Management of Oligosymptomatic Patients with Respiratory Infection in the Era of SARS-Cov2. Experience from Rural German General Practitioners and Proposition of a New Screening Model

Background: Covid-19 is causing a pandemic and forces physicians to restructure their daily work. We want to share our successful experience in the outpatient management of potentially infected patients with colleagues from other countries. Methods: We analyzed all patients with respiratory symptoms reporting to our three rural general practioner (GP) oces in North Rhine Westphalia, Germany, from 27.01-20.04.2020 (n=489 from a total of 6090 patients). A history of symptoms was taken at the doorstep following a specic questionnaire. Patients with respiratory symptoms were examined in a separated isolation area, while the others were allowed to enter the oce. Results: Eighty patients (16.36%, mean age: 47.03years+-18.08) were sent to a nasopharyngeal smear following the screening algorithm of the Robert-Koch Institute, Berlin, Germany. 5 patients (6.25%) turned out to be positive, 4 of which had established risk factors for COVID-19. Overall, the most common symptoms were cough (83.75%), sore throat (71.25%), as well as myalgia and fatigue (66.25%). The most common diagnoses were rhinopharyngitis (37.22%) and acute bronchitis (30.27%). Clinically, it was impossible to differentiate ordinary respiratory infections from COVID-19 patients in our low-risk population, although a sore throat was more common in positively tested patients (80% vs. 12%). None of our employees called in sick during this period, which emphasizes the ecacy and safety of our screening methods. We suggest a novel risk score integrating patient history, symptoms, pulmonary ultrasound and environmental risks to stratify patients as candidates for SARS-Cov2-PCR. Conclusion: A clinical distinction between ordinary respiratory infections and COVID-19 is not possible in a low-risk population. Our model to prevent unprotected physical contact, screen patients in front of the oce with protective equipment, and to examine respiratory infections in separated areas works in the GP setting without overt health risks for employees. Thus, this approach should be used as a GP standard to uphold patient care without major health risks for the personnel. We introduce a new combinatorial scoring model to assess COVID-19 probability in the GP setting.

may account for the relatively low German case-mortality rate (4.1%) compared to other European countries (19,20). As per 02.05.2020 164077 patients had been infected und 6736 had died in Germany(3). Furthermore, standard and elective examinations have been postponed to limit physical physician-patient contact to the necessary minimum (21).
The German government as well as national and federal medical institutions have made considerable efforts to prevent less critical but potenially infective patients from showing up in the GP o ce by installing telephone and video conferences to provide medical council without physical contact. In practice, however, concerned patients fearing to be infected keep showing up and need to be screened in isolation rooms in case of symptoms suggestive of COVID-19.
This requires o ce re-organisation and efforts to receive personel protective equipment (PPE) which, however, has been di cult to get for some time.
The German Robert Koch Institute (RKI) has issued recommendations for COVID-19 screening in the outpatient setting (22). However, differentiation between oligosymptomatic COVID-positives and ordinary infections seems almost impossible. Here, we present real-life data from our three large rural GP o ces in North Rhine Westphalia, Germany, between January 27th and April 20th 2020 to demonstrate the di culty to lter oligosymtomatic patients with low pretest probability but to aim at the same time to decipher a new window of opportunity to better stratify highly suspected infected individuals. Our aim is to share our experience as GP's with colleagues from other countries, where infection rates are still rising and viral doubling time is very low.

Methods
We analyzed data from our three GP o ces in rural North Rhine Westphalia, Germany, from 27.01.2020 until 20.04.2020 and selected all patients reporting symptoms of respiratory tract infection. According to the current RKI guidelines to screen patients for potential COVID-19 infection, we either chose to send patients to a nasopharyngeal smear or to treat them conservatively. Due to limited availability of smear testing in our rural area we are not able to perform the smears in our o ce, but had to transfer patients to the local hospital. Patients were put into isolation until the results of the tests are available. We have made satisfactory experience with the following procedures and algorithm: One GP with PPE consisting of a gown, goggles, caps, gloves and an FFP ( ltering face piece)-3 mask screens every patient in front of our o ce asking the following questions: 1. Are you currently suffering from a cough or sore throat? 2. Have you measured a temperature > 38.5 degrees Celsius in the last 5 days? 3. Have you had direct contact to a person tested positive for COVID-19? 4. Are you employed in a medical profession? 5. Are you suffering from loss of smell or taste? 6. Are you suffering from myalgia, fatigue and headache? 7. Are you suffering from diarrhea or vomiting? 8. Are you suffering from immunosuppressive disease?
