Successful treatment of invasive aspergillosis in chronic granulomatous disease by granulocyte transfusions followed by peripheral blood stem cell transplantation

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by impaired microbial killing and susceptibility to bacterial and fungal infections. Cure of the disease can be achieved by stem cell transplantation when performed early in its course, and before severe infections have developed. Invasive aspergillosis constitutes a very high risk for transplantation. We report a 4-year-old boy with X-linked CGD who underwent successful HLA-identical peripheral blood stem cell (PBSC) transplantation during invasive pulmonary aspergillosis and osteomyelitis of the left fourth rib, which was unresponsive to antifungal treatment. During the 2 months prior to the transplant he received G-CSF-mobilized granulocyte transfusions (GTX) from unrelated donors three times a week in addition to the antifungal treatment. This resulted in clinical improvement in his respiratory status. He also received GTX during the aplastic period after the conditioning regimen, until he had engrafted. Post-transplant superoxide generation test revealed that neutrophil function was within normal range. One year post transplant the CT scan showed almost complete clearance of the pulmonary infiltrates and a marked improvement in the osteomyelitic process. Based on other reports and our own experience, GTX can serve as important treatment in patients with CGD who have failed conventional anti-fungal treatment and for whom stem cell transplantation is the only chance for cure.     

Recombinant human interferon-gamma reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood

Monocytes from 19 of 30 patients with the classic phenotype of chronic granulomatous disease of childhood (CGD) responded to 3 days of treatment in culture with recombinant human interferon-gamma (rHuIFN-gamma) at 100 units/ml by producing superoxide after stimulation with phorbol 12-myristate 13-acetate. Cells from 15 of 16 patients with cytochrome b-positive CGD (15 with autosomal and 1 with X chromosome-linked inheritance) and cells from 4 of 14 patients with cytochrome b-negative CGD (13 with X chromosome-linked and 1 with autosomal recessive inheritance) responded. Subcutaneous rHuIFN-gamma (0.01-0.05 mg/m2) administered as a single dose, daily or every other day, for five or six doses to 3 patients whose phagocytes responded to rHuIFN-gamma in vitro resulted in significant improvement in phagocyte bactericidal activity against Staphylococcus aureus and increases in superoxide production. Studies on 1 patient's cells indicated the increases in superoxide production correlated with increased membrane cytochrome b. The effects of rHuIFN-gamma persisted for more than a week following cessation of therapy. Thus, we have demonstrated a partial correction in vivo of these CGD patients' phagocyte defect with rHuIFN-gamma. Moreover, the data suggest that a significant proportion of patients with CGD will respond to rHuIFN-gamma with augmentation of phagocyte microbicidal function.     

Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease: evidence against enhanced neutrophil oxidase activity.

Recombinant interferon-gamma (rIFN-gamma) therapy has become an effective form of prophylaxis for patients with chronic granulomatous disease (CGD). Preliminary studies with CGD suggested that rIFN-gamma treatment enhanced phagocyte oxidase activity and increased superoxide (O2-) production. We evaluated several aspects of neutrophil NADPH oxidase activity in 19 CGD patients (representing all four known types of CGD) receiving prolonged rIFN-gamma therapy (6 to 27 months). In contrast to earlier studies, we failed to detect any improvement in neutrophil NADPH oxidase activity in 18 of the 19 CGD patients as determined by (1) intact cell O2- production (continuous assay), (2) nitroblue tetrazolium (NBT) staining, (3) cytochrome b558 spectroscopy, and (4) activity levels of cytosol and membrane oxidase components using a cell-free activation system. One patient with a variant form of X-linked CGD had a transient increase in neutrophil O2- production following 3 months of rIFN-gamma therapy. However, this was not sustained, and was not associated with any change in cytochrome b levels. In some patients, rIFN-gamma therapy was associated with the appearance of a small subset of circulating monocytes (1% to 20%) that were NBT-positive. Although the functional significance of this monocyte subpopulation needs to be determined, these results suggest that one possible mechanism by which rIFN-gamma may benefit CGD patients is by partially correcting the respiratory burst defect in a subset of monocytes. We conclude that the clinical benefit of prolonged rIFN-gamma therapy in the vast majority of CGD patients is not due to enhanced neutrophil NADPH oxidase activity. The mechanism of action of rIFN-gamma in most CGD patients remains unknown.     

Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy

In very severe interstitial lung disease associated with connective tissue disease (CTD-ILD), progressing despite maximal conventional immunosuppression, there is no effective medical rescue therapy. The aim of the present study was to test whether rituximab, a monoclonal antibody that depletes peripheral B lymphocytes, is effective as rescue therapy in very severe CTD-ILD, unresponsive to conventional immunosuppression. We performed a retrospective assessment of eight patients with severe and progressive CTD-ILD treated with rituximab. In six patients, change in pulmonary function tests (PFTs) compared with pre-rituximab levels, was assessed at 9-12 months post-treatment. In two patients, who were mechanically ventilated at the time of treatment, clinical and HRCT changes were assessed. Seven out of eight patients had a favourable treatment response to rituximab, while in one patient disease severity did not change. In contrast with previous progression, we observed a median significant improvement of 22% in diffusing capacity for carbon monoxide (from a median baseline of 25%; range 16-32%; p=0.04), and a median significant improvement of 18% in forced vital capacity (from a median baseline of 45%; range 37-59%; p=0.03), in the 9-12 months following treatment with rituximab. In very severe CTD-ILD unresponsive to conventional immunosuppression, rituximab may represent an effective, potentially life-saving, therapeutic intervention.     

Interferon-gamma therapy in two patients with progressive chronic pulmonary aspergillosis.

Infection by Aspergillus species causes a wide spectrum of pulmonary disease in humans. In two patients with semi-invasive Aspergillus-induced lung disease, significantly reduced levels of interferon-gamma secretion by peripheral blood mononuclear cells were found after in vitro stimulation with the T-cell mitogen phytohaemagglutinin. Despite anti-fungal therapy, both patients exhibited progressive disease, and adjunctive interferon-gamma therapy was associated with significant clinical improvement. The data suggest that impaired production of interferon-gamma can be seen in patients with chronic pulmonary aspergillosis. Adjunctive cytokine therapy with interferon-gamma may be useful in patients with progressive disease despite adequate anti-fungal therapy.     

Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases

No controlled trials of therapy for invasive aspergillosis have been done. This review appraises 2,121 cases reported in 497 articles in the literature and analyzes 440 courses of treatment of infection at various body sites in 379 patients. The exclusion of early failures of therapy skews the results toward a favorable outcome. The rate of response to amphotericin B is 55%. Mortality from pulmonary aspergillosis in bone marrow transplant recipients exceeds 94% regardless of therapy, as does that from cerebral aspergillosis in all hosts. Amphotericin B (1 mg/[kg.d]) with flucytosine lowers mortality in neutropenic patients with pulmonary aspergillosis who did not receive a bone marrow transplant; relapse is common. Surgical debridement of aspergillus maxillary sinusitis is usually curative in nonimmunocompromised patients, whereas it increases mortality among neutropenic patients. Valve replacement is essential for aspergillus endocarditis. Both vitrectomy and intravitreal amphotericin B treatment are essential for aspergillus endophthalmitis. Flucytosine is somewhat useful clinically. Itraconazole shows efficacy in the treatment of pulmonary, skeletal, and pericardial aspergillosis. Although liposomal amphotericin B is less toxic than standard preparations of the drug, relevant data are limited. The proposed potentiation of amphotericin B by rifampin is unsupported by clinical data. Despite "conventional" therapy, mortality from invasive aspergillosis remains high; new approaches must be investigated.     

