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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 4  |  Page : 250-255

A cross-sectional study of pulmonary and extrapulmonary manifestations of COVID-19


Department of General Medicine, MVJMC and RH, Bengaluru, Karnataka, India

Date of Submission06-Apr-2021
Date of Decision05-Jun-2021
Date of Acceptance16-Jun-2021
Date of Web Publication20-Oct-2021

Correspondence Address:
Dr. Vasantha Kamath
Department of Medicine, MVJMC and RH, Hoskote, Bengaluru - 562 114, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajim.ajim_46_21

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  Abstract 


Background: While the name of the virus indicates respiratory disease, and the respiratory spread of COVID-19 has been well documented in the literature, the ongoing pandemic has shown that the virus is not confined to just the lung. Hence, physicians should be aware of the “many faces” that this singular disease can present with, for timely diagnosis and prompt initiation of best treatment options. Materials and Methods: A total of 1754 patients with confirmed COVID-19 infection were admitted at a rural tertiary care center, Karnataka, India. This study is a cross-sectional study done for a period of 6 months from July 2020 to December 2020. Demographic data, clinical manifestations, laboratory parameters, management, and outcomes were recorded and compared. Results: Out of 1754 COVID-19 patients, pulmonary manifestations were seen in 1222 patients, extrapulmonary manifestations in 360 patients, and 172 patients were asymptomatic. Males were affected more than females, with a male-to-female ratio of 1.2:1. Most common pulmonary manifestation seen was cough in 83.06%, followed by fever in 67.59%. Most common extrapulmonary manifestation seen was neurological followed by gastrointestinal in 60.83% and 35.8% patients, respectively. Fatality in patients with pulmonary manifestations was 5% and extrapulmonary manifestation was 3%. All patients were managed according to standard COVID-19 treatment protocol. Conclusion: Early recognition of COVID-19 infections remains a big challenge. COVID-19 can have diverse range of clinical manifestations. Hence, COVID-19 infection should be considered in the differential of any systemic disease during the current pandemic, even in the absence of pulmonary manifestations like fever or cough.

Keywords: Angiotensin-converting enzyme-2, cardiovascular, COVID-19, CVA, extrapulmonary, manifestations, pulmonary, vasculitis


How to cite this article:
Nivea B, Kamath V, Markanday K, Jacob M J, Mohan D. A cross-sectional study of pulmonary and extrapulmonary manifestations of COVID-19. APIK J Int Med 2021;9:250-5

How to cite this URL:
Nivea B, Kamath V, Markanday K, Jacob M J, Mohan D. A cross-sectional study of pulmonary and extrapulmonary manifestations of COVID-19. APIK J Int Med [serial online] 2021 [cited 2021 Nov 29];9:250-5. Available from: https://www.ajim.in/text.asp?2021/9/4/250/328676




  Introduction Top


Coronavirus disease 2019, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), is an ongoing pandemic continuing to wreak havoc. While the respiratory spread of COVID-19 has been well documented in the literature, the extrapulmonary manifestations are less known. It can cause symptoms by utilizing a spike protein to attach to the host angiotensin-converting enzyme-2 (ACE-2) receptor present in several other organ systems either concomitant with respiratory illness or as the only manifestation.[1] The nonspecific or extrapulmonary symptoms delay testing, diagnosis, and management. Therefore, physicians caring for, and battling on the frontlines against COVID-19 should be aware of the “many faces” that this singular disease can present for timely diagnosis and prompt initiation of treatment.[2] Our study aims to review the pulmonary and extrapulmonary manifestations of COVID-19.


  Materials and Methods Top


A total of 1754 patients tested positive for COVID-19 by real-time reverse transcription-polymerase chain reaction (RT-PCR) were admitted at a rural tertiary health-care center, Hoskote, Karnataka, India. The study design is a cross-sectional study, done for a period of 6 months from July 2020 to December 2020 (first wave of COVID-19). The confirmed diagnosis of COVID-19 was defined as a positive result by using real-time RT-PCR detection on nasopharyngeal swab. Clinical data including demographical data, symptomatology, comorbidities, laboratory parameters, treatment, and complications were recorded and compared.

Pulmonary manifestations were defined as patients with respiratory symptoms such as fever, myalgia, arthralgia, rhinorrhea, sore throat, cough, and breathlessness. Extrapulmonary manifestations were defined as patients having predominantly neurological, gastrointestinal (GI), cardiovascular, cutaneous, and uncommon respiratory symptom such as hemoptysis either concomitant with typical respiratory symptoms or as the sole manifestation.