The question: "Have you been travelling to a risk area in the last 2 weeks (initially, we explicitly named the risk areas)?" has been withdrawn, because contact restrictions have restrained travel.
If two of these questions were answered with yes, patients were directed to an isolation room, which was supplied with all basic medical devices to provide a fast clinical exam. Patient history was documented vigorously. In case of persisting suspicion following the diagnostic algorithm of the RKI for COVID-19 (23), patients were directly referred to our smear centre. If an ordinary respiratory infection was given as a diagnosis, people were instructed on the general hygiene recommendations and treated conservatively. Only patients with symptoms not suggestive of respiratory disease were allowed to enter the regular o ce.
Immunospuppression was de ned as autoimmune disease or cancer in patient history. Lung disease was de ned as chronic obstructive lung disease or asthma under medical treatment. Chronic kidney disease was de ned as a glomerular ltration rate (GFR) < 60 ml/min for at least three months. Oral anticoagulants included vitamine Kanatagonists (VKA) and new oral anticoagulants (NOAK.), platelet inhibitors included Aspirine, Clopidogrel, Ticagrelor or Prasugrel. RAAS inhibitors: renin-angiotensin-aldosterone system inhibitors.

Discussion
We analyzed data from our three GP o ces in rural Germany between the onset of Covid-19 in our country on 27.01.2020 until 20.04.2020. The mean age of our patients was 47.03 years, which is quite young considering that mortality seems to increase in COVID-19 patients beyond 65 years; patients less than 65 with little predisposing factors may be at a low risk of severe disease (5). Although we also treat more elderly patients in our o ces, this observation may mean that oligosymptomatic patients directly stay at home to reduce their physical contacts, or in case of progressing symptoms, directly report to the clinic.
Only ve out of 80 tested patients were positive for COVID-19 (positives). Due to this low number and a potential reporting bias of symptoms, we refrained from using mean comparison tests and only depicted absolute values.
However, we noticed that almost all patients in the positives suffered from a sore throat (4/5; 80%), while only 12% in the negatively tested group (negatives) showed this symptom (9/75). Furthermore, rhinitis was more prominent in the positives (60% vs. 26.67%). Although results have to be interpreted with caution, these two symptoms may be clinically particularly relevant to assess probability for COVID-19 positivity.
Known comorbidities, especially pre-existing lung and cardiovascular disease, in positives and negatives were quite low (see Table 3). The most common cardiovascular risk factor was arterial hypertension, which has already been published (5). SARS-Cov2 uses ACE-2 as a cellular entry point (24) and has raised concern about continuation of RAAS inhibitor intake in patients with chronic heart failure (25). However, recent data has shown that there is no evidence of increased disease severity or mortality in hospitalized patients on RAAS blockers (26). Additionally, pharamcological data suggests that ACE-2 expression is not increased in patients on RAAS blockers (27). Thus, current recommendations support continuation of RAAS blockers in patients with arterial hypertension and chronic heart failure (25). In our study two out of ve positively tested patients were on RAAS blockers and did not display more severe symptoms than the others. Also in the negatives RAAS blockers were the most commonly prescribed antihypertensive drugs (15 out of 23 patients received RAAS blockers) showing no difference in clinical severity.
We constantly tried to apply the algorithm provided by the RKI(23) to decide which patient needed a smear. However, it seems quite problematic to handle patients with persistent symptoms (mainly unproductive cough), who have been isolated and treated conservatively and who report to the o ce several times. A rather liberal management of smeartaking could be applied in persistent symptoms refractory to conservative methods, such as inhalation, analgetics and antiphlogistics. Although we would wish for a nationwide testing to get maximal clarity on the real number of positive, oligo-or asymptomatic COVID-19 patients, this vision is still hampered by limited availability of tests, especially in rural areas. Additionally, since a median incubation period of 5 days was estimated(28), the general practitioner will have di culties to retrieve a patient's contacts in the asymptomatic phase, which makes restriction of viral spread even more di cult.
Due to a reliable recall system from our o ces, the clinic with the smear centre and the health department, we were able to con rm that none of the patients negatively tested for COVID-19 progressed to COVID-19 positivity later on.
