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 Table of Contents  
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 81-84

A case of enteric fever complicated by hemophagocytic lymphohistiocytosis probably induced by ChAdOx1 nCoV-19 COVID-19 vaccine

Department of Internal Medicine, Pondicherry Institute of Medical Sciences, Puducherry, India

Date of Submission22-Dec-2021
Date of Decision22-Jan-2022
Date of Acceptance24-Jan-2022
Date of Web Publication8-Jul-2022

Correspondence Address:
Dr. Mathew Cherian
2D/2, Madhuban Apts, 25 Ritherdon Road, Chennai - 600 007, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrsm.jcrsm_94_21

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Although enteric fever is a relatively common disease in countries mainly belonging to South Asia (incidence of around 100/100,000 persons per year) where there is poor hygiene, its complications in the form of hemophagocytic lymphohistiocytosis (HLH) are rare but have been documented before. Here, we present the case of a 19-year-old boy diagnosed with enteric fever with secondary HLH possibly induced by the COVID-19 vaccine (COVISHIELD ChAdOx1 nCoV-19 coronavirus vaccine [Recombinant]). Although there is no proof that the vaccine could have induced secondary HLH, its possibility cannot be ruled out simultaneously. Early identification and diagnosis of HLH are of extreme importance. If not treated correctly, mortality can reach up to 40%. In this article, we would like to press upon the clinical presentation, diagnosis, and management of such a case and the possibility of this presentation being induced by the COVID-19 vaccine.

Keywords: COVID-19 vaccine, enteric fever, hemophagocytic lymphohistiocytosis

How to cite this article:
Cherian M, Thampi SJ. A case of enteric fever complicated by hemophagocytic lymphohistiocytosis probably induced by ChAdOx1 nCoV-19 COVID-19 vaccine. J Curr Res Sci Med 2022;8:81-4

How to cite this URL:
Cherian M, Thampi SJ. A case of enteric fever complicated by hemophagocytic lymphohistiocytosis probably induced by ChAdOx1 nCoV-19 COVID-19 vaccine. J Curr Res Sci Med [serial online] 2022 [cited 2023 May 30];8:81-4. Available from: https://www.jcrsmed.org/text.asp?2022/8/1/81/350145

  Introduction Top

Enteric fever is a systemic illness that presents with fever and abdominal symptoms. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome that results in excessive inflammation due to excessive abnormal immune activation. It is often recognized as primary or secondary. The diagnosis of HLH is based on the criteria that were concluded from the HLH-2004 trial.[1]

HLH associated genetic mutation may be either homozygous or compound heterozygous in children and heterozygous mutation in adults.


The presence of five of the eight of the following features:

  • Fever ≥38.5°C
  • Splenomegaly
  • Peripheral blood cytopenia
  • Hypertriglyceridemia and hypofibrinogenemia
  • Hemophagocytosis in bone marrow, spleen, lymph node, or liver
  • Low or absent natural-killer (NK) cell activity
  • Ferritin >500 ng/mL
  • Elevated soluble CD25 (soluble interleukin-2 receptor alpha) >2 standard deviation above age-adjusted laboratory-specific norms.

A scoring system developed by Fardet et al., called the HScore, incorporates nine variables to help identify the probability of HLH. An HScore ≥250 confers a 99% probability of HLH. If the score is more than 200, bone marrow may not be required to diagnose HLH.[2]

Rarely, enteric fever may be complicated by HLH. Early identification of this syndrome is crucial as it can be fatal.[3]

Here, we describe the case of a 19-year-old male with enteric fever complicated by HLH with a background of onset of symptoms on the evening of the day he received his first dose of the Covishield vaccine. A written and informed consent has been obtained from the patient to publish this case report.

  Case Report Top

A 19-year-old male presented with complaints of moderate grade fever for 7 days. He developed a fever on the evening of his first dose of COVID-19 vaccine (COVISHIELD). Later, he complained of loose stools, vomiting, and abdominal pain. He had a history of consuming outside food 3 days prior. He also had a significant previous history of cavitary pulmonary tuberculosis 1 year back.

At the onset of his symptoms, he was initially evaluated outside, where he was found to have a low platelet count of 31,000 cells/uL with no complications.

On examination, he was afebrile, tachycardic and severely dehydrated. Examination revealed mild epigastric pain. He was started on intravenous (IV) fluids.

A possibility of enteric fever was considered and started on ceftriaxone 2 g IV q12H with azithromycin 1 g orally.

Admission investigations revealed leukopenia (1390 cells/uL) and thrombocytopenia (30,000 cells/mcL) with dyselectrolytemia (sodium–122 mEq/L, potassium–3.3 mEq/L) and elevated erythrocyte sedimentation rate (28 mm/h) and C-reactive protein (69 mg/L).

