Coccidioidal Pulmonary Cavitation: A New Age

Round 1

Reviewer 1 Report

Review of Coccidioidal Pulmonary Cavitation BY Lobvedip Kooner et al.

 

Coccidioidal Infections of “Valley Fever” are a major cause of morbidity and mortality in SW United States and NW Mexico.  This paper generally seems well written and referenced.  A strength of this study is its fairly large sample size of 137 patients and its listing of presenting manifestations and locations of cavity lesions.  I think this paper will be an important addition to the literature.  I have some suggestions that may improve the quality of the paper.

HELPFUL TO INCLUDE IMAGES- If space permits, it might be useful to include several chest CT or other types of scans.  Do you have some especially good images that would be interesting and might assist pathologists, physicians and nurses in diagnosing Coccidioidal Pulmonary Cavitation?

OCCUPATIONS AND ENVIRONMENTAL EXPOSURES OF COCCIDIOIDAL PULMONARY CAVITATION PATIENTS.   \

Do you have any information about the occupational of the patients?.  If so, please include their occupations as this might be very interesting as many Valley Fever cases are spread at the workplace, .especially dusty occupations like agriculture and road construction (de Perio et al. 2019) .

The mean age of patients in the study was 43.1 years- prime working age- range 18 to 77 years.   Coccioides is spread primarily through airborne dust, and workers exposed in dusty operations such as agriculture, horticulture, pomology (fruits), ornamental landscaping, road and building construction, evacuation, and handlers of household and landscape waste .  Kern County California lies in the major agricultural area and $6.8 billion work of agricultural and horticulture products were produced in 2015 (Wikipedia, Kern County 4/14/2023).  Summers are usually hot, dry, and dusty.

Coccidiodes infections are also frequently spread in prison- were there any prisoners or prison workers in this study  (de Perio et al. 2015)?

 

REASON FOR MUCH LOWER PERCENTAGE OF IMMUNOCOMPROMISED PATIENTS AS COMPARED TO THE PANIKER ET AL,. STUDY.   In the discussion you mention “ we also reviewed far fewer immunosuppressed patients or transfplant receipts” as compared to the Panicker study.  This study had 12.1% immunocompromised of 137 patients mean age of 43.1 years (range 18 to 77 years) versus the Panicker study-  39.1% in the Panicker study of 272 patients- mean age 57.4 years (range of 17.4 to 90.4 years) (Panicker et al. 2021).  Perhaps the lower percentage of immunocompromised patients seen in this study versus the Panicker study is the probably that your study involved mostly younger patients who were working in outdoor jobs while in the Panicker study the patients were older and probably had a lower percentage of subjects doing physical outdoor labor at mean age of 57.4 years.

Perhaps say something perhaps a higher percentage of occupational exposure in your study versus the Panicker study.  The younger patients were probably exposure to heavier mean airborne Coccidioidal loads- while the older patients probably had less airborne Coccidiodal exposure but had a higher percentage of  immunosuppressing conditions

WERE ANY COVID 19 AND OTHER PATHOGENS COINFECTING WITH COCCIOIDES . 

Were any of the patients coinfected with Covid 19 or other respiratory pathogens like Aspergillus.  If so- that probably should be stated

This study took place from Dec 2010 to Sept 2022- of which included 2.5 years OF the Covid 19 tragedy.  Earlier studies have reported much higher mortality rate of Covid 19 in patients coinfected with other pathogens like Aspergillus or influenza.

You might also want to cite some references that Coccidiodal infections can accompany infections with Covid 19  ,(Heaney et al. 2021)  tuberculosis (Cadena et al. 2009), and other pathogens.

DEATHS.  Were there any deaths except for the cirrhosis patient who died?  Did I overlook something here- you probably should list deaths here?

CONCLUSION- Although the main focus of this paper is to medical describe medical aspects of Coccidioidal Pulmonary Cavitation- you might want to briefly describe methods to reduce infection risk and promptly diagnose and treat yhe disease/    If space permits, perhaps you could say something brief about the need for more surveillance for Coccidioidal infections, antibody testing, chest CT scans, and prompt treatment with antifungals .  Also perhaps say something briefly about the need for more controls like masks and dust controls at workplaces, homes and businesses.