Those ve patients tested positive were kept in quarantine for at least two weeks. If symptoms had resided by then, patients were allowed to take part in public life again. In case of persisting symptoms quarantine was upheld and ambulatory medical services were sent to examine the patients whenever necessary. Moroever, due to regular communication with the local health department we can con rm that none of the patients who were sent home without a smear and treated conservatively, experienced symptom progression, which would have forced us to organize a smear. In summary, the communication between GP o ces, hospitals with smear centres and the health department is satisfactory to ensure the best possible patient care, despite the limited smear capacity. In the future, wearables, such as smartwatches, may improve patient surveillance by constantly recording vitals and providing feedback about potential health deteriorations at home. For GPs this would be a great opportunity to improve patient care.
In Germany we have a health system based on solidarity, in which most people have health insurance and thus have easy access to health care. GP's, usually as the rst medical contacts, have to lter many patients directly in the o ce.
The Center for Disease Control (CDC) has issued similar recommendations for the public as the RKI in Germany, namely (1) (30). This generates fear of a "second wave" of infection. Similar to Germany, the CDC reported that 80% of deaths occurred in the age group > 65 years (29).
A fast incline of infection rates has occurred in Germany in February 2020, while in the US infections have risen in April (as per 21.04.2020: 802.583 total cases, 44.575 total deaths)(29) and GP's in the States will be facing the same enormous logistic problems as in Germany earlier in the year. The paramount aim of medical personnel in this crisis is to maintain optimal medical care and personal health in a high-risk environment. Thus, stringent algorithms for GP's and other medical specialties need to be introduced to achieve this goal. By segregating patients suggestive of respiratory infection and treating them under high standards of hygiene and protection, we believe that we have achieved this goal in a practicable and e cient manner. Until the date of submission, none of our employees called in sick, which may suggest that our stringent selection process prior to entering the o ce is a success. Our experience could now help colleagues in other countries with a later onset of COVID-19 than Germany to organize their o ces with the available resources. Transparency of strategies from different countries on how to deal with COVID-19 in inpatient and ambulatory settings is of paramount importance to optimize further patient care and improve educational measures (31).
Lung ultrasound seems to be a very promising tool to detect COVID-19, since it has been shown that B-lines are present in early stages of the disease. Later hyperechoic images, called "white lung", and nally consolidation can be found in lung imaging (32). Although B-lines are not speci c for COVID-19 they can easily be assessed by trained sonogrophaphers and can and should be be established in emergency departments and outpatient (GP) care.
Our data shows that it is not possible to accurately differentiate between oligosymptomatic COVID-19 patients and ordinary respiratory infection by analyzing symptoms alone. A few days ago, Arons et al. published the spread of COVID-19 in a US nursing home, in which more than half of positively tested patients were asymptomatic (33,34). This clearly demonstrates that strategies focusing only on symptoms fail to prevent further transmission. Since the capacity of testing is limited, we suggest the introduction of a new scoring system to stratify patients for COVID-19 that should be tested. This scoring system should embrace the established clinical signs of (unspeci c) respiratory symptoms. The two symptoms sore throat and rhinitis clearly prevailing in positively tested patients should be used as essential symptomatic markers to stratify for obligatory testing. Known risk factors, such as arterial hypertension, chronic obstructive lung disease and immunosuppression should be additional selection criteria for essential testing. Contact to infected patients and working in high risk areas (such as the medical profession itself) and sonographic signs of lung damage (e.g. B-lines, consolidations) should also be essential components of the score.
We provide a combinatorial score to pre-clinically estimate the risk of SARS-Cov2 infection (Fig. 2). Given the recent observations that sonography is an easy and reliable method to assess suspicion of COVID19, we here add pulmonary sonography as an integral part in our proposed scorings system to stratify patients with unclear respiratory infections for obligatory Cov2 PCR testing.
We awarded 2 points each for sonographic signs of parenchymal or interstitial pulmonary in ltration, suggestive of pneumonia or edema/congestion. 65 years as a cut-off is arbitrary, but Wang et al. (2020) showed that severe COVID- 19 infection is rare below 65, which may justify this value (5). We suggest that a total score > 5 points justi es to send Availability of data and materials:The datasets analyzed during the current study are not publicly available, but will be made available from the corresponding author on reasonable request.
Competing interests: The authors declare that they have no competing interests.
Funding: there was no funding to this study.
The results have not been presented elsewhere.
Authors' contribution: All authors read and approved the nal manuscript. SW coined the idea to systematically analyze symptoms and risk factors of patients with potential COVID-19. He created the risk score, wrote the manuscript (toether with SW) and performed the systematic analysis of data. TF collected the data from all o ces and was responsible for the compilation of the database. EW had the idea to integrate ultrasound as a modality into our score, meticulously analyzed the literature and wrote the manuscript (together with SW). Combinatorial model for preclinical assessment of COVID-19.