key: cord-1043583-qz7ppaae
authors: Samanta, Jayanta; Mahapatra, Soumya Jagannath; Kumar, Naveen; Elhence, Anshuman; Dhar, Jahnvi; Gupta, Anany; Dhooria, Anugrah; Bhalla, Ashish; Prasad, Manya; Das, Aritra; Sharma, Raju; Kochhar, Rakesh; Garg, Pramod K.
title: Virus induced acute pancreatitis and virus superinfection in the ‘Dual disease’ model of acute pancreatitis and SARS-Co-V2 infection: A multicentre prospective study
date: 2022-01-25
journal: Pancreatology
DOI: 10.1016/j.pan.2022.01.008
sha: 9f86dc0bba4e753a594697e5b9d329fb3d194c11
doc_id: 1043583
cord_uid: qz7ppaae

BACKGROUND: SARS-CoV-2 can cause acute pancreatitis (AP) and virus superinfection can occur during prolong hospitalisation. Our objective was to characterize SARS-CoV-2 related AP and study the impact of SARS-CoV-2 superinfection on outcomes in AP. METHODS: In this multicentre prospective study, all patients with AP plus SARS-CoV-2 infection between August 2020 and February 2021 were divided into groups: SARS-CoV-2-related AP and superadded SARS-CoV-2 infection in patients with AP. The two groups were compared with each other and the whole cohort was compared with non-COVID AP cohort. RESULTS: A total of 85 patients with SARS-CoV-2 plus AP (SARS-CoV-2-related AP; n = 18 and AP with SARS-CoV-2 superadded infection; n = 67) were included during the study period. They had a higher mortality [28 (32.9%) vs. 44 (19.1%), aOR 2.8 (95% CI, 1.5–5.3)] than 230 propensity matched non-COVID AP patients. Mortality in SARS-CoV-2 plus AP patients was due to critical COVID. SARS-CoV-2-induced AP (n = 18) had a higher but statistically insignificant mortality than AP plus SARS-CoV-2 superinfection [8/18 (44.4%) vs 20/67 (29.8%), p = 0.24]. On multivariable analysis, infection with SARS-CoV-2 (aHR 2.3; 95% CI, 1.4–3.7) was a predictor of in-hospital mortality in addition to OF in patients with AP. CONCLUSION: Patients with AP and SARS-CoV-2 infection have a higher mortality than matched non-COVID AP patients largely attributable to the severity of COVID-19. SARS-CoV-2 related AP has higher OF and in-hospital mortality.

Acute pancreatitis (AP) is an acute inflammatory disease of the pancreas. It runs a mild course in a majority of patients, but severe AP (SAP) occurs in around 20% of cases with a mortality of 20 to 40%. [1] [2] [3] The current pandemic by a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the worst since the Spanish flu of 1918, has affected >179 million people and has claimed >3.9 million lives worldwide due to coronavirus disease -19 (COVID-19) as of 26 th June, 2021. [4] It is projected to remain active till 2024 even after adequate control measures, particularly with the emergence of many mutants called variants of concern such as B.1.1.7 and B.1.617. [5] Although it is primarily a respiratory pathogen with predominant tropism for lungs, an increasing number of reports have documented involvement of other organs such as liver, brain, and pancreas due to expression of ACE 2 receptors which facilitate intracellular viral entry [6, 7] . Viral infections such as mumps, coxsackievirus and hepatitis E have been known to cause AP [8, 9] . SARS-CoV-2 has also been shown to cause AP, the mechanism of pancreatic injury likely being multifactorial [10, 11] . Although a few studies have shown isolated elevation of pancreatic enzymes which may not be due to pancreatitis, presence of ACE2 receptors on pancreatic acinar cells, autopsy data showing presence of SARS-CoV-2 virus within the pancreas and imaging evidence of pancreatitis, lend support to SARS-CoV-2 being directly responsible for causing AP [12] [13] [14] [15] . In addition, SARS-CoV-2 superinfection may also occur in patients with AP due to other etiologies during the course of hospitalisation for their primary illness [16] .

