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Editorial A.G.Chuchalin Slowly-resolving Pulmonology Research Institute, Federal Medical and Biological Agency of Russia; Moscow, Russia

Summary Slowly-resolving pneumonia is an important medical problem in spite of current knowledge on etiology, pathogenesis and therapeutic approaches. In Russia, uniform approach to this disease is lacking. Risk factors for the slowly-resolving pneumonia are comorbidity, age, severity of the disease and certain pathogens. A wide range of infections and non-infection diseases resemble slowly-resolving pneumonia, such as autoimmune systemic diseases, interstitial lung diseases, drug-induced lung toxicity, thoracic tumours, tuberculosis, etc. A diagnostic algorithm has been described in the article aimed at identification of the pathogen causing the pulmonary inflammation and at exclusion of diseases mimicking slowly-resolving pneu- monia. Key words: slowly-resolving pneumonia, diagnostic algorithm, , pathogen, antibacterial resistance, interstitial lung diseases.

Pneumonia is a disease of constant importance. The a role of Russian medical science in investigation of this famous Russian physician of the XIX century S.P.Botkin issue. in his clinical lectures showed prevalence of pneumonia According to the official data of the Russian in Saint-Petersburg in dependence on season, the pati- Healthcare Ministry, yearly > 400,000 of patients seek ent's gender and social status. Today this is of great signif- medical care for pneumonia in 7 th to 9 th day of the disease, icance also. S.P.Botkin discussed a role of diplococci as i.e. in presentation, in the great portion of the patients a cause of pneumonia and some clinical issues, particu- pneumonia is characterized by protracted course. larly slowly-resolving pneumonia. The current definition of slowly-resolving pneumonia Later, new pneumonia-causing pathogens were found is based on protracted or non-resolving inflammation and new clinical features were described. In middle with no response to therapy. This quite uncertain defini- 1950 th , and Legionella pneu- tion reflects a lack of evidence-based clinical trials of this mophila have been identified. Recently, new respiratory problem. This definition also implicates that aspiration infection emergencies have been discovered. At the pneumonia and nosocomial pneumonia including venti- beginning of the XXI century, world medical community lator-associated pneumonia, and pneumonia in encountered an epidemic caused by an atypical coron- immunocompromised patients do not pertain to slowly- avirus (SARS); two years ago the Middle-Asian coron- resolving pneumonia. Diagnosis of slowly-resolving avirus was identified. Since 2009 pneumonia prevalence pneumonia is usually based on comparison with criteria has been growing, mostly due to associated viral and bac- of typical course ( ≤ 2–4 days, ≤ 4–9 days, terial infection of the lower complicat- resolution of auscultative pneumonic phenomenon at the ing A (H1N1) disease. According to results of 1st week of the disease, decrease of blood leukocyte count a large international survey on pneumonia epidemiology, to the normal level to the 4 th day, decrease of C-reactive such infection is identified in 3 to 5 persons per 1,000 of protein to the normal level to the 3 rd day). Considering population. In 2013, the number of deaths from pneumo- late start of the treatment in great number of patients nia in Russia increased by 8 %. Therefore, pneumonia is mentioned above it become apparent the importance of still one of the most widespread diseases with changeable slowly-resolving pneumonia in Russia. etiology and the need of yearly characterization. Risk factors for the slowly-resolving pneumonia are Physicians of different medical specialities such as comorbidity, age, severity of the disease and certain general practitioners, infectiologists, pediatricians, pathogens. neonatologists, pneumologists, hematologists, intensive care specialists, etc., could be involved in treatment of Comorbidity a patient with pneumonia. This affects the physician's approach to this disease partly due to different medical Chronic obstructive pulmonary disease (COPD) is one of terms describing pneumonia: , croup- comorbidities that could increase risk of slowly-resolving ous pneumonia, interstitial pneumonia, pneumonia