key: cord-0040875-av5s05pn
authors: Cordonnier, Catherine
title: Pneumonia After Hematopoietic Stem Cell Transplantation
date: 2016-02-15
journal: Transplant Infections
DOI: 10.1007/978-3-319-28797-3_16
sha: 39b460667b7559c83fca1144f711afd584de0f4c
doc_id: 40875
cord_uid: av5s05pn

Pneumonia is the main cause of morbidity and mortality after hematopoietic stem cell transplantation. Two thirds of pneumonias observed after both autologous and allogeneic stem cell transplantations are of infectious origin, and coinfections are frequent. One third is due to noninfectious process, such as alveolar hemorrhage, alveolar proteinosis, or alloimmune pulmonary complications such as bronchiolitis obliterans or idiopathic interstitial pneumonitis. Most of these noninfectious complications may require treatment with corticosteroids which may be deleterious in infection. On the other hand, these complications either mimic or may be complicated with infections. Therefore, a precise diagnosis of pneumonia is of crucial importance to decide of the optimal treatment. CT scan is the best procedure for imaging of the lung. Although several indirect biomarkers, such as serum or plasma galactomannan or (1-3) β(beta)-G-glucan, can help in the etiological diagnosis, only direct invasive investigations provide the best chance to identify the cause(s) of pneumonia. Bronchoalveolar lavage (BAL) under fiberoptic bronchoscopy is the procedure of choice to identify the cause of pulmonary infection. It is safe and reproducible, and its diagnostic yield is around 50 % if the BAL fluid is processed at the laboratory according to a prespecified protocol established between the transplanter, the infectious diseases’ specialist, the pneumologist, and the laboratory, allowing the identification of the most likely hypotheses. Transbronchial biopsy does not provide significant additional information to BAL in most cases and more often complicates with bleeding and pneumothorax. In case of a noncontributory BAL, the decision to proceed to a second BAL, a transthoracic biopsy, or a surgical biopsy should be cautiously weighted in a multidisciplinary approach in regard to the benefits and risks of invasive procedures versus empirical treatment.

Pneumonia is the most common infection after transplantation, and the infection with the highest mortality. Roughly two thirds of pneumonia observed after HSCT are of infectious origin, and this observation should be a priority leading the investigations. While the infection-related mortality has decreased after HSCT over time [ 1 ] , it is not sure that the incidence of pneumonia decreased in parallel. Up to 30 % of the patients may develop pulmonary symptoms within the fi rst 100 days after allogeneic HSCT [ 2 ] . Even in T-cell-depleted allogeneic HSCT where the incidence of pneumonia seems to be low [ 3 ] , the occurrence of pneumonia signifi cantly impacts on survival. The rates of bacterial, viral, and polymicrobial pneumonia do not seem to be different during the fi rst 3 months after transplant between allogeneic and autologous HSCT recipients, while the rate of invasive fungal disease (IFD) is much higher after allogeneic HSCT [ 2 ] , due to a more severe and prolonged immune defect which also favors late infectious complications [ 4 ] .

Factors enhancing the risk of infectious pneumonia are many and include donor and recipient serologies; previous pneumonia, which may warrant secondary prophylaxis; graft source; choice of donor and conditioning; graft-versus-host disease (GVHD); and also environmental factors. One of the main concerns in pneumonia evaluation is to distinguish infectious and noninfectious pneumonia since many noninfectious causes may mimic infection. Additionally, pulmonary coinfections are frequent. This makes that the results of indirect markers, even though extremely useful in practice, should be cautiously considered as it may identify only part of the responsible pathogens. Only a direct investigation of the lung as provided by bronchoalveolar lavage (BAL), combined with the use of well-chosen indirect markers, gives the best chances to identify several causes of pneumonia.

This chapter focuses on the factors that make the lungs particularly susceptible to infections after HSCT, the main specifi cities of clinical and imaging presentation of pulmonary infections, and the principles of diagnosis and management.

After HSCT

The lungs of HSCT candidates may have been exposed to toxic insults from their underlying diseases, prior infection, and prior chemotherapy and irradiation which may compromise normal surveillance barriers. Conditioning before transplant and subsequent immunosuppressive therapy and infection all may impair native defenses and increase the risk for pulmonary infection. The ciliated and squamous epithelium, from nasopharynx to distal bronchioles, is the fi rst line of defense. Signifi cant impairment of the ciliary epithelium has been reported even years after transplant [ 5 ] . The respective role of viral or mycoplasma infection or of GVHD or radiation in this fi nding cannot be precisely determined. However, these abnormalities were found in 17 of 20 long-term allogeneic HSCT survivors and are probably underestimated in routine practice.

Alveolar macrophages act as phagocytes and secrete cytokines and chemokines providing a next level of defense. Their functions may be altered by immunosuppressive agents and viral infection. During prolonged neutropenic phases, the number of alveolar macrophages decreases, and this could favor infection from pathogens, which are normally phagocyted at the alveolar level [ 6 ] . Additionally, after allogeneic HSCT, the recipient alveolar macrophages are progressively replaced by cells of donor origin, and this may partly explain the numeric and functional impairment of the alveolar macrophage population during the fi rst months after transplant [ 7 , 8 ] .

The occurrence of infectious pneumonia relates to the interrelationship of infectious exposure or reactivation, the condition of the lungs, and the degree of immunosuppression. The changes in many transplant procedures, including various prophylaxes, and the availability of new diagnostic tools over the last decade should have changed the incidence of pneumonia after HSCT. However, there is no clear data to support this hypothesis, and one may consider that these changes have more resulted in a change in timing and causes of pneumonia rather than in incidence or mortality. The increasing use of reduced intensity conditioning (RIC) regimens has significantly decreased the formerly high rate of early bacterial pneumonias. However, concomitantly, multidrug-resistant (MDR) bacteria have become a global concern in most hematology wards [ 9 , 10 ] . The use of RICs has also changed the kinetics of many complications, delaying the onset of GVHD and the subsequent infections [ 11 , 12 ] . Preemptive and prophylactic strategies of CMV infection have also considerably reduced the incidence of CMV pneumonia which nowadays affects less than 6 % of the patients [ 13 , 14 ] . However, pneumonia due to respiratory viruses has become common. New antifungal agents have improved therapeutic options for Aspergillus infection, but non-Aspergillus molds, especially mucormycoses, are being seen with increasing frequency [ 15 -18 ] . Finally, despite signifi cant progresses, the morbidity and mortality of pneumonia after HSCT remains one of the highest of any transplant.

The timing of infectious pneumonia follows the timing of other infections according to the type of transplant and occurrence and severity of GVHD which is the main factor prolonging the infectious risk after the neutropenic phase [ 4 ] . HSCT recipients are both at risk for nosocomial and community infections according to the phase of transplant. These environmental risks cannot always be prevented, on the contrary of the reactivation risks which must be evaluated before transplant.

Pneumonia After HSCT Although changes in the transplant procedures have impacted on the infectious complications and their timing (see Chap. X), infectious pneumonia after HSCT occurs in predictable risk periods. After allogeneic transplant, early bacterial pneumonia mainly complicates myeloablative transplant, while opportunistic fungal and viral infections may affect the patient irrespectively of the type of conditioning. After autologous transplant, most pneumonias occur during the neutropenic phase , especially in myeloma patients [ 19 ] , and few of them are of fungal origin [ 16 ] .

