Clinical predictors of radiological pneumonia: A cross-sectional study from a tertiary hospital in Nepal

Sandeep Shrestha; Nagendra Chaudhary; Saneep Shrestha; Santosh Pathak; Arun Sharma; Laxman Shrestha; Om P Kurmi

doi:10.1371/journal.pone.0235598

. 2020 Jul 23;15(7):e0235598. doi: 10.1371/journal.pone.0235598

Clinical predictors of radiological pneumonia: A cross-sectional study from a tertiary hospital in Nepal

Sandeep Shrestha ¹, Nagendra Chaudhary ^1,^*, Saneep Shrestha ², Santosh Pathak ³, Arun Sharma ⁴, Laxman Shrestha ⁴, Om P Kurmi ⁵

Editor: Frederick Quinn⁶

PMCID: PMC7377451 PMID: 32702037

Abstract

Background

Despite readily availability of vaccines against both Hemophilus influenzae and Pneumococcus, pneumonia remains the most common cause of morbidity and mortality in children under the age of five years in Nepal. With growing antibiotic resistance and a general move towards more rational antibiotic use, early identification of clinical signs for the prediction of radiological pneumonia would help practitioners to start the treatment of patients. The main aim of this study was to reassess the clinical predictors of pneumonia in Nepal.

Methods

This cross-sectional study was conducted between June 2015 and November 2015 at Tribhuvan University Teaching Hospital, a tertiary hospital in Kathmandu, Nepal. Children aged 3–60 months with a clinical diagnosis of pneumonia by a physician were enrolled in the study. Radiological pneumonia was identified and categorized as per World Health Organization guidelines by an experienced radiologist blinded to patient characteristics. We calculated sensitivity and specificity of clinical signs and symptoms for radiological pneumonia.

Results

Out of 1021 children with fever, 160 cases were clinically diagnosed as pneumonia and were enrolled for this study. Among the enrolled patients, 61% had radiological pneumonia. Tachypnea had the highest sensitivity of 99%, while bronchial breathing had the highest specificity of 100%. During univariate analysis, grunting, wheezing, nasal discharge, decreased breath sounds, noisy breathing and hypoxemia were associated with radiological pneumonia. Only hypoxemia remained an independent predictor when adjusted for all the factors.

Conclusion

Tachypnea was the most sensitive sign, whereas bronchial breathing was most specific sign for radiological pneumonia.

Introduction

Pneumonia is one of the most common causes (followed by prematurity related deaths) of childhood infections attributed to about 2 million children deaths worldwide [1]. The diagnosis of pneumonia in children remains an important yet difficult clinical problem, particularly in resource poor setting. Although fast breathing has been recommended as a predictor of childhood pneumonia, no clinical sign can solely predict pneumonia [2].

The World Health Organization (WHO) uses tachypnea (age 2–11 months, ≥50/min; age 1–5 years, ≥40/min) and/or lower chest indrawing as a sole criterion to diagnose pneumonia in children with a cough or breathing difficulty [3]. In low- and middle-income countries (LMICs), including Nepal, chest x-ray usually remains the diagnostic test of choice and often, health workers, including treating physicians, use WHO guidelines to diagnose and treat pneumonia [4]. Due to difficulty in obtaining appropriate specimens from the lower respiratory tract for culture and microbiological evaluation, radiography has been considered as the best method available for diagnosing pneumonia [4–6]. However, there is still a dilemma regarding when to order a chest x-ray in a case of suspected pneumonia. Earlier studies reported the clinical predictors of radiological pneumonia when the cases associated with radiological pneumonia were usually caused by bacterial agents mostly Streptococcus pneumoniae and Hemophilus influenzae [7–9]. WHO guidelines developed earlier for the detection and management of childhood pneumonia targeted bacterial agents [3, 10].

Currently, with the introduction of Hemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines (PCV) and global expansion of their coverage, bacterial agents are on the decline and out-numbered by viral and atypical bacteria [11, 12]. The clinical presentation and the radiographic signs of pneumonia may not be the same as found earlier. Considering the change in the epidemiological pattern, the clinical predictors of pediatric pneumonia need reassessment. Hence, this hospital-based study was conducted to find the predictors of radiological pneumonia.

Methods

Study design, hospital setting, participants and diagnosis

This cross-sectional study was conducted from June 2015 to November 2015 in Tribhuvan University Teaching Hospital (TUTH), a tertiary healthcare centre in Kathmandu, Nepal, which lies at an altitude of 1400 meters (4600 ft) from the sea level. Children aged 3–60 months who visited the TUTH at an outdoor patient department or emergency unit and presented with fever, cough, and difficulty or fast breathing were enrolled in this study. All the clinical pneumonia cases included were community-acquired (CAP). No hospital-acquired pneumonia cases were included in the study. Children with pre-existing cardiac disease, chronic respiratory disease (cystic fibrosis/bronchopulmonary dysplasia), known asthma or presenting with asthma (requiring >1 bronchodilator or systemic steroids), history of foreign body aspiration, history of receiving antibiotics >1 week and with chest x-ray outside TUTH (in private clinics) were excluded from the study. Etiological diagnosis (bacterial versus viral) was not preformed in the present study.

Parents of all children enrolled in this study provided vaccination history details, including Hib and PCV vaccines. The youngest child included in this study was three months and had received at least one dose of Hib and PCV-10 vaccines. A respiratory physician examined the children for the presence of tachypnea, nasal flaring, grunting, chest indrawing, decreased air entry, bronchial breath sounds and hypoxemia. Experienced medical officers from emergency departments or senior pediatric residents blinded to radiological findings of the children, screened them at the out-patient clinic.

Study definitions and variables

WHO cut-off points were taken to define age-adjusted tachypnea- children between 2–11 months (50 or more breaths/min) and 12–59 months (40 or more breaths/min) [3]. Clinical pneumonia was defined as a child having a fever, cough, difficult and/or fast breathing. Hypoxemia was defined as oxygen saturation less than 90% in the pulse oximeter (Mini SPO₂, Criticare Systems, USA) measured by the pediatric probe.

Fever was defined as an axillary temperature of 100.4^◦ F or more. All x-rays were carried out using the same portable digital x-ray machine (SHEMADZU 500mA Shandong, Mainland China). All x-ray films were interpreted by an experienced radiologist, blinded to the clinical features of the child’s condition. The presence of consolidation, asymmetrical infiltrates, or air bronchograms was considered as radiological pneumonia. A diagnostic agreement was made between the evaluating pediatrician and radiologist in all cases.

Study outcomes

Clinical pneumonia was categorised as radiological and non-radiological pneumonia based on the x-ray findings. The sensitivity and specificity of each of the clinical predictors were then calculated.

Ethical approval

The study was approved by the Institute`s Research Committee (IRC) of Tribhuvan University Teaching Hospital (TUTH), Institute of Medicine, Kathmandu, Nepal [reference number-37 (6-11-0)], dated 26^th August 2014]. Written and oral consent were obtained from the parents.

