Abstract
Objectives
The non-O1/non-O139 Vibrio cholerae caused outbreaks or sporadic cases of gastroenteritis that was rarely seen in good sanitary condition. It was described a case of systemic multiple organ lesions that worsened because of non-O1/non-O139 V. cholerae, suggesting that serogroups have a potential virulence in enhancing pathogenicity with patients with underlying diseases compared with a healthy population.
Design or methods
Samples are identified by strain culture, polymerase chain reaction (PCR) virulence identification, and whole genome sequencing.
Results
A middle-aged man was diagnosed with cytotoxin-producing and nontoxin V. cholerae non-O1/non-O139 serogroups. Although lacking the CT toxin encoded by ctxAB gene, the pathogenesis of cholera relies on the synergistic action of many other genes, especially virulence genes.
Conclusions
This case suggested that the laborers engaging in agricultural production are at potential risk of V. cholerae infection by exposure of open wounds to contaminated water . However, epidemiological investigation should focus on the objective cause of the change of working environment. Furthermore, common diseases can possibly enhance the virulence of non-O1/non-O139 serogroups by attacking the tight junction of small intestinal epithelial cells, further triggering bacteremia, a process that may lead to death within 48–72 hours, which requires great attention.
Key words
Introduction
Vibrio cholera is a significant pathogen that could causes cholera, which is a severe acute watery diarrhea. There are more than 200 serogroups of V. cholerae, but only O1 and O139 cause the most cholera epidemics and pandemics (
Safa et al., 2010
; Salim et al., 2005
). The O1 serotype is divided into two biotypes, classic and El Tor, both consist of Ogawa and Inaba serotypes (Sack et al., 2004
). Another toxic V. cholerae serotype O139 appeared in South Asia in 1992 (Ramamurthy et al., 2003
). Although the classic V. cholerae caused the first six pandemics, the seventh pandemic was caused by the El Tor biotype (Clemens et al., 2017
). However, many non-O1/non-O139 strains have been often associated with extraintestinal infection, including septicemia (Hao et al., 2015
), wound infection, peritonitis (Lan et al., 2014
), etc. These cases are usually seen in most patients with underlying disease, like diabetes mellitus (Lu et al., 2014
), liver cirrhosis (Patel et al., 2009
), chronic renal(Xu and Forrest, 2021
), hematological diseases(Siegel and Rogers, 1982
), and immunocompromised diseases (Kadkhoda et al., 2012
).- Kadkhoda K
- Adam H
- Gilmour MW
- Hammond GW.
Nontoxigenic Vibrio cholerae Septicemia in an Immunocompromised Patient.
Case Rep Infect Dis. 2012; 2012698746https://doi.org/10.1155/2012/698746
Among all the factors, we should focus on the pre-CTX Φ phage, which is the main cause of the epidemic and mortality from non-O1/non-O139 V. cholerae in China (
Wang et al., 2014
). CTX Φ, which does not carry ctxAB, is called pre-CTX Φ and is commonly present in cases of diarrhea-causing V. cholerae infection (Boyd et al., 2000
). This mobile genetic element carry part of the virulence genes with only the ctxABgene missing (Takemura et al., 2017
); because of this, diagnostic procedures could not identify them as cholera but as diarrheal disease caused by the non-O1/non-O139 strains.However, this precursor phage may help the bacteria increase their infectivity and potential virulence by transmitting some auxiliary toxins, such as zonula occludens toxin (Zot), to other V. cholerae. Zot acts on the epithelial cells of the small intestine by affecting the structure of epithelial compaction to increase mucosal permeability (
Di Pierro et al., 2001
). Zot also has associations with mild diarrhea rather than tissue damage (Fasano et al., 1991
). Other detected genes includide rtxA (encoding repeat toxin A and C subunit), rtxAC, hlyA (encoding hemolysin), ompU (encoding the outer membrane protein specific for V. cholerae), toxRS (toxin regulatory gene), and eta. This is a huge loophole because the V. cholerae with pre-CTX Φ is probably no less virulent than the one with the ctxAB gene. It has also been suggested that the sixth and seventh epidemics originated from nontoxigenic environmental strains (Karaolis et al., 1995
). The phage could also spread through the cholera community, causing active, complicated gene recombination and horizontal transfer of ctxAB, and eventually causing nonpathogenic V. cholerae to become cholera O1/0139 (Wang et al., 2014
); this is enough to arouse attention. Early warning of infection events caused by V. cholerae carrying some virulence genes, especially those carrying pre-CTX Φ, should be regarded as an important target for prevention and control, similar to cholera, rather than just monitoring and treatment that is usually done with diarrheal diseases. The selected reported cases of non-O1/non-O139 V. cholerae bacteremia are summarized in Table 1.Table 1Cases of non-O1 V. cholerae reported in the recent 20 years.