 

 

 

Cadena J, Hartzler A, Hsue G, Longfield RN (2009): Coccidioidomycosis and tuberculosis coinfection at a tuberculosis hospital: clinical features and literature review. Medicine (Baltimore) 88, 66-76

de Perio MA, Niemeier RT, Burr GA (2015): Coccidioides exposure and coccidioidomycosis among prison employees, California, United States. Emerg Infect Dis 21, 1031-3

de Perio MA, Materna BL, Sondermeyer Cooksey GL, Vugia DJ, Su CP, Luckhaupt SE, McNary J, Wilken JA (2019): Occupational coccidioidomycosis surveillance and recent outbreaks in California. Medical mycology 57, S41-s45

Heaney AK, Head JR, Broen K, Click K, Taylor J, Balmes JR, Zelner J, Remais JV (2021): Coccidioidomycosis and COVID-19 Co-Infection, United States, 2020. Emerg Infect Dis 27, 1266-1273

Panicker RR, Bartels HC, Gotway MB, Ampel NM, Buras MR, Lim ES, Blair JE (2021): Cavitary Coccidioidomycosis: Impact of azole antifungal therapy. Medical mycology 59, 834-841

 

Generally good please proofread

Author Response

1. Images-

Response: Images were added as well as a reference to the images on lines 126-129.

2. Occupations and Environmental Exposures of coccidioidal pulmonary cavitation patients

Response: Patient occupations were not documented in the majority of records. In our institution, usually, prison workers are seen for workman compensation and only one physician is trained to see coccidioidomycosis cases from prison workers and workman compensation patients. There have only been a few and none had cavities.

 

3. Reason for a much lower percentage of immunocompromised patients as compared to the paniker et al. study.

Response: Paniker’s paper focused on cavity closures and did not provide the occupations in their manuscript. Without the data, it would be hard to draw conclusions. Additionally, animal studies have shown that a single arthroconidia can cause infection, (Crum NF. Coccidioidomycosis: A Contemporary Review. Infect Dis Ther. 2022 Apr;11(2):713-742. doi: 10.1007/s40121-022-00606-y. Epub 2022 Mar 1. PMID: 35233706; PMCID: PMC8887663.) and it would be safe to reason that the greater the inoculum the greater chance of infection; however, there is no data to show an association with inoculum size and severity of coccidioidomycosis with or without cavitation. The differences in the patient population most likely have to do with the type of patients that are seen at each institution. The Mayo Clinic has a transplant center as well as a more robust rheumatology department. Occupation and immunocompromised differences would be interesting to dig deeper into but maybe beyond the scope of this manuscript.

 

4. Were any COVID 19 or other respiratory pathogens coinfecting with coccidiodes?

Response: We excluded any patients that had coinfection with an organism that has been associated with cavity formation in humans. There were coexistent COVID-19 patients; however, we did not gather this data. Many cases may have been missed prior to testing in 2020. This may be an entirely different manuscript, where the timing of the infections may be something to pursue, but it may be beyond the scope of cavities, as the treatment would not change.

 

5. Deaths

Response: 9 patients reported deceased and were added to the manuscript. (Lines 163-164)

 

6. Conclusion- Briefly describe methods to reduce infection risk and promptly diagnose and treat the disease. Need for more surveillance for coccidioidal infections, antibody testing, chest CT scans, and prompt treatment with antifungals.

Response: Living in endemic areas is a risk factor. Unfortunately, there is no data to suggest that preventative measures change incidence rates of coccidioidal pulmonary cavitations. The suggested preventative measures are ideas to prevent primary pulmonary disease and have not been statistically recognized as preventative. We do think that earlier recognition and treatment when needed would help improve outcomes; however, there is no data. We do mention that further investigation needs to be conducted to evaluate medical therapy’s efficacy and long-term outcomes.

Reviewer 2 Report

In general, I find the manuscript very clearly written. In my opinion, the manuscript is suitable for publication after the authors have addressed the following comments:

Line 26, 93: Coccidioides spp.

Line 72: “…in a more diverse population than previously studied” please include citation of the previously published work(s).

Table 1, 2: please consider bringing data in a visual way, like Venn diagrams, allowing analyzing the results more efficiently. This is important to verify which evaluated characteristics are shared by the patients under study.

Lines 165-167: please include citation.

 

Line 182: “…other recent research.” Please include citation.