Organ Failure (OF) in SAP is mediated by a cytokine storm during initial phase of illness akin to cytokine storm recently described in critical COVID. [1, 17, 18] Thus theoretically, concomitant COVID-19 infection in patients with AP can compound this effect leading to the development of new-onset OF and worsen the clinical course. There are a few gaps in our J o u r n a l P r e -p r o o f current knowledge regarding AP and SARS-CoV-2. SARS-CoV-2 induced AP remains poorly defined and its outcome vis-a-vis AP followed by superinfection due to SARS-CoV-2 is not well known. Limited data exist on the comparison of AP patients with and without infection. [19] [20] [21] Therefore, the objectives of the present prospective study were to (i) to compare the severity and in-hospital mortality of patients with AP plus SARS-CoV-2 infection and those with AP but without SARS-CoV-2 infection, (ii) to define and study the outcome of SARS-CoV-2

induced AP compared with that in patients with AP due to other etiologies, and (iii) to study the influence of the timing of superinfection of SARS-CoV-2 during the course of AP on its outcome.

It was a multicentre study carried out at 2 tertiary care academic institutions -Postgraduate Institute of Medical Education and Research, Chandigarh and All India Institute of Medical Sciences, New Delhi, India.

Study design and period: It was a prospective observational cohort study conducted from August 2020 till February 2021. The study was started after obtaining ethical approval from institute ethics committee of both the institutes. Informed consent was taken from the patient before inclusion in the study. We followed the strengthening the reporting of observational studies in epidemiology (STROBE) statement for a cohort study. All the authors had access to the study data and have reviewed and approved the final manuscript. Exclusion criteria: Patients with recurrent acute pancreatitis and chronic pancreatitis were excluded.

Patients with AP hospitalized from January 2015 till December 2019 (i.e., before the start of pandemic to exclude every possible associated SARS-CoV-2 infection) were chosen as historical controls from our prospectively maintained database by propensity score matching in 1:4 ratio for age, sex and severity of pancreatitis.

Acute pancreatitis and severity classification AP and its severity were defined as per the revised Atlanta definition. [22] SARS-CoV-2 infection related AP: A patient was diagnosed to have SARS-CoV-2 related AP when the patient was hospitalized with RT-PCR confirmed SARS-CoV-2 infection and developed features of AP within 7 days of onset of symptoms of COVID-19 after excluding other causes of AP. The other causes of AP were excluded as follows: (i) gallstones: absence of gallstones on abdominal USG and <3 times elevation of ALT, (ii) no history of significant alcohol intake i.e. >40 gm/day for >5 years, (iii) normal serum calcium and triglyceride levels, (iv) no history of having undergone ERCP or trauma in the past one week and (v) no past history or family history of pancreatitis. 

In order to assess the relative contribution of individual disease to mortality, it is important to classify the severity of AP and COVID-19 separately in patients who have both the diseases.

It might be difficult because the severity of both the conditions is defined by organ failure.

Respiratory failure is the first and dominant organ failure in COVID-19 due to viral pneumonia that determines its severity. A CT scan of chest was done to diagnose COVID pneumonia. proportional hazard regression models to study the impact of COVID-19 and other variables on mortality. A p value of <0.05 were taken as statistically significant.

A total of 85 patients (58 males, 68.2%) with AP and COVID-19 were included during the study period. Of these, 18 had SARS-CoV-2-related AP, 23 had AP with SARS-CoV-2 'coinfection' and 44 had AP with SARS-CoV-2 'super-infection' (Table 1, Figure 2 ). The baseline parameters were similar between the 3 groups. SARS-CoV-2-related AP had milder AP (44.4%) compared with SARS-CoV-2 'co-infection' and 'super-infection' groups (21.7% and 0% respectively) (p<0.0001).

The whole cohort of COVID positive AP (n=85) was compared with age, sex and AP severity matched cohort of non-COVID AP (n=230). Baseline characteristics of the two groups are given in Table 2 The cohort of SARS-CoV-2 related AP (n=18) was compared with a propensity matched cohort of non-COVID AP (n=59) ( Table 3) . Organ failure rates such as respiratory (61.1% vs. 22.4%; p=0.002), renal (38.9% vs. 12.1%; p=0.01) and cardiovascular (44.4% vs 10.3%; p=0.001) were significantly higher in the SARS-CoV-2 related AP group and so was the need for ICU stay (62.5% vs 20.3%; p=0.001) and ventilator support (p<0.0001).