| Author/reference | Main manifestations | Diarrhea or vomiting | WBC/CRP level | Complication | Associated history&Underlying diseases | Age& Sex | Ending |
|---|---|---|---|---|---|---|---|
| Sarwar S, 2015 ( Sarwar et al., 2016 ) | Fever, chills | No | – | Bacteremia | Goat milk feeding,low birth weight | day-old male neonate | Death |
Hao et al., 2015 (Hao et al., 2015 ) | Fever (38°C), lethargy, loss of appetite | No | 15.26 × 109/L, 119.83 mg/L | Septicemia, meningitis | – | 11-day-old female infant | Survive with some neurological deficits |
Lan et al., 2014 (Lan et al., 2014 ) | Fever, palmar erythema, peripheral edema | no | Patient 1:7.37 × 109/L,–/ Patient 2: 1.75 × 109/L,–/ | Peritonitis, jaundice, Bacteremia | Hypertension, viral hepatitis | 63-year-old Female;73-year-old male | Recover with ceftriaxone |
Marek et al., 2013 (Marek et al., 2013 ) | Lethargic, dizziness and epigastric pain | severe watery diarrhea | 13.6 × 109/L, 66 mg/L | bacteremia and gastroenteritis | pancreatitis and bronchial carcinoma | 74-year-old male | Recover with i.v. ceftriaxone |
Ferreira et al., 2012 (Ferreira et al., 2012 ) | abdominal pain, fever, dizziness, dyspnea | vomiting | 16,900 /mm3(16.9 × 109/L),– | Peritonitis, Bacteremia | Liver cirrhosis | 64-year-old male | Recover with third generation cephalosporins(cefotaxime) |
Kerketta et al., 2002 (Kerketta et al., 2002 ) | Fever, poor feeding, generalized tonic seizures, lethargic with a sluggish Moro reflex, | No | 23,200/mm3 (23.2 × 109/L),– | metastatic endophthalmitis, Septicemia, Meningitis | questionable feeding | 10-day-old male neonate | Cure with cefotaxime and ampicillin |
| Kumar P, 2008( Kumar et al., 2017 ) | Dehydration, anuria, stuporous | persistent diarrhea, vomiting | – | acute gastroenteritis | – | 5-month-old female | Medicate with cefixime and monocef (cefpodoxime) but repeated infection |
Lu et al., 2014 (Lu et al., 2014 ) | chills and fever (39.5°C) | – | 10.8 × 109/L,44.4 mg/L | Bacteremia, peripheral neuropathy, and vascular disease | diabetic nephropathy, possibly consumption of ribbonfish | 70-year-old male | cure with meropenem |
| Our case report | Fever, sleepiness, extreme malaise and xerostomi | severe watery diarrhea | 5.53 × 109/L,39.4 mg/L | mucosal jaundice, | chronic liver disease, viral hepatitis, liver cirrhosis and renal insufficiency | 50-year-old male | Death |
It is true that non-O1/non-O139 V. cholerae did not reach the extent of the spread of O1 and O139 group, but in a few reported cases, can also cause serious complications, such as neurological deficits (
Hao et al., 2015
) and even death (Sarwar et al., 2016
). In this study, we combined our case with previous reports, in hopes to warn about the effects of V. cholerae on infected patients. This case is of early warning significance for global surveillance of non-O1/non-O139 V. cholerae infection and also raises concerns about human infections caused by non-Ctx producing V. cholerae.Materials and methods
Strain collection and ethics explanation
A total of 8 cases of non-O1/non-O139 V. cholerae infection were collected from all over the world from 2002–2015 excluding our case. All the strains were obtained from clinical laboratory, and the strains were used for clinical research work. The study was performed according to the ethics committee of the Changzhou Centers for Disease Control and Prevention (Changzhou, China) and in compliance with the requirements of ethical norms. All strains obtained from the clinical laboratory of the local central hospital were used for this study.