Author Response

1. Line 26 – Coccidioides spp.

Response: changed to Coccidioides species in line 26.

2. Line 72 - Citation for more diverse population than previously studied.

Response: References added.

3. Table 1- 2 please consider bringing data in a visual way, like Venn diagrams, allowing analyzing the results more efficiently. This is important to verify which evaluated characteristics are shared by the patients under study.

Response: We are unable to discern a Venn diagram from our data; however, we added 2 diagrams in place of some data on the table.

4. Lines 165-167 citation

Response: Citation added

5. Line 182 “other recent research” citation.

Response: Citation added

Reviewer 3 Report

The study is interesting because it approaches clinical and therapeutic characteristics of an often misdiagnosed infectious disease that can have serious complications. As an additional merit, the study investigates this characteristics in a diverse population regarding ethnicity and immune status.  

Nevertheless, some conclusions are not well justified according to the results and references are needed to justify some asseverations.

Minor comments:

L72: What do you mean by “define cavity classifications”? Outcomes to be investigated need to be defined in methods. References are needed for previous studies.

 

L80-82: I assume that the bibliographic search was done to compare with the findings of this study. I think it is confusing to mention it in methods because it is usually done when you are going to perform a review, systematic review or metanalysis. 

 

L173-174: “Modern times” is not accurate. You are referring to studies performed less than 50 years ago, so it should be changed for “more recently” or “in the last X years/decades”.

 

L200: The reference is Chin et al and not Redden et al. 

 

L208-211: All the hypothesized reasons have to do with time passing, that you emphasize in this paper.  

 

L213-216: The seven cases of pleural effusion in this study were not associated with cavity rupture, according to the results section. Footnote of Table 2 doesn’t refer to pleural effusion. Please reformulate this paragraph. 

 

L217-218: I don’t think this is a widely expanded notion. On the other side, in the present study 20% of patients present cavitation and dissemination at the same time. So, this sentence is not derived from the study results and in any case such asseveration needs references.  

Author Response

1. Line 72- meaning of “define cavity classifications” outcomes to be investigated need to be defined in methods- references are needed for previous studies.

Response: We changed the wording to be more specific. (Lines 70-72)

2. Line 80-82 – Bibliography search to compare with findings of this study, Reviewer

Response: This was the only way to demonstrate the references we used to compare our study to previous literature.

3. Line 173 – 174: “Modern Times” is not accurate because less than 50 years; Change to “more recent times” or “in the las X years/decades.

Response: Change it Modern Times to “more recent times” (Line 199)

4. Line 208-211: All the hypothesized reasons have to do with time passing, that you emphasize in this paper

Response: We agree that this is about time and medical practice. In lines 232-233 we state that surgery is compared to historical cohorts, which would imply the passing of time.

5. Line 213-216: The seven cases of pleural effusion in this study were not associated with cavity rupture, according to the results section. Footnote of Table 2 does not refer to pleural effusion. Reformulate paragraph.

Response: We have changed “footnote of Table 2” to  “Section IV in Methods”  this is now written on line 240 and references lines 115-117 with the definitions of effusions and ruptures.  

6. Line 217-218: Not widely expanded notion on Dissemination. Not derived from the study and in any case such asseveration needs references.

We were unable to find reference a on this commonly held view; however, we wanted to disabuse the notion with 20 percent of our cases having coexisting dissemination

Reviewer 4 Report

Dear author, 

The manuscript is very interesting in the field and is generally sound and well written. I do think that minor issues need to be dealt with prior to publication. 

1. It takes my attention that still use fluconazole instead of itraconazole, this could be the reason for using a longer or extended treatment, and for a greater number of relapses. This could be discussed in the respective section.

2. It would be very illustrative to use an X-ray photograph to indicate the cavities

3. It would also be interesting to include the results of laboratory tests (immunodiffusion, complement fixation, antigen detection, or isolation by culture). This could be correlated with the fungal burden, severity, or clinical presentation in patients.

Author Response

1. Fluconazole vs. itraconazole.

Response: A progressive, double-blind, randomized trial showed that neither fluconazole nor itraconazole showed statistically superior efficacy in nonmeningeal coccidioidomycosis. (reference given below). In addition, no study has provided statistically significant data specifically for cavitations to discern that either treatment is superior. It would be speculative to mention any possible differences that may have occurred with a different medication.