Statistical analysis

Descriptive statistics were used to report the characteristics of all children enrolled in this study. The heterogeneity between different baseline characteristics for children with radiological versus non-radiological pneumonia were tested using Chi-square test for categorical variables and t-test for continuous variables. We calculated the crude odds ratio for clinical signs and symptoms of radiological pneumonia using regression analysis. A multivariable regression analysis was carried out after adjusting for all the clinical signs and symptoms. SPSS software (version 21.0 IBM, Armonk, NY, USA) was used for data entry and analysis. Sensitivity and specificity of each variable for radiological pneumonia were calculated.

Results

Out of 4211 children visiting the out-patient and emergency unit of the pediatric department of TUTH, 1021 patients had a fever and were screened for the presence of clinical pneumonia (fever, cough and fast or difficulty breathing). Fig 1 shows the flow diagram of the enrolled children in this study.

Out of a total of 160 children enrolled, 68% were males, and about 60.6% had radiological pneumonia. Table 1 shows the baseline characteristics of children with radiological pneumonia and non-radiological pneumonia. The proportion of children with radiological pneumonia was greater in both males (59.6% versus 40.4%) and females (62.7% versus 37.3%) children when compared to non-radiological pneumonia (Table 1). Oxygen saturation (<90%) and high total leukocyte counts were found to be significantly associated with radiological pneumonia.

Table 1. Baseline characteristics of children enrolled with and without radiological pneumonia.

Parameters	Radiological pneumonia	Non-radiological pneumonia	p-value
Parameters	(Mean ± SE) or [n (%)]	(Mean ± SE) or [n (%)]	p-value
N	97 (60.6)	63 (39.4)
Age (months)	22.6 ± 1.8	21.4 ± 2.3	0.339
Gender
Male	65 (59.6)	44 (40.4)	0.707
Female	32 (62.7)	19 (37.3)	0.707
Birth weight (kg)	2.8 ± 0.04	3.0 ± .0.05	0.019
Height for age (z-score)
+2 to +3	14 (60.9)	9 (39.1)	0.927
0 to +2	38 (58.5)	27 (41.5)
0 to -2	34 (64.2)	19 (35.8)
-2 to -3	11 (57.9)	8 (42.1)
Weight for height
+2 to +3	4 (50.5)	4 (50.0)	0.346
0 to +2	21 (55.3)	17 (44.7)
0 to -2	64 (66.0)	33 (34.0)
-2 to -3	8 (47.1)	9 (52.9)
History of family smoking (Yes)	7 (63.6)	4 (36.4)	0.832
Temperature (deg F)	100.6 ± 1.1	100.7 ± 0.1	0.95
Respiratory rate (per min)	60.1 ± 1.0	58.7 ± 1.7	0.232
Oxygen saturation (%)	88.3 ± 0.5	90.6 ± 0.7	0.006
Heart rate (per min)	139.8 ± 1.8	143.3 ± 2.3	0.231
Heart sound (abnormal)	9 (69.2)	4 (30.8)	0.508
Blood examination
Hemoglobin (g/dl)	10.5 ± 0.2	10.6 ± 0.2	0.801
Total leucocyte count (per mm³)	14094.1 ± 1005.9	11735.3 ± 730.0	0.049
Absolute neutrophil count (per mm³)	-	-	-
Platelets (per mm³)	333664.9 ± 1689.1	303379.3 ± 16429.8	0.116
Complications (Yes)
No	74 (58.3)	53 (41.7)	0.002
Yes	22 (91.7)	2 (8.3)	0.002
Empyema	9 (100.0)	0	0.441
Myocarditis	4 (80.0)	1 (20.0)
Parapneumonic effusion	4 (100.0)	0
Respiratory failure	3 (100.0)	0
Septic shock	2 (66.7)	1 (33.3)

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Children with radiological pneumonia had complications such as empyema, myocarditis, parapneumonic effusion, respiratory failure and septic shock. The common signs and symptoms present in the enrolled children are reported in Figs 2 and 3, respectively. Noisy breathing and refusal to feeds were common clinical presentation in children with pneumonia and was predominant in children ≤12 months (Fig 2). On examination, tachypnea (99% in 3–12 months and 96% in 13–60 months), crepitation (75% in 3–12 months and 71% in 13–60 months), retraction (72% in 3–12 months and 45% in 13–60 months) and hypoxemia (68% in 3–12 months and 51% in 13–60 months) were common clinical signs noticed and was predominantly more in children aged 3–12 months (Fig 3).

Table 2 shows the statistical comparison of clinical features between children with and without radiological pneumonia. Noisy breathing (p = 00.2) and nasal discharge (p = 0.02) were the clinical symptoms which were significantly associated with radiological pneumonia. The sensitivity and specificity of noisy breathing were 44.3% and 30.2% respectively whereas for nasal discharge were 15.5% and 69.8% respectively. Among the clinical signs, grunting (p = 0.044), hypoxemia (p = 0.005), wheezing (p<0.001), decreased breath sounds (p<0.001), and bronchial breath sounds were significantly associated with radiological pneumonia in the children. No significant association of radiological pneumonia was observed with tachypnea, nasal flaring, retraction and crepitation (Table 2). Among various clinical variables, age-adjusted tachypnea had the highest sensitivity (99%) with low specificity (6.35%). Grunting (96.8%), bronchial breathing (100%) and decreased breath sounds (92.1%) had the highest specificity (Table 2).

Table 2. Comparison of clinical features between children with and without radiological pneumonia.

Clinical features	Radiological pneumonia			Sensitivity [95% CI]	Specificity [95% CI]
Clinical features	Yes (N, %)	No (N, %)	p-value^*
Symptoms
Noisy breathing	43 (49.4)	44 (50.6)	0.002	43/97 (44.3) [34.2–54.8]	19/63 (30.2) [19.2–43.0]
Refusal of feeds	33 (60.0)	22 (40.0)	0.907	33/97 (34.0) [24.7–44.3]	41/63 (65.1) [52.0–76.7]
Lethargy	8 (57.1)	6 (42.9)	0.78	8/97 (8.3) [3.6–15.6]	57/63 (90.5) [80.4–96.4]
Nasal discharge	15 (44.1)	19 (55.9)	0.026	15/97 (15.5) [8.9–24.2]	44/63 (69.8) [57.0–80.8]
Signs
Tachypnea	96 (61.9)	59 (38.1)	0.059	96/97 (99.0) [94.4–100.0]	4/63 (6.35) [1.76–15.5]
Nasal flaring	54 (66.7)	27 (33.3)	0.113	54/97 (55.7) [45.2–65.8]	36/63 (57.1) [44.0–69.5]
Grunting	12 (85.7)	2 (14.3)	0.044	12/97 (12.4) [6.6–20.6]	61/63 (96.8) [89.0–99.6]
Hypoxemia	65 (69.9)	28 (30.1)	0.005	65/97 (67) [56.7–76.2]	35/63 (55.6) [42.5–68.1]
Retraction	60 (65.9)	31 (34.1)	0.114	60/97 (61.9) [51.4–71.5]	32/63 (50.8) [37.9–63.6]
Wheezing	26 (42.6)	35 (57.4)	<0.001	26/97 (26.8) [18.3–36.8]	28/63 (44.4) [31.9–57.5]
Decreased breath sound	37 (88.1)	5 (11.9)	<0.001	37/97 (38.1) [28.5–48.6]	58/63 (92.1) [82.4–97.4]
Bronchial breath	27 (100.0)	0	<0.001	27/97 (27.8) [19.2–37.9]	63/63 (100.0) [94.3–100.0]
Crepitations	73 (62.9)	43 (37.1)	0.332	73/97 (75.3) [65.5–83.5]	20/63 (31.7) [20.6–44.7]

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CI, confidence interval;

*Chi square test (categorical variables).