While the need for interventions/surgery was similar, SARS-CoV-2 related AP had higher in-hospital mortality (44.4% vs. 6.8%; p<0.0001).

On Cox proportional hazard regression analysis, being infected with SARS-CoV-2 was the most significant predictor of mortality (aHR -16.02; 95% CI-3.87 -66.28) even after adjusting for age, sex, presence of comorbidities and severity of pancreatitis (Supplementary table 2 

On comparing SARS-CoV-2 related AP (n=18) with AP patients having either co-or Table 3 were treated with steroids. Respiratory failure was considered to be due to severe AP in the remaining 6 patients.

On comparing patients with AP with superadded SARS-CoV-2 infection (n=67) with a propensity matched cohort of non-COVID AP (n=176), the former had higher rates of organ failure (respiratory: 67.2% vs. 42.6%; p=0.001 and cardiovascular failure: 28.4% vs. 16 .5%; p=0.04) and higher proportion of patients with multi-organ failure (37.3% vs.

29.0%; p=0.005) (Supplementary table 4 ). These patients also had a greater need for ICU stay (56.7% vs. 42.6%; p=0.049) and mechanical ventilation (31.3% vs. 8.0%; p<0.0001) compared to non-COVID AP cohort. Superadded SARS-CoV-2 infection group had a J o u r n a l P r e -p r o o f higher in-hospital mortality (29.9%) than non-COVID controls (22.7%) but the difference was not statistically significant (p=0. 25) . The association of SARS-CoV-2 and AP has been described previously, but many aspects of this association are not well understood. 'Cytokine storm' has been thought to be the key event perpetuating organ failure both in AP and severe SARS-CoV-2 infection [1, 18] .

Whether the simultaneous occurrence of both diseases produces a synergistic effect is not clear. Two retrospective series have compared COVID positive AP with non-COVID AP.

While one study showed significantly greater proportion of persistent organ failure (57% vs. 8%) and mortality (21% vs 2%) among COVID-positive AP [19] , the other study failed to show any increased mortality, although COVID-positive patients had a higher requirement of mechanical ventilation compared with COVID-negative AP patients (28.1% vs 6.4%) [20] .

These studies were however, limited by their retrospective design, small sample size and lack of adjustment for important confounding factors affecting mortality such as severity of AP. In the present study, we found COVID-positive AP patients to have significantly higher OF and in-hospital mortality rates compared with non-COVID AP patients. A multicenter prospective cohort study [21] also showed similar findings with a higher risk of persistent OF and 30-days mortality in patients with SARS-CoV-2 infection and AP. However, the study did not provide details about the timing of SARS-CoV-2 infection, severity of COVID-19, and development of OF.

We have defined SARS-CoV-2 related AP in the present study. Any patient, with confirmed SARS-COV-2 infection, who developed features of AP within 7 days of onset of the COVID symptoms and without any other cause of AP was termed as SARS-CoV-2 induced AP. A few case series have highlighted an increase in the proportion of idiopathic cause of AP in SARS-CoV-2 infected AP patients, which varied from 25-69% suggesting SARS-CoV-2 as the likely etiology [19] [20] [21] . It is difficult to assign SARS-CoV-2 infection as a definite etiology of acute pancreatitis. In case of other viruses such as mumps, coxsackie and hepatitis viruses, the etiology of AP is considered to be due to the virus based on 2 important factors:

(i) temporal relationship of AP during the course of the primary viral illness, and (ii) absence of a documented etiology of AP such as alcohol and gallstones. We also considered the diagnosis of SARS-CoV2 related AP based on these 2 factors. In the absence of a proven cause and effect relationship, we have used the term to 'SARS-CoV-2 related AP' instead of 'SARS-CoV-2 induced AP'. An increased proportion of 'idiopathic' AP has been reported among SARS-CoV-2 infected patients and it has been suggested that it could be virusinduced, and hence might have been wrongly classified as "idiopathic' [20] . However, none of the previous studies has studied the temporal correlation between the onset of AP and onset of COVID symptoms to be able to define the entity of "SARS-CoV-2 induced AP" or study its clinical course. Virus-induced pancreatitis such as due to mumps, coxsackie and hepatitis viruses is usually mild, and systemic features of the viral illness predominate and dictate the clinical course rather than the pancreatic injury per se. A few cases of necrotizing pancreatitis, although, have also been reported [23, 24] . On the contrary, SARS-CoV-2 related AP, in our study, had worse outcomes with more OF and higher mortality than the severity matched non-COVID AP cohort. This was attributed to the severity of the COVID-19 disease as pancreatic involvement was mild in around half of these cases. Thus, involvement of organs (e.g., pancreas) other than the primary organ for which the virus has a tropism (i.e., lung for SARS-CoV-2) may be indicative of a severe disease.