Identification of strain culture
The samples collected were placed in alkaline peptone water for enrichment and subsequently selected medium TCBS (thiosulfate-citrate-bile salts-sucrose agar) for separation and culture. Suspected colonies were selected for bacterial strain identification, including glass agglutination test and agglutination reaction with diagnostic serum of O1 group and O139 group and whether the oxidase test is positive. In addition to the previously mentioned routine biochemical methods, VITEK-2 Compact was used for comprehensive biochemical identification of the strain.
PCR virulence identification
Next, diagnostic kits (Fluorescent PCR) from BioPerfectus Technologies were used. Considering the identification of virulence genes and that V. cholerae has groups, we first used a diagnostic kit for V. cholerae DNA (
Gubala and Proll, 2006
). The cycle threshold value of the sample is no more than 35, the curve is S-shaped and exponentially increasing. In the second step, we simultaneously performed diagnostic kit for V. cholerae O1/O139 group DNA (Kendall et al., 2010
) and diagnostic kit for V. cholerae toxin gene ctx DNA (Huang et al., 2009
). Ultimately, we determined that it was the non-O1/non-O139 V. cholerae with the ctx gene.Whole genome sequencing
Products from gel electrophoresis purification were sent to Genewiz Company for Sanger sequencing, and sequences were analyzed by genbank BLAST. The products were used by illumine platform for whole genome sequencing.
Results
A 50-year-old man with a 12-hour history of low-grade fever, shivering, and mental exhaustion was referred to the Third People's Hospital in September 2018. Severe watery diarrhea occurred but no vomiting was present. The patient presented with excessive daytime sleepiness, extreme malaise, and xerostomia, and was taken to the hospital. After diagnosing, he presented with a fever of 38.5°C, had facial signs of chronic liver disease, and mucosal jaundice. His spider angioma and palmar erythema were very apparent. C-reactive protein on admission was 39.4 mg/L (reference range <10 mg/L), white cell count was 5.53 × 109/L (reference range 4–10 × 109/L). Liver function tests were within reference ranges aside from Alanine transaminase (ALT) of 43U/L (reference range<40 U/L) and glutamic-oxalacetic transaminase 82U/L (reference range<40 U/L). He has a history of viral hepatitis, liver cirrhosis, and renal insufficiency. Other clinical features included icteric sclera, pot belly, and limb edema. A surgical scar was present on the abdomen. Left abdomen tenderness was distinct. Furthermore, chest and abdomen computed tomography scans showed right lung inflammation, pleural effusion, missing spleen, and seroperitoneum. Thereafter, the patient was transferred to the intensive care unit due to aggravation of his condition. He was initially treated with intravenous albumin and norepinephrine for increasing blood pressure. Biapenem, esomeprazole, and magnesiumoxalat were given intravenously for anti-infection and gastrointestinal protection. The patient discharged himself from the hospital by his and his family's own volition after receiving treatment for 12 hours; however, he died the next day.
An epidemiological investigation was undertaken. There was no history of travel, out-of-town accommodation, or taking-away repast. Exposures to unfiltered water, cold food, and seafood were negative. One person in the close contact group had an unexplained diarrhea for 1–2 months. No one else ate seafood or unfiltered fresh water or had reports of illness associated with the family. District health centers distributed effervescent tablets to patients’ families and guided them in the disinfection work. At the same time, the local center for disease control and prevention had been informed.
The blood and stool of the patient and other samples from the close contact group were obtained to test as well as food they ate and the surrounding environment. Gram stain of the positive blood culture showed gram-negative rod-shaped bacteria. After 24 hours, enriched culture with alkaline peptone buffers, the classic hemolytic colonies grew on the blood agar (Chromagar) and red colonies appeared on Vibrio chromogenic medium (Oxoid), indicating the presence of Vibrio spp. Further subcultivation showed oxidase-positive yellow colonies on TCBS. Finally, the bacterium strains were identified as V. cholerae by VITEK-2 Compact and VITEK MS System (bioMe´rieux). The positive V. cholerae was isolated from the blood and feces of the patient but negative in any other food, environmental, and samples from close contacts, including the person with unexplained diarrhea history.