Bacterial pneumonia occurring during the initial neutropenia are caused by pathogens common to all neutropenic patients or to those with comparable mucositis in the ward. The clinician should also consider the possibility of streptococcal pneumonia or ARDS related to streptococcal sepsis. These infections are particularly due to Streptococcus viri-dans and have been correlated with the presence of mucositis, the use of prophylactic quinolones, and the administration of high doses of cytarabine (see Chap. 20 ) . The approach to bacterial pneumonias early after transplantation is similar to that in other neutropenic hosts, and it should include coverage for Pseudomonas species and eventually MDR in case of previous colonization or infection [ 20 , 21 ] . Most patients are maintained on indwelling intravenous catheters throughout this period, and seeding of the lungs from bacteremia continues to be a potential risk. After recovery from neutropenia, allogeneic transplant recipients continue to be at risk for any nosocomial infections as long as they stay in the hospital (see Figure 16 -1 ). Bacterial infections occurring in the late posttransplantation period may be favored by persistent immunoglobulin defi ciency, which increases the risk of pneumonia caused by encapsulated bacteria.

Invasive pneumococcal infection occurs signifi cantly more often after allogeneic, than after autologous, transplantations and especially in case of chronic GVHD [ 22 -24 ] . They may be rapidly fatal. In a prospective study from the European Blood and Marrow Transplantation Group [ 22 ] , no pneumonia developed in seven cases of invasive infection observed before day 100, whereas it was seen in 18 of 44 (41 %) cases observed after day 100, and half of the fatal cases of late infection were associated with pneumonia. Early immunization with the 13-valent conjugate vaccine, completed by the 23-valent polysaccharide later, or a fourth dose of the conju-FIGURE 16-1. This 56-year-old patient has received an allogeneic HSCT from an unrelated donor for acute myeloid leukemia . He was smoker and suffered from chronic bronchitis before transplant. He was rehospitalized at 7 months after transplant for severe chronic GVHD and was treated with steroids. He developed febrile pneumonia after 9 days of hospitalization. The lung CT scan showed ground-glass, patchy infi ltrates of the left lower lobe. The bronchoalveolar lavage was positive for coronavirus, and the culture of protected aspiration (10 3 CFUs/mL) and the culture of the lavage fl uid (10 4 CFUs/mL) were both positive for Klebsiella pneumoniae. gate vaccine in case of GVHD could reduce the incidence of pneumococcal infection over time [ 25 , 26 ] (see Chap. 48 ) . Similarly, H. infl uenzae may cause pneumonia and sinus infection, usually past the third month after transplantation. Immunization with a conjugate vaccine against type b is recommended from 6 months after transplant.

Pneumonias from intracellular pathogens are rarely reported, but they may recur in previously exposed patients. Pneumonia due to Legionella species has occasionally been reported in the setting of outbreaks, most often as a nosocomial infection. The radiologic fi ndings may be variable; they may mimic fungal nodules, and they may not be apparent at the onset of high fever and pleuritic pain. Invasive nocardiosis, reported in 0.3-1.7 % after allogeneic transplant, mainly occurs in patients who are not receiving TMP-SMX and is often diffi cult to differentiate from fungal pneumonia [ 27 , 28 ] .

Mycobacterial infections due to M. tuberculosis , Mycobacterium aviumintracellulare complex, or other species are rarely reported. Generally, they are diagnosed at 2-18 months after transplantation, but they may develop early when prior infection has occurred (see Figure 16 -2 ) [ 29 , 30 ] .

Fungal pneumonia : Aspergillus is the most worrisome cause of IFD after allogeneic HSCT. It reportedly occurs after 0-20 % of transplantations; the most common site is the lung, and GVHD is the main risk factor (see Chap. X). A fi rst peak of incidence occurs during the neutropenic period after myeloablative conditioning regimens, particularly in patients with leukemia. The second incidence peak is generally seen later in patients with acute GVHD and receiving corticosteroids. The availability of antifungal azoles for anti-aspergillus prophylaxis has signifi cantly reduced the incidence [ 31 -33 ] . However, the mortality of Aspergillus remained close to 50 % in recent series. This infection must be considered in any case of fever, particularly in that occurring in the patient on broad-spectrum antibiotics, or of any pneumonia, whether of new onset or a previously diagnosed condition that does not resolve with appropriate therapy (see Figure  16 -3 ). A negative bronchoscopy result, even when combined with testing of galactomannan in the BAL fl uid, does not diminish the suspicion for this pathogen. Without secondary prophylaxis eventually combined with surgical removal of the main lesions, the risk of relapse of prior Aspergillus infection after HSCT has been estimated around 20 % [ 34 ] .

In addition to being found in the lung parenchyma, Aspergillus may be isolated in the tracheobronchial tree where it may be responsible for signifi cant airway obstruction. White, adherent plaques may be seen on bronchoscopy, particularly in the setting of chronic GVHD and steroid use. This infection must be differentiated from worsening bronchiolitis, so that inappropriate and dangerous increases in immunosuppression can be avoided.

Pneumonia due to Candida species is rarely reported, partly because no fi rm criteria for differentiating invasive infection from colonization based on bronchoscopy without biopsy exist. The lungs may be involved in any systemic Candida species infection.

Pneumonias due to endemic fungi, such as Histoplasma or Coccidioides species, particularly in North America, must be considered in these patients, as should the emerging fungi, including Trichosporon , Alternaria , and Fusarium [ 16 ] .

A special attention should be paid to the possibility of Mucorales after allogeneic HSCT (see Chap. 39 ). Its mortality rate is between 50 and 80 % [ 18 , 35 -37 ] . Mucormycosis shares with aspergillosis common risk factors but usually occurs later, and often after voriconazole administration, although the role of a selection pressure is debated [ 35 ] . There is no indirect available marker of mucormycosis except PCR test currently in evaluation [ 38 ] . The classical presentation of mucormycosis after transplant mostly mimics aspergillosis, but galactomannan is negative (see Figure 16 -4 ). Differentiating mucor from aspergillus infection is, however, of great importance due to different therapeutic implications. As long as there is a doubt between the two infections, the patient must be treated with liposomal amphotericin B. Pneumocystis jirovecii Pneumonia (PjP) Historically, the incidence of PjP in patients not receiving prophylaxis in the 1980s was found to be 16 % during the fi rst 6 months after transplant [ 39 , 40 ] . This incidence has dramatically decreased between 1 and 2.5 % [ 41 , 42 ] with the use of trimethoprimsulfamethoxazole (TMP-SMX) prophylaxis, but the mortality in established PjP remains around 50-70 % [ 43 -45 ] . . This 37-year-old woman received an allogeneic HSCT from her HLA-identical brother for poor-risk acute myeloid leukemia. She had a past history of pulmonary tuberculosis 10 years ago, but was intolerant to secondary prophylaxis. Three months after transplant, while she was well with no GVHD, she developed an insidious fever. Chest X-ray was normal. The lung CT scan showed diffuse micronodular infi ltrates and a sub-parietal nodule of 1.5 cm in diameter in the upper left lobe. The bronchoalveolar lavage was positive for M. tuberculosis in culture.

However, in patients receiving dapsone prophylaxis, an incidence of 7.2 % was reported after allogeneic HSCT [ 43 ] . PjP usually manifests with fever, nonproductive cough, dyspnea, and diffuse interstitial pneumonitis. In HSCT recipients, the presentation of PjP may be extremely abrupt, and the patient may quickly deteriorate and require intensive care unit (ICU) [ 46 -48 ] . Rarely, the disease may reveal by an isolated lowgrade fever and a normal chest X-ray at the beginning. In such cases, if the cause of fever is not rapidly found, a CT scan will show pulmonary ground-glass lesions and prompt a BAL [ 49 ] . The elevation of LDH is poorly helpful [ 46 ] . Most patients present with nodular infi ltrates or other pattern of diffuse interstitial pneumonia. Pleural effusion and pneumothorax are uncommon [ 44 ] . Most cases occur between 3 and 24 months after transplant, in patients with acute or chronic GVHD or in relapse of the underlying disease [ 42 , 43 , 49 , 50 ] . Most are receiving steroids, especially at a phase of tapering off, or after recent withdrawal, and do not receive, or are not compliant to, TMP-SMX prophylaxis [ 51 ] . Whether a low CD4 count is a main risk factor for developing PjP after HSCT is unknown. P. jirovecii is not cultivable in vitro. It may be identifi ed by microscopic detection, direct or indirect immunofl uorescence (IF), or nucleic acid tests (NAT) (see . Several stainings may be used for microscopic detection of trophic forms and cysts in any respiratory sample such as Giemsa to identify trophic forms and toluidine blue O or calcofl uor white to detect cysts, without signifi cant difference in their diagnostic performance. IF has a better sensitivity than conventional stainings [ 52 , 53 ] . The combination of one classical staining and IF allows the detection of both cystic and trophic forms. PCR is the most sensitive diagnostic assay to identify pneumocystis [ 54 -56 ] , although no study defi nes a clear cutoff of positivity [ 57 , 58 ] .

