Professor, Renton, Washington, USA
*Address for Correspondence: Igor Klepikov, MD, Professor, Renton, Washington, USA, Email: firstname.lastname@example.org
Dates: Submitted: 29 December 2018; Approved: 02 February 2019; Published: 04 February 2019
How to cite this article: Igor K. Acute pneumonia: Facts and realities against etiological hypotheses and beliefs. J Clin Intensive Care Med. 2019; 4: 010-017. DOI: 10.29328/journal.jcicm.1001019
Copyright: Igor K. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Acute pneumonia; Etiology; Microflora; Symbionts; Experimental model of acute pneumonia; Pleural empyema; New doctrine
Modern AP concepts are focused exclusively on the infectious nature of the disease and the presence of certain pathogens. This belief determines the principles of treatment, the lack of effectiveness of which remains a concern of health professionals. The article presents a fragment of the study devoted to the etiology of АP. 994 children aged 4 months to 14 years with various forms of so-called community-acquired pneumonia were examined and treated. Bacteriological examination of the material from the inflammation zone was carried out in 542 patients. Experiments on modeling АP and its pleural complications were performed on 44 animals. The obtained results and critical analysis of the literature data and scientific facts allow us to consider bacteria only as one of the etiological elements of АP, which is not mandatory in all cases of the disease. Scientifically based revision of existing ideas about the causes and mechanisms of AP development leads to the need for a radical change in the principles of treatment and is a strategic direction in solving the problem.
Acute pneumonia (АР) has been one of the most pressing problems in the health care system for many years. “Pneumonia is a common illness affecting approximately 450 million people a year and occurring in all parts of the world.” . Not only and not so much the high incidence of AP can cause reasonable anxiety. The results of treatment of AP indicate a lack of effectiveness of the efforts. The absence of the expected result after the started treatment is the reason for the increase in the number of hospitalizations with this disease. “Worldwide, approximately 7–13% of cases in children result in hospitalization” . “In 2011, pneumonia was the most common reason for admission to the hospital after an emergency department visit in the U.S. for infants and children” . “In the developed world between 22 and 42% of adults with community-acquired pneumonia are admitted” .
However, the maximum possible assistance that can be provided in modern clinics does not prevent high mortality. “It is a major cause of death among all age groups resulting in 4 million deaths (7% of the world’s total death) yearly” . “Pneumonia killed 920 136 children under the age of 5 in 2015, accounting for 16% of all deaths of children under five years old” . “In persons requiring hospitalization, mortality may be as high as 10%, and in those requiring intensive care it may reach 30–50%” .
Current AP statistics is an objective assessment of the quality of modern treatment of the disease, and this assessment does not give grounds to meet the results achieved even in developed countries, where there are the maximum possible conditions for the provision of medical care. ”Pediatric pleural empyema has increased substantially over the past 20 years and reasons for this rise remain not fully explained” (8). All this requires not just an analysis of the current situation of medical care for patients with АP, but a deep and reasoned assessment of existing ideas about the nature of the disease and the scientific validity of the principles of its treatment.
The first results of such research experience and clinical testing of the changed principles of treatment of АP were obtained in the recent past, but their relevance in the light of current trends is not lost. Below is a fragment of the work related to the causes of the disease.
Material and Methods
Studies were conducted in the Clinic of pediatric surgery at The State Institute for Advanced Training of Doctors (Novokuznetsk, USSR) in 1976-1985.During this period, the Department treated 994 children aged 4 months to 14 years with various forms of so-called community-acquired pneumonia and its purulent-destructive complications. Many patients from this number were selectively hospitalized in our Department in the initial period of the most aggressive forms of AP immediately at diagnosis. The reason for hospitalization of the last group of patients is that the surgical clinic was the only place of intensive care in our region with a population of about 2 million people. This group of patients was characterized by high mortality and rapid development of pleural complications. Unsatisfactory results of traditional treatment (massive doses of antibiotics, oxygen supply, methods of bronchial drainage, intravenous infusion) and a large concentration of very severe patients are forced to look for effective solutions.