The results were confirmed by PCR test, the positive strains harbored rtxA, which could be identified as V. cholerae (
Dolores and Satchell, 2013
). All the V. cholerae strains exhibited no agglutination with the O1 and O139 V. cholerae antiserum, including the Ogawa and Inaba types. The susceptibility test showed sensitivity to cefotaxime, ceftazidime, tetracycline, cefazolin, cefoxitin, gentamicin, ampicillin, ampicillin/sulbactam, chloramphenicol, ciprofloxacin, trimethoprim/sulfamethoxazole, erythrocin, nalidixan, and azithromycin.Additionally, the whole genetic sequence showed that the patient-derived strain harbored a lot of virulence genes, including Zot, rtxAC, hlyA, ompU, eta, and toxRS, but a lack of ctxA, ctxB, tcpA, and other toxigenic factors. This feather further confirmed the nontoxigenic V. cholerae, whereas those genes detected may play important roles in pathogenicity. Finally, multilocus sequence typing (MLST) was performed to identify the gene sequence type. Seven allelic genes of adk, gyrB, metE, mdh, pntA, purM, and pyrC were sequenced by Sanger. The target strain was assigned an unusual sequence type (ST271) with the relevant allelic genes designated as 38, 41, 15, 84, 18, 42, and 60, respectively (https://pubmlst.org/vcholerae/).
Discussion
No source of infection was readily apparent in this case because only blood and stool of the patient tested positive, which could not provide a complete chain of evidence. Vibrio spp. is highly correlated in summer, in densely populated or endemic infection areas (mainly related to seafood farming and consumption), with poverty and poor sanitation, in the range of water temperature and in human production activities (
Faruque et al., 1998
). Contact with open wounds is likely to be the most probable point of entry of the organism after considering other possibilities. No history of foreign travel or sea food consumption was mentioned. However, the patient farmed in the fields on a regular basis. This case happened in summer in mainland China, during which the growth and reproduction of V. cholerae were active (Petsaris et al., 2010
).Farmland environment was obtained around his workplace but proved negative. It is feasible that his wound came into contact with water that was contaminated and the bacteria entered the blood; this developed into uncontrolled bacteremia. The increasing incidence of Vibrio polluters during the summer reminds farmers and fishermen of occupational protection (
Ottaviani et al., 2009
). Presumably, this could be enough to cause infection in immunodeficient individuals, especially in places with of high incidence of V. cholerae. To the best of our knowledge, the death caused by non-O1/non-O139 is rare. Certain non-O1/non-O139 strains may have the genetic backbone of O1 strain by exchanging through other clusters, and this homology suggests that these serogroups may have pathogenicity similar to that of explosive strains (Li et al., 2002
).However, this rare case fatality rate may be determined by the heterogeneity of the virulence regions, as seen in the Table 1; most cases are cured with drugs or survive with some deficits (
Li et al., 2002
). In contrast to the backbones, the virulent regions of the 4 strains were quite heterogeneous. The presence of this heterogeneity as a result of gene exchange strongly suggests that non-O1/non-O139 strains have more possibilities, including underappreciated combinations of helper toxins that, under these combinations, allowed the mutated V. cholerae strains to exhibit higher virulence. V. cholerae is adapting to changing human production activities in order to thrive.In this case, the sequence type (ST271) differs from the verified dominant clone V. cholerae, which indicates the potential for an outbreak in the future. The acute death also demonstrated the high toxicity of ST271. It is noteworthy that infection by non-O1/non-O139 V. cholerae, carrying virulence genes including Zot, rtxA, rtxAC, hlyA, ompU, eta, and toxRS, combined with common diseases of the liver and kidney, may be the cause of the rapid onset and quick death. We can see another hypervirulent HCT strains causing persistent and recurrent diarrhea in a 5-month-old baby, as seen in Table 1 (
Kumar et al., 2017
).This highlights the necessity to keep track of whether the strain could emerge as an outbreak or as a different genotype, leading to severe outcome. It may be difficult to detect the unusual pathogenic bacteria in a world where automation in laboratories has become so advanced that traditional manual separation techniques may be forgotten. When examining the isolate, not only does the detection of the disease require a laboratory equipped with alkaline peptone water and TCBS plates to isolate the strain, but also detection methods that are quick and accurate to ensure clinical timely antibiotic therapy. The testing methods we recommend include PCR test, mass spectrometer, microorganism identification instrument, and API lath; choosing the right method can provide reliable evidence. Given the fatality rate of this disease, routine diagnostic laboratories should ensure that they are capable of testing for this isolate.