in pneumonia. Pneumonia could worsen the course of COPD alcohol abuse patients, pneumonia in immunocompro- and often has poor prognosis in these patients. Another mised patients, focal pneumonia, slowly-resolving pneu- risk factor is alcohol abuse related to decreased function- monia. In Russian medical literature slowly-resolving al activity of macrophages, aspiration, mucociliary dis- pneumonia was studied by Prof. N.S.Molchanov and his turbance, and decreased cough reflex. Cough reflex follower Prof. V.P.Silvestrov, the author of a renowned depression is also seen in patients with neurological dis- monograph on this topic, the 4 th edition of which was orders. published in 1984. Since this time our knowledge on Slowly-resolving pneumonia could develop in patients pneumonia has been dramatically improved. with congestive heart failure due to lymphatic drainage The aim of this article was to emphasize the impor- disturbance and in patients with chronic renal failure due tance of slowly-resolving pneumonia and to highlight to complement deficiency, decreased macrophage and http://www.pulmonology.ru 11 Chuchalin A.G. Slowly-resolving pneumonia functions and humoral immune insufficiency. Haemophilus influenza is a frequent cause of pneu- Slowly-resolving pneumonia could complicate malig- monia in smokers, elderly patients and in patients with nancy because of decreased immune function; moreover, COPD. Recently, conjugated vaccine against H. influen- chemotherapy facilitates airway colonization with differ- za has been used in children; this resulted in reduction in ent microorganisms. In patients with diabetes mellitus as the rate of childhood pneumonia caused by this patho- well as in patients with AIDS slowly-resolving pneumonia gen. could occur due to decreased neutrophil and cellular According to results of epidemiological studies, only immunity functions and often leads to death. 50 % of pneumonia patients recover their lung function at Cellular or humoral immunity disorders could be an 6 weeks. underlying condition in patients with slowly-resolving , especially methicillin-resist- pneumonia. Patients with primary immunodeficiency ant strains (MRSA), could often cause severe and suffer from recurrent in childhood and life- abscessing pneumonia. Recovery in these cases could long recurrent respiratory infections affecting their quali- require 3 to 5 months with residual lesions in the lung tis- ty of life. sue. Pneumonia caused by S. aureus could complicate The patient's age plays an important role in pathogen- acute viral respiratory infections (influenza) and cystic esis of slowly-resolving pneumonia. In patients < 50 years fibrosis in infants. old radiological and morphological signs of pneumonia Gram-negative microorganisms are a frequent cause typically resolve in 4 weeks. In patients older 50 years res- of nosocomial pneumonia and pneumonia in immuno- olution of pneumonia requires much longer time even in compromised patients. These pathogens could cause those without any comorbidity. slowly-resolving pneumonia lasting for 3 to 5 months Pneumonia outcome is closely related to its severity. with residual injury of the lungs after clinical recovery. Resolution of severe pneumonia could require up to 10 is not a typical pathogen in weeks. patients with severe or slowly-resolving pneumonia but radiological pneumonic signs could be seen ≥ 3 months. Pathogens Chronic inflammation rarely occurs in pneumonia caused by M. catarrhalis. The leading pathogen causing pneumonia is Streptococcus Tuberculosis (TB) infection can mimic slowly-resolv- pneumoniae. Typically, in pneumonia caused by this ing pneumonia. Diagnosis of TB is extremely difficult and pathogen fever continues ≤ 2–3 days but in cases with often requires use of molecular methods (polymerase multilobar lesions could persist up to 3 weeks as well as aus- chain reaction, expert systems, etc.). This disease should cultative phenomenon in the lungs does. Antibacterial be considered in high-risk patients including immigrants, resistance of could also con- elderly, immunocompromised patients. tribute to prolonged course of the disease. In Russia, anti- Opportunistic and endemic fungal infection could bacterial resistance is less common than in some European initiate inflammation resembling slowly-resolving pneu- countries, such as France or Spain. Radiological