This thesis reflects two recent changes relevant to the field of rehabilitation medicine. Firstly, the COVID-19 pandemic illustrated that new disorders may benefit from the involvement of rehabilitation medicine. Secondly, advances in neurobiology pave new ways for therapeutic interventions among disorders already well known in the specialty, i.e. neuromodulation for improving motor function in chronic spinal cord injury (SCI).

Paper I is a cross-sectional study on 23 adults with chronic clinically complete SCI (verified using standardized neurological examination) exploring the prevalence of residual functional connectivity, using a battery of neurophysiological tests. Unequivocal indications of residual translesional connectivity (i.e.” discomplete” SCI) were found in 17% of participants. Applying more liberal criteria, the potentially discomplete group comprised 39-52%.

Paper II is a prospective interventional study where five adults with cervical SCI received a series of paired associative stimulation (PAS) treatments. Lesions in this study were incomplete, rather than discomplete. PAS combines peripheral nerve stimulation and navigated transcranial magnetic stimulation (TMS), both targeted towards the neural structures subserving one arm. The aim was to corroborate findings from earlier studies suggesting that spinally targeted PAS improves upper extremity motor function in chronic incomplete SCI. Manual muscle testing scores in the targeted extremity increased by a mean 0,5 points (0-5 scale). Grip strength, assessed with hand dynamometry, increased by 3 kg in the stimulated hand and by 2 kg in the contralateral hand. Performance and Satisfaction of individually specified goals, as reflected by the Canadian Occupational Performance Measure (COPM), increased by 2 points. Improvements remained one month after stimulation.

Paper III: The Linköping COVID-19 study (LinCoS) included all 745 individuals hospitalized for COVID-19 during the first wave of the pandemic (March 1st−May 31st, 2020) in our region. Survivors of this cohort with persisting symptoms corresponding to the diagnosis of a Post-COVID-19 Condition (PCC) at a screening telephone interview four months post-discharge, were invited to a comprehensive, interdisciplinary clinical assessment which 85% attended (n=158). Persisting impairments were reported and corroborated, including cognitive impairment (reported by almost 50% and corroborated by neuropsychological testing in almost 40%), weakness in extremities and pain (reported by about a third of subjects, respectively), as well as a large number of other (respiratory, visual, auditory, sensory) symptoms. In total, 16% of survivors in the total regional cohort was deemed to require further rehabilitative interventions at the clinical assessment.

Paper IV: In follow-up telephone interviews at 2 years post-discharge of individuals with PCC at five months post-discharge, 84% of patients reported persisting problems affecting everyday life, although significant improvements were seen in symptom prevalence and impact compared with the situation at four months post-discharge. Cognitive, sensorimotor symptoms and fatigue were the most common persisting symptoms, and 21% had been readmitted to hospital in the interim period. Half of those on sick leave related to PCC at four months were still on sick leave. No differences in outcomes were evident between previously Intensive Care Unit (ICU)-treated and non-ICU-treated individuals.

Summary: PAS improved upper extremity motor function in patients with incomplete SCI, corroborating prior studies. Evidence of discomplete SCI was demonstrated using standard neurophysiological techniques in a substantial subset of individuals with chronic, clinically complete SCI. Thus, PAS may also be a potential therapeutic intervention for people with such lesions, but this requires further investigation. PCC is highly prevalent in the medium to long term (4-24 months) after hospital-treated COVID-19. To ensure adequate care and rehabilitation, extensive examination of patients with symptoms indicating PCC is warranted.

In conclusion, this thesis explores new frontiers in rehabilitation medicine by suggesting new possibilities for therapeutic interventions as well as identifying rehabilitation needs in new conditions that may benefit from our attention. Results of the studies on COVID-19 and SCI reported in this thesis, suggest the potential both for expansion of the specialty in terms of new diagnostic categories and the inclusion of new treatment modalities.

The aim of the present thesis is to deepen the knowledge of severe and critical COVID-19 infection - its management and outcomes among ICU patients in Sweden. This is achieved through retrospective studies of ICU patients with COVID-19 from several Swedish hospitals focusing on their management and outcomes (study I, III, IV). In addition, a prospective follow-up study was conducted on patients with post covid condition (PCC) (study II).