HSCT recipients, as other non-HIV-infected patients, are known to be infected with low burden of cysts [ 53 , 59 , 60 ] . As there is a decreasing gradient of the pneumocystis burden from upper to lower respiratory airways, this probably explains . This young patient, 20 years old, received an allogeneic HSCT from an unrelated donor for acute lymphoblastic leukemia in second remission. He got sever e acute GVHD and was not compliant to anti-mold azole prophylaxis. He developed an acute right chest pain with fever. ( a ) Both X-ray and CT scan showed a macronodular and isolated lesion of the right lower lobe. Serum galactomannan assay was negative. ( b ) The bronchoalveolar lavage smears showed hyphae characteristics of aspergillus (Gomori-Grocott stain). The culture of BAL fl uid grew to Aspergillus fumigatus. . This 28-year-old patient had received an allogeneic HSCT for acute lymphoblastic leukemia from an unrelated donor. He got severe, cutaneous, and gut GVHD and was treated with steroids. At 4 months after transplant, while still on 0.7 mg/kg of prednisone, he developed a nodular lesion of the right lower lobe. A galactomannan test was positive in serum. He refused fi broscopy and was treated for aspergillus infection with voriconazole. He then did not attend the consultations for 1 month and came back with bilateral thoracic pains and fever. The CT scan showed bilateral pleural effusion and a voluminous round, necrotic lesion surrounded by an area of consolidation in the right lower lobe. Rhizopus grew from the BAL fl uid. the diffi culties to identify P. jirovecii in induced sputum or other upper respiratory samples with conventional techniques in non-HIV-infected patients. Therefore, BAL fl uid is the preferred specimen for the diagnosis of PjP in HSCT recipients. Another argument for BAL is that half of the PjP cases in non-HIV-infected patients are associated with coinfections, especially with bacteria, CMV, and Aspergillus spp . [ 44 , 46 , 61 ] which require identifi cation and treatment.

In case a BAL cannot be done, upper respiratory tract (URT) specimens, like induced sputum, oral washings, nasal swabs, or nasopharyngeal aspirates, can be used, but with a lower expected diagnostic value than with BAL. Serum (1-3) β(beta)-D -glucan is a major cell wall component of P. jirovecii . Two meta-analyses [ 62 , 63 ] have shown its excellent sensitivity, but due to its panfungal nature and the frequency of other IFD after HSCT, it can be only a screening tool for PjP. On the other hand, its use in BAL fl uid is not recommended, due to a poor sensitivity and reproducibility [ 64 , 65 ] . The recent guidelines of the fi fth European Conference on Infections in Leukemia [ 66 ] propose a practical algorithm for the diagnostic of PjP in non-HIV-infected patients, based on the examination of BAL fl uid with IF and qPCR. The positivity or negativity of both techniques signs the presence or absence of PjP. When IF is positive, and qPCR negative, this should refl ect a technical problem, mainly of qPCR. When qPCR is the only positive assay, although no quantitative cutoff can be uniformly proposed, a high fungal burden favors a diagnosis of PjP. The concomitant positivity of serum (1-3) β(beta)-D-glucan is an additional argument favoring PjP. When BAL is not possible because the patient is too hypoxemic or refuses the procedure, serum (1-3) β(beta)-Dglucan can be helpful in conjunction with URT samples. When the clinical suspicion of PjP is high and the BAL cannot be done immediately, an empirical treatment with TMP-SMX should be started as soon as possible since it will not impair the diagnostic yield of investigative procedures before at least several days. TMP-SMX at the dose of 15-20 mg/kg of TMP plus 75-100 mg/kg of SMX, by oral or preferably IV route, is the fi rst choice for treatment [ 67 ] , even in patients who were supposed to take TMP-SMX prophylaxis as the presence of dihydropteroate synthase mutations does not signifi cantly affect the treatment effi cacy [ 68 ] . The addition of steroids for the more hypoxemic patients (PaO2 while breathing room air <70 mmHg), although well established in HIV-infected patients [ 69 ] , is debated in others.

PjP prophylaxis is strongly recommended from engraftment for at least 6 months after allogeneic HSCT and longer as far as any immunosuppressive drugs are administered [ 70 , 71 ] and for at least 3-6 months after autologous HSCT [ 70 ] . No large prospective series compare the respective prophylactic effi cacy of TMP-SMX with alternatives in HSCT recipients. However, strong arguments from both acquired immunodefi ciency syndrome prospective studies and HSCT retrospective series suggest that TMP-SMX is the best prophylactic regimen [ 43 , 72 ] , any alternative to TMP-SMXdapsone, atovaquone, or pentamidine-being inferior [ 71 ] . 

During the neutropenic phase of transplant, the incidence of herpes simplex virus (HSV) reactivation and diseaseincluding pneumonia-has fallen sharply with the wide use of prophylactic acyclovir or valaciclovir [ 73 ] .

Until the beginning of the 1990s, CMV was the most signifi cant pathogen for pneumonia after allogeneic transplant, affecting 15 % of the recipients. Preemptive and prophylactic strategies have greatly decreased its incidence, currently in the range of 1-5 % [ 14 , 74 -76 ] . It is generally a febrile disease in which the radiographic patterns are primarily interstitial but sometimes alveolar. Coinfections are frequent. The optimal approach to identify the virus in the lungs is the combination of IF and rapid culture of BAL fl uid. The identifi cation of CMV through PCR on BAL fl uid has been shown to have limited correlation with the development of CMV pneumonia and therefore is not considered as criteria for CMV pneumonia [ 77 ] (see Chap. 24 ). Therefore, as most of the laboratories abandon IF assays to more automated qPCR techniques, a careful examination of the BAL smears by an experimented cytologist is important to detect the cytological hallmarks of CMV pneumonia, knowing that the identifi cation of the characteristic inclusions in alveolar cells is a sign of advanced infection [ 78 ] (see .

Other herpesviruses, including varicella-zoster virus, EBV, and Human herpesvirus 6 (HHV-6), have been reported as causes of pneumonia in HSCT recipients. High levels of HHV-6 DNA have been found in the lung tissue of patients with idiopathic or CMV interstitial pneumonitis [ 76 ] . However, the clinical signifi cance of this fi nding, and the need for specifi c therapy, is still unclear.

Pneumonia caused by respiratory viruses has become a main concern in HSCT recipients. The list regularly enlarges [ 79 , 80 ] . The main risk factors for death are the early onset after transplant, neutropenia, lymphopenia, GVHD, steroid administration, and older age [ 79 , 81 -83 ] . Recently, an immunodefi ciency scoring system has been proposed to predict poor outcomes and better identify patients infected by respiratory syncytial virus and who should benefi t the most from antiviral therapy [ 83 ] . The incidence is lower after autologous than after allogeneic transplant [ 84 ] . Identifi cation by NAT in respiratory samples is the recommended technique and may be performed on nasopharyngeal or throat swabs, bronchial aspiration, or BAL fl uid [ 79 , 85 , 86 ] with multiplex assays. Diagnosing these patients early has several benefi ts: [ 1 ] some of these infections may be effi ciently treated (e.g., oseltamivir in infl uenza infection or ribavirin for respiratory syncytial virus); [ 2 ] all of them imply isolation and barrier measures to prevent transmission to other patients or staff; [ 3 ] respiratory viral infections early after allogeneic transplant predict the development of alloimmune lung syndrome, including bronchiolitis obliterans and idiopathic interstitial pneumonia [ 79 , 87 , 88 ] . When respiratory viruses are detected before transplant, delaying the transplant should be considered [ 89 ] .