signs of monia. Fungal invasion particularly caused by Aspergillus pneumonia caused by Streptococcus pneumonia could be could lead to necrotic lesions or to chronic course of the seen up to 3 months, especially in bacteriemic patients. disease. Fungal infection is more common in patients 1 About /2 of patients with pneumococcal bacteriemia have with acquired immune deficiency or in patients receiving protracted course of the disease. immunosuppressive therapy. Endemic fungal infections Slowly-resolving pneumonia caused by Legionella include histoplasmosis, blastomycosis, coccidioidomyco- spp. could occur in elderly patients (> 65 years old), in sis. Pulmonary inflammation in these diseases resolves smokers and in alcohol abusers. During outbreak of slowly. Legionella infection in Verkhnyaya Pyshma (2008), Antibacterial resistance of pathogens such as S. pneu- pneumonia was frequently complicated by nephritis, moniae, S. aureus, H. influenzae, Pseudomonas aerugi- myocarditis, etc. Therefore, the experience of Legionella nosa is greatly contribute to slowly-resolving course of epidemics has shown that slowly-resolving pneumonia pneumonia. In some regions resistance of could lead to chronic extrapulmonary injury. Radiolo- S. pneumoniae to cephalosporins and macrolides as high gical disorders in such cases could persist for 1 year even as 60 % with a consistent tendency to growing number of in patients without purulent complications. multidrug resistant strains. It is well known that laborato- Compared to Legionella spp., Mycoplasma pneumo- ry findings do not consistently correspond to clinical niaе is a frequent cause of pneumonia but it is uncom- data. Pneumonia caused by MRSA is typically character- monly could cause severe or slowly-resolving disease. ized by severe course. Eradication of this pathogen espe- Pneumonia caused by M. pneumoniaе is typically cially in a hospital is one of the most important problems resolved during 4 weeks but could be accompanied by in preventing in-hospital infection. There is also a grow- bullous myringitis especially in children. ing number of multi-drug resistant P. aeruginosa strains. Chlamydophila pneumoniae cause pneumonia in Empiric antibacterial therapy for pneumonia requires young patients in > 30 % of cases and is characterized by recognition regional resistance of the most common mild to moderate course; severe disease is uncommon pathogens with regard to previous therapeutic efficacy. and could occur in patients with psittacosis. Such pneu- Concerns arise about pathogen resistance to new gen- monia is usually resolved in 3 months with rare abscessing erations of antimicrobials, i.e. resistance of M. tuberculo- forms. sis to old and new antituberculosis drugs and appearance

12 Пульмонология 3’2014 Editorial of pathogens with 100 % drug resistance, i. e. Burkhol- respiratory distress syndrome could occur. Chronic deria cepacia. is effectively treated with . Thus, slowly-resolving pneumonia could be related to Acute interstitial pneumonia is a rare disease with antibacterial resistance of the causative pathogen that can progressive caused by acute respiratory affect the outcome. distress syndrome; the disease is characterized by dramat- Currently, > 5 % of pneumonia cases are diagnosed in ic course during 2–3 weeks. The mortality as high as 70 %, young patients with AIDS worldwide. This rate increases effect of steroids is controversial. up to > 50 % in endemic regions, i. e. in equatorial Africa. Certain clinical variants of pulmonary Pneumonia in AIDS patients could be caused by pneu- could also be difficultly distinguished with slowly-resolv- mocystis, atypical mycobacteria, fungi. In patients with ing pneumonia. In infiltrative pulmonary sarcoidosis, secondary immune deficiency pneumonia could be com- intrathoracic lymph nodes could have normal size. plicated by sepsis. Transbronchial biopsy is of great importance for the diag- nosis; in patients with sarcoidosis, typical granulomas Differentiation could be found. Pulmonary alveolar proteinosis is an orphan disease Slowly-resolving pneumonia should be distinguished with lipoprotein deposition in the distal airways. Diffuse with abscessing pneumonia and purulent complications, alveolar infiltrates are typically found in the chest X-ray. such as pulmonary abscess, empyema, pulmonary gan- Diagnostic method is bronchoalveolar