The complexity of this 'dual disease' model lies in unraveling the relative contribution of AP and SARS-CoV-2 infection to mortality. While OF defines the severity of both AP and COVID-19, it is difficult to delineate which of the two is the chief contributor to the severity in a particular patient. We analyzed every individual patient with AP plus SARS-CoV-2 infection and distinguished the lung involvement between the two disease entities based on typical imaging findings on the chest CT scan. While SARS-CoV2 infection exhibits groundglass opacities, vascular enlargement, lower lobe involvement and posterior predilection, AP predominantly has vascular leak syndrome, non-cardiogenic pulmonary edema, pleural effusion and/or consolidation as the causes(s) of respiratory failure and hence lacks those typical imaging findings of COVID-19. [25, 26] Earlier studies did not make this critical distinction and thus, the increased severity of AP reported [21] among COVID-positive cases could have been due to severe COVID rather than being classified as severe AP. We specifically studied this aspect and used the clinico-radiological parameters to classify the severity of AP and COVID separately, and analyzed their relative impact on the outcome, e.g., we had a case of mild AP who expired due to critical COVID, which otherwise might have been misclassified as severe AP. This enabled us to identify the key player controlling the outcome in this "dual-disease" model, rather than using blanket severity scores. This distinction is crucial for a treating physician as specific therapy e.g., steroids can be guided by individual severity of COVID and AP. The only caveat being that in patients with COVID pneumonia, it is difficult to determine the contribution of AP to respiratory failure if any.

Patients with moderate and severe pancreatitis are at risk of acquiring nosocomial SARS-CoV2 infection during an ongoing epidemic due to prolonged hospital stay [16] . SARS-

CoV2 co-infection/superinfection is of concern and its effect on disease course is not well known. In our study, superadded SARS-CoV2 infection led to a significantly higher rate of respiratory failure compared to matched AP cohort without SARS-CoV2 infection. This reiterates the fact that SARS-Co-V2 infection, when superadded to an ongoing AP, adversely affects its outcome with a synergistic effect.

AP being a systemic illness with an initial phase of systemic inflammation (SIRS) followed by compensatory anti-inflammatory syndrome (CARS) phase, virus-specific host responses may affect the course of illness [1, 16, 27] . Host response to the virus is expected to be different depending on the phase of AP in which the infection occurs. To study this hypothesis, we compared the two sub-groups of the superadded SARS-CoV-2 infection cohort, i.e., 'co-infection' and 'super-infection'. 'Co-infection' was considered when onset of AP and COVID positivity detection was within 14 days of each other, while beyond that it was termed as 'super-infection'. This 14-day cut-off was chosen to account for the incubation period of SARS-CoV-2. A recent study has shown that concomitant COVID-19 and AP at admission had a benign course. [28] Interestingly, there was no difference in organ failure and mortality between patients who had early or late super-added SARS-CoV-2 infection. This can be explained by the pathogenetic interaction of this "dual disease" with respect to time. In the initial 14 days of AP and SARS- 

*Propensity matched (1:4) with age, sex and severity (Atlanta) @ P value represents the difference in the parameter distribution between the COVID positive and COVID negative group #Adjusted for age, sex, comorbidities and severity (Atlanta) $ represented as median (interquartile range) Abbreviations: AP acute pancreatitis; COVID Coronavirus disease; aOR adjusted Odds' ratio; SIRS Systemic inflammatory response syndrome; ALI Acute lung injury; AKI Acute kidney injury; CVSF Cardiovascular system failure; OF organ failure; ICU intensive care unit; NIV non-invasive ventilation; MV mechanical ventilation; CI confidence interval J o u r n a l P r e -p r o o f 

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