Ts van der Werf

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Mycobacterium ulcerans infection in Ashanti region, Ghana.

We describe a series of 96 cases of Mycobacterium ulcerans infection (Buruli ulcer) from a new endemic focus in the Afram valley, north of Agogo, in Ghana. 63 cases were children under 13 years old. Active treatment by excision and skin grafting necessitates long stays in hospital and repeated procedures. Scarring and contracture are frequent. Eyes and other vital organs may be destroyed. In its endemic foci Buruli ulcer is a serious health burden on rural populations. Research is urgently needed, especially in prevention and non-surgical management.

Immunomodulatory Effects of Macrolide Antibiotics - Part 2 : Advantages and Disadvantages of Long-Term, Low-Dose Macrolide Therapy

The available evidence for long-term, low-dose treatment with 14- and 15-membered ring macrolides in non-cystic fibrosis (CF) bronchiectasis, COPD, chronic sinusitis, and asthma is reviewed with special attention to possible adverse effects and the emergence of resistance during long-term macrolide treatment. Macrolide maintenance therapy has been proven to be of benefit in diffuse panbronchiolitis and CF, presumably due to an anti-inflammatory mechanism of action in addition to its direct antimicrobial effect. Solid evidence to justify this treatment regimen for non-CF bronchiectasis, asthma, or sinusitis is still lacking, although a beneficial effect of long-term macrolide therapy has been found in small clinical trials on these subjects. Data from randomized trials of long-term macrolide treatment in COPD are conflicting. A sufficiently long duration of treatment and the careful selection of patients appears to be crucial. Aside from its beneficial effects, possible side effects of macrolide treatment should be taken into account, the most important of these being gastrointestinal upset and cardiac arrhythmias. Development of macrolide resistance among respiratory pathogens is very common during long-term macrolide treatment. Whether this finding is clinically significant is a matter of debate.

Fatal haemorrhage from Dieulafoy’s disease of the bronchus

A 70 year old woman with a previous history of healed tuberculosis and suspected chronic obstructive pulmonary disease presented with recurrent haemoptysis and respiratory failure from a lobar pneumonia. Massive bleeding occurred when biopsy specimens were taken during bronchoscopy which was managed conservatively, but later there was a fatal rebleed from the same site. Two different Dieulafoy’s vascular malformations were found in the bronchial tree at necropsy, one of which was the biopsied lesion in the left upper lobe. This report confirms the possibility that vascular lesions occur in the bronchial tree. It is suggested that, if such lesions are suspected at bronchoscopy, bronchial and pulmonary arteriography with possible embolotherapy should be performed.

Hormones in the critically ill patient: to intervene or not to intervene?

Abstract. Critically ill patients show a variety of hormonal changes that appear to differ considerably in acute and prolonged critical illness. Whether these endocrine alterations serve as physiological adaptation or contribute to further deterioration remains an intriguing question. We review the recent literature and discuss whether measuring circulating hormone concentrations, performing stimulation tests, and intervening with hormone substitution could contribute to the recovery of critically ill patients.

Sero-diagnosis of tuberculosis with A60 antigen enzyme-linked immunosorbent assay: failure in HIV-infected individuals in Ghana

In order to assess the diagnostic usefulness of the A60 (ANDA Biologicals, Strassbourg, France) sero-diagnostic enzyme-linked immunosorbent assay (ELISA) kit for tuberculosis in Africa, sera of 53 pulmonary smear-positive tuberculosis (TB) patients, 30 apparently healthy control subjects and 6 AIDS suspects were sampled in Agogo Hospital in the forest area of Ghana. These sera were analyzed for antibodies to HIV-1 and HIV-2, and IgG-antibodies to the A60 BCG-antigen, while the non-HIV individuals were tested for total IgG levels. One healthy control subject, all of 6 AIDS suspects and 7 of the TB patients has HIV infections. In the non-HIV TB group, the sensitivity and specifity of the A60 ELISA was 78% and 86%, respectively, which was much poorer than expected from published reports about the A60 test. The A60 test failed, completely however, to discriminate between TB and non-TB in the HIV-positive group. In the non-HIV groups, total IgG levels were significantly higher in TB patients than in controls. It seems that the usefulness of the A60 ELISA test to diagnose tuberculosis is very limited in this high-incidence area, and that it seems to be of no value in patients infected with HIV.

Early-onset phenytoin toxicity mimicking a renopulmonary syndrome

Phenytoin is a commonly used anti-epileptic drug. Adverse reactions including fever, skin reactions and lymphadenopathy are well known but atypical reactions can also occur. A patient is described with a lag time of only 4 days between onset of phenytoin and the development of a syndrome with acute lung injury and renal failure. The symptoms mimicked a renopulmonary syndrome, and resolved completely after cessation of phenytoin and addition of steroids.

