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Causes of Cystic Fibrosis

Cystic Fibrosis

Cystic Fibrosis is one of the most prevalent genetic disorders worldwide especially among some ethnicity. It is one of the leading causes of death due to genetic disorder (Sanders and Fink 2016). The cause of the genetic disorder is due to a mutation in the CFTR protein (CF transmembrane conductance regulator), which functions mainly in the maintenance of the ion flow in the trans epithelial membrane thus exhibiting an ionic balance and quantity of the fluid present in the airways (De Boeck 2020). The Cystic fibrosis infected individuals thus have a poor ciliary movement and prone to infection in the airways (Tilley et al. 2015). The cause behind this effect is yet to be discovered.

Pulmonary exacerbation is very commonly associated with Cystic fibrosis patients. It is a typical pulmonary symptom associated with the fluid volume changes, microbial infection of airways in patient with cystic fibrosis, leading to further damage to the pulmonary function (Sequeiros and Jarad 2013). Pulmonary exacerbation in cystic fibrosis is linked to multi-microbial infection in the airway tract. Chronic infection in the airway is cause by bacteria, fungus as well as to some extent viruses as evident by studies done using the sample from respiratory tract and sputum (Kiedrowski and Bomberger 2018). The chronic infections caused by various microorganisms and the consequential decrease in the lung function as well as lower response to the existing pulmonary exacerbation is the principal cause of death in the patients with cystic fibrosis (LiPuma 2010).

The cystic fibrosis pulmonary exacerbation occurs due to interplay between multiple microorganisms which affects the airway tract of the individual that poses a challenge and pathophysiological symptoms along with the genetical mode of pathophysiology (Zemanick et al. 2013). Identification of the Organism and subsequent targeted antimicrobial therapy is a very crucial step and often hard to implement due to the sample identification and coherence of microorganisms in the sample.  Different types of microorganisms require different types of media to be isolated and properly cultured show the identification and susceptibility in cystic fibrosis becomes very challenging (Lagier et al. 2015).  Often the interaction between the bacterial species as well as the fungal species is observed adding to the previous complications in isolation. In the above-mentioned diagnostic algorithm, the types of microbial population involved in cystic fibrosis associated pulmonary exacerbation is mentioned along with that the clinical manifestations that caused by the microbial infection in cystic fibrosis are summarized.

The principal bacterial species that are involved in causing exacerbation are - Pseudomonas aeruginosa, Haemophilus influenzae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia sp, Staphylococcus aureus, Mycobacteria, Ralstonia sp Cupriavidus sp, Pandoraea sp, Inquilinus limosus, Herbaspirillum sp, Escherichia coli, Morganella morganii, Klebsiella pneumonia, Serratia marcescens, Bacteroides sp. etc. (LiPuma 2010).

The fungal species involved are - A. fumigatus, Exophiala dermatitidis, Scedosporium species, Scedosporium species, S. apiospermum, S. prolificans etc. (Delfino et al. 2019).

Some of the viral species have been identified recently who has a role in cystic fibrosis such as –Respiratory syncytial virus (RSV), Influenza A and B viruses, Parainfluenza virus etc. (Eymery et al. 2019).

Pulmonary Exacerbation in Cystic Fibrosis Patients

The specimen collection in the cystic fibrosis pulmonary exacerbation is a crucial step and to isolate the microorganisms and also to identify the species there are not much options available that is to be used in specimen collection. In most of the cases the sputum from the infected cystic fibrosis patient is collected which has a multiple array of microorganisms present in the airways. Although nasopharyngeal sample collection is sometimes observed for identification and sampling of bacterial colonies that causes the infection in the Airways. Another kind of sample collection observed for bacterial population is Broncho alveolar lavage fluid and also the protected specimen bruising (PSB). The sample collection type for isolating various fungal species involved in causing pulmonary exacerbation is through collection of sputum from the infected individual with cystic fibrosis. Earlier it was assumed that there is not much influence of viral species in cystic fibrosis but recent studies capstone that there are certain viruses in the infected individual that contribute to the pathophysiology of the cystic fibrosis disease; the samples for those viruses to be identified is collected via sputum also (Dickson et al. 2014).