lavage (BAL) grene. These complications require special treatment obtaining milky BAL fluid. approach. Among drug-induced lung injury, amiodarone lung Also, slowly-resolving pneumonia should be distin- toxicity is the most known. Clinical signs include fever, guished with benign or malignant neoplasms of the lung. breathlessness and pulmonary infiltrates resembling Bronchogenic carcinoma could constrict airways leading pneumonia. Alveolar macrophages contain specific to hypoventilation of the pertinent lung segments and iodous inclusions. then to that could be an underlying condition Methotrexate is widely used in treatment of rheuma- for pneumonia development. Another malignancy that toid arthritis and could affect the lungs. This pulmonary could be associated with focal pulmonary infiltration is disease should be distinguished with rheumatoid lung and bronchoalveolar carcinoma. Controversy between radio- slowly-resolving pneumonia. The accurate diagnosis is logical findings and absent or very slight clinical signs of recommended because of different therapeutic approach- pneumonia are noted in this disease. Also, lymphomas es in these conditions. There is a large database on pul- could mimic slowly-resolving pneumonia. Clonal lym- monary injuries induced by nitrofurans and bleomycin. phoid proliferation could arise from the airway epitheli- Bleomycin is widely used in experimental study to mod- um and sometimes is difficult for differentiation requiring eling . Current therapy of pulmonary lung tissue biopsy with further immunohistochemical fibrosis includes a large group of monoclonal antibodies examination. The lungs are involved in > 38 % of the that could modify the course of the disease but also could cases of lymphoma. One of the most typical signs of lym- adversely affect the lungs. The main groups of monoclon- phoma is hilar lymph nodes enlargement. al antibodies and their adverse effects are given below: Endobronchial obstruction could be caused by carci- TNF- α inhibitors . Etanercept could induce pul- noid that is more prevalent is young patients. Lung monary infections such as pneumococcal pneumonia, involvement could occur in patients with autoimmune pulmonary tuberculosis, histoplasmosis, and non-infec- systemic diseases. Non-specific symptoms, such as fever, tion disease such as lupus erythematosus with pleura dyspnea and pulmonary infiltrates, are common in sys- involvement, pulmonary fibrosis, , worsen- temic vasculitis contributing to late diagnosis. Lung injury ing of interstitial lung disease. Infliximab could increase is generally seen in patients with Wegener's granulomato- risk of tuberculosis, cryptococcosis, histoplasmosis, sis, polyangiitis and alveolar hemorrhage. Biomarkers for Legionella infection, actinomycosis, coccidioidosis and diagnosis of these diseases including anti-neutrophil pneumonia caused by Pneumocystis jirovecii. Infliximab cytoplasmic antibodies (ANCAs) for Wegener's granulo- could also induce histiocytosis, drug-induced alveolitis, matosis and anti-erythrocyte antibodies for hemorrhagic sarcoidosis, diffuse alveolar hemorrhage syndrome, pul- pulmonary alveolitis are actively investigated. monary fibrosis, lupus erythematosus with the pleura and Cryptogenic organizing pneumonia with the lung parenchyma involvement. Tuberculosis and obliterans resembles slowly-resolving pneumonia. This aspergillosis have been described to complicate therapy disease is predominantly found in women. Main signs are with adalimumab. fever, breathlessness and pulmonary infiltrates with fail- An interleukin-1 receptor antagonist anakinra could ure of standard antibacterial therapy which should be dis- also increase risk of tuberculosis. continued and steroids should be administered in these T-cell co-stimulation inhibitor abatacept has a poten- patients. tial adverse effect related to occur- Acute and chronic eosinophilic pneumonias have dif- rence. ferent pathogenesis. Acute eosinophilic pneumonia usual- Rituximab is a chimeric monoclonal antibody against ly manifests with fever, dry cough and pleural pain. the protein CD 20 , which is primarily found on the surface Radiological signs include diffuse ground glass opacity. The of immune system B cells; adverse effects of rituximab are course of the disease is often severe; in some cases, acute pulmonary fibrosis and interstitial pneumonia. http://www.pulmonology.ru 13 Chuchalin A.G. Slowly-resolving pneumonia