Constrictive pericarditis after high-dose chemotherapy

High-dose chemotherapy with autologous stem-cell support for the adjuvant treatment of breast cancer and metastatic breast cancer has become common. This approach may offer a survival advantage over standard-dose therapy in women with earlier stage disease and in those who respond to pretransplant chemotherapy. We describe a patient who developed life-threatening constrictive pericarditis 8 weeks after high-dose chemotherapy. A 52-year-old woman presented with progressive dyspnoea and fatigue. Her past history revealed a mastectomy plus lymph-node dissection for breast cancer. Thereafter she participated in a trial comparing high-dose with standarddose chemotherapy as adjuvant treatment for breast cancer patients with four or more positive axillary lymph nodes. Treatment consisted of four courses of fluorouracil 500 mg/m, epirubicin 90 mg/m, and cyclophosphamide 500 mg/m daily every 3 weeks, followed by high-dose chemotherapy with cyclophosphamide (6 g/m), carboplatin (1600 mg/m), and thiotepa (480 mg/m) (CTC regimen) divided over 4 days. On day 7, peripheral stem-cell reinfusion was administered. 2 months after CTC a pericardial effusion developed without signs of tamponade. Transthoracic echocardiogram showed normal right and left ventricular function and a pericardial effusion of 2 cm but no evidence of right ventricular inflow limitation. No increase in viral antibody titres was noted and cultures taken from the blood, sputum, and urine were negative. The symptomless pericardial effusion was ascribed to the use of cyclophosphamide and consequently no pericardial tap was done. She was treated with furosemide. Short term followup was uneventful. After 2 weeks she was admitted because of exertional dyspnoea. Distended neck veins, pulsus paradoxus of 30 mm Hg, a decrease voltage in the electrocardiogram, and liver function disturbances were found. Transthoracic echocardiogram suggested normal left and right ventricular function and in particular no pericardial effusion. Swan-Ganz catheterisation showed, however, equalisation of right and left ventricular filling pressures compatible with constrictive pericarditis. She had a midsternal thoracotomy. Dense pericardial adhesions were seen at the right ventricular entry and pericardial stripping was performed. Cardiac performance strongly improved after surgery. Histologically, the surgical specimen revealed pericardial thickening due to proliferation of myofibroblasts. Specimens of pleural fluid and pericardial tissue were examined for microorganisms including mycobacteria, fungi, and viruses; all direct stains and cultures were negative. In addition, there was no evidence of connective-tissue diseases, mechanical trauma, myocardial infarction, or infiltration with malignant cells. The patient’s condition improved; 2 weeks later she was discharged in an excellent cardiopulmonary condition. After 3 months she fully resumed her domestic duties and job. Our patient developed a life-threatening but potentially reversible complication within 3 months of high-dose chemotherapy. The cause of this constrictive pericarditis was not established but it may be associated with high-dose chemotherapy. The CTC regimen is the most frequently used high-dose treatment schedule for breast cancer. When more frequent causes of dyspnoea such as pleural effusion, left ventricular failure, and malignancy have been excluded the clinician should be alerted to this potential complication of high-dose chemotherapy. 1 Gradishar WJ, Tallman MS, Abrams JS. High-dose chemotherapy for breast cancer. Ann Intern Med 1996; 125: 599–604. 2 Antman KH, Rowlings PA, Vaughan WP, et al. High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol 1997; 15: 1870–79. 3 de Vries EGE, ten Vergert EM, Mastenbroek CG, Dalieso O, Rodenhuis S. Breast cancer studies in the Netherlands. Lancet 1996; 348: 407–08. 4 Braverman AC, Antin JH, Plappert MT, Cook EF, Lee RT. Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens. J Clin Oncol 1991; 9: 1215–23.

Yellow fever in a traveller returning from Suriname to the Netherlands, March 2017

A Dutch traveller returning from Suriname in early March 2017, presented with fever and severe acute liver injury. Yellow fever was diagnosed by (q)RT-PCR and sequencing. During hospital stay, the patient’s condition deteriorated and she developed hepatic encephalopathy requiring transfer to the intensive care. Although yellow fever has not been reported in the last four decades in Suriname, vaccination is recommended by the World Health Organization for visitors to this country.

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

ABSTRACT Voriconazole (VCZ) exhibits great inter- and intrapatient variability. The latter variation cannot exclusively be explained by concomitant medications, liver disease or dysfunction, and genetic polymorphisms in cytochrome P450 2C19 (CYP2C19). We hypothesized that inflammatory response in patients under VCZ medication might also influence this fluctuation in concentrations. In this study, we explored the association between inflammation, reflected by the C-reactive protein (CRP) concentration, and VCZ trough concentrations over time. A retrospective analysis of data was performed for patients with more than one steady-state VCZ trough concentration and a CRP concentration measured on the same day. A longitudinal analysis was used for series of observations obtained from many study participants over time. The approach involved inclusion of random effects and autocorrelation in linear models to reflect within-person cross-time correlation. A total of 50 patients were eligible for the study, resulting in 139 observations (paired VCZ and CRP concentrations) for the analysis, ranging from 2 to 6 observations per study participant. Inflammation, marked by the CRP concentration, had a significant association with VCZ trough concentrations (P < 0.001). Covariates such as age and interacting comedication ([es]omeprazole), also showed a significant correlation between VCZ and CRP concentrations (P < 0.05). The intrapatient variation of trough concentrations of VCZ was 1.401 (confidence interval [CI], 0.881 to 2.567), and the interpatient variation was 1.756 (CI, 0.934 to 4.440). The autocorrelation between VCZ trough concentrations at two sequential time points was calculated at 0.71 (CI, 0.51 to 0.92). The inflammatory response appears to play a significant role in the largely unpredictable pharmacokinetics of VCZ, especially in patients with high inflammatory response, as reflected by high CRP concentrations.