Treosulfan-based conditioning regimen in a second matched unrelated peripheral blood stem cell transplantation for a pediatric patient with CGD and invasive aspergillosis, who experienced initial graft failure after RIC

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by a defect of phagocyte NADPH-oxidase and characterized by severe, recurrent bacterial and fungal infections. Invasive aspergillosis (IA) is the leading cause of mortality in patients with CGD. We report the case of a 3-year-old boy with CGD, who developed IA despite antifungal prophylaxis. His treatment consisted of a 10-month-long multi-drug antifungal therapy, together with surgery, but these did not cause any substantial clinical improvement. BMT in high-risk patients with CGD remains a challenge due to both, higher risk of graft rejection and inflammatory flare in the course of immune recovery. Our patient rejected the first matched unrelated donor (MUD) allograft after RIC regimen recommended by the EBMT Inborn Errors Working Party for high-risk patients. After treosulfan-based conditioning and second MUD peripheral blood stem cell transplantation both, full reconstitution of the granulocytic series and complete recovery from IA, were achieved.     

Use of high-dose intravenous immunoglobulin in systemic lupus erythematosus: report of three cases

Three patients with life-threatening manifestations of systemic lupus erythematosus (SLE), unresponsive to conventional high-dose corticosteroid and/or immunosuppressive therapy were treated with intravenous polyspecific IgG (IVIG). Following IVIG infusion, lupus encephalitis in the first patient quickly resolved and the impressive improvement of the clinical status was associated with a transient increase in C1q-binding activity. The daily infusion of IgG had to be suspended after three days in the second patient with encephalitis and nephritis, because the renal function rapidly deteriorated; subsequently, six plasma exchanges led to an almost complete recovery. Finally, leukocyte and platelet counts increased and remained within normal range following IgG therapy in the third patient having SLE-associated leuko- and thrombocytopenia. In all three patients a decrease in anti-DNA antibody levels and an increase in total complement hemolytic activity were detected after therapy.     

Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study.

Continuous intravenous epoprostenol improves exercise capacity, haemodynamics, and survival in severe primary pulmonary hypertension. Pulmonary hypertension can also be life-threatening in patients with connective tissue diseases. In a prospective open monocentre uncontrolled study, the effects of epoprostenol were evaluated in patients with severe pulmonary hypertension secondary to connective tissue diseases who were unresponsive to oral vasodilators (including calcium channel blockers) and continued to be in the New York Heart Association (NYHA) functional class III or IV despite conventional medical therapy. Seventeen patients received epoprostenol administered by a portable infusion pump associated with conventional therapy (oral anticoagulants, diuretics, supplemental oxygen). During the first six weeks of therapy, two (12%) patients died, of pulmonary oedema (n = 1) and severe sepsis (n = 1). In the fifteen remaining subjects, clinical and haemodynamic parameters improved significantly at six weeks. These patients were subsequently monitored for 80+/-48 (range 14-154) weeks after initiation of epoprostenol. Five (33%) patients died, of right heart failure (n = 2), severe sepsis (n = 2) or syncope (n = 1) and two patients were successfully transplanted 24 and 52 weeks after initiation of epoprostenol. Seven of the remaining eight patients had a persistent clinical improvement. Short-term epoprostenol therapy is effective in some patients with connective tissue diseases as demonstrated by better clinical status and haemodynamics at six weeks. However, this study reports several cases of early and late major complications including severe sepsis and pulmonary oedema. Additional information is needed to evaluate the benefit: risk ratio of long-term epoprostenol therapy in pulmonary hypertension secondary to connective tissue diseases.     

Long-term use of mesalamine enemas to induce remission in ulcerative colitis

The courses of 90 patients with left-sided ulcerative colitis that was unresponsive or intolerant to conventional therapy were retrospectively reviewed. They had been treated with 5-aminosalicylic acid enemas (mesalamine) on a long-term basis. After an initial 12-week course of treatment, 87% of the patients had improved by at least one grade of inflammation (improvement), and 54% of these were asymptomatic with normal colonic mucosa (remission). Overall, there was an 80% remission rate by 34 weeks. Remission rate was not affected by extent of sigmoid or left-sided colon disease before treatment or prior medication use for ulcerative colitis. Treatment with mesalamine enemas allowed patients to decrease or discontinue glucocorticoid treatment. Patients treated for relapse episodes responded as well as they did to the first course of treatment, whether the relapse occurred after discontinuation of mesalamine or during a tapering of the dose. In conclusion, extending mesalamine treatment to at least 34 weeks was beneficial in inducing a complete remission in 80% of patients unresponsive to conventional therapy.     