All patients with COVID-19 illness were subsequently categorized as mild, i.e., patients with uncomplicated upper respiratory tract infection may have mild symptoms such as fever, cough, sore throat, nasal congestion, malaise with no evidence of hypoxemia or breathlessness; moderate, i.e., pneumonia with no signs of severe disease, adults with the presence of clinical features of dyspnea and/or hypoxia, fever, cough, including SpO2 of 90%–≤93% on room air, respiratory rate more or equal to 24/min; severe pneumonia, i.e., adults with clinical signs of pneumonia plus one of the following; respiratory rate >30 breaths/min, severe respiratory distress, SpO2 <90% on room air, acute respiratory distress syndrome (ARDS), sepsis and septic shock. Extrapulmonary manifestations in the cases studied were identified alongside these criteria.

All patients were treated according to the standard treatment protocol of MoHFW/WHO June 03, 2020 guidelines.[3]

Statistical methods

Categorical/qualitative variables are presented using frequencies and percentages. Continuous variables are presented using mean +/− standard deviation. Any association between qualitative variables is identified using Chi-square test, and unpaired t-test is used to evaluate statistical significance between continuous variables. P <5% is considered as statistically significant.


  Results Top


A total of 1754 patients tested positive for real-time RT-PCR for COVID-19 were studied. One thousand five hundred and eighty-two patients were symptomatic, and 172 patients were asymptomatic. Among symptomatic patients, pulmonary manifestations were seen in 1222 patients and extrapulmonary manifestations were seen in 360 patients, constituting 69.7% and 20.52%, respectively [Chart 1].



COVID-19 patients with pulmonary and extrapulmonary manifestations were categorized into mild, moderate, severe COVID-19 based on SpO2 levels according to the MoHFW June 03, 2020 guidelines [Table 1].
Table 1: Categorization of COVID-19 manifestations

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Chi-square test: 7.41, df: 2, P value: 0.025. There is a statistically significant association between severity and pulmonary manifestations of COVID-19.

Males were affected more than females, with a male-to-female ratio of 1.2:1 [Table 2].
Table 2: Sex distribution in COVID-19

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Chi-square test: 1.11, df: 1, P = 0.293. The association between gender and clinical manifestation of COVID is not statistically significant.

Pulmonary manifestations of COVID-19 were more common in 40–60 years of age group. Extrapulmonary manifestations were seen predominantly in more than 60 years of age [Table 3].
Table 3: Age distribution in COVID-19

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Chi square test: 71.2, df: 2, P = 0.000. The association between age and clinical manifestation of COVID is statistically significant, i.e. pulmonary manifestations are highest in the middle age group followed by the elderly age group. However, the extrapulmonary manifestations are highest in elderly age group with almost similar probability in middle age and younger age groups.

All 1754 patients admitted were residents of rural and urban Bangalore, Karnataka. History of recent travel and contact was seen in 32.3% and 41.73%, respectively.

Among 1222 patients with pulmonary manifestations of COVID-19, most common symptom was cough seen in 83.06%, followed by fever in 67.59% and breathlessness in 63.9% [Chart 2].



Among 360 COVID-19 patients with extrapulmonary manifestations, 219 patients presented with neurological symptoms, 129 patients presented with GI symptoms, seven patients presented with cardiovascular symptoms, five patients had cutaneous presentations [Chart 3].



Neurological manifestations were seen in 219 (60.83%) patients, the most common neurological presentation was isolated headache seen in 108 patients, followed by anosmia in 84 patients, 12 patients presented with cerebrovascular accident, eight patients presented in altered sensorium, and seven patients presented with seizures. Out of 12 patients with cerebrovascular accident (CVA), 11 patients presented with ischemic stroke and one patient presented with hemorrhagic stroke.

Among 129 (35.83%) patients presenting with GI manifestations, the most common GI presentation was diarrhea in 47 patients, followed by pain abdomen in 33 patients, anorexia in 18 patients, nausea and vomiting in 18 and 13 patients, respectively.

Among the seven patients, presenting with cardiovascular symptoms, 5 of them presented with chest pain and 2 of them presented with palpitations. Out of five patients presenting with chest pain, 3 had ST elevation myocardial infarction (STEMI) and remaining 2 had unstable angina. Two patients presenting with palpitations had arrythmias.

