Professor Manuel Varela: Who was Albert Fraenkel – and what did he have to do with pneumonia?

Jul 25, 2018 by

Albert Fraenkel

An Interview with Professor Manuel Varela: Who was Albert Fraenkel – and what did he have to do with pneumonia?

Michael F. Shaughnessy –

1) Dr. Varela- I hear about it almost every day- some individual has contracted and died of pneumonia.   What exactly is it? And how does one catch it?

Pneumonia is a serious problem worldwide in terms of both its significant morbidity and mortality rates in humans.  Although the occurrence of pneumonia in human populations is complicated and represents a critical healthcare concern, pneumonia itself may be defined simply as an inflammation of the lungs. As such, pneumonia involves the infiltration of fluid into the alveoli and bronchioles of the lung, a serious condition in which the fluid build-up in the lungs can impair breathing. If the fluid is composed of pus, the condition is known as empyema.

The onset of pneumonia may be brought about merely by breathing pathogenic microbes, usually bacteria, viruses and fungi, into the lungs of the patient.

This particular method of catching the pneumonia is frequently referred to as the respiratory mode of transmission, as the various components of the patient’s respiratory tract are involved, such as the upper and lower airways. The upper airway will consist of the throat and the nasal tract, for instance, while the lungs generally constitute the lower respiratory tract. The upper airway will be loaded with many diverse species of microbes, constituting a microbiome, if you will, or microbial flora, composed of both transient and permanent microorganisms. On the other hand, the lower respiratory tract, the lungs, are largely devoid of any sort of microbes, a condition known as axenic—living tissue that’s essentially free of microorganisms.

The respiratory tract has innate defenses associated with it to provide protection to the individual from infectious microbes. A physical barrier, the mucous membrane, lines the anatomical elements of the respiratory tract.  It keeps microbes from gaining entry past the barrier and into the deeper underlying tissues and the blood. The mucous that covers this respiratory membrane barrier is thick and viscous, and it serves to trap any tiny microbes that may have been breathed into the airway.  These mucous-trapped microbes, perhaps potentially pathogenic, are then swept away using the patients cilia—short hair-like structures that arise out of the membrane barrier into the mucous that then bring up the trapped microbes to then be spit out or swallowed. This so-called mucociliary axis plays an important role in the protection from pneumonia-causing pathogens.

Some microbes are quite frequently extremely small, and these small sizes will facilitate their entry into the lower respiratory tract, where an infectious disease can commence. Pathogenic microbes that cause pneumonia can avoid destruction by white blood cells, like microphages, by possessing an external covering called a capsule, like in the case of certain bacteria. Once in the lung, the microbes will elicit an inflammatory process to produce the pneumonia.

2)  It apparently impacts the elderly more than youth- or am I off on this?   And is it due to a weakened immune system?

I think you are essentially correct. Pneumonia is clearly a serious condition in the elderly as well as in the very young. Both types of populations may not harbor a fully functional immune system. Very young people, such as infants and in young children to about 4 years of age, may not yet have their immune systems fully developed. In the elderly, sometimes the immune system may tend to weaken with aging. Similarly, other individuals with immunocompromised states, such as those observed to have genetic or acquired deficiencies in the immune system, may also be susceptible to respiratory pathogens and in suffering the pneumonia.

Older youth and adults with healthy vigorous immune systems are often quite adept at fighting off pneumonia and in eliminating potentially dangerous microbes from the body. It may be important to point out that many of the microbes that cause pneumonia have evolved many strategies for circumventing the immune defenses, even in healthy individuals. In these cases, sometimes a healthy individual may be exposed to a large inoculum, too many microbes, too large in numbers to fend off straightaway. Furthermore, a healthy person may become exposed to a particularly virulent type of pneumonia-causing microbe.  Thus, in such cases, pneumonia may manifest itself just as well.

3) I remember taking a class in Human Infectious Diseases- and clearly hearing repeatedly about Streptococcus—In this case, we are discussing Streptococcus pneumoniae—-Refresh my memory and educate our readers—Is there a difference between the Streptococci, and is Streptococcus pneumoniae a variant?