The work began with a review of theoretical ideas about the nature of АP, its causes and mechanisms of development. For this purpose, known scientific data from certain biomedical rules and laws were used. To clarify some of the nuances of the disease and obtain objective evidence of the measures taken, special studies and experiments were conducted. Here are only those materials that are relevant to the topic under discussion.
In bacteriological examination of patients, the importance was attached only to the material that was taken directly from the inflammation zone (542 patients). Therefore, the results obtained in patients with purulent complications of the main process were analyzed. It was in this category of patients there was a situation requiring removal of the contents of the lesion (pleural empyema, pleurisy, abscess), followed by microbiological examination.
4 series of experiments were carried out on 44 rabbits. The main experimental manipulation in all animals was endobronchial administration of various mixtures. These manipulations were performed under sterile conditions under intravenous thiopental sedation. A 0.6 mm diameter polyvinyl chloride catheter was inserted using a puncture of the cervical trachea. The distal end of the catheter was moved to small bronchial branches in one of the lungs. After instillation, the catheter was immediately removed. The liquid mixture for instillation in each series of experiments differed in its composition. The following materials were ingredients for the preparation of the basic compound:
1. 1 billion microbial bodies of one-day culture Staphylococcus epidermidis in 1 ml of saline;
2.1 billion Microbial bodies of one-day culture Escherichia coli in 1 ml of saline solution;
3. sterile sunflower oil;
4. horse serum is normal, which was not used only in the first series of experiments.
The culture of the above-mentioned microorganisms was chosen specifically for experiments, since these bacteria do not appear in the list of dangerous pathogens of АP and belong to the group of «harmless» symbionts. Therefore, the experiment had the following objectives:
- check the possibility of AP development involving trivial symbionts;
- to clarify the role and importance of microbial factors in the occurrence of nonspecific pneumonia.
Only the experimental conditions in series 1 and 4 are of interest for the topic of this article and the discussion below. Therefore, descriptions of 2 and 3 series of experiments are not given.
In the first experimental series (11 animals), a liquid mixture (1 ml of Staphylococcus epidermidis, 0.5 ml of Escherichia coli and 1 ml of sterile sunflower oil) was injected through a catheter into the bronchial tree. On the second and third day of the experiment, seven animals carried out jet slow intravenous infusion of rheomacrodex (30 CC/kg body weight). All animals were put to sleep on the fourth day.
All 15 rabbits 4 series of experiments received seven days before the main part of the experiment subcutaneous injection of 5 CC conventional horse serum. A week later, the above-mentioned composition of the mixture of ingredients, in which 0.05 CC of ordinary horse serum was added, was introduced into the bronchial tree. Later the animals were divided into 2 groups. Seven animals (series 4a) did not undergo additional procedures. The remaining 8 animals (series 4b) was obtained (3-4 hours after endobronchial procedures) intravenous slow infusion rheomacrodex and 0.9% sodium chloride (30 CC/kg body weight). These infusions were repeated once a day. Six animals from the last group (4b) received solutions with the addition of a dye (methylene blue).Euthanasia of all animals was performed on the fourth day after endobronchial instillations.
After euthanasia, the lungs of all animals were subjected to macro-and microscopic examination. Statistical evaluation of the study was carried out according to successive test plans, as well as by the method of controlling the average dispersion in pairs (Sachs L. «Statistische Auswertungsmethoden». Springer. Berlin, Heidelberg, New-York, 1972). These statistical methods made it possible to limit the amount of experiments to obtain reliable results.
