[Post-COVID-19 rehabilitation; a matter of customisation]. / Nazorg voor covid-19-patiënten.

In the early phase of the COVID-19 pandemic, knowledge about the natural course of recovery of COVID-19 is limited. We therefore describe - based on generic knowledge of post IC syndrome (PICS) and (pulmonary) rehabilitation - the possibilities to organize personalized rehabilitation programs in several care settings. To illustrate variety in need for rehabilitation, we described three cases of critical COVID-19 disease survivors after treatment in the intensive care unit. Some patients require immediate rehabilitation following hospitalization, but rehabilitation may also be initiated in the home environment. For the latter population monitoring of progress and recovery should be organized to assess whether a more intensified multidisciplinary rehabilitation program is needed. This may be initiated in one of the medical rehabilitation centers or in pulmonary rehabilitation centers. Post-COVID-19 rehabilitation, regardless of the specific form, should be patient-centered and multidisciplinary organized.

Pattern recognition pathways leading to a Th2 cytokine bias in allergic bronchopulmonary aspergillosis patients.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is characterised by an exaggerated Th2 response to Aspergillus fumigatus, but the immunological pathways responsible for this effect are unknown. OBJECTIVE: The aim of this study was to decipher the pattern recognition receptors (PRRs) and cytokines involved in the Aspergillus-specific Th2 response and to study Aspergillus-induced responses in healthy controls and ABPA patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were stimulated with heat-killed Aspergillus conidia, various other pathogens, or PRR ligands. PRRs and cytokine pathways were blocked with PRR-blocking reagents, anti-TNF (Etanercept or Adalimumab), IL-1Ra (Anakinra) or IFNγ (IFN-gamma). ELISA and FACS were used to analyse cytokine responses. RESULTS: Aspergillus was the only pathogen that stimulated the Th2 cytokines IL-5 and IL-13, while Gram-negative bacteria, Gram-positive bacteria, Candida albicans, chitin, ß-glucan or Toll-like receptor (TLR) ligands did not. Depletion of CD4(+) cells abolished IL-13 production. Blocking complement receptor 3 (CR3) significantly reduced IL-5 and IL-13, while blocking TLR2, TLR4 or dectin-1 had no effect. ABPA patients displayed increased Aspergillus-induced IL-5 and IL-13 and decreased IFNγ production compared with healthy controls. All biological agents tested showed the capability to inhibit Th2 responses, but also decreased Aspergillus-induced IFNγ. CONCLUSIONS AND CLINICAL RELEVANCE: Aspergillus conidia are unique in triggering Th2 responses in human PBMCs, through a CR3-dependent pathway. ABPA patients display a significantly increased Aspergillus-induced Th2/Th1 ratio that can be modulated by biologicals. These data provide a rationale to explore IFNγ therapy in ABPA as a corticosteroid-sparing treatment option, by dampening Th2 responses and supplementing the IFNγ deficiency at the same time.

Long-term quality of life outcomes in three antiretroviral treatment strategies for HIV-1 infection.

OBJECTIVE: To compare changes in quality of life (QoL) over 96 weeks in patients enrolled in a triple-therapy protocol, a treatment-intensification protocol, or an induction-maintenance therapy protocol, and to compare QoL between patients who continued and discontinued their antiretroviral regimen. PATIENTS: Naive patients enrolled in a triple-therapy protocol (zidovudine/lamivudine or stavudine/didanosine or stavudine/lamivudine supplemented with protease inhibitor therapy of choice) (n = 35), a protocol of treatment intensification (ritonavir/saquinavir or ritonavir/saquinavir/stavudine) (n = 74) in which therapy was intensified with nucleoside analogue(s) in cases of insufficient viral suppression, and a protocol of induction (saquinavir/nelfinavir/lamivudine/ stavudine) maintenance (saquinavir/nelfinavir or stavudine/nelfinavir) therapy (n = 50). MAIN OUTCOME MEASURE: Changes from baseline in QoL assessed by the Medical Outcomes Study HIV Health Survey at weeks 0, 12, 24, 36, 48, 72 and 96. RESULTS: Patients in the triple-therapy and treatment-intensification protocols showed more favourable changes in physical function, social function, mental health, energy/fatigue, health distress and overall QoL compared to patients in the induction-maintenance protocol, with patients in the first two protocols showing improvements in QoL and those in the induction-maintenance protocol showing declining or unchanged QoL. Patients who discontinued study medication due to insufficient efficacy, toxicities or at their own request showed less favourable changes in QoL compared with patients who continued their regimen. The highest proportion of discontinuations was within the induction-maintenance protocol. CONCLUSION: Antiretroviral treatment strategies that are effective and tolerable have the potential to improve patients' QoL over 96 weeks.

Toxicity and drug exposure in a quadruple drug regimen in HIV-1 infected patients participating in the ADAM study.

