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*Corresponding Author: John SM Leung
Citation: John SM Leung. (2022) Sévère exacerbation of mixed campylobacter and cryptosporidium enteritis following bnt162b vaccination against covid-19 – a vaccine and gut microbiota interaction that unveils à long-hidden disorder. Clinical Research and Clinical Trials. 6(3) ; DOI :10.31579/2693-4779/110
Copyright: © 2022 John SM Leung, this is an open access article distributed Under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Received: 23 August 2022 | Accepted: 21 September 2022 | Published: 11 October 2022
Keywords: COVID-19 vaccine; gut microbiota; vaccine-gut microbe interaction; vaccine off-target benefits
A young man with a propensity to short spells of mild self-limiting diarrhea presented with severe watery diarrhea after the first dose of BNT-162b2 anti-COVID-19 vaccine. It persisted for over two weeks and was refractory to treatment with fluoroquinolone, spasmolytic and probiotic preparation. At the end of two weeks, he became very ill with dehydration and was admitted through the accident and emergency department to a special unit in a tertiary hospital. His Multiplex panel revealed Campylobacter and Cryptosporidium species. Antibiotics were changed to azithromycin and nitazoxanide with prompt recovery. He was followed up for the next 12 months and remained well with no relapse of diarrhea. In addition, he was cleared of his previous mild recurrent diarrhea. The significance of interaction between gut microbiota and vaccination is discussed and its potential benefit emphasized.
In our fight against the COVID-19 pandemic, one of the most important measures is vaccination. With over 5 billion people vaccinated worldwide,1 it is conceivable that some adverse effects, no matter how rare, would invariably occur, and vaccine opponents are quick to exploit such incidents to justify their stand. Much has been reported on the adverse effects of vaccines against COVID-19. In order not to cause any negative effect on the promotion of vaccination, such reports are usually quick to point out the rarity of such side effects and often due to medical problems other than vaccination. This is followed by stressing of the overwhelming benefits of the vaccines in controlling the pandemic.2 While such an argument is irrefutable, it is rather defensive and we need to pack in more punch for the vaccination drive. One way is to reduce the alarms over adverse effects by understanding their mechanistic causation, another way is to demonstrate that not all side effects are necessarily detrimental and that some effects of vaccination, though off label, could be surprisingly beneficial. The following case report illustrates both points.
The patient is a 23year old male trainee in a law firm. He was prone to diarrhea since childhood which his mother blamed on “weak digestion” and “food allergy”. It was never severe and usually cleared up after two or three days. He never sought medical advice or treatment and accepted his diarrhea predisposition as part of his constitution. He grew up with a frail stature and a BMI of 19.1/M2.
In summer, 2021, the patient took his first dose of BNT162b2 vaccine given to the left deltoid muscle. This was followed immediately by severe pain and weakness around the left shoulder joint. Next day, the pain eased off a little but he started to run a fever of 38.3oC and developed severe diarrhea, over 10 times a day, and more severe than he had ever experienced. It was watery, with no blood or mucus, rather reminiscent of the “rice water diarrhea” described in cholera. After 10 days with no signs of improvement, he came to seek medical advice.
Physical examination revealed a frail thin young man. His temperature was 37.1oC, pulse rate 96 and respiratory rate 18 per minute, regular, BP 140/86, SpO2 97% on room air. He was mildly dehydrated, with a scaphoid abdomen, no tenderness, no enlargement of liver, spleen or kidneys, but very active bowel sounds. There were no palpable enlarged lymph nodes and no abnormalities detected in the heart and lungs. His left shoulder remained in pain since the vaccine injection and shoulder movements were limited both by the pain and proximal muscle weakness.
Laboratory investigations showed Hb 14.8g/dL, HCT 43.8%, MCV 89.8/fL, RBC 4.88M/uL, WBC 13K/uL, N 88.9%, L 6.2%, M 4.6%, E 0.1%, B 0.2%, platelets 264K/uL, ESR 4mm/hr, CRP 16.4mg/L, hsTroponin-I 0.01, D-dimer 0.403ug/mL, NT-proBNP 29.3pg/mL. Stool was sent for culture and following ongoing laboratory “guidelines” culture was directed towards Salmonella, Shigella, Shiga, Vibrio and Campylobacter all of which turned out with negative results. Meanwhile, he was put on empirical ciprofloxacin 250mg b.i.d., hyoscine butyl bromide 20mg t.i.d., and a Lactobacilli probiotic preparation (Lacteol® Fort) b.i.d. and urged to replenish his fluid loss with oral fluid intake.