Results and Discussion
My generation grew up in fear of Staphylococcus aureus. Even at University, I received the first revelations that any pneumonia, accompanied by purulent and destructive complications, has a staphylococcal etiology. This was a period when in such situations the diagnosis of “staphylococcal lung destruction” was made confidently and without much thought. However, if the student had to take on faith the information provided, the practitioner could already critically evaluate the sources of such information. Treatment and monitoring of patients with АP allowed to note that the results of bacteriological examination of the material taken directly from the inflammation zone in some cases showed the presence of other microorganisms instead of the expected Staphylococcus aureus. In some cases, the bacteria were not found at all in the apparent purulent fluid. Yes, Staphylococcus aureus at that time was the leader among bacteriological findings in pleural empyema, but, as it turned out, he was not the only causative agent of the process. Statistics of such bacteriological data we carried out a little later in the period when there was a decrease in the frequency of detection of staphylococci. Analysis of the results of bacteriology of the material from the inflammation zone in 542 patients showed that Staphylococcus was detected in 32.7% of studies, other microorganisms-in 33.0%, and microbial flora in 34.3% was not detected.
The results of clinical observations and statistics of bacteriological studies contradicted scientific explanations of the causes of purulent-destructive complications of АP. The main stimuli for the development of these complications were interpreted exclusively by the whole complex of pathogenic qualities of Staphylococcus. It is this microorganism that was considered the main culprit of all the troubles in the АP. It is interesting to note that in the above analysis of bacteriological studies, pneumococcus was found only in 12.7%.Then it was hard to imagine that after only a couple of decades, staphylococcal catastrophe will go down in history and not every certified specialist will be focused on these events, and pneumococcus will repeat the fate of Staphylococcus and will be presented at all levels as another Scarecrow.
But in fairness it should be noted that among the bacteriological findings of the pleural empyema were found other microorganisms(Proteus,Е.coli, Klebsiella and others), which were considered less dangerous than staphylococci .However, purulent complications of АP still developed in the presence of less aggressive microflora, and their clinical and radiological signs had no fundamental differences. When the failure of treatment of АP and the development of its severe complications are trying to associate only with the presence of a certain pathogen, but in fact such a monopoly is not confirmed, then inevitably the question arises whether the value of certain properties of a microbe in the development and negative dynamics of the inflammatory process is not exaggerated. Finding an answer to this question becomes even more relevant if you try to explain the reason for the lack of microbes in the study of pus, which was extracted from patients with complications of АP. But patients with this result of bacteriological studies were no more and no less than a third of our observations.
The cause of the so-called sterile empyema of the pleura can be two possible factors. First, this circumstance can be a consequence of effective antibacterial therapy. Antibiotics are known to torpedo the microflora, but are not a means of direct impact on the mechanisms of the current inflammatory process. Second, it is now estimated that about a third of all АP cases worldwide have viral etiology . If these data are true, antibiotics as the main modern means of treatment of АP have no reasonable application in such situations.
Some clarity in this discussion may be provided by the results of experimental studies on modeling АP and its complications. Such studies are usually resorted to in situations where it is not possible to clarify the details of the disease in clinical conditions, and animal experiments allow you to recreate a close panorama of the observed phenomenon.
Our experiments yielded the following results. In the first series of experiments, where the transbronchial infection of pulmonary tissue was combined with a violation of bronchial patency, the АP-model could not be obtained. Macro-and micro-studies of pulmonary tissue showed the presence of a stable pattern of atelectasis without signs of inflammatory reaction. Intravenous infusions carried out during this series did not make any changes to the final picture.
A fundamental change in the results was achieved in the fourth series of experiments. Preliminary sensitization of animals with horse serum and subsequent administration of a small dose of the same drug with simultaneous infection of lung tissue provoked an acute inflammatory reaction. Typical pattern of АP were detected in all observations of the series 4a.
The addition of intravenous infusions (series 4b) to such animals shortly after the start of the experiment showed the development of pleural changes. The dye, which was added in several cases, gave a color change in the area of inflammation. The presence of changes in the affected area against the background of infusions further emphasized the inflammatory nature of the observed tissue transformation. The increase in blood flow to the zone of inflammation by infusion stimulated an increase in edema and infiltration in conditions of increased vascular permeability. The results of the experiments were marked by obtaining a certificate for the invention .