The bacterial samples which were collected using various modes are now destined to be processed and cultured. To identify each and every species that are involved in the disease progression and pathophysiology the usual cultural methods r using differential media and culturing the bacterial samples on them. There are several factors that are to be taken into account when culturing the specimen such as oxygen concentration - weather aerobic or anaerobic, temperature, medium composition etc. (Zemanick et al. 2010). The identification of the fungal species from the collected sample is difficult due to their characteristic need of physicochemical requirements, the fungal cultures are to be maintained in lower temperatures compared to the bacterial ones. The medium to be provided must be a selective medium isolation of fungal species involved, there is a strong association between the bacterial and fungal species play in cystic fibrosis disease onset, so the medium should be highly specific and the growth conditions to be maintained properly too. The nasopharyngeal taken from the cystic fibrosis patient is analyzed by 16s r RNA sequencing study to identify the species of virus that are present in the airway and causing severe infections.

As the sampling and isolation of microorganisms present in the pulmonary exacerbation present in cystic fibrosis as is very difficult and complex process, there are some modern methods coming into play to intervene in this process. In contrast to the previous culturing method, in recent times the DNA samples are extracted from the specimen and DNA analysis such as high throughput DNA sequencing studies are being performed which are exceptionally accurate in identifying the types of bacteria fungus and viruses present in the sample collected (Boyd, 2013).

Nasopharyngeal swab or mouth swab test: In the modern-day test methods for identifying cystic fibrosis and associated viruses present in the respiratory airways, swab test has been proved to be beneficial in multiple studies. Nasopharyngeal samples or swab is collected from the nasal cavity out from mouth of infected individual. The collected sample is then processed and studied using polymerase chain reaction (PCR) which is extremely efficient in detecting the respiratory viruses that are present in the ongoing infection. There are useful methods developed in recent years which has benefited the patient by enabling them to collect the swab sample by himself or herself. The medical professionals also can do the process and carry the sample by maintaining a specific storage condition. Test methods which do not involve specific storage has also been developed (Emerson et al., 2013)

Microbial Populations Involved in Cystic Fibrosis Pulmonary Exacerbation

Sweat test: The disease condition in cystic fibrosis significantly alters the composition and functioning of the salivary glands as well as affects the saliva production. This effect is utilized as a standard for cystic fibrosis diagnosis by analyzing the salivary chloride concentration as well as sweat chloride concentration and also song the sweat and salary sodium concentration. One of the principal methods developed to identify cystic fibrosis is called sweat test. In this test, the chloride concentration is being measured in the samples from the patients. The values in this test varies from patient to patient depending on several factors like age, wait, and ethnicity etc. (Gonçalves et al. 2019).

Saliva Chloride test: On other hand, concentration of chloride ion and sodium in saliva are often used as variables in diagnosis of cystic fibrosis, mainly in the cases where it becomes difficult to obtain the actual amount of sweat, as well as screening of CFTR mutation is not available, or reference procedure for sweat test are not available for implementation (Gonçalves et al. 2019).

These modes of sample analysis will help in identifying the specimen better and as a result of this intervention more specific antimicrobial therapy would be provided to the patient thus the patients suffering would be minimized in the future (Harun et al. 2011).

References

Boyd, S.D., 2013. Diagnostic applications of high-throughput DNA sequencing. Annual Review of Pathology: Mechanisms of Disease, 8, pp.381-410. https://doi.org/10.1146/annurev-pathol-020712-164026


De Boeck, K., 2020. Cystic fibrosis in the year 2020: A disease with a new face. Acta paediatrica, 109(5), pp.893-899. https://doi.org/10.1111/apa.15155


Delfino, E., Del Puente, F., Briano, F., Sepulcri, C. and Giacobbe, D.R., 2019. Respiratory fungal diseases in adult patients with cystic fibrosis. Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, 13, p.1179548419849939. https://dx.doi.org/10.1177%2F1179548419849939