For five days he was monitored by tele-communication and seemed to respond, at least partially, with the diarrhea reduced to two or three times a day and semi-solid in consistency. On the 6th day he relapsed with the diarrhea worse than before. He was seen to be in marked dehydration and rushed to the accident and emergency department for admission to the special vaccine complication centre for intravenous fluid replacement, intensive monitoring and resuscitation if needed. Before we sent him off, we took a second stool specimen for the Multiplex molecular panel of gastro-intestinal pathogenic antigens. The report came out as positive for both Campylobacter and Cryptosporidium. The report was immediately sent by facsimile to the vaccine complication centre, where the management had changed the patient’s antibiotics to ceftriaxone but still with no response. He was switched to azithromycin 500mg daily and Nitazoxanide 500mg b.i.d. and his diarrhea was completely relieved within 24 hours. Remarkably, he was cured of his previous “weak digestion and food allergy” and never had another attack of diarrhea. For the first time in his adult life, he was regularly having one bowel motion a day with always formed stools. He started to gain weight, climbing from below 50 Kg to 54 Kg six months later, an all-time high record for him. His left shoulder also made a complete recovery. 12 months later a telephone follow-up confirmed that he remained fully recovered with no relapse.
According to the Centers of Disease Control (U.S.A.) official records, moderate to moderately severe diarrhea following COVID-19 vaccination is rather uncommon, ranging from zero to 1.4%, and not much different from placebo. There were no severe grade 4 diarrhea defined as requiring emergency department visit and/or hospital admission.3 However, Akaishi et al. in a case report and review of medical literature collected 9 other cases of prolonged diarrhea following COVID-19 vaccination lasting up to several months. No conclusive explanation was given by these authors and most of them were given a diagnosis of “post-vaccine non-specific intestinal inflammation.” Remarkably the stool culture was usually reported as normal flora in these reports. The present case’s stool culture was also reported as negative for the usual pathogens and the fastidious Campylobacter and Cryptosporidium only showed up in the Multiplex antigen panel. The fact that in this case the diarrhea resolved dramatically with the appropriate antibiotics is strong evidence of the pathogenic role of these organisms.
This case illustrates several important features. First, telecommunication plays a very important role in these days of pandemic lockdown, enabling us to keep close contact with the patient and our colleagues to expedite teamwork and rapid exchange of information to produce optimal management. Second, certain intestinal microbes might lie outside the conventional laboratory capabilities and guidelines and could be missed out in a routine culture study. Even if they were being cultured, their cultural requirements might be so fastidious as to yield a false negative result. In such cases, the molecular antigen panel, e.g., Multiplex, is critical to detect the culprit within a short time. Third, on rare occasions, vaccination can interact with gut microbiota in such a way as to cause the flare up of an occult chronic intestinal infection into an acute and severe form of entero-colitis. Fourth, such a side effect, though unpleasant, might reveal a long-standing health problem, hitherto hidden or neglected, and bring on its definitive treatment and lasting cure. These last two points deserve further elaboration
The gut microbiota has now been well-recognized as an important player in health and disease. [4] In particular, an interaction has been demonstrated between gut microbiota and COVID-19 vaccination [5]. showing that abundance of Bifidobacterium adolescenti is associated with higher neutralizing antibodies induced by the inactivated virus vaccine CoronaVac while abundance of Riseburia faecis correlates with higher neutralizing antibodies following BNT162b. Furthermore, abundance of Prevotella copri, Megamonas funiformis and M. hypermegale seem to reduce the side effects of both vaccines. On the other hand, vaccination is found to be followed by reduced alpha diversity of species and shifts in beta diversity in gut microbiota [5]. with increased Bacterioides caccae and Alistipes shahii following BNT162b but only increased B. caccae following CoronaVac. Thus, there appears to be a bi-directional interaction between vaccination and the gut microbiota, and the present case is another example illustrating such interaction.