Table 3 shows the validity of a combination of clinical variables for the prediction of pneumonia. Tachypnea alone has a high sensitivity but poor specificity (6%). The addition of hypoxia increased its specificity to 59% while further addition of various auscultatory findings (crepitations, bronchial breathing sounds, decreased air entry) increased specificity to 100%.

Table 3. Validity of combination of variables.

Combination of variables	Sensitivity	Specificity
Tachypnea + hypoxemia	67	59
Tachypnea + auscultatory findings	20	100
Hypoxemia+ wheezing	43	50
Hypoxemia + bronchial breath sounds	44	100
Wheezing+ bronchial breath sounds	4	100
Wheezing + hypoxemia + bronchial breath sounds	7	100

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Univariate regression analysis, it was found that noisy breathing (OR 0.34; 95% CI 0.17–0.67), nasal discharge (OR 0.42; 95% CI 0.20–0.91), wheezing (OR 0.29; 95% CI 0.15–0.57), decreased breath sounds (OR 7.15; 95% CI 2.63–19.46), and hypoxemia (OR 2.54; 95% CI 1.32–4.88) were significantly associated with radiological pneumonia (Table 4). Following adjustment for all the clinical signs and symptoms, only hypoxemia (AOR 3.41; 95% 95% CI 1.47–7.92) was independently associated with radiological pneumonia (Table 4).

Table 4. Associations between clinical variables (signs and symptoms) with radiological pneumonia.

Variables	Crude Odds ratio (95% CI)	Adjusted Odds ratio^* (95% CI)
Noisy breathing	0.34 (0.17–0.67)	0.46 (0.17–1.25)
Tachypnea	6.51 (0.71–59.64)	-
Nasal discharge	0.42 (0.20–0.91)	0.85 (0.30–1.98)
Grunting	4.30 (0.93–19.94)	1.94 (0.26–14.46)
Wheezing	0.29 (0.15–0.57)	0.72 (0.28–1.87)
Decreased breath sounds	7.15 (2.63–19.46)	3.68 (0.99–13.76)
Hypoxemia	2.54 (1.32–4.88)	3.41 (1.47–7.92)
Refusal to feed	0.96 (0.49–1.87)	0.77 (0.30–1.98)
Lethargy	0.85 (0.28–2.59)	0.15 (0.02–1.01)
Nasal flaring	1.67 (0.88–3.17)	1.72 (0.74–3.99)
Retraction	1.67 (0.88–3.18)	2.15 (0.87–5.31)
Crepitations	1.41 (0.70–2.86)	2.98 (0.06–8.12)

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CI, confidence interval;

*Each clinical variables were mutually adjusted for each other.

Discussion

In our study, tachypnea had high sensitivity and poor specificity for the diagnosis of radiological pneumonia. Although radiography is the gold standard in the diagnosis of pneumonia in low-income countries, including in Nepal, the unavailability of x-ray machines in majority of rural health settings poses a diagnostic challenge. Equally, it is not feasible to undergo a chest x-ray examination in all children with cough due to its high frequency and radiation hazards. We, therefore, still rely on simple clinical signs as laid out by WHO for diagnosing and treating pneumonia. WHO defines tachypnea as a sensitive sign of pneumonia; however, it has a poor specificity [13]. Hence, using only tachypnea as a guideline to define pneumonia leads to over-diagnosis of pneumonia resulting in over-prescription of antibiotics [14, 15]. Therefore, chest retraction was added in the definition of pneumonia, along with fast breathing in the WHO pocket book [3]. Chest retraction had a sensitivity of 62% in diagnosing radiological pneumonia with a specificity of 50.8% in the present study. This tachypnea based algorithms also significantly under-diagnose wheezy diseases. Likewise, specific signs like nasal flaring, retraction, hypoxemia, crepitations and wheezing may be present in asthma and cardiac diseases [15–17]. Using these specific signs may under-diagnose pneumonia cases. Therefore, a combination of clinical variables (signs and symptoms) that define pneumonia is required for its effective management [15, 18].

The prevalence of radiological pneumonia in this study was 61%, as has also been reported by earlier studies [19–21]. However, this was in contrast to other studies where the prevalence of radiological pneumonia was low [22–25]. Our study had strict inclusion criteria (cough, fever of 100.4° F or more, fast or difficulty breathing) in defining clinical pneumonia, whereas other studies used the earlier WHO definition of pneumonia (only cough and fast breathing) as their entry criteria. This might be the reason for the high prevalence of radiological pneumonia in the present study.

Although tachypnea, in the current study, was found to be the most sensitive sign to define pneumonia, its specificity was low, and the predictability of radiological pneumonia was insignificant. Similarly, in a study by Lynch et al. (2004) [21] and others [22–24], tachypnea had a sensitivity of above 95%, but was unable to distinguish children with and without radiological pneumonia. Likewise, Palafox et al. (2000) found that tachypnea had a sensitivity of 74% and concluded that tachypnea might be used as a useful screening clinical sign for identifying pneumonia in children [25].

Among various signs, the specificity of bronchial breath sound was 100% in diagnosing pneumonia in the present study. Similarly, grunting and decreased breath sounds had excellent specificities of 96% and 92%, respectively. This was similar to the study by Lozano et al. (1994), where decreased breath sounds had a specificity of 97% [18]. Lynch et al. (2004) concluded grunting had 100% specificity [21].

Although noisy breathing, nasal discharge, wheezing, decreased breath sounds, and hypoxemia were significantly associated with radiological pneumonia on univariate analysis, only hypoxemia was found to be independently associated with radiological pneumonia following adjustment of all the clinical signs and symptoms.

Using hypoxemia as a clinical sign had higher sensitivity (67%) with the specificity of 55.6% in predicting radiological pneumonia in the present study. In the present study, the clinical variable (hypoxemia) significantly associated with radiological pneumonia was similar to those reported by Lynch et al. (2004) [21] and Bilkis et al. [26]. The previous study conducted in the higher altitude of Nepal by Basnet et al. (2006–2008) found hypoxia in the majority proportion of children (62%) with pneumonia and predicted it as a sign of treatment failure and admission duration [27].

The sensitivity and specificity of chest retraction in predicting radiological pneumonia in the present study was about 62% and 51%, respectively with no significance in differentiating it from non-radiological pneumonia (p = 0.114). Hence, chest indrawing is probably an early indicator of respiratory distress that could be due to different disorders like pneumonia and bronchiolitis. Although using chest indrawing only as a sole clinical sign is insufficient for a diagnosis of radiological pneumonia, it might still be useful to recognise children with a high risk of hypoxemia and would benefit from oxygen therapy rather than the provision of antibiotics [28].