Measles pneumonia has rarely been reported after HSCT but may be an expected event in the setting of outbreaks [ 90 ] and may occur without a rash. Adenovirus pneumonia is a very rare but potentially life-threatening event occurring in the setting either of disseminated adenovirus infection or of usually upper and then lower respiratory tract infections [ 91 ] (see Chap. 33 ) and occur more frequently in children than in adults and in unrelated transplants or after T-cell depletion.

Reports of pulmonary toxoplasmosis are rare; it is usually seen in the setting of disseminated infection resulting from reactivation, during the fi rst year after transplantation in seropositive recipients not receiving TMP-SMX. The pattern is usually a diffuse interstitial disease, and neurologic symptoms may be absent. Toxoplasmosis may be identifi ed in BAL fl uid and blood by IF and qPCR. A prospective screening by qPCR in the patients at risk may allow a preemptive therapy [ 92 ] .

The lung is the site of numerous noninfectious injuries causing one third of pulmonary infi ltrates after HSCT. This needs to be considered because they may require specifi c treatments. Pulmonary edema, pulmonary embolism, and acute respiratory distress syndrome may occur at any time, but more often during the early phase of transplant, without any special presentation in transplant recipients and will not be detailed here.

Other noninfectious processes affecting the lung deserve specifi c consideration as they are either frequent or specifi cally observed in HSCT recipients. These noninfectious processes may be associated with infections, increasing the diffi culty to propose optimal treatment. The best identifi cation is however of crucial importance since steroids may be indicated in several noninfectious processes while they will be deleterious in most infections. The probability of their occurrence may vary by time after transplantation and type of transplant. Alveolar hemorrhage (AH) is a frequent noninfectious process affecting the lung after any HSCT, with an incidence rate of 6-41 % [ 93 -95 ] . AH is diagnosed on the basis of either a bloody aspect of the BAL fl uid-usually transientor the presence of ≥20 % of siderophages among alveolar macrophages (see Figure 16 -7 ) [ 96 ] . AH after HSCT may be an autonomous process favored by thrombocytopenia, other coagulation disorders, or renal failure [ 96 ] and by any rupture of the alveolar-capillary barrier such as in pulmonary edema, but it may also be associated with infections, like aspergillus or CMV, in two thirds of the cases [ 94 , 97 ] .

Neither clinical presentation nor imaging are specifi c of infectious or noninfectious forms [ 97 ] .

Secondary alveolar proteinosis ( AP ) is rare, occurring mostly during prolonged neutropenia. It is the result of a complex process probably combining pneumocyte II stimulation and quantitative and functional defects of the alveolar macrophages. This results in an impaired clearance of pulmonary surfactant and the accumulation of a lipoproteinaceous periodic acid-Schiff (PAS)-positive material in the alveolar space (see Figure 16 -8 ) [ 98 , 99 ] . It usually mimics an insidious pulmonary edema. The diagnosis may be suspected on the sticky aspect of the BAL fl uid and then by diffi culties to count the cells. The usual stainings do not identify AP. The cytologist must be aware of this possibility and examine the alveolar material on PAS or Black Sudan staining. Secondary AP rarely complicates with severe respiratory failure [ 99 ] . When it occurred during neutropenia, it usually improves at neutrophil recovery. However, as for AH, some cases are associated with infections.

Pulmonary venoocclusive disease is a very rare event after HSCT. It mainly manifests by pulmonary arterial hypertension, but with a normal pulmonary artery occlusion pressure. The diagnosis is extremely diffi cult. By analogy with liver veno-occlusive disease, it is hypothesized that it is due to chemotherapy and/or radiation toxicity on the small vessels [ 100 , 101 ] .

The engraftment syndrome may be observed during neutrophil recovery, at a median onset of 16 days after transplant, and usually associates ≥2 of the following criteria: fever, skin rash, weight gain due to capillary leakage, and respiratory failure without other identifi ed cause [ 102 ] . It is hypothesized that degranulation of upcoming neutrophils could induce lung injury. Engraftment syndrome is associated with a large dose of mononuclear cells infused, the use of G-CSF or GM-CSF, early neutrophil recovery, non-myeloablative conditioning, the use of amphotericin B therapy, and autologous rather than allogeneic transplant [ 102 -105 ] . An incidence up to 48 % has been reported in children after allogeneic myeloablative transplant, one fourth of them suffering from pulmonary symptoms. As severe patients may require steroids [ 104 , 105 ] , it is important to quickly rule out an infection. Idiopathic ( noninfectious ) interstitial pneumonia is a complication reported in most allogeneic HSCT studies, with a high mortality rate. This diagnosis implies to have ruled out at least the main infections classically presenting as diffuse interstitial pneumonia, especially viral pneumonia and PjP, cardiac dysfunction, and fl uid overload [ 106 ] . In myeloablative transplant, it has been associated with leukemia or myelodysplastic syndrome, severe acute and chronic GVHD, high-dose total body irradiation, and older age. In allogeneic HSCT, its incidence has been reduced from 8.4 % after myeloablative to 2.2 % after non-myeloablative conditioning [ 107 ] . A recent study showed that among 69 HSCT recipients who had developed an idiopathic pulmonary syndrome between 1992 and 2006 in Seattle, a retrospective microbiological screening of BAL material for 3 bacteria, 25 viruses searched with NAT, and galactomannan identifi ed that 56.5 % of the patients had one pathogen (mainly HHV-6, rhinovirus, CMV, and aspergillus), and this fi nding was associated with an increased mortality at day 100 [ 76 ] . This confi rms that the rate of "idiopathic" pneumonia is highly depending on how far infection is searched.

Bronchiolitis obliterans ( BO or obliterative bronchiolitis ) is an important factor contributing to death usually from 6 months after HSCT. Reported only after allogeneic HSCT, the condition has been related to older age, unrelated donor, total body irradiation, decreases in serum immunoglobulin G, and chronic GVHD, with a frequency of 3-10 % in patients with chronic GVHD who survive 120 days [ 108 ] . It seems to be prevented by T-cell depletion of the graft [ 109 ] . BO usually occurs insidiously, with cough, dyspnea, and wheezing, but may complicate with fever and mimic bronchopulmonary infection. Its hallmark is airway obstruction. The lung CT scan shows hyperinfl ated bronchiectasis, with a mosaic pattern. BAL and other endoscopic samples are of limited value as they just aim to rule out infection. As no noncontributory BAL can defi nitely rule out infection, it is preferable to perform two consecutive BALs at 1-2 weeks interval to increase the chance to not miss any pathogen. It is often associated with sinusitis and complicated by infections, especially those caused by Haemophilus infl uenzae , S. pneumoniae , Aspergillus species, and respiratory viruses. Despite immunosuppressors, the prognosis is poor.

Alveolar or nodular infi ltrates may be seen in the setting of allogeneic HSCT as a result of bronchiolitis obliterans organizing pneumonia (BOOP) -also called cryptogenic organizing pneumonia [ 108 , 110 ] . BOOP is much less common than BO and is also considered a manifestation of GVHD but has also been reported after autologous HSCT. It occurs earlier than BO, usually in the fi rst 3 months following transplant. The CT scan shows nodular opacities and patchy consolidations. Pulmonary function tests show a restrictive defect. A histologic diagnosis is strongly recommended because BOOP may mimic infection, but can be reversible with corticosteroid therapy.