BNT162b induces a number of cytokines in order to expedite an immune response with adequate levels of neutralizing antibodies against the virus. Chief among this cytokine signature are IFN- γ, IL-15 and CXCL [10][6]. Cryptosporidium infection leads to watery diarrhea but is usually self-limiting except in immuno-deficient subjects. It involves cytokines like IFN-γ, IL-15, IL-1, CXCL-10, TNF-α. [7] Campylobacter infection is capable of inducing pro-inflammatory cytokines like IFN-γ, IL-1β, IL-8 and TNF-α. [8] Therefore, all three agents, one vaccine and two bacteria are capable of inducing various inflammatory cytokines especially IFN-γ. Further downstream, IFN-γ activates substance P and prostaglandin E2 which upregulate the major mechanisms of diarrhea – cAMP, NO synthase, CFTR, CaCC and, importantly, disruption of the tight interepithelial cell junction.[8] Campylobacter species, were once considered commensals in the gut, only causing significant infection when spreaded to the urinary tract or other parts of the body. Indeed, as intracellular organisms their intestinal activities are limited by difficulties to penetrate the intestinal epithelial barrier which consists of [1] a two-tier cover of mucus comprising a superficial loose layer and a dense deep mucin layer immediately overlying the intestine epithelial cells, and [2] the tight intercellular junction between the intestinal epithelial cells. Normally, the organisms are unable to penetrate the dense mucin layer and kept in the outer loose mucus layer.[9] However, co-infection with Cryptosporidium species will cause massive loss of chlorides and water via CFTR and CaCC channels on the luminal side of colonic epithelial cells, loosening the overlying dense mucin layer. Furthermore, intestinal intercellular tight junction, exposed to high levels of IFN-γ (in this case reinforced by both Campylobacter infection and BNT162b vaccination), would become disrupted and susceptible to penetration by Campylobacter species. Once Campylobacter infection is established, the capsular polysaccharide of the bacteria may provide protection against host immunity not only for itself but also for other organisms.[10] Conceivably, synergism in Campylobacter and Cryptosporidium co-infection had been demonstrated decades ago.[11] In the present case, the addition of vaccination and further cytokine upregulation contributed to a severe exacerbation of diarrhea. The vicious cycle was only broken when appropriate antibiotics put an end to the activities of the two pathogens.
This adverse effect turned out to be a blessing in disguise. The patient was prone to diarrhea ever since he could remember. As a result, he had been under-weight all his life. He could have carried the two pathogenic organisms further on for many years. His immune system was competent enough to keep the symptoms largely at bay. Yet, a certain amount of synergism could have kept the double infection lingering on at a smoldering pace. The increase in proinflammatory cytokines, especially IFN- γ, after vaccination tipped the balance and the diarrhea escalated to a formidable level that demanded more searching investigation and appropriate treatment resulting in dramatic response, even clearing up the original dual infection. This is not an isolate example where vaccination has led to off label benefits. A well-known example is the use of BCG in the treatment of bladder cancer [12]. In another context, this author had earlier reported a case of facial palsy of nine years’ duration recovering almost completely after two doses of BNT162b vaccination [13]. Report on such unusual but beneficial vaccination side effect not only boost the morale of health workers working hard on the vaccination drive, it might help to counter the numerous negative arguments of vaccine opponents. Stretching the imagination further, it might even further the field of vaccine-based therapeutics well beyond that of BCG to benefit other disorders.
This study suffers from the usual limitations of a single case report. Most remarks tend to be anecdotal and need further support from more cases. Due to constraints in the pandemic, investigations had to be kept to a minimum and much of the cytokine levels could not be assessed. Due to the alarming severity of the reactions to the first dose, we were unable to persuade the patient to go through the second dose. Yet, he survived the next two waves of COVID-19 infection, delta and omicron, with his daily rapid antigen test never for once turned positive. Possibly, his severe vaccine reaction might have conferred particularly strong and durable protection, but he has declined to go through further booster doses.
I am grateful to the patient for permission to publish this case report.
I declare no conflict of interest in any form. This work has received no sponsorship or subsidy of any kind.
BCG, Bacille (Bacillus) Calmette-Guërin
BMI, body mass index
CaCC, calcium-activated chloride channel
cAMP, cyclic adenosine 3’,5’-mono-phosphate
CFTR, cystic fibrosis transmembrane conductancenregulator
CXCL10, C-X-C motif chemokine ligand 10
IFN- γ, interferon-gamma
IL-1, interleukine-1
IL-15, interleukine-15
NO, nitric oxide
TNF-α, tumour necrotizing factor alpha
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