No single clinical signs have been able to truly predict radiological pneumonia the revised WHO definition of pneumonia suggests tachypnea and/or retractions be used widely in the resource-poor settings to identify children with pneumonia. In the present study, tachypnea had high sensitivity but poor specificity, and its association with radiological pneumonia (p = 0.079) was statistically insignificant. Similar results were found in a study done by Lozano et al. (1994), where the specificity was low (20%) when tachypnea alone was used to diagnose radiological pneumonia. Wingerter et al. (2012) applied the WHO criteria to an urban population visiting the emergency department and found that only 111 met the WHO case definition of pneumonia out of 324 children diagnosed with radiological pneumonia (sensitivity 34.3%, 95% confidence interval: 29.1–39.7) suggesting that WHO criteria was neither sensitive nor specific in predicting pneumonia in younger children [29]. On a combination of clinical signs (tachypnea + auscultatory findings; hypoxemia + bronchial breath sounds) (Table 4), the specificity of predicting radiological pneumonia was 100% in the present study. Rothrack et al. suggested that the absence of each of the four signs (respiratory distress, tachypnea, rales, and decreased breath sounds) excludes the diagnosis of pneumonia in children [30]. Therefore, due care needs to be taken while ordering a chest x-ray or prescribing antibiotics to any children presenting with tachypnea alone.

The current study has a few limitations. First, as the present study included children up to 5 years with pneumonia, this result may not be valid for children above five years of age; however, excluding children above five years of age would not take into account the changing epidemiology and the clinical presentation of pneumonia in this age group. Second, this study did not attempt to search the etiological agents. Therefore, our study is not in a position to ascertain with a greater degree of certainty whether the change in epidemiological pattern and variation of clinical presentation of radiological pneumonia is bacterial or viral agents. Thirdly, as this study was conducted in a tertiary care hospital (respiratory physician and radiologist interpreted the data), it may be a challenge to apply these findings in the community setting where these facilities are lacking.

Conclusion

Hypoxemia was the only independent predictor for radiological pneumonia. Tachypnea was the most sensitive sign, whereas bronchial breathing was the most specific sign of radiological pneumonia in the present study. This changing pattern in the clinical presentation and epidemiology of pediatric pneumonia could be due to the introduction of new vaccines which requires a reassessment of clinical predictors of pediatric pneumonia. A larger multi-centric study along with etiological diagnosis is necessary to re-define this changing clinical pattern of pediatric pneumonia to formulate new diagnostic guidelines and empirical antibiotics. The clinician should not rely only on a single sign or symptom and should consider a combination of clinical variables before diagnosing and treating pneumonia in children.

Supporting information

S1 Checklist. STROBE checklist.

(DOC)

Click here for additional data file.^{(90.5KB, doc)}

Acknowledgments

The authors would like to acknowledge the administration and staffs of Tribhuvan University Teaching Hospital, Kathmandu, Nepal for their cooperation during the study.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0235598.r001

Decision Letter 0

Eric HY Lau

10 Oct 2019

PONE-D-19-27004

Clinical predictors of radiological pneumonia in the post vaccine era: a cross sectional study from a tertiary hospital in Nepal

PLOS ONE

Dear Dr. Chaudhary,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please address the following comments before sending out for review:

Abstract conclusion, tachypnea is not specific at all (Table 2).
The main purpose of the study is to reassess the clinical predictors of radiological pneumonia. In the introduction, please describe the existing known clinical predictors and compare the results in the discussion.
Table 2, please give the % of having the symptoms/signs. For example, the % for ‘noisy breathing’ should be 43/97=44.3%. This will help understanding the estimated sensitivity and specificity.
Please present the results of the multivariable analysis.
Please explain how combinations of signs/symptoms were determined. Why some combinations were considered (or not considered)?

We would appreciate receiving your revised manuscript by Nov 24 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Eric HY Lau, Ph.D.

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

Please address the following comments before sending out for review:

1. Abstract conclusion, tachypnea is not specific at all (Table 2).

2. The main purpose of the study is to reassess the clinical predictors of radiological pneumonia. In the introduction, please describe the existing known clinical predictors and compare the results in the discussion.

3. Table 2, please give the % of having the symptoms/signs. For example, the % for ‘noisy breathing’ should be 43/97=44.3%. This will help understanding the estimated sensitivity and specificity.

4. Please present the results of the multivariable analysis.

5. Please explain how combinations of signs/symptoms were determined. Why some combinations were considered (or not considered)?

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Jul 23;15(7):e0235598. doi: 10.1371/journal.pone.0235598.r002

Author response to Decision Letter 0

13 Nov 2019

To, 13.11.2019

Eric HY Lau, Ph.D.

Academic Editor

PLOS ONE

Dear Sir,

Thank you for providing us with the opportunity to address your valuable comments (Manuscript ID: PONE-D-19-27004). The comments were helpful and we have provided point by point response to the comments and made changes accordingly in the manuscript. We hope this revised version will be acceptable but please let us know if you need some further clarifications.

Comments:

1. Abstract conclusion, tachypnea is not specific at all (Table 2).

Action taken: Thank you for pointing out the mistake. We have corrected this mistake.

Action taken: We have revised the introduction section as suggested and also have compared the known predictors in the discussion section.

3. Table 2, please give the % of having the symptoms/signs. For example, the % for ‘noisy breathing’ should be 43/97=44.3%. This will help understanding the estimated sensitivity and specificity.

Action taken: We have given the percentage of sensitivity and specificity in the table as suggested.

4. Please present the results of the multivariable analysis.

Action taken: The results of multivariate analysis have been given in table 4.

5. Please explain how combinations of signs/symptoms were determined. Why some combinations were considered (or not considered)?

Action taken: We just wanted to see the difference of sensitivity and specificity of the individual variables and on combining it. We did not find the increase in sensitivity in detecting radiological pneumonia on adding the variables. We also have calculated the combination of other variables which are given below.

Combination of variables Sensitivity Specificity PPV NPV

Tachypnea + hypoxemia 67 59 71 54

Tachypnea + auscultatory findings 20 100 100 45

Hypoxemia+ wheezing 43 50 48 45

Hypoxemia + bronchial breath sounds 44 100 100 58

Wheezing+ bronchial breath sounds 4 100 100 38

Wheezing + hypoxemia + bronchial breath sounds 7 100 100 58

If you suggest, we do not have any problem in omitting this table.

Thanking you,

Dr. Nagendra Chaudhary

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(15KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0235598.r003

Decision Letter 1

Eric HY Lau

18 Dec 2019

PONE-D-19-27004R1

Clinical predictors of radiological pneumonia in the post-vaccine era: a cross-sectional study from a tertiary hospital in Nepal

PLOS ONE

Dear Dr. Chaudhary,

The Authors are expected to address all the criticisms by all Reviewers. In particular, please describe and discuss the findings in Figure 2 and 3 (Reviewer #1 and #3), provide description of the statistical analyses for Tables 2 and 3 (Reviewer #1), and draw conclusion directly from the study results (Reviewer #1), and clarify in the methods whether bacterial or viral CAP were identified. In additional to the above comments, please address:

Table 4. The study main findings suggested that Tachypnea had the highest sensitivity, however was not included in the multivariable model. I suggest that the authors may include all variables with p<0.1 from Table 2 in the multivariable model.
The authors now added Table 3 to show the results of various combinations of signs/symptoms. However, a description of how the authors come up with these combinations would be helpful.

We would appreciate receiving your revised manuscript by Feb 01 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Eric HY Lau, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

1. Table 4. The study main findings suggested that Tachypnea had the highest sensitivity, however was not included in the multivariable model. I suggest that the authors may include all variables with p<0.1 from Table 2 in the multivariable model.