Cutaneous presentations were seen in five patients, among which three patients presented with maculopapular rash, one patient presented with petechiae, and another patient presented with painful acral red purple papules.

Two hundred and thirty four of 360 (65%) patients with extrapulmonary manifestations of COVID-19 also had respiratory symptoms. One hundred and seventy seven patients needed regular oxygen, 44 and 33 patients required high flow nasal oxygen (HFNO) and non-invasive ventilation (NIV), respectively, 10 patients were intubated and connected to mechanical ventilator.

One thousand sixty-nine COVID-19 patients had comorbidities. 68.8% (248/360) patients with extrapulmonary manifestations had comorbidities. Diabetes mellitus was the most common comorbid condition associated with both pulmonary and extrapulmonary manifestations of COVID-19.

[Table 4] highlights the salient differences between the two groups from the onset of symptoms to diagnosis, hospitalization, and requirement of oxygen [Table 4].
Table 4: Salient differences between patients with pulmonary and extrapulmonary manifestations

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In the study, it was noted that patients presenting with pulmonary manifestations had early diagnosis, hospitalization, and oxygen requirement while the patients with extrapulmonary manifestations had prolonged duration with respect to all these parameters. This was difference was statistically significant.

Chi-square: 314., df: 1, p value: 0.000. The association between the clinical manifestations and NLR i.e., Neutrophilic Lymphocytic Ratio is statistically significant. On comparing the total study group with those with pulmonary manifestations alone, NLR ratio was found to be elevated (>3:1) in 64.72% and 97.06% respectively. This association was statistically significant with a p value of 0.000 and chi square 314 and df:1. [Table 5].
Table 5: Neutrophil lymphocyte ratio in pulmonary and extrapulmonary manifestations of COVID-19

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Laboratory parameters specific for COVID-19 were altered in patients with both pulmonary and extrapulmonary manifestations of COVID-19. However, there is no significant difference between the other laboratory parameters noted apart from NLR on drawing comparison between the two groups [Table 6].
Table 6: Laboratory parameters in COVID-19 manifestations

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Chest X-ray was done in all patients both with pulmonary and extrapulmonary manifestations of COVID-19. Nine hundred and fifty four and 292 patients with pulmonary and extrapulmonary manifestations had typical bilateral peripheral opacities on chest X-ray. High-resolution computed tomography (CT) chest was done in 950 and 252 patients with pulmonary and extrapulmonary manifestation of COVID-19, respectively, reported as COVID-19 Reporting and Data System (CORADS 6) with variable CT severity scores.

Mean duration of hospital stay was 12 and 8 days in patients with pulmonary and extrapulmonary manifestations, respectively.

In our study, 75 patients succumbed with an overall mortality being 4.2%. Sixty-six patients with pulmonary manifestations and nine patients with extrapulmonary manifestations of COVID-19 had succumbed with a case fatality rate of 5% and 3%, respectively. Main cause of mortality in patients with pulmonary manifestations was ARDS. Among patients with extrapulmonary manifestations, four patients (3.1%) with GI presentation, 3 (42.8%) with cardiovascular presentation, and 2 (0.91%) with neurological presentation had succumbed.


  Discussion Top


Human coronaviruses are large, positive-sense, single-stranded RNA viruses, of which the beta coronavirus genus has been responsible for human disease outbreaks during the past 20 years. COVID-19 presents with a myriad of pulmonary symptoms from mild upper respiratory tract infection, bilateral pneumonia, and ARDS necessitating high dependency care or ventilatory support that can progress to multiple organ failure with or without superadded bacterial sepsis.[4] However, there are certain findings that set COVID-19 apart from other viral causes of pneumonia or ARDS. These patients can turn bad to worse in hours. “Happy hypoxia” is a new term coined that means that the patient is still very much conscious and happily answering questions, even with SpO2 of 70 or lower.[4]

In our study, COVID-19 patients with pulmonary manifestations were predominantly seen than extrapulmonary manifestations with a slight male preponderance (P = 0.293).

The most common age group affected was between 40 and 60 years in patients with pulmonary manifestations, in comparison to extrapulmonary manifestation which was mostly seen in patients above 60 years of age (P = 0.000). A recent study reported fever (95.3%) as the most common presenting symptom followed by cough (65.1%) in patients with pulmonary manifestations.[5] Whereas in our study, cough was the most common symptom seen in 83.06%, followed by fever in 67.59%.