It is necessary to emphasize a very important, in our opinion, element of experiments. Despite the strict observance of the conditions for the set of materials and performing manipulations, the degree of inflammatory changes in the lungs and the severity of the pleural reaction in each case had their differences. Inflammatory changes in pulmonary tissue ranged from infiltrative changes to small foci of necrosis or abscess. Both fibrin and purulent exudate accumulations were found in the pleural cavity. In one of the observations at the autopsy was found pyopneumothorax.
Thus, the results of the experiments allowed us to draw the following conclusions. First, the presence of a microbe is not the only condition for starting АР. Bacteria can be one of the components of the etiology of the process, and severe forms of damage can develop with the participation of representatives of the symbiotic microflora. Secondly, an important condition for the beginning of the inflammatory process in the lungs is the immune response of the sensitized organism to the repeated penetration of the allergen. Third, the development of an inflammatory reaction has individual characteristics and can differ in a wide range of manifestations.
The above data of our own research were only one part of all the work done, which was aimed at clarifying the nature and mechanisms of the development of АP and improving the results of treatment. Despite significant achievements in solving this problem, the results remained little known, as they were published only in Russian . The past years have shown that the current understanding of the causes of the problem has not changed, but has focused even more on one narrow area.
Currently, all efforts in the process of diagnosis and treatment, and all proposals for the future are aimed at quickly checking the pathogens of АP for a more accurate choice of antibiotic. It should be noted that for many years all the troubles and failures in the treatment of patients with АP are considered as a result of the presence of infectious and dangerous pathogens. At the same time, the real and objective results of determining the AР agent in the early stages of the disease have not yet been obtained. The exception is a small group of patients with pleural complications, in which the material for bacteriological examination is extracted directly from the area of inflammation. In all other cases of this disease, the nature of the pathogen is tried to be judged indirectly.
For example, materials on the causes and etiology of АP published in the press release of the Center for Disease Control and Prevention are based mainly on the results of studies of the nasopharyngeal and oropharyngeal microflora, which were presented in one of the articles of the journal [11,12]. A similar approach to attempts to define the aetiology of АP is widespread and is also addressed in special manuals on this issue . It does not mention a convincing counter-argument against the practical relevance of such data. It is well known that many healthy people have in the composition of the symbiotic microflora of the nasopharynx and oropharynx opportunistic microorganisms, which are described as predominant among the pathogens of АP . But the presence of these bacteria in the body does not necessarily mean the development of acute inflammation in the lungs. In addition, to date, the list of identified АР pathogens has already exceeded 100 .
In the course of our studies, comparisons were initiated between the microflora found in the area of inflammation and the microflora isolated from the oropharynx and nasopharynx, which were carried out in parallel in patients with complicated forms of АP. The initial results showed a discrepancy between the microbial composition of these areas, so further work in this direction was discontinued, and the data of the first results were not preserved. At present, we can only regret it.
The microflora of the upper respiratory tract, from my point of view, cannot be a reliable reflection of the microbiological diagnosis of АP. At the same time, the material accumulated today on the study of the symbiotic microflora of the upper respiratory tract can give an idea of the dynamics of its composition under the influence of widely used antibacterial therapy in the world, if we analyze these data over the past decades.
Another surprising look at the causes of АP can be found in the World Health Organization documents on this issue. ”Pneumonia can be spread in a number of ways. The viruses and bacteria that are commonly found in a child’s nose or throat, can infect the lungs if they are inhaled. They may also spread via air-borne droplets from a cough or sneeze” . In other words, АP is presented as a contagious infectious disease. However, this statement is not supported by any evidence, and most importantly, there is no further indication of the isolation of patients that is so necessary in this mode of transmission. By the way, it should be recalled that АP never belonged to the category of infectious diseases and did not require the isolation of such patients.
The chosen aspirations to solve topical issues of АP only through the prism of its causative agent are clearly manifested in the modern results of pneumococcal vaccination. Already the first results of this extensive company led researchers to confusion [16,17]. Contrary to the expected success after many years of vaccination, the number of empyema of the pleura was statistically significantly increased. And the most depressing fact is not so much the end result as the lack of reasoned explanations of this phenomenon. But one explanation for these results, in my view, is the fact that АP does not refer to diseases with a strictly defined pathogen. Therefore, specific protection against pneumococcus cannot give the same effect against other bacteria. In this regard, it should be noted that the same analytical reviews provide, for example, data on a significant reduction in the number of cases of pneumococcal meningitis, for which the microbe is actually a specific pathogen.