2. The authors now added Table 3 to show the results of various combinations of signs/symptoms. However, a description of how the authors come up with these combinations would be helpful.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. In the manuscript, the name of the microorganism should be corrected as Haemophilus influenzae. It is the way it has been used in the bacteriology world since the organism has been defined.

2. In the Methods section, “Ethics Approval” statement should be replaced after “Study Outcomes”.

3. In the Statistical Analysis subsection, it was indicated that statistical analysis was performed using SPSS. The name of the company and country should be indicated as “IBM SPSS Statistics (version 21.0; IBM, Armonk, NY, US)”.

4. In Figure 2 ans 3, symptoms and signs of the patients were presented in an age-based grouping. However, this analysis type has not been indicated in the methods section. Additionally, in the results and discussion sections this analysis has not been commented in any way. These figures give no input into the manuscript. This ag- based analysis and Figure 2 and 3 are unnecessary in the manuscript.

5. In the results section, explanations of Table and Table 3 should be more informative. The frequencies and statistical differences should be explained in a more detailed fashion, since these data are the main ones that the manuscipt is based on

6. The statistical analysis of Tables 2,3, and 4 are not described sufficient detail.

7. In the first paragraph of Discussion section, there is no data discussed from the present manuscript. This paragraph is just explaining what is already known in this era and it is a repeat of introduction section.

8. The manuscript is presenting a cross-sectional analysis and it does not compare the pre and post-vaccine era data. Both in introduction section and discussion sections, the authors are referring to a change of epidemiology and its reflections on the radiology and clinical signs. However, with the data presented in the manuscript, these evaluations can not be performed. Although authors are hypothizing changes in clinical findings of pneumonia related to vaccine introduction, they did not analyze this in the manuscript.

9. Fourth paragraph of manuscript (line 232), the discussion of the data is weak in explanations.

10. The conclusion section, totally, is not appropriate as a conclusion of this manuscript. It is not supported by the data.

Reviewer #2: About the scientific paper: "Clinical predictors of radiological pneumonia in the post-vaccine era: a cross-sectional study from a tertiary hospital in Nepal"

-A)First, the design , exclusion and inclusion criterial is similar to another old historical cohort of clinical predictors of community acquired pneumonia.

-B)Use of radiological finding as gold standard , not only WHO clinical guide is right.

reassessment. Therefore, this hospital-based study was conducted to find the predictors of radiological pneumonia in the post-vaccine era".

This statement is a hypothesis of the authors of this paper and has no bibliographic work to support it.

-D)"Currently, with the introduction of Hemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines (PCV) and global expansion of their coverage,

bacterial agents are on the decline and out-numbered by viral and atypical bacteria".

In this serie you studied include infants with a single dose of conjugate vaccines, which is considered insufficient dose to ensure adequate coverage.

Data that would not emphatically exclude the possible presence of pneumococci or haemophillus as possible etiological agents.

-E)Nasal discharge is inespecific and is associated with flu, the inicial and common manifestation of respiratory symptoms, not only of pneumonia.

-F)The association of wheezing with pulmonary infiltrates in infants is the current basis for the recommendation not to do radiography in bronchiolitis,

given the frequent association of pulmonary pathological findings and possible diagnostic confusion with pneumonia.

Would this have happened in some of the patients included in this series?. The same can be said of the asthmatic crisis.

-G)The central paper hypothesis cannot be demonstrated, given that these clinical predictors are not compared with others taken in the era prevaccine in the same community and population studied.

-H)The prevalence of viruses over bacteria in the etiology of pneumonia alters the clinical presentation of pneumonia ?.

Due to the design in a single hospital and without accompanying etiological studies, it is difficult to answer this question. The works cited do not get into this disquisition.

-I)In conclusion, it is valuable to observe what the high altitude above sea level determines that hypoxemia can be a good predictor of pneumonia.

The design and casuistic are adequate and the sum of signs and symptoms help and much to be able to find and not lose cases of this disease as severe and harmful to children as pneumonia.

By making these changes, these findings could be communicated.

Reviewer #3: The authors conducted an interesting study to analyze a possible association between radiographic findings of pneumonia in children with clinical signs and symptoms. The results are equally interesting, however, some questions need clarifying or undergoing changes to make the article better quality.

a) Were the selected cases all of community-acquired pneumonia? If so, this should be made clear in the text and the expression 'pneumonia' should be replaced throughout 'community acquired pneumonia (CAP)'.

b) The authors do not clarify whether bacterial or viral CAP was identified, this is only briefly described in the discussion (in limitations). This doubt should be clarified in the methods, emphasizing that approximately 30% of the cases of CAP are mixed (viral and bacterial).

c) How was the positive predictive value (PPV) calculated? If it was calculated from the selected sample, the value is certainly overestimated. It is correct to calculate PPV based on population prevalence data using the Bayes equation.

d) An interesting analysis would be to evaluate the association/correlation between radiological findings and leukocyte count, considering that in bacterial PAC, there is a tendency for leukocytosis.

e) The analysis of age subgroups would also be very important.

f) The authors use and cite old references. I suggest the inclusion and citation of some recent references such as: DOI: 10.1016/S1473-3099(15)70017-4; DOI: 10.4046/trd.2015.78.3.196; among others.

g) All text should be revised by a native speaker of the English language and specializes in health issues.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Dr Manuel D. Bilkis

Reviewer #3: No

PLoS One. 2020 Jul 23;15(7):e0235598. doi: 10.1371/journal.pone.0235598.r004

Author response to Decision Letter 1

28 Jan 2020

REPLY TO THE COMMENTS OF THE REVIEWERS

Additional Editor Comments (if provided):

Action taken: The findings of figures 2 and 3 have been described and discussed in the results section.

In table 2, chi- square test was used as the variable were categorical and finally sensitivity, specificity, PPV and NPV were calculated using the formula (by creating 2X2 table).

Clinical variable Radiological Pneumonia Radiological Pneumonia

Yes No

Yes True Positive (TP) False Positive (FP)

No False Negative (FN) True negative (TN)

Sensitivity=TP/(TP+FN)

Specificity= TN/(TN+FP)

PPV=TP/(TP+FP)

NPV=TN/(TN+FN)

Clarification of the viral/bacterial CAP have been mentioned in the Methods

(In section: Study design, hospital setting, participants and diagnosis).

In additional to the above comments, please address:

Action taken: We have re-analysed the data to provide univariate and multivariable adjustment for Table 4 with all the clinical variables from Table 2 in the model except bronchial breath.. The model for Tachypnea did not converge following multiple adjustment and hence represented by dash. This could be due to small sample size.

2. The authors now added Table 3 to show the results of various combinations of signs/symptoms. However, a description of how the author come up with these combinations would be helpful.

Action taken: The exact diagnosis of pneumonia depends on various signs and symptoms. As you are aware that no single sign or symptom is sensitive or specific for the diagnosis of pneumonia. Therefore, practically clinician combines different signs and symptoms for the final diagnosis of pneumonia. We randomly combined 2 or 3 variables to see how the sensitivity or specificity changes and tried to give a message whether the combination of those variables may be able to predict pneumonia exactly.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: (No Response)

________________________________________

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Partly

Action taken: We have amended the manuscript based on the helpful comments from the reviewers. We believe the inferences derived in this revised version are supported by the data and is technically sound.