Dickson, R.P., Martinez, F.J. and Huffnagle, G.B., 2014. The role of the microbiome in exacerbations of chronic lung diseases. The Lancet, 384(9944), pp.691-702. https://doi.org/10.1016/S0140-6736(14)61136-3


Emerson, J., Cochrane, E., McNamara, S., Kuypers, J., Gibson, R. L., & Campbell, A. P. (2013). Home self-collection of nasal swabs for diagnosis of acute respiratory virus infections in children with cystic fibrosis. Journal of the Pediatric Infectious Diseases Society, 2(4), 345-351. https://doi.org/10.1093/jpids/pit039


Eymery, M., Morfin, F., Doleans-Jordheim, A., Perceval, M., Ohlmann, C., Mainguy, C. and Reix, P., 2019. Viral respiratory tract infections in young children with cystic fibrosis: a prospective full-year seasonal study. Virology journal, 16(1), pp.1-8. https://doi.org/10.1186/s12985-019-1208-7


Gonçalves, A. C., Marson, F. A. L., Mendonça, R. M. H., Bertuzzo, C. S., Paschoal, I. A., Ribeiro, J. D., ... & Levy, C. E. (2019). Chloride and sodium ion concentrations in saliva and sweat as a method to diagnose cystic fibrosis. Jornal de Pediatria, 95, 443-450. https://doi.org/10.1016/j.jped.2018.04.005


Gonçalves, A.C., Marson, F.A.L., Mendonça, R.M.H., Bertuzzo, C.S., Paschoal, I.A., Ribeiro, J.D., Ribeiro, A.F. and Levy, C.E., 2019. Chloride and sodium ion concentrations in saliva and sweat as a method to diagnose cystic fibrosis. Jornal de Pediatria, 95, pp.443-450. https://doi.org/10.1016/j.jped.2018.04.005


Harun, A., Blyth, C.C., Gilgado, F., Middleton, P., Chen, S.C.A. and Meyer, W., 2011. Development and validation of a multiplex PCR for detection of Scedosporium spp. in respiratory tract specimens from patients with cystic fibrosis. Journal of Clinical Microbiology, 49(4), pp.1508-1512. https://doi.org/10.1128/JCM.01810-10


Kiedrowski, M.R. and Bomberger, J.M., 2018. Viral-bacterial co-infections in the cystic fibrosis respiratory tract. Frontiers in immunology, p.3067. https://doi.org/10.3389/fimmu.2018.03067


Lagier, J.C., Edouard, S., Pagnier, I., Mediannikov, O., Drancourt, M. and Raoult, D., 2015. Current and past strategies for bacterial culture in clinical microbiology. Clinical microbiology reviews, 28(1), pp.208-236. https://dx.doi.org/10.1128%2FCMR.00110-14


LiPuma, J.J., 2010. The changing microbial epidemiology in cystic fibrosis. Clinical microbiology reviews, 23(2), pp.299-323. https://doi.org/10.1128/cmr.00068-09


Sanders, D.B. and Fink, A.K., 2016. Background and epidemiology. Pediatric Clinics, 63(4), pp.567-584.

https://doi.org/10.1016/j.pcl.2016.04.001


Sequeiros, I.M. and Jarad, N., 2013. Cystic Fibrosis Pulmonary Exacerbation–Natural History, Causative Factors and Management. In Respiratory Disease and Infection-A New Insight. IntechOpen.


Tilley, A.E., Walters, M.S., Shaykhiev, R. and Crystal, R.G., 2015. Cilia dysfunction in lung disease. Annual review of physiology, 77, pp.379-406. https://doi.org/10.1146/annurev-physiol-021014-071931


Zemanick, E.T., Harris, J.K., Wagner, B.D., Robertson, C.E., Sagel, S.D., Stevens, M.J., Accurso, F.J. and Laguna, T.A., 2013. Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations. PloS one, 8(4), p.e62917.

https://doi.org/10.1371/journal.pone.0062917

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