OBJECTIVE: To study the relationship between toxicity and the exposure to nelfinavir and saquinavir as part of a quadruple drug regimen. DESIGN: The ADAM study is a randomized study to investigate the feasibility of induction-maintenance therapy in HIV-1 infection. METHODS: HIV-1-infected patients with no prior use of antiretroviral treatment started induction therapy consisting of stavudine + lamivudine + nelfinavir + saquinavir for a period of 26 weeks. Data regarding toxicity of the quadruple regimen and exposure to the protease inhibitors were collected. RESULTS: Seven of the 65 patients enrolled had to switch therapy for reasons of toxicity within the first 26 weeks. Diarrhoea was frequently reported (49 of 65, one discontinuation), but could be relieved by using antidiarrhoeal agents. Laboratory monitoring revealed elevated liver enzymes (leading to four discontinuations) and mild to moderate elevations of triglycerides and cholesterol (nine and 23 of 65, respectively). The exposure to saquinavir and nelfinavir was lower than expected. Abdominal pain was associated with a higher exposure to nelfinavir or saquinavir. The association of nausea and abdominal distension with drug exposure appeared to vary over time. CONCLUSIONS: The quadruple drug regimen was quite well tolerated. Diarrhoea was frequently reported but could be relieved by the use of antidiarrhoeal agents. In comparison with other protease inhibitor combinations, lipid abnormalities in plasma were infrequent and mild. With the exception of diarrhoea, all gastrointestinal complaints observed were found to be associated with the level of exposure to nelfinavir or saquinavir. The exposure to the protease inhibitors was relatively low, although the virologic efficacy of the regimen used was satisfactory.

The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy.

OBJECTIVE: To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA. DESIGN: Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine]. METHODS: The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k. RESULTS: A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k. CONCLUSIONS: The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.

Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study.

BACKGROUND: Highly active antiretroviral therapy (HAART) has led to health benefits for patients infected with HIV-1. However, long-term use of multidrug regimens is difficult to sustain. Simplifying antiretroviral treatment regimens would increase patients' adherence and minimise toxicity. We investigated the feasibility of a strategy of induction therapy followed by maintenance therapy with HAART in a randomised open-label study. METHODS: From March, 1997, we enrolled patients infected with HIV-1 with at least 200 CD4 cells/microL, at least 1000 HIV-1 RNA copies/mL in plasma, and no previous exposure to antiretroviral drugs. After 26 weeks of induction therapy (stavudine, lamivudine, saquinavir, and nelfinavir) patients were randomly allocated maintenance therapy (either stavudine and nelfinavir or saquinivir and nelfinavir) or prolonged induction therapy (if the plasma HIV-1 RNA concentration at weeks 24 and 25 was <50 copies/mL). FINDINGS: In February, 1998, we discontinued randomisation after an interim analysis. 62 patients had been enrolled. 39 (91%) of the 43 patients who were followed up for at least 26 weeks had an undetectable plasma HIV-1 RNA concentration at week 16. At week 26, 31 patients were randomly allocated treatment. Of these patients 25 had a total follow-up of at least 36 weeks. At week 36, a higher proportion of patients on maintenance therapy (nine [64%] of 14) had a detectable HIV-1 RNA than patients on prolonged induction therapy (one [9%] of 11, p=0.01). The initial virion-clearance rate during induction therapy was higher in five patients on maintenance therapy with a sustained undetectable plasma HIV-1 RNA concentration than in nine patients with recurrence of a detectable plasma HIV-1 RNA concentration at week 36 (0.35 vs 0.19 per day, respectively; p=0.0008). INTERPRETATION: The induction regimen provided a rapid suppression of viral replication to below 50 copies/mL. However, suppression was not sustained in a considerable number of patients who went onto maintenance therapy. It is currently inadvisable to continue attempts at moving from induction to maintenance therapy in day-to-day practice.

Lack of thermal enhancement for taxanes in vitro.

The taxanes represent a new class of clinical chemotherapeutic agents. A series of in vitro studies were independently of each other initiated in two different institutes (Amsterdam and Madison) to test the hypothesis that hyperthermia might enhance the cytotoxicity of taxanes. Clonogenic capacity experiments (Amsterdam) included the exposure of R1- and SW 1573-cells to 1, 4, or 24 h of paclitaxel with heat 43 degrees C x 60 min in the last hour of drug treatment or at 24, 48 as well as 72 h post drug treatment. Survival assay experiments (Madison) included the exposure of L-929-cells to paclitaxel and docetaxel for 24 h with heat 41.8 degrees C x 60 min the first or last hour of drug treatment as well as 24 and 48 h post treatment. No thermal enhancement of cytotoxicity for the taxanes was observed in these human and murine cell lines, with congruent data in both institutes. In addition, high performance liquid chromatography studies at 41.8 degrees C and 43 degrees C demonstrated paclitaxel and docetaxel were heat stable.

Short report: evaluation of Helicobacter pylori eradication with bismuth sucralfate.

METHODS: In a pilot study we have evaluated the clinical efficacy of bismuth sucralfate to eradicate H. pylori. Ten consecutive patients with chronic dyspepsia and H. pylori associated gastritis were treated with bismuth sucralfate (220 mg bismuth per tablet, 4 tablets per day for 4 weeks). If a 14C urea breath test immediately after the medication was negative, a gastroscopy was performed one month later to obtain biopsies for culture and histological examination. RESULTS: Four patients experienced side effects. In none of the ten patients could eradication of H. pylori be demonstrated one month after treatment with bismuth sucralfate. CONCLUSION: Bismuth sucralfate is not effective for the treatment of H. pylori infection.