________________________________________

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Action taken: We have reviewed the statistical section and the numbers. They are correct. We have dropped Table 4 to remove the ambiguity and now the message is much simpler and clearer.

________________________________________

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Action taken: We have made all the data available and have uploaded the excel sheet of the study population.

________________________________________

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Action taken: We have checked the language and edited wherever required. Typographical or grammatical errors have been corrected as far as possible by the authors.

________________________________________

6. Review Comments to the Author

Reviewer #1:

1. In the manuscript, the name of the microorganism should be corrected as Haemophilus influenzae. It is the way it has been used in the bacteriology world since the organism has been defined.

Action taken: The microorganism “Haemophilus influenzae” has been corrected as suggested.

2. In the Methods section, “Ethics Approval” statement should be replaced after “Study Outcomes”.

Action taken: The “Ethics approval” statement has been replaced after the “Study Outcomes” as suggested.

Action taken: The modification has been done in the Statistical analysis subsection.

4. In Figure 2 and 3, symptoms and signs of the patients were presented in an age-based grouping. However, this analysis type has not been indicated in the methods section. Additionally, in the results and discussion sections this analysis has not been commented in any way. These figures give no input into the manuscript. This age- based analysis and Figure 2 and 3 are unnecessary in the manuscript.

Action taken: We thank you for your recommendation and suggestion. In figure 2 and 3, the various clinical signs and symptoms have been mentioned. We have added the details in the method section as advised by you. We feel that the figures 2 and 3 depict the frequency of various clinical signs/symptoms in ≤12 months and ≥13 months children and will help in understanding the clinical signs/symptoms in children with pneumonia. The clinical predictors also have been addressed in the discussion section as advised.

Action taken: The frequencies and explanations of tables have been elaborated as much as possible. We feel the tables are self-explanatory and adding too much of details from the tables would be repetition of the results. However, we have added the main result findings in the result section as suggested.

6. The statistical analysis of Tables 2, 3, and 4 are not described sufficient detail.

Action taken: The statistical analysis was done in SPSS software by creating two categorical variables (radiological pneumonia versus non-radiological pneumonia) and chi-square test was done to find the level of significance. This has been mentioned in the material and methods (statistical analysis) section.

Again the sensitivity, specificity, PPV and NPV was calculated by using the formula mentioned above.

Action taken: We have modified the first paragraph of the discussion section and reported the main findings from this study

8. The manuscript is presenting a cross-sectional analysis and it does not compare the pre and post-vaccine era data. Both in introduction section and discussion sections, the authors are referring to a change of epidemiology and its reflections on the radiology and clinical signs. However, with the data presented in the manuscript, these evaluations cannot be performed. Although authors are hypothizing changes in clinical findings of pneumonia related to vaccine introduction, they did not analyze this in the manuscript.

Action taken: We thank you for your valuable comments. The main objective of the present study was to reassess the clinical predictors of radiological pneumonia in the post vaccine era. We compared the clinical predictors used to diagnose pneumonia in the past (pre-vaccine era) but we agree this might have created confusion. We have therefore modified the title and also reference to it in the manuscript.

9. Fourth paragraph of manuscript (line 232), the discussion of the data is weak in explanations.

Action taken: Thank you for your valuable suggestions. We have elaborated the discussion in this paragraph as suggested by you.

10. The conclusion section, totally, is not appropriate as a conclusion of this manuscript. It is not supported by the data.

Action taken: We have modified the conclusion section which now supports the data.

Reviewer #2: About the scientific paper: "Clinical predictors of radiological pneumonia in the post-vaccine era: a cross-sectional study from a tertiary hospital in Nepal"

-A) First, the design, exclusion and inclusion criteria is similar to another old historical cohort of clinical predictors of community acquired pneumonia.

Action taken: This study is a cross-sectional study where we have tried to reassess the clinical predictors of radiological pneumonia. Previous old studies were done in the pre-immunization era. Therefore our main objective was to reassess the clinical signs/symptoms of radiological pneumonia.

-B) Use of radiological finding as gold standard, not only WHO clinical guide is right.

Action taken: We have therefore classified clinical pneumonia (as per WHO pocket book) into 2 groups (radiological pneumonia and non-radiological pneumonia) and compared different clinical variables.

-C)"The clinical presentation and the radiographic signs of pneumonia may not be the same as found earlier. Considering the change in the epidemiological pattern, the clinical predictors of pediatric pneumonia need reassessment. Therefore, this hospital-based study was conducted to find the predictors of radiological pneumonia in the post-vaccine era".

This statement is a hypothesis of the authors of this paper and has no bibliographic work to support it.

Action taken: Thank you for your valuable comments. Main objective of our study was to compare the clinical signs/symptoms of radiological pneumonia with non-radiological pneumonia. We have compared this findings with previous studies in the discussion section.

As suggested by you, we have removed the phrase “Post vaccine era” from title and other places in reassessing the clinical predictors of radiological pneumonia.

-D)"Currently, with the introduction of Hemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines (PCV) and global expansion of their coverage,

bacterial agents are on the decline and out-numbered by viral and atypical bacteria".

In this series you studied include infants with a single dose of conjugate vaccines, which is considered insufficient dose to ensure adequate coverage.

Data that would not emphatically exclude the possible presence of pneumococci or Haemophilus as possible etiological agents.

Action taken: Children aged 3-60 months were included in the present study. The Hib vaccine in Nepal is given at 6 weeks, 10 weeks and 14 weeks whereas PCV is given at 6 weeks, 10 weeks and 9 months as per the national immunization schedule. We therefore, made sure that the infant should at least receive the first dose of hib and PCV for enrolment in this study. This has been mentioned in the material and methods section.

We were unable to perform the etiological diagnosis for pneumonia in this study which we have mentioned in the limitation section. We, therefore, accept your point and consider to conduct future study as commented by you.

-E)Nasal discharge is inespecific and is associated with flu, the inicial and common manifestation of respiratory symptoms, not only of pneumonia.

Action taken: The sensitivity of nasal discharge in our study too was just 15% in predicting radiological pneumonia. The comparison, sensitivity and specificity has been mentioned in table 2.

F) The association of wheezing with pulmonary infiltrates in infants is the current basis for the recommendation not to do radiography in bronchiolitis, given the frequent association of pulmonary pathological findings and possible diagnostic confusion with pneumonia.

Would this have happened in some of the patients included in this series?. The same can be said of the asthmatic crisis.

Action taken: We agree that the diagnosis of pneumonia should include not only a single sign or symptoms but combination of them (as per WHO) along with radiology. In the present study, radiological diagnosis of pneumonia was made in children with clinical pneumonia by an experienced radiologist in a blinded condition to exclude observer bias. Therefore, as radiological pneumonia diagnosis was standardized, it is less likely that other diagnosis apart from pneumonia (bronchiolitis, asthma) were included. Still, we accept that there could be a possibility as suspected by you as we were unable to exclude bronchiolitis by determining the etiology (viral cause).

G) The central paper hypothesis cannot be demonstrated, given that these clinical predictors are not compared with others taken in the era pre-vaccine in the same community and population studied.