Although beta coronaviruses are known to cause neurologic illness in some people, there is limited understanding about the breadth of neurologic effects. Putative mechanisms of neurologic dysfunction in severe COVID-19 include direct neuroinvasion, endothelial dysfunction, and a neurotoxic effect from exuberant inflammation and cytokine release manifestations in COVID-19. The various neurological manifestations of COVID-19 noted in our study was headache (49.31%), anosmia (38.35%), CVA (5.47%), altered sensorium (3.65%), and seizures (3.19%) in the above order of frequency.

The cause of isolated headache in COVID-19 may be attributed to SARS-CoV-2 binding to ACE2 on trigeminal nerve endings within the nasal cavity and causing trigeminovascular activation, in addition to systemic inflammation.[6]

A study on presentation of new-onset anosmia during the COVID-19 pandemic reported that 17% of COVID-19 patients had only anosmia as an isolated symptom. This has been hypothesized to be a result of retrograde transmission through olfactory nerves thereby damaging the nerve endings. Therefore, anosmia can be used as a screening tool to identify asymptomatic carriers and test them.[7]

A study on large vessel occlusion stroke in COVID-19 outbreak reported 42% patient presenting with symptoms of acute ischemic stroke rather than pulmonary respiratory symptoms days before demonstrating symptoms of COVID-19, suggesting that there may be an increased risk of thrombosis even in the early phase of the disease. However, most patients with COVID-19 who had a stroke also had concurrent advanced systemic illness.[8] This is in line with the current study, where 5.47% patients presented with acute stroke. Probable pathophysiology of stroke in COVID-19 is reported to be due to a 2 fold mechanism. First, direct infection of brain endothelium, which expresses ACE-2 receptor, could pose a risk of viral-induced vasculitis. Second, ACE-2 receptor inhibition or depletion through viral infection and endocytosis on cell entry could result in reduction of ACE-2 function, thereby decreasing the formation of angiotensin and impairing cerebral vascular autoregulation. Finally, the hypoxia ensuing from severe COVID-19 pulmonary infection could also contribute to an increased risk of stroke through reduced oxygen delivery. Three main mechanisms appear to be responsible for the occurrence of ischemic strokes in COVID-19. These include a hypercoagulable state, vasculitis, and cardiomyopathy.[9]

In our study, out of 12 COVID-19 patients presenting with CVA, 1 presented with hemorrhagic stroke. The downregulation of ACE2 expression during SARS-CoV-2 infection may increase angiotensin 2 in the serum, which can impair endothelial function and contribute to dysregulation of blood pressure, thus increasing the risk of hemorrhagic stroke. As for patients with hypertension, the expression of ACE2 is already low; when SARS-CoV-2 binds to ACE2 receptors, the ability of ACE2 to lower blood pressure is concomitantly reduced, so COVID-19 infection is more likely to induce a cerebral hemorrhage in such patients. Thus, it is reasonable to hypothesize that in patients with COVID-19, the cytokine storm and elevated blood pressure can increase the risk of hemorrhagic stroke.[10]

Seizures in COVID-19 patients were first documented by Moriguchi et al.[11] Another case study on COVID-19 presenting with seizures reported a 72-year-old male patient with COVID-19 presenting with multiple episodes of generalized tonic-clonic seizures.[12] Similarly, in our study, seven patients with COVID-19 presented with seizures, they were managed with antiepileptics in addition to standard treatment protocol of COVID-19.

Other neurological manifestations of COVID-19 reported in literature include Guillain–Barre syndrome, Miller-Fisher syndrome, polyneuritis cranialis, none of which were seen in our study.[13]

Several studies have shown that 18.6% of patients with COVID-19 presented with a GI-specific symptom, including diarrhea, vomiting, or abdominal pain.[14] Similarly, in our study, 129 patients presented with GI symptoms of which diarrhea being the most common (36.4%). These patients were managed with intravenous (IV) fluids, antibiotics, probiotics along with standard treatment protocol of COVID-19. Four patients of COVID-19 with GI manifestations succumbed to severe sepsis, septic shock, MODS. The pathophysiology of GI damage in COVID-19 is probably multifactorial. Virus-mediated direct tissue damage is plausible, given the presence of ACE2 in intestinal glandular cells, as well as the visualization of viral nucleocapsid protein in gastric, duodenal, and rectal epithelial cells, and glandular enterocytes.[15] The presence of GI symptoms is an excellent early indicator of SARS-CoV-2 infection and a good predictor of severe outcomes from the disease. Hence, in patients with COVID-19, GI symptoms are not uncommon, and CT imaging of the chest followed by RT-PCR confirmation from nasopharyngeal swabs is mandatory in the current pandemic setting.