Malignant lung lesions may be seen after HSCT, either due to a primary or secondary cancer, localized relapse of the hematologic malignancy (see Figure 16-9 ) , or EBV lymphoproliferative diseases (see Chap. X).

Management of pneumonia after HSCT requires a high degree of suspicion and the early use of diagnostic procedures. The increasing availability of indirect markers of infection tends to decrease the early use of BAL. However, BAL remains the easier and safer procedure to identify both infectious and noninfectious causes of pneumonia. More invasive diagnostic procedures such as transbronchial or lung biopsy need to be selected in situations in which BAL is noncontributory while weighing the risk of increased morbidity.

A systematic approach to pneumonia in any HSCT recipient should include consideration of the following: history, clinical presentation, and imaging.

Knowledge of a patient's exposure, travel, environmental risks , and previous documented infection, the hospital epidemiology, and the pretransplant donor and recipient serologies particularly with regard to CMV and toxoplasmosis are essential. A history of recurrent MDR bacterial infection may require special consideration in choosing antibiotics [ 21 ] . Evaluation of the patient's compliance to anti-infective prophylaxis, especially to TMP-SMX, may be essential in evaluating the risk of PjP [ 51 ] . Whether the patient is neutropenic, lymphopenic, or hypogammaglobulinemic at presentation may be important to list the main infectious hypotheses.

Symptoms and signs of pneumonia may or may not be typical of a known infectious cause. However, none is very specifi c. As in all immunosuppressed patients, few fi ndings may be present, so any symptoms must be carefully and quickly evaluated, because of the consideration that any infection can rapidly progress. Fever, cough, or sputum production may be absent. Hypoxemia may be the sole fi nding, and even if the X-ray is normal, in case a chest CT scan cannot be obtained quickly, a bronchoscopic evaluation should be considered. The presence of any such symptom may, however, refl ect a noninfectious etiology. Acute thoracic pain, with or without hemoptysis, may indicate embolic disease but may also denote Aspergillus infection. Pneumothorax may reveal-or complicate-PjP, mycobacterial or Aspergillus infection, or fi brosis. The rapid onset of pneumonia is mainly consistent with bacterial pneumonia, PjP, pulmonary edema or hemorrhage, or thromboembolism, but this may also occur with viral infections in immunosuppressed patients. A subacute onset more suggests IFD, although it may present abruptly.

Posttransplantation pneumonia may be focal, multifocal, diffuse and interstitial, alveolar, or mixed. Every effort must be made to quickly obtain chest X-rays of optimal quality and/ or a high-resolution chest CT scan when easily available. X-rays in supine position are rarely helpful. Additionally, most X-ray patterns are nonspecifi c and many patients have mixed types of infi ltrates. When an X-ray appears negative or shows only minimal changes, there is good evidence that a chest CT may reveal abnormalities. CT scan has the best negative predictive value to rule out pneumonia and will show lung images 5 days before chest X-ray [ 111 ] . CT may additionally provide localization of the lesions, guiding invasive procedures, and inform on their proximity to pulmonary vessels. This information is also important to evaluate the 16. Pneumonia After Hematopoietic Stem Cell Transplantation risk of hemoptysis in aspergillosis. CT may also detect small pleural effusions. Some CT fi ndings may suggest the presence of particular infections. For example, the halo sign-a macronodule (≥1 cm in diameter) surrounded by a perimeter of ground-glass opacity-is very evocative of early aspergillosis during neutropenia [ 112 ] , but may also be seen in other infections (e.g., legionella, mycobacterial infection, mucormycosis, or viral infections). Similarly, the reversed halo sign or "atoll sign"-a focal ground-glass attenuation surrounded by a ring of consolidation-has been shown to be often due to mucormycosis in hematology patients, but may also be observed in other infections, including aspergillosis [ 113 ] . Ground-glass opacities are very nonspecifi c and consistent with any infectious and many noninfectious processes such as pulmonary edema or hemorrhage. However, even with more characteristic lesions-such as the air crescent sign which is rare after HSCT but very evocative of mold infection-a CT scan does not replace the need for identification of the pathogen for diagnosis. Magnetic resonance imaging (MRI) usually does not provide more information than CT, except in the detection of lung abscesses [ 114 ] . The usefulness of PET scan is limited for diagnosis of acute pneumonia but may be better in nodular, subacute lesions [ 115 ] , to identify extrapulmonary lesions or to follow the treatment effi cacy [ 116 -118 ] . Any workup using imaging should be completed rapidly, and it should lead quickly to a diagnostic procedure or, in most cases, to an empiric approach considering the most likely hypotheses.

Blood cultures should be performed routinely, but they are of limited value in diagnosing pneumonia except for when the pathogen has a high propensity for the blood, such as Streptococcus pneumoniae , or in neutropenia. Special culture media are required when Nocardia or atypical mycobacteria are suspected. The blood should also be quickly sampled for CMV antigenemia or quantitative real-time PCR (qPCR) in patients at risk. The microbial documentation of any other site of infection, such as skin biopsy of cerebrospinal fl uid, may be useful.

Blood biomarkers for the diagnosis of IFD include the detection of galactomannan by an enzyme-linked immunosorbent assay and of (1-3) β(beta)-D -glucan by a colorimetric assay. (1-3) β(beta)-D -glucan is a panfungal marker, while galactomannan is mainly associated with aspergillosis, although it may be positive in other mold infections, e.g., fusariosis. A meta-analysis of 27 studies showed that the galactomannan test has a sensitivity of 0.71 and a specifi city of 0.89 for proven invasive aspergillosis [ 119 ] . The assay seems to be more useful for the prospective screening of neutropenic patients rather than for diagnosing pneumonia and also more useful in neutropenic than in non-neutropenic patients [ 120 , 121 ] . The cutoff of positivity usually recom-mended is an index ≥0.5 in plasma or serum [ 121 ] . In an autopsy-based study, the sensitivity and specifi city of the serum (1-3) β(beta)-D -glucan test for the detection of IFD were 95.1 % and 85.7 %, respectively [ 122 ] . Serum (1-3) β(beta)-D -glucan test is also very useful in the indirect diagnosis of PjP [ 63 , 123 ] . Fungal NAT have also been widely investigated in HSCT recipient [ 124 ] , but no consensus on their use in clinical practice currently exists. At this time, no noninvasive test that can replace the specifi city of direct pulmonary investigation exists.

Although sputum may be analyzed to yield organisms colonizing the oropharynx, the clinical relevance of the results is not evidence based in the setting of HSCT. A positive culture may be valuable when agents that do not normally inhabit the oropharynx are isolated, especially Legionella , mycobacteria, and some fungi, or to document MDR colonization which may guide an empirical antibacterial treatment. In HSCT recipients with pneumonia, a positive sputum culture may be highly suspicious for pulmonary aspergillosis. Similarly, the presence of M. tuberculosis in the sputum may be considered the cause of the pneumonia when clinical and radiologic signs support this etiology. This assertion is to be considered with more caution for nontuberculous mycobacteria [ 125 ] .

Nasopharyngeal aspirates or washings are useful to detect respiratory viruses in patients with URT infection [ 81 , 84 ] . However, the correlation with the cause of the concomitant pneumonia is only presumptive as coinfections are frequent [ 84 ] .

The standard for diagnosing pulmonary infection after HSCT is bronchoscopic sampling with BAL [ 126 ] (Table 16-1 ) . Lavage is safe, minimally invasive, and reproducible. Its overall diagnostic yield is comparable to the one of lung biopsy, but with more infectious diagnostic and much less complications [ 126 ] .