He did not respond to ceftriaxone and azithromycin. On the 3rd day of stay, he had an episode of hypotension and desaturation and was immediately shifted to the intensive care unit. An echocardiogram showed a reduction in ejection fraction, and a possibility of myocarditis was considered. A possibility of HLH was assessed and confirmed with the significantly elevated serum ferritin, triglyceride, D-dimer levels, and an HScore of more than 200 was found (without bone marrow), which demonstrated a possibility of HLH being more than 93%. He was escalated to meropenem. He was continued on injection meropenem 2 g IV q8h and also started on injection dexamethasone 6 g IV q8h. Blood culture grew Salmonella typhi sensitive to ceftriaxone and carbapenems and hence continued on meropenem. Alternate day monitoring of the inflammatory markers showed a gradual declining trend. His general condition gradually improved. He received a total of 10 days of IV steroids in tapering doses and was in the hospital for a total of 13 days.

[Table 1] and [Table 2] show the serial trend of cell lines and inflammatory markers during his hospital stay.
Table 1: Serial trend of cell lines

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Table 2: Serial trend of inflammatory markers

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[Figure 1] shows the timeline of events.
Figure 1: Timeline of events

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  Discussion Top

In our case, enteric fever symptoms manifested within 3 days of apparent ingestion of contaminated food, presented to the hospital on the 7th day of illness, and it became complicated by HLH on the 10th day of onset of symptoms.

Compared to the other reports of enteric fever complicated with HLH in adults, the case in the report by George et al. presented to the hospital within 5 days of onset of symptoms.[4] In the pediatric age group as well, cases reported by Uribe-Londono et al., Pande et al., and Abbas et al. showed that the cases presented to the hospital in the 3rd week of onset of symptoms,[3],[5],[6] whereas in the case reported by Dange et al., the patient reported within the 1st week of onset of symptoms.[7]

In the cases reported by Pande et al. and Dange et al., steroids were used because of poor clinical response. The case reported by Pande et al. used tablet prednisolone for 10 days, whereas the case reported by Dange et al. used dexamethasone and etoposide following the HLH 2004 treatment protocol.[6],[7]

In our case, following poor clinical response, antibiotics were escalated to injection meropenem and injection dexamethasone was also initiated after establishing HLH.

In the studies, which reported COVID-19 vaccine-induced HLH, only one case report showed a positive infectious agent, which was Epstein-Barr virus, whereas the other studies exhaustively ruled out all possible triggers and came to a conclusion that the only significant event before the onset of the symptoms was the administration of the COVID-19 vaccine.[8],[9],[10]

In our case, the patient developed symptoms on the same day after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. However, whether the flare-up of symptoms was a natural course of the disease or induced by the vaccine cannot be ascertained. He had a history of outside food intake, which could have been the source of the enteric fever.

Genetic evaluation and sCD25 count and NK cell activity were not done in our case due to lack of facilities. However, proceeding with the other criteria and utilizing the HScore to conclude the diagnosis of HLH was the right step as it enabled swift administration of the required steroids to help save the life of the patient.

  Conclusion Top

While it is known that enteric fever may be complicated by HLH, a detailed vaccination history is vital, given that we are living in the COVID-19 vaccine era. This report, unfortunately, is not conclusive to suggest vaccine-induced HLH as it is only a single report and no molecular level studies done. However, there is a possibility of it occurring as it has not been disproved at the same time. More studies and further analysis of this possibility need to be done.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/ have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How i treat hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52.  Back to cited text no. 1
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the score, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014;66:2613-20.  Back to cited text no. 2
Abbas A, Raza M, Majid A, Khalid Y, Bin Waqar SH. Infection-associated hemophagocytic lymphohistiocytosis: An unusual clinical masquerader. Cureus 2018;10:e2472.  Back to cited text no. 3
George N, Sethi P, Nischal N, Kumar A, Siripurapu G, Wig N, et al. Catastrophic presentation of enteric fever with secondary hemophagocytic lymphohistiocytosis. J Assoc Physicians India 2018;66:11-2.  Back to cited text no. 4
Uribe-Londono J, Castano-Jaramillo LM, Penagos-Tascon L, Restrepo-Gouzy A, Escobar-Gonzalez AF. Hemophagocytic lymphohistiocytosis associated with Salmonella typhi infection in a child: A case report with review of literature. Case Rep Pediatr 2018;2018:6236270.  Back to cited text no. 5
Pande V, Agarkhedkar SR, Tandon A, Agarwal A. Haemophagocytic lymphohistiocytosis (HLH) in a case of enteric fever. Int J Bioassays 2016;5:4882.  Back to cited text no. 6
Dange N, Sawant V, Dash L, Kondekar A. Rare case of Salmonella meningitis and hemophagocytic lymphohistiocytosis: Dual complication in enteric fever. J Glob Infect Dis 2021;13:100.  Back to cited text no. 7
Attwell L, Zaw T, McCormick J, Marks J, McCarthy H. Haemophagocytic lymphohistiocytosis after ChAdOx1 nCoV-19 vaccination. J Clin Pathol 2021;75:282-4.  Back to cited text no. 8
Ai S, Awford A, Roncolato F. Hemophagocytic lymphohistiocytosis following ChAdOx1 nCov-19 vaccination. J Med Virol 2022;94:14-6.  Back to cited text no. 9
Tang LV, Hu Y. Hemophagocytic lymphohistiocytosis after COVID-19 vaccination. J Hematol Oncol 2021;14:87.  Back to cited text no. 10


  [Figure 1]

  [Table 1], [Table 2]


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