In the first paper (study I), all patients with respiratory failure due to COVID-19 who were admitted to an ICU in region Östergötland during the initial pandemic wave were included (n=100). The median age was 63 years, and the 60-day mortality rate was 22% across the entire pandemic wave. Divided into three consecutive tertiles, the 60-day mortality decreased from 33% in the first tertile to 15% and 18% in the subsequent two. Ninety-one percent had at least moderate acute respiratory distress syndrome (ARDS) and 88% required invasive mechanical ventilation (IMV). During the wave, the use of thromboprophylaxis increased, the steep rise in ICU admissions subsided, and ICU resources expanded. At four-month follow-up, 63% of survivors reported a decline in general health compared with their health status prior to SARS-CoV-2 infection.

In Study II, all patients with PCC at a clinical follow-up four months after hospital discharge in region Östergötland were included and interviewed two years after initial infection. Of 181 eligible patients, 165 participated in the study. The majority (84%) reported lingering problems affecting everyday life. Nevertheless, improvements were observed in both prevalence and severity of several symptoms and functional limitations compared with four months post-discharge. The most reported symptoms were cognitive, sensorimotor, and fatigue related. Comparison between ICU-treated and non-ICU-treated patients revealed no significant difference at 24-months.

In study III, factors associated with ventilator-associated lower respiratory tract infection (VA-LRTI) in COVID-19 were explored. All patients with respiratory failure requiring IMV who were admitted to an ICU in the southeast healthcare region of Sweden were included (n=536). Overall, 28.5% developed VA-LRTI, corresponding to an incidence rate of 20.8 first VA-LTRI episodes per 1000 IMV days. The incidence of VA-LRTI increased from 14.5 per 1000 days of IMV days during the first wave to 24.8 per 1000 IMV days during the subsequent two ways. Patients who developed VA-LRTI had fewer ventilator-free days, received corticosteroids more frequently, and were more often ventilated in prone position. Most detected pathogens were Enterobacteriaceae (38.9%) and Staphylococcus aureus (22.8%). Logistic regression analysis revealed significantly increased adjusted odds ratio (aOR) for first VA-LRTI for corticosteroid treatment (aOR 2.64 [95% confidence interval [CI]] [1.31–5.74]), antibiotics at intubation (aOR 2.01 95% CI [1.14–3.66]), and days of IMV (aOR 1.05 per day of IMV, 95% CI [1.03–1.07]).

In the final paper (study IV), mortality disparities among patients with COVID-19 admitted to ICUs across seven Swedish hospitals were investigated using survival analysis. All patients admitted to one of the participating ICUs with respiratory failure due to COVID-19 were included (n=747). Across the cohort, 90-day mortality varied substantially between hospitals, ranging from 8.5% to 30%. In the final cox proportional hazards model adjusted for baseline covariates, pandemic wave and with random intercept for healthcare county, the adjusted hazard ratios (aHR) for 90‑day mortality by hospital spanned from: 2.38 to 5.06, using the hospital with the lowest mortality as reference. The results remained robust after sensitivity analysis, including complete case analysis, calculation of e-values, assessment of multicollinearity, and testing of the proportional hazards assumption.

In conclusion, initial high mortality of ICU-treated COVID-19 patients in region Östergötland, quickly declined during the first pandemic wave, paralleling increased ICU resources and expanded use of thromboprophylaxis. Moreover, many ICU survivors experienced reduced general health at four-month follow-up. Many survivors developed PCC and reported lingering symptoms affecting their everyday life two years after initial infection, but with significant improvement compared to the initial follow-up. Additionally, the VALRTI incidence in southeast healthcare region of Sweden was low compared with previously published data, although it increased across the pandemic waves - possibly related to expanded use of corticosteroid treatment. Finally, during the pandemic, the initial ICU to which a patient was admitted correlated with ICU mortality. These results contribute to the ongoing discussion regarding healthcare equity in Sweden, suggesting that geographical inequities were likely present at least during the pandemic.