The clinician who consults with a pulmonary specialist for BAL should consider platelet transfusions if the patient is thrombocytopenic and should alert the microbiology laboratories to ensure that all potential organisms are sought. Oxygen saturation or arterial pressure should be assessed before the procedure. Fever, transient hypoxemia, and worsening of chest X-rays may be expected in as many as one half of patients during the few hours following the procedure [ 127 ] . When the patient is hypoxemic (paO2 < 70 mmHg spontaneously or with O2 supplementation) or tachypneic before BAL, he usually benefi ts from noninvasive ventilation immediately after the procedure. The overall diagnostic yield of BAL in infectious pneumonia occurring in hematologic patients varies between 27 and 55 % [ 2 , 95 , 128 -131 ] depending on many parameters such as the following:

-The localization of the pulmonary lesions : whether they are accessible by BAL or not.

-Whether the patient is neutropenic. The yield of the procedure is usually lower in neutropenic than in nonneutropenic patients [ 131 ] . -The type of the causal infection: for example, the diagnostic yield of BAL with conventional mycological techniques-without galactomannan tested in the BAL fl uid-for aspergillus pneumonia is usually lower than 50 %, while it is higher than 90 % in PjP or CMV pneumonia, for which one rarely needs a lung biopsy [ 67 ] . -The laboratory exams performed on fi broscopic samples .

The laboratory protocol should be established in advance in a multidisciplinary approach according to the expected, infectious and noninfectious, causes of pneumonia, eventually adapted to seasons for respiratory viruses. -The criteria used to defi ne specifi c entities. For example, it is generally believed that the presence of candida in a BAL fl uid or bronchial aspiration does not necessary mean a candida pneumonia, while the presence of aspergillus in an HSCT recipient does [ 132 ] . However, for some causes of pneumonia, there are until now no consensus defi nition. The increasing availability of NAT for many pathogens should not replace, in many instances, more classical techniques, until the need for classical techniques is shown to be no longer useful in diagnosing a given infection. -The delay elapsed between presentation and BAL and the number and duration of previous antibiotics before performing BAL [ 133 ] . The diagnostic yield of BAL has been shown to be better when it is performed early after the onset of pulmonary symptoms . In a series of 297 HSCT patients who underwent a BAL, the diagnostic yield of the procedure was 56.8 % in patients since less than 24 h versus 32.8 % in the others [ 131 ] . In another study, the diagnostic yield was 73 % in patients who underwent BAL within 4 days of presentation and 31 % thereafter [ 2 ] . This may be due to the effect of previous anti-infectives on the probability to identify a pathogen, but also to the fact that lung infl ammatory lesions may persist some time after the Transbronchial biopsy is essential for noninfectious processes and less contributive than BAL for infectious pneumonia. However, it is usually not proposed in the initial investigation of pneumonia, due to its possible complications (pneumothorax, bleeding).

BCYE buffered charcoal yeast extract, AFB acid-fast bacillus, IF immunofl uorescence, PCR polymerase chain reaction. 16 . Pneumonia After Hematopoietic Stem Cell Transplantation infection is controlled, so that delayed BAL may be performed in patients with a favorable outcome but still imaging and clinical signs. Therefore, it is recommended to do a BAL as soon as possible. -Finally, although pneumonia is less frequent after autologous than after allogeneic HSCT, the diagnostic yield of BAL has been reported to be lower in pneumonia occurring after autologous rather than after allogeneic HSCT [ 133 ] .

However, despite these variabilities, BAL, when well tolerated and correctly processed at the laboratory, represents the best diagnostic strategy for a minimum of complications. It should also be noticed that cytologic examination of BAL fl uid will also document alveolar hemorrhage [ 96 ] or alveolar proteinosis [ 99 ] .

A routine BAL protocol for HSCT recipients should include at least total and differential cell counts on cytocentrifuge preparations using May-Grünwald-Giemsa stains , as well as cytologic examination on cell pellets obtained by centrifugation and cytocentrifugation that are stained with the May-Grünwald-Giemsa stains and the Papanicolaou stain for viruses and the Gomori-Grocott method for P. jirovecii and fungi (Table 16-1 ) . Other stains are necessary to identify alveolar proteinosis (PAS) [ 99 ] , mycobacteria (Zielh), and siderophages (Perls' Prussian blue) [ 96 ] .

A sample of fl uid should be sent for bacteriologic and fungal cultures and viral tests. Galactomannan detection may be done in BAL fl uid, especially in neutropenic patients with aspergillosis [ 128 , 134 ] , but with a higher cutoff (≥1) than in serum [ 121 ] . Aspiration and BAL fl uids should be examined for Legionella pneumophila by cultures and eventually NAT and for Nocardia and mycobacteria. Due to the better sensitivity of qPCR over conventional stainings and IF assays [ 54 , 55 , 59 ] , some laboratories already use qPCR exclusively. The viruses of interest in HSCT patients are the viruses of the herpes family, adenoviruses, and respiratory viruses (i.e., respiratory syncytial virus, infl uenza, and parainfl uenza, rhinoviruses, metapneumoviruses, coronaviruses, enteroviruses, and bocavirus) which should be determined particularly in the setting of known exposures and during seasonal outbreaks [ 79 ] .

A protected bacteriologic sample ( PBS ), done by a protected brush specimen or a plugged telescoping catheter, should be processed by quantitative culture techniques. Although determined from mechanically ventilated patients, the minimal threshold bacterial concentration required to usually consider the isolated pathogen as the cause of the pneumonia is 10 3 colony-forming units (CFUs)/mL for PBS and 10 4 to 10 5 CFUs/mL in the BAL fl uid [ 135 , 136 ] .

Due to the increased risk it provides for bleeding and pneumothorax, transbronchial biopsy is not routine in acute pneumonia occurring in patients with HSCT and should not be proposed with the fi rst bronchoscopy and BAL [ 137 , 138 ] . Also, it does not add significant informations to concomitant BAL in most cases [ 133 , 138 , 139 ] .

In cases in which noncontributory bronchoscopy , one should consider performing a second BAL and/or a transbronchial biopsy or better, a transthoracic needle aspiration when the lesion(s) is nodular and subpleural [ 126 ] . After HSCT, focal lesions that develop or persist despite antibiotics are mostly of fungal origin [ 140 ] . Successful fi ne needle aspiration, guided by either ultrasound or CT, has been reported, with a complication rate around 15 %, and is useful for documenting IFD when other procedures failed [ 140 , 141 ] . The fi nal decision between lung biopsy through open or video-assisted thoracoscopy or empirical treatment to cover the most likely organisms should be made by the transplant physician and the lung specialist after weighing the risks of surgery, empirical treatment, and failure to reach a diagnosis and the etiologies most likely at that time after transplantation. Lung biopsy is more helpful when the clinical course is prolonged and the pattern is nodular or cavitary.

Because any pneumonia that occurs after HSCT may be life threatening, empirical antibiotics against the likely organisms must be started immediately. The best approach is to conduct bronchoscopic investigation with BAL as soon as possible; this should not, however, delay the initiation of treatment, especially when acute (likely bacterial) pneumonia is present or with patients who are neutropenic. Consideration should be given to the likelihood of fungus in patients with prolonged neutropenia and in those with GVHD on steroid therapy. Some empirical treatments may render subsequent testing negative, especially that for bacteria and viruses, yet they may be warranted. Some empirical treatments will not affect the chance of isolating the pathogen for at least several days after the empirical treatment is begun (e.g., TMP-SMX for P. jirovecii , antifungal agents for aspergillosis).

Daily clinical reevaluation should be performed, especially when no diagnosis is initially established and the patient does not improve. The use of noninvasive markers, when initially positive, is mostly useful to assess the treatment effi cacy: -Patients with initial positive blood cultures should be sampled for blood culture controls daily until negative. -It has been shown in aspergillus infection with an initial positive serum or plasma galactomannan test that the quantitative evolution of the test correlates with the prognosis as soon as from the fi rst week of therapy [ 142 , 143 ] .

