore the goal of this project was to evaluate the use of adenovirus-specific cytotoxic T lymphocyte (CTL) lines for the prophylaxis and treatment of adenoviral infections post-HSCT. CTLs are initiated by stimulation with donor-derived mononuclear cells transduced with a recombinant adenovirus type 5 vector pseudotyped with a type 35 fiber (MOI 200 virus particles (vp) per cell). Responder cells are expanded by weekly restimulation with autologous EBV-transformed B lymphoblastoid cell lines (LCL) transduced with the same vector using an MOI of 500 vp. Nine of the 11 CTL lines manufactured for clinical use were predominantly CD4+ (range 12–95%), but all had a CD8+ component (range 3.5–79%). In chromium release assays, all CTL lines showed specific killing of both adenovirus and EBV antigen-bearing target cells. Recognition of adenovirus and EBV targets was not significantly different; at 20:1 effector:target ratio there was 18.5 ± 14% specific lysis of adenovirus targets and 23 ± 15% lysis of EBV targets while uninfected recipient target cells were not lysed (1.5 ± 2%). We identified the hexon as the immunodominant target antigen in the CTL lines. To test the hypothesis that these polyclonal CD4+ and CD8+ hexon-specific T cells can provide protection against adenovirus infections in HSCT recipients, we administered donor-derived bi-virus-specific CTL lines to pediatric recipients of allogeneic stem cell transplant. So far, we have treated 7 patients in this phase I dose escalation study (using the continual reassessment model); 2 patients on dose level 1 (5x106/m2), 2 on dose level 2 (1.5x107/m2) and 2 on dose level 3 (4.5x107/m2). Of 6 patients who received CTL as prophylaxis, all remain negative for adenovirus and EBV and there were no adverse events attributable to CTL infusion. Post-infusion, samples for immune monitoring were collected for at least 3 months and analyzed by pentamer and IFN-g ELISPOT assays in batches to minimize inter-assay variablility. An increase in the frequency of EBV-specific T cells could be detected in the blood by 2 weeks post infusion in all evaluated patients, likely due to the presence of this latent virus in all patients. However, there was no significant rise in the adenovirus-specific T cell frequency post-infusion. The seventh patient received the bi-virus-specific CTL at a dose of 5x106/m2 as treatment for adenovirus disease. This patient had adenoviral pneumonia requiring ventilatory support. Following the CTL infusion the patient made a dramatic clinical recovery, was weaned off mechanical ventilation, and discharged a month after the infusion. In contrast to the prophylaxis group, this patient had a substantial rise in adenovirus-specific T cells detected in the peripheral blood by 4 weeks post-CTL infusion, which coincided with his clinical recovery and clearance of the virus from the tracheal aspirate, suggesting that the infused cells were effective in vivo. Adoptive immunotherapy for adenovirus appears to be safe but expansion of adenovirus-specific CTL in vivo may require the presence of antigen to stimulate the infused cells.

Adenovirus pneumonia in infants and factors for developing bronchiolitis obliterans: A 5‐year follow‐up

To describe clinical, pulmonary function, and chest tomography profiles in a 5-year follow-up of infants with adenovirus pneumonia and determine the factors that potentially contributed to the development of bronchiolitis obliterans (BO). We prospectively assessed 45 hospitalized infants with adenovirus pneumonia with additional follow-up for 5 years. At the end of the study, pulmonary function by impulse oscillometry technique (IOS) and chest tomography were performed in the 38 surviving patients (mean 5.7 years of age). We divided the population between those who developed chest tomography evidence of BO and those who did not. Most of the children developed adenovirus infection before 2 years of age. During the 5 years of follow-up, almost half (47.4%) developed BO. Children who developed BO had significantly more respiratory compromise (intensive care admission, need for mechanical ventilation and for oxygen therapy, and systemic corticosteroid and beta agonist use) during their adenovirus pneumonia episode than those who did not develop BO. Only 33.3% of children with BO had normal impedance compared with 85% in the no BO group. Children who developed BO had significantly higher levels of Zrs, R5, X5 and predicted Zrs, R5, and X5 and frequency. However, there were no differences in the beta 2 agonist response between the children with and without BO (94% vs. 80%, respectively). This study represents the spectra of adenovirus pneumonia ranging from relatively mild to severe and fatal cases. Children with severe pulmonary compromise are usually more prone to develop BO.

Severe adenovirus pneumonia (AVP) following infliximab infusion for the treatment of Crohn's disease

We report a case of severe AVP three weeks following the administration of infliximab for the treatment of Crohn's disease (CD). Since the introduction of tumor necrosis factor-alpha (TNF-alpha) antagonists, various microbiologic agents have been reported to cause pneumonia following their administration. To our knowledge, AVP following therapy with TNF-alpha antagonists has not been reported in English literature. We present a brief review of the mechanism of action of TNF-alpha antagonists and their ability to predispose to various infections including viral pneumonia by interfering with the immune response.