Preexisting cardiovascular disease seems to be linked with worse outcomes and increased risk of death in patients with COVID-19, whereas COVID-19 itself presenting solely with myocarditis, arrhythmias, acute coronary syndrome, and venous thromboembolism has also been reported, often due to underlying virus-induced myocardial injury as seen in our study.[16] Three patients of COVID-19 presenting with STEMI in our study were thrombolyzed with IV streptokinase 1.5 million units over 60 min along with standard treatment protocol of COVID-19. Shi et al. reported that among 416 hospitalized patients with confirmed COVID-19, 19.7% had myocardial injury which were manifested by elevated high-sensitivity troponin-I levels.[17] Cardiovascular involvement in COVID-19 is attributed to direct myocardial injury by altering ACE-2 signaling pathways or indirectly as a part of cytokine storm-related multiorgan dysfunction. Hypoxia and respiratory failure and the ensuing demand-supply mismatch are also detrimental to the myocardium. Furthermore, the prothrombotic state, which is established by the disease, could impede coronary flow and lead to the acute coronary syndrome.[17],[18]

According to a recent study in Belgium, urticaria and pyrexia were early symptoms of COVID-19, while the patient may not have any respiratory symptoms.[19] Similarly, in our study, three patients presented with maculopapular rash, one with petechiae and another with painful acral red, purple papules without any respiratory involvement. All patients of COVID-19 with cutaneous manifestations showed signs of resolution with standard treatment protocols of COVID-19. The skin involvement in patients with COVID-19 was not noticed at the early stages of this pandemic, but it has received much more attention recently. Commonly documented cutaneous manifestations in COVID-19 have been recently classified into main patterns, these include urticarial, confluent erythematous − maculopapular − morbilliform, papulovesicular, chilblain-like acral, livedo reticularis – livedo racemosa-like and purpuric “vasculitis.”[20] Although the underlying pathogenic mechanisms are unclear, interaction between ACE-2 in skin keratinocytes and the SARS-CoV-2 glycoprotein results in increased circulating angiotensin II, complement activation, hyperactive immune response, and microvascular injury which have been recently postulated as the mechanism of small vessel vasculitis in conjunction with COVID-19 infection.[21]

On laboratory evaluation, specific parameters such as increased NLR, altered liver function test, renal function test, elevated inflammatory markers such as D-dimer, serum ferritin, serum lactate dehydrogenase, erythrocyte sedimentation rate, and C-reactive protein were seen in both pulmonary and extrapulmonary manifestations of COVID-19, although significantly higher in patients with severe COVID-19 category. This is in line with a recent study where the association of inflammatory markers with the severity of COVID-19 was highlighted and stated that measurement of inflammatory markers might assist clinicians to monitor and evaluate the severity and prognosis of COVID-19.[22]

Another study reported significant CT imaging and clinical feature differences between pulmonary and extrapulmonary manifestations of COVID-19 patients, similar to our study.[23]

Moreover, a study concluded no significant difference in mortality which is in line with our current study where the fatality rate in patients with pulmonary and extrapulmonary manifestation is 5% and 3%, respectively.[24],[25]


  Conclusion Top


COVID-19 can have both pulmonary and extrapulmonary manifestations. Wide range of respiratory symptoms constitutes the pulmonary manifestation, whereas extrapulmonary manifestation can be neurological, GI, cardiovascular, or cutaneous. Extrapulmonary manifestations are predominantly seen in patients above 60 years of age and may evolve to develop respiratory symptoms in the course of the illness. Hence, early detection of these can alarm the medical practitioners to promptly intervene in such cases to prevent significant morbidity and mortality. With the emerging new mutant variants of this gruesome disease, leading to the devastating second wave of the pandemic in our country, it will be fascinating to unveil a multitude of such extrapulmonary manifestations. Even though the current focus of disease researchers is on respiratory symptoms in the pandemic, involvement of other systems should also be viewed with interest.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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