Serial follow-up X-rays or, preferably, lung CT scans should be repeated according to the type and severity of the pneumonia. However, some infections, although favorably evolving, may be associated with a long persistence of image abnormalities, which may take several months to decrease or disappear. In the absence of new lesions, it should not be per se a reason to reinvestigate the patient if the clinical outcome is favorable. In aspergillosis, it has been shown that a transient increase of the volume of the fungal lesions on CT scan may occur at the time of neutropenia recovery without any signifi cance of treatment failure [ 112 ] .

New investigations should be rapidly undertaken when the pneumonia does not respond to empirical treatment. Even when the cause of the pneumonia ha s been established, the occurrence of new infi ltrates should be regarded as suspicious for treatment failure or new infections, as the association or succession of several causes of pneumonia is not uncommon in this setting. When a BAL has been initially done on accessible lesions, a second one should not be considered before most of the results of the laboratory be back, except if the BAL has been performed in poor conditions or in case of new lesions. Usually, a delay of 1 week before a fi rst noncontributory BAL and a second BAL is minimal. If the initial lesion is peripheral and nodular and the BAL was noncontributive, a transthoracic fi ne needle biopsy should be considered. If the lesion is subacute or chronic and there is no response to targeted or empirical treatment, surgical biopsy may be contemplated for chronic nodular lesions.

Pneumonia is the cause of the ICU transfer in roughly one third of the cases both in allogeneic [ 144 ] and autologous [ 145 ] HSCT recipients. Although the prognosis of HSCT patients transferred in the ICU has slightly increased over time [ 146 ] , the decision of transfer remains diffi cult in terms of the emotional burden for the patient, family, and caregivers. The use of predictive scores-such as the sepsis-related organ failure assessment (SOFA) [ 147 ] -assessed at ICU transfer in HSCT recipients is debated [ 148 ] . Patients with acute respiratory failure benefi t from ICU support and can be investigated by BAL, knowing that BAL does not increase the need for mechanical ventilation [ 149 ] . The prognosis of ICU support is usually better in autologous rather than in allogeneic HSCT recipients, and those with severe acute GVHD and under corticosteroids usually do not clearly benefi t from ICU support [ 146 ] . Guidelines should be adapted to new data, but, in general, the clinician should consider the individual's chance of survival and of return to an acceptable life before transferring the patient to an ICU. The patient and the family should be provided with reasonable estimations of prognosis before transfer; in addition, the likelihood of continuing life support should be considered regularly during the course of treatment. Patients who respond to noninvasive mechanical ventilation have a better prognosis than those who required mechanical ventilation [ 150 ] .

Pneumonia is a principal determinant of posttransplantation survival . Because of the predictable timing of some infections after most types of transplantations, some prophylactic regimens have been instituted with far-reaching benefi ts. However, any change in the transplant procedure, conditioning, or immunosuppressive regimen may affect the incidence and cause of infectious pneumonia. Additionally, new pathogens are emerging, and familiar pathogens are becoming more resistant. A high level of suspicion when pneumonia occurs in a transplant recipient and vigilance in diagnosing and treating will continue to be required to prevent an increase in mortality from pneumonia. The development of indirect diagnostic procedures is essential in the evaluation of pneumonia, but their clinical pertinence must be established in large prospective studies, and, until now, they do not replace direct investigation of the lung, mainly by BAL.

Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time

Utility of early versus late fi beroptic bronchoscopy in the evaluation of new pulmonary infi ltrates following hematopoietic stem cell transplantation

Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low incidence and strong association with acute graft-versus-host disease

Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation

Acquired ciliary abnormalities of nasal mucosa in marrow recipients

Bronchoalveolar lavage during neutropenic episodes: diagnostic yield and cellular pattern

Alveolar macrophage kinetics and function after interruption of canine marrow function

Alveolar macrophage dysfunction in human bone marrow transplant recipients

The changing epidemiology of

Pneumonia After Hematopoietic Stem Cell Transplantation vancomycin-resistant Enterococcus (VRE) bacteremia in allogeneic hematopoietic stem cell transplant (HSCT) recipients

Blood stream infections in allogeneic hematopoietic stem cell transplant recipients: reemergence of gramnegative rods and increasing antibiotic resistance

Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning

Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study

Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation

Effi cacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation

Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients

Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients

Invasive non-aspergillus mold infections in transplant recipients

Mucormycosis after allogeneic haematopoietic stem cell transplantation: a french multicentre cohort study

Characteristics of and risk factors for pneumonia in patients with hematological malignancies developing fever after autologous blood stem cell transplantation

Targeted therapy against multiresistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th European Conference on Infections in Leukemia

European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the

Early and late invasive pneumococcal infection following stem cell transplantation: a European bone marrow transplantation survey

Invasive pneumococcal disease in adult hematopoietic stem cell transplant recipients: a decade of prospective population-based surveillance

Streptococcus pneumoniae infections in 47 hematopoietic stem cell transplantation recipients: clinical characteristics of infections and vaccine-breakthrough infections

Immunogenicity, safety, and tolerability of 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine in recipients of allogeneic hematopoietic stem cell transplant aged 2 years and older: an open-label study

IDSA clinical practice guideline for vaccination of the immunocompromised host

Nocardiosis in transplant recipients

Nocardiosis after bone marrow transplantation: a retrospective study

Mycobacterial infection: a diffi cult and late diagnosis in stem cell transplant recipients

Tuberculosis after hematopoietic stem cell transplantation: incidence, clinical characteristics and outcome. Spanish Group on Infectious Complications in Hematopoietic Transplantation

Voriconazole (VOR) vs itraconazole (ITR) for primary prophylaxis of invasive fungal infection (IFI) in allogeneic hematopoietic cell transplant (HCT) recipients. In: 49th ICAAC

Posaconazole or fl uconazole for prophylaxis in severe graft-versus-host disease

Randomized double-blind trial of fl uconazole versus voriconazole for prevention of invasive fungal infection (IFI) after allogeneic hematopoietic cell transplantation (HCT)

Impact of the intensity of the pretransplant conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

Mucormycosis: a new concern in the transplant ward?

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia

Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) working group on zygomycosis between

Quantitative polymerase chain reaction detection of circulating DNA in serum for early diagnosis of mucormycosis in immunocompromised patients

Nonbacterial pneumonia after allogeneic bone marrow transplantation

The value of Pneumocystis carinii antibody and antigen detection for diagnosis of Pneumocystis carinii pneumonia after marrow transplantation

Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation

Occurrence of Pneumocystis jirovecii after allogeneic stem cell transplantation: a 6-year retrospective study

High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis

Infl uence of type of cancer and hematopoietic stem cell transplantation on clinical presentation of Pneumocystis jiroveci pneumonia in cancer patients

Pneumocystis carinii pneumonia in critically ill patients with malignancy: a descriptive study

Pneumocystis pneumonia in hospitalized patients: a detailed examination of symptoms, management, and outcomes in human immunodefi ciency virus (HIV)-infected and HIV-uninfected persons

Pneumocystis jirovecii pneumonia in HIV-negative patients: a prospective study with focus on immunosuppressive drugs and markers of immune impairment

Pneumocystis carinii pneumonia in patients without acquired immunodefi ciency syndrome: associated illnesses and prior corticosteroid therapy

Pneumocystis carinii pneumonitis following bone marrow transplantation

Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections

Cotrimoxazole prophylaxis of Pneumocystis carinii infection during the treatment of childhood acute lymphoblastic leukemia-beware non compliance in older children and adolescents

Diagnosis of Pneumocystis carinii pneumonia by bronchoalveolar lavage in AIDS patients. Comparison of Diff-Quik, fungifl uor stain, direct immunofl uorescence test and polymerase chain reaction

Diagnosis of Pneumocystis carinii pneumonia: improved detection in sputum with use of monoclonal antibodies