Adenovirus Pneumonia in Adults: Radiographic and High-Resolution CT Findings in Five Patients

The purpose of this study was to describe the radiographic and high-resolution CT (HRCT) findings of adenovirus pneumonia in five patients. Adenovirus pneumonia in adults appears as bilateral patchy parenchymal opacities on chest radiographs and as bilateral ground-glass opacities with a random distribution with or without consolidation on HRCT images. These findings, however, are not specific for adenovirus pneumonia.

Pulse Methylprednisolone Therapy in Type 3 Adenovirus Pneumonia with Hypercytokinemia

Adenovirus pneumonia is uncommon but its severe infection has a mortality as high as 10%, and survivors may have residual airway damages, manifested by bronchiectasis, bronchiolitis obliterans, or pulmonary fibrosis. We report a case of adenovirus pneumonia demonstrating fatal respiratory distress. Adenovirus was isolated from pharyngeal specimens using cell culture and typed as serotype 3 by a combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. The patient characteristically showed hypercytokinemia, characterized by increased levels of lactate dehydrogenase, ferritin, and several cytokines including interferon-gamma and interleukin-6. We treated the patient with pulse methylprednisolne therapy (25 mg/kg/day, for 3 days), resulting in the rapid amelioration of respiratory distress. This is the first report describing the treatment of pulse methylprednisolone therapy in fatal adenovirus pneumonia. During the clinical course, serum Krebs von den Lungen-6 (KL-6), which is a marker for the activity of diffuse interstitial lung disease, was elevated, suggesting that serum KL-6 could be available as a marker of pulmonary prognosis in viral pneumonia.

Matched Related vs Alternative Donor Stem Cell Tranplantation (SCT) for Diamond Blackfan Anemia: A Report from the Diamond Blackfan Anemia Registry.

Background: Diamond Blackfan anemia (DBA) is a rare disorder characterized by red cell aplasia, congenital anomalies and a predisposition to cancer. Corticosteroids and red cell transfusions are the mainstays of therapy. Hematopoietic stem cell transplantation is curative in DBA, however its role in these patients is controversial.Purpose: The purpose of this report is to review the outcome and treatment-related morbidity for HLA matched sibling versus alternative donor SCT for DBA patients enrolled in the Diamond Blackfan Anemia Registry (DBAR).Methods: The DBAR is a comprehensive database of patients with DBA who are enrolled after informed consent is obtained. The patients, their families, and their physicians complete a detailed questionnaire. A review of medical records and telephone interviews are performed to complete and clarify the information provided.Results: As of May 1, 2005, 420 patients have been enrolled in the DBAR, 36 of which have met the criteria for the diagnosis of DBA and have undergone an allogeneic HLA-matched sibling or alternative donor SCT. The median age at SCT for all patients was 7 years 10 months; 7 years 4 months versus 9 years 8 months for the 21 HLA-matched sibling and 15 alternative donor SCT, respectively. The major indication for SCT was transfusion dependence. In addition, two patients developed severe aplastic anemia and one significant thrombocytopenia. The majority of HLA-matched sibling transplants were done using a non-irradiation-containing conditioning regimen. One patient undergoing an HLA-matched umbilical cord SCT using a non-myeloablative conditioning regimen is engrafted but too early to evaluate. The majority of alternative donor transplants were performed using total body irradiation. One unrelated bone marrow transplant recipient also underwent non-myeloablative conditioning and is fully engrafted one year post-transplant. Sixteen of the 21 HLA-matched sibling donor transplants are alive and well, 4 of the failures occurring in patients older than 10 years of age (11, 12, 12 and 22 years) from interstitial pneumonia of unknown etiology, uncharacterized infection, veno-occlusive disease (VOD) of the liver and, in a heavily iron-overloaded patient with hepatitis C, adenovirus pneumonia, respectively. A 21 month old died from VOD. Of the 15 alternative donor SCT, one patient received bone marrow from a 3/6-mismatched sibling; another patient received a 5/6-mismatched parental bone marrow; 8 received unrelated bone marrow; 4 unrelated cord blood; and 1 unrelated peripheral blood stem cells. Three of these 15 patients are alive. The survival for allogeneic sibling versus alternative donor SCT is 72.7% ± 10.7% versus 19.1% ± 11.9% at greater than 5 years from SCT (p=0.01) (excluding a patient with osteogenic sarcoma diagnosed after SCT) or 17.1% ± 10.8% (including the osteogenic sarcoma patient, p=0.012). For patients under 10 years of age, the survival for allogeneic sibling versus alternative donor SCT is 92.3% ± 7.4% and 16.7% ± 14.8%, respectively, at greater than 4 years from SCT (p=0.01).Conclusions: The best outcomes for stem cell transplantation in DBA patients occur when performed prior to the age of 10 years, using HLA-matched sibling donors. Given the poor survival with alternative donor SCT, these transplants should be reserved only for those DBA patients with other complications requiring transplantation, i.e. aplastic anemia, red cell allosensitization or leukemia.