Dijagnostika i lečenje COVID–19 u primarnoj zdravstvenoj zaštiti Diagnosis and treatment of COVID–19 in primary healthcare

COVID-19 pandemic is caused by the SARS-Cov-2 virus and it the outpatient for respiratory was th Nearly 100.000 medical exams were performed there, up til now. The virus transmission is carried out by airborne droplets, or rarely using contaminated hands. The entrance site of the infection is nose, mouth, or eye mucose. The infection develops in two stages. The first happens in the upper respiratory tract (URT) and lasts 5-7 days, and the second, when the virus descends to the lungs, and from there causes systemic inflammation, primarily of the blood vessels.The diagnosis is based on the personal history, clinical presentation, physical exam, specific viral tests, lab analysis, and eventually, chest X-ray. March 2021 we got antiviral favipiravir, and in January another antiviral, molnupiravir, became available. Oral corticosteroids showed promising results in patients with viral pneumonia. Primary healthcare was a dam against the secondary and tertiary healthcare this time, too. As our colleagues worldwide, we were learning in stride, and the process is on-going. The more people get exposed to the virus, either naturally or by vaccination, the sooner the pandemic will end but not entirely and probably stay with us as a seasonal infection with easier clinical presentation.


Epidemiologija
Još uvek ne postoje čvrsti dokazi o tome kako je virus od zoonoze postao antroponoza. Među ljudima virus se prenosi kapljičnim putem i ulazno mesto su sluznice nosa, usta, očiju. 1 Inkubacija traje 1-14 dana (najčešće 2-5 dana). Pacijent je zarazan 2-3 dana pre pojave simptoma i do 10-tak dana od pojave prvih simptoma. Ove karakteristike se menjaju zavisno i od soja virusa. Pacijenti u riziku za teške forme bolesti su gojazni, dijabetičari, kardiovaskularni bolesnici, kao i bolesnici sa komorbiditetima, nevakcinisani, starije osobe.  pandemic is caused by the SARS-Cov-2 virus. It was first isolated in Wuhan, China, in December 2019 and it spread worldwide. World Health Organization (WHO) proclaimed the pandemic on March 11 th , 2020. This is a tragedy of epic proportions and it`s still causing huge health, social, and economic problems all over the world. The WHO, as a cover world advisory organization endeavors continuously to coordinate the fight against the virus. In practice, different countries have different measures in their fight against the virus. The only measures that proved to be effective are isolation, face masks, and keeping physical distance. The emergence of the vaccines, at the end of 2020, gave hope in the fight against the virus but the new mutant variants partially weakened their efficacy.

Introduction
In PHC, Krusevac the Outpatient Clinic for Respiratory Infections was founded on March 24 th , 2020. Over 100.000 medical exams were performed there. The clinic also has its lab, X-ray, and its own ambulance. The number of health workers working there varies, depending on the epidemiological situation (max numbers, 16 physicians and 25 nurses). The staff is provided by the Department of General Medicine, which also provides the personnel for the vaccination against COVID 19, and treats non-COVID patients, as well.

Method
Review of the current literature and the data obtained from the electronic health records on antibiotic prescription in Outpatient Clinic for Respiratory Infections, Krusevac, from 01.01.2020. to 31.01.2022.

Epidemiology
There`s still no solid evidence on how the virus became anthroponosis from zoonosis. The virus is spread among people by inhaling viral droplets and the entrance sites are the nose, mouth, and eye mucosae. 1 The incubation period lasts from 1-14 days (most commonly 2-5 days). A patient is contagious 2-3 days before the onset of the symptoms and approximately 10 days after the onset. These characteristics are changing, depending on the virus strain. Patients at risk for the severe forms of the disease are obese, diabetics, cardiovascular patients, as well as, patients with comorbidities, unvaccinated, older persons.
leads to systemic blood vessel inflammation. From the immunological aspect, these are two different battles. The virus spreads fast in the URT and already in 3-5 days people show symptoms and become contagious. There`s a very important role of innate immunity which should be slowing down the viral replication. Activation of the innate immunity is the signal for the activation of the acquired immunity (CD4, CD8, memory B cells) which is responsible for the defense of the lower respiratory tract. And while the viral replication in the URT is fast, pneumonia occurrance isn`t and it appears 7-14 days later (the explanation for the effective protection from the severe forms of the disease and hospitalization in vaccinated patients). It`s very important to learn about the virus pathogenesis to be able to interpret the symptoms, decide on appropriate lab analysis, and diagnostic procedures, as well as, the therapy protocols.