Evaluation of PCR in bronchoalveolar lavage fl uid for diagnosis of Pneumocystis jirovecii pneumonia: a bivariate meta-analysis and systematic review

Reversible cystic lesions of Pneumocystis jirovecii pneumonia

Pneumocystis jirovecii pneumonia in non-HIV-infected patients: new risks and diagnostic tools

Real-time PCR assay-based strategy for differentiation between active Pneumocystis jirovecii pneumonia and colonization in immunocompromised patients

prospective clinical evaluation of respiratory samples from subjects at risk for Pneumocystis jirovecii infection by use of a commercial real-time PCR assay

Pneumocystis carinii pneumonia. Differences in lung parasite number and infl ammation in patients with and without AIDS

Critical care management and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection

Management and outcome patterns for adult Pneumocystis carinii pneumonia

Accuracy of beta-D-glucan for the diagnosis 16. Pneumonia After Hematopoietic Stem Cell Transplantation of Pneumocystis jirovecii pneumonia: a meta-analysis

Diagnostic accuracy of serum 1,3-beta-Dglucan for Pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis

The utility of bronchoalveolar lavage beta-D-glucan testing for the diagnosis of invasive fungal infections

Serum and bal beta-D-glucan for the diagnosis of Pneumocystis pneumonia in HIV positive patients

ECIL 5 guidelines: Pneumocystis jirovecii infections in (non HIV-infected) hematology patients: Part A: biological aspects

Pneumocystis pneumonia

Pneumocystis jirovecii multilocus gene sequencing: fi ndings and implications

Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodefi ciency syndrome. The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia

Regionally limited or rare infections: prevention after hematopoietic cell transplantation

ECIL 5 guidelines: Pneumocystis jirovecii infections in (non HIV-infected) adult and pediatric hematology patients: Part B: clinical aspects, risk factors, presentation and prevention

Toxicity and effi cacy of daily dapsone as Pneumocystis jiroveci prophylaxis after hematopoietic stem cell transplantation: a case-control study

Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia

Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebocontrolled, randomised trial

Infectious complications in cord blood and T-cell depleted haploidentical stem cell transplantation

Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies

Defi nitions of cytomegalovirus infection and disease in transplant recipients

Evaluation of three assays on alveolar lavage fl uid in the diagnosis of cytomegalovirus pneumonitis after bone marrow transplantation

The challenge of respiratory virus infections in hematopoietic cell transplant recipients

Clinical disease due to enterovirus D68 in adult hematologic malignancy patients and hematopoietic cell transplant recipients

Risk factors and containment of respiratory syncytial virus outbreak in a hematology and transplant unit

Impact of aerosolized ribavirin on mortality in 280 allogeneic haematopoietic stem cell transplant recipients with respiratory syncytial virus infections

Management of RSV infections in adult recipients of hematopoietic stem cell transplantation

Timing and severity of community acquired respiratory virus infections after myeloablative versus non-myeloablative hematopoietic stem cell transplantation

European guidelines for prevention and management of infl uenza in hematopoietic stem cell transplantation and leukemia patients: summary of ECIL-4

ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfl uenza virus, metapneumovirus, rhinovirus, and coronavirus

Airfl ow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses

Strong association between respiratory viral infection early after hematopoietic stem cell transplantation and the development of life-threatening acute and chronic alloimmune lung syndromes

Clinical outcomes associated with respiratory virus detection before allogeneic hematopoietic stem cell transplant

Measles in bone marrow transplant recipients during an outbreak in Sao Paulo

Adenovirus viremia and disease: comparison of T cell-depleted and conventional hematopoietic stem cell transplantation recipients from a single institution

Early detection of Toxoplasma infection by molecular monitoring of Toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation

Risk factors and outcome of pulmonary complications after autologous hematopoietic stem cell transplant

Outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients

Bronchoalveolar lavage in the diagnosis of pulmonary complications of bone marrow transplant patients

Alveolar hemorrhage. Diagnostic criteria and results in 194 immunocompromised hosts

Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes

Secondary pulmonary alveolar proteinosis in hematologic malignancies

Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients

Malignancy-associated pulmonary veno-occlusive disease: report of a case following autologous bone marrow transplantation and review

Pulmonary veno-occlusive disease after bone marrow transplantation

Incidence, predisposing factors, and outcome of engraftment syndrome in pediatric allogeneic stem cell transplant recipients

Marrow engraftment and clinical manifestations of capillary leak syndrome

Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation

Steroids prevent engraftment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection

An offi cial American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome

Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation

T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors

An update on pulmonary complications of hematopoietic stem cell transplantation

Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography

Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia

The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia?

Pneumonia in neutropenic patients

Integrating PET and PET/ CT into the risk-adapted therapy of lymphoma

Diagnostic contribution of positron emission tomography with [18F] Fluorodeoxyglucose for invasive fungal infections

Prevention and treatment of cancer-related infections

Potential role of 18F-FDG PET/CT in patients with fungal infections

Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis

Correlation between galactomannan antigen levels in serum and neutrophil counts in haematological patients with invasive aspergillosis

ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients

Reappraisal of the serum (1 → 3)-beta-D-glucan assay for the diagnosis of invasive fungal infections-a study based on autopsy cases from 6 years

Beta D-Glucan assay for the diagnosis of invasive fungal infections: a metaanalysis

Polymerase chain reaction for diagnosing invasive aspergillosis: getting closer but still a ways to go

Clinical signifi cance of nontuberculous mycobacteria from respiratory specimens in stem cell transplantation recipients

Bronchoalveolar lavage and lung biopsy in patients with cancer and hematopoietic stemcell transplantation recipients: a systematic review and metaanalysis

Bronchoalveolar lavage in immunocompromised patients

Bronchoalveolar lavage in immunocompromised patients with haematological malignancy-value of new microbiological methods

Pulmonary infections diagnosed by BAL: a 12-year experience in 1066 immunocompromised patients

Performance of a standardized bronchoalveolar lavage protocol in a comprehensive cancer center: a prospective 2-year study

Diagnostic value of bronchoalveolar lavage in leukemic and bone marrow transplant patients: the impact of antimicrobial therapy

Revised defi nitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus group

The infl uence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients

Galactomannan in bronchoalveolar lavage fl uid: a tool for diagnosing aspergillosis in intensive care unit patients

Evaluation of bronchoscopic techniques for the diagnosis of nosocomial pneumonia

Diagnostic tests for pneumonia in ventilated patients: prospective evaluation of diagnostic accuracy using histology as a diagnostic gold standard

Diagnosis and antimicrobial therapy of lung infi ltrates in febrile neutropenic patients: guidelines of the infectious diseases working party of the German Society of Haematology and Oncology

Safety, diagnostic yield, and therapeutic implications of fl exible bronchoscopy in patients with febrile neutropenia and pulmonary infi ltrates

Retrospective utility of bronchoscopy after hematopoietic stem cell transplant

Biopsy diagnosis and clinical outcome of persistent focal pulmonary lesions after marrow transplantation

Radiologically guided fi ne needle lung biopsies in the evaluation of focal pulmonary lesions in allogeneic stem cell transplant recipients

Voriconazole or amphotericin B as primary therapy yields distinct early serum galactomannan trends related to outcomes in invasive aspergillosis

Prognostic features of galactomannan antigenemia in galactomannan-positive invasive aspergillosis

Risk factors for ICU admission and ICU survival after allogeneic hematopoietic SCT

Clinical features of life-threatening complications following autologous stem cell transplantation in patients with lymphoma

Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients

The sepsis-related Organ Failure Assessment (SOFA) score is predictive for survival of patients admitted to the intensive care unit following allogeneic blood stem cell transplantation

To stop or not to stop: how much support should be provided to mechanically ventilated pediatric bone marrow and stem cell transplant patients?

Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial

The prognosis of acute respiratory failure in critically ill cancer patients