Action taken: We have compared the predictors of pneumonia in the past (outside Nepal) with the present study in the discussion section. We could not find any studies conducted in Nepal in the pre-vaccine era in the same community except a study conducted by Basnet et al in 2006-2008. We, therefore, in this study, have tried to reassess the clinical predictors of radiological pneumonia by comparing studies conducted on predictors of pneumonia in the past.

We, however, have tried to remove the pre and post vaccine era in the discussion wherever possible as suggested by you.

H) The prevalence of viruses over bacteria in the etiology of pneumonia alters the clinical presentation of pneumonia?

Due to the design in a single hospital and without accompanying etiological studies, it is difficult to answer this question. The works cited do not get into this disquisition.

Action taken: We have already mentioned that the etiological diagnosis could not be done in the limitation section. This could be a future research to clinically predict pneumonia with etiology.

It is already known that bacterial causes of pneumonia is on declining trend due to universal coverage of PCV and Hib vaccines in the immunisation schedule worldwide. Our findings of predictors of pneumonia has been conducted in children who have been vaccinated with Hib and PCV vaccines. Even though we were unable to perform the etiological diagnosis (mentioned as one of the limitation of the study), it is well understood that these cases of pneumonia could have been due to viral cause in majority. Therefore, we feel that this statement is justified although we accept that etiological diagnosis is required for confirmation.

I) In conclusion, it is valuable to observe what the high altitude above sea level determines that hypoxemia can be a good predictor of pneumonia. The design and casuistic are adequate and the sum of signs and symptoms help and much to be able to find and not lose cases of this disease as severe and harmful to children as pneumonia.

By making these changes, these findings could be communicated.

Action: Hypoxia is an important predictor of radiological pneumonia. This study was conducted at 1400 meters (4600 ft) from the sea level. Previous study was also conducted at the same altitude of the nation and found that hypoxia was a predictor of duration of admission and treatment failure.

We have added in the discussion section.

Action taken: All the cases were community acquired pneumonia. It has been added in the material and methods (Study design, hospital setting, participants and diagnosis).

Action taken: As etiological diagnosis was not done in the study, we are unable to classify the pneumonia cases etiologically (viral or bacterial). We already have mentioned it in the limitation section.

As suggested by you, the same has been added in the methods section.

Action: We calculated PPV and NPV using the following method.

Clinical variable Radiological Pneumonia Yes Radiological Pneumonia

Yes True Positive (TP) False Positive (FP)

No False Negative (FN) True negative (TN)

Sensitivity=TP/(TP+FN)

Specificity= TN/(TN+FP)

PPV=TP/(TP+FP)

NPV=TN/(TN+FN)

d) An interesting analysis would be to evaluate the association/correlation between radiological findings and leukocyte count, considering that in bacterial PAC, there is a tendency for leucocytosis.

Action taken: The association of TLC with radiological pneumonia has been given in table 1. We have mentioned it on the results section too. We found significantly high TLC values in radiological pneumonia when compared to non-radiological pneumonia.

e) The analysis of age subgroups would also be very important.

Action taken: We accept your suggestion that the age sub analysis would be important, however, this will mean the sample size in each age category will be too small and hence the result will likely to be biased. A much larger study would be needed to carry out sub-group analysis for age.

f) The authors use and cite old references. I suggest the inclusion and citation of some recent references such as: DOI: 10.1016/S1473-3099(15)70017-4; DOI: 10.4046/trd.2015.78.3.196; among others.

Action taken: We have updated more recent references and included the references as suggested by you.

g) All text should be revised by a native speaker of the English language and specializes in health issues.

Action taken: Thank you for the suggestion. The manuscript has been rechecked for grammatical errors.

Attachment

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PLoS One. doi: 10.1371/journal.pone.0235598.r005

Decision Letter 2

Frederick Quinn

21 Apr 2020

PONE-D-19-27004R2

Clinical predictors of radiological pneumonia: a cross-sectional study from a tertiary hospital in Nepal

PLOS ONE

Dear Dr. Chaudhary,

We would appreciate receiving your revised manuscript. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: (No Response)

**********

6. Review Comments to the Author

Reviewer #1: 1) Although most of the reviewer comments were met by the authors in the revision process, I still think that the manuscript does not add any new data into both clinical practice and the literature for further studies.

2) Since the statistical data analysis has already been explained in Results section, the numbers should not be repeated in Discussion section (all the confidence intervals, percentages and so forth).

Reviewer #2: (No Response)

Reviewer #3: The calculation of the positive predictive value (PPV) should be done using the Bayes equation, using the prevalence of real pneumonia in the child population in Nepal and not using data from the 2x2 table (see: Linn S. New patient-oriented diagnosis test characteristics analogous to the likelihood ratios conveyed information on trustworthiness. J Clin Epidemiol. 2005; 58 (5): 450–457. doi: 10.1016 / j.jclinepi.2004.07.009 - see equation 2.11).

If this cannot be done by the authors, I suggest not presenting these values in the manuscript.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Altacilio Nunes

PLoS One. 2020 Jul 23;15(7):e0235598. doi: 10.1371/journal.pone.0235598.r006

Author response to Decision Letter 2

29 Apr 2020

REPLY TO THE COMMENTS OF THE REVIEWERS

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response________________________________________

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

Action taken: We have again amended the manuscript based on the helpful comments from the reviewers. We believe the inferences derived in this revised version are supported by the data and is technically sound.________________________________________

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: No

Action taken: We have again reviewed the statistical section and the numbers. They are correct.________________________________________

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes________________________________________

5. Is the manuscript presented in an intelligible fashion and written in Standard English?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: (No Response)

Action taken: We have once again checked the language and edited wherever required. Typographical or grammatical errors have been corrected as far as possible by the authors.________________________________________

6. Review Comments to the Author

Action taken: We have mentioned the aim and objective of the study in the manuscript. The diagnosis of pneumonia in children remains an important yet difficult clinical problem. The clinical presentation and the radiographic signs of pneumonia may not be the same as found earlier. Considering the change in the epidemiological pattern, the clinical predictors of pediatric pneumonia need reassessment. Hence, this hospital-based study was conducted to find the predictors of radiological pneumonia. We therefore, feel that this study definitely adds new data to the changing epidemiology of pneumonia.

Action taken: Thank you for your suggestion. We have removed the repetition and amended the manuscript as advised.

Reviewer #2: (No Response)

If this cannot be done by the authors, I suggest not presenting these values in the manuscript.

Action taken: We agree to your suggestion sir. The study was conducted in a tertiary care hospital of Nepal where patients visit from different demographic locations. The data on prevalence of pneumonia in all of the population/ demo-graphical locations of Nepal are scarce. So, we could not apply the Bayes equation to calculate the PPV. We, therefore, as per your suggestion, have removed the PPV and NPV values from the manuscript.