Clinical presentation
Early symptoms -The majority of patients complain of subfebrile fevers (rarely high fever), chills, shivering, exhaustion, headache, myalgias, sore throat, stuffed nose, irritating cough, gastrointestinal problems (rarely in adults, more often in children). A certain number of patients complain of the loss of smell and/or taste which proved to be a good prognostic sign, as far as the severity of the disease was concerned. Patients with anosmia were significantly more rarely hospitalized and ended up in the ICU, as compared to the patients with the intact senses during the COVID-19 infection. 2 Late symptoms -They appear when the lungs are infected. They present with the continuation of febrility, cough followed by difficulty breathing, sense of breathlessness, fatigue, and loss of appetite. Pneumonia develops in these patients and very often it progresses into ARDS (Acute Respiratory Distress Syndrome).

Personal history and clinical presentation -COVID-19
is similar to any other respiratory infection in its early stages. It`s very difficult to separate it from other respiratory diseases without further diagnostics. Patients usually present with subfebrile temperatures, fatigue, headaches, myalgias. In epidemiological history they often mention contacts with diseased persons.
Physical examination -throat is usually mildly hyperemic, submandibular lymph glands are non-tender, and not enlarged, nose is often stuffed. Although pneumonia initially starts in the interstitium (therefore it would be unavailable for auscultation), in practice, auscultatory findings are very clear with crepitations above one or both lungs. Pulse oximetry can be helpful in the assessment of the disease severity but should be interpreted in line with clinical findings (it is affected by Rendgen dijagnostika -Ne preporučuje se za dijagnostikovanje COVID-a 5 . Naročito je ne treba raditi prvih dana bolesti, jer se virus tek nakon 5-7 dana spušta na pluća. Radiografski nalazi kod COVID-a nisu specifični (mogu ličiti na druge respiratorne bolesti) i treba ih tumačiti u sklopu kliničke slike.
anemia, cold fingers, nail polish, and comorbidities). The COVOD 19 treatment protocol recommendations suggest that patients with saturation of less than 94% and pneumonia or comorbidities should be sent to a hospital. But, in practice, it`s often impossible, mostly due to the overwhelmed hospital capacities. Every patient should be evaluated individually. If it was necessary, we also measured arterial tension and performed ECGs.

Viral tests:
RT-PCR (Reverse Transcription Polymerase Chain Reaction) test -is a highly sensitive and specific test. It registers one or more viral RNK genes and signifies current or recent infection. It detects viral particles for a longer period of time and is not necessarily a proof of current infection. It should be interpreted in the current clinical setting.
Rapid antigen test -It registers specific viral antigens. It is less sensitive than PCR but practical for rapid diagnosing. It should be performed at the right moment (between 1.-7. day since the disease onset, as advised by the producer, but in practice, they proved to be the most sensitive between 2.-5. day).
Serological tests -are of no use in diagnosing acute illness. First IgM antibodies appear mostly after 7 days from the disease onset 3 .
Lab results: In our outpatient clinic we had CBC (complete blood count) with leukocyte formula, CRP, and glycemia (measured by glucometer). CBC is often non-specific but lymphopenia can be present 4 (may be a predictor of the severe illness), neutrophilia with lymphocytopenia, thrombocytopenia, lower PCT (percentage of platlets volume). CRP (C-reactive protein) is emerging as a body`s response to any form of inflammation. In the COVID outpatient clinics, it proved as a very useful parameter in following the patient`s condition. Its values should be interpreted in line with clinical presentation and it`s useful for therapy decision making. We also had glucometers. Worsening of glucocontrol proved to be a bad prognostic sign in COVID.
Chest X-ray -is not recommended for COVID diagnosis 5 . It shouldn`t be performed in the early days of the disease since the virus descends to the lungs only after 5-7 days. Radiologic findings in COVID are not specific (they may resemble any other respiratory disease findings) and should be interpreted in the current clinical setting.