The dominance of the concept of АP, based on the fatal role of infection in the nature of the disease, and the gradual decrease in the effectiveness of antibiotics as the main means of treatment, logically led to the emergence of another hypothesis that more justifies the failure of hospital treatment than reflects the real situation. In recent years, all cases of AР are divided into non-hospital and intra-hospital. In this case, nosocomial diseases are considered to be more dangerous and severe form of damage, this is explained by the concentration of more virulent and antibiotic-resistant microflora in hospitals. Such assumptions are based on the results of sanitary inspection of premises and medical equipment inside such institutions. However, the obvious logic of these fears requires reasoned objective evidence, and there is no such confirmation in the literature on this issue. Ideas about the causative agents of hospital pneumonia are based, as a rule, on the results of a study of the microflora of the oropharynx and nasopharynx, as if we are talking about sinusitis or tonsillitis, and not pneumonia. In addition, most publications on the development of АP during hospitalization of patients consider the onset of the disease as a contact transfer of certain microorganisms. The last conclusion logically assumes separate isolation of all hospitalized patients, but so far quarantine conditions use only for carriers of antibiotic-resistant strains. Naturally, with the prevailing ideas about hospital-acquired pneumonia, the severity of such patients is associated with the aggressiveness of the nosocomial microflora and little attention is paid to the initial state that caused hospitalization. Patients who are sent to the hospital are mostly sick people with reduced resistance of the body and other disorders of various organs and systems. In such circumstances, AP will be more severe and more likely to lead to serious complications. From my point of view, this direction requires separate monitoring and analysis depending on the nosology of the causes of hospitalization.
Unfortunately, all the conclusions and proposals in the existing publications on the future prospects of solving the problem of АP for a long time are very similar and are of a tactical nature. For example, ”Empirical selection of antibiotic treatment is the cornerstone of management of patients with pneumonia. To reduce the misuse of antibiotics, antibiotic resistance, and side-effects, an empirical, effective, and individualized antibiotic treatment is needed” . The existing treatment principles are based on the blind choice of antibiotic and cannot guarantee its adequate choice even by a very experienced doctor. This therapy is initially designed only for situations in which there is a bacterial element of etiology, but cannot have the same effectiveness, for example, in viral pneumonia, the frequency of which, according to the publications of recent years, is steadily increasing. Such conclusions rather urge to observe and try to improve the existing principles of treatment of patients with АP, but do not plan a radical solution to the problem. In this regard, it is appropriate to recall that the first experience of antibiotics was not due to the mandatory bacteriological examination of patients before treatment. However, at that time, the blind use of antibiotics was not an obstacle to their triumph. Why today the shortcomings of rapid microflora studies in patients with АP have suddenly become one of the main reasons for failures in their treatment?
If tactics do not yield tangible results, especially for a long period, a serious revision of the disease strategy is necessary. It is the revision of the entire doctrine of the AP that made it possible to achieve significant success in subsequent treatment and to note the possibility of guaranteed prevention of complicated forms of the disease. Details of this work and its results have recently been published in English .
Thus, a purposeful look at the existing ideas about the origin and nature of AP suggests an excessive enthusiasm for the infectious concept of the disease. Further attempts to obtain methods for early recognition of the true pathogen of the process will go against the background of the emergence of new antibiotic-resistant strains, reducing the effectiveness of existing antibiotics and the need for periodic updating of this group of drugs. Analysis of the current state of the problem already indicates a gradual but steady increase in the number of complicated forms of the disease and the inability to quickly reduce its aggressiveness with the help of modern methods of treatment. Therefore, the continuation of research and efforts only in this narrow “infectious” direction leaves without due attention other important aspects of the disease and does not portend success in the future.