Of the many microbial species that are responsible for causing pneumonia in humans, the Streptococcus pneumoniae, also known as Pneumococcus,  have been considered as one of the leading causes of this serious disease worldwide. It has ranked as the number one cause of bacterial pneumonia for many years; historically, pneumonia that’s caused by the S. pneumoniae has been referred to as the pneumococcal pneumonia. Often the S. pneumoniae affect lung lobes, a state known as lobar pneumonia.

There are indeed virulent variants, called serotypes, of the S. pneumoniae that produce an assortment of capsules. In addition, the S. pneumoniae is one species of the Streptococcus genus that are of medical importance. Another species is the S. pyogenes, which is a major pathogen and causative agent of a wide variety of diseases, such as, for instance, the flesh eating disease called necrotizing fasciitis.

The S. pneumoniae are particularly pathogenic because they produce a series of virulence factors that serve to protect them from the body’s immune system and to facilitate their growth. Once the bacteria enter the upper airway, the microbe makes an attachment factor, called an adhesion protein, which allows bacterial binding to the cells of the patient’s oropharynx. The S. pneumoniae may live as a permanent resident in the upper airway, establishing a colonization in the nose or throat.

If the individual who is colonized in the pharynx with the S. pneumoniae breathes these bacteria into lungs that are damaged by a primary infection with the flu or the measles, for instance, then the pneumococcal pneumonia can gain a foothold. Other predisposing factors can facilitate this entry of S. pneumoniae into the lungs, such as in individuals with diabetes, congestive heart failure and in alcoholics.

In the lung, variants of the S. pneumoniae produce capsules, which are extensive outer coverings that provide the bacteria inside these capsules with protection from inhibitory factors, such as the patients’ white blood cells like phagocytes or macrophages. Theses protective external capsules allow the interior bacteria to grow in the lung.

The S. pneumoniae bacteria now in the lung can produce another virulence factor called phosphorylcholine which triggers the lung cells to turn on endocytosis to allow the bacteria to enter the lung cells. Next, while inside the cells of the lung, the bacteria make and release another virulence factor called pneumolysin that pokes molecular holes, called pores, in the plasma membranes of the lung cells, killing them. The resulting lung damage produces an inflammatory response that brings fluid into the lungs. Meanwhile, the S. pneumoniae bacteria can escape into the blood to cause bacteremia or to the nerves to produce meningitis, both of which are serious complications.  The bacteria can even produce a virulence factor, called secretory IgA protease, which destroys antibodies that could have neutralized the bacteria.

While the vast majority of bacterial pneumonias are caused by the S. pneumoniae, other key pneumonia causers of the bacterial class include the Klebsiella pneumoniae and the Mycoplasma pneumoniae. The Mycobacterium tuberculosis bacteria have been a terrible blight for centuries, causing the Great Consumption. The Legionella pneumophila bacteria bring about legionnaires’ disease, or Legionellosis. Other bacterial pneumonias are caused by the Haemophilus influenzae and the Coxiella burnetii, the latter of which causes the Q fever.

Viruses are known to cause pneumonia, as well, such as the Influenza virus, causative agent of the flu, the respiratory syncytial virus (RSV), and the coronavirus-associated severe acute respiratory syndrome (SARS).

4) Now, Albert Fraenkel – where was he born, when did he work and what is he most known for?

Julius Albert Fraenkel was born on the 3rd of June, in 1864 to Jewish parents in Neustadt an der Haardt, Germany.  He obtained his medical degree in the late 1880s.  His medical specialties were in the fields of obstetrics and internal medicine.  However, after suffering a terrible bout of the tuberculosis, Dr. Fraenkel switched to the study of pneumonia. He was key to the establishment of a sanatorium for TB patients. Dr. Fraenkel is widely celebrated by medical doctors for his development of a treatment for heart failure.  The treatment involved injections of strophanthin (now known as ouabain) intravenously.

5) Treatment of pneumonia?   What is the current treatment and what advances have been made?