Studies have shown that immunocompromised patients are susceptible to V. cholerae (
Jiang et al., 2018
), such as those with underlying diseases including malignancy, hypertension, diabetic nephropathy, liver cirrhosis, and pancreatitis, as listed in our Table. Most of the patients can be cured with antibiotics against gram-negative Vibrio bacteria, except for two neonates who failed to recover. One 3-day-old male neonate died (Sarwar et al., 2016
) and another 11-day-old female infant survived with some neurological deficits (Hao et al., 2015
). Newborns generally have low immune function; hence, unsanitary feeding may lead to very serious consequences. Even if they survive the disease, they will grow up with defects and have sequelae for the rest of their lives. There is growing evidence that an imbalance between the gastrointestinal microbiome and the host immune system can affect immunity to viruses (Harper et al., 2021
). In addition to respiratory symptoms, some patients with COVID-19 have complained of gastrointestinal symptoms, including diarrhea, vomiting, nausea, and abdominal pain (- Harper A
- Vijayakumar V
- Ouwehand AC
- Ter Haar J
- Obis D
- Espadaler J
- et al.
Viral Infections, the Microbiome, and Probiotics.
Front Cell Infect Microbiol. 2021; 10596166https://doi.org/10.3389/fcimb.2020.596166
Huang et al., 2020
). These findings further indicate that COVID-19 has the possibility to coinfect with V. cholerae. Comparing COVID-19 and Vibrios, COVID-19 seems to be a new potential threat that is contributing to increasing the morbidity of nontoxigenic V. cholerae. Combined with the death in our case, clinical attention should be paid to the risk of coinfection of common infectious diseases, and the proportion of common diseases in the clinical diagnosis and epidemiological investigation of infectious diseases should be increased.It was evident from the study that patients with cirrhosis who were infected with V. cholerae were more susceptible to bacteremia (
Lee et al., 2007
). Elevated serum iron levels or impaired liver filtration is thought to increase the risk of bacteremia in patients with cirrhosis (Halabi et al., 1997
). That might explain why the patient with hepatitis B presented with acute metastatic infection of multiple organs after bacterial infections. The incidence of hepatitis and other types of liver disease in China is expected to increase following the rising rate of non-O1/non-O139 V. cholerae infections. The patients on the list were mostly above the white blood cell and C-reactive protein threshold, indicating a clear bacterial infection. These observations are in contrast to a report withone patientwho had normal leukocytes and the other who had below-normal values (Lan et al., 2014
). We suspected the reason that there were no high white blood cell levels reported was that patient 1 was in the recovery period after the fever, whereas patient 2’s neutrophils were increased compared with the lymphocytes. Taking into account the antibiotic treatment, in the later stages of the course of the disease, the levels of inflammatory cells can only be used as an indicator of recovery and cannot continue to be used as an indicator of infection.Non-O1/non-O139 V. cholerae infection is a threat to safety, although the number of deaths reported worldwide is low even with the current advancement of medical approaches and equipment. This study analyzed the underlying disease, infection routine, virulence genes, and pre-CTX Φ to help healthcare workers avoid such a tragedy again.
Declaration of Competing Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding source
Our work was funded by the Six Talent Peaks Program of Jiangsu Province (SWYY-230), General project of Jiangsu Health Commission (H2018098), Young Talent Project (CZQM2020113), Changzhou Science and Technology Plan Social Development Project (CE20185048), and Applied Basic Research (CJ20210073 and CJ20210100).
Ethical approval
Not applicable.
Appendix. Supplementary materials
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Article info
Publication history
Published online: April 13, 2022
Accepted:
April 8,
2022
Received in revised form:
April 7,
2022
Received:
January 11,
2022
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