Glucocorticoids in acute asthma. A critical controlled trial

In order to determine objectively the efficacy of corticosteroids in relieving severe acute episodes of asthma, we administered infusions of hydrocortisone or placebo in a random, double-blind manner to 20 asthmatic subjects after they had been documented to be refractory to eight hours of conventional therapy. Eleven subjects received hydrocortisone (2 mg/kg bolus, then 0.5 mg/kg per hour for 24 hours) and nine received saline. All were given identical bronchodilator treatment during the study period, and all had multiple aspects of lung function serially recorded along with plasma cortisol levels. Although subjects in both groups had severe obstruction of similar magnitude at the beginning of treatment (one-second forced expiratory volume [FEV1] in placebo-treated group = 32 +/- 3 [SEM] percent of predicted, and 25 +/- 3 percent of predicted in steroid-treated group, p = NS), at the end of 24 hours, the subjects given corticosteroids had significantly greater resolution of airway obstruction (FEV1 in steroid-treated group increased 118 +/- 25 percent from control value, versus 35 +/- 22 percent with placebo). In five of nine subjects treated with placebo, pulmonary mechanics either were unchanged or deteriorated during the period of observation. There was no effect of the glucocorticoids on arterial blood gases, and no significant correlation could be found between plasma cortisol levels and the improvement in pulmonary mechanics and clinical status. These results provide objective documentation of the time course over which administration of parenteral corticosteroids speeds the recovery of asthmatic patients who are unresponsive to standard therapy.     

国内20年肺曲霉菌病临床资料汇总分析

目的 了解20年来国内报道的肺曲霉菌病的流行病学特征、临床特点、影像学特点、确诊方法、误诊情况、治疗及预后,为临床医师快速准确地诊断本病提供重要线索.方法 回顾性分析1988～2007年国内有关肺曲霉菌感染的文献资料,统计分析并总结了293例肺曲霉菌病患者的临床资料.结果 293例患者中肺曲霉球型181例(61.8%),侵袭件肺曲霉菌病107例(36.5%),变应性支气管肺曲霉菌病5例(1.7%).肺曲霉菌病好发于有肺部基础疾病及其他基础疾病的患者,男、女比例2:1;其临床表现无特异性,而影像学表现呈多样性,临床易误诊,误诊率为74.6%;确诊主要靠呼吸道分泌物涂片、培养以及病理学检查;治疗手段包括手术切除和抗真菌药物的应用.结论 肺曲霉菌病的临床表现缺乏特异性,极易导致误诊,给临床诊断带来困难,必须加深对其认识.     

伏立康唑序贯治疗对24例糖尿病合并侵袭性肺曲霉菌病的临床作用研究

目的观察在糖尿病合并侵袭性肺曲霉菌病的临床治疗中应用伏立康唑序贯疗法的疗效与不良反应。方法随机性选择该院2019年1—12月间24例确诊糖尿病合并侵袭性肺曲霉菌病的患者作为研究样本,开展一项回顾性研究,所有患者接受伏立康唑序贯治疗方案,最终统计患者的整体疗效、症状改善情况与不良反应,评估该治疗方案的应用可行性。结果所有患者均依照规定坚持用药,随访未见擅自停药者。24例患者疗效评级从“优”至“差”依次为9例、12例、2例、1例,治疗总优良率为87.50%。全体患者治疗后的胸痛(4.17%)、气促(8.33%)、呼吸困难(0.00%)、咳嗽(4.17%)、咳痰(4.17%)、咯血(0.00%)、低热发生率(0.00%)均低于治疗前(33.33%、33.33%、25.00%、20.83%、16.67%、12.50%、8.33%),胸痛、气促、呼吸困难3种症状的发生率与治疗前比较,差异有统计学意义(χ²=6.701、4.547、6.857,P<0.05)。给药期间1例肝功能异常,1例胃肠道不适,不良反应发生率为8.33%。结论针对糖尿病合并侵袭性肺曲霉菌病患者的治疗,采取伏立康唑序贯疗法可行性好,整体疗效高,可显著改善患者症状,治疗安全性令人满意。     