Modern АP concepts are focused exclusively on the infectious nature of the disease and the presence of certain pathogens. This belief determines the principles of treatment, the lack of effectiveness of which remains a concern of health professionals. The obtained results and critical analysis of the literature data and scientific facts allow us to consider bacteria only as one of the etiological elements of АP, which is not mandatory in all cases of the disease. Scientifically based revision of existing ideas about the causes and mechanisms of the development of АP leads to the need for a radical change in the principles of treatment and is a strategic direction in solving the problem.
- Ruuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia. Lancet. 2011; 377 (9773): 1264–1275. Ref.: https://goo.gl/tSjiXj
- Singh V, Aneja S. Pneumonia - management in the developing world. Paediatric Respiratory Reviews. 2011; 12: 52–59. Ref.: https://goo.gl/AsLKEr
- Weiss AJ, Wier LM, Stocks C, Blanchard J. Overview of Emergency Department Visits in the United States, 2011. HCUP Statistical Brief #174. 2006; Ref.: https://goo.gl/pUC3HB
- Lim WS, Baudouin SV, George RC, Hill AT, Jamieson C, et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 2009; 64 (Suppl 3): iii1–55. Ref.: https://goo.gl/2rrbTf
- Lodha R, Kabra SK, Pandey RM. Antibiotics for community-acquired pneumonia in children. Cochrane Database Syst Rev. 2013; 6: CD004874. Ref.: https://goo.gl/BFs6j5
- Ref.: https://goo.gl/mNbU4t
- Nair GB, Niederman MS. Community-acquired pneumonia: an unfinished battle. Med Clin North Am. 2011; 95: 1143–1161. Ref.: https://goo.gl/tVSySy
- Elemraid MA, Thomas MF, Blain AP, Rushton SP, Spencer DA, et al. Risk factors for the development of pleural empyema in children. Pediatr Pulmonol. 2015; 50: 721–726. Ref.: https://goo.gl/HEVcVL
- Klepikov I, Rikov V. A method for modeling parapneumonic pleurisy. Author’s certificate for invention. 1990; SU, No 1631574. A1.
- Klepikov I. Acute pneumonia and its purulent and destructive complications in children in the midst of a major industrial centre of Western Siberia. Dissertation for the degree of doctor of medical science. Leningrad. 1989;
- Ref.: https://goo.gl/wBGPyZ
- Jain S, Williams D, Arnold SR, Ampofo K, Bramley AM, et al. Community-Acquired Pneumonia Requiring Hospitalization among US Children. N Engl J Med. 2015; 372: 835-845. Ref.: https://goo.gl/4pqP83
- Mani CS, Murray DL. Acute Pneumonia and Its Complications. Part II: Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management. SECTION D: Lower Respiratory Tract Infections. In the book: SS Long, LK Pickering, CG Prober. Principles and Practice of pediatric infectious diseases. Edinburgh, New York: Elsevier Churchill Livingstone. 2012; 235-245.
- Davis CP. Normal Flora. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 6. Ref.: https://goo.gl/mhkfCX
- Ref.: https://goo.gl/6LA35S
- Li ST, Tancredi DJ. Empyema Hospitalizations Increased in US Children Despite Pneumococcal Conjugate Vaccine. Pediatrics. 2010: 125: 26-33. Ref.: https://goo.gl/aPX2JW
- Strachan RE, Snelling TL, Jaffé A Increased paediatric hospitalizations for empyema in Australia after introduction of the 7-valent pneumococcal conjugate vaccine. Bull World Health Organ. 2013; 91: 167-173. Ref.: https://goo.gl/MXTYqQ
- Prina E, Ranzani OT, Torres A. Community-acquired pneumonia. Lancet. 2015; 386 (9998): 1097-108. Ref.: https://goo.gl/hQgEjR
- Igor Klepikov. Acute pneumonia: a new look at the old problem. Lambert Academic Publishing. 2017; ISBN (978-3- 330-35250-6). Ref.: https://goo.gl/9G1UHA