Coronavirus disease 2019 pandemic two years later… What’s next?

Looking back on the onset of the pandemic Exactly two years ago, we published an editorial in the Croatian Medical Journal discussing a global threat from a new coronavirus epidemic caused by the SARS-CoV-2 virus, which began in China at the end of 2019 and soon spread around the world (1). The first case of COVID-19 in Croatia was recorded on February 25, 2020, while the editorial was being written. On that occasion, we warned of the danger of the rapid spread and pathogenic potential of the novel coronavirus, the need for the constant monitoring of respiratory pathogens with high epidemic potential, as well as of the importance of developing vaccines and antiviral drugs rapidly to combat this and similar viruses

Anti-Inflammatory Action of Azithromycin in Respiratory Infections

Akutne respiratorne infekcije najčešće su infektivne bolesti i razlog najčešćih posjeta ordinacijama opće prakse. Za azitromicin je poznato da ima širok spektar djelovanja na većinu uzročnika pneumonija uključujući gram-pozitivne, gram-negativne i atipične mikroorganizme s dobrom kliničkom učinkovitosti pri peroralnoj primjeni, što omogućava ambulantno liječenje bolesnika mlađih od 65 godina bez kroničnih bolesti. Danas je poznato da azitromicin osim antimikrobnog ima i znatno imunomodulatorno i u okviru toga protuupalno djelovanje. Ovdje ce biti prikazano u prvom redu potencijalno protuupalno djelovanje azitromicina u infekcijama respiratornog trakta.Acute respiratory infections are the most common infectious diseases and the most common reason for visiting a general practitioner clinic. Azithromycin is known to have a broad spectrum of action against most causes of pneumonia, including Gram-positive, Gram-negative and atypical microorganisms. Its clinical efficacy in oral administration is also good, which allows outpatient treatment of patients below 65 years of age and without chronic diseases. Today we know that in addition to antimicrobial, azithromycin also has significant immunomodulatory and anti-inflammatory properties. This article primarily focuses on its potential anti-inflammatory effects in respiratory tract infections

A word from the Editorial Board

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Immunopathogenesis of Pneumonia

Pneumonija je najvažnija upalna bolest u dišnom sustavu iako sudjeluje samo jednim postotkom u svim akutnim infekcijama dišnog sustava. Kao i u većini drugih organa i sustava organa, imunosni obrambeni mehanizmi u plućima baziraju se na mehanizmima specifične i nespecifične imunosti i njihovim komponentama koje uključuju anatomske barijere te staničnu i humoralnu imunost. Prvu liniju obrane od infekcija donjega respiratornog sustava čine elementi nespecifične imunosti, među kojima najvažniju ulogu imaju epitelne stanice i makrofagi. Mehanizmi specifične imunosti imaju snažnu ulogu u obrani od različitih patogena, visoko su sofisticirani i ovise o prepoznavanju specifičnih antigena na površini mikroorganizama te tvore snažnu obranu protiv različitih patogena koji uzrokuju pneumonije. Međutim, za razliku od nespecifične imunosti, indukcija i razvoj imunoreakcija koje sudjeluju u specifičnoj imunosti mogu trajati danima i tjednima nakon ekspozicije patogenu, a važna komponenta tog procesa jest i stvaranje memorijskih stanica koje sudjeluju u snažnoj obrani pri ponovnim susretima s istim patogenima. Mehanizmi nespecifične i specifične imunosti u pneumonijama jesu kompleksni i bit će potrebna još brojna istraživanja da bi se bolje shvatili i rabili u kreiranju novih lijekova i cjepiva te bolje primijenili u uporabi postojećih lijekova. Osim važnog antimikrobnog djelovanja antibiotika ne smijemo nikako zanemariti ni njihovo protuupalno i imunomodulatorno djelovanje koje može pomoći u racionalnijem pristupu liječenju pneumonija.Pneumonia is the most important inflammatory disease of the respiratory system, although it represents only one percent of all acute respiratory infections. As in most other organs and systems of the body, immune defence mechanisms in lungs are based on the mechanisms of specific and non-specific immunity and their components that include anatomical barriers, and cellular and humoral immunity. The first line of defence against infections of the lower respiratory system consists of the elements of non-specific immunity, among which epithelial cells and macrophages have the most important role. The mechanisms of specific immunity play an important role in the defence against a variety of pathogens, they are highly sophisticated and depend on the recognition of specific antigens on the surface of microorganisms. They also provide a strong defence against a variety of pathogens that cause pneumonia. Unlike the nonspecific immunity, the induction and development of immune reactions involved in specific immunity can last for days and weeks after the exposure to the pathogen. An important component of this process is the creation of memory cells that participate in a strong immune defence to the reinfections with the same pathogens. The mechanisms of nonspecific and specific immunity to pneumonia are complex and will require more studies for better understanding and their use in the creation of new drugs and vaccines, as well as a better use of the existing drugs. In addition to an important antimicrobial effect of antibiotics, we must not disregard their anti-inflammatory and immunomodulatory effects that can help us take a more rational approach to treating pneumonia