Treatment of invasive aspergillosis with itraconazole in a patient with chronic granulomatous disease

An 18-year-old boy with X-linked chronic granulomatous disease (CGD) developed Aspergillus fumigatus pneumonia and multifocal osteomyelitis. Treatment with amphotericin B resulted in only moderate improvement of the lesions and was accompanied by considerable toxicity. In contrast, administration of the new triazole drug itraconazole led to complete disappearance of all signs of infection. We conclude that itraconazole may be a valuable new drug for treating invasive aspergillosis in patients with CGD, although the duration of treatment remains to be established.     

肝衰竭合并曲霉菌感染的临床特征分析

目的 了解肝衰竭合并曲霉菌感染的临床特征.方法 收集我院1985年1月-2006年6月所有合并真菌感染的肝衰竭患者507例,以合并曲霉菌感染的肝衰竭患者104例为主要分析对象.两组间数据的比较用配对t检验,率的比较用χ2检验. 结果 507例肝衰竭合并真菌感染患者中,曲霉菌感染104例(20.5%).抗真菌治疗的有效率和基础疾病的治愈好转率,曲霉菌感染患者分别为36.5%和26.0%,非曲霉菌感染患者分别为57.8%和36.7%,P=0.000和P=0.049.共分离出曲霉菌108株,烟曲霉菌最为多见,共53株(49.1%),肺脏为曲霉菌主要感染部位90例次(63.8%),感染后临床表现常不典型.在抗真菌治疗有效的患者,肝功能呈好转趋势. 结论肝衰竭合并曲霉菌感染的诊断、治疗困难.对于临床上怀疑有曲霉菌感染的肝衰竭患者,早期积极治疗有助于患者恢复.     

The efficacy and tolerability of voriconazole in the treatment of chronic cavitary pulmonary aspergillosis

Voriconazole is the second oral drug licensed for the treatment of aspergillosis. A retrospective non-comparative study was conducted in 16 patients with chronic cavitary pulmonary aspergillosis (CCPA) treated with voriconazole. All patients had failed or were intolerant of itraconazole. The duration of therapy varied from 3 days to 16.5 months. Eleven patients received at least 3 months of therapy with no significant adverse events. Overall seven (64%) patients had a response at 3 months as assessed by at least some fall in inflammatory markers, weight gain and reduction in pulmonary symptoms and two (18%) remained stable. Inflammatory markers improved in 5/11 (46%) with a mean fall in CRP of 0.08 mg/l and ESR of 12.8 mm/h. Aspergillus precipitins were quantitated by numbers of arcs and serum dilution and 11 (100%) showed improvement of at least one band or fall of titre. Total serum IgE was elevated (>200 IU/mL) in 5/11, and fell by a median of 118 kIU/l. Two patients failed therapy. Of the 17 patients, five (27%) had to discontinue therapy as a result of adverse events (three in under 1 week). Adverse events included erythematous rash (5), headaches (4), hepatotoxicity (3), photosensitive rash (3), retinal flashes (3) and neurological symptoms (3). Voriconazole is a useful alternative therapy for CCPA, with a response rate of 64%, over 3 months, and continuing partial remission of disease for much longer periods.     

慢性阻塞性肺疾病合并慢性肺曲霉菌病的高危因素及临床特征分析

目的 探讨慢性阻塞性肺疾病(COPD)合并慢性肺曲霉菌病的高危因素,并分析COPD罹患不同类型慢性肺曲霉菌病的临床特征.方法 选择2015年1月至2020年5月陆军军医大学第二附属医院诊断COPD合并慢性肺曲霉菌病患者39例为观察组,选取同期COPD合并肺部感染(非曲霉非肺结核)患者39例为对照组,采集基本信息、既往病...     