Treatment of the pneumococcal pneumonia cases that are caused by the S. pneumoniae involve antibiotics.  The treatment choice largely depends upon the antibiotic susceptibility profile of the clinical isolate of the S. pneumoniae from the patient. Historically treatment included the famous penicillin. This has often been the first line of treatment choice for those S. pneumoniae strains that are susceptible to this famous antibiotic. Recently, penicillin resistant variants of the bacteria have emerged, compromising the effectiveness of this antibiotic for clinical treatment.

In such cases of S. pneumoniae resistance to penicillin, other antibiotics may be indicated, such as a cephalosporin, a fluoroquinolone, or vancomycin. Sometimes combination therapy has been invoked in which the patient is given both ceftriaxone (a cephalosporin) and the vancomycin.

Another strategy has been prevention and control of the pneumococcal pneumonia. Toward this, vaccines are available. For children 2 years of age and older and in adults who are at risk, a vaccine called 23-valent pneumococcal polysaccharide is used. This vaccine has 23 distinct individual capsular sugars in it, without the bacteria. For children younger than 2 years, a 13-valent conjugated pneumococcal vaccine is used.  Here, the vaccine capsular sugar sub-units are connected to proteins, which then help to provide a cellular mediated immune response against the S. pneumoniae, producing immunity

6) Lastly, what were Albert Fraenkel’s contributions?

Dr. Fraenkel conducted animal experiments to show that the causative agent of the pneumococcal pneumonia was the bacterium now called Streptococcus pneumoniae.  He took sliced tissue sections from the lung of a 30-year old male patient with the pneumococcal pneumonia in his right lung and found the bacteria in the human clinical samples.  Next, Dr. Fraenkel injected the bacteria into laboratory animals, killing rabbits with potency, demonstrating that the purified Streptococcus pneumoniae bacterial organism caused the pneumonia.

Prior to the work of Dr. Fraenkel, the Streptococcus pneumoniae bacterium had been described by Pasteur and Sternberg.  Pasteur had called the bacterium Microbe septicemique du salive, and Sternberg had named the same organism as Micrococcus pasteuri.  In 1886, Dr. Fraenkel had called it Pneumococcus because he had shown that it caused pulmonary disease. In 1920, the organism was then renamed to Diplococcus pneumoniae largely because of the coccus shape possessed by the bacterium. In 1974, the organism was ultimately named Streptococcus pneumoniae as it was shown that the coccus-shaped bacteria formed long chains of cells.

7) What have I neglected to ask?

A controversy arose about which microbe was the true cause of the pneumonia.  Dr. Fraenkel thought that his S. pneumoniae was the culprit while another doctor-researcher, Dr. Karl Friedlander felt that his clinical isolate, now known as Klebsiella pneumoniae was the causative agent. It turned out, after Gram-staining the respective bacteria, that both investigators had been correct.  Both microbes are now widely known to cause pneumonia, and other diseases.

I think our readers will be delighted to know that the S. pneumoniae bacteria are the very same microbes that the famous scientific investigator Dr. Frederick Griffith used to conduct his well-known bacterial transformation experiments.  Griffith used these bacteria in laboratory animals to propose that the transforming substance, i.e., the hereditary material, was DNA.  This hypothesis was confirmed by the follow-up experiments of Drs. Oswald Avery, Colin MacLeod, and Maclyn McCarty.

Unbelievably, the S. pneumoniae bacteria cause not only the feared pneumococcal pneumonia, but they are also causative agents of other infectious diseases. For example, the S. pneumoniae bacteria are involved in causing bacteremia, endocarditis, meningitis, otitis media, septicemia, and sinusitis.

Bacterial pneumonia due to the S. pneumoniae bacteria has wreaked havoc for centuries, until the case of Ms. Anne Sheafe Miller, who was the first person to survive an otherwise lethal case of the disease from the newly developed penicillin antibiotic. Unfortunately, with the emergence of newer, more virulent strains of the S. pneumoniae with multiple antimicrobial resistance mechanisms, the pneumococcal pneumonia continues to be a critical health crisis.

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