 

Galgiani JN, Catanzaro A, Cloud GA, et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. 2000;133(9):676-686. doi:10.7326/0003-4819-133-9-200011070-00009

 

2. X-ray photograph

Response: Images were added to the manuscript.

 

3. Laboratory results (immunodiffusion, CF, Ag detection, or culture)
   Response: We only used serology for diagnosis purposes. The exact timing of the formation of cavities and thus duration is unknown. A future study may include the analysis of antibody titers throughout cavitation diagnosis and treatment; however, this may be beyond the scope of this study since the titers were only used for diagnostic and inclusion purposes. In addition, the management of these cavities rely on imaging and symptoms which is in line with most recent Infectious Disease Society of America guidelines.

Reviewer 5 Report

The article "Coccidioidal Pulmonary Cavitation: A New Age" is an interesting review for the medical community, it is a well-written work, well stated. I read your submission carefully and found it suitable for publishing in JoF, however, I have a comment and suggestion:

Based on the inclusion criteria, the authors mention:

Positive coccidioidal diagnosis based on one or more of the following:

i. Serology at the Kern County Public Health Department or the University of California Davis Mycology laboratories for immunodiffusion IgG and/or Compliment fixation (Immunodiffusion IgM alone or EIA results were not qualifying)

ii. Positive respiratory secretion culture for Coccidioides spp.

iii. Positive histopathology demonstrating endosporulating spherules

It would be interesting for readers to mention the antibody titers in the spectrum of coccidioidal cavities, on the other hand, in cavitary coccidioidomycosis the presence of atypical mycelial forms has been mentioned, interestingly associated with patients with diabetes mellitus (Muñoz-Hernández et al., Eur J Clin Microbiol Infect Dis (2008) 27:813–820; Audrey et al., Diagnostic Cytopathology, Vol 40, No 2, 2011), were these types of atypical forms observed in the histopathological samples in this study?

 

References should be carefully reviewed and adhere to the journal format.

Author Response

1. Inclusion criteria: interesting for readers to mention the antibody titers in the spectrum of coccidioidal cavities.

Response: We only have titers for diagnosis purposes.  The exact timing of the formation of cavities and thus duration is unknown. An interesting study would be to track the antibody titers throughout cavitation diagnosis and treatment; however, this may be beyond the scope of this study since the titers were only used for diagnostic and inclusion purposes.

2. In coccidioidal cavities the presence of atypical mycelial forms has been mentioned and associated with patients with DM. (Munoz-Hernandez et al., Eur J Clin Microbiol Infect Dis (2008) 27:813-820 & Audrey et al., Diagnostic Cytopathology, vol 40, No 2, 2011. Were these types of atypical forms observed in the histopathological samples in this study?

Response: We only used histopathological samples as diagnostic. Mycelial forms are typically in walls of cavities, although interesting and may be a topic for additional studies, are not diagnostic. Endosporulating spherules are diagnostic.

3. References to be carefully reviewed

Response: references have been reviewed.

Reviewer 6 Report

A well written paper about the demographics and outcomes of patients with Coccidioidal pulmonary cavitation in a diverse patient population in Central California.

Comments to the authors

1. Similar to Tubercular cavities, do Coccidioidal cavities get super infected with other infections such as bacterial pneumonia or aspergillus fungal balls. What is the incidence of such in literature? and were there co-infections such as Aspergillus identified in your dataset?

2. Line 43, can be stated more clearly.

3. Exclusion criteria- why were incarcerated patients excluded?

 

None

Author Response

1. Similar to TB cavities, do coccidioidal cavities get super infections such as bacterial pneumonia or aspergillus fungal balls? What is the incidence of such in literature? And were there co-infections such as aspergillus in your data set?

Response: Superinfections are indicated in table 2 between line 166 and line 167.

Masses within cavities were presumed to be a fungal ball as indicated in table 2 as well. We did not differentiate the fungal balls, as that information was not available. We did exclude patients that were diagnosed with other cavity producing organisms in order to review only coccidioidal pulmonary cavities.

2. Line 43 can be stated more clearly.

Response: Updated this section.

3. Exclusion Criteria- why were incarcerated patients excluded?

Response: Incarcerated patients were excluded because of legal prohibition without special dispensation.