Aspergillosis complicating neoplastic disease

From 1964 to June 1971, 93 cases of aspergillosis were encountered at Memorial Sloan-Kettering Cancer Center. The 29 cases diagnosed in 1969–1970 and the 15 cases diagnosed in the first half of 1971 represented, respectively, a doubling and a quadrupling since 1964–1965. The incidence of aspergillosis in patients with leukemia was seven times greater than in patients with Hodgkin's disease or lymphoma (p < 0.0005). By the first half of 1971, 41 per cent of the patients who died with acute leukemia had evidence of aspergillosis. Fourteen patients with solid tumors resembled patients with leukemia or lymphoma in that they had at least two of the following in common: corticosteroid treatment, cytotoxic therapy and leukopenia (less than 4,000 cells/mm³). Pulmonary involvement was present in 90 of 93 cases, disseminated disease in 23. The commonest clinical pattern was unremitting fever and development of pulmonary infiltrates despite broad-spectrurh antibiotic therapy. In an increasing number of cases aspergillosis followed Pseudomonas aeruginosa infections. When present, serum aspergillus precipitins correlated well with invasive disease, but a negative test result was far less reliable. In one case of acute myelogenous leukemia the patient recovered from pulmonary aspergillosis after surgical excision of the lesion and remission of her leukemia.The incidence of aspergillosis is increasing and should be considered in the setting of progressive pulmonary infiltrates in leukemic and other heavily immunosuppressed patients who respond poorly to antibacterial therapy. Earlier diagnosis may lead to more effective therapy.     

Successful allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease with inflammatory complications and severe infection

We report two patients with chronic granulomatous disease (CGD). The first patient presented with granulomatous colitis and pulmonary aspergillosis, and the second patient with liver abscess and restrictive pulmonary disorder. Both patients underwent allogeneic hematopoietic stem cell transplantation, the first from an HLA-matched sibling donor, and the second from an HLA-matched unrelated donor, after preconditioning with fludarabine, anti-thymocyte globulin, cyclophosphamide, and total-body irradiation of 3 Gy. The engraftment was prompt and the regimen-related toxicity was mild. The patients are able to return to their daily lives with full donor chimerism, although the second patient underwent a living-related-donor orthotopic liver transplantation from his mother for chronic liver graft-versus-host disease. The conditioning regimen we used was feasible and applicable to patients with CGD accompanied by inflammatory disease and severe infection.     

外科手术治疗74例肺结核并发肺曲菌球病患者的临床价值

目的 分析外科手术治疗肺结核并发肺曲菌球病的临床价值。方法 搜集2007—2016年在广西壮族自治区龙潭医院行外科手术的74例肺结核并发肺曲菌球病患者,对手术方式、手术治疗转归、并发症、术后随访等临床资料进行回顾性分析。结果 74例患者中,择期手术68例(91.9%),急诊手术6例(8.1%);73例(98.6%)手术顺利,术中因大出血死亡1例;行肺叶切除术54例(73.0%),肺段切除术5例,全肺切除术2例,复合肺切除术9例,肺楔形切除术4例。24例(32.4%)出现术后并发症:术后大出血1例,再次开胸止血治愈;呼吸功能衰竭1例,呼吸机辅助呼吸28d后成功脱机治愈;肺不张5例,4例经纤维支气管镜吸痰后肺膨胀良好,1例纤维支气管镜吸痰无效,继发呼吸功能衰竭后自动放弃治疗出院后死亡;脓胸4例,3例细菌性脓胸经持续引流治愈,1例曲霉菌性脓胸于术后15个月行电视胸腔镜脓胸廓清术时发生肺动脉破溃大出血,改为体外循环下左余肺切除术,但因不能纠正休克而死亡;肺泡胸膜瘘5例,3例经持续胸腔引流,2例行碘伏胸膜固定术加持续胸腔引流后治愈;支气管胸膜瘘1例,给予患者持续的胸腔引流3周后瘘口逐渐闭合治愈;胸部净化残腔7例,未处理。72例患者术后获得随访,1例患者随访期间死亡。最终治愈71例(96.0%),随访1~48个月,平均(11±3)个月,未见肺结核及肺曲菌球病复发。结论 选择合适的患者行外科手术,治愈率高,并发症发生率及死亡率在可以接受的范围之内,绝大多数患者能治愈。