Detection of T-lymphocyte activation markers in differential diagnosis of infections caused by hantaviruses or leptospira

Hemoragijska vrućica s bubrežnim sindromom (HVBS) i leptospiroza su zoonoze i važne javno-zdravstvene zarazne bolesti. Još uvijek postoje brojni dijagnostički problemi u diferencijaciji HVBS-a i leptospiroze, kako na kliničkoj, tako i laboratorijskoj razini, osobito na samom početku bolesti kada su kliničke slike gotovo identične, a u rutinskim dijagnostičkim testovima za specifično dokazivanje ovih patogena također povremeno dolazi do pojave nespecifičnih reakcija. Unutar T-limfocitne populacije, našli smo statistički značajan porast (p = 0,001) postotka ukupno aktiviranih T-limfocita (TCR+HLA-DR+) u bolesnika s HVBS-om u usporedbi s bolesnicima s leptospirozom ili kontrolnom skupinom. Daljnjom analizom ranih aktivacijskih biljega na T-limfocitnoj subpopulaciji nalazimo značajan porast postotka (p = 0,003) aktiviranih citotoksičnih (CD8+CD71+), kao i postotka (p = 0,005) pomoćničkih (CD4+CD25+) limfocita u bolesnika s HVBS-om u odnosu na bolesnike s leptospirozom ili kontrolnu skupinu. Imunofenotipizacija limfocita periferne krvi može imati važnu ulogu kao pomoćna dijagnostička metoda u diferenciranju HVBS-a od leptospiroze.Hemorrhagic fever with renal syndrome (HFRS) and leptospirosis are zoonozes and important public health infectious diseases. There are still many problems in the diagnostic differentiation between HFRS and leptospiroses, at the clinical, and laboratory level, especially at the beginning of the disease when the clinical picture is almost identical, and routine diagnostic tests for specific detection of these pathogens also occasionally show nonspecific reactions. Within the T-lymphocytes population, we found a statistically significant increase (p = = 0.001) in the percentage of total activated T-lymphocytes (TCR+ HLA-DR+) in patients with HFRS infection compared to patients with leptospirosis and control group. Further analysis of the early activation markers on T-lymphocytic subpopulation found a significant increase in the percentage (p = 0.003) of activated cytotoxic (CD8+ CD71+) and percentage (p = 0.005) of activated helper (CD4+ CD25+) lymphocytes in patients with HFRS, in comparison to patients with leptospirosis and control group. Immunophenotyping of peripheral blood lymphocytes may play an important role as an additional diagnostic tool in differentiating HFRS from leptospirosis

Immunomodulatory Effect of Azithromycin

Azitromicin je antibiotik široka spektra djelovanja iz skupine makrolidnih antibiotika i ima snažno imunomodulatorno djelovanje. Bez obzira na zasad malen broj radova o ovom iznimno važnom svojstvu azitromicina, iz dostupne se literature lako razaznaje njegov potencijal imunomodulatornog djelovanja na razini stanica i tkiva te u različitim kliničkim entitetima, ponajprije u patologiji različitih akutnih i kroničnih respiratornih poremećaja i infekcija. Azitromicin se nakuplja u nizu stanica i djeluje imunomodulatorno na njih preko različitih imunosnih mehanizama (epitelne stanice, fibroblasti, monociti/makrofagi, dendritičke stanice, NK-stanice, T-limfociti, neutrofili, mastociti, eozinofili). Ograničen broj kliničkih studija upućuje na imunomodulatorno djelovanje azitromicina u različitim infekcijama, u prvom redu respiratornim, a onda i infekcijama kože i potkožnog tkiva, spolno prenosivim bolestima i infekcijama te bolestima gastrointestinalnog trakta. Većina njih u svojim se zaključcima dijelom oslanja na različite kalkulacije o imunomodulatornom djelovanju azitromicina, bazirane na studijama in vitro ili ex vivo. Učinkovito antimikrobno djelovanje azitromicina na brojne mikroorganizme, udruženo s njegovim potentnim imunomodulatornim djelovanjem, čini ovaj lijek snažnim terapeutikom ne samo u akutnim nego i u kroničnim infekcijama, ali i u nekim kliničkim entitetima i kroničnim bolestima za koje nije dokazan infektivni uzročnik.Azithromycin is a broad-spectrum antibiotic from a group of macrolide antibiotics that has a strong immunomodulatory effect. Relatively few papers focusing on this extremely important property of azithromycin have been published so far. Nevertheless, available literature reveals its enormous potential for immunomodulatory effect at the cell and tissue level and in various clinical entities, primarily in the pathology of various acute and chronic respiratory disorders and infections. Accumulating within a whole string of cells, azithromycin uses different immune mechanisms (epithelial cells, fibroblasts, monocytes/macrophages, dendritic cells, NK cells, T lymphocytes, neutrophils, mast cells, eosinophils) to exert its immunomodulatory effect. A limited number of clinical studies indicate the immunomodulatory effect of azithromycin in various infections, primarily respiratory infections, as well as in skin and subcutaneous tissue infections, sexually transmitted diseases and gastrointestinal infections and diseases. In most of these studies, conclusions regarding the immunomodulatory effect of azithromycin are, in part, based on various calculations supported by in vitro or ex vivo studies. Given its effective antimicrobial activity against numerous microorganisms, together with its potent immunomodulatory effect, azithromycin is an effective therapeutic drug indicated for the treatment of both acute and chronic infections, as well as certain clinical entities and chronic diseases for which no infectious agent has been proven