Therapy
There were 13 COVID-19 treatment protocols in Serbia and they changed as new information on the disease treatment occurred. A part of the protocole referring to primary health-Ovaj rad pisan je dok je na snazi bio 12. protokol za lečenje COVID-19 infekcije u Republici Srbiji.
care treatment recommended only vitamins (Vit C, Vit D) and antioxidants (alpha-lipoic acid). Since this is a viral infection, without specific treatment, this approach may be justified but the reality was different. There were a lot of patients with pneumonia and deterioration of saturation (and if following the protocol they should have been sent to the hospital) but due to the patient overload, it wasn`t always possible. This paper was written while the 12 th protocol for COVID-19 treatment was effective in the Republic of Serbia.
The COVID-19 treatment in PCP includes: Rest, fluid intake -many patients don`t take these recommendations seriously and they are of essential importance in a body`s fight against the virus. We often witnessed patients fainting due to dehydration (febrility, insufficient fluid intake).
Vitamin therapy -protocols recommend a higher intake of vitamin D (minimum 2000 I.U./day), vitamin C 1g/day. Alpha-lipoic acid was recommended in the first protocols for its antioxidant characteristics and as a possible anosmia treatment but it failed to be effective so it was removed from the protocol. Vitamins should be given with precaution due to their side effects in the form of nausea, diarrhea, etc.
Favipiravir -is an antiviral, primarily used in the treatment of severe forms of flu. According to studies, it leads to a decrease in the viral load 6 . Since March 2021 it was available in the COVID outpatient clinics. It`s recommended for COVID positive symptomatic patients who are expected to develop a severe form of the disease with complications. The recommendation is to introduce it until the fifth day from the symptom onset. Dosing as follows: 1.600 mg/12h, on the first day, and then 600 mg/12h for 4 more days.
Molnupiravir -is also an antiviral of the new generation, a COVID specific treatment. It works by causing mistakes in the viral genetic code and thus prevents its replication 7 . It`s recommended for patients with confirmed infection and at higher risk for the severe forms of the disease. It should also be taken within 5 days from the symptom onset. Tablets are 200mg and the recommended dosing is 800 mg/12h. Antibiotics -play no role in COVID treatment, unless there is a bacterial superinfection 8 . As far as we know now, it`s around 7%-8% in PHC patients. The confusion appeared with azithromycin in the treatment recommendations, at first (together with hydroxychloroquine) but the whole idea for its use was his immunomodulatory effect. Unfortunately, it didn`t produce a desirable effect in practice, so it was soon discontinued from the protocol. The statistics from our clinic show that at the beginning of 2020 about 50% of patients with the confirmed diagnosis of COVID got an antibiotic and 50% got symptomatic therapy. In October 2021, an antibiotic was prescribed to 65%, an antiviral to 9%, and symptomatic Kortikosteroidi -u protokolima nisu predviđeni za lečenje u PZZ (tek od 13. protokola) ali nas je aktuelna situacija i preopterećenost bolnica naterala da ih i mi koristimo kod lečenja virusnih pneumonija, što je dalo odlične terapijske odgovore kod većine pacijanata. Treba naći pravo vreme za njihovo uvođenje (ne na početku bolesti da se ne suprimira imunološki odgovor, ali svakako u kasnijem stadijumu kada se razvije pneumonija i dođe do pada saturacije) 9 . U praksi najčešće koristimo prednizon, jer preporučene doze deksametazona zahtevaju unos mnogo tableta (kod nas na tržištu su u dozi od 0.5 mg). Davati ih u jutarnjoj dozi, uz obaveznu gastroprotekciju. Polako smanjivati dozu ali ne prerano jer može doći do ponovnog skoka citokina.
Corticosteroids -were not recommended for the treatment in the PHC (only since the 13 th protocol) but the current situation and hospital overload made us use them, as well, in the treatment of viral pneumonia, which gave excellent results in the majority of patients. The timing for their introduction should be right (not at the beginning, in order not to suppress an immune response but surely later with the appearance of pneumonia and the drop in saturation) 9 . We mainly used prednisone because the recommended doses of dexamethasone require intake of a lot of tablets (in our market there is only a dose of 0.5 mg). They should be given in a single, morning dose, with gastroprotection. The dose should be tapered down slowly because there is a danger of a repeated cytokine increase.
Symptomatic therapy -we were able to give infusion therapy, parenteral vitamins, oxygen.

Conclusion
Primary healthcare made huge effort in the fight against pandemic and was a dam against the secondary and tertiary healthcare system. As our colleagues worldwide, we were learning in stride, and the process is ongoing. The entire health system is still standing, primarily thanks to the extreme effort of all health workers. Vaccination surely saved many patients` lives, who would have no chance without it otherwise. We witnessed, in our clinic, that vaccinated patients, even if they got infected, had milder symptoms and they survived. The more people get exposed to the virus, either naturally or by vaccination, the sooner the pandemic will end but not entirely and probably stay with us as a seasonal infection with easier clinical presentation.