Therefore, new information on pulmonary involve- diac disease, underlying chronic lung disease). This ment in drug metabolism has been gathered particularly should be followed by the assessment of pneumonia reso- regarding new generations of monoclonal and biological lution rate. Uncomplicated pneumonia course implicates drugs. Lung tissue is very sensitive to these drugs and resolution of the disease in 3–4 weeks. Otherwise, the tuberculosis reactivation or other bacterial and fungal diagnosis should be revised with focus on the pathogen infections, autoimmune disease such as lupus erythe- identification and non-infection factors. Image methods matosus or interstitial pneumonia could occur in including computed tomography (CT) and molecular response to this therapy. tests could be useful. CT could reveal parenchyma abnor- Slowly-resolving pneumonia requires to be differenti- malities, emphysema, nodules, interstitial disease and ated from and pulmonary infarc- evaluate extension of pulmonary inflammation. tion. Every fifth case of pulmonary infarction is accompa- Currently, novel diagnostic markers of pulmonary nied by and resolves for several weeks. inflammation and molecular methods for pathogen iden- Multiple pulmonary infarction foci could be complicated tification have being searched. Measurement of serum by abscessing pneumonia, mostly due to underlying air- procalcitonin and C-reactive protein has already become way colonization with S. aureus. routine diagnostic tools. Therapy of slowly-resolving Congestive heart failure could facilitate development pneumonia should be changed according to results of the of pneumonia which is commonly slowly-resolving in tests. If the reason of slowly-resolving course has been these patients. Pneumonia in patients with congestive still unclear, bronchoscopy and bronchoalveolar lavage heart failure generally worsens the central hemodynamics should be performed. These methods are important for and outcomes of congestive heart failure. diagnosis of tuberculosis, fungal invasion, identification of atypical pathogens, pneumocysta, etc. If neoplastic Diagnosis lung disease, vasculitis, pneumonitis, granulomatosis are suspected it is important to obtain lung tissue sample for Diagnostic algorithm in slowly-resolving pneumonia histological exanimation. In patients with enlarged medi- should include a detailed medical history and informa- astinal lymph nodes invasive diagnostic methods should tion on the regional epidemic situation. This is particular be considered enabling transbronchial biopsy (bron- important in epidemic seasons of acute respiratory viral choscopy, mediastinoscopy, endobronchial ultrasound- infections. In July, 2008, in Verkhnaya Pyshma thorough guided bronchoscopy) and the further therapy should be collection of epidemic data has provided successful diag- modify according to the results. If this diagnostic program nosis and treatment of pneumonia caused by Legionella does not allow reaching an accurate diagnosis, videotho- related to operational problems in the local water uptake racoscopy or open lung biopsy should be considered. system. During the water uptake system repair domestic water was supplied from a local lake colonized with Conclusion Legionella pneumophila that was the cause of the out- break. The outbreak was localized in 3–5 days. When ask- Therefore, the diagnostic algorithm in slowly-resolving ing the patient a physician should consider a potential of pneumonia consists of several stages and is aimed at iden- having acquired immune deficiency especially in young tification of the pathogen causing the pulmonary inflam- patients. At presentation, it is extremely important to mation and at exclusion of a wide range of diseases mim- evaluate pneumonia severity because of a high probabili- icking slowly-resolving pneumonia. Despite of new ty of slowly-resolving course in more severe cases. The knowledge and new generations of antibacterial drugs outcome of slowly-resolving pneumonia is greatly slowly-resolving pneumonia has still been a challenging dependent on primary diagnostic algorithm including clinical problem that stimulates a physician to continu- detection of co-morbidity (alcohol abuse, diabetes, car- ously improve professional skills.

14 Пульмонология 3’2014