Editorial

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Respiratorna infekcija gornjih dišnih putova praćena istovremeno Sweetovim sindromom i nodoznim eritemom

Sweet’s syndrome (SS) is a rare inflammatory condition presented with fever, leukocytosis, ery- thematous, tender plaques and histology evidence of dense neutrophilic infiltration in the dermis. It appears mostly in women between age 30-60 years. Erythema nodosum (EN), a form of pan- niculitis, is manifested as erythematous painful rounded lumps and occurs 3-5 times more often in female patients in all age groups, but mostly between the second and the fourth decades of life. Although rare, concurrent occurrence of Sweet’s syndrome and erythema nodosum is described and may be associated with autoimmune disorders, certain malignancies, gastrointestinal disease or upper respiratory tract infections. Here, we described 34-year-old saleswoman who developed con- current Sweet’s syndrome and erythema nodosum seven days after upper respiratory tract infection onset. During upper respiratory infection, she was treated with three-days azithromycin therapy, together with ibuprofen and paracetamol. Later, when she developed concurrent SS and EN, she was treated initially with clindamycin and prednisone 40 mg, followed by 60 mg of prednisone after which the patient becomes afebrile with gradual rash regression. There is limited knowledge on concurrent SS and EN, their etiopathogenesis and association with different diseases, infections and /or medications. Concurrent SS and EN in our patient was probably triggered by the upper respiratory tract infection. Although, there is no evidence that azithromycin may induce SS or EN or both, it could be considered as a possible trigger alone or together with the upper respiratory tract infection.Sweetov sindrom (SS) rijetko je upalno stanje koje se manifestira vrućicom, leukocitozom, eritem- atoznim, nježnim plakovima i histološkim dokazom guste neutrofilne infiltracije u dermisu. Pojavl- juje se uglavnom u žena u dobi od 30-60 godina. Nodozni eritem (EN), oblik panikulitisa, očituje se bolnim, eritematoznim, zaobljenim potkožnim čvorovima i javlja se 3-5 puta češće u bolesnica u svim dobnim skupinama, ali uglavnom između drugog i četvrtog desetljeća života. Iako je rijetka, istodobna pojava Sweet-ovog sindroma i nodoznog eritema opisana je i može biti povezana s autoi- munim poremećajima, određenim malignim bolestima, gastrointestinalnom bolešću ili infekcijama gornjih dišnih putova. Ovdje smo opisali 34-godišnju prodavačicu koja je razvila istodobni Sweetov sindrom i nodozni eritem sedam dana nakon početka infekcije gornjih dišnih putova. Tijekom infek- cije gornjih dišnih puteva, liječena je trodnevnom terapijom azitromicinom, zajedno s ibuprofenom i paracetamolom. Kasnije, kad je razvila istodobno SS i EN, liječena je u početku klindamicinom i prednizonom od 40 mg, a zatim sa 60 mg prednizona, nakon čega bolesnica postaje afebrilna s pos- tupnom regresijom osipa. Malo se zna o istodobnom SS i EN, njihovoj etiopatogenezi i povezanosti s različitim bolestima, infekcijama i / ili lijekovima. Istodobni SS i EN u naše bolesnice vjerojatno je potaknut infekcijom gornjih dišnih puteva. Iako nema dokaza da azitromicin može izazvati SS ili EN ili oboje, moglo bi se pretpostaviti da bi mogao biti okidač sam ili zajedno s infekcijom gornjih dišnih puteva