Attachment

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PLoS One. doi: 10.1371/journal.pone.0235598.r007

Decision Letter 3

Frederick Quinn

13 May 2020

PONE-D-19-27004R3

Clinical predictors of radiological pneumonia: a cross-sectional study from a tertiary hospital in Nepal

PLOS ONE

Dear Dr. Chaudhary

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: I still think that the manuscript does not add any new data into the literature and to the clinical practice, either. Diagnosis of pneumonia in children is not an argumentative issue with the defined clinical findings. High respiratory rate, grunting, hypoxemia, decreased breath sounds are already in practice and in literature as signs of pneumonia. Further more, the authors did not study on relation of changes in epidemiology and clinical findings. So, they can not make any comment on that. Epidemiology is the key point in giving decisions on treatment strategies, not in diagnosis of pneumonia, whether it is radiologically approved or not.

Reviewer #2: Knowing exactly the symptoms of pneumonia in children is difficult, but it is essential in developing countries.

At the time of respiratory virus pandemic, knowing the local clinical characteristics of presentation of pneumonia becomes even more important.

Reviewer #3: Decreased breathing (AOR 3.68; CI 0.99-13.76) was not independently associated, as the lower limit of 95%CI is less than 1. Please correct this, moreover, in all confidence intervals the correct form is 95%CI.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: manuel david bilkis

Reviewer #3: Yes: Altacilio Nunes

PLoS One. 2020 Jul 23;15(7):e0235598. doi: 10.1371/journal.pone.0235598.r008

Author response to Decision Letter 3

14 May 2020

REPLY TO THE COMMENTS OF THE REVIEWERS

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

________________________________________

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Yes________________________________________

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes________________________________________

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes________________________________________

5. Is the manuscript presented in an intelligible fashion and written in Standard English?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Action taken: We have made some amendments to the earlier submitted version of the manuscript . ________________________________________

6. Review Comments to the Author

Reviewer #1: I still think that the manuscript does not add any new data into the literature and to the clinical practice, either. Diagnosis of pneumonia in children is not an argumentative issue with the defined clinical findings. High respiratory rate, grunting, hypoxemia, decreased breath sounds are already in practice and in literature as signs of pneumonia. Furthermore, the authors did not study on relation of changes in epidemiology and clinical findings. So, they cannot make any comment on that. Epidemiology is the key point in giving decisions on treatment strategies, not in diagnosis of pneumonia, whether it is radiologically approved or not.

Action taken: We acknowledge the reviewer view point on the significance of novelty of this study, however, we differ on its importance of this study in resource scare settings of low-income countries in Nepal where there is requirement of decision making based on the clinical presentations. The diagnosis of pneumonia in children remains an important yet difficult clinical problem especially in low and middle income countries (LMICs) like Nepal. The clinical presentation and the radiographic signs of pneumonia may not be the same as found earlier. Inclusion of vaccination (Hib and PCV vaccines) have changed the epidemiology and presentation of pneumonia in children. Considering the change in the epidemiological pattern, the recent WHO pocket book has also modified the definition of pneumonia. This highlights that the clinical predictors of pediatric pneumonia need reassessment from time to time. Hence, this hospital-based study was conducted to find the predictors of radiological pneumonia in post vaccination era. We therefore, feel that this study highlights on the importance and selection of proper clinical presentation for the diagnosis of pneumonia in low-income countries.

Reviewer #2: Knowing exactly the symptoms of pneumonia in children is difficult, but it is essential in developing countries.

At the time of respiratory virus pandemic, knowing the local clinical characteristics of presentation of pneumonia becomes even more important.

Action taken: We agree and thank you for highlighting this issue. Although the main objective of our study was also to assess the clinical predictors of radiological pneumonia in children, however, in the current pandemic, it is important to identify both typical and atypical pneumonia cases as early as possible so both preventive and therapeutic measures can be started at an early phase.

Action taken: Thank you. We have amended the manuscript and inserted “95%” before CI as advised. We understand the adjusted odds ratio of 3.68 with a confidence interval of 0.99 – 13.76 is statistically not significant if you use a very rigid theoretical definition, however, this can be considered as borderline significance. The wide confidence interval is most probably due to low power. We think another study with adequate sample size is required to confirm our findings. We have amended the manuscript accordingly.

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PLoS One. doi: 10.1371/journal.pone.0235598.r009

Decision Letter 4

Frederick Quinn

2 Jun 2020

PONE-D-19-27004R4

Clinical predictors of radiological pneumonia: a cross-sectional study from a tertiary hospital in Nepal

PLOS ONE

Dear Dr. Dr. Chaudhary,

Please submit your revised manuscript. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: (No Response)

Reviewer #3: I repeat, decreased breath sounds (AOR 3.68; 95% CI 0.99-13.76) were not independently associated with radiological pneumonia, please remove it from text! In addition, the result is inaccurate, see the amplitude of the 95%CI.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: Yes: Altacilio Nunes

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Jul 23;15(7):e0235598. doi: 10.1371/journal.pone.0235598.r010

Author response to Decision Letter 4

2 Jun 2020

RESPONSE TO REVIEWERS` COMMENTS

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)________________________________________

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Yes________________________________________3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: No

Action taken: We have checked the statistical analysis. It is correct. ________________________________________

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes________________________________________

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes________________________________________

6. Review Comments to the Author

Reviewer #2: (No Response)

Action taken: We have removed it from the test as suggested by you and have amended the manuscript.

Attachment

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PLoS One. doi: 10.1371/journal.pone.0235598.r011

Decision Letter 5

Frederick Quinn

19 Jun 2020

Clinical predictors of radiological pneumonia: a cross-sectional study from a tertiary hospital in Nepal

PONE-D-19-27004R5

Dear Dr. Chaudhary,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #3: Okay, all the reviewers' suggestions/observations have been incorporated into the text. The quality of the manuscript has improved.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: Yes: Altacilio Nunes

PLoS One. doi: 10.1371/journal.pone.0235598.r012

Acceptance letter

Frederick Quinn

24 Jun 2020

PONE-D-19-27004R5

Clinical predictors of radiological pneumonia: a cross-sectional study from a tertiary hospital in Nepal

Dear Dr. Chaudhary:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Frederick Quinn

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. STROBE checklist.

(DOC)

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Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Clinical predictors of radiological pneumonia: A cross-sectional study from a tertiary hospital in Nepal

Sandeep Shrestha

Nagendra Chaudhary

Saneep Shrestha

Santosh Pathak

Arun Sharma

Laxman Shrestha

Om P Kurmi

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Study design, hospital setting, participants and diagnosis

Study definitions and variables

Study outcomes

Ethical approval

Statistical analysis

Results

Fig 1. Flow chart showing the selection of pneumonia participants.

Table 1. Baseline characteristics of children enrolled with and without radiological pneumonia.

Fig 2. Common presenting symptoms of enrolled children.

Fig 3. Commonly observed signs in enrolled children.

Table 2. Comparison of clinical features between children with and without radiological pneumonia.

Table 3. Validity of combination of variables.

Table 4. Associations between clinical variables (signs and symptoms) with radiological pneumonia.

Discussion

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Eric HY Lau

Roles

Author response to Decision Letter 0

Decision Letter 1

Eric HY Lau

Roles

Author response to Decision Letter 1

Decision Letter 2

Frederick Quinn

Roles

Author response to Decision Letter 2

Decision Letter 3

Frederick Quinn

Roles

Author response to Decision Letter 3

Decision Letter 4

Frederick Quinn

Roles

Author response to Decision Letter 4

Decision Letter 5

Frederick Quinn

Roles

Acceptance letter

Frederick Quinn

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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